Heterocyclic compound as well as preparation method and application thereof

Abstract

The invention relates to a heterocyclic compound, a pharmaceutical composition containing the heterocyclic compound and a preparation method of the heterocyclic compound, and further relates to application of the heterocyclic compound in preparation of drugs for treating thromboembolic diseases.

Description

Heterocyclic compound and its preparation method and application Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to heterocyclic compounds, pharmaceutical compositions containing the same and preparation methods thereof, and also relates to the use of the compounds in preparing drugs for treating thromboembolic diseases. Background Art

[0002] Stroke is an acute cerebrovascular disease, including ischemic and hemorrhagic strokes. The incidence of ischemic stroke accounts for approximately 80% of all stroke cases (International Journal of Cardiology, 2016, 222, 441-447).

[0003] 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. Furthermore, 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] 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 act as plasminogen modulators. By relaxing the plasminogen conformation, they 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). Because the SMTP series of compounds do not directly activate plasminogen and do not affect u-PA or t-PA levels, they mechanistically avoid the risk of cerebral hemorrhage associated with traditional thrombolytic drugs (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 are worthy of further study, and it is very necessary to develop thrombolytic drugs with new mechanisms, extended treatment time windows, and reduced bleeding risks.

[0005] SUMMARY OF THE INVENTION

[0006] Through extensive research, we have 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] 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] in,

[0009] Y is selected from

[0010] 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] 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] When Y is selected from When R1 and R2 are not hydroxyl groups at the same time;

[0013] n = 0, 1, 2, 3, 4 or 5;

[0014] 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 substituted by

[0015] When X is -CO2H, R1, R2, R3 and R4 are not hydroxyl groups at the same time;

[0016] The wavy line Indicates the point of attachment to the rest of the molecule.

[0017] 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, isotope-labeled form, 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] 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, isotope-labeled substance, metabolite, prodrug or mixture thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating thromboembolic diseases.

[0019] On the other hand, the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled form, metabolite, prodrug or mixture thereof, or a pharmaceutical composition of the present invention, for use in treating thromboembolic diseases.

[0020] 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] In another aspect, the present invention relates to a method for preparing the compound of the present invention, comprising the steps shown in the following scheme:

[0022] in:

[0023] R1, R2 and Y are as defined above; and

[0024] LG is a leaving group. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1: Thromboelastogram of compound 2-1 and 2-2 groups.

[0026] Figure 2: Thromboelastograms of compound 2-5 groups.

[0027] Figure 3: Thromboelastogram of compound 2-5 and 2-6 groups.

[0028] Detailed Description of the Invention

[0029] Compounds and preparation methods

[0030] One 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] in,

[0032] Y is selected from

[0033] 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 4-10Heterocyclic 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;

[0034] 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] When Y is selected from When R1 and R2 are not hydroxyl groups at the same time;

[0036] n = 0, 1, 2, 3, 4 or 5;

[0037] 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 1-6Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 The alkyl group is optionally replaced by one or more selected from C 4-10 Heterocyclic group, C 1-6 Alkoxy, Substituents substituted by

[0038] When X is -CO2H, R1, R2, R3 and R4 are not hydroxyl groups at the same time;

[0039] The wavy line Indicates the point of attachment to the rest of the molecule.

[0040] 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] In certain embodiments, n=1, 2, 3, 4, or 5.

[0042] In certain embodiments, R1 and R2 are not both hydroxyl groups.

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

[0044] in,

[0045] Y is selected from

[0046] 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] 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] R1 and R2 are not hydroxyl groups at the same time;

[0049] n = 1, 2, 3, 4 or 5;

[0050] X is selected from -CO2H and its carboxylic acid isostere, -CO2C 1-6 Alkyl, carboxylic acid choline ester, -C(=O)NHC 1-6 Alkyl and -C(=O)NHS(=O)2C 1-6Alkyl; preferably, X is -CO2H,

[0051] The wavy line Indicates the point of attachment to the rest of the molecule.

