WO2010102512A1 - C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present invention discloses C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof, especially C-aryl glucoside derivatives presented by formula (I), pharmaceutical salts and stereoisomers thereof, methods for their preparation, or pharmaceutical compositions containing the derivatives, and their use as a therapeutic agent, especially use as drugs for treating diabetes and related diseases, in which each substituent group of formula (I) is defined in the specification.

Description

 C-aryl glucoside derivative, preparation method thereof and application thereof in medicine

 The present invention relates to a C-aryl glucoside derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or all stereoisomers thereof, a process for producing the same, and a pharmaceutical composition containing the same, It is used as a therapeutic agent, particularly as a drug for treating diseases such as diabetes. n J53⁄4 grave

 Diet control and exercise therapy are two essential methods in the early stages of treating diabetes. When these methods are not sufficient to control the condition, insulin or oral hypoglycemic agents must be used for treatment. At present, drugs have been used as hypoglycemic agents, such as biguanide compounds, sulfonylurea compounds, insulin resistance improving agents, and α-glucosidase inhibitors. However, these hypoglycemic agents limit their use due to various side effects. For example, biguanide compounds are prone to cause lactic acidosis, sulfonylureas cause significant hypoglycemia, and insulin resistance improvers are prone to edema and heart failure. And α-glucosidase inhibitors cause abdominal pain, bloating, and diarrhea. In view of the above, people hope to develop a new type of diabetes treatment that is safer and can effectively lower blood sugar.

 Cellular regulation of glucose transport is achieved through regulation of the functions of glucose-transporting proteins (passive) (GLUTs) and sodium-dependent glucose (active) cotransporter proteins (SGLTs), in which SGLTs family members absorb glucose in the gut It plays a particularly important role in the process of renal glucose reabsorption, making it an ideal target for controlling blood sugar and treating diabetes.

 Plasma glucose usually passes through the glomerulus of the kidney and actively attaches to the tubular epithelial cells and is reabsorbed. In the kidney, 90% of glucose reuptake occurs in the S1 fragment epithelial cells of the proximal cortical epithelium of the renal cortex, and SGLT2 may be the major transporter responsible for this reuptake. SGLT2 is a 672 amino acid protein containing 14 transmembrane segments that are expressed primarily in the pre-S1 segment of the renal proximal tubule. Substrate specificity, sodium dependence and localization of SGLT2 are consistent with the properties of the previously described human renal cortical proximal tubules characterized by high capacity, low affinity, sodium-dependent glucose transporters. In addition, hybridization deletion studies indicated that SGLT2 is the major Na+/glucose cotransporter in the proximal tubule S1 segment, since virtually all sodium-dependent glucose transport activities encoded in rat renal cortical mRNA are specific for rat SGLT2. Antisense oligonucleotide inhibition.

 For humans, the variation in SGLT2 is associated with the heritability of renal glucosuria, which provides further evidence for the primary role of SGLT2 in renal reuptake of glucose. Therefore, it has been developed to selectively inhibit the reabsorption of glucose by the kidneys, and at the same time enhance the excretion of glucose, thereby achieving a longer-term hypoglycemic effect, making it an ideal drug for controlling blood sugar and treating diabetes.

Studies have found that C-aryl glucoside SGLT2 inhibitors are treated like oral active antidiabetic drugs. use. In particular, it has been found that these C-aryl glucoside SGLT2 inhibitors can be used to treat or delay the onset or progression of diabetes, especially type I and type II diabetes, including diabetic complications such as retinopathy, neuropathy, kidney disease or delay. Wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, high blood fatty acid or glycerol levels, obesity, hyperlipidemia including hypertriglyceridemia, X Syndrome, hypertension, atherosclerosis and related diseases, as well as for improving high-density lipid levels. The X syndrome is described in detail in Johammsson, J Clin. Endrocrinol. Metal, 82, 727-34 (1997).

 Such C-aryl glucoside SGLT2 formulations can be used alone or in combination with existing therapeutic agents, including sulfonamides, thiazolidinediones, metformin and insulin, to avoid the potential side effects of taking these other drugs. Further details regarding C-aryl glucosides and their derivatives can be found in CN 1989 132 A, CN 167 682 A and CN 1 829 729 A, all of which are incorporated herein by reference.

 In summary, SGLT inhibitor compounds, especially SGLT2 inhibitor compounds, are the most promising anti-diabetic drugs.

 It is an object of the present invention to provide a medicament which has a better inhibition of SGLT2 activity and which can be used for the treatment or palliative treatment of diabetes or the like. ' Invention content

 In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a compound of the formula (I), and their tautomers, enantiomers, diastereomers, racemates and Pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs.

 among them:

R ^l , R ² , R ³ and R ⁴ are each independently selected from a hydrogen atom, a fluorenyl group, an aryl group, an aryl fluorenyl group, —C(0)R ^a or —C(0)OR ^a , wherein the alkyl group, The aryl or aralkyl group is optionally further substituted with one or more substituents selected from halogen, nitro, hydroxy, cyano, decyloxy or aryl;

R ⁵ and R ⁶ are each independently selected from a hydrogen atom, a halogen, a nitro group, a hydroxyl group, a cyano group, a decyl group, an alkoxy group, —CF ₃ , or —OCF ₃ , preferably a hydrogen atom or a halogen;

R ⁷ and R ⁸ are each independently selected from the group consisting of a hydrogen atom, a halogen, a nitro group, a hydroxyl group, a cyano group, an alkyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ^a , -C(0) OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0)OR ^a or -C(0)NR ^b R ^e , wherein The alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, nitro, cyano, decyl, hydroxy, decyloxy, cycloalkyl, Aryl, heteroaryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0) OR ^a ,

Substituted by a substituent of -N ^b R ^c or -C(0)NR ^b R ^e ;

R ^{9 is} selected from the group consisting of hydrogen atom, halogen, nitro group, hydroxyl group, cyano group, decyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, -OR ^a , -C(0)OH, -C( 0) OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0)OR ^a or -C(0)NR ^b R ^c , wherein the sulfhydryl group, ring 垸Or a heterocycloalkyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of halogen, nitro, cyano, decyl, hydroxy, decyloxy, cycloalkyl, aryl, heteroaryl ,

-OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0)OR ^a , -NR ^b R ^c or

Substituted by a substituent of -C(0)NR ^b R ^e ;

R ^{a is} selected from the group consisting of fluorenyl, cyclodecyl, heterocycloalkyl, aryl, aralkyl or heteroaryl, wherein the fluorenyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl is optional Further one or more selected from the group consisting of halogen, nitro, hydroxy, cyano, decyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ^d , -C(0) OH,

-C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or -C(0)NR ^e R ^f Substituted by a substituent;

R ^b and R ^e are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, cyclodecyl group, heterocyclic fluorenyl group, aryl group or hetero aryl group an aryl group optionally further substituted with one or more substituents selected from halo, nitro, hydroxy, cyano, alkyl, alkoxy embankment, cycloalkyl, heterocyclyl embankment, aryl, heteroaryl ', -OR ^d, -C(0)OH, -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or -C Substituting (0) a substituent of NR ^e R ^f ;

Alternatively, R ^b and R ^e together with the attached atom form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more N, 0 or S atoms, and 3 to 8 members. The heterocyclic group is optionally further selected from one or more selected from the group consisting of halogen, nitro, hydroxy, cyano, alkyl, alkoxy, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, -OR ^d , -C(0)OH, -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or - Substituted by a substituent of C(0)NR ^e R ^f ;

R ^{d is} selected from the group consisting of an indenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, an aryl group or a heteroaryl group;

R ^e and R ^f are each independently selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group, an aryl group or a heteroaryl group;

n is 0, 1 or 2. The compound of the formula (I) may contain an asymmetric carbon atom and may therefore exist in the form of an optically pure diastereomer, a mixture of diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates. Or exist as a meso compound. The invention includes all of these forms. Mixtures of diastereomeric mixtures, diastereomeric racemates or diastereomeric racemates can be isolated by conventional methods, for example by column chromatography, thin layer chromatography and HPLC, etc. _≤ General formula (I of the invention) Preferred compounds shown include, but are not limited to: (2 & 3i?,4/?,5S,6i?)-2-[4-chloro-3-(4-ethoxy-2,6-

12 difluoro-benzyl)-naphthalene-1 -yl]-6-hydroxymethyl-tetrahydropyran

 -3,4,5-triol

 (2S,3i?,4 ?,5 & 6W)-2-[4-chloro-3-(4-ethoxy-3,5-

13 difluoro-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran

 -3,4,5-triol

 (2 & 3i?,4 5 & 6/?)-2-{4-chloro-3-[4-(tetrahydrofuran

14-3-Oxo)-benzyl]-naphthalene small group}-6-hydroxymethyl-tetrahydropyran a 3,4,5-triol or a pharmaceutically acceptable salt thereof or all stereoisomers thereof. Another aspect of the invention relates to a compound of the formula (IA), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which is an intermediate for the synthesis of a compound of the formula (:I):

R^R ^{9 is} as defined in the formula (I);

R ^{1 () is} selected from a hydrogen atom or an alkyl group. Preferred compounds of the formula (IA) of the present invention include, but are not limited to, - compounds

 Structure naming

 Numbering

 (2 & 3 4 & 5i?, 6i?)-3,4,5-tribenzyloxy-6-benzyloxylimethyl-2-[4-chloro-3-(4-ethoxy-benzyl -naphthalene-1 -yl]-tetrahydropyran-2-ol

 (2 & 3i?, 4 & 5 6i?)-3,4,5-tribenzyloxy-6-benzyloxy

2c methyl-2-[4-chloro-3-(3-fluoro-4-methoxy-benzyl)-naphthalene-1-yl]-tetrahydropyran-2-ol

 (2&3 4 & 5i?,6i?)-3,4,5-tribenzyloxy-6-benzyloxy

3c _ methyl ₂ - [4-chloro-3- (2-fluoro-4-methoxy - benzyl) --l - yl tetrahydropyran-2-ol

 (2 & 3/?,4S,5 6/?)-3,4,5-tribenzyloxy-6-benzyloxy

4e methyl-2-[4-chloro-3-(3,5-difluoro-4-methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol (2 & 3 ?,4S,5 6 ?)-3,4,5-tribenzyloxy-6-benzyloxy

5e methyl-2-[4-chloro-3-(2,3-difluoro-4-methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol

 (2 & 37?,4 & 5S,6i?)- 2-[4-chloro-3-(3-fluoro-4-hydroxy-benzyl

6d)-naphthalen-1-yl]-6-hydroxymethyl-2-methoxy-tetrahydropyran

 -3,4,5-triol

 (2S,3 ?,4 & 5i?,6i?)-3,4,5-tribenzyloxy-6-benzyloxy

7f methyl-2-[4-chloro-3-(4-ethyl-benzyl)-naphthalene-1-yl]-tetrahydropyran-2-ol

 (2 & 3i?,4S,5 & 6i?)-2-[4-chloro-3-(4-methylthio-benzyl

8e)-naphthalene-1-1-yl]-6-hydroxymethyl-2-methoxy-tetrahydropyran

 -3,4,5-triol

 (2 & 3 ?, 4 & 5S, 6i?)-2-[4-chloro-3-(4-methoxy-benzyl

9c)-naphthalene-1-yl]-6-hydroxymethyl-2-methoxy-tetrahydropyran -3,4,5-three$

 (2 & 3 4 & 5 & 6i?)-2-[4-chloro-3-(4-cyclopropyl-benzyl lOd)-naphthalen-1-yl]-6-hydroxymethyl-2-methoxy Base-tetrahydropyran

 -3,4,5-triol

 (2 & 3 4 & 5 & 6i?)-2-[4-chloro-3-(4-ethoxy-2,3-llf difluoro-benzyl)-naphthalene-1-yl]-6-hydroxy Methyl-tetrahydropyran

 -2,3,4,5-01

 (2 & 3i?,4 & 5 & 6i?)-2-[4-chloro-3-(4-ethoxy-2,6-

12f difluoro-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-2-methoxy-tetrahydropyran-3,4,5-triol

 (2&3 45,5i?,6i?)-3,4,5-tribenzyloxy-6-benzyloxy

13f methyl-2-[4-chloro-3-(4-ethoxy-3,5-difluoro-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol

 (2S, 3i?, 4 & 5S, 6i?)-2-[4-chloro-3-(4-hydroxy-benzyl)-

14c naphthalen-1-yl]-6-hydroxymethyl-2-methoxy-tetrahydropyran

 -3,4,5-triol

Or a pharmaceutically acceptable salt thereof or all stereoisomers thereof. The present invention relates to a process for the preparation of a compound of formula (I), which process comprises:

 Dehydroxy or oxirane of a compound of formula (IA) to form a compound of formula (I);

R'~R ^{9 is} as defined in the general formula (I);

The definition of R ^IQ is as described in the general formula (IA). The present invention relates to a process for the preparation of a compound of the formula (IA), which process comprises:

 The amino group and the cyano substituted naphthalene compound are reacted with a halogen to form a halogenated naphthalene compound;

K ^N

The amino group on the halogenated naphthalene compound is diazotized to form an R ⁵ -substituted naphthalene compound with a nucleophilic reagent;

The cyano group on the R ⁵ substituted naphthalene compound is hydrolyzed under basic conditions to be acidified to form a carboxy substituted naphthalene compound;

a carboxy-substituted naphthalene derivative is reacted with oxalyl chloride under basic conditions to form an acid chloride-substituted naphthalene derivative;

The acid chloride-substituted naphthalene derivative is subjected to acylation with a substituted benzene under catalytic conditions to form a ketone compound;

The carbonyl group in the ketone compound is reduced to a methylene group;

 ( 1A )

 The resulting methylene reduction product is coupled with a substituted lactone to form a compound of the formula (IA);

 among them:

R'~R ^{9 is} as defined in the general formula (I);

R ^{10 is} as defined in the general formula (IA);

 X is a halogen;

R ^ R ¹⁴ are each independently selected from a hydrogen atom, an alkyl group, an aryl group, an aryl fluorenyl group, a silane group, -C(0)R ^a or -C(0)OR ^a , wherein the fluorenyl group, the aryl group or the aryl group The thiol is optionally substituted with one or more substituents selected from halogen, nitro, hydroxy, cyano, decyloxy or aryl;

R ^{a is} selected from alkyl, cyclodecyl, heterocycloalkyl, aryl, aralkyl or heteroaryl, wherein the fluorenyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl is optional Further one or more selected from the group consisting of halogen, nitro, hydroxy, cyano, alkyl, alkoxy, cyclohexyl, heterocyclic fluorene, aryl, heteroaryl, -OR ^d , -C(0)OH , -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or -C(0)NR ^e R Substituted by a substituent of ^f ;

R ^b and R ^e are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the cycloalkyl group, the heterocyclic fluorenyl group, the aryl group or the hetero aryl group an aryl group optionally further substituted with one or more substituents selected from halo, nitro, hydroxy, cyano group: alkyl with, embankment group, cycloalkyl group embankment, embankment heterocyclyl, aryl, heteroaryl, -OR ^d, - C(0)OH, -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or -C( 0) substituted by a substituent of NR ^e R ^f ;

Alternatively, R ^b and R ^e together with the attached atoms form a 3 to 8 membered heterocyclic group, wherein the 3 to 8 membered heterocyclic group contains one or more N, 0 or S atoms, and 3 to 8 members. heterocyclyl is further optionally substituted with one or more substituents selected from halo, nitro, hydroxy, cyano, alkyl, alkoxy embankment, cycloalkyl, heterocyclyl embankment, aryl, heteroaryl, -OR ^d, -C(0)OH, -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or -C Substituting (0) a substituent of NR ^e R ^f ;

R ^{d is} selected from alkyl, cyclodecyl, heterocycloalkyl, aryl, arylalkyl or heteroaryl;

R ^e and R ^f are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, an aryl group or a heteroaryl group;

n is 0, 1 or 2. Further, the present invention relates to the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or all stereoisomers thereof, for the manufacture of a medicament for the treatment or delay of the development or onset of the following diseases, wherein The disease 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, high Triglycerideemia, X syndrome, diabetic complications or atherosclerosis or hypertension. The present invention also relates to a treatment for diabetes, diabetic retinopathy, diabetic dysmenorrhea, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, A method of obesity, hypertriglyceridemia, X syndrome, diabetic complications or atherosclerosis or hypertension, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) Or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

 The present invention also relates to a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as a medicament for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retina Disease, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome , diabetic complications or atherosclerosis or high blood pressure.

 Still further, the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or all stereoisomers thereof, and a pharmaceutically acceptable Carrier. Use of the pharmaceutical composition for the preparation of a medicament for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia Highly acquired island septicemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications or atherosclerosis or hypertension.

 The invention also relates to a treatment for diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity A method of hypertriglyceridemia, X syndrome, diabetic complications, or atherosclerosis or hypertension, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising the formula (I) Things.

 The present invention also relates to a pharmaceutical composition comprising the pharmaceutical composition of the general formula (I) for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, and diabetes. Kidney disease, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications or atherosclerosis Or high blood pressure.

