CN104817554A - Glucoside derivatives and pharmaceutical compositions thereof - Google Patents

Abstract

A class of glucoside derivatives and pharmaceutical compositions thereof, the present invention discloses a class of compounds represented by general formula (I), pharmaceutically acceptable salts thereof, easily hydrolyzed prodrug esters thereof or isomers thereof, and The pharmaceutical composition containing this compound is used as sodium-glucose cotransporter 2 inhibitor for treating or delaying diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance and other related diseases.

Description

A class of glucoside derivatives and pharmaceutical compositions thereof

technical field

The present invention relates to a class of glucoside derivatives represented by general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof, pharmaceutical compositions containing the derivatives thereof, and their use as therapeutic agents, especially Use as an inhibitor of sodium-glucose cotransporter 2 (SGLT2).

Background technique

With the improvement of people's living standards and changes in lifestyles, the number of diabetic patients has increased dramatically worldwide, and diabetes has become one of the main problems that endanger public health. According to figures released by the World Health Organization (WHO) in 2013, approximately 382 million adults worldwide suffer from diabetes. By 2035, the number of patients is expected to rise to 592 million.

Early diabetes drugs include biguanides (such as metformin), sulfonylureas (such as glimepiride), glucosidase inhibitors (such as acarbose), oxazolidinones (such as rosiglitazone )wait. The target organs of these drugs are concentrated in the liver, small intestine or pancreas, and their mode of action is to reduce blood sugar in the body by reducing the synthesis of glucose or the absorption of glucose by the small intestine. Most of the new drugs for the treatment of diabetes focus on glucagon-like peptide 1 (GLP-1), GLP-1 agonists such as exenatide, PPARγ agonists such as mogestazol, DPP -IV inhibitors such as sitagliptin, etc. GLP-1 is a peptide hormone secreted by intestinal L cells, which can increase the biosynthesis and secretion of insulin; stimulate the proliferation and differentiation of β cells and inhibit the apoptosis of β cells; inhibit the secretion of glucagon; suppress appetite And food intake, delayed gastric emptying and so on. Thereby reducing postprandial blood sugar and maintaining blood sugar at a reasonable level (Liu Yonggui, Tian Hong, Xie Xuexing, Shen Xueyan, Chen Changqing. Research progress of non-insulin drugs for the treatment of type 2 diabetes [J]. Modern Drugs and Clinics, 2013, 28 (2 ): 108-113). Although there are so many drugs to choose from, many patients are insensitive to drugs and have adverse drug reactions, making the development of new drugs for the treatment of diabetes an urgent need for people.

Inhibitors of sodium glucose co-transporter 2 (SGLT2) have been a hot field in the development of type 2 diabetes drugs in recent years. SGLT2 consists of 672 amino acid residues with low affinity and 59% homology with sodium glucose co-transporter 1 (SGLT1) (SGLT1 has high affinity, high affinity ). The main function of SGLT2 is to complete the reabsorption of 90% glucose in primary urine in the proximal convoluted tubule of the kidney (Neumiller J J, White J R Jr, Campbell R K. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2diabetes mellitus[ J]. Drugs, 2010, 70(4): 377-385.) (Wright, EM. Renal Na ⁺ -glucose cotransporters. Am J Physiol Renal Physiol. 2001, 280, F10-F18.). The researchers had previously found that phlorizin from apple trees increased urinary sugar excretion in diabetic dogs and demonstrated that phlorizin lowered blood sugar in diabetic rats. Subsequent studies have proved that phlorizin is a highly active inhibitor of SGLT2 (Ehrenkranz JR, Lewis NG, Kahn CR, Roth J et al. Phlorizin: a review. Diabetes Metab Res Rev. 2005, 21 (1): 31- 38.). Further studies have shown that specific inhibition of SGLT2 expression can increase urinary sugar excretion, lower blood sugar and glycosylated hemoglobin (HbA1c) in diabetic rats (Wancewicz EV, Siwkowski A, Meibohm B et al.Long term safety and efficacy of ISIS-388626, an optimized SGLT2 antisense inhibitor, in multiple diabetic and euglycemic species. Diabetes. 2008, 57(Suppl. 1): A96.). At the same time, SGLT1 inhibitors can also lower blood sugar, but because SGLT1 is distributed in many important organs such as the heart and brain, inhibiting SGLT1 may cause a variety of adverse reactions, and inhibiting SGLT1 in the intestine will affect the absorption of carbohydrates and cause diarrhea Wait for gastrointestinal reactions. Therefore, selective inhibition of renal SGLT2 can promote the excretion of urine sugar and reduce blood sugar in the body, which provides a new method for the treatment of diabetes.

Compared with other antidiabetic drugs, SGLT2 inhibitors have the following main advantages: (1) The hypoglycemic mechanism has nothing to do with insulin, and can be used for almost all diabetes including insulin resistance; (2) It can improve the insulin sensitivity of the liver and peripheral tissues , improve β cell function, improve insulin resistance; (3) not easy to cause hypoglycemia; (4) can reduce the percentage of glycosylated hemoglobin; (5) have a certain weight loss effect and help improve cardiovascular and cerebrovascular diseases; (6) inhibit SGLT2 No significant effect on other tissues and organs (Wang Yuli, Wang Xiaoyan, Tang Lida, etc. Research and development of new anti-diabetic drugs of sodium-glucose cotransporter 2 inhibitors[J]. Modern Drugs and Clinical. 2012,27(3):138- 141).

SGLT2 inhibitors can also be used in combination with existing therapeutic drugs (such as sulfonamides, thiazolidinediones, metformin, and insulin, etc.). Without affecting the efficacy of the drug, the dosage of the drug can be reduced, thereby avoiding or reducing the occurrence of adverse reactions, and improving the patient's compliance with treatment.

In nature, stable isotopes (Stable isotopes) that exist in a certain proportion are non-radioactive, stable in physical properties, and harmless to the human body. Among them, deuterium is a stable non-radioactive isotope of hydrogen with a weight of 2.0144. An important feature of deuterium is that its shape and volume in drug molecules are basically the same as hydrogen. That is to say, if the hydrogen in the drug molecule is selectively replaced by deuterium, the deuterated drug generally retains its original biological activity and selectivity.

