Patent Description:
Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion, impaired biological action, or both. Long-term hyperglycemia in diabetes causes chronic damage and dysfunction of various tissues, especially eyes, kidneys, heart, blood vessels, and nerves. In <NUM>, the World Health Organization reported that the incidence of diabetes in adults over the age of <NUM> was greater than <NUM>%. With the increase of population, aging and prolongation of life, the incidence of diabetes will increase. The incidence of diabetes is higher in obese people. Diabetes is projected to become the seventh leading cause of death by <NUM>.

Sodium-dependent glucose transporter (SGLT) inhibitors can inhibit the reabsorption of glucose by the kidneys, allowing excess glucose to be excreted from the urine, lowering blood glucose. It provides a new way for the treatment of diabetes and becomes a hot spot in the research of hypoglycemic drugs. Over the past decades, new targeted drugs have been developed for the treatment of diabetes. In recent years, successively marketed SGLT2 inhibitors have provided a new strategy for controlling blood glucose. The molecular structures of the successively marketed drugs are as follows:
<CHM>
<CHM>.

The SGLT family consists of several subtypes that play a role of transporting carbohydrates across the cell membrane, during which they bind to sodium ion transporters. SGLT1 is mainly expressed in the gastrointestinal passage and is mainly responsible for the absorption of glucose and galactose in the small intestine. SGLT1 is also present in the proximal straight tubule of the kidney, where it contributes to the reabsorption of blood glucose. By inhibiting SGLT1, blood glucose can be prevented from being absorbed and used back to the blood, thus achieving the goal of lowering blood glucose level.

Since SGLT1 inhibition may also provide an alternative therapy for glycemic control, the improvement of glycemic control by SGLT1 inhibition is attractive because it can be independent of renal function. Current SGLT2-selective inhibitors are ineffective in patients with moderate-to-severe renal impairment, which accounts for approximately <NUM>-<NUM>% of all diabetic patients. Inhibition of intestinal SGLT1 has potential efficacy in glycemic control. Through this action, the diabetes-related side effects of SGLT2 inhibitors, especially genital infections, can also be avoided. In <CIT>, inhibitors of sodium glucose cotransporter <NUM> (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed.

In <CIT> and <CIT>, a kind of white <NUM> (SGLT1) inhibitor of sodium glucose co-transporter <NUM> is disclosed. Further, pharmaceutical compositions comprising such inhibitors as well as synthesis method thereof are disclosed. In addition, treatment of metabolism class diseases, especially diabetes B, using such inhibitors is disclosed.

Despite recent advances in the development of intestinal SGLT1 inhibitors, there is still a need to develop new compounds with better efficacy. Through continuous efforts, the present invention have designed compounds with the structure of general formula (V) and found that compounds with such structure showed excellent effects and functions, and in a larger scope, the relationship between structure and activity efficacy have been revealed and clarified more deeply and comprehensively, which has important application value.

The description that follows is subject to this limitation.

The present disclosure provides a compound of formula (V), tautomer or pharmaceutically acceptable salt thereof,
<CHM>.

The present disclosure provides a compound of formula (I), tautomer or pharmaceutically acceptable salt thereof,
<CHM>.

The present disclosure provides a compound of formula (I-<NUM>), tautomer or pharmaceutically acceptable salt thereof,
<CHM>.

The present disclosure provides a compound of formula (I), including the compound of the following structure of general formula (II), tautomer or pharmaceutically acceptable salt thereof,
<CHM>.

The present disclosure provides a compound of formula (I), including the compound of the following general structure (II-<NUM>), tautomer or pharmaceutically acceptable salt thereof,
<CHM>.

The present invention provides a compound of formula (III), a tautomer or pharmaceutically acceptable salt thereof,
<CHM>.

The present invention provides the following compounds, tautomers or pharmaceutically acceptable salts thereof,
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

The present invention provides a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds of the present invention or a tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention provides any of the compounds described herein, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein for use in therapy.

Any of the compounds described in the present invention or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to the present invention for use in the treatment and improvement of diabetes, cardiovascular and cerebrovascular diseases, weight loss, fatty liver, metabolism-related diseases or in the treatment of tumors. Preferably, the patient has taken or is currently taking other therapeutic drugs, including hypotensive drugs, hypolipidemic drugs, antidiabetic drugs, hypoglycemic drugs, weight-loss drugs, or appetite suppressants.

Any of the compounds described in the present invention or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to the present invention, as SGLT1/SGLT2 inhibitor, for use in the treatment of diseases related to SGLT1/SGLT2 function.

As used above and elsewhere herein, the following terms and abbreviations have the meanings defined below. If not defined, all technical and scientific terms used in this specification have the meanings commonly understood by one of ordinary skill in the art.

The term "hydrogen" refers herein to -H.

The term "halogen" refers herein to -F, -Cl, -Br and -I.

The term "amino" refers herein to -NH<NUM>.

The term "hydroxyl" refers herein to -OH.

The term "nitro" refers herein to -NO<NUM>.

The term "carboxy" refers herein to -COOH.

The term "nitroso" refers herein to -NO.

The term "linking arm" herein refers to a chemical structure with a linking function composed of <NUM> to <NUM> carbon atoms, oxygen atoms, nitrogen atoms. Specifically, it refers to an alkane structure with a straight or branched chain structure (including saturated alkane, alkene and alkyne) or a similar alkane structure with a carbonyl group at one end; wherein, under the premise of forming a stable chemical structure, any carbon atom may be replaced by oxygen atom, nitrogen atom, and may also be further substituted by a substituent group, wherein the substituent group includes: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acylamino, ester group, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl and cycloalkoxy. The "linking arm" described herein include, but are not limited to, the following chemical structures:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

The term "aryl" herein refers to a <NUM>- to <NUM>- membered all-carbon monocyclic or fused polycyclic (i.e., ring that share adjacent pairs of carbon atoms) groups, polycyclic (i.e., ring with adjacent pairs of carbon atoms) group with a conjugated π electron system. Aryl groups may be covalently attached to the defined chemical structure at any carbon atom that results in a stable structure. The aryl groups described herein may be optionally substituted by one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acylamino, ester group, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl and cycloalkoxy.

The term "heteroaryl" herein refers to an aromatic group composed of <NUM> to <NUM> atoms and containing at least one heteroatom selected from N, O or S and the like. The term may be a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused ring may or may not be an aromatic group containing a heteroatom, provided the linking point is through atoms of the aromatic heteroaryl group. The heteroaryl described herein may be optionally substituted by one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, acylamino, ester group, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl and cycloalkoxy.

The term "cycloalkyl" herein refers to a cyclic alkyl group having <NUM> to <NUM> carbon atoms, having a monocyclic or polycyclic ring (including fused, bridged and spiro ring systems). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl groups described herein may be optionally substituted by one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, carboxy, amino, alkyl, oxo, alkoxy, acyl, acyloxy, acylamino ester group, amido, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl.

The term "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated aromatic ring, non-aromatic ring containing at least <NUM> to <NUM> heteroatoms selected from N, O or S; the aromatic ring, non-aromatic ring may be <NUM>- to <NUM>-membered monocyclic ring, <NUM>- to <NUM>-membered spiro ring, bicyclic ring or bridged ring, selectively substituted N, S in the heterocyclyl ring may be oxidized to various oxidation states. A <NUM>- to <NUM>-membered heterocycle is preferred. Non-limiting examples include oxiranyl, oxetanyl, oxolanyl, oxanyl, oxanyl, oxocanyl, aziridinyl, azetidinyl, azolidinyl, azacyclohexyl, azacyclopropenyl, <NUM>,<NUM>-dioxocyclopentyl, <NUM>,<NUM>-dioxocyclopentyl, <NUM>,<NUM>-dioxocyclopentyl, <NUM>,<NUM>-dioxacyclohexyl, <NUM>,<NUM>-dithiocyclohexyl, azacycloheptenyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyranyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, <NUM>,<NUM>-dioxacyclohexadienyl or the like.

