WO2015027963A1 - Aromatic ring derivative, and pharmaceutical composition and use thereof - Google Patents

Abstract

The present invention relates to an aromatic ring derivative, and pharmaceutical composition and use thereof, in particular to aromatic ring derivatives or hydrates as represented by general formula (II), solvates, stereoisomers thereof, pharmaceutically acceptable salts, co-crystals, prodrugs, a preparation method, pharmaceutical compositions containing the derivative, and medical uses in the preparation of a sodium dependent glucose transporter (SGLT) inhibitor, the definition of each substituent group in general formula (II) being the same as the definition in the specification.

Description

Aromatic ring derivatives, pharmaceutical compositions thereof and applications thereof Technical field

The present invention relates to a novel aromatic ring derivative, a pharmaceutical composition thereof and use thereof.

Background technique

Type II diabetes is the most common type of diabetes, and worldwide type II diabetes accounts for about 90% of all diabetes. The incidence of type 2 diabetes is gradually increasing due to modern unhealthy lifestyles such as reduced exercise and high-calorie diets. In patients with type II diabetes, high blood sugar is caused by the body's inability to respond effectively to insulin. Hyperglycemia is the leading cause of diabetic complications such as cardiovascular disease, stroke and renal failure, and these complications further aggravate the condition of diabetic patients.

The currently approved drugs for the treatment of type 2 diabetes are insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitors, and amylin analogues. Incretin hormone analogue, dipeptidyl peptidase inhibitor (DPP-IV), and the like. However, long-term use of these hypoglycemic agents does not achieve the expected reduction in glycated hemoglobin (HbAlc), and these hypoglycemic agents have side effects such as hypoglycemia, weight gain and cardiovascular risk. These side effects add to the burden on diabetics. Therefore, there is an urgent need to develop a new type of hypoglycemic agent with high efficacy and few side effects for type 2 diabetes.

Sodium-dependent glucose co-transporters (SGLTs) transmembrane proteins, particularly SGLT-2, are considered to be promising new hypoglycemic agents (Clinical Diabetes, 2010, 28, 5-10). SGLT-2 is encoded by the SLC5 gene and is expressed primarily in renal proximal convoluted tubules. About 90% of renal glucose reabsorption occurs in the epithelial cells of the S1 segment of the proximal renal cortex, and SGLT-2 is the primary transporter responsible for this process. SGLT-2 is a low-affinity, high-capacity transporter that allows SGLT-2 to efficiently transport glucose and sodium ions from the lumen to the tubular epithelial cytoplasm (in a molar ratio of 1:2) (Nephrol Dial Transplant, 2010) , 25, 2041-2043). In fact, renal tubular re-absorption of glucose is very efficient, and the glucose load in the kidney is about 180 g/day, but only a small amount is eventually excreted.

Studies have shown that inhibition of SGLT-2 reduces the body's ability to reabsorb glucose through the kidneys, thus allowing the body to clear glucose from the body through the urine, thereby reducing blood sugar (Endocrine Reviews, 2011, 32, 515-531). In some family members of the SGLT-2 gene mutation, there is no significant renal insufficiency, hypoglycemia or other diseases other than urinary glucose excretion (J. Am. Soc. Nephrol, 2003, 14, 2873-82). Some SGLT-2 inhibitors have been developed and shown good activity and selectivity, among which canagliflozin, Empagliflozin and Dapagliflozin are on the market, Epa Ipragliflozin, Tofogliflozin, Luseogliflozin, and Ertugliflozin are at the stage of new drug marketing or clinical research.

A series of patents for SGLT-2 inhibitors have been published.

(1) WO2012019496 discloses a compound having the following structure as a SGLT-2 protein inhibitor

among them:

Ring A is selected from aryl or heteroaryl, wherein each aryl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl Substituted with a substituent such as a heteroaryl group;

R ⁵ and R ⁶ are each independently selected from a hydrogen atom or a halogen atom;

However, the detailed description in this patent is not considered to be part of the present invention.

(2) WO2010023594 discloses a compound having the following structure as a sodium-dependent glucose transporter (SGLT) inhibitor, which is useful for treating and preventing type II diabetes.

among them:

R ¹ is C _1-4 alkyl, C _1-4 alkoxy, Cl, F, acyl, F C _1-2 alkyl, -SO ₂ -C _1-4 alkyl or C _3-6 naphthenic base;

R ² is C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkynyl,

Cl, F, acyl, F-C _1-2 alkyl, -SO ₂ -C _1-4 alkyl, C _3-6 cycloalkyl, C _5- containing 1 or 2 N, O, S heteroatoms ₆ heterocyclic group;

However, the detailed description in this patent is not considered to be part of the present invention.

(3) WO2011051864 discloses a SGLT-2 compound having the following structure:

among them:

R ^{1 is} selected from the group consisting of hydroxyl, F, Cl, -OC(=O)-C _1-4 alkyl, -OC(=O)-aryl, -OC(=O)-OC _1-4 alkyl or -OC (=O)-O-aryl;

R ^{2 is} selected from the group consisting of hydroxyl, -OC _1-4 alkyl or -O-CH ₂ CH ₂ -OR ^2a ;

Provided that when R and R ^{1 are} simultaneously a hydroxyl group, R ^{2 is} selected from a hydroxyl group or -O-CH ₂ CH ₂ -OR ^2a ;

R is selected from OH;

Alternatively, when R ¹ is selected from -OC (= O) -C _1-4 alkyl or -OC (= O) - an aryl group, the same as R ¹ or R is hydroxy;

R ^{2a is} selected from H, -C(=O)-C _1-4 alkyl, -C(=O)-aryl, -C(=O)-OC _1-4 alkyl or -C(=O) -O-aryl;

However, the detailed description in this patent is not considered to be part of the present invention.

Summary of the invention

It is an object of the present invention to provide a compound of the formula (II) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

among them:

W is selected from -O- or -NR ¹² -;

R ¹ and R ² are each independently selected from H, F, Cl, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

Alternatively, R ¹ and R ² may form =0;

R ³ , R ^3a and R ^3b are each independently selected from H, F, Cl, hydroxy, C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy being optionally further Substituted to 5 substituents selected from F, Cl, hydroxy, -CH ₂ F, -CHF ₂ or -CF ₃ ;

R ^{3C is} selected from a hydroxyl group;

R ^3C , R ¹ or R ² and any one of R ³ , R ^3a , R ^3b form a 4-5 membered ring;

R ⁸ and R ⁹ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy, -O-(CH ₂ ) _m -OR ¹³ Or -(CH ₂ ) _m -R ¹³ , the hydroxyl group, alkyl group or alkoxy group optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxyl, cyano, C _1-4 alkane Substituted with a substituent of C _1-4 alkoxy, -(CH ₂ ) _m -OR ¹³ or -(CH ₂ ) _m -R ¹³ ;

R ^{12 is} selected from H or C _1-4 alkyl;

R ^{13 is} selected from C _3-6 cycloalkyl, 3 to 6 membered heterocyclic, C _6-10 aryl, 5 to 12 membered heteroaryl, 5 to 12 membered spiro group, 4 to 12 membered bridged ring group. Or a 4- to 12-membered ring group, and the cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, spiro group, bridged ring group or cyclohexyl group is further further selected from 0 to 5 selected from F Substituted with a substituent of Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , =0, hydroxy, C _1-3 alkyl or C _1-3 alkoxy; and the snail The cyclo, bridged or bicyclic group may contain from 0 to 5 atoms or groups selected from N, O or S(=O) _n , the heteroaryl or heterocyclic group containing from 1 to 5 An atom from N, O or S;

requirement is:

When R ¹ and R ^{2 are} both H, R ⁹ is H, and W is -O-, it is selected from the following cases:

(1) R ^{3 is} selected from H, R ^{3a is} selected from H, F, Cl or C _1-4 alkyl, and R ^{3b is} selected from F, Cl, C _1-4 alkyl, monofluoro substituted C _1-4 alkane a difluoro-substituted C _1-4 alkyl group or a trifluoro-substituted C _1-4 alkyl group, and when R ^3a is H, R ^{3b is} not F or Cl;

(2) R ^3b and R ^3c form a 5-membered heterocyclic ring, and the heterocyclic ring contains 1-2 selected from O atoms;

When R ¹ and R ^{2 are} both H, W is -O-, and R ^{9 is} not H, R ^{3 is} selected from H, and R ^3a and R ^3b are each independently selected from H, F, Cl, C _1-4 alkyl. a monofluoro-substituted C _1-4 alkyl group, a difluoro-substituted C _1-4 alkyl group or a trifluoro-substituted C _1-4 alkyl group;

n is selected from 0, 1 or 2;

m is selected from 0, 1, or 2.

In the present invention, the phrase "as a selection" means that the scheme after "as a selection" and the scheme before "as a selection" are a side-by-side selection relationship, rather than a further selection in the foregoing scheme.

Preferred embodiments of the invention include a compound of the formula (II) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

W is selected from -O- or -NR ¹² -;

R ¹ and R ² are each independently selected from H, F, hydroxy, C _1-2 alkyl or C _1-2 alkoxy, preferably H, hydroxy, methyl or methoxy;

Alternatively, R ¹ and R ² may form =0;

R ³ , R ^3a and R ^3b are each independently selected from H, F, hydroxy or C _1-4 alkyl, wherein H, F, hydroxy or C _1-2 alkyl is preferred; wherein said alkyl optionally further Substituted by 0 to 5 substituents selected from F, Cl or hydroxy;

R ^{3C is} selected from a hydroxyl group;

R ^3C , R ¹ or R ² and any one of R ³ , R ^3a , R ^3b form a 4-5 membered ring;

R ^{8 is} selected from H, F, Cl, hydroxy, C _1-4 alkoxy, -O-(CH ₂ ) ₂ -O-cyclopropyl, -(CH ₂ ) _m -OR ¹³ or -(CH ₂ ) _{m -} R ¹³ , wherein preferably C _1-4 alkoxy, -O-(CH ₂ ) ₂ -O-cyclopropyl, -(CH ₂ ) _m -OR ¹³ or -(CH ₂ ) _m -R ¹³ , Further preferred is a C _1-4 alkoxy group, more preferably a C _1-2 alkoxy group, and still more preferably an ethoxy group;

R ^{9 is} selected from H, F, methyl, ethyl, methoxy or ethoxy, of which H or F is preferred;

R ^{12 is} selected from H, methyl or ethyl, of which H or methyl is preferred;

R ^{13 is} selected from C _3-6 cycloalkyl or 3 to 6 membered heterocyclic group, and said heterocyclic group contains 1 to 3 atoms selected from N, O or S;

requirement is:

When R ¹ and R ^{2 are} both H, R ⁹ is H, and W is -O-, it is selected from the following cases:

(1) R ^{3 is} selected from H, R ^{3a is} selected from H, F, Cl or C _1-4 alkyl, and R ^{3b is} selected from F, Cl, C _1-4 alkyl, monofluoro substituted C _1-4 alkane a difluoro-substituted C _1-4 alkyl group or a trifluoro-substituted C _1-4 alkyl group, and when R ^3a is H, R ^{3b is} not F or Cl;

(2) R ^3b and R ^3c form a 5-membered heterocyclic ring, and the heterocyclic ring contains 1-2 selected from O atoms;

When R ¹ and R ^{2 are} both H, W is -O-, and R ^{9 is} not H, R ^{3 is} selected from H, and R ^3a and R ^3b are each independently selected from H, F, Cl, C _1-2 alkyl. Or a difluoro-substituted C _1-4 alkyl group;

m is selected from 0 or 1.

Preferred embodiments of the invention include a compound of the formula (II) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

W is selected from -O- or -NR ¹² -;

R ¹ and R ² are each independently selected from H, F, hydroxy, methyl, ethyl, methoxy or ethoxy, with H, F, hydroxy, methyl or methoxy being preferred;

Alternatively, R ¹ and R ² may form =0;

R ³ , R ^3a and R ^3b are each independently selected from H, F, hydroxy, methyl, ethyl, -CH ₂ F, -CHF ₂ or -CF ₃ , with H, F, hydroxy, methyl, and B being preferred. Base or -CH ₂ F;

R ^{3C is} selected from a hydroxyl group;

R ^3C , R ¹ or R ² and any one of R ³ , R ^3a , R ^3b form a 4-5 membered ring;

R ^{8 is} selected from H, F, Cl, methoxy, ethoxy, cyclopropyl, -O-oxocyclopentyl or -O-(CH ₂ ) ₂ -O-cyclopropyl, of which methoxy is preferred a group, an ethoxy group, a cyclopropyl group, a -O-(CH ₂ ) ₂ -O-cyclopropyl group or an -O-oxocyclopentyl group, of which an ethoxy group or an -O-oxocyclopentyl group is further preferred. More preferably, an ethoxy group;

R ^{9 is} selected from H or F;

R ^{12 is} selected from H or methyl, wherein H is preferred;

requirement is:

When R ¹ and R ^{2 are} both H, R ⁹ is H, and W is -O-, R ^{3 is} selected from H, R ^{3a is} selected from H, F or methyl, and R ^{3b is} selected from F, -CHF ₂ or - CF ₃ , and when R ^3a is H, R ^{3b is} not F;

When R ¹ and R ^{2 are} both H, W is -O-, and R ⁹ is F, R ^{3 is} selected from H, and R ^3a and R ^3b are each independently selected from H, F, methyl, ethyl, -CH ₂ F, -CHF ₂ or -CF ₃ ;

m is selected from 0.

In a preferred embodiment of the invention, the invention relates to a compound selected from, but not limited to:

The present invention relates to a compound represented by the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the salt includes, but is not limited to, a sodium salt, a potassium salt, a calcium salt, a magnesium salt, and a cesium salt. Salt, ammonium salt, trimethylamine salt, triethylamine salt, pyridinium salt, methylpyridine salt, 2,6-lutidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, bicyclic ring Hexyl ammonium salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, trifluoroacetate, acetate, maleate, tartrate, citrate, succinic acid Salt, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronide, galacturonic acid Salt, citrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, besylate, methanesulfonate, ethanesulfonate, trifluoro Methanesulfonate or a combination thereof, preferably sodium salt, potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, hydrochloride salt, hydrobromide salt, sulfate salt, phosphorus Salts, trifluoroacetate, acetate, maleate, aspartate, glutamate, malate, or a combination thereof.

The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable cocrystal thereof, wherein the co-crystal is a co-crystal of the compound with an amino acid, an organic acid, water, and/or other solvent. Wherein the amino acid is selected from the group consisting of L-lysine, L-tryptophan, L-phenylalanine, L-threonine, L-isoleucine, L-leucine, L-valine, L- Arginine, L-histidine, L-alanine, L-aspartic acid, L-asparagine, L-cysteine, L-glutamine, L-glutamic acid, L- Methionine, L-valine, L-serine, L-tyrosine, L-glycine, L-pyroglutamic acid, D-lysine, D-tryptophan, D- Phenylalanine, D-threonine, D-isoleucine, D-leucine, D-valine, D-arginine, D-histidine, D-alanine, D- Aspartic acid, D-asparagine, D-cysteine, D-glutamine, D-glutamic acid, D-methionine, D-valine, D-serine, D-case Acid, D-glycine or D-pyroglutamic acid;

The amino acid is preferably L-phenylalanine, L-valine or L-pyroglutamic acid, and the solvent is preferably 1,2-ethanediol, 1,2-propanediol or 1-methyl-1,2-ethanediol. .