Experiments have shown that carbon-deuterium bonds are more stable than carbon-hydrogen bonds. The carbon-deuterium bond formed by the neutron-carrying deuterium and carbon vibrates at a lower frequency and is thus stronger than the carbon-hydrogen bond. This increase in strength can directly affect properties such as absorption, distribution, metabolism, and excretion of certain drugs, thereby improving the efficacy, safety, and tolerability of the drug. Therefore, it is theoretically believed that if a specific carbon-hydrogen bond to be decomposed in the drug molecule is deuterated into a corresponding carbon-deuterium bond, the decomposition process will be delayed and the deuterated drug will act in the body for a longer time , the effect is better than the original drug.

SGLT2 inhibitors have a good development prospect as a new type of diabetes treatment drug. Currently, the U.S. Food and Drug Administration (FDA) has approved Johnson & Johnson's Canagliflozin and AstraZeneca's Dapagliflozin; Japan's Pharmaceuticals and Medical Devices Administration (PMDA) has approved Astellas' Ipragliflozin. It is still necessary to develop compounds with high curative effect, good pharmacokinetic properties and good safety for the treatment of diabetes and related metabolic disorders. After continuous efforts, the present invention discloses compounds with structures shown in general formula (I), and finds that compounds with such structures exhibit excellent SGLT2 inhibitory effect and hypoglycemic effect.

Contents of the invention

The object of the present invention is to provide a class of glucoside derivatives represented by general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutical compositions containing the derivatives thereof;

Another object of the present invention is to provide the use of the above-mentioned glucoside derivatives and their pharmaceutical compositions as therapeutic agents, especially as sodium-glucose cotransporter 2 inhibitors.

The purpose of the present invention can be achieved through the following measures:

The compound represented by the general formula (I), its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester or its isomer:

in,

R ¹ is independently selected from -CH ₃ , -CH ₂ CH ₃ , halogen or -CN;

R ² is independently selected from H, D, -OH, halogen, C _1-3 alkyl, C _1-3 substituted alkyl, C _1-3 alkoxy, C _1-3 substituted alkoxy or -CN;

R ³ and R ⁴ are independently selected from H or D;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently selected from H, D, halogen, -CN, C _1-3 alkyl, C _1-3 substituted alkyl, C _1-4 alkoxy, C _1-4 substituted alkoxy, C _1-4 alkylthio or C _1-4 substituted alkylthio, the substituents are selected from D, halogen, C _1-4 alkoxy or C _1-4 alkylthio base;

At least one of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ or R ⁹ must be D.

In a preferred embodiment, the compound of the present invention can further be a compound represented by general formula (II), its pharmaceutically acceptable salt or its easily hydrolyzed prodrug ester:

In a preferred embodiment, R ¹ is independently selected from -CH ₃ , F, Cl or -CN;

In a preferred embodiment, R ² is independently selected from H, D, -OH, halogen, -OCH ₃ , -OCH ₂ CH ₃ or -CN;

In a preferred embodiment, R ³ and R ⁴ are independently selected from H or D;

In a preferred embodiment, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ are independently selected from H, D, F, Cl, -CN, -CH ₃ or -CH ₂ CH ₃ ; R ² , R ^3. At least one of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ or R ⁹ must be D.

The compound of general formula (I) may contain asymmetric carbon atoms, so it can exist in the form of optically pure diastereomers, diastereomeric mixtures, diastereomeric racemates, and mixtures of diastereomeric racemates Or exist as a meso compound. The present invention includes all such forms. Diastereomeric mixtures, diastereomeric racemates or mixtures of diastereomeric racemates can be separated by conventional methods, for example by column chromatography, thin layer chromatography, HPLC and the like.

Preferred compounds represented by general formula (I) of the present invention include, but are not limited to:

(2S,3R,4R,5S,6R)-2-{3-{Deutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6 -(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(2S,3R,4R,5S,6R)-2-{3-{Dideutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}- 6-(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(2S,3R,4R,5S,6R)-2-{3-{Deuterated[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-chlorophenyl}-6- (Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(2S,3R,4R,5S,6R)-2-{3-[Deutero(5-phenylselenophen-2-yl)methyl]-4-methylphenyl}-6-(hydroxymethyl ) Tetrahydro-2H-pyran-3,4,5-triol

(2S,3R,4R,5S,6R)-2-{3-{Deutero[5-(pentadeuteriophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6 -(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(2R,3S,4R,5R,6S)-2-(Hydroxymethyl)-6-{4-methyl-3-{[5-(pentadeuteriophenyl)selenophen-2-yl]methyl }phenyl}tetrahydro-2H-pyran-3,4,5-triol

(2S,3R,4R,5S,6R)-2-{5-{Deuterated[5-(4-fluorophenyl)selenophen-2-yl]methyl}-2-hydroxy-4-methylbenzene Base}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

(2S,3R,4R,5S,6R)-2-{3-Deutero-5-{[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl }-6-(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

or a pharmaceutically acceptable salt thereof or all stereoisomers thereof.

The present invention includes a pharmaceutical composition comprising a therapeutically effective dose of the compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable carrier.

The compound of the present invention, its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester or its isomer and pharmaceutical composition can be used in the preparation of sodium-glucose co-transporter inhibitor 2.

The compound of the present invention, its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester or its isomer and pharmaceutical composition can be prepared for treating or delaying diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy , insulin resistance, hyperglycemia, hyperinsulinemia, elevated fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, or hypertension Drugs for the development or onset of other diseases.

Detailed Description of the Invention

Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

"Hydrogen" in the present invention refers to protium (1H), which is the main stable isotope of hydrogen.

The "deuterium" mentioned in the present invention refers to a stable form isotope of hydrogen, also known as deuterium, whose element symbol is D.

The "halogen atom" mentioned in the present invention includes fluorine atom, chlorine atom, bromine atom and iodine atom.

"Alkyl" in the present invention refers to a linear or branched alkyl group derived from an alkane containing 1-8 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3- Dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1 -Methylpropyl and 1-ethyl-2-methylpropyl etc. The terms "C _1-4 alkyl" and "C _1-3 alkyl" refer to specific examples containing 1-4 and 1-3 carbon atoms among the above examples.

The term "alkoxy" in the present invention refers to -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl) groups, which further represent -O-(unsubstituted alkyl) , wherein the definition of alkyl is as above. Non-limiting examples include methoxy, ethoxy, propoxy, and the like.

