Heterocyclic compound, preparation method therefor and application thereof

Abstract

The present invention relates to a heterocyclic compound, a pharmaceutical composition comprising same, and a preparation method for the heterocyclic compound, and further relates to a use of the compound in the preparation of a drug for treating thromboembolic diseases.

Description

[Corrected 03.01.2025 according to Rule 26] Heterocyclic compounds and their preparation methods and applications [Corrected 03.01.2025 according to Rule 26] Technical field

[0001] [Corrected 03.01.2025 according to Rule 26] The present invention belongs to the field of medicine, and in particular relates to heterocyclic compounds, pharmaceutical compositions containing the same and methods for preparing the same, and also relates to the use of such compounds in the preparation of drugs for treating thromboembolic diseases. [Corrected 03.01.2025 according to Rule 26] Background Art

[0002] [Corrected 03.01.2025 according to Rule 26] Stroke is an acute cerebrovascular disease, including ischemic and hemorrhagic stroke, of which the incidence of ischemic stroke accounts for about 80% of all stroke cases (International Journal of Cardiology, 2016, 222, 441-447).

[0003] [Corrected 03.01.2025 according to Rule 26] For nearly two decades, intravenous tissue plasminogen activator (t-PA), a high molecular weight compound, has been the only recommended treatment for ischemic stroke. However, t-PA has a short therapeutic window (<4.5 hours) and carries the risk of promoting intracerebral hemorrhage (New England Journal of Medicine, 2008, 48(13), 1634-1635). Recombinant tissue plasminogen activator (rt-PA) has a half-life of only 3-5 minutes and requires continuous intravenous infusion. Moreover, for stroke caused by acute large vessel occlusion, the recanalization rate after intravenous rt-PA thrombolysis does not exceed 25% (Stroke, 2010, 41, 2254-2258).

[0004] [Corrected 03 / 01 / 2025 according to Rule 26] The SMTP series of compounds are a series of triprenylphenol (TP) compounds produced and purified from the culture broth of the filamentous fungus Stachybotrys microspora through microbial fermentation (JP2002065288A). These compounds, such as orniplabin, are known to be plasminogen regulators. By relaxing the plasminogen conformation, they can accelerate plasminogen activation mediated by urokinase-type plasminogen activator (u-PA) or t-PA, rapidly elevating plasmin levels and promoting the dissolution of thrombi by plasmin (The FEBS Journal, 2010, 277, 3675-3687). Since the SMTP series of compounds do not directly activate plasminogen and do not affect the levels of u-PA or t-PA, they mechanistically avoid the adverse risk of cerebral hemorrhage caused by thrombolytic drugs with traditional mechanisms of action (Naunyn-Schmiedeberg's Archives of Pharmacology, 2010, 382, ​​245–253). In addition to the plasminogen conformational regulation function, the SMTP series of compounds also have soluble epoxide hydrolase (sEH) inhibitory activity independent of their thrombolytic activity. sEH is a bifunctional enzyme that participates in important physiological activities such as inflammatory response and lipid metabolism (Journal of Biological Chemistry, 2014, 289(52), 35826-35838). The inhibitory effect of SMTP compounds on sEH may be related to their anti-inflammatory activity in vivo (International Journal of Molecular Sciences, 2021, 22, 954). Improved plasminogen regulators with better biological activity based on the SMTP series of compounds deserve further study, and it is very necessary to develop thrombolytic drugs with new mechanisms, extended treatment time windows, and reduced bleeding risks.

[0005] [Corrected 03.01.2025 in accordance with Rule 26] Summary of the Invention

[0006] [Corrected 03.01.2025 according to Rule 26] Through extensive research, we surprisingly discovered a class of heterocyclic compounds and their preparation methods. These compounds have good plasminogen regulatory activity, can promote thrombolysis and have anti-inflammatory effects, and are used to treat various thromboembolic diseases, such as ischemic stroke.

[0007] [Corrected 03.01.2025 in accordance with Rule 26] In one aspect, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled form, metabolite, prodrug, or mixture thereof:

[0008] [Corrected 03.01.2025 in accordance with Rule 26] Among them,

[0009] [Corrected 03.01.2025 according to Rule 26] Y is selected from

[0010] [Corrected 03.01.2025 according to Rule 26] R1 and R3 are each independently selected from carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl acyloxy, C 1- 6-alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkylaminosulfonyloxy, C 4-10 Heterocyclic sulfonyloxy, sugar group, -OP(O)(OH)2, -OP(O)2OH, -OS(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkyl amido, C 4-10 Heterocyclic amido, halogen, cyano, C 2-6 Alkenyl and C 2-6 Alkynyl; the C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkyl acyloxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylaminoacyloxy is optionally substituted by one or more groups selected from hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxyacyloxy, 4-10 membered heterocyclic group, C 1-6 Substituted with a hydroxyalkyl group or a -OP(O)(OH)2 substituent;

[0011] [Corrected 03.01.2025 according to Rule 26] R2 and R4 are each independently selected from hydrogen, hydroxyl, carboxyl, ester, C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl acyloxy, -OC(=O)-C 4-10 heterocyclic, -OP(O)2OH, -OS(O)2OH and -OS(O)2NH2, the C 4-10 The heterocyclic group is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent;

[0012] [Corrected 03.01.2025 according to Rule 26] When Y is selected from When R1 and R2 are not hydroxyl groups at the same time;

[0013] [Corrected 03.01.2025 in accordance with Rule 26] n = 0, 1, 2, 3, 4 or 5;

[0014] [Corrected 03.01.2025 according to Rule 26] X is selected from -CO2H and its carboxylic acid isosteres, -CO2C 1-6 Alkyl, -C(=O)SH, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1- 6-alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 Alkyl, the -CO2C 1-6 Alkyl, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 The alkyl group is optionally substituted with one or more selected from C 4-10 Heterocyclic group, C 1-6 Alkoxy, Substituents substituted by

[0015] [Corrected 03.01.2025 according to Rule 26] When X is -CO2H, R1, R2, R3 and R4 are not all hydroxyl groups;

[0016] [Corrected 03.01.2025 according to Rule 26] Indicates the point of attachment to the rest of the molecule.

[0017] [Corrected 03.01.2025 according to Rule 26] On the other hand, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled, metabolite, prodrug or mixture thereof and one or more pharmaceutically acceptable carriers, and optionally further comprising one or more other drugs for treating thromboembolic diseases.

[0018] [Corrected 03.01.2025 in accordance with Rule 26] On the other hand, the present invention relates to the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled, metabolite, prodrug or mixture thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for the treatment of thromboembolic diseases.

[0019] [Corrected 03.01.2025 in accordance with Rule 26] In another aspect, the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled, metabolite, prodrug or mixture thereof or a pharmaceutical composition of the present invention for use in the treatment of thromboembolic diseases.

[0020] [Corrected 03.01.2025 in accordance with Rule 26] On the other hand, the present invention relates to a method for treating thromboembolic diseases, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled, metabolite, prodrug or mixture thereof, or a pharmaceutical composition of the present invention.

[0021] [Corrected 03.01.2025 according to Rule 26] In another aspect, the present invention relates to a process for preparing a compound of the present invention, comprising the steps shown in the following scheme:

[0022] [Corrected 03.01.2025 in accordance with Rule 26] Of which:

[0023] [Corrected 03.01.2025 under Rule 26] R1, R2 and Y are as defined above; and

[0024] [Corrected 03.01.2025 according to Rule 26] LG is a leaving group. [Corrected 03.01.2025 in accordance with Rule 26]

[0025] [Corrected 03.01.2025 according to rule 26] Figure 1: Thromboelastogram of compound 2-1 and 2-2 groups.

[0026] [Corrected 03.01.2025 according to rule 26] Figure 2: Thromboelastogram of compound 2-5 groups.

[0027] [Corrected 03.01.2025 according to rule 26] Figure 3: Thromboelastogram of compound 2-5 and 2-6 groups.

[0028] [Corrected 03.01.2025 in accordance with Rule 26] Detailed Description of the Invention

[0029] [Corrected 03.01.2025 according to Rule 26] Compounds and preparation methods

[0030] [Corrected 03.01.2025 according to Rule 26] An object of the present invention is to provide a compound of formula I or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug or mixture thereof,

[0031] [Corrected 03.01.2025 in accordance with Rule 26] Among them,

[0032] [Corrected 03.01.2025 according to Rule 26] Y is selected from

[0033] [Corrected 03.01.2025 according to Rule 26] R1 and R3 are each independently selected from carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl acyloxy, C 1- 6-alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkylaminosulfonyloxy, C 4-10 Heterocyclic sulfonyloxy, sugar group, -OP(O)(OH)2, -OP(O)2OH, -OS(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkyl amido, C 4-10 Heterocyclic amido, halogen, cyano, C 2-6 Alkenyl and C 2-6 Alkynyl; the C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkyl acyloxy, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkylaminoacyloxy is optionally substituted by one or more groups selected from hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxyacyloxy, 4-10 membered heterocyclic group, C 1-6 Substituted with a hydroxyalkyl group or a -OP(O)(OH)2 substituent;

[0034] [Corrected 03.01.2025 according to Rule 26] R2 and R4 are each independently selected from hydrogen, hydroxyl, carboxyl, ester, C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl acyloxy, -OC(=O)-C 4-10 heterocyclic, -OP(O)2OH, -OS(O)2OH and -OS(O)2NH2, the C 4-10 The heterocyclic group is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent;

[0035] [Corrected 03.01.2025 according to Rule 26] When Y is selected from When R1 and R2 are not hydroxyl groups at the same time;

[0036] [Corrected 03.01.2025 in accordance with Rule 26] n = 0, 1, 2, 3, 4 or 5;

[0037] [Corrected 03.01.2025 according to Rule 26] X is selected from -CO2H and its carboxylic acid isosteres, -CO2C 1-6 Alkyl, -C(=O)SH, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1- 6-alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 Alkyl, the -CO2C 1-6 Alkyl, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 The alkyl group is optionally substituted with one or more selected from C 4-10 Heterocyclic group, C 1-6 Alkoxy, Substituents substituted by

[0038] [Corrected 03.01.2025 according to Rule 26] When X is -CO2H, R1, R2, R3 and R4 are not all hydroxyl groups;

[0039] [Corrected 03.01.2025 according to Rule 26] Indicates the point of attachment to the rest of the molecule.

[0040] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, R1 and R3 are each independently selected from carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl acyloxy, C 1-6 Alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkylaminosulfonyloxy, C 4-10 Heterocyclic sulfonyloxy, sugar group, -OP(O)(OH)2, -OP(O)2OH, -OS(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkyl amido, C 4-10 Heterocyclic amido, halogen, cyano, C 2-6 Alkenyl and C 2-6 Alkynyl; the C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkyl acyloxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylaminoacyloxy is optionally substituted by one or more groups selected from hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl-C(=O)-, 4-10 membered heterocyclic group, C 1-6 The group may be substituted with a hydroxyalkyl group or a -OP(O)(OH)2 substituent.

[0041] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, n=1, 2, 3, 4 or 5.

[0042] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, R1 and R2 are not both hydroxyl groups.

[0043] [Corrected 03.01.2025 according to Rule 26] Another object of the present invention is to provide a compound having the structure of Formula I or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled form, metabolite, prodrug or mixture thereof:

[0044] [Corrected 03.01.2025 in accordance with Rule 26] Among them,

[0045] [Corrected 03.01.2025 according to Rule 26] Y is selected from

[0046] [Corrected 03.01.2025 according to Rule 26] R1 and R3 are each independently selected from hydroxyl, C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl acyloxy, C 1-6 Alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclyl acyloxy, C 1-6 Alkylaminosulfonyloxy, C 4-10 Heterocyclic sulfonyloxy, sugar group, -OP(O)2OH, -OS(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkyl amido, C 4-10 Heterocyclic amido, halogen, cyano, C 2-6 Alkenyl and C 2-6 Alkynyl; preferably, R1 is selected from C 1-6 Alkylaminoacyloxy and C 4-10 Heterocyclyl acyloxy; R3 are each independently selected from hydrogen, hydroxy, alkoxy and carboxyl;

[0047] [Corrected 03.01.2025 according to Rule 26] R2 and R4 are each independently selected from hydrogen, hydroxyl, carboxyl, ester, C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl acyloxy, -OP(O)2OH and -OS(O)2OH; preferably, R2 is hydroxyl, and R4 is selected from carboxyl and ester groups;

[0048] [Corrected 03.01.2025 according to Rule 26] R1 and R2 are not both hydroxyl groups;

[0049] [Corrected 03.01.2025 in accordance with Rule 26] n = 1, 2, 3, 4 or 5;

[0050] [Corrected 03.01.2025 according to Rule 26] X is selected from -CO2H and its carboxylic acid isosteres, -CO2C 1-6 Alkyl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl and -C(=O)NHS(=O)2C 1-6 Alkyl; preferably, X is -CO2H,

[0051] [Corrected 03.01.2025 according to Rule 26] Indicates the point of attachment to the rest of the molecule.

[0052] [Corrected 03.01.2025 according to Rule 26] Another object of the present invention is to provide a compound having the structure of Formula I or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled form, metabolite, prodrug or mixture thereof:

[0053] [Corrected 03.01.2025 in accordance with Rule 26] Among them,

[0054] [Corrected 03.01.2025 according to Rule 26] Y is selected from

[0055] [Corrected 03.01.2025 according to Rule 26] R1 and R3 are selected from carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl acyloxy, C 1-6 Alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkylaminosulfonyloxy, C 4-10 Heterocyclic sulfonyloxy, sugar group, -OP(O)(OH)2, -OP(O)2OH, -OS(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkyl amido, C 4-10 Heterocyclic amido, halogen, cyano, C 2-6 Alkenyl and C 2-6 Alkynyl; the C 4-10 Heterocyclyl acyloxy, -OC 4-10Heterocyclic group, C 1-6 Alkyl acyloxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylaminoacyloxy is optionally substituted by one or more groups selected from hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl-C(=O)-, 4-10 membered heterocyclic group, C 1-6 Substituted with a hydroxyalkyl group or a -OP(O)(OH)2 substituent;

[0056] [Corrected 03.01.2025 according to Rule 26] R2 and R4 are selected from hydrogen, hydroxyl, carboxyl, ester, C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl acyloxy, -OC(=O)-C 4-10 heterocyclic, -OP(O)2OH, -OS(O)2OH and -OS(O)2NH2, the C 4-10 The heterocyclic group is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent;

[0057] [Corrected 03.01.2025 according to Rule 26] R1 and R2 are not both hydroxyl groups;

[0058] [Corrected 03.01.2025 in accordance with Rule 26] n = 1, 2, 3, 4 or 5;

[0059] [Corrected 03.01.2025 according to Rule 26] X is selected from -CO2H and its carboxylic acid isosteres, -CO2C 1-6 Alkyl, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 Alkyl, the -CO2C 1-6 Alkyl, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 The alkyl group is optionally substituted with one or more selected from C 4-10 Heterocyclic group, C 1-6 Alkoxy, Substituents substituted by

[0060] [Corrected 03.01.2025 according to Rule 26] Indicates the point of attachment to the rest of the molecule.

