Complex ring compound, method for preparing the same, and application thereof

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to heterocyclic compounds, pharmaceutical compositions containing the same, processes for preparing the same, and the use of such compounds in the manufacture of medicaments for the treatment of thromboembolic diseases.

Background Art

[0002] Stroke is an acute cerebrovascular disease including ischemic stroke and hemorrhagic stroke, and the incidence rate of ischemic stroke accounts for about 80% of the total stroke (International Journal of Cardiology, 2016, 222, 441 - 447).

[0003] Intravenous injection of tissue plasminogen activator (t - PA) has been the only recommended therapy for cerebral infarction as a high - molecular compound for nearly 20 years. However, t - PA has the disadvantages of a short treatment - available time (less than 4.5 hours) and a 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. In strokes caused by acute occlusion of large blood vessels, the recanalization rate after intravenous thrombolytic therapy with rt - PA does not exceed 25% (Stroke, 2010, 41, 2254 - 2258).

[0004] The SMTP series compounds are a group of compounds having a triisoprenylphenol (TP) structure produced by microbial fermentation and purification of the filamentous fungus Stachybotrys microspora (JP2002065288A). This class of compounds, such as orinplabin, promotes the activation of plasminogen mediated by urokinase-type plasminogen activator (u-PA) or t-PA by relaxing the conformation of plasminogen, rapidly increases the level of plasmin, and is known as a plasminogen modulator that promotes thrombolysis by plasmin (The FEBS Journal, 2010, 277, 3675-3687). Since the SMTP series compounds do not directly activate plasminogen and do not affect the levels of u-PA or t-PA, they can mechanistically avoid the potential harmful risks of intracerebral hemorrhage that can occur with thrombolytic agents having conventional mechanisms of action (Naunyn-Schmiedeberg's Archives of Pharmacology, 2010, 382, 245-253). In addition to the function of regulating the conformation of plasminogen, the SMTP series compounds have soluble epoxide hydrolase (sEH) inhibitory activity independent of thrombolytic activity. sEH is a bifunctional enzyme involved in important physiological activities such as inflammatory reactions and lipid metabolism (Journal of Biological Chemistry, 2014, 289 (52), 35826-35838). The inhibitory effect of the SMTP series compounds on sEH may be related to their in vivo anti-inflammatory activity (International Journal of Molecular Sciences, 2021, 22, 954). Plasminogen modulators with higher biological activity improved based on SMTP-based compounds are worthy of further research, and there is a need to develop thrombolytic drugs with a new mechanism of action, a long treatment time frame, and a low bleeding risk.

Summary of the Invention

[0005] Through many studies, we have surprisingly found a kind of heterocyclic compound and its preparation method. Such compounds have excellent plasminogen regulatory effects, can exert thrombolysis-promoting effects and anti-inflammatory effects, and are used in the treatment of various thromboembolic diseases such as ischemic stroke.

[0006] In one aspect, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or a mixture thereof:

Chemical formula

Chemical formula

Chemical formula

[0007] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled form, metabolite, prodrug, or a mixture thereof, and one or more pharmaceutically acceptable carriers, optionally further comprising one or more additional drugs for the treatment of thrombotic and embolic diseases.

[0008] In another aspect, the present invention relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled form, metabolite, prodrug, or a mixture thereof, or the pharmaceutical composition of the present invention, in the manufacture of a medicament for the treatment of thrombotic and embolic diseases.

[0009] In another aspect, the present invention relates to a compound of the present invention, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled form, metabolite, prodrug, or a mixture thereof, or the pharmaceutical composition of the present invention, for use in the treatment of thrombotic and embolic diseases.

[0010] In another aspect, the present invention relates to a method for treating a thromboembolic disease, comprising 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, isotope-labeled compound, metabolite, prodrug, or a mixture thereof, or a pharmaceutical composition of the present invention.

[0011] In another aspect, the present invention relates to a method for preparing a compound of the present invention, comprising the steps shown in the following scheme:

Chemical formula

Brief Description of the Drawings

[0012]

Figure 1

Figure 2

Figure 3

[0013] Compounds and Preparation Methods An object of the present invention is to provide a compound of formula I, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or a mixture thereof:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0014] In some embodiments, R1 and R3 are independently carboxyl, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyacyloxy, C1-6 Alkylacyloxy, C 1-6 Alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclylacyloxy, -O-C 4-10 Heterocyclyl, C 1-6 Alkylsulfamoyloxy, C 4-10 Heterocyclylsulfonyloxy, glycosyl, -O-P(O)(OH)2, -O-P(O)2OH, -O-S(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkylamide, C 4-10 Heterocyclylamide, halogen, cyano, C 2-6 Alkenyl, and C 2-6 Alkynyl are each independently selected from the group consisting of; C 4-10 Heterocyclylacyloxy, -O-C 4-10 Heterocyclyl, C 1-6 Alkylacyloxy, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 Alkylaminoacyloxy is optionally substituted with one or more substituents selected from the group consisting of hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl, C 1-6 Haloalkyl, C 1-6 Alkoxyacyloxy, C 1-6 Alkyl-C(=O)-, 4- to 10-membered heterocyclyl, C 1-6 Hydroxyalkyl, and -O-P(O)(OH)2 and is optionally substituted with one or more substituents selected from the group consisting of.

[0015] In some embodiments, n is 1, 2, 3, 4, or 5.

[0016] In some embodiments, R1 and R2 are not both hydroxy simultaneously.

[0017] Another object of the present invention is to provide a compound of formula I, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled form, metabolite, prodrug, or a mixture thereof:

Chemical formula

Chemical formula

Chemical formula

[0018] Another object of the present invention is to provide a compound of formula I, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotopically labeled form, metabolite, prodrug, or a mixture thereof:

Chemical formula

Chemical formula

Chem.

Chem.

[0019] In some embodiments, the compound of formula I of the present invention is a compound of formula II:

Chem.

[0020] In some embodiments, in the compounds having the structures of formulas I and II, R1 and R3 are independently carboxyl, hydroxy, C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkylaminoacyloxy, C 4-10 Heterocyclylacyloxy, -O-C 4-10Heterocyclyl, C 4-10 Heterocyclylsulfonyloxy, -O-P(=O)(OH)2, -O-S(O)2OH, and C 4-10 Each independently selected from the group consisting of heterocyclylamide; C 4-10 Heterocyclylacyloxy, -O-C 4-10 Heterocyclyl, or C 1-6 Alkylaminoacyloxy is optionally substituted with one or more substituents selected from the group consisting of 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- to 10-membered heterocyclyl, C 1-6 Hydroxyalkyl, and -O-P(=O)(OH)2.

[0021] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are each independently carboxyl, hydroxy, C 1-3 Alkoxy, C 1-3 Alkoxyacyloxy, C 1-3 Alkylaminoacyloxy, C 4-8 Heterocyclylacyloxy, -O-C 4-8 Heterocyclyl, C 4-8 Heterocyclylsulfonyloxy, -O-P(=O)(OH)2, -O-S(O)2OH, and C 4-8 Each independently selected from the group consisting of heterocyclylamide; C 4-8 Heterocyclylacyloxy, -O-C 4-8 Heterocyclyl, or C 1-3 Alkylaminoacyloxy is optionally substituted with one or more substituents selected from the group consisting of 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- to 8-membered heterocyclyl, C 1-3It is optionally substituted with one or more substituents selected from the group consisting of hydroxyalkyl and -O-P(=O)(OH)2.

[0022] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are independently carboxyl, hydroxy, -OC(=O)N(CH3)2, -OC(=O)-morpholinyl, -OC(=O)NHCH(CH3)2, -OC(=O)OCH3, -OC(=O)-thiomorpholine dioxide, -OC(=O)-thiomorpholine monoxide, -OC(=O)-thiomorpholine, -OC(=O)N(CH3)-tetrahydropyran, -OC(=O)-piperidine, -OSO2-morpholine, -OC(=O)-piperazine,

Chemical Structure

Chemical Structure

[0023] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are independently selected from the group consisting of carboxyl, hydroxy, -OC(=O)N(CH3)2, -OC(=O)NHCH(CH3)2, -OC(=O)OCH3, -OC(=O)-morpholinyl, -OC(=O)-thiomorpholine dioxide, -OC(=O)-thiomorpholine monoxide, -OC(=O)-thiomorpholine, -OC(=O)N(CH3)-tetrahydropyran, -OC(=O)-piperidine, -OSO2-morpholine, -OC(=O)-piperazine,

Chemical formula

[0024] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are independently selected from the group consisting of carboxyl, hydroxy, -OC(=O)N(CH3)2, -OC(=O)NHCH(CH3)2, -OC(=O)OCH3, -O-P(=O)(OH)2, methoxy, -O-S(O)2OH,

Chemical formula

Chemical formula

[0025] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are independently hydroxy, C 1-6 alkoxy, C1-6 Alkoxyacyloxy, C 1-6 Alkylacyloxy, C 1-6 Alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-6 Heterocyclylacyloxy, C 1-6 Alkylsulfamoyloxy, C 4-6 Heterocyclylsulfonyloxy, glycosyl, -O-P(O)2OH, -O-S(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkylamide, C 4-6 Heterocyclylamide, halogen, cyano, C 2-6 Alkenyl, and C 2-6 Each is independently selected from the group consisting of alkynyl.

[0026] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are independently C 1-6 Alkoxy, C 1-6 Alkoxyacyloxy, C 1-6 Alkylacyloxy, C 1-6 Alkoxyalkylaminoacyloxy, C 1-6 Alkylaminoacyloxy, C 4-6 Heterocyclylacyloxy, C 1-6 Alkylsulfamoyloxy, C 4-6 Heterocyclylsulfonyloxy, glycosyl, -O-P(O)2OH, -O-S(O)2OH, amino, C 1-6 Alkylamino, C 1-6 Alkylamide, C 4-6 Heterocyclylamide, halogen, cyano, C 2-6 Alkenyl, and C 2-6 Each is independently selected from the group consisting of alkynyl.

[0027] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are independently C 1-6 Alkylaminoacyloxy and C 4-6 Each is independently selected from the group consisting of heterocyclylacyloxy.

[0028] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are each independently selected from the group consisting of -OC(=O)N(CH3)2, -OC(=O)-piperidine ring, -OC(=O)-morpholine ring, -OC(=O)-thiomorpholine, -OC(=O)-thiomorpholine dioxide, -OC(=O)-thiomorpholine monoxide, -OC(=O)NHCH(CH3)2, and -OC(=O)CH3.

[0029] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are each independently selected from the group consisting of -OC(=O)N(CH3)2, -OC(=O)-morpholine ring, -OC(=O)NHCH(CH3)2, and -OC(=O)CH3.

[0030] In some embodiments, in the compounds having the structures of Formulas I and II, R2 and R4 are each independently hydrogen, carboxyl, hydroxy, C 1-6 alkoxy, carboxyl-substituted C 1-6 alkylacyloxy, -OC(=O)-C 4-10 heterocyclyl, -O-P(O)2OH, -O-S(O)2OH, and -O-S(O)2NH2, and C 4-10 heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl.

[0031]

[0031] In some embodiments, in the compounds having the structures of Formulas I and II, R2 and R4 are each independently hydrogen, hydroxy, C 1-6 alkoxy, carboxyl-substituted C 1-6 alkylacyloxy, -OC(=O)-C 4-10 heterocyclyl, -O-P(O)2OH, -O-S(O)2OH, and -O-S(O)2NH2, and C 4-10 heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl.

[0032] In some embodiments, in the compounds having the structures of Formulas I and II, R2 and R4 are independently carboxyl, hydroxy, C 1-6 alkoxy, carboxyl-substituted C 1-6 alkylacyloxy, -OC(=O)-piperazinyl, -O-P(O)2OH, -O-S(O)2OH, and -O-S(O)2NH2, respectively, wherein piperazinyl is optionally substituted with one or more substituents selected from C 1-6 alkyl.

[0033] In some embodiments, in the compounds having the structures of Formulas I and II, R2 and R4 are independently carboxyl, hydroxy,

Chemical formula

Chemical formula

[0034] In some embodiments, in the compounds having the structures of Formulas I and II, R2 and R4 are independently hydroxy,

Chemical formula

[0035] In some embodiments, in the compounds having the structures of Formulas I and II, R2 and R4 are independently hydrogen, hydroxy, C 1-6 alkoxy, carboxyl-substituted C 1-6 alkylacyloxy, -O-P(O)2OH, -O-S(O)2OH, and -O-S(O)2NH2, respectively; preferably, R2 and R4 are each independently hydroxy.