"Alkylthio" in the present invention refers to -S-(unsubstituted alkyl) and -S-(unsubstituted cycloalkyl) groups, which further represent -S-(unsubstituted alkyl) , wherein the definition of alkyl is as above. Non-limiting examples include methylthio, ethylthio, propylthio, and the like.

The "hydroxyl" in the present invention refers to -OH group.

The "amino" in the present invention refers to -NH ₂ group

The "cyano group" mentioned in the present invention refers to the -CN group

The "pharmaceutically acceptable salt" in the present invention refers to alkali metal, alkaline earth metal salt, ammonium, alkyl ammonium, or salt of inorganic or organic acid. Examples thereof may include sodium salt, potassium salt, calcium salt, ammonium salt, aluminum salt, triethylammonium salt, formate, acetate, propionate, butyrate, trifluoroacetate, maleic acid Salt, tartrate, citrate, stearate, succinate, ethylsuccinate, lactobionate, gluconate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxy Salts of ethanesulfonate, benzenesulfonate, p-toluenesulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, cysteine, Salts, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, hydrochloride, oxalate, picrate, salts with acrylate polymers of N-acetylcysteine .

"Pharmaceutical composition" as used in the present invention means a compound containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs or other chemical components, and other components such as physiological / pharmaceutically acceptable carrier or excipient. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.

The "prodrug" mentioned above in the present invention refers to a compound that has pharmacological effects after being transformed in vivo. The prodrug itself has no biological activity or very low activity, and becomes an active substance after metabolism in the body. The purpose of this process is to increase the bioavailability of the drug, strengthen the targeting, and reduce the toxicity and side effects of the drug.

The "isomer" mentioned above in the present invention includes all epimeric, diastereomeric and tautomeric forms. When a bond is represented by a wedge, this indicates that in three dimensions the bond will come out of the paper, while when a bond is shaded, this indicates that in three dimensions the bond will return into the paper.

The present invention further claims a pharmaceutical composition comprising any compound mentioned above, its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester or its isomer and other pharmaceutically active ingredients.

The present invention also includes any of the above-mentioned compounds, their pharmaceutically acceptable salts, their easily hydrolyzed prodrug esters or their isomers, which can be formulated into any clinically or pharmaceutically acceptable compound in a manner known in the art. Dosage forms for oral, parenteral, rectal or pulmonary administration to patients in need of such treatment. For oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants and the like can be added. For parenteral administration, it can be made into injections, including injection solutions, sterile powders for injections and concentrated solutions for injections. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, no additives can be added, and suitable additives can also be added according to the properties of the medicine. For rectal administration, it can be made into suppositories and the like. For pulmonary administration, it can be made into inhalants or sprays.

The present invention also provides the compounds of the present invention, their pharmaceutically acceptable salts, their easily hydrolyzed prodrug esters, their isomers or pharmaceutical compositions used in the preparation of treatments or preventions affected by inhibition of sodium-glucose cotransporter 2 disease or disease application.

The present invention also provides the application of the compounds of the present invention, their pharmaceutically acceptable salts, their easily hydrolyzed prodrug esters, their isomers or pharmaceutical compositions in the preparation of treatments or prevention of metabolic diseases.

The present invention also provides the use of the compound of the present invention, its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester, its isomer or pharmaceutical composition in the preparation of medicines for treating or delaying the development or onset of the following diseases Use, wherein the disease is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevation of fatty acids or glycerol, hyperlipidemia, obesity, Hypertriglyceridemia, syndrome X, complications of diabetes or atherosclerosis, or high blood pressure.

The present invention also provides the use of the compound of the present invention, its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester, its isomer or pharmaceutical composition in preparing sodium-glucose co-transporter 2 inhibitor.

The compounds of the present invention have the following characteristics:

(1) The compounds of the present invention have significant inhibitory and hypoglycemic effects on sodium-glucose cotransporter 2, and can be safely used to prevent and/treat diabetes in various mammals (including humans) and various diseases caused by diabetes. disease.

(2) The compound of the present invention exhibits better physical and chemical properties, low toxicity and less side effects.

Description of drawings

Embodiments of the present invention are described in detail below in conjunction with the accompanying drawings, wherein:

Figure 1 shows the results of the inhibition test of compounds on hSGLT2 transporting glucose in HEK293 transfected cell lines.

Detailed ways

The following preparations and examples are given to enable those skilled in the art to understand and practice the present invention more clearly. They should not be construed as limiting the scope of the invention, but merely as illustrations and representations thereof.

Example 1

(2S,3R,4R,5S,6R)-2-{3-{Deutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6 Synthesis of -(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (10)

Step A: D-gluconolactone (5.0g, 28.1mmol) and N-methylmorpholine (23.3g, 222mmol) were dissolved in THF (50mL), and trimethylchlorosilane (18.3 g, 168 mmol). Stirring was continued at this temperature for 1 hour after the addition was complete, and then the mixture was naturally warmed to room temperature and stirred overnight. Toluene (200 mL) was added, and ice water (200 mL) was added dropwise under an ice-water bath to control the inner temperature not to exceed 10°C. Separate the layers, collect the organic layer, and extract the aqueous layer with toluene (50 mL). The combined organic layers were washed successively with saturated aqueous sodium dihydrogen phosphate (70 mL×2), water (50 mL), saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (1) (13.0 g). The yield was 99.2%.

Step B: Dissolve selenophene (6.76g, 28.7mmol) in dichloromethane (75mL), add hydrobromic acid (10 drops), and then add NBS (5.08g, 28.5mmol) in portions in 40 minutes under ice-water bath ). After the addition was complete, the temperature was naturally raised to room temperature and stirring was continued for 4 hours. Water (50 mL) was added, the layers were separated, the organic layer was collected, and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were washed with water (20 mL×2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2-bromoselenophene (2) (5.10 g). The yield was 83.7%.

Step C: To a mixture containing compound 2 (2.50 g, 11.9 mmol), 4-fluorophenylboronic acid (2.0 g, 14.3 mmol), toluene (100 mL) and water (20 mL) was added sodium carbonate (3.79 g, 35.8 mmol) and tetrakis(triphenylphosphine)palladium (250 mg, 0.216 mmol), and the resulting mixture was stirred at reflux under nitrogen overnight. Cool to room temperature, filter through celite, and wash the filter cake with a small amount of methyl tert-butyl ether. The organic layer in the filtrate was collected, and the aqueous layer was extracted with methyl tert-butyl ether (40 mL×3). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether) to obtain 2-(4-fluorophenyl)selenophene (3) (1.80 g). The yield was 67.2%.

