C-glycoside aryl compounds and their use for protecting the heart and kidney

Abstract

The present invention relates to C-glycosyl aryl compounds and their use for protecting the heart and kidney. In particular, the compounds of the invention have the structure of Formula I, wherein the definitions of the various groups and substituents are as described in the specification. Methods for preparing the compounds and their use for protecting the heart and kidney are also disclosed.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically to C-glycoside aryl compounds and their use in protecting the heart and kidneys. Background Technology

[0002] Heart failure (HF) is the end-stage of many heart diseases, leading to high readmission and mortality rates, and remains an unconquered challenge in the field of cardiovascular disease. Statistics show that there are as many as 64.3 million HF patients worldwide. In my country, the prevalence of HF among residents aged 35 and above is 1.3%, or approximately 13.7 million people, and this incidence continues to rise as my country's population ages. While the "new triangle" of drugs—ARNI / ACEI / ARB, beta-blockers, and aldosterone receptor antagonists—has effectively improved the prognosis of HF patients, the mortality rate remains high, exceeding 50% within 5 years, even higher than the malignancy of some solid tumors. Furthermore, these drugs all have varying degrees of side effects, limiting their use for some patients. Therefore, the development of drugs with novel mechanisms, proven efficacy, and high safety profiles remains crucial in the field of HF treatment.

[0003] Chronic renal failure (CRF) is the end stage of various chronic kidney diseases. It is a chronic, progressive damage caused by multiple factors that prevents the kidneys from maintaining their basic functions, leading to the retention of metabolic products, electrolyte and acid-base imbalances, and involvement of various systems throughout the body. This clinical syndrome severely impacts patients' quality of life and can even be life-threatening. Epidemiological surveys have found that 30%–40% of heart failure patients also have renal insufficiency. Compared to chronic heart failure patients with normal renal function, those with renal insufficiency have a worse prognosis. Therefore, protecting the kidneys is particularly important in managing heart failure.

[0004] Cardiorenal syndrome (CRS) is a syndrome in which acute or chronic dysfunction of one organ (heart or kidney) leads to acute or chronic dysfunction of the other. The heart and kidneys are both vital organs, and heart and kidney diseases can affect each other. CRS combines a series of pathophysiological changes resulting from heart and kidney dysfunction, leading to high morbidity and mortality. With the increase in longevity and the rising survival rate of patients with heart and / or kidney insufficiency, the incidence of this disease is also significantly increasing. Studies have shown that the mortality risk of CRS is three times higher than that of patients with simple heart disease (HF) or simple chronic kidney disease.

[0005] Cardiorenal syndrome (CRS) is a complex disease process caused by multiple pathogenic factors. Traditionally, renal dysfunction in heart failure (HF) was thought to be mainly due to insufficient renal perfusion caused by reduced cardiac output, leading to renal cortical ischemia or infarction. In recent years, secondary systemic congestion, pulmonary hypertension, and elevated central venous pressure (CVP) due to right ventricular dysfunction have been considered major factors contributing to renal dysfunction. Due to the complex pathophysiological mechanisms and poor prognosis of CRS, the clinical management of CRS patients is a significant challenge. Currently, drugs used to treat CRS are mainly derived from research on heart failure, and have not been adequately studied in randomized clinical trials for CRS.

[0006] Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially approved for the treatment of diabetes. They increase glucose excretion in diabetic patients by inhibiting the reabsorption of sodium and glucose in the proximal tubules of the kidney, thereby lowering blood glucose levels in an insulin-independent manner. SGLT2i may have renal protective effects in acute and chronic renal failure through diuresis, metabolic regulation, and reduction of oxidative stress, inflammation, and cardiovascular remodeling, and are considered the most effective drugs for protecting renal function in HF patients. However, current treatment for CRS is mainly supportive therapy, which can slow disease progression but is difficult to improve the condition. Therefore, the development of novel small molecule drugs for cardiorenal syndrome is urgently needed. Summary of the Invention

[0007] The purpose of this invention is to provide a compound of Formula I, a method for its preparation, and its use in protecting the heart and kidneys.

[0008] In a first aspect, the present invention provides a compound of formula I, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0009]

[0010] in,

[0011] Rings A, R1, R2, R3, and R4 are respectively attached to different carbon atoms of the benzene ring to which they are connected;

[0012] Ring A is a 5-7 membered heterocyclic alkyl group, substituted or unsubstituted, containing 1-3 heteroatoms selected from N, O or S. The substitution refers to being substituted by 1-4 substituents selected from the following group: hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, hydroxy-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, halo-C3-C8 cycloalkoxy, hydroxy-substituted C3-C8 cycloalkoxy, C6-C10 aryl, and a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S.

[0013] R1, R2, R3, and R4 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, hydroxy-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, halo-C3-C8 cycloalkoxy, hydroxy-substituted C3-C8 cycloalkoxy, C6-C10 aryl, and 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S;

[0014] R5, R6, R7, R8, and R9 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, hydroxyl-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, halo-C3-C8 cycloalkyl. Alkoxy, hydroxyl-substituted C3-C8 cycloalkoxy, 5-10 membered heterocyclic alkyl with 1-3 Ra-substituted or unsubstituted heteroatoms selected from N, O or S, 5-10 membered heterocyclic alkoxy with 1-3 Ra-substituted or unsubstituted heteroatoms selected from N, O or S, C6-C10 aryl with 1-3 Ra-substituted or unsubstituted aryl-(CH2) m -O-, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, with 1-3 Ra-substituted or unsubstituted groups; 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, with 1-3 Ra-substituted or unsubstituted groups. m -O-;

[0015] Alternatively, in R5, R6, R7, R8, and R9, two adjacent atoms together with the carbon atoms they are attached to form a 5-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S;

[0016] Each Ra is independently selected from the following group: hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl;

[0017] Each m is independently selected from the following groups: 0, 1, 2, 3, 4.

[0018] In another preferred embodiment, ring A is a substituted 5-7 membered heterocyclic alkyl group containing one O, wherein the substitution refers to being substituted by 1-4 substituents selected from the group consisting of hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, and hydroxyl-substituted C1-C6 alkyl.

[0019] In another preferred embodiment, R1, R2, R3, and R4 are each independently selected from the group consisting of: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and hydroxyl-substituted C1-C6 alkoxy.

[0020] In another preferred embodiment, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of: H, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, 5-10 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, or S, 1-3 membered heterocyclic alkoxy containing 1-3 heteroatoms selected from N, O, or S, or 1-3 membered aryl-(CH2) containing 1-3 heteroatoms selected from N, O, or S, or 1-3 membered aryl-(CH2) containing 1-3 heteroatoms selected from N, O, or S. m -O-, 1-3 Ra-substituted or unsubstituted 5--10-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-;

[0021] Alternatively, R7 and R8 together with the carbon atom they are attached to form a 5-7 membered heterocyclic alkyl group containing one oxygen atom;

[0022] Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0023] Each m is independently selected from the following groups: 0, 1, 2, 3.

[0024] In another preferred embodiment, the compound is selected from the group consisting of: compounds of formula Ia, compounds of formula Ib, and compounds of formula Ic;

[0025]

[0026] R 11 R 12 R 13Each is independently selected from the following group: hydroxyl, hydroxyl-substituted C1-C6 alkyl;

[0027] R1, R2, R3, and R4 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and hydroxyl-substituted C1-C6 alkoxy.

[0028] R5, R6, R7, R8, and R9 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, 5-10 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), 5-10 membered heterocyclic alkoxy containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), and C6-C10 aryl-(CH2) containing 1-3 Ra-substituted or unsubstituted. m -O-, 1-3 Ra-substituted or unsubstituted 5--10-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-;

[0029] Alternatively, R7 and R8 together with the carbon atom they are attached to form a 5-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S;

[0030] Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0031] Each m is independently selected from the following groups: 0, 1, 2, 3.

[0032] In another preferred embodiment, ring A is

[0033] In another preferred embodiment, R1, R2, R3, and R4 are each independently selected from the group consisting of: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and hydroxyl-substituted C1-C6 alkoxy.

[0034] In another preferred embodiment, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxylated C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxylated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, 5-10 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, or S, 1-3 membered heterocyclic alkoxy containing 1-3 heteroatoms selected from N, O, or S, and 1-3 membered aryl-(CH2) containing 1-3 heteroatoms selected from N, O, or S. m -O-, 1-3 Ra-substituted or unsubstituted 5--10-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-;

[0035] Alternatively, R7 and R8 together with the carbon atom they are attached to form a 5-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S;

[0036] Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0037] Each m is independently selected from the following groups: 0, 1, 2, 3.

[0038] In another preferred embodiment, the compound is a compound of formula Ib-1, wherein,

[0039]

[0040] R1 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0041] R2 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0042] R3 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0043] R4 is selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy.

[0044] R5 is selected from the following group: H, C1-C6 alkyl;

[0045] R6 is selected from the following group: H, C1-C6 alkyl;

[0046] R7 is selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, 5-6 membered heterocyclic alkoxy containing 1 O, and 1-3 Ra-substituted or unsubstituted C6-C10 aryl-(CH2). m -O-, 1-3 Ra-substituted or unsubstituted 5- or 6-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-;

[0047] R8 is selected from the following group: H, hydroxyl, C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, or 5-6 membered heterocyclic alkoxy containing 1 O.

[0048] R9 is selected from the following group: H, C1-C6 alkyl, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, or 5-6 membered heterocyclic alkoxy containing 1 O;

[0049] Alternatively, R7 and R8 together with the carbon atoms they are attached to form 5-7 membered heterocyclic alkyl groups containing 1-3 O atoms;

[0050] Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0051] Each m is independently selected from the following groups: 0, 1, 2, 3.

[0052] In another preferred embodiment, the compound is a compound of formula Ib-1, wherein,

[0053] R1 is selected from the following group: H, halogens;

[0054] R2 is selected from the following group: H, halogens;

[0055] R3 is selected from the following group: H, halogens;

[0056] R4 is selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy.

[0057] R5 is H;

[0058] R6 is H;

[0059] R7 is selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, 5-6 membered heterocyclic alkoxy containing 1 O, and 1-3 Ra-substituted or unsubstituted C6-C10 aryl-(CH2). m -O-, 1-3 Ra-substituted or unsubstituted 5- or 6-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-;

[0060] R8 is selected from the following group: H, hydroxyl, C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, or 5-6 membered heterocyclic alkoxy containing 1 O.

[0061] R9 is selected from the following group: H, C1-C6 alkyl, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, or 5-6 membered heterocyclic alkoxy containing 1 O;

[0062] Alternatively, R7 and R8 together with the carbon atoms they are attached to form 5-7 membered heterocyclic alkyl groups containing 1-3 O atoms;

[0063] Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0064] Each m is independently selected from the following groups: 0, 1, 2, 3.

[0065] In another preferred embodiment, the compound is selected from the group consisting of: compounds of formula Id, compounds of formula Ie, and compounds of formula If;

[0066]

[0067] R 21 R 22 R 23 R 24 Each is independently selected from the following group: hydroxyl, C1-C6 alkyl;

[0068] R1, R2, R3, and R4 are each independently selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy;

[0069] R5, R6, R7, R8, and R9 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, hydroxy-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, halo-C3-C8 cycloalkoxy, hydroxy-substituted C3-C8 cycloalkoxy, 5-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), 5-6 membered heterocyclic alkoxy containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), and C6-C10 aryl-(CH2) containing 1-3 Ra-substituted or unsubstituted. m -O-, 1-3 Ra-substituted or unsubstituted 5- or 6-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-;

[0070] Alternatively, R7 and R8 together with the carbon atoms they are attached to form 5-7 membered heterocyclic alkyl groups containing 1-3 O atoms;

[0071] Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0072] Each m is independently selected from the following groups: 0, 1, 2, 3.

[0073] In another preferred embodiment, ring A is

[0074] In another preferred embodiment, R1, R2, R3, and R4 are each independently selected from the group consisting of H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkoxy.

[0075] In another preferred embodiment, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of: H, hydroxyl, halogen, C1-C6 alkyl, hydroxylated C1-C6 alkyl, C1-C6 alkoxy, hydroxylated C1-C6 alkoxy, C3-C8 cycloalkyl, hydroxylated C3-C8 cycloalkyl, C3-C8 cycloalkoxy, hydroxylated C3-C8 cycloalkoxy, 5-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), 5-6 membered heterocyclic alkoxy containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), and C6-C10 aryl-(CH2) containing 1-3 Ra-substituted or unsubstituted. m -O-, 1-3 Ra-substituted or unsubstituted 5- or 6-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S.m -O-;

[0076] Alternatively, R7 and R8 together with the carbon atoms they are attached to form 5-7 membered heterocyclic alkyl groups containing 1-3 O atoms;

[0077] Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0078] Each m is independently selected from the following groups: 0, 1, 2, 3.

[0079] In another preferred embodiment, the compound is a compound of formula Ie-1.

[0080]

[0081] R1 is selected from the following group: H, C1-C6 alkyl;

[0082] R2 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0083] R3 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0084] R4 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy;

[0085] R5 is selected from the following group: H, C1-C6 alkyl;

[0086] R6 is selected from the following group: H, C1-C6 alkyl;

[0087] R7 is selected from the following group: H, hydroxyl, C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, hydroxyl-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, hydroxyl-substituted C3-C8 cycloalkoxy, 5-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, 5-6 membered heterocyclic alkoxy containing 1 O, and 1-3 Ra-substituted or unsubstituted C6-C10 aryl-(CH2). m -O-, 1-3 Ra-substituted or unsubstituted 5- or 6-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-;

[0088] R8 is selected from the following group: H, hydroxyl, C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy;

[0089] R9 is selected from the following group: H, C1-C6 alkyl;

[0090] Alternatively, R7 and R8 together with the carbon atoms they are attached to form 5-7 membered heterocyclic alkyl groups containing 1-3 O atoms;

[0091] Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0092] Each m is independently selected from the following groups: 0, 1, 2, 3.

[0093] In another preferred embodiment, R1 is selected from the group consisting of: H, C1-C6 alkyl groups;

[0094] R2 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0095] R3 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl;

[0096] R4 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy;

[0097] R5 is selected from the following group: H, C1-C6 alkyl;

[0098] R6 is selected from the following group: H, C1-C6 alkyl;

[0099] R7 is a 5-6 membered heterocyclic alkoxy group containing one oxygen atom;

[0100] R8 is selected from the following group: H, hydroxyl, C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy;

[0101] R9 is selected from the following group: H, C1-C6 alkyl.

[0102] In another preferred embodiment, the compound is selected from the group consisting of:

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] A second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound of the first aspect of the present invention, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0110] In another preferred embodiment, the composition further comprises a second active ingredient selected from the group consisting of: anti-heart failure drugs, anti-coronary drugs, anti-myocardial infarction drugs, antihypertensive drugs, anti-diabetic drugs, antiplatelet drugs, anti-atherosclerotic drugs, lipid-lowering drugs, or combinations thereof.

[0111] In another preferred embodiment, the composition further comprises a second active ingredient selected from the group consisting of: aldosterone receptor antagonists, renin-angiotensin system inhibitors, beta-blockers, sodium-glucose cotransporter 2 inhibitors, menthol, or combinations thereof.

[0112] A third aspect of the invention provides the use of the compound described in the first aspect of the invention, or its tautomers, stereoisomers, or pharmaceutically acceptable salts, for the preparation of a medicament for the prevention and / or treatment of diseases selected from the group consisting of: heart failure-related diseases, kidney failure-related diseases, or combinations thereof.

[0113] In another preferred embodiment, the drug is used to prevent and / or treat diseases selected from the group consisting of: heart failure, myocardial infarction, coronary heart disease, myocardial fibrosis, myocardial hypertrophy, dilated cardiomyopathy, myocarditis, cardiotoxicosis, acute and chronic heart failure, chronic renal failure, renal failure, and cardiorenal syndrome.

[0114] In another preferred embodiment, the drug is used for purposes selected from the group consisting of:

[0115] A1) Protects cardiomyocytes;

[0116] A2) Protects kidney cells;

[0117] A3) Inhibits myocardial fibrosis;

[0118] A4) Inhibits renal fibrosis;

[0119] A5) Inhibits myocardial hypertrophy;

[0120] A6) Improves cardiac systolic and diastolic function;

[0121] A7) Improves kidney function;

[0122] A8) Improves exercise endurance.

[0123] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0124] Figure 1 To evaluate the cardioprotective effect of the compound, (A) crystal violet staining was used to evaluate the cell protective effect of the compound; (B) crystal violet staining quantitative mapping was used to characterize cell viability. Data are presented as mean ± SD, ####P<0.0001 vs Control group, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs DMSO group.

[0125] Figure 2 The effect of compound I-80 on AngII-induced cardiomyocyte hypertrophy was investigated. Data are presented as mean ± SD. ####P<0.0001 vs Control group, *P<0.05, **P<0.01 vs DMSO group.

[0126] Figure 3 To evaluate the efficacy of the selected compound in an ISO-induced heart failure model, the following data were used: (A) Experimental flowchart; (B) Representative cardiac images; (C) Heart-to-body ratio; (D) Representative echocardiographic images; (E) Serum LDH levels; (F) Serum BNP levels; (G) Maximum displacement on a treadmill; (H) Mouse grip strength test; (I) Left ventricular ejection fraction; (J) Left ventricular fractional shortening; (K) Left ventricular end-diastolic volume; (L) Left ventricular end-systolic volume. Data are presented as mean ± SD. ####P<0.0001 vs Control group, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs Model group.

[0127] Figure 4 To evaluate the efficacy of the preferred compound in a UUO-induced kidney injury model. (A) Experimental flowchart; (B) Serum creatinine level; (C) Serum urea level; (D) Representative image of kidney stained with HE; (E) Representative image of kidney stained with Masson's Law; (F) Quantitative analysis of renal fibrosis area. Data are presented as mean ± SD. ####P<0.0001 vs Control group, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs Model group.

[0128] Statistical methods: t-tests were used for comparisons between two groups, and ANOVA tests were used for comparisons between more than two groups. Detailed Implementation

[0129] Through long-term and in-depth research, the inventors have obtained a novel compound with excellent therapeutic effects on heart failure, kidney failure, or combinations thereof through structural optimization. Based on this, the inventors have completed this invention.

[0130] the term

[0131] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0132] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0133] In this invention, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups.

[0134] In this invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms and containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0135] In this invention, the term "C2-C6 ynyl" refers to a straight-chain or branched ynyl group having 2-6 carbon atoms and containing a triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0136] In this invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3-8 carbon atoms on a ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0137] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. Preferably, it is a C1-C4 alkoxy group. Similar terms have similar meanings.

[0138] In this invention, the term "heterocyclic alkyl" refers to a 5-7 membered heterocyclic alkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, including (but not limited to) the following groups:

[0139] In this invention, the terms "aromatic ring" or "aryl" have the same meaning, and are preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic cyclic group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.

[0140] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include: furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0141] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0142] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0143] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms each have a similar meaning independently. The term "multiple" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0144] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0145] compound

[0146] This invention provides a compound of formula I, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0147]

[0148] The groups are defined above.

[0149] In another preferred embodiment, in the compound, any one of rings A, R1, R2, R3, R4, R5, R6, R7, R8, and R9 is independently the corresponding group in the specific compound of the present invention.

[0150] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0151] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0152] The embodiments of this invention describe in more detail the preparation methods of the compounds of Formula I, but these specific methods do not constitute any limitation on this invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0153] Typically, the raw materials and reagents used in the preparation process of the compounds of this invention can be purchased commercially unless otherwise specified.

[0154] Pharmaceutical Compositions and Administration

[0155] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0156] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0157] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0158] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0159] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0160] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in the dosage forms of capsules, tablets, and pills.

[0161] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0162] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0163] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0164] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0165] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0166] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0167] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0168] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0169] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0170] Compared with the prior art, the present invention has the following main advantages:

[0171] (1) The compounds of the present invention have excellent cardiomyocyte survival rate;

[0172] (2) The compounds of the present invention can significantly improve angiotensin II-induced cardiomyocyte hypertrophy;

[0173] (3) The compounds of the present invention can significantly improve heart failure and / or kidney failure.

