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[]D22 +7.0 (0.1, MeOH); 1H NMR (300 MHz, CDCl3) 2.12 (ddd, = 3.6, 8.2, 13.5 Hz, 1H), 3.47-3.61 (m, 2H), 3.51 (s, overlapped, 3H), Bifenazate 3.87 (ddd, = 3.0, 5.1, 8.1 Hz, 1H), 4.10 (dd, = 6.9, 8.2 Hz, 1H), 4.49 (d, = 12.1 Hz, 1H), 4.54 (d, = 12.1 Hz, 1H), 4.57, (d, = 11.5 Hz, 1H), 4.65 d, =11.5 Hz, 1H), 4.75 (ddd, = 3.0, 3.7, 8.4 Hz, 1H), 7.21-7.40 (m, 10H); 13C NMR (75.5 MHz, CDCl3) 29.7, 58.3, 68.8, 73.7, 75.6, 78.1, 78.2, 127.8, 128.1, 128.2, 128.2, 128.6, 137.7, 175.0. the monobenzyl ethers 10a-d in 70-92% yield over two actions. Employing a Mitsunobu-like protocol with PPh3, DIAD, and DPPA in dry THF provided azides 11a-d in 57-99% yield. Finally, an oxidative removal of the different phenols were used in step c, opening of the lactone was performed with amines M-P and the final peptide coupling step was only performed in the synthesis of final products 16, 18, 19, 24, and 25 (see the experimental section). Attempts to co-crystallize inhibitor 15 with BACE-1 were performed, but these were not successful. Structure activity relationships The target compounds are summarized in Table ?11. They were synthesized from compounds 12a-d according to Scheme ?33 using appropriate R substituentsshown in Fig. (?22). Enzyme activities were measured against BACE-1, and the IC50 values are presented in Table ?11. In addition, percent inhibition in a cell-based assay was decided at the concentration 1 M for the four most potent inhibitors (compounds 25, 27, 28, and 30). Table 1 Target compounds and inhibition data. Open in a separate window Open in a separate window Initially, groups around the P1 substituent, as observed for targets 22 and 23 (IC50 values 10 M) lacking the and the = 9.0 Hz, 2H), 7.10 (d, = 9.0 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): 11.7, 15.3, 25.3, 40.0, 47.6, 55.1, 114.2, 121.9, 129.1, 147.5. Synthetic Procedures 5-Benzyloxy-2-bromo-phenol (1)A mixture of 3-benzyloxyphenol (C) (122 mg, 0.609 mmol) in dry DCM (4 mL) was cooled to -15 C and NBS (109 mg, 0.609 mmol) was added. The solution was stirred at -10 C for 40 min and for an additional 20 min at room temperature. Concentration and flash column chromatography (DCM/hexanes 7:3) gave 1 (121 mg, 71%) as a colorless oil. []D22 -10 (c 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 4.97 (s, 2H), 5.53 (bs, 1H), 6.41 (dd, = 2.7, 8.8 Hz, 1H), 6.65 (d, = 2.8 Hz, 1H), 7.28 (d, = 8.8 Hz, 1H), 7.31-7.41 (m, 5H); 13C NMR (75.5 MHz, CDCl3) 70.3, 101.3, 102.8, 109.3, 127.5, 128.2, 128.7, 132.1, 136.5, 153.0, 159.7. MS (M+H)+ calcd: 279.0; found: 279.1. 