Title of Invention	"A SUBSTITUTED ECTEINASCIDIN COMPOUND"
Abstract	The present invention relates to antitumour compounds having the five membered fused ring ecteinascidin structure of the formula (XIV). The present compounds lack a 1,4-bridging group as found in the ecteinascidins. They have at the C-l position a substituent selected from an optionally protected or derivatised aminomethylene group or an optionally protected or derivatised hydroxymethylene group.

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washed with CH2Cl2 (20 ml). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (Si02, EtOAc:MeOH 5:2) to afford 71 (16mg. 65%) as a white solid. Rf: 0.0.5 (EtOAc:MeOH 5:2). 1H NMR (300 MHz, CDC!3) d 6.50 (s. 1 H), 5.95 (d, 7=1 .5 Hz, 1 H), 5.78 (s, 1 H), 5.1 9 (bs, 1 H), 4.45 (d, 7=3. 3 Hz, 1H), 4.37 (bs,''''''''lH), 4.11 (brd, 7=4.8 Hz, 1H), 4.01 (d, 7=2.1 Hz. 1H), 3.76 (s, 1H), 3.71-3.69 (m, 1H), 3.49-3.35 (m, 1H), 3.24 (d, 7=13.5 Hz, 1H), 3.15 (d. 7=9.3 Hz, 1H), 2.95(dd,J1=S.l Hz, 7.,= 17. 7 Hz. 1H), 2.70 (d. 7=1 5.6 Hz, 1H), 2.40 (d, 7= 18.0 Hz, 1H), 2.31 (s, 3H), 2.29 (s,3H), 2.26 (s,3H), 1.96 (s,3H), 1.75-1. 66 (m, 1H), 1.52-1. 17 (m, 2H), 0.66 (t, 7=7.2 Hz, 3H). Example 66 (Formula Removed) To a solution of 45 (35 mg, 0.0672 mmol) in CH2Cl2 (0.3 mL), hydrocinnamoyl chloride ( 11.58 µl, 0.0672 mmol) and pyridine (5.43 µL, 0.0672 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HCl (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex: ethyl acetate 2:1 to ethyl acetate) to afford 72 (30 mg, 68%) as a white solid. Rf: 0.51 (ethyl acetate:MeOH 10:1). 1H NMR (300 MHz, CDC13) δ 7.23-7.12 (m, 3H), 7.05-7.00 (m. 2H). 5.97 (d. J= 1.2 Hz. 1H), 5.91 (d,J= 1.2 Hz, 1H). 5.73 (s, 1H), 5.04 (brt, 1H), 4.08 (d, J= 2.4 Hz. 1H). 4.02 (bs. 1H), 4.00 (d, J= 2.4 Hz, 1H), 3.58 (dd,J1= 4.5 Hz, J2= 13.8 Hz, 1H), 3.47 (bs. 3H). 3.33 (d. J= 7.5 Hz, 1H), 3.29 (dt, J1= 2.7 Hz, J2= 11.7 Hz, 1H), 3.00 (dd, J1= 7.8 Hz. J,= 18.3 Hz, 1H), 2.79 (d, J= 14.1 Hz, 1H), 2.58-2.50 (m, 3H). 2.32 (s, 3H), 2.29 (s. 3H), 2.03 (s. 3H), 2.01 (s, 3H), 1.94-1.76(m,4H). ESI-MS m/z: Calcd. for C37H40N407: 652.7. Found (M+Na)+: 675.3. Example 67 (Formula Removed) To a solution of 45 (45 mg, 0.0576 mmol) in CH2Cl2 (0.3 mL), phenyl acetyl chloride ( 7.61 µl, 0.0576 mmol) and pyridine (4.6 µL, 0.0576 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:ethyl acetate 3:1 to Hex:ethyl acetate 1:1) to afford 73 (25.8 mg, 70 %) as a white solid. Rf: 0.5 (Hex:ethyl acetate:MeOH 5:10:2). H NMR (300 MHz, CDCI3) δ 7.18-7.17 (m, 3H), 6.85 (bs, 2H), 6.54 (s, 1H), 5.89 (d, J= 1.5Hz, 1H), 5.83 (d,J= 1.5 Hz1H), 5.76 (s, 1H), 5.08 (bs, 1H), 4.12 (d, J= 2.1 Hz, 1H), 4.09 (d, J= 2.1 Hz, 1H), 3.98 (bs, 1H), 3.73 (s, 3H), 3.51-3.46 (m, 2H), 3.35 (d,J= 8.4 Hz, 1H), 3.25 (dt,J= 2.7 Hz, J2= 12.0 Hz. 1H), 3.03 (d,J= 8.7 Hz, 1H), 3.02-2.94 (m, 2H), 2.75 (d, J- 16.8 Hz, 1 H). 2.63 (d, J= 18.0 Hz, 1 H), 2.35 (s, 3H), 2.30 (s, 3H). 2.22 (s. 3H9, 1.98 (s, 3H), 1.80(dd,J1= 12.0Hz, J2= 16.2 Hz, 1H). ESI-MS m/z: Calcd. for C36H38N407: 638.7. Found (M+l)+: 639.2. Example 68 (Formula Removed) To a solution of 45 (30 mg, 0.0576 mmol) in CH2Cl2 (0.3 mL), propyonyl chloride ( 5 µL, 0.0576 mmol) and pyridine (4.6 µL, 0.0576 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:ethyl acetate 5:1 to Hex:ethyl acetate 1:1 to ethyl acetate) to afford 74 (23 mg, 70 %) as a white solid. Rf: 0.59 ((Hex:ethyl acetate:MeOH 5:10:2). 1HNMR (300 MHz, CDC13) δ 6.50 (s,lH), 5.97 (d,J= 1.2 Hz, 1H), 5.91 (d, J= 1.2 Hz, 1H), 5.76 (s, 1H), 5.00 (t, 1H), 4.09 (d,J= 1.2 Hz, 1H), 4.04 (bs, 2H), 3.74 (s, 3H), 3.62 (dd, J1= 6.6 Hz,J2= 13.2 Hz, 1H), 3.43 (bs, 1H), 3.37 (d,J= 8.4 Hz,1H), 3.29 (d, J= 12.0 Hz, 1H), 3.02 (dd,J1= 8.1 Hz, J2=18.3 Hz, 1H), 2.80 (d,J= 14.4 Hz,1H), 2.55 (d, J= 18.0 Hz, 1H), (2.31 (s,3H), 2.24 (s,3H), 2.00 (s, 3H), 1.78(dd,J1= 12.0Hz,J2= 15.6 Hz, 1H), 1.64-1.50 (m,2H), 0.70 (t, 7-7.8 Hz, 3H). ESI-MS m/z: Calcd. for C31H36N4O7: 576.6. Found (M+l)+: 577.2. Example 69 (Formula Removed) To a solution of 45 (15 mg, 0.0288 mmol) in CH2C12 (0.25 mL), myristoyl chloride ( 7.83 µL, 0.0288 mmol) and pyridine (2.3 µL, 0.0288 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:ethyl acetate 6:1 to Hex:ethyl acetate 1:1) to afford 75 (15 mg, 71 %) as a white solid. Rf: 0.65 (Hex:ethy acetate:MeOH 10:10:1). 1H NMR (300 MHz, CDC13) δ 6.49 (s, 1H), 5.97 (d,J= 1.2 Hz, 1H), 5.91 (d,J= 1.2 Hz, 1H), 5.72 (s, lH),4.99(t, 1H), 4.09 (d, J= 1.5 Hz, 1H), 4.05 (d, J= 1.5 Hz, lH),4.02(bs, 1H), 3.76 (s, 3H), 3.61-3.59 (m,1H), 3.39 (bs, 1H), 3.35 (d, J= 7.8 Hz, 1H), 3.29 (d, J= 12.3 Hz, 1H), 3.04 (dd,J1= 8.1 Hz, J2= 18.3 Hz, 1H), 2.78 (d, J= 15.6 Hz,1H), 2.55 (d,J= 18.3 Hz, 1H), 2.32 (s, 6H), 2.25 (s, 3H), 1.99 (s, 3H), 1.78 (dd,J,= 12.3 Hz, J2= 15.0 Hz, 1H), 1.25- 1.24 (m, 12H), 0.87 (d, J= 6.0 Hz, 3H). ESI-MS m/z: Calcd. for C42H58N4O7: 730.9. Found (M+l)+: 731.4. Example 70 (Formula Removed) To a solution of 45 (15 mg, 0.0288 mmol) in CH2C12 (0.25 mL), stearoyl chloride ( 9.7µL, 0.0288 mmol) and pyridine (2.3 µL, 0.0288 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2C12 (10 mL) and washed with 0.1 N HC1 (5 mL). The''''''''organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2 gradient Hex:ethyl acetate 3:1 to Hex:ethyl acetate 1:1) to afford 76 (16 mg, 70%) as a white solid. Rf: 0.46 (Hex:ethyl acetate:MeOH 10:10:1). 1HNMRNMR(300 MHz, CDC13) CH2C12 6.49 (s, 1H), 5.98 (d,J= 1.5 Hz, 1H), 5.91 (d. J= 1.5 Hz, 1H), 5.73 (s,1H), 4.99 (t,J=1 5.7 Hz, 1H), 4.09 (d, J= 1.8 Hz, 1H), 4.05 (d,J= 2.4 Hz, 1H),4.01 (bs, 1H), 3.76 (s, 3H), 3.61-3.59 (m, 1H), 3.38 (bs, 1H), 3.36 (d,J= 7.2 Hz, 1H), 3.28 (d, J= 12.0 Hz, 1H), 3.03 (dd,J1= 7.8 Hz, J2= 18.3 Hz, 1H), 2.78 (d, J= 15.9 Hz, 1H), 2.57 (d, J= 18.3 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.99 (s, 3H), 1.77 (dd, J,= 11.7 Hz, J2= 15.6 Hz, 1 H), 1.25-1.24 (m, 16H), 0.87 (d, J= 6.3 Hz, 3H). ESI-MS m/z: Calcd. for C46H66N4O7: 786.4. Found (M+22)+: 809.5. Example 71 (Formula Removed) To a solution of 45 (31 mg, 0.0595 mmol) in CH2C12 (0.3 mL), hexanoyl chloride ( 8.32 µL, 0.0595 mmol) and pyridine (4-8 µL, 0.0595 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hexiethyl acetate 3:2 to ethyl acetate) to afford 77 (26 mg, 70 %) as a white solid. Rf: 0.65 (ethyl acetate MeOH 10:1). 1HNMR(300MHz, CDC13) δ 6.50 (s, 1H), 5.98 (d,J= 1.5 Hz, 1H), 5.91 (d,J= 1.5 Hz, 1H), 5.74 (s, 1H), 5.00 (t, J= 5.4 Hz, 1 H), 4.09 (d, J= 2.7 Hz, 1 H), 4.05 (d, J= 2.4 Hz, 1 H), 4.01 (bs, 1H), 3.76 (s, 3H), 3.61-3.58 (m, 1H), 3.02 (dd, J1= 8.1 Hz, J3= 18.3 Hz, 1H), 2.78 (d, J= 14.4 Hz, 1 H), 2.56 (d, 7= 18.3 Hz, 1 H), 2.31 (s, 6H), 2.25 (s, 3H), 2.00 (s, 3H), 1.78 (dd, J1= 12.0Hz,J2=15.9Hz, 1H), 1.53-1.40 (m, 2H), 1.29-1.12 (m, 4H), 1.07-0.97 (m, 2H), 0.81 (t, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C34H42N407: 618.7. Found (M+l)+: 619.3. Example 72 (Formula Removed) To a solution of 45 (20 mg, 0.0384 mmol) in CH2Cl2 (0.3 mL), trans-crotonyl chloride (3.68 µL, 0.0384 mmol) and pyridine (3.1 µL. 0.0384 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2C12 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:ethyl acetate 4:1 to ethyl acetate) to afford 78 (16 mg, 71 %) as a white solid. Rf: 0.55 (ethyl acetate:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ 6.50-6.40 (m, 1 H). 6.46 (s, 1 H), 5.97 (d, J=1.5 Hz, 1 H), 5.91 (d, J=1,5 Hz, 1 H), 5.77 (s. 1 H), 5.08 (bst, 1 H), 4.10 (d. J= 1.5 Hz, 1 H), 4.05 (m, 2H), 3.78 (s, 3H), 3.67 (bs, 1H), 3.42-3.29 (m. 3H), 3.04 (dd,J1= 8.1 Hz,J2= 18.3 Hz, 1H), 2.78 (d,J= 15.3 Hz, 1H), 2.53 (d, J= 18.3 Hz, 1 H), 2.32 (s, 3H), 2.26 (s, 3H), 1.98 (s, 3H), 1.79 (dd, J,= 12.0 Hz, J2= 15.6 Hz,1H), 1.70 (dd, J2= 1.2 Hz, J2= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C32H36N4O7: 588.6. Found (M+l)+: 589.3. Example 73 (Formula Removed) To a solution of 45 (50 mg, 0.096 mmol) in CH2C12 (0.5 mL). Cbz-L-Val-OH (24.12 mg, 0.096 mmol) and carbonyl diimidazole (18.7 mg, 0.1 15 mmol) were added at 0 °C. The reaction mixture was stirred for 16 h at room temperature and then, the solution was diluted with CH2C12 (15 mL) and washed with 0.1 N HC1 (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chiomatography (SiO2, Hex:EtOAc 4:1) to afford 79 (25 mg, 34 %) as a white solid. Rf:0.7(EtOAc:MeOH5:l). 1H NMR (300 MHz, CDC13) δ 7.33-7.28 (m, 5H), 6.45 (s, 1 H), 5.96 (s, 1 H), 5.90 (bs, 1 H), 5.82 (s, 1 H), 5.53 (bs, 1 H), 5.09 (bs, 1 H), 5.05 (d, J= 3.3 Hz, 2H), 4.1 6 (bs, 1 H), 4.09 (d, J= 2.4 Hz, 1H), 4.02 (bs, 1H), 3.75 (s, 3H), 3.74 (m, 1H), 3.37-3.35 (m, 2H), 3.26-3.21 (m, 3H), 3.00 (dd, J1=8.1 Hz, J2= 18.3 Hz,1H), 2.77 (d,J= 15.6 Hz, 1H), 2.55 (d,J= 18.0 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H), 1.98 (s, 3H), 1.70-1.66 (m, 1H), 0.65 (d, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C41H47N5O9: 753.8. Found (M+l)+: 754.2. Example 74 (Formula Removed) To a solution of 72 (18 mg, 0.0275 mmol) in CH3CN/H20 (1.5 mL/0.5 mL). AgNO3 (140.5 mg, 0.827 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacua. The residue was purified by flash column chromatography (SiO2, EtOAc:MeOH 10:1) to afford 80 (13 mg, 74 %) as a white solid. Rf: 0.37 (EtOAc:MeOH 5:1). 1HNMR (300 MHz, CDC13) δ7.23-7.11 (m, 3H), 7.06-7.01 (m, 2H), 6.43 (s, 1 H), 5.95 (d, J= 1.2 Hz, 1H), 5.88 (d,J=1.2 Hz, 1H), 5.71 (bs,1H), 5.19 (bs,1H), 4.45 (d, J= 3.0 Hz, 1H), 4.37 (bs, 1H), 4.02-3.96 (m, 1 H), 3.75-3.68 (m, 2H), 3.48 (s, 3H), 3.41-3.36 (m, 2H), 3.28- 3.24 (m, 1H), 3.15 (d,J= 1.5 Hz, 1H), 3.01-2.88 (m, 2H), 2.70 (d, J= 15.9 Hz, 1H), 2.57-2.51 (m, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 2.00 (s, 6H), 1.77-1.68 (m,1H). ESI-MS m/z: Calcd. for C36H41N3O8: 643.3. Found (M- 17)+: 626.2. Example 75 (Formula Removed) To a solution of 73 (23 mg, 0.036 mmol) in CH3CN/H2O (1.5 mL/l ml), AgNO3 (183 mg, 1.08 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 mL). The solution was extracted and the organic layer was dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, gradient EtOAc:MeOH 5:1 to MeOH) to afford 81 (9.3 mg, 41 %) as a white solid. Rf:0.3(EtOAc:MeOH5:l). 1HNMR (300 MHz, CDC13) δ 7.17-7.13 (m, 3H), 6.85 (m, 2H), 6.54 (s, 1H), 5.90 (d,7= 1.5 Hz, 1H), 5.84 (d, J= 1.5 Hz, 1H), 5.22 (m, 1H), 4.43 (bs, 1H), 4.39 (d,J= 2.4 Hz, 1H), 4.00 (d, J= 2.4 Hz, 1H), 3.71 (s, 3H), 3.64-3.29 (m, 2H), 3.16 (d, J= 8.7 Hz, 1 H), 2.98-2.88 (m, 3H), 2.67 (d, J= 14.8 Hz, 1H), 2.45 (d, J= 18.3 Hz, 1H), 2.33 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 1.97 (s, 3H), 1.68 (dd, J,= 12.8 Hz, J,= 14.7 Hz, 1H). ESI-MS m/z: Calcd. for C35H39N3O8: 629.7. Found (M+- OH): 612.3. Example 76 (Formula Removed) To a solution of 74 (20 mg, 0.0346 mmol) in CH3CN/H2O (1.5 mL/l mL). AgNO3 (176.6 mg, 1.04 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc:MeOH 1:1) to afford 82 (12.9 mg, 66 %) as a white solid. Rf:0.3(EtOAc:MeOH5:l). 1H NMR (300 MHz, CDC13) δ 6.50 (s, 1 H), 5.95 (d, J= 1.2 Hz, 1 H), 5.89 (d, J= 1.2 Hz, 1 H), 5.19(d, 1H), 4.46 (d,J=3.0 Hz, lH),4.38(d,J= 1.8 Hz, lH),4.00(d, J= 2.1 Hz,1H), 3.74 (s, 3H), 3.70-3.66 (m, 1H), 3.38 (dt,J1= 2.7 Hz, J2= 13.2 Hz, 1H), 3.25 (d, J= 13.8 Hz, 1H), 3.16 (d,7= 7.5 Hz,1H), 2.96 (dd, 7,= 7.2 Hz, J= 17.7 Hz, 1H), 2.71 (d,7= 15.6 Hz,1H), 2.40 (d, J= 18.0 Hz, 1 H), 2.30 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.97 (s, 3H), 1.71 (dd, J= 11.7 Hz, J2=15.3 Hz, 1H), 1.60-1.48 (m, 2H), 0.67 (t,J=7.5 Hz, 3H). ESI-MS m/z: Calcd. for C30H37N3O8: 567.6. Found (M-17)+: 550.2. Example 77 (Formula Removed) To a solution of 77 (14 mg, 0.0226 mmol) in CH3CN/H2O (1.5 mL/1 mL). AgNO3 (115.3 mg, 0.68 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2(15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc:MeOH 5:1) to afford 83 (9 mg, 65 %) as a white solid. Rf: 0.25 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ 6.50 (s, 1 H), 5.96 (d, J= } .5 Hz, 1 H), 5.89 (d, J= ] .5 Hz, 1 H), 5.73 (bs, 1H), 4.44 (d, J= 3.6 Hz, 1H), 4.37 (s, 1H), 4.01 (d, J= 2.4 Hz, 1H), 3.77 (s, 3H), 3.73-3.64 (m, 1H), 3.39 (dt, J1= 3.0 Hz, J2= 9.3 Hz, 1H), 3.22 (d, J= 14.5 Hz, 1H), 3.16 (d, J= 7.5 Hz, 1H), 2.95 (dd, J,= 8.1 Hz, J2= 17.4 Hz, 1H), 2.70 (d,J= 14.5 Hz, 1H), 2.41 (d, J= 18.3 Hz, 1H), 2.30 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 1.96 (s,3H), 1.71 (dd,J/= 12.0Hz,J= 15.6 Hz, 1H), 1.48-1.46 (m, 2H), 1.24-1.10 (m, 4H), 1.00-0.95 (m, 2H), 0.80 (t,J= 7.2 Hz, 3H). ESI-MS m/z: Calcd. for C33R43N308: 609.7. Found (M-17)+: 592.3. Example 78 (Formula Removed) To a solution of 78 (15 mg, 0.025 mmol) in CH3CN/H20 (1.5 rnL/1 mL), AgNO3 (130 mg, 0.764 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 1:1) to afford 84 (10 mg, 71 %) as a white solid. Rf:0.19(EtOAc:MeOH5:l). 1H NMR (300 MHz, CDC13) δ 6.49 (s, 1 H), 6.47-6.37 (m, 1 H), 5.94 (d, J= 1.5 Hz, 1 H), 5.88 (d,y= 1.5 Hz, 1H), 5.77 (bs, 1H), 5.26 (d,7= 5.7 Hz, 1H), 4.93 (d,J= 14.7 Hz, 1H), 4.48 (d, J=11.1 Hz, 1H), 4.38 (d, J=2.7 Hz, 1H), 4.02 ((d,J= 2.1 Hz, 1H), 3.79 (s. 3H). 3.76-3.72 (m, 1H), 3.42 (dt,J1=2.7 Hz, J2= 12.0 Hz, 1H), 3.28 (d, J= 13.2 Hz, 1H), 3.15 (d,J= 6.6 Hz, 1H), 2.96 (dd, Jt= 8.7 Hz, J2= 18.0 Hz, 1H), 2.70 (d, J= 15.0 Hz, 1H), 2.38 (d, J= 18.0 Hz, 1 H), 2.30 (s, 3H), 2.28 (s, 3H), 1.95 (s, 3H), 1.72 (dd, J,= 12.3 Hz, J2= 17.4 Hz, 1 H), 1.98 (dd,J1=1.5Hz,J2=6.9Hz,3H). ESI-MS m/z: Calcd. for C31H37N3O8: 579.6. Found (M-17)+: 562.3. Example 79 (Formula Removed) To a solution of 43 (25 mg, 0.422 mmol) in CH2Cl2 (0.3 mL). hydrocinnamoyl chloride (6.27 µL, 0.422 mmol) and pyridine (3.41 µL, 0.422 mmol) were added at 0 °C. The reaction mixture was stirred for Ih and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex: EtOAc 4:1 to EtOAc) to afford 85 (30 mg, 68 %) as a white solid. Rf: 0.54 (EtOAcMeOH 10:1). 1HNMR (300 MHz, CDC15) δ 7.28-7.14 (m, 5H), 6.45 (s, 1H), 6.07 (brd, 1H), 5.99 (d, J= 1.2 Hz,1H), 5.90 (d,J= 1.2 Hz,1H), 5.88 (s, 1H), 5.31 (brt, 1H), 4.09-4.06 (m, 3H), 3.80- 3.75 (m, 1H), 3.73 (s, 3H), 3.57-3.51 (m, 2H), 3.38 (d,J= 7.5 Hz,1H), 3.24 (m, 1H), 3.00 (dd,J1= 8.4 Hz, J2= 18.0 Hz, 1H), 2.89-2.85 (m, 2H), 2.79 (d, J= 16.5 Hz, 1H), 2.61 (d, J= 18.0 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.79 (dd, J,= 12.3 Hz, J2= 16.2 Hz, 1H), 0.72 (d, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C40H45N5O8: 723.8. Found (M+23)+: 746.3. Example80 (Formula Removed) To a solution of 43 (25 mg, 0.422 mmol) in CH2Cl2 (0.3 mL), hydrocinnamoyl chloride (6.27 µL, 0.422 mmol) and pyridine (3.41 µL, 0.422 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2C12 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex: EtOAc 4:1 to EtOAc) to afford 85 (30 mg, 68 %) as a white solid. Rf: 0.54 (EtOAcMeOH 10:1). 1HNMR (300 MHz, CDC13) δ 7.28-7.14 (m, 5H), 6.45 (s, 1H), 6.07 (brd, 1H), 5.99 (d, J= 1.2 Hz, 1H), 5.90 (d,J= 1.2 Hz, 1H), 5.88 (s,1H), 5.31 (bit, 1H), 4.09-4.06 (m, 3H), 3.80- 3.75 (m, 1H), 3.73 (s, 3H), 3.57-3.51 (m, 2H), 3.38 (d,J= 7.5 Hz, 1H), 3.24 (m, 1IH), 3.00 (dd, J1= 8.4 Hz, J2= 18.0 Hz, 1H), 2.89-2.85 (m, 2H), 2.79 (d,J= 16.5 Hz,1H), 2.61 (d, J= 18.0 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.79 (dd, J,= 12.3 Hz, J2= 16.2 Hz, 1H), 0.72 (d, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C40H45N5O8: 723.8. Found (M+23)+: 746.3. Example 81 (Formula Removed) To a solution of 43 (33 mg, 0.0557 mmol) in CH2Cl2 (0.4 mL), phenyl acetyl chloride (7.36µL; 0.0557 mmol) and pyridine (4.5µL, 0.0557 mmol) were added at 0 °C. The reaction mixture was stirred for Ih and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:EtOAc 2:1) to afford 87 (13 mg, 32 %) as a white solid. Rf: 0.63 (Hex:EtOAc:MeOH 5:10:2). 1H NMR (300 MHz, CDC13) δ7.37-7.20 (m, 5H), 6.26 (s,1H), 6.14 (d, J= 6.6 Hz, 1H), 5.98 (d, J= 1.2 Hz, 1H), 5.83 (s, 1H), 5.27 (t,J= 6.2 Hz, 1H),4.11 (d, J=2.1 Hz,1H), 4.07 (d, J= 3.0 Hz, 1H), 4.04 (s, 1H), 3.86-3.81 (m, 1H), 3.70 (s, 3H), 3.54-3.53 (m, 2H). 3.44 (bs, 2H), 3.36 (d, J= 8.1 Hz, 1H), 3.22 (dt, J,= 2.7 Hz, J2= 12.0 Hz, 1H), 2.93 (dd, J,= 7.2 Hz, J2= 18.3 Hz, 1 H), 2.77 (d, J= 14.4 Hz, 1 H), 2.59 (d, J= 18.0 Hz, 1 H), 2.31 (s, 3H), 2.26 (s, 3H), 2.17 (s,3H), 2.01 (s, 3H), 1.78(dd,J1= 10.8 Hz, J2= 15.6 Hz, 1H), 0.65 (d, J= 6.3 Hz, 1H). ESI-MS m/z: Calcd. for C39H43N5O8: 709.8. Found (M+l)+: 710.3. ExampIe 82 (Formula Removed) To a solution of 43 (30 mg, 0.05 mmol) in CH2Cl2 (0.3 mL), propionyl chloride (4.40 µL, 0.05 mmol) and pyridine (4.0-4 µL, 0.05 mmol) were added at 0 °C. The reaction * mixture was stirred for 1h and then, the solution was diluted with CH2Cl2 (15 mL) and washed with 0.1 N HC1 (10 mL). The organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chiomatography (SiOi, gradient Hex:EtOAc 1:1 to EtOAc) to afford 88 (18 mg, 56 %) as a white solid. Rf: 0.49 (Hex:EtOAc:MeOH 1:10:2). 1H NMR (300 MHz, CDC13) δ 6.46 (s, 1 H), 6.16 (brd, 1 H), 5.99 (d, J= 1.2 Hz, 1 H), 5.95 (s, 1H), 5.90 (d, J= 1.2 Hz, 1H), 5.34 bit,1H). 4.12-4.06 (m, 3H), 3.84 (bs, 1H), 3.74 (s, 3H), 3.63 (dd, J1= 6.3 Hz, J= 12.9 Hz, 1H), 3.50-3.48 (m,1H), 3.39 (d, J= 8.1 Hz,1H), 3.23 (d, J= 11.7 Hz, 1H), 3.00 (dd, J,= 8.4 Hz, J2= 18.3 Hz, IH), 2.78 (d, J= 15.6 Hz, 1H), 2.63 (d, J= 18.3 Hz, 1 H), 2.31 (s, 3H), 2.27 (s, 3H), 1.87-1.80 (m, 1 H), 1.06 (t, J= 7.5Hz, 3H), 0.74 (d, J= 6.9 Hz, 3H). ESI-MS m/z: Calcd. for C34H41N508: 647.7. Found (M+l)+: 648.2. Example 83 (Formula Removed) To a solution of 43 (20 mg, 0.0338 mmol) in CH2Cl2 (0.3 mL), propionyl chloride (3.238 µL, 0.0338 mmol) and pyridine (2.73 µL, 0.0338 mmol) were added at 0 °C. The reaction mixture was stirred for 1h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over Na2SO4 filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2. gradient Hex:EtOAc 3:1 to AcOEt) to afford 89 (11.5 mg, 52 %) as a white solid. Rf: 0.57 (EtOAc:MeOH 10:1). 