HK1259905B - C-glycoside derivatives having fused phenyl ring or pharmaceutically acceptable salts thereof, method for preparing the same and pharmaceutical composition comprising the same - Google Patents

Description

C-glucoside derivatives having fused benzene rings or pharmaceutically acceptable salts thereof, preparation methods thereof, and pharmaceutical compositions containing the same

Technical Field

The present invention relates to C-glucoside derivatives having a fused benzene ring or pharmaceutically acceptable salts thereof, methods for preparing the same, pharmaceutical compositions containing the same, uses thereof, and methods for dually inhibiting sodium-glucose co-transporter 1 (SGLT1) and sodium-glucose co-transporter 2 (SGLT2) using the same.

Background Art

Diabetes mellitus is a disease that can develop various complications, such as peripheral and autonomic nervous system abnormalities, eye, foot and kidney disease syndromes, vascular diseases, etc., which are caused by increased blood sugar due to decreased insulin secretion and function.

It is known that diabetes is generally divided into two types: type I and type II. Type I often occurs in children, mainly due to congenital factors, and these patients need lifelong insulin injections because the pancreas cannot secrete insulin. They also need to maintain their blood sugar at an appropriate level through diet therapy and regular checkups. Type II mainly occurs in adults. Its condition is that due to lifestyle (such as eating habits, lack of exercise, obesity, etc.) and environmental factors, insulin secretion decreases or insulin resistance develops to a high enough level that prevents cells from responding to insulin. This type of disease accounts for 90-95% of the 285 million diabetic patients worldwide. Patients with type II diabetes can regulate their blood sugar by losing weight, eating a healthy diet and exercising, but due to the progressive nature of the disease, the syndrome will cause damage to the body. Therefore, patients have no other choice but to undergo insulin injections, and the main symptoms caused by high blood sugar are polyuria, thirst, listlessness, excessive appetite, weight loss, etc.

The main medications for treating diabetes are insulin and oral hypoglycemic agents. Type I diabetes is treated with insulin injections, while type II diabetes is treated with oral hypoglycemic agents alone or in combination with insulin. Currently used oral hypoglycemic agents include sulfonylureas and meglitinides for stimulating insulin secretion, biguanides (metformin) and thiazolidinediones (PPAR-γ) for improving insulin sensitivity, α-glucosidase inhibitors for inhibiting sugar digestion, insulin-based DPP-4 inhibitors, and SGLT2 inhibitors for preventing glucose reabsorption. Despite these oral hypoglycemic agents, many patients still find it difficult to lower their glycosylated hemoglobin to target levels or below. Furthermore, in a study targeting vascular risk factor regulation in diabetic patients, only 37% of participants were able to achieve glycosylated hemoglobin levels below 7.0% (Saydah, S.H. et al., J. Am. Med. Assoc. 2004, 291, 335-342). Meanwhile, existing oral hypoglycemic agents have multiple side effects, such as gastrointestinal problems, hypoglycemia, weight gain, lactic acidemia, edema, myocardial toxicity and hepatotoxicity, and are accompanied by the limited persistence of medical effect. Therefore, in the field of oral hypoglycemic agents, there is still a medical demand, and it is urgent to develop a therapeutic agent with the rapid effect of a new mechanism, which has excellent effectiveness and persistence, safety and good drug tolerance of a medical effect, and particularly can not cause hypoglycemia. Therefore, many people focus on the oral formulations of research and development SGLT2 inhibitors as a new mechanism, wherein this inhibitor is unrelated to insulin, but has suitable effectiveness, and can reduce weight simultaneously.

Sodium-glucose cotransporters (SGLTs) are transporters responsible for glucose absorption in the body. They are divided into six subtypes and are expressed in several areas of the body, with SGLT1 primarily expressed in the intestines and kidneys, and SGLT2 primarily expressed in the kidneys. SGLT1 has a high affinity for glucose but poor transport performance, while SGLT2 has a low affinity for glucose but high transport performance. Healthy people reabsorb 99% of glucose filtered by the glomeruli, but excrete only 1% or less in the urine, with 90% and 10% of this glucose being reabsorbed by SGLT2 and SGLT1, respectively. However, patients with type 2 diabetes have high expression of both SGLT1 and SGLT2, resulting in increased glucose absorption in the intestine via SGLT1 and increased glucose reabsorption in the kidneys via SGLT1/2, which also contributes to increased blood sugar levels. Consequently, research is underway to develop hypoglycemic drugs with novel mechanisms of action, in which blood sugar is normalized by inhibiting SGLT1/2 to restore pancreatic insulin secretion and improve insulin resistance in muscle and liver.

Phlorizin, extracted from the bark of an apple tree, was the first substance evaluated as an SGLT2 inhibitor. While it exhibits antidiabetic activity, it has low oral absorption and is absorbed in the intestine, leading to gastrointestinal problems and diarrhea, preventing its development as a drug. Similarly, T-1095 was developed by Tanabe Seiyaku in the 1990s as an orally absorbed SGLT2 inhibitor, but its development was halted during Phase II clinical trials. Sergliflozin or remogliflozin, an O-glucoside with a similar structure, was also halted during Phase II clinical development. C-glucosides were developed to avoid metabolism by β-glucosidase, a vulnerability of O-glucosides. Following Bristol-Myers Squibb's clinical trials of dapagliflozin in 2004, numerous pharmaceutical companies began developing this class of drugs. Then, in 2012, dapagliflozin received its first marketing authorization in Europe, and canagliflozin (Johnson & Johnson, Mitsubishi Tanabe) received its first marketing authorization in the United States in 2013. Dapagliflozin and empagliflozin (Boehringer-Ingelheim) also received marketing authorization in the United States, while ipragliflozin (Astellas), luseogliflozin (Taisho), and tofogliflozin (Chugai) each received marketing authorization in Japan. It is also known that SGLT1 plays an important role in the absorption of glucose and galactose in the small intestine and the reabsorption of glucose in the kidney (Levin, R.J., Am. J. Clin. Nutr. 1994, 59(3), 690S-698S). Therefore, it is believed that by inhibiting SGLT1, the absorption of glucose in the small intestine and the reabsorption of glucose in the kidney can be inhibited, thereby having an effect on blood sugar control. Therefore, SGLT1/2 dual inhibitors may become a new mechanism for treating diabetes. Sotagliflozin is a dual SGLT1/2 inhibitor that is currently in Phase III clinical trials for type 1 diabetes and is preparing for Phase III clinical trials for type 2 diabetes. LIK-066 is a dual SGLT1/2 inhibitor, a product of Novartis, and is also currently in Phase II clinical trials.

Summary of the Invention

Technical issues

The object of the present disclosure is to provide a novel compound or a pharmaceutically acceptable salt thereof, which has dual inhibitory activity against SGLT1/2.

Another object of the present disclosure is to provide a method for preparing the compound.

Another object of the present disclosure is to provide a pharmaceutical composition for preventing or treating SGLT1/2-related diseases, which comprises the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present disclosure is to provide use of the compound in preparing a medicament for preventing or treating SGLT1/2 related diseases.

Yet another object of the present disclosure is to provide a method for preventing or treating SGLT1/2-related diseases, which comprises administering a therapeutically effective dose of the pharmaceutical composition of the present disclosure.

Technical Solution

To achieve the above-mentioned object, the inventors of the present invention have made many efforts and identified that a C-glucoside derivative having a newly synthesized fused benzene ring exhibits dual inhibitory activity against SGLT1/2, thereby completing the present disclosure.

C-glucoside-derived compounds having fused benzene rings

The present disclosure provides a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 1]

in:

X and Y are each independently _-CH2- , -CH( _CH3 )-, -C( _CH3 ) _2- , -C(=O)-, -O-, -S- or -NH-;

m is an integer from 1 to 3;

R ₁ -R ₃ are each independently hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, -C(=O)R ₄ , cyano, hydroxy, C1-C4 alkoxy, -OCF ₃ , -SR ₅ , -S(=O)R ₆ , -S(=O) ₂ R ₇ , nitro, -NR ₈ R ₉ , aryl, heteroaryl or heterocyclic group (wherein at least one hydrogen in the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C7 cycloalkyl group may be independently unsubstituted or substituted with at least one substituent selected from the following group: halogen, hydroxyl, cyano, nitro and amino, and at least one hydrogen in the aryl, heteroaryl and heterocyclic group may be independently unsubstituted or substituted with at least one substituent selected from the following group: halogen, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, cyano, nitro and amino);

R ₄ is hydroxy, C1-C4 alkoxy, amino, mono- or di-(C1-C4 alkyl)amino;

_R5 is hydrogen or C1-C4 alkyl;

_R6 and _R7 are each independently C1-C4 alkyl or aryl (wherein the aryl may be unsubstituted or substituted with C1-C4 alkyl);

R ₈ and R ₉ are each independently hydrogen, C1-C4 alkyl, -C(=O)R ₁₀ or -S(=O) ₂ R ₁₁ ;

R ₁₀ is C1-C4 alkyl; and

R ₁₁ is a C1-C4 alkyl group or an aryl group; (wherein the aryl group may be unsubstituted or substituted with a C1-C4 alkyl group);

wherein, if m is 1, R ₁ is halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, —C(═O)R ₄ , cyano, hydroxy, C1-C4 alkoxy, —OCF ₃ , —SR ₅ , —S(═O)R ₆ , —S(═O) ₂ R ₇ , nitro, —NR ₈ R ₉ , aryl, heteroaryl or heterocyclyl.

According to one embodiment of the present disclosure,

X and Y are each independently -CH ₂ - or -O-;

m is 1 or 2;

R ₁ -R ₃ are each independently hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, hydroxy, C1-C4 alkoxy, -OCF ₃ , -SR ₅ or aryl (wherein at least one hydrogen in the C1-C4 alkyl, C2-C4 alkenyl and C3-C7 cycloalkyl may each independently be unsubstituted or substituted with halogen or hydroxy, and the hydrogen in the aryl may each independently be unsubstituted or substituted with at least one substituent selected from the following group: halogen, C1-C4 alkyl, hydroxy and C1-C4 alkoxy); and

_R5 is a C1-C4 alkyl group.

According to another embodiment of the present disclosure,

X and Y are each independently -CH ₂ - or -O-;

m is 1 or 2;

R ₁ is hydrogen, halogen, C1-C4 alkyl, C3-C7 cycloalkyl or C1-C4 alkoxy (wherein at least one hydrogen in the C1-C4 alkyl group may be independently unsubstituted or substituted by halogen);

_R2 and _R3 are each independently hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, C1-C4 alkoxy, _-OCF3 , _-SR5 or aryl (wherein at least one hydrogen in the C1-C4 alkyl, C2-C4 alkenyl and C3-C7 cycloalkyl may each independently be unsubstituted or substituted with halogen, and at least one hydrogen in the aryl may each independently be unsubstituted or substituted with at least one substituent selected from the following group: halogen, C1-C4 alkyl and C1-C4 alkoxy); and

_R5 is C1-C4 alkyl;

In the present disclosure, examples of halogen are fluorine, chlorine, bromine or iodine.

In the present disclosure, the alkyl group refers to a linear or branched monovalent hydrocarbon group, wherein examples of the alkyl group may include methyl, ethyl, n-propyl, i-propyl, and butyl.

In the present disclosure, the cycloalkyl group may include cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, and cycloheptyl.

In the present disclosure, the alkoxy group may be a linear, branched or cyclic chain, and may include methoxy, ethoxy, n-propoxy, isopropoxy, i-propoxy, n-butoxy, isobutoxy, tert-butoxy and sec-butoxy.

In the present disclosure, the alkenyl group refers to a linear or branched monovalent hydrocarbon group, wherein examples of the alkenyl group may include ethenyl, 1-propenyl, i-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl.

In the present disclosure, the aryl group refers to a monocyclic or polycyclic aryl group, wherein the monocyclic aryl group may include phenyl, biphenyl and terphenyl, and the polycyclic aryl group may include naphthyl, anthracenyl, fluorenyl, pyrenyl and the like.

In the present disclosure, the heteroaryl group refers to a group containing at least one non-carbon heteroatom in the aryl group.

In the present disclosure, the heterocyclic group refers to a group containing at least one non-carbon heteroatom in the cycloalkyl group.

In the present disclosure, the heteroatom may include O, S, and N in addition to carbon.

According to one embodiment of the present disclosure, X is -CH ₂ -.

According to another embodiment of the present disclosure, X is -O-.

According to one embodiment of the present disclosure, Y is -CH ₂ -.

According to another embodiment of the present disclosure, Y is -O-.

According to one embodiment of the present disclosure, X and Y are -CH ₂ -.

According to another embodiment of the present disclosure, X and Y are -O-.

According to one embodiment of the present disclosure, one of X and Y is _-CH2- , and the other is -O-.

According to one embodiment of the present disclosure, R ₁ is hydrogen.

According to another embodiment of the present disclosure, R ₁ is halogen. Specifically, R ₁ can be chlorine.

According to another embodiment of the present disclosure, R ₁ is a C1-C4 alkoxy group. Said R ₁ is a methoxy group.

According to another embodiment of the present disclosure, R ₁ is a C1-C4 alkyl group. The C1-C4 alkyl group may be a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, or an isopropyl group.

