Alpha-mangostin derivative as well as preparation method and application thereof

Abstract

The invention provides an alpha-mangostin derivative and a preparation method thereof. Specifically, the alpha-mangostin derivative is shown as a formula I. The alpha-mangostin derivative has an excellent neuroprotective effect, so that the alpha-mangostin derivative can be used for preparing medicines for preventing and / or treating cardiovascular and cerebrovascular diseases, nervous system diseases and inflammatory diseases. # imgabs0 #

Description

Technical Field

[0001] The invention relates to an alpha-mangostin derivative and a preparation method thereof, and application of the derivative as a neuroprotectant. Background Art

[0002] Cardiovascular and cerebrovascular diseases are a general term for cardiovascular and cerebrovascular diseases, and generally refer to ischemic or hemorrhagic diseases of the heart, brain, and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc. It has the characteristics of high morbidity, high disability rate, and high mortality rate. It is a common and frequently occurring disease that endangers human life and health, and is one of the three major causes of death in humans. Cerebrovascular diseases include ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, atherosclerosis, stenosis or occlusion of the head and neck arteries, and intracranial vascular malformations. Among the patients, stroke is the main disease.

[0003] Stroke is a disease mainly caused by cerebral vascular thrombosis or blood vessel rupture, ischemia and hypoxia of brain tissue. According to the cause of the disease, it can be divided into ischemic stroke and hemorrhagic stroke, of which ischemic stroke accounts for about 80% to 87% of all stroke types. Thrombosis and oxidative stress damage are also one of the main causes of ischemic stroke, coronary heart disease, myocardial infarction and other cardiovascular and cerebrovascular diseases. The basic lesion of arterial thrombosis is mainly the rupture of atherosclerotic plaques, which causes platelets to adhere to the rupture site and then initiate the coagulation process. Once the arterial thrombosis caused by atherosclerosis is formed, ischemia and necrosis of the arterial blood supply site may occur, such as myocardial infarction, ischemic stroke, etc.

[0004] Neuroprotective drugs are a major class of drugs for treating stroke and improving stroke prognosis because they can reduce or eliminate damage caused by ischemia and reperfusion, reduce stress responses under pathological conditions of the brain, reduce inflammatory damage, promote nerve cell regeneration and repair, and reduce the degree and scope of nerve cell lesions caused by ischemia. In addition, neuroprotective drugs are also used to treat other neurological diseases, such as brain trauma, spinal injury, amyotrophic lateral sclerosis, spinal muscular atrophy, Huntington's disease, Parkinson's disease, Alzheimer's disease, etc. At present, there are only a few drugs used in clinical practice to prevent these diseases.

[0005] Among them, edaravone has free radical scavenging and antioxidant effects, and is one of the few drugs currently on the market for the treatment of acute stroke and spinal muscular atrophy. The limitation of this drug is that it can only be used in the acute phase of clinical application, and there are side effects such as post-infarction hemorrhage and mild and moderate renal and liver function damage. Another drug used in clinical practice is 3-butylphthalide (abbreviated as butylphthalide, trade name "Enbipu"), which has the effects of anti-platelet aggregation and microcirculation reconstruction. Chinese patent ZL93117148.2 discloses the activity of anti-cerebral ischemia, but due to low bioavailability, it is limited in clinical oral medication.

[0006] α-mangostin is the main bioactive compound isolated from the husk of Garcinia mangostana L., a plant of the genus Garcinia in the family Garciniaceae. Mangosteen is also known as mangosteen, mangosteen, and phoenix fruit. In Southeast Asia, the husk of mangosteen is a traditional folk medicine for the treatment of dysentery, sprains, typhoid fever, ulcers, skin infections, anti-inflammatory and bactericidal. Modern pharmacological studies have shown that α-mangostin has pharmacological activities such as antioxidant, anti-inflammatory, anti-cancer, inhibition of apoptosis, and anti-pathogenic microorganisms. Its parent nucleus structure xanthone has significant antioxidant, anti-inflammatory, and monoamine oxidase inhibition effects. It is reported that α-mangostin derivatives are also potential effective inhibitors of phosphodiesterase 4 (PDE4), RORγt and other targets, and have great development potential in cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases and anti-tumor.

[0007] Therefore, the art needs a novel α-mangostin derivative with anti-inflammatory, antioxidant, and neuroprotective effects. Summary of the invention

[0008] The present invention aims to provide an α-mangostin derivative and a preparation method thereof, and use thereof as a neuroprotectant in the preparation of a drug for treating cardiovascular and cerebrovascular diseases, nervous system diseases and inflammatory diseases.

[0009] In the first aspect of the present invention, there is provided an α-mangostin derivative as shown in Formula I, or a pharmaceutically acceptable salt or solvate thereof:

[0010]

[0011] in,

[0012] R1 is independently hydroxyl, halogen, amino, cyano, -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, C2-C6 unsaturated alkyl, C2-C6 unsaturated heteroalkyl, -(CH=CH)-CORa, -(C1-C3 alkylene)-(CH=CH)-CORa, -O-(C1-C3 alkylene)-(CH=CH)-CORa, -OCO-(CH=CH)-CORa, -OC O-(C1-C3 alkylene)-(CH=CH)-CORa, 3-12-membered alkyl ring group, 3-12-membered heteroalkyl ring group, 5-10-membered aryl group, 5-10-membered aromatic heterocyclic group, -O-(3-12-membered alkyl ring), -O-(3-12-membered heteroalkyl ring), -O-(5-10-membered aromatic ring), -O-(3-12-membered aromatic heterocyclic ring), -O-(C1-C3 alkylene)-(5-10-membered aromatic ring), -O-(C1-C3 alkylene)-(5-10-membered aromatic heterocyclic ring);

[0013] R2 and R3 are each independently a hydrogen atom, a halogen, a hydroxyl group, an amino group, an amine group, a cyano group, -C(O)X'R8 or -X'C(O)R9, an amide group, a sulfonic acid group, a sulfonate group, a sulfonamide group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 saturated heteroalkyl group, a substituted or unsubstituted C2-C10 unsaturated alkyl group, a substituted or unsubstituted C2-C10 unsaturated heteroalkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, a substituted or unsubstituted 3-12-membered aryl group, a substituted or unsubstituted 3-12-membered aromatic heterocyclic group, or L-R';

[0014] Wherein, L is O, NH, S, SO2, substituted or unsubstituted -CH=CH-, substituted or unsubstituted -CH=CH-(C1-C3 alkylene)-, -(C1-C3 alkylene)-substituted or unsubstituted CH=CH-; R' is independently -CORb, -SO2Rc, C1-C6 alkyl, C1-C6 heteroalkyl, substituted or unsubstituted 3-12 membered heteroalkyl ring group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0015] Ra and Rb are each independently selected from -ORd and -NReRf; wherein Rd, Re and Rf are each independently hydrogen, C1-C6 alkyl, C2-C6 unsaturated alkyl, C1-C6 haloalkyl, or Re, Rf and the adjacent nitrogen atom together form a substituted or unsubstituted 3-12 membered heterocyclic ring; Rc is independently selected from hydroxyl, amino, amine, amide, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 unsaturated alkyl, C2-C6 unsaturated heteroalkyl;

[0016] (a) When R2=R3=H and R1 is hydroxyl, R is -X-Rg or -CH=CH-R6,

[0017] Wherein, X is NH, O, CH2, and Rg is independently selected from

[0018] R4 is independently a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered alkyl ring, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered heteroalkyl ring;

[0019] R5 is independently a substituted 5-10 membered aryl group, a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; wherein the substitution refers to substitution by 1-2 Rh and 0-2 Ri;

[0020] wherein Rh is independently selected from hydroxyl, cyano, C1-C6 haloalkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group, -Z-substituted or unsubstituted 3-8 membered heteroalkyl ring, Ri is independently selected from halogen, hydroxyl, cyano, amino, amine, -C(O)X'R8 or -X'C(O)R9, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, substituted or unsubstituted 3-12 membered heteroalkyl ring group, Z is NH, S or SO2, -C1-C6 alkylene, -O-C1-C6 alkylene;

[0021] R6 is independently -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0022] R7 is independently selected from a substituted or unsubstituted 3-8 membered heteroalkyl ring group, a substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0023] n is an integer selected from 2 to 20;

[0024] (b) When R2=R3=H and R1 is not hydroxyl, R is -X-Rg wherein X is NH, O, and Rg is independently selected from C1-C6 saturated heteroalkyl, C2-C6 unsaturated heteroalkyl, substituted or unsubstituted 3-8 membered alkyl ring, substituted or unsubstituted 3-8 membered heteroalkyl ring, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 3-12 membered aromatic heterocyclic group, -CO- substituted or unsubstituted 3-8 membered alkyl ring, - -CO-substituted or unsubstituted 3-8 membered alkyl ring, -CO-substituted or unsubstituted 5-10 membered aromatic ring, -CO-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, -CO-CH2-substituted or unsubstituted 3-8 membered alkyl ring, -CO-CH2-substituted or unsubstituted 3-8 membered aromatic ring, -CO-CH2-substituted or unsubstituted 5-10 membered aromatic ring, -CO-CH2-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring,

[0025] R4 is independently a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered alkyl ring, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered heteroalkyl ring;

[0026] R5 is independently C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0027] R6 is independently -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0028] (c) When R2 and R3 are not H at the same time and R1 is hydroxyl, R is -X-Rg, wherein X is NH, O, and Rg is independently selected from hydrogen atom, -C(O)X'R8 or -X'C(O)R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 unsaturated alkyl, substituted or unsubstituted C1-C6 saturated heteroalkyl, substituted or unsubstituted C2-C6 unsaturated heteroalkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 3-12 membered aromatic heterocyclic group, -(C1-C20 alkylene)-C(O)X'R8 or -(C1-C20 alkylene)-X'C(O)R9, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 5-10 membered aromatic ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, -CO-CH2-substituted or unsubstituted 3-8 membered alkyl ring, -CO-CH2-substituted or unsubstituted 3-8 membered heteroalkyl ring, -CO-CH2-substituted or unsubstituted 5-10 membered aromatic ring, -CO-CH2-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, Or Rg and R3 and their adjacent X together form a substituted or unsubstituted 5-10 membered heterocyclic ring;

[0029] R4 is independently a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered alkyl ring, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered heteroalkyl ring;

[0030] R5 is independently C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0031] R6 is independently -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0032] (d) When R2 and R3 are not H at the same time and R1 is not hydroxyl, R is -X-Rg, wherein X is NH, O, and Rg is independently selected from hydrogen atom, -C(O)X'R8 or -X'C(O)R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 unsaturated alkyl, substituted or unsubstituted C1-C6 saturated heteroalkyl, substituted or unsubstituted C2-C6 unsaturated heteroalkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group, -(C1-C20 alkylene)-C(O)X'R8 or -(C1-C20 alkylene)-X'C(O)R9, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 5-10 membered aromatic ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, -CO-CH2-substituted or unsubstituted 3-8 membered alkyl ring, -CO-CH2-substituted or unsubstituted 3-8 membered heteroalkyl ring, -CO-CH2-substituted or unsubstituted 5-10 membered aromatic ring, -CO-CH2-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, Or Rg and R3 and their adjacent X together form a substituted or unsubstituted 5-6 membered heterocyclic ring;

[0033] R4 is independently a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered alkyl ring, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered heteroalkyl ring;

[0034] R5 is independently C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0035] R6 is independently -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0036] in,

[0037] A is a substituted or unsubstituted 3-12-membered heteroalkyl ring group, or a substituted or unsubstituted 5-10-membered aromatic heterocyclic group;

[0038] is a double bond or a single bond;

[0039] Unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, -OH, -CN, -NO2, -NH2, -NCO, -OCN, -SCN, -NCS, -N3, -(C1-C3 alkylene)OH, -O(C1-C3 alkyl), -S(C1-C3 alkyl), -C(O)X'R8 or -X'C(O)R9, -SO3R8, -OSO2OR8, -NR 10 SO2OR9, -NR 10 R 11 、-SO2NR 10 R 11 、-NH-SO2-R 10 、-N + R 10 R 11 R 12 、-C(O)N(R 13 2. -SO2R 14 、-NR 15 C(O)N(R 15 )2, -B(OH)2, -B(O(C1-C6 alkyl or alkylene))2, -P(O)(OH)3, -OP(O)(OC1-C3 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 unsaturated alkyl, C1-C6 saturated heteroalkyl, C2-C6 unsaturated heteroalkyl, oxo (=O), 3-12 membered alkyl ring group, 3-12 membered heteroalkyl ring group, 5-10 membered aryl, 5-10 membered aromatic heterocyclic group, 3-12 membered heterocyclic group, -(C1-C3 alkylene)-3-12 membered heterocyclic ring, -O(C1-C6 alkylene)-3-12 membered heterocyclic ring;

[0040] X' is a bond or is oxygen or sulfur, R8 is independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, 3-12-membered alkyl ring group, 5-10-membered aryl, 3-12-membered heterocyclyl, R9 is independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, 3-12-membered alkyl ring group, 5-10-membered aryl, 3-12-membered heterocyclyl;

[0041] R 10 , R 11 and R 12 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, -C(O)X'R8 or -X'C(O)R9, or, R 10 and R 11 Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring; wherein R 10 or R 11 Not all are -C(O)X'R8 or -X'C(O)R9;

[0042] R 13 are independently selected from hydrogen or C1-C6 alkyl, or two R 13 Together with the N atom to which they are attached, they form a 4-8 membered heterocyclic ring;

[0043] R 14 Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered alkyl ring group, 3-12 membered heterocyclic group, 5-10 membered aryl group;

[0044] R 15 are independently selected from hydrogen, C1-C6 alkyl, or two R 15 Together with the N atom to which they are attached, they form a 4-8 membered heterocyclic ring;

[0045] Wherein, the heteroalkyl group, heteroalkyl ring and aromatic heterocyclic ring each independently have 1-3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.

[0046] In another preferred embodiment, R2 and R3 are not H at the same time. Not being H at the same time means that they are not H at the same time, that is, one of R2 and R3 is H and the other is not H; or both R2 and R3 are not H.

[0047] In another preferred embodiment, the term "alkyl" refers to a fully saturated cyclic or non-cyclic, branched or unbranched carbon chain portion having a specified number of carbon atoms, or if not specified, up to 30 carbon atoms. The number of carbon atoms can be 1 to 10, 1 to 8, 1 to 6 or 1 to 4, preferably C1-C6 saturated alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc., or similar groups. The number of carbon atoms can be 10 to 30, such as decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, docosyl, docosyl, triacontyl and tetracosyl, and the alkyl group can be substituted or unsubstituted.

[0048] In another preferred embodiment, the term "unsaturated alkyl" refers to a linear or branched alkyl group containing double bonds or triple bonds having a certain number of carbon atoms. The unsaturated alkyl group may be an alkenyl group, an alkynyl group or a dienyl group, for example, a C2-C6 unsaturated alkyl group includes a C2-C6 alkenyl group, a C2-C6 alkynyl group or a C2-C6 dienyl group, and may be optionally substituted by one or more substituents.

[0049] In another preferred embodiment, the term "saturated heteroalkyl" refers to a straight or branched saturated alkyl group with a certain number of carbon atoms, and the alkyl chain contains one or more heteroatoms selected from nitrogen, oxygen and sulfur. Depending on the type of heteroatoms contained, the unsaturated heteroalkyl group can be a saturated alkoxy group, a saturated alkylthio group or a saturated alkylamino group. Preferably. Wherein, a saturated alkoxy group refers to a saturated alkyl group as defined above, which is connected to the remainder of the molecule via an oxygen atom, and the same is true for an alkylthio group. A saturated alkylamino group refers to a saturated alkyl-NH2 as defined above, and the alkyl group can be substituted or unsubstituted.

[0050] In another preferred embodiment, the term "unsaturated heteroalkyl" refers to a linear or branched unsaturated alkyl group with a certain number of carbon atoms, and the alkyl chain contains one or more heteroatoms selected from nitrogen, oxygen and sulfur. Depending on the type of heteroatoms contained, the unsaturated heteroalkyl group may be an unsaturated alkoxy group, an unsaturated alkylthio group or an unsaturated alkylamino group; depending on the type of unsaturated bonds contained, the unsaturated heteroalkyl group may be a heteroalkenyl group, a heteroalkenyl group or a heteroalkenyl group. Preferably, the unsaturated heteroalkyl group includes an alkoxyalkenyl group, an alkoxyalkynyl group, an alkoxydienyl group, an alkylthioalkenyl group, an alkylthioalkynyl group, an alkylthiodienyl group, an alkylaminoalkenyl group, an alkylaminoalkynyl group, and an alkylaminodienyl group. Among them, an alkoxyalkenyl group refers to an alkenyl group, which is connected to the remainder of the molecule through an oxygen atom, and an alkylthio group is similar, and the alkyl group may be substituted or unsubstituted.

[0051] In another preferred embodiment, the unsaturated heteroalkyl group is preferably an alkoxyalkyl group, and more preferably an -O-alkenyl group.

[0052] In another preferred example, the heteroalkyl group includes a saturated heteroalkyl group and an unsaturated heteroalkyl group.

[0053] In another preferred embodiment, the term "alkoxy" refers to an alkyl group as defined above, which is connected to the remainder of the molecule via an oxygen atom. Preferably, the C1-C6 alkoxy group may include methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0054] In another preferred embodiment, the term "amide" refers to -C(O)N(R 13 )2.

[0055] In another preferred embodiment, the term "sulfonate group" refers to -SO3R8, wherein when R8 is a hydrogen atom, it refers to "sulfonic acid group".

[0056] In another preferred embodiment, the term "sulfonamide" refers to -SO2NR 10 R 11 .

[0057] In another preferred embodiment, the term "alkane ring", "alkane ring group" refers to a non-aromatic group (including saturated, partially saturated or unsaturated groups) having 3 to 12 carbon atoms (e.g., 3 to 8), having a monocyclic ring or a condensed ring (including a bridged ring system and a spirocyclic ring system). Therefore, the alkane ring or alkane ring group can be a saturated alkane ring or an unsaturated alkane ring. In the condensed ring system of a saturated alkane ring, one or more rings are saturated alkane rings. In the condensed ring system of an unsaturated alkane ring, one or more rings can be a saturated alkane ring or an unsaturated alkane ring.

[0058] In another preferred embodiment, the term "heteroalkyl ring", "heteroalkyl ring group" refers to a 3-12 membered non-aromatic group (including saturated, partially saturated or unsaturated groups), which contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, including a monocyclic or polycyclic system, and the polycyclic system can be a condensed ring, a bridged ring system and a spirocyclic system. Therefore, the heteroalkyl ring or heteroalkyl ring group can be a saturated heteroalkyl ring or an unsaturated heteroalkyl ring. In the condensed ring system, one or more rings can be an alkyl ring group, an aryl group or an aromatic heterocyclic group. In one embodiment, the nitrogen atom and / or sulfur atom of the heterocyclic group is optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties. In one embodiment, the carbon atoms of the heterocyclic group are optionally oxidized to form a (C=O) moiety.

[0059] In another preferred embodiment, the heteroalkyl ring is preferably a 5-8 membered monocyclic heteroalkyl ring, a 9-12 membered fused heteroalkyl ring, or a 7-8 membered heteroatom-containing bridge ring; more preferably, the following structure:

[0060]

[0061] In another preferred embodiment, the term "aromatic heteroyl" or "aromatic heterocyclic group" refers to a 3-12 membered aromatic group, which contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, including a monocyclic or polycyclic system, and the polycyclic system can be a condensed ring, a bridged ring system and a spirocyclic system. The term "fused aromatic heteroyl" or "fused aromatic heterocyclic group" refers to a condensed ring formed by the fusion of two or more aromatic groups, which contains one or more heteroatoms selected from nitrogen, oxygen and sulfur. Among them, one or more rings in the fused aromatic heterocycle have heteroatoms.

[0062] In another preferred embodiment, the aromatic heterocycle is preferably a 5-8 membered monocyclic aromatic heterocycle or a 9-12 membered condensed aromatic heterocycle; more preferably, the following structure:

[0063]

[0064] In another preferred embodiment, the term "heterocyclic group" or "heterocyclic group" refers to a 3-12 ring structure, more preferably a 5-12 ring, more preferably a 5-10 ring, and its ring structure includes 1 to 4 heteroatoms. The heterocycle can be a monocyclic, bicyclic, spirocyclic or polycyclic ring. The heterocyclic group includes, for example, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinoline, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenazine, phenothiazine, furan, phenoxazine, pyrrolidine, oxolane, thiopentane, oxazole, piperidine, piperazine, morpholine, lactone, lactams such as azetidinone and pyrrolidone, sultam, sultone, etc. The heterocycle may be substituted at one or more positions by substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, etc., and herein, "heterocycle" includes heteroalkyl rings and aromatic heterocycles.

[0065] In another preferred embodiment, the term "aryl" refers to an aromatic group, such as phenyl or naphthyl, which is unsubstituted or substituted by one or more (e.g. 2, 3, 4 or 5) atoms or groups selected from the following: halogen, nitro, hydroxyl, amino, cyano, haloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C2-C6 alkanoyl, substituted or unsubstituted C2-C6 alkanoylamide.

[0066] In another preferred embodiment, the term "C2-C6 ester group" refers to -CO-O-(C1-C5 alkyl) or -O-CO-(C1-C5 alkyl).

[0067] In another preferred embodiment, the term "carbonyl" is art-recognized and includes moieties that may be represented by -C(O)X'R8 or -X'C(O)R9.

[0068] In another preferred embodiment, R1 is hydroxyl, -C(O)X'R8 or -X'C(O)R9, C2-C6 unsaturated alkyl, C2-C6 unsaturated heteroalkyl, -(CH=CH)-CORa, -(C1-C3 alkylene)-(CH=CH)-CORa, -O-(C1-C3 alkylene)-(CH=CH)-CORa, -OCO-(CH=CH)-CORa, -OCO-(C1-C3 alkylene)-(CH=CH)-CORa, wherein Ra is -ORd.

[0069] In another preferred embodiment, R1 is hydroxyl, -C(O)X'R8 or -X'C(O)R9, C2-C6 unsaturated heteroalkyl, -(CH=CH)-CORa, -OCO-(CH=CH)-CORa, wherein Ra is -ORd.

[0070] In another preferred embodiment, R1 is hydroxyl, -C(O)X'R8 or -X'C(O)R9, C2-C6 unsaturated heteroalkyl, -(CH=CH)-CORa, -OCO-(CH=CH)-CORa, wherein Ra is -ORd, Rd is C1-C3 alkyl, X' is oxygen, and R9 is C1-C3 alkyl.