The term "heterocycloalkyl" refers to a non-aromatic cycloalkyl group containing at least one heteroatom selected from O, N and S and optionally containing one or more double or triple bonds. The heterocycloalkyl group as a whole may have <NUM> to <NUM> ring atoms. The heterocycloalkyl group may be covalently attached to a defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Non-limiting examples of the heterocycloalkyl group include: pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl and the like. One or more N or S atoms on the heterocycloalkyl group may be oxidized (such as morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide). The heterocycloalkyl group may also contain one or more oxo groups such as phthalimido, piperidinone group, oxazolidinone group, <NUM>,<NUM>(<NUM>,<NUM>)-dioxo-pyrimidinyl, pyridine-<NUM>(<NUM>)-keto group and the like. The heterocycloalkyl groups described herein may be optionally substituted by one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxo, acyl, acyloxy, acylamino, ester group, amido, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl.

The term "alkenyl" herein refers to an alkenyl group having <NUM> to <NUM> carbon atoms and having at least one alkenyl unsaturated site. Non-limiting examples of the alkenyl groups include ethenyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like. The alkenyl group described herein may be optionally substituted by one or more of the following substituents: deuterium, fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxyl, acyl, acylamino, ester group, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylmercapto, deuterated alkylmercapto, sulphonyl, sulfoxide group, amino, silyl, phosphonyl, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester group.

The term "alkynyl" herein refers to an alkyl group in which two adjacent carbon atoms are joined by a triple bond, wherein the alkyl group is as defined herein. Alkynyl means an unsaturated alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, <NUM>-propynyl, <NUM>-propynyl, <NUM>-, <NUM>- or <NUM>-butynyl, and the like. The alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups which are independently selected from: deuterium, fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxyl, acyl, acylamino, ester group, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylmercapto, deuterated alkylmercapto, sulphonyl, sulfoxide group, amino, silyl, phosphonyl, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester group.

The term "alkyl" herein refers to a saturated aliphatic hydrocarbyl group having from <NUM> to <NUM> carbon atoms, and the term includes both straight chain and branched chain hydrocarbyl groups. Non-limiting examples of the alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like. The alkyl groups described herein may be optionally substituted by one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, acylamino, ester group, amido, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl or heteroaryl.

The term "heteroalkyl" herein refers to an alkyl group that comprises at least one heteroatom.

The term "alkoxy" herein refers to an alkyl group attached to the remainder of the molecule through an oxygen atom (-O-alkyl), wherein the alkyl group is as defined herein. Non-limiting examples of the alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentyloxy, and the like.

The term "acylamino" herein refers to -NR<NUM>-C(O)-alkyl, -NR<NUM>-C(O)-cycloalkyl, -NR<NUM>-C(O)-cycloalkenyl, -NR<NUM>-C(O)-aryl, -NR<NUM>-C(O)-heteroaryl and -NR<NUM>-C(O)-heterocycloalkyl, wherein R<NUM> is hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl and alkyl. Wherein, the groups such as hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl and alkyl are as defined herein.

The term "acyl" herein refers to H-C(O)-, R<NUM>R<NUM>N-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C(O)-, heterocycloalkyl-C(O)-, aryl-C(O)- and heteroaryl-C(O)-, wherein the R<NUM> and R<NUM> are each independently selected from hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl. Wherein, the groups such as hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl are as defined herein.

The term "oxo" refers to the description of the oxidation state of carbon atoms, nitrogen atoms, sulfur atoms, and the like by oxygen atoms, the representative structures formed after the oxidation of carbon atoms, nitrogen atoms, sulfur atoms, and the like by oxygen atoms include but are not limited to functional groups such as hydroxyl, alkoxy, carbonyl, oxynitride, sulfoxide, and sulphone.

The term "sulfonyl" herein refers to R<NUM>R<NUM>N-S(O)<NUM>-, cycloalkyl-S(O)<NUM>-, cycloalkenyl-S(O)<NUM>-, arylS(O)<NUM>-, heteroaryl-S(O)<NUM>-, heterocycloalkyl-S(O)<NUM>- and alkyl-S(O)<NUM>-, wherein the R<NUM> and R<NUM> are each independently selected from hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl. Wherein, the groups such as hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl are as defined herein.

The term "sulfinyl" herein refers to R<NUM>R<NUM>N-S(O)-, cycloalkyl-S(O)-, cycloalkenyl-S(O)-, arylS(O)-, heteroaryl-S(O)-, heterocycloalkyl-S(O)- or alkyl-S(O)-, wherein the R<NUM> and R<NUM> are each independently selected from hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl. Wherein, the groups such as hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl are as defined herein.

The term "acyloxy" herein refers to -O-C(O)-alkyl, -O-C(O)-cycloalkyl, -O-C(O)-cycloalkenyl, - O-C(O)-aryl, -O-C(O)-heteroaryl and -O-C(O)-heterocycloalkyl, wherein the groups such as alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are as defined herein.

The term "ester group" herein refers to alkyl-O-C(O)-, cycloalkyl-O-C(O)-, cycloalkenyl-O-C(O)-, heterocycloalkyl-O-C(O)-, aryl-O-C(O)- and heteroaryl-O-C(O)-, wherein the groups such as alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl are as defined herein.

The term "optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and this description includes cases in which the event or circumstance occurs and does not occur.

The term "optionally substituted by. " means that the structure is unsubstituted or substituted by one or more substituents described in the present invention. The term "substitution" herein means the single or multiple substitution of any group by a designated substituent to the extent that such single or multiple substitution (including multiple substitutions in the same moiety) is chemically permissible, wherein each substituent can be located at any available position on the group and can be attached through any available atom on the substituent. "Any available position" refers to any position on the group, which is chemically obtainable by methods known in the art or as taught herein and does not create molecules that are excessively unstable. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and thus may be the same or different.

In various parts of the specification, substituents of the compounds of the present invention are disclosed in the form of groups or ranges. This specifically means that the present invention encompasses each of the members of such groups or ranges or subgroups of each of the members. The term "C<NUM>-<NUM> alkyl" specifically means that methyl, ethyl, C<NUM> alkyl, C<NUM> alkyl, C<NUM> alkyl and C<NUM> alkyl are disclosed separately.

The term "compounds of the present invention" herein refers to compounds of formula (III), tautomers and any pharmaceutically acceptable salts thereof.

The term "solvate" means a compound or a salt thereof combined with a stoichiometric and non-stoichiometric solvent, such as a hydrate, an ethylate, a methylate, an acetonate or the like. The compound may also be present in one or more crystalline states, i.e., as a co-crystal, a polymorph, or it may be present as an amorphous solid. All such forms are covered by the claims.

The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients that make up the formulation and/or the mammal treated by it.

The term "stereoisomer" herein refers to compounds with different chiral properties having one or more stereocenters, including the enantiomers and diastereomers.

The term "tautomer" herein refers to structural isomers with different energies that can cross the low energy barrier and thus convert to each other. One example is proton tautomers including tautomers that interconvert by proton transfer, such as enol-keto tautomers and imine-enamine tautomers, or a tautomeric form of a heteroaryl group containing a ring atom attached to ring-NH-moiety and ring=N-moiety, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole. Valence tautomers include those in which some bonding electrons recombine to interconvert.

The term "prodrug" herein refers to any derivative of the compound of the present invention that, when administered to a subject, directly or indirectly provides the compound of the present invention, an active metabolite or residue thereof. Especially preferred are those derivatives or prodrugs that increase the bioavailability, metabolic stability and tissue targeting of the compounds of the present invention.

The compounds of the present invention may be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include, but are not limited to, the following substances: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, ethane sulfonate, disulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulphate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, <NUM>-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, ethanesulfonate, hydrochloride, <NUM>-naphthalene sulfonate, oxalate, pectate, sulfate, <NUM>-phenylpropionate, picrate, trimethylacetate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and decanoate. In addition, basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halide, including chloride, bromide and iodide of methyl, ethyl, propyl and butyl groups; such as dialkylsulfate, including dimethylsulfate, diethylsulfate, dibutylsulfate and dipentylsulfate; such as long chain halide, including chloride, bromide and iodide of decyl, lauryl, myristyl, and stearyl; such as aralkyl halide, such as bromide of benzyl and phenethyl, and the like.