According to another embodiment of the present disclosure, R ₁ is a C3-C7 cycloalkyl group. The C3-C7 cycloalkyl group may be a cyclopentyl group.

According to one embodiment of the present disclosure, R ₄ is hydrogen.

According to one embodiment of the present disclosure, _R2 is a C1-C4 alkyl group. The C1-C4 alkyl group may be methyl, ethyl, propyl, butyl, isobutyl or isopropyl. At least one hydrogen in the C1-C4 alkyl group may be independently unsubstituted or substituted with halogen, particularly fluorine.

According to another embodiment of the present disclosure, R ₂ is a C1-C4 alkenyl group. The C2-C4 alkenyl group may specifically be a vinyl group.

According to another embodiment of the present disclosure, R ₂ is a C1-C4 alkoxy group, which may be a methoxy group, an ethoxy group, or an isopropoxy group.

According to another embodiment of the present disclosure, R ₂ is -OCF ₃ .

According to another embodiment of the present disclosure, R ₂ may be halogen. Specifically, R ₂ may be fluorine or chlorine.

According to another embodiment of the present disclosure, R ₂ is -SR ₅ , and said R ₅ is C1-C4 alkyl.

According to another embodiment of the present disclosure, R ₂ is an aryl group. Specifically, the aryl group can be a phenyl group.

According to one embodiment of the present disclosure, R ₃ is hydrogen.

According to another embodiment of the present disclosure, R ₃ is a C1-C4 alkoxy group. Specifically, the C1-C4 alkoxy group can be a methoxy group, an ethoxy group, or an isopropoxy group.

According to another embodiment of the present disclosure, R ₃ is a C1-C4 alkyl group. Specifically, the C1-C4 alkyl group can be a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group or an isopropyl group.

According to one embodiment of the present disclosure, R ₃ may be substituted at the 3rd position of the phenyl ring of formula i).

According to another embodiment aspect of the present disclosure, R ₃ may be substituted at the 2-position of the phenyl ring of formula i).

According to a preferred embodiment of the present disclosure, the compound represented by the above formula 1 can be selected from the following compound groups:

(2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)-4-methyl-2,3-dihydro-1H-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-methyl-2,3-dihydro-1H-inden-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-inden-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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-methyl-2,3-dihydro-1H-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-(7-(4-fluorobenzyl)-4-methyl-2,3-dihydro-1H-inden-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-inden-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-inden-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(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;

(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;

(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;

(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;

(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;

(2S,3R,4R,5S,6R)-2-(4-(4-ethoxybenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-(4-(4-ethylbenzyl)-5,6,7,8-tetrahydronaphthalen-2-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-tetrahydronaphthalen-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-tetrahydronaphthalen-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-tetrahydronaphthalen-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-tetrahydronaphthalen-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-tetrahydronaphthalen-2-yl)tetrahydro-2H-pyran-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-(4-(4-chlorobenzyl)-1-methyl-5,6,7,8-tetrahydronaphthalen-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-propyl-2,3-dihydro-1H-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol;

(2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-isopropyl-7-(4-methoxybenzyl)-2,3-dihydro-1H-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-(4-cyclopentyl-7-(4-methylbenzyl)-2,3-dihydro-1H-inden-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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol;

(2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-isobutyl-2,3-dihydro-1H-inden-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

The compounds of Formula 1 of the present disclosure may exist in the form of pharmaceutically acceptable salts. Acid addition salts formed from pharmaceutically acceptable free acids may serve as such salts. In the present disclosure, the term "pharmaceutically acceptable salt" refers to any and all organic or inorganic acid addition salts of the compounds, wherein the side effects caused by such salts at concentrations at which they are relatively nontoxic and harmless to patients do not reduce the beneficial effects of the compound of Formula 1.

The acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid solution and then precipitating the resulting salt with a water-miscible organic solvent (e.g., methanol, ethanol, acetone, or acetonitrile). Isomolar amounts of the compound and the acid can be heated in water or an alcohol (e.g., ethylene glycol monomethyl ether), and the mixture can then be evaporated and dried, or the precipitated salt can be filtered with suction.

At this time, organic acids and inorganic acids can be used in the form of free acids, among which hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and the following can be used as organic acids: methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc., but are not limited to these.

Similarly, pharmaceutically acceptable metal salts can be prepared by alkali. Alkali metal salts or alkaline earth metal salts can be obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, then filtering the undissolved compound salt, and then evaporating the remaining solution and drying. In this case, as the metal salt, it is pharmaceutically suitable to prepare, in particular, sodium salts, potassium salts or calcium salts, but is not limited thereto. Similarly, corresponding silver salts can be obtained by reacting an alkali metal salt or alkaline earth metal salt with a suitable silver salt (such as silver nitrate).

Unless otherwise indicated, the pharmaceutically acceptable salts of the present disclosure include salts of acidic or basic groups present in the compounds of Formula 1. For example, the pharmaceutically acceptable salts may include sodium, calcium, potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, mesylate, tosylate, etc., which can be prepared by methods known in the art for preparing salts.

Method for preparing C-glucoside derivative compounds having fused benzene rings

The present disclosure provides a method for preparing a C-glucoside derivative compound having a fused benzene ring as shown in Formula 1 or a pharmaceutically acceptable salt thereof.

The compounds of formula I of the present disclosure can be prepared by the following steps:

The method comprises the following steps:

(S1) reacting a compound of the following formula II with a compound of the following formula III to obtain a compound of the following formula IV; and

(S2) subjecting the compound of Formula IV to a deprotection-reduction or reduction-deprotection reaction to obtain a compound of Formula I:

[Formula II]

[Formula III]

[Formula IV]

[Formula I]

wherein X, Y, m, R ₁ , R ₂ and R ₃ are as defined in the present disclosure, and P is trimethylsilyl or benzyl.

In one embodiment of the present disclosure, if P is a trimethylsilyl group, the compound of the following formula V is obtained by deprotecting the compound of formula IV, and the compound of formula I is obtained by reducing the compound of formula V:

[Formula V]

wherein X, Y, m, R ₁ , R ₂ and R ₃ are as defined in the present disclosure.

In another embodiment of the present disclosure, if P is benzyl, the compound of the following formula VI is obtained by reducing the compound of formula IV, and the compound of formula I is obtained by deprotecting the compound of formula VI:

[Formula VI]

wherein X, Y, m, R ₁ , R ₂ , R ₃ and P are as defined in the present disclosure.

Detailed methods for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof are shown in Reaction Scheme 1 and Reaction Scheme 2, including methods for modifying the same to meet the level of those skilled in the art.

[Reaction formula 1]

The brominated compound III undergoes a lithium-halogen exchange reaction, and the resulting product is then reacted with the fully silylated gluconolactone compound II-1 to produce a lactol mixture IV-1. The resulting mixture is treated with methanesulfonic acid in methanol in the same reaction system, thereby converting it into the desilylated O-methyl lactol compound V. The anomer methoxy group of this lactol compound V is reduced with triethylsilane and boron trifluoride diethyl etherate to produce a mixture of the corresponding α,β-isomers. The necessary β-isomer I is resolved into a fully acetylated mixture of the final compounds or subjected to selective crystallization by HPLC for sample extraction.

[Reaction formula 2]

Similarly, lactol compound IV-2 is prepared by perbenzylation of gluconolactone compound II-2. The anomer hydroxyl group of compound IV-2 is then reduced with triethylsilane and boron trifluoride diethyl etherate to produce a mixture of α and β-isomers. The required β-isomer VI is decomposed by selective crystallization. The benzyl group of compound VI is deprotected using Pd/C in a hydrogen atmosphere to yield the target compound I.

Compositions comprising C-glucoside derivative compounds having fused benzene rings, uses thereof, and methods of treatment using the same

The present disclosure provides a pharmaceutical composition for preventing or treating a disease related to SGLT activity, comprising a compound represented by the following Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

The above formula 1 is as defined above.

The compounds of Formula 1 disclosed herein or their pharmaceutically acceptable salts may exhibit inhibitory activity against SGLT1, SGLT2, or both. Therefore, the compounds of Formula 1 disclosed herein or their pharmaceutically acceptable salts may be valuable for treating or preventing diabetes.

For administration, the pharmaceutical composition of the present disclosure may further include at least one pharmaceutically acceptable carrier in addition to the above-mentioned Formula 1 compound or its pharmaceutically acceptable salt. The pharmaceutically acceptable carrier may be a mixture of saline solution, sterile water, Ringer's solution, buffered saline, glucose solution, maltodextrin solution, glycerol, ethanol and at least one of the above-mentioned ingredients, wherein other conventional additives such as antioxidants, buffer solutions, antibacterial agents, etc. may also be added thereto if necessary. Similarly, in the pharmaceutical composition of the present disclosure, diluents, dispersants, surfactants, adhesives and lubricants may also be added in addition so that it can be formulated into dosage forms such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, powders, tablets, etc. for injection. Therefore, the composition of the present disclosure may be a patch, a liquid, a pill, a capsule, a powder, a tablet, a suppository, etc. Such preparations may be prepared by conventional methods known in the art for preparing preparations or by methods disclosed in the following documents: Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, wherein the composition may be formulated into various preparations according to each disease or component.

The compositions of the present disclosure can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) according to the intended method, wherein the dosage range varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, severity of the disease, etc. The daily dose of the compound of Formula 1 disclosed herein can be about 1-1000 mg/kg, preferably 5-100 mg/kg, wherein the dose can be administered once daily to the patient in divided doses.

In addition to the compound of Formula 1 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition of the present disclosure may further comprise at least one active ingredient having the same or similar pharmaceutical effects.

The present disclosure provides a method for preventing or treating diseases related to SGLT activity, comprising administering a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The term "therapeutically effective amount" used herein refers to the amount of the compound of Formula 1 that can effectively prevent or treat the SGLT activity-related disease.

Likewise, the present disclosure can inhibit SGLT1, SGLT2, or both by administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to a mammal, including a human.

The method for preventing or treating the SGLT activity-related disease of the present invention also includes treating it before the symptoms of the disease appear by administering the above-mentioned compound of Formula 1, and suppressing or avoiding the symptoms. When managing a disease, the preventive or therapeutic dose of a certain active ingredient may vary according to the nature and severity of the disease or condition, and the route of administration of the active ingredient. Its dosage and frequency may vary according to the age, weight and response of each patient. Suitable dosage and use can be easily selected by those skilled in the art by considering the factors. In addition, the method for preventing or treating the SGLT activity-related disease of the present invention may further include administering a therapeutically effective amount of an additional active agent, which helps to treat the disease together with the above-mentioned compound of Formula 1, wherein the additional active agent can show a synergistic effect or auxiliary effect together with the above-mentioned compound of Formula 1.

The present disclosure also provides the use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases associated with SGLT activity. When used in the preparation of the medicament, the compound of Formula 1 can be combined with acceptable adjuvants, diluents, carriers, etc., and can be combined with other active agents to form a composite formulation, thereby achieving synergistic effects between the active ingredients.

Matters mentioned in the uses, compositions, and methods of treatment disclosed herein are equally applicable unless they conflict with each other.

Beneficial effects

The novel C-glucoside derivatives disclosed herein can dually inhibit SGLT1 and SGLT2 and thus are valuable for the treatment or prevention of diabetes.

Specific implementation plan

The following will describe the configuration and effects of the present disclosure in detail through examples. However, the following examples are only for illustrating the present disclosure, and therefore the scope of the present disclosure is not limited to these examples.

Example 1. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)-4-methyl-2, 3-dihydro-1H-inden-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)

A mixture of ethyl sorbate (25.0 mL, 170 mmol, TCI reagent) and 1-pyrrolidinyl-1-cyclopentene (24.8 mL, 170 mmol, TCI reagent) in xylene (100 mL) was stirred and refluxed overnight at 4 ° C. After the reaction was complete, the volatile solvent was evaporated under reduced pressure. EtOAc was added to the resulting mixture. The organic layer was washed with brine, and the resulting product was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude compound was used in the following steps without additional purification. S ₈ (5.45 g, 170 mmol) was added to the crude compound. The reaction mixture was stirred at 250 ° C for 2 hours. After the reaction was complete, the resulting mixture was distilled under reduced pressure to obtain the title compound (1-1) (20.0 g, 97.9 mmol, 58%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.76(d,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),4.34(q,J＝7.2Hz,2H),3.30(t,J＝7. 6Hz,2H),2.84(t,J＝7.6Hz,2H),2.30(s,3H),2.12-2.05(m,2H),1.38(t,J＝7.2Hz,3H)

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

_Br₂ (6.0 mL, 117 mmol) and _AgNO₃ (16.6 g, 97.9 mmol) in water (20 mL) were added dropwise to a mixture of compound (1-1) (20.0 g, 97.9 mmol) in AcOH (100 mL) and concentrated _HNO₃ ( _4.4 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was completed with saturated _{Na₂S₂O₃} solution _and then extracted with EtOAc. The organic layer was dried over anhydrous _MgSO₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to yield the title compound (1-2) (22.1 g, 78.0 mmol, 80%).

