Novel molecular glue degradation agent, preparation method thereof and application of novel molecular glue degradation agent as medicine

Abstract

The invention relates to an effective amount of novel molecular glue as shown in a general formula (I), a preparation method of the novel molecular glue and application of a pharmaceutical composition containing the novel molecular glue to preparation of drugs for treating related diseases, and compared with the prior art, the novel molecular glue has a wider application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to a new type of Ikaros and Aiolos degradation agent, its preparation method and application, belonging to the field of pharmaceutical chemistry. The present application relates to a new type of molecular glue, which triggers polyubiquitination and degradation of Ikaros and Aiolos by combining Cereblon. BACKGROUND

[0002] The immunomodulatory drugs (IMiDs) mainly include the first generation of thalidomide, and the derivatives of thalidomide lenalidomide, pomalidomide, and are also widely used in clinical as anti-inflammatory and anti-tumor drugs. In 2014, the Ebert team of Harvard Medical School and the Nobel Prize in Physiology or Medicine winner Kealin Jr team published research results in two Science at the same time, proving that the molecular mechanism of immunomodulatory drugs IMiDs in treating myeloma, which can combine Cereblon (CRBN), so that ubiquitin activating enzyme (E1) can activate and transfer ubiquitin to ubiquitin binding enzyme (E2), and ubiquitin ligase (E3 ligase) can bind to the target protein, and the ubiquitin carried by E2 is transferred to the target protein. Finally, the 26S proteasome recognizes the polyubiquitin chain, thereby promoting the degradation of two downstream transcription factors IKZF1 and IKZF3. Among them, the E3 ubiquitin ligase plays an important role in substrate recruitment. The Ikaros family is a series of zinc finger protein transcription factors, which is important for certain physiological processes, especially hematopoietic cell and lymphocyte development, and genetic changes in Ikaros are associated with poor outcomes in the treatment of acute lymphoblastic leukemia (ALL). Ikaros (IKZF1) and its homolog Aiolos (IKZF3) play an important role in the proliferation of multiple myeloma cells and lymphoma cells.

[0003] According to statistics, multiple myeloma (MM) accounts for almost 1.8% of all new cancers, although the outcome of subjects with MM has been significantly improved in the past few decades, but the disease is still incurable, and the current predicted 5-year relative survival rate is only 53.9%. Since the available treatment is not curative, almost all patients will eventually progress. Therefore, the unmet medical needs in these patients are highlighted, and there is an urgent need to develop new and efficient therapeutic drugs. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a series of molecular glue drugs with potential anti-tumor activity, to provide the possibility of applying such compounds to prevent or / and treat cancer, inflammation, and immunomodulatory drugs.

[0005] The novel molecular glue compound of the present application is a compound containing an effective amount of a compound represented by the general formula (I):

[0006]

[0007] wherein,

[0008] X is selected from:

[0009] Y is selected from O, NH;

[0010] Z is selected from any one of the following structures:

[0011] wherein, R is selected from one or more of hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, R1 is selected from hydrogen, alkyl, and R2 is selected from hydrogen, alkyl, cycloalkyl.

[0012] Preferred compounds of the present application include:

[0013] X is selected from:

[0014] Y is selected from O, NH;

[0015] Z is selected from any one of the following structures:

[0016] wherein, R is selected from one or more of hydrogen, C1-C6 alkyl, alkoxy, halogen, trifluoromethyl, R1 is selected from hydrogen, C1-C6 alkyl, and R2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.

[0017] More preferred compounds of the present application include, but are not limited to:

[0018]

[0019]

[0020] Another aspect of the present application relates to a pharmaceutical composition containing a therapeutically effective amount of the compound and a suitable carrier, diluent or excipient.

[0021] The present application relates to the use of the compound or a pharmaceutical composition thereof in the preparation of a medicament for treating IKZF1 or / and IKZF3 related diseases.

[0022] The present application also relates to the use of the compound or a pharmaceutical composition thereof in the preparation of a medicament for preventing or / and treating cancer, inflammation, immunomodulatory diseases.

[0023] Detailed description of the invention

[0024] Unless otherwise stated, the terms used in the specification and claims shall have the following meanings.

[0025] Any general formula or structure shown herein, including compounds of general formula (I), is also intended to represent both unlabeled and isotopically labeled forms of said compounds. Isotopically labeled compounds have the structures shown in the molecular formulas given herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be contained in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine. In the compounds of the present invention, any atom not explicitly designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is explicitly designated as “H” or “hydrogen,” it should be understood that the position is composed of hydrogen in its isotopic composition. Therefore, in the compounds of the present invention, any atom explicitly designated as deuterium (D) is intended to represent deuterium.

[0026] "Pharmaceutical composition" refers to a mixture containing one or more of the compounds described in this invention, along with other chemical components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to promote the absorption of the active ingredient by an organism, thereby facilitating the exertion of the active ingredient's biological activity within the body.

[0027] “Cancer” refers to any malignant tumor of any tissue or cell type. Examples of cancer can include cancers that can be caused by abnormally adhering cells or cancers that can be caused by abnormal blood cells (e.g., leukemia, lymphoma, multiple myeloma). Specifically, examples of cancers that can be caused by abnormally adhering cells can include lung cancer (e.g., squamous cell carcinoma, non-small cell lung cancer such as adenocarcinoma, large cell carcinoma, and small cell carcinoma), gastrointestinal cancers (e.g., stomach cancer, colorectal cancer, small bowel cancer, rectal cancer), pancreatic cancer, kidney cancer, liver cancer, thymic cancer, spleen cancer, thyroid cancer, adrenal cancer, prostate cancer, bladder cancer, ovarian cancer, uterine cancer (e.g., endometrial cancer, cervical cancer), bone cancer, skin cancer, brain tumors, sarcomas, melanoma, germ cell tumors (e.g., neurocytoma), adenocarcinoma, squamous cell carcinoma, solid carcinoma, epithelial carcinoma, and mesothelioma. Specifically, the cancer can be leukemia, particularly acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), chronic leukemia such as chronic myeloid leukemia; adenoid cystic carcinoma; osteosarcoma; ovarian cancer; Ewing's tumor; lung adenocarcinoma and prostate cancer; lymphoma, neuroblastoma, gastrointestinal cancer, endometrial cancer, medulloblastoma, prostate cancer, esophageal cancer, breast cancer, thyroid cancer, meningioma, liver cancer, colorectal cancer, pancreatic cancer, chondrosarcoma, osteosarcoma, kidney cancer, preferably, hematologic malignancies. Attached Figure Description

[0028] Figure 1Compound 28 degrades IKZF1 and IKZF3: (A) Degradation effect of compound 28 on IKZF1 and IKZF3 in MM1S myeloma cells (red arrows indicate the target band IKZF1); (B) DC of IKZF1 and IKZF3 50 Degradation curve. Detailed Implementation

[0029] The present invention will be further described below with reference to embodiments. It should be noted that the following embodiments are for illustrative purposes only and are not intended to limit the present invention. Various modifications made by those skilled in the art based on the teachings of the present invention should be within the scope of protection of the claims of this application.

[0030] Synthetic preparation route of the compounds of this invention:

[0031] Synthesis Route 1:

[0032]

[0033] Reagents and conditions: (a) 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, dichloromethane, room temperature, 8 hours; (b) sodium borohydride, acetic acid, 100℃-25℃, nitrogen atmosphere, 12 hours.

[0034] p-Aminobenzaldehyde (1.0 equiv) was dissolved in 10 mL of dichloromethane solution, and the corresponding carboxylic acid starting material (1.1 equiv), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.2 equiv), and N,N-diisopropylethylamine (1.2 equiv) were added sequentially. The reaction was carried out at room temperature for 8 hours, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The purified solids 2a-2d were obtained by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v).

[0035] Products 2a-2d (1.0 equiv) were dissolved separately in acetic acid (10 mL), and lenalidomide (1.2 equiv) was added. The mixture was reacted at 100 °C for 4 hours under nitrogen atmosphere, then cooled to room temperature. Sodium borohydride (1.5 equiv) was slowly added, and the mixture was reacted under nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to give white solids 1-4.

[0036] Synthesis Route 2:

[0037]

[0038] Reagents and conditions: (a) 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, dichloromethane, room temperature, 8 hours; (b) sodium borohydride, acetic acid, 100℃-25℃, nitrogen atmosphere, 12 hours.

[0039] p-Aldehydebenzoic acid (1.0 equiv) was dissolved in 10 mL of dichloromethane solution, followed by amine raw material (1.1 equiv), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.2 equiv), and N,N-diisopropylethylamine (1.2 equiv) in sequence. The reaction was carried out at room temperature for 8 hours, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and purified by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v) to obtain white solids 5a-5j.

[0040] The products 5a-5j (1.0 equiv) were dissolved separately in acetic acid (10 mL), and lenalidomide (1.2 equiv) was added. The mixture was reacted at 100 °C for 4 hours under nitrogen atmosphere, then cooled to room temperature. Sodium borohydride (1.5 equiv) was slowly added, and the mixture was reacted under nitrogen atmosphere for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to give a white solid 5-14.

[0041] Synthesis Route 3:

[0042]

[0043] Reagents and conditions: (a) triphosgene, triethylamine, dichloromethane, 0℃-25℃, 6 hours; (b) sodium borohydride, acetic acid, 100℃-25℃, nitrogen atmosphere, 12 hours.

[0044] Triphosgene (0.33 equiv) was dissolved in dichloromethane. Under nitrogen and 0°C conditions, a dichloromethane solution containing p-aminobenzaldehyde (1 equiv) and triethylamine (3 equiv) was added dropwise. After reacting for 1 hour, a dichloromethane solution containing benzylamine (1 equiv) and triethylamine (3 equiv) was added. The reaction was continued at room temperature for 2 hours. The mixture was washed with 10 mL of saturated brine, and the organic phase was collected, dried, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v) to obtain a white solid 6a.

[0045] The above product 6a (1.0 equiv) was dissolved in acetic acid (10 mL), and lenalidomide (1.2 equiv) was added. The reaction was carried out at 100 °C for 4 hours under nitrogen atmosphere, followed by cooling to room temperature. Sodium borohydride (1.5 equiv) was slowly added, and the reaction was carried out under nitrogen atmosphere for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to obtain a white solid 15.