[0071] In another preferred embodiment, R1 is hydroxyl, C2-C6 unsaturated alkyl, or C2-C6 unsaturated heteroalkyl.

[0072] In another preferred embodiment, R1 is hydroxyl or C2-C6 alkoxyalkenyl.

[0073] In another preferred embodiment, R1 is hydroxyl.

[0074] In another preferred embodiment, R2 and R3 are the same or different, preferably different.

[0075] In another preferred embodiment, R2=R3=H.

[0076] In another preferred embodiment, one of R2 and R3 is H, and the other is not H.

[0077] In another preferred embodiment, R2 and R3 are each independently a hydrogen atom, a halogen, a hydroxyl group, a cyano group, -C(O)X'R8 or -X'C(O)R9, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 saturated heteroalkyl group, a substituted or unsubstituted C2-C6 unsaturated alkyl group, a substituted or unsubstituted C2-C6 unsaturated heteroalkyl group, a substituted or unsubstituted 3-8 membered alkyl ring group, a substituted or unsubstituted 5-8 membered monocyclic heteroalkyl ring group, a substituted or unsubstituted 9-12 membered fused heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, a substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group, or L-R'.

[0078] In another preferred embodiment, R2 and R3 are each independently a hydrogen atom, a halogen, a hydroxyl group, a cyano group, -C(O)X'R8 or -X'C(O)R9, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 saturated heteroalkyl group, a substituted or unsubstituted 5-8 membered monocyclic heteroalkyl ring group, a substituted or unsubstituted 9-12 membered fused heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, a substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group, or L-R'.

[0079] In another preferred embodiment, R2 and R3 are each independently a hydrogen atom, a halogen, a substituted or unsubstituted 5-8 membered monocyclic heteroalkyl ring group, a substituted or unsubstituted 9-12 membered fused heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, a substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group, or L-R'.

[0080] Wherein, the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, -OH, -CN, -NO2, -NH2, -NCO, -OCN, -SCN, -NCS, -N3, -(C1-C3 alkylene)-OH, -O-(C1-C3 alkyl), -S-(C1-C3 alkyl), -C(O)X'R8 or -X'C(O)R9, -SO3R8, -OSO2OR8, -NR 10 SO2OR9, -NR 10 R 11 、-SO2NR 10 R 11 、-N + R 10 R 11 R 12 、-NH-SO2-R 10 、-C(O)N(R 13 2. -SO2R 14 、-NR 15 C(O)N(R15 )2, -B(OH)2, -B(O(C1-C6 alkyl or alkylene))2, -P(O)(OH)3, -OP(O)(OC1-C3 alkyl)2, oxo (=O), C1-C6 alkyl, C2-C6 unsaturated alkyl, C1-C6 saturated heteroalkyl, C2-C6 unsaturated heteroalkyl, 3-12 membered alkyl ring group, 3-12 membered heteroalkyl ring group, 5-10 membered aryl, 5-10 membered aromatic heterocyclic group, 3-12 membered heterocyclic group, -(C1-C3 alkylene)-3-12 membered heterocyclic ring, -O(C1-C6 alkylene)-3-12 membered heterocyclic ring.

[0081] Wherein, the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, hydroxyl, cyano, carboxyl, -NH-SO2-(C1-C3 alkyl), oxo (=O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, N,N-dimethylamino, C1-C6 alkoxy, C1-C6 alkylhydroxyl, 3-8 membered alkyl ring, 3-8 membered heteroalkyl ring, halogen-substituted 3-8 membered heteroalkyl ring, -(C1-C3 alkylene)-3-8 membered heteroalkyl ring, 5-10 membered aromatic heterocycle.

[0082] In another preferred embodiment, L is O, NH, S, SO2, substituted or unsubstituted -CH=CH-; and R' is -CORb, -SO2Rc.

[0083] In another preferred embodiment, L is -CH=CH-; and R' is -CORb or -SO2Rc.

[0084] In another preferred embodiment, Ra and Rb are each independently selected from -ORd and -NReRf; wherein, Rd, Re and Rf are each independently hydrogen, C1-C6 alkyl, C2-C6 unsaturated alkyl, C1-C6 haloalkyl, or Re, Rf and their adjacent nitrogen atoms together form a substituted or unsubstituted 3-8 membered heteroalkyl ring.

[0085] In another preferred embodiment, Ra and Rb are each independently selected from -ORd and -NReRf; wherein Rd, Re and Rf are each independently hydrogen, C1-C4 alkyl, C2-C4 unsaturated alkyl, C1-C4 haloalkyl.

[0086] In another preferred embodiment, when X is an oxygen atom, Rg is

[0087] In another preferred embodiment, when X is an oxygen atom, the α-mangostin derivative has a structure of the following formula (A), (B), (C) or (D):

[0088]

[0089] In another preferred embodiment, when X is NH, the α-mangostin derivative has the structure of the following formula (E):

[0090]

[0091] In another preferred embodiment, the α-mangostin derivative has the structure of the following formula (F):

[0092]

[0093] In another preferred embodiment, when R2=R3=H and R1 is a hydroxyl group, R is -X-Rg or -CH=CH-R6, wherein X is NH, O, CH2, and Rg is selected from

[0094] R4 is a C1-C3 alkyl group;

[0095] R5 is a substituted 5-10 membered aryl group, a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; wherein the substitution refers to substitution by 1-2 Rh and 0-2 Ri;

[0096] wherein Rh is selected from hydroxyl, cyano, C1-C6 haloalkyl, substituted or unsubstituted 3-8 membered monocyclic heteroalkyl ring group, substituted or unsubstituted 6-8 membered bridged heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group, -Z-substituted or unsubstituted 3-8 membered heteroalkyl ring, Ri is selected from halogen, hydroxyl, cyano, amino, -C(O)X'R8 or -X'C(O)R9, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, substituted or unsubstituted 3-12 membered heteroalkyl ring group, and Z is NH, S or SO2, -C1-C6 alkylene-, -O-C1-C6 alkylene-;

[0097] R6 is a substituted or unsubstituted 3-8 membered monocyclic heteroalkyl ring group, a substituted or unsubstituted 6-8 membered bridged heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, or a substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group;

[0098] R7 is selected from a substituted or unsubstituted 3-8 membered monocyclic heteroalkyl ring group, a substituted or unsubstituted 6-8 membered bridged heteroalkyl ring group, a substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, a substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group;

[0099] n is selected from integers of 2-20.

[0100] In another preferred embodiment, when R2=R3=H and R1 is a hydroxyl group, R is -X-Rg, wherein X is NH, O, and Rg is selected from

[0101] R4 is a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-8-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-8-membered alkyl ring, a substituted or unsubstituted 3-8-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-8-membered heteroalkyl ring;

[0102] R5 is a substituted 5-10 membered aryl group, a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; wherein the substitution refers to substitution by 1-2 Rh and 0-2 Ri;

[0103] wherein Rh is selected from hydroxyl, cyano, C1-C6 haloalkyl, 3-8 membered alkyl ring, substituted or unsubstituted 3-8 membered monocyclic heteroalkyl ring, substituted or unsubstituted 6-8 membered bridged heteroalkyl ring, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group, -Z-substituted or unsubstituted 3-8 membered heteroalkyl ring, Ri is selected from halogen, hydroxyl, cyano, amino, amine, -C(O)X'R8 or -X'C(O)R9, C1-C6 alkyl, C1-C6 heteroalkyl, Z is NH, S or SO2, -C1-C6 alkylene-, -O-C1-C6 alkylene-,

[0104] R6 is a substituted or unsubstituted saturated or unsaturated 3-8-membered alkyl ring group, a substituted or unsubstituted 3-8-membered heteroalkyl ring group, a substituted or unsubstituted 5-10-membered aryl group, or a substituted or unsubstituted 3-12-membered aromatic heterocyclic group;

[0105] Ring A is a substituted or unsubstituted 3-8-membered heteroalkyl ring, or a substituted or unsubstituted 5-6-membered aromatic heterocyclic ring.

[0106] In another preferred embodiment, when R2=R3=H and R1 is a hydroxyl group, R is -X-Rg, wherein X is NH, O, and Rg is selected from

[0107] R4 is a C1-C3 alkyl group;

[0108] R5 is a substituted 5-10 membered aryl group, a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; wherein the substitution refers to substitution by 1-2 Rh and 0-2 Ri;

[0109] Wherein, Rh is selected from hydroxyl, cyano, C1-C6 haloalkyl, substituted or unsubstituted 3-8 membered monocyclic heteroalkyl ring group, substituted or unsubstituted 6-8 membered bridged heteroalkyl ring group, Ri is selected from halogen, hydroxyl, cyano, amino, amine, -C(O)X'R8 or -X'C(O)R9, C1-C6 alkyl, C1-C6 heteroalkyl, Z is NH, S or SO2, -C1-C6 alkylene-, -O-C1-C6 alkylene-;

[0110] R6 is a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-12 membered aromatic heterocyclic group; wherein the substitution means that one or more hydrogen atoms are replaced by a substituent selected from the group consisting of a hydroxyl group, a C1-C3 alkyl group, and a C1-C3 alkoxy group.

[0111] In another preferred embodiment, when R2=R3=H and R1 is a hydroxyl group, R is -CH=CH-R6;

[0112] Wherein, R6 is a substituted or unsubstituted 3-8 membered alkyl ring group, a substituted or unsubstituted 3-8 membered heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, or a substituted or unsubstituted 3-12 membered aromatic heterocyclic group.

[0113] In another preferred embodiment, n is an integer of 2-20, preferably an integer of 2-10, for example 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0114] In another preferred embodiment, when R2=R3=H and R1 is not a hydroxyl group, R is -X-Rg, wherein X is O, and Rg is selected from -CO-substituted or unsubstituted 3-8 membered heteroalkyl ring, -CO-substituted or unsubstituted C6-C10 aromatic ring, -CO-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, -CO-CH2-substituted or unsubstituted 3-8 membered alkyl ring, -CO-CH2-substituted or unsubstituted 3-8 membered heteroalkyl ring, -CO-CH2-substituted or unsubstituted 5-10 membered aromatic ring, -CO-CH2-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring,

[0115] R4 is a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-8-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-8-membered alkyl ring, a substituted or unsubstituted 3-8-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-8-membered heteroalkyl ring;

[0116] R5 is C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0117] R6 is -C(O)X'R8 or -X'C(O)R9, an amide group, a sulfonic acid group, a sulfonate group, a sulfonamide group, a substituted or unsubstituted 3-8 membered alkyl ring group, a substituted or unsubstituted 3-8 membered heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, or a substituted or unsubstituted 3-12 membered aromatic heterocyclic group.

[0118] In another preferred embodiment, when R2=R3=H and R1 is not a hydroxyl group, R is -X-Rg, wherein X is O and Rg is

[0119] R4 is a C1-C3 alkyl group, a substituted or unsubstituted 3-8 membered alkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring group;

[0120] R5 is a substituted or unsubstituted 5-10 membered aryl group, or a substituted or unsubstituted 3-12 membered aromatic heterocyclic group.

[0121] In another preferred embodiment, when R2=R3=H and R1 is a C2-C6 unsaturated alkoxy group (preferably a C2-C6 alkoxyalkylene group), R is -X-Rg, wherein X is O and Rg is

[0122] R4 is a C1-C3 alkyl group;

[0123] R5 is a substituted or unsubstituted 5-10 membered aryl group.

[0124] In another preferred embodiment, when R2 and R3 are not H at the same time and R1 is a hydroxyl group, R is -X-Rg, wherein X is O, and Rg is selected from a hydrogen atom, -C(O)X'R8 or -X'C(O)R9, -(C1-C20 alkylene)-C(O)X'R8 or -(C1-C20 alkylene)-X'C(O)R9, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 5-10 membered aromatic ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, -CO-substituted or unsubstituted 5-10 membered aromatic ring, -CO-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, -CO-CH2-substituted or unsubstituted 3-8 membered alkane ring, -CO-CH2-substituted or unsubstituted 3-8 membered heteroalkane ring, -CO-CH2-substituted or unsubstituted 5-10 membered aromatic ring, -CO-CH2-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, Or Rg and R3 and their adjacent X together form a substituted or unsubstituted 5-8 membered heterocyclic ring;

[0125] R4 is a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-8-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-8-membered alkyl ring, a substituted or unsubstituted 3-8-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-8-membered heteroalkyl ring;

[0126] R5 is C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0127] R6 is -C(O)X'R8 or -X'C(O)R9, an amide group, a sulfonic acid group, a sulfonate group, a sulfonamide group, a substituted or unsubstituted 3-8 membered alkyl ring group, a substituted or unsubstituted 3-8 membered heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, or a substituted or unsubstituted 3-12 membered aromatic heterocyclic group.

[0128] In another preferred embodiment, when R2 and R3 are not H at the same time and R1 is a hydroxyl group, R is -X-Rg, wherein X is O, and Rg is selected from a hydrogen atom, -C(O)X'R8 or -X'C(O)R9, Or Rg and R3 and their adjacent X together form a substituted or unsubstituted 5-8 membered heterocyclic ring;

[0129] R4 is a C1-C3 alkyl, -(C1-C3 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring;

[0130] R5 is a C1-C3 alkyl group, a substituted or unsubstituted 5-10 membered aryl group, or a substituted or unsubstituted 3-12 membered aromatic heterocyclic group;

[0131] R6 is a substituted or unsubstituted 5-10 membered aryl group, or a substituted or unsubstituted 3-12 membered aromatic heterocyclic group.

[0132] In another preferred embodiment, when R2 and R3 are not H at the same time and R1 is not a hydroxyl group, R is -X-Rg, wherein X is O, and Rg is selected from -C(O)X'R8 or -X'C(O)R9, -(C1-C20 alkylene)-C(O)X'R8 or -(C1-C20 alkylene)-X'C(O)R9, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C1-C Rg and R3 together with the adjacent X constitute a substituted or unsubstituted 5-6 membered heterocyclic ring.

[0133] In another preferred embodiment, when R2 and R3 are not H at the same time and R1 is not hydroxyl, R is -X-Rg, wherein X is O, and Rg is -C(O)X'R8 or -X'C(O)R9, -(C3-C20 alkylene)-C(O)X'R8 or -(C3-C20 alkylene)-X'C(O)R9, -(C3-C20 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring, -(C3-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C3-C20 alkylene)-substituted or unsubstituted 5-10 membered aromatic ring, -(C3-C20 alkylene)-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, or Rg and R3 and their adjacent X together constitute a substituted or unsubstituted 5-6 membered heterocyclic ring.

[0134] In another preferred embodiment, R5 is a substituted or unsubstituted 5-10 membered aryl group, or a substituted or unsubstituted 3-12 membered aromatic heterocyclic group, wherein the substitution refers to substitution with 1-2 Rh and 0-2 Ri;

[0135] Wherein Rh is selected from hydroxyl, cyano, C1-C6 haloalkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group, -Z-substituted or unsubstituted 3-8 membered heteroalkyl ring, Ri is selected from halogen, hydroxyl, cyano, amino, amine, -C(O)X'R8 or -X'C(O)R9, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, substituted or unsubstituted 3-12 membered heteroalkyl ring group, and Z is NH, S or SO2, -C1-C6 alkylene-, -O-C1-C6 alkylene-.

[0136] In another preferred embodiment, R5 is a substituted 5-10 membered aryl group, a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; wherein the substitution refers to substitution with 1-2 Rh and 0-2 Ri;

[0137] Wherein, Rh is selected from hydroxyl, cyano, C1-C6 haloalkyl, 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered monocyclic heteroalkyl ring group, substituted or unsubstituted 6-8 membered bridged heteroalkyl ring group, -Z-substituted or unsubstituted 3-8 membered heteroalkyl ring, Ri is selected from halogen, hydroxyl, cyano, amino, amine, -C(O)X'R8 or -X'C(O)R9, C1-C6 alkyl, C1-C6 heteroalkyl, Z is NH, S or SO2, -C1-C6 alkylene-, -O-C1-C6 alkylene-.

[0138] In another preferred embodiment, when R2 and R3 are not H at the same time, R is -X-Rg, wherein X is O, and Rg is selected from hydrogen atom, -C(O)X'R8,

[0139] R4 is a C1-C3 alkyl group;

[0140] R5 is a C1-C3 alkyl group, a substituted or unsubstituted 5-10 membered aryl group; wherein the substitution means that one or more hydrogen atoms are replaced by a group selected from the group consisting of a hydroxyl group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a 3-8 membered monocyclic heteroalkyl ring group, and a 6-8 membered bridged heteroalkyl ring group;

[0141] R6 is a substituted or unsubstituted 5-10 membered aromatic ring, wherein the substitution means that one or more hydrogen atoms are replaced by a group selected from the following group: hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, 3-8 membered monocyclic heteroalkyl ring group, 6-8 membered bridged heteroalkyl ring group.

[0142] In another preferred example, the 3-12 membered heteroalkyl ring or the 3-12 membered heteroalkyl ring includes a 3-8 membered monocyclic heteroalkyl ring, a 9-12 membered condensed heteroalkyl ring and a 5-10 membered bridged heteroalkyl ring.

[0143] In another preferred embodiment, the 3-12 membered aromatic heterocyclic group or the 3-12 membered aromatic heterocyclic group includes a 3-8 membered monocyclic aromatic heterocyclic ring and a 9-12 membered condensed aromatic heterocyclic ring.

[0144] In another preferred embodiment, R is -X-Rg, wherein X is O and Rg is

[0145] Wherein, R4 is a C1-C3 alkyl group;

[0146] R5 is a substituted or unsubstituted 5-10 membered aryl group.

[0147] In another preferred embodiment, when X' is oxygen and R8 or R9 is not hydrogen, -C(O)X'R8 or -X'C(O)R9 represents "ester". In another preferred embodiment, when X' is oxygen and R8 is hydrogen, -C(O)X'R8 represents "carboxylic acid". In another preferred embodiment, when X' is oxygen and R9 is hydrogen, -X'C(O)R9 represents "formate".

[0148] In another preferred embodiment, when X' is sulfur and R8 or R9 is not hydrogen, -C(O)X'R8 or -X'C(O)R9 represents a "thioester" group. In another preferred embodiment, when X' is sulfur and R8 is hydrogen, -C(O)X'R8 represents a "thiocarboxylic acid" group. In another preferred embodiment, when X' is sulfur and R9 is hydrogen, -X'C(O)R9 represents a "thioformate" group.

[0149] In another preferred embodiment, when X' is a chemical bond and R8 is not hydrogen, -C(O)X'R8 represents an acyl group. In another preferred embodiment, when X' is a bond and R8 is hydrogen, -C(O)X'R8 represents an "aldehyde" group.

[0150] In another preferred embodiment, R8 is independently selected from hydrogen, C1-C6 alkyl, and C2-C8 alkenyl.

[0151] In another preferred embodiment, R9 is independently selected from hydrogen, C1-C6 alkyl, and C2-C8 alkenyl.

[0152] In another preferred embodiment, -C(O)X'R8 is -COO-(C1-C6 alkyl) or -CO-(C1-C6 alkyl).

[0153] In another preferred embodiment, R 10 , R 11 and R 12 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, preferably methyl.

[0154] In another preferred embodiment, R 10 or R 11 Not all -C(O)X'R8 or -X'C(O)R9 including R 10 , R 11 Not all -C(O)X'R8;R 10 , R 11 Not all -X'C(O)R9; and R 10 , R 11 Not that one of them is -C(O)X'R8 and the other is -X'C(O)R9.

[0155] In another preferred embodiment, the substituted 5-10 membered aryl group is a 5-10 membered aryl group substituted with a hydroxyl group, preferably

[0156] In another preferred embodiment, ring A is a substituted or unsubstituted 3-8 membered (preferably 5-6 membered) heteroalkyl ring.

[0157] In another preferred embodiment, the α-mangostin derivative represented by Formula I includes the structure represented by Formula Ia, Ib, Ic or Id:

[0158]

[0159] In another preferred embodiment, when R2=R3=H and R1 is a hydroxyl group, the α-mangostin derivative represented by Formula I includes the structure represented by Formula Ia.

[0160] In another preferred embodiment, when R2=R3=H and R1 is not a hydroxyl group, the α-mangostin derivative represented by Formula I includes the structure represented by Formula Ib.

[0161] In another preferred embodiment, when R2 and R3 are not H at the same time and R1 is a hydroxyl group, the α-mangostin derivative represented by Formula I includes the structure represented by Formula Ic.

[0162] In another preferred embodiment, when R2 and R3 are not H at the same time and R1 is not a hydroxyl group, the α-mangostin derivative represented by Formula I includes the structure represented by Formula Id.

[0163] In another preferred embodiment, in formula Ic or Id, X is selected from O, and Rg is selected from -(C3-C20 alkylene)-C(O)X'R8, or -(C3-C20 alkylene)-X'C(O)R9, -(C3-C20 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring, -(C3-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C3-C20 alkylene)-substituted or unsubstituted 5-10 membered aromatic ring, -(C3-C20 alkylene)-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring.

[0164] In another preferred embodiment, R1, R2, R3, and R are each independently a corresponding group of compound 1-74.

[0165] In another preferred embodiment, the α-mangostin derivative has a structure as shown in any one of Formulas 1 to 74:

[0166]

[0167]

[0168]

[0169]

[0170] In the second aspect of the present invention, there is provided a method for preparing the α-mangostin derivative represented by formula (I) as described in the first aspect of the present invention, the method comprising the steps of:

[0171] (1) Synthesis route mainly using intermediate A-1 as starting material:

[0172]

[0173] (2) Synthesis route mainly using intermediate B-2 as starting material:

[0174]

[0175] (3) Synthesis route mainly using intermediate B-4 as starting material:

[0176]

[0177] (4) Synthesis route mainly using intermediate C-1 as starting material:

[0178]

[0179] (5) Synthesis route mainly using intermediate C-3 as starting material:

[0180]

[0181] (6) Synthetic routes mainly using some embodiments as starting materials:

[0182]

[0183] In a third aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0184] (a) a therapeutically effective amount of an α-mangostin derivative of formula (I) as described in the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof; and

[0185] (b) a pharmaceutically acceptable carrier.

[0186] In the third aspect of the present invention, there is provided the use of an α-mangostin derivative as shown in formula (I) as described in the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for preparing a medicament for treating cardiovascular and cerebrovascular diseases, nervous system diseases, and / or inflammatory diseases.

[0187] In another preferred embodiment, the cardiovascular and cerebrovascular diseases include but are not limited to ischemic cerebrovascular disease, transient ischemic attack, ischemic stroke (cerebral infarction), lacunar infarction, myocardial infarction, myocardial ischemia, heart failure, atherosclerosis, arterial restenosis, atherosclerosis, and arterial embolism.

