C-glucoside derivative containing fused phenyl ring or pharmaceutically acceptable salt thereof, process for preparing same, and pharmaceutical composition comprising same

Abstract

The present disclosure relates to C-glycoside derivatives having a fused phenyl ring or pharmaceutical acceptable salts thereof, a method for preparing the same, a pharmaceutical composition comprising the same, a use thereof and a method for dual inhibition of SGLT1 and SGLT2 using the same. A novel compound of the present disclosure has a dual inhibitory activity against SGLT1 and SGLT2, thus being valuably used as a diabetes therapeutic agent.

Claims

1. A compound represented by Formula 1 or pharmaceutically acceptable salts thereof: ##STR00140## wherein, X and Y are each independently CH.sub.2 or O; m is 1 or 2; R.sub.1 is halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.1-C.sub.4 alkoxy (wherein at least one hydrogen of the said C.sub.1-C.sub.4 alkyl may be each independently unsubstituted or substituted with halogen); R.sub.2 and R.sub.3 are each independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.4 alkoxy, OCF.sub.3, SR.sub.5, phenyl, biphenyl, terphenyl, naphthyl, anthracene, fluorene or pyrenyl (wherein at least one hydrogen of the said C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl and C.sub.3-C.sub.7 cycloalkyl may be each independently unsubstituted or substituted with halogen, and at least one hydrogen of the said phenyl, biphenyl, terphenyl, naphthyl, anthracene, fluorene or pyrenyl may be each independently unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 alkoxy); and R.sub.5 is C.sub.1-C.sub.4 alkyl.

2. The compound represented by the Formula 1 or the pharmaceutically acceptable salts thereof, according to claim 1, wherein X is CH.sub.2; Y is CH.sub.2 or O; m is 1 or 2; R.sub.1 is halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.1-C.sub.4 alkoxy (wherein the said C.sub.1-C.sub.4 alkyl is unsubstituted); R.sub.2 and R.sub.3 are each independently halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, OCF.sub.3, SR.sub.5 or phenyl (wherein at least one hydrogen of the said C.sub.1-C.sub.4 alkyl may be unsubstituted or substituted with halogen, and hydrogen of the said C.sub.2-C.sub.4 alkenyl and phenyl are unsubstituted); and R.sub.5 is C.sub.1-C.sub.4 alkyl.

3. The compound represented by the Formula 1 or the pharmaceutically acceptable salts thereof, according to claim 1, wherein such compound is selected from the group consisting of the following compounds: (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-isopropoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-propylbenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-isopropylbenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-vinylbenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-trifluoromethyl)benzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-trifluoromethoxy)benzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(3,4-dimethoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(2,4-dimethoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-methylthio)benzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-fluorobenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-fluoro-3-methylbenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-chlorobenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-(4-methoxybenzyl)-1-methyl-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1-methyl-4-(4-methylbenzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1-methyl-4-(4-trifluoromethyl)benzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1-methyl-4-(4-trifluoromethoxy)benzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1-methyl-4-(4-(methylthio)benzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-(4-chlorobenzyl)-1-methyl-5,6,7,8-tetrahydronaphthalene-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)-4-methyl-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-methyl-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-(methylthio)benzyl)-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-methyl-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-vinylbenzyl)-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-chloro-7-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-(4-methoxybenzyl)-7-methyl-2,3-dihydrobenzofuran-6-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-methyl-4-(4-vinylbenzyl)-2,3-dihydrobenzofuran-6-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(8-methoxy-5-(4-methoxybenzyl)chroman-7-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(8-methoxy-5-(4-methylbenzyl)chroman-7-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(5-(4-ethoxybenzyl)-8-methylchroman-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-methoxybenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-ethylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-chlorobenzyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-trifluoromethoxy)benzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-trifluoromethyl)benzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-isopropoxybenzyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-isopropylbenzyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(biphenyl-3-ylmethyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methylbenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-fluorobenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-butyl-7-(4-methoxybenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-butyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-butyl-7-(4-ethoxybenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-butyl-7-(4-ethylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-isopropyl-7-(4-methoxybenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-isopropyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-cyclopentyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-isobutyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol; and (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-isobutyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

4. A method for preparing the compound represented by the Formula 1 or the pharmaceutically acceptable salts thereof, wherein the method comprises following steps: (S1) reacting a compound of a following Formula II with a compound of a following Formula III to obtain a compound of a following Formula IV; and (S2) performing deprotection-reduction or reduction-deprotection for the compound of the Formula IV above to obtain a compound of a following Formula I: ##STR00141## wherein, X, Y, m, R.sub.1, R.sub.2 and R.sub.3 are as defined claim 1, and P is trimethylsilyl or benzyl.

5. The method according to claim 4, wherein, if P is trimethylsilyl, a compound of a following Formula V is obtained by deprotecting the compound of the Formula IV, and the compound of the Formula I is obtained by reducing the compound of the Formula V: ##STR00142## wherein, X and Y are each independently CH.sub.2 or O, m is 1 or 2; R.sub.1 is halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.1-C.sub.4 alkoxy (wherein at least one hydrogen of the said C.sub.1-C.sub.4 alkyl may be each independently unsubstituted or substituted with halogen); R.sub.2 and R.sub.3 are each independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.4 alkoxy, OCF.sub.3, SR.sub.5, phenyl, biphenyl, terphenyl, naphthyl, anthracene, fluorene or pyrenyl (wherein at least one hydrogen of the said C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl and C.sub.3-C.sub.7 cycloalkyl may be each independently unsubstituted or substituted with halogen, and at least one hydrogen of the said phenyl, biphenyl, terphenyl, naphthyl, anthracene, fluorene or pyrenyl may be each independently unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 alkoxy); and R.sub.5 is C.sub.1-C.sub.4 alkyl.

6. The method according to claim 4, wherein, if P is benzyl, a compound of a following Formula VI is obtained by reducing the compound of the Formula IV, and the compound of the Formula I is obtained by deprotecting the compound of the Formula VI: ##STR00143## wherein, X and Y are each independently CH.sub.2 or O, m is 1 or 2; R.sub.1 is halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.1-C.sub.4 alkoxy (wherein at least one hydrogen of the said C.sub.1-C.sub.4 alkyl may be each independently unsubstituted or substituted with halogen); R.sub.2 and R.sub.3 are each independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.4 alkoxy, OCF.sub.3, SR.sub.5, phenyl, biphenyl, terphenyl, naphthyl, anthracene, fluorene or pyrenyl (wherein at least one hydrogen of the said C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl and C.sub.3-C.sub.7 cycloalkyl may be each independently unsubstituted or substituted with halogen, and at least one hydrogen of the said phenyl, biphenyl, terphenyl, naphthyl, anthracene, fluorene or pyrenyl may be each independently unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 alkoxy); and R.sub.5 is C.sub.1-C.sub.4 alkyl.

7. A method for treating an SGLT activity-related disease in a patient, comprising, administering to the patient the compound of the Formula 1 described in claim 1 or the pharmaceutically acceptable salts thereof as an active component.

8. The method for treating an SGLT activity-related disease, according to claim 7, wherein the compound of Formula 1 or the pharmaceutically acceptable salts thereof inhibits SGLT1, SGLT2 or both thereof.

9. The method for treating an SGLT activity-related disease, according to claim 7, wherein the SGLT activity-related disease is diabetes.

Description

MODE FOR INVENTION

(1) Hereinafter, the configurations and effects of the present disclosure will be described in more detail through Examples. However, the following Examples are provided only for the purpose of illustrating the present disclosure, and thus the scope of the present disclosure is not limited thereto.

Example 1. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of ethyl 7-methyl-2,3-dihydro-1H-indene-4-carboxylate (1-1)

(2) ##STR00008##

(3) A mixture of ethyl sorbate (25.0 mL, 170 mmol, TCI reagent) in xylene (100 mL) and 1-pyrrolidino-1-cyclopentene (24.8 mL, 170 mmol, TCI agent) was stirred at reflux overnight. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. EtOAc was added into a resulting mixture. An organic layer was washed with brine, after which a resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A crude compound was used in a following step without an additional purification. S.sub.8 (5.45 g, 170 mmol) was added into the crude compound. A reaction mixture was stirred at 250 C. for 2 hours. After a reaction was completed, the resulting mixture was distilled under reduced pressure, so as to obtain the title compound (1-1) (20.0 g, 97.9 mmol, 58%).

(4) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.76 (d, J=7.6 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 3.30 (t, J=7.6 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.30 (s, 3H), 2.12-2.05 (m, 2H), 1.38 (t, J=7.2 Hz, 3H)

Step 2. Synthesis of ethyl 6-bromo-7-methyl-2,3-dihydro-1H-indene-4-carboxylate (1-2)

(5) ##STR00009##

(6) Br.sub.2 (6.0 mL, 117 mmol) and AgNO.sub.3 (16.6 g, 97.9 mmol) in water (20 mL) were added dropwise into a mixture of the compound (1-1) (20.0 g, 97.9 mmol) in AcOH (100 mL) and a concentrated HNO.sub.3 (4.4 mL) at room temperature. A resulting mixture was stirred overnight at room temperature. A reaction was completed with saturated Na.sub.2S.sub.2O.sub.3 solution, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (1-2) (22.1 g, 78.0 mmol, 80%).

(7) .sup.1H NMR (400 MHz, CDCl.sub.3); 8.02 (s, 1H), 4.34 (q, J=7.2 Hz, 2H), 3.25 (t, J=7.6 Hz, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.37 (s, 3H), 2.11-2.07 (m, 2H), 1.39 (t, J=7.2 Hz, 3H).

Step 3. Synthesis of 6-bromo-7-methyl-2,3-dihydro-1H-indene-4-carboxylic acid (1-3)

(8) ##STR00010##

(9) LiOH.H.sub.2O (9.82 g, 234 mmol) was added into a solution of the compound (1-2) (22.1 g, 78.0 mmol) in THF/MeOH/water (120 mL/40 mL/40 mL) at room temperature. A reaction mixture was stirred overnight at room temperature. After a reaction was completed, a volatile substance was removed under reduced pressure. A 1NHCl aqueous solution was added into a residue to carry out acidification, during which a resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water and dried under high vacuum, so as to obtain the title compound (1-3) (15.4 g, 60.4 mmol, 77%).

(10) .sup.1H NMR (400 MHz, CDCl.sub.3); 8.08 (s, 1H), 3.28 (t, J=7.6 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 2.13-2.09 (m, 2H).

Step 4. Synthesis of (6-bromo-7-methyl-2,3-dihydro-1H-indene-4-yl)(4-methoxyphenyl)methanone (1-4)

(11) ##STR00011##

(12) DMF (0.12 mL) and (COCl).sub.2 (2.46 mL, 29.0 mmol) were added dropwise into a solution of 6-bromo-7-methyl-2,3-dihydro-1H-indene-4-carboxylic acid (1-3) (4.94 g, 19.3 mmol) in DCM (45 mL) at 0 C. in a nitrogen atmosphere. A resulting solution was stirred overnight at room temperature, after which a resulting mixture was concentrated under vacuum, so as to obtain a crude oxychloride. 4-methoxybenzene (2.52 mL, 23.2 mmol) and AlCl.sub.3 (3.09 g, 23.2 mmol) were fractionally added into a crude oxychloride solution in DCM (45 mL) at 0 C. A resulting mixture was heated up to room temperature and stirred for 2 hours at room temperature. A resulting mixture was poured onto ice water, so as to perform an extraction with EtOAc. An organic layer was washed with brine, after which a resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (1-4) (4.84 g, 14.02 mmol, 73%).

(13) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.78 (d, J=8.8 Hz, 2H), 7.49 (s, 1H), 6.95 (d, J=8.8 Hz, 2H), 3.89 (s, 3H), 2.97-2.91 (m, 4H), 2.39 (s, 3H), 2.11-2.03 (m, 2H)

Step 5. Synthesis of 5-bromo-7-(4-methoxybenzyl)-4-methyl-2,3-dihydro-1H-indene (1-5)

(14) ##STR00012##
Triethylsilane (4.61 mL, 28.0 mmol) and BF.sub.3.OEt.sub.2 (3.55 mL, 28.0 mmol) were added dropwise into a solution of the compound (1-4) (4.84 g, 14.0 mmol) in DCM/acetonitrile (20 mL/20 mL) at 0 C. in a nitrogen atmosphere. A resulting mixture was slowly heated up to room temperature and stirred overnight at room temperature. A saturated NaHCO.sub.3 aqueous solution was slowly added into the resulting mixture, so as to perform an extraction with EtOAc. An organic layer was washed with brine, after which a resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (1-5) (4.21 g, 12.7 mmol, 91%).

(15) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.12 (s, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 3.80 (s, 2H), 3.78 (s, 3H), 2.87 (t, J=7.4 Hz, 2H), 2.75 (t, J=7.6 Hz, 2H), 2.29 (s, 3H), 2.08-2.00 (m, 2H)

Step 6. Synthesis of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(7-(4-methoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran (1-6)

(16) ##STR00013##
n-BuLi (12.4 mL, 30.9 mmol, 2.5 M in n-hexane) was added into a solution of the compound (1-5) (6.82 g, 20.6 mmol) in toluene/THF (70 mL/70 mL) at 78 C. in a nitrogen atmosphere. In 30 minutes later, perbenzylated gluconolactone (14.4 g, 26.8 mmol) in toluene (70 mL) was added into a resulting mixture at 78 C. The resulting mixture was stirred at the same temperature for 2 hours. A reaction was completed with water, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum, such that a crude intermediate was obtained and used without an additional purification. Triethylsilane (10.1 mL, 61.8 mmol) and BF.sub.3.OEt.sub.2 (7.83 mL, 61.8 mmol) were added into an intermediate solution in DCM/acetonitrile (100 mL/100 mL) at 78 C. in a nitrogen atmosphere. A resulting mixture was heated up to 60 C. for 1 hour. A saturated NaHCO.sub.3 solution was slowly added into the resulting mixture, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (1-6) (8.78 g, 11.32 mmol, 55%).

(17) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.32-7.11 (m, 19H), 7.02 (d, J=8.8 Hz, 2H), 6.87 (d, J=6.4 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 4.96-4.87 (m, 3H), 4.68-4.63 (m, 2H), 4.54-4.49 (m, 2H), 4.35 (d, J=10.4 Hz, 1H), 3.86-3.75 (m, 7H), 3.72 (s, 3H), 3.67-3.57 (m, 2H), 2.85-2.77 (m, 4H), 2.24 (s, 3H), 2.08-2.01 (m, 2H)

Step 7. Synthesis of a Target Compound

(18) ##STR00014##

(19) A suspension of the compound (1-6) (152 mg, 0.20 mmol) in THF (3 mL) and MeOH (3 mL) as well as Pd/C (20% wt %, 30 mg) was stirred at room temperature in a hydrogen atmosphere for 16 hours. A reaction mixture was filtered with a celite pad, and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the target compound (79 mg, 0.19 mmol, 95%).