4-Benzyloxy-1-bromo-2-(3-methoxy-propoxy)-benzene (2)To a cooled (0 C) solution of 1 1 (680 mg, 2.44 mmol), 3-methoxy-1-propanol (467 L, 4.87 mmol) and PPh3 (1.28 g, 4.88 mmol) in dry THF (60 mL) DIAD (960 L, 4.88 mmol) was added. The mixture was then allowed to attain room temperature overnight. Concentration and flash column chromatography (toluene) provided 2 (770 mg, 90%) as a colorless oil. []D22 -16 (0.1, MeOH); 1H NMR (300 MHz, CDCl3) 2.02-2.12 (m, 2H), 3.35 (s, 3H), 3.59 (t, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 1.88-1.99 (m, 2H), 3.27 (s, 3H), 3.41 t, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 1.89-1.99 (m, 2H), 3.27 (s, 3H), 3.42 (t, = 6.2 Hz, 2H), 4.02 (t, = 6.2 Hz, 2H), 5.02 (s, 2H), 6.49-6.59 (m, 3H), 7.11-7.19 (m, 2H), 7.29-7.45 (m, 4H); 13C NMR (75.5 MHz, CDCl3) 29.7, 58.8, 65.0, 69.4, 70.1, 102.0, 107.2, 107.3, 127.6, 128.0, 128.7, 130.0, 137.2, 160.2, 160.4. 4′-Fluoro-biphenyl-4-ol (H)Compound H was synthesized in 96% yield (colorless solid) from 4-bromophenol according to the preparation method for 3. 1H NMR (300 MHz, CD3OD) 4.92 (bs, 1H), 6.84 (d, = 8.8 Hz, 2H), 7.03 (app. t, = 8.8 Hz, 2H), 7.44 (dd, 0.1, MeOH); 1H NMR.(?22). in dry THF provided azides 11a-d in 57-99% yield. Finally, an oxidative removal of the different phenols were used in step c, opening of the lactone was performed with amines M-P and the final peptide coupling step was only performed in the synthesis of final products 16, 18, 19, 24, and 25 (see the experimental section). Attempts to co-crystallize inhibitor 15 with BACE-1 were performed, but these were not successful. Structure activity relationships The target compounds are summarized in Table ?11. They were synthesized from compounds 12a-d according to Scheme ?33 using appropriate R substituentsshown in Fig. (?22). Enzyme activities were measured against BACE-1, and the IC50 values are presented in Table ?11. In addition, percent inhibition in a cell-based assay was determined at the concentration 1 M for the four most potent inhibitors (compounds 25, 27, 28, and 30). Table 1 Target compounds and inhibition data. Open in a separate window Open in a separate window Initially, groups on the P1 substituent, as observed for targets 22 and 23 (IC50 values 10 M) lacking the and the = 9.0 Hz, 2H), 7.10 (d, = 9.0 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): 11.7, 15.3, 25.3, 40.0, 47.6, 55.1, 114.2, 121.9, 129.1, 147.5. Synthetic Procedures 5-Benzyloxy-2-bromo-phenol (1)A mixture of 3-benzyloxyphenol (C) (122 mg, 0.609 mmol) in dry DCM (4 mL) was cooled to -15 C and NBS (109 mg, 0.609 mmol) was added. The solution was stirred at -10 C for 40 min and for an additional 20 min at room temperature. Concentration and flash column chromatography (DCM/hexanes 7:3) gave 1 (121 mg, 71%) as a colorless oil. []D22 -10 (c 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 4.97 (s, 2H), 5.53 (bs, 1H), 6.41 (dd, = 2.7, 8.8 Hz, 1H), 6.65 (d, = 2.8 Hz, 1H), 7.28 (d, = 8.8 Hz, 1H), 7.31-7.41 (m, 5H); 13C NMR (75.5 MHz, CDCl3) 70.3, 101.3, 102.8, 109.3, 127.5, 128.2, 128.7, 132.1, 136.5, 153.0, 159.7. MS (M+H)+ calcd: 279.0; found: 279.1. 