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

[0053]

[0054] 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 4-10 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 Substituted with a hydroxyalkyl group or a -OP(O)(OH)2 substituent;

[0055] R2 and R4 are selected from hydrogen, hydroxyl, carboxyl, ester, C 1-6 Alkoxy, carboxyl substituted C 1-6Alkyl 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;

[0056] R1 and R2 are not hydroxyl groups at the same time;

[0057] n = 1, 2, 3, 4 or 5;

[0058] X is selected from -CO2H and its carboxylic acid isostere, -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 replaced by one or more selected from C 4-10 Heterocyclic group, C 1-6 Alkoxy, Substituents substituted by

[0059] The wavy line Indicates the point of attachment to the rest of the molecule.

[0060] In certain embodiments, the compound of formula I of the present invention is a compound of formula II:

[0061] in,

[0062] R1, R2, R3, R4, X are as defined above for the compound of formula I, and

[0063] When X is -CO2H, R1, R2, R3 and R4 are not hydroxyl groups at the same time.

[0064] 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, C4-10 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.

[0065] 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, 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 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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, C1-6 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.

[0070] 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.

[0071] In certain embodiments of 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.

[0072] 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.

[0073] 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.

[0074] In certain embodiments, in the compounds of formula I and formula II, R2 and R4 are each independently selected from hydrogen, carboxyl, hydroxyl, C1-6 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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, -OS(O)2OH, -OS(O)2NH2; preferably, R2 and R4 are each independently hydroxyl.

[0080] 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.

[0081] 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.

[0082] 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)2C 1-6 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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, wherein the -CO2CH2CH3, -CO2CH3, -CO2CH2CH3 are optionally replaced by one or more selected from morpholinyl, substituted by a substituent.

[0087] In certain embodiments, in the compounds of Formula I and Formula II, n=1, 2, 3, or 4.

[0088] In certain embodiments, in the compounds of Formula I and Formula II, n=1, 2, or 3.

[0089] In certain embodiments, in the compounds of Formula I and Formula II, n=1 or 2.

[0090] In certain embodiments, in the compound of formula II, R1 and R3 are each independently selected from hydroxyl, -OC(=O)N(CH3)2,

[0091] R2 and R4 are selected from hydroxyl groups;

[0092] X is -CO2H, and R1, R2, R3 and R4 are not hydroxyl groups at the same time.

[0093] In certain embodiments, the compound of Formula I is selected from:

[0094] In certain embodiments, the compound of Formula II is selected from:

[0095] 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:

[0096] in:

[0097] R1, R2 and Y are as defined above for the compound of formula I; and

[0098] LG is a leaving group.

[0099] In certain embodiments, the leaving group includes but is not limited to halogen, C 1-6 Alkyl acyloxy, nitrophenoxy, fluorophenoxy.

[0100] In certain embodiments, the leaving group includes but is not limited to fluoro, chloro, bromo, iodo, acetoxy, p-nitrophenoxy, p-fluorophenoxy.

[0101] 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.

[0102] Route 1: Compound I-SM-1 is subjected to a condensation reaction with an alkylamino acid chloride or a heterocyclic acid chloride to obtain a compound of formula I.

[0103] 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.

[0104] 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), etc.), 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).

[0105] 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.

[0106] Route 2: Compound I-SM-1 is reacted with isocyanate to obtain a compound of formula I.

[0107] 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.

[0108] In some embodiments, the reaction is carried out in a suitable organic solvent, which can be selected from halogenated hydrocarbons (e.g., dichloromethane (DCM), chloroform (TCM), 1,2-dichloroethane (1,2-DCE), etc.), nitriles (e.g., acetonitrile (AN), etc.), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), 1,4-dioxane, dimethyl sulfoxide (DMSO), and any combination thereof, preferably N,N-dimethylformamide (DMF).

[0109] 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).

[0110] 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:

[0111] in:

[0112] R1, R3 and X are as defined above for the compound of formula II, and R1 and R3 are the same;

[0113] R2 and R4 are hydroxyl groups; and

[0114] LG is a leaving group.

[0115] In certain embodiments, the leaving group includes but is not limited to halogen, C 1-6 Alkyl acyloxy, nitrophenoxy, fluorophenoxy.

[0116] In certain embodiments, the leaving group includes but is not limited to fluoro, chloro, bromo, iodo, acetoxy, p-nitrophenoxy, p-fluorophenoxy.

[0117] 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.

[0118] Route 1: Compound II-SM1 undergoes condensation reaction with alkylamino acid chloride or heterocyclic acid chloride to obtain compound II.

[0119] 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.

[0120] 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), etc.), 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).

[0121] 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.