(20) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.11 (s, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 4.45 (d, J=9.2 Hz, 1H), 3.88-3.84 (m, 3H), 3.74 (s, 3H), 3.68-3.64 (m, 1H), 3.56 (t, J=8.8 Hz, 1H), 3.52-3.47 (m, 1H), 3.40-3.38 (m, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.28 (s, 3H), 2.01-1.98 (m, 2H)

Examples 2 and 3

(21) Target compounds of Examples 2 and 3 were obtained by means of a method as shown in Example 1.

Example 2. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(22) ##STR00015##

(23) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.10 (s, 1H), 7.03 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.45 (d, J=8.8 Hz, 1H), 3.97 (q, J=6.8 Hz, 2H), 3.88-3.84 (m, 3H), 3.67-3.48 (m, 4H), 3.40-3.38 (m, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.28 (s, 3H), 2.02-1.97 (m, 2H), 1.35 (t, J=6.8 Hz, 3H)

Example 3. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-isopropoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(24) ##STR00016##

(25) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.11 (s, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.54-4.48 (m, 1H), 4.45 (d, J=9.2 Hz, 1H), 3.84-3.88 (m, 3H), 3.66 (dd, J=11.6, 5.2 Hz, 1H), 3.59-3.48 (m, 2H), 3.41-3.38 (m, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.74 (t, J=7.4 Hz, 2H), 2.28 (s, 3H), 2.04-1.96 (m, 2H), 1.27 (d, J=6.0 Hz, 6H)

Example 4. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of (6-bromo-7-methyl-2,3-dihydro-1H-indene-4-yl)methanol (4-1)

(26) ##STR00017##

(27) A BH.sub.3.SMe.sub.2 complex (13.7 mL, 137.2 mmol, 10.0 M in methylsulfide) was slowly added into a solution of 6-bromo-7-methyl-2,3-dihydro-1H-indene-4-carboxylic acid (1-3) (3.50 g, 13.7 mmol) in THF (50 mL) at 0 C. in a nitrogen atmosphere, after which a reaction mixture was stirred overnight at room temperature. The resulting reaction mixture was cooled at 0 C., after which a saturated NaHCO.sub.3 aqueous solution was slowly added into the resulting mixture, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.04, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (4-1) (2.33 g, 9.66 mmol, 70%).

(28) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.39 (s, 1H), 4.60 (d, J=6.0 Hz, 2H), 2.91-2.86 (m, 4H), 2.32 (s, 3H), 2.14-2.07 (m, 2H), 1.48 (t, J=5.8 Hz, 1H)

Step 2. Synthesis of 5-bromo-7-(bromomethyl)-4-methyl-2,3-dihydro-1H-indene (4-2)

(29) ##STR00018##

(30) PBr.sub.3 (1.38 mL, 14.5 mmol) was added dropwise into a solution of the compound (4-1) (2.33 g, 9.66 mmol) in toluene (45 mL) at 0 C. in a nitrogen atmosphere. A resulting mixture was slowly heated up to room temperature and stirred for 2 hours at room temperature. A saturated NaHCO.sub.3 aqueous solution was slowly added into the resulting mixture, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (4-2) (2.14 g, 7.04 mmol, 73%).

(31) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.35 (s, 1H), 4.40 (s, 2H), 2.95-2.88 (m, 4H), 2.31 (s, 3H), 2.18-2.10 (m, 2H)

Step 3. Synthesis of 5-bromo-4-methyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene (4-3)

(32) ##STR00019##

(33) The compound (4-2) (150 mg, 0.49 mmol), 4-methylphenylboronic acid (81 mg, 0.59 mmol) and K.sub.2CO.sub.3 (136 mg, 0.99 mmol) were dissolved in acetone/water (3 mL/1 mL), after which Pd.sub.2 (dba).sub.3 (90 mg, 0.10 mmol) was added into a resulting mixture. The resulting mixture was stirred at room temperature for 4 hours. A resulting reaction mixture was filtered with celite, and distributed between EtOAc and water. A water layer was extracted with EtOAc, after which a combined organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (4-3) (130 mg, 0.41 mmol, 84%).

(34) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.14 (s, 1H), 7.08 (d, J=7.6 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 3.82 (s, 2H), 2.87 (t, J=7.4 Hz, 2H), 2.75 (d, J=7.6 Hz, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.08-2.02 (m, 2H)

Step 4. Synthesis of a Target Compound

(35) ##STR00020##

(36) n-BuLi (0.25 mL, 0.62 mmol, 2.5 M in n-hexane) was added into a solution of the compound (4-3) (130 mg, 0.41 mmol) in toluene/THF (3 mL/1.5 mL) at 78 C. in a nitrogen atmosphere. In 30 minutes later, TMS-protected gluconolactone (231 mg, 0.49 mmol) in toluene (3 mL) was added into a resulting mixture at 78 C. The resulting mixture was stirred at the same temperature for 2 hours. Methane sulfonic acid (0.2 mL) and MeOH (1.6 mL) were added into the reaction mixture at the same temperature. The reaction mixture was stirred at 78 C. for 2 hours. A reaction was completed with a saturated NaHCO.sub.3 solution, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum, so as to obtain a crude intermediate, which was used without an additional purification. Triethylsilane (0.14 mL, 0.82 mmol) and BF.sub.3.OEt.sub.2 (0.11 mL, 0.82 mmol) were added into an intermediate solution in DCM/acetonitrile (2 mL/2 mL) at 78 C. in a nitrogen atmosphere. A resulting mixture was heated up to 50 C. for 1 hour. A saturated NaHCO.sub.3 solution was slowly added into the resulting mixture, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified with Prep. HPLC, so as to obtain a target compound (5.6 mg, 0.014 mmol, 3.4%).

(37) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.11 (s, 1H), 7.04-6.99 (m, 4H), 4.45 (d, J=9.2 Hz, 1H), 3.88-3.86 (m, 3H), 3.66 (dd, J=11.6, 5.6 Hz, 1H), 3.59-3.48 (m, 2H), 3.40-3.35 (m, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.04-1.96 (m, 2H)

Examples 5 to 16

(38) Target compounds of Examples 5 to 16 were obtained by means of a method as shown in Example 4.

Example 5. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(39) ##STR00021##

(40) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.12 (s, 1H), 7.06-7.02 (m, 4H), 4.45 (d, J=9.2 Hz, 1H), 3.88-3.86 (m, 3H), 3.68-3.48 (m, 3H), 3.40-3.39 (m, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.58 (q, J=7.6 Hz, 2H), 2.29 (s, 3H), 2.01-1.98 (m, 2H), 1.19 (t, J=8.0 Hz, 3H)

Example 6. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-propylbenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(41) ##STR00022##

(42) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.11 (s, 1H), 7.03 (s, 4H), 4.45 (d, J=9.2 Hz, 1H), 3.88-3.86 (m, 3H), 3.66 (dd, J=11.6, 5.6 Hz, 1H), 3.59-3.48 (m, 2H), 3.41-3.39 (m, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.74 (d, J=7.6 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 2.29 (s, 3H), 2.04-1.96 (m, 2H), 1.65-1.55 (m, 2H), 0.91 (t, J=7.2 Hz, 3H)

Example 7. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-isopropylbenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(43) ##STR00023##

(44) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.12-7.03 (m, 5H), 4.45 (d, J=9.2 Hz, 1H), 3.88-3.86 (m, 3H), 3.66 (dd, J=12.0, 5.6 Hz, 1H), 3.57 (t, J=9.2 Hz, 1H), 3.52-3.48 (m, 1H), 3.41-3.39 (m, 2H), 2.87-2.81 (m, 3H), 2.74 (t, J=7.2 Hz, 2H), 2.29 (s, 3H), 2.04-1.98 (m, 2H), 1.21 (d, J=7.2 Hz, 6H)

Example 8. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-vinylbenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(45) ##STR00024##

(46) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.33 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 7.03 (s, 1H), 6.66 (dd, J=17.6, 11.2 Hz, 1H), 5.73 (d, J=18.0 Hz, 1H), 5.17 (d, J=10.0 Hz, 1H), 4.95-4.92 (m, 2H), 4.69 (d, J=4.0 Hz, 1H), 4.38-4.37 (m, 1H), 4.22 (d, J=8.4 Hz, 1H), 3.83 (s, 2H), 3.70-3.65 (m, 1H), 3.30-3.16 (m, 1H), 2.76 (t, J=7.2 Hz, 2H), 2.71-2.66 (m, 2H), 2.17 (s, 3H), 1.94-1.90 (m, 2H)

Example 9. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-trifluoromethyl)benzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(47) ##STR00025##

(48) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.45 (d, J=8.0 Hz. 2H), 7.26 (d, J=8.4 Hz. 2H), 7.08 (s, 1H), 4.39 (d, J=8.8 Hz, 1H), 3.94 (s, 2H), 3.80 (d, J=11.2 Hz, 1H), 3.59 (dd, J=12.0, 5.2 Hz, 1H), 3.51-3.41 (m, 2H), 3.34-3.32 (m, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.22 (s, 3H), 1.95-1.92 (m, 2H)

Example 10. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-trifluoromethoxy)benzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-tiol

(49) ##STR00026##

(50) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.22 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 7.12 (d, J=8.4 Hz, 2H), 4.46 (d, J=9.2 Hz, 1H), 3.94 (s, 2H), 3.87 (d, J=12.4 Hz, 1H), 3.68-3.62 (m, 1H), 3.55-3.46 (m, 2H), 3.40-3.39 (m, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.72 (d, J=7.6 Hz, 2H), 2.29 (s, 3H), 2.02-1.99 (in. 2H)

Example 11. Preparation of (2S,3R,4R,5S,6R)-2-(7-(3,4-dimethoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(51) ##STR00027##

(52) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.12 (s, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.76 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 4.45 (d, J=8.8 Hz, 1H), 3.88-3.85 (m, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 3.66 (dd, J=12.0, 5.2 Hz, 1H), 3.59-3.48 (m, 2H), 3.41-3.39 (m, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.76 (t, J=7.4 Hz, 2H), 2.29 (s, 3H), 2.05-1.97 (m, 2H)

Example 12. Preparation of (2S,3R,4R,5S,6R)-2-(7-(2,4-dimethoxybenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(53) ##STR00028##

(54) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.17 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.4, 2.4 Hz, 1H), 4.54 (d, J=8.8 Hz, 1H), 3.97 (d, J=12.0 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 2H), 3.86 (s, 3H), 3.75 (dd, J=12.0, 5.6 Hz, 1H), 3.67-3.57 (m, 2H), 3.50-3.45 (m, 2H), 2.96 (t, J=7.6 Hz, 2H), 2.87 (t, J=7.6 Hz, 2H), 2.39 (s, 3H), 2.16-2.10 (m, 2H)

Example 13. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-methylthio)benzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(55) ##STR00029##

(56) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.14 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J=8.0 Hz, 2H), 4.46 (d, J=9.2 Hz, 1H), 3.87-3.86 (m, 3H), 3.67 (dd, J=11.6, 5.2 Hz, 1H), 3.59-3.48 (m, 2H), 3.41-3.39 (m, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.42 (s, 3H), 2.29 (s, 3H), 2.04-1.96 (m, 2H)

Example 14. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-fluorobenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(57) ##STR00030##

(58) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.24-7.21 (m, 3H), 7.05-7.00 (m, 2H), 4.54 (d, J=9.2 Hz, 1H), 3.99 (s, 2H), 3.96 (d, J=12.0 Hz, 1H), 3.79-3.73 (m, 1H), 3.65-3.59 (m, 2H), 3.49-3.48 (m, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.81 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 2.11-2.07 (m, 2H)

Example 15. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-fluoro-3-methylbenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(59) ##STR00031##

(60) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.12 (s, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.96-6.93 (m, 1H), 6.88-6.84 (m, 1H), 4.47 (d, J=9.2 Hz, 1H), 3.90-3.86 (m, 3H), 3.68-3.64 (m, 1H), 3.61-3.49 (m, 2H), 3.42-3.40 (m, 2H), 2.86 (t, J=7.2 Hz, 2H), 2.73 (t, J=7.2 Hz, 2H), 2.30 (s, 3H), 2.19 (s, 3H), 2.03-1.99 (m, 2H)

Example 16. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-chlorobenzyl)-4-methyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(61) ##STR00032##

(62) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.21 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 7.11 (s, 1H), 4.46 (d, J=8.8 Hz, 1H), 3.90-3.86 (m, 3H), 3.67 (dd, J=11.6, 5.2 Hz, 1H), 3.58-3.48 (m, 2H), 3.39-3.43 (m, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 2.29 (s, 3H), 2.04-1.97 (m, 2H)

Example 17. Preparation of (2S,3R,4R,5S,6R)-2-(8-(4-ethoxybenzyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 5-bromo-2,3-dihydro benzoic acid (17-1)

(63) ##STR00033##

(64) Br.sub.2 (3.32 mL, 64.9 mmol) was added dropwise into 2,3-dihydrobenzoic acid (10.0 g, 64.9 mmol, Aldrich reagent) in AcOH (120 mL), after which a resulting mixture was stirred at room temperature for 12 hours. A reaction was completed with a saturated Na.sub.2S.sub.2O.sub.3 aqueous solution, after which a resulting mixture was dried under reduced pressure, so as to remove a volatile substance. A resulting residue was distributed between EtOAc and water. A water layer was extracted with EtOAc, after which a combined organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. The title compound (17-1) (14.1 g, 60.3 mmol, 93%) was used in a following step without an additional purification.

(65) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.47 (s, 1H), 7.37 (s, 1H)

Step 2. Synthesis of methyl 5-bromo-2,3-dihydro benzoate (17-2)

(66) ##STR00034##

(67) SOCl.sub.2 (13.1 mL, 180.9 mmol) was added dropwise into a solution of the compound (17-1) (14.1 g, 60.3 mmol) in MeOH (200 mL) at 0 C. in a nitrogen atmosphere. A resulting mixture was stirred at reflux overnight. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (17-2) (12.5 g, 50.6 mmol, 84%).