[0046] Synthesis Route 4:

[0047]

[0048] Reagents and conditions: (a) Pyridine, dichloromethane, room temperature, 6 hours; (b) Sodium borohydride, acetic acid, 100℃-25℃, nitrogen atmosphere, 12 hours.

[0049] p-Aminobenzaldehyde (1.0 equiv) was dissolved in dichloromethane (10 mL), followed by the addition of the corresponding benzenesulfonyl chloride starting material. 0.5 mL of pyridine solution was slowly added dropwise, and the reaction was carried out at room temperature for 4 hours. After the reaction was complete, dilute hydrochloric acid solution was added dropwise until the pH was neutral. The mixture was then distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Extraction was performed with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated saline solution (20 mL × 2). The organic solvent was removed under reduced pressure, and the mixture was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to obtain white solids 7a-7d.

[0050] Products 7a-7d (1.0 equiv) were dissolved separately in acetic acid (10 mL), and lenalidomide (1.2 equiv) was added. The mixture was reacted at 100 °C for 4 hours under nitrogen atmosphere, then cooled to room temperature. Sodium borohydride (1.5 equiv) was slowly added, and the mixture was reacted under nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to give white solids 16-19.

[0051] Synthesis Route 5:

[0052]

[0053] Reagents and conditions: (a) Chloroacetyl chloride, sodium hydroxide, 0°C, 1 hour; (b) Lawson's reagent, tetrahydrofuran, reflux, 4 hours; (c) Phosphorus oxychloride, acetonitrile, reflux, 4 hours; (d) p-Hydroxybenzaldehyde, potassium carbonate, potassium iodide, dichloromethane, 45°C, 10 hours; (e) Sodium borohydride, acetic acid, 100°C-25°C, nitrogen atmosphere, 12 hours; (f) Potassium carbonate, potassium iodide, N,N-dimethylformamide, 45°C, 10 hours.

[0054] Chloroacetyl chloride (1.5 equiv) dissolved in dichloromethane (15 mL) was added dropwise to a solution of 8a (1 equiv) and triethylamine (2 equiv) in dichloromethane (30 mL). The mixture was kept at 0 °C for 2 hours, and then stirred at room temperature for 16 hours. The reaction solution was washed successively with 1N hydrochloric acid (2 × 15 mL), saturated sodium carbonate solution (2 × 15 mL), and brine (1 × 15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5:1, v / v) to give a white solid compound 9a.

[0055] Lawson's reagent (0.6 equiv) was added to a solution of tetrahydrofuran (20 mL) containing 9a (1 equiv), and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated and diluted with ethyl acetate (30 mL), washed with 1N sodium bicarbonate solution (2 × 20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 30:1, v / v) to give compound 10a as a white solid.

[0056] Phosphorus oxychloride (2 equates) was added to a 20 mL solution of acetonitrile containing 9a (1 equate) at room temperature. After the addition was complete, the solution was heated under reflux for 4 hours. The reaction mixture was concentrated and then diluted with ethyl acetate (25 mL), washed with water (2 × 15 mL), 1 N sodium bicarbonate solution (2 × 15 mL), and brine (25 mL). After drying, the solution was purified by column chromatography (petroleum ether / ethyl acetate, 20:1, v / v) to give compound 11a as a white solid.

[0057] Dissolve 10a or 11a (1.0 equiv) in 10 mL of acetonitrile, then add p-hydroxybenzaldehyde (1.2 equiv), potassium carbonate (3 equiv), and a catalytic amount of potassium iodide sequentially. React at 45 °C for 4 hours, monitoring the reaction by thin-layer chromatography. After the reaction is complete, cool the reaction mixture and filter it with diatomaceous earth. Wash the filter cake with ethyl acetate (5 mL × 3). Distill under reduced pressure, then add an appropriate amount of water and extract with ethyl acetate (15 mL × 3). Combine the organic phases, wash with saturated saline solution (20 mL × 2), dry, remove the organic solvent under reduced pressure, and purify by column chromatography (petroleum ether / ethyl acetate, 10:1, v / v) to obtain solid 12a or 13a.

[0058] Products 12a or 13a (1.0 equiv) were dissolved in acetic acid (10 mL), lenalidomide (1.2 equiv) was added, and the mixture was reacted at 100 °C for 4 hours under nitrogen atmosphere. The mixture was then cooled to room temperature, and sodium borohydride (1.5 equiv) was slowly added. The reaction was continued under nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The purified solid 20-21 was obtained by column chromatography (dichloromethane / methanol, 15:1, v / v).

[0059] Dissolve 10a or 11a (1.0 equiv) in N,N-dimethylformamide (10 mL), then add 14a (1.05 equiv), potassium carbonate (3 equiv), and a catalytic amount of potassium iodide sequentially. React at 45 °C for 4 hours, monitoring the reaction by thin-layer chromatography. After the reaction is complete, cool the reaction mixture and perform assisted filtration with diatomaceous earth. Wash the filter cake with ethyl acetate (5 mL × 3). Distill under reduced pressure, then add an appropriate amount of water and extract with ethyl acetate (15 mL × 3). Combine the organic phases, wash with saturated saline solution (20 mL × 2), dry, remove the organic solvent under reduced pressure, and purify by column chromatography (dichloromethane / methanol, 15:1, v / v) to obtain solids 22-23.

[0060] Synthesis Route 6:

[0061]

[0062] Reagents and conditions: (a) Sodium borohydride, methanol, 0℃, 2 hours; (b) Thionyl chloride, dichloromethane, N,N-dimethylformamide, room temperature, 6 hours; (c) Potassium carbonate, potassium iodide, 45℃, 10 hours.

[0063] 15a, 5b-5d, and 5h (1.0 equiv) were dissolved in methanol, and sodium borohydride (2.0 equiv) was slowly added under ice bath conditions. After the reaction was completed, an appropriate amount of water was added to the organic layer, and the mixture was distilled under reduced pressure. The organic phases were extracted with ethyl acetate (15 mL × 3), combined, and then washed with saturated saline solution (20 mL × 2). The mixture was dried, and the organic solvent was removed under reduced pressure. The mixture was purified by column chromatography (petroleum ether / ethyl acetate, 10:1, v / v) to obtain white solids 16a-16e.

[0064] 16a-16e (1.0 equiv) were dissolved separately in dichloromethane, and thionyl chloride (1.2 equiv) and a catalytic amount of N,N-dimethylformamide were slowly added. After the reaction was complete, an appropriate amount of water was added to the organic layer, and the mixture was distilled under reduced pressure. The extract was then extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The product was purified by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v) to obtain white solids 17a-17e. The above products 17a-17e (1.0 equiv) were dissolved separately in acetic acid (10 mL), and lenalidomide (1.2 equiv) was added. The mixture was reacted at 100 °C for 4 hours under nitrogen, then cooled to room temperature, and sodium borohydride (1.5 equiv) was slowly added. The mixture was then reacted under nitrogen for 2 hours. After the reaction was complete, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to obtain a white solid 24-28.

[0065] Synthesis Route 7:

[0066]

[0067] Reagents and conditions: (a) Triphosgene, triethylamine, dichloromethane, 0℃-25℃, 6 hours;

[0068] Triphosgene (0.33 equiv) was dissolved in dichloromethane. Under nitrogen and 0°C conditions, a dichloromethane solution containing the corresponding amine raw material (1 equiv) and triethylamine (3 equiv) was added dropwise. After reacting for 1 hour, a dichloromethane solution containing lenalidomide (1 equiv) and triethylamine (3 equiv) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was diluted with an appropriate amount of dichloromethane, washed with 10 mL of saturated brine, and the organic phase was collected, dried, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane, methanol, 15:1, v / v) to obtain a white solid 29-34.

[0069] Synthesis Route 8:

[0070]

[0071] Reagents and conditions: (a) Sodium carbonate, tetra(triphenylphosphine)palladium, 1,4-dioxane / water, 80°C, 18 hours; (b) Trifluoroacetic acid, dichloromethane, 0°C, 3 hours; (c) Triphosgene, triethylamine, dichloromethane, 0-25°C, 10 hours.

[0072] 19a (1.0 equiv) and aryl bromide starting material (1.5 equiv) were thoroughly dissolved in a 1,4-dioxane / water (9:1, v / v) mixed solvent (15 mL). Sodium carbonate (3.0 equiv) and tetrakis(triphenylphosphine)palladium (0.05 equiv) were added sequentially. Under N2 protection, the mixture was heated in an oil bath to 80 °C and stirred for 18 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered under reduced pressure, and the filtrate was evaporated to dryness. The filtrate was extracted, and the combined organic phases were evaporated to dryness. The resulting product was purified by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v) to give white solids 20a-20c.

[0073] Dissolve 20a-20c separately in dichloromethane (6 mL), then slowly add 6 mL of a trifluoroacetic acid / dichloromethane (1:1) mixture under ice-salt bath conditions. React for 2 hours, during which the reaction is monitored by thin-layer chromatography. After the reaction is complete, distill under reduced pressure and purify by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v) to obtain white solids 21a-21c.

[0074] Triphosgene (0.33 equiv) was dissolved in dichloromethane. Under nitrogen and 0°C conditions, a dichloromethane solution containing the corresponding amine raw material (1 equiv) and triethylamine (3 equiv) was added dropwise. After reacting for 1 hour, a dichloromethane solution containing lenalidomide (1 equiv) and triethylamine (3 equiv) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was diluted with an appropriate amount of dichloromethane, washed with 10 mL of saturated brine, and the organic phase was collected, dried, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to obtain a white solid 35-37.

[0075] Example 1

[0076] N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)phenyl)benzamide(1)

[0077]

[0078] p-Aminobenzaldehyde (1.0 equiv) was dissolved in 10 mL of dichloromethane solution, along with benzoic acid (1.1 equiv), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.2 equiv), and N,N-diisopropylethylamine (1.2 equiv). The reaction was carried out at room temperature for 8 hours, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The purified solid 2a was obtained by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v).

