Asymmetric dimeric compound with benzo [b] selenol structure as well as preparation method and application of asymmetric dimeric compound

Abstract

The invention discloses a compound with a structure as shown in a general formula (I) or pharmaceutically acceptable salt, isomer, metabolite, solvate or prodrug thereof, a preparation method and a pharmaceutical composition thereof, and application of the compound in STING-mediated diseases. # imgabs0 #

Description

Field of the Invention

[0001] The present invention relates to chemical medicine technology, and in particular to a dimer compound having a benzo[b]selenol structure, including a preparation method thereof and related uses thereof. Background of the Invention

[0003] Immune checkpoint blockade (ICB) is an effective anti-tumor strategy, but the response rate does not exceed 40% in clinical applications. One of the important reasons is the lack of effector T cell infiltration in tumor tissues. In recent years, active activation of innate immune pathways, simulating anti-tumor immune responses, activating T cells and promoting tumor infiltration are new strategies for tumor immunotherapy. Cyclic GMP-AMP synthase (cGAS) is a cytoplasmic DNA sensor, which forms a cGAS-STING response pathway with the cytoplasmic receptor interferon gene stimulator protein STING (Stimulator of interferon gene, TMEM173, MITA, etc.), and plays an important role in antiviral and anti-tumor immune responses. cGAS is a nuclease that captures and recognizes cytoplasmic double-stranded DNA (dsDNA) and catalyzes the synthesis of the second messenger cyclic dinucleoside (CDNs) 2′3′-cGAMP (cGAMP), which acts as an endogenous ligand to bind and activate the endoplasmic reticulum protein STING. At the same time, STING can also act as a cytoplasmic nucleic acid PRR to recognize cyclic dinucleosides such as c-diGMP from bacteria. After binding to CDN, STING located in the endoplasmic reticulum shifts to proximal nucleosomes such as the Golgi apparatus, endosomes, and autophagosomes. In this process, STING recognizes and recruits TNAK-binding kinase 1 (TBK1) kinase and IKK kinase at its C-terminus, thereby promoting the activation and phosphorylation of transcription factors IRF3 and NF-κ B. Activated cytokines enter the nucleus and initiate the transcription of interferon-stimulated genes (ISGs), promoting the expression and secretion of type I interferons (Interferon, IFN) such as IFNβ, and inflammatory factors such as tumor necrosis factor (TNF), interleukin 6 (IL 6), and IL1β, thereby causing downstream immune responses.

[0004] At present, several regulators developed for the key receptor STING protein of this pathway have entered the clinical stage as anti-tumor drugs and have received widespread attention. Most STING agonists are first-generation cyclic dinucleoside derivatives, which directly act on the STING ligand binding pocket as a mimetic of the second messenger cGAMP to activate the STING pathway. For example, the clinical trials of ADU-S100 (NCT03172936) and MK-1454 (NCT04220866), which were the first to enter the clinic, have been suspended, and E7766 and TAK676 are still in clinical phase I. However, due to poor stability, intratumoral injection (IT) is often used clinically. In addition, its molecular weight and polarity are both large, and its membrane permeability is poor, which limits the further development of cyclic dinucleoside derivatives in clinical practice. Therefore, finding new non-nucleoside small molecule agonists with good drugability is the main direction of this research field at present. At present, some non-nucleoside STING agonists are undergoing preclinical trials or have entered clinical phase I. They exert immune anti-tumor effects by activating the STING pathway. Summary of the invention

[0005] Purpose of the invention: The purpose of the present invention is to broaden the types of existing STING agonists, and to provide a dimeric compound having a benzo[b]selenophene structure and a preparation method, a pharmaceutical composition and use thereof. These compounds have a strong affinity for the STING protein, have good agonistic ability for the cGAS-STING pathway, and have excellent effects on anti-tumor activity.

[0006] Technical solution: The present invention provides a compound of general formula (I), a pharmaceutically acceptable salt, isomer, metabolite or solvate thereof:

[0007]

[0008] in,

[0009] L 1 and L 3 are the same or different and are each independently selected from C(R 5 )2. NR 5 , O or S;

[0010] L 2 Selected from C1-C6 alkylene, 6 Substituted C1-C6 alkylene, C1-C6 alkylene-L 4 -C1-C6 alkylene, C2-C6 alkenylene, C2-C6 haloalkenylene, C2-C6 alkynylene, C2-C6 haloalkynylene, C3-C6 cycloalkyl or 3-6 membered heterocyclic group;

[0011] X 1 and X4 Selected from C(O);

[0012] X 2 and X 5 Selected from (C(R 7 )2) p , CHR 7 CHR 7 or CH2C(R 7 )2;

[0013] X 3 and X 6 The same or different, and each independently selected from COOR 5 、C(O)N(R 5 )2、C(O)NR 5 OR 5 、C(O)ON(R 5 2. SO2R 5 、S(O)NR 5 or C(CF3)2OR 5 ;

[0014] R 1 and R 2 are the same or different and are each independently selected from hydrogen, halogen, cyano, nitro, OR 5 , SR 5 、N(R 5 2. COOR 5 、C(O)N(R 5 )2, C1~C6 alkyl, C1~C6 haloalkyl, OR 5 Substituted C1-C6 alkyl, N(R 5 )2-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic group;

[0015] R 3 and R 4 are the same or different and are each independently selected from hydrogen, halogen, cyano, OR 5 、N(R 5 )2, C1~C6 alkyl, C1~C6 haloalkyl or C3~C6 cycloalkyl;

[0016] Preferably, R 4 is selected from a hydrogen atom, a halogen, a cyano group or a nitro group;

[0017] R 5 Each is independently selected from a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a 3-6 membered heterocyclic group or a C5-C 10Aryl;

[0018] R 6 Selected from hydrogen atoms, halogens, OR 5 、N(R 5 )2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic group;

[0019] R 7 are independently selected from hydrogen, halogen, cyano, OR 5 、N(R 5 )2, C1~C6 alkyl, C1~C6 haloalkyl, OR 5 Substituted C1~C6 alkyl or C3~C6 cycloalkyl;

[0020] Optionally, the two R on different carbon atoms 7 Together with the carbon atoms between them, they can form a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group;

[0021] Optionally, two R on the same carbon atom 7 Together with the carbon atom to which they are commonly attached, they may form a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group;

[0022] m and n are each independently selected from 0, 1, 2 and 3;

[0023] p is selected from 1, 2 and 3.

[0024] In a preferred embodiment of the present invention, wherein:

[0025] L 1 and L 3 are the same or different and are each independently selected from CH2, NH or O;

[0026] L 2 Selected from C1-C6 alkylene, 6 Substituted C1-C6 alkylene, C1-C4 alkylene-L 4 -C1-C4 alkylene, C2-C4 alkenylene, C2-C4 haloalkenylene, C2-C4 alkynylene, C2-C4 haloalkynylene, C3-C6 cycloalkyl or 3-6 membered heterocyclic group, preferably C2-C5 alkylene, 6 Substituted C2-C5 alkylene or C1-C4 alkylene-L 4 -C1~C4 alkylene;

[0027] L 4 is selected from O, S, C(O), C3-C6 cycloalkyl and 3-6 membered heterocyclic group, preferably O or C(O);

[0028] X 1 and X4 Selected from C(O);

[0029] X 2 and X 5 Selected from (C(R 7 )2) p ;

[0030] X 3 and X 6 The same or different, and each independently selected from COOR 5 、C(O)N(R 5 )2、C(O)NR 5 OR 5 and C(O)ON(R 5 )2, preferably COOH, COOCH3, COOCH2CH3, C(O)NH2, C(O)NHOH, C(O)NHOCH3 or C(O)ONHCH(CH3)2;

[0031] R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, an OC1-C3 alkyl group, an OC1-C3 haloalkyl group or OH, preferably a hydrogen atom, a fluorine atom, a chlorine atom, CH3, CH2CH3, OCH3, OCH2CH3, OCH(CH3)2 or OCHF2;

[0032] R 3 and R 4 are the same or different and are each independently selected from a hydrogen atom, a fluorine atom, a C1-C3 alkyl group, preferably a hydrogen atom;

[0033] R 5 Each is independently selected from a hydrogen atom, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C3-C6 cycloalkyl group, a 3-6 membered heterocyclic group or a C5-C 10 Aryl;

[0034] R 6 It is selected from a hydrogen atom, a fluorine atom, OH, NH2, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group, preferably a hydrogen atom, a fluorine atom, CH3, CH2CH3, OH or a cyclopropyl group.

[0035] R 7 Each is independently selected from a hydrogen atom, a fluorine atom, an OC1-C3 alkyl group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkyl group substituted with an OC1-C3 alkyl group, or a C3-C6 cycloalkyl group, preferably a hydrogen atom, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2OCH3 or a cyclopropyl group;

[0036] Optionally, the two R on different carbon atoms 7 Together with the carbon atoms between them, they can form a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group;

[0037] Optionally, two R on the same carbon atom 7 Together with the carbon atom to which they are commonly attached, they may form a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group;

[0038] m and n are each independently selected from 0, 1, 2 and 3, preferably 1;

[0039] p is selected from 1, 2 and 3, preferably 2.

[0040] In another preferred embodiment of the present invention, the compound, its pharmaceutically acceptable salt, isomer, metabolite, solvate or prodrug:

[0041] L 1 and L 3 are the same or different and are each independently selected from CH2, NH or O;

[0042] L 2 Selected from C1-C6 alkylene, 6 Substituted C1-C6 alkylene, C1-C4 alkylene-L 4 -C1-C4 alkylene, C2-C4 alkenylene, C2-C4 haloalkenylene, C2-C4 alkynylene, C2-C4 haloalkynylene, C3-C6 cycloalkyl or 3-6 membered heterocyclic group;

[0043] L 4 is selected from O, S, C(O), C3-C6 cycloalkyl or 3-6 membered heterocyclic group;

[0044] X 1 and X 4 Selected from C(O);

[0045] X 2 and X 5 Selected from C1-C6 alkylene, C3-C6 cycloalkyl;

[0046] X 3 and X 6 are the same or different and are each independently selected from COOH, COO-C1~C6 haloalkyl, COO-C1~C4 alkyl, COO-NH-C1~C4 alkyl, C(O)NHOH, C(O)NH2, C(O)NHOCH3;

[0047] R 1 and R 2are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, an O-C1-C3 alkyl group, an O-C1-C3 alkyl group-O-C1-C3 alkyl group, an O-C1-C3 haloalkyl group or OH;

[0048] R 3 and R 4 are the same or different and are each independently selected from a hydrogen atom, a fluorine atom, a chlorine atom, and a C1-C3 alkyl group;

[0049] R 6 is selected from a hydrogen atom, a fluorine atom, OH, NH2, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group;

[0050] m and n are each independently selected from 0, 1, 2 or 3.

[0051] In another preferred embodiment of the present invention, wherein:

[0052] X 2 and X 5 Selected from CHR 7 CHR 7 ;

[0053] X 3 and X 6 Selected from COOH.

[0054] In another preferred embodiment of the present invention, wherein:

[0055] X 2 and X 5 Selected from CH2C(R 7 )2;

[0056] X 3 and X 6 Selected from COOH.

[0057] In another preferred embodiment of the present invention, the compound has the structure of formula (Ia):

[0058]

[0059] Wherein, each variable is as defined above.

[0060] In another preferred embodiment of the present invention, the compound has the structure of formula (Ib):

[0061]

[0062] Wherein, each variable is as defined above.

[0063] In another preferred embodiment of the present invention, the compound, its pharmaceutically acceptable salt, isomer, metabolite or solvate, wherein the compound has the structure of formula (I-1) or the structure of formula (I-2):

[0064]

[0065] Wherein, each variable is as defined above.

[0066] In another preferred embodiment of the present invention, the compound is selected from the group consisting of:

[0067]

[0068]

[0069]

[0070]

[0071] The second aspect of the present invention also provides a method for preparing these compounds, which is selected from the group consisting of:

[0072] When it is a compound represented by general formula (I-1), the synthesis route is as follows:

[0073]

[0074] Among them, R 1 , R 2 , R 7 , L 2 , m and n are as defined above, R 8 Selected from CH3, CH2CH3, C(CH3)3, R 9 Each is independently selected from CH3, CH2CH3, and Y is selected from Cl, Br, I.

[0075] In some more specific embodiments, R1 and R2 can be hydrogen atoms, fluorine atoms, chlorine atoms, CH3, CH2CH3, OCH3, OCH2CH3, OCH(CH3)2 and OCHF2, L2 can be C2-C5 alkylene, 6 Substituted C2-C5 alkylene and C1-C4 alkylene-L 4 -C1~C4 alkylene, R6 can be a hydrogen atom, a fluorine atom, CH3, CH2CH3, OH and cyclopropyl, L4 can be O and C(O), and R7 can be a hydrogen atom, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2OCH3 and cyclopropyl.

[0076] In some more specific embodiments, in the process of preparing compound 3 from compound 1, the reactant is benzyl bromide (2), the reaction reagents can be potassium carbonate, sodium carbonate, sodium hydroxide and sodium hydride, and the reaction solvent can be DMF and tetrahydrofuran.

[0077] In some more specific embodiments, in the process of preparing compound 5 from compound 3, the reactant is dimethyl diselenide (4), the reaction reagents can be DTT, mercaptoethanol, DBU and potassium carbonate, and the reaction solvent can be DMF and tetrahydrofuran.

[0078] In some more specific embodiments, in the process of preparing compound 7 from compound 5, the reactant is ethyl 2-bromoacetate (6) and the reaction solvent is DMF.

[0079] In some more specific embodiments, in the process of preparing compound 8 from compound 7, the reaction reagents can be potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide, and the reaction solvents can be DMF and acetonitrile.

[0080] In some more specific embodiments, in the process of preparing compound 9 from compound 8, the reaction reagents can be potassium carbonate, sodium hydroxide and strong lithium oxide, and the reaction solvent can be water, methanol and tetrahydrofuran.

[0081] In some more specific embodiments, in the process of preparing compound 11 from compound 9, the reactant is malonic acid monoester potassium salt (10), the reaction reagents can be CDI and MgCl2, and the reaction solvent can be DMF and tetrahydrofuran.

[0082] In some more specific embodiments, in the process of preparing compound 13 from compound 11, the reactant is halogenated ester (12), the reaction reagents can be potassium carbonate, sodium methoxide, sodium ethoxide and sodium hydride, and the reaction solvent can be DMF and tetrahydrofuran.

[0083] In some more specific embodiments, in the process of preparing compound 14 from compound 13, the reaction reagents can be potassium carbonate, sodium hydroxide, lithium hydroxide and hydrochloric acid, and the reaction solvent can be acetic acid, water and tetrahydrofuran.

[0084] In some more specific embodiments, in the process of preparing compound 15 from compound 14, the reaction reagents can be dichlorothionyl and oxalyl chloride, and the reaction solvent can be methanol, ethanol and dichloromethane.

[0085] In some more specific embodiments, in the process of preparing compound 17 from compound 15, the reactant is dihaloalkane (16), the reaction reagent can be potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium iodide and crown ether, and the reaction solvent can be DMF and tetrahydrofuran.

[0086] In some more specific embodiments, in the process of preparing compound 20 from compound 18, the reactant is N-(hydroxymethyl)phthalimide (19), and the reaction solvent is concentrated sulfuric acid.

[0087] In some more specific embodiments, in the process of preparing compound 21 from compound 20, the reaction reagents can be methyl iodide and potassium carbonate, and the reaction solvent is DMF.

[0088] In some more specific embodiments, in the process of preparing compound 22 from compound 21, the reaction reagent can be hydrazine hydrate and the reaction solvent can be methanol.

[0089] In some more specific embodiments, in the process of preparing compound 24 from compound 22, the reactant is p-4-methoxybenzyl chloride (23), the reaction reagent can be sodium hydride, and the reaction solvent is DMF.

[0090] In some more specific embodiments, in the process of preparing compound 25 from compound 24, the reaction reagent can be a borane tetrahydrofuran complex, and the reaction solvent is tetrahydrofuran.

[0091] In some more specific embodiments, in the process of preparing compound 26 from compound 25, the reaction reagents can be palladium / carbon and palladium hydroxide / carbon, and the reaction solvent can be tetrahydrofuran or methanol.

[0092] In some more specific embodiments, in the process of preparing compound 28 from compound 26, the reactant is an acyl halide compound (27), the reaction reagent can be triethylamine, and the reaction solvent is dichloromethane.

[0093] In some more specific embodiments, in the process of preparing compound 29 from compound 28, the reaction reagent can be boron tribromide and the reaction solvent can be dichloromethane.

[0094] In some more specific embodiments, in the process of preparing compound 30 from compound 29, the reactant is compound 17, the reaction reagents can be potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium iodide and crown ether, and the reaction solvent can be DMF and tetrahydrofuran.

[0095] In some more specific embodiments, in the process of preparing the compound of formula (I-1) from compound 30, the reaction reagents can be potassium carbonate, sodium hydroxide and lithium hydroxide, and the reaction solvent can be water, methanol and tetrahydrofuran.

[0096] When it is a compound represented by general formula (I-2), the synthesis route is as follows:

[0097]

[0098] Among them, R 1 , R2 , L 2 , m and n are as defined above, R 9 Each is independently selected from CH3, CH2CH3, Y is selected from Cl, Br, I, and q represents 1, 2, 3 or 4.

[0099] In some more specific embodiments, R1 and R2 can be hydrogen atoms, fluorine atoms, chlorine atoms, CH3, CH2CH3, OCH3, OCH2CH3, OCH(CH3)2 or OCHF2, L2 can be C2-C5 alkylene, 6 Substituted C2-C5 alkylene or C1-C4 alkylene-L 4 -C1~C4 alkylene, R6 can be a hydrogen atom, a fluorine atom, CH3, CH2CH3, OH or a cyclopropyl group, and L4 can be O or C(O).

[0100] In some more specific embodiments, in the process of preparing compound 31 from compound 9, the reaction reagent is copper powder and the reaction solvent is quinoline.

[0101] In some more specific embodiments, in the process of preparing compound 33 from compound 31, the reactant is substituted succinic anhydride (32), the reaction reagents can be aluminum trichloride, zinc chloride and titanium tetrachloride, and the reaction solvent can be dichloromethane and tetrahydrofuran.

[0102] In some more specific embodiments, in the process of preparing compound 34 from compound 33, the reactant is hydrogen, the reaction reagents can be palladium / carbon and palladium hydroxide / carbon, and the reaction solvent can be tetrahydrofuran and methanol.

[0103] In some more specific embodiments, in the process of preparing compound 35 from compound 34, the reaction reagents can be dichlorothionyl and oxalyl chloride, and the reaction solvent can be methanol, ethanol and dichloromethane.

[0104] In some more specific embodiments, in the process of preparing compound 36 from compound 35, the reactant is dihaloalkane (16), the reaction reagent can be potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium iodide and crown ether, and the reaction solvent can be DMF and tetrahydrofuran.

[0105] In some more specific embodiments, in the process of preparing compound 37 from compound 36, the reactant is compound 29, the reaction reagents can be potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium iodide and crown ether, and the reaction solvent can be DMF and tetrahydrofuran.

[0106] In some more specific embodiments, in the process of preparing the compound of formula (I-2) from compound 37, the reaction reagents can be potassium carbonate, sodium hydroxide and lithium hydroxide, and the reaction solvent can be water, methanol and tetrahydrofuran.