4-Benzyloxy-1-bromo-2-(3-methoxy-propoxy)-benzene (2)To a cooled (0 C) solution of 1 1 (680 Bifenazate mg, 2.44 mmol), 3-methoxy-1-propanol (467 L, 4.87 mmol) and PPh3 (1.28 g, 4.88 mmol) in dry THF (60 mL) DIAD (960 L, 4.88 mmol) was added. The mixture was then allowed to attain room temperature overnight. Concentration and flash column chromatography (toluene) provided 2 (770 mg, 90%) as a colorless oil. []D22 -16 (0.1, MeOH); 1H NMR (300 MHz, CDCl3) 2.02-2.12 (m, 2H), 3.35 (s, 3H), 3.59 (t, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 1.88-1.99 (m, 2H), 3.27 (s, 3H), 3.41 t, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 1.89-1.99 (m, 2H), 3.27 (s, 3H), 3.42 (t, = 6.2 Hz, 2H), 4.02 (t, = 6.2 Hz, 2H), 5.02 (s, 2H), 6.49-6.59 (m, 3H), 7.11-7.19 (m, 2H), 7.29-7.45 (m, 4H); 13C NMR (75.5 MHz, CDCl3) 29.7, 58.8, 65.0, 69.4, 70.1, 102.0, 107.2, 107.3, 127.6, 128.0, 128.7, 130.0, 137.2, 160.2, 160.4. 4′-Fluoro-biphenyl-4-ol (H)Compound H was synthesized in 96% yield (colorless solid) from 4-bromophenol according to the preparation method for 3. 1H NMR (300 MHz, CD3OD) 4.92 (bs, 1H), 6.84 (d, = 8.8 Hz, 2H), 7.03 (app. t, = 8.8 Hz, 2H), 7.44 (dd, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 2.03-2.20 (m, 2H), 3.35 (s, 3H), 3.37 (s, 3H), 3.63-3.73 (m, 2H), 3.79-3.88 (m, 2H), 4.36-4.46 (m, 1H), 4.59 (d, = 12.1 Hz, 1H), 4.64 (d, = 12.1 Hz, 1H), 4.69 (d, = 11.5 Hz, 1H), 4.84 (d, = 11.5 Hz, 1H), 4.92 (s, 1H), 7.26-7.44 (m, 10H); 13C NMR (75.5 MHz, CDCl3) 32.1, 54.7, 56.8, 71.1, 73.0, 73.4, 79.1, 81.4, 85.0, 107.1, 127.5, 127.5, 127.6, 127.8, 128.3, 128.4, 138.5, 138.8. 5,6-Di-O-benzyl-3-deoxy-2-O-methyl-D-glucofuranoside (7a)Compound 6 (2.31 g, 6.20 mmol) was dissolved in dioxane (65 mL) and 0.5 M H2SO4 (58 mL) was added. The solution was refluxed overnight and neutralized with saturated aqueous NaHCO3. The dioxane was evaporated and the residue was dissolved in DCM. Washing with H2O, drying, filtration, concentration and flash column chromatography (toluene/EtOAc 15:1 toluene/EtOAc 6:1) gave 7a (1.89 g, 85%) as a lightly yellowish oil. []D22 -19 (0.1, MeOH); 1H NMR (300 MHz, CDCl3) 1.86-2.02 (m, 1H), 2.05-2.20 (m, 1H), 3.34 (s, 3H), 3.40 (s, 1H), 3.58 (d, = 5.2 Hz,.Chem. 57-99% yield. Finally, an oxidative removal of the different phenols were used in step c, opening of the lactone was performed with amines M-P and the final peptide coupling step was only performed in the synthesis of final products 16, 18, 19, 24, and 25 (see the experimental section). Attempts to co-crystallize inhibitor 15 with BACE-1 were performed, but these were not successful. Structure activity relationships The target compounds are summarized in Table ?11. They were synthesized from compounds 12a-d according to Scheme ?33 using appropriate R substituentsshown in Fig. (?22). Enzyme activities were measured against BACE-1, and the IC50 values are presented in Table ?11. In addition, percent inhibition in a cell-based assay was determined at the concentration 1 M for the four most potent inhibitors (compounds 25, 27, 28, and 30). Table 1 Target compounds and inhibition data. Open in a separate window Open in a separate window Initially, groups on the P1 substituent, as observed for targets 22 