Compound based on xanthone as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a xanthone-based compound as well as a preparation method and application thereof. The invention provides a xanthone-based compound with a novel structure, experiments prove that the xanthone-based compound has an excellent inhibition effect on phosphodiesterase 4, the compound reaches the activity level of a nanomole level, the activity of part of the compound is even remarkably superior to that of a positive control Rolipram, and the xanthone-based compound can be used as a phosphodiesterase 4 inhibitor and can be used for preparing a phosphodiesterase 4 inhibitor. The compound is applied to treatment of phosphodiesterase 4 type related diseases, and has important medicinal value and wide application prospect in preparation of drugs for treating phosphodiesterase 4 type related diseases including pulmonary fibrosis.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology. More specifically, it relates to a class of xanthone-based compounds, their preparation methods, and applications. Background Technology

[0002] Phosphodiesterase type 4 (PDE4) is an important cAMP hydrolase. The PDE4 family is divided into four subtypes (PDE4A, PDE4B, PDE4C, and PDE4D), which are mainly distributed in inflammatory cells (such as neutrophils, macrophages, and T cells) and the central nervous system. PDE4 regulates the release of various inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-23 (IL-23), and leukotrienes, by degrading the intracellular second messenger cAMP. Therefore, the development of PDE4 inhibitors has important clinical value in the fields of inflammatory diseases and immune regulation.

[0003] Currently, PDE4 inhibitors have been investigated for the treatment of various diseases, such as chronic obstructive pulmonary disease (COPD), asthma, psoriasis, atopic dermatitis, rheumatoid arthritis, and depression. For example, roflumilast and crisaborole, as marketed PDE4 inhibitors, are used to treat COPD and mild to moderate atopic dermatitis, respectively. However, the number of existing PDE4 inhibitors remains limited, and there is an urgent need to explore more new and effective PDE4 inhibitor drugs for patients to choose from. Summary of the Invention

[0004] The technical problem to be solved by this invention is to overcome the limitations of existing PDE4 inhibitors and the urgent need to explore more new and effective PDE4 inhibitor drugs for patients to choose from, and to provide a class of compounds based on xanthone.

[0005] Another object of the present invention is to provide a pharmaceutical composition.

[0006] Another object of the present invention is to provide the use of the said xanthone-based compound or the said pharmaceutical composition in the preparation of PDE4 inhibitors.

[0007] Another object of the present invention is to provide the use of the said xanthone-based compound or the said pharmaceutical composition in the preparation of a treatment for PDE4-related diseases.

[0008] The above-mentioned objective of this invention is achieved through the following technical solution:

[0009] This invention protects a class of xanthone-based compounds having the structure shown in formula (I):

[0010]

[0011] In formula (I), R 1 Selected from R 5 Replace C 1～6 Alkyl, C 2～6 olefin group, C 3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each group is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 1～6 Alkyl group, C 3～6 cycloalkyl, heterocyclic, heteroaryl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, ester, and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 2～6 olefin group, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl;

[0012] The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～6 Alkyl, C 2～6 olefin group, C 3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, -NR 8 R 9 -N + R 10 R 11 R 12 Substitute heterocyclic group, heteroaryl group, or aryl group; said R 8 and R 9 Each is independently selected from hydrogen and C. 1～6 Alkyl or C1～6 Halogenated alkyl; the R 10 and R 11 Selected from C 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, ester, and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl;

[0013] The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from R' 13 Replace C 1～6 Alkyl, C 2～6 olefin group, C 3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, R 14 Substitute heterocyclic group, heteroaryl group, or aryl group; said R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 2～6 olefin group, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl;

[0014] The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group, R 17 Replace C3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 15 R 16 R 17 R can be monosubstituted, polysubstituted, or unsubstituted. 15 R 16 R 17 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, -B(OH)2, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 alkoxy, heterocyclic, heteroaryl or R 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 2～6 olefin group, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl;

[0015] Wherein, the R 3 and R 4 Not simultaneously selected from hydrogen; the R 2 When R is selected from hydrogen, 3 Selected from -OR 3 ';The R 3 When R is selected from hydrogen, 2 Selected from -OR 2 ';The C 3～6 The cycloalkyl group is a saturated monocyclic cycloalkyl group; the heterocyclic group is a 5- to 6-membered aliphatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon; the heteroaryl group is a 5- to 6-membered aromatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon.

[0016] Furthermore, the R 1 Selected from R 5 Replace C 1～6 Alkyl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each group is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6Alkoxy, halogenated C 1～6 Alkoxy, C 1～6 Alkyl group, C 3～6 cycloalkyl, heterocyclic, heteroaryl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, ester, and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～ 6-alkoxy, C 2～6 olefin group, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl;

[0017] The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～6 Alkyl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, -NR 8 R 9 -N + R 10 R 11 R 12 Substitute heterocyclic group, heteroaryl group, or aryl group; said R 8 and R 9 Each is independently selected from hydrogen and C. 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 10 and R 11 Selected from C 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, ester, and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl;

[0018] The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from R' 13 Replace C 1～6 Alkyl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, R 14 Substitute heterocyclic group, heteroaryl group, or aryl group; said R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl;

[0019] The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group or R 17 Replace C 3～6 cycloalkyl; the R 15 R can be monosubstituted, polysubstituted, or unsubstituted. 15 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, -B(OH)2, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 alkoxy, heterocyclic, heteroaryl or R 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6Alkoxy, C 2～6 olefin group, C 3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 16 R can be monosubstituted, polysubstituted, or unsubstituted. 16 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide groups; The R group... 17 R can be monosubstituted, polysubstituted, or unsubstituted. 17 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide.

[0020] Furthermore, the R 1 Selected from R 5 Replace C 1～6 Alkyl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each is independently selected from hydrogen, halogen, and C. 3～6 cycloalkyl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each is independently selected from hydrogen and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl or halogen;

[0021] The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～6 Alkyl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each is independently selected from hydrogen and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy, -NR 8 R 9 -N + R 10 R 11 Or R 12 Substituted heterocyclic group; the R 8 and R 9 Each is independently selected from hydrogen and C. 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 10 and R 11 Selected from C 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each is independently selected from hydrogen and C.1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl;

[0022] The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from R' 13 Replace C 1～6 Alkyl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each is independently selected from hydrogen and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy or R 14 Substituted heterocyclic group; the R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each is independently selected from hydrogen and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl, heteroaryl, or aryl;

[0023] The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group or R 17 Replace C 3～6 cycloalkyl; the R 15 R can be monosubstituted, polysubstituted, or unsubstituted. 15 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, -B(OH)2, carbonyl, carboxyl, heteroaryl, or R. 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide groups; The R group... 16 R can be monosubstituted, polysubstituted, or unsubstituted. 16 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide groups; The R group... 17 R can be monosubstituted, polysubstituted, or unsubstituted. 17 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide.

[0024] Preferably, the R 1 For R 5 Replace C 1～6 Alkyl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each is independently selected from hydrogen and C. 3～6 cycloalkyl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each is independently selected from hydrogen and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, fluorine, chlorine, iodine, or bromine;

[0025] The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～6 Alkyl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each is independently selected from hydrogen and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy, Or R 12 Substituted heterocyclic group; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each is independently selected from hydrogen and C. 1～6 Alkyl or halogenated C 1～6 alkyl;

[0026] The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from R' 13 Replace C 1～6 Alkyl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each is independently selected from hydrogen and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy or R 14 Substituted heterocyclic group; the R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each is independently selected from hydrogen and C. 1～6 Alkyl or halogenated C 1～6 alkyl;

[0027] The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C2～6 olefin group or R 17 Replace C 3～6 cycloalkyl; the R 15 R can be monosubstituted, polysubstituted, or unsubstituted. 15 Each group is independently selected from hydrogen, hydroxyl, mercapto, -B(OH)2, carboxyl, heteroaryl, or R. 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, hydroxyl, or amide groups; the R group... 16 R can be monosubstituted, polysubstituted, or unsubstituted. 16 Each group is independently selected from hydrogen or carboxyl groups; the R group 17 R can be monosubstituted, polysubstituted, or unsubstituted. 17 Each group is independently selected from hydrogen or carboxyl groups.

[0028] More preferably, the R 1 Selected from R 5 Replace C 1～3 Alkyl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each is independently selected from hydrogen and C. 3～6 cycloalkyl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each is independently selected from hydrogen and C. 1～3 Alkyl, Halogenated C 1～3 Alkyl, fluorine, chlorine, iodine, or bromine;

[0029] The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～3 Alkyl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each is independently selected from hydrogen and C. 1～3 Alkoxy, halogenated C 1～3 Alkoxy, Or R 12 Substituted heterocyclic group; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each is independently selected from hydrogen and C. 1～3 Alkyl or halogenated C 1～3 alkyl;

[0030] The R 3 Selected from hydrogen or -OR 3 ', the R3 'Selected from R' 13 Replace C 1～3 Alkyl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each is independently selected from hydrogen and C. 1～3 Alkoxy, halogenated C 1～3 Alkoxy or R 14 Substituted heterocyclic group; the R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each is independently selected from hydrogen and C. 1～3 Alkyl or halogenated C 1～3 alkyl;

[0031] The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group or R 17 Replace C 3～6 cycloalkyl; the R 15 R can be monosubstituted, polysubstituted, or unsubstituted. 15 Each group is independently selected from hydrogen, hydroxyl, mercapto, -B(OH)2, carboxyl, heteroaryl, or R. 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, hydroxyl, or amide groups; the R group... 16 R can be monosubstituted, polysubstituted, or unsubstituted. 16 Each group is independently selected from hydrogen or carboxyl groups; the R group 17 R can be monosubstituted, polysubstituted, or unsubstituted. 17 Each group is independently selected from either hydrogen or carboxyl groups;

[0032] Wherein, the C 3～6 The cycloalkyl group is a saturated monocyclic cycloalkyl group; the heterocyclic group is a 5- to 6-membered aliphatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N and O, with the remaining ring atoms being carbon; the heteroaryl group is a 5- to 6-membered aromatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N and O, with the remaining ring atoms being carbon.

[0033] More preferably, the R 1 Selected from R 5 Replace C 1～3 Alkyl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each is independently selected from C 3～6 cycloalkyl or R6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each is independently selected from hydrogen and C. 1～3 Alkyl, Halogenated C 1～3 Alkyl, fluorine, chlorine, iodine, or bromine;

[0034] The R 2 hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～3 Alkyl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each is independently selected from C 1～3 Alkoxy, halogenated C 1～3 Alkoxy, Or R 12 Substituted heterocyclic group; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each is independently selected from hydrogen and C. 1～3 Alkyl or halogenated C 1～3 alkyl;

[0035] The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from R' 13 Replace C 1～3 Alkyl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each is independently selected from C 1～3 Alkoxy, halogenated C 1～3 Alkoxy or R 14 Substituted heterocyclic group; the R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each is independently selected from hydrogen and C. 1～3 Alkyl or halogenated C 1～3 alkyl;

[0036] The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group or R 17 Replace C 3～6 cycloalkyl; the R 15 R can be monosubstituted, polysubstituted, or unsubstituted. 15 Each group is independently selected from hydroxyl, -B(OH)2, carboxyl, heteroaryl, or R. 18Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, hydroxyl, or amide groups; the R group... 16 R can be monosubstituted, polysubstituted, or unsubstituted. 16 Each group is independently selected from hydrogen or carboxyl groups; the R group 17 R can be monosubstituted, polysubstituted, or unsubstituted. 17 Each group is independently selected from either hydrogen or carboxyl groups;

[0037] Wherein, the C 3～6 The cycloalkyl group is a saturated monocyclic cycloalkyl group; the heterocyclic group is a 5- to 6-membered aliphatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N and O, with the remaining ring atoms being carbon; the heteroaryl group is a 5- to 6-membered aromatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N and O, with the remaining ring atoms being carbon.