(68) .sup.1H NMR (400 MHz, CDCl.sub.3); 10.85 (s, 1H), 7.51 (s, 1H), 7.23 (s, 1H), 5.69 (s, 1H), 3.96 (s, 3H)

Step 3. Synthesis of methyl 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylate (17-3)

(69) ##STR00035##

(70) 1,2-dibromoethane (8.2 mL, 94.9 mmol) was added dropwise into a mixture of the compound (17-2) (15.6 g, 63.3 mmol) in DMF (200 mL) as well as K.sub.2CO.sub.3 (26.2 g, 95.0 mmol). A reaction mixture was heated at 100 C. overnight, after which a reaction thereof was completed with water. A water layer was extracted with EtOAc, after which a combined organic layer was washed with brine, such that the resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (17-3) (11.0 g, 40.4 mmol, 64%).

(71) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.52 (d, J=2.4 Hz, 1H), 7.16 (d, J=2.8 Hz, 1H), 4.37-4.28 (m, 4H), 3.88 (s, 3H).

Step 4. Synthesis of 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid (17-4)

(72) ##STR00036##

(73) A 1NNaOH aqueous solution (30.7 mL) was added into the compound (17-3) (5.0 g, 15.4 mmol) in THF/MeOH (20 mL/40 mL) at room temperature. A reaction mixture was stirred overnight at room temperature. After a reaction was completed, a volatile substance was removed under reduced pressure. A 1NHCl aqueous solution was added into a residue to carry out acidification, during which a resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water and dried under high vacuum, so as to obtain the title compound (17-4) (3.4 g, 13.0 mmol, 85%).

(74) .sup.1H NMR (400 MHz, CDCl.sub.3); 8.00 (s, 1H), 7.83 (s, 1H), 4.52-4.50 (m, 4H)

Step 5. Synthesis of 7-bromo-5-(4-ethoxybenzyl)-2,3-dihydrobenzo[b][1,4]dioxin (17-5)

(75) ##STR00037##

(76) The title compound (17-5) was obtained with the compound (17-4) by means of a method as shown from Steps 4 to 5 of Example 1.

(77) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.09 (d, J=8.8 Hz, 2H), 6.88 (d, J=2.4 Hz, 1H), 6.81 (d, J=8.8 Hz, 2H), 6.73 (d, J=2.4 Hz, 1H), 4.26-4.22 (m, 4H), 4.01 (q, J=7.2 Hz, 2H), 3.81 (s, 2H), 1.40 (t, J=6.8 Hz, 3H)

Step 6. Synthesis of a Target Compound

(78) ##STR00038##

(79) The target compound was obtained with the compound (17-5) by means of a method as shown from Steps 6 to 7 of Example 1.

(80) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.10 (d, J=8.4 Hz, 2H), 6.78-6.74 (m, 4H), 4.21 (dd, J=10.0, 4.8 Hz, 4H), 4.00-3.95 (m, 3H), 3.87-3.78 (m, 3H), 3.66 (dd, J=12.0, 5.6 Hz, 1H), 3.44-3.29 (m, 4H), 1.35 (t, J=6.8 Hz, 3H)

Example 18. Preparation of (2S,3R,4R,5S,6R)-2-(8-(4-ethylbenzyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 7-bromo-5-(4-ethylbenzyl)-2,3-dihydrobenzo[b][1,4]dioxin (18-1)

(81) ##STR00039##

(82) The title compound (18-1) was obtained with the compound (17-4) obtained in Step 4 of Example 17 by means of a method as shown from Steps 1 to 3 of Example 4.

(83) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.13-7.10 (m, 4H), 6.88 (d, J=2.0 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 4.28-4.22 (m, 4H), 3.85 (s, 2H), 2.62 (q, J=7.6 Hz, 2H), 1.22 (t, J=7.6 Hz, 3H)

Step 2. Synthesis of a Target Compound

(84) ##STR00040##

(85) The target compound was obtained with the compound (18-1) by means of a method as shown in Step 4 of Example 4.

(86) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.10 (d, J=7.6 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 6.78 (d, J=2.0 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 4.24-4.20 (m, 4H), 3.96 (d, J=9.2 Hz, 1H), 3.91-3.81 (m, 4H), 3.66 (dd, J=12.0, 5.6 Hz, 1H), 3.42-3.32 (m, 3H), 2.58 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H)

Example 19. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)benzo[d][1,3]dioxol-5-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of methyl 6-bromobenzo[d][1,3]dioxol-4-carboxylate (19-1)

(87) ##STR00041##

(88) Dibromomethane (3.2 mL, 45.3 mmol) was added dropwise into a mixture of the compound (17-2) (7.5 g, 30.2 mmol) obtained in Step 2 of Example 17 in DMF (100 mL) as well as K.sub.2CO.sub.3 (12.5 g, 95.0 mmol). A reaction mixture was heated at 100 C. overnight, after which a reaction thereof was completed with water. A water layer was extracted with EtOAc, after which a combined organic layer was washed with brine, such that the resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (19-1) (7.6 g, 29.3 mmol, 97%).

(89) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.55 (d, J=2.0 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 6.12 (s, 2H), 3.92 (s, 3H)

Step 2. Synthesis of 6-bromobenzo[d][1,3]dioxol-4-carboxylic acid (19-2)

(90) ##STR00042##

(91) A 1NNaOH aqueous solution (58.7 mL) was added into the compound (19-1) (7.6 g, 29.3 mmol) in THF/MeOH (40 mL/80 mL) at room temperature. A reaction mixture was stirred at room temperature for 4 hours. After a reaction was completed, a volatile substance was removed under reduced pressure. A 1NHCl aqueous solution was added into a residue to carry out acidification, during which a resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water and dried under high vacuum, so as to obtain the title compound (19-2) (7.2 g, 29.3 mmol, 99%).

(92) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.59 (d, J=2.0 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 6.16 (s, 2H).

Step 3. Synthesis of 6-bromo-4-(4-methoxybenzyl)benzo[d][1,3]dioxol (19-3)

(93) ##STR00043##

(94) The title compound (19-3) was obtained with the compound (19-2) by means of a method as shown from Steps 4 to 5 of Example 1.

(95) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.13 (d, J=8.8 Hz, 2H), 6.85-6.81 (m, 3H), 6.75 (s, 1H), 5.96 (s, 2H), 3.81 (s, 2H), 3.79 (s, 3H)

Step 4. Synthesis of a Target Compound

(96) ##STR00044##

(97) The target compound was obtained with the compound (19-3) by means of a method as shown in Step 4 of Example 4.

(98) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.14 (d, J=8.4 Hz, 2H), 6.81-6.79 (m, 3H), 6.73 (s, 1H), 5.92 (s, 2H), 4.00 (d, J=9.2 Hz, 1H), 3.87-3.82 (m, 4H), 3.75 (s, 3H), 3.69-3.64 (m, 1H), 3.42-3.32 (m, 3H)

Example 20. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-(methylthio)benzyl)benzo[d][1,3]dioxol-5-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 6-bromo-4-(4-methylthio)benzyl)benzo[d][1,3]dioxol (20-1)

(99) ##STR00045##

(100) The title compound (20-1) was obtained with the compound (19-2) obtained in Step 2 of Example 18 by means of a method as shown from Steps 1 to 3 of Example 4.

(101) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.20 (d, J=8.0 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 6.83 (s, 1H), 6.76 (s, 1H), 5.97 (s, 2H), 3.83 (s, 2H), 2.47 (s, 3H)

Step 2. Synthesis of a Target Compound

(102) ##STR00046##

(103) The target compound was obtained with the compound (20-1) by means of a method as shown in Step 4 of Example 4.

(104) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.16 (s, 4H), 6.80 (s, 1H), 6.75 (s, 1H), 5.93 (s, 2H), 4.00 (d, J=9.2 Hz, 1H), 3.86-3.84 (m, 3H), 3.69-3.64 (m, 1H), 3.43-3.28 (m, 4H), 2.43 (s, 3H)

Example 21. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)benzo[d][1,3]dioxol-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(105) ##STR00047##

(106) The target compound was obtained by means of a method as shown in Example 20.

(107) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.13 (d, J=8.0 Hz, 2H), 7.07 (d, J=7.6 Hz, 2H), 6.79 (s, 1H), 6.75 (s, 1H), 5.92 (s, 2H), 4.00 (d, J=9.2 Hz, 1H), 3.90-3.81 (m, 3H), 3.67 (dd, J=12.0, 5.6 Hz, 1H), 3.45-3.29 (m, 4H), 2.58 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H)

Example 22. Preparation of (2S,3R,4R,5S,6R)-2-(4-(4-ethoxybenzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of methyl 5,6,7,8-tetrahydronaphthalene-1-carboxylate (22-1)

(108) ##STR00048##

(109) SOCl.sub.2 (4.1 mL, 56.7 mmol) was added dropwise into a solution of 5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (2.0 g, 11.3 mmol, TCI reagent) in MeOH (30 mL) at 0 C. in a nitrogen atmosphere. A resulting mixture was stirred at reflux overnight. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (22-1) (1.98 g, 10.4 mmol, 92%).

(110) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.64 (d, J=7.6 Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 3.87 (s, 3H), 3.06-3.03 (m, 2H), 2.83-2.79 (m, 2H), 1.80-1.77 (m, 4H)

Step 2. Synthesis of methyl 3-bromo-5,6,7,8-tetrahydronaphthalene-1-carboxylate (22-2)

(111) ##STR00049##

(112) A concentrated HNO.sub.3 (0.4 mL, 8.91 mmole) and Br.sub.2 (3.32 mL, 64.9 mmol) were added dropwise into a solution mixed with the compound (22-1) (1.13 g, 5.94 mmol) in AcOH (10 mL) as well as AgNO.sub.3 (1.51 g, 8.91 mmol) in water (5 mL), after which a resulting mixture was stirred at room temperature for 12 hours. A reaction was completed with a saturated Na.sub.2S.sub.2O.sub.3 aqueous solution, after which a resulting mixture was dried under reduced pressure to remove a volatile substance. A resulting residue was distributed between EtOAc and water. A water layer was extracted with EtOAc, after which a combined organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (22-2) (1.41 g, 5.24 mmol, 88%).

(113) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.78 (d, J=1.6 Hz, 1H), 7.36 (s, 1H), 3.87 (s, 3H), 2.99-2.96 (m, 2H), 2.81-2.77 (m, 2H), 1.81-1.74 (m, 4H)

Step 3. Synthesis of 3-bromo-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (22-3)

(114) LiOH.H.sub.2O (0.67 g, 15.7 mmol) was added into the compound (22-2) (1.41 g, 5.24 mmol) in THF/MeOH/water (15 mL/5 mL/5 mL) at room temperature. A reaction mixture was stirred overnight at room temperature. After a reaction was completed, a volatile substance was removed under reduced pressure. A 1NHCl aqueous solution was added into a residue to carry out acidification, during which a resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water and dried under high vacuum, so as to obtain the title compound (22-3) (1.31 g, 5.14 mmol, 98%).

(115) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.72 (s, 1H), 7.39 (s, 1H), 3.06-3.01 (m, 2H), 2.86-2.80 (m, 2H), 1.83-1.74 (m, 4H)

Step 4. Synthesis of 7-bromo-5-(4-ethoxybenzyl)-1,2,3,4-tetrahydronaphthalene (22-4)

(116) ##STR00050##

(117) The title compound (22-4) was obtained with the compound (22-3) by means of a method as shown from Steps 4 to 5 of Example 1.

(118) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.12 (s, 1H), 7.03-6.98 (m, 3H), 6.81 (d, J=8.8 Hz, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.82 (t, J=5.6 Hz, 2H), 2.74 (t, J=5.6 Hz, 2H), 2.53 (t, J=6.0 Hz, 2H), 1.73-1.70 (m, 4H), 1.40 (t, J=7.2 Hz, 3H)

Step 5. Synthesis of a Target Compound

(119) ##STR00051##

(120) The target compound was obtained with the compound (22-4) by means of a method as shown from Steps 6 to 7 of Example 1.

(121) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.02-6.99 (m, 4H), 6.77 (d, J=8.4 Hz, 2H), 4.04 (d, J=9.6 Hz, 1H), 3.97 (q, J=6.8 Hz, 2H), 3.89-3.87 (m, 3H), 3.69 (dd, J=12.0, 5.2 Hz, 1H), 3.46-3.36 (m, 4H), 2.78-2.76 (m, 2H), 2.56-2.54 (m, 2H), 1.73-1.34 (m, 4H), 1.35 (t, J=6.8 Hz, 3H)

Example 23. Preparation of (2S,3R,4R,5S,6R)-2-(4-(4-ethylbenzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 7-bromo-5-(4-ethylbenzyl)-1,2,3,4-tetrahydronaphthalene (23-1)

(122) ##STR00052##

(123) The title compound (23-1) was obtained with the compound (22-3) obtained in Step 3 of Example 22 by means of a method as shown from Steps 1 to 3 of Example 4.

(124) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.12-7.10 (m, 3H), 7.05 (s, 1H), 7.01 (d, J=8.4 Hz, 2H), 3.85 (s, 2H), 2.73 (t, J=6.4 Hz, 2H), 2.62 (q, J=7.6 Hz, 2H), 2.53 (t, J=6.0 Hz, 2H), 1.78-1.70 (m, 4H), 1.22 (t, J=7.6 Hz, 3H)

Step 2. Synthesis of a Target Compound

(125) ##STR00053##

(126) The target compound was obtained with the compound (23-1) by means of a method as shown in Step 4 of Example 4.

(127) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.06-6.99 (m, 6H), 4.03 (d, J=9.2 Hz, 1H), 3.89-3.85 (m, 3H), 3.69-3.67 (m, 1H), 3.45-3.34 (m, 4H), 2.76 (s, 2H), 2.60-2.55 (m, 4H), 1.71 (s, 4H), 1.18 (t, J=7.6 Hz, 3H)

Example 24. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-(4-methoxybenzyl)-1-methyl-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of ethyl 4-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxylate (24-1)

(128) ##STR00054##

(129) A mixture of ethyl sorbate (49.5 mL, 0.33 mol, TCI reagent) in xylene (330 mL) as well as 1-pyrrolidino-1-cyclohexene (50.24 g, 0.33 mol, TCI agent) was stirred at reflux overnight. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. EtOAc was added into the resulting mixture. An organic layer was washed with brine, after which the resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A crude compound was used in a following step without an additional purification. S.sub.8 (10.7 g, 0.33 mol) was added into the crude compound. A reaction mixture was stirred at 250 C. for 2 hours. After a reaction was completed, the resulting mixture was distilled under reduced pressure, so as to obtain the title compound (24-1) (24.7 g, 0.11 mol, 34%).