[0079] Product 2a (1.0 equiv) was dissolved in acetic acid (10 mL), and lenalidomide (1.2 equiv) was added. The mixture was reacted at 100 °C for 4 hours under nitrogen atmosphere, then cooled to room temperature. Sodium borohydride (1.5 equiv) was slowly added, and the mixture was reacted under nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to give a white solid 1. Yield: 27%, white powder. 1 H NMR (500MHz, DMSO-d6) δ11.04 (s, 1H), 10.23 (s, 1H), 7.95-7.91 (m, 2H), 7.71 (d, J=8.6Hz, 2H), 7.62-7.5 4 (m, 1H), 7.54-7.50 (m, 2H), 7.36 (d, J=8.6Hz, 2H), 7.21 (t, J=7.8Hz, 1H), 6.95-6.89 (m, 1H), 6.67-6.62 (m, 1H), 6.37 (t, J = 6.0Hz, 1H), 5.13 (dd, J = 13.3, 5.1Hz, 1H), 4.37 (d, J = 6.0Hz, 2H), 4.32 (d, J = 17.2Hz, 1 H), 4.20 (d, J=17.2Hz, 1H), 2.99-2.89 (m, 1H), 2.67-2.60 (m, 1H), 2.39-2.27 (m, 1H), 2.10-2.02 (m, 1H). 13C NMR (126MHz, DMSO-d6) δ172.98, 171.29, 168.88, 165.46, 143.35, 137.83, 134.97, 134.94, 132.10, 131.56, 1 29.11, 128.41, 127.64, 127.33, 126.78, 120.47, 112.44, 110.33, 51.58, 48.64, 45.83, 31.30, 22.84.TOF-MS m / z:calcd for:C 27 H 25 N4O4 + [M+H] + :469.1870, found:469.1853.

[0080] Example 2

[0081] N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)phenyl)-4-methylbenzamide(2)

[0082]

[0083] Synthetic method is the same as compound 1. Yield: 22%, white powder. 1 H NMR (500MHz, DMSO-d6) δ11.03 (s, 1H), 10.15 (s, 1H), 7.82 (d, J = 8.3Hz, 2H), 7.66 (d, J = 8.6Hz, 2H), 7.34 (d, J=8.3Hz, 2H), 7.31 (d, J=7.9Hz, 2H), 7.20 (t, J=7.7Hz, 1H), 6.92 (d, J=7.4Hz, 1H), 6.63 (d, J=8.1Hz , 1H), 6.38 (t, J=6.0Hz, 1H), 5.08 (dd, J=13.3, 5.1Hz, 1H), 4.36 (d, J=6.0Hz, 2H), 4.30 (d, J=17.2Hz, 1H ), 4.18(d, J=17.2Hz, 1H), 2.94-2.85(m, 1H), 2.67-2.59(m, 1H), 2.38-2.33(m, 4H), 2.08-2.01(m, 1H). 13C NMR (126MHz, DMSO-d6) δ173.41, 171.51, 169.39, 165.77, 143.53, 141.99, 138.00, 135.24, 132.25, 132.21, 129. 47, 129.26, 127.91, 127.58, 126.94, 120.85, 112.80, 110.65, 51.92, 46.17, 45.97, 31.51, 22.98, 21.29.TOF-MS m / z:calcd for:C 28 H 27 N4O4 + [M+H] + :483.2027, found:483.2016.

[0084] Example 3

[0085] N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)phenyl)-2-(4-fluorophenyl)acetamide(3)

[0086]

[0087] Synthetic method is the same as compound 1. Yield: 23%, white powder. 1 H NMR (500MHz, DMSO-d6) δ11.03 (s, 1H), 10.78 (s, 1H), 7.64-7.59 (m, 3H), 7.56-7.49 (m, 1H), 7 .26 (d, J=8.1Hz, 2H), 7.18 (t, J=7.7Hz, 1H), 7.05 (d, J=8.1Hz, 2H), 6.92 (d, J=7.4Hz, 1H), 6.5 7 (d, J=8.1Hz, 1H), 6.24 (t, J=5.9Hz, 1H), 5.12 (dd, J=13.2, 5.1Hz, 1H), 4.38-4.23 (m, 4H), 4. 20-4.10(m, 2H), 2.98-2.87(m, 1H), 2.66-2.59(m, 1H), 2.36-2.24(m, 1H), 2.08-2.00(m, 1H). 13C NMR (126MHz, DMSO-d6) δ172.94, 171.24, 171.21, 168.80, 166.25, 143.25, 135.44, 135.42, 134.43, 134.08, 133.99, 132.07, 131.89, 129.06, 128.06, 126.78, 118.87, 112.26, 110.37, 51.52, 48.62, 45.75, 45.55, 31.27, 22.81.TOF-MS m / z:calcd for:C 28 H 26 FN4O4 + [M+H] + :501.1933, found:501.1921.

[0088] Example 4

[0089] N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)phenyl)quinoline-6-carboxamide(4)

[0090]

[0091] Synthetic method is the same as compound 1. Yield: 24%, white powder. 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 10.49 (s, 1H), 9.09-9.00 (m, 1H), 8.70-8.59 (m, 1H), 8.53 (d, J=8.1Hz ,1H), 8.25 (d, J=8.8Hz, 1H), 8.13 (d, J=8.8Hz, 1H), 7.76 (d, J=8.2Hz, 2H), 7.72-7.61 (m, 1H), 7.40 (d, J=8.2H z, 2H), 7.22 (t, J=7.8Hz, 1H), 6.97-6.87 (m, 1H), 6.74-6.61 (m, 1H), 6.37 (t, J=5.9Hz, 1H), 5.13 (dd, J=13.3 , 5.0Hz, 1H), 4.51-4.15(m, 4H), 3.02-2.87(m, 1H), 2.76-2.58(m, 1H), 2.42-2.26(m, 1H), 2.10-2.00(m, 1H). 13C NMR (101MHz, DMSO-d6) δ172.98, 171.29, 168.87, 165.01, 152.27, 148.76, 143.36, 137.78, 137.20, 135.13, 132.80, 132.1 1, 129.12, 128.41, 128.08, 127.41, 127.10, 126.79, 122.31, 120.50, 112.43, 110.34, 51.58, 45.83, 31.29, 22.84.TOF-MS m / z:calcd for:C 30 H 26 N5O4 + [M+H] + :520.1979, found:520.1968.

[0092] Example 5

[0093] N-(4-chlorophenyl)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)benzamide(5)

[0094]

[0095] p-Aldehydebenzoic acid (1.0 equiv) was dissolved in 10 mL of dichloromethane solution, along with p-chloroaniline (1.1 equiv), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (1.2 equiv), and N,N-diisopropylethylamine (1.2 equiv). The reaction was carried out at room temperature for 8 hours, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The purified solid 5a was obtained by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v).

[0096] Product 5a (1.0 equiv) was dissolved in acetic acid (10 mL), and lenalidomide (1.2 equiv) was added. The mixture was reacted at 100 °C for 4 hours under nitrogen atmosphere, then cooled to room temperature. Sodium borohydride (1.5 equiv) was slowly added, and the mixture was reacted under nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The product was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to obtain a white solid 5. Yield: 19.8%, white powder. 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 10.31 (s, 1H), 7.89 (d, J = 8.2Hz, 2H), 7.80 (d, J = 8.9Hz, 2H), 7.5 3(d, J=8.2Hz, 2H), 7.40 (d, J=8.9Hz, 2H), 7.25-7.14 (m, 1H), 6.93 (d, J=7.4Hz, 1H), 6.61 (d, J=8.0Hz, 1H), 6.50 (t, J=6.1Hz, 1H), 5.13 (dd, J=13.2, 5.1Hz, 1H), 4.49 (d, J=6.0Hz, 2H), 4.34 (d, J=17.2Hz, 1H ), 4.22 (d, J=17.2Hz, 1H), 3.02-2.86 (m, 1H), 2.69-2.58 (m, 1H), 2.42-2.25 (m, 1H), 2.14-1.98 (m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.97, 171.30, 168.80, 165.26, 146.17, 143.63, 136.71, 133.66, 133.40, 132.52, 132.17, 1 28.99, 127.75, 127.63, 126.94, 126.91, 120.31, 112.53, 112.41, 110.47, 51.57, 46.39, 45.80, 31.29, 22.83.TOF-MS m / z:calcd for:C 27 H 24 ClN4O4 + [M+H] + :503.1481, found:503.1470.

[0097] Example 6

[0098] 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)-N-(p-tolyl)benzamide(6)

[0099]

[0100] Synthetic method is the same as compound 5. Yield: 20.8%, white powder. 1 H NMR (500MHz, DMSO-d6) δ11.05 (s, 1H), 10.11 (s, 1H), 7.88 (d, J = 8.2Hz, 2H), 7.63 (d, J = 8.1Hz, 2H), 7.52 (d , J=8.2Hz, 2H), 7.20 (t, J=7.7Hz, -H), 7.14 (d, J=8.1Hz, 2H), 6.93 (d, J=7.4Hz, 1H), 6.61 (d, J=8.1Hz, 1H), 6.52 (t, J=6.1Hz, 1H), 5.13 (dd, J=13.3, 5.1Hz, 1H), 4.49 (d, J=6.1Hz, 2H), 4.34 (d, J=17.1Hz, 1H), 4.22 (d , J=17.2Hz, 1H), 2.98-2.89(m, 1H), 2.67-2.60(m, 1H), 2.41-2.31(m, 1H), 2.26(s, 3H), 2.12-2.02(m, 1H). 13 C NMR (126MHz, DMSO-d6) δ172.96, 171.29, 168.81, 165.24, 143.62, 143.16, 136.68, 133.65, 132.54, 132.16, 129. 11, 128.99, 127.74, 126.91, 126.82, 120.32, 112.42, 110.49, 51.59, 45.82, 40.11, 31.30, 22.83, 20.52.TOF-MS m / z:calcd for:C 28 H 27 N4O4 + [M+H] + :483.2027, found:483.2019.