[0122] Route 2: Compound II-SM1 reacts with isocyanate to obtain a compound of formula II.

[0123] In some embodiments, the reaction is carried out at a temperature of 0-140°C, preferably 0°C, 20°C, 25°C, 40°C, 50°C, 60°C, 100°C, 140°C, and preferably 25°C.

[0124] 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), etc.), 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).

[0125] 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).

[0126] definition

[0127] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0128] 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 include other elements not expressly listed or inherent to such composition, method, or apparatus.

[0129] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting a compound of the present invention with a pharmaceutically acceptable inorganic / organic acid or inorganic / organic base, such salts being also referred to as acid addition salts or base addition salts.

[0130] 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.

[0131] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to an organism and is hydrolyzed in vivo to form a compound of the present invention or a salt thereof. Pharmaceutically acceptable esters generally include (but are not limited to) esters formed between a compound of the present invention and a pharmaceutically acceptable carboxylic acid or sulfonic acid, such esters being also referred to as carboxylate esters or sulfonate esters.

[0132] The term "isomers" refers to compounds that have the same number and types of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0133] 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. Because the compounds of the present invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Because the compounds of the present invention (or pharmaceutically acceptable salts thereof) contain asymmetric carbon atoms, they can exist as single stereoisomers, racemates, enantiomers, and mixtures of diastereomers. Generally, these compounds can be prepared as 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, a single stereoisomer of a compound is synthesized from an optically active starting material 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 diastereoisomers 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 with a specific stereochemistry are either commercially available or prepared as described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are nonsuperimposable mirror images of each other. The term "diastereomer" 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 invention.

[0134] 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 (such as in solution), a 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, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0135] 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).

[0136] The term "solvate" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) and at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetonides, etc.

[0137] 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; 1H 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.

[0138] 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.

[0139] The term "prodrug" refers to a derivative compound that is capable of providing, directly or indirectly, a compound of the present invention upon administration to a subject. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to a subject, can increase the bioavailability of the compound of the present invention (e.g., more readily absorbed into the bloodstream) or compounds that facilitate 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 present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

[0140] 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.

[0141] 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.).

[0142] The term "C 1-6 Alkylamino" or "C1-6 "Alkylamino" refers to -NH2 replaced by 1 or 2 C 1-6 The group formed by alkyl substitution, i.e. -NH-C 1-6 Alkyl or -N(C 1-6 Alkyl)2.

[0143] The term "acyloxy" refers to -OC(=O)-.

[0144] The term "C 1-6 "Alkyl acyloxy" refers to -OC(=O)-C 1-6 alkyl.

[0145] 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.

[0146] The term "C 1-6 "Alkoxyacyloxy" refers to -OC(=O)-C 1-6 Alkoxy.

[0147] The term "C 1-6 "Alkoxyalkylaminoacyloxy" refers to -OC(=O)-NH-alkyl-O-alkyl.

[0148] The term "C 4-10 "Heterocyclyloxy" refers to -OC(=O)-C 4-10 Heterocyclic group.

[0149] The term "sulfonyloxy" refers to -OS(=O)2-.

[0150] The term "C 1-6 "Hydroxyalkyl" refers to -C 1-6 Alkylene-OH.

[0151] The term "alkoxy" refers to an "alkyl" or "cycloalkyl" group (e.g., C 1-6 Alkoxy, C 3-8 Cycloalkyloxy, 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 "C1-6 -haloalkoxy", such as -OCF3, -OC2F5, etc.).

[0152] The term "C 1-6 "Alkoxycarbonyl" refers to -C(=O)-OC 1-6 alkyl.

[0153] The term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π electron system, which is optionally substituted with 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.).

[0154] 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 with one or more substituents described herein (e.g., oxo, C 1-6 The 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).

[0155] The term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, typically containing about 2 to 20 carbon atoms. For example, the term "C 2-6The 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.).

[0156] 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 2-6 Alkynyl 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.

[0157] The term "heterocyclyl" refers to 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: 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

[0158] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0159] The term "cyano" refers to a "-CN" group.

[0160] The term "hydroxy" refers to a "-OH" group.

[0161] The term "carboxyl" refers to a "-CO2H" group.

