Class of pyranose derivatives, preparation method therefor, and use thereof

Abstract

Disclosed are a class of pyranose derivatives represented by the following general formula I, stereoisomers, pharmaceutically acceptable salts, crystalline hydrates, or solvates thereof, a preparation method therefor, a pharmaceutical composition comprising this class of compounds, and a use thereof in central nervous system diseases and inflammatory diseases. The pyranose derivatives of the present invention have efficacy in significantly improving cell viability in an Aβ1-42-induced cell injury model, improving cell viability in a 6-hydroxydopamine-induced cell injury model, improving cell viability in an oxygen-glucose deprivation / reoxygenation cell injury model, and inhibiting levels of inflammatory factors in a lipopolysaccharide-induced cell inflammation model, and thus have favorable prospects for clinical applications.

Description

A class of pyranose derivatives, their preparation methods and uses

[0001] Related applications

[0002] This application claims priority to Chinese Patent Application No. 202510140168.0, entitled "A Class of Pyranose Derivatives and Their Preparation Methods and Uses", filed on February 8, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of medicinal chemistry, specifically relating to a class of pyranose derivatives, their preparation methods, pharmaceutical compositions, and their applications in central nervous system diseases and inflammatory diseases. Background Technology

[0004] Central nervous system diseases and inflammatory diseases have a significant impact on human health. Carbohydrates exist widely in the body in various forms, including monosaccharides, oligosaccharides, polysaccharides, and their conjugates, and some carbohydrate compounds possess broad pharmacological activities. Carbohydrate drugs play important biological roles in the treatment of central nervous system diseases, inflammatory diseases, diabetes, tumors, and autoimmune diseases.

[0005] Many carbohydrate compounds contain oxyglycosidic bonds, which are hydrolyzed by glycosidases in the body, affecting their stability. This significantly weakens the efficacy of compounds that are not monosaccharides or whose efficacy is solely due to the aglycone. While increasing the dosage or altering the administration route can improve efficacy in clinical applications, this does not fundamentally address the instability of oxyglycosidic bonds in vivo. In vivo, thioglycosides, C-glycosides, and N-glycosides exhibit greater chemical and enzymatic stability than oxyglycosides, indicating significant potential for non-oxyglycosidic compounds in medicinal chemistry. Pyranoses, as an important class of medicinal carbohydrates, can be modified through structural modification to improve the chemical and enzymatic instability of oxyglycosides, thereby enhancing their bioavailability and metabolic properties. Developing pyranose derivatives for the treatment and / or prevention of central nervous system and inflammatory diseases holds great promise and has significant social implications for addressing unmet clinical needs. Summary of the Invention

[0006] Purpose of the invention

[0007] To address the shortcomings of the prior art, one object of the present invention is to provide a class of pyranose derivatives or their stereoisomers, pharmaceutically acceptable salts, crystalline hydrates or solvates.

[0008] Another object of the present invention is to provide a method for preparing a class of pyranose derivatives or their stereoisomers, pharmaceutically acceptable salts, crystalline hydrates or solvates.

[0009] Another object of the present invention is to provide a pharmaceutical composition comprising a class of pyranose derivatives or stereoisomers thereof, a pharmaceutically acceptable salt, a crystalline hydrate or a solvate.

[0010] Another object of the present invention is to provide the use of a class of pyranose derivatives or stereoisomers thereof, pharmaceutically acceptable salts, crystalline hydrates or solvates, or said pharmaceutical compositions in the preparation of medicaments for treating and / or preventing diseases such as central nervous system diseases and inflammatory diseases.

[0011] Another object of the present invention is to provide a method for treating and / or preventing diseases such as central nervous system diseases and inflammatory diseases.

[0012] Technical solution

[0013] On the one hand, the present invention provides a class of pyranose derivatives represented by the following general formula I, their stereoisomers, pharmaceutically acceptable salts, crystalline hydrates or solvates.

[0014] in,

[0015] A is independently selected from CH2, NH, S, Se, CH2-CH2, NH-NH, SS, Se-Se, S(=O), S(=O)2, CH(R9), N(R 10 ), CH(R) 11 )-CH(R 12 ), N(R 13 )-N(R 14 ), O-CH2-CH2-O, S-CH2-CH2-S, O-CH(R 15 )-CH(R 16 )-O、S-CH(R 17 )-CH(R 18 )-S;

[0016] R1 and R8 are each selected independently.

[0017] R2, R3, R4, R5, R6, and R7 are each independently selected.

[0018] Alternatively, R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, R7 and R8 form substituted or unsubstituted 5-8 membered heterocyclic groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein "substituted" means selectively containing 1 to 3 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl; preferably, R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, R7 and R8 form substituted or unsubstituted 5-6 membered heterocyclic groups containing 1 or 2 heteroatoms selected from oxygen and nitrogen, wherein "substituted" means selectively containing 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl;

[0019] R9, R 10 R 11 R 12 R 13 R 14、 R 15 R 16、 R 17 R 18 Each of the following groups is independently selected from H and D: substituted or unsubstituted C1-C20 straight-chain or branched alkyl or alkanoyl groups; substituted or unsubstituted C1-C20 alkyl-OH groups; substituted or unsubstituted C2-C10 ester groups; substituted or unsubstituted C3-C20 cyclic alkyl or alkanoyl groups; substituted or unsubstituted 3-20 membered heterocyclic groups or heterocyclic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur; substituted or unsubstituted C6-C20 aryl or aromatic acyl groups; substituted or unsubstituted 5-20 membered heteroaryl or heteroaromatic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur; and substituted or unsubstituted C2-C20 straight-chain or branched alkenyl or alkenyl groups, wherein "substituted" refers to selectively containing 1 to 4 atoms selected from hydroxyl, nitro, C1-C10 alkyl, C1-C10 alkoxy, C... 1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, -NH2, C1-C10 alkylamido, C1-C10 alkyloxy, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C20 aryl group selected from hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituents of substituted or unsubstituted natural or non-natural amino acids;

[0020] R 19 R 20Each of the following groups is independently selected from H, D, substituted or unsubstituted C1-C20 straight-chain or branched alkyl groups, substituted or unsubstituted C2-C10 ester groups, substituted or unsubstituted C3-C20 cycloalkyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C14 aryl groups, substituted or unsubstituted 5-20 membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C20 straight-chain or branched alkenyl groups, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from hydroxyl, nitro, halogen, -NH2, and acetyl groups. C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, C1-C10 alkylamido, C1-C10 alkoxy, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C14 aryl group substituted with hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl;

[0021] Preferably, R 19 R 20 Each of the following groups is independently selected from H, D, substituted or unsubstituted C1-C6 straight-chain or branched alkyl groups, substituted or unsubstituted C2-C8 ester groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted 3-8 membered heterocyclic groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C6 straight-chain or branched alkenyl groups, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from hydroxyl, nitro, halogen, -NH2, acetyl C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkylamido, C1-C3 alkoxy, 3-6 member monocyclic heterocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 member heterospirocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-14 member heterocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C10 aryl groups selected from hydroxyl, nitro, -NH2, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl;

[0022] Preferably, R 19 Selected from H, C1-C6 straight-chain or branched alkyl, C1-C6 straight-chain or branched alkoxy;

[0023] More preferably, R 19Selected from H, C1-C3 straight-chain or branched alkyl groups;

[0024] Preferably, R 20 Selected from H, D, C1-C3 straight-chain or branched alkyl, C(=O)C1-C3 straight-chain or branched alkyl, substituted or unsubstituted C2-C8 ester group, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein “substituted” refers to selectively containing 1 to 4 substituents selected from hydroxyl, nitro, halogen, -NH2, acetyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkanoylamino, C1-C3 alkanoyloxy, and 3-6 membered monocyclic heterocyclic groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur;

[0025] More preferably, R 20 Selected from H, D, C1-C3 straight-chain or branched alkyl groups, C(=O)C1-C3 straight-chain or branched alkyl groups,

[0026] R 21 Selected from H, NH2, C1-C20 alkylamino,

[0027] R 26Selected from H and D, substituted or unsubstituted C1-C20 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C1-C20 alkyl-OH groups, substituted or unsubstituted C2-C10 ester groups, substituted or unsubstituted C3-C20 cycloalkyl or alkanoyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups or heterocyclic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C14 aryl or aromatic acyl groups, substituted or unsubstituted 5-20 membered heteroaryl or heteroaromatic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C20 straight-chain or branched alkenyl or enoyl groups, wherein "substituted" refers to selectively containing 1 to 4 atoms selected from hydroxyl, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C 10-Haloalkyl, C1-C10 hydroxyalkyl, halogen, -NH2, C1-C10 alkylamido, C1-C10 alkyloxy, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C14 aryl group selected from hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituents of substituted or unsubstituted natural or non-natural amino acids.

[0028] Preferably, R 26Selected from H and D, substituted or unsubstituted C1-C6 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C2-C10 ester groups, substituted or unsubstituted C3-C8 cycloalkyl or cycloalkanoyl groups, substituted or unsubstituted 3-10 membered heterocyclic groups or heterocyclic acyl groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C10 aryl or aromatic acyl groups, substituted or unsubstituted 5-10 membered heteroaryl or heteroaromatic acyl groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C2-C6 straight-chain or branched alkenyl or enoyl groups, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from hydroxyl, nitro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1- C3 hydroxyalkyl, halogen, -NH2, C1-C3 alkylamino, C1-C3 alkyloxy, 3-6 member monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 member heterospirocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 member heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C10 aryl group selected from hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 member monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituents of substituted or unsubstituted natural or non-natural amino acids.

[0029] Preferably, R 26 The group is selected from H and D, substituted or unsubstituted C1-C3 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C5-C6 cycloalkyl or cycloalkanoyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups or heterocyclic acyl groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted phenyl or phenyl acyl groups, substituted or unsubstituted 5-6 membered heteroaryl or heteroaryl groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C4 straight-chain or branched alkenyl or alkenyl groups, wherein "substituted" refers to selectively containing 1 to 3 substituents selected from hydroxyl, nitro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, halogen, -NH2, C1-C3 alkanoylamino, and C1-C3 alkanoyloxy.

[0030] More preferably, R 26 It can be H or D.

[0031] R 22 R 23 R 24 R 25Each group is independently selected from H and D, and includes substituted or unsubstituted C1-C20 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C1-C20 hydroxyalkyl groups, C1-C20 alkylcarbonyl groups, substituted or unsubstituted C2-C10 ester groups, substituted or unsubstituted C3-C20 cyclic alkyl or alkanoyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups or heterocyclic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C14 aryl or aromatic acyl groups, substituted or unsubstituted 5-20 membered heteroaryl or heteroaromatic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C20 straight-chain or branched alkenyl or alkenyl groups. The substituted substituents are selected from the group from which "substituted" refers to selectively containing 1 to 4 groups selected from hydroxyl, nitro, C1-C10 alkyl, C2-C10 alkyl, C3-C20 alkyl, C4-C1 ... 1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, -NH2, C1-C10 alkanoylamino, C1-C10 alkanoyloxy, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C14 aryl group selected from hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, substituents of substituted or unsubstituted natural or non-natural amino acids;

[0032] Preferably, R 22 R 23 R 24 R 25 Each group is independently selected from H and D, and includes substituted or unsubstituted C1-C6 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C1-C6 hydroxyalkyl groups, C1-C6 alkylcarbonyl groups, substituted or unsubstituted C2-C6 ester groups, substituted or unsubstituted C3-C10 cyclic alkyl or alkanoyl groups, substituted or unsubstituted 3-10 membered heterocyclic groups or heterocyclic acyl groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C10 aryl or aromatic acyl groups, and substituted or unsubstituted groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. The heteroatom has a 5-10 membered heteroaryl or heteroaryl group, a substituted or unsubstituted C2-C6 straight-chain or branched alkenyl or enoyl group, wherein the substituted substituent is selected from the group containing 1 to 3 substituents selected from hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, -NH2, C1-C6 alkanoylamino, C1-C6 alkanoyloxy, or a 3-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur.