[0101] Example 7

[0102] N-(cyclopropylmethyl)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)benzamide(7)

[0103]

[0104] Synthetic method is the same as compound 5. Yield: 19%, white powder. 1 H NMR (500MHz, DMSO-d6) δ11.04 (s, 1H), 8.49 (t, J = 5.7Hz, 1H), 7.79 (d, J = 8.2Hz, 2H), 7.45 (d, J = 8.2Hz, 2H), 7.18 (t, J=7.7Hz, 1H), 6.95-6.90 (m, 1H), 6.59 (d, J=8.0Hz, 1H), 6.47 (t, J=6.1Hz, 1H), 5.12 (dd, J=13.3, 5.1Hz, 1H), 4.45 (d, J=6.0Hz, 2H), 4.32 (d, J=17.2Hz, 1H), 4.21 (d, J=17.2Hz, 1H), 3.15-3.08 (m, 2H), 2.99-2.87 (m, 1H), 2. 66-2.59 (m, 1H), 2.38-2.28 (m, 1H), 2.09-2.02 (m, 1H), 1.05-0.96 (m, 1H), 0.44-0.38 (m, 2H), 0.23-0.17 (m, 2H). 13 C NMR (126MHz, DMSO-d6) δ172.97, 171.28, 168.81, 165.99, 143.20, 143.07, 133.26, 132.14, 129.10 , 127.31, 126.79, 112.39, 110.46, 51.59, 48.63, 45.86, 43.44, 31.29, 22.83, 11.06, 3.30.TOF-MS m / z:calcdfor:C 24 H 27 N4O4 + [M+H] + :447.2027, found:447.2019.

[0105] Example 8

[0106] N-Benzyl-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)benzamide(8)

[0107]

[0108] Synthetic method is the same as compound 5. Yield: 24%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 9.00 (t, J=6.0Hz, 1H), 7.85 (d, J=7.9Hz, 2H), 7.47 (d, J=7 .9Hz, 2H), 7.34-7.27(m, 4H), 7.26-7.16(m, 2H), 6.93(d, J=7.4Hz, 1H), 6.60(d, J=8.1Hz, 1H), 6. 47 (t, J=6.0Hz, 1H), 5.13 (dd, J=13.3, 5.2Hz, 1H), 4.52-4.41 (m, 4H), 4.34 (d, J=17.2Hz, 1H), 4.2 2(d, J=17.2Hz, 1H), 2.99-2.87(m, 1H), 2.69-2.58(m, 1H), 2.40-2.26(m, 1H), 2.12-2.00(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.96, 171.28, 168.79, 166.07, 143.31, 143.18, 139.73, 132.94, 132.15, 129.09, 128. 26, 127.37, 127.15, 126.87, 126.80, 126.70, 112.36, 110.46, 51.58, 45.85, 45.80, 42.56, 31.29, 22.83.TOF-MS m / z:calcd for:C 28 H 27 N4O4 + [M+H] + :483.2027, found:483.2015.

[0109] Example 9

[0110] N-(4-chlorobenzyl)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)benzamide(9)

[0111]

[0112] Synthetic method is the same as compound 5. Yield: 19%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 9.10-8.93 (m, 1H), 7.84 (d, J=8.3Hz, 2H), 7.47 (d, J=8.3H z, 2H), 7.42-7.24 (m, 4H), 7.19 (t, J=7.7Hz, 1H), 6.93 (d, J=7.4Hz, 1H), 6.59 (d, J=8.0Hz, 1H), 6. 46 (t, J=6.0Hz, 1H), 5.13 (dd, J=13.3, 5.1Hz, 1H), 4.53-4.39 (m, 4H), 4.33 (d, J=17.2Hz, 1H), 4.2 1(d, J=17.2Hz, 1H), 3.01-2.86(m, 1H), 2.72-2.57(m, 1H), 2.41-2.25(m, 1H), 2.15-2.01(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.94, 171.27, 168.79, 166.12, 143.41, 143.17, 138.79, 132.78, 132.15, 131.24, 129.04, 128.21, 127.37, 126.89, 126.79, 112.36, 110.46, 51.56, 45.83, 45.78, 41.94, 31.27, 22.82.TOF-MS m / z:calcd for:C 28 H 26 ClN4O4 + [M+H] + :517.1637, found:517.1625.

[0113] Example 10

[0114] 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)-N-(4-methoxybenzyl)benzamide(10)

[0115]

[0116] Synthetic method is the same as compound 5. Yield: 21%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 8.91 (t, J=6.0Hz, 1H), 7.83 (d, J=8.2Hz, 2H), 7.46 (d, J=8.2H z, 2H), 7.30-7.14 (m, 3H), 6.93 (d, J=7.4Hz, 1H), 6.90-6.83 (m, 2H), 6.59 (d, J=8.0Hz, 1H), 6.45 (t, J =6.1Hz, 1H), 5.13 (dd, J = 13.2, 5.1Hz, 1H), 4.53-4.36 (m, 4H), 4.33 (d, J = 17.2Hz, 1H), 4.21 (d, J = 17 .2Hz, 1H), 3.71(s, 3H), 3.03-2.85(m, 1H), 2.70-2.56(m, 1H), 2.42-2.24(m, 1H), 2.12-1.98(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.94, 171.27, 168.80, 165.94, 158.16, 143.24, 143.19, 133.03, 132.15, 131.69, 129.09, 128 .54, 127.35, 127.35, 126.84, 126.79, 113.67, 112.36, 110.46, 55.05, 51.57, 45.84, 45.79, 42.01, 31.28, 22.82.TOF-MS m / z:calcd for:C 29 H 29 N4O5 + [M+H] + :513.2132, found:513.2120.

[0117] Example 11

[0118] 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)-N-(4-methylbenzyl)benzamide(11)

[0119]

[0120] Synthetic method is the same as compound 5. Yield: 23%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 8.93 (t, J = 6.0Hz, 1H). 7.83 (d, J = 8.3Hz, 2H), 7.46 (d, J = 8.3H z, 2H), 7.26-7.15 (m, 3H), 7.15-7.04 (m, 2H), 6.93 (d, J=7.4Hz, 1H), 6.60 (d, J=8.0Hz, 1H), 6.45 (t, J =6.1Hz, 1H), 5.12 (dd, J = 13.3, 5.1Hz, 1H), 4.51-4.38 (m, 4H), 4.33 (d, J = 17.2Hz, 1H), 4.21 (d, J = 17 .2Hz, 1H), 3.01-2.84(m, 1H), 2.71-2.57(m, 1H), 2.41-2.28(m, 1H), 2.26(s, 3H), 2.13-1.99(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.95, 171.27, 168.80, 166.00, 143.27, 143.19, 136.70, 135.72, 133.00, 132.15, 129.10, 128.80, 127.36, 127.17, 126.86, 126.80, 112.36, 110.46, 51.57, 45.84, 45.79, 42.30, 31.28, 22.82, 20.67.TOF-MS m / z:calcd for:C 29 H 29 N4O4 + [M+H] + :497.2183, found:497.2174.

[0121] Example 12

[0122] 3-(1-oxo-4-((4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzyl)amino)isoindoline-2-yl)piperidin-2,6-dione (12)

[0123]

[0124] Synthetic method is the same as compound 5. Yield: 22%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 7.47 (d, J = 8.2Hz, 2H), 7.41 (d, J = 7.2Hz, 2H), 7.28-7.12 (m, 5H), 6.99-6 .91 (m, 1H), 6.66 (d, J = 8.0Hz, 1H), 6.44 (t, J = 6.0Hz, 1H), 5.13 (dd, J = 13.3, 5.1Hz, 1H), 4.82-4.65 (m, 1H), 4.55 (d, J=5.7Hz, 1H), 4.46 (d, J=6.0Hz, 2H), 4.33 (d, J=17.1Hz, 1H), 4.22 (d, J=17.1Hz, 1H), 3.93-3.72 (m, 1H), 3.6 4-3.44(m, 1H), 3.01-2.91(m, 1H), 2.87-2.79(m, 2H), 2.68-2.58(m, 1H), 2.40-2.26(m, 1H), 2.10-2.01(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.94, 171.27, 168.81, 162.32, 143.25, 141.55, 134.58, 133.09, 132.17, 129.73, 129.17, 128.67 , 127.05, 126.76, 126.45, 126.30, 126.22, 112.28, 110.46, 70.79, 62.53, 51.56, 45.80, 35.79, 31.27, 30.78, 22.82.TOF-MS m / z:calcd for:C 30 H 29 N4O4 + [M+H] + :509.2183, found:509.2167.

[0125] Example 13

[0126] 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)-N-(1-phenylethyl)benzamide (13)

[0127]

[0128] Synthetic method is the same as compound 5. Yield: 27%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 7.58-7.26 (m, 8H), 7.25-7.17 (m, 2H), 6 .96-6.91(m,1H),6.70-6.61(m,1H),6.46-6.36(m,1H),5.13(dd,1H),4.64-4 .38(m, 4H), 4.32(d, J=17.2Hz, 1H), 4.21(d, J=17.2Hz, 1H), 3.00-2.89(m, 1H) , 2.68-2.58(m, 1H), 2.39-2.26(m, 1H), 2.09-2.02(m, 1H), 1.35-1.12(m, 3H). 13 C NMR (101MHz, DMSO-d6) δ172.94, 171.26, 170.36, 168.80, 143.64, 143.26, 132.26, 132.15, 129.15, 128.84, 128.20, 127.17, 126.76, 126.59, 126.17, 125.60, 112.27, 110.44, 59.77, 51.55, 45.79, 31.27, 22.82, 20.77, 14.10.TOF-MS m / z:calcd for:C 29 H 29 N4O4 + [M+H] + : 497.2183.found: 497.2170.

