KR20150130177A - 2,3-dihydrobenzofuran derivatives as an sglt inhibitor and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention relates to a compound selected from the group consisting of dihydrobenzofuran derivatives having an inhibitory activity against a sodium-dependent glucose transporter (SGLT), which is present in intestines and kidneys, and represented by a chemical formula 1 or a pharmaceutically acceptable salt thereof, an isomer, a hydrate, and a solvate, and a pharmaceutical composition containing the same as an active ingredient. The compound or pharmaceutical composition effectively inhibits activation of the SGLT, thereby being used as a therapeutic agent for diabetes including insulin-dependent diabetes mellitus (type I diabetes mellitus), non-insulin-dependent diabetes mellitus (type II diabetes mellitus), diabetic complications, diseases caused by hyperglycemia such as obesity and the like.

Description

2,3-dihydrobenzofuran derivatives as SGLT inhibitors and pharmaceutical compositions containing them [0002] FIELD OF THE INVENTION [0003] The present invention relates to 2,3-dihydrobenzofuran derivatives, and 2,3-dihydrobenzofuran derivatives,

The present invention relates to novel dihydrobenzofuran derivatives or their pharmaceutically acceptable salts, isomers, hydrates and solvates which have inhibitory activity against the sodium-dependent glucose transporter (SGLT) present in the intestine and kidney And a pharmaceutical composition containing the same as an active ingredient.

About 300 million of the world's population are suffering from type II diabetes, characterized by hyperglycemia due to hepatic glucose uptake and peripheral insulin resistance, due to poor diet and chronic lack of exercise, and the number of patients is increasing recently. Although dieting and exercise therapy are essential for the treatment of diabetes, insulin or several oral diabetes therapies are additionally used when these therapies do not adequately control the patient's symptoms.

At present, although a biguanide compound, a sulfonylurea compound, an insulin resistance-improving agent and an? -Glucosidase inhibitor are used as therapeutic agents for diabetes, these diabetic therapeutic agents involve various side effects. For example, the biguanide compounds cause lactic acid acidosis, the sulfonylurea compounds cause severe hypoglycemia, the insulin resistance modifiers cause edema and heart failure, and the alpha -glucosidase inhibitors cause abdominal distension and diarrhea . Due to this situation, there is a need for the development of new drugs capable of treating diabetes without the side effects mentioned above.

Recently, glucose toxicity theory has been reported that hyperglycemia is involved in the progressive disorder such as the onset of diabetes and diabetic complication. In other words, the chronic hyperglycemia reduces insulin secretion and insulin sensitivity, resulting in an increase in blood glucose level Diabetes self-exacerbation [ Diabetologia (1985) 28, p119; Diabetes Care (1990) 13, p610]. Thus, by treating hyperglycemia, the above-described self-exacerbating cycle can be stopped to treat or prevent diabetes.

As one method of treating hyperglycemia, a method of directing an excessive amount of glucose directly into the urine so that the blood glucose concentration is normal can be considered. For example, inhibition of the sodium-dependent glucose transporter (SGLT) present in the proximal tubules of the kidneys inhibits glucose reabsorption in the kidneys, thereby promoting glucose excretion into the urine and reducing blood glucose levels. In fact, as a result of continuous subcutaneous administration of florigin, which has SGLT inhibitory activity, to an animal model with diabetes, hyperglycemia can be restored to normal and blood glucose level can be maintained for a long period of time, resulting in improved insulin secretion and insulin resistance Confirmed [ Journal of Clinical Investigation (1987) 79, p1510; The same document p1037; See the same document p561].

In addition, even if an animal model with diabetes is treated with an SGLT inhibitor for a long period of time, the insulin secretory response and insulin sensitivity are improved without adverse effects on the kidney of the animal or blood electrolyte imbalance, The onset and progression of nephropathy and nephropathy was prevented [ Journal of Medicinal Chemistry (1999) 42, p5311; British Journal of Pharmacology (2001) 132, p578].

Thus, from the foregoing, it can be expected that SGLT inhibitors will lower the level of blood glucose in diabetic patients to improve insulin secretion and insulin resistance, and also prevent the onset and progression of diabetes and diabetic complications.

Accordingly, it is an object of the present invention to provide novel 2,3-dihydrobenzofuran derivatives or their pharmaceutically acceptable salts, isomers, and prodrugs which have inhibitory activity against the sodium-dependent glucose transporter (SGLT) Hydrates, and solvates thereof.

Another object of the present invention is to provide a pharmaceutical composition comprising the compound as an active ingredient.

According to this object, the present invention provides a compound selected from the group consisting of a 2,3-dihydrobenzofuran derivative of the following formula (1) or a pharmaceutically acceptable salt, isomer, hydrate and solvate thereof:

≪ Formula 1 >

In this formula,

,

또는

이고; Ring B is

,

or

ego;

R ^1, R ² and R ³ are independently H, halogen, hydroxy, C _{1 respectively 8} alkyl, C _{2 - 7} alkenylene, C _2-7 alkynylene, C _{3 - 6} cycloalkyl, C _{1 - 6} alkyloxy or C _{3 - 6} cycloalkyl-oxy,

The C _{1 - 8} alkyl, C _{2 - 7} alkenylene, C _{2 - 7} alkynyl, C _{3 - 6} cycloalkyl, C _{1 - 6} alkyloxy or C _{3 -6} cycloalkyloxy is optionally with 1 to 3 fluoro a, C _{1 - 4} alkyl, C _{3 - 6} cycloalkyl, C _{1 - 8} alkyloxy, C _{3 - 6} heteroaryl cycloalkyloxy or C _{1 - 3} may be substituted with alkylsulfonyl, the C _{1 - 8} alkyl, oxy are optionally 1 to 2 C _{1 - 6} may be further substituted with cycloalkyloxy, _{- 8} alkyloxycarbonyl or C ₃

Adjacent to the R ¹ and R ² substituted at the two carbon atoms is C _{3 each} other may form a _5-alkylene bridge, wherein the C _{3 - 5} alkyl, 1 to 2 methylene in the alkylene bridge is independently O, S, SO, SO ₂ , CO or NR ⁴ , and at least one of the unsubstituted methylenes may be substituted with 1 to 4 halogens or methyl,

R < ⁴ > is H or benzyl.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising, as an active ingredient, a 2,3-dihydrobenzofuran derivative of Formula 1 or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof.

The 2,3-dihydrobenzofuran derivative of formula (I) according to the present invention or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof effectively inhibits SGLT activity, and thus insulin dependent diabetes mellitus (type I diabetes), insulin ratio Dependent diabetes mellitus (type II diabetes mellitus), diabetes mellitus, diabetic complications, obesity, and other diseases caused by hyperglycemia.

1 is a graph showing the effect of the compound of Example 1, a mixed solution of 5% 1-methyl-2-pyrrolidinone, 20% PEG and 75% 20 mM sodium diphophate as a vehicle, FIG. 2 is a graph showing blood glucose concentration over time after oral administration to mice. FIG.
2 is a graph showing the effect of the compound of Example 1, a mixed solution of 5% 1-methyl-2-pyrrolidinone, 20% PEG and 75% 20 mM sodium diphophate as a vehicle, AUC (area under curve) of 0 to 2 hours after oral administration to mice.

Hereinafter, the present invention will be described in more detail.

The term " halogen "or" halo " as used herein means fluoro, chloro, bromo or iodo.

The term "alkyl" as used herein means a linear or branched, saturated C ₁ to C ₈ hydrocarbon radical chain, specifically methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, t -Butyl, n -pentyl, isopentyl, hexyl, heptyl, oxyl, and the like, but is not limited thereto.

The term "cycloalkyl" as used herein means cyclopropane, cyclobutane, cyclopentane and cyclohexane.

The term "heterocycloalkyl" as used herein means containing one or more heteroatoms selected from O or N in the cycloalkyl ring unless otherwise indicated and includes oxetane, tetrahydrofuran, dioxolane, dioxane, pyrrolidine Or piperidine, but are not limited thereto.