(130) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.58 (d, J=7.6 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.06 (t, J=6.4 Hz, 2H), 2.64 (t, J=6.4 Hz, 2H), 2.24 (s, 3H), 1.85-1.73 (m, 4H), 1.37 (t, J=7.2 Hz, 3H)

Step 2. Synthesis of ethyl 3-bromo-4-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxylate (24-2)

(131) ##STR00055##

(132) Br.sub.2 (3.5 mL, 68.6 mmol) and AgNO.sub.3 (11.64 g, 68.6 mmol) in water (60 mL) were added dropwise into a mixture of the compound (24-1) (11.5 g, 68.6 mmol) in AcOH (450 mL) as well as a concentrated HNO.sub.3 (5.2 mL) at room temperature. A resulting mixture was stirred overnight at room temperature. A reaction was completed with saturated Na.sub.2S.sub.2O.sub.3 solution, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A crude compound (24-2) was used in a following step without an additional purification.

(133) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.87 (s, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.00 (t, J=6.4 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 2.36 (s, 3H), 1.82-1.71 (m, 4H), 1.38 (t, J=7.2 Hz, 3H).

Step 3. Synthesis of 3-bromo-4-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (24-3)

(134) ##STR00056##

(135) LiOH.H.sub.2O (3.6 g, 86.2 mmol) was added into a solution of the compound (24-2) (12.8 g, 43.1 mmol) in THF/MeOH/water (150 mL/50 mL/50 mL) at room temperature. A reaction mixture was stirred overnight at room temperature. After a reaction was completed, a volatile substance was removed under reduced pressure. A 1NHCl aqueous solution was added into a residue to carry out acidification, during which a resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water and dried under high vacuum, so as to obtain the title compound (24-3) (9.3 g, 34.4 mmol, 80%).

(136) .sup.1H NMR (400 MHz, CDCl.sub.3); 8.07 (s, 1H), 3.07 (t, J=6.4 Hz, 2H), 2.71 (t, J=6.4 Hz, 2H), 2.39 (s, 3H), 1.83-1.72 (m, 4H).

Step 4. Synthesis of 6-bromo-8-(4-methoxybenzyl)-5-methyl-1,2,3,4-tetrahydronaphthalene (24-4)

(137) ##STR00057##

(138) The title compound (24-4) was obtained with the compound (24-3) by means of a method as shown from Steps 4 to 5 of Example 1.

(139) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.16 (s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 2.67 (t, J=6.4 Hz, 2H), 2.54 (t, J=6.4 Hz, 2H), 2.31 (s, 3H), 1.77-1.68 (m, 4H).

Step 5. Synthesis of a Target Compound

(140) ##STR00058##

(141) The target compound was obtained with the compound (24-4) by means of a method as shown from Steps 6 to 7 of Example 1.

(142) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.13 (s, 1H), 7.00 (d, J=9.2 Hz, 2H), 6.77 (d, J=8.4 Hz, 1H), 4.51 (d, J=9.6 Hz, 1H), 3.89-3.85 (m, 3H), 3.73 (s, 3H), 3.67 (dd, J=11.6, 5.6 Hz, 1H), 3.60 (t, J=8.8 Hz, 1H), 3.51 (t, J=8.8 Hz, 1H), 3.41-3.39 (m, 2H), 2.65 (t, J=6.4 Hz, 2H), 2.54 (t, J=6.0 Hz, 2H), 2.24 (s, 3H), 1.75-1.64 (m, 4H)

Example 25. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1-methyl-4-(4-methylbenzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 6-bromo-5-methyl-8-(4-methylbenzyl)-1,2,3,4-tetrahydronaphthalene (25-1)

(143) ##STR00059##

(144) The title compound (25-1) was obtained with the compound (24-3) obtained in Step 3 of Example 24 by means of a method as shown from Steps 1 to 3 of Example 4.

(145) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.17 (s, 1H), 7.08 (d, J=7.6 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 3.84 (s, 2H), 2.67 (t, J=6.4 Hz, 2H), 2.54 (t, J=6.4 Hz, 2H), 2.31 (s, 6H), 1.76-1.68 (m, 4H)

Step 2. Synthesis of a Target Compound

(146) ##STR00060##

(147) The target compound was obtained with the compound (25-1) by means of a method as shown in Step 4 of Example 4.

(148) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.13 (s, 1H), 7.02 (d, J=7.6 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H), 4.51 (d, J=9.6 Hz, 1H), 3.86-3.89 (m, 3H), 3.67 (dd, J=11.6, 6.0 Hz, 1H), 3.60 (t, J=9.2 Hz, 1H), 3.51 (t, J=8.8 Hz, 1H), 3.42-3.40 (m, 2H), 2.65 (t, J=6.4 Hz, 2H), 2.54 (t, J=6.4 Hz, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.75-1.64 (m, 4H)

Examples 26 to 29

(149) Target compounds of Examples 26 to 29 were obtained by means of a method as shown in Example 25.

Example 26. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1-methyl-4-(4-trifluoromethyl)benzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol

(150) ##STR00061##

(151) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.51 (d, J=7.6 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.18 (s, 1H), 4.52 (d, J=9.2 Hz, 1H), 4.03 (s, 2H), 3.87 (dd, J=11.6, 5.6 Hz, 1H), 3.69-3.65 (m, 1H), 3.59 (t, J=8.8 Hz, 1H), 3.52 (t, J=8.8 Hz, 1H), 3.42-3.40 (m, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.51 (t, J=5.6 Hz, 2H), 2.25 (s, 3H), 1.76-1.65 (m, 4H)

Example 27. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1-methyl-4-(4-trifluoromethoxy)benzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol

(152) ##STR00062##

(153) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.19 (d, J=8.4 Hz, 2H), 7.16 (s, 1H), 7.12 (d, J=8.4 Hz, 2H), 4.52 (d, J=9.6 Hz, 1H), 3.97 (s, 2H), 3.87 (dd, J=11.6, 2.0 Hz, 1H), 3.67 (dd, J=11.6, 5.6 Hz, 1H), 3.58 (t, J=9.2 Hz, 1H), 3.51 (t, J=7.6 Hz, 1H), 3.42-3.40 (m, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.53 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 1.76-1.66 (m, 4H)

Example 28. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(1-methyl-4-(4-(methylthio)benzyl)-5,6,7,8-tetrahydronaphthalene-2-yl)tetrahydro-2H-pyran-3,4,5-triol

(154) ##STR00063##

(155) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.14 (d, J=8.0 Hz, 2H), 7.14 (s, 1H), 7.04 (d, J=8.4 Hz, 2H), 4.51 (d, J=9.6 Hz, 1H), 3.86-3.90 (m, 3H), 3.67 (dd, J=11.6, 5.6 Hz, 1H), 3.59 (t, J=9.2 Hz, 1H), 3.51 (t, J=8.8 Hz, 1H), 3.39-3.41 (m, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.54 (t, J=5.6 Hz, 2H), 2.42 (s, 3H), 2.25 (s, 3H), 1.75-1.65 (m, 4H)

Example 29. Preparation of (2S,3R,4R,5S,6R)-2-(4-(4-chlorobenzyl)-1-methyl-5,6,7,8-tetrahydronaphthalene-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(156) ##STR00064##

(157) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.20 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 7.08 (d, J=8.8 Hz, 2H), 4.51 (d, J=9.6 Hz, 1H), 3.92 (s, 2H), 3.87 (dd, J=11.6, 2.0 Hz, 1H), 3.67 (dd, J=11.6, 5.6 Hz, 1H), 3.59 (t, J=9.2 Hz, 1H), 3.52 (t, J=8.8 Hz, 1H), 3.42-3.40 (m, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.52 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 1.76-1.65 (m, 4H)

Example 30. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)-4-methyl-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of methyl 2-hydroxy-4-methylbenzoate (30-1)

(158) ##STR00065##

(159) SOCl.sub.2 (10.9 mL, 150 mmol) was added dropwise into a solution of 4-methylsalicylic acid (5.0 g, 32.9 mmol, TCI reagent) in MeOH (80 mL) at 0 C. in a nitrogen atmosphere. A resulting mixture was stirred at reflux overnight. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (30-1) (5.18 g, 31.2 mmol, 95%).

(160) .sup.1H NMR (400 MHz, CDCl.sub.3); 10.70 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 6.79 (s, 1H), 6.69 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H)

Step 2. Synthesis of methyl 2-(allyloxy)-4-methylbenzoate (30-2)

(161) ##STR00066##

(162) Allyl bromide (3.2 mL, 37.4 mmol) was added dropwise into a mixture of the compound (30-1) (5.18 g, 31.2 mmol) in DMF (40 mL) as well as K.sub.2CO.sub.3 (5.17 g, 37.4 mmol). A reaction mixture was stirred overnight at room temperature, after which a reaction thereof was completed with water. A water layer was extracted with EtOAc, after which a combined organic layer was washed with brine, such that the resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (30-2) (6.35 g, 30.8 mmol, 99%).

(163) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.73 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.76 (s, 1H), 6.15-6.02 (m, 1H), 5.53 (dd, J=17.2, 1.6 Hz, 1H), 5.30 (dd, J=10.4, 1.6 Hz, 1H), 4.61 (dd, J=3.2, 1.6 Hz, 2H), 3.88 (s, 3H), 2.36 (s, 3H)

Step 3. Synthesis of methyl 3-allyl-2-hydroxy-4-methylbenzoate (30-3)

(164) ##STR00067##

(165) The compound (30-2) (6.65 g, 32.2 mmol) was stirred in a microwave reactor at 250 C. for 1 hour. A crude compound (30-3) was used in a following step without an additional purification.

(166) .sup.1H NMR (400 MHz, CDCl.sub.3); 11.07 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 5.99-5.88 (m, 1H), 4.99 (dd, J=10.0, 1.6 Hz, 1H), 4.93 (dd, J=17.2, 2.0 Hz, 1H), 3.93 (s, 3H), 3.46 (dt, J=5.6, 1.6 Hz, 2H), 2.32 (s, 3H)

Step 4. Synthesis of methyl 2-hydroxy-4-methyl-3-(2-oxoethyl)benzoate (30-4)

(167) ##STR00068##

(168) N-methylmorpholine N-oxide (3.51 g, 30.0 mmol) and OsO.sub.4 (1.3 mL, 0.200 mmol, 4 wt % in H.sub.2O) were added into a solution of the compound (30-3) (2.06 g, 10.0 mmol) in THF/water (24 mL/8 mL) in a nitrogen atmosphere. After stirring a resulting reaction mixture at room temperature for 8 hours, a reaction with a reactant was completed with a saturated Na.sub.2S.sub.2O.sub.3 aqueous solution, so as to perform an extraction of the resulting mixture with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum, so as to obtain a crude intermediate, which was used without an additional purification. NaIO.sub.4 (10.7 g, 50.0 mmol) was added into a crude intermediate solution in THF/water (48 mL/16 mL) at room temperature in a nitrogen atmosphere. After stirring a resulting reaction mixture at room temperature for 5 hours, a reaction with a reactant was completed with a saturated Na.sub.2S.sub.2O.sub.3 aqueous solution, so as to perform an extraction of the resulting mixture with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum, after which a resulting concentrate was purified by means of a silica gel column chromatography, so as to obtain the title compound (30-4) (2.00 g, 9.61 mmol, 96%).

(169) .sup.1H NMR (400 MHz, CDCl.sub.3); 11.16 (s, 1H), 9.70 (t, J=1.6 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 3.95 (s, 3H), 3.81 (s, 2H), 2.29 (s, 3H)

Step 5. Synthesis of methyl 2-hydroxy-3-(2-hydroxyethyl)-4-methylbenzoate (30-5)

(170) ##STR00069##

(171) NaBH.sub.4 (436 mg, 11.5 mmol) was added into a solution of the compound (30-4) (2.00 g, 9.61 mmol) in EtOH (30 mL) at 0 C. in a nitrogen atmosphere. After stirring a resulting reaction mixture at 0 C. for 1 hour, a reaction with a reactant was completed with a saturated NH.sub.4Cl aqueous solution, so as to perform an extraction of the resulting mixture with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (30-5) (1.82 g, 9.04 mmol, 94%).

(172) .sup.1H NMR (400 MHz, CDCl.sub.3); 11.19 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 3.94 (s, 3H), 3.84 (dd, J=12.0, 6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.37 (s, 3H)

Step 6. Synthesis of methyl 4-methyl-2,3-dihydrobenzofuran-7-carboxylate (30-6)

(173) ##STR00070##

(174) DIAD (1.7 mL, 8.66 mmol) was slowly added dropwise into a mixture of the compound (30-5) (910 mg, 4.33 mmol) in THF (30 mL) as well as PPh.sub.3 (2.27 g, 8.66 mmol) at 0 C. in a nitrogen atmosphere. A reaction mixture was stirred overnight at room temperature. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (30-6) (813 mg, 4.23 mmol, 98%).

(175) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.65 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 4.74 (t, J=8.8 Hz, 2H), 3.89 (s, 3H), 3.13 (t, J=8.8 Hz, 2H), 2.28 (s, 3H)

Step 7. Synthesis of methyl 5-bromo-4-methyl-2,3-dihydrobenzofuran-7-carboxylate (30-7)

(176) ##STR00071##

(177) Br.sub.2 (0.66 mL, 12.8 mmol) was added dropwise into a solution of the compound (30-6) (1.23 g, 6.40 mmol) in AcOH (20 mL) at room temperature. A resulting mixture was stirred overnight at room temperature, after which a reaction with a reactant was completed with a saturated Na.sub.2S.sub.2O.sub.3 solution, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (30-7) (1.58 g, 5.83 mmol, 91%).

(178) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.92 (s, 1H), 4.76 (t, J=8.8 Hz, 2H), 3.89 (s, 3H), 3.19 (t, J=8.8 Hz, 2H), 2.33 (s, 3H)

Step 8. Synthesis of 5-bromo-4-methyl-2,3-dihydrobenzofuran-7-carboxylic acid (30-8)

(179) ##STR00072##

(180) LiOH.H.sub.2O (489 mg, 11.7 mmol) was added into a solution of the compound (30-7) (1.58 g, 5.83 mmol) in THF/MeOH/water (12 mL/4 mL/4 mL) at room temperature.

(181) A reaction mixture was stirred at room temperature for 4 hours. After a reaction was completed, a volatile substance was removed under reduced pressure. A 1NHCl aqueous solution was added into a residue to carry out acidification, during which a resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water and dried under high vacuum, so as to obtain the title compound (30-8) (1.02 g, 3.97 mmol, 68%).

(182) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.81 (s, 1H), 4.70 (t, J=8.8 Hz, 2H), 3.23 (t, J=8.8 Hz, 2H), 2.34 (s, 3H)

Step 9. Synthesis of 5-bromo-7-(4-methoxybenzyl)-4-methyl-2,3-dihydrobenzofuran (30-9)

(183) ##STR00073##

(184) The title compound (30-9) was obtained with the compound (30-8) by means of a method as shown from Steps 4 to 5 of Example 1.