[0038] Furthermore, as a preferred embodiment, the R 1 for The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from C' 1～3 alkyl,

[0039] The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from C' 1～3 alkyl, The R 4 Selected from hydrogen,

[0040] Specifically, the xanthone-based compound has any of the following structures:

[0041]

[0042] Furthermore, the xanthone-based compound is replaced by its pharmaceutically acceptable salt, its crystal form, its solvate, its stereoisomer, or its isotopic substituted compound.

[0043] This invention protects a pharmaceutical composition comprising one or more of the xanthone-based compounds.

[0044] The present invention also protects the use of the xanthone-based compounds or the pharmaceutical compositions thereof in the preparation of PDE4 (phosphodiesterase type 4) inhibitors.

[0045] The present invention also protects the use of the xanthone-based compound or the pharmaceutical composition of claim 7 in the preparation of a treatment for PDE4-related diseases.

[0046] Furthermore, the PDE4 includes PDE4D.

[0047] Furthermore, the PDE4-related diseases include chronic obstructive pulmonary disease, psoriasis, asthma, allergic dermatitis, ulcerative colitis, Crohn's disease, Alzheimer's disease, Parkinson's disease, depression, anxiety, aging, pulmonary hypertension, pulmonary fibrosis, organ fibrosis, hypertension, diabetes, fatty liver, heart failure, or cancer.

[0048] Furthermore, the cancers include liver cancer, lung cancer, glioblastoma, colorectal cancer, or blood cancer.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] This invention provides a class of novel xanthone-based compounds that, through experiments, exhibit excellent inhibitory effects on phosphodiesterase type 4 (PDE4). These compounds achieve nanomolar levels of activity, with some showing significantly better activity than the positive control Rolipram. They can be used as PDE4 inhibitors for the treatment of PDE4-related diseases and have significant pharmaceutical value and broad application prospects in the preparation of drugs for treating PDE4-related diseases, including pulmonary fibrosis. Attached Figure Description

[0051] Figure 1 The following are statistical graphs showing the in vivo activity of compound 6r in inhibiting pulmonary fibrosis: (A) Figure shows the statistical graphs of airway resistance, functional residual capacity, vital capacity, forced expiratory volume 50, mean mid expiratory flow, and lung compliance in mice after bleomycin modeling; (B) Figure shows HE staining of lung tissue (left) and HE staining score data (right); (C) Figure shows Masson staining (left) and relative collagen content data (right); (D) Figure shows the immunoblotting results of FN1, COL1A1, and α-SMA proteins; (E) Figure shows the immunoblotting results of N-cadherin, Vimenti, and E-cadherin proteins. Detailed Implementation

[0052] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0053] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0054] The reaction pathways for Examples 1-4 are as follows:

[0055]

[0056] Example 1: Synthesis of intermediates 2, 3a-3c

[0057] (1) Synthesis of 1,3,6,7-tetrahydroxy-9H-oxanthone (2)

[0058]

[0059] Mangiferin 1 (50.00 g, 118.39 mmol, 1 eq) and resorcinol (26.07 g, 236.77 mmol, 2 eq) were dissolved in 400 mL of a prepared 3N hydrochloric acid aqueous solution. The mixture was reacted at 120 °C for 12 h and then cooled to room temperature. The pH was adjusted to 5 by adding saturated NaHCO3 solution. The mixture was filtered, the precipitate was collected and washed with methanol, the filtrates were combined, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain a yellow solid compound, mangiferin 2 (22.96 g, 54.36 mmol). 1 H NMR (400MHz, DMSO-d6) δ13.16 (s, 1H), 10.55 (m, 1H), 7.36 (s, 1H), 6.85 (s, 1H), 6.32 (d, J = 2.1Hz, 1H), 6.14 (d, J = 2.0Hz, 2H); 13 C NMR(100MHz,DMSO--d6)δ178.9,164.8,162.6,157.4,154.1,150.8,143.8,111.8,108.0,102.7,101.6,97.7,93.6.ESI-HRMSm / z[M+H] + calcd for C 13 H8O6261.0323, found 261.0321.

[0060] (2) 6-((4-fluorobenzyl)oxy)-1,3,7-trihydroxy-9H-oxanthracene-9-one (3a):

[0061]

[0062] Compound 2 (400 mg, 1.53 mmol) was dissolved in 5 mL of DMF solvent, and sodium bicarbonate (179.4 mg, 1.83 mmol, 1.2 eq) and sodium iodide (114 mg, 0.76 mmol, 0.5 eq) were added, followed by 4-fluorobenzyl bromide (346 mg, 2.50 mmol, 1.5 eq). The reaction was stirred at 60 °C for 5 hours, and then the reaction was stopped. After cooling to room temperature, 50 mL of distilled water was added, and the pH was adjusted to 5-6 with 1 N hydrochloric acid solution. The mixture was extracted three times with 50 mL of ethyl acetate each time. The organic phase was dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain a yellow solid compound 3a (244.3 mg, 6.63 mmol). 1 H NMR (400MHz, DMSO-d6) δ13.04 (s, 1H), 7.57 (dd, J = 8.6, 5.6Hz, 2H), 7.41 (s, 1H), 7.29 –7.24(m,2H),7.23(s,1H),6.34(d,J=2.1Hz,1H),6.17(d,J=2.1Hz,1H),5.27(s,2H). 13 C NMR(100MHz,DMSO-d6)δ179.4,165.4(d,J=247.67Hz,J C -F),163.6,163.1,161.2,157.9,154.3,151.1,145.0,132.8,132.8,130.8, 130.7,115.9,115.7,113.3,108.3,102.2,101.8,98.3,94.1,70.1.ESI-HRMS m / z[M+H] + calcd for C 20 H 13 FO6 369.0696, found 369.0690.

[0063] (3) 6-(cyclopropylmethoxy)-1,3,7-trihydroxy-9H-oxanthracene-9-one (3b):

[0064]

[0065] Using compound 2 and bromomethylcyclopropane as raw materials, yellow solid compound 3b was synthesized by referring to the method of compound 3a. 1HNMR(400MHz,DMSO--d6)δ13.07(s,1H),7.38(s,1H),7.03(s,1H),6.31(d,J=2.1Hz,1H),6.1 5(d,J=2.1Hz,1H),3.96(d,J=7.0Hz,2H),1.32–1.27(m,1H),0.61(m,2H),0.38–0.36(m,2H). 13 C NMR(100MHz,DMSO--d6)δ178.9,164.8,162.6,157.4,154.4,150.8,144.4,11 2.4,107.5,101.7,100.7,97.8,93.6,73.5,9.9,3.3(2×C).ESI-HRMSm / z[M+H] + calcdfor C 17 H 14 O6315.0824, found 315.0823.

[0066] (4) 6-ethoxy-1,3,7-trihydroxy-9H-oxanthracene-9-one (3c):

[0067]

[0068] Using compound 2 and bromoethane as raw materials, a yellow solid compound 3c was synthesized by referring to the method of compound 3a. 1 H NMR (400MHz, DMSO-d6)δ 1 H NMR (400MHz, DMSO-d6) δ13.07(s,1H),7.38(s,1H),7.03(s,1H),6.31(d,J=2 .1Hz,1H),6.15(d,J=2.1Hz,1H),4.18(q,J=6.4Hz,2H),1.47(t,J=6.4,3H). 13 CNMR(100MHz,DMSO-d6)δ178.9,164.8,162.6,157.4,154.4,150.8,144.4,112.4,107.5,101.7,100.7,97.8,93.6,64.5,13.8.

[0069] Example 2 Synthesis of intermediates 4a-4c

[0070] (1) 9-((4-fluorobenzyl)oxy)-5,8-dihydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]oxanthracene-6-one (4a):

[0071]

[0072] Compound 3a (200 mg, 0.55 mmol) was dissolved in 10 mL of anhydrous methanol, and 3-methyl-2-butenal (104 μL, 1.09 mmol, 2 eq), calcium hydroxide (20 mg, 0.27 mmol, 0.5 eq), and calcium chloride (30 mg, 0.27 mmol, 0.5 eq) were added. The mixture was stirred at room temperature for 48 h. The reaction was then stopped. The precipitate was filtered and washed repeatedly with methanol and ethyl acetate. The filtrate was collected and concentrated to obtain the crude product. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain a yellow solid compound 4a (110 mg, 0.28 mmol). 1 H NMR(400MHz, Acetone-d6)δ13.50(s,1H),7.63(dd,J=8.5,5.6Hz,2H),7.52(s,1H),7.24–7.15(m,3H) ,6.67(d,J=10.1Hz,1H),6.29(s,1H),5.73(d,J=10.1Hz,1H),5.36(s,2H),2.09(s,1H),1.46(s,6H). 13 C NMR(100MHz,Acetone-d6)δ179.8,163.9(d,J=247.67Hz,J C -F),161.4,160.0,157.4,157.2,153.8,151.3,144.7,132.2,132.2,130.4,130.3,127.8,115.4, 115.1,114.9,113.6,108.2,104.2,102.9,101.0,94.4,78.1,70.3,27.6(C×2).ESI-HRMSm / z[M+H] + calcd for C 25 H 19 FO6 435.1166, found435.1163.

[0073] (2) 9-(cyclopropylmethoxy)-5,8-dihydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]oxanthracene-6-one (4b):

[0074]

[0075] Using compound 3b and 3-methyl-2-butenal as raw materials, a yellow solid compound 4b was synthesized by referring to the method of compound 4a. 1H NMR (400MHz, CDCl3) δ13.31(s,1H),7.64(s,1H),6.80(s,1H),6.73(d,J=10.0Hz,1H),6.28(s,1H),5.74(s,1H) ,5.58(d,J=10.0Hz,1H),3.99(d,J=7.1Hz,2H),1.47(s,6H),1.38-1.33(m,1H),0.73(m,2H),0.43-0.40(m,2H). 13 C NMR (100MHz, CDCl3) δ180.1,160.2,157.7,157.3,152.4,151.7,143.2,127.5,115.7,114.2, 108.4,104.6,103.5,99.7,94.8,78.2,74.8,28.5(2×C),10.0,3.7(2×C).ESI-HRMSm / z[M+H] + calcd forC 22 H 20 O6381.1332, found 381.1336.

[0076] (3) 9-ethoxy-5,8-dihydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]oxanthracene-6-one (4c):

[0077]

[0078] Using compound 3c and 3-methyl-2-butenal as raw materials, a yellow solid compound 4c was synthesized by referring to the method of compound 4a. 1 H NMR (400MHz, CDCl3) δ9.15 (s, 1H), 7.36 (s, 1H), 6.78 (s, 1H), 6.72 (d, J = 11.0Hz, 1H), 6.49 (s, 1H) ,6.17(d,J=11.0Hz,1H),4.20(q,J=6.0Hz,2H),3.93(s,3H),1.49(t,J=6.0Hz,3H),1.45(s,6H). 13 C NMR (100MHz, CDCl3) δ178.52,159.46,159.43,159.17,156.18,153.96,149.42,127.63,11 7.11,114.90,108.65,106.02,103.57,100.49,94.92,77.26,64.51,56.78,27.71,13.82.