[0061] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, the compound of formula I of the present invention is a compound of formula II:

[0062] [Corrected 03.01.2025 in accordance with Rule 26] Among them,

[0063] [Corrected 03.01.2025 according to Rule 26] R1, R2, R3, R4, X are as defined above for the compound of formula I, and

[0064] [Corrected 03.01.2025 according to Rule 26] When X is -CO2H, R1, R2, R3 and R4 are not all hydroxyl groups.

[0065] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R1 and R3 are each independently selected from carboxyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 4-10 Heterocyclylsulfonyloxy, -OP(=O)(OH)2, -OS(O)2OH and C 4-10 Heterocyclylamido; the C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkylaminoacyloxy is optionally substituted by one or more groups selected from hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkoxycarbonyl, C 1-6 Alkyl-C(=O)-, 4-10 membered heterocyclic group, C 1-6 The group may be substituted with a hydroxyalkyl group or a -OP(=O)(OH)2 substituent.

[0066] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R1 and R3 are each independently selected from carboxyl, hydroxyl, C 1-3 Alkoxy, C 1-3 Alkoxyacyloxy, C 1-3 Alkylaminoacyloxy, C4-8 Heterocyclyl acyloxy, -OC 4-8 Heterocyclic group, C 4-8 Heterocyclylsulfonyloxy, -OP(=O)(OH)2, -OS(O)2OH and C 4-8 Heterocyclylamido; the C 4-8 Heterocyclyl acyloxy, -OC 4-8 Heterocyclic group, C 1-3 Alkylaminoacyloxy is optionally substituted by one or more groups selected from hydroxy, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxyacyloxy, C 1-3 Alkoxycarbonyl, C 1- 3-alkyl-C(=O)-, 4-8-membered heterocyclic group, C 1-3 The group may be substituted with a hydroxyalkyl group or a -OP(=O)(OH)2 substituent.

[0067] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of formula I and formula II, R1 and R3 are each independently selected from carboxyl, hydroxyl, -OC(=O)N(CH3)2, -OC(=O)-morpholinyl, -OC(=O)NHCH(CH3)2, -OC(=O)OCH3, -OC(=O)-thiomorpholine dioxide, -OC(=O)-thiomorpholine monooxide, -OC(=O)-thiomorpholine, -OC(=O)N(CH3)-tetrahydropyran, -OC(=O)-piperidine, -OSO2-morpholine, -OC(=O)-piperazine, -O-tetrahydropyran, -OP(=O)(OH)2, methoxy, glucopyranosyl and -OS(O)2OH, wherein the -OC(=O)-piperidine, -OC(=O)-piperazine, -O-tetrahydropyran, methoxy are optionally substituted with one or more substituents selected from hydroxy, carboxyl, CH3OC(=O)-, -C(=O)CH3, -OCH3, piperidinyl, morpholinyl, hydroxy, -CH2OH, -OP(=O)(OH)2 and oxo, wherein the wavy line Indicates the point of attachment to the rest of the molecule.

[0068] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of formula I and formula II, R1 and R3 are each independently selected from carboxyl, hydroxyl, -OC(=O)N(CH3)2, -OC(=O)-morpholinyl, -OC(=O)NHCH(CH3)2, -OC(=O)OCH3, -OC(=O)-thiomorpholine dioxide, -OC(=O)-thiomorpholine monooxide, -OC(=O)-thiomorpholine, -OC(=O)N(CH3)-tetrahydropyran, -OC(=O)-piperidine, -OSO2-morpholine, -OC(=O)-piperazine, -O-tetrahydropyran, -OP(=O)(OH)2, methoxy and -OS(O)2OH, wherein -OC(=O)-piperidine, -OC(=O)-piperazine, -O-tetrahydropyran, methoxy are optionally substituted with one or more substituents selected from hydroxy, carboxyl, CH3OC(=O)-, -C(=O)CH3, -OCH3, piperidinyl, morpholinyl, hydroxy, -CH2OH and -OP(=O)(OH)2.

[0069] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of formula I and formula II, R1 and R3 are each independently selected from carboxyl, hydroxyl, -OC(=O)N(CH3)2, -OC(=O)NHCH(CH3)2, -OC(=O)OCH3, -OP(=O)(OH)2, methoxy, -OS(O)2OH, The wavy line Indicates the point of attachment to the rest of the molecule.

[0070] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R1 and R3 are each independently selected from hydroxyl, C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl acyloxy, C 1-6 Alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-6 Heterocyclyl acyloxy, C 1-6 Alkylaminosulfonyloxy, C 4-6 Heterocyclic sulfonyloxy, sugar group, -OP(O)2OH, -OS(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkyl amido, C 4-6 Heterocyclic amido, halogen, cyano, C 2-6 Alkenyl and C2-6 Alkynyl.

[0071] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R1 and R3 are each independently selected from C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl acyloxy, C 1-6 Alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-6 Heterocyclyl acyloxy, C 1-6 Alkylaminosulfonyloxy, C 4-6 Heterocyclic sulfonyloxy, sugar group, -OP(O)2OH, -OS(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkyl amido, C 4-6 Heterocyclic amido, halogen, cyano, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0072] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R1 and R3 are each independently selected from C 1-6 Alkylaminoacyloxy and C 4-6 Heterocyclyloxy.

[0073] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of formula I and formula II, R1 and R3 are each independently selected from -OC(=O)N(CH3)2, -OC(=O)-piperidine ring, -OC(=O)-morpholine ring, -OC(=O)-thiomorpholine, -OC(=O)-thiomorpholine dioxide, -OC(=O)-thiomorpholine monooxide, -OC(=O)NHCH(CH3)2 and -OC(=O)CH3.

[0074] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of formula I and formula II, R1 and R3 are each independently selected from -OC(=O)N(CH3)2, -OC(=O)-morpholine ring, -OC(=O)NHCH(CH3)2 and -OC(=O)CH3.

[0075] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R2 and R4 are each independently selected from hydrogen, carboxyl, hydroxyl, C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl acyloxy, -OC(=O)-C4-10 heterocyclic, -OP(O)2OH, -OS(O)2OH and -OS(O)2NH2, the C 4- 10 The heterocyclic group is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent.

[0076] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R2 and R4 are each independently selected from hydrogen, hydroxyl, C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl acyloxy, -OC(=O)-C 4-10 heterocyclic, -OP(O)2OH, -OS(O)2OH and -OS(O)2NH2, the C 4-10 The heterocyclic group is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent.

[0077] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R2 and R4 are each independently selected from carboxyl, hydroxyl, C 1-6 Alkoxy, carboxyl substituted C 1-6 alkylacyloxy, -OC(=O)-piperazinyl, -OP(O)2OH, -OS(O)2OH and -OS(O)2NH2, wherein the piperazine is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent.

[0078] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R2 and R4 are each independently selected from carboxyl, hydroxyl, and -OS(O)2NH2, where the wavy line Indicates the point of attachment to the rest of the molecule.

[0079] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R2 and R4 are each independently selected from hydroxyl, and -OS(O)2NH2.

[0080] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R2 and R4 are each independently selected from hydrogen, hydroxyl, C 1-6 Alkoxy, carboxyl substituted C 1-6Alkyl acyloxy, -OP(O)2OH, -OS(O)2OH, -OS(O)2NH2; preferably, R2 and R4 are each independently hydroxyl.

[0081] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, R2 and R4 are each independently selected from hydrogen, hydroxyl, C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl acyloxy, -OP(O)2OH and -OS(O)2OH; preferably, R2 and R4 are each independently hydroxyl.

[0082] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, X is selected from -CO2H and its carboxylic acid isosteres, -CO2C 1-6 Alkyl, -C(=O)SH, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 Alkyl, the -CO2C 1-6 Alkyl, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 The alkyl group is optionally substituted with one or more selected from 4-10 membered heterocyclic groups, and -C 1-6 Alkoxy is substituted with a wavy line Indicates the point of attachment to the rest of the molecule.

[0083] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, X is selected from -CO2H and its carboxylic acid isosteres, -CO2C 1-6 Alkyl, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 Alkyl, the -CO2C 1-6 Alkyl, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C1-6 The alkyl group is optionally substituted with one or more selected from 4-10 membered heterocyclic groups, Substituents, where the wavy line Indicates the point of attachment to the rest of the molecule.

[0084] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, X is selected from -CO2H, -C(=O)SH, -CO2C 1-6 Alkyl, -C(=O)SH, tetrazolyl, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl and -C(=O)NHS(=O)2N(C 1-6 Alkyl)2, the -CO2C 1-6 Alkyl and -C(=O)NHC 1-6 Alkyl groups are each optionally selected from morpholinyl and -C 1-6 Alkoxy is substituted with a wavy line Indicates the point of attachment to the rest of the molecule.

[0085] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, X is selected from -CO2H, -C(=O)NHCH3, -C(=O)SH, The wavy line Indicates the point of attachment to the rest of the molecule.

[0086] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, X is selected from -CO2H, -CO2C 1-3 Alkyl, 5-6 membered nitrogen-containing heterocyclic group, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-3 Alkylamino and -C(=O)NHS(=O)2C 1-3 Alkyl, the -CO2C 1- 3 alkyl, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-3 Alkylamino and -C(=O)NHS(=O)2C 1-3 The alkyl group is optionally substituted with one or more selected from 4-6 membered heterocyclic groups, substituted by a substituent.

[0087] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, X is selected from -CO2H, a 5-6 membered nitrogen-containing heterocyclic group, -C(=O)NHS(=O)2N(CH3)2, -C(=O)NHS(=O)2CH3, -CO2CH2CH3, -CO2CH3, -CO2CH2CH3, -C(=O)NHCH2CH2OCH3, -C(=O)NHCH3 and tetrazole, and the -CO2CH2CH3, -CO2CH3, -CO2CH2CH3 are optionally replaced by one or more selected from morpholinyl, substituted by a substituent.

[0088] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, n=1, 2, 3 or 4.

[0089] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, n=1, 2 or 3.

[0090] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compounds of Formula I and Formula II, n=1 or 2.

[0091] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, in the compound of formula II, R1 and R3 are each independently selected from hydroxyl, -OC(=O)N(CH3)2,

[0092] [Corrected 03.01.2025 according to Rule 26] R2 and R4 are selected from hydroxyl groups;

[0093] [Corrected 03.01.2025 according to Rule 26] X is -CO2H, and R1, R2, R3 and R4 are not hydroxyl groups at the same time.

[0094] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, the compound of formula I is selected from:

[0095] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, the compound of formula II is selected from:

[0096] [Corrected 03.01.2025 according to Rule 26] Another object of the present invention is to provide a method for preparing the compound of formula I of the present invention, which comprises the steps shown in the following scheme:

[0097] [Corrected 03.01.2025 in accordance with Rule 26] Of which:

[0098] [Corrected 03.01.2025 in accordance with Rule 26] R1, R2 and Y are as defined above for the compound of formula I; and

[0099] [Corrected 03.01.2025 according to Rule 26] LG is a leaving group.

[0100] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, the leaving group includes but is not limited to halogen, C 1-6 Alkyl acyloxy, nitrophenoxy, fluorophenoxy.

[0101] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, the leaving group includes but is not limited to fluorine, chlorine, bromine, iodine, acetoxy, p-nitrophenoxy, and p-fluorophenoxy.

[0102] [Corrected 03.01.2025 according to Rule 26] When R1 is selected from C 1-6 Alkylaminoacyloxy or C 4-6 When the compound is a heterocyclic acyloxy group, the compound of formula I of the present invention can be synthesized by the following synthetic route.

[0103] [Corrected 03.01.2025 according to Rule 26] Route 1: Compound I-SM-1 is subjected to condensation reaction with an alkylamino acid chloride or a heterocyclic acid chloride to obtain a compound of formula I.

[0104] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out at a temperature of 0-140°C, such as 0°C, 20°C, 25°C, 40°C, 50°C, 60°C, 100°C, 140°C, preferably 0-35°C.

[0105] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out in a suitable organic solvent, which can be selected from halogenated hydrocarbons (such as dichloromethane (DCM), chloroform (TCM), 1,2-dichloroethane (1,2-DCE)), nitriles (such as acetonitrile (AN), etc.), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), 1,4-dioxane (Dioxane), dimethyl sulfoxide (DMSO) and any combination thereof, preferably tetrahydrofuran (THF).

[0106] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out in the presence of a suitable base, which includes an organic base or an inorganic base. The organic base can be selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), potassium tert-butoxide (t-BuOK) and pyridine (Py); the inorganic base can be selected from potassium phosphate (K3PO4), sodium hydride (NaH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), cesium carbonate (Cs2CO3) and NaOH, preferably NaH.

[0107] [Corrected 03.01.2025 according to Rule 26] Route 2: Compound I-SM-1 is reacted with isocyanate to obtain a compound of formula I.

[0108] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out at a temperature of 0-140°C, such as 0°C, 20°C, 25°C, 40°C, 50°C, 60°C, 100°C, 140°C, preferably 25°C.

[0109] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out in a suitable organic solvent, which can be selected from halogenated hydrocarbons (such as dichloromethane (DCM), chloroform (TCM), 1,2-dichloroethane (1,2-DCE)), nitriles (such as acetonitrile (AN), etc.), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), 1,4-dioxane (Dioxane), dimethyl sulfoxide (DMSO) and any combination thereof, preferably N,N-dimethylformamide (DMF).

[0110] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out in the presence of a suitable base, which includes an organic base or an inorganic base. The organic base can be selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), potassium tert-butoxide (t-BuOK) and pyridine (Py); the inorganic base can be selected from potassium phosphate (K3PO4), sodium hydride (NaH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), cesium carbonate (Cs2CO3) and NaOH, preferably N,N-diisopropylethylamine (DIPEA) and triethylamine (TEA).

[0111] [Corrected 03.01.2025 according to Rule 26] Another object of the present invention is to provide a method for preparing the compound of formula II of the present invention, which comprises the steps shown in the following scheme:

[0112] [Corrected 03.01.2025 in accordance with Rule 26] Of which:

[0113] [Corrected 03.01.2025 under Rule 26] R1, R3 and X are as defined above for the compound of formula II, and R1 and R3 are the same;

[0114] [Corrected 03.01.2025 in accordance with Rule 26] R2 and R4 are hydroxyl groups; and

[0115] [Corrected 03.01.2025 according to Rule 26] LG is a leaving group.

[0116] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, the leaving group includes but is not limited to halogen, C 1-6 Alkyl acyloxy, nitrophenoxy, fluorophenoxy.

[0117] [Corrected 03.01.2025 according to Rule 26] In certain embodiments, the leaving group includes but is not limited to fluorine, chlorine, bromine, iodine, acetoxy, p-nitrophenoxy, and p-fluorophenoxy.