[0036] In some embodiments, in the compounds having the structures of Formulas I and II, R2 and R4 are each independently hydrogen, hydroxy, C 1-6 alkoxy, carboxyl-substituted C 1-6 alkylacyloxy, -O-P(O)2OH, and -O-S(O)2OH, respectively; preferably, R2 and R4 are each independently hydroxy.

[0037] In some embodiments, in the compounds having the structures of Formulas I and II, X is -CO2H and its carboxylic acid isoster, -CO2C 1-6 alkyl, -C(=O)SH, 4-10 membered heteroaryl, choline carboxylate, -C(=O)NHC 1-6 alkyl, -C(=O)NHS(=O)2C 1-6 alkylamino and -C(=O)NHS(=O)2C 1-6 alkyl, selected from the group consisting of -CO2C 1-6 alkyl, 4-10 membered heteroaryl, choline carboxylate, -C(=O)NHC 1-6 alkyl, -C(=O)NHS(=O)2C 1-6 alkylamino and -C(=O)NHS(=O)2C 1-6 alkyl is 4-10 membered heterocyclyl,

Chemical formula

Chemical formula

[0038] In some embodiments, in the compounds having the structures of Formulas I and II, X is -CO2H and its carboxylic acid isoster, -CO2C 1-6 alkyl, 4-10 membered heteroaryl, choline carboxylate, -C(=O)NHC 1-6Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 Selected from the group consisting of alkyl, -CO2C 1-6 Alkyl, 4- to 10-membered heteroaryl, choline carboxylate, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O)2C 1-6 Alkylamino and -C(=O)NHS(=O)2C 1-6 Alkyl is optionally substituted with one or more substituents selected from the group consisting of 4- to 10-membered heterocyclyl,

Chemical Structure

Chemical Structure

[0039] In some embodiments, in the compounds having the structures of Formulas I and II, X is -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 Selected from the group consisting of alkyl)2, -CO2C 1-6 Alkyl and -C(=O)NHC 1-6 Alkyl is morpholinyl,

Chemical Structure

Chemical Structure

[0040] In some embodiments, in the compounds having the structures of Formulas I and II, X is -CO2H, -C(=O)NHCH3, -C(=O)SH,

Chem.

Chem.

[0041] In some embodiments, in the compounds having the structures of Formulas I and II, X is -CO2H, -CO2C 1-3 alkyl, 5-6 membered nitrogen-containing heterocyclyl, choline carboxylate, -C(=O)NHC 1-6 alkyl, -C(=O)NHS(=O)2C 1-3 alkylamino and -C(=O)NHS(=O)2C 1-3 alkyl selected from the group consisting of, -C(=O)2C 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 alkyl is optionally substituted with one or more substituents selected from the group consisting of 4-6 membered heterocyclyl,

Chem.

[0042] In some embodiments, in the compounds having the structures of Formulas I and II, X is -CO2H, 5-6 membered nitrogen-containing heterocyclyl, -C(=O)NHS(=O)2N(CH3)2, -C(=O)NHS(=O)2CH3, -CO2CH2CH3, -CO2CH3, -CO2CH2CH3, -C(=O)NHCH2CH2OCH3, -C(=O)NHCH3, and tetrazole, -CO2CH2CH3, -CO2CH3 or -CO2CH2CH3 is morpholino,

Chem.

[0043] In some embodiments, in the compounds having the structures of Formulas I and II, n is 1, 2, 3, or 4.

[0044] In some embodiments, in the compounds having the structures of Formulas I and II, n is 1, 2, or 3.

[0045] In some embodiments, in the compounds having the structures of Formulas I and II, n is 1 or 2.

[0046] In some embodiments, in the compounds having the structures of Formulas I and II, R1 and R3 are independently hydroxy, -OC(=O)N(CH3)2,

Chemical formula

[0047] In some embodiments, the compounds of Formula I are selected from the group consisting of:

Chemical formula

[0048] In some embodiments, the compounds of Formula II are selected from the group consisting of:

Chemical formula

[0049] Another object of the present invention is to provide a method for preparing a compound of formula I of the present invention, which comprises the steps shown in the following scheme:

Chemical formula

[0050] In some embodiments, the leaving group includes, but is not limited to, halogen, C 1-6 alkylacyloxy, nitrophenoxy, and fluorophenoxy.

[0051] In some embodiments, the leaving group includes, but is not limited to, fluorine, chlorine, bromine, iodine, acetoxy, p-nitrophenoxy, and p-fluorophenoxy.

[0052] When R1 is selected from C 1-6 alkylaminoacyloxy or C 4-6 heterocyclylacyloxy, the compounds of formula I of the present invention can be synthesized and prepared by the following synthetic route.

[0053] Route 1: Condense a compound of formula I-SM-1 with an alkylaminoacyl chloride or a heterocyclylacyl chloride to obtain a compound of formula I.

[0054] In some embodiments, the reaction is carried out at a temperature of 0 to 140 °C, such as 0 °C, 20 °C, 25 °C, 40 °C, 50 °C, 60 °C, 100 °C, and 140 °C, preferably 0 to 35 °C.

[0055] In some embodiments, this reaction is carried out in a suitable solvent selected from the group consisting of 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 in tetrahydrofuran (THF).

[0056] In some embodiments, the reaction is carried out in the presence of a suitable base containing an organic base or an inorganic base. The organic base is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), potassium tert-butoxide (t-BuOK), and pyridine (Py). The inorganic base is selected from the group consisting of potassium phosphate (K3PO4), sodium hydride (NaH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), cesium carbonate (Cs2CO3), and NaOH, preferably NaH.

[0057] Route II: React the compound of formula I-SM-1 with an isocyanate to obtain the compound of formula I.

[0058] In some embodiments, the reaction is carried out at a temperature of 0 to 140 °C, for example, 0 °C, 20 °C, 25 °C, 40 °C, 50 °C, 60 °C, 100 °C, and 140 °C, preferably 25 °C.

[0059] In some embodiments, the reaction is carried out in a suitable organic solvent selected from the group consisting of 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 (Dioxan), dimethyl sulfoxide (DMSO), and any combination thereof, preferably in N,N-dimethylformamide (DMF).

[0060] In some embodiments, the reaction is carried out in the presence of a suitable base comprising an organic base or an inorganic base. The organic base is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), potassium tert-butoxide (t-BuOK), and pyridine (Py). The inorganic base is selected from the group consisting of potassium phosphate (K3PO4), sodium hydride (NaH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), cesium carbonate (Cs2CO3), and NaOH. The base is preferably N,N-diisopropylethylamine (DIPEA) or triethylamine (TEA).

[0061] Another object of the present invention is to provide a method for preparing a compound of formula II of the present invention, comprising the steps shown in the following scheme:

Chemical formula

[0062] In some embodiments, the leaving group includes, but is not limited to, halogen, C 1-6Examples include alkylacyloxy, nitrophenoxy, and fluorophenoxy.

[0063] In some embodiments, the leaving group includes, but is not limited to, fluorine, chlorine, bromine, iodine, acetoxy, p-nitrophenoxy, and p-fluorophenoxy.

[0064] R1 and R3 are each independently C 1-6 alkylaminoacyloxy or C 4-6 When each is selected from heterocyclylacyloxy, the compound of formula II of the present invention can be synthesized and prepared by the following synthetic route.

[0065] Route 1: Condense the compound of formula II-SM1 with an alkylaminoacyl chloride or a heterocyclylacyl chloride to obtain the compound of formula II.

[0066] In some embodiments, the reaction is carried out at a temperature of 0 to 140 °C, such as 0 °C, 20 °C, 25 °C, 40 °C, 50 °C, 60 °C, 100 °C, and 140 °C, preferably 0 to 35 °C.

[0067] In some embodiments, the reaction is carried out in a suitable organic solvent selected from the group consisting of 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 in tetrahydrofuran (THF).

[0068] In some embodiments, the reaction is carried out in the presence of a suitable base including an organic base or an inorganic base. The organic base is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), potassium tert-butoxide (t-BuOK), and pyridine (Py). The inorganic base is selected from potassium phosphate (K3PO4), sodium hydride (NaH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), cesium carbonate (Cs2CO3), and NaOH, preferably NaH.

[0069] Route II: React the compound of formula II-SM1 with an isocyanate to obtain the compound of formula II.

[0070] In some embodiments, the reaction is carried out at a temperature of 0 to 140 °C (0 °C, 20 °C, 25 °C, 40 °C, 50 °C, 60 °C, 100 °C, and 140 °C), preferably 25 °C.

[0071] In some embodiments, the reaction is carried out in a suitable organic solvent selected from the group consisting of 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 (Dioxane), dimethyl sulfoxide (DMSO), and any combination thereof, preferably in N,N-dimethylformamide (DMF).

[0072] In some embodiments, this step is carried out in the presence of a suitable base comprising an organic base or an inorganic base. The organic base is selected from the group consisting of N,N - diisopropylethylamine (DIPEA), triethylamine (TEA), potassium tert - butoxide (t - BuOK), and pyridine (Py). The inorganic base is selected from the group consisting of potassium phosphate (K3PO4), sodium hydride (NaH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), cesium carbonate (Cs2CO3), and NaOH. The base is preferably N,N - diisopropylethylamine (DIPEA) or triethylamine (TEA).

[0073] Definitions Unless otherwise defined in the context, all technical terms and terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to techniques employed herein are intended to refer to techniques commonly understood in the art, including variations of the techniques that are obvious to those skilled in the art and alternative equivalent techniques. The following terms are thought to be readily understandable by those skilled in the art, but nevertheless, the following definitions are presented to better explain the present invention.

[0074] Words such as "comprising", "including", "having", "involving", etc. are intended to cover non - exclusive or unrestricted inclusion. For example, a composition, method, or apparatus comprising a series of elements is not necessarily limited to the explicitly listed elements, but may also include other elements not explicitly listed, or elements specific to the composition, method, or apparatus described above.

[0075] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are substantially non-toxic to living organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by the reaction of the compounds of the present invention with pharmaceutically acceptable inorganic acids / organic acids or inorganic bases / organic bases, and are also referred to as acid addition salts or base addition salts.

[0076] For a review of suitable salts, see "Hand book of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are well known to those skilled in the art.

[0077] "Pharmaceutically acceptable esters" refer to esters of the compounds of the present invention or their salts that are substantially non-toxic to living organisms and are hydrolyzed in vivo to form the compounds of the present invention or their salts. Pharmaceutically acceptable esters generally include (but are not limited to) esters formed from pharmaceutically acceptable carboxylic acids or sulfonic acids and the compounds of the present invention (also referred to as carboxylic acid esters or sulfonic acid esters).

[0078] "Isomers" refer to compounds that have the same number and types of atoms and thus the same molecular weight, but differ in the spatial arrangement or configuration of the atoms.

[0079] "Stereoisomers" (or "optically active isomers") refer to stable isomers with a perpendicular asymmetric plane due to having at least one chiral factor (chiral center, chiral axis, chiral plane, etc.), which enables the rotation of plane-polarized light. The present invention includes these stereoisomers and their mixtures due to the presence of an asymmetric center and other chemical structures in the compounds of the present invention that can give rise to stereoisomers. Since the compounds of the present invention (or their pharmaceutically acceptable salts) contain chiral carbon atoms, they can exist in the form of a single stereoisomer, a racemate, or a mixture of enantiomers and diastereomers. Typically, these compounds can be prepared as racemates. However, if necessary, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., a single enantiomer or diastereomer, or a mixture rich in a single stereoisomer (purity 98% or higher, 95% or higher, 93% or higher, 90% or higher, 88% or higher, 85% or higher, or 80% or higher). As described below, a single stereoisomer of a compound can be synthesized from an optically active starting material containing the desired chiral center, or a mixture of enantiomeric products can be prepared and separated or resolved (e.g., separation or recrystallization after the formation of a mixture of diastereomers, chromatographic treatment, use of a chiral resolving reagent, or direct resolution of enantiomers on a chiral column). The starting material having a specific stereochemistry may be commercially available or can be prepared as described below and separated by methods well known in the art. The term "enantiomers" refers to a pair of stereoisomers that are mirror images of each other but cannot be superimposed on each other. The term "diastereomers" refers to optically active isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal amounts of a single enantiomer (i.e., an equimolar mixture of the two enantiomers of R and S). The term "non-racemic mixture" refers to a mixture containing unequal amounts of a single enantiomer. Unless otherwise specified, all stereoisomers of the compounds of the present invention are within the scope of the present invention.

[0080] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can interconvert via a low energy barrier. When tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers is achieved. For example, proton tautomers (or proton-transfer tautomers) include, but are not limited to, tautomerism by proton transfer, such as keto-enol tautomerism, imine-enamine tautomerism, amide-iminol tautomerism, etc. Unless otherwise specified, all tautomers of the compounds of the present invention are within the scope of the present invention.