[0033] Preferably, R 22 R 23 R 24 R 25 Each group is independently selected from H and D, and includes substituted or unsubstituted C1-C4 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C1-C4 hydroxyalkyl groups, C1-C4 alkylcarbonyl groups, substituted or unsubstituted C2-C6 ester groups, substituted or unsubstituted C3-C6 cyclic alkyl or alkanoyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups or heterocyclic acyl groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted phenyl or phenylacyl groups, and substituted or unsubstituted heteroatoms containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur. The 5-6 membered heteroaryl or heteroaryl group, substituted or unsubstituted C2-C4 straight-chain or branched alkenyl or enoyl group, wherein the substituted substituent is selected from the group containing 1 to 3 substituents selected from hydroxyl, nitro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, halogen, -NH2, C1-C3 alkanoylamino, C1-C3 alkanoyloxy, or 5-6 membered monocyclic heterocyclic groups containing 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;

[0034] More preferably, R 22 R 23 R 24 R 25 Each is independently selected from H, D, C1-C3 alkyl, hydroxyl-substituted C1-C3 alkyl, C1-C3 alkyl carbonyl,

[0035] Preferably, A is CH2, NH, S, Se, CH2-CH2, NH-NH, SS, or Se-Se;

[0036] More preferably, A is CH2, NH, S, or Se;

[0037] Preferably, the pyranose derivative represented by general formula I, its stereoisomers, pharmaceutically acceptable salts, crystalline hydrates, or solvates can be represented by general formula I-1, general formula I-2, general formula I-3, or general formula I-4:

[0038] The definitions of A, R1, R2, R3, R4, R5, R6, R7, and R8 are the same as those in general formula I.

[0039] In some embodiments, the pyranose derivative represented by general formula I, its stereoisomers, pharmaceutically acceptable salts, crystalline hydrates, or solvates are selected from compounds having the following structures:

[0040] According to another aspect of the invention, the invention also provides a method for preparing pyranose derivatives, their stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates represented by general formula I, general formula I-1, general formula I-2, general formula I-3, or general formula I-4, which can be carried out with reference to known synthetic methods for similar compounds in the prior art, for example, by methods 1 to 4, wherein the glycosidic bonds include four configurations: α / α, α / β, β / α, and β / β, and all starting materials used are commercially available.

[0041] Method 1:

[0042] Using a1-1 as raw material, the product a1 is obtained by reacting it with ammonium carbonate and ammonia.

[0043] Among them, R1, R2, R3 and R4 are defined as in general formula I;

[0044] Method 2:

[0045] Using a2-1 as raw material, a2-3 is obtained through iodination and selenoglycosylation, and then the glycoselenoglycoside product a2 is obtained through hydrolysis, debenzylation or hydroxyl protection.

[0046] Among them, R1, R2, R3 and R4 are defined as in general formula I;

[0047] Method 3:

[0048] Using a3-1 as a raw material, a mercapto intermediate a3-4 is obtained by reacting with acetic anhydride and thioacetic acid, followed by a deacetylation reaction. A3-4 is then reacted with a3-5 under acidic conditions such as boron trifluoride ether and trimethylsilyl trifluoromethanesulfonate, or under weakly alkaline conditions such as silver oxide, silver carbonate, cadmium carbonate, and cesium carbonate, to obtain a3-6. Finally, a glycosaminoglycan product a3 is obtained through hydrolysis, debenzylation, or dehydroxylation protection.

[0049] Among them, R1, R2, R3, R4, R5, R6, R7 and R8 are defined in the same way as in general formula I;

[0050] X is selected from Cl, Br, and I;

[0051] Method 4:

[0052] Using a4-1 as a raw material, intermediate a4-2 is obtained by reacting with thiourea. Under sodium bisulfite conditions, the sulfur protecting group is selectively removed to obtain intermediate a4-3. Under acidic conditions such as boron trifluoride ether and trimethylsilyl trifluoromethanesulfonate, or under weakly alkaline conditions such as silver oxide, silver carbonate, cadmium carbonate, and cesium carbonate, a4-6 is obtained by reacting with a4-5. Finally, the glycosaminoglycan product a4 is obtained by hydrolysis, debenzylation, or dehydroxylation.

[0053] Among them, R1, R2, R3, R4, R5, R6, R7 and R8 are defined in the same way as in general formula I;

[0054] X is selected from Cl, Br, and I.

[0055] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a pyranose derivative represented by formula I, formula I-1, formula I-2, formula I-3 or formula I-4, its stereoisomer, a pharmaceutically acceptable salt, hydrated crystal or solvate, and optionally one or more pharmaceutical excipients.

[0056] Another aspect of the present invention provides the use of pyranose derivatives, stereoisomers thereof, pharmaceutically acceptable salts, crystalline hydrates or solvates, or said pharmaceutical compositions represented by general formula I, general formula I-1, general formula I-2, general formula I-3 or general formula I-4 in the preparation of medicaments for the treatment and / or prevention of diseases of the central nervous system and inflammatory diseases.

[0057] Another aspect of the present invention provides a method for treating and / or preventing central nervous system diseases and inflammatory diseases, the method comprising administering to a subject in need a therapeutically effective amount of a pyranose derivative, stereoisomer thereof, pharmaceutically acceptable salt, crystalline hydrate or solvate, or said pharmaceutical composition represented by general formula I, general formula I-1, general formula I-2, general formula I-3 or general formula I-4.

[0058] The central nervous system diseases are selected from at least one of the following: Alzheimer's disease, frontotemporal dementia, Lewy body dementia, Parkinson's syndrome, amyotrophic lateral sclerosis, epilepsy, Huntington's disease, cerebellar ataxia, multiple sclerosis, spinal muscular atrophy, depression, anxiety disorder, mania, schizophrenia, autism, stroke, cerebral hemorrhage, cerebral embolism, cerebral infarction, cerebral arteriosclerosis, vascular dementia, and diseases caused by inflammation; the inflammatory diseases are selected from at least one of the following: multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, ankylosing spondylitis, dermatomyositis, scleroderma, pemphigus, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and inflammatory bowel disease. Beneficial effects

[0059] This invention provides a class of pyranose derivatives with novel structures, which have the following beneficial effects:

[0060] 1. The compound described in this invention has the efficacy of significantly enhancing cell viability in an Aβ1-42-induced cell damage model.

[0061] 2. The compound described in this invention has the efficacy of significantly enhancing cell viability in a 6-hydroxydopamine-induced cell damage model.

[0062] 3. The compound described in this invention has the pharmacological effect of significantly enhancing cell viability in an oxygen-glucose deprivation / reoxygenation cell injury model.

[0063] 4. The compound described in this invention has a significant inhibitory effect on the levels of lipopolysaccharide-induced cellular inflammatory factors.

[0064] 5. The compounds described in this invention are not only highly effective, but also have the characteristics of being effective orally with few toxic side effects. They can be used to treat and / or prevent central nervous system diseases and inflammatory diseases, such as Alzheimer's disease, depression, anxiety, mania, stroke, cerebral thrombosis, autoimmune diseases, or various inflammatory diseases caused by inflammatory factors, and have good clinical application prospects. Detailed Implementation

[0065] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0066] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0067] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0068] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0069] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0070] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0071] When listing a range of values, the aim is to include every value within that range and its subranges. For example, "C 1–6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 .

[0072] definition

[0073] The term "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1-20 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”).1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., a halogen, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-10 Alkyl (e.g., unsubstituted C) 1-6 Alkyl group, such as -CH3). In some embodiments, the alkyl group is a substituted C. 1-10 Alkyl (e.g., substituted C) 1-6 Alkyl groups, such as -CF3).

[0074] "Alkenyl" refers to a group consisting of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds. 2-20 Alkenyl group (“C10”). In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C10”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group).2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-10 Alkenyl. In some embodiments, the alkenyl group is a substituted C. 2-10 Alkenyl. In alkenyl groups, the C=C double bond without a specified stereochemistry (e.g., -CH=CHCH3 or) can be an (E)- or (Z)- double bond.

[0075] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 20 ring carbon atoms ("C"). 3-20 The cycloalkyl group comprises a non-aromatic cycloalkyl group with 3 to 8 carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (“C”). 3-7 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 Cycloalkyl). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example C... 3-8 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Exemplary C 3-10 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-8 Cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9)10 ), spiro[4.5]decyl(C 10 As illustrated in the foregoing examples, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused ring, bridged ring, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or may be partially unsaturated. “Cycloalkyl” also includes ring systems in which the carbon ring as defined above is fused with one or more aryl or heteroaryl groups at the junction point on the carbon ring, and in this case, the carbon number continues to refer to the number of carbons in the carbon ring system. Unless otherwise stated, each instance of a cycloalkyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C… 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-10 Cycloalkyl.

[0076] "Heterocyclic group" or "heterocyclic" refers to a group having a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the linkage of a heterocycle as defined above with one or more cycloalkyl groups is on the cycloalkyl or heterocycle, or ring systems in which a heterocycle as defined above with one or more aryl or heteroaryl groups is on the heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise stated, each instance of the heterocyclic group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted by one or more substituents (“substituted heterocyclic group”). In some embodiments, the heterocyclic group is an unsubstituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3- to 10-membered heterocyclic group.

[0077] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0078] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C"). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the groups or linkages are on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise stated, each instance of an aryl is optionally independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0079] "Aryl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl group that is optionally substituted with an aryl group. In some embodiments, the aryl group is an optionally substituted benzyl group. In some embodiments, the aryl group is a benzyl group. In some embodiments, the aryl group is an optionally substituted phenethyl group. In some embodiments, the aryl group is a phenethyl group.

[0080] "Heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) containing a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linking point is on an aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have its linking point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0081] In some embodiments, the heteroaryl group is a 5-10-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6-membered heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of the heteroaryl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted by one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0082] "Heteroaryl" is a subset of alkyl and heteroaryl, and refers to an alkyl group that is optionally substituted by a heteroaryl group.

[0083] "Unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. The term "partially unsaturated" ring systems also aims to encompass rings with multiple unsaturated sites, but not to include aromatic groups (e.g., aryl or heteroaryl). Similarly, "saturated" means a group containing no double or triple bonds, i.e., entirely composed of single bonds.

[0084] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0085] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts, wherein the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and the organic acids include, for example, benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, etc. Malonic acid, propionic acid, oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, fumaric acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucohepose, gluconic acid, ethanesulfonic acid, lactic acid, lactose, dodecyl sulfonic acid, dihydroxynaphthyl acid, salicylic acid, succinic acid, phosphorous acid, etc.; acetic acid, edetate, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid, and similar acids; also including salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain specific compounds of this invention contain basic and acidic functional groups, thus they can be converted into any base or acid addition salt. The parent form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0086] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0087] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups.

[0088] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0089] Generally, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is substituted by a permitted substituent (e.g., the substitution results in a stable compound, such as one that does not spontaneously transform, for example, through rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, the "substituted" group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent at each position may be the same or different. Typically, when substituted, the optionally substituted group herein may be substituted by 1 to 5 substituents. The substituent may be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent, or a sulfur atom substituent, if applicable.

[0090] In the pharmaceutical compositions of the present invention, various pharmaceutical formulations may be selected according to the therapeutic purpose, including but not limited to: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, and injections (e.g., lipid-soluble or oil-soluble injections).

[0091] In addition, unless otherwise stated, the reagents and solvents disclosed below were purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., Shanghai Titan Technology Co., Ltd., Shanghai Yilaide Biotechnology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd., Anhui Zesheng Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd. and Shanghai Suyuan Chemical Co., Ltd. 1 ¹H NMR was performed using Bruker's 400MHz and 500MHz instruments; ESI-MS was performed using Waters' UPLC-MS; and pharmacological activity assays were performed using TECAN's Spark microplate reader and Roche's LC96 PCR instrument.

[0092] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0093] Example 1: Synthesis of Compound 1

[0094] Take 1-1 (1.0 g, 5.55 mmol), add ethanol (5 mL), ammonium carbonate (640 mg, 6.66 mmol), and ammonia (5 mL), and react at 80 °C for 16 h. After concentrating the reaction solution, add pyridine (10 mL), and under ice bath conditions, add acetic anhydride (5 mL), and allow to return to room temperature for 12 h. Add 1 N hydrochloric acid, extract with dichloromethane, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 1-2 (440 mg, yield 22%). ESI-MS m / z 678.5 (M+H) + .

[0095] Take 1-2 (140 mg, 0.20 mmol), add methanol (1 mL), and under ice bath conditions, add 0.4 mL of 2.5 N sodium hydroxide aqueous solution, and continue the reaction for 1 h. Adjust the pH to weakly acidic by adding 1 N hydrochloric acid, concentrate, and precipitate by reversed-phase silica gel column chromatography to obtain 1 (48 mg, yield 70%). ESI-MS m / z 342.2 (M+H) + .