The present disclosure also includes isotopically labeled compounds, which are identical to those disclosed above in structure, but in which one or more atoms are replaced by an atom having the same number of protons but a different number of neutrons. Examples of the isotope incorporating into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine and iodine, such as <NUM>H, <NUM>H, <NUM>C, <NUM>C, <NUM>N, <NUM>O, <NUM>O, <NUM>S, <NUM>F, <NUM>Cl and <NUM>I, etc..

Certain isotopically labeled compounds of the present disclosure, such as those labeled with <NUM>H or <NUM>C, can be used in drug tissue distribution assays, and therefore, these <NUM>H or <NUM>C isotopes are particularly preferred because of their ease of preparation and detection. In addition, certain compounds of the present invention replaced by heavier isotopes such as <NUM>H have certain therapeutic advantages due to better metabolic stability, such as increased in vivo half-life and lower doses, etc., therefore, <NUM>H is also preferred in some cases.

The following examples are used to further illustrate the present invention, but the present invention is not limited thereto, as long as they fall under the scope of the claims. Throughout the present application, various examples of the compounds and methods of the present invention are referred herein. The various examples described are intended to provide a number of illustrative examples and should not be construed as a description of alternatives. At the same time, it should be noted that the examples (including various methods and parameters) discussed herein are merely intended to illustrate the invention and do not limit the scope of protection of the invention by any means. For the purpose of describing the present invention, specific examples are set forth below. However, it is to be understood that the present invention is not limited to these examples, and the following examples are merely intended to provide a method of practicing the present invention and do not limit the scope of the present invention by any means, as long as they fall under the scope of the claims. All the examples which do not fall under the scope of the claims are provided as reference examples.

The preparation method of the compounds disclosed herein, a tautomer or pharmaceutically acceptable salt thereof, comprises the following steps, Scheme <NUM>:
<CHM>.

SM1-<NUM> and SM2-<NUM> are reacted under certain chemical reaction conditions to prepare the compound of general formula (V), wherein each substituent is defined as before;
<CHM>
<CHM>
SM1-<NUM> and SM2-<NUM> are reacted under certain chemical reaction conditions to prepare the compound of general formula (V), wherein each substituent is defined as before;
The compounds provided by the present invention can be prepared by standard synthetic methods well known in the art, and this specification provides general methods for preparing the compounds of the present invention. The starting materials are usually commercially available, for example, purchased from companies such as Alfa Aesar®, Sigma-Aldrich®, TCI, J&K®, Shaoyuan Chemical, Energy Chemical, etc., or prepared by methods well known to those skilled in the art.

The compounds of the present invention and the corresponding preparation methods are further explained and listed below by means of examples and preparations. It should be understood that although typical or preferred reaction conditions (such as reaction temperature, time, molar ratio of reactants, reaction solvent and pressure, etc.) are given in the specific examples, other reaction conditions may also be used by those skilled in the art. Optimal reaction conditions may vary with the particular reaction substrates or solvents used, but such conditions can be determined by one skilled in the art through routine optimization.

The structures of the compounds in the following examples were characterized by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR spectrometer was used, the compound was dissolved in appropriate deuterated reagents and analyzed by <NUM>H-NMR at ambient temperature with TMS as an internal standard. NMR chemical shifts (δ) were measured in ppm and the following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet. MS was determined by mass spectrometer (ESI).

The starting materials of the reaction, intermediates and the compounds of examples can be separated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography (such as column chromatography, TLC separation and purification, etc.) and the like.

HSGF254 thin layer chromatography silica gel plate (<NUM>±<NUM>) was used for TLC, and HSGF254 thin layer chromatography thick preparation plate (<NUM> ~ <NUM>) was used for TLC separation and purification. <NUM>-<NUM> mesh silica gel was used as the carrier for column chromatography.

Commercial solvents and reagents used in the test, unless otherwise specified, can be used directly without further purification or treatment after purchase. When referring to other examples or synthetic methods, the reaction conditions (reaction temperature, reaction solvent, molar ratio of reactants or/and reaction duration) may be different. In general, the progress of the reaction can be monitored by TLC, and the appropriate time can be selected to terminate the reaction and carry out post-treatment accordingly. The purification conditions of the compounds may also vary, in general, an appropriate column chromatography eluent is selected according to the Rf value of TLC, or the corresponding compounds are separated and purified by preparative TLC.

<NUM>-Bromo-<NUM>-methylbenzoic acid (<NUM>) and dichloromethane (<NUM>) were added into a <NUM>-liter reaction flask, and dimethyl sulfoxide (<NUM>), N,N-dimethylformamide (<NUM>) were added dropwise successively, the mixture was returned to room temperature and stirred for <NUM> after dropping. The reaction solution was concentrated to dryness, dichloromethane (<NUM>), N,O-dimethylhydroxylamine hydrochloride (<NUM>) were added successively, the temperature was cooled to <NUM> in an ice bath, triethylamine (<NUM>) was added dropwise. After addition, the solution was returned to room temperature and stirred for <NUM>. The reaction solution was poured into <NUM> diluted hydrochloric acid, liquid separation was carried out, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain <NUM> of colorless liquid.

The product of the previous step (<NUM>) and tetrahydrofuran (<NUM>) were added into a <NUM> reaction flask, cooled to <NUM>, <NUM>-chlorophenylmagnesium bromide (<NUM> in Et<NUM>O) was added dropwise, and the mixture was stirred at room temperature for <NUM> after dropping. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain <NUM> of white solid. <NUM>H NMR(<NUM>,CDCl<NUM>):δ7. <NUM>(m,<NUM>),<NUM>(dd,J=<NUM>,<NUM>,<NUM>),<NUM>(m,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>. <NUM>(d,J=<NUM>, <NUM>),<NUM>(s,<NUM>).

(<NUM>-Bromo-<NUM>-methylphenyl)(<NUM>-chlorophenyl)methanone (<NUM>), acetonitrile (<NUM>) and triethylsilane (<NUM>, <NUM> mmol) were added into a <NUM> reaction flask, cooled to <NUM>, boron trifluoride ether (<NUM>) was slowly added dropwise, kept stirring at <NUM> for <NUM> after addition, and then the mixture was heated to <NUM> and stirred for <NUM>. After the reaction was completed, the reaction solution was cooled to <NUM>, and saturated aqueous sodium bicarbonate solution was slowly added until no bubbles were generated, extracted with ethyl acetate for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by column chromatography (eluting with petroleum ether) to obtain <NUM> of white solid.

(3aS,5R,<NUM>,6aS)-<NUM>-Hydroxy-<NUM>,<NUM>-dimethyltetrahydrofuro[<NUM>,<NUM>-d][<NUM>,<NUM>]dioxol-<NUM>-yl)(morpholinyl)methanone (<NUM>) and tetrahydrofuran (<NUM>) were added into a <NUM> reaction flask, cooled to <NUM>, tert-butylmagnesium chloride (<NUM> in THF, <NUM>, <NUM> mmol) was added dropwise, after addition, the mixture was continued to stir for <NUM>.

<NUM>-Bromo-<NUM>-(<NUM>-chlorobenzyl)-<NUM>-toluene (<NUM>) and tetrahydrofuran (<NUM>) were added into a <NUM> reaction flask under nitrogen protection, cooled to -<NUM>, n-butyllithium (<NUM> in hexane) was slowly added dropwise and stirred for <NUM>. Then, the newly prepared Grignard reaction solution above was added, and after addition, the mixture was returned to room temperature and continued to stir for <NUM>. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain <NUM> of white solid. <NUM>H NMR(<NUM>,CDCl<NUM>):δ7. <NUM>-<NUM>(dd,J=<NUM>,<NUM>, <NUM>), <NUM>(d,J=<NUM>, <NUM>),<NUM>-<NUM>(d,J=<NUM>, <NUM>), <NUM>-<NUM>(m,<NUM>), <NUM>-<NUM>(d,J=<NUM>,<NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(s, <NUM>),<NUM><NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>).