A further object of the present invention is to provide a pharmaceutical composition comprising an effective amount of a compound of the formula (I) or a stereoisomer, hydrate, solvate or pharmaceutically acceptable salt thereof. a co-crystal or prodrug and/or one or more additional therapeutic agents and a pharmaceutically acceptable carrier, excipient or diluent, wherein preferably 0 to 3 other therapeutic agents and a pharmaceutically acceptable carrier, Forming agent or diluent.

Other therapeutic agents preferred in the present invention include:

(a) a SGLT-2 inhibitor or a pharmaceutically acceptable salt;

The SGLT-2 inhibitors described therein are preferably dapagliflozin, canagliflozin, Atigliflozin, Empagliflozin, Ipragliflozin, Tofoglifl ozin, Luseogliflozin, Remogliflozin, Sergliflozin or Ertugliflozin; and/or

(b) a DPP-IV inhibitor or a pharmaceutically acceptable salt;

The DPP-IV inhibitors described therein are preferably linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, Denagliptin, Carmegliptin, Melogliptin, Dutogliptin, Teneligliptin, Gemigliptin, or Qug Trelagliptin; and/or

(c) biguanides, thiazolidinediones, sulfonylureas, levonides, alpha-glucosidase inhibitors or glucagon-like peptide-1 analogues, or pharmaceutically acceptable salts thereof or medicine;

The therapeutic agent biguanide therapeutic agent is preferably metformin or phenformin, and the thiazolidinedione therapeutic agent is preferably Ciglitazone, Pioglitazone, Rosiglitazone, and Qug. Troglit azone, Farglitazar or Darglitazoan, sulfonylurea therapeutic agent selected from Gli mepiride, Tolglybutamide, Gleby Glibornuride, Glibenclamide, Gliquidone, Glipizide or Gliclazipe, linaglinide is preferred as Nateglinide ), Repaglinide or Mitiglinide, the α-glucosidase inhibitor is selected from the group consisting of Acarbose, Voglibose or Miglitol. The glucagon-like peptide-1 analog is preferably Exenatide or Liraglutide.

The pharmaceutical composition of the present invention can be formulated into a solid oral preparation, a liquid oral preparation, an injection or the like. Oral directly includes tablets, dispersible tablets, dragees, granules, dry powders, capsules and solutions, and injections include small needles, Large infusion and freeze-dried powder needles.

A further object of the present invention is to provide a compound of the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal thereof or a prodrug thereof for the preparation of sodium-dependent glucose transport Application in protein inhibitors;

a sodium-dependent glucose transporter inhibitor for use in the preparation of a medicament for treating a metabolic disease;

The metabolic disease described therein is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, Obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension;

Among them, diabetes is preferably type II diabetes.

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. The nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C, and ¹⁴ C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), 氚 (T, also known as super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes including ¹⁴ N and ¹⁵ N, the fluorine isotope ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Alkyl" means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably a linear and branched group of 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, most preferably 1 to 2 carbon atoms; examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl -2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl Benzyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-Dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2-dimethylpentyl , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2 ,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethyl Base, 2,5-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl Alkyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl and n-decyl; alkyl may be substituted or unsubstituted, When substituted, the substituent may be substituted at any available point of attachment, preferably from 1 to 5 substituents selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl , thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclylene, hydroxyalkyl, =0, Carbonyl, aldehyde, carboxylic acid, carboxylate, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m - alkynyl-R ^a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from H, hydroxy , amino, carbonyl, alkyl, alkoxy, cycloalkyl, hetero Group, an aryl group, a heteroaryl group, a sulfonyl group or a trifluoromethanesulfonyloxy group, alternatively, R ^b and R ^c may form a five or six membered cycloalkyl or heterocycloalkyl; R ^a and R ^d are each independently selected from Aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged, spiro or cis a.

"Alkylene" means a straight or branched chain alkane derived from the removal of two hydrogen atoms from the above alkyl group, including -(CH ₂ ) _v - (v is an integer from 1 to 18), and the alkylene embodiment includes but not Limited to methylene, ethylene and propylene; alkylene may be substituted or unsubstituted, when substituted, the substituent is preferably from 1 to 5 selected from F, Cl, Br, I, alkyl , cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, And a cyclic group, a hydroxyalkyl group, a =0, a carbonyl group, an aldehyde, a carboxylic acid, a carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(= O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an alternative, R ^b and R ^c can Forming a five- or six-membered cycloalkyl or heterocyclic group; R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridge A ring group, a spiro group or a bicyclic group.

"Alkoxy" means an -O-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, untertiary Butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy; when substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy , haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl , =O, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a ,- (CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -( CH ₂ ) _m -alkynyl-R ^a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected From H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R ^b and R ^c may form Five or six-membered ring The alkyl or heterocyclic groups R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or And ring base.

"Alkoxyalkyl" means an alkyl group attached to an alkoxy group; alkoxyalkyl can be substituted or unsubstituted, non-limiting examples of which include methoxymethyl, methoxyethyl , ethoxymethyl, ethoxyethyl, propoxymethyl, propoxyethyl, 2-propoxymethyl, butoxypropyl, tert-butoxyethyl, pentyloxy a group, a hexyloxyethyl group, a cyclopropoxymethyl group, a cyclopropoxyethyl group, a cyclopropoxypropyl group, and a cyclohexyloxymethyl group; when substituted, the substituent is preferably 1 to 5 selected From F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, heteroaryl, hetero Ring group, bridged ring group, spiro group, cis ring group, hydroxyalkyl group, =0, carbonyl group, aldehyde, carboxylic acid, carboxylate, -(CH ₂ ) _m -C(=O)-R ^a , O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl group or -NR ^b R ^c, wherein R ^b R ^c each independently selected from H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl group, alternatively, R ^b And R ^c may form a five or six membered cycloalkyl or heterocyclic group; R ^a and R ^d are each independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, Ester group, bridged ring group, spiro group or cis ring group.

"Alkenyl" means an alkyl group as defined herein above containing at least one carbon-carbon double bond, preferably having from 2 to 20 carbon atoms, further preferably from 2 to 12 carbon atoms, more preferably 2 on the backbone Alkenyl groups may be substituted or unsubstituted to 8 carbon atoms; non-limiting examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butene , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1- Butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl- 1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octyl Alkenyl, 1-decenyl, 3-decenyl, 1-decenyl, 4-nonenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene , 1,4-hexadiene, 3-undecyl, 4-dodecenyl and 4,8,12-tetradecatrienyl; when substituted, the substituent is from 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol Hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, Carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C( =O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl- R ^a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from H, hydroxy, amino, carbonyl , alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R ^b and R ^c may form a five or six membered cycloalkyl group or Heterocyclyl; R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or bicyclic base.

"Alkynyl" means an alkyl group as defined herein above containing at least one carbon-carbon triple bond, preferably containing from 2 to 20 carbon atoms, further preferably from 2 to 8 carbon atoms, more preferably 2 on the backbone Alkynyl groups up to 4 carbon atoms; alkynyl groups may be substituted or unsubstituted; non-limiting examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl , 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexyl Alkynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl, 4-decynyl, 3-undynyl and 4-tweldium Alkynyl; when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy , nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxy Acid, carboxylate, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(= O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH2) _m -alkenyl-R ^a , OR ^d or -(CH2) _m -alkynyl-R ^a (where m, n Is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from H, hydroxy, amino, carbonyl, alkyl, alkoxy , cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic group; R ^a and R ^{d is} each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Amino" means -NH ₂ and may be substituted or unsubstituted, and when substituted, the substituent is preferably 1 to 3 or less, independently selected from alkyl, cycloalkyl, haloalkyl, sulphur Alcohol, hydroxy, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxy Acid, carboxylate, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(= O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (wherein m, n is 0, 1 or 2), an arylthio group, a thiocarbonyl group, a silyl group or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from the group consisting of H, a hydroxyl group, an amino group, a carbonyl group, An alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and alternatively, R ^b and R ^c may form a five- or six-membered cycloalkyl group or a hetero a cyclic group; R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cycloalkyl. .

"Alkylthio" means -S-alkyl or -S-(unsubstituted cycloalkyl), and non-limiting examples include methylthio, ethylthio, propylthio and butylthio.

"Acyl" or "carbonyl" refers to a -C(=O)-R ^a group, wherein R ^{a is} as defined above.

"Aldehyde" means -C(=O)-H.

"=O" refers to the customary usage in the art and refers to an oxygen atom bonded by a double bond, such as a double bond oxygen atom attached to a carbon atom in a carbonyl group.

"Sulfur" means =S.

"Halogen" means fluorine, chlorine, bromine, or iodine.

"Hydroxy" means -OH.

"Cyano" means -C≡N.

"Isocyano" means -N≡C.

"Nitro" means -NO ₂ .

"Carboxylic acid" means -C(=O)-OH.

"Carboxylic acid ester" refers to ^{-C (= O) -OR d,} R d is selected from alkyl, cycloalkyl, or heterocyclyl group.

"Haloalkyl" means a halogen-substituted alkyl group as defined herein above, and non-limiting examples include monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromo. Methyl, 1-fluoroethyl-2-yl, 2-fluoroethyl-2-yl, 1,1-difluoroethyl-2-yl, 1,2-difluoroethyl-2-yl, 1 1,1-fluoroethyl-2-yl, 1-bromoethyl-2-yl, 2-bromoethyl-2-yl and 1,1,1-tribromoethyl-2-yl.

"巯基" means -SH.

"Mercaptan" refers to a hydrocarbon in which one or more hydrogen atoms in the alkyl group are replaced by a mercapto group, non-limiting examples include methyl mercaptan, Ethyl mercaptan, 1,2-dithiol.

"Thioyl" or "thiocarbonyl" refers to a -C(=S)-R ^a group, wherein R ^{a is} as defined above.

"Hydroxyalkyl" means that the alkyl group is substituted by one or more hydroxy groups, preferably by 1, 2 or 3 hydroxy groups, the alkyl group being preferably a lower alkyl group; non-limiting examples include hydroxymethyl, 2-hydroxyl Ethyl, 1-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl and 2,3-dihydroxypropyl.

"Cycloalkyl" means a saturated monocyclic cyclic hydrocarbon group which may be substituted or unsubstituted, and the ring carbon atom includes 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; when substituted, substituents are from 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, Spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m - Alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c, where R ^b and R ^c each independently selected from H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl , Alternatively, R ^b and R ^c may form a five or six membered cycloalkyl or a heterocyclic group; R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, Heterocyclic group, carbonyl group, ester group, bridged ring group, spiro group or cis ring group.

"Heterocyclyl" means a substituted or unsubstituted saturated or unsaturated group containing at least 1 to 5 atoms or groups selected from N, O, S, S(=O) or S(=O) ₂ atoms or groups. An aromatic ring system, the non-aromatic ring system comprising 3 to 20 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms; the optionally substituted N, S in the heterocyclic ring may be oxidized to each Oxidation state; non-limiting examples include oxiranyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxacyclooctyl, aziridine, Azetidinyl, azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3 dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclopentane , 1,3-dioxanyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl , N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl , pyrazolyl, 1,4-dioxadienyl, 2H-1,2 -oxazinyl, 2,5-dihydrothiophenyl,

When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyanide , isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(= O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c ,- (CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkane a group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and optionally, R ^b and R ^c may form a five- or six-membered cycloalkyl group or a heterocyclic group; each of R ^a and R ^d Independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"Spiro" refers to a 5- to 20-membered polycyclic group that shares a carbon atom (referred to as a spiro atom) between a substituted or unsubstituted monocyclic ring, which may contain 0 to 5 double bonds, and may contain 0 to 5 atoms selected from N, O or S(=O) _n ; preferably 6 to 14 members, further preferably 6 to 12 members, more preferably 6 to 10 members, non-limiting examples of which include

When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH _{2 m} -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c ,-( CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n are 0, 1 Or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl , heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an alternative, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic group; R ^a and R ^d are each independently It is selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis-cyclyl.

"Paracyclic" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain zero or more double bonds and may be The substituted or unsubstituted, each ring in the cis ring system may contain from 0 to 5 atoms selected from N, S(=O) _n or O. It is preferably 5 to 20 members, further preferably 5 to 14 members, more preferably 5 to 12 members, still more preferably 5 to 10 members; non-limiting examples include

When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH _{2 m} -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c ,-( CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n are 0, 1 Or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl , heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an alternative, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic group; R ^a and R ^d are each independently It is selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis-cyclyl.

"Bridge ring" means any two polycyclic groups of carbon atoms which are not directly bonded, may contain 0 to 5 double bonds, and may be substituted or unsubstituted, and any ring in the ring system may contain 0. Up to 5 selected from N, S(=O) _n or O atoms or groups (where n is 0, 1, 2); ring atoms containing 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 Up to 12, further preferably 5 to 10; non-limiting examples include

And adamantane; when substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, thiol, Amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c , -(CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m, n Is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from H, hydroxy, amino, carbonyl, alkyl, alkoxy , cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic group; R ^a and R ^{d is} each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.

"Benzyl" refers to -CH ₂ - phenyl.

"Aryl" means a substituted or unsubstituted 6 to 14 membered cyclic aromatic group, including a monocyclic aromatic group and a fused ring aromatic group; preferably a 6 to 14 membered aromatic ring, further preferably a 6 to 10 membered aromatic ring, Non-limiting examples thereof include phenyl, naphthyl, anthryl and phenanthryl; the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring is bonded to the parent structure As an aryl ring, a non-limiting embodiment comprises:

When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH _{2 m} -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c ,-( CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , -OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkane Alternatively, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group or a trifluoromethanesulfonyl group, and R ^b and R ^c may form a five- or six-membered cycloalkyl group or a heterocyclic group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.

"Heteroaryl" means a substituted or unsubstituted 5 to 14 membered aromatic ring and contains 1 to 5 heteroatoms selected from N, O or S(=O) _n atoms, preferably 5 to 10 members. Further preferred is 5 to 6 members; non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl , pyridazinyl, imidazolyl, piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, piperidinyl, benzimidazole, benzopyridine, pyrrolopyridine; A heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include

When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH _{2 m} -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c ,-( CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , -OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR ^b R ^c , wherein R ^b and R ^c are each independently selected from H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkane Alternatively, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group or a trifluoromethanesulfonyl group, and R ^b and R ^c may form a five- or six-membered cycloalkyl group or a heterocyclic group. R ^a and R ^d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.