 Detailed description of the invention

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

"Mercapto" refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The fluorenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, nitro, hydroxy, amino, decyloxy, cyano, fluorenyl, fluorenyl. , heterocycloalkyl, aryl, heteroaryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0)OR ^a , -NR ^b R ^c or -C(0)NR ^b R ^c .

"Cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system comprising from 3 to 20 carbon atoms, preferably It includes 3 to 10 carbon atoms, and more preferably the cyclodecyl ring contains 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexane, cyclohexadienyl, cycloheptyl, cycloheptatrienyl Wait. Polycyclic fluorenyl groups include spiro, fused, and bridged cycloalkyl groups, and non-limiting examples include 1-naphthyl, norbornyl, adamantyl, and the like. The cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, nitro, cyano, Cyclodecyl, heterocycloalkyl, aryl, heteroaryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0)OR ^a , -NR ^b R ^c or -C(0)NR ^b R ^c .

"Heterocyclic fluorenyl" means a non-aromatic monocyclic or polycyclic ring system comprising from 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0)n (where _n It is a hetero atom of the integer 0 to 2), but does not include the ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. Preferably, the heterocyclic fluorenyl group contains 3 to 10 ring atoms, of which 1 to 4 are hetero atoms, and more preferably the heterocyclic fluorenyl group contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, and polycyclic heterocycloalkyl groups include bicyclic or Polycyclic sulfhydryl groups of polycyclic spiro, fused, and bridged rings. Heterocyclic fluorenyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, hetero Aryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S'(0) _n R\ -NHC(0)R ^a , -NH-S(0)OR ^a , - NR ^b R ^c or -C(0)NR ^b R ^c .

"3 to 8 membered heterocyclic group" means that the number of ring atoms is 3 to 8 yuan, and the atoms constituting the ring contain one or more N, 0 or S(〇) n hetero atoms, and the ring may contain 1 to 2 The double bond is a monocyclic or bicyclic non-aromatic ring group, and when the atom constituting the ring contains a nitrogen atom, a bond may be extended from the nitrogen atom. It is preferably a 4- to 6-membered heterocyclic group, more preferably 5 to 6 members, such as a pyrrolidinyl group, a piperidinyl group or a piperazinyl group. The 3 to 8 membered heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, nitro , cyano, carbonyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0)OR ^a , -NR ^b R ^c or -C(0)NR ^b R ^c .

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated π-electron system (ie, having adjacent pairs) The ring group of a carbon atom is preferably 6 to 10 members, such as a phenyl group or a naphthyl group. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, nitro, cyano, ring. Indenyl, heterocyclic fluorenyl, aryl, heteroaryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a -NH-S(0)OR ^a , -NR ^b R ^c or -C(0)NR ^b R ^c .

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5- or 6-membered heteroaryl group. For example, furyl, thienyl, pyridyl, pyrrolyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of fluorenyl, alkoxy, halogen, hydroxy, nitro, cyano, Cycloalkyl, heterocyclic fluorenyl, aryl, Heteroaryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0)OR ^a , -NR ^b R ^c or -C(0)NR ^b R ^c .

"Aralkyl" means a fluorenyl group substituted by an aryl group, and a preferred aryl fluorenyl group is an aryl lower aralkyl group having a fluorenyl group having 1 to 6 carbon atoms, more preferably attached to have 1 "Phenyl anthracene" on the thiol moiety of ~3 carbon atoms. For example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl, preferably benzyl. The aryl group in the aralkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably a mercapto group, an alkoxy group, a halogen group, a hydroxyl group, a nitro group, a cyano group, a cyclodecyl group, or a hetero group. Cycloalkyl, aryl, heteroaryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH- S(0)OR ^a , -NR ^b R ^c or -C(0)NR ^b R ^c .

"Alkoxy" means -C fluorenyl) and -0-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of fluorenyl, halogen, nitro, hydroxy, amino, cyano, cyclodecyl, hetero Cycloalkyl, aryl, heteroaryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH- S(0)OR ^a , -NR ^b R ^c or TC(0)NR ^b R ^c .

 "Halogen" means fluoro, chloro, bromo or iodo.

"Nitro" means -N0 ₂ . ·

 "Hydroxy" means -OH.

 "Amino" means -N3⁄4.

 "Cyano" means -CN.

 "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiological/pharmaceutically acceptable carriers and Shape agent. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

 Collectively referred to as "X Syndrome", also known as the disease, disease, and condition of metabolic syndrome, detailed in Johannsson J. Clin. Endocrinol. Metab., 1997; 82, 727-734.

 "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. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by a thiol group and the case where the heterocyclic group is not substituted by a thiol group. .

Wherein R ^{a to} R ^e are as defined in the formula (I). Method for synthesizing the compound of the present invention

 In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

The preparation method of the compound of the formula (I) or a pharmaceutically acceptable salt thereof or all the stereoisomers thereof of the present invention comprises the following steps:

The amino group and the cyano substituted naphthalene compound are reacted with a halogen to form a halogenated naphthalene derivative; the amino group on the halogenated naphthalene derivative is diazotized to form an R ⁵ substituted naphthalene compound with a nucleophilic reagent; and the R ⁵ substituted naphthalene derivative The cyano group on the substrate is hydrolyzed under alkaline conditions to form a carboxyl-substituted naphthalene derivative; the carboxy-substituted naphthalene derivative is reacted with oxalyl chloride under basic conditions to form an acid chloride! The naphthalene derivative is replaced by an acid chloride. The naphthalene derivative and the substituted benzene are subjected to acylation under catalytic conditions to form a ketone derivative;

 The carbonyl group in the ketone derivative is reduced to a methylene group; the resulting methylene product is coupled with a substituted lactone compound to form a compound of the formula (IA); the compound of the formula (IA) is dehydroxylated or alkoxylated to form a formula ( I) a compound. DRAWINGS

Figure 1 is the blood glucose fall time of Compounds 1, 10.

Figure 2 is a graph showing the time of sugar excretion of Compounds 1, 10. detailed description

 The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

 'Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (dMSOO deuterated chloroform (CDC1 ₃ ), deuterated methanol (CH ₃ 0D), internal standard was tetramethylsilane (tMS). The chemical shift is given in units of l (T ⁶ (ppm).

 The MS was assayed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

 The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, and the silica gel plate used for thin layer chromatography (tLC) has a specification of 0.15 mm~0.2 mm, and the thin layer chromatography separation and purification product is adopted. The specifications are 0.4 mm to 0.5 mm.

 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

 The starting materials of the present invention are known and commercially available from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela - ChemBio Inc, Dari Companies such as chemicals may be synthesized or synthesized according to methods known in the art.

 Unless otherwise specified in the examples, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere.

 An argon atmosphere or a nitrogen atmosphere is a reaction vessel connected to an argon or nitrogen balloon having a volume of about 1 L.

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

 The pressurized hydrogenation reaction uses a Parr 3916EK hydrogenation apparatus and a clear blue QL-500 hydrogen generator or

HC2-SS type hydrogenation instrument.

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

 The microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.

 There is no particular description in the examples, and 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 the optimum reaction temperature, which is 201 to 30 °C.

 The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: methylene chloride and methanol system, n-hexane and ethyl acetate systems, and the volume ratio of the solvent was based on the compound. Adjust with different polarity.

 Column chromatography eluent systems include: A: methylene chloride and methanol systems; B: 'n-hexane and ethyl acetate systems; C: dichloromethane; D: n-hexane: dichlorohexanium system; : Positive system. The volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of ammonia water and acetic acid may be added.

Example 1

qS,3ig,4i?,5S,6i?)-2-"4-Chloro-3-(4-ethoxy-benzyl)-naphthalen-1-yl1-6-hydroxymethyl-tetrahydropyran -3,4,5-triol

 First step

 1-amino-4-bromo-naphthalene-2-carbonitrile

 Amino-naphthalene-2-nitrile la (840 mg, 5 mmol) was dissolved in a mixture of 24 mL of methanol and glacial acetic acid (V: V = 5:1), cooled to 0 V in an ice bath, and liquid bromine (0.3) was added dropwise. mL, 6 mmol), stirred for 3 hours. Concentration under reduced pressure, EtOAc (3 mL), EtOAc (EtOAc)

MS m/z (ESI): 246.8 [M-l]

NMR NMR (400 MHz, DMSO-c/ ₆ , ppm): δ 8.42 (d, 1H), 8.03 (d, 1H), 7.78 (t, 1 H), 7.72 (s, 1 H), 7.62 (t, 1H), 7.15 (br.s, 2H)

 Second step

 4-bromo-1-chloro-naphthalene-2-carbonitrile

 Anhydrous copper chloride (6.9 g, 5.15 mmol) was dissolved in 200 mL of acetonitrile, tert-butyl nitrite (7.6 mL, 64.5 mmol) was added, and the reaction was stirred for 10 minutes, and 1-amino-4-bromonaphthalene was added in portions. 2-Nitrile lb (10.6 g, 43 mmol), stirring was continued for 1 hour. The reaction mixture was poured into cooled 400 mL of 20% hydrochloric acid, filtered, and the filter cake was collected. -Chloro-naphthalene-2-carbonitrile lc (llg, grey solid), Yield: 96.5%.

NMR NMR (400 MHz, DMSO-i ₆ , ppm): δ 8.34 (m, 2 Η), 8.28 (d, 1H), 7.95 (m, 2H)

 third step

 4-bromo-1-chloro-naphthalene-2-carboxylic acid

Dissolve 4-bromo-1-chloro-naphthalene-2-carbonitrile lc (7.72 g, 29 mmol) in 40 mL of a mixed solvent of ethanol and water (V: V = 3:1), and add potassium hydroxide (8.14) with stirring. g, 145 mmol), refluxed for 8 h, added 50 mL of 2M hydrochloric acid, filtered and evaporated. Bromochloro-naphthalene-2-carboxylic acid ld (5.0 g, yellow solid), Yield: 60.4%.

MS m/z (ESI): 284.6 [M-l]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.51 (dd, 1H), 8.30 (m, 1H), 8.13 (s, 1H), 7.80 (m, 2H)

 the fourth step .

 4-bromo-1-chloro-naphthalene-2-formyl chloride -'

 4-Bromo-1-chloro-naphthalene-2-carboxylic acid ld (860 mg, 3 mmol) was dissolved in 15 mL of dichloromethane, and 0.1 mL of N,N-dimethylformamide was added dropwise, and the reaction flask was placed. In a room temperature water bath, oxalyl chloride (0.3 mL, 3.6 mmol) was slowly added, and the mixture was stirred for 3 hr. The product was used directly in the next reaction without isolation.

 the fifth step

 (4-bromo - 1 -chloro-naphthalen-2-yl) -(4-ethoxy-phenyl)-methanone

 Dissolve 4-bromo-1-chloro-naphthalene-2-carbonyl chloride le (910 mg, 3 mmol) in 15 mL of dichloromethane, add phenylethyl ether (366.5 mg, 3 mmol), and leave the reaction flask at room temperature In a water bath, aluminum trichloride (360 mg, 2.7 mmol) was slowly added and allowed to react at room temperature for 12 hours. To the reaction flask, 20 mL of 1 M hydrochloric acid was added dropwise, and the mixture was extracted with dichloromethane (50 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was obtained to give the title product (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-phenyl)-methanone lf (1.0 g, orange solid). %.

MS m/z (ESI): 390.9 [M+l]

NMR NMR (400 MHz, DMSO- ₆ , ppm): 6 8.30 (d, 1H), 8.28 (d, 1H), 8.00 (s, 1H), 7.85 (d, 2H), 7.74 (m, 2H), 7.05 (d, 2H), 4.13 (q, 2H), 1.34 (t, 3H)

 Step 6

 4-bromo-1-chloro-2-(4-ethoxy-benzyl)-naphthalene

 (4-Bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-phenyl)-methanone lf (1.0 g, 2.56 mmol) was dissolved in 15 mL of acetonitrile and dichloromethane (V: V = 2: 1) In a mixed solvent, the reaction flask was placed in a room temperature water bath, and triethylsilane (1.0 mL, 6.16 mmol) and boron trifluoride etherate (0.5 mL, 3.85 mmol) were added, and the reaction was stirred at room temperature 12 hour. Add potassium hydroxide solution (0.6 g, 3 mL), add 5 mL of water, extract with diethyl ether (20 mL><3), combine the organic phase, wash with saturated sodium chloride solution (20 mL), and combine the organic phase. Drying over anhydrous magnesium sulfate, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Naphthalene lg (500 mg, white solid), Yield: 52.1%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.35 (d, 1Η), 8.19 (d, 1H), 7.61 (m, 3H), 7.13 (d, 2H), 6.83 (d, 2H), 4.23 ( s, 2H), 4.00 (q, 2H), 1.39 (t, 3H)

 Seventh step

 (2S,3i?,4S,5i?,6i?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(4-ethoxy- Benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol

4-Bromo-1-chloro-2-(4-ethoxy-benzyl)-naphthalene l _g (1.8 g, 4.8 mmol) was dissolved in 25 mL of tetrahydrofuran, dried under ice-acetone bath and cooled to -78 Ό Then slowly add 2.5 M n-butyl lithium cyclohexane solution (2.12) mL, 5.3 mmol), reaction for 30 minutes, (3/?, 4 & 5 6/?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-tetrahydropyran-2-one Lh (2.84 g, 5.3 mmol, using a known method "?rbo/2_y Res., 260 (1994), 243-250" prepared) dissolved in 10 mL of tetrahydrofuran, dropped into the reaction solution, at -78 ° C was reacted for 3 hours and warmed to 0 V. 10 mL of a saturated sodium chloride solution was added dropwise, and 10 mL of water was added, and the mixture was combined with ethyl acetate (30 mL), and the organic phase was combined, washed with saturated sodium chloride (15 mL), dried over anhydrous magnesium sulfate The residue obtained was purified by silica gel column chromatography elutd elut elut elut elut elut elut elut elut elut 4-Chloro-3-(4-ethoxy-benzyl)-naphthalenyl]-tetrahydropyran-2-ol (1.9 g, pale yellow oil), Yield: 47.5 ^ό /.

MS m/z (LC-MS): 819.2 [M-17]

 Eighth step

 (2i?,3/?,4 5 & 6S)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(4-ethoxy-benzyl) -naphthalen-1-yl]-tetrahydropyran

 Will (2 & 3i?,4 & 5 6/?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(4-ethoxy- Benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol li (1.9 g, 2.27 mmol) was dissolved in 15 mL of dichloromethane, the reaction flask was placed in a room temperature water bath, and triethyl Silicon germanium (0.47 mL, 2.96 mmol) and three layers (boron ether (0.35 mL, 2.73 mmol), stirred at room temperature for 12 hours. Add 15 mL of saturated sodium chloride solution, add 10 mL of water, use dichloromethane The mixture was extracted (30 mL×2), EtOAc (EtOAc) (EtOAcjjjjjjj , the title product (2i?, 3i?, 4i?, 5 & 65)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(4- Ethoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran 1j (1.5 g, white solid), Yield: 80.6%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.39 (d, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 7.28 (s, 10H), 7.25 (s, 5H), 7.09 ( d, 3H), 6.99 (m, 2H), 6.73 (d, 2H), 6.50 (d, 2H), 4.90 (m, 3H), 4.85 (m, 1H), 4.70 (d, 1H), 4.61 (d , 1H), 4.51 (d, 1H), 4.30 (d, 1H), 4.16 (m, 2H), 3.94 (m, 3H), 3.84 (m, 3H), 3.75 (d, 1H), 3.65 (d, 1H), 3.48 (d, 1 H), 1.36 (t, 3H)

 Step 9

 (2 & 3i?,4 ?,5 & 6/?)-2-[4-chloro-3-(4-ethoxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetra Hydropyran-3,4,5-triol will (2/?,3 47?,5 & ό ^-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-( 4-Ethoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran 1j (1.5 g, 1.83 mmol) was dissolved in 12 mL of chloroform, and 6 mL of thiol and boron trifluoride diethyl ether (3.48 mL, 27.45 mmol), the reaction was stirred for 72 hr. EtOAc was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -2-[4-chloro-3-(4-ethoxy-benzyl)-naphthalenyl] -6-hydroxymethyl-tetrahydropyran-3,4,5-triol lk (600 mg, White solid), Yield: 71.5%.