(3aS,5R,<NUM>,6aS)-<NUM>-Hydroxy-<NUM>,<NUM>-dimethyltetrahydrofuro[<NUM>,<NUM>-d][<NUM>,<NUM>]dioxol-<NUM>-yl)(morpholinyl)methanone (<NUM>), cerium chloride heptahydrate (<NUM>) and methanol (<NUM>) were added into a <NUM> reaction flask, cooled to <NUM> in an ice bath, and a solution (<NUM>) of sodium borohydride (<NUM>) in <NUM> aqueous sodium hydroxide was slowly added dropwise. After addition, the mixture was returned to room temperature and stirred for <NUM>. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain <NUM> of pale yellow solid, which was directly used in the next reaction.

(3aS,<NUM>,6R,6aS)-<NUM>-((s)-(<NUM>-(<NUM>-chlorobenzyl)-<NUM>-methylphenyl)(hydroxy)methyl)-<NUM>,<NUM>-dimethyltetrahydrofuro[<NUM>,<NUM>-d][<NUM>,<NUM>]dioxol-<NUM>-ol (<NUM>), glacial acetic acid (<NUM>) and water (<NUM>) were added into a <NUM> reaction flask, heated to <NUM> and stirred for <NUM>. The reaction solution was concentrated to dryness, azeotropically distilled with toluene for three times, the residue was dissolved in <NUM> of acetonitrile, triethylamine (<NUM>) was added, and a solution (<NUM>) of acetic anhydride (<NUM>) in acetonitrile was slowly added dropwise at <NUM> under nitrogen protection. After addition, the mixture was cooled to room temperature naturally and stirred for <NUM>. The reaction solution was diluted with ethyl acetate, water was added, and liquid separation was carried out. The aqueous phase was extracted with ethyl acetate for three times. The organic phases were combined, washed once with diluted hydrochloric acid and saturated salt solution in turn, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, purified by column chromatography to obtain <NUM> of yellow solid. <NUM>H NMR(<NUM>,CDCl<NUM>):δ7. <NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>), <NUM>(s, <NUM>), <NUM>(d,J=<NUM>,<NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s, <NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>).

(<NUM>,4R,<NUM>,<NUM>)-<NUM>-(<NUM>-(<NUM>-Chlorobenzyl)-<NUM>-methylphenyl)tetrahydro-<NUM>-pyran-<NUM>,<NUM>,<NUM>,<NUM>-tetrayl tetraacetate (<NUM>), thiourea (<NUM>), <NUM>,<NUM>-dioxane (<NUM>), trimethylsilyl trifluoromethanesulfonate (<NUM>) were added into a <NUM> reaction flask, heated to <NUM> and stirred for <NUM>. After the reaction was completed, the solution was cooled to room temperature, iodomethane (<NUM>) and N,N-diisopropylethylamine (<NUM>) were added successively, and the mixture was stirred at room temperature for <NUM>. Ethyl acetate and water were added, stirred, and liquid separation was carried out. The aqueous phase was extracted with ethyl acetate for three times, the organic phases were combined, washed once with diluted hydrochloric acid and saturated salt solution in turn, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, purified by column chromatography to obtain <NUM> of pale yellow solid. <NUM>H NMR(<NUM>,CDCl<NUM>):δ7. <NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM><NUM>(d,J=<NUM>, <NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>), <NUM>(s,<NUM>).

(<NUM>,<NUM>,4R,<NUM>,6R)-<NUM>-(<NUM>-(<NUM>-chlorobenzyl)-<NUM>-methylphenyl)-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>,<NUM>,<NUM>-triyl triacetate (<NUM>), methyl <NUM>-butenoate (<NUM>), Pd<NUM>(dba)<NUM> (<NUM>), tri-tert-butylphosphine tetrafluoroborate (<NUM>), dicyclohexylmethylamine (<NUM>) and N-methylpyrrolidone (<NUM>) were added into a <NUM> microwave reaction tube, after nitrogen replacement, the mixture was heated to <NUM> by microwave and reacted for <NUM>. This operation process was repeated for <NUM> times and for a total of <NUM> of raw materials. The reaction solutions were combined and diluted with ethyl acetate, water was added, and liquid separation was carried out. The aqueous phase was extracted with ethyl acetate for three times, the organic phases were combined, washed once with diluted hydrochloric acid and saturated salt solution in turn, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, purified by column chromatography to obtain <NUM> of pale yellow solid. <NUM>H NMR(<NUM>,CDCl<NUM>):δ7. <NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>-<NUM>(m, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM><NUM>(d,J=<NUM>, <NUM>),<NUM>-.

<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>(dd,J=<NUM>,<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>), <NUM><NUM>(s,<NUM>).

(<NUM>,<NUM>,4R,<NUM>,6R)-<NUM>-(<NUM>-(<NUM>-((E)-<NUM>-methoxy-<NUM>-oxobut-<NUM>-en-<NUM>-yl)benzyl)-<NUM>-methylphenyl)-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>,<NUM>,<NUM>-triyl triacetate (<NUM>), methanol (<NUM>), tetrahydrofuran (<NUM>), <NUM>% palladium on carbon (<NUM>) were added into a <NUM> reaction flask, hydrogen replacement was carried out for <NUM> times, and the mixture was stirred at room temperature for <NUM>. The reaction solution was filtered with diatomite, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain <NUM> of pale yellow solid.

(<NUM>,<NUM>,4R,<NUM>,6R)-<NUM>-(<NUM>-(<NUM>-(<NUM>-Methoxy-<NUM>-oxobutyl)benzyl)-<NUM>-methylphenyl)-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>,<NUM>,<NUM>-triyl triacetate (<NUM>), methanol (<NUM>), tetrahydrofuran (<NUM>) and water (<NUM>) were added into a <NUM> reaction flask, then lithium hydroxide monohydrate (<NUM>) was slowly added, and after addition, the mixture was stirred at room temperature for <NUM>. The reaction solution was diluted with water, extracted with ethyl acetate for three times, the organic phase was discarded, the pH of the aqueous phase was adjusted to <NUM> with diluted hydrochloric acid, extracted with ethyl acetate for three times, the organic phases were combined, washed once with saturated salt solution, and dried on anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain <NUM> of white solid. <NUM>H NMR(<NUM>,DMSO-d6):<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(brs, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J= <NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>), <NUM>-<NUM>(quin,J=<NUM>,<NUM>). MS:m/z <NUM>,[M-H]-.

(3aS,5R,<NUM>,6aS)-<NUM>-Hydroxy-<NUM>,<NUM>-dimethyltetrahydrofuro[<NUM>,<NUM>-d][<NUM>,<NUM>]dioxol-<NUM>-yl)(morpholinyl)methanone (<NUM>), tetrahydrofuran (<NUM>) were added into a <NUM> reaction flask, under nitrogen protection, cooled to <NUM>, tert-butylmagnesium chloride (<NUM> in THF, <NUM>) was added and stirred for <NUM>.

<NUM>-Chloro-<NUM>-iodotoluene (<NUM>), tetrahydrofuran (<NUM>) were added into a <NUM> reaction flask, under nitrogen protection, cooled to -<NUM>, n-butyllithium (<NUM> in hexane, <NUM>) was slowly add, and stirred for <NUM> minutes after addition. The newly prepared Grignard reaction solution above was added, and after addition, the mixture was returned to room temperature and stirred for <NUM>. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain <NUM> of white solid.

(<NUM>-Chloro-<NUM>-methylphenyl)(3aS,5R,<NUM>,6aS)-<NUM>-hydroxy-<NUM>,<NUM>-dimethyltetrahydrofuro[<NUM>,<NUM>-d][<NUM>,<NUM>]dioxol-<NUM>-yl)methanone (<NUM>), cerium chloride heptahydrate (<NUM>) and methanol (<NUM>) were added into a <NUM> reaction flask, cooled to <NUM> in an ice bath, and sodium borohydride (<NUM>) in <NUM> aqueous sodium hydroxide solution (<NUM>) was slowly added dropwise. After addition, the mixture was returned to room temperature and stirred for <NUM>. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate for three times, the organic phases were combined, washed with saturated salt solution once, dried on anhydrous sodium sulfate, filtered, concentrated, to obtain <NUM> of pale yellow solid.