In one embodiment of the invention, the compound of formula (I)

이고; Ring B is

ego;

R ^1, R ² and R ³ are independently H, halogen, hydroxy, C _{1 respectively 8} alkyl, C _{2 - 7} alkenylene, C _2-7 alkynylene, C _{3 - 6} cycloalkyl, C _{1 - 6} alkyloxy or C _{3 - 6} cycloalkyl-oxy,

The C _{1 - 8} alkyl, C _{2 - 7} alkenylene, C _{2 - 7} alkynyl, C _{3 - 6} cycloalkyl, C _{1 - 6} alkyloxy or C _{3 -6} cycloalkyloxy is optionally with 1 to 3 fluoro a, C _{1 - 4} alkyl, C _{3 - 6} cycloalkyl, C _{1 - 8} alkyloxy, C _{3 - 6} may be substituted with a heterocycloalkyl-oxy, or methylsulfonyl, wherein the C _{1 - 8} alkyloxy is optionally 1 to 2 C _{1 - 6} may be further substituted with cycloalkyloxy, _{- 8} alkyloxycarbonyl or C ₃

The adjacent substituted at the two carbon atoms wherein R ¹ and R ² are C _{3 each} other may form a _5-alkylene bridge, wherein the C _{3 - 5} alkyl, 1 to 2 methylene in the alkylene bridge is independently O, S , SO, SO ₂ , CO or NR ⁴ , and at least one of the unsubstituted methylenes may be substituted with 1 to 2 F or methyl,

R < ⁴ > is H or benzyl.

In another embodiment of the invention, the compound of formula (I)

또는

이고; Ring B is

or

ego;

R ¹ and R ² are each independently H, halogen, hydroxy or C _{1 - 8} is alkyl.

Specific preferred examples of the 2,3-dihydrobenzofuran derivatives of formula (1) according to the present invention are as follows, and pharmaceutically acceptable salts, isomers, hydrates or solvates thereof are also possible:

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

2) (2S, 3R, 4R, 5S, 6R) -2- (7- (4-Ethylbenzyl) -2,3- dihydrobenzofuran-5-yl) -6- hydroxymethyl-tetrahydro- 2H -Pyran-3,4,5-triol;

3) (2R, 3S, 4R , 5R, 6S) -2- hydroxymethyl -6- (7- (4- n-propyl) -2,3-dihydro-benzofuran-5-yl) -tetrahydro- -2 H -pyran-3,4,5-triol;

4) Synthesis of (2R, 3S, 4R, 5R, 6S) -2-hydroxymethyl-6- (7- (4-trifluoromethylbenzyl) -2,3-dihydrobenzofuran- - 2H -pyran-3,4,5-triol;

5) Synthesis of (2R, 3S, 4R, 5R, 6S) -2-hydroxymethyl-6- (7- (4-trifluoromethoxybenzyl) -2,3-dihydrobenzofuran- -2 H -pyran-3,4,5-triol;

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

7) (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) -2,3- Dihydro-benzofuran-5-yl] -6- (hydroxymethyl) tetrahydro- 2H -pyran-3,4,5-triol;

8) (2S, 3R, 4R, 5S, 6R) -2- (7- (4- (cyclopropylmethoxy) benzyl) -2,3-dihydrobenzofuran- Methyl) tetrahydro- 2H -pyran-3,4,5-triol;

9) (2S, 3R, 4R, 5S, 6R) -2- (7- (4-ethoxy- 3- fluorobenzyl) -2,3- dihydrobenzofuran- Lt; / RTI > methyl) tetrahydro- 2H -pyran-3,4,5-triol;

10) (2S, 3R, 4R, 5S, 6R) -2- (7- (4-ethoxy- 2- fluorobenzyl) -2,3-dihydrobenzofuran- Lt; / RTI > methyl) tetrahydro- 2H -pyran-3,4,5-triol

11) (2S, 3R, 4R, 5S, 6R) -2- (7- (4- hydroxybenzyl) -2,3- dihydrobenzofuran-5-yl) -6- (hydroxymethyl) tetrahydro -2 H -pyran-3,4,5-triol; And

12) (2S, 3S, 4R, 5R, 6S) -2- (Hydroxymethyl) -6- (7- (4- (3- (methylsulfonyl) propoxy) benzyl) -2,3-dihydro Furan-5-yl) tetrahydro- 2H -pyran-3,4,5-triol.

The category of the compounds of the present invention include all the 2,3-dihydrobenzofuran derivatives of the above formula (1) as well as pharmaceutically acceptable salts, isomers, hydrates or solvates thereof.

Such pharmaceutically acceptable salts are all possible in the form of pharmaceutically acceptable salts formed from inorganic or organic acids, for example salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and the like; Examples of the organic acid include acetic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, malic acid, tartaric acid, gluconic acid, lactic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, phthalic acid, Salts of organic acids such as acetylsalicylic acid (aspirin); Salts of amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamine, lysine, arginine, tyrosine, proline and the like; Salts of sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like; Alkali metal salts such as sodium and potassium; Or ammonium ion salts.

Further, organic base addition salts formed from organic bases such as tris (hydroxymethyl) methylamine, dicyclohexylamine and the like are also possible.

Such pharmaceutically acceptable salts of the 2,3-dihydrobenzofuran derivatives of formula (1) can be prepared by conventional methods in the art, for example, 2,3-dihydrobenzofuran derivatives of formula The furan derivative can be prepared by dissolving the furan derivative in a solvent such as methanol, ethanol, acetone or 1,4-dioxane which can be mixed with water, and then adding the free acid or a free base followed by crystallization.

The 2,3-dihydrobenzofuran derivative of formula (I) according to the present invention, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, effectively inhibits SGLT activity, thereby preventing or ameliorating a disease or condition mediated by hyperglycemia, Lt; / RTI >

Accordingly, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a 2,3-dihydrobenzofuran derivative of Formula 1 or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof.

The pharmaceutical composition of the present invention can be used for the prevention or treatment of diseases or conditions mediated by hyperglycemia by inhibiting SGLT activity, for example, diabetes, diabetes related diseases and diabetic complications.

Herein, diabetes includes insulin-dependent diabetes mellitus (type I diabetes), non-insulin dependent diabetes mellitus (type II diabetes), and other forms of diabetes caused by a specific cause.

Diabetes related diseases include, for example, obesity, hyperinsulinemia, hyperglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, hypertension, congestive heart failure, edema, hyperuricemia, But are not limited to these.

In addition, diabetic complications include both acute complications and chronic complications. Examples of acute complications include hyperglycemia (ketoacidosis), infectious diseases (skin, soft tissue, biliary system, respiratory system, urinary tract infection, etc.), chronic complications include sebaceous vasculopathy (nephropathy, retinopathy) Atherosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, lower limb arterial occlusion), neurological disorders (sensory nerves, motor nerves, autonomic nerves, etc.), and foot ulcers. Major diabetic complications include, but are not limited to, diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

In addition to the SGLT activity inhibitor, the compound of the present invention may also be used in combination with at least one therapeutic agent selected from the group consisting of a diabetic therapeutic agent, a diabetic complication therapeutic agent, a hyperlipidemia therapeutic agent, and a hypertensive agent. By combining the compound of the present invention and other medicines, an additive effect can be expected when the medicines of the present invention are used in combination with the medicines obtained by the single medicines.

Examples of the therapeutic agent for diabetes mellitus and diabetic complications which can be used in combination include insulin sensitivity enhancers (PPARγ agonists, PPARα / γ agonists, PPARδ agonists, PPARα / γ / δ agonists and the like), α- glucosidase Inhibitors, insulin secretagogues, insulin receptor antagonists, insulin receptor kinase promoters, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase 1B inhibitors, glycogen phosphorylase Inhibitors, glucose-6-phosphatase inhibitors, your inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, glucokinase activators, D-chiroinositol, glycogen peptide-1 agonists, amylin, , Amylin agonists, glucocorticoid receptor antagonists, 11? -High An inhibitor of rheumatic steroid dehydrogenase, an aldose reductase inhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptor antagonist, a sodium channel antagonist, a transcription factor NF-κB inhibitor, an IKKβ inhibitor, a lipid peroxidase inhibitor, an insulin-like growth factor-I, a platelet-derived growth factor (PDGF), a platelet-derived growth factor (PDGF) elongase, an epithelial growth factor (EGF), a nerve growth factor, a carnitine derivative, Hydroxyde-1-methylhydantoin, EGB-761, Bimochromol, throdexecid, Y-128, TAR-428 and the like.

Examples of the agent for treating diabetes mellitus and diabetic complications include, but are not limited to, the following agents.

As the biguanide compound, metformin hydrochloride, phenformin and the like can be mentioned.

Examples of the sulfonylurea type among the insulin secretagogues include glyburide (glibenclamide), glypidide, glyclazide, chloropropamide and the like, and examples of the non-sulfonylurea type include nateglinide, repaglinide, And the like.