[0079] Example 3 Synthesis of intermediates 5a-5i

[0080] (1) 9-((4-fluorobenzyl)oxy)-5-hydroxy-8-methoxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]oxanthracene-6-one (5a):

[0081]

[0082] Compound 4a (110 mg, 0.25 mmol) was dissolved in 4 mL of DMF, and anhydrous potassium carbonate (42 mg, 0.30 mmol, 1.2 eq) and methyl iodoform (19 μL, 0.30 mmol, 1.2 eq) were added. The reaction was allowed to proceed overnight at room temperature, and then the reaction was stopped. 40 mL of water was added, and the mixture was extracted three times with 40 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was separated by silica gel column chromatography to give the pale yellow solid compound 5a (75 mg, 0.16 mmol). 1 H NMR (400MHz, CDCl3) δ13.27(s,1H),7.51(s,1H),7.45(s,2H),7.09(s,2H),6.82(s, 1H),6.72(s,1H),6.27(s,1H),5.59(s,1H),5.17(s,2H),3.94(s,3H),1.47(s,6H). 13 C NMR (100MHz, CDCl3) δ179.74,163.98,161.52,160.05,157.39,157.03,154.33,151.97,147.01,131.27,131.24,129.4 0,129.32,127.49,115.88,115.67,113.49,104.74,104.55,103.30,100.99,94.80,78.11,70.47,56.31,28.36(2×C).

[0083] (2) 9-(cyclopropylmethoxy)-5-hydroxy-8-methoxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]oxanthracene-6-one (5b):

[0084]

[0085] Using compound 4b and iodomethane as raw materials, the reaction was stopped after reacting at 60°C for 20 h. Other steps, reagents, and parameters were the same as those for compound 5a to synthesize yellow solid compound 5b. 1H NMR (400MHz, CDCl3) δ13.32(s,1H),7.51(d,J=1.3Hz,1H),6.80(d,J=1.4Hz,1H),6.72(d,J=10.0Hz,1H),6.28(d,J=1.6Hz,1H) ,5.58(d,J=10.1Hz,1H),3.95(d,J=7.7Hz,5H),1.47(s,6H),1.45–1.36(m,1H),0.77–0.67(m,2H),0.42(dt,J=6.3,4.8Hz,2H). 13 C NMR (100MHz, CDCl3) δ179.83,159.96,157.44,157.08,155.05,152.25,146.92,127.43,115.56,113.05,104 .53,104.52,103.33,100.28,94.77,78.07,74.36,56.34,28.37(2×C),10.93,3.63(2×C).ESI-HRMSm / z[M+H] + calcdfor C 23 H 22 O6397.1606, found 397.1610.

[0086] (3) 9-(cyclopropylmethoxy)-5-hydroxy-8-methoxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]oxanthracene-6-one (5c):

[0087]

[0088] Using compound 4c and iodomethane as raw materials, a yellow solid compound 5c was synthesized by referring to the method of compound 5b. 1 HNMR(400MHz, CDCl3)δ9.15(s,1H),7.31(s,1H),7.29–7.20(m,2H),7.13(t,J=7.7Hz,2H),6.77(s,1H),6.71(dd,J=10.9, 0.8Hz,1H),6.44(s,1H),6.07(dd,J=10.9,6.1Hz,1H),5.15(s,2H),4.53–4.43(m,1H),3.93(s,3H),1.61(d,J=5.7Hz,3H). 13C NMR (100MHz, CDCl3) δ178.52,163.53,161.44,161.08,160.04,158.72,158.69,152.74,148.75,131.95,131.92,129.74 ,129.68,123.19,120.10,115.11,114.90,114.13,107.64,106.66,103.59,101.43,93.26,71.43,67.27,56.78,17.94.

[0089] (4) 9-(cyclopropylmethoxy)-5-hydroxy-8-(2-hydroxyethoxy)-2,2-dimethyl-2H,6H-pyrano[3,2-b]oxanthracene-6-one (5d):

[0090]

[0091] Using compound 4b and 2-bromoethanol as raw materials, a yellow solid compound 5d was synthesized by referring to the method of compound 5b. 1 HNMR (400MHz, CDCl3) δ13.24(s,1H),7.58(s,1H),6.78(s,1H),6.72(d,J=10.0Hz,1H),6.28(s,1H),5.59(d,J=10.0Hz,1H),4.2 5–4.17(m,2H),4.01–3.96(m,2H),3.94(d,J=7.0Hz,2H),1.47(s,6H),1.40–1.33(m,1H),0.76–0.66(m,2H),0.47–0.37(m,2H). 13 C NMR (100MHz, CDCl3) δ179.86,160.20,157.57,157.18,155.74,152.78,145.94,127.59,115.65,113.33,108.32, 104.70,103.41,100.65,94.94,78.25,77.48,77.16,76.84,74.40,71.91,61.28,28.50(2×C),9.97,3.65(2×C).

[0092] (5) 9-(cyclopropylmethoxy)-5-hydroxy-8-(2-methoxyethoxy)-2,2-dimethyl-2H,6H-pyrano[3,2-b]oxanthracene-6-one (5e):

[0093]

[0094] Using compound 4b and 2-bromoethyl methyl ether as raw materials, a yellow solid compound 5e was synthesized by referring to the method of compound 5b. 1 H NMR (400MHz, CDCl3) δ13.31(s,1H),7.57(s,1H),6.81(s,1H),6.72(d,J=10.0Hz,1H),6.29(s,1H),5.58(d,J=10.0Hz,1H),4 .27–4.23(m,2H),3.95(d,J=6.9Hz,2H),3.85–3.82(m,2H),1.47(s,6H),1.41–1.35(m,1H),0.71–0.66(m,2H),0.41(m,2H). 13 C NMR (100MHz, CDCl3) δ180.0,160.1,157.6,157.2,155.7,152.6,146.4,127.6,115.7,113.2,106.9,10 4.7,103.5,100.8,94.9,78.2,74.2,70.9,69.1,59.5,28.5(2×C),10.0,3.6(2×C).ESI-HRMSm / z[M+H] + calcd for C 25 H 26 O7 439.1712, found 439.1713.

[0095] (6) 9-(cyclopropylmethoxy)-8-(2-(dimethylamino)ethoxy)-5-hydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]oxanthracene-6-one (5f):

[0096]

[0097] Compound 4b (300 mg, 0.78 mmol) was dissolved in 5 mL of DMF solvent, and potassium carbonate (218 mg, 1.58 mmol, 2 eq) and 1,2-dibromoethane (593 mg, 3.15 mmol, 4 eq) were added. The mixture was heated and stirred at 60 °C for 6 hours, after which the reaction was stopped. After cooling to room temperature, 60 mL of distilled water was added, and the pH was adjusted to 5-6 with 1 N hydrochloric acid solution. The mixture was extracted three times with 60 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain the intermediate product (206 mg, 0.43 mmol). The intermediate product (50 mg, 0.10 mmol) was added to 5 mL of acetone solution, and potassium carbonate (43 mg, 0.30 mmol, 3 eq) and dimethylamine solution (10 mg, 0.20 mmol, 2 eq) were added. The mixture was stirred at room temperature for 6 hours, after which the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was separated by silica gel column chromatography to obtain a yellow solid compound 5f (38 mg, 0.08 mmol). 1 H NMR (400MHz, CDCl3) δ7.49 (s, 1H), 6.75 (d, J = 2.9Hz, 1H), 6.69 (dd, J = 10.1, 1.9Hz, 1H), 6.25 (d, J = 2. 4Hz,1H),5.55(dd,J=10.0,1.6Hz,1H),4.16(td,J=5.7,1.8Hz,2H),3.91(dd,J=6.9,2.0Hz,2H),2.8 2-2.77(m,2H),2.60(s,2H),2.35(d,J=1.4Hz,6H),2.15(d,J=1.4Hz,3H),1.44(d,J=1.5Hz,6H),1.3 5(td,J=8.0,7.4,3.6Hz,1H),1.22(d,J=1.5Hz,6H),0.67(qd,J=6.1,2.9Hz,2H),0.42–0.35(m,2H). 13 C NMR (100MHz, CDCl3) δ210.89,179.86,160.02,157.49,157.12,155.50,152.43,146.22,127.47,115.62,113.11,106.34,104.56,103. 36,100.49,94.84,78.12,77.48,77.16,76.84,74.15,69.57,67.56,57.96,53.92,45.92,31.82,29.35,28.42(2×C),9.90,3.51(2×C).

[0098] (7) 2-((9-(cyclopropylmethoxy)-5-hydroxy-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthanene-8-yl)oxy)-N,N,N-trimethylethyl-1-amine (5g):

[0099]

[0100] Compound 5f (33 mg, 0.07 mmol) was added to 1 mL of DMF solvent, followed by iodomethane (11 mg, 0.09 mmol, 1.3 eq). The reaction was carried out at 0 °C for 3 hours, after which the reaction was terminated. 20 mL of distilled water was added, and the mixture was extracted three times with 20 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Separation by silica gel column chromatography yielded a yellow solid compound of 5 g (33 mg, 0.07 mmol), with a yield of 95.86%. 1 H NMR (400MHz, CDCl3) δ12.95(s,1H),7.24(s,1H),6.60(d,J=10.0Hz,1H),6.22(s,1H),6.12(s,1H),5.59(d,J=10.1Hz,1H),4.60( d,J=4.6Hz,2H),4.39–4.26(m,2H),3.71(s,9H),3.58(d,J=7.1Hz,2H),1.47(s,6H),0.68(t,J=6.6Hz,2H),0.35(t,J=5.1Hz,2H). 13 C NMR (100MHz, CDCl3) δ178.52,159.46,159.18,158.75,156.19,152.17,149.11,127.63,117.11,115 .56,107.83,106.02,104.80,100.50,94.92,77.27,73.91,69.15,68.15,54.72,27.72,10.92,6.11.

[0101] (8) 9-(cyclopropylmethoxy)-5-hydroxy-2,2-dimethyl-8-(2-morpholinoethoxy)-2H,6H-pyrano[3,2-b]oxanthracene-6-one (5h):

[0102]

[0103] An intermediate was synthesized using compound 4b and 1,2-dibromoethane as raw materials. Then, the intermediate was reacted with morpholine as a raw material to synthesize a yellow solid compound 5h, following the method used for compound 5f. 1H NMR (400MHz, CDCl3) δ13.30(s,1H),7.55(s,1H),6.79(s,1H),6.72(d,J=10.0Hz,1H),6.29(s,1H),5.59(d,J=10.0Hz,1H),4.24(t,J=5.6Hz,2H ),3.94(d,J=6.9Hz,2H),3.76-3.73(m,4H),2.88(d,J=5.6Hz,2H),2.67 -2.64(m,4H),1.47(s,6H),1.37-1.33(m,1H),0.68(m,2H),0.41(m,2H). 13 C NMR (100MHz, CDCl3) δ180.0,160.1,157.6,157.2,155.6,152.6,146.2,127.6,115.7,113.2,106.7,104.7,103 .5,100.6,94.9,78.2,74.1,67.7,67.1(2×C),57.5,54.3(2×C),28.5(2×C),10.0,3.5(2×C).ESI-HRMSm / z[M+H] + calcd for C 28 H 31 NO7 494.2134, found494.2139.