[0162] 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., trifluoromethanesulfonate) in a specified group are replaced by other atoms or groups of atoms, provided that the specified group satisfies the valence requirements in the current case and forms a stable compound after substitution. Combinations of substituents and / or variables are permitted only if the combination can form a stable compound. 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, the 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, or may not be replaced.

[0163] 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.

[0164] The term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, as appropriate.

[0165] In this article, solid lines can be used 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).

[0166] 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.

[0167] 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 pyranose glucopyranosyl, furanose glucopyranosyl, etc.

[0168] Pharmaceutical compositions, uses and methods of treatment

[0169] 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.

[0170] Another object of the present invention is to provide 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, stereoisomer, polymorph, solvate, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0171] 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 treating thromboembolic diseases.

[0172] 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, for use in treating thromboembolic diseases.

[0173] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0174] 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 glucose and glycerol solutions 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).

[0175] The compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0176] For these administration routes, the compositions of the present invention can be administered in suitable dosage forms.

[0177] Such 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.

[0178] As used herein, the term "therapeutically effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

[0179] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage 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.

[0180] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg / kg / day (single or divided administration). For 70kg people, this will add up to about 0.007mg / day to about 3500mg / day, for example, about 0.7mg / day to about 700mg / day. In some cases, it can be enough to be not higher than the dosage level of the lower limit of the aforementioned range, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0181] The content or dosage of the compound of the present invention in the pharmaceutical composition can be 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.

[0182] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0183] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) 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.). Example

[0184] In order to make the purpose and technical scheme of the present invention clearer, the embodiments of the present invention are described in detail below in conjunction with embodiment.But those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.Unindicated specific conditions in the examples are all carried out according to the conditions of normal conditions or manufacturer's advice.Reagents used or instruments not indicated by manufacturer are all conventional products that can be obtained commercially.

[0185] In this application, when a chemical name and a structural formula are inconsistent, the structural formula shall prevail unless the context indicates that the chemical name rather than the structural formula is correct.

[0186] In conventional synthesis methods and examples and intermediate synthesis examples, the meanings of the abbreviations are shown in the following table. The structures of the compounds were determined by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).

[0187] Unless otherwise specified, the reaction temperature is room temperature (20°C to 30°C).

[0188] 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)

[0189] (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) was dissolved in dry THF (2 ml), cooled and stirred to 0°C, and then NaH (9.20 mg, 0.383 mmol, 60% purity) was added. The mixture was stirred for 0.5 hours, and 4-morpholinecarbonyl chloride (17.21 mg, 0.115 mmol) was added. The mixture was allowed to react at 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).

[0190] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0191] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0192] 1-3:

[0193] ESI-MS (m / z): 634.7 [M+H] + .

[0194] 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).

[0195] 1-3-A:

[0196] ESI-MS (m / z): 634.7 [M+H] + .

[0197] 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=6.8Hz,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(dd,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)。

[0198] 1-3-B:

[0199] ESI-MS(m / z):747.8[M+H] + 。

[0200] 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=6.8Hz,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(dd,J=12.0,5.3Hz,1H),3.67(s,6H),3.44(s,2H),2.85(dd,J=17.3,5.1Hz,1H),2.632.53(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)。

[0201] 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)

[0202] (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) was dissolved in dry tetrahydrofuran (4 mL), cooled and stirred to 0°C, then NaH (55.23 mg, 2.3 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. Dimethylaminoformyl chloride (123.74 mg, 1.15 mmol) was added dropwise, and the temperature was slowly raised to 40°C 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).

[0203] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0204] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0205] Compound 2-1:

[0206] ESI-MS (m / z) 1011.3 [M+H] + .

[0207] 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).

[0208] Mixture 2-1-A & 2-1-B:

[0209] ESI-MS (m / z): 940.3 [M+H] + .

[0210] 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=12.3,5.9 Hz, 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=7.5H z, 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).

[0211] 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)-3,5-dihydroxy-2-methyl-5-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)- -((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-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid Preparation of 2-[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)

[0212] 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. , 3.45mmol, content 60%) was stirred for 10 minutes, 4-morpholinecarbonyl chloride (137.68mg, 0.92mmol) 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 (10ml), and the product was extracted with EA (20ml). 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 (28.0mg) and a mixture of 2-2-A / 2-2-B (21.0mg).

[0213] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0214] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0215] Retention time: 12.7-13.2 min

[0216] Compound 2-2:

[0217] ESI-MS m / z(ESI):1095.3[M+H] + .