"Arylthio" means -S-aryl or -S-heteroaryl as defined herein; examples of arylthio include, but are not limited to, phenylthio, pyridylthio, furylthio, thienyl Thio-, pyrimidinylthio.

"Silyl" refers to a group formed by the substitution of one or more hydrogen atoms in a silicon methane with an alkyl group, examples including, but not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethyl Silyl and tert-butyldiphenylsilyl.

"Single bond" refers to a chemical single bond, such as "a single bond between A and B" means that there is a chemical single bond between A and B, namely: A-B.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur, such as: "Alkyl optionally substituted by F" "Alkyl can be, but is not necessarily, substituted by F, and is meant to include the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Substitution" refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom. Where the group is substituted, for example, amino, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic, 3 to 6 membered heterocyclic ring, optionally further from 0 to 4 selected from H, Substituted by a substituent of F, Cl, Br, I, hydroxy, cyano, amino, C _1-4 alkyl or C _1-4 alkoxy, the groups formed include, but are not limited to, methyl, chloromethyl, Trichloromethyl, hydroxymethyl, -CH ₂ OCH ₃ , -CH ₂ SH, -CH ₂ CH ₂ CN, -CH ₂ NH ₂ , -NHOH, -NHCH ₃ , -OCH ₂ Cl, -OCH ₂ OCH ₂ CH ₃ , -OCH ₂ CH ₂ NH ₂ , -OCH ₂ CH ₂ SH, -OCH ₂ CH ₂ OH, 1-hydroxycyclopropyl, 2-hydroxycyclopropyl, 2-aminocyclopropyl, 4-methyl Furanyl, 2-hydroxyphenyl, 4-aminophenyl, phenyl.

"Substituted or unsubstituted" refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.

“As a choice” means that the scheme after “as a choice” is a side-by-side relationship with the scheme before “as a choice” rather than a further selection in the previous scheme.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic or organic base. Or the free acid obtained by reacting with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc. Other metal salts such as iron salts, copper salts, cobalt salts; organic alkali salts such as ammonium salts, triethylamine salts, pyridinium salts, methylpyridine salts, 2,6-dimethylpyridine salts, ethanolamine salts, two Ethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, sulfonium salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, two Methylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, betaine salt, phenicillin salt, glucosamine salt, N-methylglucamine salt, theobromine salt, Tromethamine salt, sulfonium salt, piperazine salt, morpholine salt, piperidine salt, N-ethyl piperidine salt, tetramethylamine a salt, a dibenzylamine salt, and a phenylglycine alkyl ester salt; a hydrohalide salt such as a hydrofluoric acid salt, a hydrochloride salt, a hydroiodide salt, a hydrobromide salt; a mineral acid salt such as a nitrate salt or a sulfuric acid salt; Salt, perchlorate, phosphate; lower alkane sulfonate, such as methanesulfonate, triflate, ethanesulfonate; aryl sulfonate, such as besylate, p-toluenesulfonic acid Salt; organic acid salt, such as formic acid salt, fumarate, formate, trifluoroacetate, citrate, gluconate, glutamate, glycolate, isethionate, milk Acid salts, maleates, malates, mandelates, mucities, pamoate, pantothenate, stearates, succinates, sulfonates, tartrates, Malonate, 2-hydroxypropionate, citrate, salicylate, oxalate, glycolate, glucuronide, galacturonate, citrate, lysine , arginine salt, aspartate, cinnamate.

"Pharmaceutical composition" means a combination of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, or/and

(1) One or more clinically used drugs for treating and preventing diabetes, and the drugs for clinical use and for preventing diabetes include biguanide, thiazolidinedione, sulfonylurea, and leno , an α-glucosidase inhibitor, a GLP-1 analogue or a pharmaceutically acceptable salt thereof, such as metformin, phenformin, Ciglitazone, Pioglitazone, rosiglitazone ( Rosiglitazone), Troglitazone, Farglitazar, Darglitazoan, Glimepiride, Tolglybutamide, Glibomuride , Glibenclamide, Gliquidone, glipizide, gliclazipe, Nateglinide, Repaglinide, rice Mitiglinide, Acarbose, Voglibose, Miglitol, Exenatide or Liraglutide; or / with

(2) one or more SGLT-2 inhibitors, such as dapagliflozin, canagliflozin, empagliflozin, Epagli Ipragliflozin, Tofogliflozin, Luseogliflozin, Remogliflozin, Sergliflozin or Ertugliflozin; or/and

(3) one or more DPP-IV inhibitors, such as linagliptin, sitagliptin, vildagliptin, argrid Alogliptin, Saxagliptin, Denagliptin, Carmegliptin, Melogliptin, Dutogliptin, Teglettitin (Alogliptin) Teneligliptin), Gemigliptin or Trelagliptin;

(4) A mixture of other constituents, wherein the other components comprise physiological/pharmaceutically acceptable carriers and excipients; the purpose of the pharmaceutical composition is to facilitate administration of the compound to the organism.

"Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

"Excipient" refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.

"Prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying a phenolic group in the compound which can be removed by conventional procedures or in vivo to provide the parent compound. When a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form free hydroxyl groups, respectively. Examples of prodrugs include, but are not limited to, phenolic hydroxyl groups and phosphorus of the compounds of the invention The acid forms a sodium salt derivative.

"Co-crystal" or "eutectic" refers to a crystal of a compound of the invention and a cocrystal former (CCF) bonded by hydrogen bonding or other non-covalent bond, wherein the pure state of API and CCF They are all solid at room temperature and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate. The "eutectic former" includes, but is not limited to, various pharmaceutically acceptable acids, bases, nonionic compounds, water, amino acids, alcohols, or other solvents, non-limiting examples of which include alanine (Ala), hydrazine Acid (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine ( Gly), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), lysine (Lys) , arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid , propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, citric acid, gluconic acid, glucitol Acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfamic acid, tartaric acid, p-toluene Sulfonic acid, malonic acid, 2-hydroxyl Acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or three Fluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol , 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phenylephrine, ethylenediamine, glucosamine, methylglucamine, theobromine, tromethamine Alcohol, hydrazine, piperazine, piperidine, N-ethylpiperidine, methanol, ethanol, butynediol, 1,2-propanediol, (R) 1,2-propanediol, (S) 1,2-propanediol or 1-methyl-1,2-ethanediol.

"X Syndrome" refers to conditions, diseases, and conditions of metabolic syndrome. For a detailed description, see Johannsson J. Clin. Endo crinol. Metab., 1997, 82, 727-734.

"Effective dose" refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.

"Solvate" means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces, and a hydrate when the solvent is water.

"IC ₅₀ " refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

The present invention relates to the substitution of a plurality of substituents, which may be the same or different.

The present invention relates to the inclusion of a plurality of heteroatoms, each of which may be the same or different.

Detailed ways

The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).

The NMR shift (δ) is given in units of 10 ^-6 (ppm).

NMR was measured using a (Bruker ADVANCE III 400) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), internal standard. For tetramethylsilane (TMS), 1H NMR information is listed in the following format: chemical shift (multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), Number of protons).

For the determination of MS (Agilent 6120B (ESI)).

The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorba x SB-C18100x 4.6 mm).

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

Compound names were named using the ChemBioDraw ultra 12 tool.

Unless otherwise specified, conventional reagents such as sodium borohydride, sodium thiosulfate, sodium methoxide, trifluoroacetic acid, o-dichlorobenzene, sodium chlorite, 1,2-dichloroethane, etc. were purchased from Chengdu Kelon Chemical Reagent Factory. 2-iodobenzoic acid was purchased from Shanghai Demo Pharmaceutical Technology Co., Ltd.; pyridine was purchased from Xiqiao Chemical Co., Ltd.; diethylaminosulfur trifluoride was purchased from Anheji Chemical; palladium carbon was purchased from Chengdu Juhui Chemical Co., Ltd. Technology Co., Ltd.; Days-Martin purchased from Shanghai Titan Technology Co., Ltd.; methyl bromide purchased from BEHRINGER Technology; isobutyl chloroformate purchased from Suiyuan Chemical Technology (Shanghai) Co., Ltd.;

The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 2 L.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.

Bn: benzyl

Et: ethyl

Ac: acetyl

Me: methyl

w/w: quality score

V/V: volume ratio

Min: minute

Intermediate 1: ((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl )-2-formyl-6-methoxytetrahydro-2H-pyran-2-yl)methyl acetate (intermediate 1)

((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-formyl-6-methoxytetrahydro-2H -pyran-2-yl)methyl acetate

First step: (2S, 3R, 4S, 5S, 6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) -6-methoxy-tetrahydropyran-2-carbaldehyde (1B)

(2S,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxyte trahydro-2H-pyran-2 -carbaldehyde

((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6 -Methoxytetrahydro-2H-pyran-2-yl)methanol 1A (25 g, 35.3 mmol, Shanghai Karlu Blue Technology Co., Ltd.) was dissolved in 1,2-dichloroethane (300 mL) and added at room temperature. 2-iodobenzoic acid (27 g, 95.3 mmol) was heated to reflux and stirred for 6 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 1,2-dichloroethane (50mL×3). The organic phase was washed with sodium thiosulfate (100 mL×2, w/w=10%), EtOAc (EtOAc) Syrup (2S, 3R, 4S, 5S, 6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)- The crude product of 6-methoxy-tetrahydropyran-2-carbaldehyde 1B (25 g) was used in the next step without purification.

¹ H NMR (300 MHz, CDCl ₃ ): δ 9.67 (s, 1H), 7.12-7.32 (m, 16H), 6.91-6.97 (m, 4H), 6.68 (d, 2H), 4.76-4.88 (m, 3H) ), 4.63 (d, 1H), 4.41 (d, 1H), 3.59-4.19 (m, 8H), 3.23 (d, 1H), 3.00 (s, 3H), 1.31 (t, 3H).

Second step: (3S, 4S, 5R, 6S)-3,4,5-tris(benzyloxy)-6-((4-chloro-3-(4-ethoxyphenyl)phenyl)- 2-hydroxymethyl-6-methoxy-tetrahydropyran-2-yl)methanol (1C)

((3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxytetrahydro-2H-pyran-2, 2-diyl)dimethanol

(2S,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- The crude product of methoxy-tetrahydropyran-2-carbaldehyde 1B (7 g, 10 mmol) was dissolved in a mixed solvent of isopropanol / dioxane (70 mL, 18:1), and sodium hydroxide was added sequentially at room temperature ( 0.8 g, 20 mmol), aqueous formaldehyde solution (20 g, 250 mmol, w/w = 37%), and the reaction was stirred at room temperature for 48 hours. The reaction mixture was adjusted to neutral with aq. EtOAc (EtOAc) (EtOAc (EtOAc) The extract was washed with brine (100 mL) The residue was purified by column chromatography (petrole ether / ethyl acetate = 5:1 to 2:1 - dichloromethane).

A part of the above mixture (1.9 g, 2.58 mmol) was dissolved in a mixture solvent of tetrahydrofuran/methanol (20 mL, V/V = 2:3), and sodium borohydride (196 mg, 5. The reaction was stirred at room temperature for 2 hours. The reaction solution was cooled in an ice-bath, and pH was adjusted to 3 to 4 with 1M hydrochloric acid, and water (50 mL) and dichloromethane (50 mL) were added to the reaction mixture. The layers were separated, EtOAc EtOAc m. The residue was purified by column chromatography ( petroleum ether / ethyl acetate = 5:1 to 3.5:1) to afford yellow syrup (3S,4S,5R,6S)-3,4,5-tribenzyloxy -6-((4-Chloro-3-(4-ethoxyphenyl)phenyl)-2-hydroxymethyl-6-methoxy-tetrahydropyran-2-yl)methanol 1C (1.4 g , the total yield of the three-step reaction is 25%).

MS m/z (ESI): 761.1 [M+Na ⁺ ];

_{^{1 H NMR (300MHz, CDCl 3}} ): δ7.21-7.34 (m, 16H), 7.00-7.06 (m, 4H), 6.79 (d, 2H), 4.89-4.98 (m, 3H), 4.68 (d, 1H), 4.60 (d, 1H), 4.24-4.32 (m, 2H), 3.76-3.93 (m, 8H), 3.61 (brs, 1H), 3.17 (d, 1H), 2.98 (s, 3H), 2.91 (brs, 1H), 1.32 (t, 3H).

Third step: (2R, 3S, 4S, 5R, 6S)-3,4,5-tris(benzyloxy)-6-((4-chloro-3-(4-ethoxyphenyl)phenyl) )-2-hydroxymethyl-6-methoxy-tetrahydropyran-2-yl)methyl acetate (1D)

((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-(hydroxy methyl)-6- methoxytetrahydro-2H-pyran-2-yl)methyl acetate

(3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-((4-chloro-3-(4-ethoxyphenyl)phenyl)-2-hydroxy Methyl-6-methoxy-tetrahydropyran-2-yl)methanol 1C (500 mg, 0.675 mmol) was dissolved in dichloromethane (5 mL), then pyridine (534 mg, 6.75 mmol) and acetic anhydride (172 mg) , 1.69mmol). The reaction was stirred at room temperature for 24 hours. Dichloromethane (20 mL) was added to the reaction mixture, which was washed with EtOAc EtOAc EtOAc (EtOAc) 2) Washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (peel ether / ethyl acetate = 7:1) to give a colorless syrup (2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy) -6-((4-chloro-3-(4-ethoxyphenyl)phenyl)-2-hydroxymethyl-6-methoxy-tetrahydropyran-2-yl)methylacetic acid Ester 1D (330 mg, yield 63%).

MS m/z (ESI): 803.6 [M+Na ⁺ ];

¹ H NMR (300MHz, CDCl ₃ ): δ 7.26-7.37 (m, 16H), 6.99-7.09 (m, 4H), 6.74 (d, 2H), 4.88-5.01 (m, 3H), 4.60-4.63 (m) , 2H), 4.31-4.44 (m, 3H), 3.80-4.11 (m, 6H), 3.73 (brs, 1H), 3.27 (d, 1H), 3.06 (s, 3H), 2.95 (brs, 1H), 1.38 (t, 3H).

Step 4: ((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl )-2-formyl-6-methoxytetrahydro-2H-pyran-2-yl)methyl acetate (intermediate 1)

((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-formyl-6-methoxytetrahydro-2H -pyran-2-yl)methyl acetate

(2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-((4-chloro-3-(4-ethoxyphenyl)phenyl)-2 -Hydroxymethyl-6-methoxy-tetrahydropyran-2-yl)methyl acetate 1D (110 mg, 0.141 mmol) was dissolved in dichloromethane (1 mL). The oxidizing agent (90 mg, 0.211 mmol) was stirred at room temperature for 1 hour. The reaction solution was cooled in an ice bath, sodium thiosulfate (15 mL, w/w = 10%) was added and stirred for 15 min. The organic phase was washed with aq. EtOAc (EtOAc (EtOAc) ,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-formyl-6- The crude methoxytetrahydro-2H-pyran-2-yl)methyl acetate intermediate 1 (95 mg, 86%) was used in the next step without purification.