[0096] Example 2: Synthesis of Compound 32

[0097] Take 32-1 (500 mg, 1.28 mmol), add dichloromethane (5 mL), and under ice bath conditions, add iodine (420 mg, 1.65 mmol) and triethylsilane (0.3 mL, 1.89 mmol). Heat to 40 °C and react for 10 min. Add saturated NaHCO3 (1 mL) and 10% Na2S2O3 (1 mL), extract with dichloromethane, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 32-2 (440 mg, 75% yield). 1 H NMR (400MHz, CDCl3) δ6.99(d,J=4.3Hz,1H),5.46(t,J=9.6Hz,1H),5.20-5.15(m,1H),4.33(dd,J=12.7,4.2Hz,1H),4.20(dd,J=9 .9,4.4Hz,1H),4.11(dd,J=12.7,2.2Hz,1H),4.05(ddd,J=10.3,4.2,2.2Hz,1H),2.09(d,J=4.7Hz,6H),2.05(s,3H),2.02(s,3H).

[0098] Selenium (60 mg, 0.76 mmol) was added to DMF (2 mL), and sodium borohydride (86 mg, 2.27 mmol) was added at room temperature. After reacting for 40 min, triethyl phosphite (0.2 mL, 1.16 mmol) and 32-2 (300 mg, 0.66 mmol) were added, and the reaction was continued for 1 h. Glacial acetic acid (1 mL) and saturated Na2CO3 (1 mL) were added, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 32-3 (142 mg, yield 58%). 1 H NMR (400MHz, CDCl3) δ5.22-5.15(m,4H),5.11(t,J=9.4Hz,2H),5.03(d,J=9.6Hz,2H),4.25(dd,J=12.4,4.8Hz,2H),4.1 6(dd,J=12.4,2.3Hz,2H),3.68(ddd,J=10.1,4.8,2.3Hz,2H),2.11(s,6H),2.03(d,J=4.4Hz,12H),2.00(s,6H).ESI-MS m / z 765.5(M+Na) + .

[0099] Take 32-3 (50 mg, 0.07 mmol), add methanol (1 mL), and under ice bath conditions, add 2.5 N sodium hydroxide aqueous solution (0.3 mL), and continue the reaction for 1 h. Add 1 N hydrochloric acid to adjust the pH to weakly acidic, concentrate, and precipitate by reversed-phase silica gel column chromatography to obtain 32 (25 mg, yield 92%).1 H NMR (400MHz, DMSO-d6) δ5.11(d,J=17.9Hz,4H),5.00(s,2H),4.89-4.84(m,2H),4.51(s,2H),3.63(d,J=11. 8Hz,2H),3.42(dd,J=11.8,5.7Hz,2H),3.18–3.12(m,4H),3.10(d,J=7.4Hz,2H),3.08-3.04(m,2H).ESI-MS m / z 429.2(M+Na) + .

[0100] Example 3: Synthesis of Compound 59

[0101] Take 59-1 (5.0 g, 9.24 mmol), add dichloromethane (50 mL), and under ice bath conditions, add acetic anhydride (2.8 g, 27.5 mmol) and 4-dimethylaminopyridine (3.6 g, 29.5 mmol). React at room temperature for 3 h. After concentrating the reaction solution, add ethyl acetate-1N hydrochloric acid aqueous solution to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 59-2 (5.1 g, 94% yield). ESI-MS m / z 583.5 (M+H) + .

[0102] Take 59-2 (5.0 g, 8.58 mmol), add dichloromethane (50 mL), and under ice bath conditions, add thioacetic acid (2.0 g, 26.3 mmol) and trimethylsilyl trifluoromethanesulfonate (2.3 g, 10.4 mmol). React at room temperature for 10 h. After concentrating the reaction solution, wash with saturated NaHCO3 aqueous solution, separate the layers with 1N hydrochloric acid aqueous solution, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 59-3 (3.2 g, yield 63%). 1 H NMR (400MHz, CDCl3) δ7.38-7.24(m,18H),7.15-7.07(m,2H),6.25(d,J=5.3Hz,1H),4.96(d,J=10.8Hz,1H),4.79(dd,J=17.2 ,10.7Hz,2H),4.68-4.56(m,3H),4.47(dd,J=11.3,8.6Hz,2H),3.92(dd,J=9.6,5.3Hz,1H),3.79-3.55(m,5H),2.42(s,3H).

[0103] Take 59-3 (3.0 g, 5.00 mmol), add N,N-dimethylformamide (30 mL), dithiothreitol (1.2 g, 7.79 mmol), and triethylamine (103 mg, 1.02 mmol), and react at room temperature for 10 h. Add methyl tert-butyl ether (30 mL) and water (150 mL), stir, and allow to stand for separation. Add 1N hydrochloric acid aqueous solution to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 59-4 (1.1 g, yield 39%). 1 H NMR (400MHz, CDCl3) δ7.46-7.22(m,18H),7.18-7.07(m,2H),5.75(t,J=4.9Hz,1H),4.94(d,J=10.8Hz,1H),4.85-4.69(m,3H),4.66- 4.56(m,2H),4.48(d,J=11.2Hz,2H),4.21(d,J=10.1Hz,1H),3.91-3.70(m,3H),3.64(dd,J=15.5,7.2Hz,2H),1.89(d,J=4.7Hz,1H).

[0104] Take 59-4 (1.0 g, 1.80 mmol), add acetonitrile (10 mL), 59-5 (1.0 g, 2.43 mmol), and cesium carbonate (1.1 g, 3.37 mmol), and react at room temperature for 10 h. Add ethyl acetate (25 mL) and water (8 mL), stir, and allow to stand for separation. Add 1N hydrochloric acid aqueous solution to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 59-6 (0.9 g, yield 57%). 1 H NMR (400MHz, DMSO) δ7.42-7.26(m,18H),7.17(dd,J=7.4,1.9Hz,2H),5.96(dd,J=13.4,4.0Hz,1H),4.96(ddd,J=22.0,15.2,9 .8Hz,4H),4.82-4.64(m,5H),4.59-4.52(m,2H),4.04-3.92(m,4H),3.66(ddd,J=53.2,18.7,12.9Hz,6H),1.98-1.83(m,12H).

[0105] Take 59-6 (800 mg, 0.90 mmol), add methanol (5 mL) and sodium methoxide (52 mg, 0.96 mmol), and react at room temperature for 2 h. Add water (8 mL), stir, let stand, filter, add methanol to recrystallize, filter, add ethyl acetate and petroleum ether to recrystallize again, filter and dry to obtain 59-7 (450 mg, yield 69%). 1 H NMR (400MHz, MeOD) δ7.52-7.21(m,18H),7.19-7.11(m,2H),5.94(d,J=5.4Hz,1H),4. 91(s,2H),4.84(d,J=11.4Hz,1H),4.74(dd,J=19.0,11.0Hz,2H),4.58(d,J=13.3Hz, 2H),4.51(dd,J=11.7,5.2Hz,2H),4.44(d,J=9.6Hz,1H),4.36-4.29(m,1H),3.86-3. 79(m,2H),3.69(ddd,J=17.1,14.1,7.0Hz,4H),3.53-3.41(m,2H),3.40-3.35(m,2H).

[0106] Take 59-7 (400 mg, 0.56 mmol), add methanol (8 mL), tetrahydrofuran (2 mL), acetic acid (62 mg), and 10% wet palladium on carbon (820 mg), replace with a hydrogen balloon, and react at room temperature for 20 h. Filter, concentrate, add ethyl acetate and water to separate the layers, and freeze-dry the aqueous phase to give compound 59 (120 mg, yield 60%). 1 H NMR (400MHz, MeOD) δ5.75-5.73(m,1H),5.65(d,J=5.5Hz,1H),4.39(d,J=9.7Hz,1H),4.18-4.09(m,1H),3.87(dd,J=21.8,10.9Hz, 2H),3.70(dd,J=9.7,5.5Hz,1H),3.62(dd,J=11.8,6.3Hz,2H),3.55-3.36(m,3H),3.34(d,J=8.9Hz,2H),3.25-3.19(m,1H).ESI-MS m / z 376.3(M+NH4) + .

[0107] Example 4: Synthesis of Compound 60

[0108] Take 60-1 (5.0 g, 8.58 mmol), add dichloromethane (50 mL), and under ice bath conditions, add phosphorus pentachloride (3.0 g, 14.4 mmol) and boron trifluoride diethyl ether (150 mg, 1.06 mmol). React under ice bath conditions for 1 h. After the reaction mixture is separated by adding 1N hydrochloric acid aqueous solution, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 60-2 (2.5 g, yield 81%). 1 H NMR (400MHz, CDCl3) δ5.35-5.28(m,1H),5.22-5.10(m,3H),4.27(dd,J=12.6,4.8Hz,1H),4.17( dd,J=12.5,2.2Hz,1H),3.86-3.78(m,1H),2.11(s,3H),2.09(s,3H),2.04(s,3H),2.02(s,3H).

[0109] Take 59-4 (2.5 g, 4.49 mmol), add acetonitrile (50 mL), 60-2 (2.5 g, 6.81 mmol), and cesium carbonate (2.5 g, 7.67 mmol), and react at room temperature for 10 h. Concentrate the reaction solution, add ethyl acetate and 1N hydrochloric acid aqueous solution to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 60-3 (1.3 g, 33% yield). ESI-MS m / z 909.1 (M+Na) + .

[0110] Take 60-3 (1.2 g, 1.35 mmol), add methanol (15 mL) and sodium methoxide (90 mg, 1.67 mmol), and react at room temperature for 2 h. Concentrate the reaction solution, add ethyl acetate and 1N hydrochloric acid aqueous solution to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 60-4 (180 mg, yield 19%). 1 H NMR(400MHz,MeOD)δ7.30(dt,J=19.2,7.6Hz,18H),7.16(d,J=7.4Hz,2H),5.80(d,J=4.9Hz,1H),5.48(d,J=5.4Hz,1H),4.85-4.68(m,4H),4.5 9-4.48(m,4H),4.26(d,J=9.4Hz,1H),4.09(d,J=9.1Hz,1H),3.83(dd,J=11.9,7.1Hz,3H),3.70(dt,J=18.7,8.0Hz,5H),3.55(d,J=9.3Hz,2H).

[0111] Take 60-4 (180 mg, 0.25 mmol), add methanol (5 mL), tetrahydrofuran (1 mL), acetic acid (30 mg), and 10% wet palladium on carbon (500 mg), replace with a hydrogen balloon, and react at room temperature for 20 h. Filter, concentrate, add ethyl acetate and water to separate the layers, and freeze-dry the aqueous phase to give compound 60 (62 mg, yield 69%). 1 H NMR(400MHz,MeOD)δ5.47(d,J=5.4Hz,2H),4.03(dd,J=8.3,5.6Hz,2H),3.84(d,J=11.8Hz,2 H),3.76-3.71(m,2H),3.71–3.66(m,2H),3.55(dd,J=15.3,5.9Hz,2H),3.31(s,2H).ESI-MS m / z 381.1(M+Na) + .

[0112] Example 5: Synthesis of Compound 61

[0113] Take 59-5 (5 g, 12.1 mmol), acetone (50 mL), and thiourea (1.9 g), and react at 60 °C for 6 h. Cool to room temperature, filter, and dry the filter cake to obtain 61-1 (5 g). ESI-MS m / z 407.2 (M+H) + .

[0114] Take 61-1 (5 g, 12.3 mmol), add dichloromethane (50 mL), water (50 mL), and sodium bisulfite (5.1 g, 49 mmol), and heat to 40 °C and react overnight. After the reaction solution cools to room temperature, separate the liquids, dry the organic phase with saturated sodium chloride and anhydrous sodium sulfate, and concentrate to obtain a white solid 61-2 (5 g). 1 H NMR (400MHz, CDCl3) δ5.20-5.07(m,2H),4.97(t,J=9.5Hz,1H),4.84(dd,J=10.0,4.1Hz,1H),4.55(t,J=9.9Hz,1H),4.25(dd,J =12.5,4.8Hz,1H),4.16-4.10(m,1H),3.75-3.69(m,1H),2.31(d,J=10.0Hz,1H),2.12-2.07(m,9H),2.07-1.98(m,6H).ESI-MS m / z 382.1(M+NH4) + .