[0174] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0175] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0176] Example 1: Preparation of (2S,3R,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M1-1)

[0177]

[0178] S-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran ((S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran, 200 mg, 0.48 mmol) was dissolved in 2 ml of ultra-dry THF under N2 protection. Isopropyl magnesium chloride and lithium chloride (i-PrMgCl·LiCl, 1.3 M in THF, 0.74 ml, 0.96 mmol) were added dropwise at 0 °C. After reacting for 20 minutes, the mixture was moved to -20 °C. M1 ((3R,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one, 302.76 mg, 0.72 mmol) was dissolved in 1 ml of ultra-dry THF and added dropwise. After reacting for 2 hours, the reaction was stopped, quenched with 2 ml of methanol, and dried by rotary evaporation before proceeding to the next step.

[0179] Example 2: Preparation of (2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M1-2)

[0180]

[0181] M1-1 ((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran, 120 mg, 0.17 mmol) was dissolved in 2 mL of a mixture of methanol and acetonitrile (V methanol:V acetonitrile = 1:1). Triethylsilane (81.3 μl, 0.51 mmol) was added under ice bath conditions, and the mixture was stirred for 5 min. Boron trifluoride ether (47%, 91.1 μl, 0.34 mmol) was then added, and the reaction was continued under ice bath conditions for 10 min. The reaction was then stopped, and methanol was added to quench the reaction. After evaporation to dryness using a rotary evaporator, the mixture was purified by silica gel column chromatography (V ethyl acetate:V petroleum ether = 1:10) to give a white solid in 86% yield.

[0182] Example 3 Preparation of (2S,3R,4R,5S)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (the compound shown in Formula I-1).

[0183]

[0184] M1-2 ((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran, 100 mg, 0.14 mmol) was dissolved in 2 mL of a mixture of ethyl acetate and methanol (V:V:Methanol = 1:1). Palladium hydroxide (Pd(OH)₂, 10 mg, 0.07 mmol) was added, and the reaction was stopped after 30 min under a H₂ atmosphere. The reaction solution was filtered through diatomaceous earth, evaporated to dryness using a rotary evaporator, and then purified by silica gel column chromatography (V:V:dichloromethane = 1:10) to give a white solid in 92.2% yield.

[0185] 1H NMR(400MHz, DMSO-d6)δ7.36–7.31(m,2H),7.23(dd,J=8.4,2.1Hz,1H),7.12–7.07(m,2H),6.84 –6.80(m,2H),5.28(d,J=3.8Hz,1H),5.01(t,J=5.4Hz,1H),4.96(ddt,J=6.4,4.2,1.8Hz,1H),4 .91(d,J=3.4Hz,1H),4.79(d,J=6.4Hz,1H),3.97(s,2H),3.93(dt,J=3.8,1.7Hz,1H),3.88–3.7 9(m,3H),3.77–3.71(m,3H),3.63–3.52(m,2H),2.19–2.14(m,1H),1.93(dt,J=12.2,5.8Hz,1H).

[0186] Example 4: Preparation of (2R,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M2-1)

[0187]

[0188] Except for replacing M1((3R,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one) with M2((3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0189] Example 5: Preparation of (2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M2-2)

[0190]

[0191] Except for replacing M1-1((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M2-1((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 82% yield.

[0192] Example 6 Preparation of (2R,3S,4S,5R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (the compound shown in Formula I-2)

[0193]

[0194] Except for replacing (2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran with (2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran, the other steps were the same as in Example 3, yielding a white solid in 85% yield.

[0195] 1 H NMR(400MHz, DMSO-d6)δ7.42–7.30(m,2H),7.23(dt,J=8.2,2.3Hz,1H),7.14–7.07(m,2H),6.83(d d,J=8.6,4.1Hz,2H),5.34(dd,J=47.4,4.9Hz,1H),5.21–4.99(m,1H),4.96(ddd,J=6.4,4.3,2.1H z,1H),4.91(d,J=3.4Hz,1H),4.78(t,J=5.8Hz,1H),4.06–3.91(m,3H),3.84(ddd,J=18.2,10.3,6 .3Hz,3H),3.78–3.70(m,3H),3.63–3.47(m,2H),2.22–2.14(m,1H),1.93(dt,J=12.8,6.3Hz,1H).

[0196] Example 7 Preparation of (2S,3R,4S,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M3-1)

[0197]

[0198] Except for replacing M1((3R,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one) with M3((3R,4S,5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0199] Example 8 Preparation of (2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M3-2)

[0200]

[0201] Except for replacing M1-1((2S,3S,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M3-1((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 88% yield.

[0202] Example 9 Preparation of (2S,3R,4R,5R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-3)

[0203]

[0204] Except for replacing M1-2((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M3-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 80% yield.

[0205] 1 H NMR(400MHz,DMSO-d6)δ7.40–7.16(m,3H),7.09(dd,J=8.4,1.6Hz,2H),6.82(d d,J=8.6,3.5Hz,2H),5.42(d,J=4.8Hz,1H),5.00–4.91(m,2H),4.58–4.50(m,1 H),4.45(d,J=4.0Hz,1H),4.01–3.91(m,4H),3.89–3.79(m,2H),3.78–3.72(m, 3H),3.71–3.53(m,2H),2.18(dtd,J=13.4,8.2,6.3Hz,1H),1.98–1.89(m,1H).

[0206] Example 10 Preparation of (2R,3S,4R,5S)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M4-1)

[0207]

[0208] Except for replacing M1((3R,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one) with M4((3S,4R,5S)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0209] Example 11 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M4-2)

[0210]

[0211] Except for replacing M1-1((2S,3S,4R,5S)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M4-1((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 88% yield.

[0212] Example 12 Preparation of (2R,3S,4S,5S)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compounds shown in Formula I-4)

[0213]

[0214] Except for replacing M1-2((2S,3S,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M4-2((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 81% yield.

[0215] 1 H NMR (400MHz, DMSO-d6) δ7.44–7.21(m,3H),7.10(d,J=8.2Hz,2H),6.83(d,J=8.0Hz,2H ),5.12–4.86(m,3H),4.80(t,J=5.6Hz,1H),4.51(d,J=7.0Hz,1H),3.98(s,2H),3.86(d d,J=9.8,4.7Hz,2H),3.83–3.76(m,2H),3.76–3.70(m,2H),3.64(q,J=6.4Hz,1H),3.5 2(hept,J=6.4,5.7Hz,2H), 2.18(dd,J=14.0,6.8Hz,1H), 1.95(dd,J=15.0,9.5Hz,1H).

[0216] Example 13 Preparation of (2R,3S,4S,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M5-1)

[0217]

[0218] Except for replacing M1((3R,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one) with M5((3S,4S,5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0219] Example 14 Preparation of (2R,3S,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M5-2)

[0220]

[0221] Except for replacing M1-1((2S,3S,4S,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M5-1((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 84% yield.

[0222] Example 15 Preparation of (2R,3S,4R,5R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compounds shown in Formulas I-5)

[0223]

[0224] Except for replacing M1-2((2S,3S,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M5-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 90% yield.

[0225] 1 H NMR(400MHz, DMSO-d6)δ7.42–7.32(m,2H),7.30(dd,J=8.2,2.1Hz,1H),7.13–7.06(m,2H),6.82 (dd,J=8.6,3.4Hz,2H),5.43(d,J=4.8Hz,1H),5.02–4.91(m,2H),4.54(dt,J=15.8,5.7Hz,1H),4 .46(d,J=4.0Hz,1H),4.01–3.91(m,4H),3.86(dd,J=10.0,4.6Hz,1H),3.83–3.79(m,1H),3.73(d ddd,J=18.0,12.0,6.4,4.1Hz,4H),3.62(p,J=5.8Hz,1H),2.24–2.12(m,1H),1.99–1.87(m,1H).

[0226] Example 16 Preparation of (2R,3S,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M6-1)

[0227]

[0228] Except for replacing M1 ((3R,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)dihydrofuran-2(3H)-one) with M6 ((3S,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0229] Example 17 Preparation of (2S,3S,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M6-2)

[0230]

[0231] Except for replacing M1-1((2S,3S,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M6-1((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 85.7% yield.

[0232] Example 18 Preparation of (2R,3S,4R,5S)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compounds shown in Formula I-6)

[0233]

[0234] Except for replacing M1-2((2S,3S,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M6-2((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 88% yield.

[0235] 1 H NMR (400MHz, DMSO-d6) δ7.44–7.21(m,3H),7.10(d,J=8.1Hz,2H),6.83(d,J=8.0Hz,2H ),5.12–4.86(m,3H),4.80(t,J=5.6Hz,1H),4.51(d,J=7.0Hz,1H),3.98(s,2H),3.86(d d,J=9.8,4.7Hz,2H),3.83–3.76(m,2H),3.76–3.70(m,2H),3.64(q,J=6.5Hz,1H),3.5 2(hept,J=6.4,5.7Hz,2H), 2.18(dd,J=14.0,6.8Hz,1H), 1.95(dd,J=15.0,9.5Hz,1H).

[0236] Example 19 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M7-1)

[0237]

[0238] Except for replacing M1 ((3R,4S,5S)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)dihydrofuran-2(3H)-one) with M7 ((3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0239] Example 20 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M7-2)

[0240]

[0241] Except for replacing M1-1((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M7-1((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 82% yield.

[0242] Example 21 Preparation of (2S,3R,4S,5R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compounds shown in Formula I-7)

[0243]

[0244] Except for replacing M1-2((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 91% yield.

[0245] 1 H NMR (400MHz, DMSO-d6) δ7.38(d,J=8.2Hz,2H),7.28(dd,J=8.2,2.1Hz,1H),7.10(d,J=8.2Hz, 2H),6.83(d,J=8.2Hz,2H),5.05–4.86(m,3H),4.81(t,J=5.6Hz,1H),4.52(d,J=7.0Hz,1H),3. 98(s,2H),3.86(dt,J=6.8,3.4Hz,2H),3.83–3.77(m,2H),3.77–3.70(m,2H),3.65(q,J=6.2Hz ,1H),3.52(q,J=5.2Hz,2H),2.18(dtd,J=14.2,8.2,6.2Hz,1H),1.93(dt,J=12.6,5.7Hz,1H).

[0246] Example 22 Preparation of (4aR,6S,7S,7aS)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxane-7-ol (compound shown in formula M8-1)

[0247]

[0248] I-7 (1 g, 2.38 mmol) was dissolved in 10 mL of anhydrous DMF, and benzaldehyde dimethyl acetal (0.43 g, 2.85 mmol) and camphor sulfonic acid (CSA, 0.055 g, 0.24 mmol) were added sequentially. The reaction was carried out at 110 °C for 8 h under N2 protection, and then the reaction was stopped. The mixture was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, and evaporated to dryness using a rotary evaporator before proceeding to the next step.

[0249] Example 23 Preparation of (4aR,6S,7S,7aR)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxo-7-yl-4-nitrobenzoate (compound shown in formula M8-2)

[0250]

[0251] M8-1 (M8-1, 1.2 g, 2.36 mmol) was dissolved in 10 mL of anhydrous THF, followed by the sequential addition of triphenylphosphine (PPh3, 0.74 g, 2.83 mmol) and p-nitrobenzoic acid (PNB, 0.59 g, 3.54 mmol). Under N2 protection, diisopropyl azodicarbonate (DIAD, 0.57 g, 2.83 mmol) was added dropwise in an ice bath. The mixture was then transferred to room temperature and reacted for 12 h before the reaction was stopped. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography (V:V petroleum ether = 1:20) to give a white solid in 60% yield.

[0252] Example 24 Preparation of (4aR,6S,7R,7aS)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxa-7-ol (compound shown in formula M8-3)

[0253]

[0254] M8-2 (M8-2, 0.9 g, 1.37 mmol) was dissolved in 9 ml of methanol solution, and 2 ml of 10% sodium hydroxide solution was added. The reaction was stopped after 30 min at room temperature. After extraction with ethyl acetate, the mixture was washed with ammonium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain M8-3, which was then added to the next step.

[0255] Example 25 Preparation of (2S,3S,4S,5R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compounds shown in Formula I-8)

[0256]

[0257] M8-3 (M8-3, 0.6 g, 1.18 mmol) was dissolved in 5 mL of a mixture of 2N hydrochloric acid and ethyl acetate (V hydrochloric acid:V ethyl acetate = 1:1). The reaction was stopped after 1 h at room temperature. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was purified by silica gel column chromatography (V methanol:V dichloromethane = 1:10) to give a white solid in 90% yield.

[0258] 1 H NMR (600MHz, DMSO-d6) δ7.41(d,J=8.2Hz,1H),7.29(d,J=2.0Hz,1H),7.22(dd,J=8.2,2.2Hz,1H),7.12–7.07(m,2 H),6.85–6.82(m,2H),5.12(dd,J=12.0,5.9Hz,2H),4.96(ddt,J=6.4,4.1,1.8Hz,1H),4.58(d,J=6.4Hz,1H),4.2 4(dd,J=11.8,3.5Hz,1H),4.09(dd,J=11.8,5.5Hz,1H),4.00–3.96(m,3H),3.86(dd,J=10.0,4.6Hz,1H),3.84–3. 78(m,2H),3.76–3.71(m,2H),3.68(td,J=6.4,5.2Hz,1H),2.18(dtd,J=14.2,8.3,6.3Hz,1H),1.95–1.89(m,1H).

[0259] Example 26 Preparation of (4aS,6S,7S,7aR)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxane-7-ol (compound shown in formula M9-1)

[0260]

[0261] Except for replacing I-7 with I-1, the other steps are the same as in Example 22, and compound M9-1 is directly introduced to the next step.

[0262] Example 27 Preparation of (4aS,6S,7R,7aS)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxo-7-yl-4-nitrobenzoate (compound shown in formula M9-2)

[0263]

[0264] Except for replacing M8-1 with M9-1, the other steps are the same as in Example 23, yielding a white solid with a yield of 66%.

[0265] Example 28 Preparation of (4aS,6S,7R,7aR)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxa-7-ol (compound shown in formula M9-3)

[0266]

[0267] Except for replacing M8-2 with M9-2, the other steps are the same as in Example 24, and M9-3 is obtained and directly proceeded to the next step.

[0268] Example 29 Preparation of (2S,3S,4R,5S)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compounds shown in Formula I-9)

[0269]

[0270] Except for replacing M8-3 with M9-3, the other steps are the same as in Example 25, yielding a white solid with a yield of 89%.

[0271] 1 H NMR (400MHz, DMSO-d6) δ7.38–7.30(m,2H),7.23(dd,J=8.2,2.1Hz,1H),7.13–7.07(m,2H),6.85–6. 79(m,2H),5.28(d,J=3.8Hz,1H),5.00(t,J=5.2Hz,1H),4.96(ddt,J=6.4,4.1,1.8Hz,1H),4.91(d,J =3.4Hz,1H),4.78(d,J=6.2Hz,1H),3.97(s,2H),3.93(dt,J=3.6,1.5Hz,1H),3.89–3.79(m,3H),3.7 8–3.71(m,3H),3.63–3.52(m,2H),2.18(dtd,J=13.2,8.2,6.3Hz,1H),1.93(dt,J=12.2,5.3Hz,1H).

[0272] Example 30 Preparation of (4aR,6R,7R,7aS)-6-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxo-7-ol (compound shown in formula M10-1)

[0273]

[0274] Except for replacing I-7 with I-2, the other steps are the same as in Example 22, and compound M10-1 is directly introduced to the next step.

[0275] Example 31 Preparation of (4aR,6R,7S,7aR)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxo-7-yl-4-nitrobenzoate (compound shown in formula M10-2)

[0276]

[0277] Except for replacing M8-1 with M10-1, the other steps are the same as in Example 23, yielding a white solid with a yield of 72%.

[0278] Example 32 Preparation of (4aR,6R,7S,7aS)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxane-7-ol (compound shown in formula M10-3)

[0279]

[0280] Except for replacing M8-2 with M10-2, the other steps are the same as in Example 24, and M10-3 is obtained and directly proceeded to the next step.

[0281] Example 33 Preparation of (2R,3R,4S,5R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compounds shown in Formula I-10)

[0282]

[0283] Except for replacing M8-3 with M10-3, the other steps were the same as in Example 25, yielding a white solid with a yield of 91%.

[0284] 1H NMR (400MHz, DMSO-d6) δ7.39–7.30 (m, 2H), 7.23 (dd, J = 8.2, 2.1Hz, 1H), 7.10 ( d,J=8.2Hz,2H),6.86–6.78(m,2H),5.29(d,J=3.8Hz,1H),5.07–4.87(m,3H), 4.79(d,J=6.4Hz,1H),4.00–3.91(m,3H),3.84(ddd,J=14.8,11.0,6.1Hz,3H) ,3.79–3.70(m,3H),3.65–3.53(m,2H),2.23–2.14(m,1H),1.98–1.89(m,1H).

[0285] Example 34 Preparation of (4aR,6S,7S,7aR)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxane-7-ol (compound shown in formula M11-1)

[0286]

[0287] Except for replacing I-7 with I-3, the other steps are the same as in Example 22, and compound M10-1 is directly introduced to the next step.

[0288] Example 35 Preparation of (4aR,6S,7R,7aS)-6-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxo-7-yl-4-nitrobenzoate (compound shown in formula M11-2)

[0289]

[0290] Except for replacing M8-1 with M11-1, the other steps are the same as in Example 23, yielding a white solid with a yield of 71.6%.

[0291] Example 36 Preparation of (4aR,6S,7R,7aR)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxa-7-ol (compound shown in formula M11-3)

[0292]

[0293] Except for replacing M8-2 with M11-2, the other steps are the same as in Example 24, and M11-2 is directly used for the next step.

[0294] Example 37 Preparation of (2S,3S,4R,5R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-11)

[0295]

[0296] Except for replacing M8-3 with M11-3, the other steps are the same as in Example 25, yielding a white solid with a yield of 95%.

[0297] 1 H NMR(400MHz, DMSO-d6)δ7.40–7.34(m,2H),7.29(dd,J=8.2,2.1Hz,1H),7.12–7.06(m,2H),6.86– 6.80(m,2H),5.42(d,J=4.7Hz,1H),4.96(ddt,J=6.4,4.1,1.8Hz,1H),4.92(d,J=4.0Hz,1H),4.55 (d,J=1.0Hz,1H),4.45(d,J=4.0Hz,1H),4.01–3.91(m,4H),3.86(dd,J=10.0,4.6Hz,1H),3.83–3. 79(m,1H),3.78–3.68(m,4H),3.60(dt,J=11.4,5.7Hz,1H),2.22–2.14(m,1H),1.98–1.90(m,1H).

[0298] Example 38 Preparation of (4aS,6R,7R,7aR)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxa-7-ol (compound shown in formula M12-1)

[0299]

[0300] Except for replacing I-7 with I-6, the other steps are the same as in Example 22, and compound M12-1 is directly introduced to the next step.

[0301] Example 39 Preparation of (4aS,6R,7S,7aS)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxo-7-yl-4-nitrobenzoate (compound shown in formula M12-2)

[0302]

[0303] Except for replacing M8-1 with M12-1, the other steps are the same as in Example 23, yielding a white solid with a yield of 65%.

[0304] Example 40 Preparation of (4aS,6R,7S,7aR)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-2-phenyltetrahydro-4H-furan[3,2-d][1,3]dioxa-7-ol (compound shown in formula M12-3)

[0305]

[0306] Except for replacing M8-2 with M12-2, the other steps are the same as in Example 24, and M12-2 is directly used for the next step.

[0307] Example 41 Preparation of (2R,3R,4R,5S)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-12)

[0308]

[0309] Except for replacing M8-3 with M12-3, the other steps are the same as in Example 25, yielding a white solid with a yield of 89%.

[0310] 1 H NMR (400MHz, DMSO-d6) δ7.44–7.21(m,3H),7.10(d,J=8.1Hz,2H),6.83(d,J=8.0Hz,2H ),5.12–4.86(m,3H),4.80(t,J=5.6Hz,1H),4.51(d,J=7.0Hz,1H),3.98(s,2H),3.86(d d,J=9.8,4.7Hz,2H),3.83–3.76(m,2H),3.76–3.70(m,2H),3.64(q,J=6.5Hz,1H),3.5 2(hept,J=6.4,5.7Hz,2H), 2.18(dd,J=14.0,6.8Hz,1H), 1.95(dd,J=15.0,9.5Hz,1H).