[0129] Example 14

[0130] N-Benzyl-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)-N-methylbenzamide (14)

[0131]

[0132] Synthetic method is the same as compound 5. Yield: 21%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 8.94 (t, J = 6.0Hz, 1H), 7.84 (d, J = 8.3Hz, 2H), 7.47 (d, J = 8.3H z, 2H), 7.22-7.15 (m, 3H), 7.15-7.08 (m, 2H), 6.93 (d, J=7.4Hz, 1H), 6.60 (d, J=8.0Hz, 1H), 6.46 (t, J =6.1Hz, 1H), 5.13 (dd, J = 13.3, 5.1Hz, 1H), 4.50-4.39 (m, 4H), 4.33 (d, J = 17.2Hz, 1H), 4.21 (d, J = 17 .2Hz,1H), 3.00-2.88(m,1H), 2.68-2.58(m,1H), 2.40-2.29(m,1H), 2.26(s,3H), 2.10-2.01(m,1H). 13 C NMR (101MHz, DMSO-d6) δ172.96, 171.28, 168.79, 165.98, 143.27, 143.18, 136.70, 135.71, 132.99, 132.15, 129.10, 128.80, 127.36, 127.16, 126.86, 126.79, 112.35, 110.45, 51.56, 45.83, 45.79, 42.30, 31.29, 22.83, 20.69.TOF-MS m / z:calcd for:C 29 H 29 N4O4 + [M+H] + :497.2183, found:497.2171.

[0133] Example 15

[0134] 1-Benzyl-3-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)phenyl)urea(15)

[0135]

[0136] Yield: 20%, white powder. 1H NMR (500MHz, DMSO-d6) δ11.03 (s, 1H), 8.51 (s, 1H), 7.37-7.26 (m, 6H), 7.26-7.16 (m, 4H), 6.91 (d, J = 7.3Hz, 1H), 6.64 (d, J = 8.0Hz, 1H), 6.57 (t, J = 6 .0Hz, 1H), 6.29 (t, J=6.0Hz, 1H), 5.17-5.08 (m, 1H), 4.33-4.11 (m, 6H), 2. 97-2.86(m, 1H), 2.66-2.58(m, 1H), 2.37-2.25(m, 1H), 2.08-2.00(m, 1H). 13 C NMR (126MHz, DMSO-d6) δ172.95, 171.27, 168.86, 155.26, 143.39, 140.38, 139.15, 132.16, 132.05, 129.06, 128.31, 127.50, 127.11, 126.72, 117.78, 112.41, 110.23, 51.56, 48.63, 45.81, 45.77, 31.28, 22.83.TOF-MS m / z:calcd for:C 28 H 28 N5O4 + [M+H] + :498.2136, found:498.2125.

[0137] Example 16

[0138] N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)phenyl)benzenesulfonamide (16)

[0139]

[0140] p-Aminobenzaldehyde (1.0 equiv) was dissolved in dichloromethane (10 mL), followed by the addition of benzenesulfonyl chloride, and then 0.5 mL of pyridine solution was slowly added dropwise. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, dilute hydrochloric acid solution was added dropwise until the pH was neutral. The mixture was then distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to obtain a white solid 7a.

[0141] Product 7a (1.0 equiv) was dissolved in acetic acid (10 mL), and lenalidomide (1.2 equiv) was added. The mixture was reacted at 100 °C for 4 hours under nitrogen atmosphere, then cooled to room temperature. Sodium borohydride (1.5 equiv) was slowly added, and the mixture was reacted under nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The product was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to give a white solid 16. Yield: 26%, white powder. 1 H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 10.22 (s, 1H), 7.77-7.71 (m, 2H), 7.62-7.55 (m, 1H), 7 .57-7.47(m, 2H), 7.23(d, J=8.5Hz, 2H), 7.18(t, J=7.7Hz, 1H), 7.03(d, J=8.5Hz, 2H), 6.92(d , J=7.4Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 6.24 (t, J=5.9Hz, 1H), 5.11 (dd, J=13.2, 5.1Hz, 1H), 4. 34-4.10(m, 4H), 2.98-2.86(m, 1H), 2.67-2.57(m, 1H), 2.36-2.23(m, 1H), 2.08-1.98(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.94, 171.25, 168.82, 143.27, 139.66, 136.35, 135.45, 132.82, 132.07, 129. 22, 129.07, 127.93, 126.76, 126.64, 120.30, 112.29, 110.36, 51.54, 45.76, 45.60, 31.27, 22.82.TOF-MS m / z:calcd for:C 26 H 25 N4O5S + [M+H] + :505.1540, found:505.1532.

[0142] Example 17

[0143] N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)phenyl)-4-methylbenzenesulfonamide (17)

[0144]

[0145] Synthetic method is the same as compound 16. Yield: 21%, white powder. 1 H NMR (500MHz, DMSO-d6) δ11.03 (s, 1H), 10.16 (s, 1H), 7.61 (d, J=8.0Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 7.18 (t, J=7.5Hz, 1H), 7.02 (d, J=8.5Hz, 2H), 6.91 (d, J=7. 4Hz, 1H), 6.57 (d, J=8.1Hz, 1H), 6.25 (t, J=5.9Hz, 1H), 5.11 (dd, J=13.3, 5.1Hz, 1H), 4.31 -4.11(m, 4H), 2.98-2.87(m, 1H), 2.66-2.57(m, 1H), 2.35-2.23(m, 4H), 2.07-1.99(m, 1H). 13 C NMR (126MHz, DMSO-d6) δ172.96, 171.26, 168.83, 143.27, 143.18, 136.77, 136.39, 135.36, 132.08, 129.67, 129.08, 127.93, 126.76, 126.71, 120.15, 112.30, 110.36, 51.54, 45.77, 45.60, 31.28, 22.83, 20.97.TOF-MS m / z:calcd for:C 27 H 27 N4O5S + [M+H] + :519.1697, found:519.1689.

[0146] Example 18

[0147] N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)phenyl)-4-methoxybenzenesulfonamide (18)

[0148]

[0149] Synthetic method is the same as compound 16. Yield: 25%, white powder. 1H NMR (500MHz, DMSO-d6) δ11.02 (s, 1H), 10.09 (s, 1H), 7.68-7.63 (m, 2H), 7.24-7.20 ( m, 2H), 7.17 (t, J=7.7Hz, 1H), 7.05-6.97 (m, 4H), 6.93-6.89 (m, 1H), 6.56 (d, J=8.1H z, 1H), 6.26 (t, J=6.0Hz, 1H), 5.10 (dd, J=13.3, 5.1Hz, 1H), 4.27-4.15 (m, 4H), 3.77 (s, 3H), 2.97-2.84 (m, 1H), 2.66-2.58 (m, 1H), 2.37-2.25 (m, 1H), 2.08-1.98 (m, 1H). 13 C NMR (126MHz, DMSO-d6) δ173.07, 171.31, 168.96, 162.44, 143.32, 136.55, 135.36, 132.12, 131.29, 129.17, 128.96, 127.97, 126.80, 120.17, 114.42, 112.39, 110.44, 55.71, 51.63, 48.71, 45.64, 31.34, 22.86.TOF-MS m / z:calcd for:C 27 H 27 N4O6S + [M+H] + :535.1646, found:535.1637.

[0150] Example 19

[0151] 2,6-Dichloro-N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)methyl)phenyl)benzenesulfonamide (19)

[0152]

[0153] Synthetic method is the same as compound 16. Yield: 24%, white powder. 1H NMR (500MHz, DMSO-d6) δ11.03 (s, 1H), 10.14 (s, 1H), 7.52 (d, J=8.4Hz, 2H), 7.35-7.33 (m, 1H), 7.30 (d, J = 8.4Hz, 2H), 7.18 (t, J = 7.8Hz, 1H), 7.16-7.12 (m, 2H), 6.94-6.88 (m , 1H), 6.64-6.58 (m, 1H), 6.33 (t, J=6.0Hz, 1H), 5.12 (dd, J=13.3, 5.1Hz, 1H), 4.36-4. 15(m, 4H), 2.97-2.87(m, 1H), 2.65-2.58(m, 1H), 2.36-2.26(m, 1H), 2.08-2.00(m, 1H). 13 C NMR (126MHz, DMSO-d6) δ172.95, 171.26, 168.84, 143.31, 137.83, 134.47, 132.18, 132.16, 132.07, 130. 99, 130.92, 129.06, 127.43, 126.73, 119.18, 112.37, 110.29, 51.55, 45.74, 42.26, 31.28, 22.82.TOF-MS m / z:calcd for:C 26 H 23 Cl2N4O5S + [M+H] + :573.0761, found:573.0751.

[0154] Example 20

[0155] 3-(1-oxo-4-((4-((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methoxy)benzyl)amino)isoindoline-2-yl)piperidine-2,6-dione (20)

[0156]

[0157] Yield: 27.4%, white powder. 1H NMR (500MHz, DMSO-d6) δ11.03 (s, 1H), 7.89 (d, J=8.2Hz, 2H), 7.41 (d, J=8.2Hz, 2H), 7.35 (d, J=8.6Hz, 2H), 7.19 (t, J=7.7Hz, 1H), 7.06 (d, J=8.6Hz, 2H), 6.91 (d, J=7.4Hz, 1H), 6.64 (d, J= 8.1Hz, 1H), 6.32 (t, J=6.0Hz, 1H), 5.44 (s, 2H), 5.12 (dd, J=13.3, 5.2Hz, 1H), 4.36-4.14 (m, 4 H), 2.97-2.89(m, 1H), 2.65-2.59(m, 1H), 2.39(s, 3H), 2.36-2.23(m, 1H), 2.10-2.00(m, 1H). 13 C NMR (126MHz, DMSO-d6) δ172.94, 171.26, 168.83, 164.83, 162.48, 156.25, 143.29, 142.51, 132.98, 132.08, 130.08, 129 .08, 128.46, 126.75, 126.63, 120.27, 114.85, 112.36, 110.30, 59.70, 51.55, 45.79, 45.47, 31.28, 22.82, 21.16.TOF-MS m / z:calcd for:C 30 H 28 N5O4S + [M+H] + :554.1857, found:554.1845.