(3aS,<NUM>,6R,6aS)-<NUM>-((S)-(<NUM>-chloro-<NUM>-methylphenyl)(hydroxy)methyl)-<NUM>,<NUM>-dimethyltetrahydrofuro[<NUM>,<NUM>-d][<NUM>,<NUM>]dioxol-<NUM>-ol (<NUM>), glacial acetic acid (<NUM>) and water (<NUM>) were added into a <NUM> reaction flask, heated to <NUM> and stirred for <NUM>. The reaction solution was concentrated to dryness, azeotropically distilled with toluene for three times, the residue was dissolved in <NUM> of acetonitrile, triethylamine (<NUM>) was added, and a solution(<NUM>) of acetic anhydride (<NUM>) in acetonitrile was slowly added dropwise at <NUM>. After addition, the mixture was cooled to room temperature and stirred for <NUM>. The reaction solution was diluted with ethyl acetate, water was added, and liquid separation was carried out. The aqueous phase was extracted with ethyl acetate for three times. The organic phases were combined, washed once with diluted hydrochloric acid, and once with saturated salt solution, dried on anhydrous sodium sulfate, filtered and concentrated to obtain <NUM> of brown oily substance, which is directly added to the next reaction.

(2R,<NUM>,4R,<NUM>,<NUM>)-<NUM>-(<NUM>-Chloro-<NUM>-methylphenyl)tetrahydro-<NUM>-pyran-<NUM>,<NUM>,<NUM>,<NUM>-tetrayl tetraacetate (<NUM> (theoretical amount)), thiourea (<NUM>), <NUM>,<NUM>-dioxane (<NUM>), trimethylsilyl trifluoromethanesulfonate (<NUM>) were added into a <NUM> reaction flask, heated to <NUM> and stirred for <NUM>. The reaction solution was cooled to room temperature, iodomethane (<NUM>) and N,N-diisopropylethylamine (<NUM>) were added, and the mixture was stirred for <NUM>. Ethyl acetate and water were added to the reaction solution, and liquid separation was conducted. The aqueous phase was extracted with ethyl acetate for three times, the organic phases were combined, washed once with diluted hydrochloric acid, once with saturated salt solution, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by column chromatography to obtain <NUM> of pale yellow solid. <NUM>H NMR(CDCl<NUM>,<NUM>):δ7. <NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>-<NUM>(dd,J=<NUM>,<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(d, J=<NUM>. <NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>), <NUM>(s,<NUM>). MS:m/z <NUM>,[M+Na]+.

(<NUM>,<NUM>,4R,<NUM>,6R)-<NUM>-(<NUM>-Chloro-<NUM>-methylphenyl)-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>,<NUM>,<NUM>-triyl triacetate (<NUM>), bis(pinacolato)diboron (<NUM>), potassium acetate (<NUM>), palladium acetate (<NUM>), <NUM>-dicyclohexylphosphino-<NUM>',<NUM>'-dimethoxybiphenyl (<NUM>), <NUM>,<NUM>-dioxane (<NUM>) were added into a <NUM> microwave tube, after nitrogen replacement, the mixture was heated to <NUM> by microwave and stirred for <NUM>. The reaction solution was concentrated, and then purified by column chromatography to obtain <NUM> of pale yellow solid. <NUM>H NMR(CDCl<NUM>,<NUM>):δ7. <NUM>(d,J=<NUM>, <NUM>),<NUM>(dd,J=<NUM>,<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM> (t,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>(d,J=<NUM>, <NUM>), <NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>), <NUM>(s,<NUM>), <NUM>(d,J=<NUM>, <NUM>). MS:m/z <NUM>,[M+Na]+.

p-Hydroxymethylbenzaldehyde (<NUM>) and tetrahydrofuran (<NUM>) were added into a <NUM> reaction flask, cooled to <NUM> in an ice bath, and a solution of ethyl <NUM>-bromopropionate (<NUM>) in tetrahydrofuran (<NUM>) was slowly added ropwise, and the mixture was returned to room temperature and stirred for <NUM> after addition. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate for three times, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain <NUM> of colorless liquid. <NUM>H NMR(CDCl<NUM>,<NUM>):δ <NUM>(s, <NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(q,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>. <NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>).

Ethyl <NUM>-(<NUM>-Formylbenzyl)oxy)propionate (<NUM>) and methanol (<NUM>) were added into a <NUM> reaction flask, cooled to <NUM> in an ice bath, sodium borohydride (<NUM>) was added in batches. After addition, the mixture was returned to room temperature and stirred for <NUM>. The reaction solution was poured into 1N HCl aqueous solution, extracted with ethyl acetate for three times, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain <NUM> of colorless liquid. <NUM>H NMR(CDCl<NUM>,<NUM>):δ7. <NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(q,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>. <NUM>(brs, <NUM>), <NUM>(t,J=<NUM>,<NUM>).

Ethyl <NUM>-(<NUM>-(hydroxymethyl)benzyloxy)propionate (<NUM>), pyridine (<NUM>), dichloromethane (<NUM>) were added into a <NUM> reaction flask, cooled to <NUM> in an ice bath, a solution (<NUM>) of methyl chloroformate (<NUM>) in dichloromethane was added dropwise, and after addition, the mixture was returned to room temperature and stirred for <NUM>. The reaction solution was poured into 1N HCl aqueous solution, extracted with ethyl acetate for three times, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain <NUM> of colorless liquid. <NUM>H NMR(CDCl<NUM>,<NUM>):δ7. <NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(q,J=<NUM>,<NUM>), <NUM>(s,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>), <NUM>(t,J=<NUM>,<NUM>).

<NUM>,<NUM>-Bis(diphenylphosphino)butane (<NUM>), allylpalladium(II) chloride dimer (<NUM>), toluene (<NUM>), isopropanol (<NUM>) were added into a <NUM> there-necked flask, after nitrogen replacement, the mixture was stirred at room temperature for <NUM>.

(<NUM>,<NUM>,4R,<NUM>,6R)-<NUM>-(<NUM>-Methyl-<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolan-<NUM>-yl)phenyl)-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>,<NUM>,<NUM>-triyl triacetate (<NUM>), Ethyl <NUM>-((<NUM>-(((methoxycarbonyl)oxy)methyl)benzyl)oxy)propionate and isopropanol (<NUM>) were added into a <NUM> microwave reaction tube, the above catalyst was added after nitrogen replacement, and the reaction was microwaved to <NUM> for <NUM>. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain <NUM> of an oily substance. <NUM>H NMR(CDCl<NUM>,<NUM>):δ7. <NUM>(d,J=<NUM>,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM> (t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(t,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(s,<NUM>),<NUM>(d,J= <NUM>, <NUM>),<NUM>(q,J=<NUM>,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>), <NUM>(s,<NUM>),<NUM>(t,J=<NUM>,<NUM>).

(<NUM>,<NUM>,4R,<NUM>,6R)-<NUM>-(<NUM>-(<NUM>-(<NUM>-ethoxy-<NUM>-oxopropyloxy)methyl)benzyl)-<NUM>-methylphenyl)-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>,<NUM>,<NUM>-triyl triacetate (<NUM>), methanol (<NUM>), tetrahydrofuran (<NUM>), water ( <NUM>), lithium hydroxide monohydrate (<NUM>) were added into a <NUM> reaction flask, stirred at room temperature for <NUM>. The reaction solution was diluted with water, extracted with ethyl acetate for three times, the organic phase was discarded, the pH of the aqueous phase was adjusted to <NUM> with diluted hydrochloric acid, extracted with ethyl acetate for three times, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, and filtered, the filtrate was concentrated to dryness to obtain <NUM> of a colorless foam.