1HNMR (300 MHz, CDC13) δ6.82-6.70 (m, 1H), 6.46 (s, 1H), 6.11 (d, 1H),6.00(d,J= 1.5 Hz, lH),5.89(d,J=1.5Hz, lH),5.S5(s, 1H), 5.77 (dd, J,= 1.5 Hz,7^ 15.3 Hz, 1H), 5.37 (bst, 1H), 4.13-4.06 (m, 3H), 3.19 (m, 1H), 3.73 (s, 3H), 3.55 (m, 2H), 3.38 (d, J= 1.5 Hz, 1H), 3.23 (d,J= 11.4 Hz, 1H), 3.00 (dd,J,= 8.4 Hz, J,- 18.3 Hz, 1H), 2.78 (d, J= 15.0 Hz, 1H), 2.65 (d, J= 18.0 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 2.00 (s, 3H), 1.85-1.82 (m, 4H), 0.77 (d, J= 6.3 Hz, 3H). ESI-MS m/z: Calcd. for C35H41N5O8: 659.7. Found (M+l)+: 660.3. Example 84 (Formula Removed) To a solution of 43 (15 mg, 0.0253 mmol) in CH2C12 (0.3 mL), Cbz-L-Val-OH (6.39 mg, 0.0253 mmol) and carbonyl diimidazole (4.86 mg, 0.03 mmol) were added at 0 °C. The reaction mixture was stirred for 16 h at room temperature and then, the solution was diluted with CH2C12 (15 mL) and washed with 0.1 N HC1 (10 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:EtOAc 1:1 to EtOAc) to afford 90 (6.7 mg, 32 %) as a white solid. Rf: 0.79 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ 7.35 (bs, 5H), 6.46 (s, 1 H), 6.28 (d, J= 6.0 Hz, 1 H), 5.98 (d, J= 1.2 Hz, 1H), 5.89 (d,J= 1.2 Hz, 1H), 5.77 (s, 1H), 5.44 (bs, 1H), 5.30 (bs, 1H), 5.08 (s, 2H), 4.09-4.06 (m, 3H), 3.94-3.89 (m, 1H), 3.70-3.66 (m, 5H), 3.38 (d,J= 11.7 Hz, 1H), 3.01 96 (dd, J= 7.8 Hz, J2= 18.3 Hz, 1 H), 2.79 (d, J= 14.1 Hz, 1 H), 2.63 (d, J= 18.0 Hz, 1 H), 2.30 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 1.99 (s, 3H9, 1.97-1.81 (m, 2H), 0.83 (d, J= 6.6 Hz, 3H), 0.80 (d, J= 6.6 Hz, 3H), 0.75 (d, J= 6.9 Hz, 3H). ESI-MS m/z: Calcd. for C44H52N6O10: 824.9. Found (M + 1)+: 825.4. Example 85 (Formula Removed) To a solution of 62 (20 mg. 0.030 mmol) in CH3CN/H2O (1.5 mL/l mL). AgNO3 (154 mg. 0.90 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCOs (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 3:1) to afford 91 (13 mg, 66 %) as a white solid. Rf:0.18(EtOAc:MeOH 10:1). 1HNMR (300 MHz, CDC13) δ 6.49 (s, 1H), 6.16 (d, 1H), 5.98 (d,J= 1.5 Hz, 1IH), 5.89 (d,J= 1.5 Hz, lH),5.32(bs, 1H),4.41 (bs, lH),4.00(bs, 1H), 3.79 (s, 3H), 3.70-3.65 (m, 2H), 3.37-3.32 (m, 2H), 3.19-3.17 (m, 1H), 2.94 (dd,J= 9.0 Hz,J2= 15.0 Hz, 1H), 2.74 (d,J= 15.9 Hz, 1H), 2.46 (d,J= 17.1 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 2.04-2.01 (m, 2H), 1.98 (s, 3H), 1.64-1.62 (m, 1H), 1.54-1.52 (m, 2H), 0.89-0.84 (m, 6H). ESI-MS m/z: Calcd. for C34H44N4O9: 652.7. Found (M-17)+: 635.3. Example 86 (Formula Removed) To a solution of 85 (10 mg, 0.0138 mmol) in CH3CN/H20 (1.5 mL/1 ml), AgNO3 (70.4 mg, 0.414 mmol) was addend and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 4:1) to afford 92 (7 mg, 71 %) as a white solid. Rf:0.20(EtOAc:MeOH5:l). 1HNMR (300 MHz, CDC13) δ 7.25-7.13 (m, 5H), 6.47 (s, 1H), 6.13 (brd,1H), 5.97 (d,J= 1.2 Hz, 1 H), 5.88 (d, J= 1.2 Hz, 1 H). 5.34 (brt, 1 H), 4.50 (bs, 1 H), 4.40 (bs, 1 H), 4.00 (bs, 1H), 3.76 (s, 3H), 3.70-3.65 (m,''''''''3H), 3.34 (d, J= 11.7 Hz, 1H), 3.17 (d, J= 5.1 Hz, 1H), 2.98- 2.83 (m, 3H), 2.72 (t,J= 14.4 Hz, 1H), 2.44 (d, J= 19.2 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 6H), 1.97 (s, 3H), 1.72 (m, 1 H), 0.82 (d, J= 6.6 Hz, 3H). ESI-MS m/z: Calcd. for C39H46N4O9: 714.8. Found (M-17)+: 697.3. Example 87 (Formula Removed) To a solution of 86 (6 mg, 0.0087 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgNO3 (44 mg, 0.26 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiOi, gradient EtOAc to EtOAc:MeOH 5:1) to afford 93 (5 mg, 85 %) as a white solid. Rf: 0.018 (EtOAc:MeOH 5:1). 1HNMR (300 MHz, CDC13) δ6.48(s, 1H), 6.17 (d, 1H), 5.98 (d, J= 1.5 Hz, 1H). 5.89 (d, J= 1.5 Hz, 1H), 5.33 (bs, 1H), 4.51 (d, 1H), 4.40 (d, 1H), 4.00 (d, 1H), 3.78 (s, 3H), 3.76-3.65 (m, 2H), 3.36-3.32 (m, 2H), 3.18 (d,7= 6.9 Hz, 1H), 2.98-2.89 (m, 1H), 2.71 (d,J= 15.0 Hz, 1 H), 2.45 (d,J= 17.7 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 1.98 (s,3H), 1.68-1.50 (m, 3H), 1.29-1.19 (m, 6H), 0.88-0.84 (m, 6H). ESI-MS m/z: Calcd. for C36H48N4O9: 680.7. Found (M-17)+: 663.3. Example 88 (Formula Removed) To a solution of 87 (12 mg, 0.0169 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgNO3 (86 mg, 0.507 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2(15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 5:1) to afford 94 (8.8 mg, 74 %) as a white solid. Rf: 0.28 (EtOAc:MeOH 5:1). 1HNMR (300 MHz, CDC13) δ 7.34-7.18 (m, 5H), 6.37 (s, 1H), 6.20 (d, 1H), 5.96 (d, J= 1.5 Hz, 1H), 5.88(d,J=1.5Hz, lH),5.30(t, lH),4.50(bs, 1H), 4.39 (d,J= 1.8 Hz, lH),3.99(d, J=2.1 Hz, 1H), 3.73 (s, 3H), 3.69-3.60 (m, 3H), 3.37-3.30 (m, 3H), 3.17 (d,J= 18.1 Hz, 1H), 2.89 (dd, J,= 7.5 Hz, J2= 18.3 Hz, 1 H), 2.31 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 1.99 (s, 3H), 1.71 (dd, J;= 11.7 Hz, Jz= 15.0 Hz, 1H), 0.77 (d, J= 6.6 Hz, 1H). ESI-MS m/z: Calcd. for C38H44N409: 700.7. Found (M-17)+: 683.2. Example 89 (Formula Removed) To a solution of 88 (14 mg, 0.0216 mmol) in CH3CN/H20 (1.5 mL/1 mL), AgNO3 (110 mg, 0.648 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 5:1) to afford 95 (9.7 mg, 70 %) as a white solid. Rf:0.16(EtOAc:MeOH5:l). 1H NMR (300 MHz, CDC13) δ 6.48 (s, 1 H), 6. 1 0 (d, 1 H), 5.97 (d, J= 1 .2 Hz. 1 H), 5.89 (d, J= 1.2 Hz, 1H), 5.36 (bs, 1H), 4.51 (bs, 1H), 4.40 (d, J= 2.1 Hz, 1H), 4.00 (d,J= 2.1 Hz, 1H), 3.78 (s, 3H), 3.76-3.62 (m, 3H), 3.33 (d, J= 1 1 .7Hz, 1 H), 3. 1 8 (d, J= 8.4 Hz, 1 H). 2.94 (dd, J1= 8.4 Hz, J2= 1 6.5 Hz, 1 H), 2.72 (d, J= 1 5.0 Hz, 1 H), 2.45 (d, J =1 8.3 Hz, 1 H), 2.3 1 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 1 .97 (s, 3H), 1 .86 (m, 2H), 1 .73 (dd, J,= 1 2.0 Hz, J2= 1 5.0 Hz, 1H), 1.05 (t, J= 7.8 Hz, 3H), 0.83 (d, J= 6.9 Hz, 3H). ESI-MS m/z: Calcd. for C33H42N4O9 638.7. Found (M-17)+: 621.2. Example 90 (Formula Removed) To a solution of 89 ( 1 0 mg, 0.0 1 5 mmol) in CH3CN/H2O ( 1 .5 mL/1 mL). AgNO3 (77.2 mg. 0.454 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 1:1) to afford 96 (9 mg, 92 %) as a white solid. Rf: 0.016 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ 6.76-6.69 (m, 1 H), 6.47 (s, 1 H), 6. 1 8 (brd, 1 H), 5.97 (d, J= 1.5 Hz, 1H), 5.88(d,J= 1.5 Hz, 1H),5.71 (dd,J= 1.5Hz,J2= 16.2 Hz, 3H), 5.32 (bs, 1H), 4.50 (m, 1H),4.41 (m, 1H), 3.99 (m, 1H), 3.78 (m, 4H), 3.64-3.58 (m, 2H), 3.34 (d,J= 1 1.1 Hz, 1H), 3.17 (d,J= 8.6 Hz, 1H), 2.95 (dd, J,= 7.5 Hz, J2= 17.4 Hz, 1H), 2.70 (d, J- 16.2 Hz, 1H), 2.48 (d, J= 17.7 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.17 (s, 6H), 1.97 (s, 3H), 1.82- 1.74 (m, 4H), 0.88 (t, J= 5.2 Hz, 3H). ESI-MS m/z: Calcd. for C34H42N409: 650.7. Found (M-17)+: 633.3. Example 91 (Formula Removed) To a solution of 25 (100 mg, 0.177 mmol) in CH2C12 (0.5 ml), butyryl chloride (24 µL, 0.23 mmol) and pyridine (17 µL, 0.212 mmol) were added at 0 °C. The reaction mixture was stirred for 2h at room temperature and then, the solution was diluted with CH2C12 (30 mL) and washed with 0.1 N HC1 (20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, Hex:EtOAc 3:1) to afford 97 (99 mg. 88 %) as a colorless oil. Rf: 0.64 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC]3) δ 6.66 (s,1H), 6.16-6.05 (m, 1H), 5.93 (d, J= 1.2 Hz, 1H), 5.87 (d,J= 1.2 Hz, 1H), 5.40(dd,J1=1.2Hz,J2= 17.1 Hz. 1H), 5.26 (dd, J,= 1.2Hz,J2= 10.2 Hz, 1H), 5.13-5.08 (m, 2H), 4.44 (dd, J1= 3.6 Hz, J2= 1 1.1 Hz, 1H), 4.21-4.07 (m, 5H), 3.74 (m, 1H), 3.72 (s, 1H), 3.57 (s, 3H), 3.35 (d, . J= 10.5 Hz, 1H), 3.26-3.21 (m, 2H), 3.98 (dd, J,= 8.7 Hz, J2= 1 8.0 Hz, 1 H), 2.54 (d, J= 1 8.0 Hz), 2.30 (s, 3H), 2.2 1 (s, 3H), 2. 1 3 (s, 3H), 1 .92-1 .65 (m, 3H), 1 .42-1 .34 (m, 2H), 0.80 (t, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C35H43N3O9: 633.7. Found (M+l)+: 634.3. Example 92 (Formula Removed) To a solution of 25 (100 mg, 0.177 mmol) in CH2C12 (0.4 mL), trans-3-(trifluoromethyl)cinnamoyl chloride (35µL, 0.23 mmol) and pyridine (17 µL. 0.212 mmol) were added at 0 °C. The reaction mixture was stirred for1h at room temperature and then, the solution was diluted with CH2Cl2 (30 mL) and washed with 0. 1 N HC1 (20 mL). The organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO:, gradient Hex:EtOAc 6:1 to Hex:EtOAc 1:1) to afford 98 (122 mg, 90 %) as a white solid. Rf: 0.478 (Hex:EtOAcl:l). 1H NMR (300 MHz, CDCI3) 5 7.64-7.48 (m, 4H), 7.37 (d, J=15.6 Hz, 1 H), 6.62 (s, 1 H), 6.16-6.07 (m,1H), 6.12 (d,J= 15.6 Hz, 1H), 5.94 (d, J= 1.2 Hz, 1H), 5.89 (d, J= 1.2 Hz, 1H), 5.41 (dd, J1= 1.8 Hz,J3= 17.1 Hz, 1H), 5.28 (dd,J= 1.8 Hz,J2= 12.0 Hz, 1H), 5.04 (q, J= 6.0 Hz, 1H), 4.60 (dd,y/= 3.3 Hz, J2= 1 1.1 Hz, 1H), 4.22-4.15 (m, 5H), 3.90 (dd, J1= 4.2 Hz,J2=1 1.1 Hz, 1H), 3.55 (s, 3H), 3.38 (s, 3H), 3.35-3.34 (m, 1H), 3.27-3.25 (m, 1H), 3.22 (bs, 1H), 2.98 (dd,Jy= 7.8 Hz, J2= 18.0 Hz, 1H), 2.61 (d, J= 17.7 Hz, 1H), 2.29 (s, 3H), 2.16 (s, 3H), 2.00 (s, 3H), 1 .80 (dd, J1= 1 1 .7 Hz, J3= 1 5.6 Hz, 1H). ESI-MS m/z: Calcd. for C41H3F3N3O8: 761.7. Found (M+l)+: 762.3. Example 93 (Formula Removed) To a solution of 25 (68 mg, 0.12 mmol) in CH2Cl2 (0.4 mL), hydrocynnamoyl chloride (20 µL, 1.12 mmol) and pyridine (10 µL, 1.01 mmol) were added at 0 °C. The reaction mixture was stirred for 2h at room temperature and then, the solution was diluted with CH2Cl2 (30 mL) and washed with 0.1 N HC1 (20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiOi, gradient Hex:EtOAc 5:1 to Hex:EtOAc 2:1) to afford 99 (41 mg, 49 %) as a white solid. Rf: 0.47 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ 7.29-7.18 (m, 3H), 7.04-7.02 (m, 2H), 6.66 (s, 1H), 6.16-6.07 (m, IH), 5.93 (d,J= 1.2 Hz,1H), 5.87 (d, J= 1.2 Hz, 1H), 5.40 (dd. J,= 1.7 Hz,J2= 17.4 Hz, 1 H), 5.26 (dd, J,= 1 .7 Hz, J2= 1 0.2 Hz, 1 H), 5.09 (dd, J,= 6.0 Hz, J2= 8.7 Hz, 2H), 4.43 (dd, J= 3.3 Hz, J2= 11.1 Hz, 1H), 4.20-4.14 (m, 3H), 4.06 (t, J= 3.7 Hz, IH), 4.02 (d,J= 2.4 Hz, 1H), 3.72 (dd, J,= 4.5 Hz, J2= 1 1 .1 Hz, 1 H), 3.56 (s, 3H), 3.55 (s, 3H), 3.32 (brd, J= 8.7 Hz, 1H), 3.26 (dd, J,= 1.9 Hz, J2= 8.1 Hz, 1H), 3.23-3.20 (m,1H), 3.01 (brd, J= 8.1 Hz, 1H), 3.23-3.20 (m, 1H), 3.26 (dd, J,= 1.9 Hz, J2= 8.1 Hz, IH), 2.95 (d,J= 1.8 Hz, 1H), 2.71-2.64 (m, 3H), 2.53 (d, J= 1 7.7 Hz, 1 H), 2.26 (s, 3H), 2.14 (s, 6H), 1 .83 (dd, J,= 1 2.3 Hz, J2= 1 5.9 Hz,1H). ESI-MS m/z: Calcd. for C40H45F3N3O8: 695.3. Found (M+l)+: 696.3. Example 94 (Formula Removed) To a solution of 25 (100 mg, 0.177 mmol) in CH2Cl2 (0.4 mL), cynnamoyl chloride (35 mg, 0.21 mmol) and pyridine (17 µL, 0.21 mmol) were added at 0 °C. The reaction mixture was stirred for 2h at room temperature and then, the solution was diluted with CH2Cl2 (30 mL) and washed with 0.1 N HC1 (20 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex:EtOAc 6:1) to afford 100 (94 mg, 76 %) as a white solid. Rf: 0.49 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ 7.42-7.33 (m, 6H), 6.62 (s, 1H), 6.16-6.05 (m, IH), 6.10 (d, J= 15.9Hz, 1H), 5.94 (d, J= 1.2 Hz, 1H), 5.88 (d,J= 1.2 Hz, 1H), 5.43 (dd, J=3.0 Hz. J,= 17.1 Hz, 1H), 5.27 (dd,J1= 3.0 Hz, .J2=12.0 Hz,1H), 5.04 (q,J= 6.0 Hz,1H). 4.55 (dd,J= 3.9 Hz,J= 11.1 Hz, 1H), 4.22-4.15 (m,5H), 3.87 (dd,J= 4.5 Hz, J= 11.1 Hz, lH),3.55(s, 3H), 3.39 (s, 3H), 3.36-3.33 (m,1H), 3.26-3.22 (m, 2H), 2.98 (dd,J= 8.1 Hz, J= 17.7 Hz, 1H), 2.63 (d, J= 17.7 Hz, 1H), 2.29 (s, 3H), 2.03 (s, 3H), 1.82 (dd, J/= 1 1.7 Hz, J2= 15.3Hz, 1H). ESI-MS m/z: Calcd. for C40H43N3O8: 693.3. Found (M+l)+: 694.3. Example 95 (Formula Removed) To a solution of 97 (40 mg, 0.063 mmol) in CH2Cl2 (0.7 mL), acetic acid (17.8µL), Pd(PPh3) 2Cl2 (3.64 mg, 0.0052 mmol) and Bu3SnH (67.9µL, 0.252 mmol) were added at 23 °C. The reaction mixture was stinred for 2h at that temperature and then, the solution was poured into a pad of flash column (SiO2, gradient Hex:EtOAc 5:1 to Hex:EtOAc 3:1) to afford 101 (30 mg, 80 %) as a white solid. Rf: 0.4 (Hex:EtOAc 1:1). 1HNMR (300 MHz, CDC13) δ 6.65 (s, 1H), 5.90 (d, J= 1.5 Hz, 1H), 5.82 (d.J= 1.5 Hz, 1H), 5.54 (s, 1H), 5.33 (d, J= 6.0 Hz, 1H), 5.13 (d,J= 6.0 Hz, 1H), 4.54 (dd, J,= 3.6 Hz,J2= 11.4 Hz,1H), 4.18 (d, J= 2.1 Hz, 1H), 4.13 (d, J= 2.4 Hz, 1H), 4.07 (t, J= 3.3 Hz, 1H), 3.75 (dd, J,= 3.9 Hz,J,= 11.1 Hz, 1H). 3.70 (s, 3H), 3.35 (d,J= 8.4 Hz, 1H), 3.24 (dd, J1=2.7 Hz, J2=8.7Hz, lH),3.10(dd,J1=2.4Hz,J2= 15.0 Hz, 1H), 3.01 (d,J=8.1 Hz, 1 H), 2.95 (d, J= 7.8 Hz, 1H), 2.58 (d,J= 18.3 Hz, 1H), 2.29 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.89-1.66 (m, 3H), 1.36-1.25 (m, 2H), 0.77 (t, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C32H39N3O8: 593.6. Found (M+l)+: 594.8 Example 96 (Formula Removed) To a solution of 98 (37 mg, 0.0485 mmol) in CH2Cl2 (0.7 mL), acetic acid (20 µL). Pd(PPh3)2Cl2 (4 mg, 0.0057 mmol) and Bu3SnH (53 µL, 0.194 mmol ) were added at 23 °C. The reaction mixture was stirred for 5h at that temperature and then, the solution was poured into a pad of flash column (Si02: gradient Hex:EtOAc 6:1 to Hex:EtOAc 2:1) to afford 102 (25 mg, 71 %) as a white solid. Rf: 0.38 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ 7.63-7.60 (M, 2H), 7.50-7.49 (M, 2H), 7.24 (d, J= 1 5.9 Hz, 1H), 6.59 (s, 1H), 5.98 (d, J= 15.9 Hz,1H), 5.92 (d, J= 1.5 Hz,1H), 5.84 (d, J= 1.5 Hz, 1H), 5.66 (s, 1H), 5.20 (d, J= 6.0 Hz, 1H), 4.87 (d, J=6.0 Hz, 1H), 4.71 (dd, J1= 2.7 Hz, J2= 10.8 Hz, 1H), 4.16-4.15 (m, 3H), 3.93 (dd, J,= 3.3 Hz, J2= 11.1 Hz, 1H), 3.66 (s. 3H), 3.36 (brd, J= 10.2 Hz, 1H), 3.26 (brd, J= 1 1.7 Hz, 1H), 3.10 (brd. J= 15.0 Hz, 1H), 2.96 (dd,J1= 7.8 Hz, J2= 17.7 Hz,1H), 2.62 (d, J= 17.7 Hz, 1H), 2.27 (s, 3H), 2.14 (s, 3H), 1.97 (s, 3H), 1.79 (dd,J1= 12.0Hz, J2= 15.8 Hz, 1H). ESI-MS m/z: Calcd. for C38H38F3N3O8: 721.7. Found (M+l)+: 722.2. Example 97 (Formula Removed) To a solution of 99 (41 mg, 0.059 mmol) in CH2C12 (1 mL), acetic acid (25 uL), Pd(PPh3)2Cl2 (5 mg, 0.0071 mmol) and Bu3SnH (63 uL, 0.235 mmol ) were added at 23 °C. The reaction mixture was stirred for 4,5 h at that temperature and then, the solution was poured into a pad of flash column (Si02, gradient Hex:EtOAc 6:1 to Hex:EtOAc 1:1) to afford 103 (34.2 mg, 89 %) as a white solid. Rf: 0.49 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDCl3) δ 7.24-7.15 (m, 3H), 7.03-7.01 (m, 2H), 6.65 (s, 1 H). 5.89 (bs. 1H), 5.82(bs, 1H), 5.49 (s, 1H), 5.31 (d,J=6.0Hz, 1H), 5.12 (d, 7- 6.0 Hz. 1H),4.53(dd, J1=3.3Hz, J2= 11.1 Hz, 1H), 4.18(d,J=2.7Hz, 1H), 4.07 (m, 2H), 3.75 (dd,J1=3.9 Hz, J2= 11.1 Hz, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 3.32 (d, J= 7.8 Hz, 1H), 3.25 (d, J= 10.8 Hz, 1H), 3.12 (d,7- 14.7Hz, 1H), 3.00 (d,J= 7.8 Hz, 1H). 2.94 (d, J= 8.1 Hz, 1H), 2.66-2.60 (m, 3H), 2.57 (d, J= 1 8.0 Hz, 1 H), 2.28 (s. 3H); 2. 1 4 (s, 3H), 2.1 0 (bs, 3H), 1 .83-1 .74 (m, 1 H). ESI-MS m/z: Calcd. for C37H41N3O8: 655.7. Found (M+l)+: 656.3. Example 98 (Formula Removed) To a solution of 100 (40 mg, 0.0576 mmol) in CH2C12 (1 mL), acetic acid (25 µL). Pd(PPh3)2Cl2 (4.8 mg, 0.007 mmol) and Bu3SnH (62µL, 0.23 mmol) were added at 23 °C. The reaction mixture was stirred for 5 h at that temperature and then, the solution was poured into a pad of flash column (SiO2, gradient Hex:EtOAc 4:1 to Hex:EtOAc 1:1) to afford 104 (30 mg, 82 %) as a white solid. Rf: 0.41 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ 7.36 (s, 5H), 7.30 (d, J= 16.2 Hz, 1H), 6.59 (s. 1H), 5.99 (d, J= 16.2 Hz, 1H), 5.91 (d,J= 1.2 Hz, 1H), 5.84 (d,7= 1.2 Hz, 1H), 5.60 (s. 1H). 5.20 (d, J= 5.6 Hz, 1H), 4.94 (d,J= 5.6 Hz, 1H), 4.63 (dd, J,= 3.3 Hz, J1= 11.4 Hz, 3H), 4.18-4.15 (m, 3H), 3.91 (dd,J1= 3.9Hz,J2= 11.1 Hz, 1H), 3.66 (s, 3H), 3.49 (s, 3H). 3.35 (brd,J= 15.0 Hz, 1H), 3.26 (brd,J= 11.4 Hz, 1H), 3.10 (brd, J= 15.0 Hz, 1H), 2.96 (dd, J1,= 8.4 Hz,J2= 18.0 Hz, 1H), 2.63 (d,J= 18.0 Hz,1H), 2.27 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H), 1.80 (dd,J1= 12.0Hz,J2=14.4Hz, 1H). ESI-MS m/z: Calcd. for C37H39N3O8: 653.7. Found (M+ 23)+: 676.2. Example 99 (Formula Removed) To a solution of 101 (24 mg, 0.041 mmol) in CH2C12 (0.4 mL), acetyl chloride (3µL, 0.041mmol), and pyridine (3.3 µL, 0.041 mmol) were added at 0 °C. The reaction mixture was stirred for 2 h and then, the solution was diluted with CH2Cl2 (15 mL) and washed with 0.1 N HCI (5 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chiomatography (SiO2: gradient Hex:EtOAc 5:1 to Hex:EtOAc 1:1) to afford 105 (23 mg. 88 %) as a white solid. Rf: 0.40 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ 6.66 (s, 1 H), 5.97 (d, J= 1.2 Hz, 1 H), 5.91 (d. J= 1.2 Hz. 1 H). 4.58 (d, J= 3.0 Hz, 1H), 4.54 (d, J= 3.0 Hz, 1H), 4.07 (t, J= 3.3 Hz, 1H), 3.77 (dd, J,= 3.9 Hz, J2= 11.4 Hz, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 3.35 (d,J= 10.2 Hz, 1H), 3.22 (dt. J1= 2.7 Hz, J2= 11.7 Hz, 1H), 2.98 (dd,J1= 8.1 Hz, J2= 18.0 Hz, 1H), 2.80 (d, J= 13.5 Hz. 1H). 2.58 (d, J= 1 8.0 Hz, 1 H), 2.33 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H), 2.02 (s, 3H), 1.89-1.76 (m. 2H). 1.72-1.66 (m, 1H), 1.37-1.25 (m, 2H), 0.78 (t,J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C34H41N3O9: 635.7. Found (M+l)+: 636.8. Example 100 (Formula Removed) To a solution of 102 (16 mg, 0.022 mmol) in CH2C12 (0.2 mL), aceryl chloride (1.9 µL, 0.0266 mmol), and pyridine (2.15 µL, 0.0266 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HCI (7 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:EtOAc 4:1 toEtOAc) to afford 106 (12 mg, 71 %) as a white solid. Rf: 0.60 (Hex:ElOAc 1:1). 1H NMR (300 MHz, CDC13) δ 7.83 (bs, 1 H), 7.65-7.58 (m, 2H), 7.49-7.44 (m, 1H), 7.14 (d. J= 16.2 Hz, 1H), 6.62 (s, 1H), 6.06 (d,J= 16.2 Hz, 1H), 6.00 (d, J= 1.2 Hz. 1H). 5.95 (d.J= 1.2 Hz, 1H), 5.02(d,J=5.7Hz, !H),4.96(bs, 1H), 4.92 (d, J= 5.7 Hz.1H). 4.15-4.11 (m, 3H), 3.88(dd,J1=3.3Hz,J2= 11.1 Hz, 1H), 3.08 (bs, 3H), 2.93 (dd,J1= 8.1 Hz.J2= 18.3 Hz. lH),2.80(d,J= 13.2 Hz, 1H), 2.64 (d,J= 18.0 Hz, 1H),2.31 (s, 3H), 2.27 (s. 3H). 