Glycosylated phthalimide compound as well as preparation method and application thereof

Abstract

The invention provides a glycosylated phthalimide compound as shown in a formula (I), and an isomer, a solvate or a hydrate or a pharmaceutically acceptable salt of the glycosylated phthalimide compound. The invention further provides a preparation method and application of the glycosylated phthalimide compound, the isomer or the pharmaceutically acceptable salt of the glycosylated phthalimide compound in the technical scheme. The compound provided by the invention can effectively inhibit proliferation of multiple myeloma forming drug resistance to existing clinical drugs lenalidomide and pomalidomide, has higher inhibitory activity to brain glioma, and can be used as a lenalidomide and pomalidomide drug-resistant myeloma treatment drug and a potential drug for brain tumor treatment.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a glycosylated phthalimide compound, a preparation method thereof and use thereof. BACKGROUND

[0002] Multiple myeloma (MM) is a major blood system disease, which is caused by malignant proliferation of plasma cells in bone marrow, accompanied by secretion of monoclonal immunoglobulin, i.e., serum M protein, by the immune system, and eventually leads to damage and failure of organs or tissues. MM ranks second among hematological malignancies, can cause abnormal hematopoiesis, and is clinically manifested as osteolytic damage, anemia, hypercalcemia, abnormal kidney function, repeated infections, etc.

[0003] Patients diagnosed with multiple myeloma need to use immunomodulatory drugs for life to maintain life and survival. Lenalidomide and pomalidomide, as immunomodulators, are commonly used first-line drugs for treating multiple myeloma in clinical practice and are believed to exert efficacy through anti-angiogenic, anti-inflammatory and cytotoxic activities. Like other anti-tumor drugs, in addition to individual patients with primary drug resistance, lenalidomide and pomalidomide chemotherapy will gradually produce drug resistance of tumors during long-term clinical application, thereby bringing great challenges to the treatment of patients. Clinical statistics show that lenalidomide generally produces drug resistance after 1-2 years of treatment, and pomalidomide appears drug resistance in a shorter time. Drug resistance occurs in several months to several years according to the difference of individual patients (Blood (2023) 142 (2): 131 40). At present, the exploration of treatment means for tumors after the formation of drug resistance to the two drugs is an extremely arduous and urgent task. For example, a large number of screening studies have found that the combination of the commonly used potent immunosuppressant dexamethasone and other types of E3 ubiquitin ligase inhibitors can resist the drug resistance of MM to lenalidomide and pomalidomide, but the effective rate of this treatment scheme for tumor patients after drug resistance is only about 30%.

[0004] In order to cope with the threat of drug resistance of multiple myeloma to existing treatment drugs, it is currently urgent to screen and discover new drug molecules and lead compounds with anti-drug resistance properties. SUMMARY

[0005] Therefore, the purpose of the present application is to provide a glycosylated phthalimide compound, a preparation method thereof and use thereof. The glycosylated phthalimide compound provided in the present application can effectively inhibit the proliferation of multiple myeloma cells resistant to lenalidomide and pomalidomide and glioma cells insensitive to lenalidomide and pomalidomide.

[0006] The application provides a glycosylated phthalimide compound shown in formula (I), an isomer, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] A is selected from hydrogen or a methyl group; 1～3 alkyl group having 1-6 carbon atoms;

[0009] Y is selected from hydrogen, deuterium, a halogen, or a methyl group having 1-6 carbon atoms; 1～3 alkyl group having 1-6 carbon atoms;

[0010] R has a structure of formula (a):

[0011]

[0012] In formula (a), R1, R2, R3, and R4 are independently selected from hydrogen, a hydroxyl group, a C 1～3 alkyl group having 1-6 carbon atoms, or a C 1～3 alkylene group having 1-6 carbon atoms;

[0013] R1, R2, R3, and R4 contain at least three hydroxyl groups.

[0014] The glycosylation modification of the phthalimide compound in the application can effectively inhibit the proliferation of multiple myeloma cells resistant to lenalidomide and pomalidomide and brain tumor cells insensitive to lenalidomide and pomalidomide, and can be used for preparing potential drugs for treating lenalidomide and pomalidomide-resistant myeloma and for treating brain tumors.

[0015] In some specific implementations, A in the structure shown in formula (I) is selected from hydrogen or a methyl group.

[0016] In some specific implementations, Y in the structure shown in formula (I) is selected from hydrogen, deuterium, fluorine, chlorine, or a methyl group.

[0017] In some specific implementations, the configuration of the 3'-position in the structure shown in formula (I) is S, R, or a mixture of the two.

[0018] R is a glycosyl unit connected to the phenylamine group by an N-glycoside bond, and the glycosyl unit is in a cyclic structure rather than a chain open structure. In some specific implementations, R has a structure of formula (a):

[0019]

[0020] In formula (a), R1, R2, R3, and R4 are independently selected from hydrogen, a hydroxyl group, a C 1～3 alkyl group having 1-6 carbon atoms, or a C 1～3 alkylene group having 1-6 carbon atoms;

[0021] R1, R2, R3 and R4 contain at least three hydroxyl groups.

[0022] In some specific embodiments, the 1'-position configuration in the structure of formula (a) is α, β or a mixture of both.

[0023] In some specific embodiments, R has the structure of formula (a-1) to formula (a-4):

[0024]

[0025] Specifically, R has the following structure:

[0026]

[0027] R preferably has the following structure:

[0028]

[0029] The isomers of the glycosylated phthalimide compound are not particularly limited in the present application, and can be tautomers, meso forms, racemates, enantiomers, diastereomers, optical isomers, etc.

[0030] The "pharmaceutically acceptable salt" of the compound of the present application is preferably an acid salt or a base salt, which is generally considered in the art to be suitable for use in contact with human or animal tissue without excessive toxicity or carcinogenicity, and preferably without irritation, allergic reaction or other problems or complications. Such salts include inorganic acid salts and organic acid salts of basic residues such as amines, and alkali metal salts or organic salts of acidic residues such as carboxylic acids. The compound of the present application can form an internal salt, which is also a pharmaceutically acceptable salt.

[0031] In some specific embodiments, the glycosylated phthalimide compound has the structure of formula (I-1) to formula (I-28):

[0032]

[0033]

[0034]

[0035] The present application also provides a preparation method of the glycosylated phthalimide compound, isomers thereof or pharmaceutically acceptable salts thereof according to the above technical solutions, comprising the following steps:

[0036] In the presence of a catalyst, a compound represented by formula (II) is subjected to glycoside condensation reaction with a saccharide compound represented by formula (b) in a solvent to obtain a glycosylated phthalimide compound;

[0037]

[0038] The present application uses a compound represented by formula (II) and a saccharide compound represented by formula (b) as raw materials to carry out glycoside condensation reaction under the action of a catalyst to obtain a saccharide-based phthalimide compound. Specifically, the present application dissolves the compound represented by formula (II) and the saccharide compound represented by formula (b) in a solvent, and then adds a catalyst to carry out reaction. The reaction process is as follows:

[0039]

[0040] In the compound represented by formula (II), Y and A have the same definition as the compound of formula (I), which will not be repeated here. The compound represented by formula (II) is not particularly limited and can be directly purchased on the market or prepared according to the published method. For example, when A is methyl and Y is a hydrogen atom, the compound represented by formula (II) can be prepared according to the method reported in the literature Journal of Medicinal Chemistry (2023), 66(11), 7243-7252; when A is a hydrogen atom and Y is a deuterium atom, the compound represented by formula (II) can be prepared according to the method disclosed in WO2012068512; when A is a hydrogen atom and Y is a fluorine atom, the compound represented by formula (II) can be prepared according to the method reported in the literature Bioorg. Med. Chem. Lett. 13 (2003) 3415-3417; when A is a hydrogen atom and Y is a chlorine atom, the compound represented by formula (II) can be prepared according to the method disclosed in CN103819454A; when A is a hydrogen atom and Y is a methyl group, the compound represented by formula (II) can be prepared according to the method disclosed in WO2006081251.

[0041] In the saccharide compound represented by formula (b), R1, R2, R3, and R4 have the same definition as the compound of formula (I), which will not be repeated here. In some specific embodiments, the saccharide compound includes but is not limited to glucose, galactose, mannose, rhamnose, 2-deoxyglucose, D-arabinose, L-arabinose, or D-xylose, etc., which can be one or more of them.

[0042] In some embodiments, the catalyst is selected from one or more of formic acid, sodium hydrogen phosphate, trifluoroacetic acid, hydrochloric acid, and ammonium chloride, preferably trifluoroacetic acid. In some embodiments, the catalyst is used in an amount of 2wt% to 50wt% of the saccharide compound, preferably 3wt% to 40wt%, more preferably 5wt% to 30wt%. In some embodiments, the solvent is selected from water, methanol, ethanol, acetone, chloroform, N,N-dimethylformamide, etc., and can be one or more of them, for example, a mixed solution of organic solvents such as methanol, ethanol, acetone, chloroform, N,N-dimethylformamide, etc. and water, wherein the volume ratio of the organic solvent to water is 6:1 to 1:1, preferably 5:1 to 1:1, and the ratio of the organic solvent to water is targeted to improve the solubility of the reactants. Preferably, ethanol is used as a single solvent.

[0043] In some embodiments, the initial concentration of the compound of formula (II) is 0.01g / ml to 0.1g / ml, preferably 0.02g / ml to 0.05g / ml. In some embodiments, the molar ratio of the compound of formula (II) to the saccharide compound of formula (b) is 1:1 to 1:10, preferably 1:1 to 1:5.

[0044] In some embodiments, the temperature of the glycoside condensation reaction is 20°C to 200°C, preferably 50°C to 150°C, and the time is 30min to 1 week, or until the end point is detected by liquid chromatography or thin layer chromatography.

[0045] In some embodiments, the glycoside condensation reaction is generally carried out in a solvent environment after nitrogen replacement. Depending on the target product, the reaction time required is wide. Depending on the properties of the reactants, it generally takes 6 hours to 7 days to complete, and more often 48 to 72 hours.

[0046] After the reaction is completed, the resulting reaction product is preferably purified, and many methods can be used to purify the product obtained in the above reaction. For example, the mixture after the reaction is completed can be first filtered to remove precipitates that can be formed, then concentrated by distillation under reduced pressure, then an organic solvent is added to precipitate the desired target product. An ether solvent that is partially miscible with water (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol diethyl ether, or ethylene glycol dimethyl ether, etc.) is generally selected, and then the resulting precipitate is collected, for example, by filtration, and further washed with the above solvent to obtain the desired target product. The target product obtained in the above reaction can also be purified by chromatography, etc., for example, using an ion exchange resin, or using a silica gel column, or using preparative liquid chromatography. Liquid chromatography separation and purification is generally performed using methanol and water or acetonitrile and water as the mobile phase, for example, using a 1% to 75% methanol gradient elution. The above separation and purification process can be completed by using a preparative HPLC system (CXTH-LC3000) equipped with a reversed-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm).

[0047] The application also provides a pharmaceutical composition comprising the glycosylated phthalimide compound, isomer thereof or pharmaceutically acceptable salt thereof according to the above technical solution and a pharmaceutically acceptable excipient.

[0048] In some specific implementations, the pharmaceutically acceptable excipient includes, but is not limited to, a filler, a binder, a disintegrant, a lubricant, a glidant, an effervescent agent, a preservative, a solubilizer, a co-solvent, an antioxidant, an anti-photolysis agent, a pH regulator, an emulsifier, a local analgesic, a complexing agent, a non-aqueous solvent, a coating material or other excipients.

[0049] In some specific implementations, the filler in the pharmaceutically acceptable excipient includes, but is not limited to, lactose, mannitol, calcium carbonate, etc., and can be one or more of them; the binder includes, but is not limited to, sucrose, starch, povidone, sodium carboxymethyl cellulose, etc., and can be one or more of them; the disintegrant includes, but is not limited to, starch, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, effervescent disintegrant, etc., and can be one or more of them; the non-aqueous solvent includes, but is not limited to, iodized oil, soybean oil, castor oil, peanut oil, etc., and can be one or more of them; the solubilizer includes, but is not limited to, Tween 80, Tween 60, poloxamer 68, etc., and can be one or more of them; the co-solvent includes, but is not limited to, sodium benzoate, sodium salicylate, sodium p-aminobenzoate, cyclodextrin, etc., and can be one or more of them; the lubricant includes, but is not limited to, talc, stearic acid ester, silicone, etc.