[0158] Example 21

[0159] 3-(1-oxo-4-((4-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)methoxy)benzyl)amino)isoindoline-2-yl)piperidin-2,6-dione (21)

[0160]

[0161] Yield: 26%, white powder. 1H NMR (500MHz, DMSO-d6) δ11.02 (s, 1H), 7.89 (d, J = 8.2Hz, 2H), 7.41 (d, J = 8.2Hz, 2H), 7.35 (d, J=8.5Hz, 2H), 7.19 (t, J=7.7Hz, 1H), 7.05 (d, J=8.5Hz, 2H), 6.91 (d, J=7.4Hz, 1H), 6.64 (d, J= 8.1Hz, 1H), 6.32 (t, J=6.0Hz, 1H), 5.43 (s, 2H), 5.11 (dd, J=13.3, 5.1Hz, 1H), 4.39-4.13 (m, 4 H), 2.97-2.86 (m, 1H), 2.67-2.56 (m, 1H), 2.39 (s, 3H), 2.34-2.24 (m, 1H), 2.07-1.98 (m.1H). 13 C NMR (126MHz, DMSO-d6) δ172.93, 171.24, 168.82, 164.82, 162.48, 156.25, 143.29, 142.50, 132.98, 132.07, 130.08, 129 .07, 128.46, 126.75, 126.62, 120.27, 114.84, 112.36, 110.29, 59.70, 51.54, 45.78, 45.47, 31.27, 22.81, 21.16.TOF-MS m / z:calcd for:C 30 H 28 N5O5 + [M+H] + :538.2085, found:538.2073.

[0162] Example 22

[0163] 3-(1-oxo-4-((5-(p-tolyl)-1,3,4-thiadiazol-2-yl)methoxy)isoindoline-2-yl)piperidin-2,6-dione (22)

[0164]

[0165] Yield: 19%, white powder. 1H NMR (400MHz, DMSO-d6) δ10.14 (s, 1H), 7.86-7.80 (m, 2H), 7.38-7.32 (m, 3H), 7.20 (d, J=7.4Hz, 1H), 7.03 (d, J=7.9Hz, 1H), 5.38-5.18 (m, 3H), 4.37 (d, J=17.1Hz, 1H), 4.19 (d, J=17.1Hz, 1H), 3.19-3.05 (m, 1H), 2.93-2.81 (m, 1H), 2.44-2.28 (m, 4H), 2.14-2.04 (m, 1H). 13 C NMR (101MHz, DMSO-d6) δ171.59, 170.50, 169.13, 168.39, 164.41, 152.61, 141.42, 133.27, 130.04, 130.01, 129.56, 127.99, 127.66, 127.51, 126.81, 118.11, 113.85, 52.12, 45.09, 38.39, 31.31, 21.64, 21.00.TOF-MS m / z:calcd for:C 23 H 21 N4O4S + [M+H] + :449.1278, found:449.1269.

[0166] Example 23

[0167] 3-(1-oxo-4-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)methoxy)isoindoline-2-yl)piperidin-2,6-dione (23)

[0168]

[0169] Yield: 23%, white powder. 1 H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 7.90 (d, J=7.9Hz, 2H), 7.59-7.52 (m, 1H), 7.48 (d, J=8.1Hz, 1H), 7.45-7.36 (m, 3H), 5.65 (s, 2H), 5.11 (dd, J=13. 3, 5.1Hz, 1H), 4.43 (d, J = 17.5Hz, 1H), 4.28 (d, J = 17.5Hz, 1H), 3.02-2.79 (m , 1H), 2.61-2.53(m, 1H), 2.47-2.41(m, 1H), 2.39(s, 3H), 2.14-1.84(m, 1H).13 C NMR (101MHz, DMSO-d6) δ172.90, 170.98, 167.82, 164.97, 162.16, 152.57, 142.58, 133.61, 130.13, 130.10, 130.01, 126.69, 120.24, 116.45, 115.47, 60.06, 51.68, 45.11, 31.24, 22.36, 21.18.TOF-MS m / z:calcd for:C 23 H 21 N4O5 + [M+H] + :433.1506, found: 433.1492.

[0170] Example 24

[0171] N-Cyclopropyl-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)benzamide (24)

[0172]

[0173] Dissolve 15a (1.0 equiv) in methanol, and slowly add sodium borohydride (2.0 equiv) under ice bath conditions. After the reaction is complete, add an appropriate amount of water to the organic layer, distill under reduced pressure, and extract with ethyl acetate (15 mL × 3). Combine the organic phases, wash with saturated saline solution (20 mL × 2), dry, and purify by column chromatography (petroleum ether / ethyl acetate, 10:1, v / v) to obtain white solid 16a.

[0174] Dissolve 16a (1.0 equiv) in dichloromethane, slowly add thionyl chloride (1.2 equiv) and a catalytic amount of N,N-dimethylformamide. After the reaction is complete, add an appropriate amount of water, distill under reduced pressure, and extract with ethyl acetate (15 mL × 3). Combine the organic phases, wash with saturated saline solution (20 mL × 2), dry, and purify by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v) to obtain white solid 17a.

[0175] The above product 17a (1.0 equiv) was dissolved in acetic acid (10 mL), and lenalidomide (1.2 equiv) was added. The reaction was carried out at 100 °C for 4 hours under nitrogen atmosphere, followed by cooling to room temperature. Sodium borohydride (1.5 equiv) was slowly added, and the reaction was carried out under nitrogen atmosphere for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure, and an appropriate amount of water was added to the organic layer. Saturated sodium bicarbonate solution was added dropwise until the pH was neutral. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was then washed with saturated saline solution (20 mL × 2), dried, and the organic solvent was removed under reduced pressure. The product was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to give a white solid 24. Yield: 21%, white powder. 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 8.45 (d, J = 4.2Hz, 1H), 7.81 (d, J = 8.3Hz, 2H), 7.54 (d, J =8.3Hz, 2H), 7.47 (t, J = 7.8Hz, 1H), 7.36-7.26 (m, 2H), 5.30 (s, 2H), 5.09 (dd, J = 13.3, 5.1Hz, 1 H), 4.44 (d, J = 17.5Hz, 1H), 4.28 (d, J = 17.5Hz, 1H), 3.16 (d, J = 4.6Hz, 1H), 2.87-2.78 (m, 1H), 2 .63-2.52(m, 1H), 2.47-2.38(m, 1H), 2.04-1.94(m, 1H), 0.72-0.64(m, 2H), 0.58-0.51(m, 2H). 13 C NMR (101MHz, DMSO-d6) δ173.06, 171.13, 168.20, 167.42, 153.39, 139.84, 134.11, 133.44, 130.12 , 130.00, 127.48, 127.34, 115.53, 115.22, 69.11, 51.79, 45.30, 31.32, 23.17, 22.49, 5.88.TOF-MS m / z:calcd for:C 24 H 24 N3O5 + [M+H] + :434.1710, found: 434.1702.

[0176] Example 25

[0177] 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)-N-(p-tolyl)benzamide (25)

[0178]

[0179] Synthetic method is the same as compound 24. Yield: 22%, white powder. 1 H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 10.16 (s, 1H), 7.96 (d, J=7.9Hz, 2H), 7.64 (t, J= 8.4Hz, 4H), 7.49 (t, J=7.8Hz, 1H), 7.33 (t, J=8.0Hz, 2H), 7.15 (d, J=8.1Hz, 2H), 5-36 (s , 2H), 5.12 (dd, J=13.3, 5.1Hz, 1H), 4.46 (d, J=17.5Hz, 1H), 4.31 (d, J=17.5Hz, 1H).2. 98-2.85(m, 1H), 2.64-2.55(m, 1H), 2.48-2.40(m, 1H), 2.28(s, 3H), 2.04-2.00(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.88, 171.02, 168.00, 165.02, 153.28, 140.14, 136.60, 134.65, 133.40, 132.62, 130. 05, 129.85, 128.99, 127.83, 127.33, 120.34, 115.42, 115.08, 68.95, 51.65, 45.14, 31.23, 22.41, 20.50.TOF-MS m / z:calcd for:C 28 H 26 N3O5 + [M+H] + :484.1867, found:484.1854.

[0180] Example 26

[0181] N-(cyclopropylmethyl)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)benzamide (26)

[0182]

[0183] Synthetic method is the same as compound 24. Yield: 20%, white powder. 1H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 8.55 (t, J=5.7Hz, 1H), 7.87 (d, J=8.1Hz, 2H), 7.56 (d, J=8.1 Hz, 2H), 7.48 (t, J=7.8Hz, 1H), 7.37-7.28 (m, 2H), 5.32 (s, 2H), 5.12 (dd, J=13.3, 5.1Hz, 1H), 4.45 ( d, J=17.5Hz, 1H), 4.29 (d, J=17.5Hz, 1H), 3.14 (t, J=6.2Hz, 2H), 2.98-2.84 (m, 1H), 2.62-2.53 (m, 1 H), 2.48-2.38(m, 1H), 2.04-1.95(m, 1H), 1.08-0.97(m, 1H), 0.47-0.38(m, 2H), 0.27-0.18(m, 2H). 13 C NMR (101MHz, DMSO-d6) δ172.89, 171.02, 168.02, 165.80, 153.32, 139.67, 134.27, 133.39, 130.03, 12 9.85, 127.41, 127.26, 115.40, 115.08, 69.03, 51.64, 45.14, 43.49, 31.24, 22.41, 11.02, 3.30.TOF-MS m / z:calcd for:C 25 H 26 N3O5 + [M+H] + :448.1867, found: 448.1859.

[0184] Example 27

[0185] N-Benzyl-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methyl)benzamide (27)

[0186]

[0187] Synthetic method is the same as compound 24. Yield: 24%, white powder. 1H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 9.06 (t, J=6.0Hz, 1H), 7.92 (d, J=8.0Hz, 2H), 7.58 (d, J=8.0Hz, 2H), 7.48 (t, J=7.8Hz, 1H), 7.37-7.27 (m, 6H), 7.27-7.20 (m, 1H), 5-33 (s, 2H ), 5.12 (dd, J=13.3, 5.1Hz, 1H), 4.49 (d, J=6.0Hz, 2H), 4.45 (d, J=17.5Hz, 1H), 4.29 (d, J= 17.5Hz, 1H), 2.97-2.86(m, 1H), 2.64-2.55(m, 1H), 2.48-2.38(m, 1H), 2.03-1.94(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.89, 171.02, 168.02, 165.91, 153.32, 139.91, 139.65, 133.96, 133.39, 130.03, 129. 86, 128.29, 127.48, 127.34, 127.16, 126.74, 115.41, 115.06, 69.01, 51.64, 45.14, 42.60, 31.23, 22.41.TOF-MS m / z:calcd for:C 28 H 26 N3O5 + [M+H] + :484.1867, found:484.1854.