[0218] 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).

[0219] Mixture 2-2-A & 2-2-B:

[0220] ESI-MS m / z(ESI):982.6[M+H] + .

[0221] 1 H 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).

[0222] 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)

[0223] (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, 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 obtain 48 mg of the title compound.

[0224] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0225] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% ammonium bicarbonate).

[0226] ESI-MS (m / z): 1039.5 [M+H] + .

[0227] 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).

[0228] 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)

[0229] (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-E]isoindole-8(2H)-valeric acid (250 mg, 0.288 mm 1.5 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 a 10% aqueous NaOH solution was added dropwise to adjust the pH to 11. Methyl chloroformate (163.1 mg, 1.73 mmol) was added dropwise, and a 10% aqueous NaOH solution was added dropwise to control the pH to 10-11. After the addition was complete, the mixture was reacted at room temperature for 2 hours, and the pH was adjusted to 3-4 with an aqueous citric acid solution. The product was extracted with EA (30 mL), and the organic phase was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain the title compound 2-4 (130.0 mg).

[0230] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0231] Mobile phase A: acetonitrile; mobile phase B: water (0.05% ammonium formate aqueous solution).

[0232] Retention time: 7 to 9 minutes

[0233] The structural characterization data are as follows:

[0234] MS m / z(ESI):985.4[M+H] + .

[0235] 1HNMR (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).

[0236] 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-(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)

[0237] (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 to 0°C with stirring. NaH (46.03 mg, 1.15 mmol, 60% purity) was then added and 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 warmed 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).

[0238] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0239] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0240] Compound 2-5:

[0241] ESI-MS (m / z): 1191.5 [M+H] + .

[0242] 1 H 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).

[0243] Mixture 2-5-A & 2-5-B:

[0244] ESI-MS (m / z): 1030.3 [M+H] + .

[0245] 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=13.3 Hz,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 .6Hz, 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).

[0246] 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)

[0247] 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)

[0248] (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-E]isoindol-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 temperature was maintained at 0-5°C for 4 hours. The reaction solution was added to saturated aqueous sodium bicarbonate (40 mL) / ethyl acetate (80 ml) while maintaining the temperature at 0-10°C. 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).

[0249] 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)

[0250] 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 detected by high performance liquid chromatography-mass spectrometry. The reaction solution was poured into a cooled aqueous ammonium chloride solution to quench, and 0.1N aqueous hydrochloric acid solution was added dropwise to neutralize it. The organic phase was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, dried, and concentrated to obtain 60 mg of a crude product.

[0251] 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)

[0252] Dissolve the 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 HPLC to obtain 22.24 mg of the title compound.

[0253] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0254] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0255] ESI-MS (m / z): 1128.6 [M+H] + .

[0256] 1 H 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), 4.834.74 (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, 2H ), 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).

[0257] 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)

[0258] 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)

[0259] Compound 2-7-1 (50 mg, 0.057 mmol) was added to NMP (2 mL), cooled to 0-5°C with ice water, and 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 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.

[0260] 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)

[0261] 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, washed with brine, dried, and concentrated to obtain a crude product, which was purified by preparative HPLC to obtain 17 mg of the title compound.

[0262] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0263] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0264] Retention time: 8 to 10 minutes.

[0265] The structural characterization data are as follows:

[0266] MS m / z(ESI):1151.7[M+H] + .

[0267] 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).

[0268] 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)

[0269] 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)

[0270] Compound 2-7-1 (50 mg, 0.057 mmol) was added to NMP (2 mL), cooled to 0-5°C with ice water, and 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 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.

[0271] 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)

[0272] 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 allowed to react at room temperature for 2 hours. 1 N 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, washed with brine, dried, and concentrated to obtain a crude product, which was purified by preparative HPLC to obtain 5.7 mg of the title compound.

[0273] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0274] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0275] Retention time: 15.5~17.5min.

[0276] The structural characterization data are as follows:

[0277] MS m / z(ESI):1091.6[M+H] + .

[0278] 1HNMR (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).

[0279] 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 (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- 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)

[0280] (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) and cooled to 0°C with stirring. 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).

[0281] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0282] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0283] Compound 2-10:

[0284] ESI-MS (m / z): 1167.8 [M+H] + .

[0285] 1 H 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).