[0118] [Corrected 03.01.2025 according to Rule 26] When R1 and R3 are each independently selected from C 1-6 Alkylaminoacyloxy or C 4-6 When the compound is a heterocyclic acyloxy group, the compound of formula II of the present invention can be synthesized by the following synthetic route.

[0119] [Corrected 03.01.2025 according to Rule 26] Route 1: Compound II-SM1 undergoes condensation reaction with alkylamino acid chloride or heterocyclic acid chloride to obtain compound II.

[0120] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out at a temperature of 0-140°C, such as 0°C, 20°C, 25°C, 40°C, 50°C, 60°C, 100°C, 140°C, preferably 0-35°C.

[0121] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out in a suitable organic solvent, which can be selected from halogenated hydrocarbons (such as dichloromethane (DCM), chloroform (TCM), 1,2-dichloroethane (1,2-DCE)), nitriles (such as acetonitrile (AN), etc.), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), 1,4-dioxane (Dioxane), dimethyl sulfoxide (DMSO) and any combination thereof, preferably tetrahydrofuran (THF).

[0122] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out in the presence of a suitable base, which includes an organic base or an inorganic base. The organic base can be selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), potassium tert-butoxide (t-BuOK) and pyridine (Py); the inorganic base can be selected from potassium phosphate (K3PO4), sodium hydride (NaH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), cesium carbonate (Cs2CO3) and NaOH, preferably NaH.

[0123] [Corrected 03.01.2025 according to Rule 26] Route 2: Compound II-SM1 is reacted with isocyanate to obtain a compound of formula II.

[0124] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out at a temperature of 0-140°C, wherein the temperature is 0°C, 20°C, 25°C, 40°C, 50°C, 60°C, 100°C, 140°C, preferably 25°C.

[0125] [Corrected 03.01.2025 according to Rule 26] In some embodiments, the reaction is carried out in a suitable organic solvent, which can be selected from halogenated hydrocarbons (such as dichloromethane (DCM), chloroform (TCM), 1,2-dichloroethane (1,2-DCE)), nitriles (such as acetonitrile (AN), etc.), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), 1,4-dioxane (Dioxane), dimethyl sulfoxide (DMSO) and any combination thereof, preferably N,N-dimethylformamide (DMF).

[0126] [Corrected 03.01.2025 according to Rule 26] In some embodiments, this step is carried out in the presence of a suitable base, which includes an organic base or an inorganic base. The organic base can be selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), potassium tert-butoxide (t-BuOK) and pyridine (Py); the inorganic base can be selected from potassium phosphate (K3PO4), sodium hydride (NaH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), cesium carbonate (Cs2CO3) and NaOH, preferably N,N-diisopropylethylamine (DIPEA) and triethylamine (TEA).

[0127] [Corrected 03.01.2025 in accordance with Rule 26] Definition

[0128] [Corrected 03.01.2025 in accordance with Rule 26] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meanings as commonly understood by those skilled in the art. References to technology used herein are intended to refer to technologies commonly understood in the art, including those variations or equivalents readily apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better illustrate the present invention.

[0129] [Corrected 03.01.2025 pursuant to Rule 26] The terms “comprising,” “including,” “having,” “involving,” or any other variations thereof are intended to cover a non-exclusive or open-ended inclusion. For example, a composition, method, or apparatus that comprises a list of elements is not necessarily limited to only the elements expressly listed but may also include other elements not expressly listed or inherent to such composition, method, or apparatus.

[0130] [Corrected 03.01.2025 in accordance with Rule 26] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are substantially non-toxic to living organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting the compounds of the present invention with pharmaceutically acceptable inorganic / organic acids or inorganic / organic bases. Such salts are also known as acid addition salts or base addition salts.

[0131] [Corrected 03.01.2025 according to rule 26] For a review of suitable salts, see Stahl and Wermuth "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0132] [Corrected 03.01.2025 in accordance with Rule 26] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to living organisms and that hydrolyzes in vivo to form a compound of the invention or a salt thereof. Pharmaceutically acceptable esters generally include, but are not limited to, esters of a compound of the invention with a pharmaceutically acceptable carboxylic acid or sulfonic acid, which are also referred to as carboxylate esters or sulfonate esters.

[0133] [Corrected 03.01.2025 according to Rule 26] The term “isomers” refers to compounds that have the same molecular weight due to having the same number of atoms and types of atoms but differ in the arrangement or configuration of the atoms in space.

[0134] [Corrected 03.01.2025 according to Rule 26] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular asymmetric plane due to at least one chiral factor (including a chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane-polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, enantiomers, and mixtures of diastereomers. Generally, these compounds can be prepared in the form of racemates. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). As described below, single stereoisomers of a compound can be synthesized from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, for example, by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds of a particular stereochemistry are either commercially available or can be prepared as described below and resolved by methods well known in the art. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomers" or "diastereomers" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

[0135] [Corrected 03.01.2025 in accordance with Rule 26] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted via a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include, but are not limited to, interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and amide-iminoalcohol isomerization. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0136] [Corrected 03.01.2025 in accordance with Rule 26] The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. Polymorphs of a molecule can be obtained by a number of methods known to those skilled in the art. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Furthermore, polymorphs can be detected, classified, and identified using well-known techniques, including, but not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction (SCXRD), solid-state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy, and scanning electron microscopy (SEM).

[0137] [Corrected 03.01.2025 in accordance with Rule 26] The term "solvate" refers to a compound of the invention (or a pharmaceutically acceptable salt thereof) bound to at least one solvent molecule by non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrates, monohydrates, dihydrates, and trihydrates), ethanolates, and acetonides.

[0138] [Corrected 03.01.2025 according to Rule 26] The term "isotopically labeled" refers to a derivative compound formed by replacing a specific atom in a compound of the present invention with an isotope thereof. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 S and 37 Cl. For example, 12 C can be 12 C. 13 C or 14 C substitution; 1 H can be 2 H (D, deuterium) or 3 H (T, tritium) substitution; 16 O can be 18 The present invention includes isotope-labeled compounds obtained by replacing any atom in the structure with its isotope.

[0139] [Corrected 03.01.2025 according to Rule 26] The term "metabolite" refers to a derivative compound formed after metabolism of a compound of the present invention. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9th ed.) [M], McGraw-Hill International Editions, 1996.

[0140] [Corrected 03.01.2025 in accordance with Rule 26] The term "prodrug" refers to a derivative compound that, upon administration to a subject, is capable of providing, directly or indirectly, a compound of the invention. Particularly preferred derivative compounds or prodrugs are compounds that, upon administration to a subject, can increase the bioavailability of the compound of the invention (e.g., facilitate absorption into the bloodstream) or enhance the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the invention are within the scope of the invention, and various prodrug forms are well known in the art.

[0141] [Corrected 03.01.2025 in accordance with Rule 26] The term "each independently" means that at least two groups (or ring systems) present in a structure with the same or similar value ranges may have the same or different meanings in specific circumstances. For example, if substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y may be either hydrogen, or halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X may be either hydrogen, or halogen, hydroxyl, cyano, alkyl, or aryl.

[0142] [Corrected 03.01.2025 according to Rule 26] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. For example, the term "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc.), which is optionally substituted with one or more (e.g., 1 to 3) substituents described herein (e.g., when substituted with halogen, the group is "C 1-6 -haloalkyl", such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, etc.).

[0143] [Corrected 03.01.2025 according to Rule 26] The term “C 1-6 Alkylamino" or "C 1-6 "Alkylamino" refers to -NH2 replaced by 1 or 2 C1-6 The group formed by alkyl substitution, i.e. -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2.

[0144] [Corrected 03.01.2025 according to Rule 26] The term "acyloxy" refers to -OC(=O)-.

[0145] [Corrected 03.01.2025 according to Rule 26] The term “C 1-6 "Alkyl acyloxy" refers to -OC(=O)-C 1-6 alkyl.

[0146] [Corrected 03.01.2025 according to Rule 26] The term “C 1-6 Alkylaminoacyloxy" or "C 1-6 "Alkylaminoacyloxy" refers to -OC(=O)-NH-C 1-6 Alkyl or -OC(=O)-N(C 1-6 Alkyl)2.

[0147] [Corrected 03.01.2025 according to Rule 26] The term “C 1-6 "Alkoxyacyloxy" refers to -OC(=O)-C 1-6 Alkoxy.

[0148] [Corrected 03.01.2025 according to Rule 26] The term “C 1-6 "Alkoxyalkylaminoacyloxy" refers to -OC(=O)-NH-alkyl-O-alkyl.

[0149] [Corrected 03.01.2025 according to Rule 26] The term “C 4-10 "Heterocyclyloxy" refers to -OC(=O)-C 4-10 Heterocyclic group.

[0150] [Corrected 03.01.2025 according to Rule 26] The term "sulfonyloxy" refers to -OS(=O)2-.

[0151] [Corrected 03.01.2025 according to Rule 26] The term “C 1-6 "Hydroxyalkyl" refers to -C 1-6 Alkylene-OH.

[0152] [Corrected 03.01.2025 under Rule 26] The term "alkoxy" refers to an "alkyl" or "cycloalkyl" group as defined above (e.g., C 1-6 Alkoxy, C 3-8Cycloalkyloxy, etc., including methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, cyclobutyloxy, n-pentoxy, isopentoxy, n-hexyloxy or isomers thereof). For example, the term "C 1-6 "Alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, tert-butoxy, etc.), which is optionally substituted by one or more (e.g., 1 to 3) substituents described herein (e.g., when substituted by halogen, the group is "C 1-6 -haloalkoxy", such as -OCF3, -OC2F5, etc.).

[0153] [Corrected 03.01.2025 according to Rule 26] The term “C 1-6 "Alkoxycarbonyl" refers to -C(=O)-OC 1-6 alkyl.

[0154] [Corrected 03.01.2025 according to Rule 26] The term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π electron system, which is optionally substituted by one or more substituents described herein (e.g., oxo, C 1-6 alkyl (methyl, ethyl) or halogen (fluorine, chlorine, bromine) substitution). For example, the term "C 6-10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms (e.g., phenyl, naphthyl, etc.).

[0155] [Corrected 03.01.2025 according to Rule 26] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic group having a conjugated π electron system, wherein the ring has one or more carbon atoms (e.g. 1, 2, 3, 4, 5, 6, 9 or 10 carbon atoms) and one or more (e.g. 2, 3 or 4) heteroatoms or heteroatom groups independently selected from O, S, N and NH, which are optionally substituted by one or more substituents described herein (e.g. oxo, C 1-6The heteroaryl group may be substituted with alkyl (methyl, ethyl) or halogen (fluoro, chloro, bromo) groups. The heteroaryl group may be attached to the parent molecular moiety through any ring atom if valence requirements are met. For example, the term "4-10 membered heteroaryl" as used in the present invention refers to a heteroaryl group having 4 to 10 ring atoms (e.g., thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or benzo derivatives thereof).

[0156] [Corrected 03.01.2025 according to Rule 26] The term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, usually containing about 2 to 20 carbon atoms. For example, the term "C 2-6 The term "alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms (e.g., ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-hexyl, etc.), which is optionally substituted by one or more (e.g., 1 to 3) substituents (e.g., halogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, aryloxy, alkoxyalkyl, alkylthio, amino, alkylacyloxy, arylacyloxy, cycloalkylacyloxy, carboxyl, alkoxycarbonyl, etc.).

[0157] [Corrected 03.01.2025 according to Rule 26] The term “C 2-6 "Alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms ("C 2-3 Alkynyl"). The C 2-6Alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 3-methylbut-2-ynyl, 3-methylbut-1-ynyl, 3-methylpent-2-ynyl, 3-methylpent-4 ...prop-2-ynyl, 3-methylprop-2-ynyl, 3-methylprop-2-ynyl, 3-methylpent-2-ynyl, 3-methylpent-4-ynyl, 3-methylpent-4-ynyl, 3-methylpent-4-ynyl, 3-methylpent-4-ynyl, 3-methylpent-4-ynyl, 3-methylpent-4-ynyl, 3-methylpent In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0158] [Corrected 03.01.2025 according to Rule 26] The term "heterocyclyl" means a 3- to 18-membered non-aromatic cyclic group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, such as C 4-10 Heterocyclic group, C 4-8Heterocyclyl, 4-12 membered heterocyclyl, 4-8 membered heterocyclyl, 5-6 membered heterocyclyl. The heterocyclyl may be saturated or unsaturated. Unless otherwise specified in this specification, the heterocyclyl may be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused ring system, a fused ring system, a bridged ring system or a spirocyclic system. For the purposes of this application, the heterocyclyl is preferably a 4 to 12 membered non-aromatic monocyclic or bicyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, such as a 4 to 7 membered non-aromatic monocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5 to 6 membered non-aromatic monocyclic group containing 1 to 2 heteroatoms selected from nitrogen and oxygen; or a 5-12 membered non-aromatic bicyclic group, including a fused bicyclic, a fused bicyclic, a bridged bicyclic or a spirocyclic ring. The nitrogen, carbon or sulfur atoms in the heterocyclic group may be optionally oxidized, for example, by oxo; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially unsaturated or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. Examples of heterocyclic groups include, but are not limited to, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, pyrazolyl, dihydropyrazolyl, piperazinyl, piperazinonyl, piperidinyl, pyrrolyl, pyrrolidinyl, oxazinyl, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolinyl, octahydroindolinyl, octahydroisoindolinyl, pyrazolidinyl, phthalimido, azabicyclo[3.1.0]hexanyl, azaspiro[2.4]heptanyl, and groups of the formula:

[0159] [Corrected 03.01.2025 in accordance with Article 26] Preferred are morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, thiomorpholinyl monooxide, piperidinyl, pyrrolidinyl, azetidinyl, dihydropyrazolyl, tetrahydropyranyl, piperazinyl, piperazinonyl, azabicyclo[3.1.0]hexanyl, azaspiro[2.4]heptanyl, and

[0160] [Corrected 03.01.2025 in accordance with Rule 26] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0161] [Corrected 03.01.2025 in accordance with Rule 26] The term “cyano” refers to a “—CN” group.

[0162] [Corrected 03.01.2025 in accordance with Rule 26] The term “hydroxy” refers to a “-OH” group.

[0163] [Corrected 03.01.2025 in accordance with Rule 26] The term “carboxyl” refers to a “—CO2H” group.

[0164] [Corrected 03.01.2025 in accordance with Rule 26] The term "substituted" means that one or more (e.g. 1, 2, 3 or 4) atoms (e.g. hydrogen atoms) or groups of atoms (e.g. triflate) in a specified group are replaced by other atoms or groups of atoms, provided that the specified group meets the valence requirements in the current case and a stable compound is formed after the substitution. Combinations of substituents and / or variables are permitted only if such combinations result in stable compounds. If a substituent is described as "optionally substituted by...", the substituent may be unsubstituted or substituted. If a first substituent is described as optionally substituted by one or more of the substituents listed in the second substituent list, one or more hydrogen atoms in the first substituent may be replaced individually or independently by one or more of the substituents listed in the second substituent list, or may be unsubstituted.