[0081] The term "polymorph" (or "polymorphic form") refers to the solid crystalline form of a compound or complex. Polymorphs of a molecule can be obtained by many known methods by 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, sublimation, etc. Furthermore, polymorphs can be detected, classified, and identified using well-known techniques such as 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, scanning electron microscopy (SEM), etc.

[0082] The term "solvate" refers to a substance formed by the non-covalent intermolecular forces binding the compound of the present invention (or its pharmaceutically acceptable salt) with at least one solvent molecule. Common solvates include, but are not limited to, hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetonates, etc.

[0083] The term "isotope-labeled compound" refers to a derivatized compound formed by substituting a specific atom in the compound of the present invention with its isotope atom. Unless otherwise specified, the compounds of the present invention are 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 includes various isotopes of H, C, N, O, F, P, S, and Cl such as Cl. For example, 12 C is 12 C, 13 C, or 14 C can be replaced; 1 H is 2 H (D, deuterium) or 3 H (T, tritium) can be replaced; 16 O is 18 O can be replaced, etc. The present invention includes isotope-labeled substances obtained by replacing any atom in the structure with its isotope.

[0084] The term "metabolite" refers to a derivatized compound formed after the compound of the present invention is metabolized. Further information regarding metabolism can be referred to Goodman and Gilman’s: The Pharmacological Basis of Therapeutics (9th ed.) [M], McGraw-Hill International Editions, 1996.

[0085] The term "prodrug" refers to a derivatized compound that can directly or indirectly provide the compound of the present invention after administration to a subject. Particularly preferred derivatized compounds or prodrugs are compounds that can improve the bioavailability of the compound of the present invention (e.g., are more easily absorbed into the blood) or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system) when administered to a subject. Unless otherwise specified, 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.

[0086] The term "each independently" means that when at least two groups (or ring systems) present in the structure have the same or similar range of values, in some cases they may have the same meaning or different meanings. For example, when it is said that substituent X and substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, it means that when substituent X is hydrogen, substituent Y may be hydrogen or halogen, hydroxy, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X may be hydrogen or halogen, hydroxyl, cyano, alkyl, or aryl.

[0087] The term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. For example, as used herein, "C 1-6 alkyl" refers to an alkyl having 1 to 6 carbon atoms optionally substituted with one or more (e.g., 1 to 3) substituents described in the present invention (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc.). (For example, when substituted with a halogen, this group is a "C 1-6 haloalkyl", e.g., -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, etc.).

[0088] "C 1-6 alkylamino" refers to a group formed by substituting -NH2 with one or two C 1-6 alkyl groups, i.e., -NH-C 1-6 alkyl or -N(C 1-6 alkyl)2.

[0089] The term "acyloxy" refers to -O-C(=O)-.

[0090] "C 1-6 alkylacyloxy" refers to -O-C(=O)-C 1-6 alkyl.

[0091] "C1-6 The term "alkylaminoacyloxy" means -O-C(=O)-NH-C 1-6 alkyl or -O-C(=O)-N(C 1-6 alkyl)2.

[0092] "C 1-6 The term "alkoxyacyloxy" means -O-C(=O)-C 1-6 alkoxy.

[0093] "C 1-6 The term "alkoxyaminoacyloxy" means -O-C(=O)-NH-alkyl-O-alkyl.

[0094] "C 4-10 The term "heterocyclylacyloxy" means -O-C(=O)-C 4-10 heterocyclyl.

[0095] The term "sulfonyloxy" means -O-S(=O)2-.

[0096] "C 1-6 The term "hydroxyalkyl" means -C 1-6 alkylene-OH.

[0097] The term "alkoxy" refers to those of "alkyl" or "cycloalkyl" defined above that are bonded to the parent molecular moiety through an oxygen atom (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, t-butoxy, sec-butoxy, cyclobutoxy, n-pentoxy, isopentoxy, n-hexoxy, or isomers thereof, including C 1-6 alkoxy, C 3-8 cycloalkoxy, etc.). For example, the term "C 1-6 alkoxy" as used herein refers to an alkoxy group having 1 to 6 carbon atoms optionally substituted with one or more (e.g., 1 to 3) substituents described herein (e.g., methoxy, ethoxy, tert-butoxy, etc.). (For example, when substituted with a halogen, this group is "C1-6 "Haloalkoxy", such as -OCF3, -OC2F5, etc.).

[0098] "C" 1-6 The term "alkoxycarbonyl" refers to -C(=O)-OC 1-6 alkyl.

[0099] The term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated π - electron system optionally substituted with one or more substituents described herein (e.g., an oxo group, C 1-6 alkyl group (methyl, ethyl), or halogen (fluorine, chlorine, bromine)). For example, the "C 6-10 aryl" used in the present invention refers to an aryl group having 6 to 10 carbon atoms (e.g., phenyl, naphthyl, etc.).

[0100] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic group having a conjugated π - electron system with 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 in the ring, and is optionally substituted with one or more substituents described in the present invention (e.g., oxo, C 1-6 alkyl (methyl, ethyl) or halogen (fluorine, chlorine, bromine)). When the valence - bond requirements are met, the heteroaryl group can be attached to the parent molecular moiety by any ring atom. For example, the term "4 - 10 - membered heteroaryl" used in the present invention refers to a heteroaryl having 4 to 10 ring atoms (e.g., thienyl), furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl (pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or their benzo - derivatives).

[0101] The term "alkenyl" refers to a straight-chain or branched-chain aliphatic hydrocarbon group containing one or more carbon-carbon double bonds and typically containing about 2 to 20 carbon atoms. For example, the "C 2-6 alkenyl" used in the present invention refers to an alkenyl group containing 2 to 6 carbon atoms optionally substituted with 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.), such as vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-hexenyl, etc.

[0102] "C 2-6 The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, particularly a group having 2 or 3 carbon atoms ("C 2-3 alkynyl"). C 2-6The alkynyl group 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, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is an ethynyl group, a prop-1-ynyl group or a prop-2-ynyl group.

[0103] The term "heterocyclyl" means C 4-10 heterocyclyl, C 4-8Refers to a 3-18 membered non-aromatic ring group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, such as heterocyclyl, 4-12 membered heterocyclyl, 4-8 membered heterocyclyl, and 5-6 membered heterocyclyl. The heterocyclyl may be saturated or unsaturated. Unless otherwise specified in this specification, the heterocyclyl is a monocyclic, bicyclic, tricyclic or higher cyclic ring system, and may include a fused ring system, a condensed ring system, a bridged ring system, or a spiro ring system. For the purposes of this application, the heterocyclyl is preferably a 4-7 membered non-aromatic monocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered non-aromatic monocyclic group containing 1 to 2 heteroatoms selected from nitrogen and oxygen, etc., a 4-12 membered non-aromatic monocyclic group or a 4-12 membered non-aromatic bicyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; or a 5-12 membered non-aromatic bicyclic group containing a fused bicyclic ring, a condensed bicyclic ring, a bridged bicyclic ring, or a spiro ring. The nitrogen atom, carbon atom, or sulfur atom in the heterocyclyl may be optionally oxidized, for example, substituted with oxo; the nitrogen atom may be optionally quaternized; and the heterocyclyl may be partially unsaturated or fully saturated. The heterocyclyl can be bonded to the rest of the molecule by a single bond through a carbon atom or a heteroatom. Examples of heterocyclyl include azetidinyl, pyranyl, tetrahydropyranyl, thiapyranyl, tetrahydrofuryl, morpholinyl, thiomorpholinyl, pyrazolyl, dihydropyrazolyl, piperazinyl, piperazonyl, piperidinyl, pyrrolyl, pyrrolidinyl, oxazinyl, dioxolyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrazolidinyl, phthalimide, azabicyclo[3.1.0]hexyl,azaspiro[2.4]heptyl, and groups of the following formula: [Chemistry] , preferably, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, thiomorpholinyl monooxide, piperidinyl, pyrrolidinyl, azetidinyl, dihydropyrazolyl, tetrahydropyranyl, piperazinyl, piperazinonyl, azabicyclo[3.1.0]hexyl,azaspiro[2.4]heptyl, and [Chemistry] are exemplified.

[0104] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0105] The term "cyano" refers to the "-CN" group.

[0106] The term "hydroxy" refers to the "-OH" group.

[0107] The term "carboxyl" refers to the "-CO2H" group.

[0108] The term "substituted" or "substitued" means that one or more atoms (e.g., a hydrogen atom) or atomic groups (e.g., a trifluoromethanesulfonic acid group) in the specified group are replaced by other atoms or atomic groups. However, the specified group must satisfy the valence bond requirements in this case and form a stable compound after substitution. Combinations of substituents and / or variables are only allowed if the combination can form a stable compound. When a substituent is described as "optionally substituted with...", the substituent may be unsubstituted or substituted. When the first substituent is described as being optionally substituted with one or more groups in the second list of substituents, one or more hydrogen atoms in the first substituent may or may not be individually or independently substituted with one or more groups in the second list of substituents.

[0109] When the bond of a substituent is shown to pass through a bond connecting two atoms within a ring, such a substituent may be bonded to any of the ring-forming atoms within the ring.

[0110] The term "one or more" refers to one or more, for example 2, 3, 4, 5, 6, 7, 8, 9, or 10, under reasonable conditions.

[0111] The carbon-carbon bonds of the compounds of the present invention are herein represented by solid lines

Chem.

Chem.

Chem.

[0112] "Carboxylic acid electronic isostere" generally refers to a group or substituent having physical and chemical properties similar to a carboxyl group, which brings about similar, related, or opposite biological activities. These include, but are not limited to, hydroxamic acid, hydroxamate, phosphonic acid, hypophosphorous acid, sulfonic acid, sulfinic acid, sulfonamide, sulfonylurea, ureido, tetrazole, thiazolidinone, and oxazolidinone.

[0113] The term "glycosyl" refers to a series of one or more compounds containing a tetrahydropyran or tetrahydrofuran structure, and this class of compounds is substituted with one or more of -O-, hydroxy, hydroxymethyl, carboxyl, amino, acetamide, such as glucopyranosyl, glucofuranosyl, etc.

[0114] Pharmaceutical compositions, uses, and treatment methods Another object of the present invention is to provide 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 compound, metabolite, prodrug, or a mixture thereof, and one or more pharmaceutically acceptable carriers, optionally further comprising one or more additional drugs for the treatment of thromboembolic diseases.

[0115] A further object of the present invention is to provide a method for treating thromboembolic diseases, which comprises administering 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, to a subject in need thereof.

[0116] A further object of the present invention is to provide the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or a mixture thereof, or the use of a pharmaceutical composition of the present invention, in the manufacture of a medicament for the treatment of thromboembolic diseases.

[0117] A further object of the present invention is to provide a compound of the present invention, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or a mixture thereof, or a pharmaceutical composition of the present invention for use in the treatment of thromboembolic diseases.

[0118] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle administered together with a therapeutic agent, and is suitable for contact with human and animal tissues within the scope of sound medical judgment, without undue toxicity, irritation, allergic reaction, or other problems or complications, and having a reasonable benefit / risk ratio.

[0119] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include sterile liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc., but are not limited thereto. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose solutions, glycerol solutions can also be used as liquid carriers, especially in the case of injection solutions. Suitable pharmaceutical additives include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc. Further, if necessary, the pharmaceutical composition can contain a small amount of a wetting agent or emulsifier, or a pH buffer. Oral preparations can contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described, for example, in Remington’s Pharmaceutical Sciences (1990).

[0120] The pharmaceutical composition of the present invention can act systemically and / or locally. For this purpose, the pharmaceutical composition can be administered by injection (intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection), or by transdermal administration, or by oral administration, buccal administration, intranasal administration, mucosal administration, topical administration, as an ophthalmic preparation, or by inhalation, etc., via an appropriate route.

[0121] For these administration routes, the pharmaceutical composition of the present invention can be administered in an appropriate dosage form.

[0122] Such dosage forms include, but are not limited to, tablets, capsules, troches, hard candies, powders, sprays, creams, salves, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injection solutions, elixirs, and syrups.

[0123] As used herein, the term "therapeutically effective amount" refers to the amount of a compound administered that alleviates to some extent one or more symptoms of the disorder being treated.

[0124] The dosing regimen can be adjusted to obtain the optimal desired response. For example, it may be administered as a single bolus dose, or administered in several divided doses over time, or the dosage may be proportionally reduced or increased depending on the urgency of the treatment situation. It should be noted that the dosage value may be varied according to the type and severity of the condition to be alleviated, and may include a single or multiple administrations. Furthermore, it should be understood that for a particular subject, the specific dosing regimen should be adjusted over time according to the individual needs and the professional judgment of the person managing or supervising the administration of the composition.