[0104] (10) 9-(cyclopropylmethoxy)-5-hydroxy-2,2-dimethyl-8-(2-(4-methylpiperazin-1-yl)ethoxy)-2H,6H-pyrano[3,2-b]oxanthracene-6-one (5i):

[0105]

[0106] An intermediate was synthesized using compound 4b and 1,2-dibromoethane as raw materials. Then, the intermediate was reacted with methylpiperazine as a raw material to synthesize yellow solid compound 5i, following the method used for compound 5i. 1H NMR (400MHz, CDCl3) δ12.99(s,1H),7.26(s,1H),6.50(s,1H),6.44(d,J=9.8Hz,1H),6.01(s,1H),5.30(d,J=10.0Hz,1H),3.95(s,2H),3.65( d,J=6.9Hz,2H),2.62(s,2H),2.46(s,4H),2.22(s,4H),2.02(s,3H),1.18(s,6H),1.07(s,1H),0.40(d,J=9.6Hz,2H),0.12(d,J=6.0Hz,2H). 13 C NMR (100MHz, CDCl3) δ179.84,159.98,157.47,157.09,155.48,152.43,146.15,127.43,115.56,113.11,106.49, 104.52,103.35,100.48,94.77,78.07,73.95,67.68,56.88,55.07,53.58,45.99,28.36(2×C),9.87,3.37(2×C).

[0107] Example 4 Synthesis of target compound 6a-6u

[0108]

[0109] (1) 9-((4-fluorobenzyl)oxy)-8-methoxy-2,2-dimethyl-5-(pyridin-4-methoxy)-2H,6H-pyrano[3,2-b]oxanthracene-6-one (6a):

[0110] Compound 5a (10 mg, 0.02 mmol) was dissolved in 1 mL of DMF solvent, and sodium hydride (7 mg, 0.11 mmol, 5 eq) and 2-(bromomethyl)pyridine hydrobromide (11 mg, 0.04 mmol, 2 eq) were added. The mixture was stirred at 0 °C for 12 hours, after which the reaction was stopped. 20 mL of water was added, and the pH was adjusted to 5-6 with 1 N hydrochloric acid solution. The mixture was extracted three times with 20 mL of ethyl acetate each time. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was separated by semi-preparative liquid chromatography to obtain a white solid compound 6a (3 mg). 1HNMR (400MHz, CDCl3) δ8.65(s,2H),7.63(s,1H),7.53(d,J=5.2Hz,2H),7.45(d,J=3.0Hz,2H),7.09(t,J=8.7Hz,2H),6.85 (s,1H),6.64(s,1H),6.60(d,J=10.1Hz,1H),5.64(d,J=10.1Hz,1H),5.20(s,2H),5.10(s,2H),3.95(s,3H),1.46(s,6H). 13 C NMR (100MHz, CDCl3) δ174.42,163.95,161.50,158.61,158.59,153.94,153.63,150.84,149.88,147.05,146.43,131.43,131.40,130.68,1 29.36,129.27,122.28,115.95,115.87,115.79,115.66,112.51,110. 25,105.87,101.12,100.80,77.91,74.72,70.47,56.35,28.33(2×C).

[0111] (2) 4-((9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthanene-5-yl)oxy)propionic acid (6b):

[0112]

[0113] Compound 5b (20 mg, 0.05 mmol) was dissolved in 2 mL of DMF solvent, and cesium carbonate (33 mg, 0.10 mmol, 2 eq) and ethyl 3-bromopropionate (18.1 mg, 0.10 mmol, 2 eq) were added. The mixture was heated and stirred at 60 °C for 4 hours, after which the reaction was stopped. After cooling to room temperature, 20 mL of water was added, and the mixture was extracted three times with 20 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain the intermediate product (22 mg, 0.056 mmol). The intermediate product was added to 1.5 mL of DMF solvent, and a prepared sodium hydroxide solution (65 mg / mL 100 μL, i.e., 6.5 mg, 0.15 mmol) was added. The mixture was heated and stirred at 60 °C for 5 hours, after which the reaction was stopped. After cooling to room temperature, 10 mL of water was added, and the pH was adjusted to 3-4 with 1N hydrochloric acid solution. The mixture was extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was then separated by silica gel column chromatography to obtain a pale yellow solid compound, 6b. 1HNMR (400MHz, CDCl3) δ7.44(s,1H),6.94(s,1H),6.76(d,J=11.0Hz,1H),6.71(s,1H),6.17(d,J=10.8Hz,1H),4.30(t,J=4.9Hz ,2H),3.99–3.90(m,5H),2.77(t,J=4.9Hz,2H),1.45(s,6H),1.11(tt,J=9.9,6.9Hz,1H),0.69–0.53(m,2H),0.50–0.30(m,2H). 13 C NMR (100MHz, CDCl3) δ175.35,173.61,158.87,157.92,156.85,156.46,153.18,148.97,126.52,118.38, 114.43,110.48,108.32,107.23,103.58,98.02,77.27,73.91,68.83,56.79,33.98,27.72,10.92,6.11.

[0114] (3) 4-((9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthanene-5-yl)oxy)butyric acid (6c):

[0115]

[0116] Using compound 5b and ethyl 4-bromobutyrate as raw materials, yellow solid compound 6c was synthesized by referring to the method of compound 6b. 1 H NMR (400MHz, CDCl3) δ7.60(s,1H),6.78(s,1H),6.68(d,J=10.1Hz,1H),6.59(s,1H),5.69(d,J=10.1Hz,1H),4.05(t,J=6.0Hz,2H),3.97(s,3H),3. 95(d,J=7.1Hz,2H),2.77(t,J=7.1Hz,2H),2.26(p,J=6.5Hz,2H),1.46(s, 6H),1.42–1.37(m,1H),0.70(q,J=5.5,4.9Hz,2H),0.41(q,J=4.9Hz,2H). 13C NMR (100MHz, CDCl3) δ178.4,174.9,158.8,158.7,154.8,154.5,151.2,147.0,130.5,116.3,115.4,112 .5,110.3,105.7,100.7,100.0,77.9,74.4,56.5,28.5(2×C),25.7,10.0,3.7(2×C).ESI-HRMSm / z[M+H] + calcd for C 27 H 28 O8481.1818, found481.1816.

[0117] (4) 4-((9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthanen-5-yl)oxy)valerate (6d):

[0118]

[0119] Using compound 5b and ethyl 5-bromopentanoate as raw materials, a yellow solid compound 6d was synthesized by referring to the method of compound 6b. 1 H NMR (100MHz, CDCl3) δ7.37 (s, 1H), 6.81 (dd, J=26.0, 15.0Hz, 3H), 6.17 (d, J= 10.8Hz,1H),4.09(t,J=7.6Hz,2H),3.92(s,3H),3.85(d,J=7.5Hz,2H),2.30( t,J=8.1Hz,2H),1.93(tt,J=7.7,5.5Hz,2H),1.66(tt,J=8.1,5.5Hz,2H),1. 45(s,6H),1.11(tt,J=9.8,7.6Hz,1H),0.77–0.61(m,2H),0.53–0.36(m,2H). 13 C NMR (100MHz, CDCl3) δ177.13,173.61,158.87,157.92,156.85,156.46,153.18,148.97,126.52,118.38,114.43 ,110.48,108.32,107.23,103.58,98.02,77.27,73.91,72.67,56.79,34.64,28.16,27.72,22.02,10.92,6.11.

[0120] (5) 9-(cyclopropylmethoxy)-5-(4-hydroxybutoxy)-8-methoxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthanene-6-one (6e):

[0121]

[0122] Using compound 5b and 4-bromobutanol as raw materials, a yellow solid compound 6e (40%) was synthesized by referring to the method of compound 6a. 1 H NMR (400MHz, CDCl3) δ7.44 (s, 1H), 6.95 (s, 1H), 6.82 (d, J = 11.0Hz, 1H), 6.76 ( s,1H),6.17(d,J=10.8Hz,1H),4.10(t,J=4.7Hz,2H),3.96(d,J=6.8Hz,2H),3 .92(s,3H),3.68(t,J=7.7Hz,2H),2.10–1.85(m,2H),1.67(p,J=7.9Hz,2H),1 .45(s,6H),1.11(tt,J=9.9,6.9Hz,1H),0.66–0.44(m,2H),0.52–0.21(m,2H). 13 C NMR (100MHz, CDCl3) δ173.61,158.87,157.92,156.85,156.46,153.18,148.97,126.52,118.38,114.43,11 0.48,108.32,107.23,103.58,98.02,77.27,73.91,72.67,62.44,56.79,30.16,27.72,26.77,10.92,6.11.

[0123] (6) 9-(cyclopropylmethoxy)-5-(4-mercaptobutoxy)-8-methoxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthanene-6-one (6f):

[0124]

[0125] Using compound 5b and 4-bromobutyritin as raw materials, a yellow solid compound 6f (42%) was synthesized by referring to the method of compound 6a. 1H NMR (400MHz, CDCl3) δ7.52(s,1H),7.03(s,1H),6.78(t,J=5.4Hz,2H),6.17(d,J=1 0.8Hz,1H),4.13(t,J=7.4Hz,2H),4.01(d,J=7.4Hz,2H),3.90(s,3H),2.53(t,J=7. 9Hz,2H),1.88(tt,J=7.4,5.5Hz,2H),1.61(tt,J=7.9,5.5Hz,2H),1.45(s,6H),1.3 1(s,1H),1.11(ddt,J=12.2,9.8,4.9Hz,1H),0.81–0.58(m,2H),0.54–0.26(m,2H). 13 C NMR (100MHz, CDCl3) δ173.61,158.87,157.92,156.85,156.46,153.18,148.97,126.52,118.38,114.43,11 0.48,108.32,107.23,103.58,98.02,77.27,73.91,72.67,56.79,30.79,27.72,27.12,25.38,10.92,6.11.

[0126] (7)(3-((9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthanene-5-yl)oxo)propyl)boronic acid (6g):

[0127]

[0128] Using compound 5b and (2-(3-bromopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane as raw materials, a yellow solid compound 6g was synthesized by referring to the method of compound 6a. 1 H NMR (400MHz, CDCl3) δ7.58(s,1H),6.79(s,1H),6.61(s,2H),6.56(s,1H),6.48(s,1H),5.57(s,1H),4.20(s,2H),4.05 (s,2H),3.85(s,3H),1.71(s,2H),1.45(s,6H),1.33(s,1H),0.91(s,2H),0.72(d,J=5.1Hz,2H),0.47(d,J=4.9Hz,2H). 13C NMR (100MHz, CDCl3) δ173.61,158.87,157.92,156.85,156.46,153.18,148.97,126.52,118.38,114.43 ,110.48,108.32,107.23,103.58,98.02,77.27,73.91,73.01,56.79,27.72,22.57,12.28,10.92,6.11.