[0165] [Corrected 03.01.2025 according to Rule 26] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be attached to any ring atom in the ring.

[0166] [Corrected 03.01.2025 under Rule 26] The term “one or more” means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, as far as is reasonable.

[0167] [Corrected 03.01.2025 according to Rule 26] Solid lines may be used in this text Solid wedge or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0168] [Corrected 03.01.2025 in accordance with Rule 26] The term "carboxylic acid isosteres" refers to groups or substituents having physical and chemical properties similar to those of a carboxyl group, which may produce substantially similar, related, or opposite biological activities. These include, but are not limited to, hydroxamic acids, hydroxamates, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, sulfonylureas, acylureas, tetrazoles, thiazolidinones, and oxazolidinones.

[0169] [Corrected 03.01.2025 according to Rule 26] The term "glycosyl" refers to a class of compounds containing one or more tetrahydropyran or tetrahydrofuran structures, and such compounds are substituted by one or more -O-, hydroxyl, hydroxymethyl, carboxyl, amino, acetylamino groups, such as pyranosyl, furanosyl, etc.

[0170] [Corrected 03.01.2025 according to Rule 26] Pharmaceutical compositions, uses and methods of treatment

[0171] [Corrected 03.01.2025 according to Rule 26] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug or mixture thereof and one or more pharmaceutically acceptable carriers, and optionally further comprising one or more other drugs for treating thromboembolic diseases.

[0172] [Corrected 03.01.2025 according to Rule 26] A further object of the present invention is to provide a method for treating thromboembolic diseases, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0173] [Corrected 03.01.2025 according to Rule 26] Another object of the present invention is to provide use of the compound of the present invention or its pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug or mixture thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of thromboembolic diseases.

[0174] [Corrected 03.01.2025 according to Rule 26] Another object of the present invention is to provide the compound of the present invention or its pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug or mixture thereof or the pharmaceutical composition of the present invention, which is used for treating thromboembolic diseases.

[0175] [Corrected 03.01.2025 according to Rule 26] "Pharmaceutically acceptable carrier" in the present invention refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable for contact with the tissues of humans and / or other animals within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0176] [Corrected 03.01.2025 in accordance with Rule 26] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer, as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0177] [Corrected 03.01.2025 according to Rule 26] The compositions of the invention can act systemically and / or locally. For this purpose, they can be administered by a suitable route, for example by injection, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally; or orally, buccally, nasally, transmucosally, topically, in the form of an ophthalmic preparation or by inhalation.

[0178] [Corrected 03.01.2025 according to Rule 26] For these administration routes, the composition of the present invention can be administered in a suitable dosage form.

[0179] [Corrected 03.01.2025 in accordance with Rule 26] The dosage forms include but are not limited to tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0180] [Corrected 03.01.2025 according to Rule 26] As used herein, the term "therapeutically effective amount" means an amount of a compound which, when administered, will relieve to some extent one or more symptoms of the condition being treated.

[0181] [Corrected 03.01.2025 per Rule 26] The dosing regimen may be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values ​​may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0182] [Corrected 03.01.2025 according to rule 26] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or condition being treated, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. Generally speaking, the effective dose is about 0.0001 to about 50 mg per kg body weight per day, for example, about 0.01 to about 10 mg / kg / day (single or divided administration). For a 70 kg person, this will add up to about 0.007 mg / day to about 3500 mg / day, for example, about 0.7 mg / day to about 700 mg / day. In some cases, a dosage level not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0183] [Corrected 03.01.2025 according to Rule 26] The content or dosage of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, for example 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0184] [Corrected 03.01.2025 in accordance with Rule 26] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies or one or more symptoms of such disorder or condition.

[0185] [Corrected 03.01.2025 in accordance with Rule 26] As used herein, "individual" includes humans and non-human animals. Exemplary human individuals include human individuals suffering from a disease (e.g., a disease described herein) (referred to as a patient) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). [Corrected 03.01.2025 according to Rule 26] Example

[0186] [Corrected 03.01.2025 according to Rule 26] To make the objectives and technical solutions of the present invention more clear, the following embodiments of the present invention are described in detail with reference to the following examples. However, those skilled in the art will understand that the following examples are only for illustration and should not be construed as limiting the scope of the present invention. In the examples, where specific conditions are not specified, all experiments were carried out under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, where the manufacturer is not specified, are all commercially available conventional products.

[0187] [Corrected 03.01.2025 as per Rule 26] In this application, when there is a discrepancy between the chemical name and the structural formula, the structural formula shall prevail unless the context indicates that the chemical name rather than the structural formula is correct.

[0188] [Corrected 03.01.2025 according to Rule 26] In the conventional synthesis methods and the examples and intermediate synthesis examples, the meanings of the abbreviations are as shown in the following table. The structures of the compounds were determined by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).

[0189] [Corrected 03.01.2025 according to Rule 26] Unless otherwise specified, the reaction temperature is room temperature (20℃~30℃).

[0190] [Corrected 03.01.2025 according to Rule 26] Example 1: 2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-(morpholine-4-carbonyl)oxy)benzoic acid (1-3-A); 2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-(morpholine-4-carbonyl)oxy)- Preparation of 7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-hydroxybenzoic acid (1-3); 2-((2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-((morpholine-4-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-(morpholine-4-carbonyl)oxy)benzoic acid (1-3-B)

[0191] [Corrected 03 / 01 / 2025 according to Rule 26] Weigh (2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-hydroxybenzoic acid (obtained by microbial fermentation) (20 mg, 0.038 mmol, FR) and dissolve in dry THF (2 ml). Cool and stir to 0°C. Then, add NaH (9.20 mg, 0.383 mmol, 60% purity) and stir for 0.5 hour. Then, add 4-morpholinecarbonyl chloride (17.21 mg, 0.115 mmol) and return to room temperature for 2 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was poured into a cooled aqueous ammonium chloride solution to quench, and then dropped into a 3N aqueous hydrochloric acid solution for neutralization. The mixture was extracted with ethyl acetate. The organic phase was dried and concentrated, and then purified by high performance liquid chromatography to obtain compounds 1-3-A (2.34 mg), 1-3 (2.44 mg), and 1-3-B (11.63 mg).

[0192] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0193] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0194] [Corrected 03.01.2025 according to Article 26] 1-3:

[0195] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 634.7 [M+H] + .

[0196] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ12.71(s,1H),9.95(s,1H),7.34(d,J=8.6Hz,1H),7.26(d,J=2.6Hz,1H),7.00(d,J=6.8 Hz,2H),5.34(d,J=4.8Hz,1H),5.13(t,J=6.7Hz,1H),5.03(t,J=6.9Hz,1H),4.63(q,J=16.9Hz,2H),3.79(d d,J=12.0,5.3Hz,1H),3.67(s,6H),3.44(s,2H),2.85(dd,J=17.3,5.1Hz,1H),2.63–2.53(m,1H),2.13(d,J =7.5Hz,2H),2.04–1.97(m,2H),1.94–1.86(m,2H),1.58(dd,J=35.1,11.0Hz,11H),1.22(d,J=12.2Hz,3H).

[0197] [Corrected 03.01.2025 according to Article 26] 1-3-A:

[0198] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 634.7 [M+H] + .

[0199] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO) δ12.71(s,1H),9.95(s,1H),7.34(d,J=8.6Hz,1H),7.26(d,J=2.6Hz,1H),7.00(d,J=6.8 Hz,2H),5.34(d,J=4.8Hz,1H),5.13(t,J=6.7Hz,1H),5.03(t,J=6.9Hz,1H),4.63(q,J=16.9Hz,2H),3.79(d d,J=12.0,5.3Hz,1H),3.67(s,6H),3.44(s,2H),2.85(dd,J=17.3,5.1Hz,1H),2.63–2.53(m,1H),2.13(d,J =7.5Hz,2H),2.04–1.97(m,2H),1.94–1.86(m,2H),1.58(dd,J=35.1,11.0Hz,11H),1.22(d,J=12.2Hz,3H).

[0200] [Corrected 03.01.2025 according to Article 26] 1-3-B:

[0201] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 747.8 [M+H] + .

[0202] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ12.71(s,1H),9.95(s,1H),7.34(d,J=8.6Hz,1H),7.26(d,J=2.6Hz,1H),7.00(d,J=6.8 Hz,2H),5.34(d,J=4.8Hz,1H),5.13(t,J=6.7Hz,1H),5.03(t,J=6.9Hz,1H),4.63(q,J=16.9Hz,2H),3.79(d d,J=12.0,5.3Hz,1H),3.67(s,6H),3.44(s,2H),2.85(dd,J=17.3,5.1Hz,1H),2.63–2.53(m,1H),2.13(d,J =7.5Hz,2H),2.04–1.97(m,2H),1.94–1.86(m,2H),1.58(dd,J=35.1,11.0Hz,11H),1.22(d,J=12.2Hz,3H).

[0203] [Corrected 03.01.2025 according to Rule 26] Example 2: (S)-2,5-bis((2R,3S)-5-((dimethylcarbamoyl)oxy)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-1); (S)-5-(( 2R,3S)-5-((dimethylcarbamoyl)oxy)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-((E)-4,8-dimethylnona-3,6-dien-1-yl)-3,5-dihydro- Hydroxy-2-methyl-7-oxo-4,7,9-tetrahydrooxopyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-1-A); (S)-2-((2R,3S)-5-((dimethylcarbamoyl)oxy)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-3, Preparation of 4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-(2R,3S)-2-(E)-4,8-dimethylnona-2,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-4,4,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-1-B)

[0204] [Corrected 03.01.2025 according to Rule 26] Weigh (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (obtained by microbial fermentation) (200 mg, 0.230 mmol, FR) and dissolve in dry tetrahydrofuran (4 mL). Cool and stir to 0°C, then add NaH (55.23 mg, 2.3 mmol), return to room temperature and stir to react for 0.5 hour, add dimethylaminoformyl chloride (123.74 mg, 1.15 mmol) dropwise, slowly raise the temperature to 40°C and react for 3 hours. The reaction was detected by high performance liquid chromatography-mass spectrometry. The reaction was quenched by adding water under ice cooling and stirring, and then neutralized by adding 3N aqueous hydrochloric acid solution. The product was purified by high performance liquid chromatography to give 30.79 mg of a monosubstituted mixture (2-1-A and 2-1-B) and 9.94 mg of a disubstituted compound (2-1).

[0205] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0206] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0207] [Corrected 03.01.2025 according to Rule 26] Compound 2-1:

[0208] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z) 1011.3 [M+H] + .

[0209] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ13.05(s,1H),6.95(s,1H),6.91(s,1H),5.29(t,J=4.2Hz,2H),5.11(t,J=6.6Hz,2H),5 .04(t,J=6.9Hz,2H),4.73(s,1H),4.39–4.23(m,4H),3.78(d,J=5.0Hz,2H),3.52(t,J=6.6Hz,2H),3.08(d, J=2.0Hz,6H),2.93(s,6H),2.83(t,J=5.0Hz,1H),2.78(t,J=4.9Hz,1H),2.54(d,J=10.2Hz,1H),2.47(s,1H ), 2.10 (s, 4H), 2.00 (dd, J = 14.6, 7.3Hz, 5H), 1.94–1.85 (m, 5H), 1.64–1.47 (m, 24H), 1.19 (d, J = 14.7Hz, 6H).

[0210] [Corrected 03.01.2025 according to Rule 26] Mixture 2-1-A & 2-1-B:

[0211] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 940.3 [M+H] + .

[0212] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR(400MHz,DMSO)δ12.97(s,2H),9.78(d,J=21.9Hz,2H),6.93(d,J=18.6Hz,2H),6.64(d,J=13.0Hz,2H),5.29(t,J=4.8Hz,2H),5.16(t,J=4.6Hz,2H),5.11(t,J=6.6Hz,4H),5.04(t,J=6.3Hz,4H),4.74(d,J=5.9Hz,2H),4.31(d,J=8.3Hz,4H),4.19(d,J=11.6Hz,4H),3.80–3.69(m,4H),3.49(dd,J=12.3,5.9Hz,4H),3.08(d,J=2.2Hz,6H),2.93(s,6H),2.81(dd,J=16.8,3.7Hz,4H),2.54(s,2H),2.43(d,J=7.5Hz,2H),1.98(ddd,J=33.5,25.8,18.2Hz,30H),1.57(d,J=33.6Hz,46H),1.18(dd,J=14.3,11.7Hz,12H)。

[0213] [Corrected 03.01.2025 according to Rule 26] Example 3: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-((morpholine-4-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentanoic acid (2-2); (S)-5-((2 -2-((R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5 -((Morpholine-4-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-2-A); (S) 2-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyran Preparation of 2-(2-hydroxy-2-methyl-5-((morpholine-4-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-((morpholine-4-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-2-B)

[0214] [Corrected 03.01.2025 according to Rule 26] Under nitrogen protection, (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxyl-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentanoic acid (200 mg, 0.23 mmol) was added to THF (5 mL) and stirred to dissolve. The mixture was cooled to 0-5°C with ice water and NaH (138.1 mg) was added. , 3.45 mmol, content 60%) was stirred for 10 minutes, 4-morpholinecarbonyl chloride (137.68 mg, 0.92 mmol) was added, the temperature was raised to 35 ° C, and the reaction was carried out for 4 hours. The reaction solution was poured into an aqueous ammonium chloride solution (10 ml), and the product was extracted with EA (20 ml). The product was concentrated to give a crude product, which was purified by preparative high performance liquid chromatography to give the title compound 2-2 (28.0 mg) and a mixture of 2-2-A / 2-2-B (21.0 mg).

[0215] [Corrected 03.01.2025 according to rule 26] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0216] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0217] [Corrected 03.01.2025 according to Rule 26] Retention time: 12.7-13.2min

[0218] [Corrected 03.01.2025 according to Rule 26] Compound 2-2:

[0219] [Corrected 03.01.2025 according to Rule 26] ESI-MS m / z(ESI):1095.3[M+H] + .

[0220] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR(400MHz,DMSO-d6)δ6.99(s,1H),6.95(s,1H),5.29(br,2H),5.11(t,J=6.4Hz,2H),5.03 (t,J=6.4Hz,2H),4.75–4.72(m,1H),4.40–4.30(m,3H),3.78–3.77(m,2H),3.68–3.58(m,12H ),3.52–3.51(m,2H),3.46–3.42(m,3H),2.85–2.78(m,2H),2.57–2.54(m,1H),2.16–2.06(m ,4H),2.02–1.89(m,11H),1.65–1.56(m,13H),1.55–1.45(m,13H),1.21(s,3H),1.17(s,3H).

[0221] [Corrected 03.01.2025 according to Article 26] Mixture 2-2-A & 2-2-B:

[0222] [Corrected 03.01.2025 according to Rule 26] ESI-MS m / z(ESI):982.6[M+H] + .