[0107] The third aspect of the present invention provides a pharmaceutical composition comprising one or more therapeutically effective amounts of the compounds described in the first aspect of the present invention or their pharmaceutically acceptable salts, isomers, metabolites or solvates, and pharmaceutically acceptable excipients or carriers.

[0108] In a preferred embodiment, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, granules, solutions, suspensions and injections, and the administration method is oral administration or injection.

[0109] In another preferred embodiment, the pharmaceutical composition further comprises one or more second therapeutic agents, which can be used to prevent and / or treat cancer.

[0110] In another preferred embodiment, the second therapeutic agent is a traditional cytotoxic anti-tumor drug and other anti-tumor immune drugs.

[0111] The fourth aspect of the present invention provides use of the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, solvate or the pharmaceutical composition described in the third aspect of the present invention in preparing a drug for the treatment of a disease.

[0112] In a preferred embodiment, the medicament can be used to prevent and / or treat cancer or infectious diseases.

[0113] The fifth aspect of the present invention provides use of the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, solvate or the pharmaceutical composition described in the third aspect of the present invention in the preparation of a vaccine adjuvant.

[0114] In a preferred embodiment, the vaccine adjuvant can be used to prevent and / or treat cancer or infectious diseases.

[0115] The sixth aspect of the present invention provides use of the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, solvate or the pharmaceutical composition described in the third aspect of the present invention in the preparation of a STING agonist.

[0116] The seventh aspect of the present invention provides use of the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, solvate or the pharmaceutical composition described in the third aspect of the present invention in the preparation of a drug for treating STING-related diseases.

[0117] In the eighth aspect of the present invention, there is provided the use of the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, solvate or the pharmaceutical composition described in the third aspect of the present invention in combination with an immune checkpoint inhibitor for the preparation of an anti-tumor drug. The immune checkpoint inhibitor is a PD-1 / PD-L1 inhibitor, an IDO1 inhibitor and a CTLA-4 inhibitor. The compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, solvate or the pharmaceutical composition described in the third aspect of the present invention and the immune checkpoint inhibitor can be administered simultaneously or separately.

[0118] In the present invention, the tumor includes but is not limited to lung cancer, liver cancer, gastric cancer, breast cancer, melanoma, colorectal cancer, pancreatic cancer, prostate cancer, squamous cell carcinoma, glioma and leukemia.

[0119] Beneficial effects: The present invention provides compounds or pharmaceutically acceptable salts, isomers, metabolites, solvates or prodrugs thereof, preparation methods and pharmaceutical compositions thereof. These compounds have strong affinity for STING protein and good agonist ability for cGAS-STING pathway, thus broadening the types of existing STING agonists.

[0120] Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below:

[0121] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the general formula (I) of the present invention and a pharmaceutically acceptable non-toxic base, including an organic base or an inorganic base. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as betaine, caffeine, choline, N-ethylpiperidine, N,N'-dibenzylethylenediamine, diethylamine, 2-dimethylaminoethanol, arginine, ethanolamine, ethylenediamine, N-ethylmorpholine, glucosamine, methylglucosamine, 2-diethylaminoethanol, glucosamine, histidine, aminoethanol, hydroxocobalamin, lysine, morpholine, piperazine, piperidine, quaternium, polyamine resins, triethylamine, trimethylamine, tripropylamine, isopropylamine, tromethamine, etc. Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, zinc and the like.

[0122] The term "isomers" refers to compounds that have the same chemical formula but different arrangements of the atoms.

[0123] The term "metabolite" refers to a pharmaceutically active product produced by the metabolism of a compound of the invention in vivo. Such products may be produced, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by a process of contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0124] The term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0125] The term "alkyl" refers to a monovalent straight or branched saturated aliphatic hydrocarbon group having a number of carbon atoms within a specified range. For example, "C1-C6 alkyl" refers to any hexylalkyl and pentylalkyl isomers as well as n-butyl, isobutyl, sec-butyl, tert-butyl, n-propyl, isopropyl, ethyl and methyl.

[0126] The term "alkylene" refers to a divalent straight-chain saturated aliphatic hydrocarbon group having a number of carbon atoms in the specified range.

[0127] The term "alkenyl" refers to a monovalent straight or branched chain unsaturated aliphatic hydrocarbon group having a number of carbon atoms in the specified range and including one or more double bonds.

[0128] The term "alkenylene" refers to a divalent straight chain unsaturated aliphatic hydrocarbon group having a number of carbon atoms in the specified range and including one or more double bonds.

[0129] The term "alkynyl" refers to a monovalent straight or branched chain unsaturated aliphatic hydrocarbon group having a number of carbon atoms in the specified range and including one or more triple bonds.

[0130] The term "alkynylene" refers to a divalent straight chain unsaturated aliphatic hydrocarbon group having a number of carbon atoms in the specified range and including one or more triple bonds.

[0131] The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine, or fluoro, chloro, bromo or iodo.

[0132] The term "haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms have been replaced by halogen. For example, "C1-C6 haloalkyl" refers to a C1 to C6 straight or branched chain alkyl group as defined above having one or more halogen substituents.

[0133] The term "haloalkylene" refers to an alkylene group as defined above wherein one or more hydrogen atoms have been replaced by a halogen, as in a haloalkyl group as defined above.

[0134] The term "haloalkenyl" refers to an alkenyl group as defined above wherein one or more hydrogen atoms have been replaced by a halogen.

[0135] The term "haloalkenylene" refers to an alkenylene group as defined above wherein one or more hydrogen atoms have been replaced by a halogen.

[0136] The term "haloalkynyl" refers to an alkynyl group as defined above wherein one or more hydrogen atoms have been replaced by a halogen.

[0137] The term "haloalkynylene" refers to an alkynylene group as defined above wherein one or more hydrogen atoms have been replaced by a halogen.

[0138] The term "cycloalkyl" refers to a saturated or unsaturated hydrocarbon containing a ring having a specified number of carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene. Cycloalkyl can be substituted and unsubstituted.

[0139] The term "heterocyclic group" refers to a saturated or unsaturated cyclic group containing one to multiple heteroatoms (N, O or S). The term includes heteroaryl moieties. Examples of heterocyclic groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Heterocyclic groups may be substituted and unsubstituted.

[0140] The term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. DETAILED DESCRIPTION

[0141] In order to further illustrate the present invention, a series of examples are given below. These examples are purely illustrative and are only used to specifically describe the present invention, and should not be understood as limiting the present invention.

[0142] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0143] abbreviation

[0144] 1 H NMR proton nuclear magnetic resonance spectroscopy

[0145] 13 C NMR 13 C NMR spectroscopy

[0146] CDCl3 deuterated chloroform

[0147] CDI N,N'-Carbonyldiimidazole

[0148] [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2

[0149] C-Phos Pd G3′-amino-1,1′-biphenyl)]methanesulfonate palladium(II)

[0150] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0151] DCC N,N′-Dicyclohexylcarbodiimide

[0152] DMAP 4-dimethylaminopyridine

[0153] DMF N,N-Dimethylformamide

[0154] DMSO Methyl sulfoxide

[0155] DTT Thiothreitol

[0156] O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

[0157] HATU

[0158] ester

[0159] HRMS High Resolution Mass Spectrometry

[0160] NBS N-Bromosuccinimide

[0161] PdCl2(dppf)-CH2Cl21,1-Bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex

[0162] TLC Thin Layer Chromatography

[0163] Intermediate Preparation Example 1

[0164]

[0165] Step 1: Preparation of 5-(benzyloxy)-2-bromo-4-methoxybenzaldehyde (3a)

[0166] 2-Bromo-5-hydroxy-4-methoxybenzaldehyde (1a, 6.8g, 29.7mmol), potassium carbonate (8.21g, 59.4mmol) and 300mL DMF were added to a 1L reaction bottle, and then benzyl bromide (6.06g, 35.6mmol) was added to the reaction bottle and stirred at 50°C for 2h. After TLC monitoring, the reaction mixture was poured into 1.5L ice water. The filter cake was collected by suction filtration, and the filter cake was washed with water and dried to obtain a crude product. 200mL of methanol was added to the crude product and pulped at room temperature for 20min. After suction filtration, the filter cake was washed with methanol and dried to obtain 9.12g of a white solid (compound 3a), with a yield of 96%. 1H NMR (300MHz, CDCl3): δ = 10.16 (s, 1H), 7.48 (s, 1H), 7.46-7.30 (m, 5H), 7.07 (s, 1H), 5.16 (s, 2H), 3.95 (s, 3H) ppm. HRMS (ESI + ): Cacld for C 15 H 14 BrO3 + (M+H) + , 321.0121; found 321.0122.

[0167] Step 2: Preparation of 5-(benzyloxy)-4-methoxy-2-(methylseleno)benzaldehyde (5a)

[0168] Compound 3a (9.6 g, 30.0 mmol), DTT (6.216 g, 40.0 mmol) and 100 mL of DMF were added to a 250 mL reaction flask, and then dimethyl diselenide (3.8 g, 20.0 mmol) and DBU (7.6 g, 50.0 mmol) were added thereto. After nitrogen replacement, the mixture was stirred at room temperature for 24 h. After TLC monitoring of the complete reaction of the raw material 3a, the reaction solution was poured into 500 mL of water to precipitate. The crude product was filtered and washed with water to obtain a crude product. 100 mL of methanol was added to the crude product and pulped at room temperature for 20 min. The filter cake was filtered and washed with methanol and dried to obtain 5.80 g of a light yellow solid (compound 5a) with a yield of 87%. 1 H NMR (300MHz, CDCl3): δ = 10.08 (s, 1H), 7.46-7.30 (m, 6H), 6.99 (s, 1H), 5.18 (s, 2H), 3.99 (s, 3H), 2.31 (s, 3H) ppm. HRMS (ESI + ): Cacld for C 16 H 17 O3Se + (M+H) + , 337.0337; found 337.0335.

[0169] Step 3: Preparation of ethyl 2-((4-(benzyloxy)-2-formyl-5-methoxyphenyl)seleno)acetate (7a)

[0170] Compound 5a (6.61 g, 19.7 mmol) and 50 mL of DMF were added to a 250 mL reaction bottle, and then ethyl 2-bromoacetate (9.87 g, 59.1 mmol) was added and heated and stirred at 150 ° C for 3.5 h. After TLC monitoring of the complete reaction of the raw materials, the reaction solution was gradually cooled to room temperature. Then 250 mL of water was added to dilute and extracted three times with 80 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude compound 7a as a black oil. The crude product was directly used in the next step without additional purification. HRMS (ESI + ): Cacld for C 19 H 21 5S + (M+H) + , 409.0549; found 409.0547.

[0171] Step 4: Preparation of ethyl 5-(benzyloxy)-6-methoxybenzo[b]selenophene-2-carboxylate (8a)

[0172] Compound 7a and K2CO3 (6.81 g, 49.3 mmol) obtained in the previous step were added to a 250 mL reaction flask, and 70 mL of acetonitrile was added thereto. Stir it under reflux for 4 h. After TLC monitoring of the complete reaction of the raw materials, the reaction solution was gradually cooled to room temperature. After the reaction solution was concentrated, 300 mL of water was added for dilution, and then extracted three times with 80 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. 100 mL of methanol was added to the crude product and pulped at room temperature for 20 min. Filtered by suction, the filter cake was washed with methanol and dried to obtain 6.11 g of a light yellow solid (compound 8a), with a yield of 76%. 1 H NMR (300MHz, DMSO-d6): δ = 8.24 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.50-7.32 (m, 5H), 5.12 (s, 2H), 4.33 (q, J = 6.9Hz, 2H), 3.86 (s, 3H), 1.33 (t, J = 7.2Hz, 3H) ppm.HRMS (ESI + ): Cacld for C 19 H 19 oeLh + (M+H) + , 391.0443; found 391.0441.

[0173] Step 5: Preparation of 5-(Benzyloxy)-6-methoxybenzo[b]selenophene-2-carboxylic acid (9a)

[0174] Compound 8a (8.80 g, 21.61 mmol), 90 mL of methanol and 90 mL of tetrahydrofuran were added to a 500 mL reaction flask, and then 35 mL of 2N aqueous sodium hydroxide solution was added to the reaction flask. Stir it at 60 ° C for 1 h. After TLC monitoring of the complete reaction of the raw materials, the reaction solvent was removed by decompression, and the pH of the residue was adjusted to 2-3 with 1N HCl. After suction filtration, the filter cake was washed with water and dried to obtain 7.72 g of off-white solid (compound 9a), with a yield of 98%. 1 H NMR (300MHz, DMSO-d6): δ = 8.16 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.50-7.32 (m, 5H), 5.12 (s, 2H), 3.85 (s, 3H) ppm. HRMS (ESI): Cacld for C 17 H 13 oeLh - (MH) - , 360.9985; found 360.9987.

[0175] Step 6: Preparation of methyl 3-(5-(benzyloxy)-6-methoxybenzo[b]selenophene-2-yl)-3-oxopropanoate (11a)

[0176] Compound 9a (9.1 g, 25.2 mmol), CDI (12.25 g, 75.6 mmol) and 180 mL of DMF were added to a 500 mL reaction flask. Stirred at room temperature for 1 h, and then MgCl2 (7.20 g, 75.6 mmol) and potassium monomethyl malonate (11.80 g, 75.6 mmol) were added. After 5 h of reaction at room temperature, TLC monitored that the raw materials reacted completely, and then the reaction solution was poured into 900 mL of water. Filtered by suction, the filter cake was washed with water to obtain a crude product, 200 mL of methanol was added to the crude product and pulped at room temperature for 20 min. Filtered by suction, the filter cake was washed with methanol and dried to obtain 8.83 g of a yellow solid (compound 11a), with a yield of 84%. 1 H NMR (300MHz, CDCl3): δ = 8.02 (s, 1H), 7.48-7.31 (m, 7H), 5.21 (s, 2H), 3.98 (s, 3H), 3.97 (s, 2H), 3.76 (s, 3H) ppm. HRMS (ESI + ): Cacld for C 20 H 19 5S + (M+H) + , 419.0392; found 419.0394.

[0177] Intermediate Preparation Example 2

[0178]

[0179] Step 1: Preparation of methyl ethyl 2-(5-(benzyloxy)-6-methoxybenzo[b]selenophene-2-carbonyl)succinate (12a)

[0180] Compound 11a (2.20 g, 5.28 mmol), K2CO3 (1.45 g, 10.5 mmol) and 20 mL of DMF were added to a 100 mL reaction bottle, and then ethyl 2-bromoacetate (1.06 g, 6.34 mmol) was added. It was stirred at room temperature for 4 h. After TLC monitoring of the complete reaction of the raw materials, 100 mL of water was added to the reaction solution, and then extracted three times with 40 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product of compound 12a was obtained. The crude product was directly used in the next step without additional purification. HRMS (ESI + ): Cacld for C 24 H 25 7sE + (M+H) + , 505.0760; found 505.0763.

[0181] Step 2: Preparation of 4-(5-hydroxy-6-methoxybenzo[b]selenophene-2-yl)-4-oxobutanoic acid (13a)

[0182] Compound 12a obtained in the previous step and 10 mL of acetic acid were added to a 100 mL reaction bottle, and then 10 mL of concentrated hydrochloric acid was slowly added. Stir it at 90 ° C for 2 h. After TLC monitoring of the reaction of the raw materials, the reaction solution was naturally cooled to room temperature, and then 90 mL of water was added and extracted three times with 30 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was adjusted to pH 10-11 with 3N sodium hydroxide aqueous solution, then extracted three times with 30 mL of ethyl acetate, the organic phases were combined, washed once with 3N sodium hydroxide aqueous solution, and the aqueous layers were combined. The aqueous layer was adjusted to pH 2-3 with 6N HCl, filtered, and the filter cake was washed with water and dried to obtain 1.02 g of a light yellow solid (compound 13a), with a two-step yield of 59%. 1 H NMR (300MHz, DMSO-d6): δ = 12.16 (s, 1H), 9.36 (s, 1H), 8.39 (s, 1H), 7.63 (s, 1H), 7. 36 (s, 1H), 3.86 (s, 3H), 3.26 (t, J = 6.0Hz, 2H), 2.60 (t, J = 6.3Hz, 2H) ppm.HRMS (ESI- ): Cacld forC 13 H 11 5S - (MH) - , 326.9777; found 326.9775.

[0183] Step 3: Preparation of ethyl 4-(5-hydroxy-6-methoxybenzo[b]selenophene-2-yl)-4-oxobutanoate (14a)

[0184] Compound 13a (500 mg, 1.53 mmol) and 15 mL of anhydrous ethanol were added to a 100 mL reaction bottle and placed in an ice bath to cool. SOCl2 (546 mg, 4.59 mmol) was slowly dripped into the reaction solution at 0 ° C, and gradually returned to room temperature after dripping, and then stirred under reflux for 1 h. After TLC monitoring of the complete consumption of the raw materials, the reaction was naturally cooled to room temperature. After the reaction solution was concentrated, 60 mL of water was added and extracted three times with 15 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated salt water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. 2 mL of anhydrous ethanol was added to the crude product and pulped at room temperature for 20 min. Filtered by suction, the filter cake was washed with anhydrous ethanol and dried to obtain an off-white solid 516 mg (compound 14a), with a yield of 95%. 1 H NMR (300MHz, CDCl3): δ=8.08 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 4.20 (q, J=7.2Hz, 2H), 3.9 9 (s, 3H), 3.35 (t, J = 6.9Hz, 2H), 2.79 (t, J = 6.9Hz, 2H), 1.29 (t, J = 7.2Hz, 3H) ppm.HRMS (ESI + ): Cacld for C 15 H 17 5S + (M+H) + , 357.0236; found 357.0232.

[0185] As shown in Table 1 below, intermediates 14b to 14j can be prepared according to the synthesis method of intermediate 14a above, using corresponding starting materials and reactants.

[0186] Table 1

[0187]

[0188]

[0189] Intermediate Preparation Example 3

[0190]

[0191] Step 1: Preparation of 5-(benzyloxy)-6-methoxybenzo[b]selenophene (15a)

[0192] Compound 9a (3.61 g, 10.0 mmol), copper powder (3.20 g, 50.0 mmol) and 40 mL of quinoline were added to a 150 mL reaction bottle and stirred at 170 ° C for 2 hours. After the reaction of the raw materials was completed by TLC monitoring, the reaction solution was naturally cooled to room temperature, 115 mL of 6N HCl was added, and then extracted three times with 40 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain 2.57 g of white solid (compound 15a), with a yield of 81%. 1 H NMR (300MHz, CDCl3): δ=7.85 (d, J=6.0Hz, 1H), 7.56-7.44 (m, 3H), 7.41-7.27 (m, 5H), 5.20 (s, 2H), 3.97 (s, 3H)ppm. HRMS (ESI + ): Cacld for C 16 H 16 O2Se + , (M+H) + , 319.0232; found 319.0236.

