Protein degradation targeting chimera targeting AKR1C3 and application thereof

Abstract

The invention discloses a protein degradation targeting chimera targeting AKR1C3 and an application of the protein degradation targeting chimera. The invention discloses a series of compounds with a structure of a general formula (I) and application of the compounds in treatment of cancers. In-vitro cell experiments are used as carriers to evaluate the efficacy of the compound represented by the general formula (I) in degradation of aldoketoreductase 1C3 and treatment of drug-resistant cancers, and the compound represented by the general formula (I) is found to have good in-vitro activity and can be further developed into candidate molecules for treating cancers.

Description

Technical Field

[0001] This invention relates to a class of protein degradation targeting chimeras, and more particularly to a class of protein degradation targeting chimeras that target AKR1C3 and their applications, belonging to the field of medicinal chemistry technology. Background Technology

[0002] Human aldo-keto reductase (AKR) is a member of the oxidoreductase family, of which 16 families have been identified, containing 151 members. These are monomeric soluble proteins mainly found in the cytoplasm, with a molecular weight of approximately 34–37 kDa. The physiological function of most AKR members is to catalyze redox reactions in vivo, using NAD(P)H as a coenzyme to convert aldehydes or ketones in endogenous (steroids, glucuronic acid, reactive lipoaldehydes, ketone prostaglandins, neurosteroids, bile acids, and retinal) or exogenous (drugs, small carcinogenic molecules) substrates to primary or secondary alcohols. They can also catalyze the reduction of nitro groups, belonging to phase I metabolic enzymes. Due to their wide distribution and substrate sources in the body, the aldo-keto reductase family plays an important role in life activities such as steroid hormone metabolism and synthesis, drug metabolism and inactivation, regulation of oxidative stress, and detoxification of carcinogens.

[0003] In the human body, the AKR1C enzyme (Aldo-keto reductase family 1 member C) has been identified as having four isoforms, namely AKR1C1-AKR1C4. These isoforms share 86% amino acid sequence homology but have different tissue distribution preferences and substrate selectivity. They mediate different but interconnected physiological functions in the human body and are closely related to the occurrence and development of various diseases. Among them, AKR1C3 is one of the members with the most thorough phenotypic and mechanistic research and the highest "drug-targetable" potential.

[0004] AKR1C3, also known as human 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5), is closely related to hormone metabolism in the body. AKR1C3 can act as a prostaglandin F synthase (PGF), converting prostaglandin D2 (PGD2) to 9α,11β-PGF2α and prostaglandin H2 (PGH2) to PGF2α. Through its ketosterol reduction action, AKR1C3 can catalyze the conversion of the weak androgen precursors Δ4-androstene-3,17-dione (Δ4-AD) and 5α-androstane-3,17-dione (5α-dihydrotestosterone (5α-DHT)) into the potent androgens testosterone and 5α-dihydrotestosterone (5α-DHT), respectively. It can also reduce the weak estrogen estrone to the potent estrogen 17β-estradiol and convert the potent progesterone to the weak progesterone 20α-hydroxyprogesterone. These complex hormone metabolic functions suggest a close association with hormone metabolism-related diseases, especially hormone-dependent tumors such as prostate cancer, castration-resistant prostate cancer, and breast cancer. Recent studies have shown that in normal human liver, AKR1C3's metabolic detoxification function for some drugs, such as acetylhexamide and loxoprofen, exceeds that of CRBN1, indicating the important role of AKR1C3 in metabolism.

[0005] With the continuous development of various anti-tumor strategies, chemotherapy remains one of the most commonly used treatments. However, drug resistance and toxic side effects remain the core issues limiting its efficacy. AKR1C3 plays a crucial role in tumor drug resistance formation through the metabolism of carbonyl compounds (including many chemotherapeutic drugs) and the regulation of key signaling pathways. Although many AKR1C3 inhibitors have been developed, there are still no successful clinical applications, and their efficacy and selectivity remain insufficient. In recent years, targeted protein degraders (such as PROTAC) have emerged as a new strategy, offering new insights into overcoming the limitations of traditional inhibitors due to their ability to efficiently and continuously clear target proteins. Therefore, exploring and developing novel, efficient, and specific AKR1C3 degraders holds promise as a significant breakthrough in reversing drug resistance and improving the efficacy of chemotherapy, opening up new directions for tumor treatment. Summary of the Invention

[0006] Objectives of the invention: The objective of this invention is to provide a class of highly selective and active protein degradation-targeting chimeras that target AKR1C3; another objective of this invention is to provide a pharmaceutical composition; and the final objective of this invention is to provide the application of the above-mentioned protein degradation-targeting chimeras.

[0007] Technical solution: This invention provides a class of compounds as shown in general formula (I) or pharmaceutically acceptable salts thereof.

[0008]

[0009] (I)

[0010] The structural formula of AM is shown in equation (II):

[0011]

[0012] (II)

[0013] Wherein, ring A is selected from a benzene ring, an unsubstituted or substituted 5-6 membered heteroaromatic ring containing 1-2 heteroatoms independently selected from O, N, and S, wherein the substituents of the 5-6 membered heteroaromatic ring are 1-2 C atoms. 1-3 Alkyl group; ring B is selected from benzene ring or pyridine ring, and ring C is selected from benzene ring or pyridine ring;

[0014] Y is selected from -O-, -NH-, or -CH2-;

[0015] W1 and W2 are independently selected from -NH-, -C(O)-, and -CH2-;

[0016] m and n are independently selected from any integer from 1 to 3;

[0017] The structural formula of CM is shown in equation (II):

[0018]

[0019] (II)

[0020] Where Z is selected from -CH 2- Or -C(O)-;

[0021] This indicates that the bond can be stereospecific or non-stereospecific;

[0022] L comprises a chemical structure represented by formula (III) or formula (IV):

[0023]

[0024] (III)

[0025]

[0026] (IV)

[0027] Where Q and V are each independently a bond, O, NH, ;

[0028] R1, R2, and R3 are independently selected from C. 1-5 Saturated alkylene chains, or C with arbitrary substitution of D group 3-7 Saturated heterocycles, phenyl, C 5-7 Heterocyclic aromatic rings or spiro-[jk] heterocyclic groups, wherein the D group is selected from C 1-3 Alkyl, C 2-4 Alkyl, halogen, cyano; m1 and m2 are each independently chosen from 1 to 3; where j and k are each independently integers from 2 to 6;

[0029] R4 is taken from m3 is any integer from 1 to 5.

[0030] Preferably, ring A is selected from:

[0031] .

[0032] Preferably, fragments Selected from:

[0033] .

[0034] Preferably, fragments Selected from:

[0035]

[0036] Preferably, the structure of AM is shown in any of the following structures:

[0037]

[0038] Preferably, R1, R2, R3, and R4 are independently selected from:

[0039] .

[0040] Preferably, L comprises a chemical structure represented by any of the following structures:

[0041]

[0042] Preferably, the pharmaceutically acceptable salt is selected from sodium salts, hydrochlorides, maleates, and citrates; the pharmaceutically acceptable salt of the compound represented by formula (I) has the same or better pharmacological activity as the compound represented by formula (I).