[0223] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR(400MHz,DMSO-d6)δ9.77(s,2H),6.96(s,1H),6.95(s,1H),6.64(s,1H),6.62(s,1H),5.29(br,2H),5.15 -5.04(m,8H),4.63-4.54(m,2H),4.53-4.43(m,2H),4.37–4.06(m,8H), 3.80-3.72(m,4H),3.69-3.58(m,10H),3.54-3.34(m,12H),2.84-2.78( m,4H),2.55-2.53(m,2H),2.48–2.41(m,2H),2.15-2.05(s,6H),2.05–1 .87(m,14H),1.85-1.72(m,3H),1.61-1.53(m,38H),1.23-1.14(m,12H).

[0224] [Corrected 03.01.2025 according to Rule 26] Example 4: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-5-((isopropylcarbamoyl)oxy)-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentanoic acid (2-3)

[0225] [Corrected 03.01.2025 according to Rule 26] (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentanoic acid (100 mg, 0.115 mmol) was dissolved in DMF (2 ml). Triethylamine (23.29 mg, 0.230 mmol) and isopropyl isocyanate (29.38 mg, 0.345 mmol) were then added. The mixture was stirred at 25°C for 16 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was purified by HPLC to obtain 48 mg of the title compound.

[0226] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0227] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% ammonium bicarbonate).

[0228] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1039.5 [M+H] + .

[0229] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO-d6) δ7.77(dd,J=7.6,4.6Hz,2H),6.87(d,J=11.7Hz,2H),5.31(s,2H),5. 16–5.02(m,4H),4.64(s,1H),4.44–4.23(m,4H),3.77(s,2H),3.66(dd,J=12.5,6.4Hz,2H), 3.51(t,J=6.5Hz,2H),2.86–2.74(m,2H),2.54(s,1H),2.43–2.41(m,1H),2.11(d,J=8.3Hz, 4H), 1.94 (tt, J=25.2, 12.7Hz, 10H), 1.57 (d, J=31.6Hz, 24H), 1.16 (dd, J=17.0, 9.8Hz, 18H).

[0230] [Corrected 03.01.2025 according to Rule 26] Example 5: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-5-((methoxycarbonyl)oxy)-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-4)

[0231] [Corrected 03.01.2025 according to Rule 26] (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindole-8(2H)-yl)-2-((2S,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7,9-tetrahydropyrano[2,3-E]isoindole-8(2H)-pentanoic acid (250 mg, 0.288 mmol) was added to tetrahydrofuran (8 mL) and water (2 mL) and stirred to dissolve. The mixture was cooled to 0-5°C with ice water and 10% ethanol was added dropwise. Aqueous NaOH solution was added, the pH was adjusted to 11, and methyl chloroformate (163.1 mg, 1.73 mmol) was added dropwise. Simultaneously, a 10% aqueous NaOH solution was added dropwise to control the pH to 10-11. After completion of the addition, the mixture was reacted at room temperature for 2 hours. The pH was adjusted to 3-4 with aqueous citric acid solution, and the product was extracted with EA (30 ml). The organic phase was concentrated to obtain a crude product, which was purified by preparative HPLC to obtain the title compound 2-4 (130.0 mg).

[0232] [Corrected 03.01.2025 according to rule 26] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0233] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% ammonium formate in water).

[0234] [Corrected 03.01.2025 according to Rule 26] Retention time: 7-9 minutes

[0235] [Corrected 03.01.2025 according to Rule 26] The structural characterization data are as follows:

[0236] [Corrected 03.01.2025 according to Rule 26] MS m / z(ESI):985.4[M+H] + .

[0237] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),7.05(s,1H),7.05(s,1H),5.32(s,2H),5.14 -5.11(m,2H),5.09-5.02(m,2H),4.54-4.50(m,3H),4.31(s,2H),4.24-4.19(m,2H ),3.85(d,J=1.2Hz,6H),3.81-3.76(m,2H),3.54-3.48(m,4H),2.84-2.78(m,2H) ,2.55-2.51(m,2H),2.14-2.08(m,4H),2.13-1.96(m,4H),1.94-1.88(m,4H),1.79 -1.70(m,2H),1.61-1.57(m,9H),1.56 -1.50(m,13H),1.21(s,3H),1.18(s,3H).

[0238] [Corrected 03.01.2025 according to Rule 26] Example 6: (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-((1,1-dioxythiomorpholine-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-5); (S)-5-(( 2-(2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-(2R,3S)-3-((E)-4,6-dimethylhepta-3,7-dien-1-yl)-5-((1,1-dioxythiomorpholino- (S)-2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-5-A); (S)-2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[ Preparation of 2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4,8-dimethylnona-2,7-dien-1-yl)-5-(1,1-dioxythiomorpholine-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-5-B)

[0239] [Corrected 03 / 01 / 2025 according to Rule 26] (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (100 mg, 0.115 mmol, FR) was dissolved in dry THF (4 ml) and cooled with stirring to 0°C. NaH (46.03 mg, 1.15 mmol, 60% purity) was then added and the reaction was stirred for 0.5 hours. Thiomorpholine-1,1-dioxide-4-carbonyl chloride (90.96 mg, 0.460 mmol) was then added and the mixture was slowly returned to room temperature and allowed to react for 4 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was poured into a cooled aqueous ammonium chloride solution to quench, and then dropped into a 3N aqueous hydrochloric acid solution for neutralization. The mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated, and purified by high performance liquid chromatography to obtain a disubstituted compound 2-5 (54.46 mg) and a monosubstituted mixture 2-5-A and 2-5-B (16.96 mg).

[0240] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0241] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0242] [Corrected 03.01.2025 according to Rule 26] Compound 2-5:

[0243] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1191.5 [M+H] + .

[0244] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO) δ12.95(s,1H),7.18(d,J=17.7Hz,2H),5.34–5.23(m,2H),5.08(dt,J= 27.6,6.9Hz,4H),4.79(s,1H),4.33(d,J=9.4Hz,4H),4.03(s,4H),3.93–3.74(m,6H),3.5 3(s,2H),3.37(s,4H),3.27(s,4H),3.07(s,1H),2.91–2.80(m,2H),2.55(s,2H),2.11(d, J=8.4Hz, 4H), 1.95 (dt, J=15.0, 7.2Hz, 10H), 1.73–1.41 (m, 23H), 1.20 (d, J= 16.0Hz, 6H).

[0245] [Corrected 03.01.2025 according to Article 26] Mixture 2-5-A & 2-5-B:

[0246] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1030.3 [M+H] + .

[0247] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ12.91(s,2H),9.78(d,J=22.7Hz,2H),7.18(d,J=18.8Hz,2H),6.64(d,J=13.3Hz ,2H),5.29(s,2H),5.08(d,J=27.6Hz,8H),4.80–4.71(m,2H),4.32(d,J=7.6Hz,6H),4.19(d,J=9.7Hz ,2H),4.03(s,6H),3.86(s,6H),3.77(s,4H),3.55–3.47(m,4H),3.28(s,6H),2.85(dd,J=23.5,11.6 Hz, 4H), 2.56 (d, J = 8.3Hz, 4H), 2.27–1.78 (m, 30H), 1.57 (d, J = 33.8Hz, 46H), 1.18 (t, J = 14.3Hz, 12H).

[0248] [Corrected 03.01.2025 according to Rule 26] Example 7: Synthesis of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-((thiomorpholine-4-carbonyl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-7)

[0249] [Corrected 03.01.2025 according to Rule 26] Step 1: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-ylpentanoic acid methyl ester (2-7-1)

[0250] [Corrected 03.01.2025 according to Rule 26] (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindole-8(2H)-yl)-2-((2S,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindole-8 (2H)-Valeric acid (1.00 g, 1.15 mmol) was dissolved in MeOH (20 mL), cooled to -5-0°C, and SOCl2 (1.37 g, 11.51 mmol) was slowly added dropwise. The reaction mixture was kept at 0-5°C for 4 hours. The temperature was controlled at 0-10°C, and the reaction solution was added to saturated aqueous sodium bicarbonate (40 mL) / ethyl acetate (80 mL). The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (960 mg).

[0251] [Corrected 03.01.2025 according to Rule 26] Step 2: Synthesis of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-((thiomorpholine-4-carbonyl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid methyl ester (2-7-2)

[0252] [Corrected 03.01.2025 according to Rule 26] Compound 2-7-1 (50 mg, 0.057 mmol) and thiomorpholine-4-carbonyl chloride (28.13 mg, 0.170 mmol) were weighed and dissolved in N-methylpyrrolidone (2 mL). Cesium carbonate (55.34 mg, 0.170 mmol) was added and stirred for 4 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was poured into cooled aqueous ammonium chloride solution to quench the mixture. 0.1N aqueous hydrochloric acid was added dropwise to neutralize the mixture. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution, dried, and concentrated to yield 60 mg of the crude product.

[0253] [Corrected 03.01.2025 according to Rule 26] Step 3: Synthesis of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-((thiomorpholine-4-carbonyl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-7)

[0254] [Corrected 03.01.2025 according to Rule 26] Dissolve crude compound 2-7-2 (60 mg, 0.053 mmol) in methanol (2 mL) and water (0.5 mL). Add lithium hydroxide (8.82 mg, 0.210 mmol) with stirring and allow to react for 4 hours. Monitor the reaction by HPLC-MS / MS. Neutralize with 3N aqueous hydrochloric acid. Purify by preparative HPLC to yield 22.24 mg of the title compound.

[0255] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0256] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0257] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1128.6 [M+H] + .

[0258] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO) δ12.97(s,1H),6.99(d,J=18.8Hz,2H),5.29(t,J=4.4Hz,2H),5.08(dt,J=28.3,6.8 Hz,4H),4.83–4.74(m,1H),4.32(d,J=10.7Hz,4H),3.88(s,4H),3.83–3.63(m,6H),3.53(t,J=6.6Hz,2 H),3.31(s,2H),2.80(s,2H),2.77–2.61(m,8H),2.52(s,3H),2.33(dd,J=3.6,1.8Hz,1H),2.11(d,J=8 .1Hz,4H),1.95(dt,J=15.0,7.2Hz,9H),1.59(d,J=14.7Hz,10H),1.53(s,11H),1.20(d,J=15.7Hz,6H).

[0259] [Corrected 03.01.2025 according to Rule 26] Example 8: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-((methyl(tetrahydro-2H-pyran-4-yl)carbamoyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-8)

[0260] [Corrected 03.01.2025 according to Rule 26] Step 1: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-(methyl(tetrahydro-2H-pyran-4-yl)aminoacyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentanoic acid methyl ester (2-8-1)

[0261] [Corrected 03.01.2025 according to Rule 26] Compound 2-7-1 (50 mg, 0.057 mmol) was added to NMP (2 mL), cooled to 0-5°C with ice water, Cs2CO3 (55.34 mg, 0.17 mmol) was added and stirred for 10 minutes, N-methyl-N-tetrahydropyran-4-yl-carbamoyl chloride (30.17 mg, 0.17 mmol) was added, and the mixture was reacted at 25°C for 4 hours. The reaction solution was poured into ethyl acetate (20 ml) / 0.1N hydrochloric acid aqueous solution (6 ml) water, the organic phase was separated, washed with saturated sodium bicarbonate aqueous solution (5 ml), washed with brine (5 ml), and the organic phase was dried and concentrated to obtain a crude product of the title compound (82.0 mg), which was used directly in the next step.

[0262] [Corrected 03.01.2025 according to Rule 26] Step 2: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-(methyl(tetrahydro-2H-pyran-4-yl)aminoacyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentanoic acid (2-8)

[0263] [Corrected 03.01.2025 according to Rule 26] Compound 2-8-1 (80 mg, 0.055 mmol) was added to methanol (2 mL) and water (0.7 mL), and LiOH.H2O (9.22 mg, 0.22 mmol) was added. The mixture was reacted at room temperature for 2 hours. 1N hydrochloric acid was added to adjust the pH to 3-4, and ethyl acetate (20 mL) / water (50 mL) was added and stirred for 15 minutes. The organic phase was separated and washed with brine. The organic phase was dried and concentrated to obtain a crude product, which was purified by preparative HPLC to obtain 17 mg of the title compound.

[0264] [Corrected 03.01.2025 according to rule 26] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0265] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0266] [Corrected 03.01.2025 according to Rule 26] Retention time: 8-10 minutes.

[0267] [Corrected 03.01.2025 according to Rule 26] The structural characterization data are as follows:

[0268] [Corrected 03.01.2025 according to Rule 26] MS m / z(ESI):1151.7[M+H] + .

[0269] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO-d6) δ6.96 (s, 1H), 6.92 (s, 1H), 5.28 (t, J = 4.7Hz, 2H), 5.13-5.10 (m, 2H), 5.06-5.02 (m, 2H), 4.78-4.73(m,1H),4.33-4.30(m,4H),4.25-4.06(m,2H),3.95-3.92(m,4H),3.77-3.73(m,2H),3.54-3.51(m,2 H),3.40-3.38(m,3H),3.00-2.92(m,3H),2.84-2.76(m,4H),2.12-2.10(m,4H),2.03-1.96(m,4H),1.94–1.87( m,5H),1.85-1.76(m,3H),1.72-1.70(m,2H),1.65-1.55(m,13H),1.55-1.50(m,12H),1.21(s,3H),1.17(s,3H).

[0270] [Corrected 03.01.2025 according to Rule 26] Example 9: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-((piperidine-1-carbonyl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-9)

[0271] [Corrected 03.01.2025 according to Rule 26] Step 1: Preparation of (2R,2'R,3S,3S)-((S)-5-methoxy-5-oxopentane-1,4-diyl)bis(2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-3,4,7,9-tetrahydropyrano[2,3-E]isoindole-8,5-diyl)bis(piperidine-1-carboxylate) (2-9-1)

[0272] [Corrected 03.01.2025 according to Rule 26] Compound 2-7-1 (50 mg, 0.057 mmol) was added to NMP (2 mL), cooled to 0-5°C with ice water, Cs2CO3 (73.8 mg, 0.23 mmol) was added and stirred for 10 minutes, 1-piperidinyl chloride (33.4 mg, 0.23 mmol) was added, and the mixture was reacted at 25°C for 4 hours. The reaction solution was poured into ethyl acetate (20 ml) / 0.1N hydrochloric acid aqueous solution (6 ml) water, the organic phase was separated, washed with saturated sodium bicarbonate aqueous solution (5 ml), washed with brine (5 ml), and the organic phase was dried and concentrated to obtain a crude product of the title compound (62.0 mg), which was used directly in the next step.

[0273] [Corrected 03.01.2025 according to Rule 26] Step 2: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-((piperidine-1-carbonyl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-9)

[0274] [Corrected 03.01.2025 according to Rule 26] Compound 2-9-1 (62.0 mg, 0.056 mmol) was added to methanol (3 mL) and water (1 mL), and LiOH.H2O (11.8 mg, 0.028 mol) was added. The mixture was reacted at room temperature for 2 hours. 1N hydrochloric acid was added to adjust the pH to 3-4, and ethyl acetate (30 mL) / water (10 mL) was added and stirred for 15 minutes. The organic phase was separated and washed with brine. The organic phase was dried and concentrated to obtain a crude product, which was purified by preparative HPLC to obtain 5.7 mg of the title compound.