and 23 (IC50 values 10 M) lacking the and the = 9.0 Hz, 2H), 7.10 (d, = 9.0 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): 11.7, 15.3, 25.3, 40.0, 47.6, 55.1, 114.2, 121.9, 129.1, 147.5. Synthetic Procedures 5-Benzyloxy-2-bromo-phenol (1)A mixture of 3-benzyloxyphenol (C) (122 mg, 0.609 mmol) in dry DCM (4 mL) was cooled to -15 C and NBS (109 mg, 0.609 mmol) was added. The solution was stirred at -10 C for 40 min and for an additional 20 min at room temperature. Concentration and flash column chromatography (DCM/hexanes 7:3) gave 1 (121 mg, 71%) as a colorless oil. []D22 -10 (c 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 4.97 (s, 2H), 5.53 (bs, 1H), 6.41 (dd, = 2.7, 8.8 Hz, 1H), 6.65 (d, = 2.8 Hz, 1H), 7.28 (d, = 8.8 Hz, 1H), 7.31-7.41 (m, 5H); 13C NMR (75.5 MHz, CDCl3) 70.3, 101.3, 102.8, 109.3, 127.5, 128.2, 128.7, 132.1, 136.5, 153.0, 159.7. MS (M+H)+ calcd: 279.0; found: 279.1. 4-Benzyloxy-1-bromo-2-(3-methoxy-propoxy)-benzene (2)To a cooled (0 C) solution of 1 1 (680 mg, 2.44 mmol), 3-methoxy-1-propanol (467 L, 4.87 mmol) and PPh3 (1.28 g, 4.88 mmol) in dry THF (60 mL) DIAD (960 L, 4.88 mmol) was added. The mixture was then allowed to attain room temperature overnight. Concentration and flash column chromatography (toluene) provided 2 (770 mg, 90%) as a colorless oil. []D22 -16 (0.1, MeOH); 1H NMR (300 MHz, CDCl3) 2.02-2.12 (m, 2H), 3.35 (s, 3H), 3.59 (t, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 1.88-1.99 (m, 2H), 3.27 (s, 3H), 3.41 t, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 1.89-1.99 (m, 2H), 3.27 (s, 3H), 3.42 (t, = 6.2 Hz, 2H), 4.02 (t, = 6.2 Hz, 2H), 5.02 (s, 2H), 6.49-6.59 (m, 3H), 7.11-7.19 (m, 2H), 7.29-7.45 (m, 4H); 13C NMR (75.5 MHz, CDCl3) 29.7, 58.8, 65.0, 69.4, 70.1, 102.0, 107.2, 107.3, 127.6, 128.0, 128.7, 130.0, 137.2, 160.2, 160.4. 4′-Fluoro-biphenyl-4-ol (H)Compound H was synthesized in 96% yield (colorless solid) from 4-bromophenol according to the preparation method for 3. 1H NMR (300 MHz, CD3OD) 4.92 (bs, 1H), UGP2 6.84 (d, = 8.8 Hz, 2H), 7.03 (app. t, = 8.8 Hz, 2H), 7.44.Inhibitors were identified displaying IC50 values in the nanomolar range, 69 nM for the most potent compound. followed by treatment with tetrabutylammonium bromide and 4-methoxybenzyl bromide to furnish the monobenzyl ethers 10a-d in 70-92% yield over two steps. Employing a Mitsunobu-like protocol with PPh3, DIAD, and DPPA in dry THF provided azides 11a-d in 57-99% yield. Finally, an oxidative removal of the different phenols were used in step c, opening of the lactone was performed with amines M-P and the final peptide coupling step was only performed in the synthesis of final products 16, 18, 19, 24, and 25 (see the experimental section). Attempts to co-crystallize inhibitor 15 with BACE-1 were performed, but these were not successful. Structure activity relationships The target compounds are summarized in Table ?11. They were synthesized from compounds 12a-d according to Scheme ?33 using appropriate R substituentsshown