(185) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.13 (d, J=8.4 Hz, 2H), 7.04 (s, 1H), 6.82 (d, J=8.4 Hz, 2H), 4.59 (t, J=8.4 Hz, 2H), 3.78 (s, 5H), 3.16 (t, J=8.8 Hz, 2H), 2.25 (s, 3H)

Step 10. Synthesis of a Target Compound

(186) ##STR00074##

(187) The target compound was obtained with the compound (30-9) by means of a method as shown from Steps 6 to 7 of Example 1.

(188) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.11 (d, J=8.4 Hz, 2H), 7.02 (s, 1H), 6.76 (d, J=8.8 Hz, 2H), 4.54 (t, J=8.8 Hz, 2H), 4.36 (d, J=9.2 Hz, 1H), 3.86-3.83 (m, 1H), 3.77 (s, 2H), 3.73 (s, 3H), 3.66-3.62 (m, 1H), 3.51-3.44 (m, 2H), 3.37-3.35 (m, 2H), 3.14 (t, J=8.8 Hz, 2H), 2.27 (s, 3H)

Example 31. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-methyl-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(189) ##STR00075##

(190) The target compound was obtained by means of a method as shown in Example 30.

(191) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.10 (d, J=8.4 Hz, 2H), 7.03 (s, 1H), 6.75 (d, J=8.8 Hz, 2H), 4.53 (t, J=8.8 Hz, 2H), 4.36 (d, J=9.2 Hz, 1H), 3.96 (q, J=7.2 Hz, 2H), 3.85 (d, J=11.6 Hz, 1H), 3.76 (s, 2H), 3.66-3.62 (m, 1H), 3.54-3.45 (m, 2H), 3.37-3.35 (m, 2H), 3.13 (t, J=8.6 Hz, 2H), 2.26 (s, 3H), 1.34 (t, J=6.8 Hz, 3H)

Example 32. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-(methylthio)benzyl)-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 5-bromo-4-methyl-7-(4-(methylthio)benzyl)-2,3-dihydrobenzofuran (32-1)

(192) ##STR00076##

(193) The title compound (32-1) was obtained with the compound (30-8) obtained in Step 8 of Example 30 by means of a method as shown from Steps 1 to 3 of Example 4.

(194) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.18 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.04 (s, 1H), 4.59 (t, J=8.8 Hz, 2H), 3.79 (s, 2H), 3.17 (t, J=8.8 Hz, 2H), 2.46 (s, 3H), 2.25 (s, 3H)

Step 2. Synthesis of a Target Compound

(195) ##STR00077##

(196) The target compound was obtained with the compound (32-1) by means of a method as shown in Step 4 of Example 4.

(197) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.16-7.11 (m, 4H), 7.04 (s, 1H), 4.54 (t, J=8.4 Hz, 2H), 4.36 (d, J=8.8 Hz, 1H), 3.85 (d, J=12.0 Hz, 1H), 3.80 (s, 2H), 3.64 (dd, J=12.0, 5.2 Hz, 1H), 3.54-3.45 (m, 2H), 3.38-3.36 (m, 2H), 3.14 (t, J=8.4 Hz, 2H), 2.42 (s, 3H), 2.27 (s, 3H)

Examples 33 and 34

(198) Target compounds of Examples 33 and 34 were obtained by means of a method as shown in Example 32.

Example 33. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-methyl-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(199) ##STR00078##

(200) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.11 (d, J=7.2 Hz, 2H), 7.05 (s, 3H), 4.54 (t, J=8.4 Hz, 2H), 4.36 (d, J=9.2 Hz, 1H), 3.86-3.80 (m, 3H), 3.68-3.61 (m, 1H), 3.46-3.54 (m, 2H), 3.38 (s, 2H), 3.14 (t, J=8.4 Hz, 2H), 2.58 (q, J=7.6 Hz, 2H), 2.27 (s, 3H), 1.18 (t, J=7.2 Hz, 3H)

Example 34. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-vinylbenzyl)-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(201) ##STR00079##

(202) .sup.1H NMR (400 MHz, CD.sub.3OD); (7.27 (d, J=7.6 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.04 (s, 1H), 6.66 (dd, J=17.6, 11.2 Hz, 1H), 5.68 (dd, J=17.6, 1.2 Hz, 1H), 5.13 (dd, J=10.8, 0.8 Hz, 1H), 4.54 (t, J=8.8 Hz, 2H), 4.36 (d, J=9.2 Hz, 1H), 3.86-3.83 (m, 3H), 3.66-3.53 (m, 1H), 3.51-3.44 (m, 2H), 3.39-3.34 (m, 2H), 3.14 (t, J=8.8 Hz, 2H), 2.27 (s, 3H)

Example 35. Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-7-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of methyl 4-chloro-2-hydroxybenzoate (35-1)

(203) ##STR00080##

(204) SOCl.sub.2 (12.6 mL, 174 mmol) was added dropwise into a solution of 4-chlorosalicylic acid (10.0 g, 58.0 mmol, TCI reagent) in MeOH (200 mL) at 0 C. in a nitrogen atmosphere. A resulting mixture was stirred at reflux for 4 hours. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. A saturated NaHCO.sub.3 aqueous solution was slowly added into a resulting residue, after which a water layer was extracted with EtOAc. An organic layer was washed with brine, after which the resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (35-1) (7.6 g, 40.7 mmol, 70%).

(205) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.76 (d, J=8.8 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.4, 2.0 Hz, 1H), 3.95 (s, 3H)

Step 2. Synthesis of methyl 2-(allyloxy)-4-chlorobenzoate (35-2)

(206) ##STR00081##

(207) Allyl bromide (5.3 mL, 61.0 mmol) was added dropwise into a mixture of the compound (35-1) (7.59 g, 40.7 mmol) in DMF (114 mL) as well as K.sub.2CO.sub.3 (8.43 g, 61.0 mmol) at room temperature in a nitrogen atmosphere. A reaction mixture was stirred overnight at room temperature, after which a reaction thereof was completed with water. A water layer was extracted with EtOAc, after which an organic layer was washed with brine, such that the resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (35-2) (8.50 g, 37.5 mmol, 92%).

(208) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.78 (d, J=8.0 Hz, 1H), 7.26-6.95 (m, 2H), 6.07-6.02 (m, 1H), 5.53 (dd, J=17.2, 1.6 Hz, 1H), 5.34 (dd, J=10.4, 1.2 Hz, 1H), 4.63-4.61 (m, 2H), 3.89 (s, 3H)

Step 3. Synthesis of methyl 3-allyl-4-chloro-2-hydroxybenzoate (35-3)

(209) ##STR00082##

(210) The compound (35-2) (2.10 g, 9.27 mmol) was stirred in a microwave reactor at 250 C. for 1 hour. A crude compound (35-3) (2.01 g, 8.87 mmol, 96%) was used in a following step without an additional purification.

(211) .sup.1H NMR (400 MHz, CDCl.sub.3); 11.26 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.98-5.91 (m, 1H), 5.07-5.02 (m, 2H), 3.95 (s, 3H), 3.59 (d, J=6.0 Hz, 2H)

Step 4. Synthesis of methyl 4-chloro-2-hydroxy-3-(2-oxoethyl)benzoate (35-4)

(212) ##STR00083##

(213) N-methylmorpholine N-oxide (1.55 g, 13.2 mmol) and OsO.sub.4 (22.4 mL, 0.09 mmol) were added into a solution of the compound (35-3) (2.00 g, 8.82 mmol) in acetone/water (30 mL/3 mL) in a nitrogen atmosphere. After stirring a resulting reaction mixture at room temperature for 8 hours, a reaction with a reactant was completed with a saturated Na.sub.2S.sub.2O.sub.3 aqueous solution, so as to perform an extraction of a resulting mixture with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum, so as to obtain a crude intermediate, which was used without an additional purification. NaIO.sub.4 (5.61 g, 26.3 mmol) was added into a crude intermediate solution in THF/water (50 mL/30 mL) at room temperature in a nitrogen atmosphere. After stirring a resulting reaction mixture at room temperature for 5 hours, a reaction with a reactant was completed with a saturated Na.sub.2S.sub.2O.sub.3 aqueous solution, so as to perform an extraction of a resulting mixture with EtOAc.

(214) An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum, so as to obtain a crude compound (35-4) (1.90 g, 8.31 mmol, 95%), which was used without an additional purification.

(215) .sup.1H NMR (400 MHz, CDCl.sub.3); 11.32 (s, 1H), 9.73 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 3.97 (s, 5H)

Step 5. Synthesis of methyl 4-chloro-2-hydroxy-3-(2-hydroxyethyl)benzoate (35-5)

(216) ##STR00084##

(217) NaBH.sub.4 (628 mg, 16.6 mmol) was added into a solution of the compound (35-4) (1.90 g, 8.31 mmol) in MeOH (30 mL) at 0 C. in a nitrogen atmosphere. After stirring a resulting reaction mixture at 0 C. for 1 hour, a reaction with a reactant was completed with a saturated NH.sub.4Cl aqueous solution, so as to perform an extraction of a resulting mixture with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (35-5) (1.45 g, 6.29 mmol, 76%).

(218) .sup.1H NMR (400 MHz, CDCl.sub.3); 11.37 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 3.96 (s, 3H), 3.87 (dd, J=12.8, 6.0 Hz, 2H), 3.16 (t, J=6.4 Hz, 2H)

Step 6. Synthesis of methyl 4-chloro-2,3-dihydrobenzofuran-7-carboxylate (35-6)

(219) ##STR00085##

(220) DIAD (2.47 mL, 12.6 mmol) was slowly added dropwise into a mixture of the compound (35-5) (1.45 g, 6.29 mmol) in THF (30 mL) as well as PPh.sub.3 (3.30 g, 12.6 mmol) at 0 C. in a nitrogen atmosphere. A reaction mixture was stirred overnight at room temperature. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (35-6) (1.31 g, 6.16 mmol, 98%).

(221) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.69 (d, J=8.4 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 4.79 (t, J=8.8 Hz, 2H), 3.90 (s, 3H), 3.27 (t, J=8.8 Hz, 2H)

Step 7. Synthesis of methyl 5-bromo-4-chloro-2,3-dihydrobenzofuran-7-carboxylate (35-7)

(222) ##STR00086##

(223) Br.sub.2 (0.4 mL, 8.01 mmol) was added dropwise into a solution of the compound (35-6) (1.31 g, 6.16 mmol) in AcOH (20 mL) at room temperature. A resulting mixture was stirred overnight at room temperature, after which a reaction with a reactant was completed with a saturated Na.sub.2S.sub.2O.sub.3 solution, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A crude compound (35-7) (1.70 g, 5.83 mmol, 95%) was used in a following step without an additional purification.

(224) .sup.1H NMR (400 MHz, CDCl.sub.3); 8.00 (s, 1H), 4.81 (t, J=8.8 Hz, 2H), 3.91 (s, 3H), 3.31 (t, J=8.8 Hz, 2H)

Step 8. Synthesis of 5-bromo-4-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (35-8)

(225) ##STR00087##

(226) LiOH.H.sub.2O (490 mg, 11.2 mmol) was added into a solution of the compound (35-7) (1.70 g, 5.83 mmol) in THF/MeOH/water (15 mL/5 mL/5 mL) at room temperature. A reaction mixture was stirred at room temperature for 4 hours. After a reaction was completed, a volatile substance was removed under reduced pressure. A 1NHCl aqueous solution was added into a residue to carry out acidification, during which a resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water and dried under high vacuum, so as to obtain the title compound (35-8) (1.54 g, 5.54 mmol, 95%).

(227) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.93 (s, 1H), 4.76 (t, J=8.8 Hz, 2H), 3.35-3.30 (m, 2H)

Step 9. Synthesis of a Target Compound

(228) ##STR00088##

(229) The target compound was obtained with the compound (35-8) by means of a method as shown from Steps 4 to 7 of Example 1.

(230) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.14-7.10 (m, 3H), 6.77 (d, J=8.4 Hz, 2H), 4.63-4.59 (m, 3H), 3.97 (q, J=6.8 Hz, 2H), 3.86-3.78 (m, 3H), 3.68-3.64 (m, 1H), 3.49-3.47 (m, 2H), 3.39-3.37 (m, 2H), 3.25 (t, J=8.8 Hz, 2H), 1.35 (t, J=6.8 Hz, 3H)

Example 36. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-(4-methoxybenzyl)-7-methyl-2,3-dihydrobenzofuran-6-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 6-bromo-7-methyl-2,3-dihydrobenzofuran-4-carboxylic acid (36-1)

(231) ##STR00089##

(232) The title compound (36-1) was obtained with 3-hydroxy-4-methylbenzoic acid (TCI reagent) by means of a method as shown from Steps 1 to 8 of Example 30.

(233) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.15 (s, 1H), 4.52 (t, J=8.8 Hz, 2H), 3.36 (t, J=8.8 Hz, 2H), 2.20 (s, 3H)

Step 2. Synthesis of 6-bromo-4-(4-methoxybenzyl)-7-methyl-2,3-dihydrobenzofuran (36-2)

(234) ##STR00090##

(235) The title compound according to an inventive title (36-2) was obtained with the compound (36-1) by means of a method as shown from Steps 4 to 5 of Example 1.

(236) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.18 (s, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 4.52 (t, J=8.8 Hz, 2H), 4.00 (s, 2H), 3.77 (s, 3H), 3.04 (t, J=8.8 Hz, 2H), 2.16 (s, 3H)

Step 3. Synthesis of a Target Compound

(237) ##STR00091##

(238) The target compound was obtained with the compound (36-2) by means of a method as shown from Steps 6 to 7 of Example 1.

(239) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.11 (s, 1H), 7.04 (d, J=9.2 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.47 (t, J=9.2 Hz, 2H), 4.35 (d, J=9.6 Hz, 1H), 4.13 (d, J=12.0 Hz, 1H), 3.89 (d, J=16.0 Hz, 1H), 3.73 (dd, J=12.0, 2.4 Hz, 1H), 3.73 (s, 3H), 3.62-3.56 (m, 2H), 3.44-3.35 (m, 2H), 3.19-3.15 (m, 1H), 3.04-2.92 (m, 2H), 2.16 (s, 3H)

Example 37. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-methyl-4-(4-vinylbenzyl)-2,3-dihydrobenzofuran-6-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 6-bromo-7-methyl-4-(4-vinylbenzyl)-2,3-dihydrobenzofuran (37-1)

(240) ##STR00092##

(241) The title compound (37-1) was obtained with the compound (36-1) obtained in Step 1 of Example 36 by means of a method as shown from Steps 1 to 3 of Example 4.