[0311] Example 42 Preparation of (S)-3-(4-(2-chloro-6-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M13-1)

[0312]

[0313] M13 ((S)-(2-chloro-6-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl) ketone, 1 g, 2.33 mmol) was dissolved in 8 mL of toluene. Under ice bath conditions, aluminum chloride (AlCl3, 0.62 g, 4.67 mmol) and 1,1,3,3-tetramethyldisiloxane (TMDS, 0.625 mL, 3.5 mmol) were added sequentially, and the reaction was stopped after 6 h at room temperature. 2 mL of 2N hydrochloric acid was added and stirred for 30 min. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography (V:V:petroleum ether = 8:1) to give a white solid in 75% yield.

[0314] Example 43 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(3-chloro-2-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M13-2)

[0315]

[0316] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M13-1((S)-3-(4-(2-chloro-6-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0317] Example 44 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(3-chloro-2-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M13-3)

[0318]

[0319] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(3-chloro-2-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M13-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 80% yield.

[0320] Example 45 Preparation of (2S,3R,4S,5R)-2-(3-chloro-2-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-13)

[0321]

[0322] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(3-chloro-2-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M13-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 88% yield.

[0323] 1 H NMR (600MHz, DMSO-d6) δ7.63(dd,J=7.9,1.4Hz,1H),7.39(dd,J=8.0,1.3Hz,1H),7.29(t,J=7.8Hz,1H),6.96–6.91(m,2H) ,6.84–6.80(m,2H),5.14(d,J=6.4Hz,1H),4.94(ddd,J=11.8,5.9,3.8Hz,2H),4.86–4.80(m,2H),4.30(d,J=16.0Hz,1H), 4.12(d,J=16.0Hz,1H),3.86(ddd,J=10.0,7.8,4.8Hz,2H),3.80(td,J=8.2,7.0Hz,1H),3.73(tdd,J=8.2,6.2,4.5Hz,4H) ,3.62(ddd,J=11.8,5.5,3.8Hz,1H),3.55(dt,J=11.6,4.8Hz,1H),2.17(dtd,J=13.4,8.2,6.3Hz,1H),1.95–1.90(m,1H).

[0324] Example 46 Preparation of (S)-3-(4-(2-chloro-4-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M14-1)

[0325]

[0326] The steps were identical to those in Example 42, except that M14 ((S)-(2-chloro-4-iodophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone) was replaced with M14. A white solid was obtained in 68% yield.

[0327] Example 47 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(3-chloro-4-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M14-2)

[0328]

[0329] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M14-1((S)-3-(4-(2-chloro-4-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0330] Example 48 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(3-chloro-4-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M14-3)

[0331]

[0332] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(3-chloro-4-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M14-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 81% yield.

[0333] Example 49 Preparation of (2S,3R,4S,5R)-2-(3-chloro-4-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-14)

[0334]

[0335] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(3-chloro-4-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M14-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 91% yield.

[0336] 1 H NMR (400MHz, DMSO-d6) δ7.44(s,1H),7.31–7.25(m,2H),7.13–7.08(m,2H),6.86–6.80(m,2H),5.00( dd,J=7.2,2.5Hz,1H),4.96(ddt,J=6.4,4.2,1.8Hz,1H),4.92(d,J=4.6Hz,1H),4.82(t,J=5.4Hz,1H ),4.53(d,J=7.2Hz,1H),3.97(s,2H),3.89–3.83(m,2H),3.83–3.79(m,2H),3.76–3.70(m,2H),3.65 (td,J=7.2,5.3Hz,1H),3.53(q,J=5.0Hz,2H),2.18(dtd,J=14.0,8.2,6.3Hz,1H),1.97–1.90(m,1H).

[0337] Example 50: Preparation of (S)-3-(4-(2-chloro-3-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M15-1)

[0338]

[0339] The steps were identical to those in Example 42, except that M15 ((S)-(2-chloro-3-iodophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl) methyl ketone) was replaced with M15. A white solid was obtained in 73% yield.

[0340] Example 51 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(2-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M15-2)

[0341]

[0342] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M15-1((S)-3-(4-(2-chloro-3-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0343] Example 52 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (the compound shown in formula M15-3)

[0344]

[0345] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(2-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M15-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 85% yield.

[0346] Example 53 Preparation of (2S,3R,4S,5R)-2-(2-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-15)

[0347]

[0348] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M15-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 88% yield.

[0349] 1H NMR (600MHz, DMSO-d6) δ7.61(dd,J=7.6,1.8Hz,1H),7.27(d,J=7.6Hz,1H),7.21(dd,J=7.4,1.8Hz,1H ),7.13–7.09(m,2H),6.86–6.82(m,2H),5.06(d,J=4.0Hz,1H),5.04(d,J=5.4Hz,1H),4.96(ddt,J=6. 4,4.7,1.9Hz,1H),4.85(t,J=5.6Hz,2H),4.01(s,2H),3.88–3.85(m,1H),3.84–3.79(m,4H),3.76–3. 72(m,2H),3.69(ddd,J=8.2,5.6,2.7Hz,1H),3.59–3.55(m,1H),2.21–2.16(m,1H),1.95–1.91(m,1H).

[0350] Example 54 Preparation of (S)-3-(4-(5-iodo-2-methylbenzyl)phenoxy)tetrahydrofuran (compound shown in formula M16-1)

[0351]

[0352] Except for replacing M13 with M16 ((S)-(5-iodo-2-methylphenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone), the other steps were the same as in Example 42. A white solid was obtained in 56% yield.

[0353] Example 55 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M16-2)

[0354]

[0355] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M16-1((S)-3-(4-(5-iodo-2-methylbenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0356] Example 56 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M16-3)

[0357]

[0358] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-methyl-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M16-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 96% yield.

[0359] Example 57 Preparation of (2R,3S,4R,5S)-2-(hydroxymethyl)-5-(4-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-16)

[0360]

[0361] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-methyl-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M16-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 84% yield.

[0362] 1 H NMR (400MHz, DMSO-d6) δ7.08–6.95(m,5H),6.85–6.77(m,2H),4.95(ddd,J=6.2,4.3,2.1Hz,1 H),4.62(dd,J=12.0,5.3Hz,2H),4.45(d,J=6.0Hz,1H),4.38(t,J=5.6Hz,1H),3.89–3.77(m, 4H),3.73(ddd,J=12.8,6.2,3.1Hz,3H),3.60(ddd,J=10.8,5.8,3.4Hz,1H),3.56–3.48(m,1H ),3.39(dt,J=11.4,5.9Hz,1H),3.30(d,J=5.8Hz,1H),2.23–2.08(m,4H),1.98–1.88(m,1H).

[0363] Example 58 Preparation of (S)-3-(4-(3-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M17-1)

[0364]

[0365] The steps were identical to those in Example 42, except that M13 was replaced with M17 ((S)-(3-iodophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone. A white solid was obtained in 66% yield.

[0366] Example 59 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M17-2)

[0367]

[0368] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M17-1((S)-3-(4-(3-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0369] Example 60 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M17-3)

[0370]

[0371] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M17-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 92.5% yield.

[0372] Example 61 Preparation of (2R,3S,4R,5S)-2-(hydroxymethyl)-5-(3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-17)

[0373]

[0374] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M17-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 97% yield.

[0375] 1 H NMR (400MHz, DMSO-d6) δ7.13 (dt, J=18.4, 9.2Hz, 4H), 7.04 (d, J=7.6Hz, 1H), 6.9 8(d,J=7.6Hz,1H),6.82(d,J=8.2Hz,2H),4.96(d,J=5.6Hz,1H),4.74–4.57(m,2H ),4.53–4.32(m,2H),3.94–3.79(m,4H),3.80–3.64(m,4H),3.64–3.49(m,2H),3 .41(q,J=5.4Hz,1H),2.18(dq,J=14.8,7.6Hz,1H),1.93(dt,J=13.0,5.7Hz,1H).

[0376] Example 62 Preparation of (S)-3-(4-(2-fluoro-5-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M18-1)

[0377]

[0378] The steps were identical to those in Example 42, except that M13 was replaced with M18 ((S)-(2-fluoro-5-iodophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone. A white solid was obtained in 69% yield.

[0379] Example 63 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-fluoro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M18-2)

[0380]

[0381] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M18-1((S)-3-(4-(2-fluoro-5-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0382] Example 64 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-fluoro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M18-3)

[0383]

[0384] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-fluoro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M18-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 90% yield.

[0385] Example 65 Preparation of (2S,3R,4S,5R)-2-(4-fluoro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-18)

[0386]

[0387] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-fluoro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M18-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 93% yield.

[0388] 1H NMR (400MHz, DMSO-d6) δ7.26–7.18(m,2H),7.09–7.00(m,4H),6.81(d,J=8.2Hz,1H),5.00–4.94(m,1H),4 .63(d,J=5.0Hz,1H),4.60(d,J=5.4Hz,1H),4.44(d,J=6.0Hz,1H),4.37(t,J=5.6Hz,1H),3.87(dt,J=9.2, 4.6Hz,1H),3.84–3.76(m,2H),3.76–3.63(m,4H),3.59(ddd,J=10.8,5.8,3.3Hz,1H),3.55–3.48(m,1H),3 .40(dd,J=11.0,5.6Hz,1H),3.30(d,J=6.2Hz,1H),2.13(dtd,J=13.0,8.4,6.0Hz,1H),1.93–1.84(m,1H).

[0389] Example 66 Preparation of (S)-3-(4-(4-chloro-3-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M19-1)

[0390]

[0391] The steps were identical to those in Example 42, except that M13 was replaced with M19 ((S)-(4-chloro-3-iodophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone. A white solid was obtained in 58% yield.

[0392] Example 67 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(2-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M19-2)

[0393]

[0394] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M19-1((S)-3-(4-(4-chloro-3-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0395] Example 68 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M19-3)

[0396]

[0397] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(2-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M19-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 87% yield.

[0398] Example 69 Preparation of (2S,3R,4S,5R)-2-(2-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-19)

[0399]

[0400] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2-chloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M19-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 90% yield.

[0401] 1H NMR(400MHz, DMSO-d6)δ7.13(dd,J=7.8,5.8Hz,3H),7.04(d,J=7.6Hz,1H),7.01–6.96(m,1H),6.85–6.80(m, 2H), 4.96 (ddd, J=6.4, 4.1, 2.0Hz, 1H), 4.66 (dd, J=9.4, 5.3Hz, 2H), 4.48 (d, J=6.2Hz, 1H), 4.40 (t, J=5.6Hz, 1H),3.88–3.79(m,4H),3.77–3.69(m,3H),3.60(ddd,J=11.0,5.7,3.2Hz,1H),3.56–3.48(m,1H),3.40(dd,J =11.2,5.6Hz,1H),3.34–3.29(m,1H),2.19(ddd,J=13.8,8.3,6.3Hz,1H),1.93(ddd,J=12.2,6.8,4.9Hz,1H).

[0402] Example 70 Preparation of (S)-4-iodo-2-(4-(tetrahydrofuran-3-yl)oxy)benzyl)phenol (compound shown in formula M20-1)

[0403]

[0404] Except for replacing M13 with M20 ((S)-(2-hydroxy-5-iodophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone), the other steps were the same as in Example 42. A white solid was obtained in 60% yield.

[0405] Example 71 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-hydroxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M20-2)

[0406]

[0407] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M20-1((S)-4-iodo-2-(4-(tetrahydrofuran-3-yl)oxy)benzyl)phenol, the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0408] Example 72 Preparation of 4-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)tetrahydrofuran-2-yl)-2-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenol (compound shown in formula M20-3)

[0409]

[0410] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-hydroxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M20-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 90% yield.

[0411] Example 73 Preparation of (2S,3R,4S,5R)-2-(4-hydroxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-20)

[0412]

[0413] Except for replacing M7-2((2R,3R,4S,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)tetrahydrofuran-2-yl)-2-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenol) with M20-3(4-((2S,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 86% yield.

[0414] 1H NMR (600MHz, DMSO-d6) δ9.04(s,1H),7.15–7.09(m,2H),6.90(d,J=2.2Hz,1H),6.85(dd,J=8.2,2.2Hz,1H),6.81–6.76(m,2H),6.67(d ,J=8.0Hz,1H),4.94(ddt,J=6.4,4.0,1.8Hz,1H),4.61(d,J=5.0Hz,1H),4.56(d,J=5.4Hz,1H),4.38(t,J=6.0Hz,2H),3.85(dd,J=10. 0,4.7Hz,1H),3.80(td,J=8.2,6.9Hz,1H),3.77–3.70(m,4H),3.63(ddt,J=9.2,6.2,3.0Hz,1H),3.58(ddd,J=11.0,5.4,3.4Hz,1H),3 .50(qd,J=6.2,3.4Hz,1H),3.39(dd,J=11.0,5.5Hz,1H),3.29(q,J=5.8Hz,1H),2.17(dtd,J=13.4,8.2,6.3Hz,1H),1.96–1.90(m,1H).

[0415] Example 74 Preparation of (S)-3-(4-(3-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M21-1)

[0416]

[0417] The steps were identical to those in Example 42, except that M13 was replaced with M21 ((S)-(3-chloro-5-iodophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone. A white solid was obtained in 76% yield.

[0418] Example 75 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(3-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M21-2)

[0419]

[0420] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M21-1((S)-3-(4-(3-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0421] Example 76 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(3-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compounds shown in formula M21-3)

[0422]

[0423] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(3-chloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M21-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 88% yield.

[0424] Example 77 Preparation of (2S,3R,4S,5R)-2-(3-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-21)

[0425]

[0426] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(3-chloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M21-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 80% yield.

[0427] 1H NMR(400MHz,DMSO-d6)δ7.27(t,J=1.8Hz,1H),7.22(d,J=1.6Hz,1H),7.18–7.11(m,3H),6 .86–6.81(m,2H),5.02(d,J=7.0Hz,1H),4.99–4.95(m,1H),4.93(d,J=4.8Hz,1H),4.84(t, J=5.4Hz,1H),4.51(d,J=7.2Hz,1H),3.90–3.83(m,4H),3.83–3.77(m,2H),3.77–3.70(m, 2H),3.64(td,J=7.0,5.3Hz,1H),3.57–3.48(m,2H),2.22–2.13(m,1H),1.97–1.88(m,1H).

[0428] Example 78 Preparation of (S)-3-(4-(2-chloro-3-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M22-1)

[0429]

[0430] The steps were the same as in Example 42, except that M13 was replaced with M22 ((S)-(2-chloro-3-iodophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone. A white solid was obtained in 70% yield.

[0431] Example 79 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(2-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M22-2)

[0432]

[0433] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M22-1((S)-3-(4-(2-chloro-3-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0434] Example 80 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M22-3)

[0435]

[0436] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(2-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M22-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 87% yield.

[0437] Example 81 Preparation of (2S,3R,4S,5R)-2-(2-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-22)

[0438]

[0439] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M22-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 80% yield.

[0440] 1 H NMR (400MHz, DMSO-d6) δ7.25–7.16(m,3H),7.13–7.05(m,2H),6.96(t,J=7.4Hz,1H),6.90(dd,J=7.6,1.9Hz, 1H),4.88(ddd,J=5.4,3.8,1.7Hz,1H),4.69(d,J=5.4Hz,1H),4.65(d,J=5.2Hz,1H),4.51(d,J=6.0Hz,1H),4 .42(t,J=5.6Hz,1H),4.04–3.95(m,2H),3.93–3.81(m,3H),3.77(td,J=8.4,4.3Hz,1H),3.62(ddd,J=10.8,5 .7,3.3Hz,1H),3.59–3.50(m,2H),3.45–3.36(m,2H),2.18–2.09(m,1H),2.03(ddt,J=14.2,8.6,4.3Hz,1H).

[0441] Example 82 Preparation of (S)-3-(4-(5-iodo-2-methoxybenzyl)phenoxy)tetrahydrofuran (compound shown in formula M23-1)

[0442]

[0443] The steps were identical to those in Example 42, except that M13 was replaced with M23 ((S)-(5-iodo-2-methoxyphenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone. A white solid was obtained in 72% yield.

[0444] Example 83 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-methoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M23-2)

[0445]

[0446] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M23-1((S)-3-(4-(5-iodo-2-methoxybenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0447] Example 84 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-methoxy-3-(4-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M23-3)

[0448]

[0449] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-methoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M23-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 92.3% yield.

[0450] Example 85 Preparation of (2R,3S,4R,5S)-2-(hydroxymethyl)-5-(4-methoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-23)

[0451]

[0452] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-methoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M23-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 91.5% yield.

[0453] 1 H NMR (400MHz, DMSO-d6) δ7.14–7.07(m,2H),7.03(dd,J=8.2,2.2Hz,1H),6.98(d,J=2.2Hz,1H),6.85(d,J=8.2Hz,1H),6.82–6.76(m,2 H),4.94(ddt,J=6.4,4.2,1.8Hz,1H),4.63(d,J=5.0Hz,1H),4.59(d,J=5.2Hz,1H),4.43(d,J=6.0Hz,1H),4.38(t,J=5.6Hz,1H),3.8 5(dd,J=10.0,4.6Hz,1H),3.83–3.76(m,3H),3.73(d,J=5.4Hz,5H),3.65(dq,J=6.0,3.0Hz,1H),3.59(ddd,J=10.8,5.6,3.3Hz,1H), 3.51(t,J=5.6Hz,1H), 3.41(d,J=5.6Hz,1H), 3.30(d,J=6.0Hz,1H), 2.17(dtd,J=16.4,8.2,6.2Hz,1H), 1.93(dd,J=12.8,6.2Hz,1H).

[0454] Example 86 Preparation of (S)-3-(4-(2-ethoxy-5-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M24-1)

[0455]

[0456] The steps were identical to those in Example 42, except that M13 was replaced with M24 ((S)-(2-ethoxy-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone). A white solid was obtained in 76% yield.

[0457] Example 87 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-ethoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M24-2)

[0458]

[0459] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M24-1((S)-3-(4-(2-ethoxy-5-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0460] Example 88 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxyoxy)methyl)-5-(4-ethoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M24-3)

[0461]

[0462] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-ethoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the steps were the same as in Example 20, yielding a white solid in 87.6% yield.

[0463] Example 89 Preparation of (2S,3R,4S,5R)-2-(4-ethoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-24)

[0464]

[0465] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-ethoxy-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M24-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 90% yield.

[0466] 1 H NMR(400MHz, DMSO-d6)δ7.16(d,J=7.0Hz,2H),7.14–7.09(m,2H),6.91–6.86(m,1H),6.84–6.77(m,2H),4.95(t t,J=4.6,2.1Hz,1H),4.86(d,J=6.6Hz,1H),4.83(d,J=4.8Hz,1H),4.77(t,J=5.6Hz,1H),4.43(d,J=6.8Hz,1H), 3.99(q,J=7.0Hz,2H),3.85(dd,J=10.2,4.6Hz,2H),3.83–3.77(m,3H),3.76–3.71(m,3H),3.69–3.62(m,1H),3. 51(ddt,J=13.8,11.7,5.7Hz,2H),2.17(dtd,J=14.2,8.2,6.2Hz,1H),1.97–1.88(m,1H),1.31(t,J=6.8Hz,3H).

[0467] Example 90: Preparation of (S)-3-(4-(2-bromo-5-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M25-1)

[0468]

[0469] Except for replacing M13 with M25 ((S)-(2-bromo-5-iodophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone), the other steps were the same as in Example 42. A white solid was obtained in 80% yield.

[0470] Example 91 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-bromo-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M25-2)

[0471]

[0472] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M25-1((S)-3-(4-(2-bromo-5-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0473] Example 92 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-bromo-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M25-3)

[0474]

[0475] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-bromo-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M25-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 95% yield.

[0476] Example 93 Preparation of (2S,3R,4S,5R)-2-(4-bromo-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-25)

[0477]

[0478] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-bromo-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M25-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 98% yield.

[0479] 1H NMR(400MHz,DMSO-d6)δ7.26–7.18(m,2H),7.14–7.08(m,2H),6.88–6.79(m,2H),5.03– 4.94(m,2H),4.91(dd,J=16.0,4.9Hz,1H),4.82(q,J=5.6Hz,1H),4.50(dd,J=7.0,1.8H z,1H),3.99(s,1H),3.89–3.83(m,3H),3.82–3.70(m,4H),3.65(dtd,J=10.8,7.0,5.3H z,1H),3.57–3.46(m,2H),2.18(dtdd,J=13.2,8.1,6.2,1.5Hz,1H),1.99–1.87(m,1H).