[0050] In some embodiments, the pharmaceutical composition is administered orally, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., as a suppository), or via hepatic artery.

[0051] In some embodiments, the pharmaceutical composition is in the form of an oil emulsion or dispersion, in combination with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained release composition for intravenous or intramuscular injection or hepatic artery administration.

[0052] In some embodiments, the pharmaceutical composition is in the form of a solid oral preparation (e.g., a tablet or capsule), a liquid oral preparation (e.g., a liquid for oral administration), or an injection.

[0053] The present application also provides a use of the glycosylated phthalimide compound of Formula (I), an isomer, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above in the preparation of a medicament for preventing and / or treating a tumor.

[0054] In some embodiments, the tumor is selected from a hematological tumor, a myeloma, a brain tumor; preferably, the hematological tumor includes, but is not limited to, acute leukemia, chronic leukemia, lymphoma, Kaposi sarcoma; the myeloma includes, but is not limited to, multiple myeloma or myelodysplastic syndrome originating from hematopoietic stem cell tumor; the brain tumor includes, but is not limited to, brain glioma, intracranial metastasis, intracerebral teratoma, etc.

[0055] In some embodiments, the tumor is a hematological tumor, a myeloma resistant to lenalidomide and pomalidomide, and a brain tumor insensitive to lenalidomide and pomalidomide.

[0056] The glycosylated phthalimide compound of Formula (I), an isomer, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above can be used alone or in combination with one or more other active drugs ("second active compound"). It can be administered separately, including sequentially or simultaneously, or contained in the same pharmaceutical composition.

[0057] In some embodiments, examples of the second active compound include, but are not limited to, one or more of the following: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, obinutuzumab, proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), histone deacetylase inhibitors (e.g., panobinostat, ACY241), BET inhibitors (e.g., GSK778), etc.

[0058] The glycosylated phthalimide compound represented by the above formula (I), isomers thereof, solvates or hydrates thereof, or pharmaceutically acceptable salts thereof, or the above pharmaceutical composition includes any proportion of optical isomer mixture. The compound of formula (I) can contain one or more asymmetric carbon atoms, and its existence form can be optically pure enantiomer, such as enantiomeric mixture of racemate, optically pure diastereoisomer, diastereoisomer mixture, diastereoisomer of racemate or mixture of diastereoisomer of racemate. The optically active form can be obtained by, for example, resolution of racemate, asymmetric synthesis or asymmetric chromatography (chromatography using chiral adsorbent or eluent).

[0059] The present application is based on the coupling of phthalimide and cyclized glutamine compound, i.e. thalidomide parent nucleus structure, and the following strategies are used for new derivative structure design and screening:

[0060]

[0061] 1. Screening of glycosylation derivatives of thalidomide 5-amine group;

[0062] 2. Screening of glycosylation derivatives of thalidomide 4-glutamine;

[0063] 3. Screening of glycosylation of thalidomide 4-amine urea side chain connection;

[0064] 4. Screening of glycosylation of thalidomide 4-amine acetic acid side chain connection;

[0065] 5. Screening of glycosylation of thalidomide 4-amine (compound of the present application).

[0066] The present application carries out systematic glycosylation structure design and activity screening by modifying the structure of the parent molecule at different positions and introducing different side chains. The results show that the compound obtained by glycosylation of thalidomide 4-amine can effectively inhibit the proliferation of multiple myeloma resistant to existing clinical drugs lenalidomide and pomalidomide, and has higher inhibitory activity on brain glioma, and can be used as a potential drug for the treatment of lenalidomide and pomalidomide resistant myeloma and brain tumor. BRIEF DESCRIPTION OF DRAWINGS

[0067] In order to more clearly illustrate the technical solutions of the embodiments of the present application or the prior art, the drawings needed in the embodiment or prior art description will be briefly introduced below. Obviously, the drawings in the following description are only embodiments of the present application, and those skilled in the art can obtain other drawings according to the provided drawings without creating any creative labor.

[0068] Figure 1 A single crystal diffraction structure of compound I-1'. DETAILED DESCRIPTION

[0069] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work are within the protection scope of the present application.

[0070] The present application provides a glycosylated phthalimide compound shown in formula (I), an isomer, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof:

[0071]

[0072] wherein A is selected from hydrogen or C 1～3 alkyl;

[0073] Y is selected from hydrogen, deuterium, halogen or C 1～3 alkyl;

[0074] R has the structure of formula (a):

[0075]

[0076] In formula (a), R1, R2, R3 and R4 are independently selected from hydrogen, hydroxyl, C 1～3 alkyl or C 1～3 alkylene substituted with a terminal hydroxyl group;

[0077] R1, R2, R3 and R4 contain at least three hydroxyl groups.

[0078] The present application also provides a preparation method of the glycosylated phthalimide compound, the isomer or the pharmaceutically acceptable salt thereof described in the above technical solutions, comprising the following steps:

[0079] In the presence of a catalyst, a compound shown in formula (II) is subjected to glycoside condensation reaction with a saccharide compound shown in formula (b) in a solvent to obtain a glycosylated phthalimide compound;

[0080]

[0081] The present application carries out systematic glycosylation structure design and activity screening by modifying the structure of the parent molecule at different positions and introducing different side chains. The results show that the glycosylation of the amine group at position 4 of thalidomide can effectively inhibit the proliferation of multiple myeloma resistant to existing clinical drugs lenalidomide and pomalidomide, and has higher inhibitory activity on brain glioma, and can be used as a potential drug for the treatment of lenalidomide and pomalidomide-resistant myeloma and brain tumors.

[0082] The glycosylated phthalimide compounds, the preparation method thereof and the use thereof are further described below in combination with examples.

[0083] Example 1: Preparation of compounds I-1 and I-2

[0084]

[0085] Weigh 273 milligrams (1 millimole) of pomalidomide and 1.8 grams (10 millimoles) of glucose, dissolve in 9.00 milliliters of ethanol, and add 114 milligrams (1 millimole) of trifluoroacetic acid. The mixture is stirred at 73°C for 72 hours. The reaction is stopped when the reaction progress is monitored unchanged, cooled, concentrated under reduced pressure, the residue is diluted with water and methanol, filtered with a microporous filter membrane, purified by preparative high performance liquid chromatography (1% to 75% methanol gradient elution), and completed using a preparative HPLC system (CXTH-LC3000) equipped with a reversed-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Freeze-drying, respectively, to obtain the target compound I-1, 80 milligrams; compound I-2, 20 milligrams.

[0086] Compound I-1: 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.64 (dd, J = 8.5, 7.1 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.85 (d, J = 7.0 Hz, 1H), 5.42 (t, J = 5.3 Hz, 1H), 5.10-5.06 (m, 2H), 5.01 (d, J = 5.3 Hz, 1H), 4.68-4.63 (m, 1H), 4.51-4.47 (m, 1H), 3.69-3.64 (m, 1H), 3.48-3.42 (m, 2H), 3.30-3.27 (m, 1H), 3.19-3.13 (m, 2H), 2.93-2.85 (m, 1H), 2.63-2.55 (m, 2H), 2.06-2.03 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 173.27, 170.42, 169.38, 167.67, 145.71, 145.68, 145.62, 145.59, 136.76, 132.11, 119.69, 113.14, 111.02, 111.00, 110.98, 83.61, 83.54, 78.19, 78.16, 77.55, 77.50, 73.55, 73.50, 70.40, 70.30, 61.12, 49.13, 31.38, 22.56.

[0087] Compound I-2: 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 7.1 Hz, 1H), 6.95-6.94 (m, 1H), 5.65 (t, J = 2.9 Hz, 1H), 5.16-5.13 (m, 2H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (dd, J = 6.2, 2.2 Hz, 1H), 4.44-4.41 (m, 1H), 3.60-3.54 (m, 2H), 3.49-3.39 (m, 3H), 3.17-3.11 (m, 1H), 2.93-2.84 (m, 1H), 2.62-2.55 (m, 2H), 2.07-2.04 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 173.27, 170.42, 169.38, 167.67, 145.71, 145.68, 145.62, 145.59, 136.76, 132.11, 119.69, 113.14, 111.02, 111.00, 110.98, 83.61, 83.54, 78.19, 78.16, 77.55, 77.50, 73.55, 73.50, 70.40, 70.30, 61.12, 49.13, 31.38, 22.56.

[0088] Example 2: Preparation of compound I-1’

[0089] Compound I-1 was dissolved in 10 mL of a mixed solvent of deionized water and methanol (v / v, about 10:1), concentrated to about 5 mL under reduced pressure, and left to stand at room temperature to obtain crystallization of the compound (compound I-1’) (30 mg).

[0090] The obtained crystal was subjected to X-ray single crystal diffraction analysis to determine its molecular structure. An XtaLAB FR-X (Rigaku, Japan) single crystal diffractometer was used, and Oxford Cryosystems (UK) was used to collect single crystal diffraction data at 160 K, and Olex2 software was used to resolve the single crystal compound molecular structure. The single crystal diffraction results of compound I-1' are shown in Tables 1-3, and its molecular structure is shown in Figure 1 Table 1 is the single crystal X-ray structure data of compound I-1' prepared in the present application, Table 2 is the bond length data of compound I-1', and Table 3 is the bond angle data of compound I-1', Figure 1 is the single crystal diffraction structure of compound I-1'.

[0091] As can be seen from Tables 1-3 and Figure 1 It can be seen that the monosaccharide unit of compound I-1' is connected to the phenylamine group by an N-glycoside bond, and the saccharide group forms a cyclic structure rather than a chain open structure. The crystal structure of compound I-1' obtained under the experimental conditions is a solvate of water, and the stereochemical configuration of the 3'-position of the amino acid is an S-optical isomer. In addition, the chemical shifts of the carbon atoms at the 1'-position of the saccharide groups of compounds (I-1) and (I-2) of the present application are δ83.61 and 81.60 ppm, respectively, indicating a cyclic saccharide group structure.

[0092] Table 1 Single crystal X-ray structure data of compound I-1'

[0093]

[0094]

[0095] Table 2 Bond length data of compound I-1'

[0096]

[0097]

[0098] Table 3 Bond angle data of compound I-1'

[0099]

[0100]

[0101] Example 3: Preparation of compound I-3

[0102]

[0103] Preparation of N-methyl pomalidomide: N-methyl pomalidomide was prepared according to the literature method (Journal of Medicinal Chemistry (2023), 66(11), 7243-7252). Pomalidomide (273 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (2.0 mL) and dimethyl sulfoxide (2.0 mL) at room temperature, iodomethane (93 μL, 1.5 mmol) and potassium carbonate (415 mg, 3.0 mmol) were added, stirred at 25 °C for 6 h, the reaction was stopped when the raw material was consumed, EA was added to terminate the reaction, washed with saturated ammonium chloride and brine twice, the organic layer was dried over anhydrous sodium sulfate, concentrated to give 256 mg of the target product.

[0104] Weigh 261 milligrams (0.9 mmol) of N-methyl pomalidomide and 1.62 grams (10 mmol) of glucose, dissolve in 8.00 milliliters of ethanol, add 103 milligrams (0.9 mmol) of trifluoroacetic acid. The mixture was stirred at 73 °C for 72 hours. Stop the reaction when the reaction progress is unchanged, cool, concentrate under reduced pressure, dilute the residue with water and methanol, filter with a microporous filter membrane, purify by preparative high performance liquid chromatography (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Lyophilize to obtain the target compound I-3, 122 milligrams.