¹ H NMR (400MHz, CDCl ₃ ); δ8.02(s,1H),4.34(q,J＝7.2Hz,2H),3.25(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),2.37(s,3H),2.11-2.07(m,2H),1.39(t,J＝7.2Hz,3H).

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

LiOH.H ₂ O (9.82 g, 234 mmol) was added to a solution of compound (1-2) (22.1 g, 78.0 mmol) in THF/MeOH/water (120 mL/40 mL/40 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the volatiles were removed under reduced pressure. 1N aqueous HCl was added to the residue for acidification, and the resulting mixture was stirred to precipitate the crude product. The crude product was filtered, washed with water, and dried under high vacuum to obtain the title compound (1-3) (15.4 g, 60.4 mmol, 77%).

¹ H NMR (400MHz, CDCl ₃ ); δ8.08 (s, 1H), 3.28 (t, J = 7.6Hz, 2H), 2.91 (t, J = 7.6Hz, 2H), 2.38 (s, 3H), 2.13-2.09 (m, 2H).

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

DMF (0.12 mL) and (COCl) (2.46 mL, 29.0 mmol) were added dropwise to 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 under a nitrogen atmosphere. The resulting solution was stirred at room temperature overnight, after which the mixture was concentrated in vacuo to yield the crude oxychloride. ₄ -Methoxybenzene (2.52 mL, 23.2 mmol) and AlCl (3.09 g, 23.2 mmol) were added portionwise to the crude oxychloride in DCM (45 mL) at 0°C. The resulting mixture was warmed to room temperature and stirred at room temperature for 2 hours. The resulting mixture was poured onto ice water and then extracted with EtOAc. The organic layer was washed with brine, after which the product was dried _over anhydrous MgSO, filtered, and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1-4) (4.84 g, 14.02 mmol, 73%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.78(d,J＝8.8Hz,2H),7.49(s,1H),6.95(d,J＝8.8Hz,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)

Triethylsilane (4.61 mL, 28.0 mmol) and BF ₃ .OEt ₂ (3.55 mL, 28.0 mmol) were added dropwise to a solution of compound (1-4) (4.84 g, 14.0 mmol) in DCM/acetonitrile (20 mL/20 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was slowly heated to room temperature and stirred at room temperature overnight. Saturated aqueous NaHCO ₃ solution was slowly added to the resulting mixture, followed by extraction with EtOAc. The organic layer was washed with brine, and the resulting product was dried over anhydrous MgSO ₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1-5) (4.21 g, 12.7 mmol, 91%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.12(s,1H),7.05(d,J＝8.4Hz,2H),6.81(d,J＝8.4Hz,2H),3.80(s,2H),3.78(s ,3H),2.87(t,J＝7.4Hz,2H),2.75(t,J＝7.6Hz,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-methyl)- (4-Methyl-2,3-dihydro-1H-inden-5-yl)tetrahydro-2H-pyran (1-6-(2-((4-( ...

At -78 ° C in a nitrogen atmosphere, n-BuLi (12.4 mL, 30.9 mmol, 2.5 M n-hexane solution) was added to a solution of compound (1-5) (6.82 g, 20.6 mmol) in toluene/THF (70 mL/70 mL). Over the next 30 minutes, a solution of perbenzylated gluconolactone (14.4 g, 26.8 mmol) in toluene (70 mL) was added to the resulting mixture at -78 ° C. The resulting mixture was stirred for 2 hours at the same temperature. The reaction was completed with water and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give a crude intermediate, which was used without additional purification. Triethylsilane (10.1 mL, 61.8 mmol) and BF ₃ .OEt ₂ (7.83 mL, 61.8 mmol) were added to a solution of the intermediate in DCM/acetonitrile (100 mL/100 mL) at -78 ° C under a nitrogen atmosphere. The resulting mixture was heated to -60 ° C for 1 hour. Saturated NaHCO ₃ solution was slowly added to the resulting mixture, followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1-6) (8.78 g, 11.32 mmol, 55%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.32-7.11(m,19H),7.02(d,J＝8.8Hz,2H),6.87(d,J＝6.4Hz,2H),6.71(d,J＝8.0Hz,2H),4.96-4.87(m,3H),4.68-4.63(m,2H),4.54-4 .49(m,2H),4.35(d,J＝10.4Hz,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 target compound

A suspension of compound (1-6) (152 mg, 0.20 mmol) in THF (3 mL) and MeOH (3 mL) and Pd/C (20% wt%, 30 mg) were stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through a pad of Celite and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to yield the title compound (79 mg, 0.19 mmol, 95%).

¹ H NMR (400MHz, CD ₃ OD); δ7.11(s,1H),7.04(d,J＝8.4Hz,2H),6.78(d,J＝8.4Hz,2H),4.45(d,J＝9.2Hz,1H),3.88-3.84(m,3H),3.74(s,3H),3.68-3.64(m,1H) ,3.56(t,J＝8.8Hz,1H),3.52-3.47(m,1H),3.40-3.38(m,2H),2.84(t,J＝7.6Hz,2H),2.73(t,J＝7.6Hz,2H),2.28(s,3H),2.01-1.98(m,2H)

Examples 2 and 3

The target compounds of Examples 2 and 3 were obtained by the method shown in Example 1.

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

¹ H NMR (400MHz, CD ₃ OD); δ7.10(s,1H),7.03(d,J＝8.4Hz,2H),6.76(d,J＝8.8Hz,2H),4.45(d,J＝8.8Hz,1H),3.97(q,J＝6.8Hz,2H),3.88-3.84(m,3H),3.6 7-3.48(m,4H),3.40-3.38(m,2H),2.84(t,J＝7.6Hz,2H),2.73(t,J＝7.6Hz,2H),2.28(s,3H),2.02-1.97(m,2H),1.35(t,J＝6.8Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.11(s,1H),7.02(d,J＝8.4Hz,2H),6.76(d,J＝8.8Hz,2H),4.54-4. 48(m,1H),4.45(d,J＝9.2Hz,1H),3.84-3.88(m,3H),3.66(dd,J＝11.6,5. 2Hz,1H),3.59-3.48(m,2H),3.41-3.38(m,2H),2.85(t,J＝7.6Hz,2H),2. 74(t,J＝7.4Hz,2H),2.28(s,3H),2.04-1.96(m,2H),1.27(d,J＝6.0Hz,6H)

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

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

At 0 ° C. under a nitrogen atmosphere, BH ₃ .SMe ₂ complex (13.7 mL, 137.2 mmol, 10.0 M dimethyl sulfide solution) was slowly added to 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), and the reaction mixture was stirred at room temperature overnight. The resulting reaction mixture was cooled at 0 ° C., and then a saturated aqueous NaHCO ₃ solution was slowly added to the resulting mixture, followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO 4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4-1) (2.33 g, 9.66 mmol, 70%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.39 (s, 1H), 4.60 (d, J = 6.0Hz, 2H), 2.91-2.86 (m, 4H), 2.32 (s, 3H), 2.14-2.07 (m, 2H), 1.48 (t, J = 5.8Hz, 1H)

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

PBr ₃ (1.38 mL, 14.5 mmol) was added dropwise to a solution of compound (4-1) (2.33 g, 9.66 mmol) in toluene (45 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was slowly heated to room temperature and stirred at room temperature for 2 hours. Saturated aqueous NaHCO ₃ was slowly added to the resulting mixture, followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4-2) (2.14 g, 7.04 mmol, 73%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.35(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)

Compound (4-2) (150 mg, 0.49 mmol), 4-methylphenylboronic acid (81 mg, 0.59 mmol) and K ₂ CO ₃ (136 mg, 0.99 mmol) were dissolved in acetone/water (3 mL/1 mL), and Pd ₂ (dba) ₃ (90 mg, 0.10 mmol) was added to the resulting mixture. The resulting mixture was stirred at room temperature for 4 hours. The resulting reaction mixture was filtered through celite and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous MgSO ₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (4-3) (130 mg, 0.41 mmol, 84%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.14(s,1H),7.08(d,J＝7.6Hz,2H),7.02(d,J＝8.0Hz,2H),3.82(s,2H),2.87(t ,J＝7.4Hz,2H),2.75(d,J＝7.6Hz,2H),2.31(s,3H),2.29(s,3H),2.08-2.02(m,2H)

Step 4. Synthesis of target compound

n-BuLi (0.25 mL, 0.62 mmol, 2.5 M n-hexane solution) was added to a solution of compound (4-3) (130 mg, 0.41 mmol) in toluene/THF (3 mL/1.5 mL) at -78 ° C in a nitrogen atmosphere. After 30 minutes, TMS-protected gluconolactone (231 mg, 0.49 mmol) in toluene (3 mL) was added to the resulting mixture at -78 ° C. The resulting mixture was stirred at the same temperature for 2 hours. Methanesulfonic acid (0.2 mL) and MeOH (1.6 mL) were added to the reaction mixture at the same temperature. The reaction mixture was stirred at -78 ° C for 2 hours. The reaction was completed with saturated NaHCO ₃ solution and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to obtain the crude intermediate, which was used without additional purification. Triethylsilane (0.14 mL, 0.82 mmol) and _BF3.OEt2 (0.11 mL, 0.82 mmol) were added to a solution of the intermediate in DCM/acetonitrile (2 mL/2 mL) at -78°C under a nitrogen atmosphere. The resulting mixture was heated to -50°C for 1 hour. Saturated _NaHCO3 solution was slowly added to the resulting mixture, followed by extraction with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to yield the title compound (5.6 mg, 0.014 mmol, 3.4%).

¹ H NMR (400MHz, CD ₃ OD); δ7.11(s,1H),7.04-6.99(m,4H),4.45(d,J＝9.2Hz,1H),3.88-3.86(m,3H),3.66(dd,J＝11.6,5.6Hz,1H),3.59-3. 48(m,2H),3.40-3.35(m,2H),2.84(t,J＝7.6Hz,2H),2.72(t,J＝7.6Hz,2H),2.29(s,3H),2.27(s,3H),2.04-1.96(m,2H)

Examples 5-16

The target compounds of Examples 5-16 were obtained by the method 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-amino)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.12(s,1H),7.06-7.02(m,4H),4.45(d,J=9.2Hz,1H),3.88-3.86(m,3H),3.68-3.48(m,3H),3.40-3.39(m,2H),2 .85(t,J＝7.6Hz,2H),2.73(t,J＝7.6Hz,2H),2.58(q,J＝7.6Hz,2H),2.29(s,3H),2.01-1.98(m,2H),1.19(t,J＝8.0Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.11(s,1H),7.03(s,4H),4.45(d,J＝9.2Hz,1H),3.88-3.86(m,3H),3.66(dd,J＝11.6,5.6Hz,1H),3.59-3.48(m,2H),3.41-3.39(m,2H) ,2.85(t,J＝7.6Hz,2H),2.74(d,J＝7.6Hz,2H),2.52(t,J＝7.6Hz,2H),2.29(s,3H),2.04-1.96(m,2H),1.65-1.55(m,2H),0.91(t,J＝7.2Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.12-7.03(m,5H),4.45(d,J＝9.2Hz,1H),3.88-3.86(m,3H),3.66(dd,J＝12.0,5.6Hz,1H),3.57(t,J＝9.2Hz,1H),3.52-3 .48(m,1H),3.41-3.39(m,2H),2.87-2.81(m,3H),2.74(t,J＝7.2Hz,2H),2.29(s,3H),2.04-1.98(m,2H),1.21(d,J＝7.2Hz,6H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.33(d,J＝8.4Hz,2H),7.10(d,J＝8.0Hz,2H),7.03(s,1H),6.66(dd,J＝17.6,11.2 Hz,1H),5.73(d,J＝18.0Hz,1H),5.17(d,J＝10.0Hz,1H),4.95-4.92(m,2H),4.69(d,J＝4. 0Hz,1H),4.38-4.37(m,1H),4.22(d,J＝8.4Hz,1H),3.83(s,2H),3.70-3.65(m,1H),3.3 0-3.16(m,1H),2.76(t,J＝7.2Hz,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 1H-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.45(d,J＝8.0Hz,2H),7.26(d,J＝8.4Hz,2H),7.08(s,1H),4.39(d,J＝8.8Hz,1H),3.94(s,2H),3.80(d,J＝11.2Hz,1H),3.59(dd, J＝12.0,5.2Hz,1H),3.51-3.41(m,2H),3.34-3.32(m,2H),2.78(t,J＝7.6Hz,2H),2.65(t,J＝7.6Hz,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 1H-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.22(d,J＝8.4Hz,2H),7.14(s,1H),7.12(d,J＝8.4Hz,2H),4.46(d,J＝9.2Hz,1H),3.94(s,2H),3.87(d,J＝12.4Hz,1H),3.68 -3.62(m,1H),3.55-3.46(m,2H),3.40-3.39(m,2H),2.85(t,J＝7.6Hz,2H),2.72(d,J＝7.6Hz,2H),2.29(s,3H),2.02-1.99(m,2H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.12(s,1H),6.81(d,J＝8.0Hz,1H),6.76(s,1H),6.68(d,J＝8.4Hz ,1H),4.45(d,J＝8.8Hz,1H),3.88-3.85(m,3H),3.78(s,3H),3.75(s,3H) ,3.66(dd,J＝12.0,5.2Hz,1H),3.59-3.48(m,2H),3.41-3.39(m,2H),2.8 5(t,J＝7.4Hz,2H),2.76(t,J＝7.4Hz,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-dimethoxybenzyl)- Hydrogen-1H-inden-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400 MHz, CD ₃ OD); δ7.17(s,1H),6.91(d,J＝8.0Hz,1H),6.60(d,J＝2.4Hz,1H),6.47(dd,J＝8.4 ,2.4Hz,1H),4.54(d,J＝8.8Hz,1H),3.97(d,J＝12.0Hz,1H),3.91(s,3H),3.89(s, 2H),3.86(s,3H),3.75(dd,J＝12.0,5.6Hz,1H),3.67-3.57(m,2H),3.50-3.45(m, 2H),2.96(t,J＝7.6Hz,2H),2.87(t,J＝7.6Hz,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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.14(d,J＝8.0Hz,1H),7.11(s,1H),7.07(d,J＝8.0Hz,2H),4.46(d,J＝9.2Hz,1H),3.87-3.86(m,3H),3.67(dd,J＝11.6,5.2Hz, 1H),3.59-3.48(m,2H),3.41-3.39(m,2H),2.85(t,J＝7.6Hz,2H),2.73(t,J＝7.6Hz,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-amino)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.24-7.21(m,3H),7.05-7.00(m,2H),4.54(d,J＝9.2Hz,1H),3.99(s,2H),3.96(d,J＝12.0Hz,1H),3.79-3.73(m, 1H),3.65-3.59(m,2H),3.49-3.48(m,2H),2.94(t,J＝7.6Hz,2H),2.81(t,J＝7.6Hz,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-inden-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.12(s,1H),6.99(d,J＝7.2Hz,1H),6.96-6.93(m,1H),6.88-6.84(m,1H),4.47(d,J＝9.2Hz,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＝7.2Hz,2H),2.73(t,J＝7.2Hz,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-amino)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.21(d,J＝8.4Hz,2H),7.12(d,J＝8.4Hz,2H),7.11(s,1H),4.46(d,J＝8.8Hz,1H),3.90-3.86(m,3H),3.67(dd,J＝11.6,5 .2Hz,1H),3.58-3.48(m,2H),3.39-3.43(m,2H),2.85(t,J＝7.6Hz,2H),2.72(t,J＝7.6Hz,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]dioxane-6-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