 MS m/z (LC-MS): 476.2 [M+18]

 Step 10

(2 ?,3 4 ?,5 & 6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-naphthalen-1-yl] - tetrahydropyran-2-ylacetate

The crude product (2 & 3/?,4 5 & 6 -2-[4-chloro-3-(4-ethoxy-benzyl)-naphthalenyl]-6-hydroxymethyl-tetrahydropyridyl Ethyl-3,4,5-triol lk (458 mg, 1 mmol) was dissolved in 6 mL of a mixture of pyridine and dichloromethane (V: V = 1:5), and acetic anhydride (0.9 mL, 9 mmol) And 4-dimethylaminopyridine (6.1 mg, 0.05 mmol), the reaction was stirred for 12 hr. ,4/?,5 & 65)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy-benzyl)-naphthalen-1-yl]-tetrahydro Methyl pyran-2-ylacetate lm (500 mg, white solid), Yield: 79.7%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.38 (dd, IH), 8.15 (dd, IH), 7.59 (m, 2H), 7.43 (m, IH), 7.12 (dd, 2H), 6.81 ( Dd, 2H), 5.43 (m, 2H), 5.32 (m, IH), 5.07 (m, IH), 4.25 (m _: 3H), 4.18 (dd, IH), 4.00 (q, 2H), 3.97 (m , 1H), 2.09 (s, 3H), 2.07 (s, 3H), 2.01 (s, 3H), 1.47 (s, 3H), 1.39 (t, 3H)

 The eleventh step

 (2S,3 4i?,5S,6i?)-2-[4-chloro-3-(4-ethoxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran -3,4,5-three will (2 ?,3/?,4i?,5 & 65)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethoxy Methyl-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ylacetic acid methyl ester 1 m (400 mg, 0.64 mmol) dissolved in 6 mL of tetrahydrofuran, methanol and water (V: V: V = 2 : 3: 1) In a mixed solvent, lithium hydroxide monohydrate (32 mg, 0.77 mmol) and 5 mL of dichloromethane were added in sequence, and the mixture was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m.). The title product was obtained (2 & 3 47?,5 & 6 -2-[4-chloro-3-(4-ethoxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyridyl M--3,4,5-triol lC290 mg, white solid), Yield: 100%.

MS m/z (LC-MS): 476.3 [M+18]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.34 (d, 2H), 7.61-7.52 (m, 3H), 7.14 (d, 2H), 6.79 (m, 2H), 4.87 (d, IH) , 4.27 (dd, 2H), 3.98 (dd, 2H), 3.88 (d, 1H), 3.74 (m, 2H), - 3.60 (t, IH), 3.52 (m, 2H), 1.34 (t, 3H) Example 2

 (2S,3 4 5S,6i?)-2-"4-Chloro-3-(3-fluoro-4-methoxy-benzyl)-naphthalen-1-yl b-6-hydroxymethyl-tetrahydropyridyl Mutter

-3,4,5-triol

first step

 (4-bromo-1-chloro-naphthalen-2-yl)-(3-fluoro-4-methoxy-phenyl)-methanone 4-bromochloro-naphthalene-2-carbonyl chloride le (2.2 g , 6.83 mmol) dissolved in 30 mL of dichloromethane, added 1-fluoro-2-methoxybenzene (0.76 mL, 6.83 mmol), and added aluminum trichloride (820 mg, 6.15 mmol) in portions. hour. 20 mL of 1 M hydrochloric acid was added, the reaction solution was extracted with dichloromethane (20 mL×3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered, The residue obtained by purifying the eluent system B was >1⁄2 to give (4-bromo-1-chloro-naphthalen-2-yl)-(3-fluoro-4-methoxy-phenyl)-methanone 2a ( 1.86 g, yellow solid), Yield: ' 69.4%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.34-8.31 (ητ, 2Η), 7.78-7.74 (m, 3Η), 7.66-7.63 (dd, 1Η), 7.57-7.52 (m, 1H), 6.98 (t, 1H), 3.97 (s, 3H)

 Second step

 4-bromo-1-chloro-2-(3-fluoro-4-methoxy-benzyl)-naphthalene

 (4-Bromo-chloro-naphthalen-2-yl)-(3-fluoro-4-methoxy-phenyl)-methanone 2a (1.85 g, 4.70 mmol) was dissolved in 30 mL of acetonitrile and dichloromethane (V: V = 2: 1) In a mixed solvent, triethylsilane (2.4 mL, 15 mmol) and boron trifluoride diethyl ether (1.19 mL, 9.4 mmol) were added sequentially, and the reaction was stirred for 12 hours to give 1.5 g of hydr. Potassium is dissolved in 30 mL of water to form a potassium hydroxide solution, added to the reaction solution to quench the reaction, extracted with diethyl ether (30 mL×3), combined with organic phase, washed with saturated sodium chloride solution (30 mL), anhydrous magnesium sulfate Drying, filtration, and concentrating the filtrate under reduced pressure, and the residue obtained from silica gel column chromatography, eluent system B to give 4-bromo-1-chloro-2-(3-fluoro-4-methoxy-benzyl) -Naphthalene 2b (1.37 g, yellow solid), Yield: 77.1%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.33 (dd, 1Η), 8.21 (m, 1H), 7.66-7.59 (m, 3H), 6.96-6.85 (m, 3H), 4.21 (s, 2H ), 3.86 (s, 3H)

 third step

 (2 & 3/?,4 & 57?,6 ?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(3-fluoro-4 -methoxy-benzyl)-naphthalene

 -1-yl]-tetrahydropyran-2-ol

4-Bromo-1-chloro-2-(3-fluoro-4-methoxy-benzyl)-naphthalene 2b (758 mg, 2 mmol) was dissolved in 10 mL of tetrahydrofuran and added dropwise at -78 °C 2.5 M-n-butyllithium cyclohexane solution (0.8 mL, 2 mmol), stir the reaction at -78 °C for 30 minutes, add dropwise (3;?,4 & 5/?,6i?)-3,4 , a solution of 5-tribenzyloxy-6-benzyloxymethyl-tetrahydropyran-2-one 1h (1.18 g, 2.2 mmol) in 5 mL of THF. Add 10 mL of saturated sodium chloride solution, extract with ether (10 mL×3), combine the organic phases, and use saturated sodium chloride. The solution was washed (10 mL), dried over anhydrous magnesium sulfate, filtered, filtered, and the filtrate was evaporated, and the residue was purified by silica gel column chromatography with eluent system B to give (2 & 3 4 & 5 ?, 6/?)-3 ,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(3-fluoro-4-methoxy-benzyl)-naphthalen-1-yl]-tetra Hydropyran-2-ol 2c (700 mg, yellow solid), Yield: 41.7%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.61 (d, 1H), 8.36 (d, 1H), 7.77 (s, 1H), 7.52 (t, 1H), 7.30 (m, 16H), 7.10- 6.90 (m, 6H), 6.65 (m, 2H), 4.96 (d, 1H), 4.88 (dd, 2H), 4.75 (d, 1H), 4.55 (d, 1H), 4.48 (d, 1H), 4.31 -4.12 (m, 3H), 3.93-3.64 (m, 9H), 3.40 (d, 1H)

 - the fourth step

 (2/?,3i?,4i?,5&65)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(3-gas-4-A Oxy-benzyl)-naphthalene

 -1-yl]-tetrahydropyran

 Will (2 & 3i?, 4S, 5i?, 6/?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(3-fluoro- 4-Methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol 2c (500 mg, 0.60 mmol) was dissolved in 6 mL of dichloromethane. Silane (124 L, 0.77 mmol) and boron trifluoride diethyl ether (91 μί, 0.72 mmol) were stirred at room temperature for 2 hr. Add 5 mL of saturated sodium carbonate solution, extract with methylene chloride (10 mL×3, combine with organic phase, wash with saturated sodium chloride solution (10 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with eluent system C to give (2/?,3 47?,5&65 3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4- Chloro-3-(3-fluoro-4-methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran 2d (321 mg, white solid), yield: 65.6%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.38 (d, 2H), 7.58 (m, 1H), 7.43 (m, 2H), 7.28 (m, 15H), 7.10-6.90 (m, 6H), 6.50 (m, 2H), 4.91 (m, 3H), 4.82 (m, 1H), 4.70 (d, 1H), 4.61 (d, 1H), 4.29 (d, 1H), 4.31-4.12 (m, 3H) , 3.93-3.64 (m, 9H), 3.50 (d, 1H)

 the fifth step

 (2 & 3i?, 4 5 & 6 ?)-2-[4-chloro-3-(3-fluoro-4-methoxy-benzyl)-naphthalenyl-1-yl]-6-hydroxymethyl- Tetrahydropyran

 -3,4,5-triol

 (2 3/?,4 5 & 65 3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(3-fluoro-4-methoxy- Benzyl)-naphthalen-1-yl]-tetrahydropyran 2dC450 mg, 0.55 mmol) dissolved in 4 mL of chloroform, added 2 mL of ethanethiol and boron trifluoride etherate G.04 mL, 8.2 mmol), stirred 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography eluting to afford (2 & 37? 4-Methoxy-benzyl)-naphthalene small group]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol 2 (130 mg, white solid), Yield: 51.6%.

 MS m/z (LC-MS): 480.3 [M+18]

1H NMR (400 MHz, CD ₃ OD, ppm): δ 8.38 (d, 2H), 7.66-7.58 (m, 3H), 7.10-6.98 (m, 3H), 4.93 (d, 1H), 4.32 (dd, 2H), 3.94 (d, 2H), 3.86 (s, 1H), 3.77 (m, 2H), 3.64 (t, 1H), 3.57 (m, 2H) Example 3

(2S,3 4 5&67?)-2-indole 4-chloro-3-G-fluoro-4-methoxy-benzyl)-naphthalenyl 1-6-hydroxymethyl-tetrahydropyran -3,4,5-triol

 First step

(4-Bromo-chloro-naphthalen-2-yl)-(2-fluoro-4-methoxy-phenyl)-methanone 4-bromochloro-naphthalene _: 2-formyl chloride le (2.0 g, 6.58 Ment) dissolved in 35 mL of dichloromethane, added: -Fluoro-3-methoxy (0.8 mL, 7 mmol), added aluminum trichloride (840 mg, 6.3 mmol) in portions, stirred for 12 hours. . The reaction was quenched by the addition of 20 mL of EtOAc EtOAc (EtOAc)EtOAc. The resulting residue was purified to give the title product (4-bromo-1-chloro-naphthalen-2-yl)-(2-fluoro-4-methoxy-phenyl)-methanone 3a (1.12 g, white Solid), Yield: 43.3%.

MS m/z (LC-MS): 394.1 [M+1] '

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.35-8.34 (d, 1H), 8.33-8.32 (d, 1H), 7.87-7.85 (t, 1H), 7.83-7.76 (m, 3H), 6.84 -6.83 (d, 1H), 6.63-6.60 (d, 1H), 3.94-3.91 (s, 3H)

 Second step

 4-bromo-1-chloro-2-(2-fluoro-4-methoxy-benzyl)-naphthalene

 (4-Bromo-1-chloro-naphthalen-2-yl)-(2-fluoro-4-methoxy-phenyl)-methanone 3a (560 mg, 1.42 mmol) was dissolved in 15 mL of acetonitrile and dichloro In a mixed solvent of methane (V: V = 2:1), triethylsilyl sulfonium (0.68 mL, 4.26 mmol) and boron trifluoride diethyl ether (0.36 mL, 2.84 mmol) were successively added, and the reaction was stirred for 4 hours. To the reaction, a solution of potassium hydroxide (500 mg, 10 mL), EtOAc (EtOAc) The filtrate was purified by silica gel column chromatography elut elut elut elut elut elut elut Mg, white solid), Yield: 96.5%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.24-8.21 (t, 1H), 8.19 (d, 1H), 7.69-7.56 (m, 3H), 7.05-6.99 (m, 1H), 6.67-6.57 (m, 2H), 4.31-4.23 (d, 2H), 3.77-3.74 (s, 3H)

 Third

(2 & 3 4 & 5i?, 6i?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(2-fluoro-4-methoxy -benzyl)-naphthalenyl]-tetrahydropyran-2-ol Dissolve 4-bromo-chloro-2-(2-fluoro-4-methoxy-benzyl)-naphthalene 3b (520 mg, 1.36 mmol) in 10 mL of tetrahydrofuran and add 2.5 M at -78 °C. A solution of n-butyllithium in cyclohexane (0.55 mL, 1.36 mmol), stirring at -78 °C for 30 minutes, dropwise addition of (3?,4S,5i?,6W)-3,4,5-tribenzyl A solution of oxy-6-benzyloxymethyl-tetrahydropyran-2-one 1h (808 mg, 1.5 mmol) in 6 mL of THF was then evaporated. After adding 5 mL of a saturated sodium chloride solution, the mixture was extracted with ethyl acetate (30 mL×3), EtOAcjjjjjjjjjjj The residue obtained was purified by de-bending system B to give the title product (2&3 4 & 5i?, 6/?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro- 3-(2-Fluoro-4-methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol 3c (635 mg, pale yellow oil), yield: 55.6%.

 the fourth step

 (2i?,3i?,4?,5&65 3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(2-fluoro-4-methoxy) Base-benzyl)-naphthalene

 -1-yl]-tetrahydropyran

Will (2 & 3i?,4 & 5i?,6i?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(2-fluoro-4) -Methoxy-benzyl)-naphthalene small group] _: Tetrahydropyran-2-ol 3c (630 mg, 0.75 mmol) dissolved in 13 mL of acetonitrile and dichloromethane (V: V = 5; '- - ' To the λ solvent, triethylsilane (0.6 mL, 1.88 mmol) and boron trifluoride etherate (0.31 mL, 1.5 mmol) were added successively, and the reaction was stirred for 4 hours. 2 mL of triethylamine was added, and the reaction mixture was concentrated under reduced pressure. After adding 40 mL of ethyl acetate, the organic phase was washed with EtOAc (EtOAc) (EtOAc) 3i?,4i?,5&6-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(2-fluoro-4-methoxy-benzyl -Naphthalen-1-yl]-tetrahydropyran 3d (610 mg, yellow solid), Yield: 98.8%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.37 (d, 2H), 7.60-7.57 (t, 1 H), 7.45-7.41 (m, 2H), 7.36-7.30 (s, 20H), 7.10- 7.06 (t, 1 H), 7.01-6.95 (m, 2H), 6.59-6.47 (m, 3H), 4.91 -4.88 (t, 3H), 4.71-4.68 (d, 1H), 4.62-4.59 (d, 1H), 4.52-4.49 (d, 1H), 4.31-4.12 (m, 3H),

3.90-3.77 (m, 2H), 3.74-3.64 (s, 3H), 3.52-3.49 (d, 1H), 1.25-1.22 (s, 2H)

 ' the fifth step

 (2 3/?,4 ?,5 & 6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-fluoro-4-methoxy-benzyl)-naphthalene -1 -yl]-tetrahydropyran-2-ylacetate

Will (2i?,3 4i?,5 & 65)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(2-fluoro-4-methyl) Oxy-benzyl)-naphthalen-1-yl]-tetrahydropyran 3d (600 mg, 0.73 mmol) was dissolved in 10 mL of chloroform, 5 mL of ethanethiol was added, and boron trifluoride etherate (1.84 mL) was added dropwise. , 14.5 mmol), stir the reaction for 5 hours. 2 mL of triethylamine was added, and the residue was evaporated. Acetic anhydride (0.47 mL, 7.28 mmol) was added to 5 mL of pyridine, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate (100 mL). The title compound (2/?, 3?, 4 5 & 6S) was obtained by chromatography. 3,4,5-Blueacetoxy-6-[4-chloro-3-(2-fluoro-4-methoxy-benzyl)-naphthalenyl-I-yl]-tetrahydropyran-2-yl Methyl acetate 3e (280 mg, white solid), Yield: 61.0%. MS m/z (LC-MS): 647.8 [M+18]

'H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.38-8.36 (d, 1H), 8.15-7.61 (m, 1H), 7.57-7.49 (m _: 2H), 7.41-7.39 (m, 1H), 6.98-6.66 (t, 1H), 6.63-6.58 (m, 2H), 5.41-5.28 (m, 3H), 5.14-5.01 (m, 2H), 4.29-4.15 (m, 3H), 3.94-3.92 (m , 1H), 3.77 (s, 3H), 2.22-1.66 (m, 12H)

 Step 6

 (2 & 3 4 5 & 6i?)-2-[4-chloro-3(2-fluoro-4-methoxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyridyl Mutter

 -3,4,5-triol

 Will (2/?,3i?,4 ?,5 & 6 -3,4,5-triacetoxy-6-[4-chloro-3-(2-fluoro-4-methoxy-benzyl) -naphthalen-1-yl]-tetrahydropyran-2-ylacetic acid methyl ester 3e (164 mg, 0.26 mmol) was dissolved in 6 mL of tetrahydrofuran, methanol and water (V: V: V = 2: 3: 1). In the solvent, lithium hydroxide monohydrate (13.09 mg, 0.31 mmol) and 10 mL of dichloromethane were added in that order, and the reaction was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and 15 mL of water was added and extracted with ethyl acetate (30 mL×3) The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and evaporated. -Methoxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran-; 5; 4,5-triol 3 (130 mg, white solid), Yield: 100% .