[0043] The present invention provides a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0044] Preferably, the dosage form of the pharmaceutical composition is a capsule, pill, tablet, granule or injection.

[0045] The compounds of the present invention or pharmaceutically acceptable salts thereof may be used in the preparation of AKR1C3 inhibitors.

[0046] The compounds of the present invention, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, may be used in the preparation of antitumor drugs, wherein the tumor is an AKR1C3-associated tumor.

[0047] Preferably, the tumor is selected from: prostate cancer, castration-resistant prostate cancer, and breast cancer.

[0048] Preferably, the compounds of the present invention or their pharmaceutically acceptable salts or pharmaceutical compositions may be used in the preparation of drugs for the prevention or treatment of cancer or in the reversal of tumor drug resistance.

[0049] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: The present invention evaluates the ability of compounds of general formula (I) to inhibit the AKR1C3 target based on the inhibitory activity and selectivity of aldehyde reductase, and verifies that most of the compounds involved show good inhibitory ability and selectivity against AKR1C3, which greatly enriches the existing backbone types of selective AKR1C3 inhibitors, and is particularly important for the treatment of various diseases with AKR1C3 overexpression. Attached Figure Description

[0050] Figure 1 This is a schematic diagram illustrating how AKR1C3 protein degradation-targeting chimeras reverse doxorubicin resistance in breast cancer.

[0051] Figure 2 The images show immunoblotting data of intracellular AKR1C3 protein degradation targeted by the chimera, where a is the immunoblotting image and b is the quantitative fluorescence analysis image. Detailed Implementation

[0052] The technical solution of the present invention will be further described below with reference to the embodiments.

[0053] Example 1: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 1)

[0054] (1) Synthesis of 3-hydroxy-N-(2-((3,5-dimethyl-1,2-oxazol-4-yl)methoxy)phenyl)benzamide (intermediate 2)

[0055] 2-((3,5-dimethylisoxazol-4-yl)methoxy)aniline (200 mg, 0.917 mmol) and 3-hydroxybenzoic acid (151.8 mg, 1.10 mmol) were dissolved in DMF (5 ml). DIPEA (296.3 mg, 2.29 mmol) and HATU (871.7 mg, 2.29 mmol) were added to the reaction solution, and the reaction was carried out at room temperature for 6 h. After the reaction was complete, 50 ml of water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and evaporated to dryness, resulting in the precipitation of a white solid. Intermediate 2 (white solid, 300 mg) was obtained. 1 H NMR (500 MHz, Chloroform-d) δ 8.69 (s, 1H), 8.58 (s, 1H), 7.92– 7.80 (m, 1H), 7.45 (ddd, J = 7.9, 2.1, 1.2 Hz, 1H), 7.37 – 7.29 (m, 3H),7.08 – 6.86 (m, 5H), 5.26 (s, 2H), 2.36 (s, 4H), 2.34 (s, 4H).

[0056] (2) Synthesis of 3-(4-bromobutoxy)-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (intermediate 3)

[0057] Intermediate 2 (200 mg, 0.591 mmol) was dissolved in acetonitrile (30 ml), and cesium carbonate (385.4 mg, 1.18 mmol) was added. After reacting at room temperature for 15 min, 1,4-dibromobutane (510.4 mg, 2.36 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 18 h. After the reaction was completed, the solvent was dried by rotary evaporation under vacuum, and the mixture was separated by column chromatography (PE / EA = 3 / 1, v / v) to give intermediate 3 (white solid, 110 mg). 1H NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 7.91 –7.84 (m, 1H), 7.60 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.46 – 7.40 (m, 3H), 7.04– 6.98 (m, 4H), 6.97 – 6.92 (m, 1H), 5.26 (s, 2H), 4.02 (t, J = 5.8 Hz, 3H), 3.48 (t, J = 4.4 Hz, 3H), 2.36 (s, 4H), 2.34 (s, 4H), 1.91 (dtd, J = 7.5,4.4, 1.0 Hz, 2H), 1.88 – 1.80 (m, 2H).

[0058] (3) Synthesis of 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (intermediate 4)

[0059] 1-tert-Butoxycarbonylpiperazine (200 mg, 1.07 mmol) was dissolved in acetonitrile (5 ml), and potassium carbonate (295.8 mg, 2.14 mmol) was added. After reacting at room temperature for 15 min, 3-bromo-1-propanol (163.6 mg, 1.177 mmol) was added to the reaction solution, and the mixture was stirred at 70 °C for 12 h. After the reaction was complete, the solvent was dried by rotary evaporation under vacuum, and the mixture was separated by column chromatography (DCM / MeOH = 15 / 1, v / v) to give intermediate 4 (white viscous liquid, 310 mg). 1 H NMR (500 MHz, Chloroform-d) δ 4.29(t, J = 5.9 Hz, 1H), 3.66 (q, J = 6.2 Hz, 2H), 3.33 – 3.28 (m, 4H), 2.68 (t,J = 6.4 Hz, 2H), 2.63 – 2.58 (m, 4H), 1.77 (p, J = 6.3 Hz, 2H), 1.46 (s, 7H).

[0060] (4) Synthesis of 1-(3-hydroxypropyl)piperazine (intermediate 5)

[0061] Intermediate 4 (200 mg, 10.82 mmol) was dissolved in dichloromethane (10 ml), and trifluoroacetic acid (1 ml) was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, saturated sodium bicarbonate solution was added dropwise to the reaction solution until no more bubbles were produced. The mixture was extracted three times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and evaporated to dryness to give intermediate 5 (a clear, viscous liquid, 100 mg).1 HNMR (500 MHz, Chloroform-d) δ 5.25 (p, J = 3.3 Hz, 1H), 4.29 (t, J = 5.9 Hz,1H), 3.66 (q, J = 6.2 Hz, 2H), 2.89 – 2.54 (m, 10H), 1.77 (p, J = 6.4 Hz,2H).

[0062] (5) Synthesis of 3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (intermediate 6)

[0063] Intermediate 5 (200 mg, 1.39 mmol) was dissolved in acetonitrile (5 mL), and cesium carbonate (385.4 mg, 1.18 mmol) was added. The mixture was stirred at 70 °C for 15 min, and then intermediate 3 (656.2 mg, 1.39 mmol) was added to the reaction solution. The reaction was carried out at 70 °C for 15 h. After the reaction was completed, the solvent was dried by vacuum rotary evaporation, and the mixture was separated by column chromatography (DCM / MeOH = 15 / 1, v / v) to obtain intermediate 6 (pale yellow oily liquid, 600 mg). 1 H NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 7.60 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.46 – 7.40 (m, 3H), 7.05 – 6.98 (m, 4H), 6.97 – 6.92 (m, 1H), 5.26 (s, 2H), 4.29 (t, J = 5.9 Hz, 1H), 3.66 (q, J = 6.2Hz, 3H), 2.75 – 2.65 (m, 8H), 2.56 – 2.48 (m, 8H), 2.36 (s, 4H), 2.34 (s,4H), 1.82 – 1.70 (m, 5H), 1.64 – 1.54 (m, 3H).