[0105] Compound I-3: 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (dd, J = 8.5, 7.1 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.84 (d, J = 7.0 Hz, 1H), 5.43 (dd, J = 7.7, 5.7 Hz, 1H), 5.18 - 5.13 (m, 1H), 5.10 (dd, J = 5.0, 1.1 Hz, 1H), 5.02 (d, J = 5.3 Hz, 1H), 4.69 - 4.62 (m, 1H), 4.52 - 4.48 (m, 1H), 3.70 - 3.62 (m, 1H), 3.47 - 3.42 (m, 1H), 3.35 (d, J = 4.7 Hz, 1H), 3.28 (dd, J = 8.8, 5.0 Hz, 1H), 3.19 - 3.12 (m, 2H), 3.02 (d, J = 1.1 Hz, 3H), 2.94 (dd, J = 14.6, 4.1 Hz, 1H), 2.76 (d, J = 16.9 Hz, 1H), 2.56 (dd, J = 13.7, 9.2 Hz, 1H), 2.10 - 2.02 (m, 1H).

[0106] Example 4: Preparation of compound I-4

[0107]

[0108] 1) Preparation of 3'-deuterated pomalidomide was prepared according to the method disclosed in the literature WO2012068512.

[0109] 2) With 200 mg of deuterated pomalidomide as raw material, according to the same method as in Example 1, the target product I-4, 70 mg; I-4-1, 20 mg was synthesized and separated.

[0110] Compound I-4: 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.64 (dd, J = 8.5, 7.1 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.85 (d, J = 7.0 Hz, 1H), 5.42 (t, J = 5.3 Hz, 1H), 5.10-5.06 (m, 2H), 5.01 (d, J = 5.3 Hz, 1H), 4.68-4.63 (m, 1H), 3.69-3.64 (m, 1H), 3.48-3.42 (m, 2H), 3.30-3.27 (m, 1H), 3.19-3.13 (m, 2H), 2.93-2.85 (m, 1H), 2.63-2.55 (m, 2H), 2.06-2.03 (m, 1H).

[0111] Compound I-4-1: 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.64 (dd, J = 8.5, 7.1 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.85 (d, J = 7.0 Hz, 1H), 5.42 (t, J = 5.3 Hz, 1H), 5.10-5.06 (m, 2H), 5.01 (d, J = 5.3 Hz, 1H), 4.68-4.63 (m, 1H), 3.69-3.64 (m, 1H), 3.48-3.42 (m, 2H), 3.30-3.27 (m, 1H), 3.19-3.13 (m, 2H), 2.93-2.85 (m, 1H), 2.63-2.55 (m, 2H), 2.06-2.03 (m, 1H).

[0112] Example 5: Preparation of compound I-5

[0113]

[0114] 1) 3'-fluoropomalidomide was prepared according to the method reported in the literature Bioorg. Med. Chem. Lett. 13 (2003) 3415-3417.

[0115] 2) The target product I-5 was synthesized and separated according to the same method as in Example 1, with 200 mg of fluoropomalidomide as the raw material, 76 mg was obtained.

[0116] Compound I-5: 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.65 (dd, J = 8.5, 7.1 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.80 (d, J = 7.0 Hz, 1H), 5.10 - 5.06 (m, 2H), 5.00 - 4.20 (m, 3H), 3.69 - 3.00 (m, 6H), 2.93 - 2.83 (m, 1H), 2.63 - 2.53 (m, 2H), 2.06 - 2.00 (m, 1H).

[0117] Example 6: Preparation of compound I-6

[0118]

[0119] 1) 3'-chloropomalidomide was prepared according to the method reported in the literature CN103819454.

[0120] 2) The target product I-6 was synthesized and separated according to the same method as in Example 1, with 200 mg of chloropomalidomide as the raw material, 80 mg was obtained.

[0121] 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 7.63 (dd, J = 8.5, 7.1 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 7.1 Hz, 1H), 6.77 (d, J = 7.0 Hz, 1H), 5.10 - 5.03 (m, 2H), 5.00 - 4.20 (m, 3H), 3.69 - 3.00 (m, 6H), 2.93 - 2.83 (m, 1H), 2.63 - 2.53 (m, 2H), 2.06 - 2.00 (m, 1H).

[0122] Example 7: Preparation of compounds I-7 and I-21

[0123]

[0124] 1) 3'-methyl pomalidomide was prepared according to the procedure reported in the literature WO2006081251.

[0125] The procedure is as follows:

[0126]

[0127] First step: 5 grams (32.5 mmol) of 2-aminoethyl propionate hydrochloride and 2.74 grams (22.8 mmol) of magnesium sulfate were dispersed in 50 milliliters of dichloromethane, 5.86 milliliters (42.2 mmol) of triethylamine and 3.8 grams (42.2 mmol) of benzaldehyde were added. The mixture was stirred at room temperature overnight, filtered, the filtrate was washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated to give 5 grams of crude which was used directly in the next step.

[0128] Second step: at 5°C, 4 grams (t-BuOK, 35.7 mmol) of potassium tert-butoxide were added portionwise to a mixture of 5 grams (24.4 mmol) of (2S)-methyl 2-[(E)-benzylideneamino]propanoate and 3.46 grams of acrylamide (48.7 mmol) in 100 milliliters of tetrahydrofuran (THF), the addition lasted 20 minutes. The reaction was stirred at 0°C for 15 minutes. Then 6.77 grams (125.4 mmol) of ammonium chloride were added portionwise and the mixture was stirred at 0°C for another 15 minutes. The mixture was poured into 100 milliliters of ice water and concentrated under vacuum to about 100 milliliters. It was filtered and dried to give 5 grams of 3-[(E)-benzylideneamino]-3-methylpiperidine-2,6-dione as a white solid which was used directly in the next step.

[0129] Third step: at 0°C, 6.5 milliliters of hydrochloric acid aqueous solution (4M) were added to a solution of 5 grams (21.7 mmol) of 3-[(E)-benzylideneamino]-3-methylpiperidine-2,6-dione (86.86 mmol) in 40 milliliters of tetrahydrofuran (THF). The mixture was stirred at 10°C for 1 hour. After completion of the reaction, 4.7 grams of 3-amino-3-methylpiperidine-2,6-dione hydrochloride were obtained as a white solid after filtration and drying.

[0130] Fourth step: at room temperature, 2.7 grams (14 mmol) of 3-nitrophthalic anhydride, 2 grams (14 mmol) of 3-amino-3-methylpiperidine-2,6-dione hydrochloride and 2 grams (20.4 mmol) of potassium acetate were dispersed in 30 milliliters of acetic acid, the mixture was heated to reflux overnight, cooled, concentrated under reduced pressure, dispersed with water, filtered and dried to give 1.56 grams of 2-(3-methyl-2,6-dioxo-3-piperidyl)-4-nitro-1H- isoindole-1,3(2H)-dione as a light yellow solid.

[0131] Fifth Step: 1.56 g (4.9 mmol) of 2-(3-methyl-2,6-dioxo-3-piperidyl)-4-nitro-1H- isoindole-1,3(2H)-dione was dispersed in 15 mL of methanol and 3 mL of ethyl acetate, 450 mg of palladium on carbon was added, heated to 30 °C, stirred for 2 hours under hydrogen atmosphere, the palladium on carbon was removed by hot filtration, the yellow solid was precipitated upon cooling, filtered and dried to give 1.2 g of yellow solid 4-amino-2-(3-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[0132] 2) Using 100 mg of 4-amino-2-(3-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (3'-methyl pomalidomide) as starting material, synthesized according to the same procedure as Example 1. The residue was diluted with water and methanol, filtered using a micro pore filter, purified by preparative high performance liquid chromatography (1% to 17% acetonitrile gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, internal diameter: 21.2 mm). Lyophilized to give the target product I-7, 28 mg, and compound I-21, 5 mg.

[0133] Compound I-7: 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (d, J = 5.7 Hz, 1H), 7.66 - 7.52 (m, 1H), 7.17 (dd, J = 52.0, 7.8 Hz, 2H), 6.87 (d, J = 6.9 Hz, 1H), 5.41 (t, J = 6.0 Hz, 1H), 5.04 (dd, J = 36.3, 5.1 Hz, 2H), 4.63 (td, J = 8.5, 7.7, 4.3 Hz, 1H), 4.47 (td, J = 5.8, 3.0 Hz, 1H), 3.66 (dd, J = 11.4, 4.9 Hz, 1H), 3.44 (dt, J = 11.8, 6.0 Hz, 1H), 3.27 (dd, J = 8.5, 4.7 Hz, 2H), 3.15 (q, J = 8.5 Hz, 2H), 2.79 - 2.64 (m, 1H), 2.57 (dd, J = 14.0, 4.2 Hz, 2H), 2.03 (dt, J = 15.2, 5.9 Hz, 1H), 1.88 (s, 3H).

[0134] Compound I-21: 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.97 (d, J = 3.5 Hz, 1H), 5.64 (t, J = 4.3 Hz, 1H), 5.22 - 5.05 (m, 2H), 4.93 (d, J = 5.8 Hz, 1H), 4.41 (t, J = 5.8 Hz, 1H), 3.62 - 3.40 (m, 5H), 3.15 (t, J = 7.6 Hz, 1H), 2.74 - 2.63 (m, 1H), 2.62 - 2.53 (m, 2H), 2.10 - 1.99 (m, 1H), 1.88 (s, 3H).

[0135] Example 8: Preparation of compounds I-8 and I-9

[0136]

[0137] A mixture of 109 mg (0.4 mmol) of pomalidomide and 720 mg (4 mmol) of galactose was dissolved in 3.00 ml of ethanol, 46 mg (0.4 mmol) of trifluoroacetic acid was added. The mixture was stirred at 73 °C for 72 hours. The reaction was stopped when the reaction progress was monitored unchanged, cooled, concentrated under reduced pressure, the residue was diluted with water and methanol, filtered with a microporous filter membrane, purified by preparative high performance liquid chromatography (1% to 75% methanol gradient elution), completed using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Lyophilized to obtain the target compound I-8, 35 mg, compound I-9, 5 mg.

[0138] Compound I-8: 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.63 (dd, J = 8.6, 7.1 Hz, 1H), 7.29 (dd, J = 8.6, 1.6 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 5.26 (t, J = 5.3 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.85 (s, 1H), 4.65 - 4.59 (m, 2H), 4.47 (d, J = 5.0 Hz, 1H), 3.72 (t, J = 4.1 Hz, 1H), 3.59 - 3.41 (m, 5H), 2.93 - 2.85 (m, 1H), 2.63 - 2.54 (m, 2H), 2.08 - 2.03 (m, 1H).

[0139] Compound I-9: 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.66-7.62 (m, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.96 (t, J = 3.1 Hz, 1H), 5.51 (dd, J = 3.9, 1.9 Hz, 1H), 5.17 (s, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (d, J = 5.5 Hz, 1H), 4.53 (d, J = 4.6 Hz, 1H), 4.44 (q, J = 5.3, 4.9 Hz, 1H), 3.93-3.88 (m, 1H), 3.74 (s, 1H), 3.58-3.49 (m, 3H), 3.44-3.39 (m, 1H), 2.93-2.84 (m, 1H), 2.61-2.54 (m, 2H), 2.06-2.03 (m, 1H).

[0140] Example 9: Preparation of Compound I-10

[0141]

[0142] Preparation of N-methyl pomalidomide: N-methyl pomalidomide was prepared using the same method as in Example 2.

[0143] A mixture of 261 mg (0.9 mmol) of N-methyl pomalidomide and 1.62 g (10 mmol) of galactose was dissolved in 8.00 ml of ethanol and 103 mg (0.9 mmol) of trifluoroacetic acid was added. The mixture was stirred at 73 °C for 72 hours. The reaction was stopped when the reaction progress was monitored by liquid chromatography, cooled, concentrated under reduced pressure, the residue was diluted with water and methanol, filtered with a micro pore filter and purified by preparative high performance liquid chromatography (1% to 75% methanol gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Lyophilization gave the target compound I-10, 153 mg.

[0144] Compound I-10: 1H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J = 8.6, 7.1 Hz, 1H), 7.29 (dd, J = 8.6, 1.6 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 5.26 (t, J = 5.3 Hz, 1H), 5.10 - 5.00 (m, 1H), 4.85 (s, 1H), 4.65 - 4.59 (m, 2H), 4.46 (d, J = 5.0 Hz, 1H), 3.72 (t, J = 4.1 Hz, 1H), 3.60 - 3.40 (m, 5H), 3.03 (s, 3H), 2.95 - 2.85 (m, 1H), 2.65 - 2.50 (m, 2H), 2.07 - 2.03 (m, 1H).