in Fig. (?22). Enzyme activities were measured against BACE-1, and the IC50 values are presented in Table ?11. In addition, percent inhibition in a cell-based assay was determined at the concentration 1 M for the four most potent inhibitors (compounds 25, 27, 28, and 30). Table 1 Target compounds and inhibition data. Open in a separate window Open in a separate window Initially, groups on the P1 substituent, as observed for targets 22 and 23 (IC50 values 10 M) lacking the and the = 9.0 Hz, 2H), 7.10 (d, = 9.0 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): 11.7, 15.3, 25.3, 40.0, 47.6, 55.1, 114.2, 121.9, 129.1, 147.5. Synthetic Procedures 5-Benzyloxy-2-bromo-phenol (1)A mixture of 3-benzyloxyphenol (C) (122 mg, 0.609 mmol) in dry DCM (4 mL) was cooled to -15 C and NBS (109 mg, 0.609 mmol) was added. The solution was stirred at -10 C for 40 min and for an additional 20 min at room temperature. Concentration and flash column chromatography (DCM/hexanes 7:3) gave 1 (121 mg, 71%) as a colorless oil. []D22 -10 (c 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 4.97 (s, 2H), 5.53 (bs, 1H), 6.41 (dd, = 2.7, 8.8 Hz, 1H), 6.65 (d, = 2.8 Hz, 1H), 7.28 (d, = 8.8 Hz, 1H), 7.31-7.41 (m, 5H); 13C NMR (75.5 MHz, CDCl3) 70.3, 101.3, 102.8, 109.3, 127.5, 128.2, 128.7, 132.1, 136.5, 153.0, 159.7. MS (M+H)+ calcd: 279.0; found: 279.1. 4-Benzyloxy-1-bromo-2-(3-methoxy-propoxy)-benzene (2)To a cooled (0 C) solution of 1 1 (680 mg, 2.44 mmol), 3-methoxy-1-propanol (467 L, 4.87 mmol) and PPh3 (1.28 g, 4.88 mmol) in dry THF (60 mL) DIAD (960 L, 4.88 mmol) was added. The mixture was then allowed to attain room temperature overnight. Concentration and flash column chromatography (toluene) provided 2 (770 mg, 90%) as a colorless oil. []D22 -16 (0.1, MeOH); 1H NMR (300 MHz, CDCl3) 2.02-2.12 (m, 2H), Bifenazate 3.35 (s, 3H), 3.59 (t, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 1.88-1.99 (m, 2H), 3.27 (s, 3H), 3.41 t, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 1.89-1.99 (m, 2H), 3.27 (s, 3H), 3.42 (t, = 6.2 Hz, 2H), 4.02 (t, = 6.2 Hz, 2H), 5.02 (s, 2H), 6.49-6.59 (m, 3H), 7.11-7.19 (m, 2H), 7.29-7.45 (m, 4H); 13C NMR (75.5 MHz, CDCl3) 29.7, 58.8, 65.0, 69.4, 70.1, 102.0, 107.2, 107.3, 127.6, 128.0, 128.7, 130.0, 137.2, 160.2, 160.4. 4′-Fluoro-biphenyl-4-ol (H)Compound H was synthesized in 96% yield (colorless solid) from 4-bromophenol according to the preparation method for 3. 1H NMR (300 MHz, CD3OD) 4.92 (bs, 1H), 6.84 (d, = 8.8 Hz, 2H), 7.03 (app. t, = 8.8 Hz, 2H), 7.44 (dd, 0.1, MeOH); 1H NMR (300 MHz, CDCl3) 2.03-2.20 (m, 2H), 3.35 (s, 3H), 3.37 (s, 3H), 3.63-3.73 (m, 2H), 3.79-3.88 (m, 2H), 4.36-4.46 (m, 1H), 4.59 (d, = 12.1 Hz, 1H), 4.64 (d, = 12.1 Hz, 1H), 4.69 (d, = 11.5 Hz, 1H), 4.84 (d, = 11.5 Hz, 1H), 4.92 (s, 1H), 7.26-7.44 (m, 10H); 13C NMR (75.5 MHz, CDCl3) 32.1, 54.7, 56.8, 71.1, 73.0, 73.4, 79.1, 81.4, 85.0, 107.1, 127.5, 127.5, 127.6, 127.8, 128.3, 128.4, 138.5, 138.8. 5,6-Di-O-benzyl-3-deoxy-2-O-methyl-D-glucofuranoside.