[0193] Step 2: Preparation of 5-(benzyloxy)-6-methoxybenzo[b]selenophene (17a)

[0194] Add anhydrous aluminum chloride (1.26 g, 9.46 mmol) and 30 mL of dry dichloromethane to a 100 mL dry reaction bottle, and then stir at room temperature for 0.5 h. Add compound 16a (0.35 g, 3.15 mmol), and continue stirring at room temperature for 0.5 h after the addition. Add 5-(benzyloxy)-6-methoxybenzo[b]selenophene (15a, 2.00 g, 6.31 mmol), and stir at room temperature for 4 h. After TLC monitoring of the reaction of the raw materials, add 150 mL of 2N dilute hydrochloric acid to the reaction solution under ice bath conditions, and then extract three times with 40 mL of dichloromethane. Combine the organic layers, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and obtain a crude product. The crude product is purified by silica gel column chromatography (dichloromethane: methanol = 80: 1) to obtain 1.60 g of a light yellow solid (compound 17a), with a yield of 59%. 1HNMR (300MHz, CDCl3): δ=8.30 (d, 1H), 7.55-7.42 (m, 2H), 7.41-7.27 (m, 5H), 7.32 (s, 1H), 7.03 (s, 1H), 5.20 (s, 2H, 3.97 (s, 3H), 3.63 (t, J=1.2Hz, 2H)ppm.HRMS (ESI - ): Cacld forC 21 H 19 5S + (M+H) + , 431.0398; found 431.0396.

[0195] Step 3: Preparation of 4-(5-hydroxy-6-methoxybenzo[b]selenophene-2-carbonyl)-2-methylene-4-oxobutanoic acid (18a)

[0196] Compound 17a (0.45 g, 1.05 mmol), 45 mg Pd / C and 40 mL methanol were added to a 100 mL reaction bottle, and the air in the reaction bottle was replaced with hydrogen three times. The reaction was stirred at room temperature for 10 h. After TLC monitoring, the raw material reaction was complete, and then filtered through diatomaceous earth. The filtrate was concentrated and dried to obtain 333 mg of a light yellow solid (compound 18a), with a yield of 94%. 1 H NMR (300MHz, DMSO-d6): δ=12.12(s, 1H), 9.28(s, 1H), 8.16(s, 1H), 7.57(s, 1H), 7.31(s, 1H), 7.25 (s, 1H), 7.03 (s, 1H), 3.86 (s, 3H), 3.63 (t, J=1.2Hz, 2H)ppm.HRMS (ESI): Cacld forC 14 H 11 5S - , (MH) - , 338.9777; found 338.9775.

[0197] Step 4: Preparation of ethyl 4-(5-hydroxy-6-methoxybenzo[b]selenophene-2-carbonyl)-2-methylene-4-oxobutanoate (19a)

[0198] Compound 18a (203 mg, 0.60 mmol) and 6 mL of anhydrous ethanol were added to a 50 mL reaction bottle and placed in an ice bath to cool. SOCl2 (216 mg, 1.81 mmol) was slowly dripped into the reaction solution at 0 ° C. After the dripping was completed, the temperature was gradually restored to room temperature, and then the reaction was stirred under reflux for 1 h. After TLC monitoring of the complete consumption of the raw materials, the reaction was naturally cooled to room temperature. After the reaction solution was concentrated, 40 mL of water was added and extracted three times with 15 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain 207 mg of a light yellow solid (compound 19a), with a yield of 94%. 1 H NMR (300MHz, CDCl3): δ=9.14 (s, 1H), 8.30 (d, 1H), 7.55-7.42 (m, 2H), 7.57 (s, 1H), 7.31 (s, 1H), 4.23 (q, 2H), 3.97 (s, 3H), 3.82 (m, 2H), 1.45 (t, J=7.2Hz, 3H). HRMS (ESI): Cacld for C 16 H 17 5S + , (M+H) + , 369.0236; found 369.0232.

[0199] As shown in Table 2 below, intermediate 19b can be prepared according to the synthesis method of intermediate 19a above, using the corresponding starting materials and reactants.

[0200] Table 2

[0201]

[0202] Intermediate Preparation Example 4

[0203]

[0204] Step 1: Preparation of ethyl 3-(5-(benzyloxy)-6-methoxy-N-methylbenzo[b]selenophene-2-carboxamido)propanoate (21a)

[0205] Compound 9a (1 g, 2.77 mmol), HATU (1.91 g, 5.03 mmol), DIPEA (2.88 g, 12.58 mmol) and 10 mL of tetrahydrofuran were added to a 50 mL reaction bottle and stirred at room temperature for 0.5 h. The reaction solution gradually became clear, and compound 20 (0.33 g, 2.52 mmol) was added and stirred at room temperature for 2 h. After TLC monitoring of the complete reaction of the raw materials, the reaction solution was naturally cooled to room temperature, and then 50 mL of water was added and extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 1.12 g of a yellow oil (compound 21a) with a yield of 85.5%. 1 H NMR (300MHz, DMSO-d6): δ=8.24 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.50-7.32 (m, 5H), 5.12 (s, 2H), 4.12 (q, J=6.6 Hz, 2H), 3.86 (s, 3H), 3.79 (t, J=6.9Hz, 2H), 3.76 (s, 3H), 2.66 (t, J=6.9Hz, 2H), 1.24 (t, J=6.6Hz, 3H). HRMS (ESI + ): Cacld for C 23 H 26 NO5Se + (M+H) + , 476.0971; found 476.0973.

[0206] Step 2: Preparation of ethyl 3-(5-hydroxy-6-methoxy-N-methylbenzo[b]selenophene-2-carboxamido)propanoate (22a)

[0207] Compound 17a (0.60 g, 1.27 mmol), 60 mg Pd / C and 50 mL methanol were added to a 100 mL reaction bottle, and the air in the reaction bottle was replaced with hydrogen three times. The reaction was stirred at room temperature for 10 h. After TLC monitoring, the raw material reaction was complete, and then filtered through diatomaceous earth. The filtrate was concentrated and dried to obtain 432 mg of a light yellow solid (compound 22a), with a yield of 89%. 1 H NMR (300MHz, DMSO-d6): δ=8.21 (s, 1H), 7.47 (s, 1H), 7.06 (s, 1H), 4.15 (q, J=6.6Hz, 2H), 3. 78 (s, 3H), 3.32 (t, J=6.9Hz, 2H), 3.27 (s, 3H), 2.99 (m, 2H), 1.24 (t, J=6.6Hz, 3H). HRMS (ESI+ ): Cacld for C 16 H 20 NO5Se + (M+H) + , 386.0501; found 386.0504.

[0208] Intermediate Preparation Example 5

[0209]

[0210] Step 1: Preparation of 6-((1,3-dioxoisoindolin-2-yl)methyl)-2-fluoro-3-methoxybenzoic acid (25a)

[0211] Compound 23a (7.0 g, 41.1 mmol) and compound 24 (7.7 g, 43.2 mmol) were added to a 100 mL reaction bottle, and 35 mL of concentrated sulfuric acid was slowly added to the mixture at 0°C. After the addition was complete, the mixture was stirred at 0°C for 6 h. After TLC monitoring of the complete reaction of the raw materials, 175 mL of water was slowly added to the reaction solution under ice bath conditions, and the mixture was filtered by suction. The filter cake was washed with water and dried to obtain 12.6 g of off-white solid (compound 25a), with a yield of 93.3%. 1 H NMR (300MHz, DMSO-d6): δ = 7.86-7.82 (m, 2H), 7.75-7.72 (m, 2H), 7.33-7.30 (m, 1H), 7.14-7.12 (m, 1H), 5.05 (s, 2H), 3.90 (s, 3H) ppm. HRMS (ESI + ): Cacld for C 17 H 13 FNO5 + (M+H) + , 330.0772; found 330.0770.

[0212] Step 2: Preparation of methyl 6-((1,3-dioxoisoindolin-2-yl)methyl)-2-fluoro-3-methoxybenzoate (26a)

[0213] Compound 25a (5.8 g, 11.63 mmol), cesium carbonate (7.45 g, 22.92 mmol) and 30 mL of DMF were added to a 100 mL reaction bottle, and the temperature was lowered to below 0 ° C after nitrogen replacement. Methyl iodide (3.0 g, 21.16 mmol) was slowly added dropwise to the reaction solution, and the mixture was gradually restored to room temperature after dripping, and stirred at room temperature for 6 h. After TLC monitoring of the reaction of the raw materials, 150 mL of water was slowly added to the reaction solution under ice bath conditions, and extracted three times with 60 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated common salt water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.8 g of a light yellow solid (compound 26a), with a yield of 96.0%. 1 H NMR (300MHz, DMSO-d6): δ=7.85-7.82(m, 2H), 7.74-7.70(m, 2H), 7.33-7.31(m , 1H), 7.15-7.11(m, 1H), 5.05(s, 2H), 3.90(s, 3H), 3.78(s, 3H)ppm.HRMS(ESI + ): Cacld for C 18 H 15 FNO5 + (M+H) + , 344.0929; found 344.0926.

[0214] Step 3: Preparation of 7-fluoro-6-methoxyisoindolin-1-one (27a)

[0215] Compound 26a (2.2 g, 6.41 mmol), hydrazine hydrate (0.64 g, 12.8 mmol) and 30 mL of methanol were added to a 100 mL reaction bottle and stirred at 75°C for 2 h. After TLC monitoring of the complete reaction of the raw materials, the reaction solution was gradually cooled to room temperature and filtered. The filter cake was washed once with a 1 M potassium carbonate aqueous solution and then washed again with 2 N HCl. After drying, 1.08 g of off-white solid (compound 27a) was obtained, with a yield of 93%. 1 H NMR (300MHz, DMSO-d6): δ=7.84 (t, J=3.9Hz, 1H), 7.65 (d, J=8.4Hz, 1H), 4.22 (d, J=4.2Hz, 2H), 3.83 (s, 2H)ppm. HRMS (ESI + ): Cacld for C9H9FNO2 + (M+H) + , 182.0612; found 182.0614.

[0216] Step 4: Preparation of 7-fluoro-6-methoxy-2-(4-methoxybenzyl)isoindolin-1-one (29a)

[0217] Compound 27a (0.6 g, 3.31 mmol) and 30 mL of DMF were added to a 100 mL reaction bottle, and the temperature was lowered to below 0 ° C after nitrogen replacement. Then sodium hydride (0.08 g, 3.48 mmol) was added, and the mixture was stirred at 0 ° C for 10 min, and compound 28 (0.57 g, 3.64 mmol) was slowly added dropwise. After the dropwise addition, the mixture was gradually restored to room temperature and stirred at room temperature for 5 h. After TLC monitoring of the reaction of the raw materials, 50 mL of water was slowly added to the reaction solution under ice bath conditions, and extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.89 g of a light yellow solid (compound 29a), with a yield of 89.9%. 1 H NMR (300MHz, DMSO-d6): δ=7.32-7.18(m, 2H), 6.77-6.74(m, 2H), 6.72-6.63(m, 2H) , 4.71 (t, J=1.2Hz, 2H), 4.35-4.32 (m, 2H), 3.90 (s, 3H), 3.78 (s, 3H)ppm.HRMS (ESI + ): Cacld for C 17 H 17 FNO3 + (M+H) + , 302.1187; found 302.1185.

[0218] Step 5: Preparation of 4-fluoro-5-methoxy-2-(4-methoxybenzyl)isoindoline (30a)

[0219] Compound 29a (4.5 g, 15.0 mmol) and 50 mL of THF were added to a 250 mL reaction bottle. After nitrogen replacement, 90 mL of borane tetrahydrofuran complex (90.0 mmol) was slowly added dropwise, and the mixture was stirred and reacted at 80 ° C for 16 h. After TLC monitoring of the reaction of the raw materials, the reaction solution was gradually cooled to room temperature, and 90 mL of methanol was slowly added dropwise to the reaction solution under an ice bath. After the addition was complete, the reaction solution was concentrated to obtain a crude product. 40 mL of methanol was added to the crude product and pulped at room temperature for 20 min. After suction filtration, the filter cake was washed with methanol and dried to obtain 3.8 g of a white solid (compound 30a) with a yield of 89.3%. 1H NMR (300MHz, DMSO-d6): δ = 7.32-7.18 (m, 3H), 7.12-6.88 (m, 3H), 4.15 (s, 2H), 3.93-3.88 (m, 5H), 3.81 (s, 3H), 3.54 (t, J = 1.2Hz, 2H) ppm. HRMS (ESI + ): Cacld for C 17 H 19 FNO2 + (M+H) + , 288.1394; found 288.1392.

[0220] Step 6: Preparation of 4-fluoro-5-methoxyisoindoline (31a)

[0221] Compound 30a (4.0 g, 10.67 mmol), 4 g Pd / C, 25 mL methanol and 25 mL THF were added to a 250 mL reaction bottle, and the air in the reaction bottle was replaced with hydrogen three times, and the reaction was stirred at room temperature for 10 h. After TLC monitoring, the raw material reaction was complete, and the filtrate was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. 30 mL methanol was added to the crude product and pulped at room temperature for 20 min. After suction filtration, the filter cake was washed with methanol and dried to obtain 2.1 g of a white solid (compound 31a), with a yield of 89%. 1 H NMR (300MHz, DMSO-d6): δ = 6.93-6.88 (m, 1H), 6.85-6.77 (m, 1H), 4.17-4.14 (m, 1H), 3.93-3.79 (m, 3H), 3.90 (s, 3H) ppm. HRMS (ESI + ): Cacld for C9H 11 FNO1 + (M+H) + , 168.0819; found 168.0817.

[0222] Step 7: Preparation of ethyl 4-(4-fluoro-5-methoxyisoindolin-2-yl)-4-oxobutanoate (33a)

[0223] Compound 31a (3.0 g, 18.0 mmol), triethylamine (6.0 g, 60.0 mmol) and 30 mL of dichloromethane were added to a 100 mL reaction bottle, and the temperature was lowered to below 0 ° C after nitrogen replacement. Compound 32 (7.7 g, 3.48 mmol) was slowly added dropwise, and the reaction mixture was transferred to room temperature for 6 h after the addition was complete. After TLC monitoring of the reaction of the raw materials, 100 mL of water was slowly added to the reaction solution under ice bath conditions, and extracted three times with 30 mL of dichloromethane. The organic phases were combined, washed with water, washed with saturated salt water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. 30 mL of ethyl acetate was added to the crude product and pulped at room temperature for 20 min. After suction filtration, the filter cake was washed with ethyl acetate and dried to obtain 5.0 g of brown solid (compound 33a) with a yield of 94%. 1 H NMR (300MHz, DMSO-d6): δ=7.32-7.28(m, 2H), 4.62-4.58(m, 4H), 4.13(q, J=6.6Hz, 2H), 3.90 (s, 3H), 2.70-2.61 (m, 2H), 2.57-2.48 (m, 2H), 1.24 (t, J=6.6Hz, 3H)ppm.HRMS (ESI + ): Cacld for C 15 H 19 FNO4 + (M+H) + , 296.1293; found 296.1295.

[0224] Step 8: Preparation of ethyl 4-(4-fluoro-5-hydroxyisoindolin-2-yl)-4-oxobutanoate (34a)

[0225] Compound 33a (1.7 g, 5.76 mmol) and 30 mL of dichloromethane were added to a 100 mL reaction bottle. After nitrogen replacement, the temperature was lowered to below -10 °C, and boron tribromide (3.3 g, 13.25 mmol) was slowly added dropwise. The temperature was controlled not to exceed 0 °C during the addition process. After the addition was completed, the reaction system was cooled to 0 °C, and 30 mL of anhydrous ethanol was slowly added dropwise to quench the reaction. After the reaction solution was concentrated, 100 mL of water was added, and 30 mL of ethyl acetate was used for extraction three times. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oil. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 80: 1) to obtain 1.5 g of brown oil (compound 34a), with a yield of 93%. 1HNMR (300MHz, DMSO-d6): δ = 6.98-6.90 (m, 1H), 6.83-6.80 (m, 1H), 4.61-4.56 (m, 4 H), 4.13 (q, J=6.6Hz, 2H), 2.70-2.57 (m, 4H), 1.24 (t, J=6.6Hz, 3H) ppm.HRMS (ESI + ): Cacld forC 14 H 17 FNO4 + (M+H) + , 282.1136; found 282.1134.

[0226] Step 9: Preparation of ethyl 4-(6-bromo-4-fluoro-5-hydroxyisoindolin-2-yl)-4-oxobutanoate (35a)

[0227] Compound 34a (2.0 g, 7.11 mmol), 10 mL of acetonitrile and 10 mL of tetrahydrofuran were added to a 100 mL reaction bottle, and the temperature was lowered to below 0°C after nitrogen replacement. NBS (1.1 g, 6.41 mmol) was added, and then the reaction was transferred to room temperature for 4 h. After TLC monitoring of the reaction of the raw materials, the reaction solution was concentrated to obtain a crude product, 20 mL of ethyl acetate was added to the crude product and slurried at room temperature for 20 min. After suction filtration, the filter cake was washed with ethyl acetate and dried to obtain 1.9 g of a white solid powder (compound 35a), with a yield of 74%. 1 HNMR (300MHz, DMSO-d6): δ = 7.24 (s, 1H), 4.58 (s, 4H), 4.13 (q, J = 6.6Hz, 2H), 2.70-2.57 (m, 4H), 1.24 (t, J = 6.6Hz, 3H) ppm. HRMS (ESI + ): Cacld for C 14 H 16 BrFNO4 + (M+H) + , 360.0241; found 360.0242.

[0228] Step 10: Preparation of ethyl 4-(6-bromo-4-fluoro-5-(methoxymethoxy)isoindolin-2-yl)-4-oxobutanoate (36a)

[0229] Compound 35a (1.5 g, 4.17 mmol), DIPEA (1.1 g, 8.33 mmol) and 30 mL of dichloromethane were added to a 100 mL reaction bottle, and the temperature was lowered to below 0 ° C after nitrogen replacement. Bromomethyl methyl ether (0.78 g, 6.25 mmol) was slowly added dropwise, and the reaction was transferred to room temperature for 3 h after the addition was completed. After TLC monitoring of the reaction of the raw materials, 100 mL of water was slowly added to the reaction solution under ice bath conditions, and extracted three times with 30 mL of dichloromethane. The organic phases were combined, washed with water, washed with saturated salt water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1.4 g of gray solid powder (compound 36a), with a yield of 84%. 1 H NMR (300MHz, DMSO-d6): δ=7.36 (s, 1H), 6.04 (s, 2H), 4.65 (s, 2H), 4.55 (d, J=1.2Hz, 2H), 4 .13 (q, J=6.6Hz, 2H), 3.32 (s, 3H), 2.70-2.57 (m, 4H), 1.10 (t, J=6.6Hz, 3H)ppm.HRMS (ESI + ): Cacld forC 16 H 20 BrFNO5 + (M+H) + , 404.0503; found 404.0501.

[0230] Step 11: Preparation of ethyl 4-(4-fluoro-5-(methoxymethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)-4-oxobutanoate (38a)

[0231] Compound 36a (1.5 g, 3.72 mmol), compound 37 (2.36 g, 9.30 mmol), potassium acetate (1.46 g, 14.90 mmol), Pd (dppt) Cl2 (0.5 g, 0.74 mmol) and 30 mL of 1,4-dioxane were added to a 100 mL reaction bottle, and the mixture was refluxed at 100 ° C for 10 h after nitrogen replacement. After TLC monitoring of the reaction of the raw materials, 100 mL of water was slowly added to the reaction solution, and extracted three times with 30 mL of dichloromethane. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 1.48 g of a brown oil (compound 38a) with a yield of 89%. 1H NMR (300MHz, DMSO-d6): δ=7.22 (t, J=1.2Hz, 1H), 5.63 (s, 2H), 4.63 (s, 4H), 4.55 (d, J=0.9 Hz, 2H), 3.46 (s, 3H), 2.70-2.57 (m, 4H), 1.26 (s, 12H), 1.24 (t, J=6.6Hz, 3H)ppm.HRMS (ESI + ): Cacld for C 22 H 32 BFNO7 + (M+H) + , 452.2250; found 452.2252.