[0064] (6) Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (intermediate 7)

[0065] 5-Hydroxyisobenzofuran-1,3-dione (200 mg, 1.22 mmol) was dissolved in glacial acetic acid (10 ml) and stirred at room temperature. 3-Amino-2,6-piperidinidone hydrochloride (182.55 mg, 1.11 mmol) and sodium acetate (182.1 mg, 2.22 mmol) were added, and the mixture was stirred at 130 °C for 2 h. After the reaction was complete, ice water (100 ml) was added, and a large amount of white solid precipitated. This solid was filtered to give intermediate 7. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.54 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.2, 2.2 Hz, 1H), 5.30 – 5.15 (m, 1H), 2.95 – 2.79 (m, 1H), 2.68 – 2.48 (m, 3H), 2.21 –1.94 (m, 1H).

[0066] (7) Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 1)

[0067] Triphenylphosphine (293.5 mg, 1.119 mmol) was added to a two-necked flask, purged with argon, and then anhydrous tetrahydrofuran (2 ml) was injected. After stirring at -15 °C for 15 min, intermediate 7 (200 mg, 0.73 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) was injected. After stirring at -15 °C for 15 min, intermediate 6 (321.8 mg, 0.6 mmol) dissolved in anhydrous tetrahydrofuran (5 ml) was injected. Finally, after stirring at -15 °C for 15 min, DEAD (261.2 mg, 1.5 mmol) dissolved in anhydrous tetrahydrofuran (1 ml) was injected. After stirring at -15 °C for 1 h, the mixture was allowed to react at room temperature for 2 days. After the reaction was complete, the solvent was dried by rotary evaporation under vacuum, and the mixture was separated by column chromatography (DCM / MeOH = 15 / 1, v / v) to give compound 1 (25 mg, pale yellow solid). 1H NMR (500MHz, Chloroform-d) δ 9.51 (s, 1H), 8.56 (s, 1H), 7.93 – 7.84 (m, 3H), 7.63 –7.56 (m, 3H), 7.46 – 7.40 (m, 3H), 7.05 – 6.97 (m, 5H), 6.96 – 6.92 (m, 1H), 5.26 (s, 2H), 5.25 – 5.22 (m, 1H), 4.05 (t, J = 6.6 Hz, 3H), 3.99 (t, J = 6.0Hz, 2H), 2.92 – 2.83 (m, 1H), 2.76 – 2.64 (m, 7H), 2.60 – 2.46 (m, 10H), 2.36(s, 3H), 2.34 (s, 3H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 3H), 1.79 –1.70 (m, 3H), 1.64 – 1.54 (m, 3H). MS (ESI) m / z calcd for C43H48N6O9 [M+H] + 792.3483; found 792.3481.

[0068] Example 2: Synthesis of 3-(5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)pentoxy)-N-(2-((3,5-dimethylisooxazol-4-yl)methoxy)phenyl)benzamide (compound 2)

[0069] Following the synthesis of compound 1, intermediate 6 was replaced with N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-((5-(4-(3-hydroxypropyl)piperazin-1-yl)pentyl)oxy)benzamide to obtain compound 2. TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.56 (s, 1H), 7.93 – 7.84 (m, 3H), 7.63 – 7.56 (m, 3H), 7.46 – 7.40(m, 3H), 7.05 – 6.97 (m, 5H), 6.96 – 6.92 (m, 1H), 5.26 (s, 2H), 5.25 – 5.22(m, 1H), 4.05 (t, J = 6.6 Hz, 3H), 3.99 (t, J = 6.0 Hz, 2H), 2.92 – 2.83 (m,1H), 2.76 – 2.64 (m, 7H), 2.60 – 2.46 (m, 10H), 2.36 (s, 3H), 2.34 (s, 3H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 3H), 1.79 – 1.70 (m, 3H), 1.64 –1.54 (m, 3H). MS (ESI) m / z calcd for C44H50N6O9 [M+H] + 806.3639; found 806.3634.

[0070] Example 3: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 3)

[0071] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 3. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz,1H), 7.58 (d, J = 2.8 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.34 – 7.28 (m, 3H), 7.25(t, J = 7.9 Hz, 1H), 7.07 – 7.00 (m, 3H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz,1H), 5.27 (s, 2H), 5.25 – 5.22 (m, 1H), 4.05 (t, J = 6.6 Hz, 3H), 3.95 (t, J= 6.0 Hz, 2H), 2.88 (dd, J = 19.1, 7.1 Hz, 1H), 2.74 – 2.67 (m, 7H), 2.62 –2.54 (m, 2H), 2.53 – 2.48 (m, 7H), 2.36 (s, 3H), 2.34 (s, 3H), 2.13 – 2.04(m, 1H), 1.90 (p, J = 6.6 Hz, 3H), 1.79 – 1.70 (m, 3H), 1.64 – 1.54 (m, 3H).MS (ESI) m / z calcd for C43H48N6O9 [M+H] + 792.3483; found 792.3485.

[0072] Example 4: 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-3-methylpiperazin-1-yl)butoxy)phenyl)benzamide (compound 4)

[0073] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)-3-methylpiperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 4. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d)δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0,1.6 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.34 – 7.28 (m,3H), 7.25 (t, J = 7.9 Hz, 1H), 7.06 – 6.98 (m, 3H), 6.87 (ddd, J = 7.7, 2.1,1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.21 (m, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.93 – 2.84 (m, 3H), 2.84 – 2.68 (m, 5H), 2.66 –2.44 (m, 11H), 2.36 (s, 3H), MS (ESI) m / zcalcd for C44H50N6O9 [M+H] + 806.3639; found 806.3639.

[0074] Example 5: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)ethyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 5)

[0075] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(2-hydroxyethyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 5. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz,1H), 7.58 (d, J = 2.7 Hz, 1H), 7.43 – 7.35 (m, 3H), 7.34 – 7.27 (m, 3H), 7.25(t, J = 7.9 Hz, 1H), 7.07 – 7.00 (m, 3H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz,1H), 5.27 (s, 2H), 5.26 – 5.21 (m, 1H), 4.10 (t, J = 5.9 Hz, 3H), 3.95 (t, J= 6.0 Hz, 2H), 2.92 – 2.82 (m, 4H), 2.74 – 2.65 (m, 3H), 2.63 – 2.49 (m,12H), 2.36 (s, 3H), 2.34 (s, 3H), 1.81 – 1.68 (m, 2H), 1.63 – 1.53 (m, 3H).MS (ESI) m / z calcd for C42H46N6O9 [M+H] + 778.3326; found 778.3324.