[0125] The amount of the compound of the present invention to be administered depends on the subject to be treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the prescribing physician. Generally, an effective dosage ranges from about 0.0001 mg to about 50 mg per kg of body weight per day, for example, about 0.01 mg to about 10 mg per kg of body weight per day in single or divided doses. In the case of a 70-kg human, this corresponds to about 0.007 mg to about 3500 mg per day, for example, about 0.7 mg to about 700 mg. In some cases, a dosage below the lower limit of the above range may be sufficient, while in other cases, larger dosages may be employed without causing harmful side effects, provided that such larger dosages are first divided into several administrations per day.

[0126] The content or dosage of the compound of the present invention in the pharmaceutical composition is from about 0.01 mg to about 1000 mg, preferably from 0.1 to 500 mg, more preferably from 0.5 to 300 mg, still more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0127] Unless otherwise specified, as used herein, the terms "treat" or "treatment" mean reversing, alleviating, suppressing the progression of, or preventing the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition.

[0128] As used herein, the term "subject" includes humans or non-human animals. Exemplary human subjects include human subjects (referred to as patients) having a disease (e.g., as described herein), or normal subjects. As used herein, the term "non-human animal" includes all vertebrates such as non-human primates, domestic and / or breeding animals (e.g., sheep, dogs, cats, cows, pigs, etc.), non-mammals (e.g., birds, amphibians, reptiles), and mammals.

Examples

[0129] To make the objectives and technical solutions of the present invention clearer, the embodiments of the present invention will be described in detail with reference to the following examples. However, those skilled in the art will understand that the following examples are only for explaining the invention and should not be construed as limiting the scope of the invention. When specific conditions are not specified in the examples, they shall be carried out according to conventional conditions or the conditions provided by the manufacturer. When the manufacturer is not indicated for the reagents or equipment used, all are conventional products that can be purchased commercially.

[0130] In this application, when the chemical name and the structural formula do not match, the structural formula shall be given priority, except when it is inferred from the context that the chemical name rather than the structural formula is correct.

[0131] In the conventional synthesis methods, synthesis examples and intermediate synthesis examples, the meanings of each abbreviation are shown in the following table. The structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).

[0132] Unless otherwise specified, the reaction temperature is room temperature (20°C to 30°C).

[0133] [Table 1]

[0134] Example 1: Preparation of 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-(morpholino-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-(morpholino-4-carbonyl)oxy)-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-((morpholino-4-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-5-(morpholino-4-carbonyl)oxy)benzoic acid (1-3-B)

Chemical formula

[0135] (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) and cooled to 0 °C with stirring. Then, NaH (9.20 mg, 0.383 mmol, purity 60%) was added and stirred for 0.5 h. 4-Morpholinocarbonyl chloride (17.21 mg, 0.115 mmol) was added and the mixture was reacted at room temperature for 2 h. The reaction was monitored by high performance liquid chromatography combined with a mass spectrometer. The reaction was quenched by pouring into cooled aqueous ammonium chloride solution, neutralized by dropwise addition of 3 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and concentrated, and purified by high performance liquid chromatography to obtain Compound 1-3-A (2.34 mg), 1-3 (2.44 mg), and 1-3-B (11.63 mg). Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: Acetonitrile; Mobile phase B: Water (containing 0.05% formic acid).

[0136]

Table 2

[0137] 1-3: ESI-MS (m / z): 634.7[M+H] + . 11H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 9.95 (s, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 5.34 (d, J = 4.8 Hz, 1H), 5.13 (t, J = 6.7 Hz, 1H), 5.03 (t, J = 6.9 Hz, 1H), 4.63 (q, J = 16.9 Hz, 2H), 3.79 (dd, J = 12.0, 5.3 Hz, 1H), 3.67 (s, 6H), 3.44 (s, 2H), 2.85 (dd, J = 17.3, 5.1 Hz, 1H), 2.63 - 2.53 (m, 1H), 2.13 (d, J= 7.5 Hz, 2H), 2.04 - 1.97 (m, 2H), 1.94 - 1.86 (m, 2H), 1.58 (dd, J = 35.1, 11.0 Hz, 11H), 1.22 (d, J = 12.2 Hz, 3H).

[0138] 1-3-A: ESI-MS (m / z): 634.7[M+H] + . 11H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 9.95 (s, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 5.34 (d, J = 4.8 Hz, 1H), 5.13 (t, J = 6.7 Hz, 1H), 5.03 (t, J = 6.9 Hz, 1H), 4.63 (q, J = 16.9 Hz, 2H), 3.79 (dd, J = 12.0, 5.3 Hz, 1H), 3.67 (s, 6H), 3.44 (s, 2H), 2.85 (dd, J = 17.3, 5.1 Hz, 1H), 2.63 - 2.53 (m, 1H), 2.13 (d, J= 7.5 Hz, 2H), 2.04 - 1.97 (m, 2H), 1.94 - 1.86 (m, 2H), 1.58 (dd, J = 35.1, 11.0 Hz, 11H), 1.22 (d, J = 12.2 Hz, 3H).

[0139] 1-3-B: ESI-MS (m / z): 747.8[M+H] + . 11H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 9.95 (s, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 5.34 (d, J = 4.8 Hz, 1H), 5.13 (t, J = 6.7 Hz, 1H), 5.03 (t, J = 6.9 Hz, 1H), 4.63 (q, J = 16.9 Hz, 2H), 3.79 (dd, J = 12.0, 5.3 Hz, 1H), 3.67 (s, 6H), 3.44 (s, 2H), 2.85 (dd, J = 17.3, 5.1 Hz, 1H), 2.63 - 2.53 (m, 1H), 2.13 (d, J= 7.5 Hz, 2H), 2.04 - 1.97 (m, 2H), 1.94 - 1.86 (m, 2H), 1.58 (dd, J = 35.1, 11.0 Hz, 11H), 1.22 (d, J = 12.2 Hz, 3H).

[0140] Example 2: Preparation of (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)pentaanoic 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-dihydroxy-2-methyl-7-oxo-4,7,9-tetrahydropyranopyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic 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-3,4,7,9-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)pentaanoic acid (2-1-B)

Chemical formula

[0141] (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)pentaanoic acid (obtained by microbial fermentation) (200 mg, 0.230 mmol, FR) was dissolved in dry tetrahydrofuran (4 mL) and cooled to 0 °C with stirring. Then, NaH (55.23 mg, 2.3 mmol) was added and the mixture was stirred at room temperature for 0.5 h. Dimethylcarbamoyl chloride (123.74 mg, 1.15 mmol) was added dropwise and the temperature was slowly raised to 40 °C and stirred for 3 h. The reaction was monitored by high performance liquid chromatography combined with a mass spectrometer. Water was added dropwise and the mixture was cooled with ice water while stirring to quench the reaction, then added dropwise to 3 N aqueous hydrochloric acid for neutralization and purified by high performance liquid chromatography to obtain 30.79 mg of the monosubstituted product mixture (2-1-A and 2-1-B) and 9.94 mg of the disubstituted compound (2-1), respectively. Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0142] [Table 3]

[0143] Compound 2-1: ESI-MS (m / z) 1011.3 [M+H] + . 11H NMR (400 MHz, DMSO) δ 13.05 (s, 1H), 6.95 (s, 1H), 6.91 (s, 1H), 5.29 (t, J = 4.2 Hz, 2H), 5.11 (t, J = 6.6 Hz, 2H), 5.04 (t, J = 6.9 Hz, 2H), 4.73 (s, 1H), 4.39 - 4.23 (m, 4H), 3.78 (d, J = 5.0 Hz, 2H), 3.52 (t, J = 6.6 Hz, 2H), 3.08 (d, J = 2.0 Hz, 6H), 2.93 (s, 6H), 2.83 (t, J = 5.0 Hz, 1H), 2.78 (t, J = 4.9 Hz, 1H), 2.54 (d, J = 10.2 Hz, 1H), 2.47 (s, 1H), 2.10 (s, 4H), 2.00 (dd, J = 14.6, 7.3 Hz, 5H), 1.94 - 1.85 (m, 5H), 1.64 - 1.47 (m, 24H), 1.19 (d, J = 14.7 Hz, 6H).

[0144] Mixtures 2-1-A and 2-1-B: ESI-MS (m / z): 940.3[M+H]+. 11H NMR (400 MHz, DMSO) δ 12.97 (s, 2H), 9.78 (d, J = 21.9 Hz, 2H), 6.93 (d, J= 18.6 Hz, 2H), 6.64 (d, J = 13.0 Hz, 2H), 5.29 (t, J = 4.8 Hz, 2H), 5.16 (t, J = 4.6 Hz, 2H), 5.11 (t, J = 6.6 Hz, 4H), 5.04 (t, J = 6.3 Hz, 4H), 4.74 (d, J = 5.9 Hz, 2H), 4.31 (d, J = 8.3 Hz, 4H), 4.19 (d, J = 11.6 Hz, 4H), 3.80 - 3.69 (m, 4H), 3.49 (dd, J= 12.3, 5.9 Hz, 4H), 3.08 (d, J = 2.2 Hz, 6H), 2.93 (s, 6H), 2.81 (dd, J= 16.8, 3.7 Hz, 4H), 2.54 (s, 2H), 2.43 (d, J = 7.5 Hz, 2H), 1.98 (ddd, J= 33.5, 25.8, 18.2 Hz, 30H), 1.57 (d, J = 33.6 Hz, 46H), 1.18 (dd, J= 14.3, 11.7 Hz, 12H).

[0145] 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-((morpholino-4-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentaanoic acid (2-2); (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)-3-hydroxy-2-methyl-5-((morpholino-4-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic 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)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-((morpholino-4-carbonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-2-B)

Chemical formula

[0146] Under a nitrogen atmosphere, (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxy-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentaanoic acid (200 mg, 0.23 mmol) was added to THF (5 mL), stirred until dissolved, and cooled to 0 - 5 °C with ice water. NaH (138.1 mg, 3.45 mmol, 60% content) was added, and the mixture was stirred for 10 minutes. 4-Morpholinocarbonyl chloride (137.68 mg, 0.92 mmol) was added, the temperature was raised to 35 °C, and the mixture was reacted for 4 hours. The reaction solution was poured into an aqueous ammonium chloride solution (10 ml), and the product was extracted with EA (20 ml), concentrated to obtain a crude product, and purified by preparative high performance liquid chromatography to obtain the title compound 2-2 (28.0 mg) and a mixture of 2-2-A / 2-2-B (21.0 mg). Column: Waters SunFire Prep C18 OBD (5 μm * 19 mm * 150 mm). Mobile phase A: Acetonitrile; Mobile phase B: Water (containing 0.05% formic acid). Retention time: 12.7 - 13.2 minutes

[0147]

Table 4

[0148] Compound 2-2: ESI-MS m / z (ESI): 1095.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 6.99 (s, 1H), 6.95 (s, 1H), 5.29 (br, 2H), 5.11 (t, J = 6.4 Hz, 2H), 5.03 (t, J = 6.4 Hz, 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).

[0149] Mixtures 2-2-A and 2-2-B ESI-MS m / z (ESI): 982.6 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 9.77 (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).

[0150] 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)pentaanoic acid (2-3)

Chemical Structure

[0151] (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)pentaanoic acid (100 mg, 0.115 mmol) was dissolved in DMF (2 mL), then triethylamine (23.29 mg, 0.230 mmol) and isopropyl isocyanate (29.38 mg, 0.345 mmol) were added, and the reaction mixture was stirred at 25 °C for 16 h. The reaction was monitored by high performance liquid chromatography combined with mass spectrometry. The reaction solution was purified by high performance liquid chromatography to obtain 48 mg of the title compound. Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate).

[0152]

Table 5

[0153] ESI-MS (m / z): 1039.5[M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.77 (dd, J = 7.6, 4.6 Hz, 2H), 6.87 (d, J = 11.7 Hz, 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, 6.4 Hz, 2H), 3.51 (t, J = 6.5 Hz, 2H), 2.86 - 2.74 (m, 2H), 2.54 (s, 1H), 2.43 - 2.41 (m, 1H), 2.11 (d, J = 8.3 Hz, 4H), 1.94 (tt, J = 25.2, 12.7 Hz, 10H), 1.57 (d, J = 31.6 Hz, 24H), 1.16 (dd, J = 17.0, 9.8 Hz, 18H).