Insulin preparations include recombinant human insulin and animal-derived insulin. In addition, there are three kinds according to the duration of action: human type (human insulin, human neutral insulin), intermediate type (insulin-human isoprene insulin aqueous suspension, human neutral insulin-human isoprene insulin aqueous suspension, human insulin zinc aqueous suspension , Insulin zinc aqueous suspension), sustained (human crystalline insulin zinc suspension), and the like.

Examples of the? -glucosidase inhibitor include acarbose, voglibose, miglitol, and the like.

Examples of PPAR? /? Dual agonists include MK-767 (KRP-297), Tesaglitazar, LM4156, LY510929 and TY-51501 as the PPAR? Agonists and PPAR? Agonists as the PPAR? Agonists as the PPAR? Agonists. GW-501516 and the like can be mentioned as a nest.

As the tripeptidyl peptidase II inhibitor, UCL-139 and the like can be mentioned.

Examples of dipeptidyl peptidase IV inhibitors include cyproglitin, valdagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin, and the like.

Examples of the aldose reductase inhibitor include ascorbylumbolate, tallestat, epalestate, fidarestat, sorvinyl, phonalesist, lisaestat, and xanestat.

As the? -aminobutyric acid receptor antagonist, topiramate and the like can be mentioned.

Examples of the sodium channel antagonist include mercuric chloride hydrochloride.

Examples of the transcription factor NF-κB inhibitor include dexlipotam and the like.

Examples of the lipid peroxidase inhibitor include mesylate thiirilazide and the like.

Examples of the N-acetylated-α-bond-acid-dipeptidase inhibitor include GPI-5693 and the like.

Examples of carnitine derivatives include carnitine, levacecarnine hydrochloride, and the like.

Examples of the therapeutic agent for hyperlipidemia and hypertension which can be used in combination include a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibrate compound, a β ₃ -adrenaline receptor agonist, an AMPK activator, an acyl coenzyme A: cholesterol A thyroid hormone receptor agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a microsomal triglyceride transfer protein inhibitor, a lipoxygenase inhibitor, a carnitine palmitoyl transferase inhibitor, a squalene synthetase inhibitor, a low specific gravity A cholesterol ester transporting protein inhibitor, an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, an endothelin converting enzyme inhibitor, an endothelin receptor antagonist, a lipopolysaccharide receptor agonist, a lipopolysaccharide receptor promoter, a nicotinic acid derivative, a bile acid adsorbent, a sodium conjugate bile acid transporter inhibitor, An antidiabetic agent, a calcium antagonist, a vasodilator, a sympathetic blocker, a central depressant, an α ₂ -adrenergic receptor agonist, an antiplatelet agent, a uric acid production inhibitor, a urinary excretion promoter, a urinary alkalizing agent, ACE inhibitors, adiponectin receptor agonists, GPR40 agonists, GPR40 antagonists, and the like.

Examples of the agent for treating hyperlipemia and hypertension include, but are not limited to, the following agents.

Examples of the hydroxymethylglutaryl coenzyme A reductase inhibitor include pravastatin, lovastatin, pravastatin, cerivastatin, pitavastatin and the like.

Examples of the fibrate compounds include fenofibrate, bezafibrate, beclobate and binipibrate.

Examples of the squalene synthetase inhibitor include TAK-475, an? -Phosphonosulfonate derivative (US Patent No. 5712396), and the like.

Examples of acyl coenzyme A: cholesterol acyltransferase inhibitors include CI-1011, NTE-122, FCE-27677, RP-73163, MCC-147 and DPU-129.

Examples of the low specific gravity lipoprotein receptor promoter include MD-700 and LY-295427.

Examples of the microsomal triglyceride transfer protein inhibitor (MTP inhibitor) include compounds described in U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, and the like.

Examples of appetite suppressants include adrenaline-noradrenergic agonists (margin stone, ephedrine, etc.), serotonin agonists (selective serotonin reuptake inhibitor inhibitors such as fluvoxamine), adrenaline-serotonin agonists (such as sibutramine) (MC4R) agonists, alpha -melanocyte stimulating hormone (alpha-MSH), leptin, cocaine and amphetamine-regulated transcripts (CART).

Examples of thyroid hormone receptor agonists include sodium thiothiocyanate, sodium lepotriosin, and the like.

Examples of the cholesterol absorption inhibitor include ezetimibe and the like.

Examples of the lipase inhibitor include orlistat.

Examples of the carnitine palmitoyltransferase inhibitor include ethomoxyl and the like.

Examples of the nicotinic acid derivatives include nicotinic acid, nicotinic acid amide, nicomol, nicorandil and the like.

Examples of the angiotensin converting enzyme inhibitor include capril, enalpril maleate, allacrypril, and silazapril.

Examples of an anthranotropin II receptor antagonist include candesartan tecetyl, potassium kalasanate, and fesosan mesylate.

Examples of the endothelin-converting enzyme inhibitor include CGS-31447 and CGS-35066.

For example, in the treatment of diabetes and the like, the compound of the present invention and an insulin sensitivity enhancer (PPAR gamma agonist, PPAR alpha / gamma agonist, PPAR delta agonist, PPAR alpha / gamma / delta agonist and the like), glucosidase inhibitor, It is considered to be preferable to use in combination with at least one type of drug selected from the group consisting of an insulin secretagogue, an insulin secretagogue, an insulin secretagogue, an insulin secretagogue, and a dipeptidyl peptidase IV inhibitor.

Alternatively, the compound of the present invention may be combined with the compound of the present invention and a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibrate compound, a squalene synthetase inhibitor, an acyl coenzyme A: cholesterol acyltransferase inhibitor, a low specific gravity lipoprotein receptor promoter, microsomal triglyceride transfer A protein inhibitor and an appetite suppressing agent in combination with at least one kind of drug selected from the group consisting of

The pharmaceutical composition of the present invention comprises the 2,3-dihydrobenzofuran derivative represented by the above formula (1), or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof as an active ingredient, For example, tablets, capsules, troches, solutions, suspensions, or the like, or parenteral administration preparations by adding an acceptable carrier, additives, excipients and the like to the pharmaceutical composition of the present invention have.

Solid formulations for oral administration may be prepared by mixing at least one additive such as starch, calcium carbonate, sucrose, lactose, gelatin or the like in the at least one 2,3-dihydrobenzofuran derivative according to the present invention Can be prepared by mixing. In addition to simple additives, lubricants such as magnesium stearate and talc may also be used.

In addition to water and liquid paraffin which are commonly used simple diluents, various additives such as a wetting agent, a sweetening agent, a fragrance, a preservative and the like can be used as a liquid preparation for oral administration .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent or suspending agent include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, injectable esters such as ethyl oleate, and the like. Examples of the suppository include withexol, macrogol, tween 61, Cacao paper, laurin paper, glycerol paper, gelatin paper, and the like.

The human body dosage of the pharmaceutical composition of the present invention may vary depending on the age, weight, sex, dosage form, health condition, and disease severity of the patient, and is generally 0.1 mg / Day to 400 mg / day, more preferably 10 mg / day to 100 mg / day, divided doses may be administered several times a day at a predetermined time interval.

Some of the compounds of the present invention can be prepared according to a process of any one of the following Reaction Schemes 1 to 3.

[Reaction Scheme 1]

[Reaction Scheme 2]

[Reaction Scheme 3]

Hereinafter, the present invention will be described in more detail by way of examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  1: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Ethoxybenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- Hydroxymethyl - Tetrahydro - 2H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (4- Ethoxyphenyl ) Preparation of methanol

After dissolving 1-bromo-4-ethoxybenzene (743 mg) in 20 ml of THF (tetrahydrofuran), the temperature was cooled to -78 ° C. While stirring, the n-BuLi solution (2.32 ml) was slowly added thereto, followed by stirring at -78 ° C for 30 minutes. 5-Bromo-2,3-dihydrobenzofuran-7-carbaldehyde (400 mg) dissolved in 5 ml of THF was slowly added thereto, followed by stirring at -78 ° C for 2 hours. Saturated NH ₄ Cl solution was added to the reaction solution, the mixture was warmed to room temperature, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO ₄ and filtered. The organic solvent was removed under reduced pressure and then purified by column chromatography to obtain the title compound (400 mg).