[0115] Take 0.8 g (2.19 mmol) of 61-2, add acetonitrile (20 mL), 59-5 (1.4 g, 3.4 mmol), and cesium carbonate (1.0 g), and react overnight at room temperature. Add ethyl acetate and water, separate the layers, and wash the organic phase successively with 1 N hydrochloric acid, sodium bicarbonate, saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and precipitate by silica gel column chromatography to obtain 0.4 g (26.3% yield) of 61-3. 1 H NMR (400MHz, CDCl3) δ5.22(t,J=9.3Hz,2H),5.14–4.99(m,4H),4.82(d,J=10.1Hz,2H),4.27( dd,J=12.4,4.9Hz,2H),4.19-4.11(m,2H),3.69(dd,J=10.0,2.5Hz,2H),2.11-2.00(m,24H).

[0116] Take 0.3 g (0.43 mmol) of compound 61-3, add methanol (5 mL) and triethylamine (0.3 g), and heat to 60 °C and react overnight. Concentrate the reaction solution under reduced pressure, add ethanol and ethyl acetate to crystallize, filter the solid, add water (5 mL), and freeze-dry to give compound 61 (0.12 g, yield 78%). 1 H NMR(400MHz,D2O)δ4.73(d,J=10.0Hz,2H),3.81(dd,J=12.5,2.2Hz,2H),3.61(dd,J=12.5,5.9Hz,2 H),3.45-3.37(m,2H),3.38(dd,J=6.0,2.1Hz,2H),3.34-3.30(m,2H),3.27(d,J=9.3Hz,2H).ESI-MS m / z 381.2(M+Na) +

[0117] Example 6: Synthesis of Compound 62

[0118] Take 3.5 g (8.06 mmol) of 62-1, add 35 mL of dichloromethane and acetic anhydride, and add 26 mL of 33% HBr acetic acid solution under ice bath. React for 2 h under ice bath. After the reaction mixture is separated, add dichloromethane and saturated NaHCO3 aqueous solution to separate the layers. Wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 1.7 g (46% yield) of 62-2. 1H NMR (400MHz, CDCl3) δ6.62(d,J=3.9Hz,1H),5.15(t,J=9.9Hz,1H),4.73(dd,J=9.7,3.9Hz,1H),4.28(dd,J=12.6,4.3Hz,1H),4.21-4.07( m,4H),3.96(d,J=9.5Hz,1H),3.90(dd,J=11.0,4.2Hz,1H),3.81(dd,J=10.8,5.5Hz,1H),2.15(s,3H),2.12(s,3H),2.09(d,J=5.3Hz,6H).

[0119] Take 62-2 (1.5 g, 3.30 mmol), add acetonitrile (15 mL), 59-4 (1.5 g, 2.69 mmol), and cesium carbonate (1.6 g, 4.91 mmol), and react at room temperature for 10 h. Concentrate the reaction solution, add ethyl acetate and 1N hydrochloric acid aqueous solution to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 62-3 (1.0 g, yield 33%). 1 H NMR (400MHz, CDCl3) δ7.37-7.21(m,20H),5.75(d,J=4.8Hz,1H),5.08(ddd,J=12.8,9.0,4.2Hz,2H),4. 93-4.39(m,10H),4.18-4.07(m,5H),3.85-3.65(m,6H),3.59-3.50(m,2H),2.10-2.03(m,12H).ESI-MS m / z 948.4[M+NH4] + .

[0120] Take 62-3 (1.0 g, 1.07 mmol), add methanol (10 mL) and sodium methoxide (70 mg, 1.30 mmol), and react at room temperature for 2 h. Concentrate the reaction solution, add methanol and water to make a slurry, filter, and dry to obtain 62-4 (530 mg, yield 65%). 1H NMR (400MHz, CDCl3) δ7.41-7.22 (m, 19H), 7.12 (dd, J=6.4, 2.8Hz, 2H), 5.71 (d, J= 5.4Hz,1H),4.93(d,J=10.8Hz,1H),4.82-4.68(m,3H),4.62(d,J=11.6Hz,1H),4. 52(q,J=12.5Hz,2H),4.39(dd,J=19.3,8.9Hz,3H),4.27(d,J=4.7Hz,1H),3.91-3 .61(m,11H),3.55(t,J=9.2Hz,1H),3.50-3.42(m,1H),3.41-3.22(m,3H).ESI-MS m / z 780.4 [M+NH4] + .

[0121] Take 62-4 (300 mg, 0.39 mmol), add methanol (3 mL), tetrahydrofuran (1 mL), acetic acid (30 mg), and 10% wet palladium on carbon (650 mg), replace with a hydrogen balloon, and react at room temperature for 20 h. Filter, concentrate, add dichloromethane and water to separate the layers, and freeze-dry the aqueous phase to give compound 62 (112 mg, yield 71%). 1 H NMR(400MHz,MeOD)δ5.64(d,J=5.5Hz,1H),4.40(d,J=9.8Hz,1H),4.16-4.10(m,1H),3.95(dd,J=10.2,5.4Hz,1H),3.91-3.81 (m,3H),3.73-3.59(m,6H),3.50(ddd,J=33.5,20.3,12.1Hz,3H),3.35(t,J=5.3Hz,2H),3.21(dd,J=18.9,9.6Hz,2H).ESI-MS m / z 425.1(M+Na) + .

[0122] Example 7: Synthesis of Compound 70

[0123] Following the product synthesis method of Example 5, target compound 70 was synthesized using 70-1 as the starting material. 1H NMR(400MHz,MeOD)δ5.64(d,J=5.5Hz,1H),4.39(d,J=9.8Hz,1H),4.14(ddd,J =9.5,8.6,5.0Hz,1H),3.89(dd,J=11.6,2.2Hz,1H),3.85-3.80(m,1H),3.70( dd,J=9.8,5.5Hz,1H),3.66-3.60(m,5H),3.54-3.44(m,3H),3.33(d,J=1.1Hz ,1H),3.22(dd,J=10.0,8.9Hz,1H),3.05(ddd,J=8.8,5.4,3.4Hz,1H).ESI-MS m / z 395.1(M+Na) + .

[0124] Example 8: Synthesis of Compound 76

[0125] Take 76-1 (1.0 g, 2.48 mmol), add acetic anhydride (6.5 mL), acetic acid (3.5 mL), and phosphorus tribromide (1.0 g, 3.69 mmol) under ice-water bath. Heat to 100 °C and react for 3 h. Cool to room temperature, pour the reaction mixture into a saturated sodium bicarbonate aqueous solution, add ethyl acetate to separate the layers, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and concentrate to obtain crude product 76-2. Then, following the product synthesis method in Example 5, synthesize the target compound 76. 1 H NMR(400MHz,MeOD)δ5.65(d,J=5.5Hz,1H),4.35(d,J=9.7Hz,1H),4.11-4.05(m,1H),4.02(dd,J=6.6,1.9Hz,1H),3.90-3.84(m ,1H),3.72-3.65(m,2H),3.49(dd,J=17.7,8.3Hz,3H),3.26(s,2H),3.08(dd,J=9.7,2.0Hz,1H),1.27(d,J=6.6Hz,3H).ESI-MS m / z 395.1(M+Na) + .

[0126] Example 9: Synthesis of Compound 82

[0127] Take 5.0 g (12.6 mmol) of 82-1, add 50 mL of acetonitrile, 59-4 (5.0 g, 8.98 mmol), and cesium carbonate (3.0 g, 9.20 mmol), and react at room temperature for 10 h. Concentrate the reaction solution, add dichloromethane and 1N hydrochloric acid aqueous solution to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 1.6 g (34% yield) of 82-2. 1 H NMR (400MHz, CDCl3) δ7.34-7.25(m,18H),7.17-7.06(m,2H),5.77(d,J=5.2Hz,1H) ,5.21(dd,J=17.0,8.7Hz,2H),5.12(t,J=9.5Hz,1H),4.90(d,J=10.9Hz,1H),4.77- 4.56(m,5H),4.44(dd,J=17.2,11.4Hz,2H),4.13(d,J=9.4Hz,1H),4.02(d,J=9.4Hz ,1H),3.87-3.70(m,4H),3.65(s,3H),3.57(d,J=9.0Hz,1H),2.01(d,J=5.4Hz,9H).

[0128] Take 1.2 g (1.37 mmol) of 82-2, add 10 mL of tetrahydrofuran and 40 mL of 7 M amine methanol solution, and heat to 55 °C for 12 h. Concentrate the reaction solution, add ethyl acetate to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 0.8 g (80% yield) of 82-3. 1 H NMR(400MHz,MeOD)δ7.45-7.20(m,18H),7.11(dd,J=6.7,2.8Hz,2H),5.91(d,J=5.4Hz,1H),4.87 (d,J=11.0Hz,1H),4.80(d,J=11.3Hz,1H),4.71(dd,J=15.4,11.0Hz,2H),4.52(ddd,J=27.9,15.9 ,9.0Hz,5H),4.29(dt,J=10.1,3.4Hz,1H),3.82(dd,J=9.5,5.4Hz,1H),3.75(d,J=9.7Hz,1H),3.7 0(t,J=9.1Hz,1H),3.61-3.57(m,2H),3.50(dt,J=19.9,9.1Hz,3H),3.40(t,J=8.8Hz,1H).ESI-MS m / z 749.3(M+NH4) + .

[0129] Take 82-3 (500 mg, 0.68 mmol), add methanol (5 mL), tetrahydrofuran (1 mL), acetic acid (100 mg), and 10% wet palladium on carbon (900 mg), replace with a hydrogen balloon, and react at room temperature for 20 h. Filter, concentrate, add ethyl acetate and water to separate the layers, and freeze-dry the aqueous phase to give compound 82 (158 mg, yield 62%). 1 H NMR (400MHz, MeOD) δ5.66(d,J=5.5Hz,1H),4.49(d,J=9.7Hz,1H),4.16-4.08(m,1H),3.86(dd,J=11.6,2.0Hz,1H),3.78(d,J=9.8Hz,1H),3.72( ESI-MS m / z 372.1(M+1) + .

[0130] Example 10: Synthesis of Compound 88

[0131] Take 59 (150 mg, 0.42 mmol), add pyridine (5 mL), and add acetic anhydride (1.3 g, 8.4 mmol) and DMAP (50 mg, 0.42 mmol) sequentially under ice-water bath. React overnight at room temperature. Extract with ethyl acetate and 1N dilute hydrochloric acid, separate the layers, wash the organic phase with saturated sodium bicarbonate, wash with water, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to give compound 88 (150 mg, yield 51.4%). 1 H NMR(400MHz, CDCl3)δ5.94(d,J=5.7Hz,1H),5.31(t,J=9.9Hz,1H),5.20-5.13(m,2H ),5.12-5.08(m,1H),5.05(dd,J=9.6,5.4Hz,1H),5.00(dd,J=10.3,5.7Hz,1H),4.5 7(d,J=10.0Hz,1H),4.44-4.35(m,2H),4.18(dd,J=12.6,2.4Hz,1H),4.16-4.07(m, 2H), 3.72 (ddd, J=10.3, 4.6, 2.4Hz, 1H), 2.10 (d, J=2.4Hz, 6H), 2.06-1.98 (m, 18H).

[0132] Example 11: Synthesis of Compound 89

[0133] Take 59 (150 mg, 0.42 mmol), add pyridine (5 mL), and add butyric anhydride (1.3 g, 8.37 eq.) and DMAP (50 mg, 0.42 mmol) under ice-water bath. React overnight at room temperature. Extract with ethyl acetate and 1N dilute hydrochloric acid, separate the liquid, wash the organic phase with saturated sodium bicarbonate, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to give compound 89 (150 mg, yield 38.9%). 1 H NMR (400MHz, CDCl3) δ5.90(d,J=5.6Hz,1H),5.35(t,J=9.9Hz,1H),5.19(q,J =9.2Hz,2H),5.13-5.00(m,3H),4.59(d,J=10.0Hz,1H),4.38(t,J=10.6Hz,2H ),4.20(d,J=12.5Hz,1H),4.13-4.04(m,2H),3.71(d,J=7.2Hz,1H),2.37-2. 18(m,16H),1.60(ddd,J=20.1,13.6,7.3Hz,16H),0.98-0.86(m,24H).ESI-MS m / z 936.2(M+NH4) + .