[0154] 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)pentaanoic acid (2-4)

Chemical Structure

[0155] (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)-pentanoic acid (250 mg, 0.288 mmol) was added to tetrahydrofuran (8 mL) and water (2 mL), stirred to dissolve, and cooled to 0 - 5 °C with ice water (2 mL). A 10% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 11, methyl chloroformate (163.1 mg, 1.73 mmol) was added dropwise, and at the same time, a 10% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 10 - 11. After the addition, the mixture was reacted at room temperature for 2 hours. The pH was adjusted to 3 - 4 with an aqueous citric acid solution. The product was extracted with EA (30 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 2-4 (130.0 mg). Column: Waters SunFire Prep C18 OBD (5 μm * 19 mm * 150 mm). Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% ammonium formate in water). Retention time: 7 - 9 minutes

[0156]

Table 6

[0157] The structural characteristic data are as follows: MS m / z (ESI): 985.4 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.29 (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= 1.2 Hz, 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).

[0158] Example 6: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-((1,1-dioxothiomorpholino-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-5); (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-(2R,3S)-3-(((E)-4,6-dimethylhepta-3,7-dien-1-yl)-5-((1,1-dioxothiomorpholino-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic 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[2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4,8-dimethylnona-2,7-dien-1-yl)-5-(1,1-dioxothiomorpholino-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-5-B)

Chemical formula

[0159] (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)pentaanoic acid (100 mg, 0.115 mmol, FR) was dissolved in dry THF (4 mL) and cooled to 0 °C with stirring. Then, NaH (46.03 mg, 1.15 mmol, purity 60%) was added and the reaction mixture was stirred for 0.5 h. Thiomorpholine-1,1-dioxide-4-carbonyl chloride (90.96 mg, 0.460 mmol) was added, the temperature was slowly raised to room temperature, and the mixture was reacted for 4 h. The reaction was monitored by high performance liquid chromatography combined with mass spectrometry. The reaction was quenched by pouring into cooled aqueous ammonium chloride solution, neutralized by dropwise addition of 3 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and concentrated, and purified by high performance liquid chromatography to obtain the disubstituted compound 2-5 (54.46 mg) and the monosubstituted compound mixture 2-5-A and 2-5-B (16.96 mg). Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0160]

Table 7

[0161] Compound 2-5: ESI-MS (m / z): 1191.5[M+H] + . 11H NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 7.18 (d, J = 17.7 Hz, 2H), 5.34 - 5.23 (m, 2H), 5.08 (dt, J = 27.6, 6.9 Hz, 4H), 4.79 (s, 1H), 4.33 (d, J = 9.4 Hz, 4H), 4.03 (s, 4H), 3.93 - 3.74 (m, 6H), 3.53 (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= 8.4 Hz, 4H), 1.95 (dt, J = 15.0, 7.2 Hz, 10H), 1.73 - 1.41 (m, 23H), 1.20 (d, J = 16.0 Hz, 6H).

[0162] Mixtures 2-5-A and 2-5-B: ESI-MS (m / z): 1030.3[M+H] + . 1 1H NMR (400 MHz, DMSO) δ 12.91 (s, 2H), 9.78 (d, J= 22.7 Hz, 2H), 7.18 (d, J = 18.8 Hz, 2H), 6.64 (d, J = 13.3 Hz, 2H), 5.29 (s, 2H), 5.08 (d, J = 27.6 Hz, 8H), 4.80 - 4.71 (m, 2H), 4.32 (d, J = 7.6 Hz, 6H), 4.19 (d, J = 9.7 Hz, 2H), 4.03 (s, 6H), 3.86 (s, 6H), 3.77 (s, 4H), 3.55 - 3.47 (m, 4H), 3.28 (s, 6H), 2.85 (dd, J = 23.5, 11.6 Hz, 4H), 2.56 (d, J = 8.3 Hz, 4H), 2.27 - 1.78 (m, 30H), 1.57 (d, J = 33.8 Hz, 46H), 1.18 (t, J = 14.3 Hz, 12H).

[0163] Example 7: 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-((thiomorpholino-4-carbonyl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-7) [Chemical formula]

[0164] 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)-yl)pentanoate (2-7-1) (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-((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)-pentanoic acid (1.00 g, 1.15 mmol) was dissolved in MeOH (20 mL) and cooled to -5 to -0 °C. SOCl2 (1.37 g, 11.51 mmol) was slowly added dropwise, and the mixture was reacted at 0 to 5 °C for 4 hours. The reaction solution was added to a saturated aqueous solution of sodium bicarbonate (40 mL) / ethyl acetate (80 mL) with temperature controlled at 0 to 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).

[0165] Step 2: Synthesis of Methyl (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-7-oxo-5-((thiomorpholino-4-carbonyl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoate (2-7-2) Compound 2-7-1 (50 mg, 0.057 mmol) and thiomorpholine-4-carbonyl chloride (28.13 mg, 0.170 mmol) were dissolved in N-methylpyrrolidone (2 mL), cesium carbonate (55.34 mg, 0.170 mmol) was added, and the reaction mixture was stirred for 4 hours. The reaction was monitored by high performance liquid chromatography combined with a mass spectrometer. The reaction solution was quenched by pouring it into a cooled aqueous ammonium chloride solution, neutralized by dropwise addition of 0.1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and dried to obtain 60 mg of a crude product.

[0166] 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-((thiomorpholino-4-carbonyl)oxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentanoic acid (2-7) The crude compound 2-7-2 (60 mg, 0.053 mmol) was dissolved in methanol (2 mL) and water (0.5 mL), lithium hydroxide (8.82 mg, 0.210 mmol) was added with stirring, and the reaction was carried out for 4 hours. The reaction was monitored by high performance liquid chromatography combined with mass spectrometry. The reaction was neutralized by dropwise addition of 3 N aqueous hydrochloric acid and then purified by high performance liquid chromatography (HPLC) to obtain 22.24 mg of the title compound. Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: Acetonitrile; Mobile phase B: Water (containing 0.05% formic acid).

[0167]

Table 8

[0168] ESI-MS (m / z): 1128.6 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 12.97 (s, 1H), 6.99 (d, J = 18.8 Hz, 2H), 5.29 (t, J = 4.4 Hz, 2H), 5.08 (dt, J = 28.3, 6.8 Hz, 4H), 4.83 - 4.74 (m, 1H), 4.32 (d, J = 10.7 Hz, 4H), 3.88 (s, 4H), 3.83 - 3.63 (m, 6H), 3.53 (t, J = 6.6 Hz, 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, 1.8 Hz, 1H), 2.11 (d, J = 8.1 Hz, 4H), 1.95 (dt, J = 15.0, 7.2 Hz, 9H), 1.59 (d, J = 14.7 Hz, 10H), 1.53 (s, 11H), 1.20 (d, J = 15.7 Hz, 6H).

[0169] 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)pentaanoic acid (2-8)

Chemical Structure

[0170] 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)carbamoyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentanoate (2-8-1) Compound 2-7-1 (50 mg, 0.057 mmol) was added to NMP (2 mL) and cooled to 0 - 5 °C with ice water. Cs2CO3 (55.34 mg, 0.17 mmol) was added and the mixture was stirred for 10 minutes. N-methyl-N-tetrahydro-4-pyranyl-carbamoyl chloride (30.17 mg, 0.17 mmol) was added and the mixture was reacted at 25 °C for 4 hours. The reaction solution was poured into ethyl acetate (20 ml) / 0.1 N aqueous hydrochloric acid solution (6 ml). The organic phase was separated, washed with saturated aqueous sodium hydrogen carbonate solution (5 ml), washed with brine (5 ml), dried, and concentrated to obtain the crude product (82.0 mg) of the title compound, which was used directly in the next reaction.

[0171] 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)carbamoyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-e]isoindol-8(2H)-yl)pentanoic acid (2-8) Compound 2-8-1 (80 mg, 0.055 mmol) was added to methanol (2 mL) and water (0.7 mL). LiOH·H2O (9.22 mg, 0.22 mmol) was added and the mixture was reacted at room temperature for 2 hours. 1 N hydrochloric acid was added to this system to adjust the pH to 3 - 4, ethyl acetate (20 ml) / water (50 ml) was added, and the mixture was 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 high performance liquid chromatography to obtain 17 mg of the title compound. Column: Waters SunFire Prep C18 OBD (5 μm * 19 mm * 150 mm). Mobile phase A: Acetonitrile; Mobile phase B: Water (containing 0.05% formic acid). Retention time: 8 - 10 minutes.

[0172]

Table 9

[0173] The structural characteristic data are shown below: MS m / z (ESI): 1151.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.96 (s, 1H), 6.92 (s, 1H), 5.28 (t, J = 4.7 Hz, 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, 2H), 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).

[0174] 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)

Chemical formula

[0175] 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]isoindol-8,5-diyl)bis(piperidine-1-carboxylate) (2-9-1) Compound 2-7-1 (50 mg, 0.057 mmol) was added to NMP (2 mL) and cooled to 0-5 °C with ice water. Cs2CO3 (73.8 mg, 0.23 mmol) was added and the mixture was stirred for 10 minutes. 1-Piperidine formyl chloride (33.4 mg, 0.23 mmol) was added and the mixture was reacted at 25 °C for 4 hours. The reaction solution was poured into ethyl acetate (20 ml) / 0.1 N hydrochloric acid aqueous solution (6 ml). The organic phase was separated, washed with saturated sodium bicarbonate aqueous solution (5 ml), washed with brine (5 ml), dried, and concentrated to obtain the crude product (62.0 mg) of the title compound, which was used directly in the next reaction.

[0176] 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) Compound 2-9-1 (62.0 mg, 0.056 mmol) was added to methanol (3 mL) and water (1 mL). LiOH·H₂O (11.8 mg, 0.028 mol) was added, and the mixture was reacted at room temperature for 2 hours. 1 N hydrochloric acid was added to this system to adjust the pH to 3 - 4, ethyl acetate (30 ml) / water (10 ml) was added, and the mixture was 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 high-performance liquid chromatography to obtain 5.7 mg of the title compound. Column: Waters SunFire Prep C18 OBD (5 μm * 19 mm * 150 mm). Mobile phase A: Acetonitrile; Mobile phase B: Water (containing 0.05% formic acid). Retention time: 15.5 - 17.5 minutes.

[0177]

Table 10

[0178] The structural characteristic data are shown below: MS m / z (ESI): 1091.6 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 6.95 (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).

[0179] Example 10: Preparation of (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3-hydroxy-2-methyl-5-((morpholinosulfonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic 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-(((morpholinosulfonyl)oxy)-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic 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)-5-((2R,3S)-2-((E)-4.8-dimethylnona-4,7-dien-1-yl)-3-hydroxy-2-methyl-5-((morpholinosulfonyl)oxy)-7-oxo-3,6-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-10-B) [Chemical formula]

[0180] (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)pentaanoic 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, purity 60%) was added and stirred for 0.5 h. 4-Morpholinyl chloride (90.96 mg, 0.460 mmol) was added and the temperature was slowly raised to room temperature over 4 h. The reaction was monitored by high performance liquid chromatography combined with a mass spectrometer. The reaction was quenched by pouring into cooled aqueous ammonium chloride solution, neutralized by dropwise addition of 3 N aqueous hydrochloric acid, and extracted with dichloromethane. The organic phase was dried, concentrated, and purified by high performance liquid chromatography to give the disubstituted compound 2-10 (11.74 mg) and a mixture of monosubstituted products 2-10-A and 2-10-B (5.03 mg). Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0181]

Table 11

[0182] Compound 2-10: ESI-MS (m / z): 1167.8[M+H] + . 11H NMR (400 MHz, DMSO) δ 13.02 (s, 1H), 7.14 (d, J = 15.8 Hz, 2H), 5.36 (t, J = 4.9 Hz, 2H), 5.05 (dd, J = 21.2, 14.3 Hz, 4H), 4.80 - 4.74 (m, 1H), 4.35 (d, J = 8.8 Hz, 4H), 3.86 - 3.76 (m, 2H), 3.73 (dd, J = 5.7, 3.0 Hz, 8H), 3.53 (s, 2H), 3.41 (dd, J = 9.4, 4.7 Hz, 7H), 3.02 (d, J = 17.6 Hz, 2H), 2.72 (s, 2H), 2.11 (dd, J = 15.4, 7.3 Hz, 4H), 1.94 (dt, J = 14.8, 7.1 Hz, 11H), 1.56 (d, J = 33.5 Hz, 24H), 1.23 (d, J = 15.1 Hz, 6H).