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33 (S, 1H), 7.29 (d, 2H), 7.23 (s, 1H), 6.87 (d, 2H), 5.86 (d, 1H), 4.60 ( t, 2H), 4.05 (q, 2H), 3.20 (t, 2H), 2.69 (d, 1H), 1.42 (t, 3H).

Step 2: 5- Bromo -7- (4- Ethoxybenzyl ) -2,3- Dihydrobenzofuran  Produce

The compound (400 mg) obtained in the step 1 was dissolved in CH ₂ Cl ₂ (10 ml), and then the internal temperature was cooled to -50 ° C under argon. Et ₃ SiH (0.55 ml) and BF ₃ · Et ₂ O (0.22 ml) were added in this order, followed by stirring at the same temperature for 10 minutes. The reaction temperature was raised to 0 캜 and stirred for 1 hour. The organic layer was extracted after the reaction mixture was neutralized. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The organic solvent was removed under reduced pressure and then purified by column chromatography to obtain the title compound (290 mg).

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.10 (t, 3H), 6.96 (s, 1H), 6.82 (d, 2H), 4.57 (t, 2H), 4.02 (q, 2H), 3.79 ( s, 2H), 3.20 (t, 2H), 1.40 (t, 3H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- (7- (4-ethoxybenzyl) -2,3- Dihydrobenzofuran -5 days)- Tetrahydro - 2H -Pyran-2-ol < / RTI &

The compound (290 mg) obtained in Step 2 was dissolved in 10 ml of anhydrous tetrahydrofuran, and then the internal temperature was cooled to -78 ° C. The n-butyllithium solution (0.54 ml) was added slowly while stirring and then stirred at -78 캜 for 30 minutes. Was dissolved in THF 5 ml (3R, 4S, 5R, 6R) -3,4,5- tris (benzyloxy) -6 - ((benzyloxy) methyl) tetrahydro -2 H-pyran-2-one (468 mg ) Was slowly added thereto, followed by stirring at -78 ° C for 2 hours. Saturated NH ₄ Cl solution was added to the reaction solution, the mixture was warmed to room temperature, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO ₄ and filtered. After removal of the organic solvent under reduced pressure, purification by column chromatography gave the title compound (462 mg).

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33-7.10 (m, 20H), 7.10 (d, 2H), 6.96 (d, 2H), 6.73 (d, 2H), 4.88 (s, 2H), 4H), 3.69 (m, 3H), 3.20 (t, 2H), 4.63-4.55 (m, 3H), 1.40 (t, 3H).

Step 4: 7- (4- Ethoxybenzyl ) -5 - ((2S, 3S, 4R, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- (Ben Vinyoxymethyl ) - Tetrahydro - 2H -Pyran-2-yl) -2,3- Dihydrobenzofuran  Produce

The compound (462 mg) obtained in the step 3 was dissolved in CH ₂ Cl ₂ (20 ml), and then the internal temperature was cooled to -50 ° C under argon. While stirring, Et ₃ SiH (0.28 ml) and BF ₃ · Et ₂ O (0.11 ml) were added and stirred at the same temperature for 10 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and extracted with a small amount of water. The organic layer was washed with water and brine, dried over MgSO ₄ , filtered, and then purified by column chromatography to give the title compound (320 mg).

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.32-7.07 (m, 21H), 6.95 (s, 1H), 6.89 (d, 2H), 6.74 (d, 2H), 4.87 (t, 3H), 2H), 1.36 (t, 3H), 4.59 (m, 2H), 4.31 (m, 2H), 4.31 (d, 2H).

Step 5: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Ethoxybenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- Hydroxymethyl - Tetrahydro - 2H - pyran-3,4,5- Triol  Produce

The compound (320 mg) obtained in Step 4 was dissolved in 30 ml of EA / MeOH (= 2/3), 10% Pd / C (32 mg) was added and the mixture was stirred under hydrogen atmosphere for 12 hours. The reaction product was dried and filtered, and then purified by column chromatography to obtain the title compound (100 mg).

¹ H NMR spectrum (300 MHz, MeOD): δ 7.10 (d, 2H), 7.06 (s, 1H), 6.86 (s, 1H), 6.77 (d, 2H), 4.54 (t, 2H), 4.04-3.92 2H), 3.16 (m, 3H), 3.87-3.75 (m, 4H), 3.63 (t, 2H), 3.47 (m, 2H), 3.16 (t,

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 434.2171, [M + K] + m / z 455.1467

Example  2: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Ethylbenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- Hydroxymethyl - Tetrahydro - 2H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (4- Ethyl phenyl ) Preparation of methanol

The title compound (587 mg) was obtained as a white solid from Step 1 of Example 1, except that 1-bromo-4-ethylbenzene was used instead of 1- bromo-4-ethoxybenzene in Step 1 of Example 1 .

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.32-7.15 (m, 6H), 5.86 (s, 1H), 4.58 (t, 2H), 3.17 (t, 2H), 2.63 (q, 2H), 1.23 (t, 3 H).

Step 2: 5- Bromo -7- (4- Ethylbenzyl ) -2,3- Dihydrobenzofuran  Produce

The title compound (434 mg) was obtained in the same manner as in step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.21-7.07 (m, 5H), 7.01 (d, 1H), 4.60 (t, 2H), 3.84 (s, 2H), 3.23 (t, 2H), 2.62 (q, 2H), 1.25 (t, 3H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- (7- (4-ethylbenzyl) -2,3- Dihydrobenzofuran -5 days)- Tetrahydro - 2H -Pyran-2-ol < / RTI &

The title compound (712 mg) was obtained in the same manner as in step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.29-7.07 (m, 21), 7.00 (d, 1H), 6.94 (s, 1H), 6.85 (d, 2H), 4.88 (s, 2H), 4H), 3.69 (m, 3H), 3.20 (t, < RTI ID = 0.0 > 1H) 3H) 2.54 (q, 2H), 1.15 (t, 3H).

Step 4: 7- (4- Ethylbenzyl ) -5 - ((2S, 3S, 4R, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) Tetrahydro - 2H -Pyran-2-yl-2,3- Dihydrobenzofuran  Produce

The title compound (578 mg) was obtained by the same method as in the step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.29-7.07 (m, 21), 7.00 (d, 1H), 6.94 (s, 1H), 6.85 (d, 2H), 4.84 (q, 2H), (M, 2H), 3.16 (t, 2H), 2.54 (q, 2H), 4.61-4.47 2H), 1.15 (t, 3H).

Step 5: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Ethylbenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- Hydroxymethyl - Tetrahydro - 2H - pyran-3,4,5- Triol  Produce

The title compound (130 mg) was obtained by the same method as in the step 5 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.21 (dd, 1H), 7.09 (d, 2H), 7.06 (s, 1H), 6.92 (s, 1H), 6.88 (d, 2H), 4.52 ( 2H), 3.14 (t, 2H), 2.54 (q, 2H), 1.15 (m, 2H) (t, 3 H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 418.2131, [M + K] + m / z 439.1418

Example  3: (2R, 3S, 4R, 5R, 6S) -2- Hydroxymethyl -6- (7- (4- n - Propylbenzyl ) -2,3- Dihydrobenzofuran -5 days)- Tetrahydro -2H-pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (4- n - Propyl phenyl ) - Preparation of methanol

In the same manner as in the step 1 of Example 1 except that 1-bromo-4- n -propylbenzene was used instead of 1-bromo-4-ethoxybenzene in the step 1 of Example 1, the title compound ).

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.32-7.14 (m, 6H), 5.86 (s, 1H), 4.52 (t, 2H), 3.14 (t, 2H), 2.50 (t, 2H), 1.59-1.61 (m, 2H), 0.90 (t, 3H).

Step 2: 5- Bromo -7- (4- n - Propylbenzyl ) -2,3- Dihydrobenzofuran  Produce

The title compound (160 mg) was obtained by the same method as in the step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33-7.06 (m, 6H), 4.51 (t, 2H), 3.80 (s, 2H), 3.16 (t, 2H), 2.52 (t, 2H), 1.59-1.61 (m, 2H), 0.93 (t, 3H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- (7- (4- n -Propylbenzyl) -2,3- Dihydrobenzofuran -5 days) Tetrahydro - 2H -Pyran-2-ol < / RTI &

The title compound (260 mg) was obtained in the same manner as in step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.29-7.07 (m, 21), 7.00 (d, 1H), 6.94 (s, 1H), 6.85 (d, 2H), 4.88 (s, 2H), 4H), 3.69 (m, 3H), 3.20 (t, < RTI ID = 0.0 > 1H) 3H), 2.52 (t, 2H), 1.59-1.61 (m, 2H), 0.92 (t, 3H).