[0275] [Corrected 03.01.2025 according to rule 26] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0276] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0277] [Corrected 03.01.2025 according to Rule 26] Retention time: 15.5-17.5min.

[0278] [Corrected 03.01.2025 according to Rule 26] The structural characterization data are as follows:

[0279] [Corrected 03.01.2025 according to Rule 26] MS m / z(ESI):1091.6[M+H] + .

[0280] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR(400MHz,DMSO-d6)δ6.95(s,1H),6.90(s,1H),5.34 -5.29(m,2H),5.16-5.00(m,4H),4.81-4.73(m,1H),4.38-4.27(m,4H),3.82-3.77(m,2H),3.59 -3.51(m,6H),2.82-2.80(m,2H),2.17-2.10(s,4H),2.04–1.86(m,10H),1.69-1.53(m,37H),1.21(s,3H),1.17(s,3H).

[0281] [Corrected 03.01.2025 according to Rule 26] Example 10: (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-((morpholinesulfonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-10); (S)-5-((2R ,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-(2R,3S)-3-((E)-4,7-dimethyldeca-3,7-dien-1-yl)-3-hydroxy-2-methyl -5-(((Morpholinesulfonyl)oxy)-7-oxy-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-10-A); (S)-2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid Preparation of tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4,8-dimethylnona-4,7-dien-1-yl)-3-hydroxy-2-methyl-5-((morpholinesulfonyl)oxy)-7-oxy-3,6-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-10-B)

[0282] [Corrected 03 / 01 / 2025 according to Rule 26] (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (50 mg, 0.058 mmol) was dissolved in dry THF (2 ml). The mixture was cooled and stirred to 0°C. NaH (13.81 mg, 0.575 mmol, 60% purity) was then added and stirred for 0.5 hour. 4-Morpholinesulfonyl chloride (90.96 mg, 0.460 mmol) was then added and the temperature was slowly raised to room temperature for 4 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was poured into a cooled aqueous ammonium chloride solution to quench, and then dropped into a 3N aqueous hydrochloric acid solution for neutralization. The mixture was extracted with dichloromethane, and the organic phase was dried, concentrated, and purified by high performance liquid chromatography to obtain the disubstituted compound 2-10 (11.74 mg) and the monosubstituted mixture 2-10-A and 2-10-B (5.03 mg).

[0283] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0284] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0285] [Corrected 03.01.2025 according to Rule 26] Compound 2-10:

[0286] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1167.8 [M+H] + .

[0287] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO) δ13.02 (s, 1H), 7.14 (d, J = 15.8Hz, 2H), 5.36 (t, J = 4.9Hz, 2H), 5.05 (dd, J = 21. 2,14.3Hz,4H),4.80–4.74(m,1H),4.35(d,J=8.8Hz,4H),3.86–3.76(m,2H),3.73(dd,J=5.7,3.0H z,8H),3.53(s,2H),3.41(dd,J=9.4,4.7Hz,7H),3.02(d,J=17.6Hz,2H),2.72(s,2H),2.11(dd,J= 15.4, 7.3Hz, 4H), 1.94 (dt, J = 14.8, 7.1Hz, 11H), 1.56 (d, J = 33.5Hz, 24H), 1.23 (d, J = 15.1Hz, 6H).

[0288] [Corrected 03.01.2025 according to Rule 26] Mixture 2-10-A & 2-10-B:

[0289] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1018.5 [M+H] + .

[0290] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ12.90(s,2H),9.77(d,J=21.9Hz,2H),7.13(d,J=16.1Hz,2H),6.64(d,J=12.8Hz,2H),5.35(t,J=4.7Hz,2H),5 .15(t,J=4.9Hz,2H),5.11(s,4H),5.03(d,J=6.1Hz,4H),4.74(s,2H),4.35(d,J=8.9Hz,4H),4.19(d,J=10.1Hz,4H),3.81(s,2H), 3.73(d,J=3.1Hz,8H),3.54–3.45(m,4H),3.41(dd,J=9.4,4.8Hz,8H),3.02(d,J=18.4Hz,3H),2.77(dd,J=32.7,13.8Hz,6H),2.43 (d, J=7.5Hz, 2H), 2.11 (d, J=6.3Hz, 10H), 1.94 (dt, J=14.7, 7.0Hz, 20H), 1.56 (d, J=34.0Hz, 46H), 1.19 (dd, J=24.6, 14.0Hz, 12H).

[0291] [Corrected 03.01.2025 according to Rule 26] Example 11: Preparation of (S)-2,5-bis((2R,3S)-5-([1,4'-bipiperidinyl]-1'-carbonyl)oxy)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-20)

[0292] [Corrected 03 / 01 / 2025 according to Rule 26] (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (100 mg, 0.115 mmol, FR) was dissolved in dry THF (10 ml). The mixture was cooled and stirred to 0°C. NaH (46.03 mg, 1.15 mmol, 60% content) was then added. The mixture was stirred at room temperature for 0.5 hours. 1-Chlorocarbonyl-4-piperidinylpiperidine hydrochloride (122.51 mg, 0.460 mmol) was added, and the temperature was raised to 40°C for 3 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was poured into ice water for quenching, and then dropped into 3N aqueous hydrochloric acid for neutralization. After concentration under reduced pressure, the solution was purified by HPLC to obtain 33.15 mg of the title compound.

[0293] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0294] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0295] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1257.9 [M+H] + .

[0296] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO) δ8.21(s,1H),6.93(d,J=11.2Hz,2H),5.30(s,2H),5.11(t,J=6.7Hz,2H),5.04(t,J =6.8Hz,2H),4.66(dd,J=10.9,4.6Hz,1H),4.41(d,J=17.4Hz,1H),4.34–4.15(m,6H),4.04(d,J=11.4H z,2H),3.80–3.74(m,3H),3.51(s,3H),3.02(s,3H),2.91–2.74(m,5H),2.55(s,10H),2.10(s,5H),2.0 5–1.95(m,6H),1.95–1.86(m,5H),1.80(s,5H),1.53(dd,J=50.4,31.9Hz,45H),1.18(d,J=13.2Hz,6H).

[0297] [Corrected 03.01.2025 according to Rule 26] Example 12: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-22)

[0298] [Corrected 03.01.2025 according to Regulation 26] Step 1:

[0299] [Corrected 03.01.2025 according to Rule 26] (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (200 mg, 0.230 mmol) and bromotetraacetylglucoside (378.51 mg, 0.920 mmol) were dissolved in acetonitrile (4 ml). Silver oxide (266.64 mg, 1.150 mmol) was then added and the mixture was stirred at 25°C for 16 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was purified by HPLC to give 2-22-1A (8 mg), 2-22-1B (19 mg) and 2-22-1C (20 mg).

[0300] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0301] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0302] [Corrected 03.01.2025 according to Rule 26] 2-22-1A:

[0303] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1860.7 [M+H] + .

[0304] [Corrected 03.01.2025 according to Rule 26] 2-22-1B / 2-22-1C:

[0305] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1530.6 [M+H] + .

[0306] [Corrected 03.01.2025 according to Rule 26] Step 2: Synthesis of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-22)

[0307] [Corrected 03 / 01 / 2025 according to Rule 26] 2-22-1A (8 mg, 0.004 mmol) was dissolved in tetrahydrofuran (1 mL) and ethanol (0.25 mL). Lithium hydroxide (1.80 mg, 0.043 mmol) was added and stirred for 1 hour. The reaction was monitored by HPLC-MS / MS. 3N aqueous hydrochloric acid was added dropwise to the reaction solution for neutralization. The solvent was evaporated under reduced pressure and purified by HPLC to obtain 2.12 mg of the title compound.

[0308] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0309] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1193.6 [M+H] + .

[0310] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ6.89(s,1H),6.86(s,1H),5.28(t,J=5.1Hz,2H),5.21(d,J=4.3Hz,2H),5.16–5.09(m ,4H),5.03(dd,J=11.2,6.1Hz,4H),4.91(d,J=5.4Hz,2H),4.54(dd,J=10.1,5.7Hz,2H),4.24(s,6H),3.79 –3.63(m,5H),3.49(d,J=3.7Hz,5H),3.24(dd,J=21.7,7.8Hz,7H),3.05(d,J=12.9Hz,3H),2.53(s,1H),2 .46–2.44(m,1H),2.11(s,5H),1.95(dt,J=15.2,7.2Hz,10H),1.69–1.44(m,22H),1.17(d,J=13.6Hz,6H).

[0311] [Corrected 03.01.2025 in accordance with Article 26] Example 13: Preparation of (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-(2R,3S)-3-((E)-4,8D-dimethyldeca-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-22-A)

[0312] [Corrected 03.01.2025 according to Rule 26] 2-22-1B (19 mg, 0.012 mmol) was dissolved in tetrahydrofuran (1 mL) and ethanol (0.25 mL). Lithium hydroxide (2.61 mg, 0.062 mmol) was added and stirred for 1 hour. The reaction was monitored by HPLC-MS / MS. 3N aqueous hydrochloric acid was added dropwise to the reaction solution for neutralization. The solvent was evaporated under reduced pressure and purified by HPLC to obtain 3.03 mg of the title compound.

[0313] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0314] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1031.6 [M+H] + .

[0315] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ13.05–12.80(m,1H),9.75(s,1H),6.89(s,1H),6.62(s,1H),5.29(d,J=4.8Hz,1H),5.21(d,J=5. 2Hz,1H),5.16–4.99(m,6H),4.92(d,J=7.2Hz,1H),4.71(s,1H),4.54(t,J=5.8Hz,1H),4.34–4.13(m,4H),3.73(d,J= 5.4Hz,3H),3.48(s,3H),3.27(s,4H),3.05(dd,J=17.8,5.2Hz,1H),2.81(dd,J=17.7,5.2Hz,1H),2.59–2.52(m,1H), 2.43(d,J=7.4Hz,1H),2.10(s,4H),1.95(dt,J=14.8,7.1Hz,10H),1.55(dd,J=24.4,14.4Hz,21H),1.24–1.07(m,6H).

[0316] [Corrected 03.01.2025 in accordance with Article 26] Example 14: Preparation of (S)-2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4.8-dimethylnona-4,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-22-B)

[0317] [Corrected 03 / 01 / 2025 according to Rule 26] 2-22-1C (20 mg, 0.013 mmol) was dissolved in tetrahydrofuran (1 mL) and ethanol (0.25 mL). Lithium hydroxide (2.74 mg, 0.065 mmol) was added and stirred for 1 hour. The reaction was monitored by HPLC-MS / MS. 3N aqueous hydrochloric acid was added dropwise to the reaction solution for neutralization. The solvent was evaporated under reduced pressure and purified by HPLC to yield 3.73 mg of the title compound.

[0318] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0319] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1031.6 [M+H] + .

[0320] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ9.77(s,1H),6.85(s,1H),6.64(s,1H),5.27(d,J=4.9Hz,1H),5.21(d,J=5.2Hz,1H),5.1 4(dd,J=10.9,6.0Hz,4H),5.07–5.00(m,3H),4.91(d,J=7.3Hz,1H),4.55(t,J=5.8Hz,1H),4.20(d,J=20.4Hz ,6H),3.77–3.62(m,4H),3.57–3.42(m,4H),3.30–3.17(m,4H),3.10–2.99(m,2H),2.82(d,J=12.3Hz,2H),2. 47–2.40(m,1H),2.11(s,5H),1.95(dt,J=14.8,6.8Hz,9H),1.57(d,J=32.6Hz,22H),1.16(d,J=11.5Hz,6H).

[0321] [Corrected 03.01.2025 according to Rule 26] Example 15: (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-3-((4-methylpiperazine-1-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-23); (S)-5- ((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-(2R,3S)-3-((E)-4,7-dimethyldec-3-yl)-5-hydroxy-2-methyl-3-(4-methyl (S)-2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-23-A); (S)-2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2 Preparation of 2-((2R,3S)-2-((E)-4,8-dimethylnona-4,7-dien-1-yl)-5-hydroxy-2-methyl-3-((4-methylpiperazine-1-carbonyl)oxy)-7-oxy-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-23-B)

[0322] [Corrected 03.01.2025 according to Rule 26] (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (100 mg, 0.115 mmol) was dissolved in dry THF (10 ml). The mixture was cooled and stirred to 0°C. NaH (46.03 mg, 1.15 mmol, 60% content) was then added. The mixture was stirred at room temperature for 0.5 hours. 1-Chlorocarbonyl-4-methylpiperazine (91.16 mg, 0.460 mmol) was added, and the temperature was raised to 40°C for 3 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was poured into ice water to quench, and then dropped into 3N hydrochloric acid aqueous solution for neutralization. After concentration under reduced pressure, the product was purified by HPLC to obtain disubstituted compound 2-23 (8.07 mg) and monosubstituted compounds 2-23-A (3.32 mg) and 2-23-B (14.16 mg).

[0323] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0324] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0325] [Corrected 03.01.2025 according to Rule 26] 2-23:

[0326] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1122.7 [M+H] + .

[0327] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ9.94 (d, J=19.3Hz, 2H), 6.67 (d, J=13.5Hz, 2H), 5.04 (dd, J=1 5.1,7.7Hz,5H),4.95–4.87(m,2H),4.70(dd,J=10.2,5.1Hz,1H),4.30–4.15(m,4 H),3.50(d,J=7.0Hz,2H),2.99–2.90(m,2H),2.64(dd,J=15.6,9.7Hz,2H),2.18( d,J=28.9Hz,15H),2.10–1.85(m,15H),1.65–1.43(m,25H),1.27(d,J=8.4Hz,6H).

[0328] [Corrected 03.01.2025 in accordance with Rule 26] 2-23-A:

[0329] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 996.6 [M+H] + .

[0330] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO) δ9.93 (s, 1H), 9.76 (s, 1H), 6.65 (d, J = 22.3Hz, 2H), 5.20–4.97 (m, 5H), 4. 89(d,J=4.9Hz,1H),4.56(s,2H),4.37(s,3H),4.19(d,J=16.6Hz,4H),3.73(s,3H),3.47(s,2 H),2.96(d,J=13.4Hz,2H),2.86–2.76(m,2H),2.65(d,J=13.0Hz,1H),2.44(s,1H),2.33(s,1 H), 2.28–1.85 (m, 18H), 1.76 (s, 2H), 1.54 (dd, J = 26.6, 19.5Hz, 18H), 1.21 (d, J = 50.8Hz, 6H).

[0331] [Corrected 03.01.2025 according to Rule 26] 2-23-B:

[0332] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 996.6 [M+H] + .