[0183] Mixtures 2-10-A and 2-10-B: ESI-MS (m / z): 1018.5[M+H] + . 11H NMR (400 MHz, DMSO) δ 12.90 (s, 2H), 9.77 (d, J = 21.9 Hz, 2H), 7.13 (d, J = 16.1 Hz, 2H), 6.64 (d, J = 12.8 Hz, 2H), 5.35 (t, J = 4.7 Hz, 2H), 5.15 (t, J = 4.9 Hz, 2H), 5.11 (s, 4H), 5.03 (d, J = 6.1 Hz, 4H), 4.74 (s, 2H), 4.35 (d, J = 8.9 Hz, 4H), 4.19 (d, J = 10.1 Hz, 4H), 3.81 (s, 2H), 3.73 (d, J = 3.1 Hz, 8H), 3.54 - 3.45 (m, 4H), 3.41 (dd, J = 9.4, 4.8 Hz, 8H), 3.02 (d, J = 18.4 Hz, 3H), 2.77 (dd, J = 32.7, 13.8 Hz, 6H), 2.43 (d, J = 7.5 Hz, 2H), 2.11 (d, J= 6.3 Hz, 10H), 1.94 (dt, J = 14.7, 7.0 Hz, 20H), 1.56 (d, J = 34.0 Hz, 46H), 1.19 (dd, J = 24.6, 14.0 Hz, 12H).

[0184] Example 11: Preparation of (S)-2,5-bis((2R,3S)-5-([1,4'-bipiperidin]-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)pentaanoic acid (2-20)

Chemical Structure

[0185] (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)pentaanoic acid (10 mL) was dissolved in dry THF (10 mL) and cooled to 0 °C with stirring. Then, NaH (46.03 mg, 1.15 mmol, 60% content) was added and the mixture was stirred at room temperature for 0.5 h. 1-Chloroformyl-4-piperidinopiperidine hydrochloride (122.51 mg, 0.460 mmol) was added and the temperature was raised to 40 °C over 3 h. The reaction was monitored by high performance liquid chromatography combined with mass spectrometry. The reaction was quenched in ice water, neutralized by dropwise addition of 3 N aqueous hydrochloric acid, concentrated under reduced pressure, and purified by high performance liquid chromatography to give 33.15 mg of the title compound. Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0186] [Table 12]

[0187] ESI-MS (m / z): 1257.9 [M+H] + . 11H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 6.93 (d, J = 11.2 Hz, 2H), 5.30 (s, 2H), 5.11 (t, J = 6.7 Hz, 2H), 5.04 (t, J = 6.8 Hz, 2H), 4.66 (dd, J = 10.9, 4.6 Hz, 1H), 4.41 (d, J = 17.4 Hz, 1H), 4.34 - 4.15 (m, 6H), 4.04 (d, J = 11.4 Hz, 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), 2.05 - 1.95 (m, 6H), 1.95 - 1.86 (m, 5H), 1.80 (s, 5H), 1.53 (dd, J = 50.4, 31.9 Hz, 45H), 1.18 (d, J = 13.2 Hz, 6H).

[0188] 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)pentaanoic acid (2-22) [Chemical formula]

[0189] Step 1: (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)pentaanoic acid (200 mg, 0.230 mmol) and bromotetraacetylglucoside (378.51 mg, 0.920 mmol) were dissolved in acetonitrile (4 mL), silver oxide (266.64 mg, 1.150 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction was monitored by high performance liquid chromatography combined with mass spectrometry. 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). Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0190] [Table 13]

[0191] 2-22-1A: ESI-MS (m / z): 1860.7[M+H] + . 2-22-1B / 2-22-1C: ESI-MS (m / z): 1530.6[M+H] + .

[0192] 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)pentaanoic acid (2-22) [Chemical formula]

[0193] 2-22-1A (8 mg, 0.004 mmol) was dissolved in tetrahydrofuran (1 mL), lithium hydroxide (1.80 mg, 0.043 mmol) was added (0.25 mL), and the mixture was stirred for 1 hour. The reaction was monitored by high performance liquid chromatography combined with a mass spectrometer. 3 N aqueous hydrochloric acid was added dropwise to neutralize the reaction solution, followed by evaporation under reduced pressure to remove the solvent, and purification by high performance liquid chromatography (HPLC) to obtain 2.12 mg of the title compound. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0194] [Table 14]

[0195] ESI-MS (m / z): 1193.6 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 6.89 (s, 1H), 6.86 (s, 1H), 5.28 (t, J = 5.1 Hz, 2H), 5.21 (d, J = 4.3 Hz, 2H), 5.16 - 5.09 (m, 4H), 5.03 (dd, J = 11.2, 6.1 Hz, 4H), 4.91 (d, J = 5.4 Hz, 2H), 4.54 (dd, J = 10.1, 5.7 Hz, 2H), 4.24 (s, 6H), 3.79 - 3.63 (m, 5H), 3.49 (d, J = 3.7 Hz, 5H), 3.24 (dd, J = 21.7, 7.8 Hz, 7H), 3.05 (d, J = 12.9 Hz, 3H), 2.53 (s, 1H), 2.46 - 2.44 (m, 1H), 2.11 (s, 5H), 1.95 (dt, J = 15.2, 7.2 Hz, 10H), 1.69 - 1.44 (m, 22H), 1.17 (d, J = 13.6 Hz, 6H).

[0196] Example 13: Preparation of (2-22-A) (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,3S,4S,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)pentaanoic acid [Chemical Structure]

[0197] 2-22-1B (19 mg, 0.012 mmol) was dissolved in tetrahydrofuran (1 mL), and lithium hydroxide (2.61 mg, 0.062 mmol) was added (0.25 mL), and the mixture was stirred for 1 hour. The reaction was monitored by high performance liquid chromatography combined with a mass spectrometer. 3 N aqueous hydrochloric acid was added dropwise to neutralize the reaction solution, and then the solvent was removed by evaporation under reduced pressure and purified by high performance liquid chromatography to obtain 3.03 mg of the title compound. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0198] [Table 15]

[0199] ESI-MS (m / z): 1031.6 [M+H] + . 11H NMR (400 MHz, DMSO) δ 13.05 - 12.80 (m, 1H), 9.75 (s, 1H), 6.89 (s, 1H), 6.62 (s, 1H), 5.29 (d, J = 4.8 Hz, 1H), 5.21 (d, J = 5.2 Hz, 1H), 5.16 - 4.99 (m, 6H), 4.92 (d, J = 7.2 Hz, 1H), 4.71 (s, 1H), 4.54 (t, J = 5.8 Hz, 1H), 4.34 - 4.13 (m, 4H), 3.73 (d, J= 5.4 Hz, 3H), 3.48 (s, 3H), 3.27 (s, 4H), 3.05 (dd, J = 17.8, 5.2 Hz, 1H), 2.81 (dd, J = 17.7, 5.2 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.43 (d, J = 7.4 Hz, 1H), 2.10 (s, 4H), 1.95 (dt, J = 14.8, 7.1 Hz, 10H), 1.55 (dd, J = 24.4, 14.4 Hz, 21H), 1.24 - 1.07 (m, 6H).

[0200] 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)pentaanoic acid (2-22-B)

Chemical Structure

[0201] 2-22-1C (20 mg, 0.013 mmol) was dissolved in tetrahydrofuran (1 mL), lithium hydroxide (2.74 mg, 0.065 mmol) was added, and the mixture was stirred for 1 hour. The reaction was monitored by high performance liquid chromatography combined with mass spectrometry. 3 N aqueous hydrochloric acid was added dropwise to neutralize the reaction solution, and then the solvent was removed by evaporation under reduced pressure. The title compound (3.73 mg) was obtained by purification using high performance liquid chromatography. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0202]

Table 16

[0203] ESI-MS (m / z): 1031.6 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 6.85 (s, 1H), 6.64 (s, 1H), 5.27 (d, J = 4.9 Hz, 1H), 5.21 (d, J = 5.2 Hz, 1H), 5.14 (dd, J = 10.9, 6.0 Hz, 4H), 5.07 - 5.00 (m, 3H), 4.91 (d, J = 7.3 Hz, 1H), 4.55 (t, J = 5.8 Hz, 1H), 4.20 (d, J = 20.4 Hz, 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 = 12.3 Hz, 2H), 2.47 - 2.40 (m, 1H), 2.11 (s, 5H), 1.95 (dt, J = 14.8, 6.8 Hz, 9H), 1.57 (d, J = 32.6 Hz, 22H), 1.16 (d, J = 11.5 Hz, 6H).

[0204] Example 15: Preparation of (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)pentaanoic 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-dimethyldeca-3-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)pentaanoic 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[2,3-E]isoindol-8(2H)-yl)-5-((2R,3S)-2-((E)-4.8-dimethylnona-4,7-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)pentaanoic acid (2-23-B)

Chemical formula

[0205] (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)pentaanoic acid (100 mg, 0.115 mmol) was dissolved in dry THF (10 mL) and cooled to 0 °C with stirring. NaH (46.03 mg, 1.15 mmol, 60% content) was added and stirred at room temperature for 0.5 h. 1-Chloroformyl-4-methylpiperazine (91.16 mg, 0.460 mmol) was added, the temperature was raised to 40 °C and stirred for 3 h. The reaction was monitored by high performance liquid chromatography combined with mass spectrometry. The reaction mixture was quenched by pouring into ice water, neutralized by dropwise addition of 3 N aqueous hydrochloric acid, concentrated under reduced pressure and purified by high performance liquid chromatography to give the disubstituted compound 2-23 (8.07 mg), the monosubstituted compounds 2-23-A (3.32 mg) and 2-23-B (14.16 mg). Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0206] 2-23: ESI-MS (m / z): 1122.7[M+H] + . 11H NMR (400 MHz, DMSO) δ 9.94 (d, J = 19.3 Hz, 2H), 6.67 (d, J = 13.5 Hz, 2H), 5.04 (dd, J = 15.1, 7.7 Hz, 5H), 4.95 - 4.87 (m, 2H), 4.70 (dd, J = 10.2, 5.1 Hz, 1H), 4.30 - 4.15 (m, 4H), 3.50 (d, J = 7.0 Hz, 2H), 2.99 - 2.90 (m, 2H), 2.64 (dd, J = 15.6, 9.7 Hz, 2H), 2.18 (d, J = 28.9 Hz, 15H), 2.10 - 1.85 (m, 15H), 1.65 - 1.43 (m, 25H), 1.27 (d, J = 8.4 Hz, 6H).

[0207] 2-23-A: ESI-MS (m / z): 996.6[M+H] + . 1 1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 9.76 (s, 1H), 6.65 (d, J = 22.3 Hz, 2H), 5.20 - 4.97 (m, 5H), 4.89 (d, J = 4.9 Hz, 1H), 4.56 (s, 2H), 4.37 (s, 3H), 4.19 (d, J = 16.6 Hz, 4H), 3.73 (s, 3H), 3.47 (s, 2H), 2.96 (d, J = 13.4 Hz, 2H), 2.86 - 2.76 (m, 2H), 2.65 (d, J= 13.0 Hz, 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, 19.5 Hz, 18H), 1.21 (d, J = 50.8 Hz, 6H).

[0208] 2-23-B: ESI-MS (m / z): 996.6[M+H] + . 1 1H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 9.80 (s, 1H), 6.65 (s, 2H), 5.12 (dd, J = 14.5, 6.7 Hz, 2H), 5.08 - 4.97 (m, 3H), 4.89 (t, J = 5.3 Hz, 1H), 4.72 (dd, J = 10.2, 5.3 Hz, 1H), 4.21 (d, J = 7.9 Hz, 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 = 20.8 Hz, 6H).

[0209] Example 16: 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)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(sulfamoyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-28-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)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(sulfamoyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-28-B) [Chemical formula]

[0210] Step 1: Preparation of a mixture of methyl (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-(sulfamoyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaonate (2-28-1A) 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)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(sulfamoyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaonate (2-28-1B) Compound 2-7-1 (200.0 mg, 0.23 mmol) and sulfamoyl chloride (157.0 mg, 1.36 mmol) were added to DMA (6 mL). NaH (136.0 mg, 3.40 mmol, purity 60%) was added, the temperature was raised to 30 °C, and the reaction was carried out for 2 hours. The reaction solution was cooled to room temperature, poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic phase was concentrated to obtain a crude product (218 mg), which was used directly in the next reaction.

[0211] Step 2: Preparation of a mixture 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)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(sulfamoyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-28-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)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-hydroxy-2-methyl-7-oxo-3-(sulfamoyloxy)-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-28-B) A mixed solution of 2-28-1A and 2-28-1B (250.00 mg, 0.26 mmol) was added to tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide (93.34 mg, 3.90 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was adjusted to pH 4 with an aqueous citric acid solution and 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). Column: Waters SunFire Prep C18 OBD (5 μm * 19 mm * 150 mm). Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid in water). Retention time: 5.3 - 6.2 minutes.

[0212]

Table 17

[0213] The structural characteristic data are shown below: MS m / z (ESI): 948.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (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).