[0134] Example 12: Synthesis of Compound 95

[0135] Take 95-1 (3 g, 7.58 mmol), add N,N-dimethylformamide (24 mL) and potassium thioacetate (1 g, 8.68 mmol), and react at room temperature for 4 h. Add ethyl acetate and water to separate the layers, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 95-2 (2.5 g, yield 84%). 1 H NMR (400MHz, CDCl3) δ5.37-5.26(m,2H),5.24-5.08(m,2H),4.16(dd,J=10.0,1. 2Hz,1H),3.73(d,J=1.2Hz,3H),2.38(s,3H),2.02(dd,J=4.4,1.2Hz,9H).ESI-MS m / z 410.1(M+NH4) + .

[0136] Take 95-2 (1 g, 2.55 mmol), add dichloromethane (10 mL) and methanol (10 mL), and add sodium methanethiol (179 mg, 2.55 mmol) under ice-water bath. React at 0 °C for 0.5 h. Add dichloromethane and 1N hydrochloric acid aqueous solution to separate the layers, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 95-3 (680 mg, yield 76%). 1 H NMR (400MHz, CDCl3) δ5.26-5.20(m,2H),5.03-4.95(m,1H),4.57(t,J=10.0Hz,1H),4.08-4 .02(m,1H),3.75(s,3H),2.38(d,J=10.1Hz,1H),2.08(s,3H),2.02(d,J=1.5Hz,6H).ESI-MS m / z368.1(M+NH4) + .

[0137] Take 95-3 (340 mg, 0.97 mmol), add dichloromethane (6 mL), and add titanium tetrachloride (0.25 mL) dropwise under an ice-water bath. React at 0 °C for 15 h. Add dichloromethane and a saturated ammonium chloride aqueous solution to separate the layers. Wash with water, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and concentrate to obtain 95-4 (340 mg, 100% yield). ESI-MS m / z 368.1 (M+NH4). + .

[0138] Take 95-4 (330 mg, 0.94 mmol), add acetonitrile (4 mL), 95-1 (374 mg, 0.94 mmol), and cesium carbonate (461 mg, 1.41 mmol), and react at room temperature for 4 h. Add ethyl acetate and 1N hydrochloric acid aqueous solution to separate the layers, wash with saturated sodium bicarbonate aqueous solution, wash with water, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 95-5 (120 mg, yield 19%). 1 H NMR (400MHz, CDCl3) δ5.96(d,J=5.5Hz,1H),5.39(t,J=9.4Hz,1H),5.29-5.22(m,2H),5.17(td,J=9.6,3.9Hz,2H),5.12-5.06(m,1H ),5.02(dt,J=10.1,5.2Hz,1H),4.84(t,J=9.8Hz,1H),4.65(d,J=10.2Hz,1H),3.72(d,J=2.5Hz,6H),2.02(d,J=4.1Hz,18H).ESI-MS m / z 684.2(M+NH4) + .

[0139] Take 95-5 (530 mg, 0.80 mmol), add methanol (8 mL) and triethylamine (1 mL), and react at 50 °C for 7 h. Concentrate the reaction solution. Add methanol, ethyl acetate and petroleum ether, slurry, filter, and dry to obtain compound 95-6 (52 mg, yield 16%). 1 H NMR (400MHz, MeOD) δ5.63(d,J=5.1Hz,1H),4.61(d,J=8.8Hz,1H),4.44(dd,J=7.4,2.3Hz,1H),3.82-3.79(m,1H),3.77(d,J =1.5Hz,1H),3.76(s,3H),3.74(d,J=3.4Hz,3H),3.58(dd,J=8.7,7.9Hz,2H),3.55-3.51(m,1H),3.37-3.34(m,2H).ESI-MS m / z413.1(M-1) - .

[0140] Take 95-6 (250 mg, 0.60 mmol), add water (8 mL) and sodium hydroxide (48 mg, 1.20 mmol), and react at 60 °C for 1 h. Adjust the pH with 4N HCl-dioxane solution and concentrate the reaction solution. Add ethanol and slurry, then filter. Add ethyl acetate to the filtrate, slurry, filter, and dry to obtain compound 95 (136 mg, yield 58%). 1 H NMR(400MHz,D2O)δ5.78(d,J=5.5Hz,1H),4.56(d,J=9.7Hz,1H),4.33(d,J=9.5Hz, 1H),3.87(dd,J=9.4,5.6Hz,1H),3.77(d,J=9.3Hz,1H),3.58–3.45(m,5H).ESI-MS m / z 385.1(MH) - .

[0141] Example 13: Synthesis of Compound 119

[0142] Following the product synthesis method of Example 16, target compound 119 was synthesized using 119-1 as a starting material. 1H NMR(400MHz,MeOD)δ5.62(dd,J=17.1,5.4Hz,1H),4.39(d,J=9.7Hz,1H),4.18-4.10(m,1H),3.85(dt,J=17.6,8.7Hz,3H),3.72-3.66(m,2H),3 .62(dd,J=12.2,6.7Hz,2H),3.46(q,J=9.0Hz,3H),3.25-3.14(m,2H),1.69(ddt,J=27.3,13.9,7.0Hz,2H),1.52(dq,J=13.3,7.0Hz,1H),1.03 -0.86(m,6H).ESI-MS m / z 472.1(M+H) + .

[0143] Example 14: Synthesis of Compound 125

[0144] Take 125-1 (500 mg, 1.89 mmol), add dichloromethane (5 mL), N-hydroxysuccinimide (238 mg, 2.07 mmol), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (616 mg, 3.21 mmol) under ice-water bath. React at room temperature for 3 h. Add ethyl acetate and 1N hydrochloric acid to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with water, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and concentrate to obtain 125-2 (600 mg, yield 88%).

[0145] Take 125-2 (484 mg, 1.34 mmol), add dichloromethane (8 mL), tetrahydrofuran (8 mL), 59-7 (800 mg, 1.12 mmol), triethylamine (338 mg, 3.35 mmol), and 4-dimethylaminopyridine (82 mg, 0.67 mmol), and react at room temperature for 20 h. Add ethyl acetate and 1N hydrochloric acid to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with water, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 125-3 (600 mg, yield 56%). 1H NMR (400MHz, CDCl3) δ7.65-7.01(m,25H),5.84(d,J=5.7Hz,1H),5.36(dt,J=9.6,5.6Hz,1H),5.19-5.06(m,2H),5.06 -4.91(m,2H),4.84(d,J=11.1Hz,1H),4.73(dd,J=11.2,8.7Hz,2H),4.58-4.39(m,6H),4.35-4.18(m,2H),3.79(dd,J= 9.6,1.7Hz,1H),3.69(t,J=9.0Hz,1H),3.56(qd,J=7.3,5.0,3.6Hz,2H),3.41(dt,J=12.1,9.2Hz,2H),3.30(t,J=8.9 Hz,1H),3.20(dd,J=10.3,8.3Hz,1H),2.09-1.97(m,1H),1.82(d,J=9.5Hz,1H),1.12-1.01(m,1H),0.98-0.72(m,6H).

[0146] Take 125-3 (600 mg, 0.62 mmol), add methanol (12 mL), tetrahydrofuran (2 mL), acetic acid (100 mg), and 10% wet palladium on carbon (1.2 g), replace with a hydrogen balloon, and react at room temperature for 20 h. Filter, concentrate, and lyophilize to give compound 125 (200 mg, yield 62%). 1 H NMR(400MHz,D2O)δ5.57(d,J=5.4Hz,1H),4.60-4.48(m,2H),4.39-4.27(m,1H), 4.05(d,J=4.2Hz,1H),3.93(ddd,J=10.0,4.9,2.7Hz,1H),3.74(dq,J=9.4,5.4Hz ,3H),3.65(p,J=6.4,5.9Hz,1H),3.50-3.31(m,5H),1.99(d,J=3.3Hz,1H),1.42 (tt,J=13.7,7.1Hz,1H),1.27(dt,J=14.1,7.6Hz,1H),0.98-0.83(m,6H).ESI-MS m / z

[0147] 472.1(M+H) + .

[0148] Example 15: Synthesis of Compound 149

[0149] Following the product synthesis method of Example 16, target compound 149 was synthesized using 149-1 as the starting material. 1H NMR(400MHz,MeOD)δ5.65(d,J=5.5Hz,1H),4.39(d,J=9.7Hz,1H),4.20-4.11(m,1H),3.93-3.78(m,3H),3.69(dt,J=11.5,5.6Hz,2H),3.6 2(dd,J=12.0,6.9Hz,3H),3.45(dt,J=17.1,8.6Hz,3H),3.18(dt,J=30.2,10.3Hz,2H),1.29(s,2H),1.07(dd,J=15.1,11.4Hz,6H).ESI-MS m / z 522.2(M+H) + .

[0150] Example 16: Synthesis of Compound 152

[0151] Take 59 (200 mg, 0.56 mmol), add tetrahydrofuran (6 mL), pyridine p-toluenesulfonate (70 mg, 0.28 mmol), and 2,2-dimethoxypropane (290 mg, 0.56 mmol), and heat to 50 °C overnight. Concentrate the reaction solution and precipitate by silica gel column chromatography to give compound 152 (50 mg, 20% yield). 1 H NMR(400MHz,D2O)δ5.63(d,J=5.6Hz,1H),4.60(d,J=9.9Hz,1H),3.99-3.91(m,1H),3.90-3.84(m,2H),3.80(d,J=5.1Hz,1H) ,3.77-3.73(m,1H),3.70(d,J=9.3Hz,1H),3.67-3.56(m,2H),3.56-3.35(m,4H),1.48(s,6H),1.36(d,J=2.5Hz,6H).ESI-MS m / z 461.3(M+Na) + .

[0152] Example 17: Synthesis of Compound 153

[0153] Take 153-1 (2.5 g, 28.3 mmol), add dichloromethane (25 mL), N-hydroxysuccinimide (3.5 g, 31.2 mmol), and EDCI (9 g, 48.11 mmol), and react at room temperature for 2 h. Add dichloromethane and saturated NaHCO3 solution, separate the layers, wash the organic phase successively with water, then with saturated sodium chloride, dry to anhydrous sodium sulfate, and concentrate to obtain 153-2 (5 g). 1H NMR (400MHz, CDCl3) δ2.93-2.86 (m, 1H), 2.83 (d, J = 3.3Hz, 4H), 1.33 (d, J = 7.0Hz, 6H).

[0154] Take 59-7 (3 g, 4.17 mmol), add dichloromethane (30 mL), 153-2 (773 mg, 4.17 mmol), triethylamine (1.3 g, 12.5 mmol), and DMAP (300 mg), and heat to 45 °C overnight. Add dichloromethane and 1 N hydrochloric acid, separate the layers, wash the organic phase with water and saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to give compound 153-2 (500 mg, 15.2%). 1 H NMR (400MHz, CDCl3) δ7.40-7.27(m,20H),5.84(d,J=5.7Hz,1H),4.97(d,J=10.8Hz,1H),4.85 (d,J=11.1Hz,1H),4.77-4.71(m,2H),4.51(dd,J=11.6,6.0Hz,3H),4.46-4.38(m,4H),4.36- 4.26(m,2H),3.78(dd,J=9.6,5.6Hz,2H),3.70(t,J=9.0Hz,1H),3.60-3.50(m,2H),3.43-3.3 0(m,2H),3.23(dt,J=10.4,7.9Hz,1H),2.56(hept,J=6.9Hz,1H),1.13(dd,J=7.0,3.6Hz,6H).

[0155] Take 153-2 (250 mg, 0.32 mmol), add methanol (5 mL), Pd / C (400 mg) and two drops of acetic acid, replace with hydrogen, and react overnight at room temperature. After concentrating the reaction solution, add water, wash successively with dichloromethane and ethyl acetate, and freeze-dry the aqueous phase to give compound 153 (90 mg, yield 66%). 1H NMR(400MHz,MeOD)δ5.62(d,J=5.5Hz,1H),4.43-4.40(m,1H),4.39(d,J=3.3Hz ,1H),4.16(dd,J=11.9,5.4Hz,1H),4.12–4.06(m,1H),3.86(dd,J=11.7,2.4Hz, 1H),3.68(dt,J=12.7,6.4Hz,2H),3.54–3.41(m,4H),3.33(d,J=4.6Hz,1H),3. 27(d,J=9.1Hz,1H),2.60(dt,J=14.1,7.1Hz,1H),1.17(d,J=6.9Hz,6H).ESI-MS m / z 451.3(M+Na) + .