[0333] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ9.90 (s, 1H), 9.80 (s, 1H), 6.65 (s, 2H), 5.12 (dd, J = 14.5, 6.7Hz, 2H), 5. 08–4.97(m,3H),4.89(t,J=5.3Hz,1H),4.72(dd,J=10.2,5.3Hz,1H),4.21(d,J=7.9Hz,4H),3 .74(s,1H),3.48(s,2H),2.97–2.89(m,1H),2.86–2.78(m,1H),2.66–2.58(m,1H),2.46(s,1H ), 2.23 (s, 3H), 2.15 (s, 3H), 2.12–1.81 (m, 14H), 1.64–1.44 (m, 22H), 1.20 (t, J = 20.8Hz, 6H).

[0334] [Corrected 03.01.2025 according to Rule 26] Example 16: (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(aminosulfonyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-28-A ); Preparation of (S)-2-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(aminosulfonyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-28-B)

[0335] [Corrected 03.01.2025 according to Rule 26] Step 1: (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(aminosulfonyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl) methyl pentanoate (2-28-1A) and Preparation of a mixture of (S)-2-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(aminosulfonyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl) methyl pentanoate (2-28-1B)

[0336] [Corrected 03.01.2025 according to Rule 26] Compound 2-7-1 (200.0 mg, 0.23 mmol) and aminosulfonyl chloride (157.0 mg, 1.36 mmol) were added to DMA (6 mL), and NaH (136.0 mg, 3.40 mmol, 60% content) was added. The temperature was raised to 30°C and the reaction mixture was reacted for 2 hours. After cooling to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride solution and the product was extracted with ethyl acetate. The organic phase was concentrated to obtain the crude title compound (218 mg), which was used directly in the next step.

[0337] [Corrected 03.01.2025 according to Rule 26] Step 2: (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(aminosulfonyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-28-A) and Preparation of (S)2-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(aminosulfonyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-28-B) mixture

[0338] [Corrected 03.01.2025 according to Rule 26] A mixture of 2-28-1A and 2-28-1B (250.00 mg, 0.26 mmol) was added to tetrahydrofuran (5 mL) and water (5 mL), followed by the addition of lithium hydroxide (93.34 mg, 3.90 mmol). The mixture was allowed to react at room temperature for 1 hour. The pH was adjusted to 4 with aqueous citric acid solution, and the product was extracted with ethyl acetate (20 mL). The organic phase was concentrated to give a crude product, which was purified by preparative HPLC to give the title compound (24.0 mg).

[0339] [Corrected 03.01.2025 according to rule 26] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0340] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid in water).

[0341] [Corrected 03.01.2025 according to Rule 26] Retention time: 5.3-6.2 min.

[0342] [Corrected 03.01.2025 according to Rule 26] The structural characterization data are as follows:

[0343] [Corrected 03.01.2025 according to Rule 26] MS m / z(ESI):948.3[M+H] + .

[0344] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR(400MHz,DMSO-d6)δ10.04(s,1H),10.00(s,1H),9.80(s,1H),9.77(s,1H),7.66(br,4H),6.71(s,1H),6 .68(s,1H),6.65(s,1H),6.62(s,1H),5.15-5.11(m,4H),5.05-4.97(m,5H),4.74–4.63(m,4H),4.32-4.14( m,8H),3.76-3.71(m,2H),3.50-3.44(m,4H),3.09–2.90(m,4H),2.85-2.78(m,2H),2.47–2.43(m,2H),2.12 -2.03(m,8H),2.02–1.79(m,18H),1.64–1.45(m,42H),1.38(s,3H),1.35(s,3H),1.18(s,3H),1.15(s,3H).

[0345] [Corrected 03.01.2025 according to Rule 26] Example 17: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-N-methylpentanamide (2-29)

[0346] [Corrected 03.01.2025 in accordance with Article 26] (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindole-8(2H)-yl)-2-((2S,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7,9-tetrahydropyrano[2,3-E]isoindole-8(2H)-valeric acid (100 mg, 115.06 μmol) was dissolved in DMF (3 mL), and methylamine hydrochloride (15.54 mg, 230.13 μmol), HATU (131.25 mg, 345.19 μmol), DIPEA (15.54 mg, 230.13 μmol) and 4-nitropropanediol (15.54 mg, 230.13 μmol) were added. 74.35 mg, 575.31 μmol), reacted at 25°C for 12 hours, and the reaction solution was directly purified by preparative HPLC to obtain the title compound 2-29 (56.0 mg).

[0347] [Corrected 03.01.2025 according to rule 26] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0348] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid in water).

[0349] [Corrected 03.01.2025 according to Rule 26] Retention time: 8.5-9.5 min.

[0350] [Corrected 03.01.2025 according to Rule 26] The structural characterization data are as follows:

[0351] [Corrected 03.01.2025 according to Rule 26] MS m / z(ESI):882.5[M+H] + .

[0352] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.74(s,1H),8.02-7.97(m,1H),6.64(s,1H),6.62(s,1H),5.17–5.08(m,4H ),5.06-5.02(m,2H),4.70–4.65(m,1H),4.38–4.34(m,1H),4.19-4.15(m,3H),3.75-3.70(m,2H),3.52–3.41(m,2 H),2.85-2.78(m,2H),2.54(d,J=4.4Hz,2H),2.46–2.42(m,1H),2.13-2.05(m,4H),2.03–1.95(m,4H),1.92-1.8 9(m,4H),1.83-1.72(m,2H),1.60-1.55(m,9H),1.55-1.49(m,11H),1.48-1.41(m,2H),1.17(s,3H),1.15(s,3H).

[0353] [Corrected 03.01.2025 according to Rule 26] Example 18: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)-N-(2-methoxyethyl)pentanamide (2-30)

[0354] [Corrected 03.01.2025 according to Rule 26] (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindole-8(2H)-yl)-2-((2S,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7,9-tetrahydropyrano[2,3-E]isoindole-8(2H)- Valeric acid (52.63 mg, 57.53 μmol) was dissolved in THF (30 mL), cooled to 0°C, and NaH (23.01 mg, 575.31 μmol) was added. The temperature was returned to 25°C and stirring was continued for 0.5 hour. N-(2-methoxyethyl)carbamoyl chloride (41.65 mg, 287.66 μmol) was added dropwise to the reaction solution. The temperature was raised to 40°C and the reaction was allowed to react for 3 hours. The reaction solution was directly concentrated and purified by preparative HPLC to give the title compound (10.0 mg).

[0355] [Corrected 03.01.2025 according to rule 26] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0356] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0357] [Corrected 03.01.2025 according to Rule 26] Retention time: 8.5-9.5 min.

[0358] [Corrected 03.01.2025 according to Rule 26] The structural characterization data are as follows:

[0359] [Corrected 03.01.2025 according to Rule 26] MS m / z(ESI):926.5[M+H+H2O] + .

[0360] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR (400MHz, DMSO) δ9.75(d,J=6.5Hz,1H),8.15(t,J=5.5Hz,1H),6.63(d,J=8.7Hz,1H),5.20–5.08(m,2H),5.04(s,1H),4. 74(dd,J=9.2,6.1Hz,1H),4.41(d,J=17.0Hz,1H),4.17(t,J=8.5Hz,1H),3.72(d,J=10.6Hz,1H),3.47(s,1H),3.38–3.25(m, 4H),3.22–3.13(m,2H),2.82(dd,J=12.3,3.6Hz,1H),2.49–2.39(m,1H),2.10(d,J=6.9Hz,1H),2.00(dd,J=14.3,6.9Hz,1H) ,1.95–1.86(m,2H),1.77(dd,J=14.9,8.7Hz,1H),1.59(d,J=16.1Hz,4H),1.53(s,5H),1.36(s,1H),1.16(d,J=12.0Hz,2H).

[0361] [Corrected 03.01.2025 according to Rule 26] Example 19: Preparation of 2-morpholinoethyl (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)valerate (2-31)

[0362] [Corrected 03.01.2025 according to Rule 26] (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (50 mg, 0.058 mmol) was dissolved in pyridine (1 ml). 2-Morpholinoethanol (15.09 mg, 0.115 mmol) and DCC (17.81 mg, 0.086 mmol) were then added. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was purified by HPLC to obtain 1.18 mg of the title compound.

[0363] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0364] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0365] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 983.7 [M+H] + .

[0366] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO) δ9.81 (d, J = 30.4Hz, 2H), 8.44 (s, 1H), 6.64 (d, J = 14.0Hz, 2H), 5.58 (d, J = 8.0Hz, 2 H),5.08(d,J=28.1Hz,6H),4.83(d,J=5.7Hz,1H),4.19(d,J=14.0Hz,6H),3.72(s,2H),3.48(s,2H), 2.82(dd,J=12.0,5.7Hz,2H),2.43(d,J=8.2Hz,4H),2.22(d,J=3.9Hz,4H),2.09(s,3H),2.03–1.97( m,3H),1.94–1.85(m,4H),1.71(d,J=12.8Hz,3H),1.56(dd,J=24.2,9.9Hz,21H),1.28–1.02(m,12H).

[0367] [Corrected 03.01.2025 according to Rule 26] Example 20: Preparation of 35-hydroxy-3,6,9,12,15,18,21,24,27,30,33-undecaoxatriacontane (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)valerate (2-32)

[0368] [Corrected 03.01.2025 according to Rule 26] (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-((2S,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7,9-tetrahydropyrano[2,3- Isoindole-8(2H)-pentanoic acid (120.0 mg, 0.14 mmol) was dissolved in DMF (2 mL), and dodecaethylene glycol (754.8 mg, 1.38 mmol), HATU (105.0 mg, 0.27 mmol), and DIPEA (89.2 mg, 0.69 mmol) were added. The mixture was reacted at 25°C for 12 hours. The reaction solution was directly purified by preparative HPLC to give the title compound 2-32 (48.0 mg).

[0369] [Corrected 03.01.2025 according to rule 26] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0370] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0371] [Corrected 03.01.2025 according to Rule 26] Retention time: 8.5-9.5 min.

[0372] [Corrected 03.01.2025 according to Rule 26] The structural characterization data are as follows:

[0373] [Corrected 03.01.2025 according to Rule 26] MS m / z(ESI):1414.7[M+H+H2O] + .

[0374] [Corrected 03.01.2025 in accordance with Article 26] 1 H NMR(400MHz,DMSO-d6)δ9.82(s,1H),9.75(s,1H),6.66(s,1H),6.62(s,1H),5.18–5.15(m,2H),5.13 -5.09(m,2H),5.06-5.02(m,2H),4.88–4.82(m,2H),4.58(t,J=5.4Hz,2H),4.20-4.14(m ,7H),3.77–3.70(m,3H),3.56–3.52(m,2H),3.50-3.48(m,30H),3.47–3.38(m,10H),3.3 7-3.35(m,2H),2.85-2.78(m,3H),2.47-2.42(m,2H),2.13-2.07(m,4H),2.04–1.97(m,4 H),1.94–1.86(m,6H),1.63–1.54(m,10H),1.54–1.50(m,12H),1.17(s,3H),1.14(s,3H).

[0375] [Corrected 03.01.2025 according to Rule 26] Example 21: Preparation of 2-(S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoyl)oxy)-N,N,N-trimethylethane-1-amine hydrochloride (2-33)

[0376] [Corrected 03.01.2025 according to Rule 26] (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (300 mg, 0.345 mmol) was dissolved in DMF (3 ml). Choline hydrochloride (97.09 mg, 0.69 mmol) and DCC (106.83 mg, 0.518 mmol) were then added and stirred at 25°C for 12 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was acidified by adding hydrochloric acid dropwise and purified by HPLC to obtain 8.70 mg of the title compound.

[0377] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0378] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0379] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 954.7 [M+H] + .

[0380] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO) δ6.55(d,J=3.9Hz,2H),5.09(d,J=30.2Hz,4H),4.89(d,J=8.0Hz,1H),4.43(s,2H),4.14(d,J=18.0Hz,3H),3.72(d,J=4.6Hz,2H), 3.57(s,3H),3.36(s,6H),3.04(d,J=47.3Hz,9H),2.83(d,J=16.0Hz,2H),2 .45(s,2H),2.21–1.81(m,12H),1.76–1.38(m,20H),1.14(d,J=7.7Hz,6H).

[0381] [Corrected 03.01.2025 according to Rule 26] Example 22: (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-((1-oxythiomorpholine-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-6); (S)-5-( (2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-(2R,3S)-3-((E)-4,6-dimethylhepta-3,7-dien-1-yl)-5-((1-oxothiomorpholine) (S)-2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-6-A) and (S)-2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-6-A) Pyrano[2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4,8-dimethylnona-2,7-dien-1-yl)-5-(1-oxythiomorpholine-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-6-B)

[0382] [Corrected 03 / 01 / 2025 according to Rule 26] Weigh (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (500 mg, 0.575 mmol) and dissolve it in dry tetrahydrofuran (50 ml). Add triethylamine dropwise, followed by a solution of p-nitrophenyl chloroformate (406 mg, 2.06 mmol, dissolved in 5 mL of tetrahydrofuran), and stir for 2 hours. Add 1-oxothiomorpholine hydrochloride (447 mg, 2.87 mmol) and continue stirring for 2 hours. Monitor the reaction by HPLC-MS / MS. The reaction solution was concentrated under reduced pressure to obtain a crude product which was purified by HPLC to give a disubstituted compound 2-6 (27.33 mg) and a monosubstituted mixture 2-6-A and 2-6-B (17.64 mg).

[0383] [Corrected 03.01.2025 according to Rule 26] Compound 2-6:

[0384] [Corrected 03.01.2025 according to Rule 26] Purification Condition 1:

[0385] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0386] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (0.05% ammonium bicarbonate).

[0387] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1159.5 [M+H] + .

[0388] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO): δ7.06 (d, J=12.0Hz, 2H), 5.29 (s, 2H), 5.14–4.99 (m, 4H), 4.70 (s ,2H),4.34(d,J=26.4Hz,4H),4.10(s,2H),3.93(d,J=12.3Hz,4H),3.77(dd,J=11.5,6 .3Hz,4H),3.52(s,2H),3.12–2.94(m,4H),2.83(s,5H),2.54(s,1H),2.44–2.35(m,1 H), 2.11 (d, J = 7.8Hz, 4H), 2.05–1.83 (m, 10H), 1.66–1.47 (m, 20H), 1.30–1.14 (m, 8H).

[0389] [Corrected 03.01.2025 according to Article 26] Mixture 2-6-A & 2-6-B:

[0390] [Corrected 03.01.2025 according to Rule 26] Purification Condition 2:

[0391] [Corrected 03.01.2025 according to Rule 26] Chromatographic column: SunFire Prep C18 OBD 19mm×150mm×5.0μm.

[0392] [Corrected 03.01.2025 according to Rule 26] Mobile phase A: acetonitrile; mobile phase B: water (0.05% ammonium bicarbonate).

[0393] [Corrected 03.01.2025 according to Rule 26] ESI-MS (m / z): 1014.3 [M+H] + .