[0214] 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)

Chemical formula

[0215] (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)-pentanoic acid (100 mg, 115.06 μmol) was added to 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 high-performance liquid chromatography to obtain the title compound 2-29 (56.0 mg). Column: Waters SunFire Prep C18 OBD (5 μm * 19 mm * 150 mm). Mobile phase A: Acetonitrile; Mobile phase B: Water (containing 0.05% formic acid in water). Retention time: 8.5 - 9.5 minutes.

[0216]

Table 18

[0217] 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)

Chem.

[0218] (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)-pentanoic acid (52.63 mg, 57.53 μmol) was dissolved in THF (30 mL), and the solution was cooled to 0 °C. NaH (23.01 mg, 575.31 μmol) was added, the temperature was raised to 25 °C, and the mixture was stirred for 0.5 h. N-(2-Methoxyethyl)carbamoyl chloride (41.65 mg, 287.66 μmol) was added dropwise to the reaction mixture, the temperature was raised to 40 °C, and the reaction was carried out for 3 h. The reaction mixture was directly concentrated and purified by preparative high performance liquid chromatography to obtain the title compound (10.0 mg). Column: Waters SunFire Prep C18 OBD (5 μm * 19 mm * 150 mm). Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid). Retention time: 8.5 - 9.5 min.

[0219]

Table 19

[0220] The structural characteristic data are shown below: MS m / z (ESI): 926.5 [M+H+H2O] + . 11H NMR (400 MHz, DMSO) δ 9.75 (d, J = 6.5 Hz, 1H), 8.15 (t, J = 5.5 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 5.20 - 5.08 (m, 2H), 5.04 (s, 1H), 4.74 (dd, J = 9.2, 6.1 Hz, 1H), 4.41 (d, J = 17.0 Hz, 1H), 4.17 (t, J = 8.5 Hz, 1H), 3.72 (d, J= 10.6 Hz, 1H), 3.47 (s, 1H), 3.38 - 3.25 (m, 4H), 3.22 - 3.13 (m, 2H), 2.82 (dd, J = 12.3, 3.6 Hz, 1H), 2.49 - 2.39 (m, 1H), 2.10 (d, J = 6.9 Hz, 1H), 2.00 (dd, J = 14.3, 6.9 Hz, 1H), 1.95 - 1.86 (m, 2H), 1.77 (dd, J = 14.9, 8.7 Hz, 1H), 1.59 (d, J = 16.1 Hz, 4H), 1.53 (s, 5H), 1.36 (s, 1H), 1.16 (d, J = 12.0 Hz, 2H).

[0221] Example 19: Preparation of 2-morpholinylethyl (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)pentaanoate (2-31)

Chemical Structure

[0222] (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)pentaanoic acid (50 mg, 0.058 mmol) was dissolved in pyridine (1 mL), then 2-morpholinylethanol (15.09 mg, 0.115 mmol) and DCC (17.81 mg, 0.086 mmol) were added, and the mixture was stirred at 25 °C for 12 h. The reaction was monitored by high performance liquid chromatography combined with mass spectrometry. The reaction solution was purified by high performance liquid chromatography to obtain 1.18 mg of the title compound. Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0223] [Table 20]

[0224] ESI-MS (m / z): 983.7 [M+H] + . 11H NMR (400 MHz, DMSO) δ 9.81 (d, J = 30.4 Hz, 2H), 8.44 (s, 1H), 6.64 (d, J = 14.0 Hz, 2H), 5.58 (d, J= 8.0 Hz, 2H), 5.08 (d, J = 28.1 Hz, 6H), 4.83 (d, J = 5.7 Hz, 1H), 4.19 (d, J = 14.0 Hz, 6H), 3.72 (s, 2H), 3.48 (s, 2H), 2.82 (dd, J = 12.0, 5.7 Hz, 2H), 2.43 (d, J = 8.2 Hz, 4H), 2.22 (d, J = 3.9 Hz, 4H), 2.09 (s, 3H), 2.03 - 1.97 (m, 3H), 1.94 - 1.85 (m, 4H), 1.71 (d, J = 12.8 Hz, 3H), 1.56 (dd, J= 24.2, 9.9 Hz, 21H), 1.28 - 1.02 (m, 12H).

[0225] Example 20: Preparation of 35-hydroxy-3,6,9,12,15,18,21,24,27,30,33-undecaoxapentatriacontyl (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)pentanoate (2-32) [Chemical formula]

[0226] (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)-pentanoic acid (120.0 mg, 0.14 mmol) was dissolved in DMF (2 mL). Dodecyl glycol (754.8 mg, 1.38 mmol), HATU (105.0 mg, 0.27 mmol), and DIPEA (89.2 mg, 0.69 mmol) were added, and the mixture was reacted at 25 °C for 12 h. The reaction solution was purified directly by preparative high performance liquid chromatography to obtain the title compound 2-32 (48.0 mg). Column: Waters SunFire Prep C18 OBD (5 μm * 19 mm * 150 mm). Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid). Retention time: 8.5 - 9.5 min.

[0227]

Table 21

[0228] The structural characteristic data are shown below: MS m / z (ESI): 1414.7 [M +H+ H2O] + . 11H NMR (400 MHz, DMSO-d6) δ 9.82 (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 = 5.4 Hz, 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 - 2.07 (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).

[0229] 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)penta-noyl)oxy)-N,N,N-trimethylethane-1-amine hydrochloride (2-33) [Chemical formula]

[0230] (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)pentaanoic acid (300 mg, 0.345 mmol) was dissolved in DMF (3 mL), then choline chloride (97.09 mg, 0.69 mmol) and DCC (106.83 mg, 0.518 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 h. The reaction was monitored by high performance liquid chromatography combined with mass spectrometry. Hydrochloric acid was added dropwise to acidify the reaction mixture, and then the title compound (8.70 mg) was obtained by purification using high performance liquid chromatography. Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid).

[0231] [Table 22]

[0232] ESI-MS (m / z): 954.7[M+H] + . 1 H NMR (400 MHz, DMSO) δ 6.55 (d, J = 3.9 Hz, 2H), 5.09 (d, J = 30.2 Hz, 4H), 4.89 (d, J = 8.0 Hz, 1H), 4.43 (s, 2H), 4.14 (d, J = 18.0 Hz, 3H), 3.72 (d, J = 4.6 Hz, 2H), 3.57 (s, 3H), 3.36 (s, 6H), 3.04 (d, J = 47.3 Hz, 9H), 2.83 (d, J = 16.0 Hz, 2H), 2.45 (s, 2H), 2.21 - 1.81 (m, 12H), 1.76 - 1.38 (m, 20H), 1.14 (d, J = 7.7 Hz, 6H).

[0233] Example 22: (S)-2,5-bis((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-5-((1-oxothiomorpholino-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-6); (S)-5-((2R,3S)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-3,5-dihydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)-2-(2R,3S)-3-((E)-4,6-dimethylhepta-3,7-dien-1-yl)-5-((1-oxothiomorpholino-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic 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)-5-(2R,3S)-2-((E)-4,8-dimethylnona-2,7-dien-1-yl)-5-(1-oxothiomorpholino-4-carbonyl)oxy)-3-hydroxy-2-methyl-7-oxo-3,4,7,9-tetrahydropyrano[2,3-E]isoindol-8(2H)-yl)pentaanoic acid (2-6-B) [Chemical formula]

[0234] A solution 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)pentaanoic acid (500 mg, 0.575 mmol) was dissolved in dry tetrahydrofuran (50 mL), triethylamine was added dropwise, and then p-nitrophenyl chloroformate (406 mg, 2.06 mmol, dissolved in 5 mL of tetrahydrofuran) was added dropwise. The reaction mixture was stirred for 2 hours. 1-Oxothiomorpholine hydrochloride (447 mg, 2.87 mmol) was added, and stirring was continued for 2 hours. The reaction was monitored by high performance liquid chromatography combined with a mass spectrometer. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high performance liquid chromatography to obtain the disubstituted compound 2-6 (27.33 mg) and a mixture of monosubstituted products 2-6-A and 2-6-B (17.64 mg).

[0235] Compound 2-6: Purification condition 1: Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate).

[0236]

Table 23

[0237] ESI-MS (m / z): 1159.5[M+H] + . 11H NMR (400 MHz, DMSO): δ 7.06 (d, J = 12.0 Hz, 2H), 5.29 (s, 2H), 5.14 - 4.99 (m, 4H), 4.70 (s, 2H), 4.34 (d, J = 26.4 Hz, 4H), 4.10 (s, 2H), 3.93 (d, J = 12.3 Hz, 4H), 3.77 (dd, J = 11.5, 6.3 Hz, 4H), 3.52 (s, 2H), 3.12 - 2.94 (m, 4H), 2.83 (s, 5H), 2.54 (s, 1H), 2.44 - 2.35 (m, 1H), 2.11 (d, J = 7.8 Hz, 4H), 2.05 - 1.83 (m, 10H), 1.66 - 1.47 (m, 20H), 1.30 - 1.14 (m, 8H).

[0238] Mixtures 2-6-A and 2-6-B: Purification condition 2: Column: SunFire Prep C18 OBD 19 mm × 150 mm × 5.0 μm. Mobile phase A: Acetonitrile; Mobile phase B: Water (containing 0.05% ammonium bicarbonate).

[0239]

Table 24

[0240] ESI-MS (m / z): 1014.3[M+H] + . 11H NMR (400 MHz, DMSO): δ 9.79 (d, J = 11.8 Hz, 2H), 7.05 (d, J = 11.0 Hz, 2H), 6.63 (d, J = 10.7 Hz, 2H), 5.29 (s, 2H), 5.16 (s, 2H), 5.14 - 5.00 (m, 8H), 4.67 (s, 2H), 4.41 (d, J = 17.7 Hz, 2H), 4.28 (d, J = 22.5 Hz, 4H), 4.15 (d, J = 15.6 Hz, 6H), 3.92 (s, 4H), 3.76 (d, J = 10.2 Hz, 6H), 3.57 - 3.44 (m, 4H), 3.03 (d, J = 41.1 Hz, 6H), 2.92 - 2.75 (m, 8H), 2.46 (s, 2H), 2.10 (s, 8H), 2.04 - 1.76 (m, 20H), 1.57 (d, J = 33.5 Hz, 42H), 1.19 (dd, J = 24.8, 11.1 Hz, 14H).

[0241] The remaining compounds shown in the following table were prepared in the same manner as described above: [Table 25] JPEG2025520013000127.jpg231170JPEG2025520013000128.jpg122170

[0242] Biological data Test Example 1: Activation effect of the compound on plasminogen (Glu-Typ) 1. Test method (1) Preparation of the compound All the test compounds and positive compounds of the present invention were set at three concentration points of 200 μM, 150 μM, and 100 μM; the final concentration in DMSO was 2.5%. (2) Information on main reagents and instruments Plasminogen (Glu-Typ) (sigma); urokinase-type plasminogen activator (u-PA) (Aladdin); vLK-pNA (absin), multifunctional microplate reader (Thermo). (3) Test system and signal detection Plasminogen, urokinase-type plasminogen activator (u-PA), and VLK-pNA were prepared in a buffer [Tris-HCl (50 mM, pH 7.4) + NaCl (100 mM) + Tween-80 (0.01%)] to obtain stock solutions at concentrations of 100 nM (5x), 100 IU / ml (5x), and 5 mM (5x), respectively. 20 μl of 5x plasminogen (Glu-Typ), 20 μl of 5x urokinase-type plasminogen activator (u-PA), and 20 μl of 5x VLK-pNA were added to a 96-well plate. After thorough mixing, 40 μl of the test compound or positive compound was added, and a control group (without compound) was set up. The mixture was mixed well uniformly. Kinetic detection was performed using a multifunctional microplate reader manufactured by Thermo, with the detection wavelength set at 405 nm, and the activator was calculated.

[0243] 2. Test results The following results were obtained by plotting the absorbance values at 405 nm (A405) against the square of time (t 2 ), analyzing the slope of the curve, and calculating the activity multiple by dividing the slope of the compound group by the slope of the control group (see Table 1-1 and Table 1-2).

[0244]

Table 26

[0245]

Table 27

[0246] As a result, at the same concentration, compounds 2-1, 2-2 and 2-5 are shown to have a better ability to activate plasminogen than the positive compound in the test system disclosed by the present invention.

[0247] Test Example 2: Fibrinolytic effect of the compound shown by thromboelastography Apparatus and main drugs: Thromboelastograph TEG (Udibio); urokinase-type plasminogen activator (u-PA) (Aladdin); reagent 1 (main component is kaolin); reagent 2 (main component is calcium chloride).