2.08 (s, 3H), 1.91 (s, 3H), 1.69 (dd, J1= 11.7 Hz, J2= 15.9 Hz, 1H).). ESI-MS m/z: Calcd. for C40H40F3N3O9: 763.7. Found (M+l)+: 764.2. Example 101 (Formula Removed) To a solution of l03 (34 mg, 0.052 mmol) in CH2Cl2 (0.2 mL), acetyl chloride (4.4 uL, 0.062 mmol), and pyridine (5 µL, 0.062 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HCl (7 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (Si02, gradient Hex:EtOAc 4:1 toEtOAc) to afford 107 (25.5 mg, 70 %) as a white solid. Rf: 0.48 (Hex:EtOAc 1:1). ''''''''H NMR (300 MHz, CDC13) 5 7.25-7.14 (m, 3H), 7.06-7.04 (m, 2H), 6.66 (s, IH), 5.96 (d, /= 1.2 Hz, IH), 5.91 (d,J= 1.2 Hz, IH), 5.11 (d, J= 5.4 Hz, IH), 4.14 (d, J= 3.3 Hz, IH), 4.07 (d, J= 3.6 Hz, IH), 4.04 (d, J= 2.7Hz, IH), 3.78 (dd, Jt= 3.3 Hz, Jf= 10.8 Hz, IH), 3.55 (s, 3H), 3.51 (s, 3H), 3.33 (brd, J= 8.1 Hz, IH), 3.23 (dt, J,= 2.7 Hz, J?= 11.7 Hz, IH), 2.97 (dd, J1= 8.1 Hz, J2= 18.0 Hz, 1H), 2.81 (d, J=14.1 Hz, 1H), 2.63-2.52 (m, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.26-202 (m, 2H), 2.09 (s, 3H), 2.04 (s, 3H), 1.74 (dd, J1= 12.0 Hz, J2= 15.6 Hz, 1H). ESI-MS m/z: Calcd. for C39H43N309: 697.7. Found (M+l)+: 698.3. Example 102 (Formula Removed) To a solution of 104 (29 mg, 0.0443 mmol) in CH2Cl2 (0.3 mL). acetyl chloride (3.77 µL, 0.053 mmol), and pyridine (4.3 µL, 0.053 mmol) were added at 0 °C. The reaction mixture was stirred for 2 h and then, the solution was diluted with CH2Cl2 (15 mL) and washed with 0.1 N HCI (10 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:EtOAc 4:1 toEtOAc) to afford 108 (21.6 mg, 70 %) as a white solid. Rf: 0.58 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ7.47-7.44 (m, 2H), 7.35-7.34 (m, 3H), 7.29 (d, J= 15.9 Hz, 1H), 6.62 (s, 1H), 5.99 (d, J= 1.2 Hz, 1H), 5.93 (d, J= 1.2 Hz, 1H), 5.05 (d, J= 5.7 Hz, 1H), 4.94 (d, J= 5.7Hz, 1H), 4.81 (d, J=11.5 Hz, 1H), 4.16-4.11 (m, 3H), 3.34 (brd, J= 5.4 Hz, 1H), 3.24 (bs, 3H), 3.22-3.20 (m, 2H), 2.94 (dd, J,= 8.1 Hz,J2= 18.0 Hz, 1H), 2.80 (d, J= 14.1 Hz, 1H), 2.64 (d, J= 18.0 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 1.94 (s, 3H), 1.71(dd,J1=11.7Hz,J2=15.6Hz, 1H). ESI-MS m/z: Calcd. for C39H41N3O9: 695.7. Found (M+l)+: 696.2. Example 103 (Formula Removed) To a solution of 105 (16 mg, 0.025 mmol) in CH2Cl2 (0.2 mL), trifluoroacetic acid (77 µL, 1 mmol) was added at 0 °C and the reaction mixture was stirred for 3.5 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex:EtOAc 1:1) to afford 109 (12mg, 81 %) as a white solid. Rf: 0.32 (Hex:EtOAc 1:1). 1HNMR (300 MHz, CDC13) δ6.43(s, 1H), 5.97 (d, J= 1.5 Hz, 1H), 5.91 (d,J= 1.5 Hz, 1H). 5.69 (s,lH), 4.51 (dd, J1=3.3Hz,J2= 11.1 Hz, 1H), 4.10-4.05 (m, 3H), 3.78-3.77 (m, 1H), 3.75 (s, 3H), 3.33 (d,J= 8.1 Hz, 1H), 3.22 (dt, J1= 2.1 Hz,J2= 12.0 Hz, 1H), 2.96 (dd, J1= 8.4 Hz, J2= 17.7 Hz, 1 H), 2.80 (d, J= 15.6 Hz, 1 H), 2.55 (d, J= 18.0 Hz, 1 H). 2.33 (s, 3H), 2.24 (s, 3H), 2.01 (s, 3H), 1.87-1.66 (m, 3H), 1.37-1.27 (m, 2H), 0.77 (t,J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C32H31N308: 591.6. Found (M+l)+: 592.8. Example 104 (Formula Removed) To a solution of 1 06 (90 mg, 0.1178 mmol) in CH2Cl2 (0.3 mL). trifluoroacetic acid (750µL, 4.71 mmol) was added at 0 °C and the reaction mixture was stirred for 7 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (2x15 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex:EtOAc 1 :1) to afford 110 (71 mg, 84 %) as a white solid. Rf: 0.6 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ7.76 (bs, 1 H), 7.62-7.57 (m, 2H), 7.48-7.45 (m. 1 H). 7. 1 2 (d, J= 16.2 Hz,1H), 6.37 (s, 1H), 6.00 (d,J= 16.2 Hz, 1H), 5.98 (d. J= 1.2 Hz. 1H), 5.92 (d.J= 1.2 Hz, lH),5.60(bs, 1H), 4.88 (d, J= 10.2 Hz, 1H), 4.14 (bs, 1H), 4.10 (d.J= 2.4 Hz. 1H), 4.03 (d, J=2.4 Hz, lH)r 3.89 (dd, J1= 2.7 Hz, J,= 1 1.4 Hz, 1H), 3.32 (d, J= 8.4 Hz. 1H), 3.26-3.21 (m,4H), 2.91 (dd,J1=8:1 Hz, J2= 1 8.0 Hz, 1H), 2.82 (d, J= 13.8 Hz. 1H). 2.58 (d, J= 1 8.0 Hz, 1 H), 2.33 (s, 3H), 2.24 (s, 3H), 2.05 (s. 3H), 1 .89 (s, 3H). 1 .84 (dd. J1= 1 2.0 Hz, J,= 15.6Hz, 1H). ESI-MS m/z: Calcd. for C38H36F3N3O8: 719.7. Found (M+l)+: 720.3. Example 105 (Formula Removed) To a solution of 107 (20 mg, 0.286 mmol) in CfyCh (0.2 mL), trifluoroacetic acid (88 µL, 1.144 mmol) was added at 0 °C and the reaction mixture was stirred for 4 h at 23°C. ''''''''The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex:EtOAc 1:1) to afford 111 (18 mg, 96 %) as a white solid. Rf: 0.39 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ 7.23-7.16 (m, 3H), 7.06-7.04 (m, 2H), 6.43 (s.1H). 5.96 (d. J= 1.5 Hz, 1H), 5.90 (d, J= 1.5 Hz, lH),6.66(s,1H), 4.52 (dd, J,= 3.3 Hz. J2= 11.1 Hz,1H). 4.07 (s, 1 H), 4.05 (d, J= 3.3 Hz, 1 H), 4.03 (d, J= 2.4 Hz, 1 H), 3.76 (dd, J,= 3.6 Hz. J2= 11.1 Hz, 1H), 3.56 (s, 3H), 3.31 (d, J= 7.5 Hz. 1H), 3.23 (d,J= 12.0 Hz,1H), 2.95 (dd, J,= 8.1 Hz, J2= ] 8.0 Hz, 1 H), 2.80 (d, J= 15.3'''''''' Hz, 1 H), 2.63-2.58 (m, 2H), 2.53 (d. J= 18.0 Hz. 1 H), 2.33 (s, 3H), 2.61 (s, 3H), 2.21-2.09 (m, 2H), 2.13 (s, 3H), 2.02 (s. 3H). 1.85 (dd. J1= 11.7 Hz, J2= 115.3Hz, 1H). ESI-MS m/z: Calcd. for C37H39N3O8: 653.7. Found (M+l)+: 654.3. Example 106 (Formula Removed) To a solution of 108 (14 mg, 0.02 mmol) in CH2C12 (0.4 mL), trifluoroacetic acid (61.5 µL, 0.8 mmol) was added at 0 °C and the reaction mixture was stirred for 6 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex:EtOAc 2:1) to afford 112 (12 mg, 92 %) as a white solid. Rf: 0.36 (Hex:EtOAc 1:1). 1HNMR (300 MHz, CDC13) δ 7.46-7.45 (m, 2H), 7.35-7.20 (m, 4H), 6.38 (s, 1H), 6.05 (d, J= 15.9 Hz, 1H), 5.98 (d, J= 1.2 Hz, 1H), 5.93 (d, J= 1.2 Hz, 1H),5.57 (s, 1H),4.71 (d, J= 9.3 Hz, 1H), 4.17-4.13 (m, 2H), 4.08 (d.J= 1.9 Hz,1H), 3.89 (dd. J,= 3.6 Hz, J:= 11.4 Hz. 1H), 3.33 (m, 5H), 3.26-3.22 (m, 1H), 2.93 (dd, J,= 9.0 Hz,J2:= 17.4 Hz. 1H), 2.34 (s. 3H), 2.25 (s, 3H), 2.05 (s, 3H), 1.97(s,3H), 1.81 (dd,J1= 12.0 Hz, J2= 15.6 Hz, 1H). ESI-MS m/z: Calcd. for C37H37N308: 651. Found (M+l)+: 652.2. Example 107 (Formula Removed) To a solution of 109 (10 mg, 0.017 mmol) in CH3CN/H2O (1.5 mL/1 mL), AgNO3 (86 mg, 0.5 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacua. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 3:1) to afford 113 (7 mg, 71 %) as a white solid. Rf:0.41(EtOAc:MeOH5:l). 1H NMR (300 MHz, CDC13) δ 6.45 (s, 1H), 5.95 (d, J= 3.5 Hz, 1H), 5.88 (d,J= 1.5 Hz, 1H), 5.65 (bs, 1H), 4.50-4.48 (m, 2H), 4.44 (d, J= 2.1 Hz, 1H), 3.96 (d, J= 3.0 Hz, 1H), 3.76 (s, 3H), 3.74-3.70 (m, 1H), 3.30 (d,J= 12.3 Hz, 1H), 3.13 (d, J= 7.5 Hz, 1H), 2.86 (dd,J1= 5.7 Hz,J2= 18.3 Hz, 1H), 2.73 (d,7= 14.7 Hz, 1H), 2.48 (d,J= 17.7 Hz, 1H),2.33 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H), 2.00 (s, 3H), 1.86-1.55 (m, 3H), 1.42-1.23 (m, 2H), 0.75 (t,J= 7.5 Hz, 3h). -MS m/z: Calcd. for C31H38N209: 582.6. Found (M-17)+: 565.3. Example 108 (Formula Removed) To a solution of 110 (42.8 mg. 0.059 mmol) in CH3CN/H2O (1.5 mL/1 mL). AgNO3 (303 mg, 1 .78 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 5:1) to afford 114 (30 mg, 71 %) as a white solid. Rf: 0.30 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ7.75 (bs, 1H), 7.61-7.56 (m, 2H), 7.45-7.42 (m, 1H), 7.12 (d, J= 1 6.2 Hz, 1 H), 6.38 (s, 1 H), 6.02 (d, J= 1 6.2 Hz, 1 H), 5.97 (d, J= 1 .5 Hz, 1 H), 5.90 (d, J= 1.5 Hz, 1H), 5.50 (bs, 1H), 4.87 (bs,1H), 4.56 (m, 1H), 4.45 (bs, 1H), 3.92 (d, J= 2.4 Hz, 1H), 3.31 (dt,J1= 3.6 Hz,J2= 12.9 Hz, 1H), 3.21 (bs, 3H), 3.13 (d, J= 7.8 Hz, 1H), 2.82 (dd, J1= 8. 1 Hz, J2= 1 8.0 Hz, 1 H), 2.75 (d, J= 1 4.7 Hz, 1 H), 2.49 (d, J= 1 8.0 Hz, 1 H), 2.33 (s, 3H),2.21 (s, 3H), 2.05 (s, 3H), 1.89 (s, 3H), 1.78 (dd,J/= 12.0 Hz, J2= 15.6 Hz, 1H). ESI-MS m/z: Calcd. for C37H37F3N2O9: 710.6. Found (M-17)+: 693.2. Example 1 09 (Formula Removed) To a solution of 111 (12 mg, 0.018 mmol) in CH3CN/H20 (1.5 mL/1 mL). AgNO3 (93.5 mg, 0.55 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4. filtered and concentrated in vacuo. The residue was purified by flash cplumn chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 1:1) to afford 115 (10 mg. 86 %) as a white solid. Rf: 0.43 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) S 7.23-7.14 (m, 3H), 7.05-7.03 (m, 2H), 6.45 (s. 1 H), 5.93 (d, J- 1.2 Hz, 1H), 5.88 (d,J= 1.2 Hz. 1H), 5.63 (brd, 1H), 4.55-4.49 (m, 2H), 4.43 (d, J= 2.1 Hz, 1H), 3.96 (d,J= 3.1 Hz, 1H), 3.80-3.73 (m, 1H), 3.56 (bs, 3H), 3.32 (dt, J1= 3.3 Hz, J2= 12.6 Hz, lH),3.13(d,J=6.0Hz, 1H), 2.86 (dd,J1= 7.5 Hz, J2= 18.3 Hz,1H), 2.74(d,J= 14.6 Hz, 1H), 2.61-2.56 (m, 2H), 2.47 (d, J= 18.0 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 2.01 (s, 3H), 1.99-1.94 (m, 2H), 1.78 (dd,J1= 11.7 Hz,J2= 15.0 Hz, IH). ESI-MS m/z: Calcd. for C36H40N2O9: 644.7. Found (M-17)+: 627.2. Example 110 (Formula Removed) To a solution of 12 (12 mg, 0.01 8 mmol) in CH3CN/H2O (1 .5 mL/1 mL), AgNO3 (93 mg, 0.55 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO5 (10 mL) were added at 0 °C and the mixture was stirred for 1 5 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacua. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 1:1) to afford 116 (8 mg, 70 %) as a white solid. Rf:0.41 (EtOAc:MeOH5:l). ''''''''H NMR (300 MHz, CDC13) 5 7.44-7.43 (m, 2H). 7.34-7.27 (m. 4H), 6.39 (s, 1 H), 6.03 (d, J= 15.9 Hz, 1H), 5.96 (d,7= 1.5 Hz, 1H), 5.90 (d, J= 1.5 Hz, 1H). 5.55 (m, 1H), 4.47 (m, lH),4.50(m, 1H), 3.94 (d, J= 3. 6 Hz, 1H), 3.85 (dd.Jt= 3.3 Hz, J2= 11.1 Hz. lH).3.66(bs, 3H), 3.34-3.31 (m, 2H), 3.13 (d.J= 5.1 Hz, 1H), 2.93-2.73 (m, 2H). 2.53 (d.J= 18.0 Hz, 1H), 2.33 (s, 3H), 2.22 (s, 3H), 2.03 (s, 3H), 1.94-1.82 (m, 1H). ESI-MS m/z: Calcd. for C36H38N209: 642.7. Found (M-17)+: 625.2. Example 111 (Formula Removed) To a solution of 17 (6.28 g, 9.06 mmol) in CH2C12 (45.3 mL), ally] chloroformiate ( 3.85 mL, 36.24 mmol) and pyridine (2.93 mL, 36.24 mmol) were added at 0 °C. The reaction mixture was stirred for 16 h at 23°C and then, the solution was diluted with CH2C12 (150 mL) and washed with 0.1 N HC1 (2 x 100 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure to give 117 (5.96 g, 84 %) which was used in following steps with no further purification. Rf: 0.56 (CH2Cl2:EtOAc 1:1). 1H NMR (300 MHz, CDC13) 5 6.72 (s, 1H), 6.05-5.94 (m. 1H), 6.01 (s, 1H), 5.91 (s, 1H), 5.44 (dd,J1= 1.2 Hz, J2 = 17.1 Hz, 1H), 5.35 (dd, J1 = 1.2 Hz, 72 = 10.5 Hz, 1H), 5.34 (m, 1H), 5.10 (d, J =5.7 Hz, 1H), 5.05 (d, J= 5.7 Hz, 1H), 4.68 (d,7 = 5.7 Hz, 1H), 4.65 (dt, Jl = 1.2 Hz, J2 = 6 Hz, 1H), 4.18 (brd, J = 9 Hz, 2H), 4.04 (bs, 1H), 3.70 (s, 3H). 3.67-3.60 (m, 1H), 3.55 (s, 3H), 3.43-3.41 (m, 2H), 3.29-3.25 (m, 2H), 3.00 (dd, Jl = 8.7 Hz, J2 = 18.3 Hz, lH),2.90(dd,J1 =2.4 Hz, 72 = 16.2 Hz, 1H), 2.75 (d,J= 18.3 Hz, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H), 1.83 (dd, Jl = 11.4 Hz, J2 = 15.9 Hz, 1 H), 1.39 (s, 9H). 0.73 (d,J=6.9Hz,3H). 13C NMR (75 MHz, CDC13) δ172.1, 152.8, 148.6, 148.3, 144.6, 140.7, 140.6,131.5,131.2, 131.1, 130.4, 125.3,125.0, 123.3, 120.9, 119.1, 118.8,117.6, 112.9, 112.0, 101.6,99.2,71.8, 69.0, 68.4, 59.7, 59.2, 57.6, 57.3, 56.7, 55.8, 55.2,41.4, 39.9, 28.2, 26.0, 25.0, 18.6, 15.6, 9.0. ESI-MS m/z: Calcd. for C40H51N5O11: 777.8. Found (M+l)+: 778.3 Example 112 (Formula Removed) To a solution of 117 (3.96 g, 5.09 mmol) in MeOH (37.4 mL), trimerylchlorosilane ( 6.5 mL, 50.9 mmol) was added at 0 °C. The reaction mixture was stirred for 4 h at 23°C and then, the solvent was eliminated under reduced pressure. The residue was diluted with EtOAc (70 mL) and washed with a saturated aqueous solution of NaHCO2 (2 x 45 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated in vacuo to give 118 (2.77 g, 86 %) which was used in following steps with no further purification. Rf:0.61 (Hex:EtOAc 1:1). 1HNMR(300MHz, CDC13) δ 6.50 (s, 1H), 6.45 (m, IH), 6.10-6.03 (m, lH),6.00(s, 1H), 5.93 (s, lH),5.47(dd,J1= 1.2 Hz,J2= 17.1 Hz, 1H), 5.38 (dd, Jl = 1.2 Hz,72 = 10.5 Hz, 1H), 4.81-4.64 (m, 2H), 4.10-4.03 (m, 3H), 3.75 (s, 3H), 3.70-3.44 (m, 2H), 3.35 (d, 7 = 8.1 Hz, 1 H), 3.28 (dt, Jl = 2.7 Hz, 72 = 9 Hz, 1 H), 2.98 (dd, 77 = 7.8 Hz, 72 = 18 Hz, 1 H), 2.90 (dd, 77 = 2.7 Hz, 72 = 16.2 Hz, 1H), 2.78 (dd, Jl = 6.9 Hz,J2 =14.1 Hz,1H), 2.63 (d, 7= 18.3 Hz, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 1.88 (dd,77 = 13.2 Hz, 72 = 15.6 Hz, 1 H), 0.95 (d, 7 = 6.9 Hz, 3H). 13C NMR (75 MHz, CDC13) δ 175.8, 152.9, 146.6, 144.6, 142.5, 140.8, 140.6, 131.5, 131.3, 128.5, 121.1, 120.8, 118.9, 117.8, 117.0,113.2, 111.9, 101.7, 68.9, 60.6, 59.1, 56.6, 56.4, 55.7, 55.2, 50.5, 41.7, 39.4, 26.1, 25.0, 21.0, 15.6, 9.2. ESI-MS rn/z: Calcd. for C33H39N5O8: 633.6. Found (M+l)+: 634.2. Example 113 (Formula Removed) To a solution of 118 (3.52 g, 5.56 mmol) in CH2Cl2 (28 mL), phenylisothiocyanate ( 3.99 mL, 33.36 mmol) was added at 23 °C. The reaction mixture was stirred for 3 and then, the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography to afford 119 (3.5 g, 82 %) as a white solid. Rf: 0.52 (CH2Cl2:EtOAc 1:5). 1H NMR (300 MHz, CDC13) δ7.69 (bs, 1H), 7.49-7.46 (m, 2H), 7.34-7.21 (m, 2H), 6.96 (d, J = 6.9 Hz, 1H), 6.06-5.97 (m, 1H),6.03(s. lH),5.96(bs, 1H), 5.91 (s, lH),5.66(s, 1H), 5.47 (dd,Jl = 1.5 Hz, J2= 17.1 Hz, 1H), 5.37 (dd, Jl = 1.5 Hz, J2= 10.5 Hz, 1H), 5.36 (s, 1 H), 4.75-4.70 (m,2H), 4.54-4-49 (m, 1H), 4.14 (d, J= 2.4 Hz, 1H), 4.07-4.06 (m, 2H), 3.70 (s, 3H), 3.44 (m, 1H), 3.35 (d, J= 8.1 Hz, 1H), 3.21 (dt, Jl = 2.7 Hz. 72 = 6.6 Hz, 1H), 2.94-2.82 (m, 2H), 2.63 (d, J = 18 Hz, 1 H), 2.24 (s, 3H), 2.06 (s, 3H), 2.06 (s, 3H), 1.90 (dd, J7 = 11.7 Hz, .72 = 15.9 Hz, 1H), 0.71 (d, J = 6.9 Hz, 3H). !3CNMR(75MHz,CDCl3) δ 178.6, 171.9, 152.8, 146.7, 144.5, 142.6, 140.8, 140.5, 136.3, 131.3, 131.0,129.9,129.8,128.9,126.7, 125.2,124.3, 121.1, 120.6, 118.9, 117.7, 116.5, 112.8, 112.1,101.6, 68.9, 60.5, 58.9, 57.3, 56.1, 55.9, 55.1, 53.3,41.5, 39.2, 25.9, 24.6, 20.9, 15.4,9.1. ESI-MSm/z: Calcd. for C40H44N3O8S: 768.8. Found (M+l)+: 769.3. Example 114 (Formula Removed) To a solution of 119 (3.38 g, 4.4 mmol) in MeOH (22 mL), trimetylchlorosilane ( 2.3 mL, 22 mmol) was added at 0 °C. The reaction mixture was stirred for 1.5 h at 23°C and .then, the solvent was eliminated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with 0.1 N HC1 (2 x 75 mL). The aqueous phase was basified with a saturated aqueous solution of NaHCO2 and extracted with CH2Cl2 (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure to afford 120 (2.47 g. 100 %) as a white solid which was used in following steps with no further purification. Rf: 0.26 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ 6.45 (s, 1H), 6.05-5.98 (m, 1H), 5.97 (d, J = 1.2 Hz, 1H), 5.90(d,J=1.2Hz, 1H),5.44 (dd,J7 = 1.2Hz,J2= 17.1 Hz, 1H), 5.35 (dd,J = 1.2 Hz, 72 = 10.2 Hz, 1H), 4.75-4.71 (m, 2H), 4.12-4.10 (m, 1H), 3.99 (d, J = 2.4 Hz, 1H), 3.92 (bs, 1H), 3.73 (s,3H), 3.36-3.26 (m,2H), 3.06 (dd,J7 = 8.4 Hz, 72 = 18 Hz, 1H), 2.89 (dd, J] = 2.7 Hz, J2 = 15.9 Hz, 1H), 2.75-2.73 (m, 2H), 2.48 (d, J = 18 Hz, 1H), 2.32 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H), 1.85 (dd, JJ = 11.7 Hz, J2 = 15.6 Hz, 1 H). 13C NMR (75 MHz, CDC13) δ 153.0, 146.6, 144.5, 142.8, 140.7,131.5, 130.5, 128.9, 121.3, 120.9, 119.1, 117.9, 116.7, 113.8. 111.6, 101.5,69.0,60.6,59.8,58.7,56.5,56.0,55.3,44.2, 41.8,31.6,26.1,25.7,15.7,9.2. ESI-MS m/z: Calcd. for C3oH34N407: 562.6. Found (M+l)+: 563. 2. Example 115 (Formula Removed) To a solution of] 20 (2.57 g, 4.4 mmol) in CH2Cl2 (44 mL), TrocCI ( 0.9] mL. 6.6 mmol) and pyridine (0.53 mL, 6.6 mmol) were added at -20 °C. The reaction mixture was stirred for 30 min at 0°C and then, the solution was diluted with CH2Cl2 (50 mL) and washed with 0.1 N HC1 (2 x 25 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure to give 121 (3.24 g, 100 %) which was used in following steps with no further purification. Rf: 0.62 (EtOAc:MeOH 5:1). 1HNMR(300MHz, CDC13) δ 6.50 (s, 1H), 6.07-6.01 (m, 1H), 5.99 (d, J = 1.2 Hz, 1H), 5.93 (d,J= 1.2 Hz, 1H), 5.68 (s, 1H), 5.46 (dd,JJ = 1.2Hz,J2 = 17.1 Hz, 1H), 5.37 (dd, Jl = 1.2 Hz, .72 = 10.5 Hz, 1H), 4.74 (t, J =5.7 Hz, 2H), 4.63-4.62 (m, 1H),4.54 (d,J= 12 Hz, lH),4.30(d,J= 12 Hz, 1H), 4.14-4.11 (m, 2H), 4.02-4.01 (m, 2H), 3.75 (s, 3H), 3.36- 3.26 (m,3H), 3.04 (dd,J7 = 8.1 Hz,J2= 17.7 Hz, 1H), 2.91 (dd,J7 =2.4 Hz, J2 = 15.6 Hz, 1H), 2.60 (d,J = 17.7Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 1.84 (dd, Jl = 12Hz,J2= 15.9 Hz, 1H). ESI-MS m/z: Calcd. for C33H35Cl3N4O9: 738.0. Found (M+l)+: 737.2. Example 116 (Formula Removed) To a solution of121 (0.45 g, 0.60 mmol) in CH3CN (4 mL), diisopropylethylamine (2.17 mL, 12.46 mmol). hromomethyl methyl ether (0.76 mL, 9.34 mmol) and dimethylaminopyridine (8 mg, 0.062 mmol) were added at 0 °C. The reaction mixture was heated at 40°C for 5 h. Then, the reaction was diluted with CH2C12 (50 mL) and washed with 0.1 N HC1 (2 x 25 mL). The organic layer was dried over Na2SO4 filtered, and the solvent was eliminated under reduced pressure to give 122 (0.453 g, 95 %) which was used in following steps with no further purification. Rf: 0.31 (RP-18 CH3CN-H20 8:2). 1H NMR (300 MHz, CDC13) δ 6.70 (s, 1 H), 6.05-5.99 (m, 1 H), 5.97 (s, 1 H), 5.92 (s, 1 H), 5.43 (dd,J1 = 1.2 Hz,72 = 17.1 Hz, 1H), 5.34 (dd, Jl = 1.2 Hz,72= 10.5 Hz,1H), 5.10- 5.04 (m, 2H), 4.72-4.68 (m, 2H), 4.60 (t, J = 5.7 Hz, 1 H), 4.49 (d, J = 12.3 Hz, 1 H), 4.38 (d, J = 12.3 Hz, IH), 4.18 (d, J = 2.7 Hz, 1H), 4.03-4.00 (m, 2H), 3.71 (s, 3H), 3.54 (s, 3H), 3.38-3.22 (m, 4H), 3.04 (dd,J1 = 7.8 Hz, 72 = 18.3 Hz, 1H),2.91 (dd,77 =2.4 Hz, 72 = 15.9 Hz,1H), 2.61 (d,J= 18 Hz, 1H), 2.31 (s, 3H), 2.20 (s, 3H), 2.03 (s, 3H), 1.76 (dd,J1 = 11.7 Hz,J2 =15.6 Hz, 1H). ESI-MS m/z: Calcd. for C33H39Cl3N4010: 782.0. Found (M+l)+: 783.2. Example 117 (Formula Removed) To a suspension of 122 (0.45 g, 0.579 mmol) in 90 % aqueous acetic acid (6 mL), powder zinc (0.283 g, 4.34 mmol) was added and the reaction was stirred for 6 h at 23 °C. Then, the mixture was filtered through a pad of celite which was washed with CH2Cl2 (25 mL). The organic layer was washed with an aqueous sat. solution of sodium bicarbonate (pH= 9) (2 x 15 mL), dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure to give 123 (0.351 g, 100 %) which was used in following steps with no further purification. Rf: 0.38 (SiO2, EtOAc:MeOH 5:1). 