[0286] Mixture 2-10-A & 2-10-B:

[0287] ESI-MS (m / z): 1018.5 [M+H] + .

[0288] 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).

[0289] 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)

[0290] (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) and cooled to 0°C with stirring. NaH (46.03 mg, 1.15 mmol, 60% content) was then added. The mixture was stirred at room temperature for 0.5 hours. 1-Chloroformyl-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.

[0291] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0292] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0293] ESI-MS (m / z): 1257.9 [M+H] + .

[0294] 1 H 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).

[0295] 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)

[0296] Step 1:

[0297] (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 bromotetraacetyl glucoside (378.51 mg, 0.920 mmol) were dissolved in acetonitrile (4 ml), and then silver oxide (266.64 mg, 1.150 mmol) was added. The mixture was stirred and reacted at 25° C. for 16 hours. The reaction was detected by HPLC-MS / MS chromatography. The reaction solution was purified by HPLC to obtain 2-22-1A (8 mg), 2-22-1B (19 mg), and 2-22-1C (20 mg).

[0298] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0299] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0300] 2-22-1A:

[0301] ESI-MS (m / z): 1860.7 [M+H] + .

[0302] 2-22-1B / 2-22-1C:

[0303] ESI-MS (m / z): 1530.6 [M+H] + .

[0304] 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)

[0305] Dissolve 2-22-1A (8 mg, 0.004 mmol) in tetrahydrofuran (1 mL) and dextrin (0.25 mL). Add lithium hydroxide (1.80 mg, 0.043 mmol) and stir for 1 hour. Detect the reaction using HPLC-MS / MS. Neutralize the reaction solution by adding 3N aqueous hydrochloric acid. Remove the solvent by evaporation under reduced pressure. Purify the mixture by HPLC to obtain 2.12 mg of the title compound.

[0306] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0307] ESI-MS (m / z): 1193.6 [M+H] + .

[0308] 1 HNMR (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), 3.7 9-3.63 (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).

[0309] 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)

[0310] Dissolve 2-22-1B (19 mg, 0.012 mmol) in tetrahydrofuran (1 mL) and HCl (0.25 mL). Add lithium hydroxide (2.61 mg, 0.062 mmol) and stir for 1 hour. Detect the reaction using HPLC-MS / MS. Neutralize the reaction solution by adding 3N aqueous hydrochloric acid solution dropwise. Remove the solvent under reduced pressure and purify by HPLC to obtain 3.03 mg of the title compound.

[0311] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0312] ESI-MS (m / z): 1031.6 [M+H] + .

[0313] 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).

[0314] 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)

[0315] Dissolve 2-22-1C (20 mg, 0.013 mmol) in tetrahydrofuran (1 mL) and HCl (0.25 mL). Add lithium hydroxide (2.74 mg, 0.065 mmol) and stir for 1 hour. Detect the reaction using HPLC-MS / MS. Neutralize the reaction solution by adding 3N aqueous hydrochloric acid. Evaporate the solvent under reduced pressure and purify the mixture using HPLC to obtain 3.73 mg of the title compound.

[0316] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0317] ESI-MS (m / z): 1031.6 [M+H] + .

[0318] 1HNMR (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. 14 (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=20.4H z, 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).

[0319] 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)

[0320] 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 (10 mg, 0.115 mmol) and dissolve in dry THF (10 ml). Cool and stir to 0°C, then add NaH (46.03 mg, 1.15 mmol, 60% content) and recover. The reaction was stirred at room temperature for 0.5 hours, 1-chloroformyl-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 dropwise added with 3N aqueous hydrochloric acid to neutralize. After concentration under reduced pressure, the disubstituted compound 2-23 (8.07 mg) and the monosubstituted compounds 2-23-A (3.32 mg) and 2-23-B (14.16 mg) were obtained by HPLC-MS / MS.

[0321] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0322] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0323] 2-23:

[0324] ESI-MS (m / z): 1122.7 [M+H] + .

[0325] 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).

[0326] 2-23-A:

[0327] ESI-MS (m / z): 996.6 [M+H] + .

[0328] 1 H 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,2H),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,1H),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)。

[0329] 2-23-B:

[0330] ESI-MS(m / z):996.6[M+H] + 。

[0331] 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)。

[0332] 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)

[0333] 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)

[0334] 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 solution 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.