[0188] In another preferred embodiment, the nervous system diseases include but are not limited to cerebrovascular diseases, neurodegenerative diseases, and more specifically include stroke, ischemic stroke, vascular dementia, cerebral palsy, dementia, concussion, brain injury, brain reperfusion injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA).

[0189] In another preferred embodiment, the inflammatory disease includes but is not limited to proliferative inflammation, asthma, COPD and pulmonary fibrosis, psoriasis, inflammatory arthritis, rheumatoid arthritis, sepsis, septic shock, inflammatory bowel disease (IBD, including ulcerative colitis and Crohn's disease), nephritis, cystic fibrosis, keratosis, rheumatoid spondylitis, osteoarthritis, etc.

[0190] In the fourth aspect of the present invention, a method for treating cardiovascular and cerebrovascular diseases, nervous system diseases, and inflammatory diseases is provided, the method comprising: administering an α-mangostin derivative represented by formula (I) as described in the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof.

[0191] In another preferred embodiment, the subject is a human or non-human mammal. DETAILED DESCRIPTION

[0192] After long-term and in-depth research, the inventors screened and obtained a class of α-mangostin derivatives. The α-mangostin derivatives have excellent neuroprotective effects and can be used to prepare drugs for preventing and / or treating cardiovascular and cerebrovascular diseases, nervous system diseases, and inflammatory diseases. Based on the above findings, the inventors completed the present invention.

[0193] the term

[0194] Unless specifically defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0195] In the present invention, the terms "comprising", "including" or "including" indicate that various components can be used together in the mixture or composition of the present invention. Therefore, the terms "consisting mainly of" and "consisting of" are included in the term "comprising".

[0196] In the present invention, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation and allergic reaction), that is, has a reasonable benefit / risk ratio.

[0197] In the present invention, the term "effective amount" refers to the amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or preventive effect. The exact effective amount for a subject depends on the subject's size and health, the nature and extent of the condition, and the therapeutic agent and / or combination of therapeutic agents selected for administration. Therefore, it is useless to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation, which is within the judgment of the clinician.

[0198] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.

[0199] In the present invention, the term "compound of the present invention" refers to the α-mangostin derivative shown in Formula I provided by the present invention.

[0200] Some compounds of the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed. The solvates of the present invention include stoichiometric solvates such as hydrates, and also include compounds containing variable amounts of water formed when prepared by low-pressure sublimation drying.

[0201] The present invention also includes all suitable isotopic variations of the compounds of the present invention. Isotopic variations of the compounds of the present invention are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 35 S. 18 F and 36Cl. Some isotopic variants of the invention, for example, wherein a radioactive isotope (e.g. 3 H or 14 C) are used in drug and / or substrate tissue distribution studies. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred because they are easy to prepare and detect. In addition, isotopes (such as deuterium, i.e. 2 H) substitution may provide some therapeutic advantages caused by increased metabolic stability, for example, increased half-life in vivo or reduced dosage requirements and may therefore be preferred in some cases. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures, for example, using suitable reagents of appropriate isotopic variations, by the illustrative methods or the preparation described in the experimental section below.

[0202] Preparation method

[0203] The present invention provides a method for preparing the compound of the present invention, which is achieved by the following synthetic method:

[0204] Overview of the synthesis method of α-mangostin derivatives: The intermediates A-1, B-2, B-4, C-1, C-3 and some examples are used as starting materials, and different amino compounds, acids, halides, acyl halides, boric acid or boric esters are reacted with reagents such as nucleophilic substitution or Suzuki reaction to obtain key compounds, and then the corresponding products are obtained through subsequent carbonyl insertion reaction, hydrolysis reaction, etc. The main synthesis routes are as follows:

[0205] The synthetic route mainly using intermediate A-1 as the starting material:

[0206]

[0207] The synthetic route mainly using intermediate B-2 as the starting material:

[0208]

[0209] The synthetic route mainly using intermediate B-4 as the starting material:

[0210]

[0211] The synthetic route mainly using intermediate C-1 as the starting material:

[0212]

[0213] The synthetic route mainly using intermediate C-3 as the starting material:

[0214]

[0215] The synthetic routes mainly using some embodiments as starting materials are:

[0216]

[0217] The above are the main synthetic routes and methods. For other synthetic methods, please refer to the examples in the specific implementation section.

[0218] Pharmaceutical compositions and methods of administration

[0219] Since the compounds of the present invention have excellent neuroprotective activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat and prevent cardiovascular and cerebrovascular diseases, nervous system diseases, and inflammatory diseases.

[0220] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 0.1-1000 mg of the compound of the present invention per dose, and more preferably, contains 0.5-500 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0221] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0222] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention, and representative administrations include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. A particularly preferred administration is oral.

[0223] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0224] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0225] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0226] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0227] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0228] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0229] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0230] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0231] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 0.2 to 1000 mg, preferably 0.5 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0232] The main advantages of the present invention include:

[0233] 1. The present invention obtains a class of novel α-mangostin derivatives as shown in formula (I), or pharmaceutically acceptable salts or solvates thereof.

[0234] 2. The present invention further evaluated the in vitro efficacy of the derivatives in important and typical in vitro efficacy models of ischemic stroke (cerebrovascular disease), etc. First, it was found that in the experimental verification of iodoacetic acid-induced HT22 cell injury, the activity of the derivatives was better than that of the same dose of HZAM-1 and butylphthalide groups, and the activity of the compounds was better than that of the same dose of edaravone group. Secondly, in the experimental verification of oxygen-glucose deprivation-induced HT22 cell injury, some of the derivatives showed better neuroprotective effects than HZAM-1 and edaravone groups.

[0235] 3. The present invention also conducted in vitro and in vivo pharmacokinetic evaluations on the α-mangostin derivatives as shown in formula (I), or their pharmaceutically acceptable salts or solvates, and found that the derivatives showed excellent stability in human and rat liver microsome experiments, and compounds with reasonable half-lives and good areas under the drug-time curve were found in the in vivo pharmacokinetic experiments in rats, indicating that this type of α-mangostin derivatives has good physicochemical properties and potential drug value.

[0236] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0237] Intermediate A-1: ​​Preparation of 5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-6-one

[0238]

[0239] 1,3,6-trihydroxy-7-methoxy-2,8-di(3-methylbut-2-en-1-yl)-9H-xanthene-9-one (3g, 7.3mmol) was dissolved in toluene (300ml), DDQ (1.99g, 8.8mmol) was added, and the reaction solution was heated to 40°C and stirred for 4h. TLC detected that the raw material reaction was complete, and the reaction solution was cooled and concentrated to obtain a crude product, which was purified by flash column chromatography (PE / EA=4 / 1) to obtain 2.7g of a yellow solid product. 1 HNMR(400MHz, CDCl3)δ13.70(s,1H)6.84(s,1H)6.74(d,J=10.03Hz,1H)6.36(s,1H)6.25(s,1H)5.57(d,J=10.03Hz,1H)4.09(br d,J=6.36Hz,2H)3.81(s,3H)1.84(s,3H)1.70(d,J=0.98Hz,3H)1.47(s,6H).

[0240] Intermediate B-4: Preparation of 12-hydroxy-8-methoxy-5,9-di(methoxymethoxy)-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-6-one

[0241]

[0242] Step 1: Dissolve 1,3,6-trihydroxy-7-methoxy-2,8-di(3-methylbut-2-en-1-yl)-9H-oxanthene-9-one (15.0 g, 0.04 mol) in DCM (200 mL), slowly add NBS (6.5 g, 0.04 mol) in DCM (60 mL) at 0°C, and react at room temperature for 24 hours. LCMS showed that the reaction was complete, and saturated sodium sulfite solution (50 mL) was added, stirred at room temperature for 30 minutes, extracted with DCM (100 mL x 3), the organic phases were combined, dried over sodium sulfate, concentrated, and the crude product was purified by flash column chromatography (PE / EA = 4 / 1) to obtain 12.8 g of yellow solid. LC-MS: ESI m / z: 489 [M+H] + .

[0243] Step 2: Dissolve 4-bromo-1,3,6-trihydroxy-7-methoxy-2,8-di(3-methylbut-2-en-1-yl)-9H-xanthene-9-one (12.8 g, 0.03 mol) in toluene (200 mL), add DDQ (8.9 g, 0.04 mol) at 0°C, and stir overnight at 50°C. LCMS showed that the reaction was complete. After the reaction solution was concentrated, the crude product was purified by flash column chromatography (PE / EA=4 / 1) to obtain 6.2 g of a yellow solid. LC-MS: ESI m / z: 487 [M+H] + .

[0244] Step 3: Dissolve 12-bromo-5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-6-one (2.4 g, 5.0 mmol) in THF (50 mL), add sodium hydride (4.0 mg, 98.8 mmol) to the solution at 0°C, stir the reaction at 0°C for 1 h, and then add a THF (5 mL) solution of bromomethoxymethyl ether (4.1 g, 29.6 mmol) dropwise to the solution. TLC detected that the reaction was complete (PE / EA=3 / 1, RF=0.4), added water, extracted with dichloromethane, concentrated, and the crude product was purified by flash column chromatography (PE / EA=9:1) to obtain 2.4 g of a white solid. LC-MS: ESI m / z: 575 [M+H] + .

[0245] Step 4: Dissolve 12-bromo-8-methoxy-5,9-bis(methoxymethoxy)-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]oxanthene-6-one (1.0 g, 1.7 mmol) in 1,4-dioxane (50 mL), add 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2`,4`,6`-triisopropylbiphenyl (450 mg, 0.9 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.2 mmol) and potassium hydroxide (200 mg, 3.5 mmol) in water (25 mL) to the solution, heat to 100 °C under nitrogen protection and stir for 12 h. LCMS detected that the reaction was complete, and water, dichloromethane and a small amount of acetonitrile were added for mixed extraction. After concentration, the crude product was purified by flash column chromatography (PE / EA=9:1) to obtain 650 mg of yellow solid. LC-MS: ESI m / z: 513 [M+H] + .

[0246] Intermediate C-3: Preparation of 10-hydroxy-8-methoxy-5,9-di(methoxymethoxy)-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-6-one

[0247]

[0248] Step 1: Referring to the preparation method of intermediate B-4 step 1, the crude product was purified by flash column chromatography (PE / EA=10 / 1) to obtain 30 mg of a yellow solid product. LC-MS: ESI m / z: 488 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ=13.59-13.29(m,1H),6.73(d,J=10.0Hz,1H),6.62-6.49(m,1H),6.39(s,1H),5.59(d,J=10.0Hz,1H),5.23(br t,J=6.4Hz,1H),4.09(br d,J=6.4Hz,2H),3.90-3.77(m,3H),1.84(s,3H),1.73-1.66(m,3H),1.48(s,6H).

[0249] Step 2: Referring to the preparation method of intermediate B-4 step 3, the crude product was purified by rapid quasi-chromatography (PE / EA=9 / 1) to obtain 350 mg of white solid. LC-MS: ESI m / z: 575 [M+H] + .

[0250] Step 3: Referring to the preparation method of intermediate B-4 step 4, the crude product was purified by flash column chromatography (PE / EA=4 / 1) to obtain 240 mg of yellow solid. LC-MS: ESI m / z: 513 [M+H] + .

[0251] Example 1: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl 4-(3,4-dihydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0252]

[0253] Step 1: Dissolve 4-bromobenzene-1,2-diphenol (2.5 g, 13.3 mmol) in 1,4-dioxane (80 mL) and water (10 mL), add tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (6.1 mg, 20 mmol), potassium carbonate (5.5 g, 40 mmol) and Pd(dppf)Cl2 (543 mg, 0.7 mmol) to the solution in sequence, and stir the reaction solution at 90°C for 12 h under nitrogen protection. LCMS detected that the raw material reacted completely, the reaction solution was added with water, citric acid was adjusted to pH = 5-6, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reverse column chromatography to obtain 1.9 g of a yellow oily product. LC-MS: ESI m / z: 292 [M+H] + .

[0254] Step 2: In an ice-water bath, dissolve tert-butyl 4-(3,4-dihydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (900 mg, 3.0 mmol) in dichloromethane (12 mL), slowly add trifluoroacetic acid (3 mL) to the solution, and stir the reaction solution at room temperature for 2 h. LCM detection shows that the raw material reacts completely, and after concentration, 1.0 g of crude product is obtained. LC-MS: ESI m / z: 192 [M+H] + .

[0255] Step 3: Dissolve 4-(1,2,3,6-tetrahydropyridin-4-yl)benzene-1,2-diphenol (100 mg, 0.3 mmol) in dichloromethane (2 mL), add triphosgene (22 mg, 0.08 mmol) in dichloromethane (1 mL) (prepared in an ice-water bath) dropwise to the reaction solution, stir the reaction solution for 10 min, then add pyridine (20 mg, 0.25 mmol) to the reaction solution, stir at room temperature for 2 h, then stop the reaction, and keep the reaction solution for later use.

[0256] The intermediate 5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-6-one A-1 (281 mg, 1.5 mmol) was dissolved in dichloromethane (2 mL), and appropriate amounts of pyridine (the solution was alkaline), the above-mentioned standby solution and DMAP (15 mg, 0.1 mmol) were added to the reaction solution in sequence, and the reaction solution was stirred at room temperature for 12 h. LCMS detected that the raw material reaction was complete, the reaction solution was quenched by adding water, the pH was adjusted to 5-6 with dilute hydrochloric acid, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was purified by rapid column chromatography (PE / EA=2 / 1) to obtain 10 mg of a yellow solid. LC-MS: ESI m / z: 626.3[M+H] + ; 1 HNMR(400MHz,DMSO)δ13.56(s,1H),8.87(s,1H),7.39(s,1H),7.06(s,1H),6.77-6.70(m,1H),6 .67(t,J=7.6Hz,2H),6.55(d,J=7.9Hz,1H),6.46(d,J=10.1Hz,1H),6.04-5.90(m,2H),5.82(d,J =10.1Hz,1H),5.19(d,J=6.2Hz,1H),4.29(d,J=12.1Hz,1H),4.07(dd,J=16.8,10.5Hz,3H),3.9 8-3.80(m,1H),3.76(s,1H),3.68-3.47(m,4H),1.81(d,J=7.0Hz,3H),1.67(s,3H),1.49(s,7H).

[0257] Example 2: Preparation of 12-(3,4-dihydroxyphenyl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0258]

[0259] Step 1: Dissolve 4-bromobenzene-1,2-diphenol (1.5 g, 7.9 mmol) in 1,4-dioxane (40 mL), add bis-pinacol borate (2.4 g, 9.5 mmol), potassium acetate (1.94 g, 19.8 mmol) and Pd(dppf)Cl2 (730 mg, 1.0 mmol) to the solution, and stir the reaction solution at 95°C for 12 h under nitrogen protection. The reaction of the raw material was complete as determined by LCMS, and the reaction solution was concentrated. The crude product was purified by flash column chromatography (PE / EA=9 / 1) to obtain 1.3 g of a colorless intermediate.

[0260] Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzene-1,2-diphenol (100 mg, 0.4 mmol) was dissolved in 1,4-dioxane / H2O=10:1 (5 mL), 12-bromo-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]oxanthene-9-ylmethyl(phenyl)carbamate (Example 6) (175 mg, 0.3 mmol), K2CO3 (117 mg, 0.85 mmol) and Pd(dtbpf)Cl2 (20 mg, 0.03 mmol) were added to the solution, and the reaction solution was stirred at 95°C under nitrogen protection for 12 h. The reaction of the raw material was complete as determined by LCMS. The reaction solution was added with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (PE / EA = 6 / 1) to obtain 10 mg of a light yellow solid. LC-MS: ESI m / z: 650.1 [M+H] + ; 1 HNMR (400MHz, DMSO) δ13.71(s,1H),8.99(s,1H),7.55(d,J=8.0Hz,2H),7.47(t,J=7.8Hz,2H),7.35(d,J=7.3Hz,1H),7.24(s,1H),6.85(dd, J=10.1,5.0Hz,2H),6.746.66(m,2H),5.82(d,J=10.0Hz,1H),5.18(s,1H),4.06(s,2H),3.38(s,6H),1.80(s,3H),1.66(s,3H),1.42(s,6H).

[0261] Example 3: Preparation of 10-bromo-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl (E)-3-(3,4-dihydroxyphenyl)acryloyl ester

[0262]

[0263] Step 1: Dissolve the intermediate C-1 (100 mg, 0.2 mmol) in DCM (3 mL), add (E)-3-(3,4-di((tert-butyldimethylsilyl)oxy)phenyl)acrylic acid (101 mg, 0.3 mmol), EDCI (47.2 mg, 0.3 mmol), DMAP (6.3 mg, 0.1 mmol) to the reaction solution, and stir the reaction solution at room temperature for 15 h. The reaction was completed as detected by TLC (PE / EA=3 / 1, Rf=0.4), the reaction solution was concentrated, water (10 mL) was added, and ethyl acetate (20 mL×3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (PE / EA=7 / 3) to obtain 130 mg of a yellow solid product. LC-MS: ESI m / z: 877 [M+H] + .

[0264] Step 2: 10-bromo-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl(E)-3-(3,4-di((tert-butyldimethylsilyl)oxy)phenyl)acryloyl ester (100 mg, 0.1 mmol) was dissolved in THF (3 mL), 8 drops of TBAF / THF solution and 4 drops of acetic acid solution were added to the solution, and the reaction of the raw material was completed after stirring at room temperature for 2 hours. LCMS was used to detect that the reaction was complete, the reaction solution was concentrated, water (10 mL) was added, EA (20 mL×3) was extracted, dried, filtered, and the crude product was subjected to column chromatography (PE / EA=4 / 1) to obtain 30 mg of a yellow solid. LC-MS: ESI m / z: 649[M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.37(s,1H),7.90(d,J=15.9Hz,1H),7.21(s,1H),7.15(d,J=8.4Hz,1H),6.95(d,J=8.3Hz,1H),6.78(d,J=10.1Hz,1H),6. 58(d,J=15.8Hz,1H),6.45(s,1H),5.64(d,J=10.0Hz,1H),5.26(s,1H),4 .18(d,J=6.2Hz,2H),3.82(s,3H),1.87(s,3H),1.73(s,3H),1.52(s,6H).

[0265] Example 4: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl 4-(3,4-dihydroxyphenyl)piperazine-1-carboxylate

[0266]

[0267] Step 1: Dissolve 4-bromobenzene-1,2-diphenol (2 g, 10 mmol) in THF (15 mL), add NaH (8.5 g, 200 mmol) under ice bath, add bromomethoxymethyl ether (8.8 g, 60 mmol) dropwise, stir at room temperature for 2 h. LCMS detected that the raw material reacted completely, and the crude product was purified by column chromatography (PE / EA=10 / 1) to obtain 1.5 g of colorless oily intermediate. LC-MS: ESI m / z: 277 [M+H] + .

[0268] Step 2: Dissolve 4-bromo-1,2-di(methoxymethoxy)benzene (500 mg, 0.2 mmol) in toluene (8 mL), add benzylpiperazine-1-carboxylate (798.0 mg, 0.46 mmol), Pd2(dba)3 (82.8 mg, 0.01 mmol), BINAP (78.8 mg, 0.01 mmol), potassium tert-butoxide (274 mg, 0.3 mmol), and heat to 90 ° C under nitrogen protection and continue stirring for 15 h. The reaction was complete as detected by LCMS, and the crude product was purified by column chromatography (PE / EA=2 / 3) to obtain 170 mg of a yellow oily product. LC-MS: ESI m / z: 417.2 [M+H] + .

[0269] Step 3: Dissolve benzyl 4-(3,4-di(methoxymethoxy)phenyl)piperazine-1-carboxylate (170 mg, 0.4 mmol) in MeOH (8 mL), add Pd / C (8.8 mg, 0.1 mmol), and continue stirring for 15 h under hydrogen protection. Filter and concentrate the reaction to obtain 70 mg of a yellow oily product. LC-MS: ESI m / z: 283.1 [M+H] + .

[0270] Step 4: See the synthesis of step 3 in Example 1. LC-MS: ESI m / z: 717.3 [M+H] + .

[0271] Step 5: Dissolve 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-ene-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl 4-(3,4-di(methoxymethoxy)phenyl)piperazine-1-carboxylate (70 mg, 0.3 mmol) in THF (3 mL), add 6N hydrochloric acid (2 mL), and continue stirring for 2 h. LCMS detected that the raw material reacted completely, and the crude product was purified by column chromatography (PE / EA=7 / 13) to obtain 19.5 mg of a yellow solid product. LC-MS: ESI m / z: 629.7 [M+H] + .

[0272] Example 5: Preparation of 5-hydroxy-12-(1H-indol-3-yl)-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0273]

[0274] Referring to the preparation method of step 2 of Example 2, the boric acid ester in the reaction reagent is 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.4 eq.), and the crude product is purified by preparative separation to obtain 9 mg of a yellow solid. LC-MS: ESI m / z: 657 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ13.78(s,1H),8.37(s,1H),7.63-7.35(m,8H),

[0275] 7.27(d,J=7.2Hz,1H),7.15(t,J=7.5Hz,1H),6.94(s,1H),6.87(d,J=10.0Hz,1H),5.63(d,J

[0276] =10.0Hz,1H),5.26(s,1H),4.16(s,2H),3.46(d,J=32.7Hz,6H),1.86(s,3H),1.72(s,3H),

[0277] 1.43(s,6H).

[0278] Example 6: Preparation of 12-bromo-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0279]

[0280] Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=7 / 3) to obtain 360 mg of a yellow solid product. LC-MS: ESI m / z: 620.2 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ13.55(s,1H),7.52-7.36(m,5H),7.32(d,J=6.7Hz,1H),6.72(d,J=10.0Hz,1H), 5.60(d,J=10.0Hz,1H),5.16(s,1H),4.10(s,2H),3.45(s,6H),1.81(s,3H),1.66(s,3H),1.52(s,6H).

[0281] Example 7: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl (E)-3-(3,4-dihydroxyphenyl)acryloyl ester

[0282]

[0283] Step 1: Dissolve (E)-3-(3,4-dihydroxyphenyl)acrylic acid (5g, 27mmol) in DCM (50mL), add DIEA (29mL, 176mmol) at 0°C, gradually add TBSCl (20.9g, 138mmol) to make the reaction solution clear, and warm the reaction solution to room temperature to continue the reaction for 15h. LCMS detected that the raw material was completely screened, concentrated the reaction solution, added water (80mL), extracted with ethyl acetate (40mL×3), dried the organic phase with anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash column chromatography (PE / EA=9 / 1) to obtain 5.1g of white solid product. LC-MS: ESI m / z: 409[M+H] + .

[0284] Step 2: € Referring to the preparation method of step 1 in Example 3, the crude product was purified by flash column chromatography (PE / EA=9 / 1) to obtain 120 mg of a yellow solid. LC-MS: ESI m / z: 799 [M+H] + .