Example 1

(1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-7,7-dimethyl- 6,8-Dioxabicyclo[3.2.1]octane-2,3,4-triol (Compound 1)

(1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-7,7-dimethyl-6,8-dioxabicyclo[3.2.1 Octvine-2,3,4-triol

First step: (2R, 3S, 4S, 5R, 6S)-2-(acetoxymethyl)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4) -ethoxyphenyl)phenyl)-6-methoxytetrahydro-2H-pyran-2-carboxylic acid (1a)

(2R,3S,4S,5R,6S)-2-(acetoxymethyl)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)p henyl)-6-methoxytetrahydro -2H-pyran-2-carboxylic acid

(2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2- Formyl-6-methoxytetrahydro-2H-pyran-2-yl)methyl acetate intermediate 1 (120 mg, 0.154 mmol) dissolved in water / acetonitrile (2 mL, V/V =) The temperature was lowered to 0 ° C, and sodium dihydrogen phosphate (8 mg, 6%), hydrogen peroxide (35 mg, 0.308 mmol, 30%) and sodium chlorite (42 mg, 0.462 mmol) were sequentially added. The reaction was allowed to rise to room temperature for 2 hours. The reaction mixture was cooled with ice-cooled EtOAc (EtOAc) (EtOAc) ×2), the organic layer was combined, washed with brine (50 mL×1), dried over anhydrous sodium sulfate (acetoxymethyl)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6-methoxytetrahydro -2H-pyran-2-carboxylic acid 1a (115 mg, yield 94%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.49-7.16 (m, 17H), 7.10 (d, 2H), 7.00 (d, 2H), 6.74 (d, 2H), 4.90 (t, 3H), 4.71 (d, 1H), 4.60 (d, 3H), 4.27 (d, 1H), 4.10-3.93 (m, 5H), 3.82 (d, 1H), 3.34 (d, 1H), 3.01 (s, 3H), 2.03 (s, 3H), 1.38 (t, 3H).

Second step: (2R, 3S, 4S, 5R, 6S)-methyl 2-(acetoxymethyl)-3,4,5-tris(benzyloxy)-6-(4-chloro-3- (4-ethoxybenzyl)phenyl)-6-methoxytetrahydro-2H-pyran-2-carboxylate (1b)

(2R,3S,4S,5R,6S)-methyl 2-(acetoxymethyl)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxyb enzyl)phenyl)-6- methoxytetrahydro-2H-pyran-2-carboxylate

(2R,3S,4S,5R,6S)-2-(acetoxymethyl)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxy) Phenyl)phenyl)-6-methoxytetrahydro-2H-pyran-2-carboxylic acid 1a (1.40 g, 1.86 mmol), potassium carbonate (1.80 g, 13.02 mmol) dissolved in N,N- Methylformamide (20 mL) was added with methyl iodide (1.32 g, 9.30 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. It was diluted with a saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (80 mL×3). The organic layer was washed with EtOAc EtOAc m. The residue was purified by column chromatography (ethyl acetate /hexanehexanes: 1:1) to give pale yellow syrup (2R,3S,4S,5R,6S)-methyl 2-(acetoxymethyl) -3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methoxytetrahydro-2H-pyran-2 - Carboxyl ester 1b (1.35 g, yield 94%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.36 (d, 1H), 7.33 - 7.22 (m, 15H), 7.09 (dd, 2H), 7.00 (d, 2H), 6.74 (d, 2H), 4.95 (d, 3H), 4.85 (t, 1H), 4.68 (dd, 3H), 4.16 (s, 1H), 4.09 (d, 1H), 4.01-3.92 (m, 4H), 3.85-3.71 (m, 4H) ), 3.32 (d, 1H), 2.95 (s, 3H), 2.02 (s, 3H), 1.38 (t, 3H).

The third step: 2-((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl) Phenyl)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-2-yl)propan-2-ol (1c):

2-((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-(hydrox ymethyl)- 6-methoxytetrahydro-2H-pyran-2-yl)propan-2-ol

(2R,3S,4S,5R,6S)-Methyl 2-(acetoxymethyl)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4- Ethoxybenzyl)phenyl)-6-methoxytetrahydro-2H-pyran-2-carboxylate 1b (0.80 g, 1.0 mmol) was dissolved in tetrahydrofuran (70 mL), cooled to 0 ° C, Methylmagnesium bromide (6 mL) was stirred for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc EtOAc. The residue was purified by column chromatography (ethyl acetate /hexanehexanes : : : : : : : : : : : : : : : : : : : : : : Benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-2- Propane-2-ol 1c (0.65 g, yield 85%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.34-7.23 (m, 13H), 7.15 (m, 3H), 7.06 (d, 2H), 6.84 (d, 2H), 6.74 (d, 2H), 4.94 (d, 1H), 4.89-4.79 (m, 2H), 4.39-4.32 (m, 1H), 4.20 (m, 1H), 4.11-4.05 (m, 1H), 4.01-3.90 (m, 2H), 3.77 -3.69 (m, 1H), 3.66 (d, 1H), 1.61 (s, 3H), 1.38 (t, 4H), 1.08 (s, 3H).

Fourth step: ((1R, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl )-7,7-Dimethyl-6,8-dioxobicyclo[3.2.1]octane-1-yl)methanol (1d)

((1R, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-7,7-dimeth yl-6, 8-dioxabicyclo[3.2.1]octan-1-yl)methanol

2-((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl) 2-(Hydroxymethyl)-6-methoxytetrahydro-2H-pyran-2-ylpropan-2-ol 1c (0.60 g, 0.78 mmol) dissolved in dichloromethane (20 mL) After uniform addition, trifluoroacetic acid (0.46 g, 4.00 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with a saturated aqueous solution of ammonium chloride (30 mL), and evaporated. The organic phase was washed with EtOAcq. The residue was purified by column chromatography (ethyl acetate /hexanehexanesssssssssssssssssssssssssssssssssssss -5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-7,7-dimethyl-6,8-dioxobicyclo[3.2.1]octane-1-yl Methanol 1d (0.3 g, yield 52%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.40-7.23 (m, 13H), 7.15 (m, 3H), 7.06 (d, 2H), 6.84 (d, 2H), 6.74 (d, 2H), 4.94 (d, 1H), 4.89-4.79 (m, 2H), 4.39-4.32 (m, 1H), 4.20 (m, 1H), 4.11-4.05 (m, 1H), 4.01-3.90 (m, 2H), 3.77 -3.69 (m, 1H), 3.66 (d, 1H), 1.61 (s, 3H), 1.38 (t, 4H), 1.08 (s, 3H).

Step 5: (1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2-hydroxymethyl)-7, 7-Dimethyl-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (Compound 1)

(1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-7,7-dimethyl-6,8-dioxabicyclo[3.2.1 Octvine-2,3,4-triol

((1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-7 ,7-Dimethyl-6,8-dioxobicyclo[3.2.1]octane-1-yl)methanol 1d (0.30 g, 0.4 mmol), o-dichlorobenzene (0.60 g, 4.0 mmol) and palladium Carbon (0.30 g, w/w = 10%, water content 50%) was added to a methanol/tetrahydrofuran mixed solvent (20 mL, V/V = 1:1), hydrogen The reaction was carried out three times, and the reaction was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The residue was purified by column chromatography (methanol / methylene chloride = 1 : 30) to afford white solid (1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-B) Oxybenzyl)phenyl)-1-(2-hydroxymethyl)-7,7-dimethyl-6,8-dioxobicyclo[3.2.1]octane-2,3,4-tri Alcohol compound 1 (0.13 g, yield 75%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ7.42 (s, 1H), 7.38-7.32 (m, 1H), 7.08 (d, 2H), 6.80 (d, 1H), 4.10 (d, 1H), 4.05-3.95(m,3H),3.77(d,1H),3.66(d,1H),3.51(d,1H),1.52(s,2H),1.35(t,2H),1.03(s,1H) .

HPLC: 96.14%.

Example 2

(1R, 2S, 3S, 4R, 5R)-2,3,4-trihydroxy-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-1-hydroxymethyl-6 , 8-dioxabicyclo[3.2.1]octane-7-one (Compound 2)

(1R, 2S, 3S, 4R, 5R)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[ 3.2.1]octan-7-one

First step: (2R, 3S, 4S, 5R, 6S)-3,4,5-tribenzyloxy-6-((4-chloro-3-(4-ethoxyphenyl)phenyl)- 2-hydroxymethyl-6-methoxy-tetrahydropyran-2-yl)methyl acetate (2a)

(2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-(hydroxymethyl)-6-methoxytetrahydro -2H-pyran-2-carboxylic acid

(2R,3S,4S,5R,6S)-2-(Acetoxymethyl)-3,4,5-tribenzyloxy-6-(4-chloro-3-(4-ethoxybenzene) Phenyl)-6- Methoxy-tetrahydropyran-2-carboxylic acid 1a (115 mg, 0.144 mmol) was dissolved in MeOH (1 mL). The reaction was stirred at room temperature for 1 hour. The reaction solution was cooled in an ice-bath, and the pH was adjusted to 3 to 4 with 3M hydrochloric acid, and water (20mL) and ethyl acetate (20mL) were added to the mixture. The aqueous layer was extracted with ethyl acetate (10 mL×2). EtOAcjjjjjjjjjjjjjj ,6S)-3,4,5-tribenzyloxy-6-((4-chloro-3-(4-ethoxyphenyl)phenyl)-2-hydroxymethyl-6-methoxy- Tetrahydropyran-2-yl)methyl acetate 2a (100 mg, yield 93%) was used in the next step without purification.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.43-7.16 (m, 16H), 7.08 (d, 2H), 7.01 (d, 2H), 6.78 (d, 2H), 5.04-4.89 (m, 2H) , 4.84 (dd, 2H), 4.61 (d, 1H), 4.46 (t, 1H), 4.23-3.80 (m, 7H), 3.74 (d, 1H), 3.27 (d, 1H), 3.01 (s, 3H) ), 2.05 (s, 1H), 1.39 (t, 3H).

Second step: (1R, 2S, 3S, 4R, 5R)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxyphenyl)phenyl) 1-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-7-one (2b)

(1R,2S,3S,4R,5R)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxy methyl)-6,8 -dioxabicyclo[3.2.1]octan-7-one

(2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-((4-chloro-3-(4-ethoxyphenyl)phenyl)-2 -Hydroxymethyl-6-methoxy-tetrahydropyran-2-yl)methyl acetate 2a (100 mg, 0.133 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (151 mg, 1.33) Mm). The reaction was stirred at room temperature for 1 hour. Dichloromethane (20 mL) was added to the reaction mixture. EtOAc (EtOAc m. . The residue was purified by column chromatography (EtOAc/EtOAc:EtOAc:EtOAc) 5-(4-Chloro-3-(4-ethoxyphenyl)phenyl)-1-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-7-one 2b (68 mg , yield 71%).

_{^{1 H NMR (300MHz, CDCl 3}} ): δ7.55-7.12 (m, 16H), 7.09-6.98 (m, 2H), 6.97-6.84 (m, 2H), 6.83-6.65 (m, 2H), 4.99- 4.66 (m, 4H), 4.39-4.24 (m, 1H), 4.16-3.83 (m, 9H), 3.82-3.69 (m, 1H), 1.35 (t, 3H).

The third step: (1R, 2S, 3S, 4R, 5R)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-( Hydroxymethyl)-6,8-dioxobicyclo[3.2.1]octane-7-one (Compound 2)

(1R, 2S, 3S, 4R, 5R)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[ 3.2.1]octan-7-one

(1R, 2S, 3S, 4R, 5R)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-1- Hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-7-one 2d (50 mg, 0.07 mmol) in tetrahydrofuran/methanol mixed solvent (1.5 mL, V/V 1:1) Among them, o-dichlorobenzene (100 mg, 0.7 mmol) and palladium carbon (30 mg, w/w = 10%) were added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. Palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 40:1 to 20:1) to give a colorless syrup (1R,2S,3S,4R,5R)-5-(4-chloro-3) -(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-(hydroxymethyl)-6,8-dioxobicyclo[3.2.1]octane-7-one Compound 2 (24 mg, yield 77%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.54 - 7.35 (m, 3H), 7.10 (t, 2H), 6.83 (dd, 2H), 4.12-3.86 (m, 6H), 3.82-3.72 (m) , 1H), 3.70-3.63 (m, 1H), 3.58 (t, 1H), 1.35 (t, 3H).

Example 3:

(1R, 2S, 3S, 4R, 5R, 7S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-7-methoxy- 6,8-Dioxabicyclo[3.2.1]octane-2,3,4-triol (Compound 3)

(1R, 2S, 3S, 4R, 5R, 7S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-7-methoxy-6,8-dioxabicyclo[3.2.1 Octvine-2,3,4-triol

First step: ((1R, 2S, 3S, 4R, 5R, 7S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl)-7-methoxy-6,8-dioxobicyclo[3.2.1]octane-1-yl)methanol (3a)

((1R,2S,3S,4R,5R,7S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-7-metho xy-6, 8-dioxabicyclo[3.2.1]octan-1-yl)methanol

((2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl at room temperature -2-formyl -6-Methoxytetrahydro-2H-pyran-2-yl)methyl acetate intermediate 1 (0.5 g, 0.64 mmol) in methanol/tetrahydrofuran (12.5 mL, V/V = 4 To 1), trifluoromethanesulfonic acid (1.0 g, 6.40 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc EtOAc (EtOAc m. The residue was purified by column chromatography (peel ether / ethyl acetate = 8:1) to afford pale yellow syrup ((1R,2S,3S,4R,5R,7S)-2,3,4-tri Benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-7-methoxy-6,8-dioxobicyclo[3.2.1]octane-1 -Based methanol 3a (0.26 g, yield 55%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.51-7.25 (m, 13H), 7.16 (dt, 3H), 7.07 (d, 2H), 6.84 (d, 2H), 6.75 (d, 2H), 5.20 (s, 1H), 4.92-4.68 (m, 4H), 4.23 (d, 1H), 4.09 (d, 1H), 4.03-3.91 (m, 5H), 3.86 (dd, 2H), 3.79 (d, 1H) ), 3.63 (d, 1H), 3.36 (s, 3H), 1.38 (t, 3H).