[0480] Example 94 Preparation of (S)-3-(4-(5-bromo-2-chloro-4-fluorobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M26-1)

[0481]

[0482] The steps were identical to those in Example 42, except that M13 was replaced with M26 ((S)-(5-bromo-2-chloro-4-fluorophenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone. A white solid was obtained in 64% yield.

[0483] Example 95 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-(4-chloro-2-fluoro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M26-2)

[0484]

[0485] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M26-1((S)-3-(4-(5-bromo-2-chloro-4-fluorobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0486] Example 96 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-2-fluoro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M26-3)

[0487]

[0488] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-2-fluoro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M26-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 90.5% yield.

[0489] Example 97 Preparation of (2S,3R,4S,5R)-2-(4-chloro-2-fluoro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-26)

[0490]

[0491] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-2-fluoro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M26-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 95% yield.

[0492] 1 H NMR(400MHz,DMSO-d6)δ7.62(d,J=7.8Hz,1H),7.37(d,J=9.8Hz,1H),7.14–7.04(m,2H),6.8 9–6.79(m,2H),5.11(d,J=5.8Hz,1H),4.99–4.91(m,2H),4.87(t,J=5.6Hz,1H),4.83(d,J=5 .4Hz,1H),3.95(s,2H),3.85(dt,J=9.8,4.8Hz,2H),3.83–3.76(m,3H),3.76–3.70(m,2H),3 .59(ddd,J=11.6,5.6,3.9Hz,1H),3.53–3.44(m,1H),2.23–2.14(m,1H),1.98–1.88(m,1H).

[0493] Example 98 Preparation of (S)-3-(4-(2,4-dichloro-5-iodobenzyl)phenoxy)tetrahydrofuran (compound shown in formula M27-1)

[0494]

[0495] The steps were identical to those in Example 42, except that M13 was replaced with M27 ((S)-(2,4-dichloro-5-iodophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone). A white solid was obtained in 56% yield.

[0496] Example 99 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(2,4-dichloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula M27-2)

[0497]

[0498] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M27-1((S)-3-(4-(2,4-dichloro-5-iodobenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0499] Example 100 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2,4-dichloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M27-3)

[0500]

[0501] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(2,4-dichloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol) with M27-2((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 94% yield.

[0502] Example 101 Preparation of (2S,3R,4S,5R)-2-(2,4-dichloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-27)

[0503]

[0504] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2,4-dichloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M27-3((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 93.5% yield.

[0505] 1 H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.24–7.16(m,2H),7.14–7.07(m,2H),7.02(s,1H),5.0 8(dt,J=6.0,3.0Hz,1H),4.85(t,J=3.6Hz,2H),4.80(q,J=4.6,3.9Hz,2H),3.96(s,2H),3.9 0(dd,J=10.0,4.6Hz,1H),3.84(td,J=8.4,6.6Hz,1H),3.80–3.71(m,5H),3.66(ddd,J=11.8 ,5.8,2.3Hz,1H),3.51–3.44(m,1H),2.15(dtd,J=14.2,8.4,5.9Hz,1H),2.06–1.98(m,1H).

[0506] Example 102 Preparation of methyl 2,4-dichloro-5-nitrobenzoate (compound shown in formula MII)

[0507]

[0508] Mixtures MⅠ (2,4-dichloro-5-nitrobenzoic acid, 2 g, 8.47 mmol) and DMF (0.065 mL, 0.847 mmol) were dissolved in 20 mL of anhydrous DCM. Oxaloyl dichloride (1.49 mL, 16.95 mmol) was added under ice bath conditions, and the mixture was reacted at room temperature for 2 h. Then, 20 mL of anhydrous methanol was added, and the reaction was stopped after stirring for 10 min. The reaction mixture was evaporated to dryness and purified by silica gel column chromatography (V:V:Petroleum ether = 1:20) to give a white solid in 90% yield.

[0509] Example 103 Preparation of methyl 5-amino-2,4-dichlorobenzoate (compound shown in formula MⅢ)

[0510]

[0511] MII (methyl 2,4-dichloro-5-nitrobenzene, 1.8 g, 7.2 mmol) was dissolved in a mixed solution of acetic acid and water (V acetic acid:V water = 10:1). Ammonium chloride (NH4Cl, 0.77 mg, 14.4 mmol) and iron powder (Fe, 1 g, 18 mmol) were added sequentially. The reaction was stopped after 6 h at room temperature. The mixture was filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was purified by silica gel column chromatography (V ethyl acetate:V petroleum ether = 1:20) to give a white solid in 92% yield.

[0512] Example 104 Preparation of methyl 2,4-dichloro-5-iodobenzoate (compound shown in formula MⅣ)

[0513]

[0514] MⅢ (methyl 5-amino-2,4-dichlorobenzoate, 1.5 g, 6.82 mmol) was dissolved in 12 mL of a mixture of sulfuric acid and water (V sulfuric acid:V water = 1:2). Sodium nitrite (NaNO2, 0.49 g, 4.16 mmol) was added under ice bath conditions. After stirring at room temperature for 1 h, cuprous iodide (CuI, 0.065 g, 0.34 mmol) was added, and the mixture was stirred for 1 h. Then, potassium iodide (KI, 1.24 g, 7.5 mmol) was added, and the reaction was stopped after 5 h at room temperature. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography (V ethyl acetate:V petroleum ether = 1:50) to give a white solid in 90% yield.

[0515] Example 105 Preparation of tert-butyl((2,4-dichloro-5-iodobenzyl)oxy)dimethylsilane (compound shown in formula MⅤ)

[0516]

[0517] MⅣ (methyl 2,4-dichloro-5-iodobenzoate, 2 g, 6 mmol) was dissolved in 15 mL of ultra-dry tetrahydrofuran. Diisobutylaluminum hydride (DIBAL-H, 2.58 mg, 18 mmol) was added under a N2 atmosphere in an ice bath. The reaction was carried out at room temperature for 3 h, and then quenched with sodium tartrate. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After evaporation, the solution was dissolved in 10 mL of anhydrous tetrahydrofuran, and then imidazole (0.82 mg, 12 mmol), tert-butyldimethylchlorosilane (TBDMSCl, 1.37 g, 9 mmol), and dimethylaminopyridine (DMAP, 0.15 mg, 1.2 mmol) were added sequentially. The reaction was stopped after 2 h at room temperature. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography (V:V:petroleum ether = 1:30) to give a white solid in 96% yield.

[0518] Example 106 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,4-dichlorophenyl)tetrahydrofuran-2-ol (compound shown in formula MVI)

[0519]

[0520] Except for replacing (S)-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with MⅤ(tert-butyl((2,4-dichloro-5-iodobenzyl)oxy)dimethylsilane), the other steps are the same as in Example 19, and the product is directly fed into the next step.

[0521] Example 107 Preparation of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)-2-(2,4-dichloro-5-(hydroxymethyl)phenyl)tetrahydrofuran-2-ol (compound shown in formula MⅦ)

[0522]

[0523] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,4-dichlorophenyl)tetrahydrofuran-2-ol) with MVI((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), a white solid was obtained in 88% yield.

[0524] Example 108 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxymethyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzaldehyde (compound shown in formula MVIII)

[0525]

[0526] MⅦ((2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)-2-(2,4-dichloro-5-(hydroxymethyl)phenyl)tetrahydrofuran-2-ol, 1 g, 1.73 mmol) was dissolved in 10 mL of dichloromethane. Dess-Martin reagent (Dess-Martin, 1.46 g, 3.45 mmol) was added under ice bath conditions. The reaction was allowed to proceed to room temperature for 3 h, and then quenched with sodium bicarbonate. Extraction was performed with ethyl acetate, and the solution was dried over anhydrous sodium sulfate. The solution was then evaporated to dryness. Purification was achieved by silica gel column chromatography (V:V:Petroleum ether = 1:20) to give a white solid in 88.5% yield.

[0527] Example 109 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)methanol (compound shown in formula M28-1)

[0528]

[0529] M28 ((S)-3-(2-iodophenoxy)tetrahydrofuran, 200 mg, 0.69 mmol) was dissolved in 2 ml of ultra-dry tetrahydrofuran. Under nitrogen protection, the solution was moved to -80 °C. Butyllithium (39 μl, 0.42 mmol) was slowly added dropwise at -80 °C, and the mixture was stirred for 30 min. Then, MⅧ ((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxymethyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzaldehyde, 200 mg, 0.35 mmol) was added. The reaction was stopped after 3 h, and the reaction was quenched with methanol. The reaction solution was evaporated to dryness and directly added to the next step.

[0530] Example 110 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2,4-dichloro-5-(2-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M28-2)

[0531]

[0532] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(2-((((S)-tetrahydrofuran-3-yl)oxy)phenyl)methanol), the steps were the same as in Example 20. The product was a white solid with a yield of 75%.

[0533] Example 111 Preparation of (2S,3R,4S,5R)-2-(2,4-dichloro-5-(2-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-28)

[0534]

[0535] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2,4-dichloro-5-(2-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M28-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 89.6% yield.

[0536] 1H NMR (400MHz, DMSO-d6) δ7.56(s,1H),7.46(s,1H),7.21(ddd,J=8.4,7.3,1.9Hz,1H),6.94(ddd,J=12.6,7.9,1.5Hz,2H),6 .87(td,J=7.4,1.0Hz,1H),5.08(d,J=5.4Hz,1H),5.03(ddd,J=6.2,4.2,2.0Hz,1H),4.94(d,J=4.2Hz,1H),4.90(d,J=5.6H z,1H),4.73(t,J=5.4Hz,1H),3.98(d,J=15.6Hz,1H),3.93–3.82(m,2H),3.77(td,J=5.0,3.5Hz,1H),3.74–3.63(m,4H),3 .51(ddd,J=11.8,5.7,3.7Hz,1H),3.37(d,J=5.2Hz,2H),2.14(dtd,J=13.2,8.4,6.1Hz,1H),1.88(dt,J=12.2,5.3Hz,1H).

[0537] Example 112 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)methanol (compound shown in formula M29-1)

[0538]

[0539] Except for replacing M28 with M29 ((S)-3-(3-iodophenoxy)tetrahydrofuran), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0540] Example 113 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(2,4-dichloro-5-(3-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M29-2)

[0541]

[0542] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)methanol), the steps were the same as in Example 20. The product was a white solid in 80% yield.

[0543] Example 114 Preparation of (2S,3R,4S,5R)-2-(2,4-dichloro-5-(3-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-29)

[0544]

[0545] Except for replacing M7-2((2R,3R,4S,5R)-2-(2,4-dichloro-5-(3-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol) with M29-2((2S,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 91% yield.

[0546] 1 H NMR(400MHz, DMSO-d6)δ7.79(s,1H),7.56(d,J=1.6Hz,1H),7.20(t,J=7.6Hz, 1H),6.84–6.67(m,3H),5.14(dd,J=5.4,1.8Hz,1H),4.94(dd,J=22.8,4.7Hz,4 H),4.01(s,2H),3.80(dtd,J=23.8,12.1,11.0,5.5Hz,7H),3.66(dd,J=11.4,5 .1Hz,1H),3.55–3.46(m,1H),2.24–2.14(m,1H),1.92(dt,J=12.6,5.8Hz,1H).

[0547] Example 115 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-chlorophenyl)methanol (compound shown in formula M30-1)

[0548]

[0549] Except for replacing M28 with M30 (1-chloro-4-iodobenzene), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0550] Example 116 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-chlorobenzyl)phenyl)tetrahydrofuran (compound shown in formula M30-2)

[0551]

[0552] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-chlorophenyl)methanol with M30-1((5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the other steps were the same as in Example 20. White solid, 97% yield.

[0553] Example 117 Preparation of (2R,3R,4S,5R)-2-(2,4-dichloro-5-(4-chlorobenzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-30)

[0554]

[0555] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-chlorobenzyl)phenyl)tetrahydrofuran) with M30-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 91% yield.

[0556] 1H NMR (400MHz, DMSO-d6) δ7.79(d,J=4.4Hz,1H),7.56(d,J=4.4Hz,1H),7.39–7.27(m,2H),7.23–7.16(m,2H),5.12(dd,J=5.2,1.5Hz, 1H),4.97(d,J=4.0Hz,1H),4.94–4.88(m,2H),4.04(s,2H),3.81(tq,J=9.2,5.2,4.4Hz,3H),3.72–3.64(m,1H),3.55–3.46(m,1H).

[0557] Example 118 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-fluorophenyl)methanol (compound shown in formula M31-1)

[0558]

[0559] Except for replacing M28 with M31 (1-fluoro-4-iodobenzene), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0560] Example 119 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-fluorobenzyl)phenyl)tetrahydrofuran (compound shown in formula M31-2)

[0561]

[0562] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-fluorophenyl)methanol with M31-1((5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the procedure was the same as in Example 20. The product was a white solid with a yield of 89.5%.

[0563] Example 120: Preparation of (2R,3R,4S,5R)-2-(2,4-dichloro-5-(4-fluorobenzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-31)

[0564]

[0565] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-fluorobenzyl)phenyl)tetrahydrofuran) with M31-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 98% yield.

[0566] 1 H NMR(400MHz, DMSO-d6)δ7.78(d,J=3.4Hz,1H),7.64–7.49(m,1H),7.17(dtd,J=40.2,8.7,4.3Hz,4H),5.13(t,J=4.4Hz, 1H),4.94(dt,J=25.2,4.2Hz,3H),4.14–3.96(m,2H),3.81(dp,J=9.2,4.3Hz,3H),3.67(d,J=11.0Hz,1H),3.51(s,1H).

[0567] Example 121 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-((tert-butyldimethylsilyl)oxy)phenyl)methanol (compound shown in formula M32-1)

[0568]

[0569] Except for replacing M28 with M32 (tert-butyl(4-iodophenoxy)dimethylsilane), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0570] Example 122 Preparation of 4-(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)phenol (compound shown in formula M32-2)

[0571]

[0572] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-((tert-butyldimethylsilyl)oxy)phenyl)methanol), the steps were the same as in Example 20. The product was a white solid with a yield of 92%.

[0573] Example 123 Preparation of (2R,3R,4S,5R)-2-(2,4-dichloro-5-(4-hydroxybenzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-32)

[0574]

[0575] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)phenol) with M32-2(4-(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 94% yield.

[0576] 1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),7.76(s,1H),7.53(s,1H),6.97(d,J=8.2Hz,2H),6.66(d,J=8.4Hz,2H),5.13(d,J=5 .2Hz,1H),5.04–4.81(m,3H),3.90(s,2H),3.80(dt,J=17.0,4.4Hz,3H),3.67(dd,J=10.4,5.8Hz,1H),3.56–3.47(m,1H).

[0577] Example 124 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-methoxyphenyl)methanol (the compound shown in formula M33-1)

[0578]

[0579] Except for replacing M28 with M33 (1-iodo-4-methoxybenzene), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0580] Example 125 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-methoxybenzyl)phenyl)tetrahydrofuran (compound shown in formula M33-2)

[0581]

[0582] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-methoxyphenyl)methanol) with M33-1((5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the other steps were the same as in Example 20. White solid, yield 84%.

[0583] Example 126 Preparation of (2R,3R,4S,5R)-2-(2,4-dichloro-5-(4-methoxybenzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-33)

[0584]

[0585] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-methoxybenzyl)phenyl)tetrahydrofuran) with M33-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 93.4% yield.

[0586] 1 H NMR (400MHz, DMSO-d6) δ7.77(s,1H),7.54(s,1H),7.10(d,J=8.6Hz,2H),6.89–6.80(m,2H),5.13(d,J=5.2Hz, 1H),4.98–4.89(m,3H),3.96(s,2H),3.80(dt,J=16.2,4.3Hz,3H),3.71(s,4H),3.51(dd,J=10.4,5.8Hz,1H).

[0587] Example 127 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-ethoxyphenyl)methanol (the compound shown in formula M34-1)

[0588]

[0589] Except for replacing M28 with M34 (1-ethoxy-4-iodobenzene), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0590] Example 128 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-ethoxybenzyl)phenyl)tetrahydrofuran (compound shown in formula M34-2)

[0591]

[0592] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-ethoxyphenyl)methanol with M34-1((5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the procedure was the same as in Example 20. White solid, yield 92%.

[0593] Example 129 Preparation of (2R,3R,4S,5R)-2-(2,4-dichloro-5-(4-ethoxybenzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-34)

[0594]

[0595] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-ethoxybenzyl)phenyl)tetrahydrofuran) with M34-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 96% yield.

[0596] 1H NMR (400MHz, DMSO-d6) δ7.77(s,1H),7.54(s,1H),7.12–7.04(m,2H),6.87–6.79(m,2H),5.13(d,J=5.2Hz,1H),4.99–4.88(m, 3H),4.01–3.91(m,4H),3.80(dt,J=16.0,4.3Hz,3H),3.70–3.62(m,1H),3.51(dd,J=10.4,6.2Hz,1H),1.29(t,J=7.0Hz,3H).

[0597] Example 130 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-phenoxyphenyl)methanol (compound shown in formula M35-1)

[0598]

[0599] Except for replacing M28 with M35 (1-iodo-4-phenoxybenzene), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0600] Example 131 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-phenoxybenzyl)phenyl)tetrahydrofuran (compound shown in formula M35-2)

[0601]

[0602] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-phenoxyphenyl)methanol) with M35-1((5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the procedure was the same as in Example 20. The product was a white solid with a yield of 87.6%.

[0603] Example 132 Preparation of (2R,3R,4S,5R)-2-(2,4-dichloro-5-(4-phenoxybenzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-35)

[0604]

[0605] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-5-(2,4-dichloro-5-(4-phenoxybenzyl)phenyl)tetrahydrofuran) with M35-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 97% yield.

[0606] 1 H NMR (400MHz, DMSO-d6) δ7.78(s,1H),7.56(s,1H),7.37(t,J=7.8Hz,2H),7.20(d,J=8.2Hz,2H),7.12(t,J=7.4Hz,1H),7.00–6.92(m,4H),5.12 (d,J=5.2Hz,1H),4.97(d,J=3.8Hz,1H),4.91(q,J=4.4,3.6Hz,2H),4.02(s,2H),3.85–3.76(m,3H),3.71–3.63(m,1H),3.50(d,J=13.2Hz,1H).

[0607] Example 133 Preparation of 2-((4-(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)phenoxy)methyl)-5-(trifluoromethyl)furan (compound shown in formula M36-1)

[0608]

[0609] M32-2 (M32-2, 1 g, 1.5 mmol) was dissolved in anhydrous acetonitrile solution, and M36 (2-bromomethyl-5-trifluoromethylfuran, 515.2 mg, 2.25 mmol) and potassium carbonate (K2CO3, 621.9 mg, 4.5 mmol) were added. The reaction mixture was stirred at 80 °C for 5 hours, and then the reaction was stopped. Extraction was performed with ethyl acetate, and the solution was dried over anhydrous sodium sulfate. The solution was then purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 10:1) to give a white solid in 80% yield.

[0610] Example 134 Preparation of (2S,3R,4S,5R)-2-(2,4-dichloro-5-(4-((5-(trifluoromethyl)furan-2-yl)methoxy)benzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I36)

[0611]

[0612] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)phenoxy)methyl)-5-(trifluoromethyl)furan) with M36-1(2-((4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 88% yield.

[0613] 1 H NMR (400MHz, DMSO-d6) δ7.78(s,1H),7.54(s,1H),7.22(s,1H),7.11(d,J=8.3Hz,2H),6.96(d,J=8.4Hz,2H),6.81(s,1H),5. 11(d,J=4.5Hz,3H),4.97(d,J=3.9Hz,1H),4.94–4.88(m,2H),3.97(s,2H),3.81(d,J=13.7Hz,3H),3.67(s,1H),3.52(s,1H).

[0614] Example 135 Preparation of (2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(2,4-dichloro-5-(4-((4-(trifluoromethyl)benzyl)oxy)benzyl)phenyl)tetrahydrofuran (compound shown in formula M37-1)

[0615]

[0616] Except for replacing M36 (2-bromomethyl-5-trifluoromethylfuran) with 37 (1-bromomethyl-4-trifluoromethylbenzene), the other steps were the same as in Example 133, yielding a white solid in 75% yield.