Step D: Dissolve 2-methyl-5-iodobenzoic acid (2.0 g, 7.63 mmol) in anhydrous dichloromethane (50 mL), add thionyl chloride (10 mL), and stir the resulting mixture under reflux for 1 hour. The solvent was evaporated under reduced pressure, anhydrous dichloromethane (50mL) was added, and anhydrous aluminum chloride (1.22g, 9.15mmol) and compound 3 (1.80g, 7.99mmol) were added successively under an ice-water bath, and the resulting mixture was cooled at room temperature Stir overnight. Water (30 mL) was added, the layers were separated, the organic layer was collected, the aqueous layer was extracted with dichloromethane (50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether) to obtain [5-(4-fluorophenyl)selenophene-2-yl](5-iodo-2- Methylphenyl)methanone (4) (2.80 g). The yield was 74.7%. ¹ H NMR (CDCl ₃ , 400MHz) δ7.77(d, J=2.0Hz, 1H), 7.74-7.71(m, 1H), 7.64-7.58(m, 3H), 7.46-7.45(m, 1H), 7.16-7.12 (m, 2H), 7.08-7.06 (m, 1H), 2.35 (s, 3H).

Step E: Compound 4 (469mg, 1.0mmol) was dissolved in methanol (10mL), and sodium borodeuteride (250mg, 5.98mmol) was added in portions under an ice-water bath, and the resulting mixture was stirred at this temperature for 1.5 hours. The reaction was quenched with water (2 mL), and most of the solvent was evaporated under reduced pressure. Water (30 mL) was added, extracted with dichloromethane (15 mL×3), the combined organic layers were washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:30-1:10 elution) to obtain [5-(4-fluorophenyl)selenophene -2-yl](5-iodo-2-methylphenyl)-deuteromethanol (5) (372 mg). The yield was 78.8%.

Step F: Compound 5 (370mg, 0.784mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (0.5mL) was added in an ice-water bath, and then triethylsilane (0.2mL) was added dropwise. Stirring was continued for 0.5 hours. Water (20 mL) was added, and the pH was adjusted to neutral with saturated aqueous sodium bicarbonate. Separate the layers, collect the organic layer, and extract the aqueous layer with dichloromethane (20 mL). The combined organic layers were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether) to obtain 2-[deuterated (5-iodo-2-methylphenyl)methyl]-5-( 4-Fluorophenyl)selenophene (6) (310 mg). The yield was 86.7%. ¹ H NMR (CDCl ₃ , 300MHz) δ7.56(s, 1H), 7.50(d, J=8.1Hz, 1H), 7.45-7.40(m, 2H), 7.17(d, J=3.6Hz, 1H) , 7.04-6.98 (m, 2H), 6.91 (d, J=8.1Hz, 1H), 6.85 (d, J=3.9Hz, 1H), 4.08 (s, 1H), 2.27 (s, 3H).

Step G: Dissolve compound 6 (310mg, 0.680mmol) and compound 1 (412mg, 0.883mmol) in anhydrous THF (4mL), add 0.5M (trimethylsilane) dropwise at -40～-60°C under nitrogen Lithium methylate (2.7 mL, 1.35 mmol), after the addition was complete, stirring was continued for 2 hours. Then a solution of methanesulfonic acid (0.26 mL) in methanol (4 mL) was added dropwise at this temperature, and the mixture was naturally warmed to room temperature and stirred overnight. Saturated brine (20 mL) was added, extracted with ethyl acetate (15 mL×3), the combined organic layers were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=5:1 elution) to obtain (3R,4S,5S,6R)-2-{3-{ Deutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6-hydroxymethyl-2-methoxytetrahydro-2H-pyran- 3,4,5-Triol (7) (140 mg). The yield was 39.4%.

Step H: Dissolve compound 7 (140mg, 0.268mmol) in dichloromethane (20mL), then add triethylsilane (93mg, 0.780mmol) at -30～-40°C under nitrogen, and then add trifluoride After the addition of boroethyl ether (115 mg, 0.810 mmol), the temperature was naturally raised to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, water (15 mL) was added, extracted with dichloromethane (15 mL×3), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=5:1 elution) to obtain (3R,4R,5S,6R)-2-{3-{ Deutero[5-(4-fluorophenyl)selen-2-yl]methyl}-4-methylphenyl}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4, 5-Triol (8) (100 mg). The yield was 75.7%.

Step I: Compound 8 (100mg, 0.203mmol) was dissolved in THF (20mL), N-methylmorpholine (411mg, 4.06mmol) and DMAP (2.5mg, 0.0205mmol) were added, and then B was added dropwise in an ice-water bath. Acid anhydride (414mg, 4.06mmol), stirred for 0.5 hours, then naturally warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, ethyl acetate (40 mL) was added, and the resulting solution was washed successively with saturated aqueous sodium bicarbonate (10 mL), saturated aqueous sodium dihydrogen phosphate (10 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. . The solvent was evaporated under reduced pressure and dried in vacuo to obtain 130 mg of off-white solid. The solid was recrystallized from ethanol (4 mL) to give (2R,3R,4R,5S,6S)-2-acetoxymethyl-6-{3-{deutero[5-(4-fluorophenyl)selenium Phen-2-yl]methyl}-4-methylphenyl}tetrahydro-2H-pyran-3,4,5-triacetate (9) (100 mg). The yield was 74.6%.

Step J: Suspend compound 9 (100 mg, 0.151 mmol) in a mixture of THF (2 mL), methanol (3 mL) and water (1 mL), add hydrated lithium hydroxide (10 mg, 0.238 mmol), and stir the resulting mixture at room temperature 3 hours. Water (10 mL) was added, extracted with ethyl acetate (15 mL×3), the combined organic layer was washed successively with saturated aqueous sodium dihydrogen phosphate (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=5:1 elution) to obtain (2S,3R,4R,5S,6R)-2-{3 -{Deutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6-(hydroxymethyl)tetrahydro-2H-pyran-3, 4,5-Triol (10) (69 mg). The yield was 92.8%. ¹ H NMR (CD ₃ OD, 500MHz) δ7.48-7.45 (m, 2H), 7.31 (s, 1H), 7.24-7.22 (m, 2H), 7.16-7.14 (m, 1H), 7.05-7.02 ( m, 2H), 6.88-6.87(m, 1H), 4.18-4.16(m, 1H), 4.11-4.10(m, 1H), 3.89-3.86(m, 1H), 3.71-3.68(m, 1H), 3.48-3.35 (m, 4H), 2.30 (s, 3H). MS (EI, m/z): 516.1 [M+Na] ⁺ .