The second step: (1R, 2S, 3S, 4R, 5R, 7S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-7- Methoxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 3)

(1R, 2S, 3S, 4R, 5R, 7S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-7-methoxy-6,8-dioxabicyclo[3.2.1 Octvine-2,3,4-triol

((1R,2S,3S,4R,5R,7S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -7-Methoxy-6,8-dioxobicyclo[3.2.1]octane-1-yl)methanol 3a (0.23 g, 0.33 mmol) dissolved in tetrahydrofuran/methanol (12 mL, V/V In the range of 1:1), o-dichlorobenzene (0.5 g, 3.3 mmol) and palladium carbon (23 mg, w/w = 10%) were added, and the reactor was replaced with hydrogen three times, and the reaction was stirred at room temperature of 1 atm for 5 hours. The reaction solution was diluted with a dichloromethane/methanol mixture solvent (20 mL, V/V = 1:1), filtered, filtered, and evaporated. The residue was purified by column chromatography (dichloromethane / methanol = 20:1) to afford white crystals (1R,2S,3S,4R,5R,7S)-5-(4-chloro-3-(4-B) Oxybenzyl)phenyl)-1-(hydroxymethyl)-7-methoxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol compound 3 ( 0.13 g, yield 93%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ7.46-7.29 (m, 1H), 7.37 (d, 2H), 7.09 (d, 2H), 6.80 (d, 2H), 5.08 (s, 1H), 4.07-3.69 (m, 2H), 3.64-3.49 (m, 2H), 3.34-3.24 (m, 1H), 1.33 (dd, 2H), 3.54 (d, 2H), 3.31 (s, 3H), 1.35 ( t, 3H).

Example 4:

(1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-(hydroxymethyl) -8-oxo-6-azabicyclo[3.2.1]octane-7-one (Compound 4)

(1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-(hydroxymethyl)-8-oxa-6-azabicyclo [3.2.1]octan-7-one

First step (2R, 3S, 4S, 5R, 6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 2-(Hydroxymethyl)-6-methoxytetrahydro-2H-pyran-2-carboxamide (4a)

(2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-(hydroxymethyl)-6-methoxytetrahydro -2H-pyran-2-carboxamide

(2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl under ice bath 2-(Hydroxymethyl)-6-methoxytetrahydro-2H-pyran-2-carboxylic acid 2a (1.0 g, 1.33 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.67) g, 6.65 mmol) and isobutyl chloroformate (0.55 g, 3.98 mmol). The reaction was stirred at room temperature for 2 hours. Ammonia methanol solution (0.6 mL, 7 mol/L) was added, and the reaction was further stirred at room temperature for 1 hour. The reaction solution was diluted with water (20 mL), stirred for 10 min and then evaporated. The aqueous layer was extracted with dichloromethane (15 mL×2). The residue was purified by column chromatography (peel ether / ethyl acetate = 10:1) to give pale yellow syrup (2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy) -6-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-2-carboxamide 4a (500mg , yield 50%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.47 (d, 1H), 7.38 (dd, 2.1Hz, 1H), 7.34-7.26 (m, 12H), 7.22 (dd, 1.8Hz, 3H), 7.15 ( s, 1H), 7.15 (s, 1H), 7.04 (dd, 2.5 Hz, 2H), 7.01 (d, 2H), 6.73 (d, 2H), 5.52 (s, 1H), 4.83 (t, 1H), 4.78 (d, 2H), 4.67 (d, 2H), 4.54 (d, 1H), 4.43-4.33 (m, 2H), 4.14 (d, 1H), 4.06 (d, 1H), 4.01-3.92 (m, 6H), 3.88-3.83 (m, 2H), 3.49 (d, 1H), 3.04 (s, 3H), 1.37 (t, 3H).

The second step (1R, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 1-(hydroxymethyl)-8- Oxy-6-azabicyclo[3.2.1]octane-7-one (4b)

(1R, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxy methyl)-8-oxa -6-azabicyclo[3.2.1]octan-7-one

(2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 2-(Hydroxymethyl)-6-methoxytetrahydro-2H-pyran-2-carboxamide 4a (130 mg, 0.17 mmol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (298 mg) , 2.60 mmol), and reacted at 30 ° C overnight. Dichloromethane (2 mL) was added to the reaction mixture, and the mixture was evaporated. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by column chromatography (ethyl ether / ethyl acetate = 10:1) toield (1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy) -5-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-8-oxo-6-azabicyclo[3.2.1]octane- 7-keto 4b (35 mg, yield 28%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.41 (d, 1H), 7.38 (s, 1H), 7.36-7.23 (m, 11H), 7.19 (qd, 5H), 7.03 (d, 2H), 6.89 (d, 2H), 6.74 (d, 2H), 4.84 (t, 1H), 4.78 (d, 2H), 4.73 (t, 1H), 4.49 (dd, 2H), 4.27 (d, 1H), 4.05 ( d, 1H), 4.01-3.93 (m, 5H), 3.90-3.86 (m, 3H), 3.75 (d, 1H), 1.38 (t, 3H).

The third step: (1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-( Hydroxymethyl)-8-oxo-6-azabicyclo[3.2.1]octane-7-one (Compound 4)

(1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-(hydroxymethy l)-8-oxa-6- Azabicyclo[3.2.1]octan-7-one

Methanol (0.45 mL) and tetrahydrofuran (0.45 mL) were added to (1R, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-) under a hydrogen atmosphere at room temperature. Chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-8-oxo-6-azabicyclo[3.2.1]octane-7-one 4b (15 mg, 0.021 mmol), a mixed system of palladium on carbon (18 mg, w/w = 10%, water content 50%) and o-dichlorobenzene (34 mg, 0.21 mmol). The reaction was stirred overnight under a hydrogen atmosphere at room temperature. Palladium carbon (10 mg, w/w = 10%) was again added, and the reaction was further stirred for 6 hours. The reaction solution was suction filtered to remove palladium carbon and concentrated under reduced pressure. The residue was purified by a thin-layer preparative plate (dichloromethane/methanol = 20:1) to give a colorless liquid (1R, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4) -ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-(hydroxymethyl)-8-oxo-6-azabicyclo[3.2.1]octane-7-one compound 4 (6 mg, yield 63%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.45-7.36 (m, 2H), 7.32 (d, 1H), 7.07 (d, 2H), 6.78 (d, 2H), 5.35 (s, 0.5H), 4.79 (d, 1H), 4.45 (d, 1H), 4.31 (t, 0.5H), 4.02 (d, 2H), 3.99-3.94 (m, 3H), 3.93 - 3.88 (m, 3H), 3.82 (s, 1H), 1.36 (t, 3H).

Example 5:

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(di) Fluoromethyl)-6,8-dioxobicyclo[3.2.1]octane (compound 5)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(difluorom ethyl)-6,8 -dioxabicyclo[3.2.1]octane

First step: ((1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -6,8-dioxobicyclo[3.2.1]octane-1-yl)methanol (5a)

((1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabi cyclo[3.2. 1]octan-1-yl)methanol

(3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-((4-chloro-3-(4-ethoxyphenyl)phenyl)-2-hydroxy Methyl-6-methoxy-tetrahydropyran-2-yl)methanol 1C (500 mg, 0.68 mmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (386 mg, 3.38 mmol) was slowly added dropwise. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride (5 mL). The aqueous phase was extracted with dichloromethane (15 mL×2). The residue was purified by column chromatography (petrole ether / ethyl acetate = 4:1) to give colorless syrup ((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy) 5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)methanol 5a (350 mg, produced Rate 72%).

Second step: (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 6,8-dioxane [3.2.1] Octane-1-carbaldehyde (5b)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabic yclo[3.2.1 Octvine-1-carbaldehyde

((1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6, 8-Dioxodicyclo[3.2.1]octane-1-yl)methanol 5a (150 mg, 0.68 mmol) was dissolved in dichloromethane (2.0 mL). (140 mg, 0.32 mmol), and allowed to react to room temperature for 2.5 hours. The reaction solution was cooled to 0 ° C, and then quenched with aqueous sodium thiosulfate (10 mL, w/w = 10%). The aqueous layer was extracted with dichloromethane (15 mL×2). Filtration and concentration gave colorless syrup (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-carbaldehyde 5b (95 mg, yield 88%).

The third step: (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 1-(Difluoromethyl)-6,8-dioxobicyclo[3.2.1]octane (5c)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(difluorom ethyl)-6,8 -dioxabicyclo[3.2.1]octane

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8 Dioxodicyclo[3.2.1]octane-1-carbaldehyde 5b (70 mg, 0.1 mmol) was dissolved in dichloromethane (2.0 mL), the mixture was cooled to 0 ° C, and diethylamine trifluorosulfide was added ( 48 mg, 0.3 mmol), and allowed to react to room temperature for 2 hours. The reaction solution was cooled to 0.degree. C., and then evaporated and evaporated. The aqueous layer was extracted with dichloromethane (10 mL×2). The residue was purified by column chromatography (peel ether / ethyl acetate = 4:1) to give colorless syrup (1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)- 5-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-1-(difluoromethyl)-6,8-dioxobicyclo[3.2.1]octane 5c (25mg, produced Rate 34%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.46-7.23 (m, 16H), 7.22-7.11 (m, 3H), 7.06 (d, 2H), 6.86 (d, 2H), 6.74 (d, 2H) , 6.20-5.68 (m, 1H), 4.90-4.72 (m, 4H), 4.43 (d, 1H), 4.22 (d, 1H), 4.08 (dd, 7.7 Hz, 2H), 4.03-3.91 (m, 4H) ), 3.84 (dd, 5.9 Hz, 2H), 3.68 (d, 1H), 1.45-1.32 (m, 4H);

¹⁹ F NMR (377 MHz, CDCl ₃ ): δ -128.79 - -129.56 (d, 1F), -131.43 - 132.20 (d, 1F).

The fourth step: (1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(difluoromethyl)-6,8 -dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 5)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(difluoromethyl)-6,8-dioxabicyc lo[3.2.1]octane-2, 3,4-triol

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 1-(Difluoromethyl)-6,8-dioxobicyclo[3.2.1]octane 5c (15 mg, 0.021 mmol), palladium on carbon (18 mg, w/w = 10%) and o-chlorodiphenyl ( 30 mg, 0.21 mmol) was added to a methanol/tetrahydrofuran mixed solvent (1.6 mL, V/V = 1:1). The reaction system was replaced with hydrogen six times, and the reaction was stirred overnight under a hydrogen atmosphere. Palladium carbon (10 mg, w/w = 10%, water content 50%) was added, and the reaction was continued at 30 ° C for 6 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by a thin-layer preparative plate (dichloromethane/methanol = 20:1) to give a colorless liquid (1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4) -ethoxybenzyl)phenyl)-1-(difluoromethyl)-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol compound 5 (6 mg, produced The rate is 62.5%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.37 (ddd, 9.7,5.2Hz, 3H), 7.10 (d, 2H), 6.82 (d, 2H), 6.11 ~ 5.84 (m, 1H), 4.39 (d , 1H), 4.31 (t, 1H), 4.18 (d, 1H), 4.02 (dt, 4H), 3.95-3.81 (m, 3H), 3.73 (d, 1H), 1.40 (t, 3H);

¹⁹ F NMR (400 MHz, CDCl ₃ ): δ - 128.15 - -128.94 (d, 1F), -131.61 - -132.39 (d, 1F).

Example 6

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(difluoromethyl)-6, 8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 6)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(difluoromethyl)-6,8-di oxabicyclo[3.2.1] Octane-2,3,4-triol

First step: (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-6,8-dioxo Bicyclo[3.2.1]octane-1-carbaldehyde (6b)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6,8-dioxabicyclo[ 3.2.1] octane-1-carbaldehyde

((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)benzene 6,8-Dioxabicyclo[3.2.1]octane-1-yl)methanol 6a (2.10 g, 3.0 mmol, Shanghai Kalu Blue Technology Co., Ltd.) was dissolved in dichloromethane (20 mL). After cooling to 0 ° C, Dess-Martin periodinane (3.18 g, 7.5 mmol) was added and the mixture was allowed to react to room temperature for 2 hours. The reaction solution was cooled to 0 ° C, quenched with aqueous sodium thiosulfate (30 mL, w/w = 10%), stirred for 30 min, partitioned, and the aqueous layer was extracted with dichloromethane (50 mL×2). Dry over anhydrous sodium sulfate, filter and concentrate. The residue was separated by column chromatography (peel ether / ethyl acetate = 10:1) to afford white syrup (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5 -(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-carbaldehyde 6b (1.50 g, produced Rate 72%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.41 (s, 1H), 7.39-7.35 (m, 2H), 7.35-7.23 (m, 10H), 7.20-7.12 (m, 3H), 6.91-6.84 ( m,3H), 6.83-6.74 (m, 2H), 6.06-5.74 (m, 1H), 4.90-4.72 (m, 4H), 4.43 (d, 1H), 4.26 (d, 1H), 4.02 (m, 6H), 3.85 (dd, 2H), 3.68 (d, 1H), 1.41 (t, 3H).

Second step: (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-1-(difluoromethyl)-6,8-dioxobicyclo[3.2.1]octane (6c)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(d ifluoromethyl) -6,8-dioxabicyclo[3.2.1]octane

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl -6,8-Dioxabicyclo[3.2.1]octane-1-carbaldehyde 6b (0.90 mg, 1.2 mmol) was dissolved in dichloromethane (12 mL), cooled to 0 ° C, and diethylamine Sulfur fluoride diethylamine trifluoride (2.60 g, 14.4 mmol) was reacted to room temperature for 20 hours. The reaction solution was cooled to 0 ° C, diluted with methylene chloride (20 mL), EtOAc (EtOAc) The organic phases were combined and dried over sodium sulfate. Filtration, concentrating, and the residue was purified by column chromatography ( petroleum ether / ethyl acetate = 10:1) to give white syrup (1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy) -5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(difluoromethyl)-6,8-dioxobicyclo[3.2.1] Octane 6c (0.67 g, yield 74%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.41 (s, 1H), 7.39-7.35 (m, 2H), 7.35-7.23 (m, 10H), 7.20 -7.12 (m, 3H), 6.91-6.84 ( m,3H), 6.83-6.74 (m, 2H), 6.06-5.74 (m, 1H), 4.90-4.72 (m, 4H), 4.43 (d, 1H), 4.26 (d, 1H), 4.02 (m, 6H), 3.85 (dd, 2H), 3.68 (d, 1H), 1.41 (t, 3H).

The third step: (1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-difluoromethyl-6 , 8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 6)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(difluoromethyl)-6,8-di oxabicyclo[3.2.1] Octane-2,3,4-triol

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl - 1 -(Difluoromethyl)-6,8-dioxobicyclo[3.2.1]octane 6c (0.60 g, 0.8 mmol), o-dichlorobenzene (1.30 g, 8.0 mmol) and palladium on carbon ( 0.65 g) was added to a methanol/tetrahydrofuran mixed solvent (16 mL, V/V = 1:1), and the reaction system was replaced with hydrogen three times, and reacted at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by column chromatography (methanol / methylene chloride = 1 : 20) to give white solid (1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-B) Oxy-3-fluorobenzyl)phenyl)-1-difluoromethyl-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol compound 6 (0.36 g, Yield 93%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.44 (s, 1H), 7.42-7.35 (m, 2H), 6.99-6.87 (m, 3H), 6.22-5.92 (m, 1H), 4.32 (d) , 1H), 4.05 (q, 4H), 3.89 (d, 1H), 3.81 (d, 1H), 3.65 (t, 1H), 3.54 (d, 1H), 1.38 (t, 3H);

HPLC: 98.65%.