[0617] Example 136 Preparation of (2S,3R,4S,5R)-2-(2,4-dichloro-5-(4-((4-(trifluoromethyl)benzyl)oxy)benzyl)phenyl)-5-hydroxymethyltetrahydrofuran-3,4-diol (compound shown in Formula I-37)

[0618]

[0619] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(2,4-dichloro-5-(4-((4-(trifluoromethyl)benzyl)oxy)benzyl)phenyl)tetrahydrofuran) with M37-1((2R,3R,4S,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 80% yield.

[0620] 1 H NMR (400MHz, DMSO-d6) δ7.75(d,J=8.6Hz,3H),7.65(d,J=8.1Hz,2H),7.53(s,1H),7.14–7.08(m,2H),6.96–6.92(m,2H),5.18(s,2H),5.11( d,J=5.3Hz,1H),4.96(d,J=4.0Hz,1H),4.93–4.88(m,2H),3.96(s,2H),3.80(dt,J=15.3,4.3Hz,3H),3.70–3.63(m,1H),3.54–3.47(m,1H).

[0621] Example 137 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)methanol (the compound shown in formula M38-1)

[0622]

[0623] Except for replacing M28 with M38 (6-bromo-2,3-dihydrobenzo[b][1,4]dioxane), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0624] Example 138 Preparation of 6-(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)-2,3-dihydrobenzo[b][1,4]dioxin (compound shown in formula M38-2)

[0625]

[0626] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)methanol) with M38-1((5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the procedure was the same as in Example 20. White solid, 90% yield.

[0627] Example 139 Preparation of (2S,3R,4S,5R)-2-(2,4-dichloro-5-((2,3-dihydrobenzo[b][1,4]dioxane-6-yl)methyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-38)

[0628]

[0629] Except for replacing M7-2((2R,3R,4S,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)-2,3-dihydrobenzo[b][1,4]dioxin) with M38-2(6-(5-((2S,3S,4R,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 91.5% yield.

[0630] 1 H NMR (400MHz, Acetone-d6) δ7.72(s,1H),7.54(s,1H),6.76(d,J=8.8Hz,1H),6.64(dd,J=5.4,2.1Hz,2H),5.11(d,J=5.2Hz,1H),4.96( d,J=4.0Hz,1H),4.90(t,J=5.2Hz,2H),4.19(s,4H),3.90(s,2H),3.80(dt,J=14.8,4.0Hz,3H),3.69–3.62(m,1H),3.53–3.46(m,1H).

[0631] Example 140 Preparation of benzo[d][1,3]dihydroxy-5-yl(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)methanol (compound shown in formula M39-1)

[0632]

[0633] Except for replacing M28 with M39 (5-bromobenzo[d][1,3]dioxazole), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0634] Example 141 Preparation of 5-(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)benzo[d][1,3]dioxane (compound shown in formula M39-2)

[0635]

[0636] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)methanol with M39-1(benzo[d][1,3]dihydroxy-5-yl(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the procedure was the same as in Example 20. White solid, 93% yield.

[0637] Example 142 Preparation of (2S,3R,4S,5R)-2-(5-(benzo[d][1,3]dioxanepent-5-ylmethyl)-2,4-dichlorophenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-39)

[0638]

[0639] Except for replacing M7-2((2R,3R,4S,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)benzo[d][1,3]dioxane) with M39-2(5-(5-((2S,3S,4R,5S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 88% yield.

[0640] 1H NMR(400MHz,DMSO-d6)δ7.66(s,1H),7.57(s,1H),6.82–6.72(m,2H),6.52(d d,J=7.6,1.5Hz,1H),6.00(d,J=1.2Hz,2H),5.13(d,J=4.6Hz,1H),4.95(dd,J =12.0,4.0Hz,2H),4.83(t,J=5.4Hz,1H),3.96(d,J=1.8Hz,2H),3.85–3.79(m ,1H),3.76(d,J=4.2Hz,2H),3.60(dt,J=11.8,4.8Hz,1H),3.49–3.43(m,1H).

[0641] Example 143 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-morpholinophenyl)methanol (compound shown in formula M40-1)

[0642]

[0643] Except for replacing M28 with M40 (4-(4-iodophenyl)morpholine), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0644] Example 144 Preparation of 4-(4-(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)phenyl)morpholine (compound shown in formula M40-2)

[0645]

[0646] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(4-morpholinophenyl)methanol with M40-1((5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the procedure was the same as in Example 20. The product was a white solid with a yield of 95%.

[0647] Example 145 Preparation of (2R,3R,4S,5R)-2-(2,4-dichloro-5-(4-morpholinylbenzene)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-40)

[0648]

[0649] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)phenyl)morpholine) with M40-2(4-(4-(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 91% yield.

[0650] 1 H NMR (400MHz, DMSO-d6) δ7.75(s,1H),7.53(s,1H),7.05(d,J=8.2Hz,2H),6.86(d,J=8.2Hz,2H),5.13(d,J=5.2Hz,1H),4.96(d,J=4.0Hz,1H) ,4.92(t,J=5.4Hz,2H),3.93(s,2H),3.81(t,J=3.6Hz,2H),3.78(t,J=4.8Hz,1H),3.71(t,J=4.8Hz,4H),3.51(s,2H),3.04(t,J=4.8Hz,4H).

[0651] Example 146 Preparation of 5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(3-((tert-butyldimethylsilyl)oxy)-4-methoxyphenyl)methanol (compound shown in formula M41-1)

[0652]

[0653] Except for replacing M28 with M41 (tert-butyl(5-iodo-2-methoxyphenoxy)dimethylsilane), the other steps are the same as in Example 109, and the product is directly fed into the next step.

[0654] Example 147 Preparation of 5-(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)-2-methoxyphenol (compound shown in formula M41-2)

[0655]

[0656] Except for replacing M7-1(2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorophenyl)(3-((tert-butyldimethylsilyl)oxy)-4-methoxyphenyl)methanol) with M41-1((5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran-2-ol), the other steps were the same as in Example 20. White solid, yield 87.5%.

[0657] Example 148 Preparation of (2R,3R,4S,5R)-2-(2,4-dichloro-5-(3-hydroxy-4-methoxybenzyl)phenyl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (compound shown in Formula I-41)

[0658]

[0659] Except for replacing M7-2((2R,3R,4S,5S)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzyl)-2-methoxyphenol) with M41-2(5-(5-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 21, yielding a white solid in 95% yield.

[0660] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),7.79(s,1H),7.53(s,1H),6.81(s,1H),6.66(d,J=7.8Hz,1H),6.54(d,J=8.2Hz,1H),4.96 (d,J=4.0Hz,1H),3.91(s,2H),3.83(d,J=3.6Hz,2H),3.77(t,J=4.0Hz,1H),3.71(s,3H),3.67(d,J=10.2Hz,1H),3.53(s,4H).

[0661] Example 149 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M42-1)

[0662]

[0663] Except for replacing M1 ((3R,4S,5S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0664] Example 150 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M42-2)

[0665]

[0666] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M42-1((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 90% yield.

[0667] Example 151 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-42)

[0668]

[0669] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M42-2((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 98% yield.

[0670] 1H NMR(400MHz, DMSO-d6)δ7.36(d,J=8.2Hz,1H),7.31(d,J=2.0Hz,1H),7.25–7.18(m,1H),7.11(dd,J=11.4,8.5 Hz,2H),6.85–6.79(m,2H),4.96(ddt,J=6.4,4.2,1.8Hz,1H),4.67–4.59(m,2H),4.42(t,J=4.8Hz,1H),4.01–3 .84(m,4H),3.83–3.77(m,1H),3.73(ddd,J=12.8,6.5,3.2Hz,2H),3.62(q,J=6.2Hz,1H),3.54–3.50(m,1H),3. 49–3.38(m,2H),2.18(dtd,J=14.2,8.2,6.2Hz,1H),1.93(dt,J=12.4,5.7Hz,1H),1.12(dd,J=6.4,2.5Hz,3H).

[0671] Example 152 Preparation of (2S,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M43-1)

[0672]

[0673] Except for replacing M1 ((3R,4S,5S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M43 ((3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0674] Example 153 Preparation of (2S,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M43-2)

[0675]

[0676] Except for replacing M1-1 ((2S,3S,4S,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M43-1 ((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 93% yield.

[0677] Example 154 Preparation of (2S,3R,4R,5R,6S)-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-43)

[0678]

[0679] Except for replacing M1-2((2S,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M43-2((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 95% yield.

[0680] 1 H NMR(400MHz, DMSO-d6)δ7.39–7.27(m,2H),7.22(dd,J=8.2,2.1Hz,1H),7.09(dd,J=8.8,2.5Hz,2H), 6.87–6.78(m,2H),4.96(ddd,J=6.4,4.2,2.1Hz,1H),4.80(d,J=4.6Hz,1H),4.67(t,J=5.0Hz,1H),4 .44(s,1H),4.28(d,J=5.2Hz,1H),3.97(s,2H),3.88–3.72(m,5H),3.42(dq,J=5.6,3.0Hz,1H),3.23 (td,J=5.2,3.0Hz,2H),2.18(dtd,J=14.2,8.2,6.1Hz,1H),1.99–1.88(m,1H),1.22(d,J=5.0Hz,3H).

[0681] Example 155 Preparation of (2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M44-1)

[0682]

[0683] Except for replacing M1 ((3R, 4S, 5S, 6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M44 ((3R, 4S, 5S)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0684] Example 156 Preparation of (2S,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M44-2)

[0685]

[0686] Except for replacing M1-1 ((2S,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M44-1 ((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 92.5% yield.

[0687] Example 157 Preparation of (2S,3R,4S,5R,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-44)

[0688]

[0689] Except for replacing M1-2((2S,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M44-2((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 99% yield.

[0690] 1 H NMR(400MHz, DMSO-d6)δ7.36(d,J=8.2Hz,1H),7.31(d,J=2.0Hz,1H),7.25–7.18(m,1H),7.11(dd,J=11.4,8.5 Hz,2H),6.85–6.79(m,2H),4.96(ddt,J=6.4,4.2,1.8Hz,1H),4.67–4.59(m,2H),4.42(t,J=4.8Hz,1H),4.01–3 .84(m,4H),3.83–3.77(m,1H),3.73(ddd,J=12.8,6.5,3.2Hz,2H),3.62(q,J=6.2Hz,1H),3.54–3.50(m,1H),3. 49–3.38(m,2H),2.18(dtd,J=14.2,8.2,6.2Hz,1H),1.93(dt,J=12.4,5.7Hz,1H),1.12(dd,J=6.4,2.5Hz,3H).

[0691] Example 158 Preparation of (2R,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol (compound shown in formula M45-1)

[0692]

[0693] Except for replacing M1 ((3R, 4S, 5S)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one) with M45 ((3S, 4S, 5S)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0694] Example 159 Preparation of (2S,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran (compound shown in formula M45-2)

[0695]

[0696] Except for replacing M1-1 ((2S,3S,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol) with M45-1 ((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 90% yield.

[0697] Example 160 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-45)

[0698]

[0699] Except for replacing M1-2((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-6-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran) with M45-2((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 89% yield.

[0700] 1H NMR (400MHz, DMSO-d6) δ7.43–7.23(m,3H),7.10(d,J=8.2Hz,2H),6.83(dd,J=8.6,3.5Hz,2H),5.45(d, J=4.0Hz,1H),4.96(ddt,J=6.4,4.1,1.9Hz,1H),4.91(d,J=3.8Hz,1H),4.66(d,J=4.8Hz,1H),4.53–4.3 9(m,2H),3.97(d,J=3.6Hz,3H),3.90–3.81(m,3H),3.81–3.68(m,4H),3.61(ddd,J=11.0,5.7,2.2Hz,1H ), 3.42(ddd,J=13.8,6.4,4.0Hz,1H), 2.18(dtd,J=14.2,8.1,6.1Hz,1H), 1.93(dt,J=12.8,5.6Hz,1H).

[0701] Example 161 Preparation of (2R,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol (compound shown in formula M46-1)

[0702]

[0703] Except for replacing M1 ((3R, 4S, 5S, 6S)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one) with M46 ((3S, 4R, 5S, 6S)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0704] Example 162 Preparation of (2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran (compound shown in formula M46-2)

[0705]

[0706] Except for replacing M1-1 ((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol) with M46-1 ((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 94% yield.

[0707] Example 163 Preparation of (2R,3S,4S,5R,6S)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-46)

[0708]

[0709] Except for replacing M1-2((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran) with M46-2((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 88.5% yield.

[0710] 1 H NMR (400MHz, DMSO-d6) δ7.42–7.31(m,2H),7.30–7.23(m,1H),7.13–7.06(m,2H),6.83(d d,J=9.2,2.8Hz,2H),5.43(d,J=4.2Hz,1H),4.96(ddt,J=6.4,4.2,1.9Hz,1H),4.87(dd,J =18.6,4.1Hz,1H),4.64(d,J=4.6Hz,1H),4.55–4.38(m,2H),3.97(d,J=4.4Hz,3H),3.89– 3.70(m,7H),3.64–3.58(m,1H),3.44–3.39(m,1H),2.23–2.13(m,1H),1.98–1.89(m,1H).

[0711] Example 164 Preparation of (2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol (compound shown in formula M47-1)

[0712]

[0713] Except for replacing M1 ((3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one) with M47 ((3R,4S,5S)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0714] Example 165 Preparation of (2R,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-6-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran (compound shown in formula M47-2)

[0715]

[0716] Except for replacing M1-1 ((2S,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol) with M47-1 ((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 97% yield.

[0717] Example 166 Preparation of (2S,3R,4R,5R,6R)-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-47)

[0718]

[0719] Except for replacing M1-2((2S,3S,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-6-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran) with M47-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 89% yield.

[0720] 1 H NMR (400MHz, DMSO-d6) δ7.39(s,1H),7.37–7.32(m,1H),7.28(d,J=8.8Hz,1H),7.10(d,J=8.4Hz,2 H),6.82(d,J=7.8Hz,2H),4.96(s,1H),4.84–4.77(m,1H),4.72(d,J=3.7Hz,1H),4.45(d,J=8.3Hz, 2H),4.27–4.21(m,1H),3.97(s,2H),3.84(td,J=17.4,15.1,5.7Hz,2H),3.74(d,J=8.8Hz,4H),3. 49(d,J=22.8Hz,2H),3.40(s,1H),3.17(d,J=8.2Hz,1H),2.18(dt,J=8.6,4.3Hz,1H),1.94(s,1H).

[0721] Example 167 Preparation of (2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxy)methyl)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol (compound shown in formula M48-1)

[0722]

[0723] Except for replacing M1 ((3R, 4S, 5R, 6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one) with M48 ((3S, 4S, 5S)-3,4-bis(benzyloxy)-5-(benzyloxyoxymethyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 1, and the product is directly fed into the next step.

[0724] Example 168 Preparation of (2R, 3R, 4R, 5R, 6R)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran (compound shown in formula M48-2)

[0725]

[0726] Except for replacing M1-1 ((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxy)methyl)-2-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol) with M48-1 ((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 87% yield.

[0727] Example 169 Preparation of (2R,3S,4R,5S,6R)-2-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-48)

[0728]

[0729] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran) with M48-2((2R,3R,4R,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 93.5% yield.

[0730] 1H NMR (400MHz, DMSO-d6) δ7.39(d,J=2.0Hz,1H),7.34(d,J=8.2Hz,1H),7.28(dd,J=8.2,2.1Hz,1H),7.09(d,J=8.4Hz,2 H),6.85–6.79(m,2H),4.95(ddt,J=6.4,4.1,1.8Hz,1H),4.79(d,J=5.2Hz,1H),4.70(d,J=5.6Hz,1H),4.48–4.40(m, 2H),4.24(d,J=5.4Hz,1H),3.97(s,2H),3.86(dd,J=10.0,4.6Hz,1H),3.80(d,J=7.6Hz,1H),3.77–3.70(m,4H),3.53 –3.45(m,2H),3.41–3.38(m,1H),3.18(ddd,J=8.8,6.4,2.2Hz,1H),2.22–2.14(m,1H),1.93(dd,J=13.0,6.3Hz,1H).

[0731] Example 170 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(3-chloro-2-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M49-2)

[0732]

[0733] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 43, and the product is directly fed into the next step.

[0734] Example 171 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(3-chloro-2-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M49-3)

[0735]

[0736] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(3-chloro-2-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M49-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 90% yield.

[0737] Example 172 Preparation of (2R,3S,4R,5S,6S)-2-(3-chloro-2-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-49)

[0738]

[0739] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(3-chloro-2-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M49-3((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 95% yield.

[0740] 1H NMR (400MHz, DMSO-d6) δ7.45(dd,J=7.6,1.5Hz,1H),7.37(dd,J=7.8,1.4Hz,1H),7.28(t,J=7.8Hz,1H),7.01–6.96(m,2H),6.82–6 .76(m,2H),4.95(dq,J=3.8,2.1Hz,1H),4.75(d,J=5.6Hz,1H),4.69(d,J=5.8Hz,1H),4.49–4.43(m,1H),4.27(dt,J=16.8,5.3Hz,2 H),4.12(d,J=15.6Hz,1H),3.85(dd,J=10.0,4.6Hz,1H),3.82–3.77(m,1H),3.76–3.69(m,2H),3.65(td,J=9.2,5.7Hz,1H),3.54–3 .45(m,2H),3.40(ddd,J=9.2,5.9,3.3Hz,1H),2.17(dtd,J=13.2,8.3,6.3Hz,1H),1.96–1.87(m,1H),1.05(dd,J=15.6,6.4Hz,3H).

[0741] Example 173 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(3-chloro-4-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M50-2)

[0742]

[0743] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 47, and the product is directly fed into the next step.

[0744] Example 174 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(3-chloro-4-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M50-3)

[0745]

[0746] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(3-chloro-4-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M50-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 91% yield.

[0747] Example 175 Preparation of (2R,3S,4R,5S,6S)-2-(3-chloro-4-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-50)

[0748]

[0749] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(3-chloro-4-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M50-3((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 96% yield.

[0750] 1 H NMR(400MHz, DMSO-d6)δ7.39(d,J=1.4Hz,1H),7.25–7.21(m,2H),7.13–7.09(m,2H),6.82(dd,J=8.4,5.6 Hz,2H),4.99–4.93(m,1H),4.68–4.60(m,2H),4.44(d,J=5.4Hz,1H),3.97(s,1H),3.92(t,J=8.8Hz,1H),3 .89–3.82(m,2H),3.80(dd,J=8.2,7.1Hz,1H),3.73(td,J=8.2,4.3Hz,2H),3.63(q,J=7.4,7.0Hz,1H),3.5 4–3.50(m,1H),3.47–3.37(m,2H),2.21–2.15(m,1H),1.92(dt,J=12.8,5.9Hz,1H),1.12(t,J=6.8Hz,3H).

[0751] Example 176 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyl-2-(4-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol (compound shown in formula M51-2)

[0752]

[0753] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 55, and the product is directly fed into the next step.

[0754] Example 177 Preparation of (2S,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-methyl-6-(4-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran (compound shown in formula M51-3)

[0755]

[0756] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyl-2-(4-methyl-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol) with M51-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 93.5% yield.

[0757] Example 178 Preparation of (2S,3S,4R,5S,6R)-2-methyl-6-(4-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-51)

[0758]

[0759] Except for replacing M1-2((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-methyl-6-(4-methyl-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran) with M51-3((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 95% yield.

[0760] 1 H NMR(400MHz, DMSO-d6)δ7.12(d,J=3.6Hz,1H),7.10–7.05(m,2H),7.05–7.00(m,2H),6.84–6.78(m,2H) ,4.95(ddt,J=6.4,4.0,1.8Hz,1H),4.61(s,1H),4.49(s,1H),4.39(s,1H),3.86(td,J=7.2,6.8,3.2Hz, 4H),3.80(t,J=7.8Hz,1H),3.73(ddd,J=12.8,6.3,3.4Hz,2H),3.61(q,J=6.2Hz,1H),3.50(d,J=12.0Hz ,2H),3.40(s,1H),2.23–2.16(m,1H),2.15(s,3H),1.93(dt,J=12.6,5.4Hz,1H),1.12(d,J=6.4Hz,3H).