(242) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.31 (d, J=7.2 Hz, 2H), 7.18 (s, 1H), 7.09 (d, J=7.2 Hz, 2H), 6.68 (dd, J=17.6, 10.8 Hz, 1H), 5.69 (d, J=17.6 Hz, 1H), 5.41 (d, J=10.8 Hz, 1H), 4.53 (t, J=8.8 Hz, 2H), 4.06 (s, 2H), 3.09 (t, J=8.8 Hz, 2H), 2.17 (s, 3H)

Step 2. Synthesis of a Target Compound

(243) ##STR00093##

(244) The target compound was obtained with the compound (37-1) by means of a method as shown in Step 4 of Example 4.

(245) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.29 (d, J=8.4 Hz, 2H), 7.11 (s, 1H), 7.09 (d, J=7.6 Hz, 2H), 6.67 (dd, J=17.6, 10.8 Hz, 1H), 5.69 (d, J=17.6 Hz, 1H), 5.14 (d, J=10.8 Hz, 1H), 4.48 (t, J=8.8 Hz, 2H), 4.33 (d, J=9.6 Hz, 1H), 4.19 (d, J=16.0 Hz, 1H), 3.95 (d, J=16.4 Hz, 1H), 3.71 (dd, J=12.0, 2.4 Hz, 1H), 3.61-3.52 (m, 2H), 3.43-3.35 (m, 2H), 3.17-3.14 (m, 1H), 3.07-2.92 (m, 2H), 2.16 (s, 3H)

Example 38. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(8-methoxy-5-(4-methoxybenzyl)chroman-7-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of methyl 3-(allyloxy)-4-methoxybenzoate (38-1)

(246) ##STR00094##

(247) Allyl bromide (2.8 mL, 32.9 mmol) was added dropwise into a mixture of methyl isocyanilate (5.00 g, 27.4 mmol, TCI reagent) in DMF (30 mL) as well as K.sub.2CO.sub.3 (4.55 g, 32.9 mmol) at room temperature in a nitrogen atmosphere. A reaction mixture was stirred overnight at room temperature, after which a reaction thereof was completed with water. A water layer was extracted with EtOAc, after which an organic layer was washed with brine, such that the resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (38-1) (5.80 g, 26.1 mmol, 95%).

(248) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.68 (dd, J=8.0, 2.0 Hz, 1H), 7.56 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.17-6.04 (m, 1H), 5.44 (dd, J=17.6, 1.2 Hz, 1H), 5.31 (dd, J=10.4, 1.2 Hz, 1H), 4.66 (d, J=5.6 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H)

Step 2. Synthesis of methyl 2-allyl-3-hydroxy-4-methoxybenzoate (38-2)

(249) ##STR00095##

(250) The compound (38-1) (1.00 g, 4.50 mmol) was stirred in a microwave reactor at 250 C. for 1 hour. A crude compound (38-2) (0.99 g, 4.45 mmol, 99%) was used in a following step without an additional purification.

(251) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.52 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.08-5.98 (m, 1H), 5.77 (s, 1H), 5.04-4.97 (m, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.82 (d, J=6.0 Hz, 2H)

Step 3. Synthesis of methyl 3-hydroxy-2-(3-hydroxpropyl)-4-methoxybenzoate

(252) ##STR00096##

(253) A BH.sub.3.SMe.sub.2 complex (1.0 mL, 10.0 mmol, 10.0 M in methylsulfide) was slowly added into a solution of the compound (38-2) (1.91 g, 8.59 mmol) in THF (40 mL) at 10 C. in a nitrogen atmosphere, after which a reaction mixture was stirred at room temperature for 1 hour. An H.sub.2O.sub.2 (1.2 mL) solution in a saturated NaHCO.sub.3 solution (20 mL) solution was slowly added thereinto. A resulting reaction mixture was cooled at 0 C. and stirred for 30 minutes. EtOAc was added into the resulting mixture. An organic layer was washed with brine, after which the resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A crude compound (38-3) (2.06 g, 8.57 mmol, 99%) was used in a following step without an additional purification.

(254) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.44 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.57 (t, J=6.8 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H), 1.85-1.77 (m, 2H)

Step 4. Synthesis of methyl 8-methoxychroman-5-carboxylate (38-4)

(255) ##STR00097##

(256) DIAD (3.40 mL, 17.15 mmol) was slowly added into a mixture of the compound (38-3) (2.06 g, 8.57 mmol) in THF (20 mL) as well as PPh.sub.3 (4.5 g, 17.2 mmol) at 0 C. in a nitrogen atmosphere. A reaction mixture was stirred overnight at room temperature. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (38-4) (1.87 g, 8.41 mmol, 98%).

(257) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.58 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 4.27 (t, J=5.2 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.14 (t, J=6.4 Hz, 2H), 2.05-1.99 (m, 2H)

Step 5. Synthesis of 8-methoxychroman-5-carboxylic acid (38-5)

(258) ##STR00098##

(259) A mixture of the compound (38-4) (1.87 g, 8.41 mmol) in THF (5 mL) as well as 1NNaOH aqueous solution (13 mL) was stirred at reflux for 2 hours. A resulting reaction mixture was cooled at room temperature, after which the resulting mixture was acidified by means of a 1NHCl solution, so as to perform an extraction with EtOAc. A combined organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (38-5) (1.72 g, 8.26 mmol, 96%).

(260) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.59 (d, J=8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 4.19 (t, J=5.2 Hz, 2H), 3.86 (s, 3H), 3.12 (t, J=6.4 Hz, 2H), 2.01-1.95 (m, 2H)

Step 6. Synthesis of 7-bromo-8-methoxychroman-5-carboxylic acid (38-6)

(261) ##STR00099##

(262) Br.sub.2 (0.28 mL, 10.7 mmol) was added dropwise into a solution of the compound (38-5) (1.72 g, 8.26 mmol) in AcOH (20 mL) at room temperature. A resulting mixture was stirred overnight at room temperature, after which a reaction with a reactant was completed with a saturated Na.sub.2S.sub.2O.sub.3 solution, so as to perform an extraction with EtOAc. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. A crude compound (38-6) (1.86 g, 6.18 mmol, 75%) was used in a following step without an additional purification.

(263) .sup.1H NMR (400 MHz, CD.sub.3OD); 6.99 (s, 1H), 4.19 (t, J=5.2 Hz, 2H), 3.82 (s, 3H), 2.77 (t, J=6.4 Hz, 2H), 2.02-1.96 (m, 2H)

Step 7. Synthesis of 7-bromo-8-methoxy-5-(4-methoxybenzyl)chroman (38-7)

(264) ##STR00100##

(265) The title compound (38-7) was obtained with the compound (38-6) by means of a method as shown from Steps 4 to 5 of Example 1.

(266) .sup.1H NMR (400 MHz, CDCl.sub.3); 6.99-6.97 (m, 3H), 6.80 (d, J=8.8 Hz, 2H), 4.17 (t, J=4.8 Hz, 2H), 4.06 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 2.60 (t, J=6.4 Hz, 2H), 1.96-1.91 (m, 2H)

Step 8. Synthesis of a Target Compound

(267) ##STR00101##

(268) The target compound was obtained with the compound (38-7) by means of a method as shown from Steps 6 to 7 of Example 1.

(269) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.01-6.99 (m, 3H), 6.78 (d, J=8.4 Hz, 2H), 4.38 (d, J=9.6 Hz, 1H), 4.16-4.06 (m, 3H), 3.91-3.87 (m, 1H), 3.85 (s, 3H), 3.78-3.74 (m, 1H), 3.73 (s, 3H), 3.65-3.57 (m, 2H), 3.43-3.40 (m, 2H), 3.21-3.17 (m, 1H), 2.68-2.62 (m, 1H), 2.53-2.47 (m, 1H), 1.92-1.88 (m, 2H)

Example 39. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(8-methoxy-5-(4-methylbenzyl)chroman-7-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 7-bromo-8-methoxy-5-(4-methylbenzyl)chroman (39-1)

(270) ##STR00102##

(271) The title compound (39-1) was obtained with the compound (38-6) obtained in Step 6 of Example 38 by means of a method as shown from Steps 1 to 3 of Example 4.

(272) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.07 (d, J=7.6 Hz, 2H), 6.99 (s, 1H), 6.95 (d, J=8.0 Hz, 2H), 4.17 (t, J=5.2 Hz, 2H), 4.09 (s, 2H), 3.87 (s, 3H), 2.59 (t, J=6.4 Hz, 2H), 2.30 (s, 3H), 1.96-1.92 (m, 2H)

Step 2. Synthesis of a Target Compound

(273) ##STR00103##

(274) The target compound was obtained with the compound (39-1) by means of a method as shown in Step 4 of Example 4.

(275) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.03 (d, J=8.0 Hz, 2H), 6.99 (s, 1H), 6.96 (d, J=8.0 Hz, 2H), 4.38 (d, J=9.6 Hz, 1H), 4.17 (d, J=16.8 Hz, 1H), 4.12-4.03 (m, 2H), 3.88 (d, J=10.0 Hz, 1H), 3.85 (s, 3H), 3.75 (dd, J=12.0, 2.4 Hz, 1H), 3.65-3.57 (m, 2H), 3.44-3.39 (m, 2H), 3.20-3.16 (m, 1H), 2.67-2.61 (m, 1H), 2.52-2.44 (m, 1H), 2.26 (s, 3H), 1.91-1.87 (m, 2H)

Example 40. Preparation of (2S,3R,4R,5S,6R)-2-(5-(4-ethoxybenzyl)-8-methylchroman-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of 7-bromo-5-(4-ethoxybenzyl)-8-methylchroman (40-1)

(276) ##STR00104##

(277) The title compound (40-1) was obtained with 3-hydroxy-4-methylbenzoic acid (TCI reagent) by means of a method as shown from Steps 1 to 7 of Example 38.

(278) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.24 (s, 1H), 6.97 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (t, J=8.8 Hz, 2H), 4.08 (s, 2H), 3.96 (q, J=6.8 Hz, 2H), 2.60 (t, J=8.8 Hz, 2H), 2.15 (s, 3H), 1.94-1.87 (m, 2H), 1.39 (t, J=6.8 Hz, 3H)

Step 2. Synthesis of a Target Compound

(279) ##STR00105##

(280) The target compound was obtained with the compound (40-1) by means of a method as shown from Steps 6 to 7 of Example 1.

(281) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.14 (s, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.33 (d, J=9.2 Hz, 1H), 4.15-4.06 (m, 3H), 3.99-3.90 (m, 3H), 3.74 (dd, J=12.0, 2.0 Hz, 1H), 3.62-3.57 (m, 2H), 3.40-3.35 (m, 2H), 3.17-3.15 (m, 1H), 2.93 (s, 3H), 2.68-2.47 (m, 2H), 1.90-1.87 (m, 2H), 1.34 (t, J=6.8 Hz, 3H)

Example 41. Preparation of (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of (E)-pent-2-enal (41-1)

(282) ##STR00106##

(283) DCM (104 mL) was cooled at 78 C., after which (COCl).sub.2 (24 mL, 278.64 mmol) and DMSO (2.06 mL, 464.44 mmol) were added dropwise into a resulting product, such that a resulting mixture was stirred for 30 minutes. Trans-2-penten-1-ol (16.00 g, 185.76 mmol) was diluted in DCM (40 mL), after which a resulting solution was slowly added into a reaction flask for 15 minutes, such that a resulting mixture was stirred at the same temperature for 30 minutes, and then further stirred for 1 hour with a temperature rising to 0 C. Water was poured onto a resulting mixture to complete a reaction, and perform an extraction with diethyl ether. An organic layer was washed with brine, after which a resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated, so as to obtain the title compound (41-1). A resulting compound was used immediately in a following reaction without an additional purification.

(284) .sup.1H NMR (400 MHz, CDCl.sub.3); 9.52 (d, J=7.6 Hz, 1H), 6.86 (dt, J=15.6, 6.2 Hz, 1H), 6.16-6.09 (m, 1H), 2.41-2.34 (m, 2H), 1.13 (t, J=7.2 Hz, 3H)

Step 2. Synthesis of 5(2E,4E)-ethylhepta-2,4-dienoate (41-2)

(285) ##STR00107##

(286) Sodium hydride (13.00 g, 325.08 mmol) was inserted into THF (200 mL), after which a resulting solution was cooled at 78 C. Triethyl phosphonoacetate (65 mL, 325.08 mmol) was slowly added into the resulting product for 5 minutes, after which a resulting mixture was stirred at the same temperature for 30 minutes. The compound (41-1) in THF (60 mL) was slowly added dropwise into the resulting mixture, after which the resulting mixture was stirred for 30 minutes, and then further stirred for 1 hour with a temperature rising to 40 C. A resulting product was diluted with diethyl ether, after which a saturated solution of ammonium chloride was slowly added into the resulting solution, such that a resulting mixture was stirred at room temperature for 10 minutes. An organic layer was washed twice with brine, after which a resulting product layer was dried over anhydrous MgSO.sub.4, filtered and concentrated. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (41-2) (21.86 g, 141.75 mmol, 76%).

(287) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.29-7.23 (m, 1H), 6.18-6.10 (m, 2H), 5.79 (d, J=12.8 Hz, 1H), 4.19 (q, J=6.8 Hz, 2H), 2.24-2.18 (m, 2H), 1.29 (t, J=7.2 Hz, 3H), 1.05 (t, J=7.2 Hz, 3H)

Step 3. Synthesis of ethyl 7-ethyl-2,3-dihydro-1H-indene-4-carboxylate (41-3)

(288) ##STR00108##

(289) The compound (41-2) (21.80 g, 141.36 mmol) and 1-pyrrolidino-1-cyclopentene (22.67 mL, 155.50 mL) were dissolved in xylene (64 mL), after which a resulting solution was stirred at reflux for 24 hours. After cooling at room temperature, 1N HCl was added dropwise into the resulting solution to perform an extraction with EtOAc, after which a resulting extract was dried over anhydrous MgSO.sub.4, filtered and concentrated. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (41-3) (12.20 g, 55.89 mmol, 59%).

(290) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.80 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 3.30 (t, J=7.6 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.08 (q, J=7.6 Hz, 2H), 2.12-2.04 (m, 2H), 1.38 (t, J=7.2 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H)

Step 4. Synthesis of 7-ethyl-2,3-dihydro-1H-indene-4-carboxylic acid (41-4)

(291) ##STR00109##

(292) The compound (41-3) (11.50 g, 52.68 mmol) was dissolved in methanol (230 mL), after which a 2N sodium hydroxide aqueous solution (115 mL) was added dropwise into a resulting solution, such that a resulting mixture was stirred at reflux for 5 hours. Methanol was concentrated under reduced pressure, after which a resulting concentrate was cooled at 0 C., such that 1N HCl was slowly added dropwise thereinto until a mixed solution reached pH 6. A resulting solid was filtered and dried in a nitrogen atmosphere, so as to obtain the title compound (41-4) (7.60 g, 39.95 mmol, 76%).