MS m/z (LC-MS): 480.3 [M+18]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.36-8.33 (d, 2H), 7.60-7.53 (m, 3H), 7.02-6.97 (t, 1H), 6.70-6.67 (d, 1H), 6.63-6.60 (d, 1H), 4.87-4.85 (d, 1H), 4.32-4.23 (t, 2H), 4.12-4.07 (m, 1H), 3.91-3.88 (d, 2H), 3.77-3.73 (s , 3H), 3.72-3.61 (m, 2H), 3.57-3.47 (m, 2H), 1.33-1.22 (m, 3H) Example 4

 (2S,3i?,4?,5S,6WV2-r4-chloro-3-(3,5-difluoro-4-methoxy-benzyl)-naphthalene small group 6-hydroxymethyl-tetrahydropyridyl Mutter

-3.4,5-triol

first step

 1,3-difluoro-2-methoxybenzene

 2,6-Difluoro-phenol 4a (4.8 g, 36.9 mmol) was dissolved in 37 mL of acetone, and then added with methyl iodide (3.44 mL, 55.3 mmol), potassium carbonate (8.66 g, 62.7 mmol), and stirred. 36 hours. The filtrate was concentrated under reduced pressure. EtOAc (EtOAc m. The title product 1,3-difluoro-2-methoxybenzene 4b (3.2 g, yellow oil), yield: 60.4%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 6.91 (m, 3Η), 3.99 (s, 3H)

 Second step

 (4-bromo-1-chloro-naphthalen-2-yl)-(3,5-difluoro-4-methoxy-phenyl)-methanone 4-bromo-1-chloro:naphthalene-2-methyl The acid chloride le (1.06 g, 3.5 mmol) was dissolved in 20 mL of dichloromethane, and 1,3-difluoro-2-methoxybenzene 4b (504 mg, 3.5 mmol) was added, and aluminum trichloride (420) was added portionwise. Mg, 3.15 mmol), reacted at 25 ° C for 12 hours. After adding 20 mL of 1 M hydrochloric acid, the mixture was separated, and the aqueous phase was extracted with dichloromethane (20 mL×2). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified to give the title product (4-bromo-1-chloro-naphthalen-2-yl)-(3,5-difluoro-4-methoxy-phenyl)-methanone 4c (380 mg, White solid), Yield: 26.4%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.38-8.32 (m, 2H), 7.79-7.74 (m, 2H), 7.70 (s, 1H) _; 7.43-7.36 (m, 2H), 4.14-4.11 (s, 3H)

 third step

 4-bromo-small chloro-2-(3,5-difluoro-4-methoxy-benzyl)-naphthalene

(4-Bromo-1-chloro-naphthalen-2-yl)-(3,5-difluoro-4-methoxy-phenyl)-methanone 4c (540 mg, 1.3 mmol) was dissolved in 24 mL of acetonitrile In a mixed solvent of methylene chloride (V: V = 2: 1), triethylsilane (0.83 mL, 5.1 mmol) and boron trifluoride etherate (0.64 mL, 5.1 mmol) were added in sequence at 30 °C. The reaction was carried out for 12 hours. Potassium hydroxide solution (500 mg, 10 mL) was added to the reaction mixture, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjj , filtration, decompression The filtrate was concentrated, and the residue obtained was purified eluted elut elut elut elut elut elut elut elut elut elut Naphthalene 4d (170 mg, white solid), Yield: 32.9%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.36-8.34 (dd, 1Η), 8.24-8.22 (dd, 1Η), 7.69-7.62 (m, 2H), 7.60 (s, 1H), 6.78-6.72 (m, 2H), 4.21 (s, 2H), 3.96 (s, 3H)

 the fourth step

 (2&3i?,4 & 5^6/ -3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(3,5-difluoro-4-methyl) Oxy-benzyl) - 'naphthalene small group] - tetrahydropyran-2-ol - 4-bromo-1-chloro-2-(3,5-difluoro-4-methoxy-benzyl) -Naphthalene 4d (170 mg, 0.43 mmol) was dissolved in 10 mL of tetrahydrofuran, and a solution of 2.5 M n-butyllithium in cyclohexane (0.17 mL, 0.43 mmol) was added dropwise at -78 °C. Reaction at ° C for 30 minutes, (3i?, 4 & 5i?, 6 ?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-tetrahydropyran-2-one lh (255 Mg, 0.47 mmol) was dissolved in 5 mL of tetrahydrofuran, and the reaction solution was added dropwise at -78 °C. The reaction was stirred at -78 °C for 2.5 hours, warmed to room temperature, 10 mL of saturated ammonium chloride was added, and 10 mL of acetic acid was added. Ethyl acetate, EtOAc, EtOAc (EtOAc m. , the title product (2 3 ?, 4 & 5i?, 6 ?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(3,5 -difluoro-4methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran-2 - alcohol 4e (200 mg, colorless oil), rate: 54.3%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.64-8.62 (dd, 1Η), 8.37-8.35 (dd, 1Η), 7.71 (s, 1H), 7.56-7.52 (m, 1H), 7.09-7.05 (m, 1H), 6.99-6.95 (m, 2H), 6.75-6.73 (m, 2H), 6.64-6.62 (m, 2H), 6.33-6.20 (m, 16H), 4.98-4.86 (m, 3H) , 4.77-4.52 (m, 3H), 4.32-4.04 (m, 9H), 3.96 (s, 3H), 3.74-3.72 (m, 1H)

 the fifth step

 (2/?,3/?,4 ?,5S,65 3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(3,5-difluoro) 4-methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran

 Will (2 & 3i?, 4S, 5i?, 6/?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(3,5- Difluoro-4-methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol 4e (200 mg, 0.23 mmol) dissolved in 9 mL of dichloromethane and acetonitrile (V: V = 2: 1) In a mixed solvent, triethylsilane (0.11 mL, 0.7 mmol) and boron trifluoride diethyl ether (0.09 mL, 0.7 mmol) were added dropwise, and the mixture was stirred for 1.5 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. 2i?,3?,4i?,5&6S)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(3,5-difluoro- 4-Methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran 4f (200 mg, white solid), yield: >100%, used directly in the next step without isolation.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.42-8.33' (m, 2Η), 7.61-7.59 (m, 1Η), 7.47-7.44 (m, 2H), 7.40-7.10 (m, 15H), 7.10-7.06 (m, 1H), 6.99-6.96 (m, 2H), 6.75-6.70 (m, 2H), 6.50-6.47 (m, 2H), 4.96-4.85 (m, 3H), 4.77-4.51 (m , 3H), 4.30-4.03 (m, 10H), 3.96 (s, 3H), 3.74-3.71 (m, 1H) ^c

 Step 6

(2&3 ?,4 ?,5S,6i?)-2-[4-chloro-3-(3,5-difluoro-4-methoxy-benzyl)-naphthalen-1-yl]-6-hydroxyl Methyl-tetrahydropyran - 4,5-triol

 Will (2/?,3?,4/?,5S,65 3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(3,5-di) Fluoro-4-methoxy-benzyl)-naphthalen-1-yl]-tetrahydropyran 4f (200 mg, 0.24 mmol) was dissolved in 5 mL of chloroform, and 3 mL of thiol and boron trifluoride were added in sequence with stirring. Ethyl ether (0.45 mL, 3.57 mmol), stirred for 4 hr. 5 mL of saturated sodium carbonate solution was added and concentrated under reduced pressure. 5 mL of saturated sodium chloride solution was added to the residue and extracted with dichloromethane (5 mL×3). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. Fluoro-4-methoxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol 4g (114 mg, colorless oil), Rate: 100%.'

 Seventh step

(2i?,3i?,4 5 & 6S)-3,4,5-triacetoxy-6-[4-chloro-3-(3,5-difluoro-4-methoxy-benzyl) -naphthalen-1-yl]-tetrahydropyran-2-ylacetic acid methyl ester

 The crude product (2 & 3 4 ?, 5 & 6i?)-2-[4-chloro-3-(3,5-difluoro-4-methoxy-benzyl)-naphthalen-1-yl]-6 4-Hydroxymethyl-tetrahydropyran-3,4,5-triol 4 g (115 mg, 0.24 mmol) was dissolved in 5 mL of pyridine, acetic anhydride (0.23 mL, 2.4 mmol) was added, and the reaction was stirred for 12 hours. Concentrate under reduced pressure, add 20 mL of acetate, wash with saturated copper sulfate solution (5 mL×3), dry with anhydrous sulfuric acid, filter, concentrate the filtrate, and purify the residue by gel column chromatography with eluent system. (2 3i?, 4i?, 5 & 65)-3,4,5-triacetoxy 3⁄4-6-[4-chloro-3-(3,5-difluoro-4-methoxy-benzyl) Methyl 4-naphthalen-1-yl]-tetrahydropyran-2-ylacetate 4h (80 mg, white solid), yield: 51.4%.

MS m/z (ESI): 666.0 [M+18]

 Eighth step

 (2 & 3i?, 4i?, 5 & 6i?)-2-[4-chloro-3-(3,5-difluoro-4-methoxy-benzyl)-naphthalene]-6-hydroxy Methyl-tetrahydropyran

 -3,4,5-triol

 (2/?,3 4/?,5 & 65)-3,4,5-triacetoxy-6-[4-chloro-3-(3,5-difluoro-4-methoxy- Benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ylacetylmethyl ester 4h (80 mg, 0.12 mmol) was dissolved in 5 mL of tetrahydrofuran, and lithium hydroxide monohydrate (8.77 mg, 0.21 mmol) and 1 mL of water were stirred for 12 hours. After concentration under reduced pressure, a solution of 10 mL of dichloromethane and 5 mL of saturated sodium chloride was added, and the mixture was combined with methylene chloride (5 mL). Product (2 & 3i?, 4i?, 5S, 6i?)-2-[4-chloro-3-(3,5-difluoro-4-methoxy-benzyl)-naphthalen-1-yl] 6-Hydroxymethyl-tetrahydropyran-3,4,5-triol (40 1 , white solid), Yield: 66.7%.

MS m/z (ESI): 498.0 [M+l 8]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.37-8.34 (m, 2H), 7.63-7.55 (m, 3H), 6.87-6.82 (m, 2H), 4.92-4.90 (d, 1H), 4.34-4.25 (m, 2H), 3.93-3.89 (m, 4H), 3.76-3.70 (m, 2H), 3.63-3.55 (m, 3H) Example 5

 OS,3 ?,4 5S,6/?V2-"4-chloro-3- 3-difluoro-4-methoxy-benzyl)-naphthalene small group 6-hydroxymethyl-tetrahydropyran

-3,4,5-triol

first step

 1,2-difluoro-3-methoxybenzene

 2,3-Difluorophenol 5a (5 g, 38.5 mmol) was dissolved in 38 mL of acetone, followed by the addition of methyl iodide (3.59 mL, 57.7 mmol) and potassium carbonate (9.04 g, 65.4 τηψοϊ), stirring reaction ": 1 The filtrate was concentrated under reduced pressure. The residue was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title product 1,2-difluoro-3-methoxybenzene 5b (4.49 g, colorless liquid) was obtained, yield: 80.9%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 7.03 (m, 1Η), 6.80 (m, 2H), 3.94 (s, 3H)

 Second step

 (4-bromo-1-chloro-naphthalen-2-yl)-(2,3-difluoro-4-methoxy-phenyl)-methanone 4-bromo-1-chloro-naphthalene-2-methyl The acid chloride le (1.0 g, 3.3 mmol) was dissolved in 15 mL of dichloromethane, and 1,2-difluoro-3-methoxybenzene 5b (510 mg, 3.5 mmol) was added, and aluminum trichloride (430) was added in portions. Mg, 3.9 mmol), stirred for 12 hours. Add 10 mL of 1 M hydrochloric acid, extract with methylene chloride (50 mL×2), EtOAc (EtOAc m. The filtrate was purified by silica gel column chromatography using eluent system B to give (4-bromo-1-chloro-naphthalen-2-yl)-(2,3-difluoro-4-methoxy-benzene - ketone 5c (380 mg, yellow solid), Yield: 29.2%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.37-8.36 (d, 1H), 8.32-8.30 (d, 1H), 7.77-7.70 (m, 3H), 7.61 -7.57 (m, 1H), 6.86 -6.82 (t, 1H), 3.99 (s, 3H)

 third step

4-bromo-1-chloro- ² -( ² , ³ -difluoro- ⁴ -methoxy-benzyl)-naphthalene

(4-Bromo-1-chloro-naphthalen-2-yl)-(2,3-difluoro-4-methoxy-phenyl)-methanone 5c (380 mg, 0.92 mmol) was dissolved in 4 mL To the methyl chloride, 8 mL of acetonitrile was added, and triethylsilyl ruthenium (0.67 mL, 4.12 mmol) and boron trifluoride etherate (0.47 mL, 3.72 mmol) were added successively at room temperature, and the reaction was carried out at 30 ° C for 22 hours. . The reaction mixture was added with a solution of potassium hydroxide (500 mg, 10 mL), and the mixture was evaporated. Filtered, concentrated under reduced pressure /s/uϋ lioososld ίϊοί

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l6Z000/0I0ZN3/X3d IS draw 010Z OAV The mixture was separated, and the aqueous phase was extracted with methylene chloride (20 mL). -2-ylmethyl)-2-fluoro-phenol 6a (2.3 g, yellow solid), product was used in the next step without isolation.

 Second

 [4-(4-Bromo-dichloro-naphthalen-2-ylmethyl)-2-fluoro-phenoxy]-tert-butyl-dimethyl-silazane 4-(4-bromo-chlorine-naphthalene- 2-Methylmethyl)-2-fluoro-phenol 6a (2.3 g, 6.3 mmol) was dissolved in 30 mL of dichloromethane, and triethylamine (0.95 g, 9.45 mmol) and dimethylaminopyridine were added. 38 mg, 0.32 mmol) and tert-butyldimethylsilyl silane (1.04 g, 6.93 mmol) were stirred for 16 h. The reaction mixture was washed with EtOAc (EtOAc) (EtOAc) The residue obtained gave the title product [4-(4-bromo-1-chloro-naphthalen-2-ylmethyl)-2-fluoro-phenoxy]-tert-butyl-dimethyl-silanium 6b (2.76 g, white solid), Yield: 91.4%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.35 (dd, 1 Η), δ 8.22 (dd, 1H), 7.64 (m, 2H), 7.59 (s, 1H), 6.91 (d, 1H), 6.85 (m, 2H), 4.21 (s, 2H), 1.00 (s, 9H), 0.18 (s, 6H)

 third step

 (2 & 3i?,4 & 5 & 6i?)-2-[4-chloro-3-(3-fluoro-.4-hydroxy-benzyl)-naphthalene-1-yl]-6-hydroxymethyl- 2-methoxy-tetrahydropyran-3,4,5-triol

 Dissolve [4-(4-bromo-1-chloro-naphthalen-2-ylmethyl)-2-fluoro-phenoxy]-tert-butyl-dimethyl-silicone 6b (2.75 g, 5.73 mmol) In a solution of -78 V in 25 mL of tetrahydrofuran, 2.5 M of n-butyllithium in cyclohexane (2.75 mL, 6.88 mmol) was added dropwise, and the reaction was stirred at -78 °C for 1 hour, and 10 mL was added dropwise. ?,45,5i?,6i?)-3,4,5-tris-trimethylsiloxy-6-trimethylsilyloxymethyl-tetrahydropyran-2-one 6c (2.67 g, 5.73 mmol, using a well-known method "patent CN1653075" prepared tetrahydrofuran Pj| solution, the reaction was stirred at -78 for 2 hours, adding 25 mL of 0.6 M methanesulfonic acid in methanol, stirring at room temperature After 16 hours, the reaction mixture was concentrated under reduced pressure to give the title product (2 & 3i?, 4 & 5 & 6 ?)-2-[4-chloro-3-(3-fluoro-4-hydroxy-benzyl)-naphthalene- 1 -yl]-6-hydroxymethyl-2-methoxy-tetrahydropyran-3,4,5-triol 6d (650 riig, white solid), Yield: 23.7%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.94 (br.s, 1 Η), 8.34 (dd, 2H), 7.72 (br.s, 1H), 7.52 (m, 2H), 6.86 (m, 3H) ), 4.40 (d, 1H), 4.19 (d, 1H), 3.92 (m, 3H), 3.55 (m, 3H), 3.16 (s, 3H)

 the fourth step

 (2S,3i?,4i?,5S,6i?)-2-[4-chloro-3-(3-fluoro-4-hydroxy-benzyl)-naphthalene small group]-6-hydroxymethyl-tetrahydro Pyran-3,4,5-triol

Will be (2 & 3/?,4S,5 & 6 ?)-2-[4-chloro-3-(3-fluoro-4-hydroxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl 2-methoxy-tetrahydropyran-3,4,5-triol 6d (650 mg, 1.36 mmol) was dissolved in 15 mL of a mixture solvent of acetonitrile and dichloromethane (V: V = 2: 1) Triethylsilane (0.6 mL, 1.5 mmol) and boron trifluoride diethyl ether (0.3 mL, 1.5 mmol) were added and the mixture was stirred for 16 hr. 15 mL of a saturated aqueous solution of sodium hydrogencarbonate was added dropwise, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Deprotection System A Purify the resulting residue to give the title product (2 & 3/?,4 5 & 6/?)-2-[4-chloro-3-(3-fluoro-4-hydroxy-benzyl)-naphthalenyl]-6-hydroxymethyl-tetrahydro Pyran-3,4,5-triol 6e (470 mg, white solid), Yield: 77.0%.