[0129] (8) 4-((9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthanene-5-yl)oxy)-N-hydroxybutyramide (6h):

[0130]

[0131] Compound 5b (20 mg, 0.05 mmol) was dissolved in 2 mL of DMF solvent, and cesium carbonate (33 mg, 0.10 mmol, 2 eq) and ethyl 4-bromobutyrate (19.5 mg, 0.10 mmol, 2 eq) were added. The mixture was heated and stirred at 60 °C for 3 hours, after which the reaction was stopped. After cooling to room temperature, 20 mL of water was added, and the mixture was extracted three times with 20 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain the intermediate product (21 mg, 0.04 mmol). Hydroxylamine hydrochloride (13 mg, 0.19 mmol) and sodium hydroxide (19 mg, 0.48 mmol) were added sequentially to 5 mL of dry acetone. After stirring at room temperature for 10 min, the intermediate was added to the reaction mixture, and the mixture was reacted at 50 °C for 7 h. After the reaction was completed, the solvent was removed under reduced pressure, 10 mL of water was added, the pH was adjusted to 1 with 1N dilute sulfuric acid solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to give a yellow solid (10.3 mg, 0.02 mmol) over 6 hours, with a yield of 41%. 1H NMR (400MHz, CDCl3) δ7.41(s,1H),6.87(s,1H),6.76(d,J=10.9Hz,2H),6.17(d,J=10.8Hz,1H),5.88(s,1H),4.14(t,J=7.7Hz,2H),3.97(d,J=7.7Hz ,2H),3.93(s,3H),3.19(s,1H),2.25(t,J=8.1Hz,2H),2.04(p,J=7.9Hz,2 H),1.45(s,6H),1.22–1.00(m,1H),0.76–0.55(m,2H),0.51–0.27(m,2H). 13 C NMR (100MHz, CDCl3) δ173.61,171.32,158.87,157.92,156.85,156.46,153.18,148.97,126.52,118.38,114 .43,110.48,108.32,107.23,103.58,98.02,77.27,73.91,72.22,56.79,32.16,27.72,25.65,10.92,6.11.

[0132] (9) 9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-5-(pyridin-4-methoxy)-2H,6H-pyrano[3,2-b]oxanthracene-6-one (6i):

[0133]

[0134] Using compound 5b and 2-(bromomethyl)pyridine hydrobromide as raw materials, a yellow solid compound 6i was synthesized by referring to the method of compound 6a. 1 H NMR (400MHz, CDCl3) δ8.65(d,J=5.1Hz,2H),7.61(s,1H),7.56–7.49(m,2H),6.81(s,1H),6.64(s,1H),6.60(d,J=10.1Hz,1H),5.64(d,J= 10.1Hz,1H),5.11(s,2H),3.96(d,J=6.0Hz,5H),1.46(s,6H),1.40(td,J=7.5,3.9Hz,1H),0.77–0.66(m,2H),0.42(dt,J=6.0,4.8Hz,2H). 13C NMR (100MHz, CDCl3) δ174.47,158.64,158.48,154.34,153.96,151.07,149.90,146.93,146.43,130.60,122.25,1 16.37,115.32,112.45,110.31,106.38,101.62,99.99,77.86,74.73,74.32,56.36,28.34(2×C),9.90,3.62(2×C).

[0135] (10) 4-(((9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthanene-5-yl)oxy)methyl)benzoic acid (6j):

[0136]

[0137] Using compound 5b and ethyl 4-(bromomethyl)benzoate as raw materials, a pale yellow solid compound 6j was synthesized by referring to the method of compound 6b, with a yield of 80%. 1 H NMR (400MHz, CDCl3) δ8.53(d,J=7.4Hz,2H),7.45–7.32(m,3H),6.81(d,J=10.9Hz,2H),6.73(s,1H),6.17(d,J=10.8Hz,1H ),5.80(s,2H),3.96(d,J=7.7Hz,2H),3.94(s,3H),1.45(s,6H),1.18–0.99(m,1H),0.78–0.57(m,2H),0.54–0.26(m,2H). 13 CNMR (100MHz, CDCl3) δ173.61,158.87,157.91,156.69,155.37,153.18,151.56,150.70,148.97,126.52,124 .61,118.38,114.43,110.14,107.84,107.23,103.58,97.37,77.27,73.91,73.89,56.79,27.72,10.92,6.11.

[0138] (11) 4-(((9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]xanthanene-5-yl)oxy)methyl)-N-hydroxybenzamide (6k):

[0139]

[0140] Using compound 5b and ethyl 4-(bromomethyl)benzoate as starting materials, a pale yellow solid compound 6k was synthesized with a yield of 65%, following the method used for compound 6h. 1 H NMR (400MHz, CDCl3) δ7.80(d,J=7.5Hz,2H),7.48(d,J=7.5Hz,2H),7.26(s,1H),6.82(d,J=11.6Hz,1H),6.74(s,0H),6.13( s,0H),5.20(s,2H),4.02(s,1H),3.92(s,1H),2.39(s,0H),1.45(s,6H),1.11(s,1H),0.86–0.55(m,2H),0.56–0.29(m,2H). 13 CNMR (100MHz, CDCl3) δ173.61,169.19,158.87,157.91,156.69,155.37,153.18,148.97,141.96,135.70,127.82,127 .77,126.52,118.38,114.43,110.14,107.84,107.23,103.58,97.37,77.27,73.91,73.89,56.79,27.72,10.92,6.11.

[0141] (12) 4-((9-(cyclopropylmethoxy)-8-(2-methoxyethoxy)-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]oxanthone-5-yl)oxy)butyric acid (6l):

[0142]

[0143] Using compound 5d and ethyl 4-bromobutyrate as raw materials, a white solid 6l was synthesized by referring to the method of compound 6b. 1HNMR (400MHz, CDCl3) δ7.61(s,1H),6.77(s,1H),6.67(d,J=10.0Hz,1H),6.58(s,1H),5.69(d,J=10.0Hz,1H),4.25(t,J=4.7Hz,2H),4.03(d,J=6.0 Hz,2H),3.94(d,J=6.9Hz,2H),3.83(t,J=4.6Hz,2H),2.78(s,2H),2.25(s ,2H),1.46(s,6H),1.40-1.35(m,1H),0.70-0.65(m,2H),0.41(m,2H).13C NMR (100MHz, CDCl3) δ177.7,175.0,158.8,158.7,155.0,154.8,151.5,146.3,130.5,116.3,115.4,112.6,110.3,107. 8,100.8,100.4,78.0,74.5,74.2,70.9,69.0,59.4,31.6,28.5(2×C),25.8,10.0,3.6(2×C).ESI-HRMSm / z[M+H]+calcd for C 29 H 32 O9 525.2080, found 525.2082.

[0144] (13) 9-(cyclopropylmethoxy)-8-(2-methoxyethoxy)-2,2-dimethyl-5-(pyridin-4-methoxy)-2H,6H-pyrano[3,2-b]oxanthracene-6-one (6m):

[0145]

[0146] Using compound 5d and 2-(bromomethyl)pyridine hydrobromide as raw materials, a white solid compound 6m was synthesized by referring to the method of compound 6a. 1 H NMR(400MHz, CDCl3)δ8.65(s,2H),7.63(s,1H),7.53(s,2H),6.81(s,1H),6.65(s,1H),6.59 (s,1H),5.64(d,J=10.1Hz,1H),5.11(s,2H),4.30-4.20(m,2H),3.96(d,J=6.9Hz,2H),3.85 -3.79(m,2H),3.48(d,J=4.4Hz,4H),1.46(s,6H),1.42-1.36(m,1H),0.72-0.65(m,2H),0.42(q,J=4.7Hz,2H). 13C NMR (100MHz, CDCl3) δ173.79,158.65,158.50,154.87,153.95,151.31,149.73(2×C),146.67,146.25,130.60,122.27(2×C),115 .99,115.35,112.44,110.29,107.67,101.11,100.40,77.87,74.71,74.07,70.79,68.90,59.31,29.72,28.34,9.93,3.46(2×C).

[0147] (14) 3-((9-(cyclopropylmethoxy)-8-(2-methoxyethoxy)-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]oxanthracene-5-yl)oxy)cyclobutane-1-carboxylic acid (6n):

[0148]

[0149] Using compound 5d and methyl 3-bromocyclobutane-1-carboxylate as raw materials, a yellow solid compound 6n was synthesized by referring to the method of compound 6b. 1 H NMR (400MHz, CDCl3) δ10.40(s,1H),7.58(s,1H),7.02(s,1H),6.83–6.70(m,2H),6.68(dd,J=15.8, 7.8Hz,1H),6.17(d,J=10.9Hz,1H),4.34(t,J=7.1Hz,2H),4.02(d,J=7.5Hz,2H),3.81(t,J=7.2Hz, 2H),3.62(p,J=9.7Hz,1H),3.48(s,3H),2.85(ddd,J=12.4,9.6,8.0Hz,2H),2.60(ddd,J=12.4,9.6 ,8.0Hz,2H),1.45(s,6H),1.11(qdd,J=9.8,7.7,2.3Hz,1H),0.83–0.62(m,2H),0.49–0.24(m,2H). 13 C NMR (100MHz, CDCl3) δ178.54,173.61,158.75,157.32,156.88,153.16,152.17,149.11,126.52,118.38,115.56,11 0.56,109.88,107.83,104.80,99.63,77.27,74.74,73.91,73.48,68.64,57.81,31.90,30.12,27.72,10.92,6.11.

[0150] (15) 4-((9-(cyclopropylmethoxy)-8-(2-(dimethylamino)ethoxy)-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]oxanthracene-5-yl)oxy)butyric acid (6o):

[0151]

[0152] Compound 6o, a white solid, was synthesized using compound 5f and ethyl 4-bromobutyrate as raw materials, following the method used for compound 6b. 1 HNMR(400MHz,CD3OD)δ7.74 -7.68(m,1H),7.08-7.03(m,1H),6.74(d,J=10.2Hz,1H),6.66(d,J=2.4Hz,1H),5 .85(d,J=10.1Hz,1H),4.45(t,J=4.8Hz,2H),4.04-3.98(m,4H),3.67(d,J=4.9Hz, 2H),3.10(d,J=1.5Hz,6H),2.90(s,1H),2.63(t,J=7.4Hz,2H),2.20(t,J=6.9Hz, 2H),1.48(s,5H),1.33(d,J=7.3Hz,3H),0.73-0.66(m,2H),0.43(t,J=5.1Hz,2H). 13 C NMR (100MHz, CD3OD) δ114.34,73.28,73.14,63.53,55.46,47.22,47.01,46. 80,46.58,46.37,46.16,45.94,41.97,26.15(2×C),24.23,8.45,1.42(2×C).

[0153] (16) 4-((9-(cyclopropylmethoxy)-8-(2-(dimethylamino)ethoxy)-2,2-dimethyl-6-oxo-2H,6H-pyrano[3,2-b]oxanthracene-5-yl)oxy)but-2-enoic acid (6p)

[0154]

[0155] Compound 6p, a white solid, was synthesized from compound 5f and ethyl 4-bromocrotonate, following the method used for compound 6b. 1H NMR (400MHz, CDCl3) δ7.59 (s, 1H), 7.10 (d, J = 15.8Hz, 1H), 6.72 (s, 1H), 6.68 (d ,J=10.1Hz,1H),6.58(s,1H),6.27(d,J=15.7Hz,1H),5.67(d,J=10.2Hz,1H),4. 71(d,J=4.6Hz,2H),4.39(s,2H),3.89(d,J=7.0Hz,3H),3.35(s,2H),2.79(s,6H ),1.46(s,8H),1.34-1.27(m,2H),0.66(d,J=7.5Hz,2H),0.37(d,J=5.0Hz,2H). 13 C NMR (100MHz, CDCl3) δ176.83,174.23,158.67,154.60,154.36,151.66,145.19,130.98,124.43,116.29,115.48,112. 62,110.43,100.92,100.19,78.02,77.48,77.16,76.84,73.93,65.94,56.56,43.99,28.49,21.49,10.06,3.42,1.16.