[0188] Example 28

[0189] 3-(1-oxo-4-((4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzyl)oxy)isoindoline-2-yl)piperidin-2,6-dione (28)

[0190]

[0191] Synthetic method is the same as compound 24. Yield: 21%, white powder. 1H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 7.58 (d, J = 7.9Hz, 2H), 7.51 (d, J = 7.9Hz, 1H), 7.49-7.45 ( m, 2H), 7.38-7.30 (m, 3H), 7.21-7.15 (m, 3H), 5.31 (s, 2H), 5.11 (dd, J=13-3, 5.1Hz, 1H), 4.81-4. 68 (m, 1H), 4.63-4.50 (m, 1H), 4.45 (d, J = 17.5Hz, 1H), 4.29 (d, J = 17.5Hz, 1H), 3.93-3.73 (m, 1H) , 3.58-3.52(m, 1H), 2.88-2.80(m, 2H), 2.64-2.53(m, 1H), 2.48-2.36(m, 1H), 2.06-1.89(m, 2H). 13 C NMR (101MHz, DMSo-d6) δ173.01, 171.11, 168.16, 153.48, 138.30, 135.80, 134.33, 133.43, 133.09, 130.07, 130.01, 128.78 , 127.64, 127.26, 127.16, 126.60, 126.31, 115.51, 115.10, 69.16, 59.87, 51.72, 45.24, 31.29, 29.09, 22.47, 14.16.TOF-MS m / z:calcd for:C 30 H 28 N3O5 + [M+H] + :510.2023, found:510.2016.

[0192] Example 29

[0193] 1-(2,4-Difluorophenyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)urea(29)

[0194]

[0195] Triphosgene (0.33 equiv) was dissolved in dichloromethane. Under nitrogen atmosphere and 0°C, a dichloromethane solution containing the corresponding ammonia feedstock (1 equiv) and triethylamine (3 equiv) was added dropwise. After reacting for 1 hour, a dichloromethane solution containing lenalidomide (1 equiv) and triethylamine (3 equiv) was added, and the reaction was continued at room temperature for 2 hours. The reaction solution was diluted with an appropriate amount of dichloromethane, washed with 10 mL of saturated brine, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to give a white solid 29g. Yield: 34%, white powder. 1 H NMR (400MHz, DMSO-d6) δ11.04 (s, 1H), 8.88 (s, 1H), 8.77 (s, 1H), 8.16-8.09 (m, 1H), 8.09-8.05 (m, 1H), 7.49 (t, J=7.7Hz, 1H), 7.45-7.40 (m, 1H), 7.36-7.28 (m, 1H), 7.10 -7.02 (m, 1H), 5.17 (dd, J=13.3, 5.1Hz, 1H), 4.44 (d, J=17.0Hz, 1H), 4.32 (d, J=17.0 Hz, 1H), 3.00-2.85 (m, 1H), 2.66-2.57 (m, 1H), 2.44-2.30 (m, 1H), 2.10-1.99 (m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.92, 171.15, 168.03, 158.04, 155.64, 152.13, 134.55, 132.50, 131.38, 1 29.01, 123.92, 122.30, 121.96, 121.86, 117.38, 111.26, 104.12, 51.65, 45.90, 31.27, 22.74.TOF-MS m / z:calcd for:C 20 H 17 F2N4O4 + [M+H] + :415.1212, found:415.1201.

[0196] Example 30

[0197] 1-(3,5-Dichlorophenyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)urea(30)

[0198]

[0199] Synthetic method is the same as compound 29. Yield: 35%, white powder. 1 H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 9.22 (s, 1H), 8.79 (s, 1H), 7.95 (s, 1 H), 7.90 (dd, J=7.5, 1.6Hz, 1H), 7.57-7.52 (m, 2H), 7.53-7.44 (m, 2H), 5.16 (dd, J=13.3, 5.1Hz, 1H), 4.42 (d, J=17.1Hz, 1H), 4.33 (d, J=17.1Hz, 1H), 2 .97-2.90(m, 1H), 2.66-2.55(m.1H), 2.45-2.30(m, 1H), 2.09-1.98(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.86,171.10,167.89,162.29,152.07,142.03,134.14,132.6 2, 132.59, 128.88, 123.63, 121.16, 118.03, 116.41, 51.63, 46.12, 30.77, 22.65.TOF-MS m / z:calcd for:C 20 H 17 Cl2N4O4 + [M+H] + :447.0621, found: 447.0613.

[0200] Example 31

[0201] 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)-3-(4-fluorophenyl)urea (31)

[0202]

[0203] Synthetic method is the same as compound 29. Yield: 37%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 8.89 (s, 1H), 8.57 (s, 1H), 7.98 (d, J=7 .8Hz, 1H), 7.51-7.44 (m, 3H), 7.42 (d, J=7.4Hz, 1H), 7.13 (t, J=8.9Hz, 2H), 5 .16 (dd, J=13.2, 5.1Hz, 1H), 4.42 (d, J=17.0Hz, 1H), 4.32 (d, J=17.0Hz, 1H), 2.99-2.87(m, 1H), 2.65-2.56(m, 1H), 2.43-2.28(m, 1H), 2.09-2.01(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.86, 171.11, 167.99, 157.45 (d, J=238.2Hz), 152.36, 135.76 (d, J=2.4Hz), 134.74, 132.50, 131.78, 128.87, 122.76, 120.06, 119.98, 117.33, 115.48, 115.26, 51.60, 46.00, 31.24, 22.68.TOF-MS m / z:calcd for:C 20 H 18 FN4O4 + [M+H] + :397.1307, found:397.1296.

[0204] Example 32

[0205] 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)-3-(4-(trifluoromethyl)benzyl)urea (32)

[0206]

[0207] Synthetic method is the same as compound 29. Yield: 36%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 8.52 (s, 1H), 8.03-7.96 (m, 1H), 7.70 (d, J = 8.1Hz, 2H), 7.53 (d, J=8.0Hz, 2H), 7.46-7.37 (m, 1H), 7.38-7.32 (m, 1H), 6.95 (t, J=6.0Hz, 1H), 5.14 (dd, J=13.3, 5.1Hz, 1H), 4.42 (d, J=5.9Hz, 2H), 4.37 (d, J=17.0Hz, 1H), 4.27 (d, J=1 7.0Hz, 1H), 2.99-2.84(m, 1H), 2.68-2.57(m, 1H), 2.39-2.24(m, 1H), 2.09-2.00(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.92, 171.15, 168.19, 155.08, 145.24, 135.42, 132.39, 130.97, 128.82, 127.75, 127.49 (d, J=31.6Hz), 125.24, 125.22 (d, J=11.4Hz), 125.21, 125.17, 122.17, 116.67, 51.64, 46.00, 42.52, 31.28, 22.76.TOF-MS m / z:calcd for:C 22 H 20 F3N4O4 + [M+H] + :461.1431, found:461.1425.

[0208] Example 33

[0209] 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)-3-(naphth-1-yl)urea(33)

[0210]

[0211] Synthetic method is the same as compound 29. Yield: 32%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 8.98 (s, 1H), 8.91 (s, 1H), 8.18-8.08 (m, 2H), 8.03- 7.98(m, 1H), 7.98-7.92(m, 1H), 7.67(d, J=8.2Hz, 1H), 7.64-7.53(m, 2H), 7.53-7.46(m, 2 H), 7.44 (d, J=6.4Hz, 1H), 5.20 (dd, J=13.3, 5.1Hz, 1H), 4.51 (d, J=16.9Hz, 1H), 4.39 (d, J =16.9Hz, 1H), 3.02-2.88(m, 1H), 2.67-2.58(m, 1H), 2.46-2.31(m, 1H), 2.14-2.04(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.88, 171.16, 168.05, 152.71, 134.88, 133.98, 133.72, 132.49, 131.40, 128.95, 128.4 7, 126.11, 126.01, 125.98, 125.88, 125.77, 123.25, 121.35, 117.80, 117.18, 51.61, 45.95, 31.26, 22.75.TOF-MS m / z:calcd for:C 24 H 21 N4O4 + [M+H] + :429.1557, found:429.1549.

[0212] Example 34

[0213] 1-Benzyl-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)urea (34)

[0214]

[0215] Synthetic method is the same as compound 29. Yield: 35%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 8.40 (s, 1H), 8.04 (d, J = 8.0Hz, 1H), 7.42 (t, J = 7.8Hz, 1H), 7.39-7.28 (m, 5H), 7.28-7.22 (m, 1H), 6.82 ( t, J=5.9Hz, 1H), 5.14 (dd, J=13.2, 5.1Hz, 1H), 4.41-4.20 (m, 4H), 2.99 -2.87(m, 1H), 2.66-2.57(m, 1H), 2.38-2.25(m, 1H), 2.09-2.00(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.86, 171.12, 168.11, 154.91, 140.00, 135.51, 132.33.130.71, 1 28.77, 128.35, 127.20, 126.82, 121.84, 116.42, 51.57, 45.87, 42.87, 31.23, 22.72.TOF-MS m / z:calcd for:C 21 H 21 N4O4 + [M+H] + :393.1557, found:393.1548.

[0216] Example 35

[0217] 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)-3-((4′-methoxy-[1,1'-biphenyl]-4-yl)methyl)urea(35)

[0218]

[0219] 19a (1.0 equiv) and 4-bromoanisole (1.5 equiv) were thoroughly dissolved in a 1,4-dioxane / water (9:1, v / v) mixed solvent (15 mL). Sodium carbonate (3.0 equiv) and tetrakis(triphenylphosphine)palladium (0.05 equiv) were added sequentially. The mixture was heated in an oil bath to 80 °C and stirred for 18 hours under N2 protection. After the reaction was complete, the mixture was cooled to room temperature, filtered under reduced pressure, and the filtrate was evaporated to dryness. The filtrate was extracted, and the organic phases were combined and silica gel was added to form a slurry. The slurry was then purified by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v) to give a white solid 20a.