MS m/z (ESI): 466.2 [M+18]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.33 (dd, 2H), 7.60 (m, 3H), 6.86 (m, 3H), 4.90 (d, 1H), 4.26 (m, 2H), 3.90 ( m, 1H), 3.74 (m, 2H), 3.55 (m, 3H)

 the fifth step

 (2 & 3i?,4/?,5 & 6i?)-2-[4-chloro-3-(4-ethoxy-3-fluoro-benzyl)-naphthalenyl]-6-hydroxymethyl -tetrahydropyran

 -3,4,5-triol

 (2 & 3 4 5 & 6/?)-2-[4-chloro-3-trifluoro-4-hydroxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyridyl Ethyl-3,4,5-triol 6e (224 mg, 0.5 mmol) was dissolved in 5 mL of hydrazine, hydrazine-dimethylformamide, and cesium carbonate (179.2 mg, 0.55 mmol) and ethyl iodide (44 L) , 0.55 mmol), the reaction was stirred at 50 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure and purified tolulujjjjjjjjjjjjjjjjjjjj (4-ethoxy-3-fluoro-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol 6 (140 mg, white solid) Yield: 58.7%.

MS m/z (ESI): 494.1 M+.l 8]

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.33 (dd, 2H), 7.60 (m, 3H), 6.96 (m, 3H), 4.90 (d, 1H), 4.26 (m, 2H), 4.05 ( q, 2H), 3.90 (m, 1H), 3.74 (m, 2H), 3.55 (m, 3H), 1.38 (t, 3H) Example 7

 (2S,3 4i?,5S,6i?)-2-"4-Chloro-3-(4-ethyl-benzyl)-naphthalen-1-yl 6-hydroxymethyl-tetrahydropyran-3, 4,5-triol

First

 4-bromo-1-chloro-naphthalene-2-formaldehyde

 4-Bromochloro-naphthalene-2-carbonitrile lc (2.66 g, 10 mmol) was dissolved in 20 mL of toluene, and 20 mL of a solution of diisobutylaluminum hydride (10 mL, 11 mmol) in toluene was added. The reaction was stirred for 2 hours under ice bath, 20 mL of a mixed solvent of toluene and methanol (V: V = 1: 1) and 20 mL of 2 M hydrochloric acid were added, stirred for 30 minutes, filtered, and the filter cake was rinsed with 50 mL of ethyl acetate and added. 20 mL of water, extracted with ethyl acetate (20 mL×2), EtOAc (EtOAc) -Chloro-naphthalene-2-carbaldehyde 7a (1.7 g, yellow solid), Yield: 63.2%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): 5 10.70 (s, 1Η), 8.5 l(d, 1H), 8.3 l(d, 1H), 8.23(d, 1H), 7.83(m, 1H), 7.76 (m, 1H)

 Second step

 L-(4-ethyl-phenyl)magnesium bromide

 Dissolve 1-bromo-4-ethyl-benzene 7b (1.66 g, 8.97 mmol) in 15 mL of tetrahydrofuran to make a 7b solution in tetrahydrofuran. Add magnesium (218 mg, 8.97 mmol) to the reaction flask and add iodine. (catalytic amount) and a small amount of 7b tetrahydrofuran solution, the reaction was initiated by heating, and the 7b tetrahydrofuran solution was further added dropwise, and the reaction was stirred for 30 minutes under reflux to obtain the title product 1-(4-ethyl-phenyl)magnesium bromide 7c. Used directly in the next step.

 third step

 (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethyl-phenyl)-methanol

 4-Bromo-1-chloro-naphthalene-2-carboxaldehyde 7a (410 mg, 1.52 mmol) was dissolved in 5 mL of tetrahydrofuran and added

1-(4-Ethyl-phenyl)magnesium bromide 7c (1.87 g, 8.97 mmol) was stirred at 30 ° C for 2 hr. Add 5 mL of a saturated sodium chloride solution, add 1 mL of 2 M hydrochloric acid, and extract with ethyl acetate (10 mL >< 3), and the organic phase is combined, dried over anhydrous magnesium sulfate, and filtered. Elution system B pure The residue obtained was purified to give the title compound (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethyl-phenyl)-methanol 7d (330 mg, yellow oil), yield: 57. .

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.29 (m, 1H), 8.2 l (m, 1H), 7.92 (s, 1H), 7.61 (m, 2H), 7.33 (d, 2H), 7.14 (d, 2H), 6.45(s, 1H), 2.61 (q, 2H), 1.19(t, 3H)

 the fourth step

 4-bromo-1-chloro-2-(4-ethyl-benzyl)-naphthalene

 (4-Bromo-chloro-naphthalen-2-yl)-(4-ethyl-phenyl)-methanol 7d (290 mg, 0.77 mmol) was dissolved in 8 mL of methylene chloride. The silane (0.37 mL, 2.32 mmol) and boron trifluoride etherate (0.20 mL, 1.54 mmol) were stirred for 30 min. After adding 5 mL of a saturated sodium carbonate solution and ethyl acetate (10 mL, 3), -ethyl-benzyl)-naphthalene 7e (270 mg, yellow solid), yield: 97.5%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.33 (d, 1 Η), 8.20 (d, 1H), 7.65-7.41 (m, 3H), 7.16-7.08 (m, 4H), 4.26 (s, 2H) ), 2.6 l(q, 2H), 1.21(t, 3H)

 the fifth step

(2&3 where ^5i?,6i?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(4-ethyl-benzyl)-naphthalene -1-yl]-tetrahydropyran-2-ol

 Dissolve 4-bromo-1-chloro-2-(4-ethyl-benzyl)-naphthalene 7e (370 mg, 1.03 mmol) in 8 mL of tetrahydrofuran and add 2.5 M n-butyl at -78 °C. Lithium cyclohexane solution (0.41 mL, 1.03 mmol), stirred for 30 minutes, added 2 mL (3i?, 4 & 5i?, 6i?)-3,4,5-tribenzyloxy-6-benzyloxymethyl Base-tetrahydropyran-2-one 1 h (610 mg, 1.13 mmol), and the reaction was stirred at -78 °C for 2 hours. A small amount of a saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate (EtOAc) (EtOAc) (2 & 3i?, 4 & 5i?, 6i?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(4-ethyl-benzyl -Naphthalen-1-yl]-tetrahydropyran-2-ol 7f (400 mg, yellow oil), Yield: 47.4%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.6 l(d, 1Η), 8.35(d, 1H), 7.77(s, 1H), 7.52(t, 1H), 7.36-7.22(m, 16H) , 7.14-6.96(m, 7H), 6.65(d, 2H), 4.96(d, 1H), 4.89(q, 2H), 4.76(d, 1H), 4.57(d, 1H), 4.45(d, 1H) ), 4.36(d, 1H), 4.24-4.12(m, 5H), 3.97(d, 1H), 3.72(d, 1H), 3.60(d, 1H), 3.41(s, 1H), 2.58(q, 2H), 1.19(t, 3H)

 Step 6

(2i?,3i?,4i?,5&65)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(4-ethyl-benzyl) -naphthalen-1-yl]-tetrahydropyran

(2 & 3 4 & 5 6/?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(4-ethyl-benzyl) -naphthalen-1-yl]-tetrahydropyran-2-ol 7f (390 mg, 0.48 mmol) was dissolved in 5 mL of dichloromethane, and then triethylsilane (0.22 mL, 1.43 mmol) With boron trifluoride etherate (0.12 mL, 0.95 mmol), the reaction was stirred at room temperature for 48 hours. Add 5 mL of saturated sodium carbonate solution, and extract with ethyl acetate (20 mL >< 3). The organic phase is washed with saturated sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was purified by column chromatography using eluent B to give the title product. (2 3i?,4W,5 & 65)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(4-ethyl-benzyl)- Naphthyl-yl]-tetrahydropyran 7 _g (210 mg, yellow oil), Yield: 55.0%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.39 (m, 2 Η), 7.58 (t, 1H), 7.49 (s, 1H), 7.43 (t, 1H), 7.31-7.23 (m, 15H), 7.12-6.97(m, 7H), 6.50(d, 2H), 4.92-4.89(m, 3H), 4.8 l(s, 1H), 4.69(d, 1H), 4.6 l(d, 1H), 4.5 l (d, 1H), 4.35(d, 1H), 4.20(d, 1H), 4.15(d, 1H), 3.86-3.82(m, 4H), 3.76(d, 1H), 3.68(d, 1H), 3.49(d, 1H), 2.57(q, 2H), 1.17(t, 3H)

 Step 7

 (2 & 3i?, 4i?, 5 & 6i?)-2-[4-chloro-3-(4-ethyl-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyridyl -3-3,4,5-triol will (2i?,3/?,4i?,5 & 65)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4 -Chloro-3-(4-ethyl-benzyl)-naphthalen-1-yl]-tetrahydropyran 7g (210 mg, 0.26 mmol) was dissolved in 3 mL of chloroform, followed by 2 mL of ethanethiol and trifluoro Boron ether (0.5 mL, 3.92 mmol) was stirred and the reaction was stirred for 16 h. 5 mL of a saturated sodium carbonate solution was added, and the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated (2 & 3 4/?,5 & 6/?)-2-[4-chloro-3-(4-ethyl-benzyl)-naphthalenyl]-6-hydroxymethyl-tetrahydropyran- 3,4,5-triol 7h (220 mg, white solid) was used in the next step without isolation.

MS m/z (ESI): 460.0 [M+l 8]

 Eighth step

 (2i?, 3i?, 4i?, 5 & 6S)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethyl-benzyl)-naphthalene]- Methyl tetrahydropyran-2-ylacetate

Will (2 & 3i?,4 ?,5 & 6i?)-2-[4-chloro-3-(4-ethyl-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydro Pyran-3,4,5-triol 7h (220 mg, 0.26 mmol) was dissolved in 5 mL of pyridine, acetic anhydride (0.25 mL, 2.6 mmol) was added, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The filtrate was purified by column chromatography on silica gel eluting with eluent to afford the title product (2 3 ?, 4i?, 5 & 65)-3,4,5-triacetoxy-6-[4- Methyl chloro-3-(4-ethyl-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ylacetate 7i (120 mg, white solid), yield: 75%. - 'H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.38 (d, 1 Η), 8.15 (d, 1H), 7.58 (m, 2H), 7.44 (s, 1H) _: 7.11 (m, 4H), 5.42(m, 2H), 5.30(m, 1H), 5.07(s, 1H), 4.33-4.25(m, 3H), 4.17(d, 1H), 3.96-3.93(m, 1H), 2.60(q, 2H), 2.07(d, 6H), 2.00(s, 3H), 1.44(s, 3H), 1.20(t, 3H)

 Step 9

(2 & 3/?, 4i?, 5S, 6i?)-2-[4-chloro-3-(4-ethyl-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydro Pyran-3,4,5-triol will (2 3/?,4/?,5&65)-3,4,5-triacetoxy-6-[4-chloro-3-(4-ethyl Methyl-benzyl)-naphthalenyl]-tetrahydropyran-2-ylacetate 7i (110 mg, 0.18 mmol) was dissolved in 6 mL of methanol, dichloromethane and water (V: V: V=3: 2: 1) To a mixed solvent, lithium hydroxide monohydrate (15 mg, 0.36 mmol) was added, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Product (2&3 4/?, 5 & 6i?)-2-[4-chloro-3-(4-ethyl-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran- 3,4,5-triol 7 (70 mg, yellow solid), Yield: 87.5%.

 MS m/z (ESI): 460.1 [M+18]

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.33 (d, 1H), 8.08 (d, 1H), 7.47 (t, 1H), 7.40 (m, 2H) _; 6.99 (q, 4H), 4.70 ( d, 1H), 4.18(q, 2H), 3.7 l(d, 1H), 3.69-3.50(m, 5H), 2.47(q, 2K), 1.10(t, 3H) Example 8

 (~2&3/?,4 5 & 6W)-2-"4-Chloro-3-(4-methylthio-benzyl)-naphthalenyl 1-6-hydroxymethyl-tetrahydropyran-3 , 4,5-three

 First

 1-(4-methylthio-phenyl)magnesium bromide

 Dissolve 1-bromo-4-methylthiobenzene 8a (2.03 g, 10 mmol) in 10 mL of tetrahydrofuran to prepare a solution of 8a in tetrahydrofuran. Add magnesium (243 mg, 10 mmol) to the reaction flask and add Iodine (catalytic amount), a small amount of a solution of 8a in tetrahydrofuran was added, and the reaction was initiated by heating. The solution of 8a in tetrahydrofuran was further added dropwise, and the reaction was refluxed for 30 minutes to obtain the title product 1-(4-methylthio-phenyl) bromide. Magnesium 8b, used directly in the next reaction.

 Second step

 (4-bromo- 1 -chloro-naphthalen-2-yl)-(4-methylthio-phenyl)-methanol

 4-Bromo-1-chloro-naphthalene-2-carbaldehyde 7a (808 mg, 3 mmol) was dissolved in 10 mL of tetrahydrofuran, and 1-(4-methylthio-phenyl)magnesium bromide 8b was added under ice bath ( 10 mL, 10 mmol), stir the reaction for 2 hours. A small amount of a saturated sodium chloride solution was added, and 10 mL of EtOAc (EtOAc) was evaporated. The filtrate was purified by silica gel column chromatography elutd elut elut elut elut elut 8c (490 mg, yellow solid), Yield: 41.5%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.3 l (m, 1H), 8.24 (m, 1H), 8.09 (s, 1H), 7.63 (m, 2H), 7.36 (d, 2H), 7.22 (d, 2H), 6.46(s, 1H), 2.45(s, 3H) Third

 4-bromo - 1 -chloro-2-(4-methylthio-benzyl) -naphthalene

 (4-Bromo-1-chloro-naphthalen-2-yl)-(4-methylsulfanyl-phenyl)-methanol 8c (490 mg, 1.24 mmol) was dissolved in dichloromethane (20 mL) Triethylsilyl sulfonium (0.59 mL, 3.72 mmol) and boron trifluoride etherate (0.31 mL, 2.49 mmol) were added sequentially, and the mixture was stirred for 1.5 hr. Add 10 mL of saturated sodium carbonate solution, extract with methylene chloride (20 mL×3), EtOAc (EtOAc)EtOAc. The title product 4-bromo-1 -chloro-2-(4-methylthio-benzyl)-naphthalene 8d (440 mg, white solid).

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.33 (d, 1 Η), 8.2 l (d, 1H), 7.63 (m, 3H), 7.2 l (d, 2H) _; 7.19 (d, 2H), 4.26(s, 2H), 2.46(s, 3H)

 the fourth step

 (2 & 3i?,4S,5 & 6/?)-2-[4-chloro-3-(4-methylthio-benzyl)-naphthalene-1-yl]-6-hydroxymethyl-2 -methoxy-tetrahydropyran-3,4,5-triol

 Dissolve 4-bromo-chloro-2-(4-methylthio-benzyl)-naphthalene 8d (440 mg, 1.16 mmol) in 10 mL of tetrahydrofuran and add 2.5 M n-butyllithium at -78 °C. Cyclohexyl hydrazine solution (0.52 mL, 1 : 28 mmol), stir the reaction for 30 minutes, add 10 mL (3i?, 4 & 5^6i?)-3,4,5-three-three at -78 °C Methylsiloxy-6-trimethylsilyloxymethyl-tetrahydropyran-2-one 6c (542 mg, 1.16 mmol) in tetrahydrofuran, kept at -78 °C for 2 hours, then added 10 mL A solution of 0.6 M methanesulfonic acid in methanol was stirred at room temperature for 16 hours. 5 mL of a saturated sodium carbonate solution was added, and the mixture was evaporated to dryness. EtOAc was evaporated. The residue obtained is purified by eluent system A to give the title product (2S, 3i?, 4 & 5 & 6i?)-2-[4-chloro-3-(4-methylthio-benzyl)- Naphthalene-1-yl]-6-hydroxymethyl-2-methoxy-tetrahydropyran-3,4,5-triol 8e (1 70 mg, white solid), Yield: 29.8%.

MS m/z (ESI): 513.1 [M+23]

 the fifth step

 (2&3 ?,4 5 & 6 -2-[4-chloro-3- 4-methylthio-benzyl)-naphthalenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5 -three

 Alcohol

 Will (2 & 3 4 & 5 & 6/?)-2-[4-chloro-3-(4-methylthio-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-2- Methoxy-tetrahydropyran-3,4,5-triol 8e (170 mg, 0.35 mmol) was dissolved in 6 mL of acetonitrile and dichloromethane (V: V = 2: 1) in a mixed solvent, followed by three Ethyl silicon germanium (0.17 mL, 1.04 mmol) and boron trifluoride etherate (0.088 mL, 0.69 mmol) were stirred for 16 h. 5 mL of saturated sodium carbonate solution was added, and the mixture was extracted with ethyl acetate (10 mL×4), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, filtered, evaporated, evaporated, To give the title product (2 & 3/?, 4i?, 5S, 67?)-2-[4-chloro-3-(4-methylthio-benzyl)-naphthalenyl]-6-hydroxy Methyl-tetrahydropyran-3,4,5-triol 8 (130 mg, white solid), Yield: 81.3%.