[0394] [Corrected 03.01.2025 in accordance with Article 26] 1H NMR (400MHz, DMSO): δ9.79(d,J=11.8Hz,2H),7.05(d,J=11.0Hz,2H),6.63(d,J=10.7Hz,2H),5.29(s,2H), 5.16(s,2H),5.14–5.00(m,8H),4.67(s,2H),4.41(d,J=17.7Hz,2H),4.28(d,J=22.5Hz,4H),4.15(d,J=15 .6Hz,6H),3.92(s,4H),3.76(d,J=10.2Hz,6H),3.57–3.44(m,4H),3.03(d,J=41.1Hz,6H),2.92–2.75(m,8 H), 2.46 (s, 2H), 2.10 (s, 8H), 2.04–1.76 (m, 20H), 1.57 (d, J = 33.5Hz, 42H), 1.19 (dd, J = 24.8, 11.1Hz, 14H).

[0395] [Corrected 03.01.2025 according to Rule 26] The remaining compounds shown in the following table were prepared in a similar manner to the above:

[0396] [Corrected 03.01.2025 according to Rule 26] Biological data

[0397] [Corrected 03.01.2025 according to Rule 26] Experimental Example 1: Activation of Plasminogen (Glu-Typ) by Compounds

[0398] [Corrected 03.01.2025 according to Regulation 26] 1. Test method

[0399] [Corrected 03.01.2025 according to Rule 26] (1) Compound preparation

[0400] [Corrected 03.01.2025 according to Rule 26] Three concentration points were set for the test compounds and positive compounds of the present invention, namely 200 μM, 150 μM, and 100 μM; the final DMSO concentration was 2.5%.

[0401] [Corrected 03.01.2025 according to Rule 26] (2) Information on main reagents and instruments

[0402] [Corrected 03.01.2025 according to Rule 26] Plasminogen (Glu-Typ) (Sigma); Urokinase-type plasminogen activator (u-PA) (Aladdin); VLK-pNA (absin); Multifunctional microplate reader (Thermo).

[0403] [Corrected 03.01.2025 according to Rule 26] (3) Test system and signal detection

[0404] [Corrected 03.01.2025 according to Rule 26] Use buffer [Tris-HCl (50mM, pH 7.4) + NaCl (100mM) + Tween-80 (0.01%)] to prepare Plasminogen stock solution with a concentration of 100nM (5×), urokinase-type plasminogen activator (u-PA) stock solution with a concentration of 100IU / ml (5×), and VLK-pNA stock solution with a concentration of 5mM (5×). 20 μl of 5× plasminogen (Glu-Typ), 20 μl of 5× urokinase-type plasminogen activator (u-PA) and 20 μl of 5× VLK-pNA were added to a 96-well plate respectively. After mixing evenly, 40 μl of the test compound or positive compound was added to the 96-well plate. A control group (no compound) was set up and mixed evenly. Kinetic detection was performed using a Thermo multifunctional microplate reader at a wavelength of 405 nm and detection was performed once every 1 min to calculate the activation multiple.

[0405] [Corrected 03.01.2025 according to Rule 26] 2. Test results

[0406] [Corrected 03.01.2025 according to Rule 26] According to the absorbance value at 405nm wavelength (A405) and the square of time (t 2 ) were used to draw a curve, and the slope of the curve was used for analysis. The activation fold was calculated by dividing the slope of the compound group by the slope of the control group, and the following results were obtained (Table 1-1 and Table 1-2).

[0407] [Corrected 03.01.2025 according to Rule 26] Table 1-1 Efficacy of compounds in activating plasminogen

[0408] [Corrected 03.01.2025 according to Rule 26] Table 1-2 Efficacy of compounds in activating plasminogen

[0409] [Corrected 03.01.2025 according to Rule 26] The results showed that under the test system disclosed in the present invention, compounds 2-1, 2-2 and 2-5 at the same concentration had better activation efficacy on plasminogen than the positive compound.

[0410] [Corrected 03.01.2025 according to Rule 26] Experimental Example 2: Fibrinolytic Effect of Thromboelastography Compounds

[0411] [Corrected on 03.01.2025 according to Rule 26] Main instruments and reagents: Thromboelastograph (Udi Biotech); Urokinase-type plasminogen activator (u-PA) (Aladdin); Reagent 1 (the main ingredient is kaolin); Reagent 2 (the main ingredient is calcium chloride).

[0412] [Corrected 03.01.2025 according to Rule 26] 1. Test method:

[0413] [Corrected on 03.01.2025 according to Rule 26] (1) Test group settings: uPA group: urokinase-type plasminogen activator (u-PA) (1000 U / ml); positive compound / compound 2-1 / compound 2-2 group: test compound (200 μM) + u-PA (1000 U / ml); blank group: solvent.

[0414] [Corrected 03.01.2025 according to Rule 26] (2) Compound Solution Preparation: Dissolve the compound in 0.5 mg / ml tromethamine to a 4 mM stock solution and adjust the pH to 9. Dilute to a 2 mM 10X stock solution, with a final assay concentration of 200 μM. u-PA is prepared in saline to a 50,000 U / ml stock solution, diluted to a 10X stock solution of 10,000 U / ml, with a final assay concentration of 1,000 U / ml.

[0415] [Corrected 03.01.2025 according to Rule 26] (3) Test: Take 100 μL of u-PA and add it to a sample cup (containing Reagent 1) containing 800 μL of rat whole blood (anticoagulated with sodium citrate). Then add 100 μL of the compound to be tested and mix thoroughly by inversion. Then take 340 μL from the sample cup and add it to a reaction cup containing 20 μL of Reagent 2. Run the instrument and obtain the results shown in Table 2-1, Table 2-2, Table 2-3 and Figures 1, 2 and 3. The compound concentrations in Table 2-1, Table 2-2 and Figures 1 and 2 are 200 μM; the compound concentrations in Table 2-3 and Figure 3 are 100 μM.

[0416] [Corrected 03.01.2025 according to Rule 26] Table 2-1 Thromboelastometry data

[0417] [Corrected 03.01.2025 according to Rule 26] Table 2-2 Thromboelastometry data

[0418] [Corrected 03.01.2025 according to Rule 26] Table 2-3 Thromboelastometry data

[0419] [Corrected 03.01.2025 according to Rule 26] In this test system, according to the Ma values ​​and in combination with Figures 1 and 2, compounds 2-1, 2-2, 2-5 and 2-6 can directly affect the intensity of blood clot formation (Ma) and prevent thrombosis, and their thrombolytic activity is better than that of the positive compounds.

[0420] [Corrected 03.01.2025 according to Rule 26] The structure of the positive compound is as follows:

Claims

1. [Corrected 03.01.2025 in accordance with Rule 26] A compound or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein the compound is: in, Y is selected from R1 and R3 are each independently selected from carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy acyloxy, C 1-6 Alkyl acyloxy, C 1- 6-alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkylaminosulfonyloxy, C 4-10 Heterocyclic sulfonyloxy, sugar group, -OP(O)(OH)2, -OP(O)2OH, -OS(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkyl amido, C 4-10 Heterocyclic amido, halogen, cyano, C 2-6 Alkenyl and C 2-6 Alkynyl; the C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 Alkyl acyloxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 The alkylaminoacyloxy group is optionally substituted by one or more selected from hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Haloalkyl, C 1-6 Alkoxy acyloxy, 4-10 membered heterocyclic group, C 1-6 Substituted by hydroxyalkyl, -OP(O)(OH)2 substituent; R2 and R4 are each independently selected from hydrogen, hydroxyl, carboxyl, ester, C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl acyloxy, -OC(=O)-C 4-10 heterocyclic group, -OP(O)2OH, -OS(O)2OH and -OS(O)2NH2, the C 4-10 The heterocyclic group is optionally substituted by one or more selected from C 1-6 substituted by an alkyl substituent; When Y is selected from When R1 and R2 are not hydroxyl groups at the same time; n=0, 1, 2, 3, 4 or 5; X is selected from -CO2H and its carboxylic acid isostere, -CO2C 1-6 Alkyl, -C(=O)SH, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1- 6-alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 Alkyl, the -CO2C 1-6 Alkyl, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 The alkyl group is optionally substituted with one or more selected from C 4-10 Heterocyclic group, C 1-6 Alkoxy, Substituents of When X is -CO2H, R1, R2, R3 and R4 are not hydroxyl groups at the same time; The wavy line Indicates the point of attachment to the rest of the molecule.

2. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: R1 and R3 are each independently selected from carboxyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkoxy acyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 4-10 Heterocyclylsulfonyloxy, -OP(=O)(OH)2, -OS(O)2OH and C 4-10 Heterocyclic amido; the C 4-10 Heterocyclyl acyloxy, -OC 4-10 Heterocyclic group, C 1-6 The alkylaminoacyloxy group is optionally substituted by one or more selected from hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy acyloxy, C 1-6 Alkoxycarbonyl, C 1-6 Alkyl-C(=O)-, 4-10 membered heterocyclic group, C 1-6 The group may be substituted with a hydroxyalkyl group or a -OP(=O)(OH)2 substituent.

3. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug or mixture thereof, wherein: R1 and R3 are each independently selected from carboxyl, hydroxyl, C 1-3 Alkoxy, C 1-3 Alkoxy acyloxy, C 1-3 Alkylaminoacyloxy, C 4-8 Heterocyclyl acyloxy, -OC 4-8 Heterocyclic group, C 4-8 Heterocyclylsulfonyloxy, -OP(=O)(OH)2, -OS(O)2OH and C 4-8 Heterocyclic amido; the C 4-8 Heterocyclyl acyloxy, -OC 4-8 Heterocyclic group, C 1-3 The alkylaminoacyloxy group is optionally substituted by one or more selected from hydroxy, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy acyloxy, C 1-3 Alkoxycarbonyl, C 1-3 Alkyl-C(=O)-, 4-8 membered heterocyclic group, C 1-3 The group may be substituted with a hydroxyalkyl group or a -OP(=O)(OH)2 substituent.

4. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: R1 and R3 are each independently selected from carboxyl, hydroxyl, -OC(=O)N(CH3)2, -OC(=O)-morpholinyl, -OC(=O)NHCH(CH3)2, -OC(=O)OCH3, -OC(=O)-thiomorpholine dioxide, -OC(=O)-thiomorpholine monooxide, -OC(=O)-thiomorpholine, -OC(=O)N(CH3)-tetrahydropyran, -OC(=O)-piperidine, -OSO2-morpholine, -OC(=O)-piperazine, -O-tetrahydropyran, -OP(=O)(OH)2, methoxy, glucopyranosyl and -OS(O)2OH, wherein -OC(=O)-piperidine, -OC(=O)-piperazine, -O-tetrahydropyran, methoxy is optionally substituted with one or more substituents selected from hydroxy, carboxyl, CH3OC(=O)-, -C(=O)CH3, -OCH3, piperidinyl, morpholinyl, hydroxy, -CH2OH, -OP(=O)(OH)2 and oxo, The wavy line Indicates the point of attachment to the rest of the molecule.

5. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: R1 and R3 are each independently selected from carboxyl, hydroxyl, -OC(=O)N(CH3)2, -OC(=O)NHCH(CH3)2, -OC(=O)OCH3, -OP(=O)(OH)2, methoxy, -OS(O)2OH, The wavy line Indicates the point of attachment to the rest of the molecule.

6. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: R2 and R4 are each independently selected from hydrogen, carboxyl, hydroxyl, C 1-6 Alkoxy, carboxyl substituted C 1-6 Alkyl acyloxy, -OC(=O)-C 4-10 heterocyclic group, -OP(O)2OH, -OS(O)2OH and -OS(O)2NH2, the C 4-10 The heterocyclic group is optionally substituted by one or more selected from C 1-6 The alkyl group is substituted with an alkyl substituent.

7. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: R2 and R4 are each independently selected from carboxyl, hydroxyl, C 1-6 Alkoxy, carboxyl substituted C 1-6 alkylacyloxy, -OC(=O)-piperazinyl, -OP(O)2OH, -OS(O)2OH and -OS(O)2NH2, wherein the piperazine is optionally substituted by one or more selected from C 1-6 The alkyl group is substituted with an alkyl substituent.

8. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: R2 and R4 are each independently selected from carboxyl, hydroxyl, and -OS(O)2NH2, The wavy line Indicates the point of attachment to the rest of the molecule.

9. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: n=1, 2 or 3.

10. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: X is selected from -CO2H and its carboxylic acid isostere, -CO2C 1-6 Alkyl, -C(=O)SH, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1- 6-alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 Alkyl, the -CO2C 1-6 Alkyl, 4-10 membered heteroaryl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 The alkyl group is optionally substituted with one or more selected from 4-10 membered heterocyclic groups, and -C 1-6 is substituted by an alkoxy substituent, The wavy line Indicates the point of attachment to the rest of the molecule.

11. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: X is selected from -CO2H, -CO2C 1-6 Alkyl, -C(=O)SH, tetrazolyl, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkyl and -C(=O)NHS(=O)2N(C 1-6 Alkyl)2, the -CO2C 1-6 Alkyl and -C(=O)NHC 1-6 The alkyl groups are each optionally selected from morpholinyl and -C 1-6 is substituted by an alkoxy substituent, The wavy line Indicates the point of attachment to the rest of the molecule.

12. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, wherein: X is selected from -CO2H, -C(=O)NHCH3, The wavy line Indicates the point of attachment to the rest of the molecule.

13. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof, The compound is selected from:

14. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug or mixture thereof, wherein the compound is: in, R1, R2, R3, R4, X are as defined in any one of claims 1 to 12, and When X is -CO2H, R1, R2, R3 and R4 are not hydroxyl groups at the same time.

15. [Corrected 03.01.2025 in accordance with Rule 26] A compound according to claim 14 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite and prodrug thereof, wherein the compound is selected from:

16. [Corrected 03.01.2025 according to Rule 26] A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug or a mixture thereof and one or more pharmaceutically acceptable carriers, and optionally further comprising one or more other drugs for treating thromboembolic diseases.

17. [Corrected 03.01.2025 in accordance with Rule 26] Use of a compound according to claims 1 to 15 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug or mixture thereof or a pharmaceutical composition according to claim 16 in the preparation of a medicament for the treatment of thromboembolic diseases.

18. [Corrected 03.01.2025 in accordance with Rule 26] A compound as claimed in claims 1 to 15 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled substance, metabolite, prodrug or mixture thereof or a pharmaceutical composition as claimed in claim 16 for use in the treatment of thromboembolic diseases.

19. [Corrected 03.01.2025 as per Rule 26] A method for treating thromboembolic diseases, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound as claimed in claims 1 to 15 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled, metabolite, prodrug or mixture thereof or a pharmaceutical composition as claimed in claim 16.

20. [Corrected 03.01.2025 in accordance with Rule 26] A process for preparing a compound of formula I, comprising the steps shown in the following scheme: in: R1, R2 and Y are as defined in any one of claims 1 to 15; and LG is a leaving group.

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