Step 4: 7- (4- n - Propylbenzyl ) - ((2S, 3S, 4R, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- (Ben Vinyoxymethyl ) Tetrahydro - 2H -Pyran-2-yl) -2,3- Dihydrobenzofuran  Produce

The title compound (0.210 mg) was obtained in the same manner as in step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.29-7.07 (m, 21), 7.00 (d, 1H), 6.94 (s, 1H), 6.85 (d, 2H), 4.84 (q, 2H), 2H), 3.16 (t, 2H), 2.52 (t, 2H), 4.63-4.30 (m, 2H) 2H), 1.59-1.61 (m, 2H), 0.92 (t, 3H).

Step 5: (2R, 3S, 4R, 5R, 6S) -2- Hydroxymethyl -6- (7- (4- n - Propylbenzyl ) -2,3- Dihydrobenzofuran -5 days)- Tetrahydro - 2H - pyran-3,4,5- Triol  Produce

The title compound (66 mg) was obtained in the same manner as in step 5 of Example 1.

¹ H NMR spectrum (300 MHz, MeOD): δ 7.14-7.12 (m, 3H), 7.07-7.02 (m, 2H), 6.98 (s, 1H), 4.54 (t, 2H), 4.00 (d, 1H) 2H), 3.83 (m, 1H), 3.46-3.19 (m, 5H), 3.16 (t, 2H), 2.51 (t, 2H), 1.59-1.61 , 3H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 432.2383, [M + K] + m / z 453.1681

Example  4: (2R, 3S, 4R, 5R, 6S) -2- Hydroxymethyl -6- (7- (4- Trifluoromethylbenzyl ) -2,3- Dihydrobenzofuran -5 days) Tetrahydro - 2H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (4- Trifluoromethylphenyl ) Preparation of methanol

Bromo-4-trifluoromethylbenzene instead of 1-bromo-4-ethoxybenzene in Step 1 of Example 1, the title compound 600 mg).

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.61 ~ 7.50 (m, 4H), 7.18 (d, 2H), 5.95 (d, 1H), 4.64 (t, 2H), 3.25 (t, 2H), 2.80 (d, 1 H).

Step 2: 5- Bromo -7- (4- Trifluoromethylbenzyl ) -2,3- Dihydrobenzofuran  Produce

The title compound (345 mg) was obtained by the same method as in the step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.52 (d, 2H), 7.32 (d, 2H), 7.18 (s, 1H), 7.00 (s, 1H), 4.57 (t, 2H), 3.90 ( s, 2 H), 3.21 (t, 2 H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- [7- (4-trifluoromethylbenzyl) -2,3- Dihydrobenzofuran -5 days]- Tetrahydro -2 H -Pyran-2-ol < / RTI &

The title compound (398 mg) was obtained in the same manner as in step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.41 (d, 2H), 7.32 ~ 7.12 (m, 22H), 6.94 (d, 2H), 4.86 (d, 3H), 4.61 (m, 5H), 2H), 4.43 (d, 2H), 4.04 (m, 2H), 4.01-3.79 (m, 5H), 3.71 (d,

Step 4: 7- (4- Trifluoromethylbenzyl ) -5 - ((2S, 3S, 4R, 5R, 6R) -3,4,5-tris Benzyloxy ) -6 - (( Benzyloxymethyl ) Tetrahydro -2 H -Pyran-2-yl) -2,3- Dihydrobenzofuran  Produce

The title compound (300 mg) was obtained in the same manner as in step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.42 (d, 2H), 7.33-7.15 (m, 21H), 6.98 (s, 1H), 6.90 (d, 2H), 4.90 (m, 3H), 2H), 3.41 (d, 1H), 3.47 (m, 2H), 4.61 (d, 2H).

Step 5: (2R, 3S, 4R, 5R, 6S) -2- Hydroxymethyl -6- (7- (4- Trifluoromethylbenzyl ) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

The title compound (120 mg) was obtained in the same manner as in step 5 of Example 1.

¹ H NMR spectrum (300 MHz, MeOD): δ 7.39 (d, 2H), 7.25 (d, 24), 7.07 (s, 1H), 6.89 (s, 1H), 4.42 (t, 2H), 3.97 (d 2H), 3.55 (m, 3H), 3.23 (d, IH), 3.02 (t, 2H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 458.1786, [M + K] + m / z 479.1079

Example  5: (2R, 3S, 4R, 5R, 6S) -2- Hydroxymethyl -6- (7- (4- Trifluoromethoxybenzyl ) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (4- Trifluoromethoxyphenyl ) Preparation of methanol

Bromo-4-trifluoromethoxybenzene instead of 1-bromo-4-ethoxybenzene in Step 1 of Example 1, the title compound (690 mg).

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.28-7.10 (m, 5H), 6.99 (s, 1H), 5.95 (d, 1H), 4.57 (t, 2H), 3.20 (t, 2H), 2.85 (d, 1 H).

Step 2: 5- Bromo -7- (4- Trifluoromethoxybenzyl ) -2,3- Dihydrobenzofuran  Produce

The title compound (355 mg) was obtained in the same manner as in step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.28-7.10 (m, 5H), 7.00 (s, 1H), 4.57 (t, 2H), 3.85 (s, 2H), 3.20 (t, 2H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- (7- (4-Trifluoromethoxybenzyl) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H -Pyran-2-ol < / RTI &

The title compound (480 mg) was obtained in the same manner as in step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33-6.96 (m, 26H), 4.89-4.85 (m, 3H), 4.67-4.41 (m, 7H), 4.15-4.07 (m, 2H), 3.94 -3.72 (m, 5 H), 3.18 (d, 1 H), 3.15 (t, 2 H).

Step 4: 7- (4- Trifluoromethoxybenzyl ) - (2S, 3S, 4R, 5R, 6R) -3,4,5-tris Benzyloxy ) -6- ( Benzyloxymethyl ) Tetrahydro -2 H -Pyran-2-yl) -2,3- Dihydrobenzofuran  Produce

The title compound (361 mg) was obtained in the same manner as in step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.36-7.15 (m, 22H), 7.03-6.87 (m, 4H), 4.91-4.84 (m, 3H), 4.64-4.54 (m, 7H), 4.36 (d, IH), 4.11 (d, IH), 3.89-3.42 (m, 7H), 3.15 (t, 2H).

Step 5: (2R, 3S, 4R, 5R, 6S) -2- Hydroxymethyl -6- (7- (4- Trifluoromethoxybenzyl ) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

The title compound (87 mg) was obtained in the same manner as in step 5 of Example 1.

¹ H NMR spectrum (300 MHz, MeOD): δ 7.32 (d, 2H), 7.17-7.11 (m, 3H), 7.02 (s, 1H), 4.54 (t, 2H), 4.02 (d, 1H), 3.91 -3.85 (m, 3H), 3.47 (m, 1H), 3.38-3.20 (m, 4H), 3.17 (t, 2H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 474.1740, [M + K] + m / z 495.1034

Example  6: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Fluorobenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (4- Fluorophenyl ) - Preparation of methanol

(460 mg) was obtained as yellow crystals from Step 1 of Example 1, using 1-bromo-4-fluorobenzene instead of 1-bromo-4-ethoxybenzene, ≪ / RTI >

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.39-7.34 (m, 2H), 7.22-7.18 (m, 2H), 7.04-6.99 (m, 2H), 5.86 (d, 1H), 4.59 (t , ≪ / RTI > 2H), 3.20 (t, 2H).

Step 2: 5- Bromo -7- (4- Fluorobenzyl ) -2,3- Dihydrobenzofuran  Produce

The title compound (250 mg) was obtained in the same manner as in step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.19-7.14 (m, 3H), 6.99-6.93 (m, 3H), 4.56 (t, 2H), 3.82 (s, 2H), 3.20 (t, 2H ).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- (7- (4-fluorobenzyl) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H -Pyran-2-ol < / RTI &

The title compound (395 mg) was obtained in the same manner as in step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33-6.85 (m, 26H), 4.88-4.85 (m, 3H), 4.66-4.43 (m, 7H), 4.03-3.82 (m, 8H), 3.50 (d, 1 H), 3.18 (t, 2 H).