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

_Br₂ (3.32 mL, 64.9 mmol) was added dropwise to 2,3-dihydrobenzoic acid (10.0 g, 64.9 mmol, Aldrich reagent) in AcOH (120 mL ₎ , and the resulting mixture _was stirred at room temperature for 12 hours. The reaction was completed with saturated aqueous _{Na₂S₂O₃} , and the resulting mixture was dried under reduced pressure to remove volatiles. The resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous _MgSO₄ , filtered, and concentrated in vacuo. The title compound (17-1) (14.1 g, 60.3 mmol, 93%) was used in the following step without additional purification.

¹ H NMR (400MHz, CDCl ₃ ); δ7.47(s,1H),7.37(s,1H)

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

_SOCl₂ (13.1 mL, 180.9 mmol) was added dropwise to a solution of compound (17-1) (14.1 g, 60.3 mmol) in MeOH (200 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred under reflux overnight. After the reaction was complete, the volatile solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield the title compound (17-2) (12.5 g, 50.6 mmol, 84%).

¹ H NMR (400MHz, CDCl ₃ ); δ10.85(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]dioxane-5-carboxylate (17-3)

1,2-Dibromoethane (8.2 mL, 94.9 mmol) was added dropwise to a mixture of compound (17-2) (15.6 g, 63.3 mmol) and K ₂ CO ₃ (26.2 g, 95.0 mmol) in DMF (200 mL). The reaction mixture was heated at 100°C overnight and then reacted with water to completion. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine. The resulting product was dried over anhydrous MgSO ₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to yield the title compound (17-3) (11.0 g, 40.4 mmol, 64%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.52 (d, J = 2.4Hz, 1H), 7.16 (d, J = 2.8Hz, 1H), 4.37-4.28 (m, 4H), 3.88 (s, 3H).

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

1N-NaOH aqueous solution (30.7 mL) was added to compound (17-3) (5.0 g, 15.4 mmol) in THF/MeOH (20 mL/40 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the volatile substances were removed under reduced pressure. 1N-HCl aqueous solution was added to the residue for acidification, during which the resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water and dried under high vacuum to obtain the title compound (17-4) (3.4 g, 13.0 mmol, 85%).

¹ H NMR (400MHz, CDCl ₃ ); δ8.00(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]dioxane (17-5)

The title compound (17-5) was obtained from compound (17-4) by the method described in Step 4-5 of Example 1.

¹ H NMR (400MHz, CDCl ₃ ); δ7.09(d,J＝8.8Hz,2H),6.88(d,J＝2.4Hz,1H),6.81(d,J＝8.8Hz,2H),6.73(d,J＝2. 4Hz,1H),4.26-4.22(m,4H),4.01(q,J＝7.2Hz,2H),3.81(s,2H),1.40(t,J＝6.8Hz,3H)

Step 6. Synthesis of target compound

The target compound was obtained using compound (17-5) by the method described in Steps 6-7 of Example 1.

¹ H NMR (400MHz, CD ₃ OD); δ7.10(d,J＝8.4Hz,2H),6.78-6.74(m,4H),4.21(dd,J＝10.0,4.8Hz,4H),4.00-3.95(m,3 H),3.87-3.78(m,3H),3.66(dd,J＝12.0,5.6Hz,1H),3.44-3.29(m,4H),1.35(t,J＝6.8Hz,3H)

Example 18. Preparation of (2S,3R,4R,5S,6R)-2-(8-(4-ethylbenzyl)-2,3-dihydrobenzo[b][1,4] dioxan-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]dioxane (18-1)

The title compound (18-1) was obtained by the method described in Step 1-3 of Example 4 using the compound (17-4) obtained in Step 4 of Example 17.

¹ H NMR (400MHz, CDCl ₃ ); δ7.13-7.10(m,4H),6.88(d,J＝2.0Hz,1H),6.75(d,J＝2.0Hz,1H),4.28-4.22(m,4H),3.85(s,2H),2.62(q,J＝7.6Hz,2H),1.22(t,J＝7.6Hz,3H)

Step 2. Synthesis of target compound

The target compound was obtained using compound (18-1) by the method described in Step 4 of Example 4.

¹ H NMR (400MHz, CD ₃ OD); δ7.10(d,J＝7.6Hz,2H),7.05(d,J＝8.0Hz,2H),6.78(d,J＝2.0Hz,1H),6.75(d,J＝2.0Hz,1H),4.24-4.20(m,4H),3.96(d,J ＝9.2Hz,1H),3.91-3.81(m,4H),3.66(dd,J＝12.0,5.6Hz,1H),3.42-3.32(m,3H),2.58(q,J＝7.6Hz,2H),1.19(t,J＝7.6Hz,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]dioxole-4-carboxylate (19-1)

Dibromomethane (3.2 mL, 45.3 mmol) was added dropwise to a mixture of compound (17-2) (7.5 g, 30.2 mmol) obtained in Step 2 of Example 17 in DMF (100 mL) and K ₂ CO ₃ (12.5 g, 95.0 mmol). The reaction mixture was heated at 100° C. overnight and then reacted with water to completion. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine. The resulting product was then dried over anhydrous MgSO ₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (19-1) (7.6 g, 29.3 mmol, 97%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.55 (d, J = 2.0Hz, 1H), 7.08 (d, J = 1.6Hz, 1H), 6.12 (s, 2H), 3.92 (s, 3H)

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

1N-NaOH aqueous solution (58.7 mL) was added to compound (19-1) (7.6 g, 29.3 mmol) in THF/MeOH (40 mL/80 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the volatile substances were removed under reduced pressure. 1N-HCl aqueous solution was added to the residue for acidification, during which the resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water and dried under high vacuum to obtain the title compound (19-2) (7.2 g, 29.3 mmol, 99%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.59 (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]dioxole (19-3)

The title compound (19-3) was obtained from compound (19-2) by the method described in Step 4-5 of Example 1.

¹ H NMR (400MHz, CDCl ₃ ); δ7.13 (d, J = 8.8Hz, 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 target compound

The target compound was obtained using compound (19-3) by the method described in Step 4 of Example 4.

¹ H NMR (400MHz, CD ₃ OD); δ7.14(d,J＝8.4Hz,2H),6.81-6.79(m,3H),6.73(s,1H),5.92(s,2H),4.00(d, J＝9.2Hz,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]dioxole (20-1)

The title compound (20-1) was obtained by the method described in Step 1-3 of Example 4 using the compound (19-2) obtained in Step 2 of Example 18.

¹ H NMR (400MHz, CDCl ₃ ); δ7.20 (d, J = 8.0Hz, 2H), 7.14 (d, J = 8.4Hz, 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 target compound

The target compound was obtained using compound (20-1) by the method described in Step 4 of Example 4.

¹ H NMR (400MHz, CD ₃ OD); δ7.16(s,4H),6.80(s,1H),6.75(s,1H),5.93(s,2H),4.00(d,J＝9.2Hz ,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]dioxetine (penten-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

The target compound was obtained by the method described in Example 20.

¹ H NMR (400MHz, CD ₃ OD); δ7.13(d,J＝8.0Hz,2H),7.07(d,J＝7.6Hz,2H),6.79(s,1H),6.75(s,1H),5.92(s,2H),4.00(d,J＝9.2Hz,1H) ,3.90-3.81(m,3H),3.67(dd,J＝12.0,5.6Hz,1H),3.45-3.29(m,4H),2.58(q,J＝7.6Hz,2H),1.19(t,J＝7.6Hz,3H)

Example 22. Preparation of (2S,3R,4R,5S,6R)-2-(4-(4-ethoxybenzyl)-5,6,7,8-tetrahydronaphthalene-2- methyl)-6-(hydroxymethyl)

Tetrahydro-2H-pyran-3,4,5-triol

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

_SOCl₂ (4.1 mL, 56.7 mmol) was added dropwise to 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 under a nitrogen atmosphere. The resulting mixture was stirred at reflux overnight. After the reaction was complete, the volatile solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield the title compound (22-1) (1.98 g, 10.4 mmol, 92%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.64(d,J＝7.6Hz,1H),7.21(d,J＝7.2Hz,1H),7.13(t,J＝7.6Hz,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)

Concentrated _HNO₃ (0.4 mL, 8.91 mmole) and _Br₂ (3.32 mL, 64.9 mmol) were added dropwise to a solution of compound (22-1) (1.13 g, 5.94 mmol) in AcOH (10 mL) and _AgNO₃ (1.51 g, 8.91 mmol ₎ in water ( ₅ mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction was completed with saturated aqueous _{Na₂S₂O₃} , and the resulting mixture was dried under reduced pressure to remove volatiles. The resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous _MgSO₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to yield the title compound (22-2) (1.41 g, 5.24 mmol, 88%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.78 (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)

LiOH.H ₂ O (0.67 g, 15.7 mmol) was added to compound (22-2) (1.41 g, 5.24 mmol) in THF/MeOH/water (15 mL/5 mL/5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the volatiles were removed under reduced pressure. 1N aqueous HCl was added to the residue for acidification, and the resulting mixture was stirred to precipitate the crude product. The crude product was filtered, washed with water, and dried under high vacuum to obtain the title compound (22-3) (1.31 g, 5.14 mmol, 98%).

¹ H NMR (400MHz, CD ₃ OD); δ7.72(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)

The title compound (22-4) was obtained from compound (22-3) by the method described in Step 4-5 of Example 1.

¹ H NMR (400MHz, CDCl ₃ ); δ7.12(s,1H),7.03-6.98(m,3H),6.81(d,J＝8.8Hz,2H),4.01(q,J＝7.2Hz,2H),3.82(t,J＝5. 6Hz,2H),2.74(t,J＝5.6Hz,2H),2.53(t,J＝6.0Hz,2H),1.73-1.70(m,4H),1.40(t,J＝7.2Hz,3H)

Step 5. Synthesis of target compound

The target compound was obtained using compound (22-4) by the method described in Steps 6-7 of Example 1.

¹ H NMR (400MHz, CD ₃ OD); δ7.02-6.99(m,4H),6.77(d,J＝8.4Hz,2H),4.04(d,J＝9.6Hz,1H),3.97(q,J＝6.8Hz,2H),3.89-3.87(m,3H),3.69(d d,J＝12.0,5.2Hz,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＝6.8Hz,3H)

Example 23. Preparation of (2S,3R,4R,5S,6R)-2-(4-(4-ethylbenzyl)-5,6,7,8-tetrahydronaphthalen-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)

The title compound (23-1) was obtained by the method described in Step 1-3 of Example 4 using the compound (22-3) obtained in Step 3 of Example 22.

¹ H NMR (400MHz, CDCl ₃ ); δ7.12-7.10(m,3H),7.05(s,1H),7.01(d,J＝8.4Hz,2H),3.85(s,2H),2.73(t,J＝6.4Hz, 2H),2.62(q,J＝7.6Hz,2H),2.53(t,J＝6.0Hz,2H),1.78-1.70(m,4H),1.22(t,J＝7.6Hz,3H)

Step 2. Synthesis of target compound

The target compound was obtained using compound (23-1) by the method described in Step 4 of Example 4.