[0156] Example 18: Synthesis of Compound 158

[0157] Take 158-1 (5 g, 19.2 mmol), add N,N-dimethylformamide (40 mL), benzyl 2-bromoethyl ether (4.8 mL, 28.8 mmol), and add NaH (1.2 g, 28.8 mmol) in portions at 0 °C. React at room temperature for 3 h. Add ethyl acetate and saturated ammonium chloride to the reaction solution for extraction, separate the layers, wash the organic phase with water and saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 158-2 (5 g, 66% yield). 1 H NMR (400MHz, CDCl3) δ7.36-7.26(m,5H),5.87(d,J=3.7Hz,1H),4.57(d,J=7.2Hz,3H),4.33(dt,J=7.6,5.9Hz,1H),4.15-4.05(m,2H),4 .00(dd,J=8.6,5.7Hz,1H),3.95(d,J=3.0Hz,1H),3.78(ddd,J=4.7,3.9,1.8Hz,2H),3.65-3.60(m,2H),1.42(s,3H),1.34-1.29(m,6H).

[0158] Take 158-2 (5 g, 12.6 mmol), add methanol (50 mL), Pd / C (500 mg), purge with hydrogen, and react overnight at room temperature. Filter the reaction solution through diatomaceous earth and concentrate to obtain 158-3 (3.5 g, 91% yield). 1H NMR (400MHz, CDCl3) δ5.91 (d, J=3.6Hz, 1H), 4.54 (d, J=3.7Hz, 1H), 4.35 (ddd, J=8.9, 6.1,4.6Hz,1H),4.19-4.07(m,2H),4.06-3.99(m,2H),3.85(ddd,J=11.2,5.7,2.7Hz, 1H),3.78-3.70(m,1H),3.65(dtd,J=12.2,5.8,2.5Hz,1H),3.56(ddd,J=11.2,6.4,2 .6Hz,1H),3.41(t,J=6.6Hz,1H),1.49(s,3H),1.44(s,3H),1.36(s,3H),1.32(s,3H).

[0159] Take 158-3 (3.5 g, 11.5 mmol), add TFA / AcOH / H2O (1 mL / 15 mL / 3 mL), heat to 70 °C and react for 6 h. Concentrate the reaction solution, add water, and concentrate again. Add Ac2O (50 mL) and TFA (2 mL) sequentially at 0 °C, and react overnight at room temperature. Extract with ethyl acetate and saturated NaHCO3, separate the layers, wash the organic phase with 1N hydrochloric acid, saturated NaHCO3, and saturated NaCl water, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 158-4 (3.5 g, 70% yield). ESI-MS m / z 452.3 (M+NH4) + .

[0160] Take 158-4 (600 mg, 1.38 mmol), add dichloromethane (5 mL), acetic anhydride (0.2 mL), and add 33% HBr in AcOH solution (4 mL) at 0 °C. Incubate the reaction for 2 h. Add dichloromethane and saturated NaHCO3 to separate the layers. Wash the organic phase with water, then with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 158-5 (550 mg, yield 89%). 1 H NMR (400MHz, CDCl3) δ6.62(d,J=3.9Hz,1H),5.14(t,J=9.9Hz,1H),4.73(dd,J=9.7,3.9Hz,1H),4.28(dd,J =12.6,4.3Hz,1H),4.20-4.06(m,4H),3.98-3.86(m,2H),3.80(dt,J=11.0,4.9Hz,1H),2.17-2.05(m,13H).

[0161] Take 158-5 (550 mg, 1.22 mmol), add acetonitrile (6 mL), 61-2 (440 mg, 1.22 mmol), and add cesium carbonate (591 mg, 1.83 mmol) at 0 °C. React overnight at room temperature. Extract with ethyl acetate and 1N hydrochloric acid, separate the liquid, wash the organic phase with saturated NaHCO3, wash with water, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 158-6 (530 mg, yield 59%). 1 H NMR (400MHz, CDCl3) δ5.22(t,J=9.3Hz,1H),5.13-4.98(m,4H),4.82(d,J=10.1Hz,1H),4.74(d,J=10.1Hz,1H),4.29- 4.07(m,6H),3.76(q,J=4.8Hz,2H),3.67(ddd,J=9.9,4.6,2.5Hz,1H),3.63-3.54(m,2H),2.15-1.97(m,24H).ESI-MS m / z 756.3(M+NH4) + .

[0162] Take 158-6 (530 mg, 0.72 mmol), add methanol (8 mL) and triethylamine (1 mL), and heat to 55 °C and react overnight. Concentrate the reaction solution and add ethanol to concentrate it again. Add ethanol and ethyl acetate and beat until smooth, then filter. Add water to the filter cake and freeze-dry to give compound 158 (150 mg, yield 52%). 1 H NMR(400MHz,MeOD)δ4.69(t,J=9.8Hz,2H),3.95(dt,J=9.9,4.6Hz,1H),3.91-3.81(m,3H),3.69(t, J=4.7Hz,2H),3.62(dd,J=12.5,5.8Hz,3H),3.37(dt,J=14.6,9.2Hz,4H),3.28-3.21(m,3H).ESI-MS m / z 425.1(M+Na)+

[0163] .

[0164] Example 19: Synthesis of Compound 161

[0165] Take 161-1 (600 mg, 1.54 mmol), add dichloromethane (8 mL) and 33% hydrobromic acid-acetic acid solution (3 mL), and react at room temperature for 0.5 h. Add dichloromethane and water to separate the layers, wash with saturated NaHCO3 aqueous solution, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and concentrate to obtain 161-2 (630 mg).

[0166] Take 161-2 (630 mg, 1.54 mmol), add dichloromethane (15 mL), 161-3 (560 mg, 1.54 mmol), and cesium carbonate (1 g, 3.07 mmol), and react at room temperature for 4 h. Add dichloromethane and water to separate the layers, wash with 1N hydrochloric acid aqueous solution, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 161-4 (520 mg, yield 49%). 1 HNMR(400MHz, CDCl3)δ5.60(d,J=9.5Hz,1H),5.23(t,J=9.3Hz,1H),5.16-5.02(m,4H),4.81(dd,J=15.4,10.3Hz,2H),4.26(ddd ,J=12.3,7.3,4.8Hz,2H),4.22-4.11(m,3H),3.73-3.62(m,2H),2.11(d,J=5.8Hz,6H),2.07-1.99(m,15H),1.94(s,3H).ESI-MS m / z694.2(M+1) + .

[0167] Take 161-4 (300 mg, 0.43 mmol), methanol (8 mL), and triethylamine (1 mL), and react at 55 °C for 20 h. Concentrate the reaction solution, add ethanol and ethyl acetate, slurry, filter, add water to the filtrate and freeze-dry to obtain compound 161 (150 mg, yield 87%). 1 H NMR(400MHz,MeOD)δ4.69(d,J=9.9Hz,1H),3.93-3.84(m,2H),3.76(t,J=10.2Hz,1H),3.68-3.58(m,2H),3.48-3 .41(m,1H),3.38-3.31(m,2H),3.30-3.29(m,2H),3.29-3.22(m,2H),3.18(t,J=9.3Hz,1H),1.97(s,3H).ESI-MS m / z 398.1(MH) - .

[0168] Example 20: Synthesis of Compound 163

[0169] Take 59-7 (500 mg, 0.70 mmol), add N,N-dimethylformamide (5 mL), and add 60% sodium hydride (167 mg, 4.18 mmol) and benzyl bromide (714 mg, 4.17 mmol) under ice-water bath. React at room temperature for 20 h. Add ethyl acetate and saturated ammonium chloride aqueous solution to separate the layers, wash with water, wash with saturated sodium chloride, dry to anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 163-1 (700 mg, yield 93%). 1 H NMR (400MHz, CDCl3) δ7.37-7.16(m,40H),5.86(d,J=4.6Hz,1H),5.03-4.87(m,4H),4.86-4.72(m,5H),4. 54(dd,J=20.7,10.3Hz,2H),4.48-4.41(m,5H),4.34-4.23(m,2H),3.91-3.80(m,2H),3.77-3.39(m,9H).

[0170] Take 163-1 (600 mg, 0.56 mmol), add dichloromethane (6 mL) and m-chloroperoxybenzoic acid (340 mg, 1.97 mmol), and react at room temperature for 5 h. Add ethyl acetate and saturated sodium thiosulfate aqueous solution to separate the layers, wash with saturated sodium bicarbonate aqueous solution, wash with water, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate, and precipitate by silica gel column chromatography to obtain 163-2 (350 mg, yield 57%). 1 H NMR (400MHz, CDCl3) δ7.29 (dddd, J=21.3, 17.9, 10.3, 7.7Hz, 40H), 5.51 (d, J=6. 1Hz,1H),5.01(d,J=9.9Hz,1H),4.91-4.83(m,3H),4.83-4.67(m,6H),4.67-4.5 5(m,4H),4.54-4.45(m,4H),4.34(d,J=10.0Hz,1H),4.17-4.08(m,2H),3.96(dd ,J=9.5,6.1Hz,1H),3.87-3.68(m,3H),3.58(t,J=9.3Hz,2H),3.51-3.42(m,2H).

[0171] Take 163-2 (350 mg, 0.32 mmol), add methanol (6 mL), tetrahydrofuran (1 mL), acetic acid (20 mg), and 10% wet palladium on carbon (700 mg), replace with a hydrogen balloon, and react at room temperature for 20 h. Filter, concentrate, add ethyl acetate and water to separate the layers, and freeze-dry the aqueous phase to give compound 163 (100 mg, yield 81%). 1H NMR(400MHz,MeOD)δ5.40(d,J=6.3Hz,1H),4.71(d,J=9.7Hz,1H),4.24(t,J=9.2Hz,1H),4.06-4.00(m,1H),3.97(dd, J=9.6,6.3Hz,1H),3.93-3.81(m,3H),3.71-3.62(m,2H),3.40(dt,J=24.4,9.1Hz,3H),3.26(d,J=9.4Hz,1H).ESI-MS m / z 413.1(M+Na) + .

[0172] Pharmacological experiments

[0173] Test Example 1: Aβ Cell Model Viability Assay

[0174] Cell culture and neuronal differentiation experiments: SH-SY5Y (human neuroblastoma cell line, Procell, CL-0208) cells were cultured in complete medium (DMEM / F12 (1:1) medium, 10% FBS and 1% pen / strep) and passaged in a 37℃, 5% CO2 incubator. After 48 h of culture in complete medium, the medium was changed to induce differentiation into neurons. The medium was then changed to neurobasal medium (containing B27 supplement and GlutaMAX) and 10 μM all-trans-retinoic acid (ATRA), with half-medium changes every 48 h. Maintaining these conditions for 5 days yielded cultured and differentiated neuron-like cells.

[0175] Amyloid beta(Aβ)1-42 oligomerization and cell viability assay: To form Amyloid beta(Aβ)1-42 oligomers, Amyloid beta(Aβ)1-42 protein was dissolved in serum-free DMEM / F12 medium to prepare a 100 μM system and incubated at 4°C for at least 24 hours. The Amyloid beta(Aβ)1-42 oligomers were added to differentiated cells at a final concentration of 10 μM, either alone or together with treatment compounds. CCK8 activity was detected using a microplate reader after 48 hours. The Amyloid beta(Aβ)1-42 oligomer treatment group was used as the model group, and its CCK8 activity data were normalized. The results of compound treatments were compared with the model group data using an unpaired t-test and the Mann-Whitney test.

[0176] The experimental results are shown in Table 1. In the embodiments of this application, compounds 32, 59, 60, 70, 76, 89, 149, and 158 showed better cell viability enhancement than the positive control, while compounds 62, 82, 88, and 161 had similar efficacy to the positive control.

[0177] Table 1. Activity data of compounds in Aβ cell model

[0178] Note: * represents cell viability; more * indicate stronger cell viability.