Step 4: 7- (4- Fluorobenzyl ) -5 - ((2S, 3S, 4R, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- (Ben Vineoxy Yl) Tetrahydro -2 H -Pyran-2-yl) -2,3- Dihydrobenzofuran  Produce

The title compound (320 mg) was obtained by the same method as in the step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.32-6.87 (m, 26H), 4.90-4.84 (m, 3H), 4.64-4.54 (m, 5H), 4.36 (d, 1H), 4.11 (d 2H), 3.19 (t, 2H), 3.87-3.74 (m, 7H), 3.60-3.40 (m, 2H).

Step 5: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Fluorobenzyl ) -2,3- Dihydrobenzofuran -5-yl] -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

The title compound (140 mg) was obtained in the same manner as in step 5 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.19-7.10 (m, 3H), 6.96-6.88 (m, 3H), 4.56 (t, 2H), 4.06 (d, 1H), 3.92-3.43 (m , 8H), 3.19 (t, 3H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 408.1827, [M + K] + m / z 429.1119

Example  7: (2S, 3R, 4R, 5S, 6R) -2- (7 - ((2,3- Dihydrobenzo [b] [1,4] dioxin Yl) methyl ) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (2,3- Dihydrobenzo [b] [1,4] dioxin -6 days) Preparation of methanol

Except that 6-bromo-2,3-dihydrobenzo [1,4] dioxine was used instead of 1-bromo-4-ethoxybenzene in the step 3 of Example 1, Compound (240 mg) was obtained.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.22-7.19 (m, 2H), 6.90-6.79 (m, 3H), 5.76 (d, 1H), 4.58 (t, 2H), 4.22 (s, 4H ), 3.17 (t, 2H).

Step 2: 6 - ((5- Bromo -2,3- Dihydrobenzofuran -7 days) methyl ) -2,3- Dihydrobenzo [b] [1,4] dioxine  Produce

The title compound (197 mg) was obtained in the same manner as in step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.13 (s, 1H), 6.97 (s, 1H), 6.78-6.66 (m, 3H), 4.56 (t, 2H), 4.21 (s, 4H), 3.80 (s, 2 H), 3.18 (t, 2 H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6 - (( Benzyloxy ) methyl ) -2- (7 - ((2,3-di B] < RTI ID = 0.0 > [1, 4] Dioxin-6-yl) methyl ) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H -Pyran-2-ol

The title compound (200 mg) was obtained by the same method as in the step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.32-7.17 (m, 22H), 6.96 (m, 1H), 6.72-6.67 (m, 2H), 4.89-4.66 (m, 3H), 4.66-4.58 (m, 7H), 4.51 (m, 1H), 4.19 (s, 4H), 3.93-3.45 (m, 5H), 3.16 (m, 2H), 3.01 (t, 2H).

Step 4: 6 - ((5- ((2S, 3S, 4R, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6 - (( Benzyloxymethyl ) Tetrahydro -2 H -Pyran-2-yl) -2,3- Dihydrobenzofuran -7 days) methyl ) -2,3- Dihydrobenzo [b] [1,4] dioxine  Produce

The title compound (150 mg) was obtained by the same method as in the step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.17-6.97 (m, 19H), 6.81 (s, 1H), 6.73 (m, 2H), 6.53 (m, 3H), 4.74-4.68 (m, 3H ), 4.49-4.39 (m, 5H), 4.15 (d, IH), 4.00 (s, 4H), 3.97 t, 2H).

Step 5: (2S, 3R, 4R, 5S, 6R) -2- (7 - ((2,3- Dihydrobenzo [b] [1,4] dioxin Yl) methyl ) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

The title compound (32 mg) was obtained in the same manner as in step 5 of Example 1.

¹ H NMR spectrum (300 MHz, MeOD): δ 7.01 (s, 1H), 6.84 (s, 1H), 6.56 (s, 3H), 4.38 (t, 2H), 4.04 (s, 4H), 3.89 (d (M, 4H), 3.31-3.19 (m, 3H), 3.04 (t, 3H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 448.1967, [M + K] + m / z 469.1259

Example  8: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Cyclopropylmethoxy ) Benzyl) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) - (4- ( Cyclopropylmethoxy ) Phenyl ) Preparation of methanol

(1-bromo-4- (cyclopropylmethyl) benzene was used instead of 1-bromo-4-ethoxybenzene in the step 1 of Example 1, the title compound 684 mg).

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.30 (d, 2H), 7.28 (s, 1H), 7.22 (s, 1H), 6.89 (d, 2H), 5.85 (d, 1H), 4.60 ( 2H), 3.80 (d, 2H), 3.20 (t, 2H), 2.67 (d, 1H), 1.27 (m, 1H), 0.65 (m, 2H), 0.35

Step 2: 5- Bromo -7- (4- ( Cyclopropylmethoxy ) Benzyl) -2,3- Dihydrobenzofuran  Produce

The title compound (495 mg) was obtained in a similar manner to Step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.12 (d, 3H), 6.96 (s, 1H), 6.82 (d, 2H), 4.56 (t, 2H), 3.78 (m, 4H), 3.19 ( t, 2H), 1.27 (m, 1H), 0.63 (m, 2H), 0.32 (m, 2H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- (7- (4- (4 Cyclopropylmethoxy ) Benzyl) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H -Pyran-2-ol < / RTI &

The title compound (720 mg) was obtained in the same manner as in step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33-10 (m, 20H), 7.10 (d, 2H), 6.96 (d, 2H), 6.73 (d, 2H), 4.88 (s, 2H), 4H), 3.69 (m, 3H), 3.20 (t, 2H), 4.63-4.55 (m, 3H), 1.25 (m, 1H), 0.61 (m, 2H), 0.31 (m, 2H).

Step 4: 7- (4- ( Cyclopropylmethoxy ) Benzyl) -5- (2S, 3S, 4R, 5R, 6R) -3,4,5-tris Benzyloxy ) -6- ( Benzyloxymethyl ) Tetrahydro -2 H -Pyran-2-yl) -2,3- Dihydrobenzofuran  Produce

The title compound (482 mg) was obtained in the same manner as in step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.32-7.07 (m, 21H), 6.95 (s, 1H), 6.89 (d, 2H), 6.74 (d, 2H), 4.87 (t, 3H), 2H), 1.25 (m, IH), 4.59 (m, 2H), 4.31 (d, 2H) 0.60 (m, 2 H), 0.32 (m, 2 H).

Step 5: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Cyclopropylmethoxy ) Benzyl) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

The title compound (140 mg) was obtained in the same manner as in step 5 of Example 1.

¹ H NMR spectrum (300 MHz, MeOD): δ 7.21 (dd, 1H), 7.09 (d, 2H), 7.06 (s, 1H), 6.92 (s, 1H), 6.88 (d, 2H), 4.52 (t 2H), 3.14 (d, IH), 3.86-3.70 (m, 6H), 3.61 (m, 2H), 3.46 , ≪ / RTI > 2H), 0.31 (m, 2H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 460.2334, [M + K] + m / z 481.1623

Example  9: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Ethoxy -3- Fluorobenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (4- Ethoxy -3- Fluorophenyl ) Preparation of methanol

Bromo-1-ethoxy-2-fluorobenzene was used instead of 1-bromo-4-ethoxybenzene in the step 1 of Example 1, the title compound Compound (684 mg).

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.22 (dd, 2H), 7.15-7.06 (m, 2H), 6.91 (t, 1H), 5.81 (d, 1H), 4.60 (t, 2H), 4.09 (q, 2H), 3.19 (t, 2H), 2.73 (d, IH), 1.44 (t, 3H).

Step 2: 5- Bromo -7- (4- Ethoxy -3- Fluorobenzyl ) -2,3- Dihydrobenzofuran  Produce

The title compound (619 mg) was obtained in the same manner as in step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.16 (s, 1H), 6.97-6.86 (m, 4H), 4.57 (t, 2H), 4.07 (q, 2H), 3.77 (s, 2H), 3.20 (t, 2H), 1.43 (t, 3H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- (7- (4-ethoxy-3- Fluorobenzyl ) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H -Pyran-2-ol < / RTI &

The title compound (918 mg) was obtained in the same manner as in step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33-7.16 (m, 20H), 6.96-6.75 (m, 5H), 4.89-4.85 (m, 2H), 4.66-4.55 (m, 5H), 4.41 (d, 1H), 4.09-4.06 (m, 1H), 4.04-3.69 (m, 10H), 3.50 (dd, ).