(293) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.69 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 3.21 (t, J=7.6 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H), 2.61 (q, J=7.6 Hz, 2H), 2.07-2.02 (m, 2H), 1.17 (t, J=7.6 Hz, 3H)

Step 5. Synthesis of 6-bromo-7-ethyl-2,3-dihydro-1H-indene-4-carboxylic acid (41-5)

(294) ##STR00110##

(295) The compound (41-4) (7.60 g, 39.95 mmol) was dissolved in acetic acid (140 mL), after which nitric acid (4.56 mL, 59.92 mmol) and bromine (3.07 mL, 59.92 mmol) were added dropwise in order into a resulting mixed solution. Silver nitrate (10.18 g, 59.92 mmol) was dissolved in water (50 mL), after which a resulting solution was slowly added dropwise into a reaction mixture, after which a resulting mixture was stirred at room temperature for 12 hours. A reaction mixture was cooled at 0 C., after which a saturated solution of sodium thiosulfate was slowly added dropwise into a resulting mixture, so as to complete a reaction. A resulting mixture was extracted twice with EtOAc, after which an organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. A concentrated solution was dried under vacuum to obtain the title compound (41-5), which was used in a following step without an additional purification.

Step 6. Synthesis of 5-bromo-4-ethyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene (41-6)

(296) ##STR00111##

(297) The title compound (41-6) was obtained with the compound (41-5) by means of a method as shown from Steps 1 to 3 of Example 4.

(298) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.13 (s, 1H), 7.10-7.02 (m, 4H), 3.82 (s, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.75 (t, J=7.6 Hz, 2H), 2.71 (q, J=7.6 Hz, 2H), 2.31 (s, 3H), 2.08-2.01 (m, 2H), 1.25 (t, J=7.6 Hz, 3H)

Step 7. Synthesis of a Target Compound

(299) ##STR00112##

(300) The target compound was obtained with a compound (41-6) by means of a method as shown from Steps 6 to 7 of Example 1.

(301) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.08 (s, 1H), 6.98 (s, 4H), 4.39 (d, J=9.2 Hz, 1H), 3.82-3.79 (m, 3H), 3.63-3.59 (m, 1H), 3.55 (t, J=9.2 Hz, 1H), 3.47-3.43 (m, 1H), 3.35 (d, J=6.0 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.78-2.71 (m, 1H), 2.67 (t, J=7.6 Hz, 2H), 2.63-2.58 (m, 1H), 2.22 (s, 3H), 1.99-1.91 (m, 2H), 1.10 (t, J=7.6 Hz, 3H)

Examples 42 to 60

(302) Target compounds of Examples 42 to 60 were obtained by means of a method as shown in Example 41.

Example 42. Preparation of (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-methoxybenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(303) ##STR00113##

(304) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.07 (s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 4.41 (d, J=9.6 Hz, 1H), 3.83-3.80 (m, 3H), 3.70 (s, 3H), 3.61 (dd, J=11.2, 3.7 Hz, 1H), 3.55 (t, J=9.2 Hz, 1H), 3.47-3.43 (m, 1H), 3.35 (d, J=5.2 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.78-2.73 (m, 1H), 2.68 (t, J=7.6 Hz, 2H), 2.64-2.58 (m, 1H), 1.99-1.92 (m, 2H), 1.11 (t, J=7.2 Hz, 3H)

Example 43. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(305) ##STR00114##

(306) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.12 (s, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 4.45 (d, J=9.6 Hz, 1H), 4.00 (dd, J=7.2, 6.8 Hz, 2H), 3.67-3.54 (m, 2H), 3.51-3.48 (m, 1H), 3.43-41 (n, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.83-2.61 (m, 5H), 2.04-1.96 (m, 3H), 1.35 (t, J=6.8 Hz, 4H), 1.15 (t, J=7.6 Hz, 3H)

Example 44. Preparation of (2S3R,4R,5S,6R)-2-(4-ethyl-7-(4-ethylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(307) ##STR00115##

(308) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.13 (s, 1H), 7.05 (s, 4H), 4.43 (d, J=9.6 Hz, 1H), 3.84 (d, J=4.8 Hz, 3H), 3.76-3.57 (m, 3H), 3.52-3.48 (m, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.83-2.78 (m, 1H), 2.73 (t, J=6.8 Hz, 2H), 2.68-2.61 (m, 1H), 2.59 (dd, J=8.0, 7.6 Hz, 3H), 2.04-1.96 (m, 3H), 1.21-1.07 (m, 5H)

Example 45. Preparation of (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(309) ##STR00116##

(310) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.17-7.13 (m, 3H), 6.97-6.92 (m, 2H), 4.45 (d, J=9.2 Hz, 1H), 3.90-3.84 (m, 3H), 3.68-3.64 (m, 1H), 3.64-3.57 (m, 1H), 3.52-3.48 (m, 1H), 3.43-3.40 (m, 2H), 2.89 (t, J=7.4 Hz, 2H), 2.83-2.76 (m, 1H), 2.73-2.63 (m, 3H), 2.04-1.97 (m, 2H), 1.15 (t, J=7.6 Hz, 3H)

Example 46. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-chlorobenzyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(311) ##STR00117##

(312) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.22 (d, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.13 (s, 1H), 4.45 (d, J=9.2 Hz, 1H), 3.91 (s, 2H), 3.86 (d, J=11.6 Hz, 1H), 3.63 (dd, J=11.6, 4.0 Hz, 1H), 3.56 (t, J=9.2 Hz, 1H), 3.52-3.48 (m, 1H), 3.40 (d, J=5.2 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.84-2.78 (m, 1H), 2.71 (t, J=7.6 Hz, 2H), 2.68-2.65 (m, 1H), 2.05-1.97 (m, 2H), 1.15 (t, J=7.6 Hz, 3H)

Example 47. Preparation of (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-trifluoromethoxy)benzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(313) ##STR00118##

(314) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.24 (d, J=8.4 Hz, 2H), 7.16 (s, 1H), 7.13 (d, J=8.8 Hz, 2H), 4.45 (d, J=9.2 Hz, 1H), 3.95 (s, 2H) 3.86 (d, J=12.0 Hz, 1H), 3.66 (dd, J=12.0, 4.0 Hz, 1H), 3.59 (t, J=9.2 Hz, 1H), 3.56-3.48 (m, 1H), 3.41 (d, J=5.6 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.84-2.79 (m, 1H), 2.72 (t, J=7.6 Hz, 2H), 2.69-2.63 (m, 1H), 2.05-1.98 (m, 2H), 1.16 (t, J=7.6 Hz, 3H)

Example 48. Preparation of (2S,3R,4R,5S,6R)-2-(4-ethyl-7-(4-trifluoromethyl)benzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(315) ##STR00119##

(316) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.53 (d, J=7.6 Hz, 2H), 7.35 (d, J=7.6 Hz, 2H), 7.17 (s, 1H), 4.46 (d, J=9.2 Hz, 1H), 4.01 (s, 2H), 3.86 (d, J=11.6 Hz, 1H), 3.69-3.65 (m, 1H), 3.62-3.57 (m, 1H), 3.53-3.48 (m, 1H), 3.41-3.40 (m, 2H), 2.92-2.88 (m, 2H), 2.84-2.77 (m, 1H), 2.77-2.64 (m, 3H), 2.05-1.98 (m, 2H), 1.16 (t, J=7.6 Hz, 3H)

Example 49. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-isopropoxybenzyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(317) ##STR00120##

(318) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.12 (s, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.55-4.48 (m, 1H) 4.44 (d, J=9.6 Hz, 1H), 3.87 (s, 1H), 3.68-3.57 (m, 2H), 3.52-3.48 (m, 1H), 3.43-3.39 (m, 2H), 3.31-3.18 (m, 2H), 2.88 (t, J=7.2 Hz, 2H), 2.83-2.63 (m, 4H), 2.04-1.97 (m, 2H), 1.27 (d, J=6.0 Hz, 6H), 1.15 (t, J=7.2 Hz, 3H)

Example 50. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-isopropylbenzyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(319) ##STR00121##

(320) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.14 (s, 1H), 7.07 (dd, J=8.4, 4.8 Hz, 4H), 4.44 (d, J=9.2 Hz, 1H), 3.88-3.81 (m, 2H), 3.68-3.58 (m, 2H), 3.52-3.48 (m, 1H), 3.41-3.39 (m, 2H), 3.28-3.03 (m, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.85-2.78 (m, 1H), 2.74 (t, J=7.6 Hz, 2H), 2.68-2.63 (m, 1H), 2.04-1.98 (m, 2H), 1.21 (d, J=6.8 Hz, 6H), 1.15 (t, J=7.2 Hz, 3H)

Example 51. Preparation of (2S,3R,4R,5S,6R)-2-(7-(biphenyl-3-ylmethyl)-4-ethyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(321) ##STR00122##

(322) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.52 (d, J=7.6 Hz, 2H), 7.37 (t, J=7.6 Hz, 4H), 7.27 (d, J=7.2 Hz, 2H), 7.16 (s, 1H), 7.10 (d, J=6.8 Hz, 1H), 4.42 (d, J=9.2 Hz, 1H), 3.96 (s, 1H), 3.84-3.81 (dd, J=12.4, 11.2, 1H), 3.62-3.55 (m, 2H), 3.47 (t, J=8.4 Hz, 1H), 3.67-3.58 (m, 2H), 2.86 (t, J=6.8 Hz, 2H), 2.80-2.73 (m, 3H), 2.65-2.60 (m, 2H), 2.00-1.95 (m, 2H), 1.12 (t, J=7.2 Hz, 3H)

Example 52. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(323) ##STR00123##

(324) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.07 (s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 4.38 (d, J=9.6 Hz, 1H), 3.82-3.80 (m, 3H), 3.70 (s, 3H), 3.61 (dd, J=12.0, 5.6 Hz, 1H), 3.55 (t, J=8.8 Hz, 1H), 3.45 (t, J=8.8 Hz, 1H), 3.34 (d, J=6.8 Hz, 2H), 2.83 (t, J=6.8 Hz, 2H), 2.75-2.66 (m, 3H), 2.57-2.50 (m, 1H), 1.99-1.91 (m, 2H), 1.55-1.48 (m, 2H), 0.96 (t, J=7.6 Hz, 3H)

Example 53. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methylbenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(325) ##STR00124##

(326) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.08 (s, 1H), 6.99 (s, 4H), 4.38 (d, J=8.8 Hz, 1H), 3.83-3.80 (m, 3H), 3.64-3.59 (m, 1H), 3.55 (t, J=8.8 Hz, 1H), 3.45 (t, J=8.8 Hz, 1H), 3.35 (d, J=5.6 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H), 2.75-2.66 (m, 3H), 2.56-2.50 (m, 1H), 2.23 (s, 3H), 1.99-1.91 (m, 2H), 1.55-1.50 (m, 2H), 0.97 (t, J=7.6 Hz, 3H)

Example 54. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(327) ##STR00125##

(328) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.08 (s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 4.40 (d, J=9.2 Hz, 1H), 3.96 (dd, J=7.2, 6.8 Hz, 2H), 3.83-3.82 (m, 1H), 3.62 (dd, J=6.4, 5.2 Hz, 1H), 3.55 (t, J=8.4 Hz, 1H), 3.45 (t, J=8.4 Hz, 1H) 3.38-3.36 (m, 2H), 3.27 (s, 2H), 2.83 (t, J=7.2 Hz, 2H), 2.74-2.67 (m, 3H), 2.58-2.52 (m, 1H), 1.99-1.93 (m, 2H), 1.56-1.50 (m, 2H). 1.31 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H)

Example 55. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(329) ##STR00126##

(330) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.13 (s, 1H), 7.05 (s, 4H), 4.44 (d, J=8.4 Hz, 1H), 3.88 (s, 2H), 3.67-3.63 (m, 1H), 3.59 (t, J=4.8 Hz, 1H), 3.49 (t, J=7.6 Hz, 1H), 2.88 (t, J=7.6 Hz, 2H), 2.79-2.71 (m, 3H), 2.61-2.55 (m, 4H), 2.03-1.95 (m, 3H), 1.59-1.54 (m, 3H), 1.19 (t, J=7.6 Hz, 3H), 1.01 (t, J=7.2 Hz, 3H)

Example 56. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-fluorobenzyl)-4-propyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(331) ##STR00127##

(332) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.17-7.13 (m, 3H), 6.97-6.92 (m, 2H), 4.43 (d, J=9.6 Hz, 1H), 3.90-3.84 (m, 3H), 3.68-3.63 (m, 1H), 3.60-3.56 (m, 1H), 3.51-3.47 (m, 1H), 3.43-3.39 (m, 2H), 2.88 (t, J=7.4 Hz, 2H), 2.80-2.70 (m, 3H), 2.62-2.54 (m, 1H), 2.03-1.96 (m, 2H), 1.59-1.52 (m, 2H), 1.01 (t, J=7.2 Hz, 3H)

Example 57. Preparation of (2S,3R,4R,5S,6R)-2-(4-butyl-7-(4-methoxybenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(333) ##STR00128##

(334) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.03-7.01 (m, 3H), 6.76 (d, J=8.4 Hz, 2H), 4.45 (d, J=8.4 Hz, 1H), 4.19 (br s, 1H), 4.05 (br s, 1H), 3.81 (s, 2H), 3.75-3.66 (m, 6H), 3.46-3.40 (m, 1H), 2.85 (t, J=7.2 Hz, 2H), 2.72 (t, J=7.2 Hz, 2H), 2.70-2.63 (m, 1H), 2.60-2.51 (m, 1H), 2.03-1.97 (m, 2H), 1.46-1.35 (m, 4H), 0.92 (t, J=6.8 Hz, 3H)

Example 58. Preparation of (2S,3R,4R,5S,6R)-2-(4-butyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(335) ##STR00129##

(336) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.05-6.98 (m, 5H), 4.45 (d, J=8.4 Hz, 1H), 4.30 (br s, 1H), 4.15 (br s, 1H), 3.84 (s, 2H), 3.80-3.69 (m, 3H), 3.43 (m, 1H), 2.85 (t, J=7.2 Hz, 2H), 2.72 (t, J=7.2 Hz, 2H), 2.68-2.62 (m, 1H), 2.60-2.51 (m, 1H), 2.26 (s, 3H), 2.03-1.95 (m, 2H), 1.50-1.38 (m, 4H), 0.92 (t, J=6.8 Hz, 3H)

Example 59. Preparation of (2S,3R,4R,5S,6R)-2-(4-butyl-7-(4-ethoxybenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(337) ##STR00130##