<NUM>H NMR(DMSO-d6,<NUM>):δ12. <NUM>(brs,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>-<NUM>(m,SH),<NUM> (brs, <NUM>),<NUM>(brs, <NUM>),<NUM>(s,<NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(s,<NUM>),<NUM>(t,J=<NUM>. <NUM>,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>).

<NUM>C NMR(DMSO-d6, <NUM>):δ173. <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>, <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>. MS:m/z <NUM>,[M+Na]+.

Tetrahydrofuran (<NUM>), water (<NUM>), bromoethylamine hydrobromic acid (<NUM>), were successively added into a <NUM> reaction flask, cooled to <NUM>, and sodium bicarbonate (<NUM>), <NUM>-dimethylaminopyridine (<NUM>), di-tert-butyl dicarbonate (<NUM>) were added, and stirred at <NUM> for <NUM> after addition. The reaction solution was filtered, the filtrate was subjected to liquid seperation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed once with saturated salt solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain <NUM> of a pale yellow liquid.

N-methylpropargylamine (<NUM>), tetrahydrofuran (<NUM>), water (<NUM>), potassium carbonate (<NUM>, <NUM>. 8mmol) and a solution (<NUM>) of <NUM>-(Boc-amino)ethyl bromide (<NUM>) in tetrahydrofuran were successively added into a <NUM> reaction flask, and stirred at room temperature for <NUM> after addition. The reaction solution was extracted with ethyl acetate for three times, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered and concentrated to obtain <NUM> of a pale yellow oily substance. The obtained crude product was dissolved in acetonitrile (<NUM>), concentrated hydrochloric acid (<NUM>) was slowly added dropwise, stirred at room temperature for <NUM>, the reaction solution was concentrated under reduced pressure, dissolved in <NUM> of acetonitrile, potassium carbonate (<NUM>, <NUM> mmol) was added, and stirred at <NUM> for <NUM>, cooled to room temperature, filtered with diatomite, washed with acetonitrile, and the filtrate was concentrated to dryness to obtain <NUM> of a pale yellow liquid. MS: m/z <NUM>,[M+H]+.

<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-methylpropionic acid (<NUM>) and dichloromethane (<NUM>) were added into a <NUM> reaction flask successively, cooled to <NUM> in an ice bath, CDI (<NUM>) was slowly added. After addition, the mixture was stirred at <NUM> for <NUM> minutes. N<NUM>-Methyl-N<NUM>-(prop-<NUM>-yn-<NUM>-yl)eth-<NUM>,<NUM>-diamine (<NUM>) was added, and after addition, the mixture was returned to room temperature and stirred for <NUM>. The reaction solution was diluted with dichloromethane, water was added, and the liquid separation was carried out, the aqueous phase was extracted with dichloromethane for three times, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain <NUM> of a pale yellow liquid. The product was dissolved in acetonitrile (<NUM>), concentrated hydrochloric acid (<NUM>) was slowly added dropwise, stirred at room temperature for <NUM>, the reaction solution was concentrated to dryness, acetonitrile (<NUM>) was added to dissolve, potassium carbonate (<NUM>) was added, stirred at <NUM> for <NUM>, and cooled to room temperature, filtered with diatomite, washed with acetonitrile, and the filtrate was concentrated under reduced pressure to obtain <NUM> of a pale yellow liquid. MS:m/z <NUM>,[M+H]+.

<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-methylpropionic acid (<NUM>) and dichloromethane (<NUM>) were added into a <NUM> reaction flask successively, cooled to <NUM> in an ice bath, CDI (<NUM>) was slowly added. After addition, the mixture was stirred at <NUM> for <NUM> minutes. N,N-Dimethylethylenediamine (<NUM>) was added, and after addition, the mixture was returned to room temperature and stirred for <NUM>. The reaction solution was diluted with dichloromethane, water was added, and the liquid separation was carried out, the aqueous phase was extracted with dichloromethane for three times, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, and concentrated under reduced pressure to obtain <NUM> of a pale yellow liquid. The product was dissolved in acetonitrile (<NUM>), concentrated hydrochloric acid (<NUM>) was slowly added dropwise, stirred at room temperature for <NUM>, the reaction solution was concentrated to dryness, acetonitrile (<NUM>) was added to dissolve, potassium carbonate (<NUM>, 30mmol) was added, stirred at <NUM> for <NUM>, and cooled to room temperature, filtered with diatomite, washed with acetonitrile, and the filtrate was concentrated under reduced pressure to obtain <NUM> of a pale yellow liquid. MS:m/z <NUM>,[M+H]+.

Tert-butyl <NUM>-(methylamino)ethylcarbamate (<NUM>), acetonitrile (<NUM>), potassium carbonate (<NUM>) and ethyl bromoacetate (<NUM>) were successively added into a <NUM> reaction flask, heated to <NUM> and stirred for <NUM>. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain <NUM> of pale yellow oily substance.

Ethyl N-(<NUM>-((tert-butoxycarbonyl)amino)ethyl)-N-methylglycine (<NUM>), tetrahydrofuran (<NUM>), lithium hydroxide monohydrate (<NUM>) and water (<NUM>) were successively added into a <NUM> reaction flask, and stirred at room temperature for <NUM>. The reaction solution was concentrated under reduced pressure, the concentrated residue was dissolved in dichloromethane (<NUM>). HATU (<NUM>), DIPEA (<NUM>) and N-methylpropargylamine (<NUM>) were added successively, and the mixture was stirred at room temperature for <NUM>. The reaction solution was diluted with dichloromethane, water was added, and the liquid separation was carried out. The organic phase was washed once with saturated salt solution, dried on anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain <NUM> of pale yellow oily substance. The product was dissolved in acetonitrile (<NUM>), and concentrated hydrochloric acid (<NUM>) was slowly added dropwise, and the mixture was stirred at room temperature for <NUM>. The reaction solution was concentrated, acetonitrile (<NUM>) was added to dissolve, potassium carbonate (<NUM>) was added, and the mixture was stirred at <NUM>° C for <NUM>. The reaction solution was cooled to room temperature, filtered with diatomite, washed with acetonitrile, and the filtrate was concentrated to obtain <NUM> of pale yellow liquid.

<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-methylpropionic acid (<NUM>) and dichloromethane (<NUM>) were added into a <NUM> reaction flask successively, cooled to <NUM> in an ice bath, CDI (<NUM>) was slowly added. After addition, the mixture was stirred at <NUM> for <NUM> minutes. <NUM>-((<NUM>-Aminoethyl)(methyl)amino)-N-methyl-N-(prop-<NUM>-yn-<NUM>-yl)acetamide (<NUM>) was added, and returned to room temperature and stirred for <NUM> after addition. Dichloromethane was added into the reaction flask to dilute, water was added, and the liquid separation was carried out. The aqueous phase was extracted with dichloromethane for three times, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain <NUM> of pale yellow oily substance. The product was dissolved in acetonitrile (<NUM>), and concentrated hydrochloric acid (<NUM>) was slowly added dropwise, and the mixture was stirred at room temperature for <NUM>. The reaction solution was concentrated to dryness, acetonitrile (<NUM>) was added to dissolve, potassium carbonate (<NUM>, <NUM>. 8mmol) was added, and the mixture was stirred at <NUM>° C for <NUM>. The reaction solution was cooled to room temperature, filtered with diatomite, washed with acetonitrile, and the filtrate was concentrated to dryness under reduced pressure to obtain <NUM> of pale yellow oily substance. MS:m/z <NUM>,[M+H]+.

<NUM>-(<NUM>-(<NUM>-methyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>-yl)benzyl)phenyl)butyric acid (<NUM>), N-(<NUM>-aminoethyl)pyrrolidine (<NUM>), tetrahydrofuran (<NUM>), N,N-diisopropyl ethylamine (<NUM>, <NUM>. 66mmol) and <NUM>-(<NUM>-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (<NUM>) were added into a <NUM> single-neck flask, and stirred at room temperature for <NUM> hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added to dilute, extracted with ethyl acetate, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain <NUM> of a white solid. <NUM>H NMR(<NUM>,CD<NUM>OD<NUM>):δ=<NUM>-<NUM>(m,<NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>), <NUM>-<NUM>(m,<NUM>). MS:m/z <NUM>,[M+H]+.