 MS m/z (ESI): 478.0 [M+18]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.36 (d, 2H), 7.63-7.55 (m, 3H), 7.19 (s, 4H), 4.90(d, 1H), 4.33(q, 2H), 3.92(d, 1H), 3.75(m, 2H), 3.60(t, 1H), 3.55(m, 2H), 2.44(s, 3H) 9

 OS, 3i?, 4 5S, 6j?)-2-"4-chloro-3-(4-methoxy-benzyl), naphthalene small group 6-hydroxymethyl-tetrahydropyran-3,4 5-triol

 First step

 (4-bromo-1-chloro-naphthalen-2-yl)-(4-methoxy-phenyl)-methanone

 Dissolve 4-bromo-1-chloro-naphthalene-2-carbonyl chloride le (2.12 g, 7 mmol) in 35 mL of dichloromethane, add anisole (0.76 mL, 7 mmol). Add aluminum trichloride (840 mg, 6.3 mmol), stir the reaction at room temperature for 16 hours, add 20 mL of 1 M hydrochloric acid, extract with dichloromethane (100 mL×2), and wash the organic phase with saturated sodium chloride solution. (30 mL), EtOAc (3 mL, dry. -Chloro-naphthalen-2-yl)-(4-methoxy-phenyl)-methanone 9a (1.5 g, yellow solid), yield: 57.3%. MS m/z (ESI): 377.1 [M+1]

 Second step

 4-bromo-1-chloro-2-(4-methoxy-benzyl)-naphthalene

 (4-Bromo-1-chloro-naphthalen-2-yl)-(4-methoxy-phenyl)-methanone 9a (1.3 g, 3.46 mmol) was dissolved in 45 mL of acetonitrile and dichloromethane (V: V = 2: 1) In a mixed solvent, triethylsilyl ruthenium (2.46 mL, 15.57 mmol) and boron trifluoride diethyl ether (1.28 mL, 10.38 mmol) were successively added, and the reaction was stirred for 4 hours. The reaction mixture was concentrated under reduced vacuo.mjjjjjjjjjjjjj Mg, white solid), Yield: 58.9%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.36-8.33 (d, 1H), 8.21 -8.19 (d, 1H), 7.66-7.58 (m, 3H), 7.16-7.13 (d, 2H), 6.86 -6.82 (d, 2H), 4.24 (s, 2H), 3.78 (s, 3H)

Third (2S,3 4S,5 & 6i?)-2-[4-chloro-3-(4-methoxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-2-methoxy -tetrahydropyran

 -3,4,5-triol

 Dissolve 4-bromo-1-chloro-2-(4-methoxy-benzyl)-naphthalene 9b (620 mg, 1.99 mmol) in 20 mL of tetrahydrofuran and add 2.5 M n-butyl at -78 °C. Base lithium ruthenium solution (0.95 mL, 2.38 mmol), stir at -78 °C for 1 hour, add 10 mL (3i?, 4 & 5 6/?)-3,4,5-three- A solution of trimethylsiloxy-6-trimethylsilyloxymethyl-tetrahydropyran-2-one 6c (930 mg, 1.99 mmol) in tetrahydrofuran was stirred at -78 °C for 3 hours. 3 mL of 2 M methanesulfonic acid in methanol was added and the reaction was stirred at room temperature for 16 'hr. Add 15 mL of saturated sodium bicarbonate solution and concentrate under reduced pressure. EtOAc (EtOAc) (EtOAc) The filtrate was concentrated under reduced pressure to give the title product (2 & 3i?, 4S, 5S, 6i?)-2-[4-chloro-3-(4-methoxy-benzyl)-naphthalen-1-yl]-6 -Hydroxymethyl-2-methoxy-tetrahydropyran-3,4,5-triol 9c (280 mg, white solid), Yield: 29.6%.

 the fourth step

 (2S,3i?,4 ?,5 & 6Α)-2-[4-chloro-3-(4-methoxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyridyl -3-3,4,5-triol will (2 & 3/?,4&5 & 6 -2-[4-chloro-3-(4-methoxy-benzyl)-1--1-yl]-6- Hydroxymethyl-2-methoxy-tetrahydropyran-3,4,5-triol 9c (175 mg, 0.37 mmol) was dissolved in ήπί acetonitrile and dichloromethane (V: V = 3: 4) In a mixed solvent, boron trifluoride diethyl ether (0.94 mL, b.74 mmol) and triethylsilane (0.18 mL, 1.12 mmol) were added to the mixture under ice-cooling, and the reaction was stirred for 16 hours. The residue obtained by purification of the layer chromatography eluent system A gave the title product (2 & 3i?, 4i?, 5 & 6i?)-2-[4-chloro-3-(4-methoxy-benzyl) -naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol 9 (100 mg, pale yellow solid), Yield: 61.0% MS m/z (ESI) : 462.1 [M+18]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.35-8.32 (d, 2H), 7.60-7.52 (m, 3H), 7.16-7.13 (d, 2H), 6.82-6.79 (d, 2H), 4.88-4.84 (d, 1H), 4.32-4.22 (m, 3H), 3.91 -3.88 (d, 2H), 3.88-3.70 (m, 5H), 3.61-3.57 (m, 2H), 3.52-3.47 (m , 3H) Example 10

 (2 3 ?,4/?,5&67?)-2-"4-Chloro-3-(4-cyclopropyl-benzyl)-naphthalen-1-yl 6-hydroxymethyl-tetrahydropyran-3 ,4,5-triol

first step

 (4-bromo-1-chloro-naphthalen-2-yl)-(4-cyclopropyl-phenyl)-methanone

 4-Bromo-1-chloro-naphthalene-2-carbonyl chloride le (1.7 g, 5.6 mmol) was dissolved in 40 mL of dichloromethane, then cyclopropylbenzene (0.7 mL, 5.6 mmol). Aluminum trichloride (0.67 g, 5 mmol) was stirred for 64 hours. Under ice bath, 20 mL of 2 M hydrochloric acid was added dropwise, and extracted with dichloromethane (60 mL×3). The organic phase was washed with water (15 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was reduced by silica gel column chromatography The eluent system A was purified to give the title compound (4 bromo-dichloro-naphthalen-2-yl)-(4-cyclopropyl-yl-phenyl)-methanone 10a (1.36 g, yellow solid). Yield: 63.0%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.45-8.41 (d, 1Η), 8.40-8.34 (d, 1H), 7.81-7.57 (d, 5H), 7.18-7.16 (d, 2H), 2.03 -1.97 (m, 1H), 1.15-1.06 (m, 2H), 0.91-0.79 (d, 2H)

 Second step

 (4-bromo-1-chloro-naphthalen-2-yl)-(4-cyclopropyl-phenyl)-methanol

 (4-Bromo-chloro-naphthalen-2-yl)-(4-cyclopropyl-phenyl)-methanone 10a (1.36 g, 3.52 mmol) was dissolved in 45 mL of methanol and tetrahydrofuran (V: V = 5 : 4) Potassium borohydride (284.8 mg, 5.28 mmol) was added in portions in a mixed solvent, and stirred for 2.5 hours. After adding 15 mL of 1 M hydrochloric acid, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, The product (4-bromo-1-chloro-naphthalen-2-yl)-(4-cyclopropyl-phenyl)-methanol 10b (1.36 g, brown oil) was used for the next step without isolation.

 third step

 4-bromo-1-chloro-2-(4-cyclopropyl-benzyl)-naphthalene

 (4-Bromo-1-chloro-naphthalen-2-yl)-(4-cyclopropyl-phenyl)-methanol 10b (1.36 g, 3.52 mmol) was dissolved in dichloromethane (25 mL) Silica (1.7 mL, 10.56 mmol) and boron trifluoride etherate (1.35 mL, 10.56 mmol) were stirred for 16 h. Add 15 'iL of saturated sodium carbonate solution, add 20 mL of dichloromethane, and separate the mixture. The aqueous phase is extracted with dichloromethane (30 mL). The organic phase is combined, dried over anhydrous magnesium sulfate, filtered, The obtained residue was purified to silicagel elut elut elut elut elut elut Yield: 57.7%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.42 (d, 1Η), 8.31 -8.28 (d, 1H), 7.72-7.64 (m, 3H), 7.23-7.21 (d, 2H), 7.11-7.09 (d, 2H), 2.00-1.93 (m, 1H), 1.06-0.98 (m, 2H), 0.83-0.77 (m, 2H)

 the fourth step

 (2 & 3/?,4&5&6/ζ)-2-[4-chloro-3-(4-cyclopropyl-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-2-methoxy -tetrahydropyran

 -3,4,5-triol

 4-Bromo-1-chloro-2-(4-cyclopropyl-- benzyl)-naphthalene 10c (750 mg, 2 mmol) was dissolved in 20 mL of tetrahydrofuran, and 1.6 M was added dropwise at -78 °C. Butyllithium in cyclohexane (1.5 mL, 2.4 mmol), stir the reaction at -78 for 5 hours, add 10 mL (3?,4S,5?,6/?)-3,4,5 a solution of tris-trimethylsiloxy-6-trimethylsilyloxymethyl-tetrahydropyran-2-one 6c (933 mg, 2 mmol) in tetrahydrofuran, stirred at -78 for 3.5 hours. 10 mL of 2 M methanesulfonic acid in methanol was added and the reaction was stirred at room temperature for 16 hours. After adding 20 mL of a saturated aqueous solution of sodium hydrogencarbonate, EtOAc (3 mL), EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH & 3 4 & 5S,6/?)-2-[4-Chloro-3-(4-cyclopropyl-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-2-methoxy- Tetrahydropyran-3,4,5-triol 10 «1 (400 1 ^, white solid), Yield: 41.3%.

MS m/z (ESI): 507.3 [M+23]

 the fifth step

 (2 & 3/?, 4i?, 5 & 6i?)-'2-[4-chloro-3-(4-cyclopropyl-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetra Hydropyran-3,4,5-triol will be (2 & 3i?,4 & 5 & 67?)-2-[4-chloro-3-(4-cyclopropyl-benzyl)-naphthalene ]-6-Hydroxymethyl-2-methoxy-tetrahydropyran-3,4,5-triol 10d (400 mg, 0.83 mmol) dissolved in 23 mL of dichloromethane and acetonitrile (V: V = 2: 1) In a mixed solvent, triethylsilane (0.3 mL, 1.8 mmol) and boron trifluoride diethyl ether (0.5 mL, 4 mmol) were added, and the mixture was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and purified tolulujjjjjjjjjjjjjjjjj -Benzyl)-naphthalenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol 10 (261 mg, white solid), Yield: 69.6%. MS m/z (ESI): 472.3 [M+l 8]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.37-8.34 (d, 2H), 7.63-7.54 (m, 3H), 7.13-7.11 (d, 2H), 6.99-6.97 (d, 2H), 4.89-4.87 (s, 1H), 4.36-4.29 (m, 2H), 3.93-3.90 (d, 2H), 3.76-3.70 (m, 2H), 3.63-3.58 (m, 2H), 3.54-3.49 (m , 3H), 3.33-3.32 (d, 2H), 1.88-1.83 (m, 1H), 0.94-0.90 (m, 2H), 0.64-0.60 (m, 2H) Example 11

 (2&3 Where 4/?, 5&6 ?)-2-"4-Chloro-3-(4-ethoxy-2,3-difluoro-benzyl)-naphthalen-1-yl1-6-hydroxymethyl -tetrahydropyran

 -3,4,5-triol

1-ethoxy- 2,3-difluoro-benzene

 2,3-Difluoro-phenol 11a (6.5 g, 50 mmol) was dissolved in 100 mL of acetone, potassium carbonate (10.3 g, 75 mmol) and ethyl iodide (5.2 mL, 65 mmol) were added and stirred at room temperature. After 3 hours, the reaction was refluxed at 70 ° C for 3 hours. The reaction mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

NMR NMR (400 MHz, CDCI3, ppm) δ 7.03-6.17 (m, _; 1H), 6.82-6.75 (m, 2H), 4.19-4.13 (q

2H), 1.51-1.30 (t, 3H)

 Second step

 (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-2,3-difluoro-phenyl)-methanone 4-bromo-1-chloro-naphthalene-2-methyl The acid chloride le (2.23 g, 7.36 mmol) was dissolved in 30 mL of dichloromethane, and 1-ethoxy-2,3-difluoro-benzene 11b (1.16 g, 7.36 mmol) and aluminum trichloride (0.98 g) were added. , 7.36 mmol), stir the reaction for 16 hours. After adding 20 mL of 4 M hydrochloric acid, the mixture was separated, and the aqueous phase was extracted with methylene chloride (25 mL <&lt;&gt;&gt;3), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The resulting residue was purified to give the title product (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-2,3-difluoro-phenyl)-methanone. 1.47 g, yellow solid), Yield: 47.0%.

 NMR NMR (400 MHz, CDCI3, ppm): δ 8.41-8.33 (m, 2H), 7.81-7.73 (m, 3H), 7.62-7.58 (m, 1H), 6.87-6.83 (m, 1H), 4.27- 4.22 (q, 2H), 1.55-1.47 (t, 3H)

 third step

 (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-2,3-difluoro-phenyl)-methanol (4-bromo-chloro-naphthalen-2-yl)- (4-Ethoxy-2,3-difluoro-phenyl)-methanone llc (1.42 g, 3.34 mmol) dissolved in 45 mL of ethanol and tetrahydrofuran (V: V = 2: 1) in a mixed solvent, batch Potassium borohydride (270 mg, 5 mmol) was added, and the reaction was stirred for 2.5 hours. After adding 20 mL of 1 M hydrochloric acid, the organic phase is evaporated and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. (4-Bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-2,3-difluoro-phenyl)-methanol lld (1.37 g, yellow solid), yield: 95.8%.

 the fourth step

4-bromo-chloro-2-(4-ethoxy-2,3-difluoro-benzyl)-naphthalene (4-Bromo-chloro-naphthalen-2-yl)-(4-ethoxy-2,3-difluoro-phenyl)-methanol lld (1.37 g, 3.2 mmol) was dissolved in 30 mL of acetonitrile and dichloro To a mixed solvent of formazan (V: V = 2:1), triethylsilane (1.6 mL, 10 mmol) and boron trifluoride diethyl ether (1.27 mL, 6.6 mmol) were added, and the reaction was stirred for 16 hours. Dissolve 1.5 g of sodium hydroxide in 20 mL of water, dilute the reaction solution, and separate the liquid. The aqueous phase is extracted with ethyl acetate (30 mL×3). The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut eluting g, white solid), Yield: 82.6%. '

 NMR NMR (400 MHz, DMSO-, ppm): δ 8.33-8.20 (m, 1H), 8.20-8.18 (m, 1H), 7.86 (s, 1H), 7.83-7.77 (m, 2H), 6.97-6.89 (m, 2H), 4.30 (s, 2H), 4.13-4.08 (q, 2H), 1.35-1.32 (t, 3H)

 the fifth step

 (2 & 3i?, S, 5 & 6i?)-2-[4-chloro-3-(4-ethoxy-2,3-difluoro-benzyl)-naphthalene small group]-6-hydroxyl Base-tetrahydropyran

 -2,3,4,5-tetraol

 Dissolve 4-bromo-1-chloro-2-(4-ethoxy-2,3-difluoro-benzyl)-naphthalene (500 mg, 1.21 mmol) in 15 mL of tetrahydrofuran: at -78 °C A 1.6 M solution of n-butyllithium in cyclohexane (0.79 mL, 1.27; mmol) was added dropwise, and the reaction was stirred at -78 °C for 10 minutes, and 10 mL. (3?, 4 & 5i?, 6i? a solution of -3,4,5-tris-trimethylsiloxy-6-trimethylsilyloxymethyl-tetrahydropyran-2-one 6c (593 mg, 1.27 mmol) in tetrahydrofuran, at - 78 The reaction was stirred for 2 hours under stirring, and naturally allowed to react to room temperature for 16 hours. 10 mL of 2 M hydrochloric acid was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was separated, EtOAc (EtOAc) (EtOAcjjjjjjjjjjj -[4-chloro-3-(4-ethoxy-2,3-difluoro-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran-2,3,4, 5-tetraol llf (460 mg, dark yellow oil), Yield: 74.7%.