[0076] Example 6: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 6)

[0077] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(4-(4-hydroxybutyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 6. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz,1H), 7.58 (d, J = 2.7 Hz, 1H), 7.44 – 7.33 (m, 3H), 7.33 – 7.28 (m, 3H), 7.25(t, J = 7.9 Hz, 1H), 7.08 – 6.99 (m, 3H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz,1H), 5.27 (s, 2H), 5.26 – 5.19 (m, 1H), 3.99 (t, J = 6.0 Hz, 3H), 3.95 (t, J= 6.0 Hz, 2H), 2.92 – 2.82 (m, 1H), 2.76 – 2.65 (m, 5H), 2.61 – 2.55 (m, 2H),2.55 – 2.46 (m, 11H), 2.36 (s, 3H), 2.34 (s, 3H), 2.08 (s, 1H), 1.79 – 1.70(m, 5H), 1.67 – 1.54 (m, 5H). MS (ESI) m / z calcd for C44H50N6O9 [M+H] + 806.3639; found 806.3634.

[0078] Example 7: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 7)

[0079] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(5-hydroxypentyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 7. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz,1H), 7.58 (d, J = 2.7 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.33 – 7.28 (m, 2H), 7.25(t, J = 7.9 Hz, 1H), 7.08 – 7.00 (m, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz,1H), 5.27 (s, 2H), 5.25 – 5.22 (m, 1H), 4.00 (t, J = 6.3 Hz, 2H), 3.95 (t, J= 6.0 Hz, 2H), 2.92 – 2.84 (m, 1H), 2.75 – 2.67 (m, 4H), 2.61 – 2.54 (m, 2H),2.54 – 2.48 (m, 6H), 2.42 (t, J = 6.1 Hz, 2H), 2.36 (s, 2H), 2.34 (s, 2H), 2.11 – 2.03 (m, 1H), 1.81 – 1.68 (m, 4H), 1.62 – 1.53 (m, 4H), 1.49 – 1.40(m, 2H). MS (ESI) m / z calcd for C45H52N6O9 [M+H] + 820.3796; found 820.3795.

[0080] Example 8: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(3-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)propoxy)phenyl)benzamide (compound 8)

[0081] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(3-(4-(3-hydroxypropyl)piperazin-1-yl)propoxy)phenyl)benzamide to obtain compound 8. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz,1H), 7.58 (d, J = 2.8 Hz, 1H), 7.42 – 7.36 (m, 3H), 7.33 – 7.28 (m, 3H), 7.25(t, J = 7.9 Hz, 1H), 7.06 – 6.98 (m, 3H), 6.87 (ddd, J = 7.9, 2.2, 1.2 Hz,1H), 5.27 (s, 2H), 5.25 – 5.20 (m, 1H), 4.04 (dt, J = 9.7, 6.6 Hz, 5H), 2.91– 2.85 (m, 1H), 2.74 – 2.65 (m, 11H), 2.61 – 2.48 (m, 8H), 2.36 (s, 3H), 2.34(s, 3H), 2.08 (d, J = 4.7 Hz, 1H), 1.90 (p, J = 6.6 Hz, 5H). MS (ESI) m / zcalcd for C42H46N6O9 [M+H] + 778.3326; found 778.3324.

[0082] Example 9: Synthesis of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)nicotinamide (compound 9)

[0083] Following the synthesis of compound 1, intermediate 6 was replaced with 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)nicotinamide to obtain compound 9. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.73(s, 1H), 9.51 (s, 1H), 8.88 (d, J = 1.2 Hz, 1H), 8.45 (dd, J = 5.2, 1.4 Hz,1H), 7.90 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.36 (ddd, J = 8.0,2.1, 1.2 Hz, 1H), 7.31 (t, J = 2.1 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.08 –6.99 (m, 3H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.28 (s, 2H), 5.26 – 5.21(m, 1H), 4.05 (t, J = 6.6 Hz, 3H), 3.95 (t, J = 6.0 Hz, 2H), 2.93 – 2.82 (m,1H), 2.74 – 2.66 (m, 8H), 2.63 – 2.47 (m, 10H), 2.36 (s, 3H), 2.34 (s, 3H), 2.13 – 2.02 (m, 1H), 1.90 (p, J = 6.6 Hz, 3H), 1.83 – 1.65 (m, 2H), 1.64 –1.55 (m, 2H). MS (ESI) m / z calcd for C42H47N7O9 [M+H] + 793.3435; found 793.3430.

[0084] Example 10: Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)isonicotinamide (compound 10)

[0085] Following the synthesis of compound 1, intermediate 6 was replaced with 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)isonicotinamide to obtain compound 10. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 9.37 (s, 1H), 8.43 – 8.36 (m, 3H), 7.90 (d, J = 7.9 Hz, 1H), 7.68(d, J = 4.5 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.36 (ddd, J = 8.0, 2.1, 1.2Hz, 1H), 7.31 (t, J = 2.1 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.02 (dd, J =7.9, 2.7 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.36 (s, 2H), 5.26 –5.20 (m, 1H), 4.05 (t, J = 6.6 Hz, 3H), 3.95 (t, J = 6.0 Hz, 2H), 2.92 – 2.83(m, 1H), 2.74 – 2.66 (m, 8H), 2.63 – 2.54 (m, 3H), 2.54 – 2.48 (m, 7H), 2.36(s, 3H), 2.34 (s, 3H), 2.12 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 3H), 1.78 –1.70 (m, 3H), 1.63 – 1.55 (m, 3H). MS (ESI) m / z calcd for C42H47N7O9 [M+H] + 793.3435; found 793.3439.

[0086] Example 11: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)-3-oxopropyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 11).

[0087] Following the synthesis of compound 1, intermediate 6 was replaced with 3-(4-(4-(3-(2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamido)phenoxy)butyl)piperazin-1-yl)propionic acid to obtain compound 11. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 9.25 (s, 1H), 8.89 (s, 1H), 7.92 – 7.84 (m, 3H), 7.64 (dd, J = 7.9,2.2 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.41 – 7.37 (m, 3H), 7.33 – 7.29 (m,3H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J =7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.22 (m, 1H), 3.95 (t, J = 6.0Hz, 2H), 2.91 – 2.80 (m, 4H), 2.74 – 2.67 (m, 3H), 2.62 – 2.48 (m, 17H), 2.36(s, 3H), 2.34 (s, 3H), 2.12 – 2.05 (m, 1H), 1.78 – 1.70 (m, 3H), 1.62 – 1.56(m, 3H). MS (ESI) m / z calcd for C43H47N7O9 [M+H] + 805.3435; found 805.3436.

[0088] Example 12: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 12).

[0089] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-(4-(4-(3-aminopropyl)piperazin-1-yl)butoxy)phenyl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 12. TLC detection showed a single point, and yellow fluorescence was observed under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s,1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H),7.41 – 7.36 (m, 3H), 7.35 (d, J = 2.1 Hz, 1H), 7.33 – 7.28 (m, 3H), 7.25 (t,J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.94 (dd, J = 7.8, 2.1 Hz,1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.60 (t, J = 5.0 Hz, 1H), 5.27 (s,2H), 5.25 – 5.21 (m, 1H), 3.95 (t, J = 6.0 Hz, 2H), 3.24 (td, J = 5.9, 4.9Hz, 3H), 2.92 – 2.84 (m, 1H), 2.74 – 2.67 (m, 5H), 2.63 – 2.47 (m, 14H), 2.36 (s, 3H), 2.34 (s, 3H), 2.13 – 2.03 (m, 1H), 1.90 (p, J = 5.9 Hz, 3H), 1.79 –1.69 (m, 3H), 1.63 – 1.54 (m, 3H). MS (ESI) m / z calcd for C43H49N7O8 [M+H] + 791.3643; found 791.3645.