<NUM>-(<NUM>-(<NUM>-methyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>-yl)benzyl)phenyl)butyric acid (<NUM>), <NUM>-methyl-<NUM>-piperazineethylamine (<NUM>), tetrahydrofuran (<NUM>), N,N-diisopropyl ethylamine (<NUM>) and <NUM>-(<NUM>-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (<NUM>) were added into a <NUM> single-neck flask, and stirred at room temperature for <NUM> hours after addition. After the reaction was completed, saturated aqueous ammonium chloride solution was added to dilute, extracted with ethyl acetate, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain <NUM> of a white solid. <NUM>H NMR(<NUM>,CD<NUM>OD<NUM>):δ=<NUM>-<NUM>(m,<NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>). MS:m/z <NUM>,[M+H]+.

<NUM>-(<NUM>-(<NUM>-methyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>-yl)benzyl)phenyl)butyric acid (<NUM>), <NUM>-(<NUM>-aminoethyl)piperazine (<NUM>), tetrahydrofuran (<NUM>), N,N-diisopropyl ethylamine (<NUM>) and <NUM>-(<NUM>-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (<NUM>) were added into a <NUM> single-neck flask, and stirred at room temperature for <NUM> hours after addition. After the reaction was completed, saturated aqueous ammonium chloride solution was added to dilute, extracted with ethyl acetate, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain <NUM> of a white solid. <NUM>H NMR(<NUM>,CD<NUM>OD<NUM>):δ7. <NUM>-<NUM>(m,<NUM>),<NUM>(d,J=<NUM>,<NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>(t,J=<NUM>,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>). MS:m/z <NUM>,[M+H]+.

<NUM>-(<NUM>-(<NUM>-methyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>-yl)benzyl)phenyl)butyric acid (<NUM>), N<NUM>-benzyl-N<NUM>-methylethane-<NUM>,<NUM>-diamine (<NUM>), tetrahydrofuran (<NUM>), N,N-diisopropyl ethylamine (<NUM>) and <NUM>-(<NUM>-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (<NUM>) were added into a <NUM> single-neck flask, and stirred at room temperature for <NUM> hours after addition. After the reaction was completed, saturated aqueous ammonium chloride solution was added to dilute, extracted with ethyl acetate, the organic phases were combined, washed once with saturated salt solution, dried on anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain <NUM> of a white solid. <NUM>H NMR(<NUM>,CD<NUM>OD):δ=<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(m,<NUM>). <NUM>,[M+H]+.

<NUM>-(<NUM>-(<NUM>-Methyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran -<NUM>-yl)benzyl)phenyl)butyric acid (prepared by the method of <NPL>) (<NUM>, <NUM> mmol), N,N-dimethylformamide (<NUM>), N,N-diisopropylethylamine (<NUM>, <NUM>. 4mmol), N<NUM>-methyl-N<NUM>-(prop-<NUM>-yn-<NUM>-yl)ethane-<NUM>,<NUM>-diamine (Compound 1B) (<NUM>, <NUM> mmol), <NUM>-(<NUM>-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (<NUM>, <NUM> mmol) were added successively into a <NUM> reaction flask, and stirred at room temperature for <NUM> hours. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography (dichloromethane: methanol = <NUM>:<NUM>) to obtain a white solid (<NUM>). <NUM>H NMR(<NUM>,DMSO-d6):δppm <NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(t,J=<NUM>, <NUM>), <NUM>-<NUM>(d,J=<NUM>, <NUM>),<NUM>-<NUM>(d,J=<NUM>, <NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(t, J=<NUM>, <NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(t,J=<NUM>,<NUM>),<NUM>-<NUM>(t,J=<NUM>,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s,<NUM>),<NUM>-<NUM>(t,J=<NUM>,<NUM>),<NUM>-<NUM>(m,<NUM>). <NUM>C NMR(<NUM>,DMSO-d6):δppm <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>. <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>; MS[M+H]+=<NUM>.

The compound was obtained by referring to the similar preparation scheme in Example <NUM>, ESI-MS: <NUM> [M+H]+.

The specific preparation method was as follows:
<CHM>.

<NUM>-(<NUM>-(<NUM>-Methyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>-yl)benzyl)phenyloxy)propionic acid (<NUM>), N,N-dimethylformamide (<NUM>), N,N-diisopropylethylamine (<NUM>), N<NUM>-methyl-N<NUM>-(prop-<NUM>-yn-<NUM>-yl)ethane-<NUM>,<NUM>-diamine (<NUM>), <NUM>-(<NUM>-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (<NUM>) was added successively into a <NUM> reaction flask, and stirred at room temperature for <NUM> hours after addition. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain a white solid (<NUM>).

The compound was obtained by referring to the similar preparation scheme in Example <NUM>.

<NUM>-(<NUM>-(<NUM>-Methyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>-yl)benzyl)benzyl)oxy)propionic acid (<NUM>), N,N-dimethylformyl (<NUM>), N,N-diisopropylethylamine (<NUM>), N<NUM>-methyl-N<NUM>-(prop-<NUM>-yn-<NUM>-yl)eth-<NUM>,<NUM>-diamine (<NUM>), <NUM>-(<NUM>-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (<NUM>) was added successively into a <NUM> reaction flask, and stirred at room temperature for <NUM> hours. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain <NUM> of a white solid. <NUM>H NMR(<NUM>,DMSO-d6):δ7. <NUM>(s, <NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(s, <NUM>),<NUM>(s, <NUM>),<NUM>(s, <NUM>),<NUM> (s,<NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(d,J=<NUM>, <NUM>),<NUM>(s,<NUM>),<NUM>(s,<NUM>),<NUM>(s, <NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>-<NUM>(m,<NUM>),<NUM>(m,<NUM>),<NUM>(s,<NUM>). <NUM>C NMR(<NUM>,DMSO-d6):<NUM>,<NUM>,<NUM>, <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>. <NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>. MS:m/z <NUM>,[M+H]+.

The compound was obtained by referring to the similar preparation scheme in Example <NUM>, ESI-MS: <NUM>[M+H]+.

(E)-<NUM>-(<NUM>-(<NUM>-Methyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>-yl)benzyl)phenyl)vinylacetic acid (<NUM>), N,N-dimethylformamide (<NUM>), N,N-diisopropylethylamine (<NUM>), N<NUM>-methyl-N1-(prop-<NUM>-yn-<NUM>-yl)ethane-<NUM>,<NUM>-diamine (<NUM>), <NUM>-(<NUM>-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (<NUM>) was added successively into a <NUM> reaction flask, and stirred at room temperature for <NUM> hours after addition. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain a white solid (<NUM>).

<NUM>-(<NUM>-(<NUM>-Ethynyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>-yl)benzyl)phenyloxy)propionic acid (<NUM>), N,N-dimethylformamide (<NUM>), N,N-diisopropylethylamine (<NUM>), N<NUM>-methyl-N<NUM>-(prop-<NUM>-yn-<NUM>-yl)ethane-<NUM>,<NUM>-diamine (<NUM>), <NUM>-(<NUM>-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (<NUM>) was added successively into a <NUM> reaction flask, and stirred at room temperature for <NUM> hours after addition. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain a white solid (<NUM>).

The compound was obtained by referring to the similar preparation scheme in Example <NUM>, ESI-MS: <NUM>[M+H]+.

<NUM>-(<NUM>-(<NUM>-Methyl-<NUM>-((<NUM>,3R,4R,<NUM>,6R)-<NUM>,<NUM>,<NUM>-trihydroxy-<NUM>-(methylthio)tetrahydro-<NUM>-pyran-<NUM>-yl)benzyl)pheny)valeric acid (<NUM>), N,N-dimethylformamide (<NUM>), N,N-diisopropylethylamine (<NUM>), N<NUM>-methyl-N<NUM>-(prop-<NUM>-yn-<NUM>-yl)ethane-<NUM>,<NUM>-diamine (<NUM>), <NUM>-(<NUM>-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (<NUM>) was added successively into a <NUM> reaction flask, and stirred at room temperature for <NUM> hours after addition. The reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane for three times, the organic phases were combined, washed with saturated salt solution, dried on anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain a pale yellow solid (<NUM>).