Example 7

(1R, 2S, 3S, 4R, 5R, 7S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxo Bicyclo[3.2.1]octane-2,3,4,7-tetrol (compound 7)

(1R,2S,3S,4R,5R,7S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabi cyclo[3.2.1]octane- 2,3,4,7-tetraol

(1R, 2S, 3S, 4R, 5R)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-1-(hydroxymethyl) )-6,8-dioxo The ring [3.2.1] octane-7-one compound 2 (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL). EtOAc EtOAc minute. Saturated brine (5 mL) and ethyl acetate (10 mL) were added dropwise, and the mixture was evaporated. The combined organic layers were dried with anhydrous sodium The residue was separated by column chromatography (peel ether / ethyl acetate = 10:1) to give a colorless syrup (1R,2S,3S,4R,5R,7S)-5-(4-chloro-3-( 4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxobicyclo[3.2.1]octane-2,3,4,7-tetraol compound 7 (24 mg , yield 48%).

_{^{1 H NMR (400MHz, CD 3}} OD): δ7.53 (d, 1H), 7.44 (dd, 1H), 7.36 (d, 1H), 7.09 (d, 2H), 6.78 (d, 2H), 5.44 ( s, 1H), 4.03 (s, 2H), 3.98 (q, 2H), 3.87 (dd, 2H), 3.78 (d, 1H), 3.54 (t, 1H), 3.47 (d, 1H), 1.35 (t) , 3H).

Example 8

(1R,6R,7R,8S,9S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,5,10-trioxatricyclo[4.3.1.01, 4] decane-7,8,9-triol (compound 8)

(1R,6R,7R,8S,9S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,5,10-trioxatricyclo[4.3.1.01,4]de cane-7,8, 9-triol

(1R, 2S, 3S, 4R, 5R, 7S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6, 8-Dioxodicyclo[3.2.1]octane-2,3,4,7-tetrol Compound 7 (60 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL). 0.13 mmol). The reaction was stirred at room temperature for 1.5 hours. Dichloromethane (20 mL) and saturated brine (10 mL) were added to the mixture and the mixture was evaporated. The combined organic layers were dried with anhydrous sodium The residue was separated by column chromatography (dichloromethane/methanol = 20:1) to give colorless syrup (1R,6R,7R,8S,9S)-6-(4-chloro-3-(4-ethoxy) Benzyl)phenyl)-3,5,10-trioxatricyclo[4.3.1.01,4]nonane-7,8,9-triol compound 8 (12 mg, yield 22%).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.41 (s, 1H), 7.35 (s, 2H), 7.08 (d, 2H), 6.80 (d, 2H), 5.10 (s, 1H), 4.94 ( d, 1H), 4.57 (d, 1H), 4.05-3.94 (m, 4H), 3.83 (s, 1H), 3.77 (d, 1H), 3.69 (d, 1H), 1.35 (t, 3H).

Example 9

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(fluoromethyl)-6,8- Dioxodicyclo[3.2.1]octane-2,3,4-triol (compound 9)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(fluoromethyl)-6,8-diox Abicyclo[3.2.1]octane-2,3,4-triol

First step: (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-1-(fluoromethyl)-6,8-dioxobicyclo[3.2.1]octane (9a)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(f luoromethyl) -6,8-dioxabicyclo[3.2.1]octane

Under the nitrogen atmosphere, ((1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluoro) Benzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)methanol 6a (500 mg, 0.69 mmol) dissolved in dry dichloromethane (2 mL) 78 ° C. Triethylamine (487 mg, 4.83 mmol) was added, and DAST (669 mg, 4.14 mmol) was added dropwise. Heat to reflux and stir the reaction for 1 hour. A saturated sodium hydrogencarbonate solution (10 mL) was added to the mixture and the layers were separated. The aqueous layer was extracted with dichloromethane (10 mL×2). The residue was separated with EtOAc (EtOAc (EtOAc)EtOAc (EtOAc) 5-(4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(fluoromethyl)-6,8-dioxobicyclo[3.2.1]octane 9a (240 mg, yield 47%).

_{^{1 H NMR (300MHz, CDCl 3}} ): δ7.42-7.12 (m, 21H), 6.99 (dd, 2H), 6.92-6.73 (m, 4H), 5.01-4.85 (m, 3H), 4.74-4.66 ( m,1H), 4.52(d,1H), 4.18(dd,1H),4.07(ddd,4H),3.98-3.86(m,3H),3.86-3.63(m,4H),3.31(d,1H) , 3.08 (s, 3H), 1.42 (t, 4H);

¹⁹ F NMR (300 MHz, CDCl ₃ ): δ-134.59 (s, 1F), -230.11 (s, 1F).

Second step: (1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(fluoromethyl)- 6,8-Dioxabicyclo[3.2.1]octane-2,3,4-triol (Compound 9)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(fluoromethyl)-6,8-diox abicyclo[3.2.1] Octane-2,3,4-triol

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) at room temperature Phenyl)-1-(fluorine) Methyl)-6,8-dioxobicyclo[3.2.1]octane 9a (240 mg, 0.33 mmol), o-dichlorobenzene (482 mg, 83.3 mmol) and palladium on carbon (288 mg, w/w = 10%, The water content of 50% was dissolved in a mixed solvent of methanol/tetrahydrofuran (2 mL, V/V = 1:1), and the reaction was stirred for 3 hours under a hydrogen atmosphere. The reaction solution was suction filtered, and the filtrate was concentrated. The residue was separated by column chromatography (dichloromethane / methanol = 25:1) to afford white solid (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4- ethoxy) 3-fluorobenzyl)phenyl)-1-(fluoromethyl)-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol compound 9 (130 mg, produced Rate 86%).

^{1 H NMR (400MHz, MeOD)} : δ7.41 (d, 3H), 7.01-6.86 (m, 3H), 4.76 (d, 0.5H), 4.64 (d, 0.5H), 4.55 (d, 0.5H) , 4.43 (d, 0.5H), 4.18 (d, 1H), 4.09-4.00 (m, 4H), 3.79 (d, 1H), 3.65 (t, 1H), 3.58-3.49 (m, 2H), 1.38 ( t,3H);

¹⁹ F NMR (400 MHz, MeOD): δ - 136.55 (s, 1F), δ - 236.23 (s, 1F).

Example 10

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)1-fluoroethyl)-6,8 -dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 10)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-fluoroethyl)-6,8-dioxabic yclo[3.2. 1]octane-2,3,4-triol

First step: (S)-1-((1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy) Benzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)ethanol (10a)

(S)-1-((1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8 -di oxabicyclo[3.2.1]octan-1-yl)ethanol

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) in a nitrogen atmosphere at room temperature Benzene ,6,8-Dioxabicyclo[3.2.1]octane-1-carboxylic acid 5a (800 mg, 1.13 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to 0 ° C, and methyl magnesium bromide was added. 1.5 mL, 3 mol/L, 4.5 mmol) was stirred for 1.5 hours. Methanol (3 mL) was added to the reaction mixture, and stirring was continued for 5 minutes. Saturated brine (30 mL) was added, and extracted with ethyl acetate (40 mL×4), and brine (30 mL×2). The combined organic layers were dried with anhydrous sodium The residue was separated by column chromatography (EtOAc/EtOAc (EtOAc:EtOAc:EtOAc) (Benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)ethanol 10a (420 mg, yield 50%).

1H NMR (400MHz, CDCl ₃ ): δ 7.35-7.34 (d, 1H), 7.31-7.19 (m, 11H), 7.13-7.06 (m, 3H), 7.00-6.98 (d, 2H), 6.83-6.81 (d, 2H), 6.68-6.66 (d, 2H), 4.91-4.83 (m, 2H), 4.73-4.66 (t, 2H), 4.31-4.19 (dd, 1H), 4.15-4.12 (dd, 1H) , 4.08-3.71 (m, 10H), 3.61-3.58 (dd, 1H), 1.33-1.29 (t, 3H), 1.22-1.17 (m, 3H);

MS m / z (APCI): 741.3 [M + H 2 O].

Second step: (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -1-((S)-1-fluoroethyl)-6,8-dioxobicyclo[3.2.1]octane (10b)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((S)-1-fluo Roethyl)-6,8-dioxabicyclo[3.2.1]octane

(S)-1-((1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)ethanol 10a (575 mg, 0.8 mmol) dissolved in dichloromethane (16 mL), dry ice-ethanol under nitrogen In a low temperature system, diethylaminosulfur trifluoride (642 mg, 4.0 mmol) was added. The reaction was stirred for 30 minutes while maintaining the dry ice-ethanol low temperature system, and the reaction was further stirred at room temperature for 1.5 hours. The reaction solution was cooled to 0 ° C, methanol (3 mL) was added and stirred for 5 min. Saturated aqueous sodium chloride solution (500 mL) was added and extracted with dichloromethane (50 mL×3). The combined organic layers were dried with anhydrous sodium sulfate and filtered and evaporated. The residue was separated by column chromatography (EtOAc/EtOAc:EtOAc:EtOAc:EtOAc:EtOAc: Oxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((S)-1-fluoroethyl)-6,8-dioxobicyclo[3.2 .1] Octane 10b (530 mg, yield 57.9%).

MS m / z (APCI): 758.3 [M + H 2 O].

The third step: (1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-fluoroethyl )-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 10)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-((R)-1-fluoroethyl)-6,8-dioxabic yclo[3.2. 1]octane-2,3,4-triol

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) 1-((S)-1-fluoroethyl)-6,8-dioxobicyclo[3.2.1]octane 10b (530 mg, 0.73 mmol) in a mixed solvent of methanol and tetrahydrofuran (19 mL, V/ In V = 1: 1), o-chlorodiphenyl (1.08 g, 7.33 mmol) and palladium carbon (1.3 g, w/w = 10%, water content 50%) were added, and the reaction system was replaced with hydrogen three times to maintain a hydrogen atmosphere. The reaction was stirred for 2 hours. Filter and filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to give Compound 10, which was purified (yield: methylene chloride/methanol = 16:1) to afford white solid (1S, 2S, 3S, 4R, 5S)-5-(4 -Chloro-3-(4-ethoxybenzyl)phenyl)-1-((S)-1-fluoroethyl)-6,8-dioxobicyclo[3.2.1]octane-2, 3,4-triol compound 10-A (isomer 1,142 mg, Rf=0.35, yield 42%) and (1S,2S,3S,4R,5S)-5-(4-chloro-3-( 4-ethoxybenzyl)phenyl)-1-((R)-1-fluoroethyl)-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol Compound 10-B (isomer 2, 65 mg, Rf = 0.30, yield 19%).

HPLC conditions: Agilent 1260 analytical instrument, Agilent Zorbax SB-C18 4.6 x 100 mm reverse phase column, flow rate 1.0 ml.min ^-1 , injection volume 1 μl, gradient elution, 77% water: 23% acetonitrile for 16 minutes 10% water: 90% acetonitrile for 4 minutes, 100% acetonitrile for 3 minutes, UV detection wavelength 254nM;

Compound 10 isomer 1 (10-A): Rt = 9.79 min, 95.18%;

¹ H NMR (400 MHz, CD ₃ OD): δ 7.41 (S, 1H), 7.37-7.33 (S, 2H), 7.10-7.08 (d, 2H), 6.81-6.79 (d, 2H), 4.93-4.76 (m, 1H), 4.21-4.18 (dd, 1H), 4.03 (S, 2H) 4.01-3.96 (m, 2H), 3.84-3.83 (d, 1H), 3.70-3.59 (m, 2H), 3.51- 3.49 (d, 1H), 1.51-1.43 (dd, 3H), 1.37-1.34 (t, 3H).

Compound 10 isomer 2 (10-B): Rt = 9.75 min, 97.95%;

1H NMR (400MHz, CD ₃ OD): δ 7.42-7.40 (d, 1H), 7.36-7.35 (d, 2H), 7.10-7.08 (d, 2H), 6.81-6.79 (d, 2H), 4.99- 4.78 (m, 1H), 4.19-4.17 (d, 1H), 4.03 (S, 2H), 4.01-3.96 (m, 2H), 3.91-3.89 (d, 1H), 3.65-3.59 (m, 1H), 3.54-3.46 (m, 2H), 1.38-1.35 (t, 3H), 1.34-1.28 (m, 3H).

Example 11

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-((R)-1-fluoroethyl )-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 11)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-((R)-1-fluoroethyl)-6,8-dioxabicyclo [3.2.1]octane-2,3,4-triol

First step: (S)-1-((1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy) 3-fluorobenzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)ethanol (11a)

(S)-1-((1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phen yl )-6,8-dioxabicyclo[3.2.1]octan-1-yl)ethanol

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3) in a nitrogen atmosphere at room temperature -fluorobenzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-carboxylic acid 6b (0.73 g, 1.0 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ° C, Methylmagnesium bromide (1.3 mL, 3 mol/L, 4.0 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was lowered to 0 ° C, methanol (3 mL) was added and stirring was continued for 5 min. Saturated ammonium chloride solution (50 mL) was added, stirred for 2 minutes and layered. The aqueous layer was extracted with EtOAc (30 mL×4) It was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated. The residue was separated with EtOAc (EtOAc/EtOAcEtOAcEtOAcEtOAc Tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1 -Base) Ethanol 11a (250 mg, yield 53%).

Ms m/z (ESI): 739.3 [M+H ⁺ ];

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.41-7.40 (d, 1H), 7.39-7.26 (m, 12H), 7.22-7.14 (m, 3H), 6.90-6.88 (d, 3H), 6.83- 6.74 (m, 2H), 4.98-4.91 (m, 2H), 4.85-4.69 (m, 2H), 4.39-4.22 (m, 2H), 4.11-3.78 (m, 9H), 3.68-3.66 (dd, 1H) ), 1.43-1.42 (t, 3H), 1.25-1.24 (d, 3H).

Second step: (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-1-((S)-1-fluoroethyl)-6,8-dioxobicyclo[3.2.1]octane (11b)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-((S) -1-fluoroethyl)-6,8-dioxabicyclo[3.2.1]octane

(S)-1-((1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3) -fluorobenzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)ethanol 11a (0.25 g, 0.34 mmol) dissolved in dichloromethane (6 mL), nitrogen atmosphere Next, the temperature was lowered to -78 ° C, and diethylaminosulfur trifluoride (0.27 g, 1.69 mmol) was added, and the reaction was stirred for 30 minutes, and the reaction was further stirred at room temperature for 2 hours. The reaction solution was cooled to 0 ° C, methanol (3 mL) was added and stirred for 10 min. Saturated aqueous sodium chloride (40 mL) and saturated sodium bicarbonate (30 mL) were evaporated. The organic phases were combined and washed with brine brine (50 mL×2). Dry over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was separated by thin-layer chromatography (petroleum ether / ethyl acetate = 10:1 to 4:1) to give colorless oil (1S, 2S, 3S, 4R, 5S)-2,3,4-tri ( Benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-((S)-1-fluoroethyl)-6,8-di Oxybicyclo[3.2.1]octane 11b (120 mg, yield 48%).