[0248] 1. Test method (1) Test group setting: 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: vehicle. (2) Preparation of compound solution: The compound was prepared using a 0.5 mg / ml tromethamine solution to obtain a 4 mM stock solution, adjusted to pH 9, and diluted to a 2 mM 10x stock solution. u-PA was prepared as a 50,000 U / ml stock solution using physiological saline and diluted to a 10,000 U / ml 10x stock solution. The final test concentration was 1000 U / ml. (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), 100 μL of the test compound was added, and the cup was inverted and mixed well. 340 μL of the sample from the sample cup was added to a reaction cup containing 20 μL of reagent 2, and the apparatus was operated. The results are shown in Table 2-1, Table 2-2, Table 2-3, Figure 1, Figure 2, and Figure 3. The compound concentrations shown in Table 2-1, Table 2-2, Figure 1, and Figure 2 were 200 μM; the compound concentrations shown in Table 2-3 and Figure 3 were 100 μM.

[0249]

Table 28

[0250]

Table 29

[0251]

Table 30

[0252] In this test system, according to the Ma values combined with FIGS. 1 and 2, it can be seen that Compounds 2-1, 2-2, 2-5 and 2-6 directly affect the strength (Ma) of the formed thrombus and can prevent thrombosis, and have thrombolytic activity superior to that of the positive compound.

[0253] The structure of the positive compound is as follows:

Chemical formula

Claims

1. A compound or its pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, polymorphs, isotope-labeled compounds, metabolites, prodrugs, or mixtures thereof, wherein the compound is 【Chemistry 1】 And, During the ceremony, Y is 【Chemistry 2】 Selected from the group consisting of; R 1 and R 3 are each independently carboxyl, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyacyloxy, C 1-6 alkylacyloxy, C 1-6 alkoxyalkylaminoacyloxy, C 1-6 alkylaminoacyloxy, C 4-10 heterocyclylacyloxy, -O-C 4-10 heterocyclyl, C 1-6 alkylsulfamoyloxy, C 4-10 heterocyclylsulfonyloxy, glycosyl, -O-P(O)(OH) 2 -O-P(O) 2 OH, -O-S(O) 2 OH, amino, C 1-6 alkylamino, C 1-6 alkylamide, C 4-10 heterocyclylamide, halogen, cyano, C 2-6 alkenyl, and C 2-6 alkynyl are each independently selected from the group consisting of; C 4-10 heterocyclylacyloxy, -O-C 4-10 heterocyclyl, C 1-6 alkylacyloxy, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylaminoacyloxy is optionally substituted with one or more substituents selected from the group consisting of hydroxy, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 haloalkyl, C 1-6 alkoxyacyloxy, 4- to 10-membered heterocyclyl, C 1-6 hydroxyalkyl, and -O-P(O)(OH) 2 and is optionally substituted with one or more substituents selected from the group consisting of; R 2 and R 4 These are independently hydrogen, hydroxyl, carboxyl, ester group, and C 1-6 alkoxy and carboxyl-substituted C 1-6 Alkylacyloxy, -OC(=O)-C 4-10 Heterocyclyl, -OP(O) 2 OH, -OS(O) 2 OH, and -OS(O) 2 NH 2 Each of the following groups is selected: C 4-10 Heterocyclines are C 1-6 It is optionally substituted with one or more substituents selected from alkyl groups; Y 【Transformation 3】 If selected from, R 1 and R 2 It is not hydroxyl at the same time; N is 0, 1, 2, 3, 4, or 5; X is -CO 2 H and its carboxylic acid isoster, -CO 2 C 1-6 Alkyl, -C(=O)SH, 4-10 member heteroaryl, choline carboxylate, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O) 2 C 1-6 Alkylamino and -C(=O)NHS(=O) 2 C 1-6 Selected from the group consisting of alkyl groups, -CO 2 C 1-6 Alkyl, 4-10 member heteroaryl, choline carboxylate, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O) 2 C 1-6 Alkylamino and -C(=O)NHS(=O) 2 C 1-6 Alkyl is C 4-10 Heterocyclyl, C 1-6 Alkoxy, 【Chemistry 4】 It is optionally substituted with one or more substituents selected from the group consisting of; and X is -CO 2 If H, then R 1 , R 2 , R 3 and R 4 It is not hydroxyl at the same time; wavy line 【Transformation 5】 This represents the point of attachment to the rest of the molecule: Compounds or their pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, polymorphs, isotope-labeled compounds, metabolites, prodrugs, or mixtures thereof.

2. R 1 and R 3 are independently selected from the group consisting of carboxyl, hydroxy, C[[INTENTIONAL LINE BREAK]] 1-6 alkoxy, C[[INTENTIONAL LINE BREAK]] 1-6 alkoxyacyloxy, C[[INTENTIONAL LINE BREAK]] 1-6 alkylaminoacyloxy, C[[INTENTIONAL LINE BREAK]] 4-10 heterocyclylacyloxy, -O-C[[INTENTIONAL LINE BREAK]] 4-10 heterocyclyl, C[[INTENTIONAL LINE BREAK]] 4-10 heterocyclylsulfonyloxy, -O-P(O)(OH)[[INTENTIONAL LINE BREAK]] 2 -O-S(O)[[INTENTIONAL LINE BREAK]] 2 OH, and C[[INTENTIONAL LINE BREAK]] 4-10 heterocyclylamide; C[[INTENTIONAL LINE BREAK]] 4-10 heterocyclylacyloxy, -O-C[[INTENTIONAL LINE BREAK]] 4-10 heterocyclyl, or C[[INTENTIONAL LINE BREAK]] 1-6 alkylaminoacyloxy is optionally substituted with one or more substituents selected from the group consisting of hydroxy, carboxyl, C[[INTENTIONAL LINE BREAK]] 1-6 alkyl, C[[INTENTIONAL LINE BREAK]] 1-6 alkoxy, C[[INTENTIONAL LINE BREAK]] 1-6 alkoxyacyloxy, C[[INTENTIONAL LINE BREAK]] 1-6 alkoxycarbonyl, C[[INTENTIONAL LINE BREAK]] 1-6 alkyl-C(=O)-, 4-10 member heterocyclyl, C[[INTENTIONAL LINE BREAK]] 1-6 hydroxyalkyl, and -O-P(O)(OH)[[INTENTIONAL LINE BREAK]] 2 : The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

3. R 1 and R 3 are each independently selected from the group consisting of carboxyl, hydroxy, C 1-3 alkoxy, C 1-3 alkoxyacyloxy, C 1-3 alkylaminoacyloxy, C 4-8 heterocyclylacyloxy, -O-C 4-8 heterocyclyl, C 4-8 heterocyclylsulfonyloxy, -O-P(=O)(OH) 2 , -O-S(O) 2 OH, and C 4-8 heterocyclylamide; C 4-8 heterocyclylacyloxy, -O-C 4-8 heterocyclyl, or C 1-3 alkylaminoacyloxy is optionally substituted with one or more substituents selected from the group consisting of 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 heterocyclyl, C 1-3 hydroxyalkyl, and -O-P(=O)(OH) 2 : The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

4. R 1 and R 3 However, independently, carboxyl, hydroxyl, -OC(=O)N(CH 3 ) 2 -OC(=O)-morpholinyl, -OC(=O)NHCH(CH 3 ) 2 -OC(=O)OCH 3 -OC(=O)-thiomorpholine dioxide, -OC(=O)-thiomorpholine monooxide, -OC(=O)-thiomorpholine, -OC(=O)N(CH 3 )-tetrahydropyrano, -OC(=O)-piperidine, -OSO 2 -morpholine, -OC(=O)-piperazine, 【Transformation 6】 -O-tetrahydropyrano, -OP(=O)(OH) 2 methoxy, glucopyranosyl and -OS(O) 2 Each is selected from the group consisting of OH, and -OC(=O)-piperidine, -OC(=O)-piperazine, -O-tetrahydropyran, or methoxy is hydroxy, carboxyl, CH 3 OC(=O)-, -C(=O)CH 3 ,-OCH 3 , piperidinyl, morpholinyl, hydroxy, -CH 2 OH, -OP (=O)(OH) 2 , and are optionally substituted with one or more substituents selected from the group consisting of oxo, wavy line 【Transformation 7】 This represents the point of attachment to the rest of the molecule: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

5. R 1 and R 3 However, independently, carboxyl, hydroxyl, -OC(=O)N(CH 3 ) 2 -OC(=O)NHCH(CH 3 ) 2 -OC(=O)OCH 3 -OP(=O)(OH) 2 methoxy, -OS(O) 2 OH, 【Transformation 8】 Each is selected from the group consisting of, wavy line 【Chemistry 9】 This represents the point of attachment to the rest of the molecule: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

6. R 2 and R 4 However, independently, hydrogen, carboxyl, hydroxyl, C 1-6 alkoxy and carboxyl-substituted C 1-6 Alkylacyloxy, -OC(=O)-C 4-10 Heterocyclyl, -OP(O) 2 OH, -OS(O) 2 OH, and -OS(O) 2 NH 2 Each of the following groups is selected: C 4-10 Heterocyclines are C 1-6 Optionally substituted with one or more substituents selected from alkyl groups: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

7. R 2 and R 4 However, independently, carboxyl, hydroxyl, C 1-6 alkoxy and carboxyl-substituted C 1-6 Alkylacyloxy, -OC(=O)-piperazinyl, -OP(O) 2 OH, -OS(O) 2 OH, and -OS(O) 2 NH 2 Each of the following groups is selected, and piperazine is C 1-6 Optionally substituted with one or more substituents selected from alkyl groups: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

8. R 2 and R 4 However, independently, carboxyl, hydroxyl, 【Chemistry 10】 and -OS(O) 2 NH 2 Each is selected from the group consisting of, wavy line 【Chemistry 11】 This represents the point of attachment to the rest of the molecule: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

9. n is 1, 2, or 3: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

10. X, -CO 2 H and its carboquinate isoster, -CO 2 C 1-6 Alkyl, -C(=O)SH, 4-10 member heteroaryl, choline carboxylate, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O) 2 C 1-6 Alkylamino and -C(=O)NHS(=O) 2 C 1-6 Selected from the group consisting of alkyl groups, -CO 2 C 1-6 Alkyl, 4-10 member heteroaryl, choline carboxylate, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O) 2 C 1-6 Alkylamino and -C(=O)NHS(=O) 2 C 1-6 Alkyl is a 4-10 membered heterocycline. 【Chemistry 12】 and -C 1-6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys. wavy line 【Chemistry 13】 This represents the point of attachment to the rest of the molecule: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

11. X, -CO 2 H, -CO 2 C 1-6 Alkyl, -C(=O)SH, tetrazolyl, -C(=O)NHC 1-6 Alkyl, -C(=O)NHS(=O) 2 C 1-6 Alkyl and -C(=O)NHS(=O) 2 N(C 1-6 Alkyl) 2 Selected from the group consisting of -CO 2 C 1-6 Alkyl and -C(=O)NHC 1-6 Alkyl is morpholinyl, 【Chemistry 14】 and -C 1-6 It is optionally substituted with one or more substituents selected from the group consisting of alkoxys. wavy line 【Chemistry 15】 This represents the point of attachment to the rest of the molecule: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

12. Xが、-CO 2 H、-C(=O)NHCH 3 、 【Chemistry 16】 Selected from the group consisting of, wavy line 【Chemistry 17】 This represents the point of attachment to the rest of the molecule: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

13. The compound, [Chemistry 18] Selected from the group consisting of: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

14. The compound, 【Chemistry 19】 And, During the ceremony, R 1 , R 2 , R 3 , R 4 , and X are as defined in claim 1, and X is -CO 2 If H, then R 1 , R 2 , R 3 and R 4 It is not hydroxyl at the same time: The compound described in claim 1, or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, polymorph, isotope-labeled compound, metabolite, prodrug, or mixture thereof.

15. The compound, 【Chemistry 20】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound according to claim 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, prodrug, or mixture thereof, selected from the group consisting of the above.

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 compound, metabolite, prodrug, or mixture thereof, and one or more pharmaceutically acceptable carriers, optionally further comprising one or more additional drugs for the treatment of thromboembolic diseases.

17. A pharmaceutical product for the treatment of thromboembolic diseases, comprising the compounds described in Claims 1 to 15, or pharmaceutically acceptable salts, esters, solvates, stereoisomers, tautomers, polymorphs, isotope-labeled compounds, metabolites, prodrugs, or mixtures thereof.

18. A pharmaceutical composition for the treatment of thromboembolic diseases, comprising the pharmaceutical composition described in Claim 16.

19. A method for preparing a compound of formula I, comprising the steps shown in the following scheme: 【Chemistry 21】 During the ceremony: R 1 , R 2 and Y are as defined in any one of claims 1 to 15; and LG is a leaving group, in this case.

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