[0232] Step 12: Preparation of ethyl 4-(4-fluoro-6-hydroxy-5-(methoxymethoxy)isoindolin-2-yl)-4-oxobutanoate (39a)

[0233] Compound 38a (0.7 g, 1.55 mmol), sodium perborate tetrahydrate (0.84 g, 5.43 mmol), 5 mL of tetrahydrofuran and 5 mL of water were added to a 50 mL reaction bottle, and the reaction was carried out at room temperature for 5 h after nitrogen replacement. After TLC monitoring of the reaction of the raw materials, 30 mL of water was slowly added to the reaction solution, and extracted three times with 10 mL of dichloromethane. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 0.48 g of a light yellow solid (compound 39a), with a yield of 91%. 1 HNMR (300MHz, DMSO-d6): δ = 6.98 (s, 1H), 6.43 (s, 2H), 5.04 (s, 2H), 4.65 (s, 2H), 4.6 3-4.57 (m, 2H), 3.45 (s, 3H), 2.70-2.57 (m, 4H), 1.24 (t, J=6.6Hz, 3H)ppm.HRMS (ESI + ): Cacld forC 16 H 21 FNO6 + (M+H) + , 342.1347; found 342.1345.

[0234] Step 13: Preparation of ethyl 4-(4-fluoro-6-methoxy-5-(methoxymethoxy)isoindolin-2-yl)-4-oxobutanoate (40a)

[0235] Compound 39a (0.5 g, 1.46 mmol), potassium carbonate (0.71 g, 5.13 mmol) and 10 mL of DMF were added to a 50 mL reaction bottle, and the temperature was lowered to below 0 ° C after nitrogen replacement. Methyl iodide (0.52 g, 3.67 mmol) was slowly added dropwise, and the reaction was transferred to room temperature for 3 h after the addition was complete. After TLC monitoring of the reaction of the raw materials, 50 mL of water was slowly added to the reaction solution under ice bath conditions, and extracted three times with 30 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.45 g of brown solid (compound 40a), with a yield of 86%. 1 H NMR (300MHz, DMSO-d6): δ=6.61 (t, J=1.2Hz, 1H), 5.04 (s, 2H), 4.71 (s, 2H), 4.65 (s, 2H), 4.67- 4.59 (m, 2H), 3.96 (s, 3H), 3.45 (s, 3H), 2.70-2.57 (m, 4H), 1.24 (t, J=6.6Hz, 3H)ppm.HRMS (ESI + ): Cacld for C 17 H 23 FNO6 + (M+H) + , 356.1504; found 356.1502.

[0236] Step 14: Preparation of ethyl 4-(4-fluoro-5-hydroxy-6-methoxyisoindolin-2-yl)-4-oxobutanoate (41a)

[0237] Compound 39a (1.0 g, 2.82 mmol), 2.8 mL of trifluoroacetic acid and 10 mL of dichloromethane were added to a 50 mL reaction bottle and reacted at room temperature for 2 h under nitrogen protection. After TLC monitoring of the reaction of the raw materials, 50 mL of water was slowly added to the reaction solution, and extracted three times with 20 mL of dichloromethane. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 0.8 g of a white solid (compound 40a), with a yield of 92%. 1 H NMR (300MHz, DMSO-d6): δ = 6.98 (s, 1H), 4.70 (s, 2H), 4.65 (s, 2H), 4.61-4.58 (m, 2H), 3.83 (s, 3H), 2.68-2.55 (m, 4H), 1.22 (t, J = 5.4Hz, 3H) ppm. HRMS (ESI + ): Cacld forC 15 H 19 FNO5 +(M+H) + , 312.1242; found 312.1245.

[0238] As shown in Table 3 below, intermediates 41b to 41n can be prepared according to the synthesis method of intermediate 41a above using corresponding starting materials and reactants.

[0239] Table 3

[0240]

[0241]

[0242] Example 1

[0243]

[0244] Step 1: Preparation of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]selenophene-2-yl)-4-oxobutanoate (43a)

[0245] Compound 41a (2 g, 15.3 mmol), Cs2CO3 (6.29 g, 19.3 mmol) and 20 mL of DMF were added to a 100 mL reaction bottle, and 1,3-dibromopropane (24.66 g, 12.21 mmol) was added, and the mixture was stirred at 45 °C for 3 h. After the reaction of the raw materials was complete, 100 mL of water was added for dilution, and then 30 mL of ethyl acetate was used for extraction three times. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain 1.94 g of a light yellow solid (compound 43a), with a yield of 70%. 1 H NMR (300MHz, CDCl3): δ=6.78 (t, J=1.2Hz, 1H), 4.49 (t, J=5.1Hz, 2H), 4.43 (q, J=6.6Hz, 2H), 4.76-4.68 (m, 4 H), 3.83 (s, 3H), 3.53 (t, J = 5.1Hz, 2H), 2.71-2.56 (m, 4H), 2.18 (m, 2H), 1.24 (t, J = 6.6Hz, 3H) ppm.HRMS (ESI + ): Cacld for C 18 H 24 BrFNO5 + (M+H) +, 432.0816; found 432.0814.

[0246] Step 2: Preparation of ethyl 4-(5-(3-((2-(4-ethoxy-4-oxobutanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]selenophene-2-yl)-4-oxobutanoate (C59)

[0247] Compound 43a (250 mg, 0.58 mmol), compound 14a (206 mg, 0.58 mmol), Cs2CO3 (565 mg, 1.74 mmol) and 6 mL DMF were added to a 50 mL reaction bottle, and the resulting reaction solution was stirred at 50 ° C for 8 h. After TLC monitoring of the reaction of the raw materials, 50 mL of water was added, and then extracted three times with 12 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 360 mg of a yellow solid (compound C59), with a yield of 88%. 1 H NMR (300MHz, DMSO-d6): δ = 8.04 (s, H), 7.22 (s, H), 7.14 (s, H), 6.69 (d, J = 4.8Hz, H), 4.23 (t, J = 5.4Hz, 4H), 4.12 (q, J = 7.2Hz, 4H), 4.05- 4.01 (m, 4H), 3.85 (s, 6H), 3.31 (t, J = 5.7Hz, 2H), 3.12 (t, J = 8.1Hz, 2H), 2.70-2.62 (m, 4H), 2.58-2.53 (m, 2H), 1.20 (t, J = 7.2Hz, 6H) ppm. 13 C NMR (75MHz, DMSO-d6): δ=200.54, 171.34, 150.45, 146.63, 142.36, 146.76, 131.42, 120.14, 111.58, 110.85, 10 2.97, 69.32, 66.45, 60.56, 56.29, 56.12, 53.24, 51.91, 38.09, 30.49, 30.21, 29.19, 28.68, 14.19ppm.HRMS (ESI + ): Cacld for C 33 H 39 FNO 10 Se + (M+H) + , 708.1718; found 708.1719.

[0248] Example 2

[0249]

[0250] Preparation of 4-(5-(3-((2-(3-carboxypropionyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-methoxybenzo[b]selenophene-2-yl)-4-oxobutanoic acid (C1)

[0251] Compound C59 (150 mg, 0.21 mmol), 2 mL of methanol and 2 mL of tetrahydrofuran were added to a 50 mL reaction bottle, and 0.6 mL of 2N sodium hydroxide aqueous solution was added, and the mixture was stirred at 55 °C for 1 h. After the reaction of the raw materials was complete as monitored by TLC, the reaction solution was concentrated, and the pH of the residue was adjusted to 2-3 with 1N HCl, and then extracted three times with 15 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain 101 mg of a yellow solid (compound C1), with a yield of 73%. 1 H NMR (300MHz, DMSO-d6): δ=12.16 (s, 2H), 8.12 (s, H), 7.32 (s, 1H), 7.12 (s, 1H), 6.70 (d, J=4.8Hz, 1H), 4.23 (t, J=5.1Hz, 4H ), 4.12-4.08 (m, 4H), 3.76 (s, 6H), 3.31 (t, J=5.7Hz, 2H), 3.21 (t, J=8.1Hz, 2H), 2.69-2.68 (m, 4H), 2.64-2.60 (m, 2H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=200.68, 175.35, 174.93, 172.28, 151.65, 151.60, 151.53, 150.94, 149.64, 139.12, 138.66, 138.32, 135.20, 133.05, 120.22, 111.58, 110.85, 102.98, 69.31, 66.45, 56.29, 56.12, 53.26, 53.23, 51.93, 38.33, 30.49, 29.15, 28.48ppm.HRMS (ESI + ): Cacld for C 29 H 29 FNO 10 Se - (MH) - , 650.0946; found 650.0945.

[0252] Example 3

[0253]

[0254] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14b and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C2. 1 H NMR (300MHz, DMSO-d6): δ=12.09 (s, 2H), 8.13 (s, 1H), 7.29 (s, 1H), 7.14 (s, 1H), 6.72 (d, J=4.8Hz, 1H), 4.33 (t, J=5.1Hz, 4H), 4.25- 4.14 (m, 4H), 3.77 (s, 6H), 3.16-3.03 (m, 2H), 2.73 (q, J=8.1Hz, 1H), 2.68-2.65 (m, 4H), 2.64-2.62 (m, 2H), 1.22 (d, J=7.8Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=197.85, 180.50, 174.93, 172.28, 151.65, 151.54, 150.95, 149.64, 146.64, 139.12, 138.45, 138.05, 136.48, 133 .69, 119.85, 111.58, 110.86, 102.98, 102.96, 69.33, 69.31, 66.45, 56.12, 51.24, 49.09, 44.94, 36.32, 30.49, 28.48, 17.65ppm.HRMS (ESI + ): Cacld for C 30 H 31 FNO 10 Se - (MH) - , 664.1103; found 664.1101.

[0255] Example 4

[0256]

[0257] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14c and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C3. 1H NMR (300MHz, DMSO-d6): δ=12.08 (s, 2H), 8.13 (s, 1H), 7.29 (s, 1H), 7.13 (s, 1H), 6.72 (d, J=4.8Hz, 1H), 4.32 (t, J=5.1Hz, 4H), 4.25- 4.14 (m, 4H), 3.78 (s, 6H), 3.16-3.03 (m, 2H), 2.73 (q, J=8.1Hz, 1H), 2.68-2.65 (m, 4H), 2.64-2.62 (m, 2H), 1.22 (d, J=7.8Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=197.87, 181.40, 173.92, 171.32, 150.63, 149.60, 149.54, 149.96, 148.64, 138.23, 137.15, 136.54, 132.58, 11 8.76, 111.57, 110.85, 102.97, 69.32, 69.30, 65.44, 57.32, 56.35, 51.27, 51.20, 49.12, 44.92, 36.31, 30.54, 28.46, 17.57ppm.HRMS (ESI + ): Cacld for C 30 H 31 FNO 10 Se - (MH) - , 664.1103; found 664.1102.

[0258] Example 5

[0259]

[0260] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C4. 1H NMR (300MHz, DMSO-d6): δ=12.11 (s, 2H), 8.11 (s, 1H), 7.28 (s, 1H), 7.15 (s, 1H), 6.71 (d, J=4.8Hz, 1H), 4.29 (t, J=5.1Hz, 4H), 4.27-4.15 (m, 4H) , 3.80 (s, 6H), 3.15-3.05 (m, 2H), 2.72 (q, J=7.8Hz, 1H), 2.65-2.63 (m, 4 H), 2.63-2.61 (m, 2H), 1.21 (d, J=8.1Hz, 2H), 0.93 (t, J=7.2Hz, 3H)ppm. 13 C NMR (75MHz, DMSO.d6): δ=198.43, 179.26, 174.89, 172.31, 151.65, 151.56, 151.06, 149.57, 147.78, 142.61, 139.56, 138.65, 136.78, 133.75 , 120.25, 119.69, 110.76, 102.87, 69.31, 66.44, 56.34, 56.11, 51.22, 51.24, 49.12, 42.67, 30.47, 29.16, 27.58, 27.20, 12.08ppm.HRMS (ESI + ): Cacld for C 31 H 33 FNO 10 Se - (MH) - , 678.1259; found 678.1260.

[0261] Example 6

[0262]

[0263] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14e and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C5. 1H NMR (300MHz, DMSO-d6): δ=12.10 (s, 2H), 8.11 (s, 1H), 7.28 (s, 1H), 7.16 (s, 1H), 6.71 (d, J=4.8Hz, 1H), 4.29 (t, J=5.1Hz, 4H), 4.27-4.14 (m, 4H) , 3.78 (s, 6H), 3.15-3.05 (m, 2H), 2.71 (q, J=7.8Hz, 1H), 2.65-2.63 (m, 4 H), 2.63-2.61 (m, 2H), 1.19 (d, J=8.1Hz, 2H), 0.93 (t, J=7.2Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.42, 180.25, 175.12, 173.24, 152.08, 151.68, 151.12, 149.56, 147.77, 141.58, 139.62, 137.64, 135.96, 134.69 , 120.24, 119.72, 109.89, 101.86, 69.34, 66.43, 56.32, 56.13, 51.20, 51.26, 48.96, 43.78, 30.36, 29.15, 27.49, 27.21, 11.87ppm.HRMS (ESI + ): Cacld for C 31 H 33 FNO 10 Se - (MH) - , 678.1259; found 678.1261.

[0264] Example 7

[0265]

[0266] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14f and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C6. 1 H NMR (300MHz, DMSO-d6): δ=12.18 (s, 2H), 8.10 (s, 1H), 7.31 (s, 1H), 7.19 (s, 1H), 6.69 (d, J=4.8Hz, 1H), 4.18 (t, J=5.1Hz, 4H), 4.12-4.09 (m, 4H), 3.76-3.73 (m, 6H), 3.30 (t, J=5.1Hz, 2H), 3.20 (t, J=8.1Hz, 2H), 2.69-2.65 (m, 4H), 2.63-2.59 (m, 2H)ppm.13 C NMR (75MHz, DMSO-d6): δ=199.97, 175.45, 174.64, 172.67, 151.63, 151.61, 150.96, 150.54, 149.53, 139.34, 138.56, 138.43, 135.19, 133.12, 199.98, 111.43, 110.86, 102.89, 69.32, 66.23, 56.32, 55.87, 53.36, 53.43, 52.02, 38.27, 30.45, 29.21, 27.89ppm.HRMS (ESI + ): Cacld for C 29 H 29 FNO 10 Se - (MH) - , 650.0946; found 650.0948.

[0267] Example 8

[0268]

[0269] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14g and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C7. 1 H NMR (300MHz, DMSO-d6): δ=12.17 (s, 2H), 8.09 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 6.68 (d, J=5.1Hz, 1H), 4.29 (t, J=4.8Hz, 4H), 4.26-4.1 5 (m, 4H), 3.78-3.74 (m, 6H), 3.19-3.02 (m, 2H), 2.71 (q, J = 8.1Hz, 1H), 2.67-2.64 (m, 4H), 2.63-2.61 (m, 2H), 1.18 (d, J = 7.2Hz, 3H) ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.86, 181.37, 173.91, 171.28, 150.57, 149.63, 149.47, 149.89, 148.58, 138.32, 137.14, 136.47, 132.62, 11 8.68, 110.80, 110.78, 102.89, 69.29, 69.26, 65.43, 57.18, 56.67, 51.32, 51.27, 49.25, 44.86, 36.28, 30.52, 29.32, 17.63ppm.HRMS (ESI+ ): Cacld for C 30 H 31 FNO 10 Se - (MH) - , 664.1103; found 664.1102.

[0270] Example 9

[0271]

[0272] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14h and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C8. 1 H NMR (300MHz, DMSO-d6): δ = 12.12 (s, 2H), 8.11 (s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 6.71 (d, J = 4.8Hz, 1H), 4.29 (t, J = 5.4Hz, 4H), 4.26-4.1 3 (m, 4H), 3.85-3.79 (m, 6H), 3.15-3.04 (m, 2H), 2.72 (q, J = 8.1Hz, 1H), 2.67-2.64 (m, 4H), 2.62-2.61 (m, 2H), 1.19 (d, J = 7.8Hz, 3H) ppm. 13 C NMR (75MHz, DMSO-d6): δ=199.03, 180.90, 174.11, 170.93, 150.48, 149.54, 149.43, 149.76, 148.65, 138.26, 137.25, 136.54, 133.21, 11 7.54, 110.79, 110.65, 102.76, 69.31, 69.17, 65.27, 57.26, 56.87, 51.28, 51.17, 49.32, 44.76, 35.26, 31.48, 29.20, 18.02ppm.HRMS (ESI + ): Cacld for C 30 H 31 FN0 10 Se - (MH) - , 664.1103; found 664.1101.

[0273] Example 10

[0274]

[0275] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14i and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C9. 1 H NMR (300MHz, DMSO-d6): δ=12.16 (s, 2H), 8.12 (s, 1H), 7.31 (s, 1H), 7.14 (s, 1H), 6.70 (d, J=4.8Hz, 1H), 4.28 (t, J=5.1Hz, 4H), 4.26-4.13 (m, 4H), 3 .84-3.79(m, 6H), 3.14-3.07(m, 2H), 2.71(q, J=7.8Hz, 1H), 2.64-2.61(m , 4H), 2.60-2.59 (m, 2H), 1.20 (d, J=8.1Hz, 2H), 0.93 (t, J=7.2Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=197.03, 181.12, 174.12, 173.32, 152.71, 151.29, 151.06, 148.43, 147.69, 140.08, 138.61, 137.27, 136.04, 132.98 , 120.11, 119.68, 108.76, 100.83, 68.21, 66.20, 57.02, 55.76, 51.38, 51.05, 47.87, 42.56, 31.20, 29.43, 27.74, 26.85, 12.08ppm.HRMS (ESI + ): Cacld for C 31 H 33 FNO 10 Se - (MH) - , 678.1259; found 678.1261.

[0276] Embodiment 11

[0277]

[0278] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14j and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C10. 1H NMR (300MHz, DMSO-d6): δ=12.12 (s, 2H), 8.10 (s, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 6.69 (d, J=4.8Hz, 1H), 4.28 (t, J=5.4Hz, 4H), 4.26-4.12 (m, 4H), 3 .77-3.73(m, 6H), 3.14-3.06(m, 2H), 2.69(q, J=7.8Hz, 1H), 2.67-2.64(m , 4H), 2.66-2.62 (m, 2H), 1.16 (d, J=7.8Hz, 2H), 0.94 (t, J=7.2Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.31, 180.17, 173.10, 172.85, 153.03, 152.57, 150.37, 148.24, 147.35, 141.63, 138.58, 137.32, 136.12, 133.61 , 121.21, 120.03, 109.13, 100.74, 68.15, 67.24, 57.01, 56.12, 51.54, 51.36, 48.12, 44.32, 30.19, 29.56, 28.02, 26.86, 15.12ppm.HRMS (ESI + ): Cacld for C 31 H 33 FNO 10 Se - (MH) - , 678.1259; found 678.1258.