[0335] 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 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)pentanoic acid (2-28-B)

[0336] 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), and lithium hydroxide (93.34 mg, 3.90 mmol) was added. The mixture was reacted 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 obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain the title compound (24.0 mg).

[0337] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0338] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid in water).

[0339] Retention time: 5.3~6.2min.

[0340] The structural characterization data are as follows:

[0341] MS m / z(ESI):948.3[M+H] + .

[0342] 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).

[0343] 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)

[0344] (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-E]isoindol-8(2H)-yl) Indole-8(2H)-pentanoic 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 μmo), and DIPEA 74.35 mg, 575.31 μmol) 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 2-29 (56.0 mg).

[0345] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0346] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid in water).

[0347] Retention time: 8.5~9.5min.

[0348] The structural characterization data are as follows:

[0349] MS m / z(ESI):882.5[M+H] + .

[0350] 1 H 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).

[0351] 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)

[0352] (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-E]isoindol-8(2H)-yl) 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).

[0353] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0354] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0355] Retention time: 8.5~9.5min.

[0356] The structural characterization data are as follows:

[0357] MS m / z(ESI):926.5[M+H+H2O] + .

[0358] 1H 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).

[0359] 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)

[0360] (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.

[0361] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0362] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0363] ESI-MS (m / z): 983.7 [M+H] + .

[0364] 1 HNMR (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, 2H), 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).

[0365] 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)

[0366] (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-E]isoindol-8(2H)-yl) E] 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).

[0367] Chromatographic column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm).

[0368] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0369] Retention time: 8.5~9.5min.

[0370] The structural characterization data are as follows:

[0371] MS m / z(ESI):1414.7[M+H+H2O] + .

[0372] 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), 3.37-3.35(m, 2H), 2.85-2.78(m, 3H), 2.47-2.42(m, 2H), 2.13-2.0 7(m, 4H), 2.04-1.97(m, 4H), 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).

[0373] 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)

[0374] (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. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by HPLC-MS / MS. The reaction solution was acidified by the addition of hydrochloric acid and purified by HPLC to obtain 8.70 mg of the title compound.

[0375] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0376] Mobile phase A: acetonitrile; mobile phase B: water (containing 0.05% formic acid).

[0377] ESI-MS (m / z): 954.7 [M+H] + .

[0378] 1 HNMR (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).

[0379] 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-dimethylhept-3,7-dien-1-yl)-5-((1-oxothiomorpholine)-1-yl)-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) -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-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) and (S)-2-(2R,3S)-2-(E)-4,8-dimethylnona-3,7-dien-1-yl) 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)

[0380] (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) was dissolved in dry tetrahydrofuran (50 ml). Triethylamine was added dropwise, followed by a solution of p-nitrophenyl chloroformate (406 mg, 2.06 mmol, dissolved in 5 mL of tetrahydrofuran). The mixture was stirred for 2 hours. 1-Oxothiomorpholine hydrochloride (447 mg, 2.87 mmol) was added, and the reaction was stirred for another 2 hours. The reaction was monitored 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).

[0381] Compound 2-6:

[0382] Purification condition 1:

[0383] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0384] Mobile phase A: acetonitrile; mobile phase B: water (0.05% ammonium bicarbonate).

[0385] ESI-MS (m / z): 1159.5 [M+H] + .

[0386] 1 H 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).

[0387] Mixture 2-6-A & 2-6-B:

[0388] Purification condition 2:

[0389] Chromatographic column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm.

[0390] Mobile phase A: acetonitrile; mobile phase B: water (0.05% ammonium bicarbonate).

[0391] ESI-MS (m / z): 1014.3 [M+H] + .

[0392] 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).

[0393] The remaining compounds shown in the following table were prepared in a similar manner as above:

[0394] Biological data

[0395] Experimental Example 1: Activation of Plasminogen (Glu-Typ) by Compounds

[0396] 1. Test methods

[0397] (1) Compound preparation

[0398] Three concentration points were set for the test compound and the positive compound of the present invention, namely 200 μM, 150 μM, and 100 μM; the final concentration of DMSO was 2.5%.

[0399] (2) Main reagents and instrument information

[0400] Plasminogen (Glu-Typ) (Sigma); urokinase-type plasminogen activator (u-PA) (Aladdin); VLK-pNA (absin); multifunctional microplate reader (Thermo).