[0179] Test Example 2: 6-Hydroxydopamine (6-OHDA)-induced cell damage model experiment

[0180] SH-SY5Y (human neuroblastoma cell line, Procell, CL-0208) was selected. After cell incubation, the cell suspension was gently pipetted to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1500 rpm for 3 min to collect the cells. After centrifugation, the supernatant was discarded, and the cells were seeded into 96-well cell culture plates at a seeding density of 5000 cells per well (final volume: 100 uL). The plates were incubated at 37°C with 5% CO2 for 48 h. The culture medium was then replaced with differentiation medium (Neurobasal medium (containing B27 supplement and GlutaMAX) and 10 uM all-trans-retinoic acid (ATRA)) and cultured for another 5 days.

[0181] Ascorbic acid was prepared into a 0.1% solution using physiological saline. 6-OHDA was then prepared into a 100mM stock solution using the 0.1% ascorbic acid solution and stored in the dark. 6-OHDA was diluted to 60µM using Neurobasal medium to establish a cell damage model. The compound was prepared to the required molar concentration using medium containing 60µM 6-OHDA. The old medium in each well was removed, and 100µL of the mixed compound medium was added. The Model group received 100µL of medium containing 60µM 6-OHDA, while the control group received 100µL of Neurobasal medium. The mixtures were incubated for 24 hours, then the same freshly prepared drug was added, and the incubation continued for another 24 hours.

[0182] Discard the old culture medium from the 96-well plate and wash twice with differentiation medium. Mix CCK-8 and differentiation medium at a ratio of 1:10, add 100 μL to each well, and incubate for 4 h. Measure the absorbance (OD) at 450 nm using a microplate reader.

[0183] The experimental results are shown in Table 2. The pharmacological effects of compounds 32, 59, 62, 70, 89, 125, and 149 in the embodiments of this application are comparable to those of the positive control, while compounds 60, 153, 158, and 161 have a certain effect on enhancing cell viability.

[0184] Table 2. Activity data of compounds in a 6-OHDA-induced cell damage model

[0185] Note: * represents cell viability; more * indicate stronger cell viability.

[0186] Test Example 3: Oxygen-Glucose Deprivation-Reoxygenation (OGD-R) Cell Model

[0187] Cell culture: SH-SY5Y (human neuroblastoma cell line, Procell, CL-0208) were cultured in complete medium: DMEM / F12 (1:1) medium (10% FBS and 1% pen / strep). The old medium was removed and the cells were washed once with PBS. Then, 1 mL of 0.25% trypsin was added, and the cells were incubated at 37°C for 2-3 min. The digestion was terminated by adding the appropriate medium. The cell suspension was gently pipetted to separate the aggregated cells. The cell suspension was transferred to sterile centrifuge tubes and centrifuged at 2000 rpm for 3 min to collect the cells. After centrifugation, the supernatant was discarded, and the cells were seeded into 96-well cell culture plates at a density of 10,000 cells per well (final volume: 100 μL). The plates were incubated at 37°C under 5% CO2 conditions.

[0188] Oxygen-glucose deprivation-reoxygenation model: SH-SY5Y cells were de-cultured using old culture medium and 100 μL of sugar-free, phenol red-free, and serum-free DMEM medium was added. The cells were then placed in a nitrogen bag, sealed, and cultured in an incubator (37°C, 5% CO2) for 10 h to establish a cell damage model.

[0189] CCK8 cell viability assay: CCK-8 cells were mixed with culture medium (phenol red-free DMEM / F12 + 10% FBS) at a ratio of 1:10, and 100 μL was added to each well of a 96-well plate and incubated for 4 h. The absorbance (OD) at 450 nm was measured using a microplate reader.

[0190] The experimental results are shown in Table 3. The pharmacological effects of compounds 59, 82, and 158 in the embodiments of this application are comparable to those of the positive control, while compounds 1, 60, 62, 70, 76, 89, 95, 149, 152, and 161 have certain effects on enhancing cell viability.

[0191] Table 3. Activity data of compounds in the OGD-R cell model

[0192] Note: * represents cell viability; more * indicate stronger cell viability.

[0193] Test Example 4: Lipopolysaccharide (LPS)-induced inflammatory cell model

[0194] LPS-induced in vitro inflammatory cell models are of great significance for drug screening of various central nervous system diseases and inflammatory diseases.

[0195] Cell seeding: Raw264.7 cells (approximately 200,000 / well) were seeded into 12-well transparent flat-bottom cell culture plates using complete culture medium (DMEM / F12 (1:1) medium) with 1 mL of culture medium per well, and cultured overnight at 37°C with 5% CO2 in a cell culture incubator.

[0196] Cellular drug administration: The positive compound dexamethasone (DEX) and the test compound were diluted 1:1000 to the corresponding final concentration (1 uL / well) and pre-incubated for 2-3 h, with three auxiliary wells for each drug concentration. The positive compound and the test compound were prepared as stock solutions at a 10,000-fold concentration to be tested. Using low-serum medium (DMEM + 1% FBS + 1% PS), the positive and test drugs were first diluted 100-fold, then 50-fold. Finally, 250 uL of the diluted positive or test drug and 250 uL of 200 ng / ml LPS were added to each well and mixed thoroughly (500 uL of low-serum medium was added to the Blank group, and 250 uL of 200 ng / ml LPS and 250 uL of low-serum medium were added to the LPS group). Incubate in a cell culture incubator (37℃, 5% CO2) for 12-15 hours; after incubation, remove the cell supernatant and add 500uL of Trizol reagent to each well to extract RNA.

[0197] RNA extraction and reverse transcription: Lyse cells thoroughly with 500 μL Trizol (ABclonal, RM30129-100 ml) per well in 12-plate plates, transfer to 1.5 mL EP tubes, and lyse for 5 min. Pre-cool the plate at 4°C, add 100 μL chloroform, vortex vigorously for 15 s, let stand for 5 min to allow separation, and centrifuge at 12000 rpm, 4°C for 10 min. RNA should be on the top aqueous phase. Transfer the upper aqueous phase to a new EP tube, add an equal volume of isopropanol, invert to mix, and let stand for 10 min. Centrifuge at 12000 rpm, 4°C for 10 min, and the RNA precipitate should be at the bottom. Discard the supernatant, add 75% ethanol and wash gently at 12000 rpm, 4°C for 2 min (wash twice). Discard the ethanol, allow the RNA precipitate to air dry in a laminar flow hood until semi-dry, then dissolve in 10-20 μL DEPC water for RNA concentration analysis (A260 / 280 between 1.8 and 2.0). RNA samples should be stored at -80℃ for long-term preservation, and the concentration should be checked before each use. Take 1 μg of RNA template and immediately perform subsequent reverse transcription. Prepare system 1 according to the reverse transcription kit (Tiangen, KR116-02). After mixing, in vitro, and incubate at 42℃ for 3 min in a PCR instrument. Immediately place on ice and prepare system 2. After mixing, in vitro and perform reverse transcription in the PCR instrument according to the program set (Step 1, Temp: 42℃, Time: 15 min; Step 2, Temp: 95℃, Time: 3 min). After the program is completed, immediately place on ice and test the cDNA concentration. Dilute all cDNA samples to 100 ng / μL and store at -20℃.

[0198] Quantitative Real-Time PCR: Prepare cDNA template, primers, and SYBR Green qPCR Mix (Selleck, B21703), and thaw on ice. Calculate the required primers, water, and SYBR Green qPCR Mix according to the gene arrangement and number of wells (prepare for three wells). Add 18 μL of the mixed primers, water, and SYBR Green qPCR Mix to a 96-well plate according to the gene arrangement. Finally, add 2 μL of template to the bottom of each well in the same order (remember to change pipette tips). After adding all the template, seal the plate with sealing film, centrifuge at 1000 rpm for 1 min, and then detect the results using a qPCR instrument (Roche, LC96). Primer sequence information is as follows:

[0199] The experimental results are shown in Table 4. Compounds 59, 149, and 158 showed the strongest inhibitory activity against IL-6, comparable to the positive control. Compounds 62, 70, 76, 88, 89, 152, and 161 showed some inhibitory activity against IL-6. Compounds 70 and 158 showed the strongest inhibitory activity against TNF-α, comparable to the positive control. Compounds 59, 89, 95, 149, and 161 showed some inhibitory activity against TNF-α. Compounds 59, 60, 62, 76, 89, and 161 showed some inhibitory activity against IL-1β.

[0200] Table 4. Inhibitory activity of compounds against different inflammatory factors

[0201] Note: * indicates the compound's inhibitory activity against inflammatory factors; more * indicate stronger activity.

[0202] Test Example 5: Forced Swim Test

[0203] Drug: The compound of this invention is mixed with 5% DMSO and then added. Mix HS15 thoroughly, then add 90% physiological saline to prepare a solution of appropriate concentration. Prepare and use immediately. Use dextromethorphan (10 mpk) + quinidine (30 mpk) as a positive control.

[0204] Animals: Male C57 mice, approximately 22g. Animals were randomly divided into a blank control group (Vehicle group) and each test drug group, with 8 animals in each group. Mice in each group were intraperitoneally injected with either the solvent prescription or the test drug.

[0205] Experimental Procedure: Forced swimming tests were conducted on mice 0.5 hours after drug administration. The water level in the forced swimming device was 45 cm, and the water temperature was 25℃. Before the experiment, the mice were placed in the experimental room for 1 hour to acclimatize. At the start of the experiment, the mice were placed in the device for 6 minutes. The entire process was recorded by a camera, and only the immobile time of the mice in the last 4 minutes was counted when analyzing the data.

[0206] The experimental results are shown in Table 5 below:

[0207] Table 5

[0208] The data above show that compounds 59, 60, 89, and 158 exhibited significant antidepressant-like effects, while compounds 62 and 149 also had certain antidepressant effects.

[0209] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A class of pyranose derivatives represented by general formula I, their stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates. in, A is independently selected from CH2, NH, S, Se, CH2-CH2, NH-NH, SS, Se-Se, S(=O), S(=O)2, CH(R9), N(R 10 ), CH(R) 11 )-CH(R 12 ), N(R 13 )-N(R 14 ), O-CH2-CH2-O, S-CH2-CH2-S, O-CH(R 15 )-CH(R 16 )-O、S-CH(R 17 )-CH(R 18 )-S; R1 and R8 are each selected independently. R2, R3, R4, R5, R6, and R7 are each independently selected. Alternatively, R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, R7 and R8 form a substituted or unsubstituted 5-8 membered heterocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein "substituted" means selectively containing 1 to 3 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl; R9, R 10 R 11 R 12 R 13 R 14、 R 15 R 16、 R 17 R 18 Each of the following groups is independently selected from H and D: substituted or unsubstituted C1-C20 straight-chain or branched alkyl or alkanoyl groups; substituted or unsubstituted C1-C20 alkyl-OH groups; substituted or unsubstituted C2-C10 ester groups; substituted or unsubstituted C3-C20 cyclic alkyl or alkanoyl groups; substituted or unsubstituted 3-20 membered heterocyclic groups or heterocyclic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur; substituted or unsubstituted C6-C20 aryl or aromatic acyl groups; substituted or unsubstituted 5-20 membered heteroaryl or heteroaromatic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur; and substituted or unsubstituted C2-C20 straight-chain or branched alkenyl or alkenyl groups. The term "substituted" refers to the selective presence of 1 to 4 atoms selected from hydroxyl, nitro, C1-C10 alkyl, C1-C10 alkoxy, C... 1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, -NH2, C1-C10 alkylamido, C1-C10 alkyloxy, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C20 aryl group selected from hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituents of substituted or unsubstituted natural or non-natural amino acids; R 19 R 20 Each of the following groups is independently selected from H, D, substituted or unsubstituted C1-C20 straight-chain or branched alkyl groups, substituted or unsubstituted C2-C10 ester groups, substituted or unsubstituted C3-C20 cycloalkyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C14 aryl groups, substituted or unsubstituted 5-20 membered heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C20 straight-chain or branched alkenyl groups, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from hydroxyl, nitro, halogen, -NH2, and acetyl groups. C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, C1-C10 alkylamido, C1-C10 alkoxy, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C14 aryl group substituted with hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; R 21 Selected from H, NH2, C1-C20 alkylamino, R 26 Selected from H and D, substituted or unsubstituted C1-C20 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C1-C20 alkyl-OH groups, substituted or unsubstituted C2-C10 ester groups, substituted or unsubstituted C3-C20 cycloalkyl or alkanoyl groups, substituted or unsubstituted 3-20 membered heterocyclic groups or heterocyclic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C14 aryl or aromatic acyl groups, substituted or unsubstituted 5-20 membered heteroaryl or heteroaromatic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C20 straight-chain or branched alkenyl or enoyl groups, wherein "substituted" refers to selectively containing 1 to 4 atoms selected from hydroxyl, nitro, C1-C10 alkyl, C1-C10 alkoxy, C1-C 10-Haloalkyl, C1-C10 hydroxyalkyl, halogen, -NH2, C1-C10 alkylamido, C1-C10 alkyloxy, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C14 aryl group selected from hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, substituents of substituted or unsubstituted natural or non-natural amino acids; R 22 R 23 R 24 R 25 Each of the following groups is independently selected from H and D: substituted or unsubstituted C1-C20 straight-chain or branched alkyl or alkanoyl groups; substituted or unsubstituted C1-C20 hydroxyalkyl groups; C1-C20 alkylcarbonyl groups; substituted or unsubstituted C2-C10 ester groups; substituted or unsubstituted C3-C20 cyclic alkyl or alkanoyl groups; substituted or unsubstituted 3-20 membered heterocyclic groups or heterocyclic acyl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur; substituted or unsubstituted C6-C14 aryl or aromatic acyl groups; substituted or unsubstituted 5-20 membered heteroaryl or heteroaryl groups containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur; substituted or unsubstituted C2-C20 straight-chain or branched alkenyl or alkenyl groups. The substituted substituents are selected from the group from which "substituted" refers to selectively containing 1 to 4 groups selected from hydroxyl, nitro, C1-C10 alkyl, C2-C10 alkyl, C3-C20 alkyl, C4-C10 alkyl, C3-C10 alkyl, C4 ... 1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 hydroxyalkyl, halogen, -NH2, C1-C10 alkylamido, C1-C10 alkyloxy, 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterospirocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-20 membered heterocyclic group containing 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C14 aryl group selected from hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 membered monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituents of substituted or unsubstituted natural or non-natural amino acids.