[0145] Example 10: Preparation of compound I-11

[0146]

[0147] 1) Preparation of 3'-deuterated pomalidomide was prepared according to the method disclosed in the literature WO2012068512.

[0148] 2) The target product I-11, 35 mg; I-11-1, 5 mg was synthesized and separated according to the same method as example 8 with 100 mg of deuterated pomalidomide as raw material.

[0149] Compound I-11: 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J = 8.6, 7.1 Hz, 1H), 7.29 (dd, J = 8.6, 1.6 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 5.26 (t, J = 5.3 Hz, 1H), 5.10 - 5.00 (m, 1H), 4.85 (s, 1H), 4.65 - 4.59 (m, 2H), 4.46 (d, J = 5.0 Hz, 1H), 3.72 (t, J = 4.1 Hz, 1H), 3.60 - 3.40 (m, 5H), 3.03 (s, 3H), 2.95 - 2.85 (m, 1H), 2.65 - 2.50 (m, 2H), 2.07 - 2.03 (m, 1H).

[0150] Compound I-11-1: 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.66-7.62 (m, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.96 (t, J = 3.1 Hz, 1H), 5.51 (dd, J = 3.9, 1.9 Hz, 1H), 5.17 (s, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (d, J = 5.5 Hz, 1H), 4.53 (d, J = 4.6 Hz, 1H), 3.93-3.88 (m, 1H), 3.74 (s, 1H), 3.58-3.49 (m, 3H), 3.44-3.39 (m, 1H), 2.93-2.84 (m, 1H), 2.61-2.54 (m, 2H), 2.06-2.03 (m, 1H).

[0151] Example 11: Preparation of compound I-12

[0152]

[0153] 1) Preparation of 3'-fluoropomalidomide according to the method reported in the literature Bioorg. Med. Chem. Lett. 13 (2003) 3415-3417.

[0154] 2) The target product I-12, 77 mg, was synthesized and separated according to the same method as Example 8, using 200 mg of fluoropomalidomide as raw material.

[0155] Compound I-12: 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.66-7.62 (m, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.96 (t, J = 3.1 Hz, 1H), 5.51 (dd, J = 3.9, 1.9 Hz, 1H), 5.17 (s, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (d, J = 5.5 Hz, 1H), 4.53 (d, J = 4.6 Hz, 1H), 3.93-3.88 (m, 1H), 3.74 (s, 1H), 3.58-3.49 (m, 3H), 3.44-3.39 (m, 1H), 2.93-2.84 (m, 1H), 2.61-2.54 (m, 2H), 2.06-2.03 (m, 1H).

[0156] Example 12: Preparation of compound I-13

[0157]

[0158] 1) 3'-fluoropomalidomide was prepared according to the method reported in the literature CN103819454.

[0159] 2) The target product I-13 was synthesized and separated according to the same method as in Example 8, using 200 mg of fluoropomalidomide as the raw material, and 88 mg was obtained.

[0160] Compound I-13: 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.63 (dd, J = 8.6, 7.1 Hz, 1H), 7.29 (dd, J = 8.6, 1.6 Hz, 1H), 7.16 (d, J = 7.1 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 5.11 - 5.00 (m, 1H), 4.83 (s, 1H), 4.65 - 4.55 (m, 2H), 4.45 (d, J = 5.0 Hz, 1H), 3.71 (t, J = 4.1 Hz, 1H), 3.59 - 3.40 (m, 5H), 2.95 - 2.80 (m, 1H), 2.65 - 2.50 (m, 2H), 2.05 - 2.00 (m, 1H).

[0161] Example 13: Preparation of compounds I-14 and I-22

[0162]

[0163] 1) 3'-methylpomalidomide was prepared according to the method reported in the literature WO2006081251.

[0164] 2) The target product I-14 was synthesized according to the same method as in Example 8, using 420 mg of 3'-methylpomalidomide as the raw material. The residue was diluted with water and methanol, filtered with a microporous filter, and purified by preparative high performance liquid chromatography (1% - 20% acetonitrile gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reversed-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). After lyophilization, 48 mg of the target product I-14 and 3 mg of compound I-22 were obtained.

[0165] Compound I-14: 1H NMR (400 MHz, DMSO-d6) δ 10.98 (d, J = 5.6 Hz, 1H), 7.60 (dd, J = 8.5, 7.1 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 5.25 (dd, J = 6.8, 5.5 Hz, 1H), 4.91 - 4.75 (m, 1H), 4.70 - 4.52 (m, 2H), 4.43 (d, J = 5.2 Hz, 1H), 3.81 - 3.67 (m, 1H), 3.63 - 3.37 (m, 5H), 2.70 (dd, J = 13.5, 7.4 Hz, 1H), 2.61 - 2.53 (m, 2H), 2.10 - 1.98 (m, 1H), 1.88 (s, 3H).

[0166] Compound I-22: 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.60 (ddd, J = 8.4, 7.1, 3.7 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.10 (dd, J = 7.1, 4.7 Hz, 1H), 6.99 (d, J = 3.5 Hz, 1H), 5.50 (t, J = 4.3 Hz, 1H), 5.15 (s, 1H), 4.98 (dd, J = 6.5, 5.5 Hz, 1H), 4.52 (d, J = 4.7 Hz, 1H), 4.48 - 4.37 (m, 1H), 3.90 (dt, J = 9.4, 4.8 Hz, 1H), 3.73 (t, J = 4.0 Hz, 1H), 3.64 - 3.38 (m, 4H), 2.78 - 2.64 (m, 1H), 2.61 - 2.52 (m, 2H), 2.12 - 1.97 (m, 1H), 1.88 (q, J = 2.1 Hz, 3H).

[0167] Example 14: Preparation of compound I-15

[0168]

[0169] A sample of 109 mg (0.4 mmol) of pomalidomide and 720 mg (4 mmol) of mannose was dissolved in 3.6 ml of ethanol and 46 mg (0.4 mmol) of trifluoroacetic acid was added. The mixture was stirred at 73 °C for 48 hours. The reaction was stopped when the reaction progress was monitored by liquid chromatography unchanged, cooled, concentrated under reduced pressure, the residue was diluted with water and methanol, filtered with a micro pore filter and purified by preparative high performance liquid chromatography (1% to 75% methanol gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Lyophilization gave the target compound I-15, 45 mg.

[0170] Compound I-15: 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.64 (dd, J = 8.6, 7.1 Hz, 1H), 7.33 (d, J = 9.5 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 5.24 (t, J = 5.2 Hz, 1H), 5.13 - 5.04 (m, 2H), 4.91 (d, J = 4.8 Hz, 1H), 4.82 (d, J = 4.8 Hz, 1H), 4.43 - 4.37 (m, 1H), 3.76 (t, J = 4.4 Hz, 1H), 3.66 - 3.61 (m, 1H), 3.46 - 3.39 (m, 3H), 3.25 - 3.20 (m, 1H), 2.92 - 2.85 (m, 1H), 2.61 - 2.54 (m, 2H), 2.05 - 2.02 (m, 1H).

[0171] Example 15: Preparation of compound I-16

[0172]

[0173] Preparation of N-methyl pomalidomide: N-methyl pomalidomide was prepared using the same method as in Example 2.

[0174] Take 261 milligrams (0.9 mmol) of N-methyl pomalidomide and 1.62 grams (10 mmol) of mannose, dissolve in 8.00 milliliters of ethanol, add 103 milligrams (0.9 mmol) of trifluoroacetic acid. The mixture is at 73°C for 48 hours. The reaction is stopped when the reaction process is monitored by liquid chromatography unchanged, cooled, concentrated under reduced pressure, the residue is diluted with water and methanol, filtered with a microporous filter, purified by preparative high performance liquid separation (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Freeze-drying to obtain the target compound I-16, 163 milligrams.

[0175] Compound I-16: 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (dd, J = 8.6, 7.1 Hz, 1H), 7.33 (d, J = 9.5 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 5.23 (t, J = 5.2 Hz, 1H), 5.13-5.04 (m, 2H), 4.90 (d, J = 4.8 Hz, 1H), 4.82 (d, J = 4.8 Hz, 1H), 4.45-4.37 (m, 1H), 3.76 (t, J = 4.4 Hz, 1H), 3.66-3.60 (m, 1H), 3.50-3.40 (m, 3H), 3.25-3.20 (m, 1H), 3.03 (s, 3H), 2.92-2.85 (m, 1H), 2.61-2.55 (m, 2H), 2.05-2.01 (m, 1H).

[0176] Example 16: Preparation of compound I-17

[0177]

[0178] 1) 3'-deuterated pomalidomide was prepared according to the method disclosed in the literature WO2012068512.

[0179] 2) The target product I-17, 45 mg, was synthesized and separated according to the same method as Example 14, using 100 mg of deuterated pomalidomide as raw material.

[0180] Compound I-17: 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.64 (dd, J = 8.6, 7.1 Hz, 1H), 7.33 (d, J = 9.5 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 5.24 (t, J = 5.2 Hz, 1H), 5.13-5.04 (m, 2H), 4.91 (d, J = 4.8 Hz, 1H), 4.82 (d, J = 4.8 Hz, 1H), 3.76 (t, J = 4.4 Hz, 1H), 3.66-3.61 (m, 1H), 3.46-3.39 (m, 3H), 3.25-3.20 (m, 1H), 2.92-2.85 (m, 1H), 2.61-2.54 (m, 2H), 2.05-2.02 (m, 1H).

[0181] Example 17: Preparation of compound I-18

[0182]

[0183] 1) Preparation of 3'-fluoropomalidomide according to the method reported in the literature Bioorg. Med. Chem. Lett. 13 (2003) 3415-3417.

[0184] 2) The target product I-18, 75 mg, was synthesized and separated according to the same method as in Example 14, using 200 mg of fluoropomalidomide as raw material.

[0185] Compound I-18: 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.64 (dd, J = 8.6, 7.1 Hz, 1H), 7.33 (d, J = 9.5 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 5.24 (t, J = 5.2 Hz, 1H), 5.13-5.04 (m, 2H), 4.91 (d, J = 4.8 Hz, 1H), 4.82 (d, J = 4.8 Hz, 1H), 3.76 (t, J = 4.4 Hz, 1H), 3.66-3.61 (m, 1H), 3.46-3.39 (m, 3H), 3.25-3.20 (m, 1H), 2.92-2.85 (m, 1H), 2.61-2.54 (m, 2H), 2.05-2.02 (m, 1H).

[0186] Example 18: Preparation of compound I-19

[0187]

[0188] 1) 3'-chloro-pomalidomide was prepared according to the method reported in the literature CN103819454.

[0189] 2) The target product I-19 was synthesized and separated according to the same method as Example 14, using 200 mg of chloro-pomalidomide as raw material, and 88 mg of target product I-19 was obtained.

[0190] Compound I-19: 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.65 (dd, J = 8.6, 7.1 Hz, 1H), 7.31 (d, J = 9.5 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 7.1 Hz, 1H), 5.13-5.00 (m, 2H), 4.91 (d, J = 4.8 Hz, 1H), 4.82 (d, J = 4.8 Hz, 1H), 4.43-4.35 (m, 1H), 3.75 (t, J = 4.4 Hz, 1H), 3.66-3.60 (m, 1H), 3.46-3.5 (m, 3H), 3.25-3.20 (m, 1H), 2.92-2.82 (m, 1H), 2.61-2.50 (m, 2H), 2.05-2.00 (m, 1H).

[0191] Example 19: Preparation of compound I-20

[0192]

[0193] 1) 3'-methyl-pomalidomide was prepared according to the method reported in the literature WO2006081251.

[0194] 2) The target product I-20 was synthesized according to the same method as Example 14, using 420 mg of 3'-methyl-pomalidomide as raw material. The residue was diluted with water and methanol, filtered with a microporous filter, and purified by preparative high performance liquid chromatography (1% to 20% acetonitrile gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). After freeze-drying, 130 mg of target product I-20 was obtained.