[0156] (17) 2-((9-(cyclopropylmethoxy)-2,2-dimethyl-6-oxo-5-(pyridin-4-methoxy)-2H,6H-pyrano[3,2-b]xanthanen-8-yl)oxy)-N,N,N-trimethylethyl-1-amine(6q):

[0157]

[0158] Compound 6q, a white solid, was synthesized from compound 5g and 2-(bromomethyl)pyridine hydrobromide, following the method used for compound 6a. 1 H NMR (400MHz, CDCl3) δ8.68 (d, J = 5.1Hz, 2H), 7.60 (s, 2H), 7.58 (s, 1H), 6.70 (s, 1H),6.62(s,1H),6.60(d,J=10.2Hz,1H),5.67(d,J=10.1Hz,1H),5.06(s,2H),4 .52(t,J=4.6Hz,2H),4.23(t,J=4.6Hz,2H),3.85(d,J=7.1Hz,2H),3.63(s,10H ),1.47(s,7H),1.33–1.29(m,2H),0.69(d,J=7.5Hz,2H),0.36(d,J=5.0Hz,2H).13 C NMR (100MHz, CDCl3) δ174.04,158.92,158.67,154.88,153.85,152.36,149.20,147.66,144.15,131.04,122.90,115.86,115.36,1 12.72,110.50,110.10,101.34,100.36,78.20,77.48,77.37,77.16,76.85,74.82,74.28,65.36,64.69,55.41,28.52,10.12,3.66.

[0159] (18) 4-((9-(cyclopropylmethoxy)-2,2-dimethyl-8-(2-morpholinoethoxy)-6-oxo-2H,6H-pyrano[3,2-b]xanthanene-5-yl)oxy)butyric acid (6r):

[0160]

[0161] Compound 6r, a white solid, was synthesized from compound 5h and ethyl 4-bromobutyrate, following the method used for compound 6b. 1 H NMR (400MHz, CDCl3) δ7.64 (s, 1H), 6.84 (d, J = 10.0Hz, 1H), 6.78 (s, 1H), 6.26 (s, 1H), 5. 58(d,J=10.0Hz,1H),4.23(t,J=5.6Hz,2H),4.12(td,J=6.6,6.0,2.9Hz,4H),3.93(d,J= 6.9Hz,2H),3.77–3.73(m,4H),2.87(t,J=5.5Hz,2H),2.73(t,J=7.3Hz,2H),2.68–2.61( m,4H),2.24(p,J=6.6Hz,2H),1.48(s,6H),1.25(s,3H),0.71–0.65(m,2H),0.40(m,2H). 13 C NMR (100MHz, CDCl3) δ174.8,173.6,161.0,158.3,154.3,154.0,150.9,146.0,127.1,115.9,115.7,108.0,106.9,102.4,100.3,9 6.5,78.1,74.0,68.1,67.5,67.1(2×C),60.5,57.5,54.3(2×C),30.8,28.4,24.6(2×C),14.4,10.1,3.5(2×C).ESI-HRMSm / z[M+H] +calcd for C 32 H 37 NO9 580.2502, found580.2503.

[0162] (19) 4-((9-(cyclopropylmethoxy)-2,2-dimethyl-8-(2-morpholinoethoxy)-6-oxo-2H,6H-pyrano[3,2-b]oxanthracene-5-yl)oxy)but-2-enoic acid (6s):

[0163]

[0164] Compound 6S, a white solid, was synthesized from compound 5h and ethyl 4-bromocrotonate, following the method used for compound 6b. 1 H NMR (400MHz, CDCl3) δ7.55 (s, 1H), 7.11 (dt, J = 15.7, 4.6Hz, 1H), 6.72 (s, 1H), 6.6 1(d,J=10.2Hz,1H),6.56(s,1H),6.31-6.14(m,1H),5.66(d,J=10.1Hz,1H),4.65( dd,J=4.7,1.9Hz,2H),4.38(t,J=4.7Hz,2H),3.90(t,J=4.7Hz,4H),3.86(d,J=7. 0Hz,2H),3.25(t,J=4.8Hz,3H),3.11(s,4H),1.41(s,6H),1.33-1.24(m,1H),0.68 -0.59(m,2H), 0.37-0.29(m,2H). 13 CNMR (100MHz, CDCl3) δ174.64,158.87,158.62,154.82,154.03,151.89,145.06,143.54,130.91,122.30,115.92,115 .25,112.67,110.16,108.59,101.09,100.28,78.16,74.12,73.37,65.46,65.16,56.66,53.26,28.38,9.93,3.37(2x C).

[0165] (20) 9-(cyclopropylmethoxy)-2,2-dimethyl-8-(2-morpholinoethoxy)-5-(pyridin-4-methoxy)-2H,6H-pyrano[3,2-b]oxanthracene-6-one (6t):

[0166]

[0167] Using compound 5h and 2-(bromomethyl)pyridine hydrobromide as raw materials, a white solid compound 6t was synthesized by referring to the method of compound 6a. 1 H NMR (400MHz, CDCl3) δ8.69-8.62(m,2H),7.62(s,1H),7.52(d,J=5.9Hz,2H),6.79(s,1H), 6.64(s,1H),6.60(d,J=10.1Hz,1H),5.64(d,J=10.1Hz,1H),5.10(s,2H),4.24(t,J=5.5Hz ,2H),3.94(d,J=6.9Hz,2H),3.75(t,J=4.7Hz,4H),2.89(t,J=5.5Hz,2H),2.66(q,J=3.8,3 .0Hz,4H),1.46(s,5H),1.38–1.32(m,1H),0.71-0.65(m,2H),0.40(dt,J=6.3,4.7Hz,2H). 13 C NMR (100MHz, CDCl3) δ174.55,158.76,158.66,154.85,154.08,151.43,150.01,149.92,146.53,146.12,130.75,122.40,116.09,115.48,112.5 9,110.40,107.74,101.23,100.31,78.01,77.48,77.16,76.84,74.86,7 4.05,67.42,67.00,57.46,54.19,28.46(2×C),10.03,3.47(2×C),1.15.

[0168] (21) 4-((9-(cyclopropylmethoxy)-2,2-dimethyl-8-(2-morpholinoethoxy)-6-oxo-2H,6H-pyrano[3,2-b]xanthanen-5-yl)oxy)butyric acid (6u):

[0169]

[0170] Using compound 5h and ethyl 4-bromobutyrate as raw materials, a white solid, compound 6u, was synthesized by referring to the method of compound 6b, with a yield of 15.06%. 1H NMR(400MHz,D2O)δ6.66(s,1H),6.07(s,1H),5.65(s,1H),5.55(s,2H),4.04(s,2H),3.38(s,4H),3.24(s, 5H), 3.15 (d, J = 24.1Hz, 4H), 2.78 (s, 3H), 2.23 (s, 2H), 1.67 (s, 2H), 1.21 (s, 6H), 0.93 (s, 1H), 0.46 (s, 2H). 13 C NMR (100MHz, D2O) δ 177.42, 173.53, 157.99, 157.16, 153.77, 153.29, 150.14, 144.34, 130.90, 113.70, 112.04, 108.87, 105.95, 100.08, 99.25, 99.18, 78.13, 74.29, 73.84, 55.29, 51.30, 49.34, 42.88, 30.46, 28.00, 24.91, 9.15, 3.11. Example 5 Synthesis of target compounds 8a-8c

[0171]

[0172] (1)1,3,6,8-Tetrahydroxy-9H-xanthen-9-one(M):

[0173] Prepared according to the literature (Lin, Shuimu; Koh, Jun-Jie; Aung, Thet Tun; et al. SymmetricallySubstituted Xanthone Amphiphiles Combat Gram-Positive Bacterial Resistancewith Enhanced Membrane Selectivity. Journal of Medicinal Chemistry, 2017, 60(4), 1362-1378.).

[0174] |(2)6-(cyclopropylmethoxy)-1,3,7-trihydroxy-9H-oxanthracene-9-one(7):

[0175]

[0176] Compound M (500 mg, 1.92 mmol, 1 eq) was dissolved in 5 mL of DMF solvent. Sodium carbonate (202 mg, 1.92 mmol, 1 eq) and bromomethylcyclopropane (130 mg, 0.96 mmol, 0.5 eq) were added. The mixture was stirred at 50 °C for 12 hours, after which the reaction was stopped. After cooling to room temperature, 50 mL of distilled water was added, and the pH was adjusted to 5-6 with 1 N hydrochloric acid solution. The mixture was extracted three times with 50 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain a yellow solid compound 7 (248 mg, 0.78 mmol). 1 H NMR (400MHz, DMSO-d6) δ9.85(s,1H),9.23(s,1H),6.49(d,J=1.5Hz,1H),6.34(d,J=1.5Hz,1H),6.30(d,J=1.2Hz,1H),6.11( d,J=1.5Hz,1H),4.94(s,1H),3.72(d,J=7.5Hz,2H),1.11(qdd,J=9.9,7.6,2.4Hz,1H),0.79–0.51(m,2H),0.51–0.24(m,2H). 13 C NMR(100MHz,DMSO-d6)δ182.99,167.05,164.35,162.47,162.02,158.64,15 8.23,104.29,102.28,98.83,98.05,93.91,93.80,73.12,10.92,6.11(2xC).

[0177] (3)9-(cyclopropylmethoxy)-5,7-dihydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one(8):

[0178]

[0179] Compound 7 (200 mg, 0.64 mmol, 1 eq) was dissolved in 10 mL of anhydrous methanol, and 3-methyl-2-butenal (122 μL, 1.28 mmol, 2 eq), calcium hydroxide (24.3 mg, 0.32 mmol, 0.5 eq), and calcium chloride (35.5 mg, 0.32 mmol, 0.5 eq) were added. The mixture was stirred at room temperature for 48 h. The reaction was then stopped. The precipitate was filtered and washed repeatedly with methanol and ethyl acetate. The filtrate was collected and concentrated to obtain the crude product. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain a yellow solid compound 8 (72.6 mg, 0.19 mmol). 1H NMR (400MHz, CDCl3) δ11.55(s,1H),9.15(s,1H),6.72(d,J=10.9Hz,1H),6.50(s,1H),6.46(d,J=1.5Hz,1H),6.34(d,J=1.5Hz,1H), 6.17(d,J=10.9Hz,1H),3.83(d,J=7.8Hz,2H),1.45(s,6H),1.11(qdd,J=9.9,7.7,2.3Hz,1H),0.84–0.61(m,2H),0.61–0.18(m,2H). 13 C NMR (100MHz, CDCl3) δ183.03,167.05,162.02,159.82,159.64,158.23,156.67,127.63,117 .11,105.61,104.29,100.46,98.05,94.76,93.80,77.27,73.12,27.72,10.92,6.11(2xC).