¹ H NMR (400MHz, CD ₃ OD); δ7.06-6.99(m,6H),4.03(d,J＝9.2Hz,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＝7.6Hz,3H)

Example 24. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-(4-methoxybenzyl)-1-methyl- 5,6,7,8-tetrahydronaphthalen-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)

A mixture of ethyl sorbate (49.5 mL, 0.33 mol, TCI reagent) in xylene (330 mL) and 1-pyrrolidinyl-1-cyclohexene (50.24 g, 0.33 mol, TCI reagent) was stirred under reflux overnight. After the reaction was complete, the volatile solvent was evaporated under reduced pressure. EtOAc was added to the resulting mixture. The organic layer was washed with brine, and the resulting product was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The crude compound was used in the following steps without additional purification. S ₈ (10.7 g, 0.33 mol) was added to the crude compound. The reaction mixture was stirred at 250 ° C for 2 hours. After the reaction was complete, the resulting mixture was distilled under reduced pressure to obtain the title compound (24-1) (24.7 g, 0.11 mol, 34%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.58(d,J＝7.6Hz,1H),7.02(d,J＝8.0Hz,1H),4.32(q,J＝7.2Hz,2H),3.06(t,J＝6. 4Hz,2H),2.64(t,J＝6.4Hz,2H),2.24(s,3H),1.85-1.73(m,4H),1.37(t,J＝7.2Hz,3H)

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

Br ₂ (3.5 mL, 68.6 mmol) and AgNO ₃ (11.64 g, 68.6 mmol) in water (60 mL) were added dropwise to a mixture of compound (24-1) (11.5 g, 68.6 mmol) in AcOH (450 mL) and concentrated HNO ₃ (5.2 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was completed with saturated Na ₂ S ₂ O ₃ solution and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo. The crude compound (24-2) was used in the following step without additional purification.

¹ H NMR (400MHz, CDCl ₃ ); δ7.87(s,1H),4.32(q,J＝7.2Hz,2H),3.00(t,J＝6.4Hz,2H),2.70(t,J＝6.4Hz,2H),2.36(s,3H),1.82-1.71(m,4H),1.38(t,J＝7.2Hz,3H).

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

LiOH.H ₂ O (3.6 g, 86.2 mmol) was added to a solution of compound (24-2) (12.8 g, 43.1 mmol) in THF/MeOH/water (150 mL/50 mL/50 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the volatiles were removed under reduced pressure. 1N aqueous HCl was added to the residue for acidification, and the resulting mixture was stirred to precipitate a crude product. The crude product was filtered, washed with water, and dried under high vacuum to obtain the title compound (24-3) (9.3 g, 34.4 mmol, 80%).

¹ H NMR (400MHz, CDCl ₃ ); δ8.07 (s, 1H), 3.07 (t, J = 6.4Hz, 2H), 2.71 (t, J = 6.4Hz, 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)

The title compound (24-4) was obtained from compound (24-3) by the method described in Step 4-5 of Example 1.

¹ H NMR (400MHz, CDCl ₃ ); δ7.16(s,1H),7.02(d,J＝8.8Hz,2H),6.82(d,J＝8.0Hz,2H),3.82(s,2H),3.79(s ,3H),2.67(t,J＝6.4Hz,2H),2.54(t,J＝6.4Hz,2H),2.31(s,3H),1.77-1.68(m,4H).

Step 5. Synthesis of target compound

The target compound was obtained using compound (24-4) by the method described in Steps 6-7 of Example 1.

¹ H NMR (400MHz, CD ₃ OD); δ7.13(s,1H),7.00(d,J＝9.2Hz,2H),6.77(d,J＝8.4Hz,1H),4.51(d,J＝9.6Hz,1H),3.89-3.85(m,3H),3.73(s,3H),3.67(dd,J＝11.6,5.6Hz, 1H),3.60(t,J＝8.8Hz,1H),3.51(t,J＝8.8Hz,1H),3.41-3.39(m,2H),2.6 5(t,J＝6.4Hz,2H),2.54(t,J＝6.0Hz,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-tetrahydronaphthalen-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)

The title compound (25-1) was obtained by the method described in Step 1-3 of Example 4 using the compound (24-3) obtained in Step 3 of Example 24.

¹ H NMR (400MHz, CDCl ₃ ); δ7.17(s,1H),7.08(d,J＝7.6Hz,2H),6.99(d,J＝8.0Hz,2H),3.84(s,2H), 2.67(t,J＝6.4Hz,2H),2.54(t,J＝6.4Hz,2H),2.31(s,6H),1.76-1.68(m,4H)

Step 2. Synthesis of target compound

The target compound was obtained using compound (25-1) by the method described in Step 4 of Example 4.

¹ H NMR (400MHz, CD ₃ OD); δ7.13(s,1H),7.02(d,J＝7.6Hz,2H),6.97(d,J＝8.4Hz,2H),4.51(d,J＝9.6Hz,1H),3.86-3.89(m,3H),3.67(dd,J＝11.6,6.0Hz,1H),3.60(t, J＝9.2Hz,1H),3.51(t,J＝8.8Hz,1H),3.42-3.40(m,2H),2.65(t,J＝6.4Hz ,2H),2.54(t,J＝6.4Hz,2H),2.26(s,3H),2.24(s,3H),1.75-1.64(m,4H)

Examples 26-29

The target compounds of Examples 26-29 were obtained by the method 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-tetrahydronaphthalen-2-yl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.51(d,J＝7.6Hz,2H),7.29(d,J＝8.0Hz,2H),7.18(s,1H),4.52(d,J＝9.2Hz,1H),4.03(s,2H),3.87(dd,J＝11.6,5.6Hz,1H),3.69-3.65(m, 1H),3.59(t,J＝8.8Hz,1H),3.52(t,J＝8.8Hz,1H),3.42-3.40(m,2H),2.6 6(t,J＝6.0Hz,2H),2.51(t,J＝5.6Hz,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-tetrahydronaphthalen-2-yl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.19(d,J＝8.4Hz,2H),7.16(s,1H),7.12(d,J＝8.4Hz,2H),4.52(d,J＝ 9.6Hz,1H),3.97(s,2H),3.87(dd,J＝11.6,2.0Hz,1H),3.67(dd,J＝11.6,5. 6Hz,1H),3.58(t,J＝9.2Hz,1H),3.51(t,J＝7.6Hz,1H),3.42-3.40(m,2H),2 .66(t,J＝6.0Hz,2H),2.53(t,J＝6.0Hz,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-tetrahydronaphthalen-2-yl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.14(d,J＝8.0Hz,2H),7.14(s,1H),7.04(d,J＝8.4Hz,2H),4.51(d,J＝9.6Hz,1H),3.86-3.90(m,3H),3.67(dd,J＝11.6,5.6Hz,1H),3.59(t, J＝9.2Hz,1H),3.51(t,J＝8.8Hz,1H),3.39-3.41(m,2H),2.66(t,J＝6.0Hz ,2H),2.54(t,J＝5.6Hz,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-amino)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.20(d,J＝8.4Hz,2H),7.14(s,1H),7.08(d,J＝8.8Hz,2H),4.51(d,J＝ 9.6Hz,1H),3.92(s,2H),3.87(dd,J＝11.6,2.0Hz,1H),3.67(dd,J＝11.6,5. 6Hz,1H),3.59(t,J＝9.2Hz,1H),3.52(t,J＝8.8Hz,1H),3.42-3.40(m,2H),2 .66(t,J＝6.0Hz,2H),2.52(t,J＝6.0Hz,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)

_SOCl₂ (10.9 mL, 150 mmol) was added dropwise to a solution of 4-methylsalicylic acid (5.0 g, 32.9 mmol, TCI reagent) in MeOH (80 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at reflux overnight. After the reaction was complete, the volatile solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield the title compound (30-1) (5.18 g, 31.2 mmol, 95%).

¹ H NMR (400MHz, CDCl ₃ ); δ10.70(s,1H),7.71(d,J＝8.0Hz,1H),6.79(s,1H),6.69(d,J＝8.4Hz,1H),3.93(s,3H),2.34(s,3H)

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

Allyl bromide (3.2 mL, 37.4 mmol) was added dropwise to a mixture of compound (30-1) (5.18 g, 31.2 mmol) in DMF (40 mL) and K ₂ CO ₃ (5.17 g, 37.4 mmol). The reaction mixture was stirred at room temperature overnight, after which the reaction was completed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine. The resulting product was dried over anhydrous MgSO ₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to yield the title compound (30-2) (6.35 g, 30.8 mmol, 99%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.73(d,J＝8.0Hz,1H),6.79(d,J＝8.4Hz,1H),6.76(s,1H),6.15-6.02(m,1H),5.53(dd,J＝17. 2,1.6Hz,1H),5.30(dd,J＝10.4,1.6Hz,1H),4.61(dd,J＝3.2,1.6Hz,2H),3.88(s,3H),2.36(s,3H)

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

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

¹ H NMR (400MHz, CDCl ₃ ); δ11.07(s,1H),7.63(d,J＝8.4Hz,1H),6.71(d,J＝8.4Hz,1H),5.99-5.88(m,1H),4.99(dd,J＝10. 0,1.6Hz,1H),4.93(dd,J＝17.2,2.0Hz,1H),3.93(s,3H),3.46(dt,J＝5.6,1.6Hz,2H),2.32(s,3H)

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

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

¹ H NMR (400MHz, CDCl ₃ ); δ11.16(s,1H),9.70(t,J＝1.6Hz,1H),7.71(d,J＝8.0Hz,1H),6.77(d,J＝8.0Hz,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)

_NaBH₄ (436 mg, 11.5 mmol) was added to a solution of compound (30-4) (2.00 g, 9.61 mmol) in EtOH (30 mL) at 0°C under a nitrogen atmosphere. The resulting reaction mixture was stirred at 0°C for 1 hour, then the reaction was completed with saturated aqueous _NH₄Cl solution, and the resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (30-5) (1.82 g, 9.04 mmol, 94%).

¹ H NMR (400MHz, CDCl ₃ ;

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

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

¹ H NMR (400MHz, CDCl ₃ ); δ7.65 (d, J = 8.0Hz, 1H), 6.70 (d, J = 8.0Hz, 1H), 4.74 (t, J = 8.8Hz, 2H), 3.89 (s, 3H), 3.13 (t, J = 8.8Hz, 2H), 2.28 (s, 3H)

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

_Br₂ (0.66 mL, 12.8 mmol) was added dropwise to a solution of compound (30-6) (1.23 g, 6.40 mmol) in AcOH ( _{20 mL} ) at room temperature. The resulting mixture was stirred at room temperature overnight, then dried with saturated aqueous _{Na₂S₂O₃} , and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to yield the title compound (30-7) (1.58 g, 5.83 mmol, 91%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.92 (s, 1H), 4.76 (t, J = 8.8Hz, 2H), 3.89 (s, 3H), 3.19 (t, J = 8.8Hz, 2H), 2.33 (s, 3H)

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

LiOH.H ₂ O (489 mg, 11.7 mmol) was added to a solution of compound (30-7) (1.58 g, 5.83 mmol) in THF/MeOH/water (12 mL/4 mL/4 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the volatiles were removed under reduced pressure. 1N aqueous HCl was added to the residue for acidification, and the resulting mixture was stirred to precipitate the crude product. The crude product was filtered, washed with water, and dried under high vacuum to obtain the title compound (30-8) (1.02 g, 3.97 mmol, 68%).

¹ H NMR (400MHz, CD ₃ OD); δ7.81 (s, 1H), 4.70 (t, J = 8.8Hz, 2H), 3.23 (t, J = 8.8Hz, 2H), 2.34 (s, 3H)

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

The title compound (30-9) was obtained from compound (30-8) by the method described in Step 4-5 of Example 1.

¹ H NMR (400MHz, CDCl ₃ ); δ7.13(d,J＝8.4Hz,2H),7.04(s,1H),6.82(d,J＝8.4Hz,2H),4.59(t,J＝8.4Hz,2H),3.78(s,5H),3.16(t,J＝8.8Hz,2H),2.25(s,3H)

Step 10. Synthesis of target compound

The target compound was obtained using compound (30-9) by the method described in Steps 6-7 of Example 1.

¹ H NMR (400MHz, CD ₃ OD); δ7.11(d,J＝8.4Hz,2H),7.02(s,1H),6.76(d,J＝8.8Hz,2H),4.54(t,J＝8.8Hz,2H),4.36(d,J＝9.2Hz,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＝8.8Hz,2H),2.27(s,3H)

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

The target compound was obtained by the method described in Example 30.

¹ H NMR (400MHz, CD ₃ OD); δ7.10(d,J＝8.4Hz,2H),7.03(s,1H),6.75(d,J＝8.8Hz,2H),4.53(t,J＝8.8Hz,2H),4.36(d,J＝9.2Hz,1H),3.96(q,J＝7.2Hz,2H),3.85(d,J ＝11.6Hz,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＝8.6Hz,2H),2.26(s,3H),1.34(t,J＝6.8Hz,3H)

Example 32. Preparation of (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-7-(4-(methylthio)benzyl 1-[(2-[(2-((2-((2-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triol)-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)

The title compound (32-1) was obtained by the method described in Step 1-3 of Example 4 using the compound (30-8) obtained in Step 8 of Example 30.