[0195] Compound I-20: 1H NMR (400 MHz, DMSO-d6) δ 10.98 (d, J = 5.5 Hz, 1H), 7.61 (dd, J = 8.5, 7.1 Hz, 1H), 7.45 - 7.31 (m, 1H), 7.23 (dd, J = 8.6, 2.3 Hz, 1H), 7.09 (d, J = 7.1 Hz, 1H), 5.22 (dd, J = 7.0, 5.3 Hz, 1H), 5.15 - 5.01 (m, 1H), 4.90 (dd, J = 5.0, 1.7 Hz, 1H), 4.79 (d, J = 4.8 Hz, 1H), 4.37 (q, J = 6.1 Hz, 1H), 3.79 - 3.72 (m, 1H), 3.67 - 3.57 (m, 1H), 3.48 - 3.35 (m, 3H), 3.27 - 3.15 (m, 1H), 2.76 - 2.65 (m, 1H), 2.62 - 2.52 (m, 2H), 2.15 - 1.96 (m, 1H), 1.87 (s, 3H).

[0196] Example 20: Preparation of compounds I-23 and I-24

[0197]

[0198] A mixture of 273 mg (1 mmol) of pomalidomide and 1.5 g (10 mmol) of L-arabinose was dissolved in 10 ml of ethanol and 114 mg (1 mmol) of trifluoroacetic acid was added. The mixture was stirred at 73 °C for 48 hours. The reaction was stopped when the reaction progress was monitored unchanged, cooled, concentrated under reduced pressure, the residue was diluted with water and methanol, filtered with a microporous filter membrane, purified by preparative high performance liquid chromatography (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). The target compound I-23, 88 mg, and the target compound I-24, 19 mg, were obtained.

[0199] Compound I-23: 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.63 (dd, J = 8.5, 7.2 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.18 (t, J = 8.0 Hz, 2H), 5.63 (dd, J = 5.8, 3.6 Hz, 1H), 5.13 - 5.04 (m, 2H), 4.99 (d, J = 3.7 Hz, 1H), 4.63 (dd, J = 6.0, 1.3 Hz, 1H), 3.82 - 3.78 (m, 2H), 3.67 - 3.58 (m, 2H), 3.44 (dd, J = 10.7, 4.8 Hz, 1H), 2.92 - 2.84 (m, 1H), 2.61 - 2.52 (m, 2H), 2.05 - 2.02 (m, 1H).

[0200] Compound I-24: 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.63 (dd, J = 8.5, 7.2 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.18 (t, J = 8.0 Hz, 2H), 5.63 (dd, J = 5.8, 3.6 Hz, 1H), 5.13 - 5.04 (m, 2H), 4.99 (d, J = 3.7 Hz, 1H), 4.63 (dd, J = 6.0, 1.3 Hz, 1H), 3.82 - 3.78 (m, 2H), 3.67 - 3.58 (m, 2H), 3.44 (dd, J = 10.7, 4.8 Hz, 1H), 2.92 - 2.84 (m, 1H), 2.61 - 2.52 (m, 2H), 2.05 - 2.02 (m, 1H).

[0201] Example 21: Preparation of compound I-25

[0202]

[0203] Take 273 milligrams (1 mmol) of pomalidomide and 1.5 grams (10 mmol) of D-xylose, dissolve in 10 milliliters of ethanol, add 114 milligrams (1 mmol) of trifluoroacetic acid. The mixture is stirred at 73°C for 48 hours. Stop the reaction when the reaction progress is unchanged, cool, concentrate under reduced pressure, dilute the residue with water and methanol, filter with a microporous filter membrane, purify by preparative high performance liquid separation (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Freeze-drying to obtain the target compound I-25, 118 milligrams.

[0204] Compound I-25: 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (d, J = 1.9 Hz, 1H), 7.65-7.62 (m, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 5.41 (dd, J = 5.9, 4.8 Hz, 1H), 5.18 (d, J = 4.6 Hz, 1H), 5.07 (dd, J = 15.2, 5.0 Hz, 2H), 4.65 (t, J = 7.1 Hz, 1H), 3.71 (dd, J = 10.4, 4.3 Hz, 1H), 3.36 (s, 1H), 3.30-3.24 (m, 2H), 3.18 (q, J = 7.5 Hz, 1H), 2.93-2.85 (m, 1H), 2.59 (d, J = 17.8 Hz, 2H), 2.06-2.02 (m, 1H).

[0205] Example 22: Preparation of compound I-26

[0206]

[0207] Take 273 milligrams (1 mmol) of pomalidomide and 1.5 grams (10 mmol) of D-xylose, dissolve in 10 milliliters of ethanol, add 114 milligrams (1 mmol) of trifluoroacetic acid. The mixture is stirred at 73°C for 48 hours. Stop the reaction when the reaction progress is unchanged, cool, concentrate under reduced pressure, dilute the residue with water and methanol, filter with a microporous filter membrane, purify by preparative high performance liquid separation (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Freeze-drying to obtain the target compound I-25, 118 milligrams.

[0208] Compound I-26:1 H NMR (400 MHz, DMSO-d6) δ 11.11 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.6, 7.1 Hz, 1H), 7.32 (dd, J = 28.3, 8.5 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 6.80 (dd, J = 54.4, 7.4 Hz, 1H), 5.10 - 5.03 (m, 2H), 4.96 (dd, J = 14.5, 4.9 Hz, 2H), 4.45 - 4.33 (m, 1H), 3.67 - 3.60 (m, 1H), 3.58 - 3.52 (m, 1H), 3.50 - 3.43 (m, 1H), 3.28 - 3.24 (m, 1H), 3.12 - 3.04 (m, 1H), 2.93 - 2.84 (m, 1H), 2.61 - 2.54 (m, 2H), 2.18 - 2.12 (m, 1H), 2.05 - 2.02 (m, 1H), 1.54 (q, J = 11.4 Hz, 1H).

[0209] Example 23: Preparation of compound I-27

[0210]

[0211] Pomalidomide, 545 mg (2 mmol) and rhamnose monohydrate, 3.5 g (20 mmol) were weighed out and dissolved in 20 ml of ethanol, and trifluoroacetic acid, 228 mg (2 mmol) was added. The mixture was stirred at 73°C for 48 hours. The reaction was stopped when the reaction progress was monitored unchanged, cooled, concentrated under reduced pressure, the residue was diluted with water and methanol, filtered with a microporous filter membrane, purified by preparative high performance liquid chromatography (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). After lyophilization, the target compound I-27, 340 mg, was obtained.

[0212] Compound I-27: 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.63 (dd, J = 8.5, 7.1 Hz, 1H), 7.29 (d, J = 9.5 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 7.0 Hz, 1H), 5.24 (t, J = 5.8 Hz, 1H), 5.10 - 5.04 (m, 2H), 4.85 (dd, J = 11.0, 5.3 Hz, 2H), 3.77 - 3.75 (m, 1H), 3.41 - 3.37 (m, 2H), 3.19 - 3.13 (m, 1H), 2.92 - 2.83 (m, 1H), 2.61 - 2.53 (m, 2H), 2.06 - 2.01 (m, 1H), 1.11 (d, J = 6.1 Hz, 3H).

[0213] Example 24: Preparation of compound I-28

[0214]

[0215] Pomalidomide, 273 mg (1 mmol) and D-arabinose, 1.5 g (10 mmol) were weighed out and dissolved in 10 ml of ethanol, and 114 mg (1 mmol) of trifluoroacetic acid was added. The mixture was stirred at 73°C for 48 hours. The reaction was stopped when the reaction progress was monitored unchanged, cooled, concentrated under reduced pressure, the residue was diluted with water and methanol, filtered with a microporous filter, purified by preparative high performance liquid chromatography (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). The target compound I-28, 83 mg, was obtained.

[0216] Compound I-28: 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.62 (dd, J = 8.5, 7.1 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 7.1 Hz, 1H), 5.32 (dd, J = 4.7, 2.5 Hz, 1H), 5.20 - 5.19 (m, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.81 (s, 1H), 4.64 (dd, J = 5.7, 1.6 Hz, 1H), 3.78 - 3.74 (m, 1H), 3.66 - 3.60 (m, 3H), 3.46 (dd, J = 11.6, 3.1 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.62 - 2.53 (m, 2H), 2.05 - 2.03 (m, 1H).

[0217] Example 25: Preparation of compound 45

[0218]

[0219] Weigh out 219 mg (0.8 mmol) of 5-amino pomalidomide and 1.44 g (1.6 mmol) of glucose, dissolve in 8 mL of ethanol, add 91 mg (0.8 mmol) of trifluoroacetic acid. Stir the mixture at 73 °C for 72 hours. Stop the reaction when the reaction progress is monitored unchanged, cool, concentrate under reduced pressure, dilute the residue with water and methanol, filter with a micro pore filter, purify by preparative high performance liquid chromatography (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Lyophilize to obtain the target compound 45, 96 mg.

[0220] Compound 45: 1 H NMR (600 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.62 (dd, J = 7.9, 2.7 Hz, 2H), 7.11 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 - 5.02 (m, 2H), 4.99 (d, J = 5.6 Hz, 1H), 4.93 (d, J = 5.3 Hz, 1H), 4.56 (t, J = 8.1 Hz, 1H), 4.45 (t, J = 5.8 Hz, 1H), 3.67 - 3.64 (m, 1H), 3.46 - 3.42 (m, 1H), 3.30 - 3.27 (m, 2H), 3.22 - 3.17 (m, 1H), 3.16 - 3.11 (m, 1H), 2.91 - 2.85 (m, 1H), 2.60 - 2.52 (m, 2H), 2.02 - 2.00 (m, 1H).

[0221] Example 26: Preparation of compound 46

[0222]

[0223] Take 273 milligrams (1 mmol) of 5-amino pomalidomide and 1.8 grams (10 mmol) of galactose, dissolve in 10 milliliters of ethanol, add 228 milligrams (2 mmol) of trifluoroacetic acid. The mixture is stirred at 73°C for 72 hours. Stop the reaction when the reaction progress is unchanged, cool, concentrate under reduced pressure, dilute the residue with water and methanol, filter with a microporous filter membrane, purify by preparative high performance liquid separation (1%-75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed phase C18 column (Innoval AQ C18, length: 250mm, inner diameter: 21.2mm). Freeze-drying to obtain the target compound 46, 106 milligrams.

[0224] Compound 46: 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.63 (dd, J = 12.6, 8.0 Hz, 2H), 7.11 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.85 (dd, J = 5.6, 4.1 Hz, 2H), 4.59 (t, J = 5.5 Hz, 1H), 4.53 (t, J = 8.1 Hz, 1H), 4.48 (d, J = 4.2 Hz, 1H), 3.73 (t, J = 3.8 Hz, 1H), 3.58-3.49 (m, 3H), 3.45-3.40 (m, 2H), 2.93-2.83 (m, 1H), 2.60-2.53 (m, 2H), 2.04-1.99 (m, 1H).

[0225] Example 27: Preparation of compound 29

[0226]

[0227] Take 273 milligrams (1 mmol) of 5-amino pomalidomide and 1.8 grams (10 mmol) of galactose, dissolve in 10 milliliters of ethanol, add 228 milligrams (2 mmol) of trifluoroacetic acid. The mixture is stirred at 73°C for 72 hours. Stop the reaction when the reaction progress is unchanged, cool, concentrate under reduced pressure, dilute the residue with water and methanol, filter with a microporous filter membrane, purify by preparative high performance liquid separation (1%-75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed phase C18 column (Innoval AQ C18, length: 250mm, inner diameter: 21.2mm). Freeze-drying to obtain the target compound 46, 106 milligrams.

[0228] Compound 29: 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.4, 2.1 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.93 (dd, J = 8.6, 6.8 Hz, 2H), 4.85 (d, J = 5.2 Hz, 1H), 4.80 (d, J = 5.0 Hz, 1H), 4.40 (t, J = 5.8 Hz, 1H), 3.77 - 3.74 (m, 1H), 3.69 - 3.65 (m, 1H), 3.47 - 3.36 (m, 3H), 3.26 - 3.22 (m, 1H), 2.93 - 2.84 (m, 1H), 2.60 - 2.53 (m, 2H), 2.02 - 1.99 (m, 1H).