[0285] Step 3: Referring to the preparation method of step 3 of Example 3, the crude product was purified to obtain 10.3 mg of a yellow solid. LC-MS: ESI m / z: 571 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.57(s,1H),7.86(d,J=15.9Hz,1H),7.24(s,1H),7.20(s,1H),7.14(s,1H),6.96(d,J=8.0Hz,1H),6.78(d,J=9.6Hz,2H),6 .54(d,J=15.8Hz,1H),6.30(s,1H),5.62(d,J=10.1Hz,1H),5.28(s,1H),4 .21(d,J=6.0Hz,2H),3.82(s,3H),1.88(s,3H),1.73(s,3H),1.51(s,6H).

[0286] Example 8: Preparation of 5,9,10-trihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-6-one

[0287]

[0288] Referring to the preparation method of step 5 of Example 4, the crude product was purified by column chromatography (PE / EA=3 / 1) to obtain 9.7 mg of a yellow solid. LC-MS: ESI m / z: 425 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ13.75(s,1H),6.73(d,J=10.0Hz,1H),6.30(s,1H),5.57(d,J=10.0Hz,1H), 5.24(t,J=6.4Hz,1H),4.03(d,J=6.3Hz,2H),3.84(s,3H),1.83(s,3H),1.68(s,3H),1.46(s,6H).

[0289] Example 9: Preparation of (E)-3-(5-hydroxy-8-methoxy-2,2-dimethyl-9-((methyl(phenyl)carbamoyl)oxy)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-10-yl)acrylic acid

[0290]

[0291] Step 1: Referring to the preparation method of step 2 in Example 2, the crude product was purified by column chromatography (PE / EA=2 / 1) to obtain 138 mg of a yellow solid. LC-MS: ESI m / z: 506 [M+H] + .

[0292] Step 2: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=0%-35%) to obtain 160 mg of a yellow solid. LC-MS: ESI m / z: 640 [M+H] + .

[0293] Step 3: Ethyl (E)-3-(5-hydroxy-8-methoxy-2,2-dimethyl-9-((methyl(phenyl)carbamoyl)oxy)-7-(3-methylbut-2-ene-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-10-yl)acrylate (160 mg, 0.3 mmol) was dissolved in EtOH (15 mL) and water (1.5 mL), and lithium hydroxide (59.9 mg, 2.5 mmol) was slowly added to the solution. The reaction was allowed to proceed at room temperature for 16 h. LCMS showed that the reaction was complete. Dilute hydrochloric acid was slowly added under an ice bath until the pH value was 6-7, and a white flocculent solid was precipitated. The solid was filtered, and the solid was washed with a small amount of pure water and MTBE, respectively. The obtained solid was dissolved in acetonitrile and water, and lyophilized to obtain 125 mg of a light yellow solid. LC-MS: ESI m / z: 592 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.30(s,1H),12.73(s,1H),7.70(d,J=16.4Hz,1H),7.50(s,3H),7.37(s,1H),6.61(d,J=10.0Hz,1H),6.49(s ,1H),5.79(d,J=10.1Hz,1H),5.15(s,1H),4.04(s,2H),3.65(d,J=18.1Hz,2H),3.38(s,3H),1.77(s,3H),1.63(s,3H),1.44(s,6H).

[0294] Example 10: Preparation of 12-(4-(dimethylamino)piperidin-1-yl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0295]

[0296] Step 1: Dissolve intermediate B-2 (243.7 mg, 0.5 mmol) in DMSO (5 mL), add N, N-dimethylpiperidin-4-amine (256 mg, 2 mmol), CuI (17 mg, 0.1 mmol), K2CO3 (276 mg, 2 mmol) and L-proline (57.6 mg, 0.5 mmol) to the reaction solution in sequence, and stir the reaction solution at 110 ° C for 12 h under nitrogen protection. TLC (DCM / MeOH=10 / 1, Rf=0.3) detected that the reaction was complete, the reaction solution was filtered and concentrated, and the crude product was purified by flash column chromatography (DCM / MeOH=10 / 1) to obtain 100 mg of yellow liquid. LC-MS: ESI m / z: 535 [M+H] + .

[0297] Step 2: Referring to the preparation method of step 1 in Example 6, the crude product was purified by flash column chromatography (DCM / MeOH=10 / 1) to obtain 10 mg of a yellow solid. LC-MS: ESI m / z: 668.6 [M+H] + ; 1 HNMR (400MHz, DMSO) δ13.42(d,J=11.9Hz,1H),7.65-7.46(m,5H),7.43-7.30(m,1H),6.65(t,J=10.5Hz,1H),5.81(t,J=9.0Hz,1H),5.13(d,J=26. 0Hz,1H),4.03(t,J=12.9Hz,1H),3.28(d,J=11.5Hz,5H),3.09(s,2H),2. 74(s,6H),2.04(d,J=10.8Hz,2H),1.80(s,5H),1.66(s,3H),1.51(s,6H).

[0298] Example 11: Preparation of 12-(3-(dimethylamino)pyrrolidin-1-yl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0299]

[0300] Step 1: Referring to the preparation method of step 1 in Example 10, the crude product was purified by flash column chromatography (DCM / MeOH=10:1) to obtain 90 mg of a yellow liquid. LC-MS: ESI m / z: 521 [M+H] + .

[0301] Step 2: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (DCM / MeOH=10 / 1) to obtain 10 mg of a yellow solid. LC-MS: ESI m / z: 645.5 [M+H] + ; 1 HNMR (400MHz, DMSO) δ13.44(s,1H),7.61-7.45(m,5H),7.36(d,J=7.4Hz,1H),6.65(d,J=10.0Hz,1H),5.80(d,J=10.0Hz,1H),5.15(s,1H ),4.04(d,J=5.0Hz,2H),3.28(d,J=9.4Hz,8H),2.41(s,5H),2.20(s,1H),1.96(s,1H),1.78(s,3H),1.64(s,3H),1.50(d,J=4.5Hz,6H).

[0302] Example 12: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(4-morpholinophenyl)carbamate

[0303]

[0304] Step 1: Dissolve 4-morpholinoaniline (500 mg, 2.8 mmol) in THF (5 mL), slowly add 60% NaH (80.8 mg, 3.4 mmol) and react at room temperature for 3 h. Add iodomethane (597.3 mg, 4.2 mmol) and the reaction is complete as determined by LCMS. The crude product is purified by column chromatography (PE / EA=2 / 3) to obtain 260 mg of a white solid product. LC-MS: ESI m / z: 193 [M+H] + .

[0305] Step 2: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=3 / 7) to obtain 17.3 mg of a yellow solid. LC-MS: ESI m / z: 626.7 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.59 (s, 1H), 7.34 (s, 3H), 7.27 (t, J = 11.2Hz, 1H), 6.9 8(d,J=8.9Hz,2H),6.79(d,J=10.0Hz,1H),6.30(s,1H),5.63(d,J=10.1Hz,1H ),5.23(s,1H),4.17(d,J=13.7Hz,2H),3.98-3.86(m,4H),3.55(s,3H),3.43( s,3H),3.27-3.16(m,4H),1.87(s,3H),1.72(s,3H),1.60(s,6H),1.52(s,6H).

[0306] Example 13: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylbenzo[d]thiazol-2-yl(methyl)carbamate

[0307]

[0308] Step 1: Dissolve benzo[d]thiazol-2-amine (500 mg, 3.3 mmol) in DCM (5 mL), add ethyl chloroformate (541.9 mg, 5.0 mmol) and TEA (1.7 g, 16.6 mmol) and react at room temperature for 16 h. The reaction of the raw material was complete as detected by TLC (PE / EA=3 / 1, Rf=0.4), and the crude product was purified by column chromatography (PE / EA=7 / 3%) and dried to obtain 230 mg of a white solid product. LC-MS: ESI m / z: 223 [M+H] + .

[0309] Step 2: Referring to the preparation method of step 1 in Example 6, the crude product was purified by column chromatography (PE / EA=7 / 3) and dried to obtain 105 mg of a white solid product. LC-MS: ESI m / z: 164 [M+H] + .

[0310] Step 3: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=2 / 1) to obtain 16.4 mg of a yellow solid. LC-MS: ESI m / z: 599 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.46(s,1H),7.87(d,J=8.0Hz,1H),7.80(d,J=7.5Hz,1H),7.50-7.42(m,1H),7.37-7.28(m,2H),6.78-6.71(m,1H),6.28(d ,J=0.5Hz,1H),5.59(d,J=10.0Hz,1H),5.27-5.19(m,1H),4.17(d,J=6.5 Hz,2H),3.99(s,3H),3.82(s,3H),1.84(s,3H),1.70(s,3H),1.47(s,6H).

[0311] Example 14: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl 4-(3,4-dihydroxyphenyl)piperidine-1-carboxylate

[0312]

[0313] Step 1: Referring to the preparation method of Example 4, the crude product was purified by column chromatography (PE / EA=1 / 1) to obtain 20 mg of a yellow solid. LC-MS: ESI m / z: 628.3 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.54 (s, 1H), 7.18 (d, J = 6.5Hz, 1H), 6.81-6.70 (m, 3H), 6. 65(d,J=9.1Hz,1H),6.25(s,1H),5.58(d,J=10.0Hz,1H),5.52-5.27(m,1H),5.22( s,1H),4.51-4.18(m,2H),4.14(d,J=3.8Hz,2H),3.83-3.73(m,3H),3.19-2.96(m ,1H),2.73(t,J=10.6Hz,1H),2.05(s,2H),1.84(s,3H),1.68(s,5H),1.47(s,6H).

[0314] Example 15: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(4-(4-methylpiperazin-1-yl)phenyl)carbamate

[0315]

[0316] Referring to the preparation method of Example 12, the crude product was purified by silica gel column chromatography (PE / EA=7 / 3) to obtain 86.9 mg of a yellow solid. LC-MS: ESI m / z: 640.1 [M+H] + ; 1 HNMR (400MHz, DMSO) δ13.53(s,1H),7.45(s,1H),7.34(s,2H),7.00(d,J=8.9Hz,2H),6.63(d,J=10.1Hz,1H),6.40(s,1H),5.79(d,J=10.1Hz, 1H),5.15(s,1H),4.02(s,2H),3.50(s,3H),3.29(s,3H),3.18(s,4H), 2.52-2.51(m,4H),2.28(s,3H),1.78(s,3H),1.64(s,3H),1.46(s,6H).

[0317] Example 16: Preparation of 8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-5-((3-methylbut-2-en-1-yl)oxy)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0318]

[0319] Step 1: Referring to the synthesis description of step 3 of Example 1, the amino compound in the reaction reagent is N-methylaniline (2.0 eq.), and the crude product is purified by flash column chromatography (PE / EA=7 / 3) to obtain 200 mg of a yellow solid. LC-MS: ESI m / z: 542 [M+H] + .

[0320] Step 2: Dissolve the intermediate 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate (80 mg, 0.2 mmol) in DMF (3 mL), add 1-bromo-3-methylbut-2-ene (32.6 mg, 0.2 mmol), K2CO3 (61.2 mg, 0.5 mmol), heat to 85°C for 15 h, add water (20 mL), extract twice with ethyl acetate (20 mL×3), dry the organic phase with anhydrous sodium sulfate, and purify the crude product by column chromatography (PE / EA=9 / 1) to obtain 46.2 mg of an oily transparent solid. LC-MS: ESI m / z: 610 [M+H] + ; 1HNMR (400MHz, CDCl3) δ7.46-7.34 (m, 4H), 7.27 (d, J = 9.3Hz, 1H), 7.16 (s, 1 H),6.71(d,J=10.1Hz,1H),6.49(s,1H),5.61(d,J=10.1Hz,1H),5.56(t,J= 7.4Hz,1H),5.21(s,1H),4.53(d,J=7.4Hz,2H),4.09(d,J=5.7Hz,2H),3.4 3(s,6H),1.80(s,3H),1.73(s,3H),1.63(s,3H),1.61(s,3H),1.44(s,6H).

[0321] Example 17: Preparation of (E)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-12-(3-(4-methylpiperazine-1-yl)-3-carbonylprop-1-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0322]

[0323] Step 1: Dissolve the intermediate D-1 (50 mg, 0.1 mmol) in DCM (2 mL), add N-methylpiperazine (20 mg, 0.2 mmol), TCFH (117 mg, 0.4 mmol), NMI (68 mg, 0.8 mmol) to the solution in sequence, and stir the reaction solution at room temperature for 15 h. TLC (PE / EA = 1 / 1, Rf = 0.4) detected that the raw material reacted completely, concentrated the reaction solution, and purified the crude product by rapid column chromatography (PE / EA = 2 / 3) to obtain 50 mg of a colorless oily product. LC-MS: ESI m / z: 561 [M+H] + .

[0324] Step 2: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=3 / 7) to obtain 15.5 mg of a yellow product. LC-MS: ESI m / z: 694.6 [M+H] + ; 1HNMR(400MHz,DMSO)δ13.88(s,1H),7.81(d,J=16Hz,1H),7.65(s,1H),7.55(s,1H) ,7.53(s,1H),7.50-7.45(m,2H),7.44(d,J=4Hz,1H),7.33(t,J=8Hz,1H),6.65(d, J=12Hz,1H),5.85(d,J=12Hz,1H),5.14(s,1H),4.01(s,2H),3.63(s,6H),3.60-3. 37(m,4H),2.40-2.30(m,4H),2.23(s,3H),1.76(s,3H),1.62(s,3H),1.51(s,6H).

[0325] Example 18: Preparation of (E)-3-(3,4-dihydroxyphenyl)-N-(5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl)acrylamide

[0326]

[0327] Step 1: Refer to the preparation method of step 1 in Example 4. Obtain 12 g of product. LC-MS: ESI m / z: 283.1 [M+H] + ; 1 HNMR(400MHz,DMSO)δ7.61(d,J=16Hz,1H),7.51(d,J=2Hz,1H),7.34(dd,J=8.5,1.9Hz,1H),7.1 5(d,J=8.4Hz,1H), 6.54(d,J=16Hz,1H), 5.27(d,J=1.9Hz,4H), 3.74(s,3H), 3.44(d,J=8Hz,6H).

[0328] Step 2: Dissolve methyl (E)-3-(3,4-di(methoxymethoxy)phenyl) acrylate (12g, 42.5mmol) in 100ml EtOH:H2O=5:1, slowly add NaOH (5.1g, 127.5mmol) to the reaction solution, and react at room temperature for 2h. LCMS detected that the raw material reacted completely, slowly added 1N hydrochloric acid to the reaction solution under ice bath, adjusted the pH to 4-5, filtered the precipitated solid, washed and dried, and obtained 8g of white solid product. LC-MS: ESI m / z: 269.1[M+H] + .

[0329] Step 3: Add (E)-3-(3,4-di(methoxymethoxy)phenyl)acrylic acid (1 g, 3.7 mmol), ammonium chloride (1 g, 18.6 mmol), triethylamine (1.9 g, 18.6 mmol), and HATU (2.8 g, 7.5 mmol) to 5 ml of DMF and react at room temperature for 10 h. LCMS monitoring showed that the raw materials were completely reacted. The reaction solution was poured into 30 ml of water, and the filtered solid was mixed with silica gel and purified by silica gel column chromatography (eluent: EA / PE = 50%-75%). The product was obtained by spin drying to obtain a white solid (280 mg). 1 HNMR(400MHz,DMSO)δ7.52(s,1H),7.34(dd,J=8.7,7.1Hz,2H),7.17(dt,J=14.7,5.0Hz ,2H),7.06(s,1H),6.49(d,J=15.8Hz,1H),5.25(d,J=2.2Hz,4H),3.43(d,J=8.5Hz,6H).

[0330] Step 4: See the preparation method of step 2 in Example 2. The crude product was purified by silica gel column chromatography (eluent: EA / PE=1 / 3) to obtain 148 mg of a light yellow solid.

[0331] Step 5: Add (E)-3-(3,4-di(methoxymethoxy)phenyl)-N-(5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl)acrylamide (100 mg, 0.2 mmol) to 5 ml of 1N hydrochloric acid solution and react at room temperature for 16 h. The reaction of the raw material was complete as monitored by LCMS. The crude product was purified by silica gel column chromatography (eluent: EA / PE=100 / 1) to obtain 23 mg of a yellow solid product. LC-MS: ESI m / z: 569.9 [M+H] + ; 1 HNMR(400MHz,DMSO)δ13.74(s,1H),9.90(s,1H),8.50(s,1H),7.51(d,J=1 5.5Hz,1H),7.18-7.08(m,2H),6.99(d,J=8.5Hz,1H),6.82(d,J=8.1Hz,1H) ,6.64(d,J=10.2Hz,1H),6.47(s,1H),5.79(d,J=10.1Hz,1H),5.24(s,1H), 4.08(d,J=5.7Hz,2H),3.76(s,3H),1.83(s,3H),1.66(s,3H),1.47(s,6H).

[0332] Example 19: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-12-(4-methylpiperazin-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0333]

[0334] Referring to the preparation method of Example 10, 15 mg of a light yellow solid product was obtained. LC-MS: ESI m / z: 640.2 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.56 (s, 1H), 7.53-7.43 (m, 5H), 7.36 (s, 1H), 6.76 (d, J = 8Hz, 1H), 5.64 (d, J = 8Hz, 1H), 5.20(s,1H),4.14(s,2H),3.50(s,6H),3.20-3.16(m,8H),2.88(s,3H),1.86(s,3H),1.70(s,3H),1.61(s,6H). Example 20: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-10-morpholino-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0335]

[0336] Referring to the preparation method of Example 10, the crude product was purified by flash column chromatography (EA / PE=1 / 1) to obtain 4.8 mg of a yellow solid. LC-MS: ESI m / z: 627 [M+H] + ; 1 HNMR (400MHz, DMSO) δ7.51(dd,J=15.9,8.5Hz,4H),7.35(d,J=7.2Hz,1H),6.65(d,J=10.0Hz,1H),6.47(s,1H),5.82(d, J=10.1Hz,1H),5.17(s,1H),4.02(s,3H),3.76(s,7H),3.61(s,3H),3.13(s,3H),1.79(s,3H),1.64(s,3H),1.47(s,6H).

[0337] Example 21: Preparation of 10,12-dibromo-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0338]

[0339] Step 1: Referring to the preparation method of intermediate B-4 step 1, the crude product was purified by column chromatography (PE / EA=3 / 1) to obtain 235 mg of the product. LC-MS: ESI m / z: 566.2 [M+H] + .

[0340] Step 2: See the preparation method of step 3 in Example 1. The crude product was purified by column chromatography (PE:EA=1 / 1) to obtain 37.9 mg of a yellow solid, LC-MS: ESI m / z: 699.6 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.31(s,1H),7.44(dd,J=15.7,8.3Hz,4H),7.31(s,1H),6.73(d,J=10.0Hz,1H),5.63(d,J=10.0Hz,1 H), 5.14 (s, 1H), 4.09 (d, J = 6.1Hz, 2H), 3.63 (s, 3H), 3.48 (d, J = 9.6Hz, 3H), 1.81 (s, 3H), 1.66 (s, 3H), 1.55 (d, J = 7.7Hz, 6H).

[0341] Example 22: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl(4-cyano-3-(trifluoromethyl)phenyl)methyl)carbamate

[0342]

[0343] Step 1: Dissolve 4-amino-2-(trifluoromethyl)benzonitrile (500 mg, 2.7 mmol) in THF (5 mL), slowly add 60% NaH (129 mg, 3.2 mmol) THF solution, and react at room temperature for 3 h. Add iodomethane (572 mg, 4 mmol) and detect the complete reaction of the raw material by TLC (PE / EA=10 / 1, Rf=0.4). Concentrate the reaction solution and purify the crude product by flash column chromatography (PE / EA=7 / 3) to obtain 200 mg of white solid. LC-MS: ESI m / z: 200 [M+H] + .

[0344] Step 2: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=7 / 3) to obtain 21.5 mg of a yellow solid. LC-MS: ESI m / z: 634.19 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.49(s,1H),7.98-7.90(m,2H),7.83(d,J=6.5Hz,1H),7.26(s,1H),6.78(d,J=10.5Hz,1H),6.30(s,1H ),5.63(d,J=10.1Hz,1H),5.25(s,1H),4.18(d,J=5.7Hz,2H),3.73(s,3H),3.65(s,3H),1.87(s,3H),1.73(s,3H),1.52(s,6H).

[0345] Example 23: Preparation of 5-hydroxy-12-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0346]

[0347] Referring to the preparation method of step 2 of Example 2, the crude product was purified by flash column chromatography (PE / EA=1 / 1) to obtain 45 mg of a yellow solid. LC-MS: ESI m / z: 652.2 [M+H] + ; 1 HNMR (400MHz, DMSO) δ13.68(s,1H),8.26(s,1H),8.06(s,1H),7.70(s,1H),7.56(d,J=7. 5Hz,2H),7.50(t,J=7.7Hz,2H),7.36(t,J=7.0Hz,1H),6.70(d,J=10.0Hz,1H),5.85(d,J =10.0Hz,1H),5.18(s,1H),5.00(t,J=5.3Hz,1H),4.32(t,J=5.7Hz,2H),4.04(d,J=5.5H z, 2H), 3.84 (q, J = 5.6Hz, 2H), 3.71-3.38 (m, 6H), 1.79 (s, 3H), 1.65 (s, 3H), 1.53 (s, 6H).

[0348] Example 24: Preparation of (E)-5-hydroxy-8-methoxy-2,2-dimethyl-12-(3-(methylamino)-3-carbonylprop-1-en-1-yl)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0349]

[0350] Step 1: (E)-3-(5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)acrylic acid (100 mg, 0.2 mmol) was dissolved in DMF (5 mL), and HATU (240 mg, 0.6 mmol), DIEA (165 mg, 1.3 mmol) and dimethylamine hydrochloride (55 mg, 0.8 mmol) were added to the solution at 0°C, and the reaction solution was stirred at room temperature for 12 h. LCMS detected that the reaction of the raw material was complete, the reaction solution was quenched by adding water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative purification (ACN / H2O=9:1) to obtain 50 mg of solid. LC-MS: ESI m / z: 492 [M+H] + .

[0351] Step 2: See the preparation method of step 3 in Example 1. The crude product was purified by flash column chromatography (DCM / MeOH=20 / 1) to obtain 29.3 mg of a yellow solid. LC-MS: ESI m / z: 625.1 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.87(s,1H),7.96(d,J=15.8Hz,1H),7.47-7.39(m,4H),7.32(d,J=9.0Hz,2H),6.82(d,J=15.9Hz,1H),6.70(d,J=10.0Hz,1H) ,5.95(s,1H),5.58(d,J=10.0Hz,1H),5.14(s,1H),4.05(d,J=6.3Hz,2H), 3.46(s,6H),2.98(d,J=4.9Hz,3H),1.80(s,3H),1.65(s,3H),1.48(s,6H).