MS m/z (APCI): 758 [M+H ₂ O];

The third step: (1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-((R)-1 -fluoroethyl)-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 11)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-((R)-1-fluoroethyl)-6,8-dioxabicyclo [3.2.1]octane-2,3,4-triol

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) at room temperature Phenyl)-1-((S)-1-fluoroethyl)-6,8-dioxobicyclo[3.2.1]octane 11b (140 mg, 0.73 mmol) is dissolved in a mixed solvent of methanol and tetrahydrofuran ( 5 mL, V/V = 1:1), o-chlorodiphenyl (278 mg, 1.89 mmol) was added, and the reaction system was replaced with nitrogen three times, and palladium carbon (168 mg, w/w = 10%, water content 50%) was added. The reaction system was replaced with hydrogen three times, and the reaction was stirred under a hydrogen atmosphere for 2 hours. The reaction solution was filtered, and the filter cake was washed with methanol/tetrahydrofuran (10 mL×3, V/V 1:1). The filtrate was concentrated under reduced pressure, and the residue was obtained from crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-((S)-1-fluoroethyl)-6,8-dioxobicyclo[3.2.1 Octane-2,3,4-triol compound 11-A (isomer 1,48 mg, Rf=0.30, yield 53%)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-((R)-1-fluoroethyl -6,8-Dioxabicyclo[3.2.1]octane-2,3,4-triol compound 11-B (isomer 2, 20 mg, Rf = 0.25, yield 22%).

HPLC conditions: Agilent 1260 analytical instrument, Agilent Zorbax SB-C18 4.6 x 100 mm reverse phase column, flow rate 1.0 ml.min ^-1 , injection volume 4 μL, gradient elution, 77% water: 23% acetonitrile for 16 minutes, 10% water: 90% acetonitrile for 4 minutes, 100% acetonitrile for 3 minutes, UV detection wavelength 254nM;

Compound 11 isomer 1 (11-A): Rt = 9.76 min, 94.58%;

_{^{1 H NMR (400MHz, CD 3}} OD): δ7.63 (s, 1H), 7.407-7.404 (d, 2H), 7.002-6.915 (m, 3H), 5.022-4.796 (m, 1H), 4.22-4.208 (d, 1H), 4.104-4.052 (m, 4H), 3.946-3.925 (d, 1H), 3.685-3.645 (m, 1H), 3.580-3.541 (t, 2H), 1.417-1.382 (m, 3H) , 1.352-1.308 (m, 3H);

MS m/z (ESI): 471.1 [M+H ⁺ ].

Compound 11 isomer 2 (11-B): Rt = 9.84 min, 97.01%;

_{^{1 H NMR (400MHz, CD 3}} OD): δ7.43 (s, 1H), 7.38-7.37 (d, 2H), 6.98-6.89 (m, 3H), 4.98-4.77 (m, 1H), 4.22-4.19 (dd, 1H), 4.08-4.03 (m, 4H), 3.86-3.84 (d, 1H), 3.71-3.62 (m, 2H), 3.56-3.48 (m, 1H), 1.51-1.43 (dd, 3H) , 1.40-1.36(t, 3H);

MS m/z (ESI): 471.1 [M+H ⁺ ].

Example 12

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2,2-difluoroethyl)-6,8 - dioxabicyclo[3.2.1]octane-2,3,4-triol (compound 12)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2,2-difluoroethyl)-6,8-dioxabic yclo[3.2.1] Octane-2,3,4-triol

First step: (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -1-(2-methoxyl) Vinyl)-6,8-dioxabicyclo[3.2.1]octane (12a)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2-methox yvinyl)-6 , 8-dioxabicyclo[3.2.1]octane

(Methoxymethyl)triphenylphosphonium chloride (3.8 g, 11.1 mmol) was added to dry tetrahydrofuran (37 mL) and cooled to 0. Potassium bis(trimethylsilyl)amide (11.1 mL, 1 mol/L toluene solution, 11.1 mmol) was added dropwise to the system with vigorous stirring, and the reaction was further stirred for 1 hour. (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8 - Dioxodicyclo [3.2.1] octane-1-carbaldehyde 5b (2.4 g, 3.7 mmol) was dissolved in tetrahydrofuran (10 mL), and this solution was added dropwise to the reaction system, stirred vigorously and allowed to warm to room temperature. , the reaction was 4 hours. The reaction system was poured into a saturated ammonium chloride solution (100 mL), ethyl acetate (100 mL) was added, The aqueous phase was extracted with dichloromethane (100 mL×2). The residue was purified by column chromatography ( petroleum ether / ethyl acetate = 20:1 to 8:1) to afford colorless oil (1S, 2S, 3S, 4R, 5S)-2,3,4-tri ( Benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2-methoxyvinyl)-6,8-dioxabicyclo[3.2 .1] Octane 12a (1.4 g, yield 57%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.44 (s, 1H), 7.34 (s, 2H), 7.33-7.21 (m, 11H), 7.15 (dt, 6.9Hz, 3H), 7.05 (d, 2H ), 6.84 (d, 2H), 6.73 (d, 2H), 6.00 (d, 1H), 4.83 (dd, 4H), 4.56 (dd, 2H), 4.23 (t, 1H), 4.13-4.02 (m, 1H), 4.02-3.91 (m, 5H), 3.87 (d, 1H), 3.78 (d, 1H), 3.66 (d, 1H), 3.53 (s, 3H), 1.38 (t, 3H).

Second step: 2-((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl)acetaldehyde (12b)

2-((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxa bicyclo[ 3.2.1]octan-1-yl)acetaldehyde

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1- (2-Methoxyvinyl)-6,8-dioxabicyclo[3.2.1]octane 12a (2.14 g, 2.93 mmol) was dissolved in dichloromethane (47 mL). Under vigorous stirring, formic acid (11.7 mL) was added dropwise, and the mixture was allowed to warm to room temperature overnight. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate (200 mL), and extracted with dichloromethane (200 mL×3). The organic phases were combined and dried over sodium sulfate. Filter and concentrate. The residue is purified by column chromatography (petroleum ether / ethyl acetate = 15:1 to 7:1) to give a colorless oil 2-((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl -6,8-Dioxabicyclo[3.2.1]oct-1-yl)acetaldehyde 12b (2.06 g, yield 98%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ9.61 (t, 1H), 7.45-7.39 (m, 1H), 7.39-7.30 (m, 5H), 7.29 (d, 2H), 7.28-7.22 (m, 5H), 7.21-7.11 (m, 3H), 7.05 (d, 2H), 6.91-6.83 (m, 2H), 6.78-6.70 (m, 2H), 4.89 (d, 1H), 4.86 (d, 1H) , 4.78 (d, 1H), 4.64 (d, 1H), 4.43 (d, 1H), 4.21 (d, 1H), 4.00 (d, 1H), 3.94 (dd, 3H), 3.81 (d, 1H), 3.77 (d, 1H), 3.74-3.65 (m, 1H), 2.79-2.65 (m, 2H), 1.38 (t, 3H).

The third step: (1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -1-(2,2-difluoroethyl)-6,8-dioxabicyclo[3.2.1]octane (12c)

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2,2-difluo roethyl) -6,8-dioxabicyclo[3.2.1]octane

2-((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) under nitrogen Phenyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl)acetaldehyde 12b (756 mg, 1.06 mmol) was dissolved in dichloromethane (11 mL). Diethylaminosulfur trifluoride (1.7 g, 10.6 mmol) was added dropwise with vigorous stirring, and the mixture was allowed to react to room temperature overnight. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen sulfate (60 mL) and evaporated. The organic phases were combined and dried over sodium sulfate. Filter and concentrate. The residue was purified by column chromatography (EtOAc (EtOAc:EtOAc:EtOAc) -5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2,2-difluoroethyl)-6,8-dioxabicyclo[3.2.1] Octane 12c (150 mg, yield 19.3%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.47-7.26 (m, 11H), 7.25-7.21 (m, 2H), 7.21-7.12 (m, 3H), 7.06 (d, 2H), 6.88 (d, 2H), 6.75 (d, 2H), 6.00 (tt, 1H), 4.93 (d, 1H), 4.88 (d, 1H), 4.77 (d, 1H), 4.70 (d, 1H), 4.35 (d, 1H) ), 4.20 (t, 1H), 4.11-4.03 (m, 1H), 4.00 (d, 1H), 3.99-3.90 (m, 3H), 3.80 (d, 1H), 3.75 (d, 1H), 3.66 ( t, 2H), 2.47-2.28 (m, 1H), 2.28-2.12 (m, 1H), 1.38 (t, 3H);

¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-111.60 (d, 1H), -113.19 (d, 1H).

The fourth step: (1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2,2-difluoroethyl) -6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (compound 12)

(1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2,2-difluoroethyl)-6,8-dioxabic yclo[3.2.1] Octane-2,3,4-triol

(1S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) 1-(2,2-difluoroethyl)-6,8-dioxabicyclo[3.2.1]octane 12c (220 mg, 0.3 mmol), palladium on carbon (264 mg, w/w = 10%, A water content of 50%) and o-chlorodiphenyl (438 mg, 3 mmol) were added to a methanol/tetrahydrofuran mixed solvent (1.5 mL, V/V = 1:1). The reaction system was replaced with hydrogen six times, and the reaction was stirred under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 25:1) to afford white solid (1S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy) Benzyl)phenyl)-1-(2,2-difluoroethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol compound 12 (100 mg, Yield 71.4%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.40-7.21 (m, 2H), 7.15 (d, 1H), 6.97 (d, 2H), 6.69 (d, 2H), 6.00 (t, 1H), 4.30 -4.03 (m, 2H), 3.99-3.75 (m, 4H), 3.55 (dd, 5H), 1.31 - 1.25 (m, 3H);

¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-112.08 (dd, 1H), -114.29 (dd, 1H);

MS m/z (APCI): 471.0 [M+H ⁺ ];

HPLC: 98.85%.

Example 13

(3aS,6S,7R,8R,8aS)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexahydro-2H-3a,6-epoxyfuran [3,2 -c]oxazepine-7,8-diol (compound 13)

(3aS,6S,7R,8R,8aS)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexahydro-2H-3a,6-epoxyfuro[3,2-c]oxepine-7,8- Diol

First step: 2-((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl)ethanol (13a)

2-((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxa bicyclo[ 3.2.1]octan-1-yl)ethanol

2-((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) at room temperature Phenyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl)acetaldehyde 12b (322 mg, 0.45 mmol) was dissolved in methanol (2.5 mL), cooled to 0 ° C Sodium borohydride (25.5 mg, 0.67 mmol) was stirred for 2 hours. A saturated ammonium chloride solution (5 mL), water (20 mL) was evaporated. The residue was purified by column chromatography (EtOAc (EtOAc:EtOAc:EtOAc) Oxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl)ethanol 13a (291 mg , yield 98%).

Second step: (3aS, 6S, 7R, 8S, 8aS)-7,8-bis(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexahydro -2H-3a,6-epoxy furo[3,2-c]oxepine(13b)

(3aS,6S,7R,8S,8aS)-7,8-bis(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexahydro-2H-3a,6-epoxyfuro[3,2 -c]oxepine

2-((1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) under nitrogen Phenyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl)ethanol 13a (270 mg, 0.38 mmol) was dissolved in dichloromethane (3.8 mL). Diethylaminosulfur trifluoride (341 mg, 1.9 mmol) was added dropwise with vigorous stirring, and the mixture was allowed to react to room temperature overnight. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate (60 mL) and extracted with dichloromethane (60mL×3). The organic phases were combined and dried over sodium sulfate. Filter and concentrate. The residue was purified by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc -(4-chloro-3-(4-ethoxybenzyl)phenyl)hexahydro-2H-3a,6-furo[3,2-c]oxazepine 13b (180 mg, yield 78%) .

_{^{1 H NMR (400MHz, CDCl 3}} ): δ7.41 (s, 1H), 7.37-7.27 (m, 6H), 7.17 (ddd, 4H), 7.05 (d, 2H), 6.81 (d, 2H), 6.74 (d, 2H), 4.87 (d, 1H), 4.70 (d, 1H), 4.40 (d, 1H), 4.29 (d, 1H), 4.18 (td, 3.6 Hz, 1H), 4.05-3.98 (m, 3H), 3.98-3.89 (m, 4H), 3.77 (d, 1H), 3.65 (d, 2H), 2.48 (dd, 1H), 1.97-1.85 (m, 1H), 1.38 (t, 3H).

The third step: (3aS, 6S, 7R, 8R, 8aS)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexahydro-2H-3a,6-epoxyfuran [3,2-c]oxazepine-7,8-diol (compound 13)

(3aS,6S,7R,8R,8aS)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexahydro-2H-3a,6-epoxyfuro[3,2-c]oxepine-7,8- Diol

(3aS,6S,7R,8S,8aS)-7,8-bis(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)hexahydrogenate at room temperature -2H-3a,6-epoxyfuro[3,2-c]oxazepine 13b (180 mg, 0.25 mmol), palladium on carbon (216 mg, w/w = 10%, water content 50%) and o-chlorodichloride Benzene (367 mg, 2.5 mmol) was added to a methanol/tetrahydrofuran mixed solvent (2.5 mL, V/V = 1:1). The reaction system was replaced with hydrogen six times, and the reaction was stirred under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 25:1) to afford white solid (3aS,6S,7R,8R,8aS)-6-(4-chloro-3-(4-ethoxy) Benzyl)phenyl)hexahydro-2H-3a,6-epoxyfuro[3,2-c]oxazepine-7,8-diol compound 13 (120 mg, yield 88%).

^{1 H NMR (400MHz, MeOD)} : δ7.42 (s, 1H), 7.40-7.30 (m, 2H), 7.08 (d, 2H), 6.85-6.75 (m, 2H), 4.18 (t, 1H), 4.10 (tt, 1H), 4.03 (s, 2H), 4.02-3.93 (m, 3H), 3.85-3.70 (m, 1H), 3.59 (t, 2H), 3.53 (d, 1H), 2.53-2.38 ( m, 1H), 2.01-1.90 (m, 1H), 1.35 (t, 3H);

MS m/z (APCI): 433.0 [M+H ⁺ ];

HPLC: 96.19%.

Biological test

1. SGLT-2 in vitro inhibition test

The activity of the compounds of the invention was evaluated using the SGLT-2 in vitro inhibition assay.