[0229] Example 28: Preparation of compound 30

[0230]

[0231] The following procedure was used for the synthesis:

[0232]

[0233] 1) Pomalidomide 273 mg (1 mmol) was weighed and dissolved in 20 mL of tetrahydrofuran, p-nitrophenyl chloroformate 302 mg (1.5 mmol) was added, and the reaction was stirred at 70 °C for 1 hour. The reaction was then concentrated and used in the next step.

[0234] 2) The intermediate was weighed and dissolved in 9 mL of N,N- dimethylformamide. Tetraacetylglucosamine 312 mg (0.9 mmol) and N,N- diisopropylethylamine 313 μL (1.8 mmol) were added sequentially at 0 °C, and the reaction was stirred at room temperature overnight. After the reaction was completed, ethyl acetate was added, and the reaction was washed with saturated ammonium chloride three times and brine once. The organic phase was dried and concentrated, and the target compound was purified by column chromatography to give 320 mg of the target compound with a yield of 55.0%.

[0235] 3) Take 130 mg (0.2 mmol) of tetraacetyl protected glucosamine-pomalidomide and 184 mg (1 mmol) of zinc acetate, dissolve in 4 ml of methanol, reflux and stir until the reaction is completed. Dilute the residue with water and methanol, filter with a micro-porous filter membrane, and purify by preparative high performance liquid chromatography (1% to 40% methanol gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Lyophilize to obtain 36 mg of the target compound 30.

[0236] Compound 30: 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.91 (s, 1H), 8.59 (d, J = 8.6 Hz, 1H), 8.48-8.47 (m, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 5.16-5.04 (m, 3H), 4.93 (d, J = 5.1 Hz, 1H), 4.68 (t, J = 9.0 Hz, 1H), 4.55 (t, J = 6.1 Hz, 1H), 3.65 (dd, J = 11.8, 5.6 Hz, 1H), 3.45-3.41 (m, 1H), 3.22-3.21 (m, 1H), 3.14-3.03 (m, 3H), 2.95-2.86 (m, 1H), 2.64-2.56 (m, 2H), 2.10-2.07 (m, 1H).

[0237] Example 29: Preparation of compound 31

[0238]

[0239] Synthesized using the following process:

[0240]

[0241] 1) Take 1.5 g (5.4 mmol) of 4-fluoro-substituted pomalidomide and 852 mg (6.5 mmol) of glycine tert-butyl ester, dissolve in 25 ml of N-methyl pyrrolidone, add 1.9 ml (10.9 mmol) of N,N-diisopropyl ethylamine, and react at 90°C for 12 h. After the reaction is completed, add ethyl acetate, wash with saturated ammonium chloride three times, wash with brine once, dry the organic phase, and purify by column chromatography to obtain 1.18 g of the target product at a yield of 56.5%.

[0242] 2) The product from step 1, 1.18 g (3.05 mmol) was dissolved in 15 mL of dichloromethane and 15 mL of trifluoroacetic acid and stirred at room temperature overnight. The product, pomalidomide-linker acid, was obtained as a crude product by rotary evaporation.

[0243] 3) Pomalidomide-linker acid, 99 mg (0.3 mmol), was dissolved in 3 mL of N,N- dimethylformamide and tetraacetylglucosamine, 104 mg (0.3 mmol), N,N,N',N'-tetramethyl- O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate, 137 mg (0.36 mmol), and N,N- diisopropylethylamine, 156 μL (0.9 mmol), were added sequentially and stirred at room temperature overnight. After the reaction was completed, ethyl acetate was added and washed with saturated ammonium chloride three times, brine once, and the organic phase was dried and concentrated. The target compound, 208 mg (90% purity), was obtained in 94.5% yield by slurry purification with isopropanol and ethyl acetate.

[0244] 4) Tetraacetylated glucosamine-linker-pomalidomide, 85 mg (0.13 mmol), and zinc acetate, 55 mg (0.6 mmol), were dissolved in 2 mL of methanol and stirred at reflux. After the reaction was completed, the residue was diluted with water and methanol, filtered with a microfiltration membrane, and purified by preparative high-performance liquid chromatography (1% to 40% methanol gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reverse-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). The target compound, 31, was obtained in 25 mg.

[0245] Compound 31: 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.71 (d, J = 9.1 Hz, 1H), 7.60 (dd, J = 8.5, 7.1 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 6.94 - 6.85 (m, 2H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 5.02 (d, J = 4.8 Hz, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.92 (d, J = 5.3 Hz, 1H), 4.76 (t, J = 9.0 Hz, 1H), 4.51 (t, J = 5.7 Hz, 1H), 3.98 (d, J = 5.5 Hz, 2H), 3.67 - 3.62 (m, 1H), 3.44 - 3.39 (m, 1H), 3.23 - 3.16 (m, 1H), 3.15 - 3.03 (m, 3H), 2.94 - 2.85 (m, 1H), 2.63 - 2.55 (m, 2H), 2.07 - 2.00 (m, 1H).

[0246] Example 30: Preparation of compound 32

[0247]

[0248] The following procedure was used for the synthesis:

[0249]

[0250] 1) Weigh 431 mg of glucosamine hydrochloride (2 mmol) and dissolve it in 2.43 ml of pyridine. Add 258 mg of tetrabutylammonium bromide (0.8 mmol) and 1.27 ml of trimethylchlorosilane (10 mmol). Stir the reaction at 25°C for 2 hours. When the reaction is complete, add ethyl acetate. Wash the organic phase with saturated sodium chloride solution, dry it, concentrate it and dry it in vacuo to obtain 650 mg of a white solid with a yield of 69.4%.

[0251] 2) Weigh 47 mg of tetra-trimethylsilyl-protected glucosamine (0.1 mmol) and dissolve it in 3 ml of dichloromethane and 2.5 ml of sodium bicarbonate solution. At 0°C, add 71 mg of triphosgene (0.24 mmol). Gradually bring the temperature to room temperature and react for 1 hour. Dilute with dichloromethane and extract with saturated sodium chloride solution. Dry it, concentrate it and proceed to the next step.

[0252] 3) Dissolve the intermediate in dichloromethane. Add 30 mg of pomalidomide (0.11 mmol) and 34 μl of N,N-diisopropylethylamine (0.2 mmol). Add 1 ml of N,N-dimethylformamide as a solvent. Stir overnight at room temperature. Dry it in vacuo and purify it by preparative thin layer chromatography (0.9% methanol in dichloromethane) to obtain 25 mg of the target compound 32.

[0253] Compound 32: 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.35 (s, 1H), 8.90 (s, 1H), 7.60 (dd, J = 8.6, 7.1 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 7.0 Hz, 1H), 6.66 (t, J = 6.3 Hz, 1H), 5.74 (s, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.62 (dd, J = 3.2, 1.4 Hz, 1H), 4.18 (dd, J = 2.9, 1.4 Hz, 1H), 3.97 - 3.92 (m, 1H), 3.76 - 3.54 (m, 5H), 3.43 - 3.32 (m, 3H), 3.15 - 3.08 (m, 2H), 2.93 - 2.84 (m, 1H), 2.62 - 2.53 (m, 2H), 2.06 - 2.01 (m, 1H), 1.31 - 1.22 (m, 15H).

[0254] Example 31: Preparation of compound 33

[0255]

[0256] Synthesized using the following procedure:

[0257]

[0258] 1) Synthesis of pomalidomide-acetic acid intermediate, same procedure as Example 29.

[0259] 2) Pomalidomide-acetic acid intermediate 50 mg (0.15 mmol) was weighed out and dissolved in 0.5 mL of N,N-dimethylformamide. N-hydroxysuccinimide 19 mg (0.165 mmol) and N,N'-dicyclohexylcarbodiimide 34 mg (0.165 mmol) were added sequentially and stirred at room temperature overnight. The active ester was added dropwise to a solution of D-glucosamine hydrochloride 15 mg (0.07 mmol) in 33 mg (0.38 mmol) of sodium bicarbonate in water and stirred at room temperature for 1 hour. The pH was adjusted to 5-6 with HOAc and the residue was diluted with water and methanol, filtered through a micro-pore filter and purified by preparative HPLC (1% to 75% methanol gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reverse phase C18 column (Innoval AQ C18, length: 250 mm, internal diameter: 21.2 mm). Compound 33 was obtained, 30 mg.

[0260] Compound 33: 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.97 (dd, J = 16.7, 8.5 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.94 - 6.88 (m, 2H), 6.56 (dd, J = 19.4, 5.3 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.97 - 4.89 (m, 2H), 4.74 - 4.43 (m, 2H), 3.95 (dd, J = 20.5, 4.3 Hz, 2H), 3.70 - 3.58 (m, 2H), 3.54 - 3.40 (m, 3H), 3.17 - 3.06 (m, 2H), 2.94 - 2.85 (m, 1H), 2.62 - 2.55 (m, 2H), 2.05 - 2.02 (m, 1H).

[0261] Example 32: Preparation of compound 34

[0262]

[0263] The following procedure was used for the synthesis:

[0264]

[0265] 1) Take pomalidomide 273 mg (1 mmol), dissolve it in 2 ml of N,N- dimethylformamide and 2 ml of dimethyl sulfoxide, add potassium carbonate 415 mg (3 mmol) and tert-butyl bromoacetate 218 μl (1.5 mmol), stir the reaction at 25 °C for 6 hours, after the reaction is complete, add ethyl acetate, wash the organic phase with saturated ammonium chloride and saturated sodium chloride solution, dry, concentrate and dry under vacuum, obtaining 376 mg of a yellow solid, with a yield of 97.2%.

[0266] 2) Take the compound obtained in the previous step 376 mg (0.97 mmol), dissolve it in 4 ml of dichloromethane and 2 ml of trifluoroacetic acid, stir the reaction at room temperature for 4 hours, concentrate, proceed to the next step.

[0267] 3) Weigh out pomalidomide-linker-acid 66 mg (0.2 mmol) and dissolve in 1 mL of N,N-dimethylformamide. Add N-hydroxysuccinimide 25 mg (0.22 mmol) and N,N'-dicyclohexylcarbodiimide 45 mg (0.22 mmol) sequentially and stir at room temperature overnight. Add D-glucosamine hydrochloride 35 mg (0.16 mmol) in 84 mg (1.00 mmol) of aqueous sodium bicarbonate dropwise and stir at room temperature for 1 hour. Adjust the pH to 5-6 with HOAc. Dilute the residue with water and methanol, filter through a micro-pore filter and purify by preparative HPLC (1% to 75% methanol gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reverse phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Obtain the target compound 34, 36 mg.

[0268] Compound 34: 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.01 (dd, J = 7.7, 6.0 Hz, 2H), 6.59 - 6.44 (m, 3H), 5.13 (dd, J = 13.1, 5.3 Hz, 1H), 4.96 - 4.49 (m, 3H), 4.47 - 4.17 (m, 3H), 3.71 - 3.40 (m, 4H), 3.30 - 3.20 (m, 1H), 3.13 - 3.00 (m, 2H), 2.79 (d, J = 16.3 Hz, 1H), 2.72 - 2.57 (m, 1H), 2.09 - 2.05 (m, 1H).

[0269] Example 33: Preparation of Compound 35

[0270]

[0271] Synthesized using the following procedure:

[0272]

[0273] 1) Pomalidomide-bromoacetate coupling procedure same as Example 32.

[0274] 2) Weigh out pomalidomide-linker-acid 66 mg (0.2 mmol) and dissolve in 1 mL of N,N-dimethylformamide. Add N-hydroxysuccinimide 25 mg (0.22 mmol) and N,N'-dicyclohexylcarbodiimide 45 mg (0.22 mmol) sequentially and stir at room temperature overnight. Add D-galactosamine hydrochloride 47 mg (0.22 mmol) in 84 mg (1.00 mmol) of aqueous sodium bicarbonate dropwise and stir at room temperature for 1 hour. Adjust the pH to 5-6 with HOAc. Dilute the residue with water and methanol, filter through a micropore filter and purify by preparative HPLC (1% to 75% methanol gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reverse phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Obtain the target compounds 35, 36 mg.