 MS m/z (ESI): 493.1 [M-18]

 Step 6

 (2 & 3i?, 4i?, 5S, 6i?)-2-[4-chloro-3-(4-ethoxy-2,3-difluoro-benzyl)-naphthalen-1-yl]-6 -hydroxymethyl-tetrahydropyran

 -3,4,5-triol

 Will (2 & 3 ?,4 & 5 & 6i?)-2-[4-chloro-3-(4-ethoxy-2,3-difluoro-benzyl)-naphthalen-1-yl]-6 -Hydroxymethyl-tetrahydropyran-2,3,4,5-tetraol llf (460 mg, 0.9 mmol) was dissolved in 15 mL of a mixed solvent of dichloromethane and acetonitrile (V: V = 1: 2). Triethylsilyl ruthenium (0.43 mL, 2.7 mmol) and boron trifluoride etherate (0.23 mL, 1.8 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hours. 2 g of potassium hydroxide was dissolved in 20 mL of water, 3 mL was added dropwise to the reaction solution, 10 mL of water was added, and the liquid phase was separated. The aqueous phase was extracted with dichloromethane (10 mL×3), and the organic phase was combined. The title compound (2 & 3/?, 4i?, 5 & 6i?)-2-[[[[[[[[[[[ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ 4-chloro-3-(4-ethoxy-2,3-difluoro-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol 11 (40 mg, yellow solid), Yield: 9.0%.

 MS m/z (ESI): 512.2 [M+18]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.39-8.35 (t, 2H), 7.63-7.58 (m, 3H), 6.78-6.77 (m, 2H), 4.91 (m, 1H), 4.34-4.32 (d, 2H), 4.12-4.07 (q, 2H), 3.94-3.91 (dd, 1H): 3.75-3.70 (m, 2H), 3.64 -3.50 (m, 3H), 1.42-1.39 (t, 3H) Example 12

 (2&37?, /?, 5&67?)-2-Γ4-chloro-3-(-ethoxy-2,6-difluoro-benzyl)-naphthalenyl 1-6-hydroxymethyl-tetrahydropyridyl Mutter

 -3,4,5-triol

 First step

 1-ethoxy-3,5-difluoro-benzene

 3,5-Difluoro-phenol 12a (2.6 g, 20 mmol) was dissolved in 30 mL of acetone, potassium carbonate (4.14 g, 30 mmol) and ethyl iodide (3.25 mL, 40 mmol) were added and stirred at room temperature After 16 hours, the reaction was carried out at 50 ° C for 3 hours. The reaction mixture was filtered, washed with EtOAc EtOAc EtOAc (EtOAc) Oxy-3,5-difluoro-benzene 12b (2.2 g, pale yellow oil), Yield: 69.6%.

NMR NMR (400 MHz, CDCl _a , ppm): δ 6.48-6.41 (m, 3Η), 4.06-4.01 (q, 2H), 1.47-1.44 (t, 3H)

 Second step

 (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-2,6-difluoro-phenyl)-methanone 4-bromo-1-chloro-naphthalene-2-methyl Acid chloride le (3.04 g, 10 mmol) was dissolved in 50 mL of dichloromethane and added

1-Ethoxy-3,5-difluoro-benzene 12b (1.58 g, 10 mmol) was added to an aluminum chloride (1.2 g, 9 mmol), and the mixture was warmed to room temperature, and the reaction was stirred for 16 hours. Add 20 mL of 1 M hydrochloric acid, separate the liquid, and extract the aqueous phase with methylene chloride (40 mL×2). The organic phase is combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous The filtrate was purified by silica gel column chromatography eluting to elute to elute to afford the title product (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-2,6-di Fluoro-phenyl)-methanone 12c (980 mg, white solid), Yield: 23.1%.

 MS m/z (ESI): 427.0 [M+l]

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.46-8.43 (dd, 1H), 8.35-8.33 (dd, 1H), 7.95-7.94 (s, 1H), 7.80-7.73 (m, 2H), 6.54-6.49 (dd, 2H), 4.14-4.09 (q, 2H), 1.51-1.47 (t, 3H)

 (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-2,6-difluoro-phenyl)-methanol (4-bromo-1-chloro-naphthalen-2-yl) -(4-Ethoxy-2,6-difluoro-phenyl)-methanone 12c (860 mg, 2.02 mmol) was dissolved in 40 mL of methanol and tetrahydrofuran (V: V = 1 : 1). Potassium borohydride (218 mg, 4.1 mmol) was added and the reaction was stirred for 16 hours. Add 10 mL of acetone, concentrate the reaction solution under reduced pressure, and dissolve the residue with 50 mL of dichloromethane, washed with water (50 mL×2), washed with saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered, The filtrate was concentrated to give the title product (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-2,6-difluoro-phenyl)-methanol 12d (860 mg, pale yellow) Solid), used directly in the next reaction without isolation.

 the fourth step

 4-bromo-1-chloro-2-(4-ethoxy-2,6-difluoro-benzyl)-naphthalene

 Dissolve (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-2,6-difluoro-phenyl)-methanol 12d (855 mg, 2 mmol) in 20 mL of dichloro To the formazan, triethylsilane (0.96 mL, 6 mmol) and boron trifluoride etherate (0.51 mL, 4 mmol) were added and the mixture was stirred for 16 hr. Dissolve 0.5 g of sodium hydroxide in 20 mL of water, drip into the reaction solution, separate the liquid, extract the aqueous phase with methylene chloride (20 mL), and mix the organic phase with saturated sodium chloride solution (20 mL), and combine organic The residue was dried over magnesium sulfate, filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjj Base-2,6-difluoro-benzyl)-naphthalene 12e (520 mg, white solid), Yield: 63.2%.

 the fifth step

 (2 & 3i?,4 & 5 & 6i?)-2-[4-chloro-3-(4:ethoxy-2,6-difluoro-benzyl)-naphthalen-1-yl]-6- Hydroxymethyl-2-methoxy-tetrahydropyran-3,4,5-triol

 Dissolve 4-bromo-chloro-2-(4-ethoxy-2,6-difluoro-benzyl)-naphthalene 12e (520 mg, 1.26 mmol) in 20 mL of tetrahydrofuran and drop at -78 °C Add 1.6 M n-butyllithium cyclohexane solution (0.87 mL, 1.4 mmol), stir the reaction at -78 °C for 30 minutes, and add 5 mL (3 ?, 4 & 5i?, 6/?)-3 ,4,5-tris-trimethylsiloxy-6-trimethylsilyloxymethyl-tetrahydropyran-2-one 6c (590 mg, 1.26 mmol) in tetrahydrofuran at -78 V The reaction was stirred for 3 hours, and 5 mL of a 0.6 M solution of methanesulfonic acid in methanol was added, and the mixture was allowed to warm to room temperature, and the reaction was stirred for 16 hours. After adding 10 mL of a saturated sodium hydrogencarbonate solution, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified from silica gel column chromatography to elute to afford the title product (2 & 3 4 & 5 & 6i?)-2-[4-chloro-3-(4) -ethoxy-2,6-difluoro-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-2-methoxy-tetrahydropyran-3,4,5-triol 12f ( 130 mg, colorless oil), Yield: 19.7%.

 Step 6

 (2S,3i?,4/?,5S,6i?)-2-[4-chloro-3-(4-ethoxy-2,6-difluoro-benzyl)-naphthalen-1-yl] 6-hydroxymethyl-tetrahydropyran

 -3,4,5-triol

(2 & 37?, 4&5 & 6W)-2-[4-chloro-3-(4-ethoxy-2,6-difluoro-benzyl)-naphthalenyl]-6-hydroxymethyl- 2-Methoxy-tetrahydropyran-3,4,5-triol 12f (130 mg, 0.25 mmol) was dissolved in 20 mL of dichloromethane and acetonitrile (V: V = l : 1) In a mixed solvent, triethylsilyl (80 μί, 0.5 mmol) and boron trifluoride etherate (47) were added to the ice bath.

0.37 mmol), the reaction was stirred at room temperature for 16 hours. After adding 10 mL of a saturated sodium carbonate solution, the reaction mixture was stirred for 10 minutes, and the mixture was evaporated.jjjjjjjjjjjjjjh Title product (2S, 3i?, 4i?, 5S, 6?)-2-[4-chloro-3-(4-ethoxy-2,6-difluoro-benzyl)-naphthalen-1-yl] -6-Hydroxymethyl-tetrahydropyran '-3,4,5-triol 12" ('40 mg, white solid), Yield: 32.6%.

 MS m/z (ESI): 512.0 [M+18]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.36-8.33 (m, 2H), 7.60-7.54 (nl, 2H), 7.42 (s, 1H), 6.58-6.56 (dd, 2H), 4.80- 4.78 (m, 1H), 4.29-4.27 (m, 2H), 4.05-4.00 (m, 2H), 3.91 (m, 1H), 3.70-3.66 (m, 2H), 3.56-3.45 (m, 3H), 1.41-1.34 (t, 3H) Example 13

 (2&3 4/?,5&6/?)-2-"4-Chloro-3-(4-ethoxy-3,5-difluoro-benzyl)-naphthalene small group 1-6-hydroxymethyl-tetra Hydropyran

 -3,4,5-triol

 First step

 2-ethoxy-1,3-difluoro-benzene

Dissolve 2,6-difluoro-phenol 13a (3.9 g, 30 mmol) in 250 mL of acetone, add potassium carbonate (6.2 g, .45 mmol) and ethyl iodide (5 mL, 60 mmol) at 40 ° The reaction was carried out for 16 hours at C. The reaction mixture was filtered, washed with EtOAc EtOAc EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Oxy-1,3-difluoro-benzene 13b (3.8 g, colorless oil;), Yield: 80.2%.

'Η NMR (400 MHz, CDC1 ₃ , ppm): 6 6.96-6.86 (m, 3H), 4.23-4.17 (q, 2H), 1.41-1.37 (t, 3H)

 Second step

 (4-bromo-chloro-naphthalen-2-yl)-(4-ethoxy-3,5-difluoro-phenyl)-methanone 4-bromo-1-chloro-naphthalene-2-carbonyl chloride (3.5 g, 11.5 mmol) dissolved in 50 mL of dichloromethane, 2-ethoxy-1,3-difluoro-benzene 13b (1.82 g, 11.5 mmol) and aluminum trichloride (1.38 g, 10.35) Methyl), reacted at 35 ° C for 16 hours. Add 50 mL of 1 M hydrochloric acid, separate the liquid, and extract the water by 4' mesh with dichloromethane (100 mL×2). The organic phase is combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue was purified to give the title compound (4-bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-3,5-difluoro-phenyl)-methanone 13c (1.37 g). , pale yellow solid), Yield: 28.0%.

1H NMR (400 MHz, CDC1 ₃ , ppm): δ 8.41-8.34 (m, 2H), 7.79-7.76 (m, 2H), 7.72 (s, 1H): 7.42-7.40 (m, 2H), 4.42-4.36 (q, 2H), 1.46-1.42 (t, 3H)

 third step

 (4-bromo- 1 -chloro-naphthalen-2-yl)-(4-ethoxy-3,5-difluoro-phenyl)-methanol

'(4-Bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-3,5-difluoro-benzene^)-.methanone 13c (1.35 g, 3.2'mmol) was dissolved in 40 mL of a mixed solvent of methanol and tetrahydrofuran (V: V = 1 : 1), potassium borohydride (24 mg, 6.4 mmol) was added, and the reaction was stirred for 1 hour. After adding 10 mL of acetone, the reaction mixture was evaporated, evaporated, evaporated, evaporated -Bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-3,5-difluoro-phenyl)-methanol 13d (1.3 g, yellow oil), used directly without isolation One step reaction.

 the fourth step

 4-bromo-1-chloro-2-(4-ethoxy-3,5-difluoro-benzyl)-naphthalene

 (4-Bromo-1-chloro-naphthalen-2-yl)-(4-ethoxy-3,5-difluoro-phenyl)-methanol 13d (1.37 g, 3.2 mmol) was dissolved in 30 mL of dichloro To the formazan, triethylsilyl sulfonium (1.5 mL, 9.6 mmol) and boron trifluoride etherate (0.8 mL, 6.4 mmol) were added, and the mixture was stirred for 16 hours. Dissolve 0.5 g of sodium hydroxide in 20 mL of water, dilute the reaction solution, and separate the liquid. The aqueous phase is extracted with dichloromethane (50 mL×2). The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut Colorless oil), Yield: 79.5%.

 • the fifth step

 (2 & 3/?,4 & 5i?,6i?)-3,4,5-tribenzyloxy-6-1⁄2oxymethyl-2-[4-chloro-3-(4-ethoxyl) -3,5-difluoro-benzyl)-naphthalenyl]-tetrahydropyran-2-ol

Dissolve 4-bromo-chloro-2-(4-ethoxy-3,5-difluoro-benzyl)-naphthalene 13e (1.05 g, 2.55 mmol) in 30 mL of tetrahydrofuran and drop at -78 °C Into a 1.6 M n-butyllithium cyclohexane solution (1.75 mL, 2.8 mmol), stir for 20 minutes, add 10 mL (3i?, 4 & 5i?, 6i?)-3,4,5-tribenzyloxy -6-Benzyloxymethyl-tetrahydropyran-2-one 1 h (1.5 g, 2.8 mmol), mp. Add 20 mL of saturated ammonium chloride solution, The organic layer was combined with EtOAc (EtOAc) (EtOAcjjjjjjjjjjjjj Product (2&3/?,4 & 5/?,6i?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(4-ethoxyl) -3,5-Difluoro-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol 13f (1.86 g, pale yellow oil), Yield: 83.8%.

 Step 6

 (2/?,3i?,4 5S,65)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(4-ethoxy-3) ,5-difluoro-benzyl)-naphthalen-1-yl]-tetrahydropyran

Will (2 & 3i?,4 & 5/?,6/?)-3,4,5-tribenzyloxy-6-benzyloxymethyl-2-[4-chloro-3-(4-ethyl Oxy-3,5-difluoro-benzyl)-naphthalen-1-yl]-tetrahydropyran-2-ol 13f (1.86 g, 2.14 mmol) was dissolved in 20 mL of dichloromethane. Triethylsilyl sulfonium (0.41 mL, 2.57 mmol) and boron trifluoride etherate (0.3 mL, 2.35 mmol) were added sequentially, and the mixture was stirred at room temperature for 3 hr. After adding 20 mL of saturated sodium carbonate solution, the mixture was separated, and the aqueous phase was extracted with dichloromethane (60 mL×2). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title product (2i?, 3i?, 4 5 & 65)-3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3. -(4-Ethoxy-3,5-difluoro-benzyl)-naphthalenyl]-tetrahydropyran 13 _g (1.83 g, white solid), Yield: 100%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 8.41-8.39 (m, 2H), 7.64-7.62 (m, 1H), 7.45 (m, 2H), 7.32-7.26 (m, 15H), 7.01-7.00 (m, 3H), 6.75-6.73 (m, 2H), 6:51-6.49 (m, 2H), 4.95-4.91 (m, 2H), 4.62-4.53 (m, 4H), 4.26-4.13 (m, 6H), 3.89-3.79 (m, 6H), 3.55-3.53 (m, 1H), 1.48-1.34 (t, 3H)

 Seventh step

 (2 & 3i?, 4i?, 5S, 6i?)-2-[4-chloro-3-(4-ethoxy-3,5-difluoro-benzyl)-naphthalene small group]-6-hydroxyl Methyl-tetrahydropyran

 -3,4,5-triol

Will (2/?,4?,5&65 3,4,5-tribenzyloxy-2-benzyloxymethyl-6-[4-chloro-3-(4-ethoxy-3,5) -Difluoro-benzyl)-naphthalen-1-yl]-tetrahydropyran 13 _g (1.83 g, 2.14 mmol) was dissolved in 20 mL of dichloromethane, and boron trifluoride diethyl ether (4.07 mL) , 32.1 mmol), 7 mL of ethanethiol was added dropwise, and the reaction was stirred for 16 hours. 20 mL of water was added, and the mixture was evaporated, evaporated, evaporated, evaporated. The residue was dissolved in 20 mL of pyridine, 26 mL of acetic acid was added, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) Drying over anhydrous magnesium sulfate, EtOAc, EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4-chloro-3-(4-ethoxy-3,5-difluoro-benzyl)-naphthalenyl]-6-hydroxymethyl-tetrahydropyran-3,4,5-triol 13 ( 560 mg, white solid), Yield: 52.8%.

 MS m/z (ESI): 512.2 [M+18]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.38-8.33 (m, 2H), 7.63-7.57 (m, 3H), 6.87-6.83 (m, 2H), 4.92-4.90 (d, 1H), 4.30-4.29 (m, 2H), 4.13-4.08 (m, 2H), 3.93-3.90 (dd, 1H), 3.74-3.70 (m, 2H), 3.61-3.53 (m, 3H), 1.34-1.26 (t , 3H) Example 14

 (2S, 3 where 4i?, 5 & 6i?V2--chloro-3-indol-4-^-tetrahydrofuran-3-oxy)-benzyl-1-naphthalen-1-yl}-6-hydroxymethyl-tetrahydro

first step

 4-(4-bromo-1-chloro-naphthalen-2-ylmethyl)-phenol

 4-Bromochloro-2-(4-methoxy-benzyl)-naphthalene 9b (13.0 g, 35.9 mmol) was dissolved in 100 mL of dichloromethane, and 1 M boron tribromide was slowly added dropwise in an ice bath. (9.9 g, 39.5 mmol) of dichloromethane solution, stir the reaction at room temperature for 3 hours, add a small amount of saturated sodium carbonate solution under ice bath, add concentrated hydrochloric acid to adjust the pH to 1, add 200 mL of water, and dispense. The aqueous phase was extracted with EtOAc (EtOAc (EtOAcMeOHMeOHMeOHMeOHMeOH Phenol 14a (12.5 g, yellow solid) was used in the next step without isolation.