[0220] Dissolve 20a in dichloromethane (6 mL), then slowly add 6 mL of a trifluoroacetic acid / dichloromethane (1:1) mixture under ice-salt bath conditions. The reaction is monitored by thin-layer chromatography for 2 hours. After the reaction is complete, distill under reduced pressure, add saturated sodium bicarbonate solution to adjust the pH to weakly alkaline, and then purify by column chromatography (petroleum ether / ethyl acetate, 15:1, v / v) to obtain a white solid 21a.

[0221] Triphosgene (0.33 equiv) was dissolved in dichloromethane. Under nitrogen atmosphere and 0°C, a dichloromethane solution of 21a (1 equiv) and triethylamine (3 equiv) was added dropwise. After reacting for 1 hour, a dichloromethane solution of lenalidomide (1 equiv) and triethylamine (3 equiv) was added, and the reaction was continued at room temperature for 2 hours. The reaction solution was diluted with an appropriate amount of dichloromethane, washed with 10 mL of saturated brine, and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol, 15:1, v / v) to give a white solid 35%. Yield: 37%, white powder. 1 H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 8.41 (s, 1H), 8.05 (d, J=8.0Hz, 1H), 7.61 -7.55(m, 4H), 7.43(t, J=7.8Hz, 1H), 7.40-7.32(m, 3H), 7.06-6.98(m, 2H), 6.8 4(t, J=5.9Hz, 1H), 5.14 (dd, J=13.2, 5.1Hz, 1H), 4.45-4.23 (m, 4H), 3.79 (s, 3H ), 2.98-2.86(m, 1H), 2.66-2.57(m, 1H), 2.40-2.26(m, 1H), 2.08-2.00(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.87, 171.13, 168.13, 158.83, 154.94, 138.48, 138.46, 135.53, 132.34, 132.31, 130. 71, 128.79, 127.79, 127.63, 126.15, 121.85, 116.43, 114.36, 55.18, 51.59, 45.90, 42.59, 31.24, 22.73.TOF-MS m / z:calcd for:C 28 H 27 N4O5 + [M+H] + :499.1976, found:499.1965.

[0222] Example 36

[0223] 1-(4-(benzofuran-6-yl)benzyl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)urea(36)

[0224]

[0225] Synthetic method is the same as compound 35. Yield: 31%, white powder. 1 H NMR (400MHz, DMSO-d6) δ11.00 (s, 1H), 8.42 (s, 1H), 8.09-8.00 (m, 2H), 7.94-7.86 (m , 1H), 7.71-7.61(m, 3H), 7.62-7.55(m, 1H), 7.47-7.38(m, 3H), 7.35(d, J=7.3Hz, 1H) , 7.05-6.97 (m, 1H), 6.86 (t, J=5.9Hz, 1H), 5.14 (dd, J=13.2, 5.1Hz, 1H), 4.45-4.22 (m, 4H), 2.99-2.85 (m, 1H), 2.66-2.54 (m, 1H), 2.40-2.26 (m, 1H), 2.10-1.97 (m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.87, 171.13, 168.12, 154.95, 153.90, 146.69, 139.22, 138.82, 135.53, 135.30, 132.34, 130.71, 1 28.79, 127.89, 127.81, 126.96, 123.46, 121.86, 119.22, 116.44, 111.56, 106.99, 51.59, 45.90, 42.58, 31.24, 22.73.TOF-MS m / z:calcd for:C 29 H 25 N4O5 + [M+H] + :509.1819, found:509.1807.

[0226] Example 37

[0227] 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)-3-(4-(thiophen-2-yl)benzyl)urea(37)

[0228]

[0229] Synthetic method is the same as compound 35. Yield: 32%, white powder. 1 H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 8.42 (s, 1H), 8.03 (d, J=7.9Hz, 1H), 7.68-7.59 ( m, 2H), 7.52 (d, J=5.0Hz, 1H), 7.48 (d, J=3.6Hz, 1H), 7.43 (t, J=7.8Hz, 1H), 7.39-7.32 ( m, 3H), 7.17-7.09 (m, 1H), 6.84 (t, J=5.9Hz, 1H), 5.14 (dd, J=13.3, 5.1Hz, 1H), 4.45-4. 20(m, 4H), 3.00-2.85(m, 1H), 2.67-2.56(m, 1H), 2.41-2.24(m, 1H), 2.12-1.94(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.92, 171.18, 168.15, 154.97, 143.20, 139.55, 135.52, 132.40, 132.36, 130.78, 1 28.82, 128.50, 127.98, 125.49, 125.44, 123.54, 121.92, 116.49, 51.59, 45.92, 42.57, 31.26, 22.75.TOF-MS m / z:calcd for:C 25 H 23 N4O4S + [M+H] + :475.1435, found:475.1427.

[0230] Example 38

[0231] 2-(2,6-dioxadiazine-3-yl)-4-(4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzyl)amino)isoindole-1,3-dione (38)

[0232]

[0233] The synthesis method is the same as that of compound 5, using pomalidomide as the raw material. Yield: 18%, white powder. 1H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 7.49 (d, J = 8.2Hz, 2H), 7.43 (d, J = 7.2Hz, 2H), 7.34-7.15 (m, 5H), 6.99-6.93 (m, 1H), 6.72 (d, J=8.0Hz, 1H), 6.46 (t, J=6.0Hz, 1H), 5.13 (dd, J=13.3, 5.1Hz, 1H), 4.82-4.65 (m, 1H), 4.55 (d, J=5.7Hz, 1H), 4.46 (d, J=6.0Hz, 2H), 3.93-3.72 (m, 1H), 3.64-3.44 (m, 1 H), 3.01-2.91(m, 1H), 2.87-2.79(m, 2H), 2.68-2.58(m, 1H), 2.40-2.26(m, 1H), 2.11-2.03(m, 1H). 13 C NMR (101MHz, DMSO-d6) δ172.96, 171.28, 168.83, 167.92, 162.35, 143.57, 141.89, 134.78, 133.19, 132.27, 129.75, 129.19, 128.69, 127.07, 126.77, 126.47, 126.32, 126.23, 112.29, 110.45, 70.79, 62.53, 51.56, 35.79, 31.27, 30.78, 22.82.TOF-MS m / z:calcd for:C 30 H 27 N4O5 + [M+H] + :523.1976, found:523.1968.

[0234] Example 39 In vitro bioactivity test

[0235] 1) 6000 MM1S cells per well were cultured in 96-well plates. After overnight culture, the culture medium was removed from the wells, and 50 μL of different concentrations of compounds prepared with complete culture medium were added, mixed well, and cultured for another 6 days. Cell viability was measured using a Cell Counting Kit-8 (CCK-8). 10 μL of CCK-8 was added directly to each well, mixed well, and incubated in an incubator for 1 hour. The fluorescence intensity of the system was then measured using a Thermo microplate reader. IC50 50The results, calculated using GraphPad Prism software with baseline correction, are shown in Table 1. The results indicate that all compounds of this invention possess good anti-proliferative activity, with some compounds exhibiting antitumor activity significantly superior to the first-line treatment drug lenalidomide. Compound 28 shows activity superior to CC-92480, currently the most promising clinical investigational drug, demonstrating the significant development potential of these compounds in this field.

[0236] Table 1: Antiproliferative activity of MM1S myeloma cells

[0237]

[0238]

[0239] Note: IC 50 The value is the mean ± standard deviation of three independent experiments.

[0240] 2) Protein imprinting detection

[0241] Protein levels were determined using a standard Western blotting method. MM1S cells were cultured with different concentrations of the compound for 24 hours, and after cell collection, total protein was extracted using 1×RIPA lysis buffer (NCM Biotechnology Co., Ltd., China). Then, equal volumes of protein (4-40 μg / lane) in the total cell lysate were separated by polyacrylamide gel electrophoresis with sodium dodecyl sulfate (8%, 10%, or 12%), wet-transferred onto PVDF membranes (Merck Millipore, Germany), blotted overnight with primary antibody IKZF1 or IKZF3, and then incubated at 37°C for 1 hour with allotype-specific secondary antibody. The bound immune complexes were detected using a ChemiDOC XRS system (BioRad Laboratories, Hercules, CA). Experimental results are shown in the appendix. Figure 1 The results showed that compound 28 can exert its anti-tumor effect by efficiently degrading IKZF1 and IKZF3 in a dose-dependent manner.

Claims

1. A compound comprising an effective amount of a compound of formula (I): ###0001### wherein, X is selected from O, S, NH; Y is selected from O, NH; Z is selected from any one of the following structures: ###0002### R is selected from one or more of hydrogen, C1-C6 alkyl, alkoxy, halogen, trifluoromethyl, R1 is selected from hydrogen, C1-C6 alkyl, R2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.

2. A compound of formula (I) as defined in claim 1 : ###0003### wherein, X is selected from O, S, NH; Y is selected from O, NH; Z is selected from any one of the following structures: ###0004### R is selected from one or more of hydrogen, C1-C6 alkyl, alkoxy, halogen, trifluoromethyl, R1 is selected from hydrogen, C1-C6 alkyl, R2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl. X is selected from:

3. A compound of formula (I) as defined in any one of claims 1-2 selected from: ###0005### ###0006### 4. A pharmaceutical composition comprising a compound as defined in any one of claims 1-3 and a suitable carrier or excipient. wherein R is selected from one or more of hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, R1is selected from hydrogen, alkyl, R2is selected from hydrogen, alkyl, cycloalkyl.

5. Use of a compound as defined in any one of claims 1-3 for the manufacture of a medicament for the treatment of a disease associated with IKZF1 or / and IKZF3. X is selected from:

6. Use of a compound as defined in any one of claims 1-3, or a pharmaceutical composition as defined in claim 4, for the manufacture of a medicament for the prevention or / and treatment of a cancer, inflammation, immunomodulatory. ​ wherein, ​ ​ ​ ​ ​

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