[0761] Example 179 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-fluoro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M52-2)

[0762]

[0763] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 63, and the product is directly fed into the next step.

[0764] Example 180 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-fluoro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M52-3)

[0765]

[0766] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-fluoro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M52-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 87.5% yield.

[0767] Example 181 Preparation of (2R,3S,4R,5S,6S)-2-(4-fluoro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-52)

[0768]

[0769] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-fluoro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M52-3((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 96% yield.

[0770] 1H NMR(400MHz, DMSO-d6)δ7.25–7.20(m,2H),7.18(d,J=2.0Hz,1H),7.14(dd,J=8.4,2.2Hz,1H),7.09–7.0 2(m,2H),6.87(d,J=8.4Hz,1H),5.00(td,J=4.6,2.1Hz,1H),4.62(d,J=5.6Hz,1H),4.49(d,J=5.6Hz,1H) ,4.39(d,J=5.0Hz,1H),3.92–3.81(m,4H),3.78–3.67(m,3H),3.60(q,J=6.4Hz,1H),3.53–3.45(m,2H),3 .38(td,J=5.6,2.8Hz,1H),2.14(dtd,J=13.2,8.5,6.0Hz,1H),1.92–1.83(m,1H),1.11(d,J=6.4Hz,3H).

[0771] Example 182: Preparation of (S)-3-(4-(3-iodo-2-methylbenzyl)phenoxy)tetrahydrofuran (compound shown in formula M53-1)

[0772]

[0773] Except for replacing M13 with M53 ((S)-(3-iodo-2-methylphenyl)(4-(tetrahydrofuran-3-yl)oxy)phenyl)methyl ketone), the other steps were the same as in Example 42. A white solid was obtained in 70% yield.

[0774] Example 183 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyl-2-(2-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol (compound shown in formula M53-2)

[0775]

[0776] Except for replacing S-3-(4-(2-chloro-5-iodobenzyl)phenoxy)tetrahydrofuran with M53-1((S)-3-(4-(3-iodo-2-methylbenzyl)phenoxy)tetrahydrofuran), the other steps are the same as in Example 149, and the product is directly fed into the next step.

[0777] Example 184 Preparation of (2S,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-methyl-6-(2-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran (compound shown in formula M53-3)

[0778]

[0779] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyl-2-(2-methyl-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol) with M53-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 92.5% yield.

[0780] Example 185 Preparation of (2S,3S,4R,5S,6R)-2-methyl-6-(2-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-53)

[0781]

[0782] Except for replacing M1-2((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-methyl-6-(2-methyl-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran) with M53-3((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 90.5% yield.

[0783] 1H NMR (600MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.10(t,J=7.6Hz,1H),7.05–7.01(m,3H),6.85–6.78(m,2H),4.95(ddt,J=6. 4,4.2,1.9Hz,1H),4.63(d,J=5.8Hz,1H),4.52(d,J=5.6Hz,1H),4.43(d,J=4.8Hz,1H),4.24(d,J=9.4Hz,1H),3.89(d,J=2.2 Hz,2H),3.86(dd,J=10.0,4.6Hz,1H),3.81(q,J=7.8Hz,1H),3.73(ddd,J=12.8,7.5,3.2Hz,2H),3.68–3.60(m,2H),3.53(t ,J=4.0Hz,1H),3.43(ddd,J=9.2,6.0,3.3Hz,1H),2.19(s,3H),2.18–2.13(m,1H),1.96–1.90(m,1H),1.10(d,J=6.2Hz,3H).

[0784] Example 186 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyl-2-(3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol (compound shown in formula M54-2)

[0785]

[0786] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 59, and the product is directly fed into the next step.

[0787] Example 187 Preparation of (2S,3R,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-methyl-6-(3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran (compound shown in formula M54-3)

[0788]

[0789] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyl-2-(3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-2-ol) with M54-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 85.9% yield.

[0790] Example 188 Preparation of (2S,3S,4R,5S,6R)-2-methyl-6-(3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-54)

[0791]

[0792] Except for replacing M1-2((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-2-methyl-6-(3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran) with M54-3((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 93% yield.

[0793] 1H NMR (400MHz, DMSO-d6) δ7.27–7.18(m,2H),7.15(d,J=7.4Hz,2H),7.12(d,J=2.2Hz,1H),7.08(dt,J=7.0,1.6Hz,1H),6 .85–6.79(m,2H),4.96(ddt,J=6.4,4.2,1.8Hz,1H),4.62(d,J=5.6Hz,1H),4.52(d,J=5.8Hz,1H),4.42(d,J=5.0Hz,1H) ,3.89(d,J=9.4Hz,1H),3.87–3.83(m,3H),3.80(dd,J=8.2,7.0Hz,1H),3.76–3.69(m,2H),3.64–3.58(m,1H),3.49(dq, J=18.4,5.2,4.4Hz,2H),3.39(d,J=9.4Hz,1H),2.23–2.13(m,1H),1.93(dt,J=12.2,5.3Hz,1H),1.12(d,J=6.4Hz,3H).

[0794] Example 189 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-bromo-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M55-2)

[0795]

[0796] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 91, and the product is directly fed into the next step.

[0797] Example 190 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-bromo-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M55-3)

[0798]

[0799] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-bromo-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M55-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 88% yield.

[0800] Example 191 Preparation of (2R,3S,4R,5S,6S)-2-(4-bromo-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-55)

[0801]

[0802] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-bromo-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M55-3((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 91% yield.

[0803] 1 H NMR (400MHz, DMSO-d6) δ7.25–7.06(m,5H),6.86–6.79(m,2H),4.96(ddt,J=6.6,4.3,1 .9Hz,1H),4.67–4.50(m,2H),4.42(t,J=4.8Hz,1H),4.05–3.91(m,1H),3.91–3.77(m, 4H),3.73(ddd,J=12.8,6.5,3.2Hz,2H),3.65–3.57(m,1H),3.53–3.35(m,3H),2.18(d td,J=15.8,8.2,6.3Hz,1H),1.93(dt,J=12.2,5.5Hz,1H),1.12(dd,J=6.4,1.6Hz,3H).

[0804] Example 192 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-2-fluoro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M56-2)

[0805]

[0806] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 95, and the product is directly fed into the next step.

[0807] Example 193 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-2-fluoro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M56-3)

[0808]

[0809] Except for replacing M1-1 ((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-2-fluoro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M56-2 ((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 90% yield.

[0810] Example 194 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-2-fluoro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-56)

[0811]

[0812] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-2-fluoro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M56-3((2R,3R,4R,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 95% yield.

[0813] 1 H NMR(400MHz, DMSO-d6)δ7.49(d,J=7.4Hz,1H),7.33(d,J=9.6Hz,1H),7.11–7.03(m,2H),6.87–6.79(m,2H),4 .96(ddt,J=6.4,4.3,1.9Hz,1H),4.71(dd,J=8.8,5.8Hz,2H),4.44(d,J=5.4Hz,1H),4.24(d,J=9.4Hz,1H),3 .98(s,2H),3.86(dd,J=10.0,4.6Hz,1H),3.83–3.77(m,1H),3.77–3.71(m,2H),3.67(p,J=6.6Hz,1H),3.60– 3.50(m,2H),3.43(ddd,J=9.2,5.8,3.3Hz,1H),2.22–2.14(m,1H),1.98–1.88(m,1H),1.12(d,J=6.2Hz,3H).

[0814] Example 195 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-methoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M57-2)

[0815]

[0816] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 83, and the product is directly fed into the next step.

[0817] Example 196 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-methoxy-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M57-3)

[0818]

[0819] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-methoxy-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M57-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 94% yield.

[0820] Example 197 Preparation of (2R,3S,4R,5S,6S)-2-(4-methoxy-3-(4-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-57)

[0821]

[0822] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-methoxy-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M57-3((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 88% yield.

[0823] 1H NMR(400MHz,DMSO-d6)δ7.15(dd,J=8.4,2.2Hz,1H),7.12–7.07(m,3H),6.90(d,J=8.4Hz,1H),6.8 1–6.77(m,2H),4.94(ddt,J=6.4,3.9,1.8Hz,1H),4.62(d,J=5.6Hz,1H),4.47(d,J=5.6Hz,1H),4.4 0(d,J=5.0Hz,1H),3.89–3.77(m,5H),3.77–3.69(m,5H),3.58(q,J=6.4Hz,1H),3.52–3.49(m,1H), 3.48–3.43(m,1H),3.39–3.35(m,1H),2.20–2.15(m,1H),1.96–1.89(m,1H),1.10(d,J=6.4Hz,3H).

[0824] Example 198 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(2-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M58-2)

[0825]

[0826] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 67, and the product is directly fed into the next step.

[0827] Example 199 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(2-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M58-3)

[0828]

[0829] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(2-chloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M58-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 91% yield.

[0830] Example 200: Preparation of (2R,3S,4R,5S,6S)-2-(2-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-58)

[0831]

[0832] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(2-chloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M58-3((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 96% yield.

[0833] 1 H NMR (400MHz, DMSO-d6) δ7.23–7.15(m,2H),7.15–7.07(m,3H),6.83(dd,J=8.6,3.7Hz,2H),4.96(dd d,J=6.4,4.3,2.1Hz,1H),4.63(dd,J=5.6,1.8Hz,1H),4.50(dd,J=20.2,5.5Hz,1H),4.44–4.38(m, 1H),3.91–3.83(m,4H),3.78–3.72(m,2H),3.71–3.56(m,2H),3.55–3.44(m,2H),3.40(dd,J=5.8,3 .3Hz,1H),2.19(dt,J=13.8,7.1Hz,1H),1.93(dt,J=12.6,5.8Hz,1H),1.11(dd,J=6.4,2.8Hz,3H).

[0834] Example 201 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(3-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M59-2)

[0835]

[0836] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 75, and the product is directly fed into the next step.

[0837] Example 202 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(3-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M59-3)

[0838]

[0839] Except for replacing M1-1((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(3-chloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M59-2((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 97% yield.

[0840] Example 203 Preparation of (2R,3S,4R,5S,6S)-2-(3-chloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-59)

[0841]

[0842] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(3-chloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M59-3((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 93% yield.

[0843] 1 H NMR(400MHz, DMSO-d6)δ7.24–7.10(m,5H),6.83(dd,J=8.4,6.4Hz,2H),4.96(dtt,J=5.0 ,3.3,1.8Hz,1H),4.59(dd,J=56.4,5.4Hz,2H),4.43(dd,J=12.2,5.2Hz,1H),3.95–3.78 (m,5H),3.77–3.69(m,2H),3.61(dd,J=8.8,4.5Hz,1H),3.55–3.48(m,1H),3.46–3.35(m ,2H),2.18(dtd,J=12.4,8.3,6.2Hz,1H),1.98–1.91(m,1H),1.12(dd,J=6.4,3.5Hz,3H).

[0844] Example 204 Preparation of (2R,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(2,4-dichloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol (compound shown in formula M60-2)

[0845]

[0846] Except for replacing M7 ((3R, 4R, 5R, 6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one) with M42 ((3S, 4R, 5R)-3,4-bis(benzyloxy)-5-(benzyloxyoxy)methyl)dihydrofuran-2(3H)-one), the other steps are the same as in Example 99, and the product is directly fed into the next step.

[0847] Example 205 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(2,4-dichloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound shown in formula M60-3)

[0848]

[0849] Except for replacing M1-1 ((2S,3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(2,4-dichloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-2-ol) with M60-2 ((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 94% yield.

[0850] Example 206 Preparation of (2R,3S,4R,5S,6S)-2-(2,4-dichloro-5-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-60)

[0851]

[0852] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(2,4-dichloro-5-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M60-3((2R,3R,4R,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 95% yield.

[0853] 1H NMR(400MHz,DMSO-d6)δ7.55(d,J=13.4Hz,2H),7.13–7.03(m,2H),6.88–6.78(m,2H),4.96(td,J=4.6,2.2Hz,1H) ,4.73(dd,J=5.6,4.4Hz,2H),4.46(d,J=5.6Hz,1H),4.39(d,J=9.4Hz,1H),3.99(s,2H),3.86(dd,J=10.0,4.6Hz,1 H),3.79(dd,J=8.2,7.0Hz,1H),3.73(ddd,J=10.8,6.5,3.2Hz,2H),3.69–3.59(m,2H),3.53(dd,J=6.0,3.3Hz,1H ),3.45(ddd,J=9.2,5.8,3.4Hz,1H),2.18(dtd,J=14.2,8.2,6.2Hz,1H),1.96–1.89(m,1H),1.11(d,J=6.4Hz,3H).

[0854] Example 207 Preparation of 4-(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenol (compound shown in formula MXVI-1)

[0855]

[0856] Except for replacing 3,4-bisbenzyloxy-5-benzyloxymethyldihydrofuran-2(3H)one with (3S,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-one and 2,4-dichlorobenzoic acid with 2-chloro-5-iodobenzoic acid, the synthetic steps were the same as in synthesis M32-2. A white solid was obtained in 72% yield.

[0857] Example 208 Preparation of 4-(4-chloro-3-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenol (compound shown in formula MXVI-2)

[0858]

[0859] Except for replacing 3,4-bisbenzyloxy-5-benzyloxymethyldihydrofuran-2(3H)one with (3S,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-one and 2,4-dichlorobenzoic acid with 4-chloro-5-iodobenzoic acid, the synthetic steps were the same as those in M32-2. A white solid was obtained in 68% yield.

[0860] Example 209 Preparation of (2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(phenyl)methanol (compound shown in formula M61-1)

[0861]

[0862] Except for replacing 5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)benzaldehyde with 2-chloro-5-((2R,3S,4R,5R)-3,4-bisbenzyloxy-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2,4-dichlorobenzaldehyde and replacing MVIII with M61 (bromobenzene), the other steps were the same as in Example 109, yielding a white solid in 85% yield.

[0863] Example 210 Preparation of (2R,3R,4R,5R,6S)-2-(3-benzyl-4-chlorophenyl)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran (the compound shown in formula M61-2).

[0864]

[0865] Except for replacing M1-1((2S,3S,4S,5S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(phenyl)methanol) with M61-1((2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 96% yield.

[0866] Example 211 Preparation of (2R,3S,4R,5S,6S)-2-(3-benzyl-4-chlorophenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (the compound shown in Formula I-61).

[0867]

[0868] Except for replacing M1-2((2S,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran) with M61-2((2R,3R,4R,5R,6S)-2-(3-benzyl-4-chloro)-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 90% yield.

[0869] 1 H NMR (400MHz, DMSO-d6) δ7.38(d,J=8.3Hz,1H),7.35–7.23(m,4H),7.20(h,J=3.4Hz,3H),4.64(dd,J=9.9,5.3Hz,2H),4.43(d,J=5. 2Hz,1H),4.12–3.99(m,2H),3.95–3.89(m,1H),3.63(q,J=6.4Hz,1H),3.55–3.49(m,1H),3.47–3.36(m,2H),1.13(d,J=6.4Hz,3H).

[0870] Example 212 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-62).

[0871]

[0872] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenol) with MXVI-1(4-(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 88% yield.

[0873] 1H NMR (400MHz, DMSO-d6) δ9.17 (s, 1H), 7.24–7.11 (m, 3H), 7.00 (d, J = 8.4Hz, 2H) ,6.71–6.62(m,2H),4.62(d,J=5.7Hz,1H),4.51(d,J=5.7Hz,1H),4.41(d,J=5 .0Hz,1H),3.89(d,J=9.2Hz,1H),3.80(s,2H),3.61(q,J=6.4Hz,1H),3.50(dq ,J=18.0,5.6,4.8Hz,2H),3.40(dd,J=5.8,3.3Hz,1H),1.12(d,J=6.3Hz,3H).

[0874] Example 213 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-methoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran (the compound shown in formula M63-1).

[0875]

[0876] Except for replacing M32-2 with MXVI-1 and M36 with M63 (iodomethane), the other steps were the same as in Example 133, yielding a white solid with a yield of 73%.

[0877] Example 214 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-methoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-63).

[0878]

[0879] Except for replacing M1-2 ((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-methoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M63-1 ((2R,3R,4R,5R,6S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 90% yield.

[0880] 1H NMR (400MHz, DMSO-d6) δ7.37(d,J=8.2Hz,1H),7.30(d,J=2.0Hz,1H),7.23(dd,J =8.2,2.1Hz,1H),7.14–7.07(m,2H),6.88–6.82(m,2H),4.65(d,J=5.3Hz,1H),4 .62(d,J=5.3Hz,1H),4.43(d,J=5.2Hz,1H),4.04–3.89(m,3H),3.71(s,3H),3.6 3(q,J=6.3Hz,1H),3.55–3.50(m,1H),3.47–3.36(m,2H),1.13(d,J=6.3Hz,3H).

[0881] Example 215 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran (the compound shown in formula M64-1).

[0882]

[0883] Except for replacing M63 (iodomethane) with M64 (iodoethane), the other steps were the same as in Example 213, yielding a white solid in 80% yield.

[0884] Example 216 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-64).

[0885]

[0886] Except for replacing M1-2 ((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M64-1 ((2R,3R,4R,5R,6S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 87% yield.

[0887] 1H NMR (400MHz, DMSO-d6) δ7.36(d,J=8.2Hz,1H),7.30(d,J=2.0Hz,1H),7.22(dd,J=8 .2,2.2Hz,1H),7.09(dd,J=9.0,2.4Hz,2H),6.87–6.80(m,2H),4.63(dd,J=14.1,5. 2Hz,2H),4.43(d,J=5.2Hz,1H),4.06–3.88(m,5H),3.63(q,J=6.3Hz,1H),3.52(dd, J=5.4,2.9Hz,1H),3.48–3.37(m,2H),1.30(d,J=6.8Hz,3H),1.14(t,J=6.7Hz,3H).

[0888] Example 217 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-isopropoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran (the compound shown in formula M65-1).

[0889]

[0890] Except for replacing M63 (iodomethane) with M65 (2-bromopropane), the other steps were the same as in Example 213, yielding a white solid in 78% yield.

[0891] Example 218 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-isopropoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-65).

[0892]

[0893] Except for replacing M1-2 ((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-isopropoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M65-1 ((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 85% yield.

[0894] 1H NMR(400MHz,DMSO-d6)δ7.37(d,J=8.2Hz,1H),7.31(d,J=2.1Hz,1H),7.26– 7.19(m,1H),7.08(d,J=8.4Hz,2H),6.85–6.78(m,2H),4.68–4.50(m,3H),4. 43(d,J=5.2Hz,1H),4.02–3.87(m,3H),3.63(q,J=6.2Hz,1H),3.52(t,J=4.0 Hz,1H),3.47–3.35(m,2H),1.91(s,2H),1.24(s,6H),1.13(d,J=6.4Hz,3H).

[0895] Example 219 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(3-(4-butoxybenzyl)-4-chlorophenyl)-6-methyltetrahydro-2H-pyran (the compound shown in formula M66-1).

[0896]

[0897] Except for replacing M63 (iodomethane) with M66 (1-iodobutane), the other steps were the same as in Example 213, yielding a white solid in 75% yield.

[0898] Example 220 Preparation of (2R,3S,4R,5S,6S)-2-(3-(4-butoxybenzyl)-4-chlorophenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-66).

[0899]

[0900] Except for replacing M1-2 ((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(3-(4-butoxybenzyl)-4-chlorophenyl)-6-methyltetrahydro-2H-pyran) with M66-1 ((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 89% yield.

[0901] 1H NMR(400MHz, DMSO-d6)δ7.40–7.33(m,1H),7.29(d,J=2.2Hz,1H),7.26–7.18(m,1H),7.13–7.05(m,2 H),6.87–6.79(m,2H),4.65(d,J=5.2Hz,1H),4.61(d,J=5.1Hz,1H),4.43(d,J=5.2Hz,1H),3.97(d,J =5.4Hz,2H),3.91(dd,J=8.4,4.4Hz,3H),3.62(q,J=6.2Hz,1H),3.55–3.49(m,1H),3.42(dt,J=14.9 ,4.7Hz,2H),1.65(q,J=7.0Hz,2H),1.46–1.39(m,2H),1.13(d,J=6.3Hz,3H),0.92(t,J=7.3Hz,3H).