¹ H NMR (400MHz, CDCl ₃ ); δ7.18(d,J＝8.8Hz,2H),7.14(d,J＝8.4Hz,2H),7.04(s,1H),4.59(t,J＝8.8Hz,2H),3.79(s,2H),3.17(t,J＝8.8Hz,2H),2.46(s,3H),2.25(s,3H)

Step 2. Synthesis of target compound

The target compound was obtained using compound (32-1) by the method described in Step 4 of Example 4.

¹ H NMR (400MHz, CD ₃ OD); δ7.16-7.11(m,4H),7.04(s,1H),4.54(t,J＝8.4Hz,2H),4.36(d,J＝8.8Hz,1H),3.85(d,J＝12.0Hz,1H),3.80(s,2H ),3.64(dd,J＝12.0,5.2Hz,1H),3.54-3.45(m,2H),3.38-3.36(m,2H),3.14(t,J＝8.4Hz,2H),2.42(s,3H),2.27(s,3H)

Examples 33 and 34

The target compounds of Examples 33 and 34 were obtained by the method shown in Example 1.

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

¹ H NMR (400MHz, CD ₃ OD); δ7.11(d,J＝7.2Hz,2H),7.05(s,3H),4.54(t,J＝8.4Hz,2H),4.36(d,J＝9.2Hz,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＝8.4Hz,2H),2.58(q,J＝7.6Hz,2H),2.27(s,3H),1.18(t,J＝7.2Hz,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

¹ H NMR (400 MHz, CD ₃ OD); δ7.27(d,J＝7.6Hz,2H),7.16(d,J＝8.0Hz,2H),7.04(s,1H),6.66(dd,J＝1 7.6,11.2Hz,1H),5.68(dd,J＝17.6,1.2Hz,1H),5.13(dd,J＝10.8,0.8Hz,1H), 4.54(t,J＝8.8Hz,2H),4.36(d,J＝9.2Hz,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＝8.8Hz,2H),2.27(s,3H)

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

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

_SOCl₂ (12.6 mL, 174 mmol) was added dropwise to a solution of 4-chlorosalicylic acid (10.0 g, 58.0 mmol, TCI reagent) in MeOH (200 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at reflux for 4 hours. After the reaction was complete, the volatile solvent was evaporated under reduced pressure. Saturated aqueous _NaHCO₃ was slowly added to the resulting residue, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, and the resulting product was dried over anhydrous _MgSO₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (35-1) (7.6 g, 40.7 mmol, 70%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.76 (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)

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

¹ H NMR (400MHz, CDCl ₃ ); δ7.78(d,J＝8.0Hz,1H),7.26-6.95(m,2H),6.07-6.02(m,1H),5.53(dd,J＝1 7.2,1.6Hz,1H),5.34(dd,J＝10.4,1.2Hz,1H),4.63-4.61(m,2H),3.89(s,3H)

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

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

¹ H NMR (400MHz, CDCl ₃ ;

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

N-methylmorpholine N-oxide (1.55 g, 13.2 mmol) and OsO ₄ (22.4 mL, 0.09 mmol) were added to a solution of compound (35-3) (2.00 g, 8.82 mmol) in acetone/water (30 mL/3 mL) under a nitrogen atmosphere. After the reaction mixture was stirred at room temperature for 8 hours, the reaction was completed with a saturated aqueous solution of Na ₂ S ₂ O ₃ , and the resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO ₄ , filtered, and concentrated in vacuo to obtain the crude intermediate, which was used without additional purification. NaIO ₄ (5.61 g, 26.3 mmol) was added to a solution of the crude intermediate in THF/water (50 mL/30 mL) under a nitrogen atmosphere at room temperature. After the reaction mixture was stirred at room temperature for 5 hours, the reaction was completed with a saturated aqueous solution of Na ₂ S ₂ O ₃ , and the resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to give crude compound (35-4) (1.90 g, 8.31 mmol, 95%), which was used without additional purification.

¹ H NMR (400MHz, CDCl ₃ ); δ11.32 (s, 1H), 9.73 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 6.98 (d, J = 8.4Hz, 1H), 3.97 (s, 5H)

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

_NaBH₄ (628 mg, 16.6 mmol) was added to a solution of compound (35-4) (1.90 g, 8.31 mmol) in MeOH (30 mL) at 0°C under a nitrogen atmosphere. After the resulting reaction mixture was stirred at 0°C for 1 hour, the reaction was completed with saturated aqueous _NH₄Cl solution, and the resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (35-5) (1.45 g, 6.29 mmol, 76%).

¹ H NMR (400MHz, CDCl ₃ ); δ11.37 (s, 1H), 7.67 (d, J = 8.8Hz, 1H), 6.94 (d, J = 8.8Hz, 1H), 3.96 (s, 3H), 3.87 (dd, J = 12.8, 6.0Hz, 2H), 3.16 (t, J = 6.4Hz, 2H)

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

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

¹ H NMR (400MHz, CDCl ₃ ); δ7.69 (d, J = 8.4Hz, 1H), 6.88 (d, J = 8.4Hz, 1H), 4.79 (t, J = 8.8Hz, 2H), 3.90 (s, 3H), 3.27 (t, J = 8.8Hz, 2H)

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

_Br₂ (0.4 mL, 8.01 mmol) was added dropwise to a solution of compound (35-6) (1.31 g, 6.16 mmol) in AcOH ( _{20 mL} ) at room temperature. The resulting mixture was stirred overnight at room temperature, after which the reaction was completed with saturated _{Na₂S₂O₃} solution and extracted with EtOAc. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The crude compound (35-7) (1.70 g, 5.83 mmol, 95%) was used in the following step without additional purification.

¹ H NMR (400MHz, CDCl ₃ ); δ8.00 (s, 1H), 4.81 (t, J = 8.8Hz, 2H), 3.91 (s, 3H), 3.31 (t, J = 8.8Hz, 2H)

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

LiOH.H ₂ O (490 mg, 11.2 mmol) was added to a solution of compound (35-7) (1.70 g, 5.83 mmol) in THF/MeOH/water (15 mL/5 mL/5 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the volatiles were removed under reduced pressure. 1N aqueous HCl was added to the residue for acidification, and the resulting mixture was stirred to precipitate the crude product. The crude product was filtered, washed with water, and dried under high vacuum to obtain the title compound (35-8) (1.54 g, 5.54 mmol, 95%).

¹ H NMR (400MHz, CD ₃ OD); δ7.93 (s, 1H), 4.76 (t, J = 8.8Hz, 2H), 3.35-3.30 (m, 2H)

Step 9. Synthesis of target compound

The target compound was obtained using compound (35-8) by the method described in Step 4-7 of Example 1.

¹ H NMR (400MHz, CD ₃ OD); δ7.14-7.10(m,3H),6.77(d,J＝8.4Hz,2H),4.63-4.59(m,3H),3.97(q,J＝6.8Hz,2H),3.86-3.78(m,3 H),3.68-3.64(m,1H),3.49-3.47(m,2H),3.39-3.37(m,2H),3.25(t,J＝8.8Hz,2H),1.35(t,J＝6.8Hz,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)

The title compound (36-1) was obtained by the method described in Step 1-8 of Example 30 using 3-hydroxy-4-methylbenzoic acid (TCI reagent).

¹ H NMR (400MHz, CDCl ₃ ); δ7.15 (s, 1H), 4.52 (t, J = 8.8Hz, 2H), 3.36 (t, J = 8.8Hz, 2H), 2.20 (s, 3H)

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

The title compound (36-2) according to the present invention was obtained using compound (36-1) by the method described in Step 4-5 of Example 1.

¹ H NMR (400MHz, CDCl ₃ ); δ7.18(s,1H),7.05(d,J＝8.8Hz,2H),6.80(d,J＝8.8Hz,2H),4.52(t,J＝8.8Hz,2H),4.00(s,2H),3.77(s,3H),3.04(t,J＝8.8Hz,2H),2.16(s,3H)

Step 3. Synthesis of target compound

The target compound was obtained using compound (36-2) by the method described in Steps 6-7 of Example 1.

¹ H NMR (400MHz, CD ₃ OD); δ7.11(s,1H),7.04(d,J＝9.2Hz,2H),6.78(d,J＝8.8Hz,2H),4.47(t,J＝9.2Hz,2H),4.35(d,J＝9.6Hz,1H),4.13(d,J＝12.0Hz,1H),3.89(d,J＝ 16.0Hz,1H),3.73(dd,J＝12.0,2.4Hz,1H),3.73(s,3H),3.62-3.56(m,2 H),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)

The title compound (37-1) was obtained by the method described in Step 1-3 of Example 4 using the compound (36-1) obtained in Step 1 of Example 36.

¹ H NMR (400MHz, CDCl ₃ ); δ7.31(d,J＝7.2Hz,2H),7.18(s,1H),7.09(d,J＝7.2Hz,2H),6.68(dd,J＝17.6,10.8Hz,1H),5.69(d,J＝1 7.6Hz,1H),5.41(d,J＝10.8Hz,1H),4.53(t,J＝8.8Hz,2H),4.06(s,2H),3.09(t,J＝8.8Hz,2H),2.17(s,3H)

Step 2. Synthesis of target compound

The target compound was obtained using compound (37-1) by the method described in Step 4 of Example 4.

¹ H NMR (400MHz, CD ₃ OD); δ7.29(d,J＝8.4Hz,2H),7.11(s,1H),7.09(d,J＝7.6Hz,2H),6.67(dd,J＝17.6,10.8H z,1H),5.69(d,J＝17.6Hz,1H),5.14(d,J＝10.8Hz,1H),4.48(t,J＝8.8Hz,2H),4.33(d,J＝ 9.6Hz,1H),4.19(d,J＝16.0Hz,1H),3.95(d,J＝16.4Hz,1H),3.71(dd,J＝12.0,2.4Hz,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)

Allyl bromide (2.8 mL, 32.9 mmol) was added dropwise to a mixture _of methyl isovanillate (5.00 g, 27.4 mmol, TCI reagent) in DMF (30 mL) and _K₂CO₃ (4.55 g, 32.9 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, after which the reaction was completed with water. The aqueous layer was extracted with EtOAc, and the organic layer was washed with brine. The resulting product was dried over anhydrous _MgSO₄ , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to yield the title compound (38-1) (5.80 g, 26.1 mmol, 95%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.68(dd,J＝8.0,2.0Hz,1H),7.56(s,1H),6.90(d,J＝8.8Hz,1H),6.17-6.04(m,1H),5.44(dd, J＝17.6,1.2Hz,1H),5.31(dd,J＝10.4,1.2Hz,1H),4.66(d,J＝5.6Hz,2H),3.93(s,3H),3.89(s,3H)

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

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

¹ H NMR (400MHz, CDCl ₃ ); δ7.52(d,J＝8.4Hz,1H),6.76(d,J＝8.8Hz,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＝6.0Hz,2H)

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

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

¹ H NMR (400MHz, CD ₃ OD); δ7.44(d,J＝8.4Hz,1H),6.85(d,J＝8.8Hz,1H),3.91(s,3H),3.84(s,3H),3.57(t,J＝6.8Hz,2H),3.03(t,J＝7.6Hz,2H),1.85-1.77(m,2H)

Step 4. Synthesis of 8-methoxychroman-5-carboxylic acid methyl ester (38-4)

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

¹ H NMR (400MHz, CDCl ₃ ); δ7.58(d,J＝8.4Hz,1H),6.74(d,J＝8.4Hz,1H),4.27(t,J＝5.2Hz,2H),3.92(s,3H),3.85(s,3H),3.14(t,J＝6.4Hz,2H),2.05-1.99(m,2H)

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

A mixture of compound (38-4) (1.87 g, 8.41 mmol) in THF (5 mL) and 1N-NaOH aqueous solution (13 mL) was stirred under reflux for 2 hours. The resulting reaction mixture was cooled at room temperature, after which the resulting mixture was acidified with 1N-HCl solution and then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to obtain the title compound (38-5) (1.72 g, 8.26 mmol, 96%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.59 (d, J = 8.8Hz, 1H), 6.84 (d, J = 8.8Hz, 1H), 4.19 (t, J = 5.2Hz, 2H), 3.86 (s, 3H), 3.12 (t, J = 6.4Hz, 2H), 2.01-1.95 (m, 2H)

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

_Br₂ (0.28 mL, 10.7 mmol) was added dropwise to a solution of compound (38-5) (1.72 g, 8.26 mmol) in AcOH ( _{20 mL} ) at room temperature. The resulting mixture was stirred overnight at room temperature, after which the reaction was completed with saturated _{Na₂S₂O₃} solution and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The crude compound (38-6) (1.86 g, 6.18 mmol, 75%) was used in the following step without additional purification.