Step 4: 7- (4- Ethoxy -3- Fluorobenzyl ) -5- (2S, 3S, 4R, 5R, 6R) -3,4,5-tris Benzyloxy ) -6- ( Benzyloxymethyl ) Tetrahydro -2 H -Pyran-2-yl) -2,3- Dihydrobenzofuran  Produce

The title compound (752 mg) was obtained in the same manner as in step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.39-7.27 (m, 13H), 7.20-7.15 (m, 7H), 6.95-6.87 (m, 5H), 6.73 (t, 1H), 4.90-4.84 2H), 3.85-3.75 (m, 7H), 3.55-3.47 (m, 3H), 4.64-4.51 , 2H), 3.20 (t, 2H), 1.40 (t, 3H).

Step 5: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Ethoxy -3- Fluorobenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

The title compound (130 mg) was obtained by the same method as in the step 5 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.08 (s, 1H), 6.95-6.86 (m, 3H), 6.80 (t, 1H), 4.52 (t, 2H), 4.14 (br, 1H), 1H), 2.85 (br, IH), 3.84-3.58 (m, 3H) 2.57 (br, 1 H), 1.39 (t, 3 H).

^{MS (ESI +, m / z} ): [M + NH 4] + 45202075, [M + K] + m / z 473.1371

Example  10: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Ethoxy -2- Fluorobenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (4- Ethoxy -2- Fluorophenyl ) Preparation of methanol

Bromo-4-ethoxy-2-fluorobenzene was used instead of 1-bromo-4-ethoxybenzene in Step 1 of Example 1, the title compound Compound (624 mg) was obtained.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33-7.22 (m, 2H), 7.15 (s, 1H), 6.68 (dd, 1H), 6.59 (dd, 1H), 6.11 (d, 1H), 4.61 (t, 2H), 4.00 (q, 2H), 3.19 (t, 2H), 2.86 (d,

Step 2: 5- Bromo -7- (4- Ethoxy -2- Fluorobenzyl ) -2,3- Dihydrobenzofuran  Produce

The title compound (494 mg) was obtained in the same manner as in step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.14 (s, 1H), 7.05 (t, 1H), 6.96 (s, 1H), 6.62-6.57 (m, 2H), 4.58 (t, 2H), 3.99 (q, 2H), 3.80 (s, 2H), 3.20 (t, 2H), 1.40 (t, 3H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- (7- (4-ethoxy-2- Fluorobenzyl ) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H -Pyran-2-ol < / RTI &

The title compound (343 mg) was obtained in the same manner as in step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33-7.16 (m, 20H), 7.00-6.95 (m, 3H), 6.53-6.50 (m, 2H), 4.89-4.85 (m, 3H), 4.67 2H), 2.87 (d, IH), 1.34 (t, 3H), 4.38 (d, IH) ).

Step 4: 7- (4- Ethoxy -2- Fluorobenzyl ) -5 - ((2S, 3S, 4R, 5R, 6R) -3,4,5-tris Benzyloxy ) -6- ( Benzyloxymethyl ) Tetrahydro -2 H -Pyran-2-yl) -2,3- Dihydrobenzofuran  Produce

The title compound (268 mg) was obtained by the same method as in the step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.33-7.27 (m, 13H), 7.20-7.16 (m, 6H), 7.01 (t, 1H), 6.96 (s, 1H), 6.91-6.88 (m 2H), 6.56-6.50 (m, 2H), 4.94-4.84 (m, 3H), 4.65-4.50 (m, 5H), 4.34 (d, , 9H), 3.55-3.47 (m, 2H), 3.19 (t, 2H), 1.37 (t, 3H).

Step 5: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Ethoxy -2- Fluorobenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

The title compound (109 mg) was obtained by the same method as in the step 5 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.08-7.02 (m, 2H), 6.89 (s, 1H), 6.58-6.53 (m, 2H), 4.53 (t, 2H), 4.03 (d, 1H 1H), 3.97-3.60 (m, 3H), 3.82-3.59 (m, 7H), 3.47 2.42 (br, 1 H), 1.36 (t, 3 H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 452.2075, [M + K] + m / z 473.1371

Example  11: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Hydroxybenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

Step 1: (5- Bromo -2,3- Dihydrobenzofuran -7-yl) (4 - (( tert -Butyl) Dimethylsilyloxy ) Phenyl ) Preparation of methanol

In the same manner as in the step 1 of Example 1 except that (4-bromophenoxy) (tert-butyl) dimethylsilane was used instead of 1-bromo-4-ethoxybenzene in the step 1 of Example 1 The title compound (290 mg) was obtained.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.07-6.99 (m, 3H), 6.62 (d, 2H), 6.50 (s, 1H), 5.63 (d, 1H), 4.40 (t, 2H), 2.99 (t, 2H), 0.78 (s, 9H), 0.01 (s, 6H).

Step 2: (4 - ((5- Bromo -2,3- Dihydrobenzofuran -7 days) methyl ) Phenoxy ) ( tert -Butyl) Dimethylsilane  Produce

The title compound (242 mg) was obtained by the same method as in the step 2 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.08 (s, 1H), 6.85 (d, 2H), 6.55 (d, 2H), 6.52 (s, 1H), 4.38 (t, 2H), 3.60 ( s, 2H), 2.98 (t, 2H), 0.79 (s, 9H), 0.01 (s, 6H).

Step 3: (3R, 4S, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6- ( Benzyloxymethyl ) -2- (7- (4 - ((tert-butyl) Dimethylsilyloxy ) Benzyl) -2,3- Dihydrobenzofuran -5 days) Tetrahydro -2 H -Pyran-2-ol < / RTI &

The title compound (0.390 mg) was obtained in the same manner as in step 3 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.22-6.80 (m, 26H), 4.86-4.74 (m, 2H), 4.60-4.30 (m, 9H), 3.98 (d, 1H), 3.81-3.28 (m, 6H), 3.00 (t, 2H), 0.80 (s, 9H), 0.02 (s, 6H).

Step 4: 4 - ((5- ((2S, 3S, 4R, 5R, 6R) -3,4,5- Tris ( Benzyloxy ) -6 - (( Benzyloxy ) methyl ) Tetrahydro -2 H -Pyran-2-yl) -2,3- Dihydrobenzofuran -7 days) methyl ) Preparation of phenol

The title compound (70 mg) was obtained by the same method as in the step 4 of Example 1.

¹ H NMR spectrum _{(300 MHz, CDCl 3):} δ 7.10-6.41 (m, 26H), 4.64-4.56 (m, 3H), 4.37-4.31 (m, 8H), 4.27 (d, 1H), 3.85 (d , ≪ / RTI > 1H), 3.58-3.08 (m, 6H), 2.93 (t, 2H).

Step 5: (2S, 3R, 4R, 5S, 6R) -2- (7- (4- Hydroxybenzyl ) -2,3- Dihydrobenzofuran -5-yl) -6- ( Hydroxymethyl ) Tetrahydro -2 H - pyran-3,4,5- Triol  Produce

The title compound (6 mg) was obtained in the same manner as in step 5 of Example 1.

¹ H NMR spectrum (300 MHz, MeOD): δ 7.01 (s, 1H), 6.94 (d, 2H), 6.84 (s, 1H), 6.55 (d, 2H), 4.40 (t, 2H), 3.67 (d , 2H), 3.48-3.20 (m, 7H), 3.01 (t, 2H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 406.1858, [M + K] + m / z 427.1156

Example  12: (2S, 3S, 4R, 5R, 6S) -2- ( Hydroxymethyl ) -6- (7- (4- (3- ( Methylsulfonyl ) Propoxy) benzyl) -2,3- Dihydrofuran -5 days) Tetrahydro - 2H - pyran-3,4,5- Triol  Produce

Bromo-3- (methylsulfonyl) propane (35.5 mg, 0.12 mmol) was dissolved in 2 mL of dimethylformamide, And potassium carbonate (17.4 mg, 0.13 mmol) were added, and the mixture was stirred at 100 占 폚 for 48 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated to obtain 7- (4- (3- (methylsulfonyl) propoxy) benzyl) -5- (Benzyloxy) methyl) tetrahydro- 2H -pyran-2-yl) -2,3-dihydrobenzo [ Furan. This was obtained in the same manner as in Step 5 of Example 1, without further purification, to give the title compound (7 mg).

¹ H NMR spectrum (300 MHz, MeOD): δ 7.04-7.01 (m, 3H), 6.84 (s, 1H), 6.69 (d, 2H), 4.43 (t, 2H), 3.98-3.89 (m, 3H) , 3.73-3.69 (m, 4H), 3.30-3.16 (m, 6H), 3.05 (t, 2H), 2.89 (s, 3H), 2.13 (m, 2H).