[0279] Example 12

[0280]

[0281] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 19a and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C11. 1 H NMR (300MHz, DMSO-d6): δ = 12.55 (s, 1H), 12.17 (s, 1H), 8.09 (s, 1H), 6.98 (s, 1H), 6.78 (s, 1H), 6.67-6.64 (m, 2H), 6.09 (d, J =2.1Hz, 1H), 4.26 (t, J = 5.1Hz, 4H), 4.25-4.13 (m, 4H), 3.77 (s, 6H), 3.59 (s, 2H), 2.67-2.64 (m, 4H), 2.38-2.29 (m, 2H)ppm.13 C NMR (75MHz, DMSO-d6): δ=198.63, 174.93, 172.28, 171.23, 151.65, 151.53, 150.94, 149.64, 146.63, 143.86, 138.66, 138.50, 136.87, 133. 12, 133.05, 128.96, 120.06, 111.58, 110.71, 102.96, 69.33, 66.45, 56.29, 56.12, 53.26, 53.23, 51.93, 48.74, 29.19, 28.48ppm.HRMS (ESI + ): Cacld for C 30 H 29 FNO 10 Se - (MH) - , 662.0946; found 662.0944.

[0282] Embodiment 13

[0283]

[0284] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 19b and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C12. 1 H NMR (300MHz, DMSO-d6): δ = 12.18 (s, 1H), 12.17 (s, 1H), 8.11 (s, 1H), 7.24 (s, 1H), 7.19 (s, 1H), 6.73 (d, J = 1.2Hz, 1H), 4.25 (t, J=5.1Hz, 4H), 4.27-4.15(m, 4H), 3.84(s, 6H), 3.42-3.32(m, 2H), 2.68-2.58(m, 4H), 2.32-2.26(m, 2H), 2.07-1.88(m, 4H)ppm. 13C NMR (75MHz, DMSO-d6): δ=204.08, 176.54, 174.93, 172.28, 151.63, 150.94, 149.64, 146.63, 139.20, 138.66, 138.56, 138.39, 137.34, 133.15 , 120.26, 111.78, 111.03, 102.94, 70.33, 69.31, 56.29, 56.12, 53.23, 51.93, 49.00, 42.37, 30.49, 29.19, 28.48, 22.39, 21.77ppm.HRMS (ESI + ): Cacld for C 31 H 31 FNO 10 Se - (MH) - , 676.1103; found 676.1105.

[0285] Embodiment 14

[0286]

[0287] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 22a and one molecule of intermediate 41a were connected via 1,3-dibromopropane to prepare compound C13. 1 H NMR (300MHz, DMSO-d6): δ = 12.25 (s, 1H), 12.15 (s, 1H), 8.11 (s, 1H), 7.56 (s, 1H), 7.10 (s, 1H), 6.63 (d, J = 1.2Hz, 1H), 4.35 (t, J=5.1Hz, 4H), 4.30-4.25(m, 4H), 3.83(s, 6H), 3.37-3.32(m, 5H), 2.65-2.58(m, 4H), 2.57-2.51(m, 2H), 2.25-2.18(m, 2H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=175.48, 174.92, 172.32, 168.67, 151.62, 151.61, 151.32, 149.62, 146.63, 141.55, 138.54, 137.43, 135.32, 133 .15, 120.26, 111.82, 102.97, 102.93, 69.33, 66.41, 56.19, 53.23, 51.93, 51.89, 46.58, 34.96, 33.42, 30.47, 29.16, 28.32ppm.HRMS (ESI+ ): Cacld for C 30 H 32 FN2O 10 Se - (MH) - , 679.1212; found 679.1211.

[0288] Embodiment 15

[0289]

[0290] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14c and one molecule of intermediate 41b were connected via 1,3-dibromopropane to prepare compound C14. 1 H NMR (300MHz, DMSO-d6): δ=12.12 (s, 2H), 8.12 (s, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 6.63 (t, J=1.2Hz, 1H), 4.28 (t, J=5.1H z, 4H), 4.25-4.15 (m, 4H), 3.85 (s, 6H), 3.16-3.04 (m, 2H), 2.68-2.56 (m, 3H), 2.28-2.21 (m, 3H), 1.26-1.17 (m, 6H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.43, 180.50, 177.62, 170.14, 151.65, 151.60, 151.54, 149.64, 146.64, 142.62, 139.12, 138.65, 136.48, 134.79 , 119.85, 119.69, 111.56, 102.96, 69.31, 66.45, 56.29, 56.12, 51.25, 51.21, 49.11, 44.94, 38.98, 37.52, 29.19, 17.65, 17.29ppm.HRMS (ESI + ): Cacld for C 31 H 33 FNO 10 Se - (MH) - , 678.1259; found 678.1257.

[0291] Example 16

[0292]

[0293] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14b and one molecule of intermediate 41c were connected via 1,3-dibromopropane to prepare compound C15. 1 H NMR (300MHz, DMSO-d6): δ=12.11 (s, 2H), 8.12 (s, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 6.62 (t, J=1.2Hz, 1H), 4.30 (t, J=5.1H z, 4H), 4.26-4.17 (m, 4H), 3.84 (s, 6H), 3.15-3.03 (m, 2H), 2.67-2.55 (m, 3H), 2.28-2.23 (m, 3H), 1.26-1.17 (m, 6H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=201.78, 181.45, 176.32, 170.21, 151.69, 151.58, 150.23, 148.63, 146.43, 142.61, 138.96, 137.04, 135.52, 134.75 , 119.73, 119.32, 110.28, 102.95, 68.29, 65.29, 56.31, 56.10, 51.35, 51.26, 48.29, 44.92, 39.03, 37.51, 28.42, 16.65, 16.20ppm.HRMS (ESI + ): Cacld for C 31 H 33 FNO 10 Se - (MH) - , 678.1259; found 678.1258.

[0294] Embodiment 17

[0295]

[0296] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14e and one molecule of intermediate 41d were connected via 1,3-dibromopropane to prepare compound C16. 1H NMR (300MHz, DMSO-d6): δ=12.13 (s, 2H), 7.98 (s, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 6.63 (t, J=0.9Hz, 1H), 4.36 (t, J=5.4Hz, 4H), 4.30-4.26 (m, 4H) , 3.84 (s, 6H), 3.08 (d, J = 8.1Hz, 1H), 2.96 (d, J = 15.3Hz, 1H), 2.68-2.45 (m, 3H), 2.27-2.24 (m, 3H), 1.56 (q, J=7.2Hz, 4H), 1.02-0.95 (m, 6H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=199.21, 179.29, 179.26, 170.59, 151.65, 151.64 ,150.96,146.64,142.61,139.16,138.50,136.48,133.76,133.69,119.8 6, 111.57, 110.84, 101.68, 69.32, 67.41, 56.38, 56.21, 51.22, 49.11, 43. 32, 42.14, 42.54, 36.25, 29.18, 26.31, 25.14, 11.97, 11.48ppm.HRMS (ESI + ): Cacld for C 33 H 37 FNO 10 Se - (MH), 706.1572; found 706.1573.

[0297] Embodiment 18

[0298]

[0299] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41f were connected via 1,3-dibromopropane to prepare compound C17. 1H NMR (300MHz, DMSO-d6): δ = 12.12 (s, 2H), 7.98 (s, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 6.62 (t, J = 0.9Hz, 1H), 4.36 (t, J = 5.4Hz, 4H), 4.30-4.26 (m, 4H), 3.83 (s, 6H), 3.09 (d, J = 8.1Hz, 1H), 2.95 (d, J = 15.3Hz, 1H), 2.68-2.47 ( m, 3H), 2.28-2.21 (m, 3H), 1.55 (q, J=7.2Hz, 4H), 1.03-0.94 (m, 6H)ppmm. 13 C NMR (75MHz, DMSO-d6): δ=200.17, 178.32, 179.45, 172.12, 151.78, 151.32 ,150.65,147.01,141.21,139.37,138.46,136.47,133.65,132.41,118.7 4, 111.24, 110.32, 102.31, 69.12, 67.45, 56.33, 56.52, 52.10, 49.29, 43. 41, 42.25, 41.85, 35.36, 28.81, 25.30, 25.10, 12.37, 12.24ppm.HRMS (ESI + ): Cacld for C 33 H 37 FNO 10 Se - (MH), 706.1572; found 706.1573.

[0300] Embodiment 19

[0301]

[0302] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14a and one molecule of intermediate 41g were connected via 1,3-dibromopropane to prepare compound C60. 1H NMR (300MHz, DMSO-d6): δ=12.09 (s, 2H), 8.02 (s, 1H), 7.14 (s, 1H), 6.90 (s, 1H), 6.03 (s, 2H), 6.58 (d, J=5.1Hz, 1H), 4.32 (t, J= 4.8Hz, 4H), 4.06-4.02(m, 4H), 3.83(s, 3H), 3.31-3.29(m, 5H), 2.96(t, J=8.1Hz, 2H), 2.69-2.63(m, 4H), 2.56-2.51(m, 2H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=200.74, 175.47, 174.35, 172.26, 151.61, 150.95, 149.78, 146.62, 142.62, 139.47, 139.12, 135.20, 133.43, 131.41 , 121.26, 111.58, 110.87, 108.57, 104.56, 95.42, 69.31, 66.48, 56.46, 56.12, 53.23, 51.98, 38.33, 30.93, 29.04, 28.90, 28.47ppm.HRMS (ESI + ): Cacld for C 30 H 31 FNO 11 Se - (MH) - , 680.1052; found 680.1051.

[0303] Embodiment 20

[0304]

[0305] Preparation of 4-(5-(3-((2-(3-carboxypropionyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-6-hydroxybenzo[b]selenophene-2-yl)-4-oxobutanoic acid (C18)

[0306] Compound C60 (150 mg, 0.22 mmol) and 2 mL of dichloromethane were added to a 50 mL reaction bottle, and 1 mL of trifluoroacetic acid was added. The reaction solution was stirred at room temperature for 2 h. After TLC monitoring, the reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain 70 mg of a yellow solid (compound C18), with a yield of 50%. 1H NMR (300MHz, DMSO-d6): δ=12.11 (s, 2H), 9.45 (s, 1H), 8.10 (s, 1H), 7.12-7.09 (m, 2H), 6.58 (d, J=5.1Hz, 1H), 4.32 (t, J=4.8 Hz, 4H), 4.05-4.02 (m, 4H), 3.83 (s, 3H), 3.28-3.25 (m, 2H), 2.85 (t, J=8.4Hz, 2H), 2.68-2.61 (m, 4H), 2.48-2.45 (m, 2H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=199.67, 176.58, 175.30, 173.82, 152.32, 151.56, 148.62, 146.63, 142.32, 139.61, 138.29, 137.26, 136.39, 135. 21, 132.09, 118.49, 111.57, 110.36, 105.44, 68.68, 66.42, 56.27, 53.85, 51.97, 38.37, 31.27, 30.73, 29.56, 28.20ppm.HRMS (ESI′): Cacld forC 28 H 27 FNO 10 Se - (MH) - , 636.0790; found 636.0789.

[0307] Embodiment 21

[0308]

[0309] Referring to the preparation methods described in Examples 19 and 20, one molecule of intermediate 14b and one molecule of intermediate 41g were connected via 1,3-dibromopropane to prepare compound C19. 1 H NMR (300MHz, DMSO-d6): δ = 12.10 (s, 2H), 9.23 (s, 1H), 8.11 (s, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 6.71 (d, J = 4.8Hz, 1H), 4.25 (t, J = 5.1Hz, 4H), 4. 25-4.12 (m, 4H), 3.85-3.79 (m, 3H), 3.14-3.02 (m, 2H), 2.68 (q, J = 8.4Hz, H), 2.67-2.64 (m, 4H), 2.63-2.60 (m, 2H), 1.15 (d, J = 7.8Hz, 3H) ppm. 13C NMR (75MHz, DMSO-d6): δ=197.76, 180.61, 174.39, 171.89, 151.07, 150.42, 148.84, 146.64, 142.62, 139.23, 138.07, 137.95, 136.36, 132.72, 118.13, 111.56, 106.45, 105.21, 69.47, 68.62, 56.17, 51.13, 49.17, 45.94, 36.32, 30.47, 29.23, 28.47, 17.62ppm.HRMS (ESI + ): Cacld forC 29 H 29 FNO10Se - (MH) - , 650.0946; found 650.0945.

[0310] Embodiment 22

[0311]

[0312] Referring to the preparation methods described in Examples 19 and 20, one molecule of intermediate 14c and one molecule of intermediate 41g were connected via 1,3-dibromopropane to prepare compound C20. 1 H NMR (300MHz, DMSO-d6): δ = 12.13 (s, 2H), 9.22 (s, 1H), 8.11 (s, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 6.73 (d, J = 4.8Hz, 1H), 4.23 (t, J = 5.1Hz, 4H), 4. 24-4.13(m, 4H), 3.84-3.80(m, 3H), 3.10-3.03(m, 2H), 2.67(q, J=8.4H z, 1H), 2.67-2.64 (m, 4H), 2.62-2.60 (m, 2H), 1.15 (d, J=7.8Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.20, 180.39, 172.36, 171.74, 151.23, 150.37, 148.83, 147.26, 141.08, 138.37, 137.53, 136.93, 136.21, 132.24, 117.32, 110.73, 106.20, 105.35, 69.29, 67.52, 56.62, 51.29, 48.25, 45.30, 36.45, 31.27, 29.39, 28.56, 18.07ppm.HRMS (ESI +): Cacld for C 29 H 29 FNO 10 Se - (MH) - , 650.0946; found 650.0945.

[0313] Embodiment 23

[0314]

[0315] Referring to the preparation methods described in Examples 19 and 20, one molecule of intermediate 14d and one molecule of intermediate 41g were connected via 1,3-dibromopropane to prepare compound C21. 1 H NMR (300MHz, DMSO-d6): δ = 12.09 (s, 2H), 9.28 (s, 1H), 8.10 (s, 1H), 7.19 (s, 1H), 7.17(s, 1H), 6.71(d, J=5.1Hz, 1H), 4.27(t, J=5.4Hz, 4H), 4.25-4.12( m, 4H), 3.84-3.78 (m, 3H), 3.14-3.05 (m, 2H), 2.72 (q, J=7.8Hz, 1H), 2.66-2 .62(m, 4H), 2.62-2.60(m, 2H), 1.70-1.67(m, 2H), 0.94(d, J=6.3Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.27, 179.62, 174.93, 172.27, 150.97, 148.73, 148.46, 146.60, 142.17, 139.39, 138.01, 137.54, 136.47, 133 .13, 118.71, 111.57, 110.89, 106.43, 70.47, 69.45, 56.13, 51.73, 50.25, 43.53, 42.65, 30.49, 29.19, 28.48, 26.20, 11.98ppm.HRMS (ESI + ): Cacld for C 30 H 31 FNO 10 Se - (MH) - , 664.1103; found 664.1102.

[0316] Embodiment 24

[0317]

[0318] Referring to the preparation methods described in Examples 19 and 20, one molecule of intermediate 14e and one molecule of intermediate 41g were connected via 1,3-dibromopropane to prepare compound C22. 1 H NMR (300MHz, DMSO-d6): δ=12.10(s, 2H), 9.27(s, 1H), 8.09(s, 1H), 7.20(s, 1H), 7.16 (s, 1H), 6.71 (d, J = 5.1Hz, 1H), 4.27 (t, J = 5.4Hz, 4H), 4.26-4.14 ( m, 4H), 3.82-3.77 (m, 3H), 3.13-3.06 (m, 2H), 2.72 (q, J=7.8Hz, 1H), 2.65-2 .61 (m, 4H), 2.62-2.60 (m, 2H), 1.71-1.68 (m, 2H), 0.96 (d, J=6.3Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=197.31, 180.25, 174.23, 172.41, 151.04, 149.26, 148.49, 146.82, 142.63, 138.64, 138.23, 137.17, 135.93, 132 .40, 117.24, 111.49, 110.27, 107.31, 70.52, 68.51, 55.37, 51.62, 50.30, 44.05, 43.64, 30.85, 29.32, 28.05, 27.21, 12.43ppm.HRMS (ESI + ): Cacld for C 30 H 31 FNO 10 Se - (MH), 664.1103; found 664.1101.

[0319] Embodiment 25

[0320]

[0321] Referring to the preparation method described in Examples 19 and 20, one molecule of intermediate 14g and one molecule of intermediate 41i were connected via 1,3-dibromopropane to prepare compound C23. 1H NMR (300MHz, DMSO-d6): δ = 12.10 (s, 2H), 9.34 (s, 1H), 8.11 (s, 1H), 7.21 (s, 1H), 7.12 (s, 1H), 6.61 (t, J = 5.1Hz, 1H), 4.28 (t, J =4.8Hz, 4H), 4.25-4.12(m, 4H), 3.84(s, 3H), 3.14-3.06(m, 2H), 2.59-2.51(m, 3H), 2.25-2.21(m, 3H), 1.25-1.18(m, 6H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=197.87, 180.45, 177.28, 170.13, 150.96, 150.43, 148.64, 146.64, 142.62, 139.35, 138.10, 137.72, 136.48, 132 .71, 118.91, 111.56, 106.43, 106.25, 69.46, 66.45, 56.32, 51.74, 49.28, 45.74, 38.89, 37.62, 36.31, 30.31, 17.77, 16.20ppm.HRMS (ESI + ): Cacld for C 30 H 31 FNO 10 Se - (MH) - , 664.1103; found 664.1104.

[0322] Embodiment 26

[0323]

[0324] Referring to the preparation methods described in Examples 19 and 20, one molecule of intermediate 14h and one molecule of intermediate 41h were connected via 1,3-dibromopropane to prepare compound C24. 1 H NMR (300MHz, DMSO-d6): δ = 12.12 (s, 2H), 9.35 (s, 1H), 8.11 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 6.60 (t, J = 5.4Hz, 1H), 4.25 (t, J =4.8Hz, 4H), 4.24-4.11(m, 4H), 3.82(s, 3H), 3.13-3.07(m, 2H), 2.58-2.53(m, 3H), 2.24-2.20(m, 3H), 1.25-1.18(m, 6H)ppm. 13C NMR (75MHz, DMSO-d6): δ=199.27, 180.23, 176.44, 171.60, 151.24, 150.53, 148.34, 146.52, 141.37, 139.49, 138.40, 137.73, 137.23, 131 .29, 117.38, 111.54, 106.63, 106.27, 68.46, 66.52, 56.17, 52.39, 49.73, 46.72, 38.87, 37.33, 36.40, 31.68, 16.32, 16.04ppm.HRMS (ESI + ): Cacld for C 30 H 31 FNO 10 Se - (MH) - , 664.1103; found 664.1102.

[0325] Embodiment 27

[0326]

[0327] Referring to the preparation method described in Examples 19 and 20, one molecule of intermediate 14i and one molecule of intermediate 41k were connected via 1,3-dibromopropane to prepare compound C25. 1 H NMR (300MHz, DMSO-d6): δ=12.10(s, 2H), 9.45(s, 1H), 7.96(s, 1H), 7.20(s, 1H), 7.13 (s, 1H), 6.61 (t, J=1.2Hz, 1H), 4.34 (t, J=5.1Hz, 4H), 4.32-4.27 ( m, 4H), 3.82 (s, 3H), 3.12 (d, J = 8.4Hz, 1H), 2.94 (d, J = 15.6Hz, 1H), 2.65-2. 44(m, 3H), 2.28-2.21(m, 3H), 1.52(q, J=7.5Hz, 4H), 1.01-0.95(m, 6H)ppm. 13C NMR (75MHz, DMSO-d6): δ=199.21, 179.32, 179.14, 170.28, 150.71, 150.48, 148.73, 146.44, 142.16, 140.53, 138.15, 137.78, 136.48, 132.37, 11 8.95, 110.86, 110.42, 106.32, 69.57, 67.45, 56.38, 51.39, 49.18, 43.2 5, 43.14, 42.56, 36.83, 29.16, 26.37, 25.13, 11.76, 11.43ppm.HRMS (ESI + ): Cacld for C 32 H 35 FNO 10 Se - (MH) - , 692.1416; found 692.1415.