¹ H NMR (400MHz, CD ₃ OD); δ6.99 (s, 1H), 4.19 (t, J = 5.2Hz, 2H), 3.82 (s, 3H), 2.77 (t, J = 6.4Hz, 2H), 2.02-1.96 (m, 2H)

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

The title compound (38-7) was obtained from compound (38-6) by the method described in Step 4-5 of Example 1.

¹ H NMR (400MHz, CDCl ₃ ); δ6.99-6.97(m,3H),6.80(d,J＝8.8Hz,2H),4.17(t,J＝4.8Hz,2H),4.06( s,2H),3.87(s,3H),3.77(s,3H),2.60(t,J＝6.4Hz,2H),1.96-1.91(m,2H)

Step 8. Synthesis of target compound

The target compound was obtained using compound (38-7) by the method described in Step 6-7 of Example 1.

¹ H NMR (400MHz, CD ₃ OD); δ7.01-6.99(m,3H),6.78(d,J＝8.4Hz,2H),4.38(d,J＝9.6Hz,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)benzene (dihydropyran-7-yl)tetrahydro-2H-pyran-3,4,5-triol

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

The title compound (39-1) was prepared by the method described in Step 1-3 of Example 4 using the compound (38-6) obtained in Step 6 of Example 38.

¹ H NMR (400MHz, CDCl ₃ ); δ7.07(d,J＝7.6Hz,2H),6.99(s,1H),6.95(d,J＝8.0Hz,2H),4.17(t,J＝5.2Hz,2H ),4.09(s,2H),3.87(s,3H),2.59(t,J＝6.4Hz,2H),2.30(s,3H),1.96-1.92(m,2H)

Step 2. Synthesis of target compound

The target compound was obtained using compound (39-1) by the method described in Step 4 of Example 4.

¹ H NMR (400MHz, CD ₃ OD); δ7.03(d,J＝8.0Hz,2H),6.99(s,1H),6.96(d,J＝8.0Hz,2H),4.38(d,J＝9.6H z,1H),4.17(d,J＝16.8Hz,1H),4.12-4.03(m,2H),3.88(d,J＝10.0Hz,1H),3.85(s ,3H),3.75(dd,J＝12.0,2.4Hz,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)

The title compound (40-1) was obtained by the method described in Step 1-7 of Example 38 using 3-hydroxy-4-methylbenzoic acid (TCI reagent).

¹ H NMR (400MHz, CDCl ₃ ); δ7.24(s,1H),6.97(d,J＝8.8Hz,2H),6.78(d,J＝8.8Hz,2H),4.10(t,J＝8.8Hz,2H),4.08(s,2H), 3.96(q,J＝6.8Hz,2H),2.60(t,J＝8.8Hz,2H),2.15(s,3H),1.94-1.87(m,2H),1.39(t,J＝6.8Hz,3H)

Step 2. Synthesis of target compound

The target compound was obtained using compound (40-1) by the method described in Steps 6-7 of Example 1.

¹ H NMR (400MHz, CD ₃ OD); δ7.14(s,1H),6.98(d,J＝8.8Hz,2H),6.76(d,J＝8.8Hz,2H),4.33(d,J＝9.2Hz,1H),4.15-4.06(m,3H),3.99-3.90(m,3H),3.74(dd,J＝12.0 ,2.0Hz,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＝6.8Hz,3H)

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

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

DCM (104 mL) was cooled at -78 ° C, and then (COCl) ₂ (24 mL, 278.64 mmol) and DMSO (2.06 mL, 464.44 mmol) were added dropwise to the resulting product, and the resulting mixture was stirred for 30 minutes. Trans-2-penten-1-ol (16.00 g, 185.76 mmol) was diluted in DCM (40 mL), and the resulting solution was slowly added to the reaction flask over 15 minutes. The resulting mixture was stirred at the same temperature for 30 minutes, and then further stirred for 1 hour while the temperature was raised to 0 ° C. Water was poured on the resulting mixture to complete the reaction, and then extracted with diethyl ether. The organic layer was washed with brine, and the resulting product was dried over anhydrous MgSO ₄ , filtered and concentrated to obtain the title compound (41-1). The resulting compound was used in the following reaction without additional purification.

¹ H NMR (400MHz, CDCl ₃ ); δ9.52 (d, J＝7.6Hz, 1H), 6.86 (dt, J＝15.6, 6.2Hz, 1H), 6.16-6.09 (m, 1H), 2.41-2.34 (m, 2H), 1.13 (t, J＝7.2Hz, 3H)

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

Sodium hydride (13.00 g, 325.08 mmol) was placed in THF (200 mL), and the resulting solution was cooled at -78 ° C. Triethylphosphonoacetate (65 mL, 325.08 mmol) was slowly added to the resulting product over 5 minutes, and the resulting mixture was stirred at the same temperature for 30 minutes. Compound (41-1) in THF (60 mL) was slowly added dropwise to the resulting mixture, and the resulting mixture was stirred for 30 minutes and then further stirred for 1 hour while the temperature was raised to -40 ° C. The resulting product was diluted with ether, and then a saturated solution of ammonium chloride was slowly added to the resulting solution, and the resulting mixture was stirred at room temperature for 10 minutes. The organic layer was washed twice with brine, and the resulting product layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound (41-2) (21.86 g, 141.75 mmol, 76%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.29-7.23(m,1H),6.18-6.10(m,2H),5.79(d,J＝12.8Hz,1H),4.19(q,J ＝6.8Hz,2H),2.24-2.18(m,2H),1.29(t,J＝7.2Hz,3H),1.05(t,J＝7.2Hz,3H)

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

Compound (41-2) (21.80 g, 141.36 mmol) and 1-pyrrolidinyl-1-cyclopentene (22.67 mL, 155.50 mL) were dissolved in xylene (64 mL), and the resulting solution was stirred under reflux for 24 hours. After cooling to room temperature, 1N HCl was added dropwise to the resulting solution, and the solution was extracted with EtOAc. The extract was then dried over anhydrous MgSO ₄ , filtered, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound (41-3) (12.20 g, 55.89 mmol, 59%).

¹ H NMR (400MHz, CDCl ₃ ); δ7.80(d,J＝8.0Hz,1H),7.06(d,J＝8.0Hz,1H),4.34(q,J＝7.2Hz,2H),3.30(t,J＝7.6Hz,2H),2.88(t ,J＝7.6Hz,2H),2.08(q,J＝7.6Hz,2H),2.12-2.04(m,2H),1.38(t,J＝7.2Hz,3H),0.88(t,J＝7.2Hz,3H)

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

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

¹ H NMR (400MHz, CD ₃ OD); δ7.69(d,J＝8.0Hz,1H),7.01(d,J＝8.0Hz,1H),3.21(t,J＝7.6Hz,2H),2.85( t,J＝7.6Hz,2H),2.61(q,J＝7.6Hz,2H),2.07-2.02(m,2H),1.17(t,J＝7.6Hz,3H)

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

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

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

The title compound (41-6) was obtained from compound (41-5) by the method described in Step 1-3 of Example 4.

¹ H NMR (400MHz, CDCl ₃ ); δ7.13(s,1H),7.10-7.02(m,4H),3.82(s,2H),2.90(t,J＝7.6Hz,2H),2.75(t,J＝7. 6Hz,2H),2.71(q,J＝7.6Hz,2H),2.31(s,3H),2.08-2.01(m,2H),1.25(t,J＝7.6Hz,3H)

Step 7. Synthesis of target compound

The target compound was obtained using compound (41-6) by the method described in Steps 6-7 of Example 1.

¹ H NMR (400MHz, CD ₃ OD); δ7.08(s,1H),6.98(s,4H),4.39(d,J＝9.2Hz,1H),3.82-3.79(m,3H) ,3.63-3.59(m,1H),3.55(t,J＝9.2Hz,1H),3.47-3.43(m,1H),3.35(d,J＝6 .0Hz,2H),2.84(t,J＝7.6Hz,2H),2.78-2.71(m,1H),2.67(t,J＝7.6Hz,2H) ,2.63-2.58(m,1H),2.22(s,3H),1.99-1.91(m,2H),1.10(t,J＝7.6Hz,3H)

Examples 42-60

The target compounds of Examples 42-60 were obtained by the method shown in Example 41.

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

¹ H NMR (400MHz, CD ₃ OD); δ7.07(s,1H),7.02(d,J＝8.8Hz,2H),6.75(d,J＝8.8Hz,2H),4.41(d,J＝9.6Hz,1 H),3.83-3.80(m,3H),3.70(s,3H),3.61(dd,J＝11.2,3.7Hz,1H),3.55(t,J＝9.2Hz,1 H),3.47-3.43(m,1H),3.35(d,J＝5.2Hz,2H),2.84(t,J＝7.6Hz,2H),2.78-2.73(m,1H ),2.68(t,J＝7.6Hz,2H),2.64-2.58(m,1H),1.99-1.92(m,2H),1.11(t,J＝7.2Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.12(s,1H),7.06(d,J＝8.4Hz,2H),6.78(d,J＝8.4Hz,2H),4.45(d,J＝9.6Hz,1H),4.00(dd,J＝7.2,6.8Hz,2H),3.67-3.54(m,2H),3. 51-3.48(m,1H),3.43-41(m,2H),2.88(t,J＝7.6Hz,2H),2.83-2.61(m,5H),2.04-1.96(m,3H),1.35(t,J＝6.8Hz,4H),1.15(t,J＝7.6Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.13(s,1H),7.05(s,4H),4.43(d,J＝9.6Hz,1H),3.84(d,J＝4.8Hz,3H),3.76-3.57(m,3H),3.52-3.48(m,3H),2.89(t,J＝7.2Hz ,2H),2.83-2.78(m,1H),2.73(t,J＝6.8Hz,2H),2.68-2.61(m,1H),2.59(dd,J＝8.0,7.6Hz,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-amino)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.17-7.13(m,3H),6.97-6.92(m,2H),4.45(d,J＝9.2Hz,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＝7.4Hz,2H),2.83-2.76(m,1H),2.73-2.63(m,3H),2.04-1.97(m,2H),1.15(t,J＝7.6Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.22(d,J＝8.0Hz,2H),7.14(d,J＝8.0Hz,2H),7.13(s,1H),4.45(d,J＝9.2Hz,1H ),3.91(s,2H),3.86(d,J＝11.6Hz,1H),3.63(dd,J＝11.6,4.0Hz,1H),3.56(t,J＝9.2Hz ,1H),3.52-3.48(m,1H),3.40(d,J＝5.2Hz,2H),2.89(t,J＝7.6Hz,2H),2.84-2.78(m,1 H),2.71(t,J＝7.6Hz,2H),2.68-2.65(m,1H),2.05-1.97(m,2H),1.15(t,J＝7.6Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.24(d,J＝8.4Hz,2H),7.16(s,1H),7.13(d,J＝8.8Hz,2H),4.45(d,J＝9.2Hz,1H ),3.95(s,2H)3.86(d,J＝12.0Hz,1H),3.66(dd,J＝12.0,4.0Hz,1H),3.59(t,J＝9.2Hz, 1H),3.56-3.48(m,1H),3.41(d,J＝5.6Hz,2H),2.89(t,J＝7.2Hz,2H),2.84-2.79(m,1 H),2.72(t,J＝7.6Hz,2H),2.69-2.63(m,1H),2.05-1.98(m,2H),1.16(t,J＝7.6Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.53(d,J＝7.6Hz,2H),7.35(d,J＝7.6Hz,2H),7.17(s,1H),4.46(d,J ＝9.2Hz,1H),4.01(s,2H),3.86(d,J＝11.6Hz,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),2.8 4-2.77(m,1H),2.77-2.64(m,3H),2.05-1.98(m,2H),1.16(t,J＝7.6Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.12(s,1H),7.05(d,J＝8.8Hz,2H),6.76(d,J＝8.8Hz,2H),4.55-4.4 8(m,1H)4.44(d,J＝9.6Hz,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＝7.2Hz,2H),2.83-2 .63(m,4H),2.04-1.97(m,2H),1.27(d,J＝6.0Hz,6H),1.15(t,J＝7.2Hz,3H)