 Second step

[4-(4-Bromo-chloro-naphthalen-2-ylmethyl)-phenoxy]-tert-butyl-dimethyl-silazane 4-(4-bromo-1-chloro-naphthalene-2- Methyl)-Phenol 14a (12.5 g, 35.9 mmol) was dissolved in 250 mL of dichloromethane, triethylamine (7.51 mL, 53.85 mmol) and 4-dimethylaminopyridine (219 mg, 1.80 mmol). After reacting for 15 minutes, tert-butyldimethylsilyl chloride (5.95 g, 39.5 mmol) was added, the reaction was stirred for 64 hours, a small amount of 1 M hydrochloric acid was added, and the reaction solution was washed with 1 M hydrochloric acid (50 mL×2), with saturated sodium hydrogen carbonate. The solution was washed with 50 ml of EtOAc (EtOAc) (EtOAc) Residue [4-(4-Bromo-1-chloro-naphthalen-2-ylmethyl)-phenoxy]-tert-butyl-dimethyl-silane 14b (16 g, pale yellow solid), yield: 96.5%.

 third step

 (2 & 3 4 & 5 & 6i?)-2-[4-chloro-3-(4-hydroxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-2-methoxy-tetra Hydropyran

 -3; 4,5-triol

 [4-(4-Bromo-1-chloro-naphthalen-2-ylmethyl)-phenoxy]-tert-butyl-dimethyl-silicone 14b (600 mg, 1.3 mmol) was dissolved in 20 mL of tetrahydrofuran A 1.6 M n-butyllithium cyclohexane solution (0.9 mL, 1.43 mmol) was added dropwise at -78 °C, and the reaction was stirred for 40 minutes, and 10 mL (3?, 4S, 5i?, 6i?) was added. 3,4,5-Tris-trimethylsiloxy-6-trimethylsilyloxymethyl-tetrahydropyran-2-one 6c (607 mg, 1.3 mmol) in tetrahydrofuran, at -78 ° The reaction was stirred for 3 hours at C, 6 mL of 0.6 M methanesulfonic acid in methanol was added, the reaction was stirred at room temperature for 16 hours, 15 mL of saturated sodium bicarbonate solution was added, and the reaction mixture was concentrated under reduced pressure. The extract (30 mL×3), EtOAc (3 mL), EtOAc (EtOAc) 4-chloro-3-(4-hydroxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-2-methoxy-tetrahydropyran-3,4,5-triol 14c (400 Mg, colorless oil), used directly in the next reaction without isolation.

 the fourth step

 (2 & 3i?, 4i?, 5 & 6i?)-2-[4-chloro-3-(4-hydroxy-benzyl)-naphthyl]-6-hydroxymethyl-tetrahydropyran-3, 4,5-triol will be (2 & 3 4 & 5 & 67?)-2-[4-chloro-3-(4-hydroxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl- 2-Methoxy-tetrahydropyran-3,4,5-triol 14c (400 mg, 0.3 mmol) was dissolved in a mixture of 24 mL of dichloromethane and acetonitrile (V: V = 2: 1). Add boron trifluoride etherate (0.3 mL, 2.1 mmol) and triethylsilyl ruthenium (0.3 mL, 1.8 mmol) at 0 °C, stir the reaction at room temperature for 16 hours, add 10 mL of sodium bicarbonate solution to quench the reaction, reduce The reaction mixture was concentrated with EtOAc (EtOAc) (EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The title product (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-hydroxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetrahydropyran -3,4,5-triol 14 < 1 (85 03⁄4, white solid), Yield: 65.9%.

MS m/z (ESI): 431.1 [M+l]

 the fifth step

 (R)- 4-sulfonic acid tetrahydrofuran-3-tolyl ester

 W Tetrahydrofuran-3-ol 14e (705 mg, 8 mmol) was dissolved in 8 mL of pyridine, p-toluenesulfonyl chloride (1.83 g, 9.6 mmol) was added, the reaction was stirred for 16 hours, and the reaction mixture was concentrated under reduced pressure. The ethyl ester was dissolved, and washed with a 1 M citric acid solution (20 mL×2), washed with a saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The obtained residue was purified to give the titled product (?), 4-sulfonic acid, THF, THF (yield: white oil). Yield: 88.7%.

NMR NMR (400 MHz, CDC1 ₃ , ppm): δ 7.80 (d, 2Η), 7.35 (d, 2H), 5.12 (m, 1H), 3.91-3.78 (m, 4H), 2.46 (s, 3H), 2.12-2.06 (m, 2H) Step 6

 (2 & 3i?, 4 5S, 6i?)-2-{4-chloro-3-[4-(tetrahydrofuran-3-oxo)-benzyl]-naphthalene small group}-6-hydroxymethyl-tetrahydro Pyran

 -3,4,5-triol

 Will (2 & 3/?,4/?,5 & 6i?)-2-[4-chloro-3-(4-hydroxy-benzyl)-naphthalen-1-yl]-6-hydroxymethyl-tetra Hydropyran-3,4,5-triol 14d (100 mg, 0.23 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and (/?)-4-sulfonic acid tetrahydrofuran-3-toluene was added. The ester 14f (84 mg, 0.35 mmol) and cesium carbonate (128 mg, 0.36 mmol) were stirred at 75 ° C for 4 hours, and (R)-4-sulfonic acid tetrahydrofuran-3-tolyl ester 14f (84) was added. Mg, 0.35 mmol) and cesium carbonate (128 mg, 0.33⁄4 mmol) were stirred at 50 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The resulting residue was purified to give the title product (2 & 3i?, 4/?, 5 & 6i?)-2- {4-chloro-3-[4-((5)-tetrahydrofuran-3-oxy). )-Benzyl]-naphthalen-1-yl}-6-hydroxymethyl-tetrahydropyran-3,4,5-triol 14 (100 mg, white solid), Yield: 86.2%.

MS m/z (ESI): 518.2 [M+18]

NMR NMR (400 MHz, CD ₃ OD, ppm): δ 8.36 (d, 2H), 7.63-7.54 (m, 3H), 7.18 (d, 2H), 6.81 (d, 2H), 4.98-4.95 (m, 1Η); 4.90 (d, 1H), 4.30 (dd, 2H), 3.84-3.81 (m, 5H), 3.74-3.69 (m, 2H), 3.60 (t, 1H), 3.52-3:48 (m , 2H)

Test Example: Effect of Single Oral Administration of the Compound of the Invention on Random Blood Glucose in db/db Mice Test Purpose:

 After observing the compound of Example 1, 10, the blood glucose was randomized to the type 2 diabetes db/db mice after a single oral administration, and the urine volume of the mice was collected and the urine sugar was detected. Determine the duration and dose-effect relationship of its efficacy. experimental design

 7 to 8 weeks old db/db mice, selected mice with onset, 3⁄4 blood glucose, insulin and body weight were divided into different compound groups, and a positive control group and a solvent control group were set. After subcutaneous injection of each group of animals, blood glucose levels and urine sugar values at different time points after administration were measured. Compound-induced hypoglycemic effects were observed.

Test animal

 Species, strain: db/db mice (B6.Cg-m +/+ Leprdb/J), wild type mice

 Source: Introduced in Jackson, USA (stock number 000697), preserved and propagated by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, certificate number: SCXK (Shanghai; ) 2008-0017 Weight: db/db mice: 37.9±0.5g;

 Sexual ij : db/db mice: 6 males, 6 females

 Feeding conditions: SPF animal room breeding, temperature: 22~24 °C, humidity: 70~90%, light:

 150~300Lx, 12 hours and nights (7:00~19:00 is 昼).

Test substance and control drug Example 1, 10 compounds

 Mode of administration

 Oral administration, the administration volume is 10 mL/kg.

 Test method

 'Mice, according to non-mouse, were grouped according to non-fasting blood glucose and body weight, 6 in each group, half male and half female, respectively, blank control and different compound administration groups. Each group of animals was given a single oral administration of the test drug and solvent, and blood glucose was measured before, and 0.5, 1, 2, 4, and 6 hours after administration. The urine glucose detection period was 0 to 3, 3 to 6, 6 ~ 12 and 12~24 j, when. Observe the hypoglycemic effect of the test substance and the maintenance time.

 test results:

 The blood glucose decline rates of Compounds 1 and 10 are shown in Table 1 and Figure 1. The sugar release amounts are shown in Table 2 and Figure 2.

 Table 1 Blood glucose reduction schedule

Table 2 Schedule of sugar consumption

Claims

Claims:

A compound represented by the formula (I): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

 among them:

R' R^R ³ and R ⁴ are each independently selected from a hydrogen atom, an alkyl group, an aryl group, an aryl fluorenyl group, -C(0)R ^a or -C(0)OR ^a , wherein the fluorenyl group, the aryl group Or an aryl group optionally further substituted with one or more substituents selected from halogen, nitro, hydroxy, cyano, decyloxy or aryl;

R ⁵ and R ⁶ are each independently selected from a hydrogen atom, a halogen, a nitro group, a hydroxyl group, a cyano group, an alkyl group, a decyloxy group, a —CF ₃ , or —OCF ₃ , a _3⁄4 /hydrogen atom or a halogen;

R ⁷ and R ⁸ 3⁄4 are independently selected from the group consisting of a hydrogen atom, an i-, a nitro group, a hydroxyl group, a cyano group, a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, -OR ^a , -C ( 0) OH, -C(0)OR ^a , -S(0) _n R\ -NHC(0)R ^a , -NH-S(0)OR ^a or -C(0)NR ^b R ^e , where The fluorenyl, cyclodecyl, heterocycloalkyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, nitro, cyano, decyl, hydroxy, alkoxy, cyclodecyl, Aryl, heteroaryl, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0) Substituted by a substituent of OR ^a , -N ^b R ^c or -CCC NRbRe;

R ^{9 is} selected from the group consisting of a hydrogen atom, a halogen, a nitro group, a hydroxyl group, a cyano group, a decyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ^a , -C(0)OH, -C( 0) OR ^a , -S(0) _n R ^a > -NHC(0)R ^a , -NH-S(0)OR ^a or -C(0)NR ^b R ^e , wherein the alkyl group, ring 垸Or a heterocycloalkyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of halogen, nitro, cyano, fluorenyl, hydroxy, decyloxy, cyclodecyl, aryl, heteroaryl Base, -OR ^a , -C(0)OH, -C(0)OR ^a , -S(0) _n R ^a , -NHC(0)R ^a , -NH-S(0)OR ^a , -NR Substituting a substituent of ^b R ^c or -C(0)NR ^b R ^e ;

R ^{a is} selected from an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, heterocycloalkyl group, aryl group, heteroaryl group is optional Further one or more selected from the group consisting of halogen, nitro, hydroxy, cyano, alkyl, decyloxy, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, -OR ^d , -C(0) OH, -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or -C(0)NR ^e Substituted by a substituent of R ^f ; ''

R ^b and R ^e are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, heterocycloalkyl group, aryl group or hetero group an aryl group optionally further substituted with one or more substituents selected from halo, nitro, hydroxy, cyano, alkyl, alkoxy embankment, cycloalkyl, heterocyclyl embankment, aryl, heteroaryl, -OR ^d, - C(0)OH, -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or -C( 0) substituted by a substituent of NR ^e R ^f ; Alternatively, R ^b and R ^e together with the attached atom form a 3-8 membered heterocyclic group, wherein the 3 to 8 membered heterocyclic group contains one or more N, 0 or S atoms, and 3 to 8 members. The heterocyclic group is optionally further one or more selected from the group consisting of halogen, nitro, hydroxy, cyano, alkyl, decyloxy, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, -0R ^d , -C(0)OH, -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or - Substituted by a substituent of C(0)NR ^e R ^f ;

R ^{d is} selected from the group consisting of fluorenyl, cyclodecyl, heterocycloalkyl, aryl, arylalkyl or heteroaryl;

R ^e and R ^f are each independently selected from a hydrogen atom, an alkyl group, a cyclodecyl group, an aryl group or a heteroaryl group;

 n is 0, 1 or 2. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is selected from the group consisting of:

3. A compound of the formula (IA), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which is an intermediate for the synthesis of a compound of the formula (I) according to claim 1:

 ( IA )

 among them:

R^R ^{9 is} as defined in claim 1,

R ^{1Q is} selected from a hydrogen atom or a fluorenyl group.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is selected from the group consisting of:

A method of preparing a compound of formula (I) according to claim 1, the method comprising:

: ( IA )

 Dehydroxy or oxirane of a compound of formula (IA) to form a compound of formula (I);

R^R ⁹ is as defined in claim 1;

The definition of R ¹⁰ is as described in Requirement 3.

6. A method of preparing a compound of the formula (A) according to claim 3, the method comprising -

The amino group and the cyano substituted naphthalene compound are reacted with a halogen to form a halogenated naphthalene derivative;

The amino group on the halogenated naphthalene compound is diazotized to form an R ⁵ -substituted naphthalene derivative with a nucleophilic reagent;

The cyano group on the R ⁵ substituted naphthalene compound is hydrolyzed under basic conditions to be acidified to form a carboxy substituted naphthalene derivative;

a carboxy-substituted naphthalene derivative is reacted with oxalyl chloride under basic conditions to form an acid chloride-substituted naphthalene derivative;

The acid chloride-substituted naphthalene derivative is subjected to acylation with a substituted benzene under catalytic conditions to form a 1|derivative;

 The carbonyl group in the ketone compound is reduced to a methylene group;

 The resulting methylene product is coupled with a lactone compound to form a compound of the formula (IA);

 among them:

R^R ⁹ is as defined in claim 1;

R ¹⁰ is as defined in claim 3;

 X is a halogen;

_R i' to _R ' ⁴ are each independently selected from a hydrogen atom, an alkyl group, an aryl group, an aryl fluorenyl group, a silicon fluorenyl group, -C(0)R ^a or -C(0)OR ^a , wherein the alkyl group, The aryl or aralkyl group is optionally further substituted with one or more substituents selected from halogen, nitro, hydroxy, cyano, decyloxy or aryl;

R ^{a is} selected from a decyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an aryl group, an arylalkyl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, heterocyclic fluorenyl group, aryl group, heteroaryl group is optional Further one or more selected from the group consisting of halogen, nitro, hydroxy, cyano, decyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ^d , -C(0) OH, -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or -C(0)NR ^e Substituted by a substituent of R ^f ;

R ^b and R ^e are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, cyclodecyl group, heterocyclic fluorenyl group, aryl group or hetero aryl group an aryl group optionally further substituted with one or more substituents selected from halo, nitro, hydroxy, cyano, alkyl, alkoxy embankment, embankment cycloalkyl group, a heterocyclic group embankment, aryl, heteroaryl, -OR ^d, - C(0)OH, -C(0)OR ^d , -S(0) _n R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d , -NR ^e R ^f or -C( 0) substituted by a substituent of NR ^e R ^f ;

Alternatively, R ^b and R ^e together with the attached atom form a 3-8 membered heterocyclic group, wherein the 3 to 8 membered heterocyclic group contains one or more ^^, 0 or S atoms, and 3 to 8 The heterocyclic group is optionally further selected from one or more selected from the group consisting of halogen, nitro, hydroxy, cyano, alkyl, alkoxy, cyclodecyl, heterocycloalkyl, aryl, Heteroaryl, -OR ^d , -C(0)OH, -C(0)OR ^d , -S(0),,R ^d , -NHC(0)R ^d , -NH-S(0)OR ^d Substituted by a substituent of -NR ^e R ^f or -C(0)NR ^e R ^f ;

R ^{d is} selected from an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an aryl group, an arylalkyl group or a heteroaryl group;

R ^e and R ^f are each independently selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, an aryl group or a heteroaryl group;

 n is 0, 1 or 2.

7. The use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the manufacture of a medicament for the treatment or delay of the development or onset of a disease selected from the group consisting of Diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia , X syndrome, diabetic complications or atherosclerosis or hypertension.

8. A treatment for diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, high Triglycerideemia, X syndrome, diabetes complicated; f or atherosclerotic hard 4fe or hypertension, the method comprising administering to a patient in need of treatment an effective treatment of a compound according to claim 1 or '2 Or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as a medicament for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy , diabetic dysmenorrhea, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome , diabetic complications or atherosclerosis or high blood pressure.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

11. Use of a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment or delay of the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetes Kidney disease, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications or atherosclerosis Or high blood pressure.

12. A treatment for diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, high A method of triglycerideemia, X syndrome, diabetic complications, or atherosclerosis or hypertension, the method comprising administering to a patient in need of treatment a therapeutically effective amount of the medicament according to claim 10 Composition.

13. The pharmaceutical composition according to claim 10, which is a medicament for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance , hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications or atherosclerosis or hypertension.