2. The pyranose derivative represented by general formula I according to claim 1, its stereoisomers, pharmaceutically acceptable salts, hydrates, or solvates, characterized in that, Preferably, R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7, R7 and R8 form a substituted or unsubstituted 5-6 membered heterocyclic group containing one or two heteroatoms selected from oxygen and nitrogen, wherein "substituted" means selectively containing one to three substituents selected from C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; Preferably, R 19 R 20 Each of the following groups is independently selected from H, D, substituted or unsubstituted C1-C6 straight-chain or branched alkyl groups, substituted or unsubstituted C2-C8 ester groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted 3-8 membered heterocyclic groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C10 aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituted or unsubstituted C2-C6 straight-chain or branched alkenyl groups, wherein "substituted" refers to selectively containing 1 to 4 heteroatoms selected from hydroxyl, nitro, halogen, -NH2, acetyl C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkylamido, C1-C3 alkoxy, 3-6 member monocyclic heterocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 member heterospirocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-14 member heterocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C10 aryl groups selected from hydroxyl, nitro, -NH2, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; Preferably, R 19 Selected from H, C1-C6 straight-chain or branched alkyl, C1-C6 straight-chain or branched alkoxy; More preferably, R 19 Selected from H, C1-C3 straight-chain or branched alkyl groups; Preferably, R 20 Selected from H, D, C1-C3 straight-chain or branched alkyl, C(=O)C1-C3 straight-chain or branched alkyl, substituted or unsubstituted C2-C8 ester group, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein "substituted" refers to selectively containing 1 to 4 substituents selected from hydroxyl, nitro, halogen, -NH2, acetyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkanoylamino, C1-C3 alkanoyloxy, and 3-6 membered monocyclic heterocyclic groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur; More preferably, R 20 Selected from H, D, C1-C3 straight-chain or branched alkyl groups, C(=O)C1-C3 straight-chain or branched alkyl groups, Preferably, R 26 Selected from H and D, substituted or unsubstituted C1-C6 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C2-C10 ester groups, substituted or unsubstituted C3-C8 cycloalkyl or cycloalkanoyl groups, substituted or unsubstituted 3-10 membered heterocyclic groups or heterocyclic acyl groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C10 aryl or aromatic acyl groups, substituted or unsubstituted 5-10 membered heteroaryl or heteroaromatic acyl groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C2-C6 straight-chain or branched alkenyl or enoyl groups, wherein "substituted" refers to selectively containing 1 to 4 atoms selected from hydroxyl, nitro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1- C3 hydroxyalkyl, halogen, -NH2, C1-C3 alkylamino, C1-C3 alkyloxy, 3-6 member monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 member heterospirocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 5-10 member heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, unsubstituted or substituted C6-C10 aryl group selected from hydroxyl, nitro, -NH2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or two adjacent substituents together with the connected ring atom to form a 3-10 member monocyclic heterocyclic group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and substituents of substituted or unsubstituted natural or non-natural amino acids; Preferably, R 26 Selected from H and D, substituted or unsubstituted C1-C3 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C5-C6 cycloalkyl or cycloalkanoyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups or heterocyclic acyl groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted phenyl or phenyl acyl groups, substituted or unsubstituted 5-6 membered heteroaryl or heteroaryl groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C2-C4 straight-chain or branched alkenyl or alkenyl groups, wherein "substituted" refers to selectively containing 1 to 3 substituents selected from hydroxyl, nitro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, halogen, -NH2, C1-C3 alkanoylamino, and C1-C3 alkanoyloxy; More preferably, R 26 For H or D; Preferably, R 22 R 23 R 24 R 25 Each group is independently selected from H and D, and includes substituted or unsubstituted C1-C6 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C1-C6 hydroxyalkyl groups, C1-C6 alkylcarbonyl groups, substituted or unsubstituted C2-C6 ester groups, substituted or unsubstituted C3-C10 cyclic alkyl or alkanoyl groups, substituted or unsubstituted 3-10 membered heterocyclic groups or heterocyclic acyl groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted C6-C10 aryl or aromatic acyl groups, and substituted or unsubstituted groups containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. The heteroatom has a 5-10 membered heteroaryl or heteroaryl group, a substituted or unsubstituted C2-C6 straight-chain or branched alkenyl or enoyl group, wherein the substituted substituent is selected from the group containing 1 to 3 substituents selected from hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halogen, -NH2, C1-C6 alkanoylamino, C1-C6 alkanoyloxy, or a 3-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. Preferably, R 22 R 23 R 24 R 25 Each group is independently selected from H and D, and includes substituted or unsubstituted C1-C4 straight-chain or branched alkyl or alkanoyl groups, substituted or unsubstituted C1-C4 hydroxyalkyl groups, C1-C4 alkylcarbonyl groups, substituted or unsubstituted C2-C6 ester groups, substituted or unsubstituted C3-C6 cyclic alkyl or alkanoyl groups, substituted or unsubstituted 3-6 membered heterocyclic groups or heterocyclic acyl groups containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur, substituted or unsubstituted phenyl or phenylacyl groups, and substituted or unsubstituted heteroatoms containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur. The 5-6 membered heteroaryl or heteroaryl group, substituted or unsubstituted C2-C4 straight-chain or branched alkenyl or enoyl group, wherein the substituted substituent is selected from the group containing 1 to 3 substituents selected from hydroxyl, nitro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, halogen, -NH2, C1-C3 alkylamide, C1-C3 alkyloxy, or 5-6 membered monocyclic heterocyclic groups containing 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; More preferably, R 22 R 23 R 24 R 25 Each is independently selected from H, D, C1-C3 alkyl, hydroxyl-substituted C1-C3 alkyl, C1-C3 alkyl carbonyl, Preferably, A is CH2, NH, S, Se, CH2-CH2, NH-NH, SS, or Se-Se; More preferably, A is CH2, NH, S, or Se.

3. The pyranose derivative represented by general formula I according to claim 1, its stereoisomers, pharmaceutically acceptable salts, crystalline hydrates or solvates, characterized in that, It is represented by general formula I-1, general formula I-2, general formula I-3 or general formula I-4: The definitions of A, R1, R2, R3, R4, R5, R6, R7, and R8 are the same as those in general formula I of claim 1 or 2.

4. The pyranose derivative represented by general formula I according to claim 1, its stereoisomers, pharmaceutically acceptable salts, crystalline hydrates or solvates, characterized in that, Selected from compounds having the following structures:

5. A method for preparing a pharmaceutically acceptable salt, hydrated crystal, or solvate of a pyranose derivative, stereoisomer, or thereof represented by general formula I, general formula I-1, general formula I-2, general formula I-3, or general formula I-4 according to any one of claims 1 to 4, wherein the glycosidic bond comprises one of four configurations: α / α, α / β, β / α, or β / β. Method 1: Using a1-1 as raw material, the product a1 is obtained by reacting it with ammonium carbonate and ammonia. in, R1, R2, R3 and R4 are the same as those defined in general formula I of claim 1; Method 2: Using a2-1 as raw material, a2-3 is obtained through iodination and selenoglycosylation, and then the glycoselenoglycoside product a2 is obtained through hydrolysis, debenzylation or hydroxyl protection. Wherein, R1, R2, R3 and R4 are the same as those defined in general formula I of claim 1; Method 3: Using a3-1 as a raw material, a mercapto intermediate a3-4 is obtained by reacting with acetic anhydride and thioacetic acid, followed by a deacetylation reaction. A3-4 is then reacted with a3-5 under acidic conditions such as boron trifluoride ether and trimethylsilyl trifluoromethanesulfonate, or under weakly alkaline conditions such as silver oxide, silver carbonate, cadmium carbonate, and cesium carbonate, to obtain a3-6. Finally, a glycosaminoglycan product a3 is obtained through hydrolysis, debenzylation, or dehydroxylation protection. Wherein, R1, R2, R3, R4, R5, R6, R7 and R8 are the same as those defined in general formula I of claim 1; X is selected from Cl, Br, and I; Method 4: Using a4-1 as a raw material, intermediate a4-2 is obtained by reacting with thiourea. Under sodium bisulfite conditions, the sulfur protecting group is selectively removed to obtain intermediate a4-3. Under acidic conditions such as boron trifluoride ether and trimethylsilyl trifluoromethanesulfonate, or under weakly alkaline conditions such as silver oxide, silver carbonate, cadmium carbonate, and cesium carbonate, a4-6 is obtained by reacting with a4-5. Finally, the glycosaminoglycan product a4 is obtained by hydrolysis, debenzylation, or dehydroxylation. Wherein, R1, R2, R3, R4, R5, R6, R7 and R8 are the same as those defined in general formula I of claim 1; X is selected from Cl, Br, and I.

6. A pharmaceutical composition comprising a therapeutically effective amount of a pyranose derivative, a stereoisomer thereof, of any one of formula I, I-1, I-2, I-3 or I-4 as claimed in any one of claims 1 to 4, and a pharmaceutically acceptable salt, hydrated crystal or solvate thereof, and optionally one or more pharmaceutical excipients.

7. Use of a pyranose derivative, its stereoisomer, pharmaceutically acceptable salt, crystalline hydrate or solvate, or pharmaceutical composition according to any one of claims 1 to 4, of formula I, formula I-1, formula I-2, formula I-3 or formula I-4 in the preparation of a medicament for the treatment and / or prevention of diseases of the central nervous system and inflammatory diseases.

8. The use according to claim 7, characterized in that, The central nervous system diseases are selected from at least one of the following: Alzheimer's disease, frontotemporal dementia, Lewy body dementia, Parkinson's syndrome, amyotrophic lateral sclerosis, epilepsy, Huntington's disease, cerebellar ataxia, multiple sclerosis, spinal muscular atrophy, depression, anxiety disorder, mania, schizophrenia, autism, stroke, cerebral hemorrhage, cerebral embolism, cerebral infarction, cerebral arteriosclerosis, vascular dementia, and diseases caused by inflammation; the inflammatory diseases are selected from at least one of the following: multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, ankylosing spondylitis, dermatomyositis, scleroderma, pemphigus, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and inflammatory bowel disease.

9. A method for treating and / or preventing central nervous system diseases and inflammatory diseases, the method comprising administering to a subject in need a therapeutically effective amount of a pyranose derivative, its stereoisomer, a pharmaceutically acceptable salt, crystalline hydrate or solvate, or a pharmaceutical composition according to any one of claims 1 to 4, of general formula I, general formula I-1, general formula I-2, general formula I-3 or general formula I-4.

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