[0352] Example 25: Preparation of 12-cyano-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0353]

[0354] Step 1: Dissolve B-2 (243 mg, 0.5 mmol) in NMP (10 mL), add Zn(CN)2 (117 mg, 1.0 mmol) and Pd(t-Bu3p)2 (26 mg, 0.05 mmol), replace with nitrogen three times at room temperature, react at 100 ° C for 1 h, and the reaction is complete by LCM detection. Add water (20 mL), extract with EA (20 mL × 3) three times, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography (PE / EA = 3 / 1) to obtain 180 mg of a light yellow intermediate. LC-MS: ESI m / z: 434.1 [M+H] + .

[0355] Step 2: See the preparation method of step 3 in Example 1. The crude product was purified by flash column chromatography (PE:EA=10 / 1) to obtain 30 mg of a light yellow solid. LC-MS: ESI m / z: 567.6 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ14.09(d,J=27.1Hz,1H),7.47(dt,J=14.2,7.4Hz,6H),6.72(d,J=10.2Hz,1H),5.69(d,J= 10.2Hz, 1H), 5.17 (s, 1H), 4.13 (s, 2H), 3.50 (s, 6H), 1.88 (d, J = 17.9Hz, 3H), 1.71 (s, 3H), 1.66 (d, J = 44.6Hz, 5H).

[0356] Example 26: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-propyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0357]

[0358] 12-Bromo-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]oxanthene-9-ylmethyl(phenyl)carbamate (Example 6) (155 mg, 0.3 mmol) was dissolved in toluene (3 mL), and propylboric acid (38 mg, 0.5 mmol), Pd(cinnamyl)Cl2 (13 mg, 0.03 mmol), di-tert-butyl((2S,3S)-3-(tert-butyl)-4-ethyl-2,3-dihydrobenzo[d][1,3]oxaphosphorazol-2-yl)phosphine oxide (38.4 mg, 0.1 mmol) and K3PO4 (106 mg, 0.8 mmol) were added to the solution in sequence, and the reaction solution was stirred at 100°C for 4 h under nitrogen protection. LCMS detected that the reaction was complete, the reaction solution was filtered and concentrated, and the crude product was purified by flash column chromatography (PE / EA=6 / 1) to obtain 15 mg of yellow solid. LC-MS: ESI m / z: 584.2 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ13.52(s,1H),7.51-7.42(m,4H),7.33(s,2H),6.79(d,J=10.0Hz,1H),5.61(d,J=10.0Hz,1H),5 .23(s,1H),4.15(s,2H),3.49(s,6H),2.80-2.69(m,2H),1.85(s,3H),1.70(s,3H),1.50(s,6H),0.98(t,J=7.4Hz,3H).

[0359] Example 27: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(2,2,2-trifluoroethoxy)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0360]

[0361] Step 1: Dissolve intermediate B-4 (200 mg, 0.4 mmol) in DMF (10 mL), add potassium carbonate (270 mg, 1.95 mmol) and 1,1,1-trifluoro-2-iodoethane (205 mg, 1.0 mmol) to the reaction solution at room temperature, and stir the reaction solution at 60°C for 12 h. TLC (PE / EA=3 / 1, RF=0.4) detected that the reaction was complete, the reaction solution was added with water, extracted with ethyl acetate, the organic phase was dried over sodium sulfate, filtered, concentrated, and the crude product was purified by flash column chromatography (HEP / EA=4 / 1) to obtain 44 mg of yellow oil. LC-MS: ESI m / z: 595 [M+H] + .

[0362] Step 2: 8-methoxy-5,9-bis(methoxymethoxy)-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-12-(2,2,2-trifluoroethoxy)-2H,6H-pyrano[3,2-b]xanthene-6-one (44 mg, 0.1 mmol) was dissolved in THF (2 mL), and 6 mol / L hydrochloric acid solution was added to the solution at room temperature. The reaction solution was stirred at 25°C for 12 h. LCMS detected that the reaction was complete, saturated sodium bicarbonate was added to the reaction solution to make it weakly alkaline, and then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column chromatography (PE / EA=4 / 1) to obtain 33 mg of a yellow solid. LC-MS: ESI m / z: 507[M+H] + .

[0363] Step 3: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (HEP / EA=8 / 1) to obtain 11.4 mg of a yellow solid. LC-MS: ESI m / z: 640.3 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.29(s,1H),7.46-7.37(m,4H),7.31(s,2H),6.73(d,J=10.1Hz,1H),5.60(d,J=10.1 Hz,1H),5.16(s,1H),4.36(q,J=8.5Hz,2H),4.10(s,2H),3.45(s,6H),1.81(s,3H),1.66(s,3H),1.51(s,6H).

[0364] Example 28: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(2-carbonyl-2H-chromen-4-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0365]

[0366] Step 1: 4-hydroxy-2H-chromene-2-one (2.0 g, 12.3 mmol) was dissolved in toluene (60 mL), the solution was heated to 120°C and stirred for 30 min, the solution was cooled to 70-80°C, tetrabutylammonium bromide (6.0 g, 18.4 mmol) was added to the solution, the reaction mixture was heated to 120°C and stirred for 10 min, then the reaction solution was cooled to 70-80°C, phosphorus pentoxide (4.4 g, 30.7 mmol) was added to the solution, the reaction solution was heated to 120°C and stirred for 12 h. The reaction was complete as detected by LCMS, the reaction solution was quenched by adding water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column chromatography (PE / EA=4 / 1) to obtain 2.5 g of a white solid intermediate. LC-MS: ESI m / z: 225 [M+H] +; 1 HNMR (400MHz, CDCl3) δ7.90 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 11.3, 4.4 Hz, 1H), 7.41 (dd, J = 12.6, 7.9 Hz, 2H), 6.92 (s, 1H).

[0367] Step 2: The intermediate 4-bromo-2H-chromen-2-one (200 mg, 0.9 mmol) was dissolved in 1,4-dioxane (8 mL), and diboric acid pinacol ester (454 mg, 1.8 mmol), potassium acetate (175 mg, 1.8 mmol) and Pd(dppf)Cl2 (72 mg, 0.09 mmol) were added to the solution in sequence, and the reaction solution was heated to 100 ° C and stirred for 3 h under nitrogen protection. LCMS detected that the reaction was complete, and the reaction solution was directly used in the next step.

[0368] Step 3: Referring to the preparation method of step 2 in Example 2, the crude product was purified by flash column chromatography (PE / EA=5 / 1) to obtain 35.5 mg of a yellow solid. LC-MS: ESI m / z: 686 [M+H] + ; 1HNMR(400MHz,DMSO)δ13.75(s,1H),7.65(s,1H),7.53(d,J=8.1Hz,1H),7.43(dt,J =15.5,7.8Hz,4H),7.35-7.31(m,1H),7.29(s,2H),7.26(d,J=7.2Hz,1H),6.69(d,J =10.1Hz,1H),6.58(s,1H),5.79(d,J=10.1Hz,1H),5.13(s,1H),4.01(s,2H),3.41( d,J=41.8Hz,3H),3.30(s,3H),1.76(s,3H),1.62(s,3H),1.32(s,3H),1.24(s,3H).

[0369] Example 29: Preparation of (E)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(3-carbonyl-3-((2,2,2-trifluoroethyl)amino)prop-1-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0370]

[0371] Step 1: (E)-3-(5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)acrylic acid (100 mg, 0.2 mmol) was dissolved in DMF (5 mL), and HATU (240 mg, 0.6 mmol), DIEA (165 mg, 1.3 mmol) and 2,2,2-trifluoroethylamine (55 mg, 0.6 mmol) were added to the solution at 0°C, and the reaction solution was stirred at room temperature for 12 h. LCMS detected that the raw material was completely reacted, the reaction solution was added with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative separation (ACN / H2O=9 / 1) to obtain 80 mg of solid. LC-MS: ESI m / z: 560 [M+H] + .

[0372] Step 2: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (HEP / EA=2 / 1) to obtain 67.1 mg of a yellow solid. LC-MS: ESI m / z: 693 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.76 (s, 1H), 8.00 (d, J = 15.9Hz, 1H), 7.44 (d, J = 6.5 Hz,4H),7.34(d,J=6.7Hz,1H),7.23(s,1H),6.77(s,1H),6.67(d,J=3.9Hz,1 H),6.64(d,J=1.9Hz,1H),5.56(d,J=10.0Hz,1H),5.05(s,1H),4.07(s,2H) ,3.92(d,J=6.2Hz,2H),3.49(s,6H),1.77(s,3H),1.62(s,3H),1.47(s,6H).

[0373] Example 30: Preparation of 5-hydroxy-8,12-dimethoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0374]

[0375] Step 1: Dissolve the intermediate B-2 (200 mg, 0.4 mmol) in DMF (2 mL), add sodium methoxide (132 mg, 2.4 mmol) and CuBr (2.9 mg, 0.02 mmol) to the solution, and stir the reaction solution at 85 ° C for 12 h. LCMS detected that the reaction of the raw material was complete, and water (10 mL) was added to quench, EA (10 mL × 3) was extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash column chromatography (PE / EA = 9 / 1) to obtain 50 mg of a colorless oily product. LC-MS: ESI m / z: 440 [M+H] + .

[0376] Step 2: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=17 / 3) to obtain 10 mg of a light yellow solid. LC-MS: ESI m / z: 572.2 [M+H] + ; 1HNMR (400MHz, DMSO) δ13.23(s,1H),7.63(s,1H),7.56(d,J=7.3Hz,2H),7.49(t,J=7.8Hz,2H),7.35(t,J=7.4Hz,1H),6.66(d,J=10.1Hz,1H) ,5.83(d,J=10.0Hz,1H),5.16(s,1H),4.04(d,J=5.7Hz,2H),3.84(s,3H),3.54(s,3H),3.42(s,3H),1.78(s,3H),1.64(s,3H),1.51(s,6H).

[0377] Example 31: Preparation of 2-((5-hydroxy-8-methoxy-2,2-dimethyl-9-((methyl(phenyl)carbamoyl)oxy)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)oxy)propanoic acid

[0378]

[0379] Step 1: Dissolve B-4 (150 mg, 0.3 mmol) in DMF (7.5 mL), add potassium carbonate (162 mg, 1.2 mmol) and methyl 2-bromopropionate (122 mg, 0.7 mmol) to the solution at room temperature, and stir the reaction solution at 60 ° C for 12 h. LCMS detected that the reaction was complete, the reaction solution was added with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column chromatography (PE / EA=2 / 1). 180 mg of yellow oil was obtained. LC-MS: ESI m / z: 599 [M+H] + .

[0380] Step 2: Referring to the preparation method of Example 8, the crude product was purified by flash column chromatography (PE / EA=3 / 1) to obtain 66 mg of a yellow solid. LC-MS: ESI m / z: 511 [M+H] + .

[0381] Step 3: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=6 / 1) to obtain 35.0 mg of a yellow solid. LC-MS: ESI m / z: 644.2 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.28(s,1H),7.41(dd,J=9.6,7.6Hz,4H),7.31(s,2H),6.73(d,J=10.1Hz,1H),5.58(d,J=10.1Hz,1H),5.17(s,1 H), 4.60 (q, J = 6.8Hz, 1H), 4.09 (d, J = 4.7Hz, 2H), 3.80 (s, 3H), 3.44 (s, 6H), 1.81 (s, 3H), 1.66 (s, 3H), 1.62 (d, J = 6.8Hz, 3H), 1.49 (s, 6H).

[0382] Step 4: Referring to the preparation method of step 5 of Example 4, the crude product was purified by column chromatography (DCM / MeOH=20 / 1) to obtain 10 mg of a yellow solid. LC-MS: ESI m / z: 630.3 [M+H] + ; 1 HNMR (400MHz, DMSO) δ13.21(s,1H),8.07(s,1H),7.52(s,2H),7.46(s,3H),7.33(s,1H),6.62(d,J=10.1Hz,1H),5.78(d,J=10.1Hz, 1H), 5.14 (s, 1H), 4.66 (s, 1H), 4.50 (d, J = 7.1Hz, 1H), 4.00 (s, 2H), 3.51 (s, 2H), 3.38 (s, 3H), 1.76 (s, 3H), 1.61 (s, 3H), 1.44 (s, 9H).

[0383] Example 32: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(1H-pyrazol-4-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0384]

[0385] Referring to the preparation method of step 2 of Example 2, the crude product was purified by flash column chromatography (PE / EA=3 / 1) to obtain 19 mg of a yellow solid. LC-MS: ESI m / z: 608.2 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.93(s,1H),8.63(s,1H),8.08(s,1H),7.42(t,J=7.7Hz,2H),7.32(s,1H),7.24(d,J=7.4Hz,2H),6.91(s,1H),6.82(d ,J=10.0Hz,1H),5.65(d,J=10.0Hz,1H),5.30(s,1H),4.14(d,J=6.2Hz ,2H),3.86(s,3H),3.67(s,3H),1.88(s,3H),1.74(s,3H),1.53(s,6H).

[0386] Example 33: Preparation of ethyl (E)-3-(5-hydroxy-8-methoxy-2,2-dimethyl-9-((methyl(phenyl)carbamoyl)oxy)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)acrylate

[0387]

[0388] Step 1: Refer to the preparation of Example 6 to obtain 1.6 g of yellow solid. LC-MS: ESI m / z: 620 [M+H] + .

[0389] Step 2: Referring to the preparation method of step 2 in Example 2, the crude product was purified by flash column chromatography (EA / PE=10 / 1) to obtain 13 mg of a yellow solid. LC-MS: ESI m / z: 640 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ14.03 (s, 1H), 8.16 (d, J = 16.3Hz, 1H), 7.51-7.33 (m, 6H), 6.93 (d, J = 16.3Hz, 1H), 6.78 (d, J = 10.0Hz, 1H), 5.67 (d, J = 10. 0Hz,1H),5.21(s,1H),4.36(q,J=7.1Hz,2H),4.14(d,J=6.0Hz,2H),3.5 0(s,6H),1.86(s,3H),1.71(s,3H),1.59(s,6H),1.43(t,J=7.1Hz,3H).

[0390] Example 34: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-12-(6-methyl-2-carbonylchroman-4-yl)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0391]

[0392] Example 33 (50 mg, 0.08 mmol) was dissolved in DCE (5 mL) and p-methylphenol (12 mg, 0.1 mmol) and p-methylbenzenesulfonic acid (30 mg, 0.2 mmol) were added to the reaction at room temperature. The reaction solution was stirred at 80°C for 12 h. LCMS detected that the raw material was completely reacted. The reaction solution was added with water, extracted with dichloromethane, and concentrated. The crude product was purified by flash column chromatography (PE / EA=3 / 1) to obtain 10 mg of a yellow solid. LC-MS: ESI m / z: 702.3 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ13.65(s,1H),7.44-7.38(m,4H),7.29(s,2H),7.03-6.98(m,2H),6.75-6.68(m,2H),5.53(d,J=10.0Hz,1H),5.15-5.09 (m,1H),4.10(s,2H),3.44(s,6H),3.09(dd,J=17.4,7.4Hz,2H),2.18(s ,3H),1.81(s,3H),1.66(s,3H),1.45(s,3H),1.25(s,3H),1.09(s,3H).

[0393] Example 35: Preparation of 12-chloro-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0394]

[0395] Step 1: α-mangostin (1.0 g, 2.4 mmol) was dissolved in DCM (20 mL), and a solution of N-chlorosuccinimide (NCS) (293 mg, 2.2 mmol) in DCM (10 mL) was added dropwise to the solution at 40°C, and the reaction solution was stirred at 40°C for 12 h. LCMS detected that the reaction was complete, and the reaction solution was cooled and added with water, extracted with dichloromethane, and concentrated. The crude product was purified by flash column chromatography (PE / EA=2 / 1) to obtain 230 mg of a yellow solid. LC-MS: ESI m / z: 445 [M+H] + .

[0396] Step 2: Refer to the synthesis method of intermediate B-2. The crude product was purified by flash column chromatography (PE / EA=3 / 1) to obtain 120 mg of yellow solid. LC-MS: ESI m / z: 443 [M+H]+ .

[0397] Step 3: Refer to the synthesis method of Example 6. The reaction was complete when detected by LCM. The crude product was purified by flash column chromatography (PE / EA=9 / 1) to obtain 69.5 mg of a yellow solid. LC-MS: ESI m / z: 576.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ13.45(s,1H),7.42-7.34(m,5H),7.29(d,J=6.6Hz,1H),6.71(d,J=10.0Hz,1H),5.58 (d,J=10.0Hz,1H),5.13(s,1H),4.06(d,J=5.7Hz,2H),3.42(s,6H),1.78(s,3H),1.63(s,3H),1.50(s,6H).

[0398] Example 36: Preparation of 12-(4-fluorophenyl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0399]

[0400] Referring to the preparation method of step 2 of Example 2, the boronic acid in the reaction reagent is (4-fluorophenyl)methanediol, and the crude product is purified by flash column chromatography (PE / EA=3 / 1) to obtain 29 mg of a yellow solid. LC-MS: ESI m / z: 636.2 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ13.76(s,1H),7.41(ddd,J=14.3,12.0,6.8Hz,7H),7.17(t,J=8.8Hz,2H),7.06(s,1H),6.84(d, J=10.0Hz,1H),5.64(d,J=10.0Hz,1H),5.23(s,1H),4.15(s,2H),3.45(s,5H),1.86(s,3H),1.71(s,3H),1.44(s,6H).

[0401] Example 37: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-12-(1-methyl-1H-pyrazol-3-yl)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0402]

[0403] Referring to the preparation method of step 2 of Example 2, the boric acid ester in the reaction reagent is 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.4 eq.), and the reaction is complete as detected by LCMS. The crude product is purified by flash column chromatography (PE / EA=3 / 1) to obtain 19 mg of a yellow solid. LC-MS: ESI m / z: 622.1 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.82(s,1H),7.48(d,J=2.2Hz,1H),7.42(dd,J=15.7,7.1Hz,4H),7.34(d,J=7.7Hz,1H),7.20(s,1H),6.82(d,J=10.0Hz ,1H),6.40(d,J=2.2Hz,1H),5.62(d,J=10.0Hz,1H),5.22(s,1H),4.14( s,2H),4.05(s,3H),3.45(s,6H),1.85(s,3H),1.70(s,3H),1.46(s,6H).

[0404] Example 38: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-12-(1-methyl-2-carbonyl-1,2-dihydroquinolin-4-yl)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0405]

[0406] Step 1: 4-Hydroxy-1-methylquinolin-2(1H)-one (2g, 11.4mmol) was dissolved in toluene (60mL), the solution was heated to 120°C and stirred for 30min, the solution was cooled to 70-80°C, tetrabutylammonium bromide (6.0g, 18.4mmol) was added to the solution, the reaction mixture was heated to 120°C and stirred for 10min, then the reaction solution was cooled to 70-80°C, phosphorus pentoxide (4.4g, 30.7mmol) was added to the solution, the reaction solution was heated to 120°C and stirred for 12h. The reaction was complete as detected by LCMS, the reaction solution was concentrated and quenched with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column chromatography (PE / EA=1 / 1) to obtain 1.9g of a pink solid intermediate. LC-MS: ESI m / z: 238[M+H] + .

[0407] Step 2: Dissolve the intermediate 4-bromo-1-methylquinolin-2(1H)-one (100 mg, 0.4 mmol) in 1,4-dioxane (4 mL), add diboric acid pinacol ester (214 mg, 0.8 mmol), potassium acetate (83 mg, 0.8 mmol) and Pd(dppf)Cl2 (34 mg, 0.1 mmol) to the solution in sequence, and heat the reaction solution to 100 ° C and stir for 3 h under nitrogen protection. LCMS monitors the reaction to be complete. The reaction solution is directly used in the next step.

[0408] Step 3: Referring to the synthesis method of step 2 in Example 2, the crude product was purified by flash column chromatography (HEP / EA=1 / 1) to obtain 12.0 mg of a yellow solid. LC-MS: ESI m / z: 699.6 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.76(s,1H),7.57(t,J=7.7Hz,1H),7.46(d,J=8.4Hz,1H),7.38( t,J=7.7Hz,2H),7.31(d,J=7.3Hz,2H),7.27(s,1H),7.25(s,1H),7.09(t,J=7.3Hz,1H),6 .92(s,1H),6.80(d,J=10.0Hz,1H),6.69(s,1H),5.57(d,J=10.1Hz,1H),5.17(s,1H),4. 09(s,2H),3.86(s,3H),3.36(s,6H),1.81(s,3H),1.67(s,3H),1.32(s,3H),1.23(s,3H).

[0409] Example 39: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-12-morpholino-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0410]

[0411] Referring to the preparation method of Example 10, 10 mg of a light yellow solid product was obtained. LC-MS: ESI m / z: 627.1 [M+H] + ; 1HNMR (400MHz, DMSO) δ13.43(s,1H),7.59-7.51(m,3H),7.50-7.42(m,2H),7.36-7.29(m,1H),6.62(d,J=8Hz,1H),5.78(d,J=8 Hz,1H),5.12(s,1H),4.02(s,2H),3.75(t,J=4Hz,4H),3.47-3.25(m,6H),3.09(s,4H),1.75(s,3H),1.61(s,3H),1.48(s,6H).

[0412] Example 40: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(pyridin-4-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0413]

[0414] Referring to the preparation method of step 2 of Example 2, the crude product was purified by flash column chromatography (PE / EA=3 / 1) to obtain 50 mg of a yellow solid. LC-MS: ESI m / z: 619.1 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.83(s,1H),8.73(d,J=5.6Hz,2H),7.43(dt,J=11.6,7.6Hz,7H),7.35(d,J=7.0Hz,1H),7.09(s,1H), 6.84(d,J=10.0Hz,1H),5.66(d,J=10.0Hz,1H),5.22(s,1H),4.15(s,2H),3.45(s,6H),1.86(s,3H),1.71(s,3H),1.46(s,6H).

[0415] Example 41: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(pyrimidin-5-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0416]

[0417] Referring to the preparation method of step 2 of Example 2, the crude product was purified by flash column chromatography (PE / EA=3 / 1) to obtain 20 mg of a yellow solid. LC-MS: ESI m / z: 620 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.83(s,1H),9.24(s,1H),8.88(s,2H),7.48-7.39(m,4H),7.35(d,J=6.8Hz,1H),7.12(s,1H),6.8 3(d,J=10.1Hz,1H),5.66(d,J=10.0Hz,1H),5.20(s,1H),4.15(s,2H),3.45(s,6H),1.85(s,3H),1.71(s,3H),1.47(s,6H).