[0328] Embodiment 28

[0329]

[0330] Referring to the preparation methods described in Examples 19 and 20, one molecule of intermediate 14j and one molecule of intermediate 41j were connected via 1,3-dibromopropane to prepare compound C26. 1 H NMR (300MHz, DMSO-d6): δ=12.11(s, 2H), 9.45(s, 1H), 7.94(s, 1H), 7.19(s, 1H), 7.13 (s, 1H), 6.62 (t, J=0.9Hz, 1H), 4.32 (t, J=5.1Hz, 4H), 4.31-4.26 ( m, 4H), 3.82 (s, 3H), 3.10 (d, J = 8.4Hz, 1H), 2.94 (d, J = 15.6Hz, 1H), 2.64-2. 42(m, 3H), 2.27-2.23(m, 3H), 1.51(q, J=7.5Hz, 4H), 1.02-0.94(m, 6H)ppmr. 13C NMR (75MHz, DMSO-d6): δ=198.34, 180.05, 179.27, 171.42, 151.36, 150.53, 148.74, 146.52, 142.31, 141.73, 138.53, 137.64, 136.96, 131.43, 11 7.84, 110.27, 110.10, 107.28, 69.31, 67.52, 56.74, 51.82, 49.38, 44.1 4, 43.32, 42.75, 36.46, 29.16, 26.36, 25.17, 11.75, 11.20ppm.HRMS (ESI + ): Cacld for C 32 H 35 FNO 10 Se - (MH) - , 692.1416; found 692.1415.

[0331] Embodiment 29

[0332]

[0333] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 1,4-dibromobutane to prepare compound C27. 1 H NMR (300MHz, DMSO-d6): δ=12.09 (s, 2H), 8.10 (s, 1H), 7.27 (s, 1H), 7.16 (s, 1H), 6.89 (d, J=4.2Hz, 1H), 4.26 (t, J=5.1Hz, 4H), 4.26-4.17 (m, 4H) , 3.82 (s, 6H), 3.16-3.04 (m, 2H), 2.71 (q, J=7.5Hz, 1H), 2.66-2.61 (m, 4 H), 1.93-1.86 (m, 4H), 1.45 (d, J = 8.1Hz, 2H), 0.91 (t, J = 7.5Hz, 3H) ppm. 13C NMR (75MHz, DMSO-d6): δ=198.23, 179.64, 174.83, 172.84, 151.54, 151.72, 150.96, 146.65, 142.71, 139.29, 138.43, 138.15, 136.83, 133.79, 11 9.89, 111.74, 110.62, 102.86, 72.73, 71.38, 56.19, 56.01, 51.21, 49.3 9, 43.63, 42.39, 30.58, 28.92, 26.47, 26.31, 26.02, 11.78ppm.HRMS (ESI + ): Cacld for C 32 H 35 FNO 10 Se - (MH) - , 692.1416; found 692.1414.

[0334] Embodiment 29

[0335]

[0336] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 1,5-dibromopentane to prepare compound C28. 1 H NMR (300MHz, DMSO-d6): δ=12.10 (s, 2H), 8.09 (s, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 6.86 (d, J=3.9Hz, 1H), 4.23 (t, J=5.1Hz, 4H), 4.25-4.18 (m, 4H), 3.85-3.82(m, 6H), 3.16-3.06(m, 2H), 2.70(q, J=7.5Hz, 1H), 2.66-2.61 (m, 4H), 1.85-1.81 (m, 4H), 1.63-1.58 (m, 4H), 0.93 (t, J=7.2Hz, 3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=198.13, 179.24, 174.39, 172.27, 151.58, 150.02 ,149.63,147.71,142.26,139.17,138.56,137.82,136.34,133.79,119.8 9, 111.45, 110.73, 102.86, 72.52, 69.26, 56.51, 56.43, 51.25, 49.19, 43. 23, 42.58, 30.49, 29.25, 29.07, 28.13, 26.42, 23.51, 11.72ppm.HRMS (ESI + ): Cacld for C 33 H 37 FNO 10 Se - (MH) - , 706.1572; found 706.1571.

[0337] Embodiment 30

[0338]

[0339] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 3-chloro-2-chloromethylpropene to prepare compound C29. 1 H NMR (300MHz, DMSO-d6): δ=12.11(s, 2H), 8.10(s, 1H), 7.21(s, 1H), 7.19(s , 1H), 6.89 (d, J=3.9Hz, 1H), 5.62 (s, 1H), 5.41 (s, 1H), 4.21 (t, J=5.4Hz, 4 H), 4.26-4.20 (m, 4H), 3.86-3.83 (m, 6H), 3.15-3.02 (m, 2H), 2.69 (q, J=7. 5Hz, 2H), 2.65-2.60 (m, 3H), 1.70-1.65 (m, 2H), 0.94 (t, J=7.2Hz, 3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=198.63, 178.62, 174.38, 172.41, 150.57, 150.1 1, 148.64, 146.53, 142.63, 139.47, 139.04, 137.62, 137.41, 137.23, 133 .34, 120.04, 115.23, 111.36, 110.85, 102.47, 72.63, 71.53, 56.93, 56.4 5, 51.47, 49.19, 43.36, 42.71, 30.48, 28.36, 26.20, 12.04ppm.HRMS (ESI + ): Cacld for C 32 H 33 FNO 10 Se - (MH) - , 690.1259; found 690.1258.

[0340] Embodiment 31

[0341]

[0342] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 2,2′-dibromodiethyl ether to prepare compound C30. 1 H NMR (300MHz, DMSO-d6): δ=12.10 (s, 2H), 8.11 (s, 1H), 7.19 (s, 1H), 7.08 (s, 1H), 6.70 (d, J=5.1Hz, 1H), 4.45 (t, J=5.1Hz, 4H), 4.32-4.25 (m, 4 H), 3.86 (s, 6H), 3.84-3.80 (m, 4H), 3.21-3.04 (m, 2H), 2.65 (q, J=6.9Hz, 2H), 2.63-2.58 (m, 3H), 1.64-1.59 (m, 2H), 0.95 (t, J=5.7Hz, 3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=198.41, 179.39, 174.23, 172.51, 151.68, 151.45, 151.10, 149.40, 142.39, 139.28, 138.72, 138.25, 136.45, 133.79, 11 9.38, 111.28, 110.52, 102.42, 71.58, 71.23, 70.13, 69.86, 56.32, 56.1 1, 51.24, 49.19, 43.23, 42.51, 30.47, 28.34, 26.18, 11.72ppm.HRMS (ESI + ):cacld for C 32 H 35 FNO 11 Se - (MH) - , 708.1365; found 708.1364.

[0343] Embodiment 32

[0344]

[0345] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 1,3-dibromo-2,2-dimethylpropane to prepare compound C31. 1 H NMR (300MHz, DMSO-d6): δ=12.12(s, 1H), 12.10(s, 1H), 8.13(s, 1H), 7.17(s, 1 H), 7.03 (s, 1H), 6.89 (d, J=6.9Hz, 1H), 4.46 (t, J=4.8Hz, 4H), 3.83-3.81 (m, 6H ), 3.80-3.78(m, 4H), 3.30-3.27(m, 1H), 3.10-3.07(m, 1H), 2.68-2.61(m, 2H) , 2.63-2.49 (m, 3H), 1.78-1.69 (m, 2H), 1.00 (s, 6H), 0.92 (t, J=7.2Hz, 3H)ppm. 13CNMR (75MHz, DMSO-d6): δ=198.35, 179.46, 174.93, 172.84, 151.41, 150.3 2, 149.44, 146.71, 142.61, 139.12, 138.28, 137.63, 136.46, 133.75, 120. 53, 113.12, 110.42, 103.31, 78.18, 76.09, 56.52, 56.01, 51.42, 49.19, 43 .26, 42.43, 39.71, 30.49, 28.48, 24.20, 24.05, 23.74, 11.68ppm.HRMS (ESI + ): Cacld for C 33 H 37 FNO 10 Se - (MH) - , 706.1572; found 706.1571.

[0346] Embodiment 33

[0347]

[0348] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 1,1-bis(bromomethyl)cyclopropane to prepare compound C32. 1 H NMR (300MHz, DMSO-d6): δ = 12.10 (s, 1H), 12.09 (s, 1H), 8.10 (s, 1H), 7.09 (s, 1H), 7. 01 (s, 1H), 6.97 (d, J = 5.4Hz, 1H), 4.45 (t, J = 6.9Hz, 4H), 3.85-3.82 (m, 6H), 3.80-3.7 8(m, 4H), 3.31-3.26(m, 1H), 3.09-3.06(m, 1H), 2.66-2.62(m, 2H), 2.60-2.52(m, 3H) , 1.72-1.66 (m, 2H), 0.91 (t, J=7.5Hz, 3H), 0.68-0.59 (m, 2H), 0.32-0.21 (m, 2H)ppm. 13C NMR (75MHz, DMSO-d6): δ=198.21, 179.43, 174.83, 172.27, 151.45, 150.70 ,149.34,147.53,142.61,139.32,137.87,137.42,136.18,133.35,120.9 3, 113.41, 110.26, 103.31, 77.85, 75.29, 56.59, 56.02, 51.23, 49.29, 43. 43, 42.15, 30.49, 28.48, 26.20, 24.03, 11.98, 11.75, 11.69ppm.HRMS (ESI + ):cacld for C 33 H 35 FNO 10 Se - (MH) - , 704.1416; found 704.1415.

[0349] Embodiment 34

[0350]

[0351] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 1,3-dibromobutane to prepare compound C33. 1 H NMR (300MHz, DMSO-d6): δ=12.08(s, 1H), 12.07(s, 1H), 7.98(s, 1H), 7.22(s, 1H), 7.14(s , 1H), 6.92 (d, J=1.2Hz, 1H), 4.46 (t, J=6.3Hz, 4H), 4.15-4.11 (m, 2H), 3.86-3.82 (m, 6H), 3.80-3.76(m, 1H), 3.30-3.25(m, 1H), 3.06-3.01(m, 1H), 2.65-2.60(m, 2H), 2.58-2.51(m , 3H), 2.32-2.23(m, 2H), 1.69-1.63(m, 2H), 1.54-1.48(m, 3H), 0.94(t, J=6.9Hz, 3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=199.12, 179.42, 174.83, 172.47, 152.89, 152.13, 150.57, 145.96, 142.41, 139.42, 138.65, 137.90, 136.28, 133.76, 12 0.40, 111.28, 110.74, 102.86, 75.87, 65.92, 56.43, 56.37, 51.41, 49.1 9, 43.32, 42.67, 35.43, 30.46, 28.61, 26.43, 19.63, 11.72ppm.HRMS (ESI + ): Cacld for C 32 H 35 FNO 10 Se - (MH) - , 692.1416; found 692.1415.

[0352] Embodiment 35

[0353]

[0354] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 1,2-dibromoethane to prepare compound C34. 1 H NMR (300MHz, DMSO-d6): δ = 12.10 (s, 1H), 12.09 (s, 1H), 8.01 (s, 1H), 7.24 ( s, 1H), 7.16 (s, 1H), 6.97 (d, J=2.4Hz, 1H), 4.53-4.49 (m, 4H), 4.42 (t, J=5. 7Hz, 4H), 3.85-3.81 (m, 6H), 3.32-3.26 (m, 1H), 3.05-3.00 (m, 1H), 2.67-2. 62(m, 2H), 2.56-2.52(m, 3H), 1.67-1.62(m, 2H), 0.92(t, J=6.3Hz, 3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=197.43, 178.52, 175.04, 172.62, 151.66, 151.50, 149.64, 146.67, 143.87, 139.01, 138.35, 138.04, 137.62, 133 .79, 119.48, 111.53, 110.69, 102.42, 69.84, 68.05, 56.53, 56.31, 51.24, 49.39, 43.63, 42.15, 30.37, 28.74, 26.18, 12.07ppm.HRMS (ESI + ): Cacld forC 30 H 31 FNO 10 Se - (MH) - , 664.1103; found 664.1101.

[0355] Embodiment 36

[0356]

[0357] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 1,3-dibromo-2-methylpropane to prepare compound C35. 1 H NMR (300MHz, DMSO-d6): δ = 12.11 (s, 1H), 12.10 (s, 1H), 8.04 (s, 1H), 7.22 (s, 1H) ), 7.14 (s, 1H), 6.92 (d, J = 1.8Hz, 1H), 4.45 (t, J = 5.4Hz, 4H), 4.00-3.94 (m, 2H) , 3.85-3.83(m, 6H), 3.80-3.72(m, 2H), 3.29-3.22(m, 1H), 3.10-3.03(m, 1H), 2 .65-2.61(m, 3H), 2.54-2.49(m, 3H), 1.65-1.61(m, 2H), 0.94-0.89(m, 6H)ppm. 13C NMR (75MHz, DMSO-d6): δ=198.47, 180.31, 175.01, 171.23, 152.41, 151.32, 149.34, 146.64, 142.73, 139.52, 138.47, 138.32, 136.57, 133.58, 12 0.28, 111.74, 110.25, 103.18, 74.74, 72.91, 56.24, 56.17, 51.58, 49.1 9, 43.42, 42.78, 33.48, 30.31, 29.24, 25.17, 13.56, 11.82ppm.HRMS (ESI + ): Cacld for C 32 H 35 FNO 10 Se - (MH) - , 692.1416; found 692.1417.

[0358] Embodiment 37

[0359]

[0360] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41a were connected via 1,3-dibromoacetone to prepare compound C36. 1 H NMR (300MHz, DMSO-d6): δ=12.10(s, 1H), 12.08(s, 1H), 8.02(s, 1H), 7.24(s , 1H), 7.13 (s, 1H), 6.91 (d, J=1.5Hz, 1H), 5.14-5.12 (m, 4H), 4.42 (t, J=5.1 Hz, 4H), 3.86-3.83 (m, 6H), 3.28-3.23 (m, 1H), 3.13-3.06 (m, 1H), 2.64-2.6 0 (m, 2H), 2.52-2.47 (m, 3H), 1.67-1.63 (m, 2H), 0.93 (t, J=6.0Hz, 3H) ppmm. 13C NMR (75MHz, DMSO-d6): δ=203.78, 198.52, 181.04, 174.98, 171.52, 152.21, 151.54, 149.89, 146.62, 142.73, 139.64, 138.85, 138.23, 136.65 , 133.58, 120.45, 111.62, 110.79, 103.67, 74.32, 72.85, 56.51, 56.06, 51.23, 49.69, 43.37, 42.96, 33.41, 29.24, 25.19, 12.52ppm.HRMS (ESI + ): Cacld for C 31 H 31 FNO 11 Se - (MH) - , 692.1052; found 692.1051.

[0361] Embodiment 38

[0362]

[0363] Preparation of (2S)-4-(5-(3-((2-(3-carboxypropanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)-2-hydroxypropoxy)-6-methoxybenzo[b]selenophene-2-yl)-2-ethyl-4-oxobutanoic acid (C37)

[0364] Compound C36 (100 mg, 0.14 mmol), 6 mL of tetrahydrofuran and 3 mL of water were added to a 100 mL reaction bottle, and sodium borohydride (21 mg, 0.56 mmol) was added four times. The reaction mixture was stirred at room temperature for 30 min. TLC monitored the complete reaction of the raw materials, 40 mL of 2N HCl was added, and then extracted three times with 15 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1) to obtain 80 mg of a light yellow solid (compound C38), with a yield of 80%. 1H NMR (300MHz, DMSO-d6): δ = 12.11 (s, 1H), 12.06 (s, 1H), 8.03 (s, 1H), 7.21 (s, 1H), 7.12 ( s, 1H), 6.89 (d, J=1.2Hz, 1H), 5.67 (s, 1H), 4.71-4.60 (m, 1H), 4.43 (t, J=4.8Hz, 4H), 4.3 2-4.2l(m, 2H), 4.01-3.92(m, 2H), 3.87-3.84(m, 6H), 3.25-3.21(m, 1H), 3.12-3.07(m, 1H), 2.62-2.59(m, 2H), 2.51-2.45(m, 3H), 1.68-1.64(m, 2H), 0.95(t, J=6.3Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=197.87, 178.84, 174.51, 171.82, 150.87, 150.73, 150.47, 146.20, 142.19, 138.68, 137.57, 137.46, 136.06, 133.14 , 119.63, 111.58, 110.13, 102.30, 71.96, 70.81, 68.11, 55.85, 55.62, 50.87, 48.65, 43.19, 42.43, 30.05, 28.02, 25.75, 11.57ppm.HRMS (ESI + ): Cacld for C 31 H 33 FNO 11 Se - (MH) - , 694.1208; found 694.1209.

[0365] Embodiment 40

[0366]

[0367] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14a and one molecule of intermediate 41b were connected via 1,3-dibromopropane to prepare compound C38. 1H NMR (300MHz, DMSO-d6): δ = 12.13 (s, 2H), 8.11 (s, 1H), 7.31 (s, 2H), 7.10 (s, 1H), 6.64 (d, J = 4.2Hz, 1H), 4.27 (s, 4H), 4.10-4. 06 (m, 4H), 3.81 (s, 3H), 3.78 (s, 3H), 3.30 (t, J = 5.7Hz, 2H), 3.20 (t, J = 7.8Hz, 2H), 2.71-2.67 (m, 4H), 2.63-2.59 (m, 2H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=200.87, 175.51, 175.10, 172.61, 151.10, 149.96, 149.81, 146.65, 142.52, 139.23, 138.45, 136.02, 132.64, 131.87, 111.78, 111.14, 109.31, 107.89, 66.68, 66.51, 56.29, 56.23, 53.52, 53.43, 38.50, 30.65, 29.72, 29.28, 28.64ppm.HRMS (ESI + ): Cacld for C 29 H30NO 10 Se - (MH) - , 632.1040; found 632.1041.

[0368] Embodiment 41

[0369]

[0370] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14b and one molecule of intermediate 41b were connected via 1,3-dibromopropane to prepare compound C39. 1 H NMR (300MHz, DMSO-d6): δ=12.11(s, 1H), 12.09(s, 1H), 8.13(s, 1H), 7.29( s, 2H), 7.09 (s, 1H), 6.62 (d, J=3.9Hz, 1H), 4.25 (s, 4H), 4.11-4.07 (m, 4H) , 3.79(s, 3H), 3.76(s, 3H), 3.22-3.19(m, 1H), 3.10-3.06(m, 1H), 2.61-2. 57(m, 2H), 2.50-2.43(m, 3H), 2.26-2.21(m, 2H), 1.20(t, J=5.7Hz, 3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=197.94, 180.56, 175.07, 172.54, 151.17, 150.03, 149.73, 146.78, 142.73, 139.25, 138.13, 136.65, 132.96, 132 .71, 111.72, 110.87, 109.25, 107.62, 66.62, 66.54, 56.27, 56.24, 51.56, 51.43, 45.12, 36.43, 30.62, 29.79, 28.54, 17.61ppm.HRMS (ESI + ): Cacld forC 30 H 32 NO 10 Se - (MH) - , 646.1197; found 646.1196.