The introduction of the "alkynyl" functional group into some compounds of the present invention has two advantages: on the one hand, the "alkynyl" functional group can use "Click chemistry" to connect bioluminescent markers, which is beneficial to accurately determine the distribution of the compound in the body. For example, "click chemistry" occurs between the compounds of present invention and "azide" compounds with fluorescent chromophores, under the catalysis of copper salts, to generate fluorescent compounds with "triazole structure". The compounds of the present invention can also be linked with other biological compounds with biomarker functions to form new chemical substances that are easy to detect, which is of great significance to fully study the effectiveness and safety of such compounds. On the other hand, the "alkynyl" functional group connects with other pharmacophore groups through "Click chemistry", which is conducive to finding candidate compounds with better comprehensive properties. Examples were as follows:.

The compound of Example <NUM>, copper sulfate, and <NUM>-hydroxy-<NUM>-azidocoumarin (refer to <NPL> ; <NPL>,S3326/<NUM>-S3326/<NUM> ; <NPL>; <NPL>; <NPL>) were reacted at room temperature to obtain a product, Rf: <NUM> (dichloromethane:methanol=<NUM>:<NUM>).

The compound of Example <NUM>, copper sulfate, and cyclopropyl azide (refer to <NPL> ; <NPL> ; <NPL>) were reacted at room temperature to obtain a product. Rf: <NUM> (dichloromethane:methanol=<NUM>:<NUM>). The compound has similar biological activity to that of Example <NUM>, and has better lipid solubility and water solubility than the compound of Example <NUM>.

The inhibitory activity of SGLT1 was tested with reference to the method described in document (<NPL>, Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter <NUM>(SGLT1) Inhibitor Restricted to the Intestinal Lumen,for the Treatment of Diabetes).

wherein A represents: activity IC<NUM><<NUM>, B represents <NUM><IC<NUM><<NUM>, C represents IC<NUM>><NUM>,.

The experimental results show that the compounds of the present invention have significant activity of inhibiting SGLT1.

In the mouse glucose tolerance test, the compounds of the present invention have the effect of improving the blood glucose level of the test animals.

The compounds of the present invention help to reduce body weight, and in in vivo pharmacodynamic studies, the compounds of the present invention reduced the body weight of experimental animals.

The compounds of the present invention have very low or no absorption in vivo, and pharmacokinetic studies have shown that the compounds of the present invention are hardly detected in experimental animals, and have almost no side effects on other organs in the body.

Inhibitory activity testing was performed with reference to a similar method described in document (<NPL>; <NPL>; <NPL>; <NPL>).

In this experiment, the in vitro activity assay was evaluated using the uptake of <NUM>-NBDG (<NUM>-Deoxy-<NUM>-[(<NUM>-nitro-<NUM>,<NUM>,<NUM>-benzoxadiazol-<NUM>-yl)amino]-D-glucose , CAS <CIT>) by human embryonic kidney epithelial cells (HEK293, stably expressing human SGLT1), and the SGLT1 inhibitory activity of the target compound was determined by measuring its half-maximal inhibitory concentration (IC<NUM>).

HEK293 cells that can stably express human SGLT1 gene were inoculated into a <NUM>-well clear-bottom black plates containing DMEM medium. The cells were incubated at <NUM>, <NUM>% CO<NUM> in a cell incubator. The medium in the <NUM>-well plate was aspirated, and the plate was treated with low-glucose serum-free DMEM medium, and washed once with non-specific uptake buffer and once with Na+-dependent uptake buffer. Uptake buffer containing test compound was added to each well of cells, followed by uptake buffer containing <NUM>-NBDG for glucose uptake, and the cell plate was incubated at <NUM>, <NUM>% CO<NUM>. The compounds were gradiently diluted. The uptake reaction was stopped by removing the culture medium, and after washing the cells with ice-cold uptake buffer, the washing solution was removed. The cells were lysed by adding NaOH, and the content of <NUM>-NBDG in the cells was detected by a fluorescence microplate reader. The protein concentration of the lysate was measured by BCA method, the uptake of <NUM>-NBDG was quantified by fluorescence intensity/protein content, and the obtained data were analyzed using GraphPad Prism to determine the median inhibitory concentration (IC<NUM>) of the compound to be tested.

The comparative compound <NUM> is the compound numbered "<NUM>" in the document (<NPL>, Discovery of LX2761,a Sodium-Dependent Glucose Cotransporter <NUM>(SGLT1)Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes). It was prepared and identified according to the synthetic method described in the document.

The experimental results show that the compounds of the examples of the present invention, for example Example <NUM>, has significant activity of inhibiting SGLT1.

(<NUM>) From day <NUM> to day <NUM>, the observation of animal defecation after continuous administration is summarized as follows:.

(<NUM>) The results of oral glucose tolerance test (OGTT) on day <NUM> are shown in <FIG>.

Experimental summary: (<NUM>) From day <NUM> to day <NUM>, the compound <NUM> of Example <NUM> was continuously administered, in the high dose group (<NUM>/kg), only <NUM> animal had loose stools on day <NUM>, and the animals did not have loose stools on day <NUM> to day <NUM>; in the low-dose group (<NUM>/kg), the animals did not have loose stools after continuous administration for <NUM> days.

(<NUM>) On day <NUM>, in the oral glucose tolerance test (OGTT), the results in <FIG> show that both the high and low dose groups of the compound of Example <NUM> can significantly reduce the blood glucose level of mice.

The experimental results show that: the compounds of Example <NUM> and Example <NUM> had almost no absorption in vivo, and the absolute bioavailability values were all less than <NUM>%; while the absolute bioavailability of the comparative compound <NUM> is <NUM>%, and the absolute bioavailability of dapagliflozin was <NUM>%. Therefore, the comparison compound <NUM> and dapagliflozin were both absorbed into the blood after oral administration, and their exposure to organs in the body (e.g., brain, heart and other organs) may lead to potential and unpredictable toxicity.

In addition to being expressed in the kidney, SGLT1 also exists in intestinal epithelial cells and organs such as the heart and the brain. Compared with the comparative compounds <NUM> and dapagliflozin, the compounds of Example <NUM> and Example <NUM> of the present invention were hardly detected in vivo after oral administration. Therefore, according to preliminary experimental evidence, it is inferred that the compounds of Example <NUM> and Example <NUM> of the present invention have no side effects on various organs such as the heart and brain.

The experimental results show that the combination of the compound of Example <NUM> and sitagliptin can significantly reduce the blood glucose level of diabetic model animals, and there is a dose-effect relationship.

Methods: The collected rat feces were processed, and the feces suspension was obtained for the determination of metabolic stability. The mixed reaction system consisting of the rat feces suspension and the compound of Example <NUM> was incubated at <NUM> for <NUM>, <NUM>, <NUM> and <NUM>. The compound of Example <NUM> in the incubation system was analyzed to determine the total amount of remaining compound. Wherein, "+" represents the remaining percentage being: <<NUM>%; "++" represents the remaining percentage being: <NUM>% to <NUM>%; "+++" represents the remaining percentage being: <NUM>% to <NUM>%; "++++" means the remaining percentage being: ><NUM>%.

The test results showed that after the compound of Example <NUM> was incubated with microorganisms in rat feces for about <NUM> hours, the remaining compound of Example <NUM> was still relatively abundant (><NUM>%). It was illustrated that the compound of Example <NUM> could still maintain high stability under the metabolism of intestinal microorganisms.

Claim 1:
A compound of formula (III), a tautomer or pharmaceutically acceptable salt thereof,
<CHM>
wherein, X is selected from methyl, or ethynyl;
R<NUM> is selected from hydrogen, methyl, or ethyl;
R<NUM> is selected from hydrogen, or methyl;
m2=<NUM>;
n2 = <NUM>;
Y1 is a linking group selected from the following structures:
<CHM>
<CHM>