[0418] Example 42: Preparation of methyl (E)-3-(8-methoxy-2,2-dimethyl-9-((methyl(phenyl)carbamoyl)oxy)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-5-yl)acrylate

[0419]

[0420] Step 1: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=4 / 1) to obtain 140 mg of a yellow solid product. 1 HNMR (400MHz, CDCl3) δ = 13.35 (s, 1H), 7.45-7.40 (m, 4H), 7.33 (brd, J = 6.5Hz, 1H), 7.25 (br s,1H),6.74(d,J=10.0Hz,1H),6.25(s,1H),5.58(d,J=10.0Hz,1H),5.19(br s,1H),4.18-4.04(m,2H),3.54-3.35(m,6H),1.82(s,3H),1.67(s,3H),1.47(s,6H).

[0421] Step 2: Dissolve 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate (170 mg, 0.3 mmol) in DCM (3 mL), add DMAP (76 mg, 0.6 mmol) and Tf2O (124 mg, 0.4 mmol) to the solution at 0°C, and stir the reaction solution at room temperature for 15 h. LCMS detected that the raw material was completely converted, the reaction solution was concentrated, and the crude product was purified by flash column chromatography (PE / EA=7 / 3) to obtain 120 mg of a yellow solid product. LC-MS: ESI m / z: 674[M+H] + .

[0422] Step 3: Referring to the preparation method of step 2 in Example 2, the crude product was purified by thin layer chromatography to obtain 6.2 mg of a yellow solid product. LC-MS: ESI m / z: 624 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ8.35(d,J=16.1Hz,1H),7.43(d,J=6.7Hz,5H),7.24( s,1H),6.77(s,1H),6.67(d,J=10.2Hz,1H),5.89(d,J=16.1Hz,1H),5.73(d ,J=10.2Hz,1H),5.14(s,1H),4.33(q,J=7.1Hz,2H),4.09(d,J=6.0Hz,2H), 3.47(s,6H),1.83(s,3H),1.66(s,3H),1.49(s,6H),1.39(t,J=7.1Hz,3H).

[0423] Example 43: 5-Hydroxy-8-methoxy-2,2-dimethyl-12-(1-methyl-2-carbonyl-1,2-dihydropyridin-4-yl)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0424]

[0425] Referring to the preparation method of step 2 of Example 2, the boric acid ester in the reaction reagent is 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.4 eq.), and the crude product is purified by flash column chromatography (PE / EA=3 / 2) to obtain 7.8 mg of brown solid. LC-MS: ESI m / z: 649.1 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.76(s,1H),7.46-7.36(m,4H),7.30(d,J=7.0Hz,2H),7.16(s,1H),6.77(d,J=10.0Hz,1H),6.67(d,J=1.6Hz,1H),6. 22(dd,J=7.0,1.8Hz,1H),5.60(d,J=10.0Hz,1H),5.16(s,1H),4.10(s ,2H),3.64(s,3H),3.41(s,6H),1.81(s,3H),1.66(s,3H),1.43(s,6H).

[0426] Example 44: Preparation of 12-(4-cyanophenyl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0427]

[0428] Referring to the preparation method of step 2 of Example 2, the boronic acid in the reaction reagent is (4-cyanophenyl)boronic acid (0.5 eq.), and the reaction of the raw material is complete by LCMS detection. The crude product is purified by flash column chromatography (PE / EA=1 / 1) to obtain 10 mg of a yellow solid. LC-MS: ESI m / z: 643.4 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.76(s,1H),7.73(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),7.45-7.34(m,5H),7.01(s,1H),6.79( d,J=10.0Hz,1H),5.61(d,J=10.0Hz,1H),5.16(s,1H),4.10(s,2H),3.41(s,6H),1.81(s,3H),1.67(s,3H),1.40(s,6H).

[0429] Example 45: Preparation of 5-hydroxy-12-(1H-indol-3-yl)-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-9-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-2H,6H-pyrano[3,2-b]xanthene-6-one

[0430]

[0431] Step 1: Referring to the preparation method of step 2 in Example 2, the crude product was purified by flash column chromatography (PE / EA=5 / 1) to obtain 280 mg of a yellow solid. LC-MS: ESI m / z: 624 [M+H] + .

[0432] Step 2: Dissolve tert-butyl 3-(5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)-1H-indole-1-carboxylate (220 mg, 0.4 mmol) in ACN (8 mL) and DCM (4 mL), add (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate (290 mg, 0.7 mmol) and Ag2O (327 mg, 1.4 mmol) to the solution, and stir the reaction solution at room temperature for 12 h. LCMS detected that the reaction was complete, the reaction solution was filtered, washed with dichloromethane and acetonitrile, concentrated, and the crude product was purified by flash column chromatography (PE / EA=2 / 1) to obtain 300 mg of a yellow solid. LC-MS: ESI m / z: 954 [M+H] + .

[0433] Step 3: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((12-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (150 mg, 0.2 mmol) was dissolved in DCM (4 mL), trifluoroacetic acid (1 mL) was added to the solution under ice-water bath conditions, and the reaction solution was stirred at room temperature for 1 h. LCMS detected that the reaction was complete, and the reaction solution was concentrated and the crude product was used for later use.

[0434] The above crude product was dissolved in methanol (4 mL) and potassium carbonate (150 mg, 0.96 mmol) was added to the solution under ice-water bath conditions and stirred at room temperature for 2 h. LCMS detected that the reaction was complete, the reaction solution was quenched by adding water, the solution was adjusted to acidity (PH = 4-5) with dilute hydrochloric acid, extracted with dichloromethane, concentrated, and the crude product was purified by flash column chromatography (DCM / MeOH = 6 / 1) to obtain 4.7 mg of yellow solid. LC-MS: ESI m / z: 686.2 [M+H] + ; 1HNMR (400MHz, DMSO) δ14.05(s,1H),11.28(s,1H),7.48-7.43(m,2H),7.34(d,J=8.1Hz,1H),7.11(t,J=7.4Hz,1 H),7.00(t,J=7.3Hz,1H),6.71(d,J=10.0Hz,1H),6.67(s,1H),5.77(d,J=10.0Hz,1H),5.38(d,J=5.4Hz,1H),5 .12(d,J=3.9Hz,1H),5.03(d,J=3.9Hz,1H),4.97(d,J=7.3Hz,1H),4.50(t,J=5.8Hz,1H),4.22(s,1H),3.79(s, 4H), 3.53-3.45 (m, 2H), 3.28 (s, 1H), 3.24 (d, J = 4.3Hz, 3H), 3.18 (s, 1H), 1.41 (s, 3H), 1.33 (s, 3H), 1.23 (s, 6H).

[0435] Example 46: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-12-(4-(morpholinomethyl)phenyl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0436]

[0437] Step 1: See the preparation method of step 2 of Example 2. The boric acid ester in the reaction reagent is 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.7 eq.). The crude product is purified by flash column chromatography (PE / EA=3 / 2) to obtain 100 mg of a yellow solid intermediate. LC-MS: ESI m / z: 646 [M+H] + .

[0438] Step 2: The intermediate 12-(4-formylphenyl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate (100 mg, 0.2 mmol) was dissolved in DCM (3 mL), morpholine (27 mg, 0.3 mmol) and NaBH(OAC)3 (65 mg, 0.3 mmol) were added to the solution, and the reaction solution was stirred at room temperature for 15 h. LCMS detected that the raw material was completely converted, the reaction solution was added with water (20 mL), extracted with DCM (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column chromatography (PE / EA=3 / 7) to obtain 20.4 mg of a yellow solid. LC-MS: ESI m / z: 717.2[M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.76(d,J=6.9Hz,1H),7.45-7.34(m,8H),7.31(d,J=7.5Hz,1H),7.04(s,1H),6.82(d,J=10.0Hz,1H),5.61(d,J= 10.0Hz,1H),5.20(s,1H),4.13(s,2H),3.89-3.75(m,4H),3.61(s,2H),3.42(s,6H),2.58(s,4H),1.83(s,3H),1.68(s,3H),1.42(s,6H).

[0439] Example 47: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-9-(2-(4-methylthiooxazol-5-yl)ethoxy)-2H,6H-pyrano[3,2-b]xanthene-6-one

[0440]

[0441] Intermediate A-1 (150 mg, 0.4 mmol) was dissolved in acetone (4 mL), and K2CO3 (150 mg, 1.1 mmol), catalytic amount of KI, 5-(2-chloroethyl)-4-methylthioazole (71 mg, 0.4 mmol) were added to the solution in sequence, and the reaction solution was stirred at 70°C for 24 h. LCMS detected that the reaction of the raw material was complete, and the reaction solution was quenched by adding water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column chromatography (PE / EA=7 / 3) to obtain 29 mg of a yellow solid. LC-MS: ESI m / z: 534 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.71(s,1H),8.62(s,1H),6.73(s,1H),6.74(d,J=9.9Hz,1H),6.22(s,1H),5.57(d,J=9.9Hz,1H),5.22(t,J=6.7Hz ,1H),4.26(t,J=6.4Hz,2H),4.12(d,J=6.1Hz,2H),3.71(s,3H),3.37(t,J=6.3Hz,2H),2.49(s,3H),1.84(s,3H),1.68(s,3H),1.46(s,6H).

[0442] Example 48: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0443]

[0444] Step 1: See the preparation method of step 2 in Example 2.

[0445] Step 2: Dissolve tert-butyl 3-(5-hydroxy-8-methoxy-2,2-dimethyl-9-((methyl(phenyl)carbamoyl)oxy)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (40 mg, 0.05 mmol) in 1,4-dioxane (3 mL), add HCl-Dioxane (3 mL) to the solution, stir the reaction solution at room temperature for 3 h and then concentrate, and purify the crude product by flash column chromatography (EA / PE=3 / 2) to obtain 8 mg of yellow solid. LC-MS: ESI m / z: 658.8 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.75 (s, 1H), 8.37 (s, 1H), 7.88 (d, J = 7.5Hz, 1H), 7.52 (s ,1H),7.41(d,J=7.2Hz,2H),7.38-7.35(m,2H),7.30(s,1H),7.17(s,1H),6.94(s ,1H),6.85(dd,J=10.0,2.8Hz,1H),5.63(dd,J=10.0,2.4Hz,1H),5.22(s,1H),4 .13(s,1H),3.42-3.21(m,6H),1.84(s,3H),1.72(d,J=21.6Hz,3H),1.41(s,7H).

[0446] Example 49: Preparation of 5-hydroxy-12-isopropoxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0447]

[0448] Step 1: Referring to the synthesis description of step 1 in Example 31, the crude product was purified by flash column chromatography (PE / EA=4 / 1) to obtain 200 mg of a white solid. LC-MS: ESI m / z: 555 [M+H] + .

[0449] Step 2: Referring to the preparation method of Example 8, the crude product was purified by flash column chromatography (HEP / EA=3 / 1) to obtain 149 mg of a yellow solid. LC-MS: ESI m / z: 467 [M+H] + .

[0450] Step 3: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (HEP / EA=9 / 1) to obtain 42.4 mg of a yellow solid. LC-MS: ESI m / z: 600.3 [M+H] + . 1 HNMR (400MHz, CDCl3) δ13.28(s,1H),7.42(t,J=4.5Hz,4H),7.30(s,2H),6.74(d,J=10.0Hz,1H),5.58(d,J=10.1Hz,1H), 5.18(s,1H),4.34-4.27(m,1H),4.11(s,2H),3.45(s,6H),1.81(s,3H),1.66(s,3H),1.50(s,6H),1.36(d,J=6.2Hz,6H).

[0451] Example 50: Preparation of 8-methoxy-2,2-dimethyl-9-((methyl(phenyl)carbamoyl)oxy)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-5-ylmethyl fumarate

[0452]

[0453] Step 1: See the synthesis method of Step 3 in Example 1.

[0454] Step 2: 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-ene-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate (100mg, 0.2mmol) was dissolved in tetrahydrofuran (3ml), sodium hydride (15mg, 0.4mmol) was added to the solution under ice bath and stirred for 30 minutes, then methyl (E)-4-chloro-4-carbonylbut-2-enoate (41mg, 0.3mmol) was added, the reaction solution was slowly warmed to room temperature and continued to stir for 2h. LCMS detected that the raw material reacted completely, the reaction solution was quenched by adding water (20ml), extracted with ethyl acetate (20ml×3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column chromatography (PE / EA=5 / 1) to obtain 60mg of white solid product. LC-MS:ESI m / z:654.3[M+H] + ; 1 HNMR (400MHz, CDCl3) δ = 7.47-7.39 (m, 4H), 7.31 (br s,1H),7.25-7.20(m,2H),7.14-7.05(m,1H),6.67(s,1H),6.45(d,J=10.0Hz,1H),5.74(d,J=10.1Hz,1H),5.09(br s,1H),4.00(br s,2H),3.88(s,3H),3.43(br s,6H),1.75(s,3H),1.64(s,3H),1.49(s,6H).

[0455] Example 51: Preparation of (E)-3-(5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-10-yl)acrylic acid

[0456]

[0457] Step 1: Referring to the preparation method of step 2 in Example 2, the crude product was purified by column chromatography (PE / EA=3 / 2) to obtain 145 mg of a yellow solid. LC-MS: ESI m / z: 507 [M+H] + .

[0458] Step 2: Refer to the preparation method of step 3 of Example 9 to obtain 106.2 mg of yellow solid. LC-MS: ESI m / z: 478.8 [M+H] + ; 1 HNMR (400MHz, DMSO) δ8.09(d,J=16.1Hz,1H),7.11(d,J=16.1Hz,1H),6.64(d,J=10.1Hz,1H),6.41(s,1H),5. 77(d,J=9.9Hz,1H),5.23(s,1H),4.01(d,J=6.5Hz,2H),3.71(s,3H),1.80(s,3H),1.66(s,3H),1.46(s,6H).

[0459] Example 52: Preparation of (E)-9-(3,4-dimethoxyphenylvinyl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-6-one

[0460]

[0461] Referring to the preparation method of step 2 of Example 2, the crude product was purified by column chromatography (PE / EA=1 / 1) to obtain 13 mg of a yellow solid, LC-MS: ESI m / z: 555.3 [M+H] + ; 1 HNMR (400MHz, DMSO) δ13.66(s,1H),7.76(s,1H),7.58(d,J=16.0Hz,1H),7.26(dd,J=18.2,13.0Hz,3H),7.01(d,J=8.2Hz,1H),6.63(d,J=10.1Hz,1H), 6.36(s,1H),5.78(d,J=10.1Hz,1H),5.21(s,1H),4.06(d,J=5.6Hz,2H),3. 86(s,3H),3.82(s,3H),3.74(s,3H),1.82(s,3H),1.66(s,3H),1.47(s,6H).

[0462] Example 53: Preparation of 10-bromo-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0463]

[0464] Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=10 / 1) to obtain 10 mg of a light yellow solid. LC-MS: ESI m / z: 622.2 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ = 13.32 (s, 1H), 7.51-7.40 (m, 4H), 7.33 (br d,J=6.7Hz,1H),6.74(d,J=10.0Hz,1H),6.41(s,1H),5.60(d,J=10.1Hz,1H),5.16(br s,1H),4.11(br d,J=5.7Hz,2H),3.90-3.33(m,6H),1.82(s,3H),1.66(s,3H),1.48(s,6H).

[0465] Example 54: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9,10-diyl diacetate

[0466]

[0467] Example 8 (60 mg, 0.1 mmol) was dissolved in pyridine (9 mL), acetic anhydride (44 mg, 0.4 mmol) was added to the solution at room temperature, and the reaction solution was stirred at 70°C for 6 h. LCMS monitored the reaction to be complete. Water was added, and the organic phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (eluent: PE / EA=4 / 1) to obtain 28.2 mg of a white solid. LC-MS: ESI m / z: 509.3 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.34(s,1H),6.72(d,J=8Hz,1H),6.24(s,1H),5.59(d,J=12Hz,1H),5.22(s,1 H), 4.11 (d, J = 8Hz, 2H), 3.77 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H), 1.82 (s, 3H), 1.69 (s, 3H), 1.46 (s, 6H).

[0468] Example 55: Preparation of 8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-5,9,10-triyl triacetate

[0469]

[0470] See the preparation method of Example 54, wherein acetic anhydride is 7 equivalents. 13.6 mg of white solid is obtained. LC-MS: ESI m / z: 551.4 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ6.61(s,1H),6.48(d,J=12Hz,1H),5.72(d,J=8Hz,1H),5.19(t,J=4Hz,1H),4.03(d ,J=4Hz,2H),3.76(s,3H),2.47(s,3H),2.40(s,3H),2.37(s,3H),1.81(s,3H),1.67(s,3H),1.47(s,6H).

[0471] Example 56: Preparation of 5,10-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl dimethylcarbamate

[0472]

[0473] Example 8 (20 mg, 0.04 mmol) was dissolved in pyridine (3 mL), dimethylaminoformyl chloride (5 mg, 0.04 mmol) was added, and the mixture was reacted at room temperature for 2 h. LCMS detected that the main product was the target molecular weight, and the reaction solution was concentrated and purified by Prep-TLC (developing solvent: PE:EA=2:1) ​​to obtain 11.3 mg of a yellow solid product. LC-MS:ESI m / z:496.1[M+H] + ; 1HNMR (400MHz, CDCl3) δ13.65(s,1H),6.79(d,J=12Hz,1H),6.29(s,1H),5.63(d,J=12Hz,1H),5.29(t,J=8H z, 1H), 4.12 (d, J = 4Hz, 2H), 3.89 (s, 3H), 3.34 (s, 3H), 3.14 (s, 3H), 1.88 (s, 3H), 1.74 (s, 3H), 1.51 (s, 6H).

[0474] Example 57: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9,10-diyl bis(dimethylcarbamate)

[0475]

[0476] See the preparation method of Example 56, wherein dimethylaminoformyl chloride is 2 equivalents, and 10 mg of a yellow solid product is obtained. LC-MS: ESI m / z: 567.3 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.44(s,1H),6.73(d,J=8Hz,1H),6.25(s,1H),5.58(d,J=12Hz,1H),5.22(t,J=8Hz,1H),4.11( d,J=8Hz,2H),3.79(s,3H),3.18(s,3H),3.15(s,3H),3.07(s,3H),3.05(s,3H),1.82(s,3H),1.68(s,3H),1.48(s,6H).

[0477] Example 58: Preparation of methyl (E)-3-(5-hydroxy-8-methoxy-2,2-dimethyl-9-((methyl(4-morpholinophenyl)carbamoyl)oxy)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)acrylate

[0478]

[0479] Step 1: Obtain 30 mg of yellow oily solid product. LC-MS: ESI m / z: 493.2 [M+H] + .

[0480] Step 2: Refer to the preparation method of step 3 in Example 1. 15.7 mg of yellow solid product was obtained. LC-MS: ESI m / z: 711.5 [M+H]+ ; 1 HNMR (400MHz, CDCl3) δ14.00 (s, 1H), 8.12 (d, J = 16Hz, 1H), 7.40-7.20 (m, 3H), 6.90-6.80 (m, 3H), 6.74 (d, J = 12Hz, 1H), 5.63 (d, J = 12Hz, 1H),5.15(s,1H),4.09(s,1H),3.90-3.80(m,8H),3.59(s,3H),3.53(s,2H),3.20-3.10(m,4H),1.81(s,3H),1.66(s,3H),1.56(s,6H).

[0481] Example 59: Preparation of ethyl (E)-3-(5-hydroxy-8-methoxy-2,2-dimethyl-9-((methyl(4-morpholinophenyl)carbamoyl)oxy)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)acrylate

[0482]

[0483] Step 1: Refer to the preparation method of step 2 in Example 2. Obtain 100 mg of a yellow oily product. LC-MS: ESI m / z: 507.2 [M+H] + .

[0484] Step 2: Refer to the preparation method of step 3 in Example 1. Obtain 22.6 mg of yellow solid product. LC-MS: ESI m / z: 725.6 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ14.00 (s, 1H), 8.12 (d, J = 16Hz, 1H), 7.30-7.20 (m, 3H), 6.9 0-6.80(m,3H),6.74(d,J=12Hz,1H),5.63(d,J=12Hz,1H),5.16(s,1H),4.40-4.32 (m,2H),4.31-4.20(m,2H),3.90-3.80(m,5H),3.53(s,3H),3.38(s,2H),3.20-3.1 0(m,4H),1.81(s,3H),1.66(s,3H),1.58(s,3H),1.54(s,3H),1.39(t,J=8Hz,3H).

[0485] Example 60: Preparation of 12-(3-fluoro-4-hydroxyphenyl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0486]

[0487] See the preparation method of step 2 in Example 2. The crude product was purified by silica gel column chromatography (eluent: PE / EA=2 / 3) to obtain 10.7 mg of a yellow solid product. LC-MS: ESI m / z: 652.3 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ13.75(s,1H),7.50-7.40(m,4H),7.38-7.30(m,1H),7.15(s,1H),7.12-7.07(m,3H),6.83(d,J= 8Hz,1H),5.64(d,J=12Hz,1H),5.24(d,J=16Hz,2H),4.15(s,2H),3.45(s,6H),1.85(s,3H),1.71(s,3H),1.48(s,6H).

[0488] Example 61: Preparation of 12-(3-cyano-4-hydroxyphenyl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0489]

[0490] See the preparation method of step 2 in Example 2. The crude product was purified by silica gel column chromatography (eluent: PE / EA=2 / 3) to obtain 15 mg of a yellow solid product. LC-MS: ESI m / z: 659.3 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.74(s,1H),7.57(s,1H),7.50-7.40(m,5H),7.34(s,1H),7.06(s,1H),6.99(d,J=8Hz,1H),6.81(d, J=8Hz,1H),6.36(s,1H),5.64(d,J=12Hz,1H),5.20(s,1H),4.14(s,2H),3.46(s,6H),1.86(s,3H),1.71(s,3H),1.43(s,6H).

[0491] Example 62: Preparation of 12-(1H-benzo[d]imidazol-5-yl)-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0492]

[0493] See the preparation method of step 2 in Example 2. 15 mg of light yellow solid product was obtained. LC-MS: ESI m / z: 658.4 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.73 (s, 1H), 8.19 (s, 1H), 7.71 (d, J = 28Hz, 1H), 7.40-7.28 (m, 7H), 6.99 (s, 1H), 6.81 (d ,J=8Hz,1H),5.59(d,J=8Hz,1H),5.21(s,1H),4.12(s,2H),3.39(s,6H),1.83(s,3H),1.68(s,3H),1.26(s,6H).