[0090] Example 13: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)-2-oxoethyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 13).

[0091] Referring to the synthesis of compound 1, intermediate 6 was replaced with 2-(4-(4-(3-(2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamido)phenoxy)butyl)piperazin-1-yl)acetic acid to obtain compound 13. TLC detection showed a single point, and yellow fluorescence was observed under UV light at 254 nm and 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.59 (s, 1H),9.51 (s, 1H), 8.89 (s, 1H), 7.92 – 7.84 (m, 1H), 7.63 (dd, J = 7.9, 2.2 Hz,1H), 7.52 (d, J = 2.2 Hz, 1H), 7.42 – 7.35 (m, 1H), 7.34 – 7.22 (m, 1H), 7.04(dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s,1H), 5.26 – 5.21 (m, 1H), 3.95 (t, J = 6.0 Hz, 1H), 3.38 (s, 1H), 2.91 – 2.80(m, 2H), 2.62 – 2.53 (m, 3H), 2.51 (t, J = 6.0 Hz, 1H), 2.36 (s, 1H), 2.34(s, 1H), 2.08 (d, J = 4.6 Hz, 1H), 1.79 – 1.70 (m, 1H), 1.64 – 1.54 (m, 1H).MS (ESI) m / z calcd for C42H45N7O9 [M+H] + 791.3279; found 791.3277.

[0092] Example 14: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperidin-1-yl)butoxy)phenyl)benzamide (compound 14)

[0093] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperidin-1-yl)butoxy)phenyl)benzamide to obtain compound 14. The TLC detection showed a single point, and yellow fluorescence was observed under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s,1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.34 – 7.28 (m, 2H), 7.25 (t,J = 7.9 Hz, 1H), 7.06 – 6.98 (m, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H),5.27 (s, 2H), 5.25 – 5.21 (m, 1H), 3.95 (dt, J = 9.0, 6.1 Hz, 4H), 2.91 –2.83 (m, 1H), 2.79 – 2.70 (m, 2H), 2.68 – 2.61 (m, 2H), 2.61 – 2.50 (m, 4H), 2.36 (s, 3H), 2.34 (s, 3H), 2.12 – 2.05 (m, 1H), 1.83 – 1.65 (m, 6H), 1.62(ttd, J = 8.0, 6.0, 1.1 Hz, 2H), 1.58 – 1.49 (m, 3H), 1.48 – 1.37 (m, 2H). MS(ESI) m / z calcd for C44H49N5O9 [M+H] + 791.3530; found 791.3536.

[0094] Example 15: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperidin-4-yl)butoxy)phenyl)benzamide (compound 15)

[0095] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(1-(3-hydroxypropyl)piperidin-4-yl)butoxy)phenyl)benzamide to obtain compound 15, which showed a single point under TLC and yellow fluorescence under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s,1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.44 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9Hz, 1H), 7.07 – 6.96 (m, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s,2H), 5.26 – 5.19 (m, 1H), 4.05 (t, J = 6.6 Hz, 2H), 3.99 (t, J = 5.8 Hz, 2H), 2.93 – 2.83 (m, 1H), 2.79 (ddd, J = 11.9, 8.2, 5.6 Hz, 2H), 2.74 – 2.64 (m,4H), 2.63 – 2.49 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.14 – 2.03 (m, 1H), 1.88 (p, J = 6.5 Hz, 2H), 1.79 (ddt, J = 12.3, 8.2, 5.6 Hz, 2H), 1.70 (tt, J= 7.7, 5.8 Hz, 2H), 1.54 (ddt, J = 12.3, 8.1, 5.6 Hz, 2H), 1.46 – 1.34 (m,3H), 1.34 – 1.22 (m, 2H). MS (ESI) m / z calcd for C44H49N5O9 [M+H] + 791.3530; found 791.3532.

[0096] Example 16: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)azacyclobutane-1-yl)butoxy)phenyl)benzamide (compound 16)

[0097] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(3-(3-hydroxypropyl)azacyclobutane-1-yl)butoxy)phenyl)benzamide to obtain compound 16. TLC detection showed a single point, and yellow fluorescence was observed under UV light at 254 nm and 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.7 Hz,1H), 7.58 (d, J = 2.7 Hz, 1H), 7.44 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J= 7.9 Hz, 1H), 7.08 – 6.98 (m, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.23 (m, 1H), 3.95 (dt, J = 8.6, 6.2 Hz, 4H), 2.96 (dd,J = 10.2, 4.1 Hz, 2H), 2.92 – 2.82 (m, 1H), 2.71 (dd, J = 10.2, 4.2 Hz, 2H), 2.62 – 2.50 (m, 4H), MS (ESI)m / z calcd for C42H45N5O9 [M+H] + 763.3217; found 763.3215.

[0098] Example 17: Synthesis of 2-((3,5-dimethylisoxazo-4-yl)methoxy)-N-(3-(4-(9-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-3,9-diazaspiro(5,5)undecane-3-yl)butoxy)phenyl)benzamide (compound 17)

[0099] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(9-(3-hydroxypropyl)-3,9-diazaspiro[5.5]undecane-3-yl)butoxy)phenyl)benzamide to obtain compound 17. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 – 7.35 (m, 3H),7.33 – 7.28 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.07 – 7.00 (m, 3H), 6.87(ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.19 (m, 1H), 4.05 (t,J = 6.6 Hz, 3H), 3.95 (t, J = 6.0 Hz, 2H), 2.92 – 2.83 (m, 1H), 2.75 (s, 1H), 2.63 – 2.52 (m, 17H), 2.36 (s, 3H), 2.34 (s, 3H), 2.12 – 2.05 (m, 1H), 1.88 (p, J = 6.5 Hz, 3H), 1.79 – 1.70 (m, 3H), 1.67 – 1.57 (m, 13H). MS (ESI) m / zcalcd for C48H56N6O9 [M+H] + 860.4109; found 860.4105.

[0100] Example 18: Synthesis of 2-((3,5-dimethylisoxazo-4-yl)methoxy)-N-(3-(4-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-2,7-diazaspiro(3,5)nonane-7-yl)butoxy)phenyl)benzamide (compound 18)

[0101] Referring to the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(2-(3-hydroxypropyl)-2,7-diazaspiro[3.5]nonane-7-yl)butoxy)phenyl)benzamide to obtain compound 18. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.38 (ddd, J = 8.0, 2.0,1.2 Hz, 2H), 7.33 – 7.28 (m, 3H), 7.25 (t, J = 7.9 Hz, 1H), 7.07 – 7.00 (m,3H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.21 (m, 1H), 4.05 (t, J = 6.6 Hz, 3H), 3.95 (t, J = 6.0 Hz, 2H), 2.90 (d, J = 7.0 Hz, 1H), 2.86 (s, 6H), 2.77 (t, J = 5.3 Hz, 3H), 2.61 – 2.58 (m, 6H), 2.58 – 2.51 (m,4H), 2.36 (s, 3H), 2.34 (s, 3H), 2.12 – 2.04 (m, 1H), 1.91 (tt, J = 6.5, 5.2Hz, 3H), 1.74 (ttd, J = 7.7, 5.9, 0.9 Hz, 3H), 1.67 – 1.58 (m, 8H). MS (ESI)m / z calcd for C46H52N6O9 [M+H] + 832.3796; found 832.3799.