^{MS (ESI +, m / z} ): [M + NH 4] + m / z 526.2118

The compounds prepared in Examples 1 to 12 were evaluated as follows.

Test Example  One: Oral glucose tolerance  Measure( oGTT )

The pharmacological efficacy of the compound prepared in Example 1 was confirmed by oral glucose tolerance assay using C57BL / 6 male mice (8 weeks old, manufactured by Orient and supplied). A total of six mice were fasted for 16 hours and then weighed and divided into three groups. Thereafter, a mixture of 5% 1-methyl-2-pyrrolidinone, 20% PEG and 75% 20 mM sodium diphosphate as a vehicle, And kanagliprojin known as SGLT2 inhibitor as a control substance were orally administered at a dose of 10 mg / kg. After 30 minutes, 2 g / kg of glucose was orally administered to all subjects. Thereafter, blood was obtained by applying a small wound to the tail vein of the test mouse tail at -2, 0, 0.25, 0.5, 1, and 2 hours, based on the time of oral glucose administration, and the blood was collected using an Onetouch blood glucose meter Lifescan, Inc., USA). The results are shown in FIGS. 1 and 2. FIG. FIG. 1 is a graph showing blood glucose concentration in each hour, and FIG. 2 is a graph showing an area under curve (AUC) in a period of 0 to 2 hours.

As shown in FIGS. 1 and 2, the compound of Formula 1 according to the present invention is superior to kanagliptrolain, which is a typical SGLT2 inhibitor, in blood glucose control.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (9)

A compound selected from the group consisting of a 2,3-dihydrobenzofuran derivative of the formula (1) or a pharmaceutically acceptable salt, isomer, hydrate and solvate thereof:
≪ Formula 1 >

In this formula,
Ring B is

,

or

ego;
R ^1, R ² and R ³ are independently H, halogen, hydroxy, C _{1 respectively 8} alkyl, C _{2 - 7} alkenylene, C _2-7 alkynylene, C _{3 - 6} cycloalkyl, C _{1 - 6} alkyloxy or C _{3 - 6} cycloalkyl-oxy,
The C _{1 - 8} alkyl, C _{2 - 7} alkenylene, C _{2 - 7} alkynyl, C _{3 - 6} cycloalkyl, C _{1 - 6} alkyloxy or C _{3 -6} cycloalkyloxy is optionally with 1 to 3 fluoro a, C _{1 - 4} alkyl, C _{3 - 6} cycloalkyl, C _{1 - 8} alkyloxy, C _{3 - 6} heteroaryl cycloalkyloxy or C _{1 - 3} may be substituted with alkylsulfonyl, the C _{1 - 8} alkyl, oxy are optionally 1 to 2 C _{1 - 6} may be further substituted with cycloalkyloxy, _{- 8} alkyloxycarbonyl or C ₃
Adjacent to the R ¹ and R ² substituted at the two carbon atoms is C _{3 each} other may form a _5-alkylene bridge, wherein the C _{3 - 5} alkyl, 1 to 2 methylene in the alkylene bridge is independently O, S, SO, SO ₂ , CO or NR ⁴ , and at least one of the unsubstituted methylenes may be substituted with 1 to 4 halogens or methyl,
R < ⁴ > is H or benzyl.
The method according to claim 1,
Ring B is

ego;
R ^1, R ² and R ³ are independently H, halogen, hydroxy, C _{1 respectively 8} alkyl, C _{2 - 7} alkenylene, C _2-7 alkynylene, C _{3 - 6} cycloalkyl, C _{1 - 6} alkyloxy or C _{3 - 6} cycloalkyl-oxy,
The C _{1 - 8} alkyl, C _{2 - 7} alkenylene, C _{2 - 7} alkynyl, C _{3 - 6} cycloalkyl, C _{1 - 6} alkyloxy or C _{3 -6} cycloalkyloxy is optionally with 1 to 3 fluoro a, C _{1 - 4} alkyl, C _{3 - 6} cycloalkyl, C _{1 - 8} alkyloxy, C _{3 - 6} may be substituted with a heterocycloalkyl-oxy, or methylsulfonyl, wherein the C _{1 - 8} alkyloxy is optionally 1 to 2 C _{1 - 6} may be further substituted with cycloalkyloxy, _{- 8} alkyloxycarbonyl or C ₃
The adjacent substituted at the two carbon atoms wherein R ¹ and R ² are C _{3 each} other may form a _5-alkylene bridge, wherein the C _{3 - 5} alkyl, 1 to 2 methylene in the alkylene bridge is independently O, S , SO, SO ₂ , CO or NR ⁴ , and at least one of the unsubstituted methylenes may be substituted with 1 to 2 F or methyl,
R < ⁴ > is H or benzyl.
The method according to claim 1,
Ring B is

or

ego;
R ¹ and R ² are each independently H, halogen, hydroxy or C _{1 - 8} is alkyl.
The method according to claim 1,
Wherein the compound is selected from the group consisting of:
1) (2S, 3R, 4R, 5S, 6R) -2- (7- (4- ethoxybenzyl) -2,3- dihydrobenzofuran-5-yl) -6- hydroxymethyl-tetrahydro- 2H -pyran-3,4,5-triol;
2) (2S, 3R, 4R, 5S, 6R) -2- (7- (4-Ethylbenzyl) -2,3- dihydrobenzofuran-5-yl) -6- hydroxymethyl-tetrahydro- 2H -Pyran-3,4,5-triol;
3) (2R, 3S, 4R , 5R, 6S) -2- hydroxymethyl -6- (7- (4- n-propyl) -2,3-dihydro-benzofuran-5-yl) -tetrahydro- -2 H -pyran-3,4,5-triol;
4) Synthesis of (2R, 3S, 4R, 5R, 6S) -2-hydroxymethyl-6- (7- (4-trifluoromethylbenzyl) -2,3-dihydrobenzofuran- - 2H -pyran-3,4,5-triol;
5) Synthesis of (2R, 3S, 4R, 5R, 6S) -2-hydroxymethyl-6- (7- (4-trifluoromethoxybenzyl) -2,3-dihydrobenzofuran- -2 H -pyran-3,4,5-triol;
6) (2S, 3R, 4R, 5S, 6R) -2- (7- (4-fluorobenzyl) -2,3- dihydrobenzofuran-5-yl) -6- (hydroxymethyl) tetrahydro -2 H -pyran-3,4,5-triol;
7) (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl) -2,3- Dihydro-benzofuran-5-yl] -6- (hydroxymethyl) tetrahydro- 2H -pyran-3,4,5-triol;
8) (2S, 3R, 4R, 5S, 6R) -2- (7- (4- (cyclopropylmethoxy) benzyl) -2,3-dihydrobenzofuran- Methyl) tetrahydro- 2H -pyran-3,4,5-triol;
9) (2S, 3R, 4R, 5S, 6R) -2- (7- (4-ethoxy- 3- fluorobenzyl) -2,3- dihydrobenzofuran- Lt; / RTI > methyl) tetrahydro- 2H -pyran-3,4,5-triol;
10) (2S, 3R, 4R, 5S, 6R) -2- (7- (4-ethoxy- 2- fluorobenzyl) -2,3-dihydrobenzofuran- Lt; / RTI > methyl) tetrahydro- 2H -pyran-3,4,5-triol
11) (2S, 3R, 4R, 5S, 6R) -2- (7- (4- hydroxybenzyl) -2,3- dihydrobenzofuran-5-yl) -6- (hydroxymethyl) tetrahydro -2 H -pyran-3,4,5-triol; And
12) (2S, 3S, 4R, 5R, 6S) -2- (Hydroxymethyl) -6- (7- (4- (3- (methylsulfonyl) propoxy) benzyl) -2,3-dihydro Furan-5-yl) tetrahydro- 2H -pyran-3,4,5-triol.
A pharmaceutical composition comprising the compound of claim 1 as an active ingredient.
6. The method of claim 5,
A pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, excipient or excipient.
6. The method of claim 5,
Wherein said pharmaceutical composition has an inhibitory activity against a sodium-dependent glucose receptor (SGLT).
Wherein said pharmaceutical composition is used for the prophylaxis or treatment of a disease or condition mediated by hyperglycemia.
9. The method of claim 8,
Wherein said disease or condition is diabetes, diabetes related disease or diabetic complication.

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