[0494] Example 63: Preparation of 5-hydroxy-12-(4-(2-hydroxyethyl)piperazine-1-yl)-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0495]

[0496] Step 1: See the preparation method of step 1 in Example 10. The crude product was purified by flash column chromatography (eluent: PE / EA=4 / 1) to obtain 40 mg of yellow oily product tert-butyl 4-(5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)piperazine-1-carboxylate. LC-MS: M+H + =593.

[0497] Step 2: Referring to the preparation method of step 3 of Example 1, the crude product was purified by flash column chromatography (PE / EA=5 / 1) to obtain 40 mg of a yellow oily product. LC-MS: ESI m / z: 726 [M+H] + .

[0498] Step 3: Dissolve tert-butyl 4-(5-hydroxy-8-methoxy-2,2-dimethyl-9-((methyl(phenyl)carbamoyl)oxy)-7-(3-methylbut-2-ene-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)piperazine-1-carboxylate (25 mg, 0.04 mmol) in DCM (8 mL), and then slowly add 4N (2.5 mL) of methanolic hydrochloric acid to the solution under ice-water conditions. Stir at 25 ° C for 24 h. LCMS monitors the reaction to be complete. Add water, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by flash column chromatography (eluent: DCM / MeOH=10 / 1) to obtain 18 mg of a yellow solid. LC-MS: ESI m / z: 626 [M+H] + .

[0499] Step 4: Dissolve 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(piperazine-1-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate (13 mg, 0.02 mmol) in acetonitrile (2 mL), add K2CO3 (14 mg, 0.1 mmol) and 2-bromoethanol (10 mg, 0.1 mmol) to the solution at room temperature, and stir the reaction solution at 70°C for 3 h. LCMS monitored the reaction to be complete. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by flash column chromatography (eluent: DCM / MeOH=20 / 1) to obtain 5 mg of a yellow solid. LC-MS: ESI m / z: 670.3[M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.51(s,1H),7.50-7.40(m,4H),7.35(s,2H),6.78(d,J=12Hz,1H),5.62(d,J=8Hz,1H),5.21(s,1 H),4.14(s,2H),3.80-3.75(m,2H),3.49(s,6H),3.27(s,4H),2.80-2.75(m,6H),1.85(s,3H),1.70(s,3H),1.55(s,6H).

[0500] Example 64: Preparation of 7-hydroxy-4-methoxy-10,10-dimethyl-5-(3-methylbut-2-en-1-yl)-1-hydro-6H,10H-pyrano[2',3':6,7]oxantheno[4,3-d]oxazole-2,6-dione

[0501]

[0502] Step 1: C-2 (200 mg, 0.4 mmol) was dissolved in toluene (15 mL), and diphenylamine (100 mg, 0.5 mmol), sodium tert-butoxide (70 mg, 0.7 mmol), BINAP (110 mg, 0.2 mmol) and Pd(dpa)3 (80 mg, 0.1 mmol) were added in sequence, replaced with nitrogen three times at room temperature, and reacted at 110°C for 12 h. LCMS monitored the reaction to be complete. Water was added, EA was extracted three times, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE:EA=6 / 1) to obtain 130 mg of a light yellow product. LC-MS: ESI m / z: 676 [M+H] + .

[0503] Step 2: Dissolve 10-((diphenylmethylene)amino)-8-methoxy-5,9-bis(methoxymethoxy)-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-6-one (120 mg, 0.2 mmol) in THF (12 mL), then add concentrated sulfuric acid (1.2 mL) to H2O (6 mL) and add dropwise to the solution. Stir at 40 ° C for 12 h. LCMS monitors the reaction to be complete. Add saturated sodium bicarbonate to make it weakly acidic, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography (eluent: PE / EA=2 / 1) to obtain 5.5 mg of yellow solid. LC-MS: ESI m / z: 424 [M+H] + .

[0504] Step 3: Dissolve 10-amino-5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[3,2-b]xanthene-6-one (5 mg, 0.01 mmol) in acetonitrile (3.0 mL), then add CDI (10 mg, 0.03 mmol) and stir at 70 ° C for 3 h. LCMS monitored the reaction to be complete, concentrated the reaction solution, and purified the crude product by silica gel column chromatography (eluent: PE / EA=4 / 1) to obtain 3 mg of yellow solid. LC-MS: ESI m / z: 450.5 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.53 (s, 1H), 6.78 (d, J = 8Hz, 1H), 6.30 (s, 1H), 5.65 (d, J = 12Hz, 1H), 5.23 (t, J = 4Hz, 1H), 4.19 (d, J = 8Hz, 2H), 4.12 (s, 3H), 1.89 (s, 3H), 1.73 (s, 3H), 1.52 (s, 6H).

[0505] Example 65: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0506]

[0507] See the preparation method of step 2 in Example 2. 25 mg of light yellow solid product was obtained. LC-MS: ESI m / z: 674.9 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ13.75(s,1H),8.79(s,1H),8.56(s,1H),7.45-7.35(m,4H),7.19-7.05(m,5H),6.84(d,J =12Hz,1H),5.63(d,J=12Hz,1H),5.22(s,1H),4.15(s,2H),3.42(s,6H),1.85(s,3H),1.71(s,3H),1.42(s,6H).

[0508] Example 66: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-12-(3-(methylsulfonylamino)phenyl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0509]

[0510] Step 1: Refer to the preparation method of step 2 in Example 2. Obtain 40 mg of yellow solid product. LC-MS: ESI m / z: 633.3 [M+H] + .

[0511] Step 2: Obtain 11 mg of light yellow solid product. LC-MS: ESI m / z: 711.3 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.73(s,1H),7.45-7.32(m,5H),7.31-7.20(m,3H),7.07(s,1H),6.80(d,J=12Hz,1H),6.51(s ,1H),5.60(d,J=8Hz,1H),5.17(s,1H),4.09(s,2H),3.40(s,6H),3.08(s,3H),1.81(s,3H),1.66(s,3H),1.41(s,6H).

[0512] Example 67: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-12-(4-(methylsulfonylamino)phenyl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0513]

[0514] See the preparation method of Example 66. Obtained 18 mg of light yellow solid product. LC-MS: ESI m / z: 711.5 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.78 (s, 1H), 7.48-7.40 (m, 8H), 7.08 (s, 1H), 6.84 (d, J = 12Hz, 1H), 6.57 (s, 1H), 5.6 4(d,J=8Hz,1H),5.22(s,1H),4.15(s,2H),3.45(s,6H),3.20(s,3H),1.86(s,3H),1.71(s,3H),1.44(s,6H).

[0515] Example 68: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0516]

[0517] See the preparation method of step 2 in Example 2. 25 mg of light yellow solid product was obtained. LC-MS: ESI m / z: 658.6 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.80 (s, 1H), 9.45 (s, 1H), 8.365 (d, J = 4Hz, 1H), 7.40-7.29 (m, 6H), 7.13 (d, J = 8Hz, 1H), 6.82 (d, J = 8Hz, 1H), 6. 265(d,J=4Hz,1H),5.60(d,J=12Hz,1H),5.18(s,1H),4.10(s,2H),3.41(d,J=32Hz,6H),1.83(d,J=8Hz,6H),1.37(s,3H),1.32(s,3H).

[0518] Example 69: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-12-(6-carbonyl-1,6-dihydropyridin-3-yl)-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0519]

[0520] See the preparation method of step 2 in Example 2. Obtain 10 mg of a light yellow solid product. LC-MS: ESI m / z: 635.5 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.77(s,1H),7.74(d,J=8Hz,1H),7.61(s,1H),7.48-7.33(m,6H),7.20(s,1H),6.87(d,J=8Hz,1H),6. 83(d,J=12Hz,1H),5.66(d,J=8Hz,1H),5.21(s,1H),4.15(s,2H),3.44(d,J=8Hz,6H),1.86(s,3H),1.72(s,3H),1.48(s,6H).

[0521] Example 70: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-12-(1-methyl-6-carbonyl-1,6-dihydropyridin-3-yl)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0522]

[0523] See the preparation method of step 2 in Example 2. Obtain 10 mg of a light yellow solid product. LC-MS: ESI m / z: 649.6 [M+H] + ; 1HNMR (400MHz, CDCl3) δ13.73 (s, 1H), 7.49-7.33 (m, 8H), 7.14 (s, 1H), 6.83 (d, J = 12Hz, 1H), 5.66 (d,J=12Hz,1H),5.21(s,1H),4.14(s,2H),3.47(s,9H),1.86(s,3H),1.71(s,3H),1.48(s,6H).

[0524] Example 71: Preparation of (E)-3-(5-hydroxy-8-methoxy-2,2-dimethyl-9-((methyl(4-morpholinophenyl)carbamoyl)oxy)-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-12-yl)fatty acid

[0525]

[0526] See the preparation method of step 2 of Example 64. 10 mg of yellow solid product was obtained. LC-MS: ESI m / z: 697.8 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ14.05(s,1H),8.22(d,J=16Hz,1H),7.38-7.27(m,3H),6.96-6.88(m,3H),6.74(d,J=8Hz,1H),5.64(d,J=12Hz,1 H), 5.16 (s, 1H), 4.10 (s, 2H), 3.89-3.83 (m, 5H), 3.53 (s, 3H), 3.38 (s, 2H), 3.17 (t, J = 4Hz, 4H), 1.82 (s, 3H), 1.67 (s, 3H), 1.56 (s, 6H).

[0527] Example 72: Preparation of 12-cyano-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(4-morpholinophenyl)carbamate

[0528]

[0529] See the preparation method of step 3 in Example 1. 38 mg of yellow solid product was obtained. LC-MS: ESI m / z: 652.4 [M+H] + ; 1HNMR (400MHz, CDCl3) δ14.01(s,1H),7.38(s,1H),7.27(d,J=8Hz,2H),6.95(s,1H),6.93(d,J=8Hz,1H),6.67(d,J=12Hz,1H),5.63(d,J=8Hz,1H) ,5.11(s,1H),4.13(s,2H),3.40-3.83(m,5H),3.52(s,3H),3.37(s,2H) ,3.20-3.14(m,5H),1.81(s,3H),1.66(s,3H),1.58(s,3H),1.55(s,3H).

[0530] Example 73: Preparation of 10-cyano-5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-ylmethyl(phenyl)carbamate

[0531]

[0532] Step 1: Obtain 50 mg of yellow oily product. LC-MS: ESI m / z: 434.2 [M+H] + .

[0533] Step 2: Refer to the preparation method of step 3 in Example 1. Obtain 28 mg of yellow solid product. LC-MS: ESI m / z: 567.5 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.12(s,1H),7.48-7.42(m,4H),7.34(d,J=8Hz,1H),6.71(d,J=8Hz,1H),6.42(s,1H ), 5.61 (d, J = 12Hz, 1H), 5.10 (s, 1H), 4.15 (s, 2H), 3.67-3.43 (m, 6H), 1.66 (s, 3H), 1.56 (s, 3H), 1.48 (s, 6H).

[0534] Example 74: Preparation of 5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-6-carbonyl-2H,6H-pyrano[3,2-b]xanthene-9-yl(4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)phenyl)(methyl)carbamate

[0535] Step 1: Refer to the preparation method of step 4 of Example 63. Obtain 800 mg of white solid product. LC-MS: ESI m / z: 221.1 [M+H] + .

[0536] Step 2: Refer to the preparation method of step 3 in Example 4. Obtain 650 mg of white solid product. LC-MS: ESI m / z: 191.1 [M+H] + .

[0537] Step 3: Obtain 260 mg of white solid product. LC-MS: ESI m / z: 205.1 [M+H] + .

[0538] Step 4: Refer to the preparation method of step 3 in Example 1. 48 mg of yellow solid product was obtained. LC-MS: ESI m / z: 639.4 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ13.55 (s, 1H), 7.25-7.19 (m, 3H), 6.73 (d, J = 12Hz, 1H), 6.64- 6.58(m,2H),6.24(s,1H),5.57(d,J=8Hz,1H),5.18(s,1H),4.66(s,1H),4.40(s,1H ),4.12-4.00(m,2H),3.92-3.84(m,2H),3.57(d,J=12Hz,1H),3.50(s,3H),3.36(s, 3H), 3.18 (d, J = 8Hz, 1H), 2.08-1.94 (m, 2H), 1.81 (s, 3H), 1.66 (s, 3H), 1.46 (s, 6H).

[0539] In order to more fully explain the implementation of the present invention, the following effect examples 1 to 4 are provided. These examples are only to explain and illustrate the neuroprotective effects of the compounds of the present invention, but not to limit the scope of the present invention. Any one of the compounds of the present invention can be used to prepare therapeutic drugs.

[0540] Effect Example 1: Effect of α-mangostin derivatives on iodoacetic acid-induced HT22 cell injury experiment The iodoacetic acid-induced HT22 cell injury experiment is one of the classic models of oxidative stress injury (the main mechanism of nerve damage), and the selected cells HT22 are also sensitive cells in the neural cell line, so it is considered to be a pharmacodynamic model very close to the pathogenesis.

[0541] 1.1 Experimental Materials

[0542] Iodoacetic acid, 2-Iodoacetic acid, abbreviated as IAA, molecular formula ICH2COOH, CAS number 64-69-7, raw material white to light yellow powder, purchased from Sigma, USA, item number I4386, batch number BCCD9748, stock solution: 5mM, dissolved in ultrapure water. CellTiter-Glo staining solution, abbreviated as CTG, used to detect cell viability, purchased from Promega, item number G7573, batch number 0000540793. Positive control drug: 3-methyl-1-phenyl-2-pyrazol-5-one, Edaravone, abbreviated as EDA, molecular formula C 10 H 10 N2O, CAS No. 89-25-8, raw material white powder, purchased from MCE, item No. HY-B0099, batch No. 34226, stock solution: 60mM, dissolved in DMSO. Butylphthalide, also known as 3-n-butylphthalide, butylphthalide, abbreviated as NBP, molecular formula C 12 H 14 O2, CAS No. 6066-49-5, purchased from the China National Institute for Food and Drug Control, specification 200 mg / vial, packaged in brown ampoule. HZAM-1 was prepared by the method of patent CN 109956952 B.

[0543] 1.2 Experimental methods

[0544] HT22 cells were cultured at 3×10 4 The cells were plated at a density of 100 μL / well in a 96-well culture plate and cultured for 24 hours before using the IAA (iodoacetic acid) model.

[0545] Normal group: 0.5% DMSO was added, and the cells were cultured for 2 h before being replaced with normal culture medium for 24 h.

[0546] Model group: Add different concentrations of IAA, the final drug concentration is 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625 μM, continue to culture HT22 cells for hypoxia treatment, change to normal culture medium after 2 hours, and continue to culture for 24 hours. Then, add 50 μL CTG directly to the culture medium of the normal group and model group, and the OD value on the microplate reader is measured after 20 minutes. 562 Read the plate and calculate the cell viability to determine the appropriate IAA model conditions.

[0547] Test group: Detect the protective effect of different compounds on HT22 cells damaged by IAA. 4The cells were inoculated into 96-well culture plates at a density of 100 μL / well. After culturing for 24 hours, IAA was added to model the cells, and the final drug concentration was 5 μM. After culturing for 2 hours, the culture medium was replaced with a medium containing no IAA but the test compound (DMEM / 10% FBS / 1×Penicillin-Streptomycin) for 24 hours, and the final concentration of the test drug was 3 μM. The average value was taken for duplicate well tests.

[0548] Positive control group: After 2 hours of IAA (5 μM) treatment, the culture medium was replaced with a medium containing EDA (3-methyl-1-phenyl-2-pyrazol-5-one) without IAA and cultured for 24 hours. The final concentration of the positive control drug was 60 μM. Then, the test group and the positive control group were replaced with normal culture medium, 50 μL CTG was added, and the OD value was measured on the microplate reader after 20 minutes. 562 Read the plate, calculate the cell survival rate, and analyze the neuroprotective effect of the test compound.

[0549] Evaluation criteria: The cell survival rate of the model group was 30-40%, and the cell survival rate after drug treatment was >40%, indicating a cytoprotective effect. The cell survival rate of the drug-treated group was 40-60%, indicating a moderate cytoprotective effect; the cell survival rate was 60-80%, indicating a strong cytoprotective effect; the cell survival rate was 80-100%, indicating an extremely strong cytoprotective effect, eliminating most of the oxidative damage; the cell survival rate was >100%, indicating that not only all oxidative damage was eliminated, but also helped HT22 cells to restore normal cell division and proliferation.

[0550] Survival rate = (mean OD of the test group - mean OD of the blank control wells) / (mean OD of the normal group - mean OD of the blank control wells) × 100%.

[0551] 1.3 Experimental Results

[0552] Table 1 Cell survival rate of α-mangostin derivatives on IAA-induced HT22 cells (mean ± SD, the concentration of the tested compounds was 3 μM)

[0553]

[0554]

[0555] The results are shown in Table 1. The experimental results show that compared with the model group, butylphthalide and HZAM-1 have moderate cell protection, and edaravone has a strong cell protection. The antioxidant activity of the compounds of the present invention exceeds that of the same dose of butylphthalide and HZAM-1, and the neuroprotective effect of most compounds is better than that of the positive control drug edaravone (EDA) at the same concentration. Examples 1-5, 7-20, 22, 23, 30, 31, 33, 42, 54, 55, 58-60, 62 have extremely strong cell protection, and Examples 1-5, 7-9, 14, and 33 show that not only the oxidative damage of cells is eliminated, but also the division and proliferation of damaged cells can be restored. In summary, it is proved that α-mangostin derivatives have excellent neuroprotective effects, and HT22 cells are extremely well protected from the inhibition of IAA on cell glycolysis and the destruction of nerve cell membranes.

[0556] Effect Example 2: Effect of α-mangostin derivatives on oxygen-glucose deprivation-induced HT22 cell injury experiment The oxygen-glucose deprivation-induced HT22 cell injury experiment is an important and typical in vitro pharmacodynamic model for ischemic stroke disease (cerebrovascular disease), etc., and is considered to be an in vitro screening model that is very close to the pathogenesis.

[0557] 2.1 Experimental Materials

[0558] The normal culture medium was composed of 500 mL DMEM (purchased from Gibco, catalog number 11965092), 50 mL FBS (purchased from Corning, catalog number 35-081-CV), and 1 mL Penicillin-Streptomycin (purchased from Hyclone, catalog number SV30010). The sugar-free culture medium was composed of 500 mL sugar-free DMEM (purchased from Corning, catalog number 17-207-CV), 50 mL FBS (purchased from Corning, catalog number 35-081-CV), and 1 mL Penicillin-Streptomycin (purchased from Hyclone, catalog number SV30010). DMSO was purchased from Sigma, USA (catalog number D2650). CellTiter-Glo staining solution was purchased from Promega (catalog number G7588). Edaravone (EDA) was purchased from MCE (catalog number HY-B0099). HZAM-1 is prepared by the method of patent CN 109956952 B.

[0559] 2.2 Experimental methods

[0560] HT22 cells were cultured at 3×10 4The cells were inoculated into a 96-well culture plate at a density of 100 μL / well and cultured for 24 hours before OGD modeling. The original ordinary culture medium in the 96-well plate was discarded and washed twice with sugar-free culture medium.

[0561] Normal group: Add normal culture medium containing sugar and oxygen and continue to culture for 4 hours. Then, continue to culture for 24 hours.

[0562] Model group: Add sugar-free culture medium containing 0.5% DMSO, place in hypoxic environment (0.1% O2, 5% CO2, 94.9% N2, 37°C) for 4 hours, then change to normal ordinary culture medium to restore sugar and oxygen, and continue to culture for 24 hours.

[0563] Test group: Detect the protective effect of different compounds on HT22 cells injured by OGD. Add sugar-free medium containing the test compound, the final concentration of the test drug is 1, 3μM, place in anoxic environment and continue to culture for 4 hours, then change to normal medium containing the same test compound and the same final concentration of the drug, and continue to culture for 24 hours. The average value is taken for duplicate test.

[0564] Positive control group: Add sugar-free medium containing EDA, the final drug concentration is 3μM, place in anoxic environment and continue to culture for 4h, then change to ordinary medium containing the same final concentration of EDA, and continue to culture for 24h. Then, the normal group, model group, test group and positive control group are replaced with ordinary medium without drugs, 50μL CTG is added, and the OD value is measured on the microplate reader after 20min. 562 The plates were read, the cell survival rate was calculated, and the protective effects of the tested compounds against OGD injury were analyzed.

[0565] Evaluation criteria: In the oxygen-glucose deprivation experiment, the cell survival rate of the model group was normalized to 100%, and the changes in the survival rate of each experimental group relative to the model group were mainly examined. Typical compounds with excellent cell protection in the iodoacetic acid experiment were selected for testing. A relative cell survival rate >100% indicates a cell protection effect. The relative survival rate of the drug-treated group reached 100-110%, indicating a strong cell protection effect; the relative survival rate reached 110-120%, indicating an extremely strong cell protection effect; the relative survival rate >120%, indicating a perfect cell protection effect, eliminating most of the damage caused by oxygen-glucose deprivation.

[0566] Relative cell survival rate = (mean OD of the test group - mean OD of the blank control wells) / (mean OD of the model group - mean OD of the blank control wells) × 100%.

[0567] 2.3 Experimental Results

[0568] The relative survival rate test results of the test compounds and positive drug EDA on OGD-induced HT22 cell damage are shown in Table 2.

[0569] Table 2 Relative cell survival rate of α-mangostin derivatives on OGD-induced HT22 damage (mean ± SD)

[0570]

[0571]

[0572] The experimental results show that compared with the model group, the control drug HZAM-1 has a weaker effect on eliminating the damage caused by oxygen-glucose deprivation, and edaravone has a stronger cell protective effect. Among the compounds described in the present invention, Examples 5, 8, 12-13, and 33 have cell protective effects at a concentration of 3 μM, and Examples 1 to 4, 7, and 9 have extremely strong cell protective effects at concentrations of 1 μM and 3 μM, and the effect is significantly better than that of the positive drug edaravone, among which Examples 2, 7, and 9 show stronger cell protective effects at concentrations of 1 μM and 3 μM, and have excellent neuroprotective effects and potential clinical application value.

[0573] Effect Example 3: Metabolic Stability of α-mangostin Derivatives in Liver Microsomes of Humans and Rats

[0574] 1. Solution Preparation

[0575] Weigh 1 mg of the test compound (substrate), dissolve it in DMSO to 10 mM, and dilute it to 10 μM in 0.6% acetonitrile-water solution. Prepare the liver microsome experimental system, in which the NADPH generation system only includes glucose-6-phosphate, NADP+, and glucose-6-phosphate dehydrogenase, and prepare the stock solution as shown in Table 3 below.