[0902] Example 221 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (the compound shown in formula M67-1).

[0903]

[0904] Except for replacing M63 (iodomethane) with M67 ((S)-3-bromotetrahydrofuran), the other steps were the same as in Example 213, yielding a white solid in 80% yield.

[0905] Example 222 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (the compound shown in Formula I-67).

[0906]

[0907] Except for replacing M1-2 ((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M67-1 ((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 95% yield.

[0908] 1 H NMR (400MHz, DMSO-d6) δ7.37(d,J=8.2Hz,1H),7.31(d,J=2.1Hz,1H),7.23(dd,J=8.2,2.1Hz,1H),7.10(d,J=8. 4Hz,2H),6.86–6.80(m,2H),4.96(ddd,J=6.4,4.3,2.0Hz,1H),4.70–4.58(m,2H),4.43(d,J=5.2Hz,1H),3.96( dd,J=19.1,4.1Hz,2H),3.92–3.83(m,2H),3.80(t,J=7.7Hz,1H),3.77–3.71(m,2H),3.63(q,J=6.3Hz,1H),3.5 2(s,1H),3.42(d,J=14.0Hz,2H),2.18(dtd,J=14.3,8.2,6.2Hz,1H),2.02–1.92(m,1H),1.13(d,J=6.4Hz,3H).

[0909] Example 223 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(cyclopentoxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (the compound shown in formula M68-1).

[0910]

[0911] Except for replacing M63 (iodomethane) with M68 (bromocyclopentane), the other steps were the same as in Example 213, yielding a white solid in 79% yield.

[0912] Example 224 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-(cyclopentoxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-68).

[0913]

[0914] Except for replacing M1-2 ((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(cyclopentoxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M68-1 ((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 96% yield.

[0915] 1 H NMR (400MHz, DMSO-d6) δ7.40–7.34(m,1H),7.30(s,1H),7.22(d,J=9.1Hz,1H ),7.11–7.05(m,2H),6.80(d,J=8.1Hz,2H),4.75(s,1H),4.65(d,J=13.9Hz,2 H),4.43(d,J=4.6Hz,1H),4.00–3.83(m,3H),3.62(s,1H),3.52(s,1H),3.40 (s,2H),1.87(s,2H),1.68(s,4H),1.57(d,J=10.9Hz,2H),1.14–1.10(m,3H).

[0916] Example 225 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(2-chloro-5-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound of formula M69-1).

[0917]

[0918] Except for replacing MXVI-1 with MXVI-2, the other steps are the same as in Example 224, yielding a white solid with a yield of 82%.

[0919] Example 226 Preparation of (2R,3S,4R,5S,6S)-2-(2-chloro-5-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-69).

[0920]

[0921] Except for replacing M1-2 ((2S,3S,4S,5S)-2-(2-chloro-5-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol) with M69-1 ((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), a white solid was obtained in 93% yield.

[0922] 1H NMR (400MHz, DMSO-d6) δ7.41 (s, 1H), 7.29 (dd, J = 8.1, 2.2Hz, 1H), 7.15–7.0 5(m,3H),6.92–6.85(m,2H),4.76–4.60(m,2H),4.55–4.45(m,2H),4.41(d,J =9.2Hz,1H),3.88–3.79(m,4H),3.65(q,J=6.9Hz,2H),3.54(s,1H),3.49–3. 42(m,3H),1.93(d,J=16.2Hz,2H),1.59–1.50(m,2H),1.12(d,J=6.3Hz,3H).

[0923] Example 227 Preparation of (2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(3,4-dimethoxyphenyl)methanol (the compound shown in formula M70-1).

[0924]

[0925] Except for replacing M61 with M70 (4-bromo-1,2-dimethoxybenzene), the other steps were the same as in Example 209, yielding a white solid. Yield: 85%.

[0926] Example 228 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(3,4-dimethoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran (the compound shown in formula M70-2).

[0927]

[0928] Except for replacing M1-1((2S,3S,4S,5S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(3,4-dimethoxyphenyl)) with M70-1((2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(3,4-dimethoxyphenyl))tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 98% yield.

[0929] Example 229 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(3,4-dimethoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-70).

[0930]

[0931] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(3,4-dimethoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M70-2(2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 88% yield.

[0932] 1 H NMR (400MHz, DMSO-d6) δ7.37 (dd, J=8.3, 2.2Hz, 1H), 7.30 (d, J=2.6Hz, 1H), 7.2 6–7.20(m,1H),6.85(dt,J=4.7,2.5Hz,2H),6.66(d,J=8.1Hz,1H),4.68–4.63(m ,1H),4.63–4.58(m,1H),4.43(dd,J=5.2,2.2Hz,1H),3.98(s,2H),3.93–3.89(m ,1H),3.70(t,J=1.5Hz,6H),3.62(d,J=6.7Hz,2H),1.12(dd,J=6.3,2.3Hz,3H).

[0933] Example 230 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-((tetrafluoromethyl)benzyl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound of formula M71-1).

[0934]

[0935] Except for replacing M63 (iodomethane) with M71 (1-bromomethyl-4-trifluoromethylbenzene), the other steps were the same as in Example 213, yielding a white solid in 79% yield.

[0936] Example 231 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-((4-(trifluoromethyl)benzyl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-71).

[0937]

[0938] Except for replacing M1-2 ((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((tetrafluoromethyl)benzyl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M71-1 ((2R,3S,4S,5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 86% yield.

[0939] 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J=7.8Hz,2H),7.56(d,J=8.1Hz,2H),7.4 0(d,J=8.0Hz,1H),7.27(s,2H),7.14(d,J=8.0Hz,2H),6.90(d,J=8.0Hz,2H),5 .12(s,2H),4.05(t,J=13.7Hz,3H),3.88(s,1H),3.81(q,J=6.8Hz,1H),3.68(d ,J=9.9Hz,2H),2.68(s,1H),2.22(s,1H),1.94(s,1H),1.29(d,J=11.5Hz,3H).

[0940] Example 232 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-((5-(trifluoromethyl)furan-2-yl)methoxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound of formula M72-1).

[0941]

[0942] Except for replacing M63 (iodomethane) with M72 (2-bromomethyl-5-trifluoromethylfuran), the other steps were the same as in Example 213, yielding a white solid in 85% yield.

[0943] Example 233 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-((5-(trifluoromethyl)furan-2-yl)methoxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-72).

[0944]

[0945] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-((5-(trifluoromethyl)furan-2-yl)methoxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M72-1((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 80% yield.

[0946] 1 H NMR(400MHz,Chloroform-d)δ7.40(d,J=8.3Hz,1H),7.26(s,2H),7.14(d,J=8.0Hz,2H),6.90(d,J=8.1Hz,2H),6.79(s,1H),6.49(s,1H),5.02(s ,2H),4.14–4.00(m,3H),3.88(s,1H),3.80(q,J=6.5Hz,1H),3.68(d,J=9 .5Hz,2H),2.72(s,1H),2.25(s,1H),1.98(s,1H),1.38(d,J=7.1Hz,3H).

[0947] Example 234 Preparation of 5-((2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(hydroxy)methyl)-2-methoxyphenol (compound M73-1).

[0948]

[0949] Except for replacing M61 with M70 (5-bromo-2-methoxyphenol), the other steps were the same as in Example 209, yielding a white solid. Yield: 78%.

[0950] Example 235 Preparation of 5-(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)-2-methoxyphenol (compound M73-2).

[0951]

[0952] Except for replacing M1-1((2S,3S,4S,5S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(hydroxy)methyl)-2-methoxyphenol) with M73-1((2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(hydroxy)methyl)-2-methoxyphenol), the other steps were the same as in Example 2, yielding a white solid in 96% yield.

[0953] Example 236 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(3-hydroxy-4-methoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-73).

[0954]

[0955] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)-2-methoxyphenol) with M72-2(5-(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)-2-methoxyphenol), the other steps were the same as in Example 3, yielding a white solid in 96% yield.

[0956] 1 H NMR(400MHz,Chloroform-d)δ7.39(t,J=7.8Hz,1H),7.26(d,J=17.4Hz,2H),6.85(d,J=8.0Hz,1H),6.75(s,1H),6.69(d,J=8.1Hz ,1H),4.07(t,J=13.0Hz,3H),3.86(s,5H),3.68(s,2H),2.64(s,1H),2.30(d,J=49.9Hz,1H),2.04(s,1H),1.37(d,J=6.7Hz,3H).

[0957] Example 237 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(3-(4-((4-bromo-2-chlorobenzyl)oxy)benzyl)-4-chlorophenyl)-6-methyltetrahydro-2H-pyran (compound of formula M74-1).

[0958]

[0959] Except for replacing M63 (iodomethane) with M74 (4-bromo-1-bromomethyl-2-chlorobenzene), the other steps were the same as in Example 213, yielding a white solid in 80% yield.

[0960] Example 238 Preparation of (2R,3S,4R,5S,6S)-2-(3-(4-((4-bromo-2-chlorobenzyl)oxy)benzyl)-4-chlorophenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-74).

[0961]

[0962] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(3-(4-((4-bromo-2-chlorobenzyl)oxy)benzyl)-4-chlorophenyl)-6-methyltetrahydro-2H-pyran) with M74-1((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 89% yield.

[0963] 1 H NMR (400MHz, DMSO-d6) δ7.63–7.55(m,1H),7.54–7.46(m,1H),7.43–7.35(m,3H),7.32(d,J= 2.1Hz,1H),7.23(dd,J=8.3,2.1Hz,1H),7.13(d,J=8.4Hz,2H),7.00–6.91(m,2H),5.12(s,2 H), 4.64 (dd, J = 11.0, 5.2Hz, 2H), 4.43 (d, J = 5.2Hz, 1H), 4.00 (d, J = 5.2Hz, 2H), 3.92 (d, J = 8. 5Hz,1H),3.63(q,J=6.4Hz,1H),3.55–3.49(m,1H),3.48–3.38(m,2H),1.13(d,J=6.4Hz,3H). 13C NMR(101MHz,DMSO-d6)δ157.04,152.91,149.74,144.40,138.07,135.57,134.88,132.22,130.57,130.29,130.10,1 29.91,129.84,127.93,127.84,115.13,81.76,74.55,72.20,71.61,70.39,67.29,38.11,17.58.HRMS(ESI)m / zcalcd C 26 H 26 Cl2O5Na + [M+Na] + 511.1050, found 511.1039.

[0964] Example 239 Preparation of benzo[d][1,3]dioxacyclopenten-5-yl(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)phenyl)methanol (compound of formula M75-1).

[0965]

[0966] Except for replacing M61 with M75 (5-bromobenzo[D][1,3]dioxane), the other steps were the same as in Example 209, yielding a white solid in 72% yield.

[0967] Example 240 Preparation of 5-(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)benzo[d][1,3]dioxane (compound M75-2).

[0968]

[0969] Except for replacing M1-1 ((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)phenyl)methanol) with M75-1 (benzo[d][1,3]dioxacyclopenten-5-yl(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 88% yield.

[0970] Example 241 Preparation of (2R,3S,4R,5S,6S)-2-(3-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-4-chlorophenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-75).

[0971]

[0972] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)benzo[d][1,3]dioxane) with M75-2(5-(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 93% yield.

[0973] 1 H NMR (400MHz, DMSO-d6) δ7.37(d,J=8.2Hz,1H),7.31(d,J=2.1Hz,1H),7.23(dd,J=8.2,2.0H z,1H),6.82(d,J=7.9Hz,1H),6.75(d,J=1.7Hz,1H),6.66(dd,J=7.9,1.7Hz,1H),5.96(d,J =1.1Hz,2H),4.64(dd,J=11.0,5.2Hz,2H),4.43(d,J=5.3Hz,1H),4.01–3.89(m,3H),3.63( q,J=6.4Hz,1H),3.55–3.49(m,1H),3.42(td,J=7.8,7.0,4.3Hz,2H),1.13(d,J=6.3Hz,3H).

[0974] Example 242 Preparation of (2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol (compound M76-1).

[0975]

[0976] Except for replacing M61 with M76 (6-bromo-2,3-dihydrobenzo[b][1,4]dioxane), the other steps were the same as in Example 209, yielding a white solid in 78% yield.

[0977] Example 243 Preparation of 6-(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)-2,3-dihydrobenzo[b][1,4]dioxane (compound M76-2).

[0978]

[0979] Except for replacing M1-1((2S,3S,4S,5S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol) with M76-1((2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 84% yield.

[0980] Example 244 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-76).

[0981]

[0982] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)-2,3-dihydrobenzo[b][1,4]dioxane) with M76-2(6-(2-chloro-5-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 90% yield.

[0983] 1H NMR (400MHz, Chloroform-d) δ7.39(d,J=8.1Hz,1H),7.27(s,2H),6.79(d,J=8.2Hz,1H),6.69(d,J=7.0Hz,2H),4.24( d,J=2.2Hz,4H),4.11–3.95(m,3H),3.92–3.65(m,4H),2.77(s,1H),2.29(s,1H),2.03(s,1H),1.38(d,J=6.5Hz,3H).

[0984] Example 245 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(2-chloro-5-(4-ethoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound of formula M78-1).

[0985]

[0986] Except for replacing MXVI-1 with MXVI-2, the other steps are the same as in Example 215, yielding a white solid with a yield of 73%.

[0987] Example 246 Preparation of (2R,3S,4R,5S,6S)-2-(2-chloro-5-(4-ethoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-78).

[0988]

[0989] Except for replacing M1-2 ((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(2-chloro-5-(4-ethoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M78-1 ((2R,3R,4R,5R,6S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 90% yield.

[0990] 1H NMR (400MHz, DMSO-d6) δ7.41(d,J=2.2Hz,1H),7.29(d,J=8.2Hz,1H),7.12(d,J=8.3Hz,2H),7.07 (dd,J=8.2,2.2Hz,1H),6.84(d,J=8.3Hz,2H),4.69(d,J=5.8Hz,1H),4.62(d,J=5.6Hz,1H),4.47 (d,J=5.2Hz,1H),4.41(d,J=9.5Hz,1H),3.97(q,J=7.0Hz,2H),3.86(s,2H),3.65(dt,J=12.9,6. 0Hz,2H),3.54(t,J=4.4Hz,1H),3.48–3.42(m,1H),1.30(t,J=6.9Hz,3H),1.12(d,J=6.4Hz,3H).

[0991] Example 247 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-2-(2-chloro-5-(4-((R)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (compound of formula M79-1).

[0992]

[0993] Except for replacing MXVI-1 with MXVI-2, the other steps are the same as in Example 221, yielding a white solid with a yield of 80%.

[0994] Example 248 Preparation of (2R,3S,4R,5S,6S)-2-(2-chloro-5-(4-((R)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-79).

[0995]

[0996] Except for replacing M1-2 ((2S,3S,4S,5S)-3,4,5-tribenzyloxy-2-(2-chloro-5-(4-(((R)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M79-1 ((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 95% yield.

[0997] 1H NMR (400MHz, DMSO-d6) δ7.36(t,J=5.4Hz,1H),7.31(s,1H),7.23(d,J=9.1Hz,1H),7.10(d ,J=8.7Hz,2H),6.83(d,J=7.6Hz,2H),4.96(s,1H),4.70–4.61(m,2H),4.43(d,J=4.4Hz,1 H),3.99(d,J=4.6Hz,1H),3.92(d,J=9.8Hz,1H),3.89–3.80(m,2H),3.74(d,J=10.4Hz,2H ),3.62(s,1H),3.54–3.49(m,1H),2.18(s,1H),1.98–1.88(m,1H),1.12(d,J=5.2Hz,3H).

[0998] Example 249 Preparation of (2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran (the compound shown in formula M80-1).

[0999]

[1000] Except for replacing M63 (iodomethane) with M80 (4-bromotetrahydro-2H-pyran), the other steps were the same as in Example 213, yielding a white solid in 82% yield.

[1001] Example 250 Preparation of (2R,3S,4R,5S,6S)-2-(4-chloro-3-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound shown in Formula I-80).

[1002]

[1003] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-(((tetrahydro-2H-pyran-4-yl)oxy)benzyl)phenyl)-6-methyltetrahydro-2H-pyran) with M80-1((2R,3R,4R,5S)-3,4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-5-(4-chloro-3-(4-((((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 90% yield.

[1004] 1H NMR (400MHz, DMSO-d6) δ7.37(dd,J=8.2,2.0Hz,1H),7.31(s,1H),7.23(d,J=8.4Hz,1H),7.09(dd,J=8.5,2 .1Hz,2H),6.91–6.85(m,2H),4.68–4.64(m,1H),4.63–4.60(m,1H),4.53–4.45(m,1H),4.43(dd,J=5.4,1. 9Hz,1H),4.04–3.94(m,2H),3.92(d,J=8.8Hz,1H),3.82(dd,J=11.6,5.7Hz,2H),3.63(q,J=6.8Hz,1H),3. 54–3.50(m,1H),3.49–3.38(m,4H),1.93(d,J=13.4Hz,2H),1.59–1.51(m,2H),1.13(dd,J=6.3,2.0Hz,3H). 13 CNMR(101MHz,DMSO-d6)δ154.92,145.03,142.65,140.58,138.13,134.85,130.08,129.10,127.92,116 .31,89.27,81.74,75.53,74.53,72.19,71.77,65.00,51.19,32.27,29.44,29.16,17.58.HRMS(ESI)m / z calcd C 24 H 29 ClO6Na + [M+Na] + 471.1545, found 471.1533.

[1005] Example 251 Preparation of 5-((4-chloro-3-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(hydroxy)methyl)-2-methoxyphenol (compound M81-1).

[1006]

[1007] Except for replacing MXVI-1 with MXVI-2, the other steps are the same as in Example 234, yielding a white solid with a yield of 86%.

[1008] Example 252 Preparation of 5-(4-chloro-3-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)-2-methoxyphenol (compound M81-2).

[1009]

[1010] Except for replacing M1-1((2S,3S,4S,5S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(hydroxy)methyl)-2-methoxyphenol) with M81-1(5-((4-chloro-3-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)phenyl)(hydroxy)methyl)-2-methoxyphenol), the other steps were the same as in Example 2, yielding a white solid in 94% yield.

[1011] Example 253 Preparation of (2R,3S,4R,5S,6S)-2-(2-chloro-5-(3-hydroxy-4-methoxybenzyl)phenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-81).

[1012]

[1013] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)-2-methoxyphenol) with M81-2(5-(4-chloro-3-((2R,3R,4R,5R,6S)-3,4,5-tribenzyloxy-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 98% yield.

[1014] 1 H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.36(d,J=8.1Hz,1H),7.27(s,1H),7.21 (d,J=8.3Hz,1H),6.80(s,1H),6.67(dd,J=8.1,4.5Hz,1H),6.54(d,J=8.4Hz, 1H), 4.63 (d, J = 18.0Hz, 2H), 4.43 (d, J = 4.2Hz, 1H), 3.91 (d, J = 15.4Hz, 3H), 3. 71(d,J=2.9Hz,3H),3.62(d,J=7.4Hz,1H),3.52(s,1H),1.12(d,J=6.6Hz,3H).

[1015] Example 254 Preparation of benzo[d][1,3]dioxacyclopenten-5-yl(4-chloro-3-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)phenyl)methanol (compound of formula M82-1).

[1016]

[1017] Except for replacing MXVI-1 with MXVI-2, the other steps are the same as in Example 239, yielding a white solid with a yield of 85%.

[1018] Example 255 Preparation of 5-(4-chloro-3-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)benzo[d][1,3]dioxane (compound M82-2).

[1019]

[1020] Except for replacing M1-1 ((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)phenyl)methanol) with M82-1 (benzo[d][1,3]dioxacyclopenten-5-yl(4-chloro-3-(((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)phenyl)tetrahydrofuran), the other steps were the same as in Example 2, yielding a white solid in 98% yield.

[1021] Example 256 Preparation of (2R,3S,4R,5S,6S)-2-(5-(benzo[d][1,3]dioxacyclopenten-5-ylmethyl)-2-chlorophenyl)-6-methyltetrahydro-2H-pyran-3,4,5-triol (compound of formula I-82).

[1022]

[1023] Except for replacing M1-2((2S,3S,4S,5S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)benzo[d][1,3]dioxane) with M82-2(5-(4-chloro-3-((2R,3R,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)benzyl)phenyl)tetrahydrofuran), the other steps were the same as in Example 3, yielding a white solid in 95% yield.