[0275] Compound 35: 1 H NMR (400 MHz, DMSO-d6) δ 7.84 - 7.76 (m, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 6.9 Hz, 2H), 6.54 (s, 2H), 6.41 (dd, J = 13.3, 5.1 Hz, 1H), 5.14 (dd, J = 13.1, 5.2 Hz, 1H), 4.92 - 4.88 (m, 1H), 4.60 - 4.51 (m, 1H), 4.47 - 4.20 (m, 4H), 3.97 - 3.91 (m, 1H), 3.84 - 3.40 (m, 5H), 3.09 - 2.98 (m, 1H), 2.84 - 2.75 (m, 1H), 2.73 - 2.60 (m, 1H), 2.11 - 2.05 (m, 1H).

[0276] Example 34: Preparation of Compound 36

[0277]

[0278] Synthesized using the following procedure:

[0279]

[0280] 1) Pomalidomide-bromoacetate coupling procedure same as Example 32.

[0281] 2) Weigh out pomalidomide-linker-acid 66 mg (0.2 mmol) and dissolve in 1 mL of N,N-dimethylformamide. Add N-hydroxysuccinimide 25 mg (0.22 mmol) and N,N'-dicyclohexylcarbodiimide 45 mg (0.22 mmol) sequentially and stir at room temperature overnight. Add D-mannosamine hydrochloride 47 mg (0.22 mmol) in 84 mg (1.00 mmol) of aqueous sodium bicarbonate dropwise and stir at room temperature for 1 hour. Adjust the pH to 5-6 with HOAc, dilute the residue with water and methanol, filter through a micropore filter, and purify by preparative high performance liquid chromatography (1% to 75% methanol gradient elution) using a preparative HPLC system (CXTH-LC3000) equipped with a reverse phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). Compound 36, 37 mg, is obtained.

[0282] Compound 36: 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (dd, J = 8.1, 2.9 Hz, 1H), 7.47 (dd, J = 8.5, 7.0 Hz, 1H), 7.01 (dd, J = 7.7, 5.6 Hz, 2H), 6.59 - 6.50 (m, 2H), 6.47 (dd, J = 6.1, 3.8 Hz, 1H), 5.14 - 5.06 (m, 1H), 4.88 - 4.69 (m, 2H), 4.61 - 4.09 (m, 4H), 3.94 - 3.61 (m, 2H), 3.60 - 3.35 (m, 3H), 3.26 - 2.97 (m, 2H), 2.84 - 2.76 (m, 1H), 2.72 - 2.59 (m, 1H), 2.14 - 2.02 (m, 1H).

[0283] Example 35: Preparation of Compound 37

[0284]

[0285] Synthesized using the following procedure:

[0286]

[0287] 1) Pomalidomide-bromoacetate coupling procedure as in Example 32.

[0288] 2) Take pomalidomide-linker-acid 133 mg (0.4 mmol), dissolve in 3 mL of N,N- dimethylformamide, add 1 -amino glucose 360 mg (2 mmol) in 4 mL of methanol, then add 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate 304 mg (0.8 mmol), triethylamine 111 μL (0.8 mmol) sequentially, stir at room temperature overnight. After the reaction is complete, adjust the pH to 5-6 with HOAc, dilute the residue with water and methanol, filter with a micro-pore filter, purify by preparative HPLC (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) equipped with a reverse phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). The target compound 37 is obtained, 83 mg.

[0289] Compound 37: 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 8.9 Hz, 1H), 7.47 (dd, J = 8.4, 7.0 Hz, 1H), 7.01 (dd, J = 7.7, 6.0 Hz, 2H), 6.54 (s, 2H), 5.18 - 5.12 (m, 1H), 4.99 (d, J = 4.8 Hz, 1H), 4.94 - 4.83 (m, 2H), 4.67 (t, J = 9.0 Hz, 1H), 4.57 - 4.52 (m, 1H), 4.41 - 4.19 (m, 2H), 3.64 - 3.59 (m, 1H), 3.44 - 3.39 (m, 1H), 3.16 - 2.97 (m, 4H), 2.87 - 2.75 (m, 1H), 2.72 - 2.61 (m, 1H), 2.13 - 2.04 (m, 1H).

[0290] Example 36: Preparation of Compound 38

[0291]

[0292] Synthesized using the following procedure:

[0293]

[0294] 1) Pomalidomide-bromoacetate coupling procedure as in Example 32.

[0295] 2) Take pomalidomide-linker-acid 33 mg (0.1 mmol), dissolve in 1 mL of N,N- dimethylformamide, add 1-amino galactose 90 mg (0.5 mmol) in 1 mL of methanol, then add 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate 76 mg (0.2 mmol), triethylamine 28 μL (0.2 mmol) sequentially, stir at room temperature overnight. After the reaction is completed, adjust pH to 5-6 with HOAc, dilute the residue with water and methanol, filter with a micro-pore filter, purify by preparative HPLC (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). The target compound 38 is obtained, 13 mg.

[0296] Compound 38: 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (dd, J = 9.0, 6.7 Hz, 1H), 7.47 (dd, J = 8.5, 7.0 Hz, 1H), 7.01 (dd, J = 7.7, 6.1 Hz, 2H), 6.54 (s, 2H), 5.17 - 5.11 (m, 1H), 4.83 - 4.52 (m, 4H), 4.47 - 4.40 (m, 1H), 4.35 (d, J = 15.4 Hz, 1H), 4.22 (dd, J = 16.2, 13.0 Hz, 1H), 3.68 (t, J = 3.6 Hz, 1H), 3.52 - 3.36 (m, 4H), 3.30 (d, J = 14.0 Hz, 1H), 3.08 - 2.99 (m, 1H), 2.85 - 2.75 (m, 1H), 2.74 - 2.58 (m, 1H), 2.13 - 2.03 (m, 1H).

[0297] Example 37: Preparation of Compound 39

[0298]

[0299] Synthesized using the following procedure:

[0300]

[0301] 1) Pomalidomide-bromoacetic acid coupling procedure same as Example 32.

[0302] 2) Take pomalidomide-linker-acid 133 mg (0.4 mmol), dissolve it in 3 mL of N,N- dimethylformamide, add 1-amino mannose 360 mg (2.0 mmol) in 4 mL of methanol, then add 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate 304 mg (0.8 mmol), triethylamine 111 μL (0.8 mmol) in sequence, stir overnight at room temperature. After the reaction is completed, adjust the pH to 5-6 with HOAc, dilute the residue with water and methanol, filter with a micro-pore filter membrane, purify by preparative high performance liquid chromatography (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). The target compound 39 is obtained, 83 mg.

[0303] Compound 39: 1 H NMR (600 MHz, DMSO-d6) δ 8.44 (dd, J = 9.2, 4.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.01 (dd, J = 10.5, 7.7 Hz, 2H), 6.52 (s, 2H), 5.17 - 5.10 (m, 1H), 5.00 (d, J = 9.1 Hz, 1H), 4.89 (dd, J = 9.6, 4.9 Hz, 1H), 4.77 (d, J = 5.0 Hz, 1H), 4.70 (d, J = 5.0 Hz, 1H), 4.48 - 4.45 (m, 1H), 4.43 - 4.23 (m, 2H), 3.69 - 3.62 (m, 1H), 3.53 (q, J = 5.1 Hz, 1H), 3.44 - 3.37 (m, 1H), 3.37 - 3.33 (m, 1H), 3.30 (d, J = 10.0 Hz, 1H), 3.09 - 2.98 (m, 2H), 2.82 - 2.78 (m, 1H), 2.70 - 2.62 (m, 1H), 2.09 - 2.05 (m, 1H).

[0304] Example 38: Preparation of compound 40

[0305]

[0306] Take 78 milligrams (0.3 mmol) of lenalidomide and 162 milligrams (0.9 mmol) of glucose, dissolve in 3 milliliters of ethanol, add 36 milligrams (0.6 mmol) of acetic acid. The mixture is stirred at 78°C for 12 hours. The reaction is stopped when the reaction progress is monitored unchanged, cooled, concentrated under reduced pressure, the residue is diluted with water and methanol, filtered with a microporous filter membrane, purified by preparative high performance liquid separation (1%-75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). The target compound 40, 40 milligrams, is obtained.

[0307] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.32-7.27 (m, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.23 (dd, J = 42.3, 8.0 Hz, 1H), 5.15-5.10 (m, 1H), 5.00 (d, J = 3.9 Hz, 1H), 4.94-4.86 (m, 2H), 4.52-4.43 (m, 2H), 4.38-4.19 (m, 2H), 3.71-3.65 (m, 1H), 3.47-3.41 (m, 1H), 3.30-3.24 (m, 3H), 3.18-3.08 (m, 1H), 2.97-2.88 (m, 1H), 2.66-2.59 (m, 1H), 2.39-2.26 (m, 1H), 2.07-1.99 (m, 1H).

[0308] Preparation of compound 41

[0309]

[0310] To the above compound 40 (168 mg, 0.4 mmol) in water (4.0 mL), 0.2 mL of acetic acid and NaBH3CN (50 mg, 0.8 mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, acetic acid was added to the reaction solution to adjust the pH to 5-6, followed by the addition of 2 mL of water and 2 mL of methanol and continued stirring. Filtered with a microporous filter membrane, purified by preparative high performance liquid separation (1%-75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm) was completed, to obtain the target compound open-chain glucose-lenalidomide (compound 41) 76 milligrams. m.p. 154-155°C.

[0311] Compound 41: 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.43 (s, 1H), 5.13 - 5.08 (m, 1H), 4.27 - 4.10 (m, 3H), 3.83 - 3.79 (m, 1H), 3.70 (dd, J = 4.4, 1.9 Hz, 1H), 3.59 (dd, J = 10.8, 3.2 Hz, 1H), 3.53 - 3.46 (m, 3H), 3.42 - 3.33 (m, 5H), 3.11 - 3.05 (m, 1H), 2.97 - 2.88 (m, 1H), 2.64 - 2.59 (m, 1H), 2.36 - 2.27 (m, 1H), 2.06 - 2.00 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 173.41, 171.70, 169.41, 144.23, 144.20, 132.50, 129.68, 127.04, 112.55, 112.51, 110.60, 72.49, 72.46, 72.00, 71.50, 71.44, 70.41, 70.39, 63.84, 52.02, 51.99, 46.35, 46.14, 31.71, 23.23. FT-IR: 3379.45, 2921.08, 1683.75, 1611.76, 1504.68, 1454.98, 1355.28, 1241.02, 1200.57, 1082.81, 762.99 cm -1 HRMS (ESI) m / z: Calcd. for C 19 H 25 N3O8[M+H]+: 424.1714; Found: 424.1716. R (HPLC, 1-75% MeOH in H2O, 0-15 min) = 9.63 min; purity: 95.17%.

[0312] Preparation of compound 42

[0313]

[0314] To a solution of compound I-1 ((86 mg, 0.2 mmol) in water (2.0 mL), 0.1 mL of acetic acid and NaBH3CN ((25 mg, 0.4 mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, acetic acid was added to the reaction solution to adjust the pH to 5-6, followed by the addition of 2 mL of water and 2 mL of methanol and continued stirring. Filtered with a microporous membrane, purified by preparative high performance liquid chromatography (1% to 75% methanol gradient elution), using a preparative HPLC system (CXTH-LC3000) and equipped with a reversed-phase C18 column (Innoval AQ C18, length: 250 mm, inner diameter: 21.2 mm). The target compound open-chain glucose-pomalidomide (compound 42) was obtained 35 mg. m.p. 160-161 °C.