The test method is as follows: The test compound is dissolved in DMSO (dimethyl sulfoxide) to prepare a stock solution, which is then diluted to the desired concentration. One day before the start of the experiment, hSGLT-2 cells were plated in 96-well plates and cultured in F12 complete medium. After 48 hours of culture, each well of cells was washed 3 times with a buffer of pH 7.4. 100 μl of a buffer containing different test compounds and [14C]-α-methyl-glucoside (10 μCi/mL) was added to each well. After incubation at 37 ° C for 2 hours, the reaction was stopped and washed 5 times with buffer. The cells were fully lysed by the addition of 20 μl of pre-cooled 100 mM NaOH per well. Finally, 80 μl of Microscint 40 was added to each well and examined with a MicroBeta Trilux (PerkinElmer) liquid scintillation test. The test results are shown in Table 1.

Table 1 results of SGLT-2 in vitro inhibition test

Compound number	IC50(SGLT-2)/nM
		Compound 5	4.53
Compound 6	10.81
		Compound 7	38.48
Compound 9	13.92
		Compound 10-A	3.84

Compound 10-B	3.04
		Compound 12	4.87

Conclusion: The compounds of the invention significantly inhibit SGLT-2 activity.

2. Urine sugar test

Research purposes

The activity of the compounds of the present invention in rats was evaluated using a urine glucose test.

Test compound

Compound 5, Compound 6, Compound 8, Compound 9, Compound 10-A, Compound 10-B, Compound 11-A, Compound 11-B.

Test animal

SD (Sprague Dawley) rats, 8 weeks old, male, purchased from Chengdu Dashuo Biotechnology Co., Ltd., animal production certificate number: SOXK (chuan) 2008-24.

experiment method

First, 8.0 mg of the test compound was weighed, dissolved in 0.4 mL of DMSO, and then added with 7.6 mL of physiological saline, and mixed to prepare a 1.0 mg/mL solution. The glucose was weighed and dissolved in ultrapure water to prepare a 50% glucose solution for use. After the SD rats were fasted for 18 hours, the urine volume and body weight of each animal were measured, and the animals were grouped according to the body weight, and 3 rats per group. The rats were then individually loaded into metabolic cages. The test compound was administered to each animal at 10 mg/kg, and the control group was administered with physiological saline. After 15 minutes, all animals received oral glucose solution (4 g/kg). After 1 hour, the animals were added with feed. After 24 hours, the urine of the animals was collected, and the urine sugar content was tested using a urine sugar kit. The test results are shown in Table 2.

Table 2 urine sugar test results

Compound number	Urine sugar amount (mg)
		Saline control	0.22
Compound 5	2135
		Compound 6	1013
Compound 9	911
		Compound 10-A	1304
Compound 10-B	1379
		Compound 11-A	579
Compound 11-B	741

Conclusion: The compounds of the invention can significantly increase the amount of urine sugar.

3. Pharmacokinetic parameters

Research purposes

The peak plasma concentration (Cmax), area under the curve (AUG), half-life (T _1/2 ), and bioavailability (F) of the compounds of the present invention were tested in SD rats.

Test compound

Compound 5

Test animal

SD rats, 180-240 g, male, 6 rats, purchased from Shanghai Slack Test Animals Co., Ltd., animal production certificate number: SCXK (SH) 2007000546479.

experiment method

SD rats were fasted to water overnight, 3 rats were orally administered with 10 mg/kg, and the solvent was 0.5% MC (1% Tween 80); 3 rats were injected intravenously at a dose of 1 mg/kg, and the solvent was 10% ethanol + 45 % propylene glycol + 45% water. The oral administration group collected blood at 0, 15 and 30 minutes and 1, 2, 4, 8, 12 and 24 hours before and after administration; the intravenous administration group before administration and after administration 0, 5 and 15 Blood was collected at minutes and 1, 2, 4, 8, 12, and 24 hours. Plasma samples were processed after centrifugation with Verapamil and glibenclamide as internal standards. The API4000 LC/MS was used to test and calculate the pharmacokinetic parameters. The test results are shown in Table 3.

Table 3 pharmacokinetic parameters

Conclusion: The pharmacokinetic data of the compounds of the examples of the present invention are better, and the oral bioavailability is high.

Claims (16)

1. a compound of the formula (II): or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

   

   among them:

   W is selected from -O- or -NR ¹² -;

   R ¹ and R ² are each independently selected from H, F, Cl, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

   Alternatively, R ¹ and R ² may form =0;

   R ³ , R ^3a and R ^3b are each independently selected from H, F, Cl, hydroxy, C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy being optionally further Substituted to 5 substituents selected from F, Cl, hydroxy, -CH ₂ F, -CHF ₂ or -CF ₃ ;

   R ^{3C is} selected from a hydroxyl group;

   R ^3C , R ¹ or R ² and any one of R ³ , R ^3a , R ^3b form a 4-5 membered ring;

   R ⁸ and R ⁹ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy, -O-(CH ₂ ) _m -OR ¹³ , -(CH ₂ ) _m -OR ¹³ or -(CH ₂ ) _m -R ¹³ , the hydroxyl group, alkyl group or alkoxy group optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, cyano, C _1-4 alkyl, C _{1-4 alkoxy, - (CH 2) m -OR} 13 or - (CH _{2) m} -R ^{13 is} substituted with a substituent;

   R ^{12 is} selected from H or C _1-4 alkyl;

   R ^{13 is} selected from C _3-6 cycloalkyl, 3 to 6 membered heterocyclic, C _6-10 aryl, 5 to 12 membered heteroaryl, 5 to 12 membered spiro group, 4 to 12 membered bridged ring group. Or a 4- to 12-membered ring group, and the cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, spiro group, bridged ring group or cyclohexyl group is further further selected from 0 to 5 selected from F Substituted with a substituent of Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , =0, hydroxy, C _1-3 alkyl or C _1-3 alkoxy; and the snail The cyclo, bridged or bicyclic group may contain from 0 to 5 atoms or groups selected from N, O or S(=O) _n , the heteroaryl or heterocyclic group containing from 1 to 5 An atom from N, O or S;

   requirement is:

   Selected from the following:

   When R ¹ and R ^{2 are} both H, R ⁹ is H, and W is -O-, it is selected from the following cases:

   (1) R ^{3 is} selected from H, R ^{3a is} selected from H, F, Cl or C _1-4 alkyl, and R ^{3b is} selected from F, Cl, C _1-4 alkyl, monofluoro substituted C _1-4 alkane a difluoro-substituted C _1-4 alkyl group or a trifluoro-substituted C _1-4 alkyl group, and when R ^3a is H, R ^{3b is} not F or Cl;

   (2) R ^3b and R ^3c form a 5-membered heterocyclic ring, and the heterocyclic ring contains 1-2 selected from O atoms;

   When R ¹ and R ^{2 are} both H, W is -O-, and R ^{9 is} not H, R ^{3 is} selected from H, and R ^3a and R ^3b are each independently selected from H, F, Cl, C _1-4 alkyl. a monofluoro-substituted C _1-4 alkyl group, a difluoro-substituted C _1-4 alkyl group or a trifluoro-substituted C _1-4 alkyl group;

   n is selected from 0, 1 or 2;

   m is selected from 0, 1, or 2.
2. A compound according to claim 1 or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

   W is selected from -O- or -NR ¹² -;

   R ¹ and R ² are each independently selected from H, F, hydroxy, C _1-2 alkyl or C _1-2 alkoxy;

   Alternatively, R ¹ and R ² may form =0;

   R ³ , R ^3a and R ^3b are each independently selected from H, F, hydroxy or C _1-4 alkyl, and the alkyl group is optionally further substituted with 0 to 5 substituents selected from F, Cl or hydroxy groups. Replace

   R ^{3C is} selected from a hydroxyl group;

   R ^{8 is} selected from H, F, Cl, hydroxy, C _1-4 alkoxy, -O-(CH ₂ ) ₂ -O-cyclopropyl, -(CH ₂ ) _m -OR ¹³ or -(CH ₂ ) _m -R ¹³ ;

   R ^{9 is} selected from H, F, methyl, ethyl, methoxy or ethoxy;

   R ^{12 is} selected from H, methyl or ethyl;

   R ^{13 is} selected from C _3-6 cycloalkyl or 3 to 6 membered heterocyclic group, and said heterocyclic group contains 1 to 3 atoms selected from N, O or S;

   requirement is:

   When R ¹ and R ^{2 are} both H, R ⁹ is H, and W is -O-, it is selected from the following cases:

   (1) R ^{3 is} selected from H, R ^{3a is} selected from H, F, Cl or C _1-2 alkyl, and R ^{3b is} selected from F, Cl, C _1-2 alkyl, monofluoro substituted C _1-2 alkane a difluoro-substituted C _1-2 alkyl group or a trifluoro-substituted C _1-2 alkyl group, and when R ^3a is H, R ^{3b is} not F or Cl;

   (2) R ^3b and R ^3c form a 5-membered heterocyclic ring, and the heterocyclic ring contains 1 O atom;

   When R ¹ and R ^{2 are} both H, W is -O-, and R ^{9 is} not H, R ^{3 is} selected from H, and R ^3a and R ^3b are each independently selected from H, F, Cl, C _1-2 alkyl. Or a difluoro-substituted C _1-4 alkyl group;

   m is selected from 0 or 1.
3. A compound according to claim 2, or a stereoisomer, hydrate, solvate thereof, pharmaceutically acceptable Salt, co-crystal or prodrug, of which:

   W is selected from -O- or -NR ¹² -;

   R ¹ and R ² are each independently selected from H, F, hydroxy, methyl, ethyl, methoxy or ethoxy;

   Alternatively, R ¹ and R ² may form =0;

   R ³ , R ^3a and R ^3b are each independently selected from H, F, hydroxy, methyl, ethyl, -CH ₂ F, -CHF ₂ or -CF ₃ ;

   R ^{8 is} selected from the group consisting of H, F, Cl, methoxy, ethoxy, cyclopropyl, -O-oxocyclopentyl or -O-(CH ₂ ) ₂ -O-cyclopropyl;

   R ^{9 is} selected from H or F;

   R ^{12 is} selected from H or methyl;

   requirement is:

   When R ¹ and R ^{2 are} both H, R ⁹ is H, and W is -O-, it is selected from the following cases:

   (1) R ^{3 is} selected from H, R ^{3a is} selected from H, F or methyl, R ^{3b is} selected from F, -CHF ₂ or -CF ₃ , and when R ^3a is H, R ^{3b is} not F;

   (2) R ^3b and R ^3c form a 5-membered heterocyclic ring, and the heterocyclic ring contains 1 O atom;

   When R ¹ and R ^{2 are} both H, W is -O-, and R ⁹ is F, R ^{3 is} selected from H, and R ^3a and R ^3b are each independently selected from H, F, methyl, ethyl, -CH ₂ F, -CHF ₂ or -CF ₃ .
4. A compound according to any one of claims 1 to 3, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, the compound of which is selected from the group consisting of:

   

   
5. The compound according to any one of claims 1 to 4, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the salt is selected from the group consisting of sodium salts, Potassium salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, triethylamine salt, pyridinium salt, methylpyridine salt, 2,6-lutidine salt, ethanolamine salt, diethanolamine salt, three Ethanolamine salt, cyclohexylamine salt, dicyclohexylammonium salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, trifluoroacetate, acetate, maleate , tartrate, citrate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate , glucuronate, galacturonate, citrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, besylate, methane An acid salt, an ethanesulfonate salt, a triflate salt or a combination thereof.
6. The compound according to any one of claims 1 to 4, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein the eutectic is the compound a co-crystal formed with an amino acid, an organic acid, water, and/or other solvent, wherein the amino acid is selected from the group consisting of L-lysine, L-tryptophan, L-phenylalanine, L-threonine, L-isoluminescence Acid, L-leucine, L-valine, L-arginine, L-histidine, L-alanine, L-aspartic acid, L-asparagine, L-cysteine Acid, L-glutamine, L-glutamic acid, L-methionine, L-valine, L-serine, L-tyrosine, L-glycine, L-pyroglutamic acid, D -lysine, D-tryptophan, D-phenylalanine, D-threonine, D-isoleucine, D-leucine, D-valine, D-arginine, D - histidine, D-alanine, D-aspartic acid, D-asparagine, D-cysteine, D-glutamine, D-glutamic acid, D-methionine, D-valine, D-serine, D-tyrosine, D-glycine or D-pyroglutamic acid.
7. The compound according to claim 6 or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein said co-crystal is said compound with amino acid, water and/or Or a co-crystal formed by another solvent selected from the group consisting of L-phenylalanine, L-valine or L-pyroglutamic acid, the solvent being selected from the group consisting of 1,2-ethanediol, 1,2- Propylene glycol or 1-methyl-1,2-ethanediol.
8. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 7, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt thereof, or a total of A crystal or prodrug and/or one or more additional therapeutic agents and a pharmaceutically acceptable carrier or excipient.
9. The pharmaceutical composition according to claim 8 wherein said other therapeutic agent comprises:

   (a) a SGLT-2 inhibitor or a pharmaceutically acceptable salt, and/or

   (b) a DPP-IV inhibitor or a pharmaceutically acceptable salt, and/or

   (c) biguanides, thiazolidinediones, sulfonylureas, levonides, alpha-glucosidase inhibitors or glucagon-like peptide-1 analogues, or pharmaceutically acceptable salts thereof or medicine.
10. The pharmaceutical composition according to claim 9, wherein said SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, cangliflozin, aglilipin, epagliflozin, empagliflozin, tovre Net, Lusley Net, Regal, Net, or Nete.
11. The pharmaceutical composition according to claim 9, wherein said DPP-IV inhibitor is selected from the group consisting of linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, and dinacol Ting, carbagliptin, meglitin, dygliptin, tiglietine, gigliptin or troglitazone.
12. The pharmaceutical composition according to claim 9, wherein the biguanide therapeutic agent is selected from metformin or phenformin, and the thiazolidinedione therapeutic agent is selected from the group consisting of ciglitazone, pioglitazone, rosiglitazone, Troglitazone, glitazone or daglitazone, sulfonylurea therapeutic agent selected from the group consisting of glimepiride, tolbutamide, glibenclamide, glibenclamide, gliclazin, glibenclamide Pyrazine or gliclazide, the therapeutic agent of the linnaphine is selected from the group consisting of nateglinide, repaglinide or mitiglinide, and the alpha-glucosidase inhibitor is selected from the group consisting of acarbose, voglibose or Miglitol, a glucagon-like peptide-1 analog is selected from exenatide or liraglutide.
13. The compound according to any one of claims 1 to 7, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal thereof or prodrug thereof, for preparing a sodium-dependent glucose transporter inhibitor Application in .
14. The use according to claim 13, wherein the sodium-dependent glucose transporter inhibitor is used for the preparation of a medicament for treating a metabolic disease.
15. The use according to claim 14, wherein said metabolic disease is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or glycerol High levels, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension.
16. The use according to claim 15, wherein said diabetes is type II diabetes.