[0180] (4) 9-(cyclopropylmethoxy)-5-hydroxy-7-methoxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthanene-6-one (8a):

[0181]

[0182] Compound 8 (20 mg, 0.05 mmol, 1 eq) was dissolved in 1 mL of DMF solvent, and cesium carbonate (29 mg, 0.15 mmol, 3 eq) and iodomethane were added. The mixture was stirred at 50 °C for 12 hours, after which the reaction was stopped. 20 mL of water was added, and the mixture was extracted three times with 20 mL of ethyl acetate each time. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was separated by semi-preparative liquid chromatography to obtain solid compound 8a (10.3 mg). 1 H NMR (400MHz, CDCl3) δ8.06(s,16H),6.79(s,1H),6.79–6.55(m,32H),6.49(d,J=1.4Hz,16H),6.44(d,J=1.4Hz,16H),6.17(d,J= 11.0Hz,17H),3.97(s,48H),3.82(d,J=7.5Hz,33H),1.45(s,96H),1.16–1.09(m,13H),0.72–0.68(m,25H),0.47–0.43(m,25H). 13C NMR (100MHz, CDCl3) δ179.39,166.12,161.59,159.82,159.64,158.21,156.66,127.63,117.11 ,106.94,105.61,100.46,95.96,94.76,94.69,77.26,73.12,56.78,27.71,10.92,6.10(2xC).

[0183] (5) 9-(cyclopropylmethoxy)-5-hydroxy-7-(2-hydroxyethoxy)-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthanene-6-one (8b):

[0184]

[0185] Compound 8 (20 mg, 0.05 mmol, 1 eq) and 2-bromoethyl methyl ether (10.4 mg, 0.075 mmol, 1.5 eq) were dissolved in 1 mL of DMF solvent. Sodium hydride (6.0 mg, 0.25 mmol, 5 eq) was added, and the mixture was reacted at 0 °C for 1 hour. Then, the mixture was allowed to rise naturally to room temperature and stirred continuously for 11 hours before the reaction was stopped. 20 mL of water was added, and the pH was adjusted to 5-6 with 1N dilute hydrochloric acid. The mixture was extracted three times with 20 mL of ethyl acetate each time. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was separated by semi-preparative liquid chromatography to obtain solid compound 8b (10.8 mg). 1 H NMR (400MHz, CDCl3) δ8.06(s,16H),6.79(s,1H),6.79–6.55(m,32H),6.49(d,J=1.4Hz,16H),6.44(d,J=1.4Hz,16H),6.17(d,J= 11.0Hz,17H),3.97(s,48H),3.82(d,J=7.5Hz,33H),1.45(s,96H),1.16–1.09(m,13H),0.72–0.68(m,25H),0.47–0.43(m,25H). 13 C NMR (100MHz, CDCl3) δ179.39,166.12,161.59,159.82,159.64,158.21,156.66,127.63,117.11 ,106.94,105.61,100.46,95.96,94.76,94.69,77.26,73.12,56.78,27.71,10.92,6.10(2xC).

[0186] (6) 9-(cyclopropylmethoxy)-5-hydroxy-2,2-dimethyl-7-(2-(4-methylpiperazin-1-yl)ethoxy)-2H,6H-pyrano[3,2-b]xanthanen-6-one (8c):

[0187]

[0188] Compound 8 (20 mg, 0.05 mmol, 1 eq) and 1-(2-bromoethyl)-4-methylpiperazine (15.5 mg, 0.075 mmol, 1.5 eq) were dissolved in 1 mL of DMF solvent. Sodium hydride (6.0 mg, 0.25 mmol, 5 eq) was added, and the mixture was reacted at 0 °C for 1 hour. Then, the mixture was allowed to rise naturally to room temperature and stirred continuously for 11 hours before the reaction was stopped. 20 mL of water was added, and the pH was adjusted to 5-6 with 1N dilute hydrochloric acid. The mixture was extracted three times with 20 mL of ethyl acetate each time. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was separated by semi-preparative liquid chromatography to obtain solid compound 8c (11.9 mg). 1 H NMR (400MHz, CDCl3) δ9.15(s,1H),6.70(d,J=10.8Hz,1H),6.64(d,J=1.4Hz,1H),6.58(d,J=1 .4Hz,1H),6.50(s,1H),6.17(d,J=11.0Hz,1H),4.27(d,J=1.8Hz,2H),4.12(t,J=4.3Hz,2H), 2.74(t,J=4.3Hz,2H),2.48(dt,J=14.0,5.1Hz,4H),2.29(t,J=5.1Hz,2H),2.16(s,3H),2.13 –2.07(m,2H),1.45(s,6H),1.11(tt,J=9.9,1.7Hz,1H),0.87–0.71(m,2H),0.65–0.49(m,2H). 13 C NMR (100MHz, CDCl3) δ179.38,164.69,162.40,159.82,159.64,158.14,156.67,127.63,117.11,108.82,105. 61,100.46,97.71,95.52,94.76,77.27,73.12,67.45,55.00,54.48,54.03,46.05,27.72,10.92,6.11(2xC).

[0189] Test Example 1: Detection of the inhibitory effect of the compound of the present invention on PDE4 enzyme activity.

[0190] Step 1: Remove the PDE4D(86-413) enzyme solution from the -80°C freezer, thaw it on ice, and then store it in a 4°C freezer. Add the tritium-substituted substrate [8- 3 The H-cAMP stock solution was diluted 100 times with pure water to obtain the stock solution, and then a buffer solution (20 mM magnesium chloride, 50 mM tris(hydroxymethyl)aminomethane hydrochloride (pH = 7.5), 1 mM dithiothreitol) was added at a ratio of 4 μl of [8-] to 54 μl of buffer solution. 3 The substrate was diluted proportionally with the H-cAMP stock solution, and the cpm value of the blank control for scintillation counting was controlled to be 20,000-30,000.

[0191] Step 2: Determine the required enzyme concentration.

[0192] Add 40 μl of enzyme solutions diluted with buffer at gradient concentrations to 60 μl of diluted substrate. Use 40 μl of buffer solution as a blank for the negative control group. Incubate at room temperature for 15 min. Stop the reaction by adding 200 μl of 0.2 M zinc sulfate solution and 200 μl of 0.2 M barium hydroxide solution sequentially. After mixing the precipitate thoroughly by vortexing, centrifuge at 14000 rpm for 5 min. Take 430 μl of the supernatant and transfer it to a scintillation tube containing 2.5 ml of scintillation fluid. Vortex the sample thoroughly and then measure using a liquid scintillation analyzer. [8- 3 The enzyme concentration with a hydrolysis rate between 50% and 70% for H-cAMP is used as the concentration required for the assay.

[0193] Step 3: Determine the inhibitory activity of the compound and the positive control rolipram on the enzyme.

[0194] Take 58 μl of substrate solution diluted with buffer, gently add 2 μl of DMSO solution of different concentrations, mix well, and add 2 μl of DMSO to both the negative and positive control groups. Then, determine the test results based on enzyme concentration, add 40 μl of enzyme solution suitable for the hydrolysis range, and add 40 μl of buffer solution to the negative control group as a blank. Incubate at room temperature for 15 min. Stop the reaction by adding 200 μl of 0.2 M zinc sulfate solution and 200 μl of 0.2 M barium hydroxide solution sequentially. After the precipitate is mixed thoroughly by vortexing, centrifuge at 14000 rpm for 5 min. Take 430 μl of the supernatant and transfer it to a scintillation tube containing 2.5 ml of scintillation fluid. Vortex the sample to mix thoroughly, and then measure using a liquid scintillation analyzer.

[0195] Step 4: Calculate the compound inhibition rate and IC50. 50

[0196] The conversion rate of the compound at various concentrations was calculated using Microsoft Excel software (conversion rate = 1 - CPM).inhibitor / CPM ctrl ), and then calculate the relative activity of the enzyme at this inhibitor concentration (relative activity = conversion rate / conversion rate of positive control) and the inhibition rate (inhibition rate = 1 - relative activity). Test the inhibition rates of at least 8 different concentrations of the compound on PDE4 enzyme (the inhibition rate at each concentration is tested at least 3 times), and obtain the IC 50 value. The results are shown in Table 1.

[0197] Table 1 PDE4 inhibition activity (inhibition rate or IC 50 ) results

[0198]

[0199] Table 2 Selectivity of compound 6r

[0200]

[0201] The results in Table 1 show that the xanthone-based compounds 6a - 6u and 8a - 8c provided in the present invention exhibit excellent inhibitory effects on phosphodiesterase type 4. Most of the compounds reach the activity level of nanomolar, and the activities of some compounds are even significantly better than the positive control Rolipram. They can be used as phosphodiesterase type 4 inhibitors and applied to the treatment of phosphodiesterase type 4-related diseases.

[0202] As can be seen from Table 2, for the representative xanthone-based compound 6r, the inhibition IC 50 for other PDE subtypes are all greater than 536 nM, and the selectivity multiples are above 35 times. Especially for PDE1 / 2 / 3 / 5 / 8 / 9, the selectivity multiples are above 100 times, indicating that 6r is a highly active and highly selective PDE4 inhibitor.

[0203] Test Example 2 In vivo activity study of compound 6r in inhibiting pulmonary fibrosis

[0204] Forty-eight SPF-grade C57BL / 6 male mice, 6 - 7 weeks old, weighing 18 - 22 g, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (License No.: SCXK(Beijing)2021 - 0006). The environmental temperature was 20 - 25 °C, and the humidity was 50 - 70%. They were allowed to eat and drink freely.

[0205] Fifteen minutes before anesthesia, mice were subcutaneously injected with atropine to inhibit glandular secretion, followed by intramuscular anesthesia with Sutent-50. Airway infusion was performed using a needle. Normal control mice were given 0.1 mL of physiological saline, while all other groups were given 0.1 mL of bleomycin to induce the model. Immediately after injection, mice were suspended on a rodent board to ensure even drug distribution. After modeling, the control group (Con) and the model group (Mod) received equal volumes of solvent. The positive control group was administered pirfenidone (PFD) 300 mg / kg orally, while the experimental groups were administered compound 6r (2.5 mg / kg) orally. Twenty-one days after administration, mice were anesthetized for invasive pulmonary function testing, followed by enucleation and blood collection. Thoracotomy and bronchial ligation were performed, and lung tissue sections from the left fixed mice were obtained for routine HE staining and Masson staining. The specific experimental groups were as follows: C57BL / 6 mice were randomly divided into 4 groups, with 12 mice in each group: Sham group - sham operation group, Mod group - bleomycin airway infusion group (3mg / mL), PFD group - positive drug pirfenidone group (300mg / kg, po), and 6r group - compound 6r group (2.5mg / kg, po).

[0206] Data in the figure are expressed as mean ± standard error (SEM), n≥8. One-way ANOVA was used for comparisons between groups. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. Results are as follows: Figure 1 As shown in Figure (A), compared with the control group, after bleomycin treatment, mice showed increased airway resistance and varying degrees of decrease in functional residual capacity, vital capacity, forced expiratory volume 50, mean mid expiratory flow, and lung compliance. However, after 21 days of treatment with the positive control drug pirfenidone and compound 6r, all of the above indicators significantly improved, indicating that compound 6r can effectively improve respiratory function in mice with pulmonary fibrosis, thereby alleviating pulmonary fibrosis.