1HNMR(300MHz, CDC13) δ6.68 (s, 1H), 6.06-5.99 (m, 1H), 5.97 (d, J= 1.5 Hz, 1H), 5.91 (d,J=1.25Hz, 1H), 5.44(dd,j; = 1.5 Hz, 72 = 17.4 Hz, 1H), 5.36 (dd, J1 = 1.5 Hz, J2 = 10.2 Hz, 1H), 5.08 (q, J = 5.1 Hz, 2H), 5.74-4.70 (m, 2H), 4.02 (d, J = 3 Hz, 1H), 4.00 (d, .7 =2.4 Hz, 1H), 3.91 (m, 1H), 3.71 (s, 3H), 3.56 (s, 3H), 3.37-3.35 (m, 1H), 3.29 (t, .7 = 2.7 Hz, 1H), 3.08 (dd, Jl = 7.5 Hz, J2 = 18 Hz, 1H), 2.90 (dd, Jl = 2.7 Hz, J2 = 15.9 Hz, lH),2.74(dd,J1 = 2.4 Hz, J2 = 5.1 Hz, 2H), 2.48 (d,/ = 18 Hz, 1H), 2.35 (s, 3H), 2.20 (s, 3H), 2.05 (s, 3H), 1.80 (dd, J1 = 12 Hz, J2 = 15.9 Hz, 2H). ESI-MS m/z: Calcd. for C32H38N4O8: 606.6. Found (M+l)+: 607.3. Example 118 (Formula Removed) To a solution ofl 20 (100 mg. 0.177 mmol) in CH2C12 (0.7 mL). cinnamoyl chloride ( 29.5 mg, 0.177 mmol) and pyridine (14.37 fiL, 0.177 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (15 mL) and washed with 0.1 N HC1 (10 mL). The organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:EtOAc 2:1 to Hex:EtOAc 1:3) to afford 124 (86 mg, 70 %) as a white solid. Rf: 0.77 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ 7.39-7.26 (m, 5H), 7.25 (d, J = 15.6 Hz. 1 H), 6.44 (s, 1 H), 6.01 (d, J=1.2Hz, 1H), 5.94 (d, J=1.2HzJH), 5.68 (s, 1H), 5.65 (d, J = 15.6 Hz, 1H), 5.44 (dd, Jl = 1.2 Hz, J2= 17.1 Hz, 1H), 5.35 (dd, Jl = 1.2 Hz, J2= 10.5 Hz, 1H), 5.18 (t, J = 6 Hz, 1H), 4.73-4.69 (m, 2H), 4.11-4.09 (m, 3H), 3.66-3.58 (m, 2H), 3.65 (s, 3H), 3.38-3.31 (m, 3H), 3.02 (dd, Jl = 8.4 Hz, J2 = 3 8.3 Hz, 1 H), 2.92 (dd, J1 = 2.7 Hz, J2 - 15.6 Hz, 1 H), 2.59 (d, J = 18.3 Hz, 1 H), 2.31 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.89 (dd, J1 = 12.3 Hz,J2=16.2Hz, 1H). I3CNMR(75 MHz, CDC13) δ 165.5, 152.7, 146.6, 144.4, 142.6, 140.7, 140.5, 140.1, 134.7, 131.2, 130.6,129.3, 128.7, 128.4, 127.6, 120.8, 120.5, 120.3, 118.9, 117.6, 116.5, 113.2, 111.8, 101.6, 68.8, 60.4, 59.0, 56.2, 56.1, 55.7, 55.0, 41.5, 40.6, 25.9, 25.1, 15.5, 9.0. ESI-MS m/z: Calcd. for C39H4oN4O8: 692.7. Found (M+l)+: 693.2. Example 119 (Formula Removed) To a solution of 124 (495 mg, 0.713 mmol) in CH2C12 (28 mL), acetic acid (163 µL), Pd(PPh3)2Cl2 (50 mg, 0.0713 mmol) and Bu3SnH (384 uL, 1.42 mmol) were added at 0 °C. The reaction mixture was stirred for 2 h at 23°C and then, the solution was poured into a pad of flash column (SiO2, gradient Hex:EtOAc 1:1 to EtOAc) to afford 125 (435 mg, 100 %) as a white solid. Rf: 0.22 (Hex:EtOAc 1:2). 1H NMR (300 MHz, CDC13) δ 7.36-7.33 (m, 5H), 7.28 (d, J = 15.9 Hz, 1 H), 6.45 (s, 1 H), 5.90 (s, lH),5.83(s} lH),5.55(d, J= 15.6 Hz, 1H), 5.24 (t, J= 12.9 Hz, 1H), 4.17 (d, J = 1.8 Hz, 1H), 4.10-4.07 (m, 2H), 3.72 (s, 3H), 3.46-3.32 (m, 3H), 3.14-3.00 (m, 2H), 2.54 (d, J= 18 Hz, 1H), 2.32 (s, 3H), 2.05 (s, 6H), 1.89 (dd, J, = 12 Hz,72 = 15.3 Hz, 1H). 13C NMR (75 MHz, CDC13) 6 165.7, 146.9,145.1, 144.2,143.0, 140.8, 136.5, 134.5, 130.6, 129.4, 128.9, 127.9, 127.7, 120.8, 119.8, 117.8,114.1, 112.9, 107.1, 100.8,60.5,59.2,56.4, 56.0, 55.1,41.4, 30.7, 25.5, 25.3, 15.5, 8.9. ESI-MS m/z: Calcd. for C35H36N406: 608. 6. Found (M+l)+: 609.2. Example 120 (Formula Removed) To a solution of l25 (86 mg: 0.1 24 mmol) in CH3CN/H2O (1.5 mL/1 mL). AgNO3 (632 mg, 3.72 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq satNaHC03 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 mL). The solution was extracted and the organic layer was dried over Na^SO^, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO?, gradient EtOAc to EtOAc:MeOH 2:1) to afford 126 (70 mg, 83 %) as a white solid. Rf: 0.07 (EtOAc:MeOH 5:1). 1''''''''H NMR (300 MHz, CDC13) δ 7.40-7.28 (m, 5H), 7.25 (d, J = 15.6 Hz, 1 H), 6.48 (s, 1 H), 6.00-5.94 (m, 1H), 5.96 (s, 1H), 5.92 (s, lH),5.89(s, 1H), 5.53 (d, J = 15.6 Hz, 1H), 5.42-5.36 (m,2H), 5.31 (dd,J1 = 1.2 Hz, J2 = 10.8 Hz, 1H), 4.71-4.65 (m, 2H), 4.51 (d, J = 3 Hz, 1H), 4.42 (bs, 1H), 4.07 (bs, 1H), 3.79 (dd, J, = 6.9 Hz, J2 = 12.9 Hz, 1H), 3.68 (s, 3H), 3.62-3.59 (m, 1H), 3.41-3.37 (m, 1H), 3.16 (d, J= 7.8 Hz, 1H), 2.95 (dd, J, = 7.5 Hz, J2 = 17.4 Hz, 1H), 2.88-2.83 (m, 1H), 2.43 (d, J = 18 Hz, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.81 (dd, J, = 11.7 Hz, J2 = 15.3 Hz, 1 H). 13C NMR (75 MHz, CDC!3) δ165.5, 152.9, 146.7, 144.5, 144.4, 142.7, 141.0, 140.0, 134.6, 131.4, 130.7, 129.2, 128.8, 128.5, 127.8, 127.7, 124.6, 121.2, 120.9, 118.9, 116.5, 114.9, 114.7, 111.3, 101.6, 93.3, 92.33 83.2, 68.9, 60.6, 57.8, 56.8, 56.6, 56.3, 52.5, 52.2, 41.6, 26.1, 24.6,15.6,9.1. ESI-MS m/z: Calcd. for C38H41N3O9: 683.7. Found (M-17)+: 666.3 Example 121 (Formula Removed) To a solution of 120 (1.61 g, 2.85 mmol) in CH2C12 (4 mL), hydrocinnamoyl chloride * ( 423 µL, 2.85 mmol) and pyridine (230 µL, 2.85 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (50 mL) and washed with 0.1 N HC1 (30 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:EtOAc 2:1 to EtOAc) to afford 127 (1.64 g, 83 %) as a white solid. Rf: 0.63 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDCI3) δ 7.26-7-14 (m, 3H), 7.04-7.01 (rn, 2H), 6.44 (s, 1H), 6.07-5.99 (m, 1H), 5.97 (d, J =1.5 Hz, 1H), 5.91 (d, 7 =1.5 Hz, 1 H), 5.75 (bs, 1H), 5.45 (dd, J, = 1.5 Hz, ,72 = 17.4 Hz, 1H), 5.36 (dd,J1 = 1.5 Hz, .72= 10.2 Hz, 1H), 5.03 (t, J = 5.7Hz, 1H), 5.74-5.66 (m, 2H), 4.09 (d, J = 2.4 Hz, 1H), 4.01 (bs, 1H), 3.97 (d, J = 2.7 Hz, 1H), 3.62 (dds J, = 8.4 Hz, J2 = 13.5 Hz, 1 H), 3.42 (s, 3H), 3.37-3.28 (m, 3H), 3.04-2.87 (m, 3H), 2.67-2.46 (m, 4H), 2.29 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.83-1.79 (m, 1 H). 13CNMR(75 MHz, CDC13) δ 171.8, 152.8, 146.7,144.5, 144.4,142.7, 140.9,140.8, 140.6, 131.4, 130.7, 128.9, 128.4, 128.2, 128.1, 126.0, 120.8, 120.4, 118.9, 117.6, 116.6, 113.0, 111.9,101.6, 68.9, 60.3, 59.0, 56.3, 56.2, 55.6, 55.1, 41.6, 40.3, 37.7, 31.0, 25.9, 25.2,15.5, 9.1. ESI-MS m/z: Calcd. for C39H42N4O8: 694.3. Found (M+l)+: 695.3. Example 122 (Formula Removed) To a solution of!27 (50 mg, 0.072 mmol) in CH3CN/H2O (1.5 mL/1 mL), AgNO3 (444 mg, 2.16 mmol) was added and the reaction was stirred at 23 °C for 24 h. Then, brine (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0 °C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (15 mL). The solution was extracted and the organic layer was dried over Na2SO4, filtered and concentrated in vacua. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAc:MeOH 3:1) to afford 128 (30 mg, 61 %) as a white solid. Rf: 0.65 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ 7.22-7.11 (m, 3H), 7.06-7.03 (m, 2H), 6.43 (s, 1H), 6.08-5.98 (m, 1H), 5.96 (d, J= 1.5 Hz, 1H), 5.90 (d, J= 1.5 Hz, 1H), 5.66 (bs, 1H), 5.44 (dd, J, = 1.5 Hz, J2 = 17.4 Hz, 1H), 5.36 (dd, J, = 1.5 Hz, 72 = 10.5 Hz, 1H), 4.78-4.65 (m, 2H), 4.44 (d, J= 3 Hz, 1H), 4.36 (bs, 1H), 3.99 (td, Jl = 2.1 Hz, J2 = 9.9 Hz, 1H), 3.78-3.67 (m, 1H), 3.56 (dt, J7 = 1.5 Hz, 72= 11.1 Hz, 1H), 3.43 (s, 3H), 3.30-3.12 (m, 2H), 3.02-2.89 (m, lH),2.83(dd,J1 =2.7Hz,J2= 15.9 Hz, 1H), 2.62-2.51 (m, 2H), 2.36 (d, J= 18.6 Hz, 1H), 2.27 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.86-1.66 (m, 3H). 13CNMR(75MHz,CDCl3) δ 171.6, 146.7,141.2, 141.1, 131.5, 130.5, 128.9, 128.3, 128.2, 128.2, 125.9, 124.7, 121.1, 121.0, 118.8, 111.3, 101.6,94.0,83.2,68.8,60.3,57.9,56.6, 56.3, 52.3, 52.0, 41.7, 41.6, 41.1, 37.9, 31.1, 31.0, 26.1, 24.6,15.5, 9.2.. ESI-MS m/z: Calcd. for C38H43N309: 685.7. Found (M-17)+: 668.3. Example 123 (Formula Removed) To a solution of 127 (1.64 g. 2.36 mmol) in CH3CN (12 mL), diisopropylethylamine (8.22 mL, 47.2 mmol), bromomethyl methyl ether (2.89 mL, 35.4 mmol) and dimethylaminopyridine (29 mg. 0.236 mmol) were added at 0 °C. The reaction mixture was heated at 40°C for 5 h. Then, the reaction was diluted with CH2C!2 (80 mL) and washed with 0.1 N HC1 (3 x 25 mL). The organic layer was dried overNa2SO4. filtered, and the solvent was eliminated under reduced pressure to give 129 (1.46 g, 84 %) which was used in following steps with no further purification. Rf: 0.24 (RP-18 CH3CN-H2O 8:2). 1HNMR (300 MHz, CDC13) δ 7.27-7.11 (m, 3H), 7.05-7.02 (m, 2H), 6.67 (s,1H), 6.08-5.98 (m, lH),5.96(d, .7 =1.2 Hz, lH),5.90(d, 7= 1.2 Hz,1H), 5.44 (dd, Jl = 1.2 Hz, J2 = 17.1Hz,lH),5.34(dd,J7 = 1.2 Hz,J2 = 10.5 Hz, lH),5.05(d, J= 6 Hz, 1H), 5.00 (d, J = 6 Hz, IH), 4.97(t, J=5.1 Hz, 1H), 4.75-4.68 (m, 2H), 4.16 (d, J= 2.7 Hz, 1H), 3.98-3.97 (m,1H), 3.68-3.67 (m, 1H), 3.65-3.61 (m, 1H), 3.52 (s, 3H), 3.35 (s, 3H), 3.32-3.26 (m, 3H), 3.05-2.86 (m, 3H), 2.59-2.48 (m, 2H), 2.30 (s, 3H), 2.02 (s, 3H), 1.94 (s, 3H), 1.91-1.67 (m, 3H). 13C NMR (75 MHz, CDC13) δ 171.4, 152.7, 148.5, 148.3,144.5, 140.9, 140.8, 140.4, 131.1, 130.9, 130.4, 130.1, 128.4, 128.2, 126.0, 124.6, 123.7, 120.3, 119.0, 112.9, 111.8, 101.6, 99.1, 68.9, 59.4, 59.1, 57.5, 56.7, 56.3, 55.4, 55.1, 41.5,40.2, 37.7, 30.9, 25.8, 25.2, 15.5, 9A ESI-MS m/z: Calcd. for C41H46N4O9: 738.8. Found (M+ 23)+: 761.2. Example 124 (Formula Removed) To a solution of 129 (1.46 g; 1.97 mmol) in CH2C12 (40 mL), acetic acid (450 uL), Pd(PPh3)2Cl2 (138 mg, 0.197 mmol) and Bu3SnH (1.06 mL, 3.95 mmol) were added at 0 °C. The reaction mixture was stirred for 5 h at 23°C and then, the solution was poured into a pad of flash column (SiO2, gradient Hex:EtOAc 1:1 to EtOAc) to afford 130 (1.1 g, 85 %) as a white solid. Rf: 0.22 (Hex:EtOAc 1:2). 1H NMR (300 MHz, CDC13) δ 7.21-7.12 (m, 3H), 6.98-6.95 (m, 2H), 5.86 (s. 1H), 5.84 (s, lH),5.79(bs, 1H), 5.26 (d, 7= 6 Hz, lH),5.11(d, 7= 6 Hz, lH),5.05(t, 7 =5.7 Hz, 1H), 4.19 (d, 7= 2.4 Hz, 1H), 4.03 (d, 7 = 2.4 Hz, 1H), 3.99 (bs, 1H), 3.65 (s, 3H), 3.56 (s, 3H), 3.53-3.42 (m, 2H), 3.34 (d, J= 8.7 Hz, 1H), 3.27 (brd, 7= 11.7 Hz, 1H), 3.11 (d, 7= 15 Hz, IH), 2.99 (dd,77 = 8.4 Hz,72 = 18.3 Hz, IH), 2.64-2.52 (m, 3H), 2.29 (s, 3H), 2.08 (s, 3H), 2.06 (s,3H), 1.84 (t, 7= 7.8 Hz, 2H), 1.71 (dd, J1= 12.9 Hz, J2= 13.5 Hz, 1H). 13CNMR(75 MHz,CDCl3) δ 171.7, 149.0,147.6, 140.6, 132.1, 131.9, 130.9, 130.5, 128.5, 128.4, 128.3, 128.0, 126.0, 124.9, 124.6, 123.1, 117.6, 100.8,99.6,59.6,58.9,57.6,56.6, 56.5, 55.6, 55.1, 41.5, 37.8, 31.5, 31.1, 25.9, 25.1, 22.6, 15.5, 8.8. ESI-MS m/z: Calcd. for C37H42N4O7: 654.7. Found (M++ Na): 655.1 Example 125 (Formula Removed) To a solution of!30 (130 mg, 0.198 mmol) in CH2C12 (1 mL), trifluoroaceryl anhydride (41.9 µL, 0.297 mmol) and pyridine (24 µL, 0.297 mmol) were added at 0 °C. The reaction mixture was stirred for 2.5 h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HC1 (7 mL). The organic layer was dried over Na2SO4 filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:EtOAc 4:1 to Hex:EtOAc 1:4) to afford 131 (93 mg, 62 %) as a white solid. Rf: 0.30 (Hex:EtOAc 1:2). 1H NMR (300 MHz, CDC13) δ 7.25-7.16 (m, 3H), 7.04-7.02 (m, 2H), 6.78 (s, 1H), 6.02 (d, J=1.2Hz, lH),5.95(d, J= 1.2 Hz, 1H), 5.11 (d, J = 6.6 Hz, 1H), 4.98 (d, J = 6.6 Hz, 1H), 4.95 (t, J = 6.3 Hz, 1H), 4.61 (bs, 1H), 4.30 (s, 1H), 4.08 (s, 1H), 3.96 (d, J = 7.2 Hz, 1H), 3.66-3.54 (m, 1H), 3.50 (s, 3H), 3.39 (s, 3H), 3.19 (dd, Jl = 7.8 Hz, J2 = 18.3 Hz, 1H), 2.88 (d, J = 18.6 Hz, 1 H), 2.79 (dd, J1 - 2.7 Hz, J2 = 15.9 Hz, 1 H), 2.66-2.62 (m, 1 H), 2.57 (s, 3H), 2.06 (s, 6H), 1.94-1.87 (m, 1H), 1.77-1.68 (m, 2H). ESI-MS m/z: Calcd. for C39H41F3N4O8: 750.7. Found (M+ Na)+: 751.2. Example 126 (Formula Removed) To a solution of 130 (130 mg, 0.198 mmol) in CH2Cl2 (2 mL), chloroacetyl chloride ( 23.65 µL, 0.297 mmol) and pyridine (24 µL, 0.297 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (10 mL) and washed with 0.1 N HC1 (7 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2; gradient Hex:EtOAc 2:1 to Hex:EtOAc 1:1) to afford 132 (130 mg, 90 %) as a white solid. Rf:0.31 (Hex:EtOAc 1:2). 1H NMR (300 MHz, CDC13) δ 7.24-7.15 (m, 3H), 7.07-7.05 (m, 2H), 6.69 (s, 1H). 6.00 (d, J = 1.5 Hz, 1 H), 5.94 (d, J = 1.5 Hz, 1 H), 5.11 (d, J = 5.7 Hz, 1 H), 5.04 (d. J = 5.7 Hz, lH),4.93(m, 1 H), 4.36 (s, 2H), 4.16 (d, J=2.7Hz, 1H), 4.01 (m, 2H), 3.64 (dd, J] -6.9 Hz, J2 = 12.3 Hz, 1H), 3.54 (s, 3H), 3.40 (s, 3H), 3.38-3.35 (m, 2H), 2.29 (dt, JI = 3 Hz,J2 = 12 Hz, 1H), 3.03(dd,J7 = 7.8 Hz, J2 = 18 Hz, 1H), 2.77 (dd,J7 = 2.4 Hz, J2 = 16.2 Hz, 1H), 2.58-2.52 (m, 3H), 2.32 (s, 3H), 2.02 (s, 3H), 1.92-1.85 (m, 1H), 1.76-1.65 (m, 2H). 13C NMR (75 MHz, CDC13) δ 171.6, 164.9, 148.3, 144.6, 140.9, 140.8, 139.8, 132.1, 131.9, 131.1,130.0, 128.2, 126.0, 125.0, 124.6, 123.5,120.1, 117.5, 113.0, 111.5, 101.7,99.1,64.9, 59.7, 58.9, 57.7, 56.6, 56.4, 55.2, 55.1, 41.5, 40.2, 39.9, 37.7, 30.9, 26.3, 25.1, 15.4, 9.1. ESI-MS m/z: Calcd. for C39H43ClN4O8: 730.2. Found (M+l)+: 731.1. Example 127 (Formula Removed) To a solution of 130 (130 mg, 0.198 mmol) in CH2Cl2 (2 mL), chloropropionyl chloride ( 28.35 µL, 0.297 mmol) and pyridine (24 µL, 0.297 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (10 ml) and washed with 0.1 N HCl (7 mL). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex:EtOAc I :l) to afford 133 (94 mg, 64 %) as a white solid. Rf: 0.43 (Hex:EtOAc 1:2). 1H NMR (300 MHz, CDC13) δ 7.23-7.12 (m, 3H), 7.06-7.04 (m, 2H), 6.69 (s, 1H), 5.97 (s, 1H), 5.92 (s, 1H), 5.08 (d, J = 6 Hz, 1H), 5.00 (d, J = 6 Hz, 1H), 4.97 (m, 1H), 4.16 (bs, 1H), 4.00 (m, 1H), 3.88 (t, J = 6.9 Hz, 2H), 3.75 (t, J= 6.9 Hz, 2H), 3.59 (dd,J7 = 6.3 Hz, J2 = 12.3 Hz, 1H), 3.53 (s, 3H), 3.37 (s, 3H), 3.03-3.26 (m, 1H), 3.17-2.97 (m, 3H), 2.83- 2.73 (m, 2H), 2.58-2.52 (m, 3H), 2.31 (s, 3H), 2.03 (s, 6H), 1.93-1.86 (m, 1H), 1.79-1.64 (m, 2H). 13C NMR (75 MHz, CDC13) δ171.9,167.8, 148.3, 144.7, 140.8, 132.1, 132.0, 131.1, 130.2, 128.2, 126.1, 125.2, 124.6, 123.7, 122.2, 120.2, 117.6,114.7, 112.9,111.8, 101.7,99.3,74.9, 65.0, 59.6, 59.0, 57.7, 56.7, 56.4, 55.4, 55.1, 41.5, 38.5, 37.8, 37.2, 31.0, 26.4, 25.2, 15.5, 9.3. ESI-MS m/z: Calcd. for C40H45ClN4O8: 744.2. Found (M+l)+: 745.0. Example 128 (Formula Removed) To a solution ofl 30 (160 mg. 0.244 mmol) in CH2Cl2 (2 mL), heptafluoroburyryl chloride ( 54.5 µL, 0.366 mmol) and pyridine (40µL, 0.49 mmol) were added at 0 °C. The reaction mixture was stirred for 2 h and then, the solution was diluted with CH2Cl2 (15 mL) and washed with 0.1 N HC1 (10 mL). The organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2,, gradient Hex:EtOAc 2:1 to Hex:EtOAc 1:4) to afford 134 (120 mg, 63 %) as a white solid. Rf: 0.40 (Hex:EtOAc 1:2). 1H NMR (300 MHz, CDC13) δ 7.25-7.16 (m, 3H), 7.04-7.02 (m, 2H), 6.77 (s, 1H), 6.02 (d, J= 1.5 Hz, 1H), 5.96 (d, J= 1.5 Hz, 1H), 5.11 (d,J = 6.6 Hz,1H),4.95(d, J = 6.6 Hz, 1H), 4.94 (m, 1H), 4.58 (m, 1H), 4.25 (bs, 1H), 4.06 (bs, 1H), 3.88 (d, J = 6.9 Hz, 1H), 3.64 (dd, Jl = 7.5 Hz, J2 = 12.9 Hz, 1H), 3.55-3.53 (m, 1H), 3.49 (s, 3H), 3.38 (s, 3H), 3.17 (dd, JI =8.1Ez,J2 = 18.9 Hz, lH),2.85(d: J= 18.3 Hz, 1H), 2.77 (dd, Jl =2.7 Hz, J2 = 16.2 Hz, 1H), 2.60-2.57 (m, 3H), 2.56 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1.96-1.88 (m, 1H), 1.79- 1.69(m,2H). ESI-MS m/z: Calcd. for C41H41F7N4O8: 850.7. Found (M+l)+: 851.3. Example 129 (Formula Removed) To a solution of 131 (93 mg, 0.123 mmol) in CH2Cl2 (1 mL), trifluoroacetic acid (381 µL, 4.95 mmol) was added at 0 °C and the reaction mixture was stirred for 6 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 135 (65 mg, 75 %) as a white solid which was used in following steps with no further purification. Rf: 0.26 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ7.24 - 7.15 (m, 3H), 7.04 - 7.01 (m, 2H), 6.45 (s, 1 H), 6.03 (d, J=1.5Hz, IH), 5.97(d, J= 1.5 Hz, 1H), 5.62 (s, lH),4.97(m, lH),4.09(d, J= 1.8 Hz, 1H), 4.03 (bs,1H), 3.99 (d, J = 2.4 Hz,1H), 3.73 (dd, Jl= 7.5 Hz, J2 = 12 Hz, 1H), 3.38 (s, 3H), 3.34 - 3.28 (m, 3H), 3.05 (dd, Jl= 8.4 Hz,J2 = 18.3 Hz, 1H), 2.75 (dd, Jl= 3.3 Hz, J2 = 16.5 Hz, 1H), 2.60 - 2.47 (m, 3H), 2.30 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 1.91 - 1.65 (m, 3H). ESI-MS m/z: Calcd. for C37H37F3N4O7: 706.2. Found (M+l)+: 707.2. Example 130 (Formula Removed) To a solution of 132(130 mg, 0.177 mmol) inC2Cl2(1 mL), trifluoroacetic acid (545µL. 7.08 mmol) was added at 0 °C and the reaction mixture was stirred for 3.5 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 136 (118 mg, 97 %) as a white solid which was used in following steps with no further purification. Rf: 0.27 (Hex:EtOAc''''''''l:l). 1H NMR (300 MHz, CDC13) δ 7.23 - 7.13 (m, 3H), 7.06 - 7.03 (m. 2H), 6.45 (s, 1H), 5.98 (d, J= 1.2 Hz,1H), 5.91 (d, J= 1.2 Hz, lH),5.04(t, J = 4.5 Hz,1H), 4.37 (bs, 2H), 4.13 (d, J = 2.1 Hz,1H), 4.03 (bs,2H), 3.68-3.61 (dd, 3\= 7.2 Hz, J2 = 12.3 Hz 1H), 3.40 (s 3H), 3.37 - 3.28 (m, 3H), 3.02 (dd, Jl= 8.4 Hz: J2 = 18.6 Hz1H), 2.75 (dd, Jl= 2.7 Hz, J2= 15.9 Hz 1H), 2.58 - 2.50 (m, 3H), 2.32 (s, 3H), 2.01 (s, 6H), 1.94 - 1.67 (m, 3H). 13C NMR (75 MHz, CDC13) δ 171.8, 165.0, 146.8, 144.6, 142.9, 141.0, 140.9, 139.8, 132.0, 130.3, 129.4, 128.5, 128.3, 126.0, 120.8, 120.1, 117.4, 116.1,113.0,111.5, 101.7,60.5,58.7, 56.3, 56.2, 55.2, 55.0, 41.5, 40.4, 39.5, 37.7, 31.0, 29.6, 26.4, 25.3, 15.5, 9.2. ESI-MS m/z: Calcd. for C37H39C1N4O7: 686.2. Found (M+l)+: 687.2. Example 131 (Formula Removed) To a solution of 133 (94 mg, 0.126 mmol) in CH2Cl2 (1 mL), trifluoroacetic acid (385 µL, 5.0 mmol) was added at 0 °C and the reaction mixture was stirred for 2.5 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (1 5 mL) and extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 137 (1 1 8 mg, 97 %) as a white solid which was used in following steps with no further purification. Rf: 0.24 (Hex:EtOAc 1:1). 