[0102] Example 19: Synthesis of 2-((3,5-dimethylisoxazo-4-yl)methoxy)-N-(3-(4-(8-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-2,8-diazaspiro(4,5)decane-2-yl)butoxy)phenyl)benzamide (compound 19)

[0103] Referring to the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(8-(3-hydroxypropyl)-2,8-diazaspiro[4.5]decane-2-yl)butoxy)phenyl)benzamide to obtain compound 19. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.42 – 7.36 (m, 3H), 7.34 – 7.28 (m, 3H), 7.25 (t, J = 7.9 Hz, 1H), 7.06 – 6.99 (m, 3H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.23 (m, 1H), 4.05 (t,J = 6.6 Hz, 3H), 3.95 (t, J = 6.0 Hz, 2H), 2.92 – 2.84 (m, 1H), 2.82 – 2.70(m, 5H), 2.66 – 2.61 (m, 3H), 2.61 – 2.48 (m, 11H), 2.36 (s, 3H), 2.34 (s,3H), 2.12 – 2.05 (m, 1H), 1.88 (p, J = 6.6 Hz, 3H), 1.78 – 1.66 (m, 6H), 1.65– 1.58 (m, 5H), 1.45 (ddd, J = 12.6, 6.1, 3.4 Hz, 3H). MS (ESI) m / z calcd forC47H54N6O9 [M+H] + 846.3952; found 846.3951.

[0104] Example 20: Synthesis of 2-((3,5-dimethylisoxazo-4-yl)methoxy)-N-(3-(4-(6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-2,6-diazaspiro(3,3)heptane-2-yl)butoxy)phenyl)benzamide (compound 20)

[0105] Referring to the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(6-(3-hydroxypropyl)-2,6-diazaspiro[3.3]heptane-2-yl)butoxy)phenyl)benzamide to obtain compound 20. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.07 – 7.01 (m, 2H), 6.87 (ddd, J =7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.27 – 5.21 (m, 1H), 4.05 (t, J = 6.6Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.92 (s, 4H), 2.90 (s, 4H), 2.89 – 2.85(m, 1H), 2.75 (t, J = 5.3 Hz, 2H), 2.62 – 2.52 (m, 4H), 2.36 (s, 3H), 2.34(s, 3H), 2.12 – 2.02 (m, 1H), 1.91 (tt, J = 6.5, 5.3 Hz, 2H), 1.74 (ttd, J =7.7, 5.9, 0.9 Hz, 2H), 1.67 – 1.57 (m, 2H). MS (ESI) m / z calcd for C44H48N6O9[M+H] + 804.3483; found 804.3482.

[0106] Example 21: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4'-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-(1,4'-bipiperidin)-1'-yl)butoxy)phenyl)benzamide (compound 21)

[0107] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)-[1,4′-bipiperidine]-1′-yl)butoxy)phenyl)benzamide to obtain compound 21. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.43 – 7.36 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.06 – 6.96 (m, 2H), 6.87 (ddd, J =7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.21 (m, 1H), 3.95 (dt, J = 9.0,6.1 Hz, 4H), 3.00 – 2.76 (m, 5H), 2.74 – 2.60 (m, 4H), 2.61 – 2.46 (m, 5H), 2.36 (s, 3H), 2.34 (s, 3H), 2.14 – 2.03 (m, 1H), 1.92 – 1.66 (m, 8H), 1.66 –1.49 (m, 7H), 1.48 – 1.40 (m, 2H). MS (ESI) m / z calcd for C49H58N6O9 [M+H] + 874.4265; found 874.4261.

[0108] Example 22: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)ethoxy)phenyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 22)

[0109] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 22. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.43 – 7.35 (m, 2H),7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.06 – 7.01 (m, 2H), 6.90 – 6.83 (m,3H), 6.81 – 6.76 (m, 2H), 5.27 (s, 2H), 5.26 – 5.20 (m, 1H), 4.46 (t, J = 4.9Hz, 2H), 4.40 – 4.33 (m, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.32 – 3.18 (m, 4H), 2.92 – 2.83 (m, 1H), 2.80 – 2.71 (m, 4H), 2.65 – 2.49 (m, 2H), 2.43 (t, J =6.0 Hz, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.16 – 2.01 (m, 1H), 1.80 – 1.69 (m,2H), 1.65 – 1.51 (m, 2H). MS (ESI) m / z calcd for C48H50N6O10 [M+H] + 870.3588; found 870.3585.

[0110] Example 23: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propoxy)phenyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 23)

[0111] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(4-(3-hydroxypropoxy)phenyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 23. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.43 – 7.35 (m, 2H),7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.07 – 7.00 (m, 2H), 6.89 – 6.83 (m,3H), 6.81 (d, J = 1.4 Hz, 1H), 6.80 (d, J = 1.3 Hz, 1H), 5.27 (s, 2H), 5.26 –5.19 (m, 1H), 4.17 (t, J = 6.4 Hz, 2H), 4.13 (t, J = 6.4 Hz, 2H), 3.95 (t, J= 6.0 Hz, 2H), 3.29 – 3.21 (m, 4H), 2.93 – 2.79 (m, 1H), 2.78 – 2.72 (m, 4H), 2.63 – 2.51 (m, 2H), 2.43 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.23 (p, J = 6.5 Hz, 2H), 2.15 – 2.04 (m, 1H), 1.80 – 1.68 (m, 2H), 1.64 –1.51 (m, 2H). MS (ESI) m / z calcd for C49H52N6O10 [M+H] + 884.3745; found 884.3741.

[0112] Example 24: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)azacyclobutane-1-yl)piperidin-1-yl)butoxy)phenyl)benzamide (compound 24)

[0113] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-(3-hydroxypropyl)azacyclobutane-1-yl)piperidin-1-yl)butoxy)phenyl)benzamide to obtain compound 24. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.43 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.07 – 6.99 (m, 2H), 6.87 (ddd, J =7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.21 (m, 1H), 3.95 (dt, J = 8.6,6.2 Hz, 4H), 2.98 (dd, J = 10.1, 4.3 Hz, 2H), 2.92 – 2.76 (m, 3H), 2.76 –2.62 (m, 4H), 2.62 – 2.52 (m, 4H), 2.43 (p, J = 1.73 (ddddd, J = 12.4, 9.7, 7.1, 4.1, 1.1 Hz, 4H),1.67 – 1.47 (m, 6H). MS (ESI) m / z calcd for C47H54N6O9 [M+H] +846.3952; found 846.3956.