Example 2

(2S,3R,4R,5S,6R)-2-{3-{Dideutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}- Synthesis of 6-(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (15)

Step A: Dissolve compound 4 (300mg, 0.639mmol) in anhydrous THF (10mL), add sodium borodeuteride (80mg, 1.91mmol), then add boron trifluoride diethyl ether (364mg, 2.56mmol) dropwise in an ice-water bath ). Stirring was continued at this temperature for 20 minutes after the addition was complete, then the temperature was raised to room temperature and stirred for 1 hour, and then the temperature was raised to reflux and stirred overnight. Saturated brine (20 mL) was added, extracted with dichloromethane (15 mL×3), the combined organic layers were washed successively with saturated aqueous sodium bicarbonate (15 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether) to obtain 2-[dideuterio(5-iodo-2-methylphenyl)methyl]-5- (4-Fluorophenyl)selenophene (11) (220 mg). The yield was 75.3%. ¹ H NMR (CDCl ₃ , 500MHz) δ7.57(s, 1H), 7.51(d, J=8.0Hz, 1H), 7.45-7.42(m, 2H), 7.18(d, J=3.5Hz, 1H) , 7.04-7.01 (m, 2H), 6.92 (d, J=8.0Hz, 1H), 6.86 (d, J=3.5Hz, 1H), 2.28 (s, 3H).

Steps B, C, D and E refer to steps G, H, I and J in Example 1, respectively, to obtain (2S, 3R, 4R, 5S, 6R)-2-{3-{dideuterio[5-( 4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (15 ). ¹ H NMR (CD ₃ OD, 300MHz) δ7.50-7.45 (m, 2H), 7.31 (s, 1H), 7.24-7.23 (m, 2H), 7.16-7.14 (m, 1H), 7.07-7.01 ( m, 2H), 6.89-6.88(m, 1H), 4.12-4.09(m, 1H), 3.90-3.86(m, 1H), 3.72-3.67(m, 1H), 3.47-3.40(m, 4H), 2.30(s, 3H). MS (EI, m/z): 517.1 [M+Na] ⁺ .

Example 3

(2S,3R,4R,5S,6R)-2-{3-{Deuterated[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-chlorophenyl}-6- Synthesis of (Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (16)

For the preparation method of compound 16, refer to Example 1, wherein 2-methyl-5-iodobenzoic acid in step D of Example 1 is replaced by 2-chloro-5-iodobenzoic acid. ¹ H NMR (CD ₃ OD, 300MHz) δ7.51-7.46(m, 3H), 7.39-7.36(m, 1H), 7.33-7.30(m, 1H), 7.24-7.23(m, 1H), 7.07- 7.02(m, 2H), 6.98-6.97(m, 1H), 4.31-4.27(m, 1H), 4.14-4.11(m, 1H), 3.89-3.85(m, 1H), 3.72-3.67(m, 1H ), 3.43-3.39 (m, 4H). MS (EI, m/z): 536.1 [M+Na] ⁺ .

Example 4

(2S,3R,4R,5S,6R)-2-{3-[Deutero(5-phenylselenophen-2-yl)methyl]-4-methylphenyl}-6-(hydroxymethyl ) Synthesis of tetrahydro-2H-pyran-3,4,5-triol (17)

For the preparation method of compound 17, refer to Example 1, wherein 4-fluorophenylboronic acid in step C of Example 1 is replaced with phenylboronic acid. ¹ H NMR (CD ₃ OD, 500MHz) δ7.47-7.44(m, 2H), 7.32-7.20(m, 6H), 7.16-7.14(m, 1H), 6.88(d, J=3.9Hz, 1H) , 4.19-4.16(m, 1H), 4.12-4.09(m, 1H), 3.89-3.86(m, 1H), 3.68-3.66(m, 1H), 3.47-3.37(m, 4H), 2.30(s, 3H). MS (EI, m/z): 498.1 [M+Na] ⁺ .

Example 5

(2S,3R,4R,5S,6R)-2-{3-{Deutero[5-(pentadeuteriophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6 Synthesis of -(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (18)

For the preparation method of compound 18, refer to Example 1, wherein 4-fluorophenylboronic acid in step C of Example 1 is replaced by 2,3,4,5,6-pentadeuteriophenylboronic acid. ¹ H NMR (CD ₃ OD, 300MHz) δ7.32-7.22(m, 3H), 7.16-7.14(m, 1H), 6.89-6.88(m, 1H), 4.19-4.16(m, 1H), 4.12- 4.09 (m, 1H), 3.90-3.86 (m, 1H), 3.70-3.67 (m, 1H), 3.47-3.37 (m, 4H), 2.30 (s, 3H). MS (EI, m/z): 503.1 [M+Na] ⁺ .

Example 6

(2R,3S,4R,5R,6S)-2-(Hydroxymethyl)-6-{4-methyl-3-{[5-(pentadeuteriophenyl)selenophen-2-yl]methyl Synthesis of }phenyl}tetrahydro-2H-pyran-3,4,5-triol (19)

For the preparation method of compound 19, please refer to Example 1, wherein 4-fluorophenylboronic acid in Step C of Example 1 is replaced by 2,3,4,5,6-pentadeuteriophenylboronic acid, and sodium borodeuteride in Step E of Example 1 Substitute with sodium borohydride. ¹ H NMR (CD ₃ OD, 300MHz) δ7.38(s, 1H), 7.29-7.27(m, 1H), 7.25-7.23(m, 1H), 7.16-7.14(m, 1H), 6.89-6.88( m, 1H), 4.20(s, 2H), 4.11(d, J=9.3Hz, 1H), 3.89-3.86(m, 1H), 3.72-3.66(m, 1H), 3.47-3.35(m, 4H) , 2.30(s, 3H). MS (EI, m/z): 502.1 [M+Na] ⁺ .