1H NMR (300 MHz, CDC13) δ 7.25-7.14 (m, 3H), 7.05-7.03 (m, 2H), 6.44 (s. 1H), 5.98 (d, J= 1.5 Hz, 1H), 5.92 (d, J= 1.5 Hz,1H), 5.82 (s,1H), 5.20 (t, J=4.8Hz. lH),4.07(d, J = 2.1 Hz, 1H), 5.82(s,1H), 5.20 (t, J= 4.8 Hz, 1H),4.07 (d, J-2.1 Hz, 1H). 4.01 (bs, 11H), 3.98 (d, J = 2.4 Hz, 1H), 3.93-3.84 (m, 2H), 3.63 (ddd, Jl = 1 .5 Hz, J2 = 6.9 Hz, J3 = 12 Hz, 1H), 3.44 (bs, 3H), 3.37-3.26 (m, 3H), 3.1 1-3.06 (m, 2H), 3.01 (dd. Jl = 8.4 Hz, J2 = 18.3 Hz, IH), 2.80 (brd, J= 13.8 Hz, 1H), 2.58-2.47 (m, 3H), 2.29 (s, 3H), 2.03 (s, 3H), 2.01 (s,3H), 1.93-1. 68 (m,3H). 13CNMR(75MHz,CDCl3) δ 171.7, 168.0, 146.7, 144.6,142.8,142.1, 141.0,140.8, 140.1, 130.7, 129.0, 128.2, 126.0, 122.2, 120.9, 1 16.7, 114.7, 113.1, 111.7, 102.3, 101.7, 72.0, 60.4, 59.1, 56.4, 56.3, 55.7, 55.2, 41.7, 40.3, 38.8, 37.8, 37.1, 31.0, 26.4, 25.2, 15.5, 9.4. ESI-MS m/z: Calcd. for C38H41ClN4O7: 700.2. Found (M+23)+: 723.1. Example 132 (Formula Removed) To a solution of 134 (46 mg, 0.054 mmol) in CH2C12 (1 mL), trifluoroacetic acid (166 µL, 2.16 mmol) was added at 0 °C and the reaction mixture was stirred for 10 h at 23°C. The reaction was quenched at 0°C with saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (2x10 mL). The combined organic layers were dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure to give 138 (35 mg, 80 %) as a white solid which was used in following steps with no further purification. Rf: 0.26 (Hex:EtOAc 1.1) 1H NMR (300 MHz, CDC13) δ 7.23 - 7.12 (m, 3H), 7.04 - 7.01 (m, 2H), 6.45 (s, 1H), 6.03 (d, J = 1.5 Hz, 1H), 5.97 (d,J = 1.5 Hz, 1H),5.64(s, 1H), 4.98 (m, 1H), 4.09 (d.J= 2.1 Hz, 1H), 4.03 (bs, 1H), 3.98 (d, J = 2.4 Hz, 1H), 3.75 (dd, Jl = 9.6 Hz, J2 = 14.1 Hz. 1H), 3.35 (s, 3H), 3.29 - 3.24 (m, 3H), 3.04 (dd, Jl= 7.8 Hz, J2 = 1 8.0 Hz, 1 H), 2.74 (dd, Jl= 3.0 Hz, J2 - 16.8 Hz, 1H), 2.57 - 2.45 (m, 3H), 2.30 (s, 3H), 2.03 (s, 6H), 1.92 - 1.64 (m, 3H). ESI-MS m/z: Calcd. for C39H37F7N4O7: 806.7. Found (M+l)+: 807.3. Example 133 (Formula Removed) To a solution of 136 (45 mg, 0.065 mmol) in CH2C12 (0.3 ml), acetyl chloride (4.65 µL, 0.065 mmol). and pyridine (5.2 µL, 0.065 mmol) were added at 0 °C. The reaction mixture was stirred for -4 h and then, the solution was diluted with CH2Cl2 (15 mL) and washed with 0.1 N HCl (7 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient Hex:EtOAc 5:1 to EtOAc) to afford 139 (27 mg, 57 %) as a white solid. Rf: 0.36 (Hex:EtOAc 1:2). 1H NMR (300 MHz, CDC13) δ 7.26 - 7.14 (m, 3H), 7.07 - 7.04 (m, 2H), 6.84 (s, 1H), 6.00 (d, J=1.2 Hz, 1H), 5.94 (d,7 = 1.2 Hz, 1H), 4.94 (t, J= 5.1 Hz, 1H), 4.39 - 4.38 (m, 2H), 4.02 (bs, 2H), 3.67 (d, J=3 Hz, 1H), 3.60-3.54 (m, 1H), 3.47-3.35 (m, 3H), 3.42 (s, 3H), 3.26 (dt,J=4.8Hz,J2 = 8.7Hz 1 H), 3.02 (dd.J1= 8.1 Hz, J2 = 18.3 Hz, 1H), 2.64 - 2.38 (m, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1.95 - 1.69 (m, 3H). ESI-MS m/z: Calcd. for C39H41ClN408: 729.2. Found (M+23)+: 752.3. Example 134 (Formula Removed) To a solution of 2 (15 mg, 0.0273 mmol) in CH2C12 (0.2 mL), acetyl chloride (1.94 µL, 0.0273 mmol), and pyridine (2.20 µL, 0.0273 mmol) were added at 0 °C. The reaction mixture was stirred for 20 minutes and then, the solution was diluted with CH2Cl2 (15 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAcMeOH 5:1) to afford 140 (9 mg, 56 %) as a light yellow solid. Rf: 0.56 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ6.52 (s, 1H), 6.40 (s, 1H), 5.73 (d,J= 7.5 Hz,1H), 4.95 (d,J= 6.9 Hz, 1H), 4.20 (d, J= 1.5 Hz, 1 H), 4.00 (s, 3H), 3.86 (d, J= 4.5 Hz,1H), 3.79 (s, 3H), 3.78-3.77 (m,1H), 3.40-3.35 (m, 2H), 3.24 (dt,,Jt= 3.6 Hz, J2= 11.4 Hz, 1H), 3.17 (d, J= 7.8 Hz, 1H), 3.11 (d,J= 7.5 Hz,1H), 3.04 (dd, J1= 3.6 Hz,J2= 18.6 Hz, 1 H), 2.92 (dt,, J,= 3.3 Hz, J2= 14.1 Hz,1H), 2.43 (d, J= 18.0 Hz, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 1.89 (s, 3H), 1.79 (s, 3H), 1.75 (dd, J,= 2.7 Hz, J2= 6.9 Hz, 1 H), 0.99 (d, J= 7.5 Hz, 3H). ESI-MS m/z: Calcd. for C31H37N507: 591.6. Found (M+l)+: 592.3. (Formula Removed) Example 135 To a solution of 2 (15 mg, 0.0273 mmol) in CH2Cl2 (0.2 mL), trifluoroacetyl anhydride (3.85 µL, 0.0273 mmol was added at 23 °C. The reaction mixture was stirred for 30 minutes and then, the solution was diluted with CH2Cl2(15 mL) and washed with 0.1 N HC1 (5 mL). The organic layer was dried over sodium sulphate, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, gradient EtOAc to EtOAcMeOH 4:1) to afford 141 (12.1 mg, 69 %) as a light yellow solid. Rf: 0.73 (EtOAc:MeOH 5:1). 1H NMR (300 MHz, CDC13) δ6.90 (d, J= 6.6 Hz, 1 H), 6.56 (s, 1 H), 5.11 (d, J= 6.6 Hz, 1 H), 4.47 (bs, 1H), 4.23 (bs, 1H), 3.97 (s, 3H), 3.93 (bs,1H), 3.85-3.81 (m,1H), 3.77 (s, 3H), 3.40-3-36 (m, 2H), 3.23 (dd,J= 7.2 Hz, J2= 18.6 Hz, 1H), 3.13-3.08 (m, 3H), 1.86 (s, 3H), 1.74 (dd, J,= 10.8 Hz, J2= 16.8 Hz, 1 H), 1.07 (d, J= 6.9 Hz, 3H). ESI-MS m/z: Calcd. for C31H34F3N5O7: 645.6. Found (M+l)+: 646.3. Example 136 (Formula Removed) To a solution of 45 (30 mg, 0.058 mrnol) in CH2Cl2 (0.87 mL), DIPEA (1 5.0 mL. 0.086 mmol), EDC-HCl (27.6 mg,0.145 mmol), N-Boc-Phenylalanine (22.9 mg. 0.086mmol) and DMAP (0.7 mg, 0.006 mmol) were added at room temperature and the reaction mixture was stirred for 4h. Then, the solution was diluted with CH2Cl2 (1 0 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex: EtOAc 1:2) to afford 174 (17 mg, 38%) as a white solid. Rf = 035 Hex:AcOEt 1:2. 1H NMR (300 MHz, CDC13) 7.24-7.1 5 (m, 3H), 7.05-7.02 (m, 2H), 6.43 (s, 1H), 5.88 (s, 1H), 5.78 (s,1H), 5.64 (s, 1H), 5.63 (bs, 1H), 4.80 (bs, 1H), 3.98 (s, 1H), 3.85 (bs, 2H), 3.75 (bs, 1H), 3.58 (bs,1H), 3.53 (bs, 3H), 3.38 (m, 1H), 3.17-3.10 (m, 3H) 2.90 (dd, J, = 8.7 Hz, J2=17.l Hz, 1 H), 2.73 (d, J = 1 4.4 Hz, 1 H), 2.57 (m, 1 H), 2.43-2.37 (m, 1 H), 2.25 (s, 3H), 2.24 (s, 3H), 2.10 (s, 3H), 1.94 (s, 3H), 1.76 (dd,J1 = 12.3 Hz, J. = 15.6 Hz, 1H), 1.19 (bs, 9H). 13C NMR (75 MHz, CDC13) 171.2, 168.8, 146.6, 144.6, 142.8, 140.6, 137,0, 330.7, 129.5, 129.0, 128.4, 126.8, 121.1, 121.0, 117.8, 116.7, 113.3, 313.8, 101.5,60.5,59.7,57.0, 56.4, 55.3, 41.9, 41.6, 38.7, 31.6, 29.7, 28.2, 26.5, 25.2, 22.6, 20.3, 15.7, 14.1, 9.3. ESI-MS m/z: Calcd. for C42H49N5O9: 767.87. Found (M+l)+: 768.3. Example 137 (Formula Removed) To a solution of 45 (30 mg, 0.058 mmol) in CH2Cl2 (0.87 ml), DIPEA (15.0 mL, 0.086 mmol), EDC-HC1 (27.6 mg, 0. 1 45 mmol), N-Boc-Valine (18.8 mg. 0.086 mmol) and DMAP (0.7 mg. 0.006 mmol) were added at room temperature and the reaction mixture was stirred for 4 h. Then, the solution was diluted with CHaCl2 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHC03 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2. Hex: EtOAc 1:2) to afford 175 (18 mg, 43%) as a white solid. Rf =0.25 Hex :EtOAc 1:1. 1H NMR (300 MHz, CDC13) 6 6.42 (s, 1H), 5.97 (s, 1H), 5.82 (s, 1H), 5.73 (bs, 1H), 5.50 (bs, 1H), 4.82 (bs, 1H), 4.15 (bs, 1H), 4.03 (bs, 1H), 3.96 (bs, 1H), 3.72 (s, 3H), 3.61 (m, 1H), 3.41-3.15 (m, 3H), 2.96 (dd, J1 = 8.4 Hz, J2= 18.3 Hz, 1H), 2.72 (d, J= 16.5 Hz, 1H), 2.53 (d,J= 18 Hz, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 1.93 (s, 3H), 1.81 (dd,J1 =14.1 Hz, J2 = 14.7 Hz, 1H), 1.34 (s, 9H), 0.83-0.76 (m, 2H), 0.61 (d, J= 6.3 Hz, 3H), 0.54 (d, J= 6.3 Hz, 3H). 13CNMR(75 MHz, CDC13) δ 171.6, 168.7, 155.4, 146.8, 144.5, 142.9, 140.7, 130.7, 128.8, 121.0, 120.6, 1 1 7.7, 1 16.8, 1 13.3, 1 1 1.9, 101.4, 60.6, 60.0, 59.3, 57.2, 56.3, 55.2, 41 .7, 29.7, 29.3, 28.2, 26.2, 25.2, 22.6, 20.3, 18.9, 17.7, 15.7, 14.1, 9.3. ESI-MS m/z: Calcd. for C38H49N5O9: 719.82. Found (M+l)+: 720.3. Example 138 (Formula Removed) To a solution of 45 (38 mg, 0.073 mmol) in CH2Cl2 (1.09 mL), DIPEA (19.0 mL. 0.109 mmol), EDC-HC1 (34.9 mg. 0.1 82 mmol), N-Boc-Proline (23.5 mg, 0.109 mmol) and DMAP (0.8 mg, 0.007 mmol) were added at 23 °C and the reaction mixture was stirred for 4.5 h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex: EtOAc 1 :1) to afford 176 (33 mg, 63%) as a white solid. Rf=0.14Hex:EtOAcl:2. 1H NMR (300 MHz, CDC13) δ 6.49 (s, 1H), 6.02 (bs. 1H), 5.90 (s, 1H), 5.74 (s, 1H), 4.19 (bs, 1H), 4.09 (bs, 1H), 3.98 (bs, 1H), 3.76 (s, 3H), 3.38 (d, J= 6 Hz, 2H), 3.22 (d, 7= 1 1.7 Hz, 1H), 3.15-2.99 (m, 2H), 2.80 (d, J = 15.3 Hz, 1H), 2.63-2.58 (m, 1H), 2.32 (s. 3H), 2.26 (s, 6H), 1 .99 (s, 3H), 1 .78- 1 .62 (m, 1 H), 1 .50-0.83 (m, 7H), 1 .2 1 (s, 9H). ESI-MS m/z: Calcd. for C38H47N5O9: 717.81. Found (M+l)+: 718.3. Example 139 (Formula Removed) To a solution of 45 (50 mg, 0.144 mmol) in CH2Cl2 (0.96 mL), DIPEA (41.8 mL. 0.240 mmol), EDC-HCI (46.0 mg, 0.240 mmol), N-Boc-Arginine hidrochloride hydrate (47.2 * mg, 0.144 mmol) and DMAP (1.1 mg, 0.01 mmol) were added at 23 °C and the reaction mixture was stirred for 4 h. Then, the solvent was removed under vacuum and the residue was purified by flash column chromatography (SiO2, Hex: EtOAc 1:2) to afford 177 (58 mg, 78%) as a white solid. Rf= 0.40 MeOH:EtOAc 1:5. 1HNMR (300 MHz, CDC13) δ 7.53 (bs, 1H), 6.95 (bs, 3H), 6.54 (bs, 1H), 6.48 (s,1H), 6.07 (s, 1H), 6.00 (bs,1H), 5.88(s,1H), 5.11 (bs, 1H), 4.23 (s, 1H),4.08(s, lH),4.02(s, 1H), 3.76 (s,3H), 3.70 (bs, 1H), 3.48 (bs,1H), 3.37 (d,J= 6.9 Hz, 1H), 3.18 (d,J = 10.2 Hz, 1H), 3.00-2.94 (m, 3H), 2.82-2.70 (m, 2H), 2.34 (s, 3H), 2.25 (s, 6H), 1.99 (s, 3H), 1.73 (brt, J = 14.1 Hz, 1H), 1.40(s, 9H), 1.25 (bs, 3H), 0.95-0.85 (m, 2H). ESI-MS m/z: Calcd. for C39H52N809: 776.88. Found (M+l)+: 777.3. Example 140 (Formula Removed) To a solution of 45 (50 mg, 0.096 mmol) in CH2Cl2 (1.44 mL), DIPEA (25.8 mL, 0.144 mmol), EDC-HCl (46.0 mg, 0.2,40 mmol), N-Boc-Tryptophan (43.8 mg, 0.144 mmol) and DMAP (1.2 mg, 0.009 mmol) were added at 23 °C and the reaction mixture was stirred for 4 h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex: EtOAc 1:2) to afford 178 (57 mg, 74%) as a white solid. Rf=0.12Hex:EtOAcl:l. 1H NMR (300 MHz, CDC13) δ8.50 (bs, 1H), 7.73-7.71 (m, 1H), 7.13-7.12 (m, 3H), 6.51 (s, 1H), 5.72 (s, 1H), 5.36 (bs, 1H), 5.28 (bs, 1H), 4.95 (bs, 1H), 4.41 (bs, 1H), 4.05 (s, 1H), 3.70 (s, 3H), 3.50 (bs, 2H), 3.30-3.17 (m, 4H), 2.89-2.82 (m, 3H), 2.40 (s, 3H), 2.29 (s, 3H), 2.19(s, 3H), 2.03 (s, 3H), 1.49 (s, 9H), 1.26-1.25 (m, 2H). ESI-MS m/z: Calcd. for C44H50N6O9: 806.90. Found (M+l)+: 807.3. Example 141 (Formula Removed) To a solution of 178 (43 mg, 0.053 mmol) in CH3CN/H2O (3 mL/2 mL), AgNO3 (271 mg, 1.60 mmol) was added and the reaction was stirred at 23°C for 17 h. Then, Aq sat NaCl (10 mL) and Aq sat NaHCO3 (10 mL) were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 mL). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc:MeOH 5:1) to afford 179 (24 mg, 56%) as a white solid. Rf= 0.38 EtOAc:MeOH 5:1. 1HNMR(300MHz, CDC13) δ 8.40 (s, lH),7.66(bs, 1H), 7.25-7.21 (m, 1H), 7.16-7.09 (m, 2H), 6.45 (s,1H), 5.75 (bs, 1H), 5.55 (bs, 1H), 5.45 (s, 1H), 5.25 (bs, 1H). 4.36 (bs.1H), 4.16 (bs,1H), 4.05 (bs, 1H), 3.95 (s, 1H), 3.69 (s, 3H), 3.35-3.02 (m, 6H), 2.83-2.73 (m, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.99 (s, 3H), 1.77 (dd, J = 12 Hz, J3 = 15.3 Hz 1H). ESI-MS m/z: Calcd. for C43H51N5O10: 797.89. Found (M-17)+: 780. Example 142 (Formula Removed) To a solution of 45 (50 mg, 0.0960 mmol) in CH2C12 (0.7 mL), 2-Chloronicotinoyl chloride (17.7 mg, 0.101 mmol) and pyridine (8.1mL, 0.101 mmol) were added at 0 °C. The reaction mixture was stirred for 1.5 h and then, the solution was diluted with CH2Cl2 (5 mL) and washed with 0.1 N HC1 (3 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex: EtOAc 1:1) to afford 180 (45 mg, 71%) as a white solid. Rf=0.18Hex:EtOAcl:2. 1H NMR (300 MHz, CDC13) δ 8.32-8.29 (m, 1H), 7.38-7.34 (m, 1H), 7.14-7.09 (rn, 1H), 6.14(s, 1 H), 5.97 (d, .7=1. 2 Hz, 1H), 5.92-5.91 (m, 2H), 5.75 (d,J= 2.1 Hz, 1H), 4.18 (d, J = 2.1 Hz, 1H), 4.15 (s, 1H), 4.07 (s, 1H), 3.91-3.73 (m, 2H), 3.68 (s, 3H), 3.36 (d,J= 7.5 Hz, 1H), 3.31 (dt, J, = 2.4 Hz, J2=11.l Hz, 1H), 2.92 (dd, J, = 8.1 Hz, J2 = 1 8 Hz, 1H), 2.80 (d, J= 16.2 Hz, 1H), 2.58 (d, J = 1 8 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 1.99 (s, 3H), 1.91 (s, 3H) 1.97-1.83 (m, 1H). I3C NMR (75 MHz, CDC13) δ 168.6, 164.8, 150.3, 147.2, 146.5, 144.6, 142.5, 140.6, 139.0, 130.9, 130.5, 128.8, 122.3, 120.8, 120.3, 1 17.6, 116.3, 112.7, 112.1, 101.6, 60.6, 58.8, 56.5, 56.3, 55.6, 55.1, 41.6, 39.8, 31.5, 26.2, 24.9, 20.3, 15.5, 9.3. ESI-MS m/z: Calcd. for C34H34ClN5O7: 659.2. Found (M+l)+: 660.1. Example 143 (Formula Removed) To a solution of 180 (39 mg, 0.059 mmol) in CH3CN/H2O (3 mL/2 ml), AgNO3 (301mg, 1.77 mmol) was added and the reaction was stirred at 23°C for 17 h. Then. Aq sat NaCl (10 mL) and Aq sat NaHC03 (10 mL) solutions were added at 0°C and the mixture was stirred for 15 min, filtered through a pad of celite and washed with CH2Cl2 (20 mL). The solution was decanted and the organic layer was dried and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc:MeOH 5:1) to afford 181 (28 mg, 73%) as a white solid. Rf= 0.24, EtOAc:MeOH 5:1. 1H NMR (300 MHz, CDC13) δ 8.33-8.31 (m, 1 H), 7.40-7.35 (m, 1 H), 7.16-7.09 (m, 2H), 6.20 (s, 1H), 5.98 (d,J = 1.2 Hz, 1H), 5.96 (s, 1H), 5.92 (d, J= 1.2 Hz, 1H).5.63(bs, 1H), 4.60 (bs, 1H), 4.47 (bs, 1H), 4.02-3.95 (m, 2H), 3.69 (s, 3H), 3.65-3.56 (m, 1H), 3.48 (s, 3H), 3.43-3.38 (m, 1H), 3.17 (brd, J= 7.2 Hz, 1H), 2.88 (dd, J, = 8.7 Hz, J = 18.3 Hz, 1H), 2.74 (d,J= 15.3 Hz, 1H), 2.40 (d, J = 18.3 Hz, 1 H), 2.32 (s, 3H), 2.26 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.77 (dd, J, = 12 Hz, J3 = 15 Hz, 1H). 13C NMR (75 MHz, CDC13) δ 168.1, 165.0, 150.0, 147.2,146.5, 144.4, 142.5, 140.9, 138.7, 131.5, 130.2,128.9,122.3, 121.1, 120.7, 116.1, 114.4, 111.4, 101.5, 82.6, 60.6, 57.8, 56.2, 52.1, 41.6, 31.5, 26.4, 24.5, 22.6, 20.3, 15.6,14.1, 9.3. ESI-MS m/z: Calcd. for C33H35C1N4O8: 650.2 Found (M-17)+: 633.3. Example 144 (Formula Removed) To a solution of 45 (30 mg, 0.058 mmol) in CH2Cl2 (0.87 mL). DIPEA (15.0 mL, 0.086 mmol), EDC-HCl (27.6 mg, 0.145 mmol), cyclohexylacetic acid (12.2 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred for 5 h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) anS a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex: EtOAc 1:2) to afford 182 (10 mg, 27%) asti white solid. Rf=0.11 Hex:EtOAcl:l. 1H NMR (300 MHz, CDC13) δ 6.50 (s,1H), 5.98 (d,J= 1.2 Hz, 1H), 5.91 (d,J= 1.2 Hz, 1H), 5.75 (s, 1H), 5.02-4.91 (m, 1H), 4.11 (bs, 1H), 4.04 (d,J= 2.1 Hz, 1H),4.01 (bs, IH), 3.78 (s, 3H), 3.72-3.69 (m, 1H), 3.38-3.29 (m, 3H), 3.05 (dd, J, = 7.8 Hz, J3 = 18.0 Hz, IH), 2.77 (d,J = 15.6 Hz, 1H), 2.54 (d,J= 18.6 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 1.98 (s, 3H), 1.79 (dd,y, = 11.7 Hz,J = 15.6 Hz, IH), 1.59-0.61 (m, 13H). ESI-MS m/z: Calcd. for C36H44N4O7: 644.76. Found (M+l)+: 645.3. Example 145 (Formula Removed) To a solution of 45 (30 mg, 0.058 mmol) in CH2Cl2 (0.87 mL), DIPEA (1 5.0 mL. 0.086 mmol), EDC-HCl (27.6 mg, 0.145 mmol), cyclohexylacetic acid (12.2 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred for 5 h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex: EtOAc 1 :2) to afford 183 (17 mg, 38%) as a white solid. Rf=0.13Hex:EtOAc 1:1. 1H NMR (300 MHz, CDCl3) δ6.87 (s, 1H), 5.99 (d, J= 1 .2 Hz? 1 H), 5.92 (d, J= 1 .2 Hz, 1H),4.95 (t, J- 5.7 Hz, 1H), 4.08 (bs, 1H), 4.00 (bs, 1H), 3.71 (s, 3H), 3.64 (d, J= 1.8 Hz, 2H), 3.38 (d,J= 6.6 Hz,1H), 3.33-3.32 (m, 1H), 3.27 (d, J= 1 1 .7 Hz, 1H), 3.06 (dd, J, = 7.8 Hz, J2 = 1 8.0 Hz, 1 H), 2.65-2.59 (m, 1 H), 2.50-2.47 (m, 1 H), 2.35 (s, 3H), 2.27 (s, 6H), 1 .99 (s, 3H), 1 .78-1 .74 (m, 1 H) 1 .60-0.62 (m, 26H). ESI-MS m/z: Calcd. for C44H56N4O8: 768.94. Found (M+l)+: 769.3. Example 146 (Formula Removed) To a solution of 45 (30 mg, 0.058 mmol) in CH2C12 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HCI (27.6 mg, 0.145 mmol), cyclohexylpropionic acid (13.5 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred at 23 °C for 6 h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 1 0% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2. Hex: EtOAc 1 :2) to afford 184 (15 mg, 39%) as a white solid. Rf=0.15Hex:EtOAcl:l. 1HNMR(300MHz, CDC13) δ 6.50 (s,1H), 5.98 (s, 1H),5.91 (s, 1H), 5.74 (s.1H), 5.01 (t, J= 5.1 Hz, 1H), 4.09 (bs,1H), 4.06 (s,1H), 4.02 (bs,1H), 3.76 (s, 3H). 3.64-3.58 (m, 1H), 3.42-3.41 (m, 1H), 3.36 (d, J= 7.5 Hz, 1H), 3.28 (d, J = 12.3 Hz, 1H), 3.05 (dd, J = 8.6 Hz, J, = 1 8 Hz, 1 H), 2.79 (d, J = 1 4.7 Hz, 1 H), 2.57 (d, J =18 Hz, 1 H), 2.32 (s, 3H), 2.30 (s, 3H),2.25 (s,3H), 1.99 (s,3H), 1.77 (dd,J1= 12.0 Hz, J2= 15.9 Hz, 3H), 1.62-0.71 (m, 15H). ESI-MS m/z: Calcd. for C37H46N4O7: 658.78. Found (M''''''''+l)+: 659.3. Example 147 (Formula Removed) To a solution of 45 (30 mg, 0.058 mmol) in CH2Cl2 (0.87 mL), DIPEA (15.0 mL, 0.086 mmol), EDC-HC1 (27.6 mg, 0.145 mmol), cyclohexylpropionic acid (13.5 mg, 0.086 mmol) and DMAP (0.7 mg, 0.006 mmol) were added at 0°C and the reaction mixture was stirred for 6 h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0. 1 N HC1 (5 mL) and a solution of 1 0% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex: EtOAc 1 :2) to afford 185 (21 mg, 46%) as a white solid. Rf=0.17Hex:EtOAcl:l. 1H NMR (300 MHz, CDC13) δ 6.86 (s, 1H), 5.99 (s, 1H), 5.92 (s, 1H), 4.97 (t, J= 5.4 Hz, 1H), 4.10 (d,J= 2.4 Hz, 1H), 4.01 (bs, 1H), 3.70 (s, 3H), 3.64 (d, J= 2.4 Hz, 3H), 3.51 (bs, 1H),3.37 (d, J= 8.1 Hz, 1H), 3.23 (d, J= 11.1 Hz, 1H), 3.02 (dd,J= 7.8 Hz,J2= 18 Hz, 1H), 2.69-2.59 (m, 4H), 2.35 (s, 3H), 2.26 (s, 6H), 2.00 (s, 3H), 1.76-0.72 (m, 30H). I3C NMR (75 MHz, CDC13) δ 173.1, 171.5, 168.2, 147.9, 144.7, 142.5, 140.7, 140.3, 130.9, 130.6, 127.7, 123.3, 120.0, 117.5, 113.1, 111.9, 101.6,60.5,59.0,57.3,56.7,55.2,55.0, 41.6, 39.9, 37.2, 33.5, 33.0, 32.9, 32.9, 32.8, 32.5, 32.4, 31.9, 31.7, 29.7, 29.3, 26.6, 26.5, 26.2,24.9,20.3,15.8,14.1,9.4. ESI-MS m/z: Calcd. for C46H6oN408: 796.4. Found (M+l)+: 797.5. Example 148 (Formula Removed) To a solution of 72 (1 1 1 mg, 0.162 mmol) in CH2C12 (0.81 ml), DIPEA (56.3 mL, 0.324 mmol), butyryl chloride (33.6 ml, 0.324 mmol) and DMAP (1.96 mg. 0.016 mmol) were added at 0 °C and the reaction mixture was stirred for 5 h at this temperature. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 1 0% NaHC03 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-1 8, CH3CN: H2O 1 :1) to afford 186 (65.4 mg. 54%) as a white solid. Rf=0.21 Hex:EtOAcl:2. 1H NMR (300 MHz, CDC13) δ 7.24-7.15 (m, 3H), 7.12-7.04 (m, 2H), 6.84 (s, 1H), 5.98 (d, J = 1.2 Hz, 1H), 5.92 (d, J- 1.2 Hz, 1H), 4.97 (t, J= 5.7 Hz, 1H), 4.03 (m, 3H), 3.63 (d, J = 2.7 Hz, 1H), 3.50 (m, 2H), 3.44 (s, 3H), 3.37 (d, J= 8.4 Hz, 1 H), 3.24 (dt, J, = 2.7 Hz, J2 = 1 1 .7 Hz, 1 H), 3.02 (dd, J, = 8. 1 Hz, J2 = 1 8.3 Hz, 1 H), 2.65-2.54 (m, 7H), 2.35 (s, 3H), 2.25 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.87-1.75 (m, 3H), 1.08 (t, J= 7.5 Hz, 3H). 13CNMR(75 MHz, CDC13) δ171.7, 170.8, 168.2, 147.8, 144.7, 142.5, 140.8, 140.6, 140.3, 131.1, 130.5, 128.3,128.2, 127.6, 126.0, 123.2, 117.5, 112.9, 111.8, 101.6,60.2,59.0,57.3, 56.6, 55.1, 54.9, 41.5, 39.9, 37.8, 36.0, 31.0, 26.5, 24.8, 22.6, 20.2, 18.5, 15.6, 13.7, 9.3. ESI-MS m/z: Calcd. for C41H46N4O8: 722.83. Found (M+l)+: 723.2. Example 149 (Formula Removed) To a solution of 72 (80 mg, 0.122 mmol) in CH2C12 (0.61 mL), DIPEA (64.0 mL, 0.367 mmol), hexanoyl chloride (49.5 mL, 0.367mmol) and DMAP (1.50 mgr 0.012 mmol) were added at 0 °C and the reaction mixture was stirred at this temperature for 5h. Then, the solution was diluted with CH2C12 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H2O 6:4) to afford 187 (86.1 mg, 94%) as a white solid. Rf=0.25Hex:EtOAc 1:2 1H NMR (300 MHz, CDC13) δ 7.20-7.06 (m, 3H), 6.99-6.97 (m, 2H), 6.77 (s, 1H), 5.91 (s, 1H), 5.85 (s, 1H), 4.90 (m, 1H), 3.96 (d, J = 3 Hz, 2H), 3.57-3.55 (m, 1H), 3.43 (bs, 2H), 3.36 (bs, 3H), 3.29 (brd, J= 10.5 Hz, 1H), 3.18 (d,J= 11.7 Hz, 1H), 2.97 (dd, J, = 4.8 Hz, J, = 12 Hz, 1H), 2.58-2.46 (m, 6H), 2.28 (s, 3H), 2.18 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H), 1.86- 1.66 (m, 7H), 1.41-1.38 (m, 2H), 0.86-0.81 (m, 3H). I3C NMR (75 MHz, CDC13) δ 171.7, 171.0, 168.2, 147.8, 144.7, 142.5, 140.8, 140.6, 140.3, 131.1, 130.5, 128.3, 128.2, 127.6, 126.0, 117.5, 112.9, 111.8, 101.6,60.2,59.0,57.3,56.6, 55.1, 55.0, 41.5, 39.9, 37.8, 34.1, 31 .3, 31.1, 29.6, 24.8, 24.7, 22.3, 20.2, 15.6, 13.8. ESI-MS m/z: Calcd. for C43H50N4O8: 750.88. Found (M+l)+: 751.3. Example 150 (Formula Removed) To a solution of 85 (80 mg, O.I 10 mmol) in CH2Cl2 (0.55 mL), DIPEA (57.7 mL, 0.331 mmol), butyryl chloride (34.4 mL, 0.331 mmol) and DMAP (1.30 mg, 0.011 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 5 h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HCl (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H2O I:I) to afford 188 (70.1 mg, 80%) as a white solid. Rf= 0.54 MeOH:EtOAc 1:5. 1H NMR (300 MHz, CDC13) δ 7.28-7.14 (m, 5H), 6.80 (s, 1H), 6.07 (d, J= 6.6 Hz, 1H), 6.00 (d, J = 1.5 Hz, IH), 5.90 (d, J= 1.5 Hz, 1H), 5.35 (t,J= 5.4 Hz, 1H), 4.12 (d, J=2.4 Hz,1H), 4.05 (bs,1H), 3.89 (bit, J= 6.9 Hz, 1H), 3.66 (s, 3H), 3.64-3.63 (m,1H), 3.59-3.45 (m, 2H), 3.40 (brd, J = 7.8 Hz,1H), 3.20 (dt, J, = 2.7 Hz,.J = 12 Hz, 1H), 3.00 (dd, J, = 8.1 Hz, J2 = 18 Hz,1H), 2.87 (t, .7=8.1 Hz, 2H), 2.71 (d,J= 18.6 Hz, 1H), 2.66-2.61 (m, 1H), 2.58 (t, J= 7.2 Hz, 2H), 2.41-2.35 (m, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 2.00 (s, 3H), 1.90-1.77 (m, 3H), 1.08 (t,J= 1.2 Hz, 3H), 0.69 (d,J= 6.9 Hz, 3H). I3C NMR (75 MHz, CDC13) δ 172.0, 171.3, 170.8,168.5, 147.7,144.7, 142.5, 140.6,140.5, 140.3, 131.0, 130.7, 128.4, 128.2, 127.7,126.1, 123.1,120.3, 117.5, 112.7, 111.8,101.6, 60.3, 59.1, 57.3, 57.2, 55.4, 54.9, 48.2, 41.5, 39.5, 38.0, 36.0, 31.4, 26.8, 26.6, 24.6, 20.1, 18.5,18.1,15.7,13.7,9.2. ESI-MS m/z: Calcd. for C44H51N5O9: 793.9. Found (M+l)+: 794.3. Example 151 (Formula Removed) To a solution of 85 (80 mg, 0.110 mmol) in CH2C12 (0.55 mL), DIPEA (57.7 mL, 0.331 mmol), hexanoyl chloride (46.3 mL, 0.331 mmol) and DMAP (1.30 mg, 0.011 mmol) were added at 0 °C and the reaction mixture was stirred at 23°C for 5 h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed succesively with 0.1 N HC1 (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure. The residue was purified by column chromatography (RP-18, CH3CN: H2O 1:1) to afford 189 (80 mg, 88%) as a white solid. Rf= 0.23 Hex:EtOAc 1:3. 1H NMR (300 MHz, CDC13) δ 7.21-7.08 (m, 5H), 6.74 (s, 1 H), 6.00 (d, J =6.9 Hz, 1 H), 5.94 (d,J= 1.5 Hz, IH), 5.84 (d,J = 1.5 Hz, IH), 5.24 (t, J= 5.4 Hz, 1H), 4.06 (bs, 1H), 4.00 (bs, 1H), 3.83 (t, J- 6 Hz, 1H), 3.59 (s, 3H), 3.57 (m, 1H), 3.53-3.40 (m, 2H), 3.33 (d, J = 7.8 Hz, 1H), 3.14 (d, J= 11.7 Hz, 1H), 2.94 (dd, J, = 8.4 Hz, J = 18 Hz, IH), 2.81 (t, J = 1.5 Hz, 2H), 2.65 (d, J= 18 Hz, 1H), 2.60-2.54 (m,1H), 2.52 (t, J = 7.2 Hz, 2H), 2.35-2.29 (m, 2H), 2.27 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 1.95 (s, 3H), 1.76-1.60 (m, 3H), 1.35-1.29 (m, 2H), 1.84 (m, 2H), 0.85-0.78 (m, 3H), 0.62 (t, J= 6.6 Hz, 3H). I3CNMR(75 MHz,CDCl3) δ172.0, 171.3, 171.1, 168.4, 147.8,144.8, 142.6,140.7,140.5, 131.2, 130.6, 128.4, 128.3, 127.7, 326.2, 123.1, 120.3, 117.5, 112.6, 112.0, 101.7,60.4,59.1, 57.4, 57.2, 55.4, 54.9, 48.3, 41.5, 39.6, 38.1, 34.1, 33.6, 31.5, 31.3, 26.7, 24.7,22.3, 20.2, 18.2,15.7,13.9,9.3. ESI-MS m/z: Calcd. for C46H5SN5O9: 821.96. Found (M+l)+: 822.3. Example 152 (Formula Removed) To a solution of 53 (100 mg, 0.145 mmol) in CH2C12 (0.72 mL), DIPEA (50.6 mL, 0.291 mmol) and acetyl chlorrtie (20.7 mL, 0.291 mmol) were added at 0 °C and the reaction mixture was stirred for 4 h at 23 °C. Then, the solution was diluted with CH2C12 (10 mL), and washed successively with 0.1 N HC1 (5 mL), and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2S04, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex: EtOAc 1:2) to afford 190 (27 mg, 25%) as a white solid. Rf= 0.24 Hex:EtOAc 1:1. 1H NMR (300MHz, CDC13) δ 6.82 (s, 1H), 6.02 (d, J= 0.9 Hz, 1H), 5.92 (d, J = 0.9 Hz, 1H), 5.30 (bs, 1H), 4.14 (d,J= 2.7 Hz, 1H), 4.10 (s, 1H), 3.90-3.73 (m, 2H), 3.68 (s, 3H), 3.67 (bs, 1H), 3.49 (bs, 1H), 3.42 (brd, 7= 8.1 Hz, 1H), 3.24-3.20 (m, 1H), 3.01 (dd, J, = 8.4 Hz,J2= 18.3 Hz, 1H), 2.78 (d, J= 18 Hz, 1H), 2.64 (brd,J = 15.6Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.02 (s, 3H), 1.77 (dd, J, = 11.7 Hz, J2 = 15.6 Hz, 1 H), 0.65 (d, J=6.6 Hz, 3H). I3C NMR (75 MHz, CDC13) δ 170.2, 168.6, 168.1, 167.6,147.9, 144.9, 142.8, 140.5, 131.5, 131.0,127.7,123.2,120.3, 117.5, 112.3,112.2, 101.7, 60.4,59.0, 57.4, 57.2, 55.2,54.9, 48.6,41.5,39.1, 36.6,29.7,26.7,24.6,20.7,20.2, 17.6, 15.5, 9.2. ESI-MS m/z: Calcd. for C35H38N5O9: 729.70. Found (M+l)+: 730.3. Example 153 (Formula Removed) To a solution of 53 (150 mg; 0.218 mmol) in CH2CI2 (1.09 mL). DIPEA (151.9 mL; 0.87 mmol), butyryl chloride (90.6 mL, 0.87 mmol) and DMAP (2.70 mg. 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h.. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H20 4:1) to afford 191 (20.2 mg, 12%) as a white solid. Rf=0.3Hex:EtOAcl:l. 1HNMR (300 MHz, CDC13) δ 6.81 (s, 1H), 6.03 (d, J= 1.2 Hz, 1H), 5.92 (d,J= 1.2 Hz, 1H), 5.16 (t, J= 5.4 Hz, 1H), 4.13 (d, J= 2.1 Hz, 1H), 4.10 (bs, 1H), 3.87-3.82 (m, 1H), 3.80-3.74 (m, 1), 3.68 (s, 3H), 3.64 (d, J= 3 Hz, 1H), 3.52-3.47 (m, 1H), 3.42 (brd, J= 7.2 Hz, 1H), 3.24-3.20 (m, 1H), 3.02 (dd, J, = 8.1 Hz, J2= 18.3 Hz, 1H), 2.77 (d, J= 17.7 Hz, 1H), 2.64 (brd, J= 16.2 Hz, 1H), 2.58 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 2.02 (s, 3H), 1.87-1.73 (m, 3H), 1.08 (t, J= 7.2 Hz, 3H), 0.68 (d,J= 6.6 Hz, 3H). I3CNMR(75MHz, CDC13) δ 172.8, 172.1, 170.4, 157.8, 150.0, 146.9, 144.8, 142.6, 142.5, 133.3,132.8,129.6, 125.3, 122.3, 119.5, 118.4, 115.7, 114.3, 114.2, 103.8,62.4, 61.0, 59.4, 59.2, 57.2, 57.0, 50.6, 43.6, 41.2, 38.1,31.7,28.7,26.6, 22.2, 20.6,19.7, 17.5, 15.7, 11.2. ESI-MS m/z: Calcd. for C37H42F3N5O9: 757.75. Found: 758.5 (M+l)+, 780.5 (M+23)+. Example 154 (Formula Removed) To a solution of 53 (150 mg, 0.218 mmol) in CH2C12 (1.09 mL), DIPEA (151.9 mL, 0.87 mmol), acetyl chldride (62.0 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 5 h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4. filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H2O 1:1) to afford 192 (111 mg, 62%) as a white solid. Rf= 0.25 Hex:EtOAc 1:1. 1H NMR (300 MHz, CDC13) δ 6.80 (s, 1H), 5.87 (s, 1 H), 5.81 (s, 1H), 4.70 (dd, J, = 2.4 Hz, J2 = 9.9 Hz, 1H), 4.20 (d, J= 6.3 Hz, 1H), 4.09 (s, IH), 3.74 (s, 3H), 3.60 (s, 3H), 3.28 (d,J = 7.5 Hz, 1H), 3.17 (d, J= 12 Hz, 1H), 3.07 (dd,J = 7.2 Hz, J2 = 18.3 Hz, 1H), 2.93 (d,J= 13.2 Hz, 1H), 2.66 (d, J= 15.3 Hz, 1H), 2.53 (d, J= 17.7 Hz, 1H), 2.47-2.20 (m, 1H), 2.37 (s, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.72 (t,J= 14.4 Hz, 1H), 1.53 (d,J= 6.9 Hz, 3H). 13C NMR (75 MHz, CDC13) δ 174.1, 168.6, 168.4, 167.5, 147.7, 144.8, 142.2, 140.4, 131.1, 130.5,126.9,123.3,120.4, 117.5, 112.4, 111.8, 101.1,60.7,60.6,57.6,57.2,56.6,55.3, 52.7,48.3,41.5, 31.6, 29.7, 26.4, 25.5, 23.0, 22.6,20.7, 20.5,20.2,17.8, 15.9, 14.1, 9.5. ESI-MS m/z: Calcd. for C39H42F3N5O11: 813.7. Found (M+1)+: 814.3. Example 155 (Formula Removed) To a solution of 53 j150 mg, 0.23 8 mmol) in CH2CI2 (1.09 mL), DIPEA (151.9 mL, 0.87 mmol), butyryl chloride (90.6 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H2O 4:1) to afford 193 (58 mg, 30%) as a white solid. Rf=0.38Hex:EtOAcl:l. 1H NMR (300 MHz, CDC13) δ 6.85 (s, 1H), 5.99 (d, J= 1.2 Hz, 1H), 5.90 (d, J= 1.2 Hz, 1H), 5.47-5.42 (m, 2H), 4.09-4.08 (m, 2H), 3.69 (s, 3H), 3.66 (m, 1H), 3.41 (d,J= 7.5 Hz, 1H), 3.28-3.18 (m, 2H), 3.07 (dd, J, = 8.1 Hz, J2= 18 Hz, 1H), 2.66 (d,J= 18.6 Hz, 1H), 2.61-2.39 (m, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.01 (s, 3H), 1.95-1.79 (m, 6H), 1.72-1.59 (m, 6H) 1.09 (t, J= 7.5 Hz, 3H), 0.99-0.94 (m, 6H), 0.85 (d, J= 6.9 Hz, 3H). 13CNMR(75MHz,CDCl3) δ 171.2, 170.7, 169.1, 168.4, 148.1, 145.0, 142.7, 140.9,140.6, 131.2, 130.5,128.4, 123.4, 119.9,117.6, 113.0, 112.1, 101.9, 60.7, 59.5, 57.6, 56.5, 55.7, 55.2,41.8,41.4, 36.3, 35.8, 29.9, 27.0,25.3, 20.5, 20.0,18.8,18.3,15.8,14.0,13.8, 13.4, 12.7, 9.6. ESI-MS m/z: Calcd. for C45H54F3N5O11: 897.93. Found (M+l)+: 898.3. Example 156 (Formula Removed) To a solution of 53 (150 mg, 0.218 mmol) in CH2Cl2 (1.09 mL), DIPEA (151.9 mL, 0.87 mmol), hexanoyl chloride (121.9 mL, 0.87 mmol) and DMAP (2.70 mg, 0.02 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HCI (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H2O 4:1) to afford 194 (37.5 mg, 22%) as a white solid. Rf=0.32Hex:EtOAcl:l. 1H NMR (300 MHz, CDC13) δ 6.80 (s, 1H), 6.02 (d, J= 1.2 Hz, 1H), 5.92 (d,J= 1.2 Hz, 1H), 5.22 (t,J= 5.7 Hz, 1H), 4.13 (d, J= 2.4 Hz, 1H), 4.09 (s, 1H), 3.88-3.81 (m, 1H), 3.80- 3.71 (m, 1H), 3.67 (s, 3H), 3.64 (d, J= 3 Hz, 1H), 3.52-3.43 (m, 1H), 3.41 (brd, J= 6.6 Hz, 1H), 3.23-3.19 (m, 1H), 3.00 (dd, J, = 8.7 Hz, J2= 18.6 Hz, 1H),2.77 (d, J= 18Hz, 1H), 2.67-2.56 (m, 3H), 2.33 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 2.01 (s, 3H), 1.82-1.74 (m, 4H), 1.43-1.38 (m, 3H), 0.97-0.88 (m, 3H), 0.67 (d, J= 6.9Hz, 3H). 13CNMR(75 MHz,CDCl3) δ171.2, 170.3,168.6,148.2,145.1,143.0,140.8,140.7, 131.7, 131.1, 127.8, 123.5, 120.6, 1 17.7, 1 12.5, 102.0, 60.7, 59.2, 57.6, 57.4, 55.4, 55.2, 48.9, 41.8, 34.4, 31.8, 31.6, 29.9, 26.9, 25.0, 24.8, 22.9, 22.5, 20.4, 17.9, 15.8, 14.3, 14.1, 9.5. ESI-MS m/z: Calcd. for C39H46F3N5O9: 785.81. Found: 786 (M+l)+, 805.5 (M+23)+. Example 157 (Formula Removed) To a solution of 53 (150 mg, 0.218 mmol) in CH2C12 (1.09 mL), DIPEA (75.9 mL, 0.436 mmol), and decanoyl chloride ( 92.7mL, 0.436 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HC1 (5 mL), and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H2O 1:1) to afford 195 (75 mg, 41%) as a white solid. Rf=0.32Hex:EtOAcl:l. 1H NMR (300 Hz, CDC13) δ 6.82 (s, 1H), 6.03 (d, J = 1.5 Hz, 1H), 5.93 (d, J= 1.5 Hz, 1H), 5.26 (bs, 1H), 4.15 (s, 1H), 4.11 (s, 1H), 3.89-3.75 (m, 2H), 3.68 (s, 3H), 3.65 (bs, 1H), 3.52- 3.44 (m, 1H), 3.43 (d, J= 8.1 Hz, 1H), 3.22 (brd, J= 11.4 Hz, 1H), 3.03 (dd, J, = 7.8 Hz, J2 = 17.4 Hz, 1H), 2.78 (d, J= 17.7 Hz, 1H), 2.69-2.56 (m, 3H), 2.34 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H), 2.03 (s, 3H), 1.83-1.74 (m, 3H), 1.83-1.74 (m, 12H), 0.90-8.88 (m, 3H), 0.68 (d, J = 6 Hz, 3H). 13CNMR(75Hz,CDCl3) δ 171.0, 170.1, 168.4,148.0, 144.8,142.8, 140.5, 131.5, 130.8, 127.5,123.3,120.3,117.5,112.3,112.2,101.7, 60.4, 59.0, 57.4, 57.2, 55.1, 55.0,48.6, 41.5, 39.1,34.2, 31.8, 29.4,29.2, 26.7, 25.0, 24.6, 22.6, 20.2, 17.6,15.5,14.0, 9.2. ESI-MS m/z: Calcd. for C43H54F3N5O9: 841.91. Found (M+l)+: 842.3. Example 158 (Formula Removed) To a solution of 53 (.150 mg, 0.218 mmol) in CH2C12 (1.09 ml). DIPEA (75.9 mL, 0.436 mmol), and stearoyl chloride (147.3 mL, 0.436 mmol) were added at 0 °C and the reaction mixture was stirred at 23 °C for 4h. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HC1 (5 mL) and a solution of 10% NaHCOs (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (RP-18, CH3CN: H2O 1:1) to afford 196 (86 mg, 41 %) as a white solid. Rf= 0.42 Hex:EtOAc 1:1. 1H NMR (300 MHz, CDC13) δ 6.81 (s, lH),6.03(s, lH),5.92(s, 1H), 5.21 (bs, lH),4.14(s, 1H), 4.10 (s, 1H), 3.88-3.74 (m, 2H), 3.67 (s, 3H), 3.64 (d, J= 3 Hz, 1H), 3.49 (brd,.J = 14.7 Hz, 1H), 3.42 (d,J= 8.1 Hz, 1H), 3.22 (brd, J= 11.4 Hz, 1H), 3.02 (dd, J, = 8.7 Hz, J,= 18.6 Hz, 1 H), 2.78 (d, J - 18Hz, I H), 2.68-2.56 (m, 3H), 2.33 (s, 3H), 2.25 (s, 3H), 2.02 (s, 3H), 1.82-1.73 (m, 3H), 1.42-1.19 (m, 28H), 0.87 (t,J= 7.2 Hz, 3H), 0.67 (d,7= 6.6 Hz, 3H). I3C NMR (75 MHz, CDC13)δ 171.0, 170.2, 168.5, 147.9,144.8,142.8, 140.4, 131.4, 130.9, 127.5, 123.3, 120.4, 117.5, 112.4, 112.1, 101.7, 60.4, 58.9, 57.4, 57.2, 55.2,55.0,48.6,41.5, 39.0, 34.2, 31.9,29.7,29.6, 29.4, 29.3,29.2,26.7, 25.1, 24.6, 22.7, 20.2, 17.6, 15.5, 14.1, 9.2. ESI-MS m/z: Calcd. for C51H70F3N5O9: 953.5. Found (M+l)+: 954.4. Example 159 (Formula Removed) To a solution of 45 (10 mg? 0.019 mmol) in CH2Cl2 (0.095 mL), triethylamine (2.94 mL, 0.021 mmol) and allyl bromide (2.0 mL, 0.023 mmol) were added at 23 °C. The reaction mixture was stirred for 6 h-and then, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO2. MeOH: EtOAc 1:5) to afford 197 (3.8 mg, 35%) as a white solid. Rf=0.19EtOAc:MeOH5:l. 1H NMR (300 MHz, CDCl3) δ 6.43 (s, lH),5.95(s, lH),5.89(s, 1H), 5.62-5.59 (m, 1H), 4.94-4.84 (m,, 2H), 4.19 (s, 1H), 4.08 (s,1H), 3.98 (t, J= 4.5 Hz, 1H), 3.76 (s, 3H), 3.32- 3.26 (m, 2H), 3.07 (dd, J, = 7.5 Hz, J2 = 17.4 Hz, 1H), 2.89 (d, J= 6 Hz, 2H), 2.80 (d, J = 3.9 Hz, IH), 2.76 (d,J= 3.3 Hz, 1 H), 2.57-2.52 (m, 2H), 2.33 (s, 6H), 2.24 (s, 3H), 1.99 (s, 3H), 1.88-1.79 (dd,J1 = 12.9 Hz, J2= 15.9 Hz, 1H). ESI-MS m/z: Calcd. for C31H36N406: 560.64. Found (M+l)+: 561.3. Example 160 (Formula Removed) To a solution of 1 46 (50 mg, 0.096 mmol) in CH2Cl2 (0.96 mL)? pyridine (1 1.7 mL, 0.144 mmol), and cinnamoyl chloride (24.0 mg, 0.144 mmol) were added at 23 °C and the reaction mixture was stirred for 18 h at that temperature. Then, the solution was diluted with CH2Cl2 (10 mL) and washed successively with 0.1 N HCI (5 mL) and a solution of 10% NaHCO3 (5 ml). The organic layer was dried over Na2SO4, filtered, and the solvent was eliminated under reduced pressure. The residue was purified by flash column chromatography (SiO2, Hex:EtOAc 1 :2) to afford 198 (54 mg, 86%) as a white solid. Rf = 0.45 Hex:EtOAc 1:1. 1H NMR (300 MHz, CDC13) δ 7.41-7.37 (m, 6H), 6.38 (s, 1H), 6.19-6.03 (m, 1H), 6.08 (d,J = 15.9 Hz, 1H), 5.93 (d,J = 1.5 Hz, 1H), 5.88 (d, J= 1.5 Hz, 1H), 5.62 (s, 1H), 5.38 (dd, J, = 1.5 Hz,J =17.1 Hz, lH),5.26(dd,J1 = 1.5Hz,J2= 10.5 Hz, I H), 4.47 (dd,J = 3.6 Hz,J = 1 0.8 Hz, 1H), 4.23-4. 11 (m, 5H), 3.89 (dd,J= 4.8 Hz,J3 = 11.1 Hz, 1H),3.51 (s, 3H), 3.34 (brd,J=8.4Hz, 1H), 3.27-3.21 (m, 2H), 2.97 (dd,7, = 7.8 Hz, J; = 17.7 Hz, 1H),2.28 (s, 3H), 2.15 (s, 3H), 2.04 (s, 3H), 1 .91 (dd, J, = 12 Hz, J2 = 15.6 Hz, 1H). I3C NMR (75 MHz, CDC13) δ 166.5, 148.8, 146.7, 144.7, 144,5, 142.7, 139.5, 134.4, 134.1, 131.1, 130.6, 129.1, 128.7, 128.2, 121.9, 121.2, 118.5, 117.8, 116.8, 112.9, 112.7, 101.5, 74.7, 65.2, 60.7, 60.6, 57.4, 56.8, 56.6, 55.7,41.9, 31.8, 26.7, 25.5, 22.9, 15.9, 14.4, 9.7. ESI-MS m/z: Calcd. for C38H39N3O7: 649.7. Found (M+l)+: 650.3. Example 161 (Formula Removed) To a solution of 161 (78.5 mg. 0.146 mmol) and the cysteine derivative (81.1 mg, 0.247 mmol) in anhydrous CH2C12 (7.3 mL), DMAP (50 mg, 0.41 mmol) and EDC.HC1 (78.1 mg. 0.41 mmol) were added at 23 oC. The reaction mixture was stirred at 23 oC under Argon atmosphere for 1.5 h. The mixture was diluted with CH2C12 (20 mL) and extracted with an aqueous saturated solution of sodium bicarbonate (25 mL). The aqueous phase was extracted with additional CH2C12 (20 mL) and the combined organic extracts were dried over Na2SO4, filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (inner diameter of the column 2 cm, height of silica 10 cm) with mixtures of ethyl acetate/hexane in a gradient manner, from 1:4 to 3:1 as eluent. Compound 199 (113 mg, 88%) was obtained as a pale yellow solid. Rf = 0.36 Hex:EtOAc 1:1. 