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

¹ H NMR (400 MHz, CD ₃ OD); δ7.14(s,1H),7.07(dd,J＝8.4,4.8Hz,4H),4.44(d,J＝9.2Hz,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),3.28-3.0 3(m,2H),2.89(t,J＝7.2Hz,2H),2.85-2.78(m,1H),2.74(t,J＝7.6Hz,2H),2.6 8-2.63(m,1H),2.04-1.98(m,2H),1.21(d,J＝6.8Hz,6H),1.15(t,J＝7.2Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.52(d,J＝7.6Hz,2H),7.37(t,J＝7.6Hz,4H),7.27(d,J＝7.2Hz,2H),7.16(s,1H ),7.10(d,J＝6.8Hz,1H),4.42(d,J＝9.2Hz,1H),3.96(s,1H),3.84-3.81(dd,J＝12.4,1 1.2,1H),3.62-3.55(m,2H),3.47(t,J＝8.4Hz,1H),3.67-3.58(m,2H),2.86(t,J＝6.8H z,2H),2.80-2.73(m,3H),2.65-2.60(m,2H),2.00-1.95(m,2H),1.12(t,J＝7.2Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.07(s,1H),7.01(d,J＝8.8Hz,2H),6.74(d,J＝8.8Hz,2H),4.38(d,J＝9.6Hz,1 H),3.82-3.80(m,3H),3.70(s,3H),3.61(dd,J＝12.0,5.6Hz,1H),3.55(t,J＝8.8Hz,1 H),3.45(t,J＝8.8Hz,1H),3.34(d,J＝6.8Hz,2H),2.83(t,J＝6.8Hz,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＝7.6Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.08(s,1H),6.99(s,4H),4.38(d,J＝8.8Hz,1H),3.83-3.80(m,3H) ,3.64-3.59(m,1H),3.55(t,J＝8.8Hz,1H),3.45(t,J＝8.8Hz,1H),3.35(d, J＝5.6Hz,2H),2.83(t,J＝7.2Hz,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＝7.6Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.08(s,1H),7.01(d,J＝8.8Hz,2H),6.74(d,J＝8.8Hz,2H),4.40(d,J＝9.2Hz,1H),3.96(dd ,J＝7.2,6.8Hz,2H),3.83-3.82(m,1H),3.62(dd,J＝6.4,5.2Hz,1H),3.55(t,J＝8.4Hz,1H),3.45 (t,J＝8.4Hz,1H)3.38-3.36(m,2H),3.27(s,2H),2.83(t,J＝7.2Hz,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＝7.2Hz,3H),0.97(t,J＝7.2Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.13(s,1H),7.05(s,4H),4.44(d,J＝8.4Hz,1H),3.88(s,2H),3.67-3.63(m,1H),3.59(t,J＝4.8Hz,1H),3.49(t,J＝7.6Hz,1H),2.88 (t,J＝7.6Hz,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＝7.6Hz,3H),1.01(t,J＝7.2Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.17-7.13(m,3H),6.97-6.92(m,2H),4.43(d,J＝9.6Hz,1H),3.9 0-3.84(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＝7.4Hz,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＝7.2Hz,3H)

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

¹ H NMR (400MHz, CDCl ₃ ); δ7.03-7.01 (m, 3H), 6.76 (d, J = 8.4Hz, 2H), 4.45 (d, J = 8.4Hz, 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＝7.2Hz,2H),2.72(t,J＝7.2Hz,2 H),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＝6.8Hz,3H)

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

¹ H NMR (400MHz, CDCl ₃ ); δ7.05-6.98 (m, 5H), 4.45 (d, J = 8.4Hz, 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＝7.2Hz,2H),2.72(t,J＝7.2Hz,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＝6.8Hz,3H)

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

¹ H NMR (400MHz, CD ₃ OD); δ7.07(s,1H),7.01(d,J＝8.4Hz,2H),6.72(d,J＝8.4Hz,2H),4.38(d,J＝9.2Hz,1H),3.94(q,J ＝7.2Hz,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＝7.6Hz,2H),2.78-2.51(m,1H),2.67(t,J＝7.6Hz,2H),2.59-2.52(m,1H),1.9 9-1.93(m,2H),1.52-1.44(m,2H),1.44-1.37(m,2H),1.31(t,J＝6.8Hz,3H),0.93(t,J＝6.8Hz,3H)

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

¹ H NMR (400 MHz, CD ₃ OD); δ7.08(s,1H),7.01(s,4H),4.38(d,J=9.2Hz,1H),3.83-3.79(m,3H),3.6 3-3.59(m,1H),3.58-3.53(m,1H),3.46-3.42(m,1H),3.35-3.34(m,2H),2.83( t,J＝7.6Hz,2H),2.78-2.67(m,3H),2.59-2.50(m,3H),1.98-1.91(m,2H),1.5 4-1.44(m,2H),1.44-1.34(m,2H),1.14(t,J＝7.2Hz,3H),0.93(t,J＝7.2Hz,3H)

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

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

(Carboethoxymethylene)triphenylphosphine (24.10 g, 69.34 mmol) was dissolved in DCM (101 mL), and the resulting solution was cooled at 0 ° C. Isobutyraldehyde (5.0 g, 69.34 mmol, Aldrich) was slowly added dropwise to the resulting product, and the resulting mixture was stirred at room temperature for 24 hours. The solvent in the reaction mixture was concentrated under reduced pressure, and then diethyl ether was added dropwise to the resulting concentrate, and the resulting solid was filtered and removed. The resulting filtrate was collected and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (61-1) (8.48 g, 59.63 mmol, 86%).

¹ H NMR (400MHz, CDCl ₃ ); δ6.95(dd,J＝15.6,6.8Hz,1H),5.77(dd,J＝15.6,1.2Hz,1H),4.19(q,J＝7.2Hz,2H),2.50-2.42(m,1H),1.29(t,J＝7.2Hz,3H),1.06(d,J＝6.8Hz,6H)

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

Lithium aluminum hydride (6.79 g, 178.9 mmol) and aluminum chloride (7.95 g, 59.63 mmol) were diluted in ether (500 mL), and the resulting solution was cooled at -78 ° C. The title compound (61-1) (8.48 g, 59.63 mmol) according to the present invention in ether (50 mL) was slowly added dropwise to the reaction mixture, and the resulting mixture was stirred at the same temperature for 2 hours. Water was slowly added dropwise to the resulting mixture, and the reaction was completed, and the resulting solid was filtered and removed. The organic layer was washed with salt water, and the resulting product was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The concentrated solution was vacuum dried to obtain the title compound (61-2), which was used in the following steps without additional purification.

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

Step 3. Synthesis of target compound

The target compound was obtained using compound (61-2) by the method described in Step 1-7 of Example 41.

¹ H NMR (400MHz, CD ₃ OD); δ7.13 (s, 1H), 7.05 (d, J = 8.4Hz, 2H), 6.78 (d, J = 8.4Hz, 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＝7.2Hz,2H),2.67-2.61(m,2H),1.99-1.92(m,2H),1.32-1.30(m,6H)

Examples 62 and 63

The target compounds of Examples 62 and 63 were obtained by the method shown in Example 61.

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

¹ H NMR (400MHz, CD ₃ OD); δ7.14(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＝7.2Hz,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- Inden-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

¹ H NMR (400MHz, CD ₃ OD); δ7.10 (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,2 H),2.89(t,J＝7.2Hz,2H),2.61(t,J＝7.2Hz,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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol

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

n-BuLi (14.5 mL, 36.29 mmol, 2.5 M n-hexane solution) was added to a solution of isopentyltriphenylphosphonium bromide (15.0 g, 36.29 mmol) in THF (50 mL) at -78 ° C in a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 1 hour. 4-Oxobut-2-enoic acid ethyl ester (1.55 g, 12.09 mmol) was slowly added dropwise to the resulting mixture, and the resulting mixture was stirred for 30 minutes while the temperature was raised to room temperature. The reaction mixture was cooled at 0 ° C, and a saturated ammonium chloride solution was added dropwise to the resulting product to complete the reaction, followed by extraction with diethyl ether. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography to obtain the title compound (64-1) (1.89 g, 10.37 mmol, 86%).

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

Step 2. Synthesis of target compound

The target compound was obtained using compound (64-1) by the method described in Step 3-7 of Example 41.

¹ H NMR (400MHz, CDCl ₃ ); δ7.07-7.01(m,5H),4.49(d,J＝8.4Hz,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＝7.2H z,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＝6.4Hz,6H)

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

The target compound was obtained using compound (64-1) by the method described in step 2 of Example 64.

¹ H NMR (400MHz, CDCl ₃ ); δ7.11-7.05(m,5H),4.50(d,J＝8.4Hz,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＝7.2Hz,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＝7.2Hz,3H),0.94(d,J＝6.4Hz,6H)

Experimental Example 1. Cloning of human SGLT1 and SGLT2 genes and construction of cell lines expressing human SGLT1 and SGLT2

The human SGLT1 (hSGLT1) and human SGLT2 (hSGLT2) genes were amplified by PCR from a human marathon-ready cDNA library (Clontech). The resulting amplified sequences were then combined with the pcDNA 3.1(+) vector, a mammalian expression vector, to prepare the recombinant expression vectors pcDNA3.1(+)/hSGLT1 and pcDNA3.1(+)/hSGLT2. The resulting recombinant expression vectors were transformed into Chinese Hamster Ovarian cells, and stably transformed clones were selected by clonal selection using resistance to G418 (a selective marker included in the vector). Among the selected clones, clones expressing hSGLT1 and hSGLT2 were selected based on their activity in a ¹⁴ C-α-methyl-D-glucopyranoside ( ¹⁴ C-AMG) transport assay.

Experimental Example 2. Inhibitory effect on human SGLT1 and SGLT2 activity

To analyze sodium-dependent glucose transport, cells expressing hSGLT1 and hSGLT2 were seeded at 1 x 10 ⁵ cells per well in 96-well culture plates and cultured in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS). On day 1 of culture, the cells were incubated in a pre-treated buffer solution (10 mM HEPES, 5 mM tris, 140 mM choline chloride, 2 mM KCl, 1 mM CaCl ₂ , and 1 mM MgCl ₂ , pH 7.4 ₎ at 37°C/5% CO 2 for 10 minutes. Then, the resulting cells were cultured in an uptake buffer solution (10 mM HEPES, 5 mM _tris , 140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl ₂ and 1 mM AMG, pH 7.4) containing 14C-AMG (8 μM) and a compound of the present disclosure or a dimethyl sulfoxide (DMSO) vehicle for 2 hours at 37° _C /5% CO 2. After culture, the cells were washed twice with a wash buffer solution (pretreatment buffer solution containing 10 mM AMG at room temperature) and then their radioactivity was measured using a liquid scintillation counter. According to nonlinear regression analysis, SigmaPlot (Document Analytical Biochemistry 429: 70-75, Molecular and Cellular Biochemistry 280: 91–98, 2005) was used to measure the IC ₅₀ of each compound. The results of the SGLT1/2 in vitro assay are shown in Table 1 below.

[Table 1]

Experimental Example 3. Experiment on measurement of urinary glucose excretion (UGE test)

For the drug efficacy of the compounds prepared in the examples, 1 mg/kg of the compounds were orally administered to normal mice, followed by a UGE test. As a result, it was confirmed that the compounds of the present disclosure increased urine glucose levels (mg/24h) and decreased blood glucose levels (mg/dl).

Therefore, the compounds of the present disclosure may be expected to be valuable for the treatment or prevention of diabetes.

Experimental Example 4. Experiment for measuring antidiabetic activity

To investigate the drug efficacy of the compounds prepared in the Examples, 2 mg/kg of the compounds were orally administered to db/db mice and DIO mice for 4 weeks, and changes in blood glucose levels were measured. As a result, a significant decrease in blood glucose levels was confirmed.

Likewise, to investigate the pharmaceutical efficacy of the compound prepared in the above example, the compound was orally administered to OB/OB mice for 2 weeks, and then changes in blood sugar levels were measured. As a result, a significant decrease in blood sugar levels was confirmed.

Therefore, the compounds of the present disclosure may be expected to be valuable for the treatment or prevention of diabetes.

Experimental Example 5. Experiment on measuring oral glucose resistance

To determine the drug efficacy of the compound prepared in Example, postprandial glucose was measured in normal mice. As a result, it was confirmed that blood glucose AUC0-4h:mg·h/dL was significantly reduced within 4 hours after administration of the compound (1 mg/kg).

These results were also found in the experiment on db/db mice, thereby confirming that blood glucose AUC0-4h:mg·h/dL was significantly decreased within 4 hours after administration of the compound (2 mg/kg).

Similarly, in experiments on db/db mice, it was confirmed that blood glucose AUC0-4h:mg·h/dL was also significantly reduced within 4 hours after administration of the compound (10 mg/kg).

Therefore, the compounds of the present disclosure may be expected to be valuable for the treatment or prevention of diabetes.

Although specific parts of the present disclosure have been described in detail above, it will be apparent to those skilled in the art that these detailed descriptions are merely illustrative of specific embodiments and should not be construed as limiting the scope of the present disclosure. Therefore, it should be understood that the substantial scope of the present disclosure should be defined by the appended claims and their equivalents.

Claims (5)

1. Compounds selected from the following group or their pharmaceutically acceptable salts: (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(7-(4-methoxybenzyl)-4-methyl-2,3-dihydro-1H-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-4-methyl-2,3-dihydro-1H-inden-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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-4-methyl-2,3-dihydro-1H-inden-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-inden-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-inden-5-yl)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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(7-(4-chlorobenzyl)-4-methyl-2,3-dihydro-1H-inden-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-ethyl-7-(4-methylbenzyl)-2,3-dihydro-1H-inden-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-inden-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-inden-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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-(4-butyl-7-(4-methoxybenzyl)-2,3-dihydro-1H-inden-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-inden-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-inden-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-inden-5-yl)tetrahydro-2H-pyran-3,4,5-triol; (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-isobutyl-7-(4-methylbenzyl)-2,3-dihydro-1H-inden-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. 2. A pharmaceutical composition for treating or preventing diseases related to SGLT activity, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. The pharmaceutical composition according to claim 2, wherein the composition inhibits SGLT1, SGLT2, or both. 4. The pharmaceutical composition of claim 2, wherein the SGLT activity-related disease is diabetes. 5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of diseases related to SGLT activity.