[1024] 1 H NMR (400MHz, DMSO-d6) δ7.41(d,J=2.2Hz,1H),7.29(d,J=8.2Hz,1H),7.10(dd,J=8.2,2.3Hz,1H ),6.82(d,J=7.9Hz,1H),6.79(d,J=1.6Hz,1H),6.70(dd,J=7.9,1.7Hz,1H),5.95(d,J=2.9Hz,2 H),4.70(d,J=5.8Hz,1H),4.63(d,J=5.6Hz,1H),4.47(d,J=5.3Hz,1H),4.41(d,J=9.5Hz,1H),3 .84(d,J=4.6Hz,2H),3.72–3.63(m,2H),3.54(t,J=4.5Hz,1H),3.48(s,1H),1.14–1.11(m,3H).

[1025] Drug efficacy evaluation

[1026] Effects Example 1: Protective effect of the compound on rat cardiomyocytes (H9c2 cells)

[1027] H9c2 cells were seeded at a density of 100,000 cells / mL into 96-well plates, 100 μL per well. Cells were divided into a normal control group, a model group, an empagliflozin positive control group, and a compound-treated group. After 24 h of normal culture, the culture medium was discarded. Normal culture medium was added to the normal control group, GD (glucose-deficient medium) was added to the model group, and GD medium and the corresponding concentration of the drug were added to the drug-treated group. Modeling was completed 28-32 h later. The culture medium was discarded, and 100 μL of DMEM medium containing 10% Cell Counting Kit-8 (CCK-8) was added. The cells were incubated at 37°C in the dark for 2 h. The absorbance (optical density, OD value) was measured using a BioTek microplate reader at a wavelength of 450 nm.

[1028] The cardiomyocyte survival rate data for each group are shown in Table 1. The higher the survival rate, the stronger the cell protection effect. The maximum cell protection effect of the positive control drug empagliflozin (EMPA) was 63.62% at a concentration of 100 μM.

[1029] As shown in Table 1, most C-glycoside aryl compounds exhibited excellent cardioprotective effects, and their maximum protective effect was superior to that of the positive control drug EMPA, indicating that the pentose sugar and non-glucose hexose structures are beneficial for improving activity.

[1030] Table 1. Cardiomyocyte viability assays of empagliflozin and compounds I-1 to I-82 in a GD model (1 μM to 100 μM).

[1031]

[1032]

[1033] The data are the mean ± SD, n = 3. #### P<0.0001 vs control group * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001 vs Model group.

[1034] Effect Example 2: Protective effect of preferred compounds on cardiomyocytes

[1035] To further verify the cardioprotective effects of these compounds, I-25, I-31, I-73, and I-80, which showed significant cardioprotective effects, were tested for their primary cardioprotective activity. Primary cardiomyocytes were extracted from suckling rats and seeded at a density of 330,000 cells / mL into 24-well plates (300 μL per well). Cells were divided into a normal control group, a model group, an empagliflozin positive control group, and a compound group. Cells were cultured normally for 24 hours, then the culture medium was discarded. Normal culture medium was added to the normal control group, GD (glucose-deficient medium) was added to the model group, and GD medium and the corresponding concentration of the drug were added to the drug control group. After 24 hours of modeling, the culture medium was discarded, and the cells were placed on ice and washed twice with pre-chilled PBS for 3–5 minutes each time. The cells were then fixed with pre-chilled methanol at -20°C for 10 minutes. The methanol was removed, and the cells were allowed to return to room temperature. Sufficient 0.5% crystal violet staining solution was added, and the cells were incubated at room temperature for 10 minutes. The crystal violet was removed, and the cells were washed with water until the stain did not fade. The cells were dried in a 37°C oven and photographed under a microscope. The experimental results are as follows: Figure 1 (AD), where DMSO is the model group and control refers to the normal control group.

[1036] from Figure 1 It can be seen that: in the model group, the myocardial cells were shrunken and the total number of cells decreased significantly, while in the drug-treated group, the total number of myocardial cells was significantly greater than that in the model group, and the cell morphology was stretched.

[1037] The results showed that I-25, I-31, I-73, and I-80 could significantly improve cell survival under glucose-deficient conditions, and their efficacy was significantly better than that of empagliflozin, further demonstrating that ribose... and trehalose The cell-protective efficacy of the sugar structure is superior to that of the glucose structure.

[1038] Figure 1 The data corresponding to B is shown in Table 2.

[1039] Table 2. Cell viability (fold change) stained with crystal violet

[1040] Cell viability (number of changes) Control 1±0.01 DMSO <![CDATA[0.46±0.03 #### ]]> EMPA 1μM <![CDATA[0.59±0.04 * ]]> EMPA 10μM <![CDATA[0.59±0.02 * ]]> I-25 1μM <![CDATA[0.74±0.05 **** ]]> I-25 10μM <![CDATA[0.79±0.02 **** ]]> I-31 1μM <![CDATA[0.70±0.10 *** ]]> I-31 10μM <![CDATA[0.72±0.05 **** ]]> I-73 1μM <![CDATA[0.68±0.01 *** ]]> I-73 10μM <![CDATA[0.77±0.08 **** ]]> I-80 1μM <![CDATA[0.85±0.07 **** ]]> I-80 10μM <![CDATA[0.86±0.01 **** ]]>

[1041] Note: Survival rate of the control group is taken as 1. ####P<0.0001 vs Control group, *P<0.05,**P<0.01,***P<0.001,****P<0.0001 vs DMSO group.

[1042] Example 3: Protective effect of the preferred compound on cardiomyocyte hypertrophy

[1043] To further verify the protective effect of this type of compound against myocardial hypertrophy, we investigated the effect of I-80 on cardiomyocyte hypertrophy. We used a primary cardiomyocyte hypertrophy model induced by angiotensin II at a concentration of 10 μM, and treated the cells with I-80 at concentrations of 10 μM and 50 μM. Cell morphology and size were then observed by staining with pluvialisin.

[1044] The results showed that primary cardiomyocytes induced with 10 μM angiotensin II exhibited significant cell hypertrophy, and the surface area of ​​cardiomyocytes decreased significantly after administration of 10 μM and 50 μM I-80, respectively. Figure 2 ).

[1045] The results showed that I-80 could significantly improve angiotensin II-induced cardiomyocyte hypertrophy.

[1046] Figure 2 The corresponding data is shown in Table 3.

[1047] Table 3. Size of primary cardiomyocytes

[1048] Surface area (change factor) control 1.00±0.28 DMSO <![CDATA[1.97±0.63 ### <!-- 101 -->]]> I-80 10μM <![CDATA[1.29±0.60 * ]]> I-80 50μM <![CDATA[1.25±0.43 ** ]]>

[1049] Note: Cardiac cell size in the control group is taken as 1. ###P<0.001 vs Control group, *P<0.05, **P<0.01 vs DMSO group.

[1050] Example 4: Evaluation of the efficacy of the preferred compound in an isoproterenol-induced mouse model of heart failure.

[1051] Previous research by our group indicated that the effective dose of the lead compound empagliflozin was 30 mg / kg in both isoproterenol (ISO) and myocardial infarction (MI)-induced heart failure models. Therefore, to investigate whether the preferred compound improved the anti-heart failure efficacy in in vivo models, we selected a lower dose—5 mg / kg—for efficacy evaluation in an ISO-induced heart failure model. After model establishment and treatment, mice underwent behavioral training and testing to measure changes in their motor function. Figure 3 A). Simultaneously, small animal ultrasound was used to evaluate cardiac function indicators in mice, calculating key indicators closely related to cardiac function such as left ventricular ejection fraction (EF) and fractional shortening (FS) to comprehensively assess the improvement in cardiac function. After the experiment, mice were euthanized by cervical dislocation and dissected. The hearts of the mice were weighed, and their heart-to-body ratio was calculated to assess myocardial hypertrophy.

[1052] This experiment used 9-10 week old male C57BL / 6 mice to induce mouse modeling by simultaneously administering the compound and subcutaneously injecting ISO. The compound was administered at a dose of 5 mg / kg for 14 consecutive days, while the ISO injection dose was adjusted according to different stages of the experimental design: 40 mg / kg for the first two days, reduced to 20 mg / kg from days 3 to 7, and adjusted to 10 mg / kg in the last week. Behavioral training was conducted on days 15-17, echocardiography was performed on day 18, and dissection was performed on day 19.

[1053] Observation of mouse heart size and calculation of heart-to-body ratio revealed that the hearts of mice in the model group were significantly larger than those in the blank control group, indicating successful model establishment in this experiment. No cardiac hypertrophy was observed in the groups administered I-25 / I-31 / I-73 / I-80. Figure 3 B,C).

[1054] Compared with the model group, the preferred compounds significantly improved left ventricular systolic dysfunction, namely, significantly increased ejection fraction and fractional shortening. Figure 3 IJ), and improve the phenomenon of increased left ventricular end-diastolic / end-systolic volume caused by modeling ( Figure 3 KL). Subsequently, we further examined the levels of brain natriuretic peptide (BNP), a marker of heart failure, and lactate dehydrogenase (LDH), an auxiliary diagnostic indicator of heart disease, in mouse serum. Compared with the model group, all four preferred compounds significantly reduced the levels of LDH and BNP in mouse serum, with I-80 showing a more significant effect in reducing the serum heart failure marker BNP. Figure 3(E, F). After treatment, the mice's motor abilities, including running ability and instantaneous grip strength, were assessed. The preferred compounds were found to improve both running displacement and instantaneous grip strength, indicating that they improved the mice's overall motor abilities.

[1055] In summary, I-25 / I-31 / I-73 / I-80 exhibited superior efficacy at lower doses, including significant improvement in cardiac structure, cardiac function indicators, and exercise capacity in mice.

[1056] Figure 3 The data for C, 3E, 3F, 3G, 3H, 3I, 3J, 3K, and 3L are shown in Table 4.

[1057] Table 4. Pharmacological evaluation of the compounds in the ISO-induced heart failure model.

[1058]

[1059]

[1060] Note: ##P<0.01, ###P<0.001, ####P<0.0001 vs Control group, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs DMSO group.

[1061] Example 5: Efficacy evaluation of the preferred compound in a mouse model of renal failure induced by unilateral ureteral ligation.

[1062] Having initially established the good efficacy of the compound in a heart failure model, and recognizing that its effective dose is lower than that of the first-line drug empagliflozin, we further investigated its efficacy in a mouse renal failure model to verify its dual benefits to both the heart and kidneys. Based on our previous research in a unilateral ureteroscopic ligation (UUO) injury model, we found that empagliflozin has good efficacy at a dose of 20 mg / kg. To assess whether the effective dose of the preferred compound in the renal failure model is also lower than that of empagliflozin, we set up doses of 5 mg / kg and 20 mg / kg for the positive control and 5 mg / kg for the preferred compound to evaluate its efficacy in this renal failure model. The experiment used 9- to 10-week-old male mice, and the UUO model was established in the mice. Drug administration began on the third day after surgery and continued for two weeks, followed by dissection and tissue collection. Figure 4 A). By measuring serum creatinine and urea levels in mice, we found that empagliflozin at a dose of 5 mg / kg reduced creatinine levels in mice compared to the UUO model group, but less significantly than at a dose of 20 mg / kg. Notably, empagliflozin at a dose of 20 mg / kg had a comparable effect on reducing creatinine levels to the preferred compound at a dose of 5 mg / kg. Figure 4B). Empagliflozin did not significantly reduce urea levels at a dose of 5 mg / kg, but it was effective at a dose of 20 mg / kg, and the preferred compound reduced urea levels comparable to empagliflozin at 20 mg / kg. Figure 4 C).

[1063] To further observe the morphology of kidney tissue, we performed histological section hematologic staining on mouse kidney tissue. The results showed that the model group exhibited numerous vacuoles near the glomeruli (Model vs. Control). At a dose of EMPA-5 mg / kg, the tissue morphology was similar to that of the model group, showing no improvement. However, at doses of EMPA-20 mg / kg and the preferred compound at 5 mg / kg, a significant reduction and reduction in the size of vacuoles near the glomeruli was observed, indicating that it improved the kidney tissue structure. Figure 4 D). Furthermore, we stained kidney tissue sections with Sirius red to observe the degree of renal fibrosis. The results showed that large areas of deep red were observed in both the model group and the empagliflozin group at a dose of 5 mg / kg, indicating severe renal fibrosis; however, the deep red area at 20 mg / kg for empagliflozin and at 5 mg / kg for the preferred compound was significantly smaller than that in the model group. Figure 4 E). After quantitative analysis of the red fibrosis area, we found that the drugs in these three groups were equally effective in reducing the degree of fibrosis. Figure 4 F).

[1064] Therefore, the results of this experiment show that EMPA at a dose of 20 mg / kg and the four preferred compounds at a dose of 5 mg / kg can improve renal tissue fibrosis and have a significant anti-renal failure effect.

[1065] Figure 4 The data for B, 4C, and 4F are shown in Table 5.

[1066] Table 5. Pharmacodynamic evaluation of the compounds in the UUO-induced kidney injury model.

[1067]

[1068]

[1069] Note: ####P<0.0001 vs Control group, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs DMSO group.

[1070] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula I, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof. in, Rings A, R1, R2, R3, and R4 are respectively attached to different carbon atoms of the benzene ring to which they are connected; Ring A is a 5-7 membered heterocyclic alkyl group, substituted or unsubstituted, containing 1-3 heteroatoms selected from N, O or S. The substitution refers to being substituted by 1-4 substituents selected from the following group: hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, hydroxy-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, halo-C3-C8 cycloalkoxy, hydroxy-substituted C3-C8 cycloalkoxy, C6-C10 aryl, and a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S. R1, R2, R3, and R4 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, hydroxy-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, halo-C3-C8 cycloalkoxy, hydroxy-substituted C3-C8 cycloalkoxy, C6-C10 aryl, and 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S; R5, R6, R7, R8, and R9 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, hydroxyl-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, halo-C3-C8 cycloalkyl. Alkoxy, hydroxyl-substituted C3-C8 cycloalkoxy, 5-10 membered heterocyclic alkyl with 1-3 Ra-substituted or unsubstituted heteroatoms selected from N, O or S, 5-10 membered heterocyclic alkoxy with 1-3 Ra-substituted or unsubstituted heteroatoms selected from N, O or S, C6-C10 aryl with 1-3 Ra-substituted or unsubstituted aryl-(CH2) m -O-, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, with 1-3 Ra-substituted or unsubstituted groups; 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, with 1-3 Ra-substituted or unsubstituted groups. m -O-; Alternatively, in R5, R6, R7, R8, and R9, two adjacent atoms together with the carbon atoms they are attached to form a 5-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S; Each Ra is independently selected from the following group: hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl; Each m is independently selected from the following groups: 0, 1, 2, 3, 4.

2. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of: compounds of formula Ia, compounds of formula Ib, and compounds of formula Ic; R 11 R 12 R 13 Each is independently selected from the following group: hydroxyl, hydroxyl-substituted C1-C6 alkyl; R1, R2, R3, and R4 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and hydroxyl-substituted C1-C6 alkoxy. R5, R6, R7, R8, and R9 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, 5-10 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), 5-10 membered heterocyclic alkoxy containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), and C6-C10 aryl-(CH2) containing 1-3 Ra-substituted or unsubstituted. m -O-, 1-3 Ra-substituted or unsubstituted 5--10-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-; Alternatively, R7 and R8 together with the carbon atom they are attached to form a 5-7 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S; Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl; Each m is independently selected from the following groups: 0, 1, 2, 3.

3. The compound according to claim 1, characterized in that, The compound is a compound of formula Ib-1, wherein, R1 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl; R2 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl; R3 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl; R4 is selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy. R5 is selected from the following group: H, C1-C6 alkyl; R6 is selected from the following group: H, C1-C6 alkyl; R7 is selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, 5-6 membered heterocyclic alkoxy containing 1 O, and 1-3 Ra-substituted or unsubstituted C6-C10 aryl-(CH2). m -O-, 1-3 Ra-substituted or unsubstituted 5- or 6-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-; R8 is selected from the following group: H, hydroxyl, C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, or 5-6 membered heterocyclic alkoxy containing 1 O. R9 is selected from the following group: H, C1-C6 alkyl, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, or 5-6 membered heterocyclic alkoxy containing 1 O; Alternatively, R7 and R8 together with the carbon atoms they are attached to form 5-7 membered heterocyclic alkyl groups containing 1-3 O atoms; Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl; Each m is independently selected from the following groups: 0, 1, 2, 3.

4. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of: compounds of formula Id, compounds of formula Ie, and compounds of formula If; R 21 R 22 R 23 R 24 Each is independently selected from the following group: hydroxyl, C1-C6 alkyl; R1, R2, R3, and R4 are each independently selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy; R5, R6, R7, R8, and R9 are each independently selected from the following group: H, hydroxyl, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, halo-C3-C8 cycloalkyl, hydroxy-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, halo-C3-C8 cycloalkoxy, hydroxy-substituted C3-C8 cycloalkoxy, 5-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), 5-6 membered heterocyclic alkoxy containing 1-3 heteroatoms selected from N, O, or S (1-3 Ra-substituted or unsubstituted), and C6-C10 aryl-(CH2) containing 1-3 Ra-substituted or unsubstituted. m -O-, 1-3 Ra-substituted or unsubstituted 5- or 6-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-; Alternatively, R7 and R8 together with the carbon atoms they are attached to form 5-7 membered heterocyclic alkyl groups containing 1-3 O atoms; Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl; Each m is independently selected from the following groups: 0, 1, 2, 3.

5. The compound according to claim 1, characterized in that, The compound is a compound of formula Ie-1. R1 is selected from the following group: H, C1-C6 alkyl; R2 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl; R3 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl; R4 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy; R5 is selected from the following group: H, C1-C6 alkyl; R6 is selected from the following group: H, C1-C6 alkyl; R7 is selected from the following group: H, hydroxyl, C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy, C3-C8 cycloalkyl, hydroxyl-substituted C3-C8 cycloalkyl, C3-C8 cycloalkoxy, hydroxyl-substituted C3-C8 cycloalkoxy, 5-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, 5-6 membered heterocyclic alkoxy containing 1 O, and 1-3 Ra-substituted or unsubstituted C6-C10 aryl-(CH2). m -O-, 1-3 Ra-substituted or unsubstituted 5- or 6-membered heteroaryl-(CH2) containing 1-3 heteroatoms selected from N, O or S. m -O-; R8 is selected from the following group: H, hydroxyl, C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy; R9 is selected from the following group: H, C1-C6 alkyl; Alternatively, R7 and R8 together with the carbon atoms they are attached to form 5-7 membered heterocyclic alkyl groups containing 1-3 O atoms; Each Ra is independently selected from the following group: halogen, C1-C6 alkyl, halo-C1-C6 alkyl; Each m is independently selected from the following groups: 0, 1, 2, 3.

6. The compound according to claim 5, characterized in that, R1 is selected from the following group: H, C1-C6 alkyl; R2 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl; R3 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl; R4 is selected from the following group: H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy; R5 is selected from the following group: H, C1-C6 alkyl; R6 is selected from the following group: H, C1-C6 alkyl; R7 is a 5-6 membered heterocyclic alkoxy group containing one oxygen atom; R8 is selected from the following group: H, hydroxyl, C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, hydroxyl-substituted C1-C6 alkoxy; R9 is selected from the following group: H, C1-C6 alkyl.

7. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

8. A pharmaceutical composition, characterized in that, The compound of claim 1, or its tautomers, stereoisomers, or pharmaceutically acceptable salts, comprising a pharmaceutically acceptable carrier and a safe and effective amount thereof.

9. Use of the compound of claim 1, or its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, Used to prepare a medicament for the prevention and / or treatment of diseases selected from the group consisting of: heart failure-related diseases, kidney failure-related diseases, or combinations thereof.

10. The use as described in claim 9, characterized in that, The drug is used to prevent and / or treat diseases selected from the group consisting of: heart failure, myocardial infarction, coronary heart disease, myocardial fibrosis, myocardial hypertrophy, dilated cardiomyopathy, myocarditis, cardiotoxicosis, acute and chronic heart failure, chronic renal failure, renal failure, and cardiorenal syndrome.

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