[0315] Compound 42: 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.58 (dd, J = 8.6, 7.1 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.68 (t, J = 5.8 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.44 (s, 3H), 3.80-3.75 (m, 1H), 3.67 (dd, J = 5.1, 1.9 Hz, 1H), 3.60 (dd, J = 10.8, 3.3 Hz, 1H), 3.53-3.49 (m, 2H), 3.45 (dd, J = 8.1, 1.9 Hz, 2H), 3.43-3.38 (m, 2H), 3.24-3.18 (m, 1H), 2.93-2.84 (m, 1H), 2.61-2.54 (m, 2H), 2.08-1.98 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ

[0316] 173.29, 170.56, 169.43, 167.81, 147.14, 136.70, 132.58, 117.85, 110.91, 109.67, 109.64, 71.90, 71.54, 71.50, 70.77, 63.88, 49.02, 45.23, 31.45, 22.64. FT-IR: 3391.65, 1697.27, 1625.11, 1510.91, 1411.54, 1362.51, 1260.74, 1199.47, 1036.91, 742.04, 607.96 cm -1 HRMS (ESI) m / z: Calcd. for C 19 H 23N3O9[M+Na]+: 460.1330; Found: 460.1341.t R (HPLC, 20% MeOH in H2O) = 16.21 min; purity: 97.79%.

[0317] Comparative Example 3: Preparation of compound 43

[0318]

[0319] Example 40 was prepared using the same method as Example 40, starting from compound I-8. Yield 25.3%, m.p. 170-171 °C.

[0320] Compound 43: 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.59 (dd, J = 8.6, 7.1 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.72 (s, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.92 (t, J = 6.8 Hz, 1H), 3.74 (t, J = 6.5 Hz, 1H), 3.52-3.48 (m, 1H), 3.45-3.36 (m, 8H), 3.34-3.31 (m, 2H), 2.93-2.84 (m, 1H), 2.61-2.55 (m, 2H), 2.06-2.00 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 173.29, 170.57, 169.40, 167.81, 147.18, 136.71, 132.61, 117.80, 110.82, 109.56, 70.51, 70.47, 69.76, 68.28, 68.26, 63.61, 49.01, 45.95, 31.45, 22.64. FT-IR: 3382.50, 2953.23, 1685.47, 1622.65, 1509.34, 1415.67, 1367.19, 1325.52, 1262.60, 1207.61, 1106.95, 1023.42, 929.88, 747.29, 609.64, 471.21 cm -1 HRMS (ESI) m / z: Calcd. for C 19 H 23 N3O9[M+H]+: 438.1507; Found: 438.1509.t R(HPLC, 1-75% MeOH in H2O, 0-15 min) = 10.28 min; purity: 98.60%.

[0321] Comparative Example 4: Preparation of compound 44

[0322]

[0323] Example 40 was prepared using the same method as Example 40, starting from compound I-15. Yield 42.9%, m.p. 178-179°C.

[0324] Compound 44: 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.58 (dd, J = 8.6, 7.1 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.70 (t, J = 5.9 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.98 (d, J = 6.0 Hz, 1H), 4.43 (dd, J = 12.6, 6.5 Hz, 2H), 4.35 (t, J = 5.6 Hz, 1H), 4.19 (d, J = 7.4 Hz, 1H), 3.68 - 3.55 (m, 6H), 3.51 - 3.45 (m, 1H), 3.43 - 3.37 (m, 1H), 2.93 - 2.84 (m, 1H), 2.61 - 2.55 (m, 2H), 2.04 - 2.01 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 173.29, 170.56, 169.48, 167.83, 147.33, 136.69, 132.55, 117.96, 110.78, 109.58, 109.55, 71.70, 71.13, 69.92, 69.14, 69.09, 64.36, 49.01, 46.22, 31.46, 22.65. FT-IR: 3392.12, 2896.11, 1697.02, 1624.90, 1510.25, 1411.38, 1361.79, 1260.14, 1199.56, 1019.35, 880.94, 813.96, 740.82, 606.62, 470.88 cm -1 .HRMS (ESI) m / z: Calcd. for C 19 H 23 N3O9[M+H]+: 438.1507; Found: 438.1508. R(HPLC, 30% MeOH in H2O) = 7.92 min; purity: 99.87%.

[0325] Experimental Example 1: Anti-cancer efficacy of the compounds in vitro

[0326] (1) Experimental method:

[0327] (1.1) Cytotoxicity test: The cytotoxicity test was performed by MTT method.

[0328] For the biological activity of the compounds, U251 (brain glioma cells) was used as the research object, and the growth of the cells was observed under the action of the lenalidomide derivatives, and the proliferation of the tumor cells was determined by MTT method. The specific operation is as follows (taking U251 cells as an example): 100 microliters of U251 tumor cells about 2500 per well were inoculated in a 96-well culture plate, and after overnight incubation in a 37℃, 5% carbon dioxide concentration incubator, 100 microliters of the screened sample was added to each well (sample concentration: the compound was first dissolved in DMSO (100 mM), and then diluted with culture medium to different concentrations, and the final content of DMSO was 0.5%), and the drug was acted for 96 hours, and MMT detection was performed.

[0329] (1.2) Half inhibitory concentration, IC 50 :

[0330] 1) Cell survival rate (%) = (drug treatment group OD value / control group OD value) x 100. The experiment of each drug concentration was repeated 4 groups, and the average OD value was used to calculate the cell survival rate.

[0331] 2) The drug concentration corresponding to 50% of the cell survival rate of the control group is the half inhibitory concentration of the drug to the tumor cells, that is, the IC 50 value of the drug.

[0332] (2) Experimental results:

[0333] The derivatives prepared in each embodiment were tested for half inhibitory concentration IC 50 Results, as shown in Table 4, Table 4 provides the biological activity of the compounds provided in the present application to brain tumors and drug-resistant myeloma.

[0334] Experimental Example 2: Lenalidomide and pomalidomide-resistant tumor inhibition experiment

[0335] 1. Construction of lenalidomide and pomalidomide-resistant human myeloma cells

[0336] (1) Cell culture

[0337] Human myeloma cell line MM.1S was from ATCC cell bank. Cell culture was according to the product instruction: medium: RPMI-1640 + 10% fetal bovine serum (FBS) + penicillin and streptomycin (PS). Growth conditions: gas phase: 95% air + 5% carbon dioxide; temperature: 37°C; passage method: 1:2 to 1:4, 3 times per week; freezing condition: serum-free freezing solution, storage in liquid nitrogen

[0338] (2) Drug-resistant cell line construction

[0339] Drug-resistant myeloma cells were constructed by using drug concentration gradient increasing method. MM.1S cells in logarithmic growth phase were continuously cultured in medium added with low concentration of lenalidomide or pomalidomide, and the fresh drug-containing medium was replaced every 3-4 days. After about 4 weeks, the IC 50 was determined by MTT method. When the cells recovered normal morphology and the proliferation was no longer inhibited by the drug, the drug concentration was gradually increased by 1.25 times each time, the initial concentration of lenalidomide was 500 nM, and the stimulation was terminated when the concentration approached 5 mM; the initial concentration of pomalidomide was 500 nM, and the stimulation was terminated when the concentration approached 10 mM. The above operation was repeated, and finally the cells could stably grow and be passaged in medium containing higher concentration of lenalidomide and pomalidomide. After drug withdrawal for 1 month, the biological characteristics and resistance index (RI) of the cells were detected again. If RI > 5, it is considered that the drug resistance of the drug-resistant cell line meets the requirements.

[0340] The resistance index (RI) was calculated as follows:

[0341]

[0342] 2. Anti-drug resistance activity of the compound

[0343] (1) Anti-drug resistance coefficient of the compound

[0344] The anti-drug resistance coefficient of the compound refers to the fold increase of the half inhibitory concentration of the drug against drug-resistant cells compared with non-drug-resistant cells. It is calculated according to the following formula:

[0345] Anti-drug resistance coefficient (RI) = IC 50 of drug-resistant cells / IC 50

[0346] (2) Experimental results

[0347] The anti-drug resistance results of the compounds prepared in each example against lenalidomide and pomalidomide-resistant myeloma cells are shown in Table 4.

[0348] Table 4 Biological activity (IC50 Value, unit: micromole; Anti-drug resistance coefficient RI, unit: fold)

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355] From Table 4, it can be seen that the glycosylated phthalimide compound provided by the present application can effectively inhibit the proliferation of lenalidomide and pomalidomide resistant multiple myeloma cells and lenalidomide and pomalidomide insensitive glioma cells, and can be used for preparing potential drugs for treating lenalidomide and pomalidomide resistant myeloma and for treating brain tumors.

[0356] The above description of the embodiments is only used to help understand the method of the present application and its core idea. It should be noted that for those skilled in the art, without departing from the principles of the present application, some improvements and modifications can be made to the present application, and these improvements and modifications also fall within the protection scope of the claims of the present application.

Claims

1. A glycosylated phthalimide compound represented by Formula (I), an isomer thereof, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof: ###0001### Formula (I) wherein: R has the structure of Formula (a): ###0002### Formula (a) R1, R2, R3 and R4 contain at least three hydroxyl groups. wherein A is selected from hydrogen or C 1～3 alkyl; Y is selected from hydrogen, deuterium, halogen or C 1～3 alkyl; R has the structure of Formula (a-1) to (a-4): ###0003### Formula (a-1) Formula (a-2) Formula (a-3) Formula (a-4) R has the following structure: ###0004### R has the structure of Formula (I-1) to (I-28): ###0005### Formula (I-1) Formula (I-2) Formula (I-3) Formula (I-4) Formula (I-5) Formula (I-6) Formula (I-7) Formula (I-8) Formula (I-9) Formula (I-10) Formula (I-11) Formula (I-12) Formula (I-13) Formula (I-14) Formula (I-15) Formula (I-16) Formula (I-17) Formula (I-18) Formula (I-19) Formula (I-20) Formula (I-21) Formula (I-22) Formula (I-23) Formula (I-24) Formula (I-25) Formula (I-26) Formula (I-27) Formula (I-28) In formula (a), R1, R2, R3and R4are independently selected from hydrogen, hydroxyl, C 1～3 alkyl or a terminal hydroxyl substituted C 1～3 alkylene group; 5. A method for preparing a glycosylated phthalimide compound, an isomer thereof, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, comprising the following steps: subjecting a compound represented by Formula (II) to glycosidic condensation with a saccharide compound represented by Formula (b) in a solvent in the presence of a catalyst to obtain a glycosylated phthalimide compound; ###0006### Formula (II) ###0007### Formula (b) wherein: R has the structure of Formula (a); R1, R2, R3 and R4 contain at least three hydroxyl groups; R has the structure of Formula (a-1) to (a-4); R has the following structure; R has the structure of Formula (I-1) to (I-28); the catalyst is selected from one or more of formic acid, sodium hydrogen phosphate, trifluoroacetic acid, hydrochloric acid and ammonium chloride; the amount of the catalyst is 2 wt% to 50 wt% of the saccharide compound; the solvent is selected from one or more of water, methanol, ethanol, acetone, chloroform and N,N-dimethylformamide; the initial concentration of the compound represented by Formula (II) is 0.01 g / mL to 0.1 g / mL; the molar ratio of the compound represented by Formula (II) to the saccharide compound represented by Formula (b) is 1:1 to 1:10; and the temperature of the glycosidic condensation is 20°C to 200°C, and the time is 30 min to 1 week.

2. The glycosylated phthalimide compound, isomer thereof, solvate or hydrate thereof, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, 7. A pharmaceutical composition comprising a glycosylated phthalimide compound, an isomer thereof, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

3. The glycosylated phthalimide compound, isomer thereof, solvate or hydrate thereof, or pharmaceutically acceptable salt thereof according to claim 2, characterized in that, 8. Use of a glycosylated phthalimide compound, an isomer thereof, a solvate or hydrate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating a tumor.

4. The glycosylated phthalimide compound, isomer thereof, solvate or hydrate thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that, The tumor is a hematological tumor, a myeloma or a brain tumor. The tumor is a brain tumor that is insensitive to lenalidomide or pomalidomide or a multiple myeloma or myelodysplastic syndrome that is resistant to lenalidomide or pomalidomide. ​ 6. The production method according to claim 5, characterized by, ​ ​ ​ ​ ​ ​ ​ ​ 9. Use according to claim 8, characterized in that, ​ 10. Use according to claim 9, characterized in that, ​

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