[0371] Embodiment 42

[0372]

[0373] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14c and one molecule of intermediate 41b were connected via 1,3-dibromopropane to prepare compound C40. 1 H NMR (300MHz, DMSO-d6): δ=12.10(s, 1H), 12.08(s, 1H), 8.11(s, 1H), 7.27( s, 2H), 7.09 (s, 1H), 6.62 (d, J=3.9Hz, 1H), 4.23 (s, 4H), 4.12-4.08 (m, 4H) , 3.76(s, 3H), 3.75(s, 3H), 3.21-3.18(m, 1H), 3.12-3.07(m, 1H), 2.61-2. 57(m, 2H), 2.51-2.43(m, 3H), 2.25-2.20(m, 2H), 1.20(t, J=5.7Hz, 3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=197.87, 180.53, 175.06, 172.51, 151.14, 150.03, 149.72, 146.74, 142.75, 139.43, 138.27, 136.65, 132.89, 132 .75, 111.70, 110.82, 109.43, 107.53, 66.74, 66.35, 56.28, 56.22, 51.53, 51.25, 45.58, 36.32, 30.57, 30.02, 28.37, 17.54ppm.HRMS (ESI + ): Cacld forC 30 H 32 NO 10 Se - (MH) - , 646.1197; found 646.1195.

[0374] Embodiment 43

[0375]

[0376] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 41b were connected via 1,3-dibromopropane to prepare compound C41. 1 H NMR (300MHz, DMSO-d6): δ = 12.14 (s, 1H), 12.11 (s, 1H), 8.10 (s, 1H), 7.25 (s, 2H) , 7.08 (s, 1H), 6.60 (d, J=4.2Hz, 1H), 4.25 (s, 4H), 4.10-4.06 (m, 4H), 3.80 (s, 3H ), 3.76 (s, 3H), 3.20-3.17 (m, 1H), 3.11-3.06 (m, 1H), 2.60-2.55 (m, 2H), 2.53-2 .46 (m, 3H), 2.27-2.23 (m, 2H), 1.19 (d, J = 7.8Hz, 2H), 0.91 (t, J = 6.9Hz, 3H) ppm. 13CNMR (75MHz, DMSO-d6): δ=198.11, 178.98, 174.67, 172.13, 150.68, 149.57, 149.40, 146.38, 142.36, 138.85, 137.78, 136.21, 132.64, 132.3 2, 111.35, 110.56, 108.74, 107.35, 66.22, 66.18, 55.85, 55.82, 51.42, 51.31, 43.27, 42.33, 30.22, 29.36, 28.27, 25.86, 11.69ppm. HRMS (ESI + ): Cacld for C 31 H 34 NO 10 Se - (MH) - , 660.1353; found 660.1352.

[0377] Embodiment 44

[0378]

[0379] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14e and one molecule of intermediate 41b were connected via 1,3-dibromopropane to prepare compound C42. 1 H NMR (300MHz, DMSO-d6): δ = 12.13 (s, 1H), 12.12 (s, 1H), 8.11 (s, 1H), 7.23 (s, 2H) , 7.09 (s, 1H), 6.61 (d, J=4.2Hz, 1H), 4.23 (s, 4H), 4.11-4.08 (m, 4H), 3.81 (s, 3H ), 3.75 (s, 3H), 3.21-3.16 (m, 1H), 3.10-3.05 (m, 1H), 2.61-2.55 (m, 2H), 2.51-2 .46 (m, 3H), 2.26-2.21 (m, 2H), 1.17 (d, J = 7.5Hz, 2H), 0.92 (t, J = 6.9Hz, 3H) ppm. 13CNMR (75MHz, DMSO-d6): δ=198.06, 178.97, 174.66, 172.16, 150.68, 149.55, 149.46, 146.32, 142.31, 138.85, 137.78, 136.21, 132.58, 132.1 7, 111.30, 110.59, 108.84, 107.37, 66.13, 66.09, 55.85, 55.84, 51.13, 51.06, 43.27, 42.38, 30.22, 29.36, 28.22, 25.93, 11.71ppm. HRMS (ESI + ): Cacld for C 31 H 34 NO 10 Se - (MH) - , 660.1353; found 660.1351.

[0380] Embodiment 45

[0381]

[0382] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14a and one molecule of intermediate 411 were connected via 1,3-dibromopropane to prepare compound C43. 1 H NMR (300MHz, DMSO-d6): δ=12.15 (s, 2H), 8.10 (s, 1H), 7.21 (s, 1H), 7.18 (s, 1H), 7.09 (d, J=4.8Hz, 1H), 4.21 (t, J=5.1Hz, 4 H), 4.16-4.11 (m, 4H), 3.78 (s, 6H), 3.30 (t, J=5.4Hz, 2H), 3.20 (t, J=6.9Hz, 2H), 2.68-2.65 (m, 4H), 2.62-2.58 (m, 2H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=200.51, 175.19, 174.77, 172.14, 151.69, 150.78, 146.43, 145.95, 142.19, 138.95, 138.15, 135.14, 133.25, 128.87,121.56,111.42,110.65,106.53,69.46,66.28,56.13,55.96,52.92,52.76,38.17,30.33,29.04,28.98,28.32ppm.HRMS (ESI +): Cacld for C 29 H 29 ClNO 10 Se - (MH) - , 666.0651; found 666.0652.

[0383] Embodiment 46

[0384]

[0385] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14b and one molecule of intermediate 411 were connected via 1,3-dibromopropane to prepare compound C44. 1 H NMR (300MHz, DMSO-d6): δ = 12.12 (s, 1H), 12.10 (s, 1H), 8.11 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 7.09 (d, J = 4.8Hz, 1H), 4.33 (t, J = 5.1Hz, 4H) , 4.25-4.14 (m, 4H), 3.77 (s, 6H), 3.15-3.03 (m, 2H), 2.71 (q, J=7.8Hz, 1H), 2.67-2.63 (m, 4H), 2.63-2.60 (m, 2H), 1.20 (d, J=7.8Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=197.77, 180.42, 174.86, 172.24, 151.78, 150.87, 146.56, 146.07, 142.53, 139.04, 137.96, 136.43, 134.31, 128 .40, 121.50, 111.53, 110.72, 106.62, 69.55, 66.37, 56.23, 56.04, 50.78, 50.22, 44.84, 36.24, 30.43, 29.13, 28.41, 17.57ppm.HRMS (ESI + ): Cacld forC 30 H 31 ClNO 10 Se - (MH) - , 680.0807; found 680.0808.

[0386] Embodiment 47

[0387]

[0388] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14c and one molecule of intermediate 411 were connected via 1,3-dibromopropane to prepare compound C45. 1 H NMR (300MHz, DMSO-d6): δ = 12.11 (s, 1H), 12.10 (s, 1H), 8.13 (s, 1H), 7.27 (s, 1H), 7.17 (s, 1H), 7.10 (d, J = 4.2Hz, 1H), 4.32 (t, J = 5.4Hz, 4H) , 4.26-4.15 (m, 4H), 3.76 (s, 6H), 3.17-3.04 (m, 2H), 2.70 (q, J = 7.8Hz, 1H), 2.67-2.62 (m, 4H), 2.60-2.57 (m, 2H), 1.19 (d, J = 7.2Hz, 3H) ppm. 13 C NMR (75MHz, DMSO-d6): δ=197.74, 180.36, 174.79, 172.15, 151.74, 150.80, 146.49, 145.53, 142.34, 138.97, 137.83, 136.31, 134.24, 128 .36, 121.42, 111.44, 110.71, 106.55, 69.47, 66.30, 56.14, 55.97, 50.72, 50.15, 44.78, 36.17, 30.34, 29.06, 28.34, 17.53ppm.HRMS (ESI + ): Cacld forC 30 H 31 ClNO 10 Se - (MH) - , 680.0807; found 680.0806.

[0389] Embodiment 48

[0390]

[0391] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 411 were connected via 1,3-dibromopropane to prepare compound C46. 1H NMR (300MHz, DMSO-d6): δ=12.10(s, 1H), 12.08(s, 1H), 8.10(s, 1H), 7.32(s , 1H), 7.16 (s, 1H), 6.89 (d, J=4.2Hz, 1H), 4.21 (t, J=5.4Hz, 4H), 4.26-4.16 (m, 4H), 3.81 (s, 6H), 3.14-3.08 (m, 2H), 2.71 (q, J=7.2Hz, 1H), 2.65-2.61 ( m, 4H), 2.60-2.52 (m, 2H), 1.19 (d, J = 7.8Hz, 2H), 0.93 (t, J = 6.9Hz, 3H) ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.14, 179.04, 174.71, 172.18, 151.62, 150.73, 146.41, 145.86, 142.39, 139.10, 137.81, 136.26, 134.16, 128.31 , 121.32, 111.35, 110.64, 106.43, 69.42, 66.21, 56.07, 55.90, 50.65, 50.08, 43.30, 42.46, 30.23, 28.97, 28.26, 25.98, 11.762ppm.HRMS (ESI + ): Cacld for C 31 H 33 ClNO 10 Se - (MH) - , 694.0964; found 694.0965.

[0392] Embodiment 49

[0393]

[0394] Referring to the preparation methods described in Examples 1 and 2, one molecule of intermediate 14f and one molecule of intermediate 411 were connected via 1,3-dibromopropane to prepare compound C47. 1HNMR (300MHz, DMSO-d6): δ=12.11 (s, 1H), 12.10 (s, 1H), 8.09 (s, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 6.78 (d, J=5.4Hz, 1H), 4.34 (t, J=5.4H z, 4H), 4.14-4.10 (m, 4H), 3.78-3.74 (m, 6H), 3.36 (t, J = 5.1Hz, 2H), 3.21 (t, J = 7.8Hz, 2H), 2.67-2.62 (m, 4H), 2.60-2.56 (m, 2H) ppnm. 13 C NMR (75MHz, DMSO-d6): δ=200.74, 175.42, 175.01, 172.33, 151.93, 149.89, 147.65, 146.20, 142.43, 139.45, 138.61, 135.26, 133.47, 129.12, 121.85, 111.54, 110.31, 106.78, 69.70, 66.53, 56.52, 56.37, 53.18, 53.23, 38.44, 30.57, 29.24, 29.26, 28.51ppm.HRMS (ESI + ): Cacld for C 29 H 29 ClNO 10 Se - (MH) - , 666.0651; found 666.0650.

[0395] Embodiment 50

[0396]

[0397] Referring to the preparation method described in Examples 1 and 2, one molecule of intermediate 14b and one molecule of intermediate 411 were connected via 1,3-dibromopropane to prepare compound C48. 1 H NMR (300MHz, DMSO-d6): δ = 12.12 (s, 1H), 12.09 (s, 1H), 8.10 (s, 1H), 7.19 (s, 1H), 7.13 (s, 1H), 6.78 (d, J = 5.1Hz, 1H), 4.25 (t, J = 4.2Hz, 4H), 4. 20-4.15(m, 4H), 3.80-3.75(m, 6H), 3.18-3.06(m, 2H), 2.72(q, J=7.2H z, 1H), 2.68-2.63 (m, 4H), 2.60-2.56 (m, 2H), 1.17 (d, J=6.9Hz, 3H)ppm.13 C NMR (75MHz, DMSO-d6): δ=197.72, 180.37, 174.81, 172.18, 151.73, 149.69, 147.45, 145.94, 142.45, 139.23, 137.75, 136.34, 134.25, 128 .40, 121.43, 111.31, 110.13, 106.54, 69.56, 66.62, 56.35, 56.16, 50.77, 50.14, 44.80, 36.19, 30.36, 29.08, 28.36, 17.57ppm.HRMS (ESI + ): Cacld forC 30 H 31 ClNO 10 Se - (MH) - , 680.0807; found 680.0806.

[0398] Embodiment 51

[0399]

[0400] According to the preparation method described in Examples 1 and 2, one molecule of intermediate 14c and one molecule of intermediate 411 were connected via 1,3-dibromopropane to prepare compound C49. 1 H NMR (300MHz, DMSO-d6): δ = 12.11 (s, 1H), 12.09 (s, 1H), 8.09 (s, 1H), 7.22 (s, 1H), 7.11 (s, 1H), 6.79 (d, J = 5.4Hz, 1H), 4.23 (t, J = 4.5Hz, 4H), 4. 19-4.15(m, 4H), 3.82-3.76(m, 6H), 3.17-3.08(m, 2H), 2.71(q, J=7.5H z, 1H), 2.67-2.61 (m, 4H), 2.59-2.54 (m, 2H), 1.19 (d, J=7.2Hz, 3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=197.65, 180.31, 174.75, 172.12, 151.67, 149.63, 147.39, 145.74, 142.43, 139.16, 137.71, 136.25, 134.14, 128 .24, 121.36, 111.25, 110.05, 106.50, 69.34, 66.26, 56.22, 56.13, 50.68, 50.14, 44.76, 36.11, 30.30, 29.02, 28.30, 17.48ppm.HRMS (ESI + ): Cacld forC 30 H 31 ClNO 10 Se - (MH) - , 680.0807; found 680.0808.

[0401] Embodiment 52

[0402]

[0403] According to the preparation method described in Examples 1 and 2, one molecule of intermediate 14d and one molecule of intermediate 411 were connected via 1,3-dibromopropane to prepare compound C50. 1 H NMR (300MHz, DMSO-d6): δ=12.17(s, 1H), 12.15(s, 1H), 8.14(s, 1H), 7.29(s, 1H), 7.13(s, 1H), 6.68(d, J=5.1Hz, 1H), 4.25(t, J=4.8Hz, 4H), 4.23-4.15(m , 4H), 3.86-3.80 (m, 6H), 3.13-3.08 (m, 2H), 2.68 (q, J=7.2Hz, 1H), 2.63-2.5 8 (m, 4H), 2.46-2.40 (m, 2H), 1.18 (d, J = 7.8Hz, 2H), 0.94 (t, J = 7.2Hz, 3H) ppm. 13C NMR (75MHz, DMSO-d6): δ=198.25, 179.15, 174.82, 172.19, 151.72, 149.71, 147.43, 145.93, 142.50, 139.23, 137.78, 136.37, 134.27, 128.45 , 121.44, 111.32, 110.14, 106.56, 69.41, 66.34, 56.39, 56.16, 50.73, 50.06, 43.41, 42.53, 30.34, 29.09, 28.37, 26.09, 11.83ppm.HRMS (ESI + ): Cacld for C 31 H 33 ClNO 10 Se - (MH) - , 694.0964; found 694.0963.

[0404] Embodiment 53

[0405]

[0406] According to the preparation method described in Examples 1 and 2, one molecule of intermediate 14e and one molecule of intermediate 411 were connected via 1,3-dibromopropane to prepare compound C51. 1 H NMR (300MHz, DMSO-d6): δ=12.16(s, 1H), 12.13(s, 1H), 8.12(s, 1H), 7.28(s, 1H), 7.11(s, 1H), 6.67(d, J=4.8Hz, 1H), 4.22(t, J=4.8Hz, 4H), 4.20-4.15(m , 4H), 3.86-3.81 (m, 6H), 3.14-3.07 (m, 2H), 2.65 (q, J=7.5Hz, 1H), 2.62-2.5 5 (m, 4H), 2.45-2.39 (m, 2H), 1.19 (d, J = 8.1Hz, 2H), 0.93 (t, J = 7.2Hz, 3H) ppm. 13C NMR (75MHz, DMSO-d6): δ=198.36, 179.32, 174.89, 172.34, 151.91, 149.86, 147.63, 146.16, 142.67, 139.40, 137.95, 136.54, 134.45, 128.59 , 121.68, 111.51, 110.29, 106.76, 69.68, 66.34, 56.54, 56.36, 50.93, 50.36, 43.53, 42.71, 30.52, 29.25, 28.54, 26.26, 12.04ppm.HRMS (ESI + ): Cacld for C 31 H 33 ClNO 10 Se - (MH) - , 694.0964; found 694.0963.

[0407] Embodiment 54

[0408]

[0409] According to the preparation method described in Examples 1 and 2, one molecule of intermediate 14c and one molecule of intermediate 41m were connected via 1,3-dibromopropane to prepare compound C52. 1 H NMR (300MHz, DMSO-d6): δ=12.11 (s, 2H), 8.10 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 6.78 (t, J=1.5Hz, 1H), 4.25 (t, J=5.1H z, 4H), 4.22-4.14 (m, 4H), 3.83 (s, 6H), 3.16-3.05 (m, 2H), 2.68-2.56 (m, 4H), 2.27-2.23 (m, 2H), 1.22-1.15 (m, 6H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=200.45, 179.81, 179.72, 169.91, 151.73, 151.05, 146.47, 145.92, 142.64, 137.78, 136.52, 133.15, 133.03, 129.57 , 122.65, 112.11, 108.81, 106.61, 69.85, 66.73, 56.31, 56.15, 54.04, 53.85, 46.59, 38.34, 36.80, 34.02, 29.52, 17.37, 17.31ppm.HRMS (ESI +): Cacld for C 31 H 33 ClNO 10 Se - (MH) - , 694.0964; found 694.0965.

[0410] Embodiment 55

[0411]

[0412] According to the preparation method described in Examples 1 and 2, one molecule of intermediate 14e and one molecule of intermediate 41n were connected via 1,3-dibromopropane to prepare compound C53. 1 H NMR (300MHz, DMSO-d6): δ=12.11 (s, 2H), 8.03 (s, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 6.70 (t, J=1.2Hz, 1H), 4.34 (t, J=5.1Hz, 4H), 4.29-4.24 (m, 4H) , 3.82 (s, 6H), 3.12 (d, J = 8.4Hz, 1H), 2.95 (d, J = 15.0Hz, 1H), 2.67-2.48 (m, 3H), 2.26-2.2l (m, 3H), 1.61 (q, J=6.9Hz, 4H), 1.03-0.96 (m, 6H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.36, 179.35, 179.28, 170.61, 151.88, 150.97 ,146.62,146.10,142.63,139.14,138.07,136.53,134.48,128.55,121.6 0, 111.60, 110.83, 106.72, 69.64, 66.47, 56.32, 56.15, 51.14, 50.33, 43. 55, 43.44, 42.67, 36.41, 29.23, 26.27, 25.14, 12.00, 11.52ppm.HRMS (ESI + ): Cacld for C 33 H 37 ClNO 10 Se - (MH), 722.1277; found 722.1276.