Example 7

(2S,3R,4R,5S,6R)-2-{5-{Deuterated[5-(4-fluorophenyl)selenophen-2-yl]methyl}-2-hydroxy-4-methylbenzene Synthesis of Di}-6-(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (31)

Step A: Dissolve 2-methyl-4-hydroxybenzoic acid (3.04g, 20.0mmol) in DMF (50mL), add iodomethane (9.12g, 64.2mmol) and potassium carbonate (8.28g, 60.0mmol), and obtain The mixture was stirred overnight at 50°C. Cool to room temperature, add water (200 mL), and extract with methyl tert-butyl ether (50 mL×3). The combined organic layers were washed with water (30 mL×3), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain methyl 4-methoxy-2-methylbenzoate (20) (3.89 g). The product was directly used in the next reaction without purification.

Step B: Crude compound 20 (3.66g) was dissolved in methanol (73mL), iodine (5.0g, 19.7mmol) and silver nitrate (5.14g, 30.3mmol) were added, and the resulting mixture was stirred at 30°C overnight. The insoluble matter was removed by filtration, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was collected, and most of the solvent was evaporated under reduced pressure, then dissolved in ethyl acetate (80 mL), washed with water (20 mL×2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:25-1:10 elution) to obtain 5-iodo-4-methoxy-2- Methyl toluate (21) (5.7 g). The overall yield of the two-step reaction of steps A and B is 99%. ¹ H NMR (CDCl ₃ , 500 MHz) δ8.37 (s, 1H), 6.64 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 2.60 (s, 3H).

Step C: Compound 21 (2.4 g, 7.84 mmol) was dissolved in methanol (50 mL), THF (25 mL) and 4M aqueous sodium hydroxide solution (25 mL) were added, and the resulting mixture was stirred at room temperature for 5 hours. Most of the solvent was evaporated under reduced pressure, water (50 mL) was added, the pH value was adjusted to 2-3 with 2M hydrochloric acid, extracted with ethyl acetate (40 mL×3), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5-iodo-4-methoxy-2-methylbenzoic acid (22) (2.1 g). The yield was 91.7%.

Step D: Compound 22 (1.26 g, 4.31 mmol) was dissolved in anhydrous dichloromethane (50 mL), thionyl chloride (15 mL) was added, and the resulting mixture was stirred under reflux for 1 hour. The solvent was evaporated under reduced pressure, then anhydrous dichloromethane (50 mL) was added, and anhydrous aluminum chloride (750 mg, 5.62 mmol) and compound 3 (970 mg, 4.31 mmol) were successively added in an ice-water bath. Naturally warmed to room temperature, the resulting mixture was stirred overnight at room temperature. Water (30 mL) was added, the organic layer was collected, the aqueous layer was extracted with dichloromethane (50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:10-1:2 elution) to obtain [5-(4-fluorophenyl)-selenium Phen-2-yl]-(5-iodo-4-methoxy-2-methylphenyl)methanone (23) (1.50 g). The yield is 69.7%. ¹ H NMR (CDCl ₃ , 500MHz) δ7.92(s, 1H), 7.61-7.58(m, 3H), 7.43(d, J=4.5Hz, 1H), 7.13-7.09(m, 2H), 6.73( s, 1H), 3.94(s, 3H), 2.42(s, 3H).

Step E: Compound 23 (500 mg, 1.0 mmol) was dissolved in methanol (10 mL) and dichloromethane (20 mL), and sodium borodeuteride (126 mg, 3.0 mmol) was added in portions under an ice-water bath, and the resulting mixture was Stirring was continued for 1 hour. The reaction was quenched with water (2 mL), and most of the solvent was evaporated under reduced pressure. Then water (30 mL) was added, extracted with dichloromethane (20 mL×3), the combined organic layers were washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:5 elution) to obtain deuterated [5-(4-fluorophenyl)selenophene-2 -yl]-(5-iodo-4-methoxy-2-methylphenyl)methanol (24) (500 mg). The yield was 99.5%.

Step F: Compound 24 (500mg, 0.995mmol) was dissolved in dichloromethane (20mL), trifluoroacetic acid (1mL) was added in an ice-water bath, and triethylsilane (0.5mL) was added dropwise, and the resulting mixture was cooled at room temperature Stir for 1 hour. Water (20 mL) was added, and the pH was adjusted to neutral with saturated aqueous sodium bicarbonate. Separate the layers, collect the organic layer, and extract the aqueous layer with dichloromethane (50 mL). The combined organic layers were washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether) to obtain 2-[deutero(5-iodo-4-methoxy-2-methylphenyl)methanol yl]-5-(4-fluorophenyl)selenophene (25) (390 mg). The yield was 80.6%.

Step G: Dissolve compound 25 (390mg, 0.802mmol) in anhydrous dichloromethane (20mL), add 4.0M boron tribromide in dichloromethane solution (0.6mL) at -40°C, then warm to -20 °C and continued to stir for 2 hours. The reaction solution was poured into ice water, extracted with dichloromethane (15 mL×3), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:30 elution) to obtain 4-{deutero[5-(4-fluorophenyl)selenium Phen-2-yl]methyl}-2-iodo-5-methylphenol (26) (290 mg). The yield was 76.6%.

Step H: Compound 26 (300 mg, 0.635 mmol) was dissolved in acetone (20 mL), chloromethyl methyl ether (256 mg, 3.18 mmol) and potassium carbonate (439 mg, 3.18 mmol) were added, and the resulting mixture was stirred at room temperature overnight. Most of the solvent was evaporated under reduced pressure, water (20 mL) was added, extracted with ethyl acetate (15 mL×3), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:20 elution) to obtain 2-{deutero[5-iodo-4-methoxymethyl Oxy-2-methylphenyl]methyl}-5-(4-fluorophenyl)selenophene (27) (220 mg). The yield was 67.1%.