[0401] (3) Test system and signal detection

[0402] Plasminogen stock solutions were prepared at 100 nM (5×), 100 IU / ml (5×), and 5 mM (5×) in a buffer solution [Tris-HCl (50 mM, pH 7.4) + NaCl (100 mM) + Tween-80 (0.01%)]. 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 and mixed thoroughly. After that, 40 μl of the test compound or positive compound was added to the 96-well plate. A control group (no compound) was also set up and mixed thoroughly. Kinetic analysis was performed using a Thermo multi-function microplate reader at a wavelength of 405 nm and a 1-min detection interval. The activation fold was calculated.

[0403] 2. Test results

[0404] 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).

[0405] Table 1-1 Efficacy of compounds in activating plasminogen

[0406] Table 1-2 Efficacy of compounds in activating plasminogen

[0407] 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 plasminogen activation effects than the positive compound.

[0408] Experimental Example 2: Fibrinolytic Effects of Thromboelastography Compounds

[0409] Main instruments and reagents: Thromboelastograph (Udi Biotechnology); urokinase-type plasminogen activator (u-PA) (Aladdin); reagent 1 (the main ingredient is kaolin); reagent 2 (the main ingredient is calcium chloride).

[0410] 1. Test method:

[0411] (1) Experimental 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.

[0412] (2) Compound Solution Preparation: Dissolve the compound in 0.5 mg / ml tromethamine to a 4 mM stock solution, adjust the pH to 9, and then dilute to a 2 mM 10X stock solution, with a final test concentration of 200 μM. u-PA was prepared in physiological saline to a 50,000 U / ml stock solution, diluted to a 10X stock solution of 10,000 U / ml, with a final test concentration of 1000 U / ml.

[0413] (3) Test: 100 μL of u-PA was added to a sample cup (containing Reagent 1) containing 800 μL of rat whole blood (anticoagulated with sodium citrate), followed by 100 μL of the test compound, and the mixture was mixed by inversion. Then, 340 μL of the sample cup was added to a reaction cup containing 20 μL of Reagent 2, and the instrument was run. The results were shown in Tables 2-1, 2-2, and 2-3, as well as in Figures 1, 2, and 3. The compound concentrations in Tables 2-1, 2-2, and Figures 1 and 2 were 200 μM; the compound concentrations in Tables 2-3 and 3 were 100 μM.

[0414] Table 2-1 Thromboelastometry data

[0415] Table 2-2 Thromboelastometry data

[0416] Table 2-3 Thromboelasticity data

[0417] 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.

[0418] The structures of the positive compounds are as follows:

Claims

1. A compound or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-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 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; 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; 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. The compound according to claim 1 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 1-6 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.

3. The 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 Alkoxyacyloxy, 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 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.

4. The compound according to any one of claims 1 to 3, 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, -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 the group consisting of 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. The compound according to any one of claims 1 to 4, 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, -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. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-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, -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.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-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 substituted by an alkyl substituent.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-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. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug, or mixture thereof, wherein: n=1, 2 or 3.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-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, carboxyl 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 substituted by an alkoxy substituent, The wavy line Indicates the point of attachment to the rest of the molecule.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-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 Alkyl groups are each optionally selected from morpholinyl and -C 1-6 substituted by an alkoxy substituent, The wavy line Indicates the point of attachment to the rest of the molecule.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-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. The 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, The compound is selected from:

14. The 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, and 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. The compound according to claim 14 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope-labeled form, metabolite and prodrug thereof, wherein the compound is selected from:

16. 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 mixture thereof, and one or more pharmaceutically acceptable carriers, and optionally further comprising one or more other drugs for treating thromboembolic diseases.

17. Use of the compound of claims 1-15 or its pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, polymorphs, isotope-labeled substances, metabolites, prodrugs or mixtures thereof, or the pharmaceutical composition of claim 16 in the preparation of a medicament for treating thromboembolic diseases.

18. The compound of claims 1-15 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled substance, metabolite, prodrug or mixture thereof, or the pharmaceutical composition of claim 16, for use in treating thromboembolic diseases.

19. A method for treating thromboembolic diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claims 1 to 15 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled, metabolite, prodrug, or mixture thereof, or the pharmaceutical composition of claim 16.

20. A method 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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