[0576] Table 3: Liver microsome experimental system (total volume 200 μL)

[0577]

[0578] Reaction time 0, 10, 20, 30 min

[0579] 2. Sample Processing

[0580] Add substrate, liver microsomes, MgCl2, potassium phosphate buffer, and water to a 96-well plate and vortex gently to mix. Pre-incubate the microsome mixture in a 37°C water bath for 5 min, and then initiate the reaction by adding the NADPH generating system. After incubation for 0, 10, 20, and 30 min, mix 40 μL of the reaction mixture with 100 μL of acetonitrile (with internal standard 100 ng / mL) to terminate the reaction. After the incubation, centrifuge the mixture at 4600 rpm for 10 min at 4°C. Take 60 μL of the supernatant, dilute it 1:1 with water, and inject 5 μL for LC-MS / MS analysis.

[0581] 3. Chromatographic conditions

[0582] A Waters XBridge C18 column (50 mm × 2.1 mm, 5 μm) was used, with an injection volume of 5 μL. The flow rate was 1 mL / min, and the running time was 1.5 min. The mobile phase A was water containing 0.1% formic acid, and B was acetonitrile containing 0.1% formic acid. The gradient elution program is shown in Table 4 below:

[0583] Table 4: Gradient elution program

[0584]

[0585] 4. Mass spectrometry conditions

[0586] High performance liquid chromatography tandem mass spectrometry (LC-MS / MS) was used, model API 4500 (AB Sciex). Electrospray ionization (ESI) conditions and multiple reaction monitoring (MRM) mode were used to detect the eluted compounds. The drying gas temperature was 450°C, the pressure was 50 psi, and the nebulizing gas pressure was 20 psi.

[0587] 5. Experimental conclusion:

[0588] This experiment was conducted by measuring the half-life of the original drug. 1 / 2 (min) and clearance rate Cl int The experimental results showed that the α-mangostin derivatives had excellent stability in rat liver microsomes and human liver microsomes, such as the t 1 / 2 (min) were 64.2min, 76.0min, 357.1min, 51.8min, 88.6min and 378.0min, respectively. int The t in human liver microsomes was 22 μl / min / mg, 18 μl / min / mg, 4 μl / min / mg, 27 μl / min / mg, 16 μl / min / mg, and 4 μl / min / mg, respectively. 1 / 2 (min) were 398.3min, 92.6min, 403min, 100.3min, 403min and 403min respectively, Cl int (μl / min / mg) were 3μl / min / mg, 15μl / min / mg, 3μl / min / m, 14μl / min / mg, 3μl / min / mg and 3μl / min / mg respectively. Other compounds also had similar properties.

[0589] Effect Example 4: Pharmacokinetics of α-mangostin derivatives in rats

[0590] 1. Experimental methods:

[0591] 1.1 Solution preparation and animal experiments

[0592] Male SD rats, weighing about 200 grams, were purchased from Shanghai Xipu-Bikai Experimental Animal Co., Ltd., with 3 rats in each group. Each test compound was administered orally (PO) and intravenously (IV).

[0593] The injection dose was 1 mg / kg, and the test compound was prepared into a 0.1 mg / mL solution using the same solvent and injected into the tail vein at a volume of 10 mL / kg. Blood was collected at 5, 15, 30, 60, 120, 240, 480, 720, and 1440 minutes after administration to determine the blood drug concentration.

[0594] The oral dose was 10 mg / kg. The test compound was first prepared into a 1 mg / mL solution with a solvent (DMA:Solutol-HS-15:Saline=10:10:80) and then gavaged at a volume of 10 mL / kg. Blood was collected at 15, 30, 60, 120, 240, 480, 720, and 1440 minutes after administration to determine the blood drug concentration.

[0595] Accurately weigh 1 mg of the test compound and dissolve it in methanol / water solution (MeOH:H2O=4:1, v / v) to make a 100 μg / mL stock solution. Take an appropriate amount of the stock solution and dilute it with methanol / water solution to a series of standard solutions with mass concentrations of 20, 40, 100, 200, 400, 1000 ng / mL, 2, 4, 10, 20, 40, 100 μg / mL. Also prepare QC solutions with mass concentrations of 2 and 5 μg / mL for use.

[0596] Take 2.5 μL of each concentration standard solution and QC solution, dissolve in 47.5 μL of mouse blank plasma, transfer into a 96-well plate, and prepare standard plasma samples with mass concentrations of 1, 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, and 5000 ng / mL, as well as QC plasma samples with mass concentrations of 100 and 250 ng / mL for later use.

[0597] 1.2 Plasma sample processing

[0598] Each blood collection volume was about 200 μL, stored in an EDTA-2K anticoagulation tube, and centrifuged at 5500 rpm for 10 min to separate plasma. Take 20 μL of the test plasma sample, standard plasma sample, and QC plasma sample at each time point, mix them with 100 μL acetonitrile (with internal standard 100 ng / mL), shake at room temperature for 10 min, and then centrifuge at 3700 rpm for 18 min at 4 ° C. Take 60 μL of the supernatant, dilute it 1:1 with water, shake it at room temperature for 10 min, and then inject 5 μL for LC-MS / MS analysis.

[0599] 2. Sample measurement method

[0600] 2.1 Chromatographic conditions

[0601] The chromatographic conditions are the same as those in Effect Example 3.

[0602] 2.2 Mass spectrometry conditions

[0603] High performance liquid chromatography tandem mass spectrometry (LC-MS / MS), model API 4500 (AB Sciex), was used. Electrospray ionization (ESI) conditions and multiple reaction monitoring (MRM) mode were used to detect the eluted compounds. The ion source temperature was 450°C, the spray gas and auxiliary heating gas pressures were both 50 psi, the air curtain gas pressure was 20 psi, and the collision chamber outlet voltage was 13.0 V. The declustering voltages of the internal standard and the test compound were 79, 130, and 135 eV, respectively, and the collision energies were 19, 24, and 41 eV, respectively.

[0604] 3. Experimental conclusion

[0605] The experimental results show that the α-mangostin derivatives have good physical and chemical properties. For example, the terminal elimination half-life of Examples 3 and 10 after intravenous injection in rats was t 1 / 2 The results were 1.4 hours and 15.9 hours, respectively, which were significantly better than the same dose of edaravone (t 1 / 2 about 17.4min) and butylphthalide (t 1 / 2 The areas under the drug-time curves of Examples 3 and 10 were 12902 hr*nM and 7778 hr*nM, respectively. Example 3 was significantly superior to the same dose of edaravone (AUC INF 8000hr*nM) and butylphthalide (AUC INF AUC of 2200hr*nM INF , other compounds also have similar properties.

[0606] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. An α-mangostin derivative as shown in Formula I, or a pharmaceutically acceptable salt or solvate thereof: in, R1 is independently hydroxyl, halogen, amino, cyano, -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, C2-C6 unsaturated alkyl, C2-C6 unsaturated heteroalkyl, -(CH=CH)-CORa, -(C1-C3 alkylene)-(CH=CH)-CORa, -O-(C1-C3 alkylene)-(CH=CH)-CORa, -OCO-(CH=CH)-CORa, -OC O-(C1-C3 alkylene)-(CH=CH)-CORa, 3-12-membered alkyl ring group, 3-12-membered heteroalkyl ring group, 5-10-membered aryl group, 5-10-membered aromatic heterocyclic group, -O-(3-12-membered alkyl ring), -O-(3-12-membered heteroalkyl ring), -O-(5-10-membered aromatic ring), -O-(3-12-membered aromatic heterocyclic ring), -O-(C1-C3 alkylene)-(5-10-membered aromatic ring), -O-(C1-C3 alkylene)-(5-10-membered aromatic heterocyclic ring); R2 and R3 are each independently a hydrogen atom, a halogen, a hydroxyl group, an amino group, an amine group, a cyano group, -C(O)X'R8 or -X'C(O)R9, an amide group, a sulfonic acid group, a sulfonate group, a sulfonamide group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 saturated heteroalkyl group, a substituted or unsubstituted C2-C10 unsaturated alkyl group, a substituted or unsubstituted C2-C10 unsaturated heteroalkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, a substituted or unsubstituted 3-12-membered aryl group, a substituted or unsubstituted 3-12-membered aromatic heterocyclic group, or L-R'; Wherein, L is O, NH, S, SO2, substituted or unsubstituted -CH=CH-, substituted or unsubstituted -CH=CH-(C1-C3 alkylene)-, -(C1-C3 alkylene)-substituted or unsubstituted CH=CH-; R' is independently -CORb, -SO2Rc, C1-C6 alkyl, C1-C6 heteroalkyl, substituted or unsubstituted 3-12 membered heteroalkyl ring group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; Ra and Rb are each independently selected from -ORd and -NReRf; wherein Rd, Re and Rf are each independently hydrogen, C1-C6 alkyl, C2-C6 unsaturated alkyl, C1-C6 haloalkyl, or Re, Rf and the adjacent nitrogen atom together form a substituted or unsubstituted 3-12 membered heterocyclic ring; Rc is independently selected from hydroxyl, amino, amine, amide, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 unsaturated alkyl, C2-C6 unsaturated heteroalkyl; (a) When R2=R3=H and R1 is hydroxyl, R is -X-Rg or -CH=CH-R6, Wherein, X is NH, O, CH2, and Rg is independently selected from R4 is independently a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered alkyl ring, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered heteroalkyl ring; R5 is independently a substituted 5-10 membered aryl group, a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; wherein the substitution refers to substitution by 1-2 Rh and 0-2 Ri; wherein Rh is independently selected from hydroxyl, cyano, C1-C6 haloalkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group, -Z-substituted or unsubstituted 3-8 membered heteroalkyl ring, Ri is independently selected from halogen, hydroxyl, cyano, amino, amine, -C(O)X'R8 or -X'C(O)R9, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, substituted or unsubstituted 3-12 membered heteroalkyl ring group, Z is NH, S or SO2, -C1-C6 alkylene-, -O-C1-C6 alkylene-; R6 is independently -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; R7 is independently selected from a substituted or unsubstituted 3-8 membered heteroalkyl ring group, a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; n is an integer selected from 2 to 20; (b) when R2=R3=H and R1 is not hydroxyl, R is -X-Rg, wherein X is NH, O, and Rg is independently selected from C1-C6 saturated heteroalkyl, C2-C6 unsaturated heteroalkyl, substituted or unsubstituted 3-8 membered alkyl ring, substituted or unsubstituted 3-8 membered heteroalkyl ring, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 3-12 membered aromatic heterocyclic group, -CO- substituted or unsubstituted 3-8 membered alkyl ring, -CO-substituted or unsubstituted 3-8 membered alkyl ring, -CO-substituted or unsubstituted 5-10 membered aromatic ring, -CO-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, -CO-CH2-substituted or unsubstituted 3-8 membered alkyl ring, -CO-CH2-substituted or unsubstituted 3-8 membered heteroalkyl ring, -CO-CH2-substituted or unsubstituted 5-10 membered aromatic ring, -CO-CH2-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, R4 is independently a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered alkyl ring, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered heteroalkyl ring; R5 is independently C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; R6 is independently -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; (c) When R2 and R3 are not H at the same time and R1 is hydroxyl, R is -X-Rg, wherein X is NH, O, and Rg is independently selected from hydrogen atom, -C(O)X'R8 or -X'C(O)R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 unsaturated alkyl, substituted or unsubstituted C1-C6 saturated heteroalkyl, substituted or unsubstituted C2-C6 unsaturated heteroalkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group, -(C1-C20 alkylene)-C(O)X'R8 or -(C1-C20 alkylene)-X'C(O)R9, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 5-10 membered aromatic ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, -CO-CH2-substituted or unsubstituted 3-8 membered alkyl ring, -CO-CH2-substituted or unsubstituted 3-8 membered heteroalkyl ring, -CO-CH2-substituted or unsubstituted 5-10 membered aromatic ring, -CO-CH2-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, Or Rg and R3 and their adjacent X together form a substituted or unsubstituted 5-10 membered heterocyclic ring; R4 is independently a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered alkyl ring, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered heteroalkyl ring; R5 is independently C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; R6 is independently -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; (d) When R2 and R3 are not H at the same time and R1 is not hydroxyl, R is -X-Rg, wherein X is NH, O, and Rg is independently selected from hydrogen atom, -C(O)X'R8 or -X'C(O)R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 unsaturated alkyl, substituted or unsubstituted C1-C6 saturated heteroalkyl, substituted or unsubstituted C2-C6 unsaturated heteroalkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group, -(C1-C20 alkylene)-C(O)X'R8 or -(C1-C20 alkylene)-X'C(O)R9, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 5-10 membered aromatic ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, -CO-CH2-substituted or unsubstituted 3-8 membered alkyl ring, -CO-CH2-substituted or unsubstituted 3-8 membered heteroalkyl ring, -CO-CH2-substituted or unsubstituted 5-10 membered aromatic ring, -CO-CH2-substituted or unsubstituted 3-12 membered aromatic heterocyclic ring, Or Rg and R3 and their adjacent X together form a substituted or unsubstituted 5-6 membered heterocyclic ring; R4 is independently a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-12-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered alkyl ring, a substituted or unsubstituted 3-12-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-12-membered heteroalkyl ring; R5 is independently C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; R6 is independently -C(O)X'R8 or -X'C(O)R9, amide, sulfonic acid, sulfonate, sulfonamide, substituted or unsubstituted 3-8 membered alkyl ring group, substituted or unsubstituted 3-8 membered heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; in, Ring A is a substituted or unsubstituted 3-12-membered heteroalkyl ring, or a substituted or unsubstituted 5-10-membered aromatic heterocyclic ring; is a double bond or a single bond; Unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, -OH, -CN, -NO2, -NH2, -NCO, -OCN, -SCN, -NCS, -N3, -(C1-C3 alkylene)OH, -O(C1-C3 alkyl), -S(C1-C3 alkyl), -C(O)X'R8 or -X'C(O)R9, -SO3R8, -OSO2OR8, -NR 10 SO2OR9, -NR 10 R 11 、-SO2NR 10 R 11 、-NH-SO2-R 10 、-N + R 10 R 11 R 12 、-C(O)N(R 13 2. -SO2R 14 、-NR 15 C(O)N(R 15 )2, -B(OH)2, -B(O(C1-C6 alkyl or alkylene))2, -P(O)(OH)3, -OP(O)(OC1-C3 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 unsaturated alkyl, C1-C6 saturated heteroalkyl, C2-C6 unsaturated heteroalkyl, oxo (=O), 3-12 membered alkyl ring group, 3-12 membered heteroalkyl ring group, 5-10 membered aryl, 5-10 membered aromatic heterocyclic group, 3-12 membered heterocyclic group, -(C1-C3 alkylene)-3-12 membered heterocyclic ring, -O(C1-C6 alkylene)-3-12 membered heterocyclic ring; X' is a chemical bond or is oxygen or sulfur, R8 is independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, 3-12-membered alkyl ring group, 5-10-membered aryl, 3-12-membered heterocyclic group, R9 is independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, 3-12-membered alkyl ring group, 5-10-membered aryl, 3-12-membered heterocyclic group; R 10 , R 11 and R 12 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C8 alkenyl, -C(O)X'R8 or -X'C(O)R9, or, R 10 and R 11 Together with the nitrogen atom to which they are attached, they form a 4-8 membered heterocyclic ring; wherein R 10 or R 11 Not all are -C(O)X'R8 or -X'C(O)R9; R 13 are independently selected from hydrogen or C1-C6 alkyl, or two R 13 Together with the N atom to which they are attached, they form a 4-8 membered heterocyclic ring; R 14 Independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered alkyl ring group, 3-12 membered heterocyclic group, 5-10 membered aryl group; R 15 are independently selected from hydrogen, C1-C6 alkyl, or two R 15 Together with the N atom to which they are attached, they form a 4-8 membered heterocyclic ring; Wherein, the heteroalkyl group, heteroalkyl ring and aromatic heterocyclic ring each independently have 1-3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S.

2. The α-mangostin derivative as shown in formula I according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, When X is an oxygen atom, the α-mangostin derivative has a structure of the following formula (A), (B), (C) or (D): When X is NH, the α-mangostin derivative has the structure of the following formula (E): or The α-mangostin derivative has the structure of the following formula (F):

3. The α-mangostin derivative as shown in Formula I as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is independently hydroxyl, -C(O)X'R8 or -X'C(O)R9, C2-C6 unsaturated alkyl, C2-C6 unsaturated heteroalkyl, -(CH=CH)-CORa, -(C1-C3 alkylene)-(CH=CH)-CORa, -O-(C1-C3 alkylene)-(CH=CH)-CORa, -OCO-(CH=CH)-CORa, -OCO-(C1-C3 alkylene)-(CH=CH)-CORa, wherein Ra is -ORd.

4. The α-mangostin derivative as shown in formula I as claimed in claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 and R3 are each independently a hydrogen atom, a halogen, a hydroxyl group, a cyano group, -C(O)X'R8 or -X'C(O)R9, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 saturated heteroalkyl group, a substituted or unsubstituted C2-C6 unsaturated alkyl group, a substituted or unsubstituted C2-C6 unsaturated heteroalkyl group, a substituted or unsubstituted 3-8 membered alkyl ring group, a substituted or unsubstituted 5-8 membered monocyclic heteroalkyl ring group, a substituted or unsubstituted 9-12 membered fused heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, a substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group, or L-R'.

5. The α-mangostin derivative as shown in formula I according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, When R2=R3=H and R1 is hydroxyl, R is -X-Rg or -CH=CH-R6, in, X is NH, O, and Rg is independently selected from R4 is independently a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted 3-8-membered alkyl ring group, a -(C1-C3 alkylene)-substituted or unsubstituted 3-8-membered alkyl ring, a substituted or unsubstituted 3-8-membered heteroalkyl ring group, or a -(C1-C3 alkylene)-substituted or unsubstituted 3-8-membered heteroalkyl ring; R5 is independently a substituted 5-10 membered aryl group, a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; wherein the substitution refers to substitution by 1-2 Rh and 0-2 Ri; wherein Rh is independently selected from hydroxyl, cyano, C1-C6 haloalkyl, substituted or unsubstituted 3-8 membered monocyclic heteroalkyl ring group, substituted or unsubstituted 6-8 membered bridged heteroalkyl ring group, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-8 membered monocyclic aromatic heterocycle, substituted or unsubstituted 9-12 membered fused aromatic heterocycle, -Z-substituted or unsubstituted 3-8 membered heteroalkyl ring, Ri is independently selected from halogen, hydroxyl, cyano, amino, amine, -C(O)X'R8 or -X'C(O)R9, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, substituted or unsubstituted 3-12 membered heteroalkyl ring group, Z is NH, S or SO2, -C1-C6 alkylene, -O-C1-C6 alkylene; R6 is independently a substituted or unsubstituted 3-8 membered monocyclic heteroalkyl ring group, a substituted or unsubstituted 6-8 membered bridged heteroalkyl ring group, a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, or a substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group; R7 is independently selected from a substituted or unsubstituted 3-8 membered monocyclic heteroalkyl ring group, a substituted or unsubstituted 6-8 membered bridged heteroalkyl ring group, a substituted or unsubstituted 5-8 membered monocyclic aromatic heterocyclic group, a substituted or unsubstituted 9-12 membered fused aromatic heterocyclic group; n is an integer selected from 2 to 20; When R2=R3=H and R1 is not hydroxyl, R is -X-Rg, Where X is O, Rg is R4 is independently C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring group, -(C1-C3 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring group; R5 is independently a substituted or unsubstituted 5-10 membered aryl group, or a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; When R2 and R3 are not H at the same time and R1 is hydroxyl, R is -X-Rg, Wherein, X is O, Rg is independently selected from hydrogen atom, -C(O)X'R8 or -X'C(O)R9, Or Rg and R3 and their adjacent X together form a substituted or unsubstituted 5-8 membered heteroalkyl ring or a 5-8 membered aromatic heterocyclic ring; R4 is independently C1-C3 alkyl, substituted or unsubstituted 3-8 membered alkyl ring, -(C1-C3 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring; R5 is independently C1-C3 alkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 3-12 membered aromatic heterocyclic group; R6 is independently a substituted or unsubstituted 5-10 membered aryl group, or a substituted or unsubstituted 3-12 membered aromatic heterocyclic group; When R2 and R3 are not H at the same time and R1 is not hydroxyl, R is -X-Rg, Wherein, X is O, and Rg is independently selected from -C(O)X'R8 or -X'C(O)R9, -(C1-C20 alkylene)-C(O)X'R8 or -(C1-C20 alkylene)-X'C(O)R9, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered alkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 3-8 membered heteroalkyl ring, -(C1-C20 alkylene)-substituted or unsubstituted 5-10 membered aromatic ring , -(C1-C20 alkylene)-substituted or unsubstituted 3-12 membered aromatic heterocycle, -CO-CH2-substituted or unsubstituted 3-8 membered alkane ring, -CO-CH2-substituted or unsubstituted 3-8 membered heteroalkane ring, -CO-CH2-substituted or unsubstituted 5-10 membered aromatic ring, -CO-CH2-substituted or unsubstituted 3-12 membered aromatic heterocycle, or Rg and R3 and their adjacent X together constitute a substituted or unsubstituted 5-6 membered aromatic heterocycle or a 5-6 membered heteroalkane ring.

6. The α-mangostin derivative as shown in formula I according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, characterized in that: R1, R2, R3, and R are each independently a corresponding group of compound 1-74.

7. The α-mangostin derivative as shown in formula I according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The α-mangostin derivative has a structure as shown in any one of Formulas 1 to 74:

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (a) a therapeutically effective amount of an α-mangostin derivative represented by formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof; and (b) a pharmaceutically acceptable carrier.

9. The use of an α-mangostin derivative represented by formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, characterized in that: Used for preparing medicines for treating cardiovascular and cerebrovascular diseases, nervous system diseases, and / or inflammatory diseases.

10. The use according to claim 9, characterized in that The cardiovascular and cerebrovascular diseases include, but are not limited to, ischemic cerebrovascular disease, transient ischemic attack, ischemic stroke (cerebral infarction), lacunar cerebral infarction, myocardial infarction, myocardial ischemia, heart failure, atherosclerosis, arterial restenosis, atherosclerosis, and arterial embolism; The nervous system diseases include, but are not limited to, cerebrovascular diseases, neurodegenerative diseases, and more specifically include stroke, ischemic stroke, vascular dementia, cerebral palsy, dementia, concussion, brain injury, brain reperfusion injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and multiple system atrophy (MSA); The inflammatory diseases include, but are not limited to, proliferative inflammation, asthma, COPD and pulmonary fibrosis, psoriasis, inflammatory arthritis, rheumatoid arthritis, sepsis, septic shock, inflammatory bowel disease (IBD, which includes ulcerative colitis and Crohn's disease), nephritis, cystic fibrosis, keratosis, rheumatoid spondylitis, and osteoarthritis.

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