1H NMR (300 MHz, CDCl3) δ: 7.76 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 7.8 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 6.54 (s, 1H), 5.80 (s, 1H), 5.74 (s, 1H), 5.10 (d, J = 5.7 Hz, 1H), 5.08 (d, J = 5.7 Hz, 1H), 4.50 (dd, J = 4.9 Hz, J = 11.8 Hz, 1H), 4.20-4.05 (m, 4H), 4.02 (s, 3H), 3.81 (s, 3H), 3.61 (d, J = 13.8 Hz, 1H), 3.55 (d, J= 13.8 Hz, 1H), 3.50 (s, 3H), 3.21 (m, 1H), 3.06 (m, 1H), 3.00 (d, J - 6.0 Hz, 2H), 2.90 (dd, J = 8.9 Hz, J = 17.4 Hz, 1H), 2.79 (s, 1H), 2.56 (m, 1H), 2.50 (dd, J - 4.8 Hz, J = 14.9 Hz, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.80(s,3H), 1.75(m,2H). ESI-MS m/z: Calcd. for C46H48N4010S: 848.3. Found: 849.3 (M+l)+, 871.3 (M+23)+. HPLC: Conditions: Column: Simmetry C18, Mobile phase: CH3CN/H2O in gradient from 50 to 100% in 25 minutes. 0 = 1 mL/min, t= 40 °C. Retention time: 16.04 minutes. HPLC purity in area: 89.29%. Example 162 (Formula Removed) To a solution of 161 (80 mg, 0.148 mmol) and the cysteine derivative (76 mg, 0.223 mmol) in anhydrous CH2C12 (6.8 mL), DMAP (45 mg, 0.37 mmol) and EDC.HCI (71 mg, 0.37 mmol) were added at 23 °C. The reaction mixture was stirred at 23 °C under Argon atmosphere for 2.5 h Then, the mixture was diluted with CH2Cl2 (20 mL) and extracted with an aqueous saturated solution of sodium bicarbonate (25 mL). The aqueous phase was extracted with additional CH2Cl2 (20 mL) and the combined organic extracts were dried over Na2SO4, filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (inner diameter of the column 2 cm, height of silica 10 cm) with mixtures of ethyl acetate/hexane in gradient from 1:4 to 3:1 as eluent. Compound 200 (83 mg, 65%) was obtained as a pale yellow solid. Rf=0.5Hex:EtOAcl:l. 1H NMR (300 MHz, CDC13) δ: 7.71 (m, 3H), 7.49 (d, J = 7.3 Hz, 1H), 7.36 (t, J = 7.3 Hz, 2H), 7.32- 7.23 (m, 2H), 6.65 (s, 1H), 5.80 (s, 1H), 5.79 (s, 1H), 5.13 (d, J = 6.1 Hz, 1H), 5.11 (d, J = 6.1 Hz, 1H), 5.05 (d, J = 6.1 Hz, 1H), 5.01 (d, J = 6.3 Hz, 1H), 4.76 (dd, J = 3.9 Hz, J = 11.9 Hz, 1H), 4.15- 4.03 (m, 4H), 3.96 (t, J = 4.0 Hz, 1H), 3.87 (s, 3H), 3.55 (s, 3H), 3.51 (s, 3H), 3.34-3.29 (m, 2H), 3.24 (dd, J = 5.5 Hz, J = 13.5 Hz, 1H), 3.03 (m, 1H), 2.97 (t,J = 7.5 Hz, 1H), 2.44-2.35 (m,3H), 2.29 (s,3H), 2.14 (s,3H), 1.98(dd,J =8.06,J = 15.1Hz,2H), 1.75(s, 3H). I3C NMR (75 MHz, CDC13) δ 196.98, 161.13, 158.21, 149.01, 148.78, 145.05, 144.91, 141.01, 140.69, 140.07, 137.53, 132.76, 131.15, 129.41, 127.70, 127.67, 127.21, 126.83, 125.28, 125.05, 124.94, 122.51, 119.84, 119.73, 116.61, 110.26, 104, 57, 101.40, 99.23, 96.70, 70.25, 63.15, 60.40, 58.89, 57.52, 56.98, 56.72, 56.15, 55.06, 47.22, 41.37, 38.26, 35.22,29.57,25.34,15.62,7.26. ESI-MS m/z: Calcd. for C47H49N3OnS: 863.97. Found: 865.0 (M+l)+, 887.1 (M+23)+. HPLC: Conditions: Column: Simmetry C18, Mobile phase: CH3CN/H2O in gradient from 50 to 100% in 25 minutes. 0 = 1 mL/min. t= 40 °C. Retention time: 15.36 minutes. HPLC purity in area: 91.56%. Example 163 (Formula Removed) To a solution of 161 (418 mg, 0.77 mmol) and the cysteine derivative (321 mg, 0.77 mmol) in anhydrous CH2C12 (35 ml), DMAP (235 mg? 1.92 mmol) and EDC.HCI (369 mg, 1.92 mmol) were added at 23 °C and the reaction was stirred under Argon atmosphere for 2 h. The mixture was diluted with CH2C12 (20 mL) and extracted with an aqueous saturated solution of sodium bicarbonate (25 mL). The aqueous phase was extracted with additional CH2C12 (20 mL) and the combined organic extracts were dried over Na2SO4 filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (inner diameter of the column 3 cm, height of silica 11 cm) with mixtures of ethyl acetate/hexane in a gradient manner, from 1:3 to 3:1 as eluent. Compound 201 (372 mg, 52%) was obtained as a pale yellow solid. Rf= 0.41 Hex:EtOAc 1:1. 1H-RMN (CDC13, 300 MHz) δ 7.76-7.64 (m, 4H), 7.41-7.30 (m, 4H), 6.54 (s, 1H major isomer), 6.51 (s, 1H, minor isomer), 5.69 (s, 1H, minor isomer), 5.67 (s, 1H, major isomer), 5.60 (s, 1H minor isomer), 5.51 (s, 1H major isomer), 5.08 (s, 2H), 4.26 (t, J= 5.1 Hz, 1H minor isqmer), 4.23 (t, J = 4.9 Hz,1H major isomer), 4.07-4.03 (m, 3H), 3.98- 3.88 (m, 3H), 3.84 (s, 3H), 3.71 (dt, J1 = 5.6 Hz, J3 = 10.0 Hz, 1H), 3.49 (s, 3H, major isomer), 3.49 (s, 3H, minor isomer), 3.40 (dt, J1 = 5.6 Hz, J2 = 9.5 Hz, IH), 3.18 (m, 3H). 3.11 (m. 1H). 2.91-2.82 (m, IH), 2.48-2.28 (m, 2H), 2.24 (s, 3H), 2.16 (s, 3H, major isomer), 2.14 (s. 3H. minor isomer), 2.03 (s, 3H), 1.91 (dt, J, = 8.8 Hz, J2 = 14.4 Hz, IH), 1.76 (s, 3H, minor isomer). 1.76 (s, 3H major isomer), 0.85 (s, 9H minor isomer), 0.85 (s, 9H major isomer). 0.04 and 0.01 (s, 6H both isomers). ESI-MS m/z: Calcd. for C51H61N3O,oSSi: 935.4. Found: 936.4 (M+l)+, 958.3 (M+23)+. Example 164 (Formula Removed) To a solution of 25 (2 mg, 0.0035 mmol) and an excess amount of the cysteine derivative in anhydrous CH2Cl2 (0.2mL), an excess amounts of DMAP and EDC.HCI were added at 23 °C. The reaction mixture was stirred at 23 °C under Argon atmosphere for 14 h. Then, the mixture was diluted with CH2Cl2 (10 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The aqueous phase was extracted with additional CH2C12 (10 mL). The combined organic layers were dried over Na2S04, filtered and the solvent was eliminated under reduced pressure. The crude of the reaction was purified by flash column chromatography (SiO2, Hex:EtOAc 4:1) to afford 202 as a pale yellow solid. 1H NMR (300 MHz, CDCl3) (poor resolution) 5 7.78.7,62 (m, 4H), 7.41-7.26 (m, 4H), 6.73 (s, 1H), 6.10 (m, 1H), 5.92 (d, J = 1.3 Hz, 1H), 5.88 (d, J = 1.3 Hz, 1H), 5.40-5.22 (m, 2H), 5.11 (s, 3H), 5.02 (d, J = 13.8 Hz: 1H). 4.29-4.02 (m, 6H), 3.97 (m, 1H), 3.72 (d, J = 12.5 Hz, 2H), 3.70 (s, 3H), 3.58 (s, 3H), 3.51 (d,J = 12.3 Hz, 2H), 3.50 (s, 3H). 3.49-3.20 (m. 4H), 2.54-2.28 (m, 4H), 2.40 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H). Fermentation Procedures Example A Seed medium YMP3 containing 1% glucose; 0.25% beef extract; 0.5% bacto-peptone; 0.25% Nad; 0.8% CaC03 was inoculated with 0.1% of a frozen vegetative stock of the microorganism, strain A2-2 of Pseudomonas fluorescens, and incubated on a rotary shaker (250 rpm) at 27°C. After 30 h of incubation, the seed culture was added to a agitated-vessel fermentor with a production medium composed of 2% dextrose; 4% mannitol, 2% dried brewer''''''''s yeast (Vitalevor® Biolux, Belgium}; 1% (NH4)2SO4 0.04% K2HP04; 0.8 KC1; 0.001% FeCl3; 0.1% L-Tyr; 0.8% CO3Ca; 0.05% PPG-2000; 0.2% anti-foam silicone (ASSAF-100, RHODIA UK). The sterilisation was carried out at 122°C 30 minutes. The volume inoculated was a 2% (v/v). The temperature was 27°C (0 to 16h) and 24°C from 16h to final process (41 hours). The dissolve oxygen-pressure was upper to 25%. The pH was controlled at 6.0 with diluted sulphuric acid since 28 hours till final process. The overpressure was 0.5 bar. A 1% mannitol or sorbitol was added from 16 h to final process (for two days running) and 2% for three days fermentation-process. After 41 or 64 hours, the fermentation broth must be extracted for recovery safracin B or KCN treatment in the clarified broth for recovery safracin B - cyano. Example B Obtention of safracin B cyano from the crude extract. A clarification or filtration from the fermentation broth at pH 6 removes the solids. The clarified broth was adjusted a pH 9.5 with diluted sodium hydroxide and extracted twice with 2:1 (v/v) ethyl acetate, methylene chloride or butyl acetate. The extraction was carried out into an agitated-vessel during 20'''''''', the temperature of the mixture was maintained at 8 to 10°C. The two phases were separated by a liquid-liquid centrifuge. The organic phase was dried with sodium sulphate anhydrous or frozen and then filtered for removing ice. This organic phase (ethyl acetate layer) was evaporated until obtention of an oil-crude extract. Example C Obtention of safracin B cyano from the clarified broth. A clarification or filtration from the fermentation broth at pH 6 removes the solids. The clarified broth was adjusted at pH 3.9 with concentrated acetic acid. 0.5 grams per litre of KCN are added to the clarified broth an incubated at 20°C during 1 hour with agitation. Then, the temperature was decreased at 15°C and the pH was adjusted at 9.5 with diluted sodium hydroxide and extracted with 2:1.5 (v/v) ethyl acetate. The extraction was carried out into an agitated-vessel during 20 minutes, the temperature of the mixture was maintained at 8 to 10°C. The two phases were separated by a liquid-liquid centrifuge. The organic phase was dried with sodium sulphate anhydrous. This organic phase (ethyl acetate layer) was evaporated until obtention of an oil-crude extract. This extract was purified by flash column chromatography (SiO?, gradient 20:1 to 10: to 5:1 ethyl acetate:methanol) to afford quantitatively compound 2 as a light yellow solid. Rf: 0.55 (ethyl acetate:methanol5:l); .tR= 19.9 min [HPLC, Delta Pack C4, 5um, 300 A, 150x3 mm, X=2I5 run, flow= 0.7 ml/min, temp= 50°C, grad.: CH3CN-aq. NaOAc (lOmM) 85% - 70% (20'''''''')]; 1H NMR (300 Mhz, CDC13): δ6.54 (dd, J1 = 4.4Hz, J3 =8.4 Hz, 1 H),6.44 (s, 1H), 4.12 (d, J = 2.4 Hz, 1H), 4.04 (d, J = 2.4 Hz, 1H), 4.00 (s, 3H), 3.87 (bs, 1H), 3.65 (ddd, J, = 1.5 Hz, J2 = 8.7 Hz, J3 = 9.9 Hz, 1H), 3.35 (br. D, J= 8.4 Hz, 1 H), 3.15-2.96 (m, 4H), 2.92 (q, J= 7.2 Hz, IH), 2.47 (d,y= 18.3 Hz, 1H), 2.29 (s, 3H), 2.18 (s, 3H) 1.83 (s, 3H), 1.64 (ddd, J, = 2.7 Hz, J2 = 11.1 Hz, J3 = 14.1 Hz, 1H), 0.79 (d, J= 1.2 Hz, 3H); I3C NMR (75 Mhz, CDCl3): δ 186.0 (q), 175.9 (q), 156.2 (q), 146.8(q), 142.8(q), 140.7(q), 136.6 (q), 130.5 (q), 128.8 (q), 127.0 (q), 120.5 (s), 117.4 (q), 116.5 (q), 60.8 (t), 60.4 (s), 58.7 (t), 56.2 (s), 55.7 (s); 54.8 (s), 54.8 (s), 54.4 (s), 50.0 (s), 41.6 (t), 39.8 (d), 25.2 (d), 24.4 (d), 21.2 (t), 15.5(t),8.4 (t). ESI-MS m/z: Calcd for C29H35N5O6: 549.6. Found (M+Na)+: 572.3. Example D A medium (50 1) composed of dextrose (2%), mannitol (4%), dry brewer''''''''s yeast (2%), ammonium sulphate (1%), potassium secondary phosphate (0.04%), potassium chloride (0.8%), iron (III) chloride 6-hydrate (0.001%), L-tyrosine (0.1%), calcium carbonate (0.8%), poly- (propylene glycol) 2000 (0.05%) and antifoam ASSAF 1000 (0.2%) was poured into a jar-fermentor with 75 1 total capacity and, after sterilisation, inoculated with seed culture (2%) of A2-2 strain (PERM BP-14) and aerated cultivation under agitation was carried out at 27°C to 24°C for 64 hours (aeration of 75 1 per minute and agitation from 350 to 500 rprn). The pH was controlled by automatic feeding of diluted sulphuric acid from 27 hours to final process. A 2% mannitol was added from 16 hours to final process. The cultured medium (45 1) thus obtained was, after removal of cells by centrifugation, adjusted to pH 9.5 with diluted sodium hydroxide, extracted with 25 litres of ethyl acetate twice. The mixture was carried out into an agitated-vessel at 8°C for 20 minutes. The two phases were separated by a liquid-liquid centrifuge. The organic phases were frozen at -20°C and filtered for removing ice and evaporated ice and evaporated until obtention of a 40 g oil-dark-crude extract. After introduction of the cyanide group and purification, 3.0 grams of safracin B cyano were obtained. Example E A medium (50 1) composed of dextrose (2%), mannitol (4%), dry brewer''''''''s yeast (2%), ammonium sulphate (1%), potassium secondary phosphate (0.02%, potassium chloride (0.2%), Iron (III) chloride 6-hydrate (0.001%, L-tyrosine (0.1%), calcium carbonate (0.8%, poly- (propylene glycol) 2000 (0.05%) and antifoam ASSAF 1000 (0.2%) was poured into a jar-fermentor with 75 1 total capacity and, after sterilisation, inoculated with seed culture (2%) of A2-2 strain (PERM BP-14) and aerated cultivation under agitation was carried out at 27°C to 24°C for 41 hours (aeration of 75 1 per minute and agitation from 350 to 500 rpm). The pH was controlled by automatic feeding of diluted sulphuric acid from 28 hours to final process. A 1% mannitol was added from 16 hours to final process. The cultured medium (45 1) thus obtained was, after removal of cells by centrifugation, adjusted to pH 3.9 with 200 ml of cone, acetic acid. 25 grams of potassium cyanide 97% were added and after 1 hour of agitation at 20°C, the pH was adjusted to 9.5 with 1500 ml of a solution 10% sodium hydroxide. Then, extracted with 35 litres of ethyl acetate. The mixture was carried out into an agitated -vessel at 8°C for 20 minutes. The two phases were separated by a liquid-liquid centrifuge. The organic phase was dried by sodium sulphate anhydrous and evaporated until obtention of a 60 g oil-dark-crude extract. After chromatography, 4.9 grams of safracin B cyano were obtained. REFERENCES European Patent 309,477. US Patent 5,721,362. Sakai, R., Jares-Erijman, E.A., Manzanares, I., Elipe, M.V.S.. and Rinehart. K..L. J. Am. Chem. Soc. (1996) 118, 9017-9023 Martinez, E.J., Owa, T., Schreiber, S.L. and Corey, E.J. Proc. Natl. Acad. Sci. USA. 1999, 96,3496-3501. Japanese Kokai JP-A2 59/225189. Japanese Kokai JP-A2 60/084288. Arai, T,; Kubo, A. In The Alkaloids, Chemistry and Pharmacology; Brossi, A. Ed.; Academic: New York, 1983, Vol 21; pp 56-110. Remers, W. A.: In The Chemistry ofAnriiumor Antibiotics; Vol. 2; Wiley; New York, 1988, pp 93-118. GulavitaN. K.; Scheuer, P. J.: Desilva, E. D. Abst. Indo-United States Symp. on Bioactive Compounds from Marine Organisms, Goa, India, Feb. 23-27, 1989, p 28. Arai, T; Takahashi, K; Kubo, A. J. Antibiol, 1977, JO, 1015-1018. Arai. T.; Takahashi, K.; Nakahara, S.; Kubo, A. Experientia 1980, 36, 1025-1028. Mikami, Y.; Takahashi, K; Yazawa, K.; Hour-Young, C; Arai, T.; Saito, N.; Kubo, A. J. Antibiot. 1988,47,734-740, Arai, T.; Takahashi, K.; Ishiguro, K.; Yazawa, K. J. Antibiot. 1980, 33, 951-960. Yazawa, K.; Takahashi, K.; Mikami, Y.; Arai, T.; Saito, N.; Kubo, A. J. Antibiot. 1986, 39, 1639-1650. Arai, T.; Yazawa, K.; Takahashi, K.; Maeda. A.; Mikami. Y. Antimicrob. Agent Chemother. 1985,25,5-11. Takahashi, K.; Yazawa, K.; Kishi; K.; Mikami, Y.; Arai, T.; Kubo: A. J. Antibiot. 1982. 35. 196-201. Yazawa, K.; Asaoka, T.; Takahashi, K.; Mikami, Y.; Arai, T. J. Antibiot. 1982, 35. 915-917. Frincke, ]. M.; Faulkner, D. J. J. Am. Chem. Soc. 1982, 104, 265-269. He, H. -Y.; Faulkner, D. J. J. Org. Chem. 1989, 54, 5822-5824. Kubo, A.; Saito, N.; Kitahara, Y.; Takahashi, K.; Tazawa, K.; Arai, T. Chem Pharm. Bull. 1987,35,440-442. Trowitzsch-Kienast, W.; Irschik, H.; Reichenback, H.; Wray, V.; Hofle, G. Liebigs Ann. Chem. 1988,475-481. Ikeda, Y.; Idemoto, H.; Hirayama, F.; Yamamoto, K.; Iwao, K.; Asano, T.; Munakata, T. J. Antibiot. 1983,36,1279-1283. Asaoka, T.; Yazawa, K.; Mikami, Y. Arai, T.; Takahashi, K. J. Antibiot. 1982, 35, 1708- 1710. Lown, J. W.; Hanstock, C. C.; Joshua, A. V.; Arai, T; Takahashi, K. J. Antibiot. 1983, 36, 1184-1194. Munakata et al. United States Patent 4, 400, 752, 1984. Y. Ikeda et al. The Journal of Antibiotics. VOL XXXVI, N°10, 1284, 1983. R. Cooper, S. Unger. The Journal of Antibiotics. VOL XXXVIII, N°l, 1985. Corey et al. United States Patent 5, 721, 362. 1998. Corey et al. J. Am. Chem. Soc. vol 118 pp 9202-92034,1996. Proc. Natl. Acad. Sci. USA. Vol. 96, pp 3496-3501, 1999. WE CLAIM: 1. A substituted ecteinascidin compound of the formula: wherein: R5 is OH; acetyloxy or other acyloxy group up to 4 carbon atoms; R18is-OH; and R21is-CN; characterised in that R1 is selected from the group consisting of -CH2-NHRa and -CH2-ORa, where Ra is selected from the group consisting of alkyl-CO-; haloalkyl-CO-; haloalkyl-O-CO-; arylalkenyl-CO- wherein the aryl group is selected from phenyl, biphenyl and naphthyl; heteroaryl-CO- wherein the heteroaryl contains one, two or three heteroatoms selected from nitrogen, sulphur and oxygen; alkenyl-CO-; and amino acid acyl. 2. A compound as claimed in claim 1, which is of the formula: (Formula Removed) wherein R1, R5, R18, and R21 are as defined in claim 1. 3. A compound as claimed in claim 1, which is of the formula: (Formula Removed) wherein R1, R5,and R21 are as defined in claim 1. 4. A compound as claimed in claim 2 or claim 3, wherein R1 is -CH2-NHRa. 5. A compound as claimed in claim 2 or claim 3, wherein Ra is -aa-Rb where aa is amino acid acyl and Rb is selected from the group consisting of H; alkyl-CO-; haloalkyl-CO-; haloalkyl-O-CO-; arylalkyl-CO- wherein the aryl group is selected from phenyl, biphenyl and naphthyl; arylalkenyl-CO- wherein the aryl group is selected from phenyl, biphenyl and naphthyl; heteroaryl-CO-wherein the heteroaryl contains one, two or three heteroatoms selected from nitrogen, sulphur and oxygen; alkenyl-CO-; amino acid acyl; and a protecting group. 6. A compound as claimed in claim 5, wherein said amino acid acyl is further substituted with at least one Ra group as defined in claim 1. 7. A compound as claimed in claim 5 or claim 6, wherein R1 is -CH2-NH-aa-Rb where aa is an amino acid and Rb is selected from the group consisting of hydrogen; protecting group; arylalkenyl-CO- wherein the aryl group is selected from phenyl, biphenyl and naphthyl; haloalkyl-CO-; alkyl-CO-; arylalkyl-CO- wherein the aryl group is selected from phenyl, biphenyl and naphthyl; and amino acid acyl. 8. A compound as claimed in claim 7, wherein R1 is -CH2-NH-aa-Rb where aa is alanine and Rb is selected from the group consisting of hydrogen, Boc, PhNHCS-, CF3CO-, trans(trifluoromethyl)cinnamoyl, cinnamoyl, C3F7CO- butyryl, 3- chloropropionoyl, hydrocinnamoyl, phenylacetyl, and acetyl; aa is valine and Rb is selected from the group consisting of Cbz and Boc; aa is phenylalanine and Rb is Boc; aa is proline and Rb is Boc; aa is arginine and Rb is Boc; or aa is tryptophan and Rb is Boc. 9. A compound as claimed in claim 4, wherein R1 is -CH2-NHRa where Ra is selected from the group consisting of alkyl-CO; alkenyl-CO-; arylalkenyl-CO wherein the aryl group is selected from phenyl, biphenyl and naphthyl; and heteroaryl-CO-wherein the heteroaryl contains one, two or three heteroatoms selected from nitrogen, sulphur and oxygen -. 