(338) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.07 (s, 1H), 7.01 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 4.38 (d, J=9.2 Hz, 1H), 3.94 (q, J=7.2 Hz, 2H), 3.83-3.79 (m, 3H), 3.63-3.59 (m, 1H), 3.58-3.53 (m, 1H), 3.46-3.42 (m, 1H), 3.35-3.34 (m, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.78-2.51 (m, 1H), 2.67 (t, J=7.6 Hz, 2H), 2.59-2.52 (m, 1H), 1.99-1.93 (m, 2H), 1.52-1.44 (m, 2H), 1.44-1.37 (m, 2H), 1.31 (t, J=6.8 Hz, 3H), 0.93 (t, J=6.8 Hz, 3H)

Example 60. Preparation of (2S,3R,4R,5S,6R)-2-(4-butyl-7-(4-ethylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(339) ##STR00131##

(340) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.08 (s, 1H), 7.01 (s, 4H), 4.38 (d, J=9.2 Hz, 1H), 3.83-3.79 (m, 3H), 3.63-3.59 (m, 1H), 3.58-3.53 (m, 1H), 3.46-3.42 (m, 1H), 3.35-3.34 (m, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.78-2.67 (m, 3H), 2.59-2.50 (m, 3H), 1.98-1.91 (m, 2H), 1.54-1.44 (m, 2H), 1.44-1.34 (m, 2H), 1.14 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H)

Example 61. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-isopropyl-7-(4-methoxybenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of (E)-ethyl 4-methylpent-2-enoate (61-1)

(341) ##STR00132##

(342) (Carbethoxymethylene)triphenylphosphorane (24.10 g, 69.34 mmol) was dissolved in DCM (101 mL), after which a resulting solution was cooled at 0 C., such that isobutyraldehyde (5.0 g, 69.34 mmol, aldrich) was slowly added dropwise into a resulting product, and then a resulting mixture was stirred at room temperature for 24 hours. A solvent of a reaction mixture was concentrated under reduced pressure, after which ether was added dropwise into a resulting concentrate, such that a resulting solid was filtered and removed. A resulting filtrate was collected and concentrated under reduced pressure, after which a resulting residue was purified by means of a silica gel column chromatography, so as to obtain the title compound (61-1) (8.48 g, 59.63 mmol, 86%).

(343) .sup.1H NMR (400 MHz, CDCl.sub.3); 6.95 (dd, J=15.6, 6.8 Hz, 1H), 5.77 (dd, J=15.6, 1.2 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 2.50-2.42 (m, 1H), 1.29 (t, J=7.2 Hz, 3H), 1.06 (d, J=6.8 Hz, 6H)

Step 2. Synthesis of (E)-4-methylpent-2-en-1-ol (61-2)

(344) ##STR00133##

(345) Lithium aluminum hydride (6.79 g, 178.9 mmol) and aluminum chloride (7.95 g, 59.63 mmol) were diluted in diethyl ether (500 mL), after which a resulting solution was cooled at 78 C. A compound according to an inventive title (61-1) (8.48 g, 59.63 mmol) in diethyl ether (50 mL) was slowly added dropwise into a reaction mixture, after which a resulting mixture was stirred at the same temperature for 2 hours. Water was slowly added dropwise into the resulting mixture, after which a reaction was completed, such that a resulting solid was filtered and removed. An organic layer was washed with brine, after which the resulting product was dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. A concentrated solution was dried under vacuum to obtain the title compound (61-2), which was used in a following step without an additional purification.

(346) .sup.1H NMR (400 MHz, CDCl.sub.3); 5.65 (d, J=6.4 Hz, 1H), 5.60 (t, J=6.0 Hz, 1H), 4.09 (d, J=5.2 Hz, 2H), 2.35-2.27 (m, 1H), 1.00 (d, J=6.8 Hz, 6H)

Step 3. Synthesis of a Target Compound

(347) ##STR00134##

(348) The target compound was obtained with the compound (61-2) by means of a method as shown from Steps 1 to 7 of Example 41.

(349) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.13 (s, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 4.55 (br s, 1H), 3.87-3.85 (m, 3H), 3.74 (s, 3H), 3.68-3.64 (m, 1H), 3.62-3.56 (m, 1H), 3.51-3.47 (m, 2H), 3.40-3.38 (m, 2H), 3.02 (t, J=7.2 Hz, 2H), 2.67-2.61 (m, 2H), 1.99-1.92 (m, 2H), 1.32-1.30 (m, 6H)

Examples 62 and 63

(350) Target compounds of Examples 62 and 63 were obtained by means of a method as shown in Example 61.

Example 62. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-isopropyl-7-(4-methoxybenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

(351) ##STR00135##

(352) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.14 (s, 1H), 7.02 (s, 4H), 4.55 (br s, 1H), 3.86-3.84 (m, 3H), 3.67-3.64 (m, 1H), 3.62-3.57 (m, 1H), 3.52-3.48 (m, 2H), 3.40-3.38 (m, 2H), 3.00 (t, J=7.2 Hz, 2H), 2.67-2.63 (m, 2H), 2.27 (s, 3H), 1.98-1.91 (m, 2H), 1.32-1.30 (m, 6H)

Example 63. Preparation of (2S,3R,4R,5S,6R)-2-(4-cyclopentyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(353) ##STR00136##

(354) .sup.1H NMR (400 MHz, CD.sub.3OD); 7.10 (br s, 1H), 7.98 (s, 4H), 4.50 (br s, 1H), 3.82-3.79 (m, 3H), 3.63-3.59 (m, 1H), 3.58-3.48 (m, 1H), 3.46-3.42 (m, 1H), 3.35-3.33 (m, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.23 (s, 3H), 1.97-1.78 (m, 9H), 1.74-1.64 (m, 2H)

Example 64. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-isobutyl-7-(4-methylbenzyl)-2,3-dihydro-1H-indene-5-yl)tetrahydro-2H-pyran-3,4,5-triol

Step 1. Synthesis of (2E,4E)-ethyl 7-methylocta-2,4-dienoate (64-1)

(355) ##STR00137##

(356) n-BuLi (14.5 mL, 36.29 mmol, 2.5 M in n-hexane) was added into a solution of isopentyltriphenylphosphonium bromide (15.0 g, 36.29 mmol) in THF (50 mL) at 78 C. in a nitrogen atmosphere, after which a resulting mixture was stirred at the same temperature for 1 hour. Ethyl 4-oxobut-2-enoate (1.55 g, 12.09 mmol) was slowly added dropwise into the resulting mixture, after which the resulting mixture was stirred for 30 minutes with a temperature rising to room temperature. A reaction mixture was cooled at 0 C., after which a saturated solution of ammonium chloride was added dropwise into a resulting product, so as to complete a reaction and perform an extraction with diethyl ether. An organic layer was dried over anhydrous MgSO.sub.4, filtered and concentrated under reduced pressure. A resulting concentrate was purified by means of a silica gel column chromatography, so as to obtain the title compound (64-1) (1.89 g, 10.37 mmol, 86%).

(357) .sup.1H NMR (400 MHz, CDCl.sub.3); 5.60 (dd, J=15.2, 11.2 Hz, 1H), 6.17 (t, J=11.2 Hz, 1H), 5.91-5.84 (m, 2H), 4.21 (q, J=7.2 Hz, 2H), 2.20 (t, J=7.2 Hz, 2H), 1.72-1.65 (m, 1H), 1.29 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.8 Hz, 6H)

Step 2. Synthesis of a Target Compound

(358) ##STR00138##

(359) The target compound was obtained with the compound (64-1) by means of a method as shown from Steps 3 to 7 of Example 41.

(360) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.07-7.01 (m, 5H), 4.49 (d, J=8.4 Hz, 1H), 3.88-3.85 (m, 3H), 3.78-3.74 (m, 1H), 3.72-3.65 (m, 3H), 3.49-3.44 (m, 1H), 2.88 (t, J=7.2 Hz, 2H), 2.80-2.75 (m, 2H), 2.66-2.61 (m, 1H), 2.49-2.44 (m, 1H), 2.30 (s, 3H), 2.03-1.98 (m, 2H), 1.86-1.79 (m, 1H), 0.94 (d, J=6.4 Hz, 6H)

Example 65. Preparation of (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-iso butyl-2,3-dihydro-1H-indene-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(361) ##STR00139##

(362) The target compound was obtained with a compound (64-1) by means of a method as shown in Step 2 of Example 64.

(363) .sup.1H NMR (400 MHz, CDCl.sub.3); 7.11-7.05 (m, 5H), 4.50 (d, J=8.4 Hz, 1H), 3.89-3.87 (m, 3H), 3.81-3.74 (m, 1H), 3.73-3.66 (m, 3H), 3.51-3.46 (m, 1H), 2.88 (t, J=7.2 Hz, 2H), 2.82-2.76 (m, 2H), 2.66-2.58 (m, 3H), 2.49-2.44 (m, 1H), 2.03-1.97 (m, 2H), 1.86-1.79 (m, 1H), 1.21 (t, J=7.2 Hz, 3H), 0.94 (d, J=6.4 Hz, 6H)

Experimental Example 1. Human SGLT1, SGLT2 Gene Cloning and Construction of Cell Lines for Expressing Human SGLT1, SGLT2

(364) Human SGLT1 (hSGLT1), human SGLT2 (hSGLT2) genes were amplified from a human marathon-ready cDNA library (Clontech)) by means of an PCR method, after which resulting amplified sequences were combined with a pcDNA 3.1(+) vector, which was a mammalian expression vector, so as to prepare recombinant expression vectors pcDNA3.1(+)/hSGLT1, pcDNA3.1(+)/hSGLT2. Resulting recombinant expression vectors were transformed into Chinese Hamster Ovarian cells, after which stably transformed clones were selected by means of a colony picking method by using a resistance to G418, a selective marker included in the vector. Out of selected clones, clones for expressing hSGLT1 and hSGLT2 were selected based on activity in analysis of .sup.14C--methyl-D-glucopyranoside (.sup.14C-AMG) transport.

Experimental Example 2. Inhibitory Effect on Human SGLT1, SGLT2 Activity

(365) To analyze a sodium-dependent glucose transport, cells for expressing hSGLT1 and hSGLT2 were seeded at 110.sup.5 cells per well into a 96-well culture plate, after which resulting cells were cultured in an RPMI 1640 medium containing 10% fetal bovine serum (FBS). In 1 day after culture, the resulting cells were cultured in a pre-treatment buffer solution (10 mM HEPES, 5 mM tris, 140 mM choline chloride, 2 mM KCl, 1 mM CaCl.sub.2 and 1 mM MgCl.sub.2, pH 7.4) under 37 C./5% CO.sub.2 conditions for 10 minutes. Then, the resulting cells were cultured in a uptake buffer solution (10 mM HEPES, 5 mM tris, 140 mM NaCl, 2 mM KCl, 1 mM CaCl.sub.2, 1 mM MgCl.sub.2 and 1 mM AMGS pH 7.4) containing 14C-AMG (8 M) and a compound of the present disclosure or a dimethyl sulfoxide (DMSO) vehicle under 37 C./5% CO.sub.2 conditions for 2 hours. After culture, the cells were washed twice with a washing buffer solution (a pre-treatment buffer solution containing 10 mM AMG at room temperature), after which a radiation thereof was measured by using a liquid scintillation counter. IC.sub.50 of each compound was measured according to a non-linear regression analysis by using SigmaPlot (Document Analytical Biochemistry 429: 70-75, Molecular and Cellular Biochemistry 280: 91-98, 2005). SGLT1/2 in-vitro assay results are shown in a following Table 1.

(366) TABLE-US-00001 TABLE 1 Compound SGLT1 (IC.sub.50, nM) SGLT2 (IC.sub.50, nM) Canagliflozin 550 4.9 Example 1 9.1 1.3 Example 2 76 3.0 Example 3 142 Example 5 40 2.8 Example 6 190 Example 7 296 Example 13 15 1.2 Example 16 14.3 Example 34 295 Example 41 41.82 3.68 Example 42 60.51 2.73 Example 52 235.63 9.04 Example 53 94.72 1.83 Example 57 373.28 5.86 Example 58 288.61 12.06 Example 61 198.68 2.04 Example 62 92.74 1.46 Example 64 518.28 19.10 Example 65 1611.05 37.97

Experimental Example 3. Experiment on Measurement of Urinary Glucose Excretion (UGE Test)

(367) With regard to a pharmaceutical efficacy of a compound prepared in the Example, 1 mg/kg of such compound was orally administered into a normal mouse, after which an UGE test was performed. As a result, it was identified that the compound of the present disclosure increased a urine glucose (mg/24 h) and decreased a blood glucose level (mg/dl).

(368) Accordingly, the compound of the present disclosure is expected to be valuably used in treatment or prevention of diabetes.

Experimental Example 4. Experiment on Measurement of Anti-Diabetes Activity

(369) With regard to a pharmaceutical efficacy of a compound prepared in the Example, 2 mg/kg of such compound was orally administered into each db/db mouse and DIO mouse for 4 weeks, after which a change in blood sugar level was measured. As a result, it was identified that the blood sugar level was remarkably decreased.

(370) Also, with regard to a pharmaceutical efficacy of the compound prepared in the Example above, such compound was administered into an OB/OB mouse for 2 weeks, after which a change in blood sugar level was measured. As a result, it was identified that the blood sugar level was remarkably decreased.

(371) Accordingly, the compound of the present disclosure is expected to be valuably used in treatment or prevention of diabetes.

Experimental Example 5. Experiment on Measurement of Oral Glucose Resistance

(372) To identify a pharmaceutical efficacy of a compound prepared in the Example, a post prandial glucose was measured with regard to a normal mouse. As a result, it was identified that a blood glucose AUC0-4 h: mg-h/dL in 4 hours after administration of the compound (1 mg/kg) was significantly decreased.

(373) Such result was also found in an experiment with a db/db mouse, thus it was identified that blood glucose AUC0-4 h: mg-h/dL in 4 hours after administration of the compound (2 mg/kg) was significantly decreased.

(374) Also, in the experiment with the db/db mouse, it was also identified that blood glucose AUC0-4 h: mg-h/dL in 4 hours after administration of the compound (10 mg/kg) was significantly decreased, too.

(375) Accordingly, the compound of the present disclosure is expected to be valuably used in treatment or prevention of diabetes.

(376) While specific portions of the present disclosure have been described in detail above, it is apparent to those skilled in the art that such detailed descriptions are set forth to illustrate exemplary embodiments only, but are not construed to limit the scope of the present disclosure. Thus, it should be understood that the substantial scope of the present disclosure is defined by the accompanying claims and equivalents thereto.