Step I: Dissolve compound 27 (260mg, 0.504mmol) and compound 1 (305mg, 0.653mmol) in anhydrous THF (3mL), add 0.5M (trimethylsilane) dropwise at -40～-60°C under nitrogen Lithium methylate (1.9 mL). After the addition was complete, stirring was continued for 2.5 hours. The resulting mixture was added dropwise with a solution of methanesulfonic acid (0.19 mL) in methanol (2 mL) at this temperature, and then allowed to warm to room temperature and stirred overnight. Add saturated brine (20 mL), and extract with ethyl acetate (15 mL×3). The combined organic layers were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with ethyl acetate) to obtain (3R,4S,5S,6R)-2-{5-{deuterated[5-(4 -fluorophenyl)selen-2-yl]methyl}-2-hydroxy-4-methylphenyl}-6-hydroxymethyl-2-methoxytetrahydro-2H-pyran-3,4 ,5-Triol (28) (90 mg). The yield was 33.2%.

Step J: Dissolve compound 28 (90mg, 0.167mmol) in dichloromethane (2mL), then add triethylsilane (62mg, 0.533mmol) at -30～-40°C under nitrogen, and then add trifluoride Boroethyl ether (76 mg, 0.535 mmol). After the addition, the temperature was naturally raised to room temperature and stirring was continued for 6 hours. Water (15 mL) was added, the layers were separated, the organic layer was collected, the aqueous layer was extracted with dichloromethane (15 mL×2), and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:1-5:1 elution) to obtain (3R,4R,5S,6R)-2- {5-{deutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-2-hydroxy-4-methylphenyl}-6-(hydroxymethyl)tetrahydro-2H - Pyran-3,4,5-triol (29) (55 mg). The yield is 64.8%.

Step K: Dissolve compound 29 (55mg, 0.108mmol) in THF (10mL), add N-methylmorpholine (219mg, 2.16mmol) and DMAP (1.32mg, 0.011mmol), then add B Acid anhydride (221mg, 2.16mmol), stirred for 0.5 hours, then naturally warmed to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, ethyl acetate (30 mL) was added, washed successively with 10% citric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and dried in vacuo to obtain 72 mg of off-white solid. The solid was suspended in ethanol (2 mL), heated to reflux and continued to stir for 0.5 hours, then slowly cooled to room temperature, filtered, and the filter cake was collected to obtain (2R, 3R, 4R, 5S, 6S)-2-acetoxymethanol Base-6-{5-[deutero(5-(4-fluorophenyl)selenophen-2-yl)methyl]-2-hydroxy-4-methylphenyl}tetrahydro-2H-pyran- 3,4,5-Triacetate (30) (52 mg). The yield was 71.2%.

Step L: Suspend compound 30 (52 mg, 0.0724 mmol) in a mixture of THF (2 mL), methanol (2 mL) and water (1 mL), add hydrated lithium hydroxide (5 mg, 0.119 mmol), and stir the resulting mixture at room temperature 1 hour. Add water (15 mL), adjust the pH value to 2-3 with 2M hydrochloric acid, extract with ethyl acetate (15 mL×3), and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=10:1 elution) to obtain (2S,3R,4R,5S,6R)-2-{5 -{Deutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-2-hydroxyl-4-methylphenyl}-6-(hydroxymethyl)tetrahydro-2H-pyridine Fran-3,4,5-triol (31). ¹ H NMR (CD ₃ OD, 300MHz) δ7.49-7.45 (m, 2H), 7.23-7.21 (m, 2H), 7.06-7.00 (m, 2H), 6.87-6.85 (m, 1H), 6.65 ( s, 1H), 4.52(d, J=9.3Hz, 1H), 4.08-4.07(m, 1H), 3.89-3.85(m, 1H), 3.74-3.68(m, 1H), 3.59-3.41(m, 4H), 2.21(s, 3H). MS (EI, m/z): 532.0 [M+Na] ⁺ .

Example 8

(2S,3R,4R,5S,6R)-2-{3-Deutero-5-{[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl Synthesis of }-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (43)

Step A: NBS (5.89g, 33.1mmol) was added in batches to a solution of 2-methyl-5-nitrobenzoic acid (5.0 g, 27.6mmol) in concentrated sulfuric acid (20mL) at 60°C. Stirring was continued at this temperature for 1 hour. The reaction solution was poured into ice water, filtered and dried to obtain 3-bromo-2-methyl-5-nitrobenzoic acid (32) (6.3g). The yield was 73.2%.

Step B: Compound 32 (6.3 g, 24.2 mmol) was dissolved in methanol (50 mL), concentrated sulfuric acid (5 mL) was added, and the resulting mixture was stirred under reflux overnight. Most of the solvent was evaporated under reduced pressure, dichloromethane (200 mL) was added, washed with water (50 mL), saturated sodium bicarbonate solution (50 mL) and saturated brine (25 mL) successively, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether) to obtain methyl 3-bromo-2-methyl-5-nitrobenzoate (33) (4.3g) . The yield is 64.8%.

Step C: Dissolve compound 33 (3.08g, 11.2mmol) in DMF (30mL), add heavy water (1mL) and 5% palladium carbon (300mg), and deuterate the resulting mixture in deuterium gas at 60°C for 72 hours . After filtering through celite, water (120 mL) was added to the filtrate, extracted with ethyl acetate (50 mL×6), the combined organic layers were washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:40-1:30 elution) to obtain 5-amino-3-deuterium-2-methyl Methyl benzoate (34) (570 mg). The yield was 30.6%. MS (EI, m/z): 167.1 [M+H] ⁺ .

Step D: Compound 34 (520mg, 3.13mmol) was dissolved in a mixture of sulfuric acid (1mL) and water (10mL), and a solution of sodium nitrite (227mg, 3.29mmol) in water (10mL) was added dropwise at 0-5°C , and continued to stir for 30 minutes after the dropwise addition. Then, a solution of potassium iodide (1.56 g, 9.40 mmol) in water (10 mL) was added dropwise to the reaction solution, and stirring was continued at 0-5° C. for 1 hour after the dropwise addition. Extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether=1:50 elution) to obtain 3-deuterium-5-iodo-2-benzoic acid methyl ester (35 ) (830 mg). The yield is 95.7%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.09 (s, 1H), 7.82 (s, 1H), 3.82 (s, 3H), 2.50 (s, 3H).

Step E: Compound 35 (830 mg, 3.0 mmol) was dissolved in methanol (10 mL), 10% potassium hydroxide solution (45 mL) was added, and the resulting mixture was stirred at room temperature for 6 hours. Adjust the pH value to 2-3 with dilute hydrochloric acid, extract with ethyl acetate (30 mL×3), and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3-deuterium-5-iodo-2-benzoic acid (36) (800 mg). The yield is 100%.