[0207] HE and Masson staining images of lung tissue further validated the above results, such as... Figure 1Figures (B) and (C) show that the alveoli in the control group mice were arranged in an orderly manner with almost no collagen deposition; while the lung structure in the model group mice was disordered, with inflammatory cell infiltration and obvious collagen deposition. Furthermore, compared with the model group, both the pirfenidone and compound 6r treatment groups significantly reduced lung tissue collagen deposition and improved the pathological condition of the lung tissue in mice with pulmonary fibrosis. These results indicate that compound 6r has a significant therapeutic effect on bleomycin-induced pulmonary fibrosis in mice.

[0208] Further results of Western blot analysis are as follows: Figure 1 As shown in (D) and (E), the levels of fibroblast-myofibroblast transition (FMT) marker proteins changed to varying degrees after treatment with compound 6r. Specifically, the expression levels of FN1, COL1A1, and α-SMA proteins decreased after treatment with compound 6r. Furthermore, the levels of lung epithelial-mesenchymal transition (EMT) marker proteins also changed after treatment with compound 6r. Specifically, the expression levels of N-cadherin and Vimentin proteins decreased, while the expression level of E-cadherin protein increased. These results suggest that compound 6r can reverse FMT and EMT, thereby alleviating the progression of pulmonary fibrosis in mice.

[0209] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A class of compounds based on xanthone, characterized in that, The oxanthone-based compound has the structure shown in formula (I): In formula (I), R 1 Selected from R 5 Replace C 1～6 Alkyl, C 2～6 olefin group, C 3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each group is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 1～6 Alkyl group, C 3～6 cycloalkyl, heterocyclic, heteroaryl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, ester, and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 2～6 olefin group, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl; The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～6 Alkyl, C 2～6 olefin group, C 3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, -NR 8 R 9 -N + R 10 R 11 R 12 Substitute heterocyclic group, heteroaryl group, or aryl group; said R 8 and R 9 Each is independently selected from hydrogen and C. 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 10 and R 11 Selected from C 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, ester, and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl; The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from R' 13 Replace C 1～6 Alkyl, C 2～6 olefin group, C 3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, R 14 Substitute heterocyclic group, heteroaryl group, or aryl group; said R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 2～6 olefin group, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl; The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group, R 17 Replace C 3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 15 R 16 R 17 R can be monosubstituted, polysubstituted, or unsubstituted. 15 R 16 R 17 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, -B(OH)2, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 alkoxy, heterocyclic, heteroaryl or R 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 2～6 olefin group, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl; Wherein, the R 3 and R 4 Not simultaneously selected from hydrogen; the R 2 When R is selected from hydrogen, 3 Selected from -OR 3 ';The R 3 When R is selected from hydrogen, 2 Selected from -OR 2 ';The C 3～6 The cycloalkyl group is a saturated monocyclic cycloalkyl group; the heterocyclic group is a 5- to 6-membered aliphatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon; the heteroaryl group is a 5- to 6-membered aromatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon.

2. The compound based on xanthone according to claim 1, characterized in that, The R 1 Selected from R 5 Replace C 1～6 Alkyl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each group is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 1～ 6-alkyl acyl, C 3～6 cycloalkyl, heterocyclic, heteroaryl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, ester, and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 2～6 olefin group, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl; The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～6 Alkyl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, -NR 8 R 9 -N + R 10 R 11 R 12 Substitute heterocyclic, heteroaryl, or aryl groups; the R 8 and R 9 Each is independently selected from hydrogen and C. 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 10 and R 11 Selected from C 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, carboxyl, ester, and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl; The R 3 Selected from hydrogen or -OR 3 ', the R 3 Selected from hydrogen, R 13 Replace C 1～6 Alkyl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, R 14 Substitute heterocyclic group, heteroaryl group, or aryl group; said R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl, heterocyclic, heteroaryl, or aryl; The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group or R 17 Replace C 3～6 cycloalkyl; the R 15 R can be monosubstituted, polysubstituted, or unsubstituted. 15 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, -B(OH)2, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 3～6 cycloalkyl, C 1～6 Alkoxy, halogenated C 1～6 alkoxy, heterocyclic, heteroaryl or R 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, amide, and C. 1～6 Alkyl group, C 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 2～6 olefin group, C 3～6 Cycloalkyl, heterocyclic, heteroaryl, or aryl; the R 16 R can be monosubstituted, polysubstituted, or unsubstituted. 16 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide groups; The R group... 17 R can be monosubstituted, polysubstituted, or unsubstituted. 17 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide.

3. The oxanthone-based compound according to claim 1, characterized in that, The R 1 Selected from R 5 Replace C 1～6 Alkyl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each is independently selected from hydrogen, halogen, and C. 3～6 cycloalkyl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each is independently selected from hydrogen and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl or halogen; The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～6 Alkyl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each is independently selected from hydrogen and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy, -NR 8 R 9 -N + R 10 R 11 Or R 12 Substituted heterocyclic group; the R 8 and R 9 Each is independently selected from hydrogen and C. 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 10 and R 11 Selected from C 1～6 Alkyl or C 1～6 Halogenated alkyl; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each is independently selected from hydrogen and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl; The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from R' 13 Replace C 1～6 Alkyl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each is independently selected from hydrogen and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy or R 14 Substituted heterocyclic group; the R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each is independently selected from hydrogen and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, C 1～6 Alkoxy, halogenated C 1～6 Alkoxy, C 3～6 cycloalkyl, heteroaryl, or aryl; The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group or R 17 Replace C 3～6 cycloalkyl; the R 15 R can be monosubstituted, polysubstituted, or unsubstituted. 15 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, -B(OH)2, carbonyl, carboxyl, heteroaryl, or R. 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide groups; The R group... 16 R can be monosubstituted, polysubstituted, or unsubstituted. 16 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide groups; The R group... 17 R can be monosubstituted, polysubstituted, or unsubstituted. 17 Each group is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, mercapto, carbonyl, carboxyl, ester, or amide.

4. The oxanthone-based compound according to claim 1, characterized in that, The R 1 For R 5 Replace C 1～6 Alkyl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each is independently selected from hydrogen and C. 3～6 cycloalkyl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each is independently selected from hydrogen and C. 1～6 Alkyl, Halogenated C 1～6 Alkyl, fluorine, chlorine, iodine, or bromine; The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～6 Alkyl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each is independently selected from hydrogen and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy, or R 12 Substituted heterocyclic group; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each is independently selected from hydrogen and C. 1～6 Alkyl or halogenated C 1～6 alkyl; The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from R' 13 Replace C 1～6 Alkyl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each is independently selected from hydrogen and C. 1～6 Alkoxy, halogenated C 1～6 Alkoxy or R 14 Substituted heterocyclic group; the R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each is independently selected from hydrogen and C. 1～6 Alkyl or halogenated C 1～6 alkyl; The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group or R 17 Replace C 3～6 cycloalkyl; the R 15 R can be monosubstituted, polysubstituted, or unsubstituted. 15 Each group is independently selected from hydrogen, hydroxyl, mercapto, -B(OH)2, carboxyl, heteroaryl, or R. 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, hydroxyl, or amide groups; the R group... 16 R can be monosubstituted, polysubstituted, or unsubstituted. 16 Each group is independently selected from hydrogen or carboxyl groups; the R group 17 R can be monosubstituted, polysubstituted, or unsubstituted. 17 Each group is independently selected from hydrogen or carboxyl groups.

5. The oxanthone-based compound according to claim 1, characterized in that, The R 1 Selected from R 5 Replace C 1～3 Alkyl; the R 5 R can be monosubstituted, polysubstituted, or unsubstituted. 5 Each is independently selected from hydrogen and C. 3～6 cycloalkyl or R 6 Substituted aryl; the R 6 R can be monosubstituted, polysubstituted, or unsubstituted. 6 Each is independently selected from hydrogen and C. 1～3 Alkyl, Halogenated C 1～3 Alkyl, fluorine, chlorine, iodine, or bromine; The R 2 Selected from hydrogen or -OR 2 ', the R 2 'Selected from R' 7 Replace C 1～3 Alkyl; the R 7 R can be monosubstituted, polysubstituted, or unsubstituted. 7 Each is independently selected from hydrogen and C. 1～3 Alkoxy, halogenated C 1～3 Alkoxy, or R 12 Substituted heterocyclic group; the R 12 R can be monosubstituted, polysubstituted, or unsubstituted. 12 Each is independently selected from hydrogen and C. 1～3 Alkyl or halogenated C 1～3 alkyl; The R 3 Selected from hydrogen or -OR 3 ', the R 3 'Selected from R' 13 Replace C 1～3 Alkyl; the R 13 R can be monosubstituted, polysubstituted, or unsubstituted. 13 Each is independently selected from hydrogen and C. 1～3 Alkoxy, halogenated C 1～3 Alkoxy or R 14 Substituted heterocyclic group; the R 14 R can be monosubstituted, polysubstituted, or unsubstituted. 14 Each is independently selected from hydrogen and C. 1～3 Alkyl or halogenated C 1～3 alkyl; The R 4 Selected from hydrogen, R 15 Replace C 1～6 Alkyl, R 16 Replace C 2～6 olefin group or R 17 Replace C 3～6 cycloalkyl; the R 15 R can be monosubstituted, polysubstituted, or unsubstituted. 15 Each group is independently selected from hydrogen, hydroxyl, mercapto, -B(OH)2, carboxyl, heteroaryl, or R. 18 Substituted aryl; the R 18 R can be monosubstituted, polysubstituted, or unsubstituted. 18 Each group is independently selected from hydrogen, hydroxyl, or amide groups; the R group... 16 R can be monosubstituted, polysubstituted, or unsubstituted. 16 Each group is independently selected from hydrogen or carboxyl groups; the R group 17 R can be monosubstituted, polysubstituted, or unsubstituted. 17 Each group is independently selected from either hydrogen or carboxyl groups; Wherein, the C 3～6 The cycloalkyl group is a saturated monocyclic cycloalkyl group; the heterocyclic group is a 5- to 6-membered aliphatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N and O, with the remaining ring atoms being carbon; the heteroaryl group is a 5- to 6-membered aromatic monocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N and O, with the remaining ring atoms being carbon.

6. The oxanthone-based compound according to any one of claims 1 to 5, characterized in that, The oxanthone-based compounds are replaced by their pharmaceutically acceptable salts, crystal forms, solvates, stereoisomers, or isotopic substituted compounds.

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises one or more of the xanthone-based compounds according to any one of claims 1 to 6.

8. The use of any of the xanthone-based compounds of claims 1 to 6 or the pharmaceutical composition of claim 7 in the preparation of PDE4 inhibitors.

9. The use of any of the xanthone-based compounds of claims 1 to 7 or the pharmaceutical composition of claim 7 in the preparation of a treatment for PDE4-related diseases.

10. The application according to claim 9, characterized in that, The PDE4-related diseases include chronic obstructive pulmonary disease, psoriasis, asthma, allergic dermatitis, ulcerative colitis, Crohn's disease, Alzheimer's disease, Parkinson's disease, depression, anxiety, aging, pulmonary hypertension, pulmonary fibrosis, organ fibrosis, hypertension, diabetes, fatty liver, heart failure, or cancer.

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