[0114] Example 25: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 25)

[0115] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(piperidin-4-yl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 25, which showed a single point under TLC and yellow fluorescence under UV light at 254 nm and 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s,1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.38 (ddd, J = 8.0, 2.0, 1.2 Hz, 2H), 7.33 – 7.28(m, 3H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.99 (dd,J = 7.3, 2.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.22 (m, 1H), 3.95 (t, J = 6.0 Hz, 2H), 3.46 (ddd, J = 12.5, 8.0, 5.3Hz, 3H), 3.28 (ddd, J = 12.3, 7.9, 5.1 Hz, 3H), 2.91 – 2.80 (m, 1H), 2.73 –2.65 (m, 5H), 2.64 – 2.48 (m, 12H), 2.36 (s, 3H), 2.34 (s, 3H), 2.12 – 2.05(m, 1H), 2.05 – 1.93 (m, 2H), 1.79 – 1.70 (m, 6H), 1.63 – 1.54 (m, 2H). MS(ESI) m / z calcd for C45H51N7O8 [M+H]+ 817.3799; found 817.3792.

[0116] Example 26: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 26).

[0117] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 26, which showed a single point under TLC and blue fluorescence under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.72 (d, J = 7.2 Hz,1H), 7.42 – 7.36 (m, 4H), 7.33 – 7.28 (m, 3H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.99 (dd, J = 7.3, 2.2 Hz, 1H), 6.87 (ddd, J =7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.21 (m, 1H), 3.95 (t, J = 6.0Hz, 2H), 3.43 (ddd, J = 12.4, 8.6, 5.9 Hz, 3H), 3.25 (ddd, J = 12.4, 8.6, 6.0Hz, 3H), 2.93 – 2.84 (m, 1H), 2.78 – 2.71 (m, 3H), 2.63 – 2.47 (m, 16H), 2.36(s, 3H), 2.34 (s, 3H), 2.13 – 2.04 (m, 1H), 1.89 (ddt, J = 12.0, 8.6, 5.9 Hz,3H), 1.84 – 1.77 (m, 1H), 1.77 – 1.71 (m, 2H), 1.68 – 1.53 (m, 6H). MS (ESI)m / z calcd for C46H53N7O8 [M+H] + 831.3956; found 831.3950.

[0118] Example 27: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4'-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)azacyclobutane-1-yl)-(1,4'-bipiperidin)-1'-yl)butoxy)phenyl)benzamide (compound 27)

[0119] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-(3-hydroxypropyl)azacyclobutane-1-yl)-[1,4′-bipiperidine]-1′-yl)butoxy)phenyl)benzamide to obtain compound 27. The TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1 H NMR (500MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.7 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 – 7.36 (m,2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.08 – 6.98 (m, 2H), 6.87 (ddd,J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.22 (m, 1H), 3.95 (dt, J =8.7, 6.2 Hz, 4H), 2.98 (dd, J = 10.1, 4.3 Hz, 2H), 2.93 – 2.79 (m, 3H), 2.79– 2.62 (m, 8H), 2.61 – 2.49 (m, 5H), 2.43 (p, J = 4.8 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.13 – 2.04 (m, 1H), 1.96 (tp, J = 5.9, 4.3 Hz, 1H), 1.92 –1.80 (m, 4H), 1.73 (ddddd, J = 12.4, 9.7, 7.1, 4.1, 1.1 Hz, 4H), 1.66 – 1.45(m, 8H). MS (ESI) m / z calcd for C52H63N7O9 [M+H] + 929.4687; found 929.4681.

[0120] Example 28: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(3-(4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)azacyclobutane-1-yl)piperidin-1-yl)azacyclobutane-1-yl)butoxy)phenyl)benzamide (compound 28).

[0121] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(3-(4-(3-(3-(3-hydroxypropyl)azacyclobutane-1-yl)piperidin-1-yl)azacyclobutane-1-yl)butoxy)phenyl)benzamide to obtain compound 28, which showed a single point under TLC and blue fluorescence under UV light at 254 nm and 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.7 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 – 7.36(m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.08 – 6.98 (m, 2H), 6.87(ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.20 (m, 1H), 3.95 (dt,J = 8.7, 6.2 Hz, 4H), 3.06 – 2.95 (m, 5H), 2.93 – 2.84 (m, 1H), 2.81 – 2.67(m, 6H), 2.62 – 2.51 (m, 6H), 2.43 (p, J = 4.8 Hz, 1H), 2.36 (s, 3H), 2.34(s, 3H), 2.17 – 2.03 (m, 1H), 1.96 (tp, J = 5.9, 4.3 Hz, 1H), 1.92 – 1.83 (m,2H), 1.79 – 1.68 (m, 4H), 1.65 – 1.53 (m, 6H). MS (ESI) m / z calcd for C50H59N7O9 [M+H] + 901.4374; found 901.4376.

[0122] Example 29: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(3''-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-(1,3':1',3''-triazacyclobutane)-1''-yl)butoxy)phenyl)benzamide (compound 29).

[0123] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(3-(3-hydroxypropyl)-[1,3′:1′,3″-triazacyclobutane]-1″-yl)butoxy)phenyl)benzamide to obtain compound 29. The TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.08 – 7.00 (m, 2H), 6.87 (ddd, J =7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.22 (m, 1H), 3.95 (dt, J = 8.7,6.2 Hz, 4H), 3.12 (p, J = 3.1 Hz, 1H), 3.07 – 2.93 (m, 7H), 2.91 – 2.83 (m,1H), 2.82 – 2.65 (m, 6H), 2.61 – 2.51 (m, MS (ESI) m / z calcd for C48H55N7O9 [M+H] + 873.4061; found 873.4061.

[0124] Example 30: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(2-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl))-7-azaspiro(3,5)nonane-2-yl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 30).

[0125] Referring to the synthesis of compound 1, intermediate 6 was replaced with N-(3-(4-(4-(7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)butoxy)phenyl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 30. The TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.72 (d, J =7.2 Hz, 1H), 7.43 – 7.36 (m, 3H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.99 (dd, J = 7.3, 2.2 Hz, 1H), 6.87 (ddd, J= 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.21 (m, 1H), 3.95 (t, J = 6.0Hz, 2H), 3.52 – 3.44 (m, 4H), 2.98 (p, J = 5.5 Hz, 1H), 2.92 – 2.85 (m, 1H), 2.77 – 2.67 (m, 4H), 2.64 – 2.59 (m, 4H), 2.59 – 2.53 (m, 2H), 2.51 (t, J =6.0 Hz, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.20 – 2.03 (m, 1H), 1.95 (dd, J =11.3, 5.6 Hz, 2H), 1.81 – 1.67 (m, 8H), 1.64 – 1.51 (m, 2H). MS (ESI) m / zcalcd for C48H55N7O8 [M+H] + 857.4112; found 857.4110.