[0413] Embodiment 56

[0414]

[0415] Preparation of 1,1,1-trifluoropropane-2-yl (2S)-2-ethyl-4-(6-(3-((4-fluoro-6-methoxy-2-(4-oxo-4-((1,1,1-trifluoropropane-2-yl)oxy)butanoyl)isoindolin-5-yl)oxy)propoxy)-5-methoxybenzo[b]selenophene-2-yl)-4-oxobutanoate (C54)

[0416] Compound C10 (95 mg, 0.14 mmol), 1,1,1-trifluoro-2-propanol (66 mg, 0.58 mmol), DCC (89 mg, 0.43 mmol), DMAP (3.5 mg, 0.029 mmol) and 3 mL of dichloromethane were added to a 25 mL reaction bottle, and the resulting mixture was stirred at room temperature for 8 h. After TLC monitoring of the reaction of the raw materials, 9 mL of dichloromethane was added for dilution, suction filtered, and the filtrate was concentrated. 6 mL of ethyl acetate was added to the resulting residue and placed in an ice bath for 10 min, suction filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain 78 mg of a light yellow solid (compound C54), with a yield of 64%. 1 H NMR (300MHz, DMSO-d6): δ=8.01(s, 1H), 7.23(s, 1H), 7.10(s, 1H), 6.87(d, J=1.5H z, 1H), 5.15-4.98 (m, 2H), 4.50-4.47 (m, 4H), 4.34-4.25 (m, 4H), 3.85-3.82 (m, 6H ), 3.24-3.19(m, 1H), 3.11-3.05(m, 1H), 2.61-2.57(m, 2H), 2.50-2.45(m, 3H), 2. 32-2.28(m, 2H), 1.65-1.59(m, 2H), 1.38-1.32(m, 6H), 0.94(t, J=6.0Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.18, 174.52, 172.24, 171.96, 151.73, 151.63, 149.9 2, 147.66, 142.71, 139.42, 138.63, 137.98, 136.56, 133.87, 128.42, 126.18, 119. 97, 111.52, 110.31, 103.04, 69.71, 69.30, 68.88, 66.53, 56.56, 56.37, 51.39, 49 .27, 42.81, 42.65, 31.37, 30.36, 29.27, 25.38, 15.73, 15.54, 11.71ppm.HRMS (ESI + ): Cacld for C37 H 41 F7 10 Se + (M+H) + , 872.1778; found 872.1776.

[0417] Embodiment 57

[0418]

[0419] Preparation of (S)-4-(6-(3-((2-(4-amino-4-oxobutanoyl)-4-fluoro-6-methoxyisoindolin-5-yl)oxy)propoxy)-5-methoxybenzo[b]selenophene-2-yl)-2-ethyl-4-oxobutanamide (C55)

[0420] Compound C10 (95 mg, 0.14 mmol), N-methylmorpholine (44 mg, 0.43 mmol) and 3 mL of tetrahydrofuran were added to a 25 mL reaction bottle, and isobutyl chloroformate (59 mg, 0.43 mmol) was added dropwise under an ice bath. After the addition was complete, the reaction was transferred to room temperature and stirred for 1 h. Subsequently, 0.1 mL of ammonia water was added dropwise under an ice bath again, and the resulting reaction solution was stirred at room temperature for 4 h. After TLC detected that the raw material reaction was complete, 15 mL of water was added and extracted three times with 10 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 72 mg of a yellow solid (compound C55) with a yield of 76%. 1 HNMR (300MHz, DMSO-d6): δ=7.98 (s, 1H), 7.19 (d, J=6.0Hz, 2H), 6.86 (d, J=7.2Hz, 2H), 6.69 ( t, J=1.2Hz, 1H), 6.58 (d, J=7.8Hz, 1H), 6.38 (s, 1H), 4.69-4.60 (m, 4H), 4.25-4.17 (m, 4H), 3 .83(d, J=3.0Hz, 6H), 3.02-2.98(m, 1H), 2.94-2.87(m, 1H), 2.78-2.69(m, 1H), 2.63-2.53(m , 2H), 2.52-2.45 (m, 2H), 2.26 (q, J=6.3Hz, 2H), 1.62-1.56 (m, 2H), 0.93 (t, J=6.9Hz, 3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=198.52, 177.03, 174.43, 172.47, 151.88, 151.73, 149.82, 146.82, 142.73, 139.30, 138.73, 138.23, 136.66, 133.47 , 120.07, 111.76, 111.04, 103.46, 69.59, 66.63, 56.47, 56.30, 51.49, 49.37, 45.56, 42.67, 31.96, 30.37, 29.37, 25.46, 12.23ppm.HRMS (ESI + ): Cacld for C 31 H 37 FN3O8Se + , (M+H) + , 678.1724; found 678.1722.

[0421] Embodiment 58

[0422]

[0423] Preparation of (S)-2-ethyl-4-(6-(3-((4-fluoro-2-(4-(hydroxyamino)-4-oxobutanoyl)-6-methoxyisoindolin-5-yl)oxy)propoxy)-5-methoxybenzo[b]selenophene-2-yl)N-hydroxy-4-oxobutanamide (C56)

[0424] Compound C1 (95 mg, 0.14 mmol), HATU (164 mg, 0.43 mmol), N, N-diisopropylethylamine (130 mg, 1.01 mmol) and 3 mL DMF were added to a 25 mL reaction bottle, and the resulting mixture was stirred at room temperature for 30 min. Hydroxylamine hydrochloride (40 mg, 0.58 mmol) was then added, and the reaction was stirred for 4 h at room temperature. After TLC monitoring of the complete reaction of the raw materials, 15 mL of water was added to the reaction solution, and then extracted three times with 10 mL of ethyl acetate. The organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 45 mg of a light yellow solid (compound C56), with a yield of 46%. 1HNMR (300MHz, DMSO-d6): δ=9.10-9.05(m, 2H), 8.78-8.72(m, 2H), 8.02(s, 1H), 7.17(d , J=6.0Hz, 2H), 6.61 (t, J=1.2Hz, 1H), 4.69-4.61 (m, 4H), 4.24-4.15 (m, 4H), 3.82 (d, J =3.0Hz, 6H), 3.03-2.96(m, 1H), 2.92-2.86(m, 1H), 2.78-2.68(m, 1H), 2.65-2.54(m, 2 H), 2.50-2.44(m, 2H), 2.24-2.19(m, 2H), 1.62-1.56(m, 2H), 0.97(t, J=6.3Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.19, 174.47, 172.00, 170.82, 151.71, 151.52, 149.71, 146.68, 142.63, 139.19, 138.62, 138.12, 136.55, 133.86 , 119.86, 111.65, 110.93, 103.13, 69.43, 67.52, 56.36, 56.19, 51.38, 49.26, 42.76, 42.63, 30.25, 29.26, 28.13, 25.27, 12.14ppm.HRMS (ESI + ): Cacld for C 31 H 37 F3O 10 Se + , (M+H) + , 710.7623; found 710.7622.

[0425] Embodiment 59

[0426]

[0427] Preparation of (S)-2-ethyl-4-(6-(3-((4-fluoro-6-methoxy-2-(4-(methoxyamino)-4-oxobutanoyl)isoindolin-5-yl)oxy)propoxy)-5-methoxybenzo[b]selenophene-2-yl)-N-methoxy-4-oxobutanamide (C57)

[0428] Referring to the preparation method described in Example 58, the raw material hydroxylamine hydrochloride was replaced with methoxylamine hydrochloride, and compound C57 was prepared by the same synthetic method. 1HNMR (300MHz, DMSO-d6): δ=8.23 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.17 (d, J=6.3Hz, 2H) , 6.62 (t, J=0.9Hz, 1H), 4.63-4.57 (m, 4H), 4.26-4.14 (m, 4H), 3.85 (d, J=3.3Hz, 6H), 3.58 (d, J=3.0Hz, 6H), 3.04-2.98(m, 1H), 2.91-2.85(m, 1H), 2.76-2.69(m, 1H), 2.64-2.56(m , 2H), 2.51-2.43(m, 2H), 2.23-2.18(m, 2H), 1.64-1.56(m, 2H), 0.93(t, J=7.2Hz, 3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.14, 173.68, 171.95, 171.62, 151.75, 151.50 ,149.69,146.69,142.84,139.17,138.60,138.10,136.53,133.84,119.9 4, 111.63, 110.91, 103.11, 69.86, 66.50, 60.39, 60.25, 56.34, 56.17, 51. 26, 49.41, 43.56, 42.53, 30.03, 29.24, 28.42, 25.15, 12.09ppm.HRMS (ESI + ): Cacld for C 33 H 41 F3O 10 Se + , (M+H) + , 738.1936; found 738.1935.

[0429] Embodiment 60

[0430]

[0431] Referring to the preparation method described in Example 58, the raw material hydroxylamine hydrochloride was replaced with N-isopropylhydroxylamine hydrochloride, and compound C58 was prepared by the same synthesis method. 1HNMR (300MHz, DMSO-d6): δ=7.98 (s, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 6.62 (d, J=6.3Hz, 1H), 5.16 (t, J =0.9Hz, 1H), 4.62-4.58 (m, 4H), 4.55-4.49 (m, 1H), 4.25-4.16 (m, 4H), 3.86 (d, J = 4.5Hz, 6H), 3.24- 3.19 (m, 2H), 3.13-3.05 (m, 2H), 2.75-2.68 (m, 1H), 2.66-2.62 (m, 1H), 2.59-2.54 (m, 3H), 2.27-2.2 3 (m, 2H), 1.69-1.52 (m, 2H), 1.23 (d, J = 5.7Hz, 6H), 1.17 (t, J = 6.0Hz, 6H), 0.94 (t, J = 7.5Hz, 3H) ppm. 13 C NMR (75MHz, DMSO-d6): δ=198.13, 173.40, 172.15, 171.31, 151.64, 150.89, 149.6 8, 146.68, 142.61, 139.16, 138.65, 138.49, 136.54, 133.83, 119.83, 111.62, 110 .90, 103.01, 69.37, 67.49, 56.33, 56.16, 51.31, 51.28, 51.15, 49.23, 43.78, 42. 74, 29.95, 29.91, 29.23, 25.19, 20.35, 20.30, 20.25, 20.21, 11.67ppm.HRMS (ESI + ): Cacld for C 37 H 49 F3O 10 Se + , (M+H) + , 794.2562; found 794.2563.

[0432] Example 60 Based on THP1-Lucia, RAW-Lucia luciferase reporter gene experiment

[0433] THP1-dual TM The cells (Invivogen: thpd-nfis) were diluted with culture medium and 100 μL of the cell suspension was inoculated into a 96-well plate so that each well contained 1×10 5cells. Then, 100 μL of the compound to be tested was added to a 96-well plate (the final concentration of the compound was 10 μM, and the final volume of each well was 200 μL) and incubated at 37°C for 24 hours. Then, 50 μL of the supernatant was aspirated into a new 96-well white plate, and 50 μL of QUANT-Luc reagent was added. After thorough mixing, the assay was performed immediately using an ELISA reader. The experiment was set up with 3 replicate wells. The test results were expressed as folds, which were calculated by (test well-blank well) / (negative well-blank well). The test results are shown in the table below, with 2',3'-cGAMP as the positive control, where *** indicates an excitation fold of more than 20 times, ** indicates an excitation fold of 10 to 20 times, and * indicates an excitation fold of 1 to 10 times.

[0434] Table 4. Agonist activity of the compounds of the present invention in luciferase reporter gene assay

[0435]

[0436]

[0437] As can be seen from Table 4, the compounds of the present invention have good agonist activity on the cGAS-STING pathway.

[0438] Example 60 Interferon β induction experiment based on THP1 cells

[0439] The secretion of cytokine IFNβ was determined by enzyme-linked immunosorbent assay (ELISA). THP1 cells were seeded in 96-well plates (10% PBS, RPMI 1640 medium without serum) so that the number of cells per well was 5-7×10 5 The test compound was prepared into a 10mM DMSO stock solution, diluted with culture medium to the target concentration and added to a 96-well plate containing cells (the final concentration of the compound was 20μM, and the final volume of each well was 200μL), and incubated at 37°C, 5% CO2 for 3.5h. The cells were then collected and centrifuged at 4°C, 1000rpm for 20 minutes, and the supernatant was collected for ELISA determination. The experiment was set up with 3 replicates. The results are shown in the table below. 2',3'-cGAMP was used as a positive control, and the test results were expressed as a percentage of activity relative to a 20μM concentration of 2',3'-cGAMP.

[0440] Table 5 Effect of the compounds of the present invention on IFNβ-induced secretion in THP1 cells

[0441]

[0442] As can be seen from Table 5, the representative compounds of the present invention have good activity in inducing THP1 cells to secrete IFNβ.

Claims

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt, isomer, metabolite or solvate thereof: in, L 1 and L 3 are the same or different and are each independently selected from C(R 5 )2. NR 5 , O or S; L 2 Selected from C1-C6 alkylene, 6 Substituted C1-C6 alkylene, C1-C6 alkylene-L 4 -C1-C6 alkylene, C2-C6 alkenylene, C2-C6 haloalkenylene, C2-C6 alkynylene, C2-C6 haloalkynylene, C3-C6 cycloalkyl or 3-6 membered heterocyclic group; X 1 and X 4 Selected from C(O); X 2 and X 5 Selected from (C(R 7 )2) p , CHR 7 CHR 7 or CH2C(R 7 )2; X 3 and X 6 The same or different, and each independently selected from COOR 5 、C(O)N(R 5 )2、C(O)NR 5 OR 5 、C(O)ON(R 5 2. SO2R 5 、S(O)NR 5 or C(CF3)2OR 5 ; R 1 and R 2 are the same or different and are each independently selected from hydrogen, halogen, cyano, nitro, OR 5 , SR 5 、N(R 5 2. COOR 5 、C(O)N(R 5 )2, C1~C6 alkyl, C1~C6 haloalkyl, OR 5 Substituted C1-C6 alkyl, N(R 5 )2-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic group; R 3 and R 4 are the same or different and are each independently selected from hydrogen, halogen, cyano, OR 5 、N(R 5 )2, C1~C6 alkyl, C1~C6 haloalkyl or C3~C6 cycloalkyl; R 5 Each is independently selected from a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 cycloalkyl group, a 3-6 membered heterocyclic group or a C5-C 10 Aryl; R 6 Selected from hydrogen atoms, halogens, OR 5 、N(R 5 )2, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic group; R 7 are independently selected from hydrogen, halogen, cyano, OR 5 、N(R 5 )2, C1~C6 alkyl, C1~C6 haloalkyl, OR 5 Substituted C1~C6 alkyl or C3~C6 cycloalkyl; Optionally, the two R on different carbon atoms 7 Together with the carbon atoms between them, they can form a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group; Optionally, two R7 on the same carbon atom may form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group together with the carbon atom to which they are commonly attached; m and n are each independently selected from 0, 1, 2 and 3; p is selected from 1, 2 and 3.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, solvate or prodrug thereof, characterized in that: L 1 and L 3 are the same or different and are each independently selected from CH2, NH or O; L 2 Selected from C1-C6 alkylene, 6 Substituted C1-C6 alkylene, C1-C4 alkylene-L 4 -C1-C4 alkylene, C2-C4 alkenylene, C2-C4 haloalkenylene, C2-C4 alkynylene, C2-C4 haloalkynylene, C3-C6 cycloalkyl or 3-6 membered heterocyclic group; L 4 is selected from O, S, C(O), C3-C6 cycloalkyl or 3-6 membered heterocyclic group; X 1 and X 4 Selected from C(O); X 2 and X 5 Selected from C1-C6 alkylene, C3-C6 cycloalkyl; X 3 and X 6 are the same or different and are each independently selected from COOH, COO-C1~C6 haloalkyl, COO-C1~C4 alkyl, COO-NH-C1~C4 alkyl, C(O)NHOH, C(O)NH2, C(O)NHOCH3; R 1 and R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, an O-C1-C3 alkyl group, an O-C1-C3 alkyl group-O-C1-C3 alkyl group, an O-C1-C3 haloalkyl group or OH; R 3 and R 4 are the same or different and are each independently selected from a hydrogen atom, a fluorine atom, a chlorine atom, and a C1-C3 alkyl group; R 6 is selected from a hydrogen atom, a fluorine atom, OH, NH2, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group; m and n are each independently selected from 0, 1, 2 or 3.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, solvate or prodrug thereof, characterized in that: The compound has a structure of formula (Ia) or a structure of formula (Ib): Wherein, each variable is defined as in claims 1-2.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, isomer, metabolite or solvate thereof, characterized in that: The compound has a structure of formula (I-1) or a structure of formula (I-2): Wherein, each variable is defined as in claims 1-2.

5. The compound according to claim 1, or its pharmaceutically acceptable salt, isomer, metabolite, or solvate, characterized in that: The compound is selected from the following structures:

6. A method for preparing the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isomer, metabolite or solvate thereof, characterized in that: The following steps are involved: When it is a compound represented by the general formula (I-1), the compound of the general formula 1 and the compound 2 are subjected to a substitution reaction under alkaline conditions to obtain a benzyl-protected compound of the general formula 3, the compound 3 and the compound 4 are reacted under alkaline conditions to obtain the compound 5, the compound 5 and the compound 6 are subjected to a substitution reaction to obtain the compound 7, the compound 7 is subjected to an intramolecular condensation to obtain the compound 8, the compound 8 is hydrolyzed under alkaline conditions to obtain the compound 9, the compound 9 and the compound 10 are subjected to condensation and desalination to obtain the compound 11, the compound 11 and the compound 12 are subjected to a nucleophilic substitution reaction under alkaline conditions to obtain the compound 13, the compound 13 is hydrolyzed under strong acid to decarboxylate and debenzylate to obtain the compound 14, the compound 14 is protected by an ester group to obtain the compound 15, the compound 15 and the compound 16 are subjected to a substitution reaction under alkaline conditions to obtain the compound 1 7, compound 18 and compound 19 are subjected to electrophilic substitution to obtain compound 20, compound 20 is protected by methyl ester to obtain compound 21, compound 21 is subjected to hydrolysis and then acylation to obtain compound 22, compound 22 and compound 23 are subjected to substitution reaction to obtain p-methoxybenzyl (PMB) protected compound 24, compound 24 is subjected to borane reduction to obtain compound 25, compound 25 is subjected to PMB protection group removal under palladium carbon conditions to obtain compound 26, compound 26 and compound 27 are subjected to substitution reaction under alkaline conditions to obtain compound 28, compound 28 is demethylated under boron tribromide to obtain compound 29, compound 17 and compound 29 are dimerized under alkaline conditions to obtain compound 30, and compound 30 is finally hydrolyzed under alkaline conditions to obtain a compound of general formula (I-1), and the synthetic route is as follows: Among them, R 1 , R 2 , R 7 , L 2 , m and n are as described in claims 1-5, R 8 Selected from CH3, CH2CH3, C(CH3)3, R 9 Each is independently selected from CH3, CH2CH3, Y is selected from Cl, Br, I; When it is a compound represented by general formula (I-2), compound 31 is obtained by decarboxylation reaction of compound 9, compound 31 and compound 32 are subjected to Friedel-Crafts acylation reaction to obtain compound 33, compound 33 is debenzylated to obtain compound 34, compound 34 is protected by ester to obtain compound 35, compound 35 and compound 16 are subjected to substitution reaction under alkaline conditions to obtain compound 36, compound 36 and compound 29 are condensed and dimerized under alkaline conditions to obtain compound 37, which is hydrolyzed under alkaline conditions to obtain the compound of general formula (I-2), and the synthesis route is as follows: Among them, R 1 , R 2 , L 2 , m and n are as described in claims 1-5, R 9 Each is independently selected from CH3, CH2CH3, Y is selected from Cl, Br, I, and q represents 1, 2, 3 or 4.

7. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 5 or pharmaceutically acceptable salts, isomers, metabolites or solvates thereof, and a pharmaceutically acceptable excipient or carrier.

8. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, isomer, metabolite or solvate thereof, or the pharmaceutical composition according to claim 7 in the preparation of drugs for activating the cGAS-STING pathway.

9. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, isomer, metabolite or solvate thereof, or the pharmaceutical composition according to claim 7 in the preparation of a method for preventing and / or treating STING-related diseases.

10. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, isomer, metabolite or solvate thereof, or the pharmaceutical composition according to claim 7 in the preparation of an immune adjuvant.

Images