10. A compound as claimed in claim 9, wherein R1 is -CH2-NHRa where Ra is selected from the group consisting of acetyl, isovaleryl, decanoyl, and cinnamoyl. 11. A compound as claimed in claim 9 wherein R1 is -CH2-NHRa where Ra is selected from the group consisting of propionyl, myristoyl, stearoyl, hexanoyl, crotonyl, and chloronicotinoyl. 12. A compound as claimed in any one of claims 1, 2 or 3, wherein R' is -CH2-ORa where Ra is selected from the group consisting of a protected cysteine; alkyl-CO- and arylalkenyl-CO- wherein the aryl group is selected from phenyl, biphenyl and naphthyl. 13. A compound as claimed in claim 12, wherein R1 is -CH2-ORa where Ra is selected from the group consisting of butyryl; trans(trifluoromethyl)cinnamoyl and cinnamoyl. 14. A compound as claimed in any one of claims 1, 2 or 3, wherein R5 is -OCOCH3. 15. A substituted ecteinascidin compound as claimed in claim 1 having the following general structure I: (Structure Removed) wherein Ra, R5, R18, R1, and R21 are each independently selected from the groups defined below: (Formula Removed) 16. A substituted ecteinascidin compound as claimed in claim 1 having the following general structure (II): (Formula Removed) wherein Ra, R5, R18, R1, and R21 are each independently selected from the groups defined below: (Formula Removed) 17. A compound according to claim 1 having the following general structure I. (Formula Removed) wherein Rb, R5, R1, R18 and R21 are each independently selected from the groups defined below: R1 is -CH2-NH-CO-CHCH3-NHRb (Formula Removed) 18. A compound according to claim 1 having the following general structure II: (Formula Removed) wherein Rb, R5, R1, R18 and R21 are each independently selected from the groups defined below: (Formula Removed) 19. A substituted ecteinascidin compound as claimed in claim 1 having the following general structures (III) and (IV): (Formula Removed) wherein R', X2, R1, and R6 are each independently selected from the groups defined below: (Formula Removed) 20. A substituted ecteinascidin compound as claimed in claim 1 having the following general structure V: (Formula Removed) wherein X2, R1, R6, and R are each independently selected from the groups defined (Formula Removed) below: 21. A substituted ecteinascidin compound as claimed in claim 1, wherein the compound is selected from the group consisting of: (7R,13S,14R,16R)-16-({[(2S)-2-[(tert- butoxycarbonyl)amino]propanoyl]amino}methyl)-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R,13S,14R,16R)-16-({[(2S)-2-aminopropanoyl]amino}methyl)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-({[(2S)-2-[(3- phenyl)-thioureido]propanoyl]amino}methyl)-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-[(acetylamino)methyl]-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-[(acetylamino)methyl]-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethy 1-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b)][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[({3-methylbutanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-16-[(decanoylamino)methyl]-8-hydroxy-9-methoxy- 4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13- epiminofl ,3]dioxolo[7,8Jisoquino[3,2-b]I3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[({(2E)-3-[3-(trifluoromethyl)phenyl]prop-2-enoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R,16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[(trifluoroacetyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-5-(allyloxy)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2S)-2-[(trifluoroacetyl)amino]propanamide of formula (Formula Removed) [{7R, 13S, 14R16R)-14-cyano-5,8-dihydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2S)-2-[(trifluoroacetyl)amino]propanamide of formula (Formula Removed) [(7R, 13S, 14R, 16R)-14-cyano-5,8-dihydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2S)-2-aminopropanamide of formula (Formula Removed) [(7R, 13S, 14R, 16R)-14-cyano-5,8-dihydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2S)-2-[(3-phenyl)-thioureido]propanamide of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-({[(2S)-2-[3-acetyl-3-phenyl-thioureido]propanoyl]amino}methyl)-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-1b][3]benzazocin-5-yl acetate of formula (Formula Removed) {7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[((2E)-3-phenylprop-2-enoyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-16-{[(heptafluorobutyryl)amino]methyl}-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-({[(2S)-2-(butyrylamino)propanoyl]amino}methyl)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[({(2E)-3-phenylprop-2-enoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-[({(2S)-2-[(3-chloropropanoyl)amino]propanoyl}amino)methyl]-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) {7R, 13S, 14R, 16R)-16-[(butyrylamino)methyl]-14-cyano-8-hydroxy-9-methoxy- 4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13- epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) 22. A substituted ecteinascidin compound selected from the group consisting of: (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16- [(propanoylamino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13- epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[(tetradecanoylamino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16- [(stearoylamino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13- epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-16-[(hexanoylamino)methyl]-8-hydroxy-9-methoxy- 4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13- epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-{[(2E)-but-2-enoylamino]methyl}-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-[({(2S)-2-[benzyloxycarbonylamino]-3- methylbutanoyl}amino)methyl]-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[(3-phenylpropanoyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]-dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 1 AR, 16R)-14-cyano-16-({[(2S)-2-(hexanoylamino)propanoyl]amino}methyl)-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[(phenylacetyl)amino]propanoyl}amino)methyl]-6,7,12,13-14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-({[(2S)-2-(propanoylamino)propanoyl]amino}methyl)-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-[({(2S)-2-[(2E)-but-2-enoylamino]propanoyl}amino)methyl]-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-5-(allyloxy)-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl butyrate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-5-(allyloxy)-14-cyano-9-methoxy-8-methoxymethoxy-4-10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-[3-(trifluoromethyl)phenyl]acrylate of formula (Formula Removed) [(7R, 13S, 14R,16R)-5-(allyloxy)-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-14-cyano-5-hydroxy-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-1b][3]benzazocin-16-yl]methyl butyrate of formula (Formula Removed) [{7R, 13S, 14R, 16R)-14-cyano-5-hydroxy-9-methoxy-8-methoxymethoxy-4-10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-6][3]benzazocin-16-yl]methyl (2£)-3-[3-(trifluoromethyl)phenyl]acrylate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-14-cyano-5-hydroxy-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-5-(acetyloxy)-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl butyrate of formula (Formula Removed) [(7R, 13S, 14R 16R)-5-(acetyloxy)-14-cyano-9-methoxy-8-methoxymethoxy-4-10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-[3-(trifluoromethyl)phenyl]acrylate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-5-(acetyloxy)-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) [(7R, 13S.14R,16R)-5-(acetyloxy)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl butyrate of formula (Formula Removed) [(7R,13S,14R,16R)-5-(acetyloxy)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-1b][3]benzazocin-16-yl]methyl (2E)-3-[3-(trifluoromethyl)phenyl]acrylate of formula (Formula Removed) [(7R, 13S,14R, 16R)-5-(acetyloxy)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) Allyl (7R, 13S, 14R, 16R)-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-16-[({(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl carbonate of formula Allyl (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-aminopropanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl carbonate of formula (Formula Removed) Allyl (7R, 13S, 14R,16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-({[(2S)-2-[(3-phenyl)-thioureido]propanoyl]amino}methyl)-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl carbonate of formula (Formula Removed) Allyl (7R, 13S, 14R, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-({[(2E)-3-phenylprop-2-enoyl]amino}methyl)-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-1b][3]benzazocin-5-yl carbonate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-14-cyano-5,8-dihydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylprop-2-enamide of formula (Formula Removed) [(6S,7R,9R, 15R)-7-cyano-1 -hydroxy-2,11 -dimethoxy-3,12,16-trimethyl-10,13-dioxo-5,6,7,9,10,13,14,15-octahydro-14aH-6,15-epiminoisoquino[3,2-b][3]benzazocin-9-yl]methyl (2S)-2-(acetylamino)propanamide of formula (Formula Removed) [(6S,7R,9R,15R)-7-cyano-1-hydroxy-2,11-dimethoxy-3,12,16-trimethyl-10,13-dioxo-5,6,7,9,10,13,14,15-octahydro-14aH-6,15-epiminoisoquino[3,2-1b][3]benzazocin-9-yl]methyl (2S)-2-[(trifluoroacetyl)amino]propanamide of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-({[(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl]amino}methyl)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-({[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino}methyl)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-({[(2S)-[(1 -tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl]amino}methyl)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 1 4R, 16R-16-({[(2S)-2-[(tert-butoxycarbonyl)amino]-5-guanidinopentanoyl]amino}methyl)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-({[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1 H-indol-3-yl)propanoyl]amino}methyl)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2- b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S.14R,16R)-16-({[(2-chloropyridin-3-yl)carbonyl]amino}methyl)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-16-{[(cyclohexylacetyl)amino]methyl}-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) [{7R, 13S, 14R, 16R)-5-(acetyloxy)-14-cyano-16-{[(cyclohexylacetyl)amino]methyl}-9- methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13- epimino[1,3]dioxolo[7,8]isoquino[3,2-6][3]benzazocin-8-yl] 2-cyclohexylacetate of formula (Formula Removed) (7R, 13S, 14R, 16R)-14-cyano-16-{[(3-cyclohexylpropanoyl)amino]methyl}-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-5-(acetyloxy)-14-cyano-16-{[(3- cyclohexylpropanoyl)amino]methyl}-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-8-yl] 3-cyclohexylpropanoate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-5-(acetyloxy)-14-cyano-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[(3-phenylpropanoyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-8-yl] butanoate of formula (Formula Removed) [{7R, 13S, 14R,16R)-5-(acetyloxy)-14-cyano-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[(3-phenylpropanoyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-8-yl] hexanoate of formula [{7R, 13S, 14R, 16R)-5-(acetyloxy)-14-cyano-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[(trifluoroacetyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-8-yl] butanoate of formula (Formula Removed) (7R, 13S, 14R, 16R)-8-(acetyloxy)-14-cyano-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[N-acetyl-N-trifluoroacetylamino]propanoyl}-N-acetylamino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) [(7R,13S,14R,16R)-5-(acetyloxy)-16-[({(2S)-2-[N-butanoyl-N- trifluoroacetylamino]propanoyl}-A/-butanoylamino)methyl]-14-cyano-9-methoxy- 4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13- epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-8-yl] butanoate of formula (Formula Removed) [(7R, 13S.14R,16R)-5-(acetyloxy)-14-cyano-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[(trifluoroacetyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-i>][3]benzazocin-8-yl] hexanoate of formula (Formula Removed) [{7R, 13S, 14R, 16R)-5-(acetyloxy)-14-cyano-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[(trifluoroacetyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-8-yl] decanoate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-5-(acetyloxy)-14-cyano-9-methoxy-4,10,17-trimethyl-16-[({(2S)-2-[(trifluoroacetyl)amino]propanoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-8-yl] stearoate of formula (Formula Removed) (7R, 13S, 14R, 16R)-16-{[allylamino]methyl}-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-6][3]benzazocin-5-yl acetate of formula (Formula Removed) [{7R, 13S, 1 AR, 16R)-5-(allyloxy)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) [(7R, 13S, 14R, 16R)-5-(allyloxy)-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2Z)-2-methoxymethoxy-3-(9-fluorenylmethylthio)prop-2-enoate (Formula Removed) 23. A compound as claimed in claim 1 which is (7R, 13S, 1 AR, 16R)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-16-[({(2E)-3-[3-(trifluoromethyl)phenyl]prop-2-enoyl}amino)methyl]-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-5-yl acetate of formula (Formula Removed) 24. A compound as claimed in claim 22 which is [{7R, 13S, 14R, 16R)-5-(allyloxy)-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) 25. A compound as claimed in claim 22 , which is [(7R, 13S, 14R, 16R)-14-cyano-5-hydroxy-9-methoxy-8-methoxymethoxy-4-10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-[3-(trifluoromethyl)phenyl]acrylate of formula (Formula Removed) 26. A compound as claimed in claim 22 , which is [(7R, 13S.14R.16R)-14-cyano-5-hydroxy-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) 27. A compound as claimed in claim 22 , which is [(7R, 13S, 14R, 16R)-5-(acetyloxy)-14-cyano-9-methoxy-8-methoxymethoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) 28. A compound as claimed in claim 22 , which is [(7R13S, 1AR, 16R)-5-(acetyloxy)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) 29. A compound as claimed in claim 22 which is [(7R, 13S, 14R, 16ft)-5-(allyloxy)-14-cyano-8-hydroxy-9-methoxy-4,10,17-trimethyl-6,7,12,13,14,16-hexahydro-6aH-7,13-epimino[1,3]dioxolo[7,8]isoquino[3,2-b][3]benzazocin-16-yl]methyl (2E)-3-phenylacrylate of formula (Formula Removed) 30. A compound of the formula: (Formula Removed) wherein: R5 is -OR", where R" is selected from the group consisting of H; alkyl-CO-; cycloaikyl-CO-; and haloalkyl-CO-; R18 is -OR, where R is selected from the group consisting of H, alkyl-CO-; cycloalkylalkyl-CO-; and (Formula Removed) R21 is-CN; characterised in that R1 is -CH2-ORa, where Ra is selected from the group consisting of alkyl-CO-; haloalkyl-CO-; cycloalkylalkyl-CO-; haloalkyl-O-CO-; arylalkenyl-CO- wherein the aryl group is selected from phenyl, biphenyl and naphthyl; heteroaryl-CO- where the heteroaryl contains one, two or three heteroatoms selected from nitrogen, sulphur and oxygen; alkenyl-CO-; alkenyl; and amino acid acyl. 31. A compound as claimed in claim 30, which is of the formula: (Formula Removed) wherein R1, R5, R18, and R21 are as defined in claim 30. 32. A compound as claimed in claim 30, which is of the formula: (Formula Removed) wherein R1, R5, R18, and R21 are as defined in claim 30. 33. A compound as claimed in claim 30, 31 or 32, wherein R1 is -CH2-ORa where Ra is selected from the group consisting of a protected cysteine; alkyl-CO-; arylalkenyl-CO- wherein the aryl group is selected from phenyl, biphenyl and naphthyl; a cysteine derivative of the formula ProtSH-S-CH2-C(=NOProtOH)-CO- where ProtSH is a protecting group for thiol and ProtOH is a protecting group hydroxy; and a cysteine derivative of formula ProtSH-S-CH=C(-OProtOH)-CO-, where ProtSH is a protecting group for thiol and ProtOH is a protecting group for hydroxy. 34. A compound as claimed in claim 33, wherein R1 is -CH2-ORa where Ra is selected from the group consisting of S-Fm-O-TBDMS-cysteine; butyryl; (trifluoromethyl)cinnamoyl; cinnamoyl; a cysteine derivative of the formula ProtSH-S- CH2-C(=NOProtOH)-CO- where ProtSH is Fm and ProtOH is methoxy; and a cysteine derivative of formula ProtSH-S-CH=C(-OProtOH)-CO-, where ProtSH is Fm and ProtOH is MOM. 35. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 34. 36. A compound as claimed in any of claims 1 to 34 for the preparation of a pharmaceutical composition for use in the treatment of a tumor.

Documents:

6180-DELNP-2007-Abstract-(21-03-2012).pdf

6180-delnp-2007-abstract.pdf

6180-delnp-2007-Claims (07-2-2008).pdf

6180-DELNP-2007-Claims-(21-03-2012).pdf

6180-delnp-2007-claims.pdf

6180-DELNP-2007-Correspondence Others-(01-11-2011).pdf

6180-DELNP-2007-Correspondence Others-(21-03-2012).pdf

6180-delnp-2007-correspondence-others.pdf

6180-delnp-2007-description (complete).pdf

6180-DELNP-2007-Form-1-(01-11-2011).pdf

6180-DELNP-2007-Form-1-(21-03-2012).pdf

6180-delnp-2007-form-1.pdf

6180-DELNP-2007-Form-2-(21-03-2012).pdf

6180-delnp-2007-form-2.pdf

6180-DELNP-2007-Form-3-(21-03-2012).pdf

6180-delnp-2007-form-3.pdf

6180-delnp-2007-form-5.pdf

6180-DELNP-2007-GPA-(21-03-2012).pdf

6180-DELNP-2007-Petition-137-(21-03-2012)-1.pdf

6180-DELNP-2007-Petition-137-(21-03-2012).pdf

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