Steps F, G, H, I, J, K and L refer to steps D, E, F, G, H, I and J in Example 7, respectively, to obtain (2S, 3R, 4R, 5S, 6R)-2 -{3-Deutero-5-{[5-(4-Fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6-(Hydroxymethyl)tetrahydro-2H -pyran-3,4,5-triol (43). ¹ H NMR (CD ₃ OD, 300MHz) δ7.49-7.45(m, 2H), 7.31(s, 1H), 7.23-7.22(m, 2H), 7.07-7.01(m, 2H), 6.88(d, J=3.6Hz, 1H), 4.19(s, 2H), 4.12-4.09(m, 1H), 3.90-3.86(m, 1H), 3.72-3.66(m, 1H), 3.44-3.34(m, 4H) , 2.30(s, 3H). MS (EI, m/z): 516.0 [M+Na] ⁺ .

Inhibition test of compounds on hSGLT2 transporting glucose in HEK293 transfected cell lines

1. Experimental steps

1. First, inoculate stably transfected HEK293-hSGLT2 cells at 2×10 ⁵ cells/well in a 24-well plate, and pre-culture for 3 days.

2. Then wash the cells with pretreatment buffer (10mM HEPES, 5mM Tris, 140mM choline chloride, 2mM KCl, 1mM CaCl ₂ , 1mM MgCl ₂ , pH 7.4), add an appropriate amount of pretreatment buffer, and put it in the incubator for 37 Incubate at °C for 20 minutes.

3. Remove the pretreatment buffer and use the transfer buffer (10mM HEPES, 5mM Tris, 140mM NaCl, 2mM KCl, 1mM CaCl ₂ , 1mM MgCl ₂ , pH 7.4) to prepare a final concentration of 20uM ¹⁴ C-methylα-D- Glucoside ( ¹⁴ C-AMG) and the compound to be tested at a final concentration of 50 nM were then added to corresponding wells as wells for the compound to be tested.

4. Set the wells without the compound to be tested (other conditions are the same as above) as positive control wells. In addition, no compound to be tested was added and the pretreatment buffer (without Na ⁺ ) was used instead of the transfer buffer (other conditions were the same as above), as negative control wells. Incubate at 37°C for 2 hours and 30 minutes in an incubator.

5. Wash the cells with pre-cooled washing buffer (pretreatment buffer containing 10mM AMG), and finally add 0.2M NaOH to dissolve the cells, collect the cell fragments and add an appropriate amount of scintillation fluid, mix well and then detect the isotope ¹⁴ C on the machine Radiation intensity (CPM value).

6. The calculation formula is as follows:

2. Experimental results

Some of the synthesized compounds 10, 15, 16, 17, 18, 19, 31 and 43 were tested according to the above experimental procedures, and the results of the inhibition test of the compounds on hSGLT2 transporting glucose in HEK293 transfected cell lines at a concentration of 50 nM are shown in Fig. 1. These compounds exhibit good inhibitory effects on hSGLT2.

Claims (6)

1. The compound represented by the general formula (I), its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester or its isomers: in, R ¹ is independently selected from -CH ₃ , -CH ₂ CH ₃ , halogen or -CN; R ² is independently selected from H, D, -OH, halogen, C _1-3 alkyl, C _1-3 substituted alkyl, C _1-3 alkoxy, C _1-3 substituted alkoxy or -CN; R ³ and R ⁴ are independently selected from H or D; R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently selected from H, D, halogen, -CN, C _1-3 alkyl, C _1-3 substituted alkyl, C _1-4 alkoxy, C _1-4 substituted alkoxy, C _1-4 alkylthio or C _1-4 substituted alkylthio, the substituents are selected from D, halogen, C _1-4 alkoxy or C _1-4 alkylthio base; At least one of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ or R ⁹ must be D. 2. The compound represented by the general formula (I) according to claim 1, its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester or its isomers, including the compound represented by the general formula (II) The compound, its pharmaceutically acceptable salt or its readily hydrolyzable prodrug ester: R ¹ is independently selected from -CH ₃ , F, Cl or -CN; R ² is independently selected from H, D, -OH, halogen, -OCH ₃ , -OCH ₂ CH ₃ or -CN; R ³ and R ⁴ are independently selected from H or D; R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ are independently selected from H, D, F, Cl, -CN, -CH ₃ or -CH ₂ CH ₃ ; At least one of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ or R ⁹ must be D. 3. The compound according to any one of claims 1 to 2, its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester or its isomer, wherein the compound is selected from the group consisting of: (2S,3R,4R,5S,6R)-2-{3-{Deutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6 -(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2S,3R,4R,5S,6R)-2-{3-{Dideutero[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl}- 6-(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2S,3R,4R,5S,6R)-2-{3-{Deuterated[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-chlorophenyl}-6- (Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2S,3R,4R,5S,6R)-2-{3-[Deutero(5-phenylselenophen-2-yl)methyl]-4-methylphenyl}-6-(hydroxymethyl ) Tetrahydro-2H-pyran-3,4,5-triol (2S,3R,4R,5S,6R)-2-{3-{Deutero[5-(pentadeuteriophenyl)selenophen-2-yl]methyl}-4-methylphenyl}-6 -(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2R,3S,4R,5R,6S)-2-(Hydroxymethyl)-6-{4-methyl-3-{[5-(pentadeuteriophenyl)selenophen-2-yl]methyl }phenyl}tetrahydro-2H-pyran-3,4,5-triol (2S,3R,4R,5S,6R)-2-{5-{Deuterated[5-(4-fluorophenyl)selenophen-2-yl]methyl}-2-hydroxy-4-methylbenzene Base}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2S,3R,4R,5S,6R)-2-{3-Deutero-5-{[5-(4-fluorophenyl)selenophen-2-yl]methyl}-4-methylphenyl }-6-(Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. 4. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable carrier. 5. The compound represented by the general formula (I) according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester or its isomers, or according to claim 4 Use of the pharmaceutical composition in the preparation of sodium-glucose co-transporter 2 (SGLT2) inhibitors. 6. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its easily hydrolyzed prodrug ester or its isomer, or the pharmaceutical composition according to claim 4 when preparing Use in a medicament for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, Elevated fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, complications of diabetes, atherosclerosis, or high blood pressure.