[0126] Example 31: Synthesis of 2-((3,5-dimethylisoxazo-4-yl)methoxy)-N-(3-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 31)

[0127] Referring to the synthesis of compound 1, intermediate 6 was replaced with N-(3-(4-(4-(azacyclobutane-3-ylmethyl)piperazin-1-yl)butoxy)phenyl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 31. TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1 H NMR (500 MHz, Chloroform-d)δ 9.51 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.72 (d, J =7.2 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.94 (dd, J = 7.3,2.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.21 (m, 1H), 3.95 (t, J = 6.0 Hz, 2H), 3.84 (dd, J = 10.4, 4.6 Hz, 2H), 3.59 (dd,J = 10.4, 4.6 Hz, 2H), 2.92 – 2.83 (m, 1H), 2.75 (dt, J = 11.4, 4.4 Hz, 2H), 2.64 – 2.47 (m, 12H), 2.36 (s, 3H), 2.34 (s, 3H), 2.17 (hept, J = 4.6 Hz, 1H), 2.12 – 2.03 (m, 1H), 1.80 – 1.69 (m, 2H), 1.65 – 1.51 (m, 2H). MS (ESI)m / z calcd for C44H49N7O8 [M+H] +803.3643; found 803.3648.

[0128] Example 32: Synthesis of 2-((3,5-dimethylisoxazo-4-yl)methoxy)-N-(3-(3-(4-(4-(1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)azacyclobutane-3-yl)piperazin-1-yl)phenoxy)propoxy)phenyl)benzamide (compound 32)

[0129] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(3-(4-(4-(1-(3-hydroxypropyl)azacyclobutane-3-yl)piperazin-1-yl)phenoxy)propoxy)phenyl)benzamide to obtain compound 32. TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1H NMR (500MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 – 7.35 (m,2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.07 – 7.00 (m, 2H), 6.90 – 6.83(m, 3H), 6.83 – 6.77 (m, 2H), 5.27 (s, 2H), 5.26 – 5.21 (m, 1H), 4.17 (t, J =6.4 Hz, 2H), 4.12 (t, J = 6.4 Hz, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.33 – 3.25(m, 4H), 3.10 (p, J = 4.1 Hz, 1H), 2.98 (dd, J = 9.4, 4.0 Hz, 2H), 2.92 –2.84 (m, 1H), 2.80 – 2.75 (m, 4H), 2.75 – 2.70 (m, 4H), 2.63 – 2.52 (m, 2H),2.36 (s, 3H), 2.34 (s, 3H), 2.23 (p, J = 6.5 Hz, 2H), 2.15 – 2.02 (m, 1H),1.89 (p, J = 6.5 Hz, 2H). MS (ESI) m / z calcd for C51H55N7O10 [M+H] + 925.4010; found 925.4016.

[0130] Example 33: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)ethynyl)piperidin-1-yl)butoxy)phenyl)benzamide (compound 33)

[0131] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((4-(4-ethynylpiperidin-1-yl)but-2-yn-1-yl)oxy)phenyl)benzamide to obtain compound 33. TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm.1 H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 8.89 (s, 1H), 8.04 – 7.98 (m, 2H), 7.86 (dd, J = 8.0, 1.7 Hz,1H), 7.70 (dd, J = 6.6, 2.2 Hz, 1H), 7.43 – 7.36 (m, 2H), 7.31 (s, 2H), 7.25(t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1,1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.21 (m, 1H), 3.95 (t, J = 6.0 Hz, 2H), 2.95 – 2.83 (m, 1H), 2.78 (ddd, J = 11.7, 7.2, 4.5 Hz, 2H), 2.67 – 2.48 (m,7H), 2.36 (s, 3H), 2.34 MS (ESI) m / z calcd for C43H39N5O8 [M+H] + 753.2799; found 753.2796.

[0132] Example 34: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)ethynyl)piperidin-1-yl)but-2-yn-1-yl)oxy)phenyl)benzamide (compound 34)

[0133] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-ethynylpiperidin-1-yl)butoxy)phenyl)benzamide to obtain compound 34, which showed a single point under TLC and blue fluorescence under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 8.03 – 7.98 (m, 2H), 7.86 (dd, J = 8.0, 1.7 Hz, 1H), 7.70 (dd,J = 6.6, 2.2 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.34 – 7.28 (m, 2H), 7.26 (d, J =8.0 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.81 (ddd, J = 7.9, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.22 (m, 1H), 4.77 (t, J = 2.5 Hz, 2H), 3.74 (t, J= 2.5 Hz, 2H), 2.95 – 2.82 (m, 3H), 2.70 (ddd, J = 11.0, 6.2, 3.5 Hz, 2H), 2.67 – 2.51 (m, 3H), 2.36 (s, 3H), 2.34 (s, 3H), 2.13 – 2.01 (m, 1H), 1.89(dtd, J = 11.9, 6.1, 3.4 Hz, 2H), 1.64 (dtd, J = 11.8, 6.0, 3.5 Hz, 2H). MS(ESI) m / z calcd for C43H43N5O8 [M+H] + 757.3112; found 757.3110.

[0134] Example 35: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)propyl)piperidin-1-yl)but-2-yn-1-yl)oxy)phenyl)benzamide (compound 35)

[0135] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-((4-(4-(3-aminopropyl)piperidin-1-yl)but-2-yn-1-yl)oxy)phenyl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 35. TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d)δ 9.51 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.7 Hz, 1H), 7.77 (d, J =7.9 Hz, 1H), 7.43 – 7.27 (m, 5H), 7.26 (d, J = 8.0 Hz, 1H), 7.04 (dd, J =7.9, 1.2 Hz, 1H), 6.95 (dd, J = 7.9, 2.2 Hz, 1H), 6.81 (ddd, J = 7.9, 2.1,1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.21 (m, 1H), 5.12 (t, J = 4.9 Hz, 1H), 4.77 (t, J = 2.5 Hz, 2H), 3.74 (t, J = 2.5 Hz, 2H), 3.24 (td, J = 5.6, 4.9Hz, 2H), 2.94 – 2.78 (m, 3H), 2.70 – 2.49 (m, 4H), 2.36 (s, 3H), 2.34 (s,3H), 2.19 – 2.01 (m, 1H), 1.86 (dddd, J = 12.8, 7.1, 5.6, 4.5 Hz, 2H), 1.70 –1.47 (m, 5H), 1.45 – 1.32 (m, 2H). MS (ESI) m / z calcd for C44H46N6O8 [M+H] + 786.3377; found 786.3375.

[0136] Example 36: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)ethynyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 36)

[0137] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-ethynylpiperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 36, which showed a single point under TLC and blue fluorescence under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H),8.89 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 6.7 Hz, 1H), 7.86 (dd, J= 8.0, 1.7 Hz, 1H), 7.72 (dd, J = 6.7, 2.1 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.31(s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd,J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.22 (m, 1H), 3.95 (t, J =6.0 Hz, 2H), 3.13 – 3.08 (m, 4H), 2.92 – 2.83 (m, 1H), 2.74 – 2.63 (m, 4H),2.62 – MS (ESI) m / zcalcd for C42H42N6O8 [M+H] + 758.3064; found 758.3061.

[0138] Example 37: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)prop-2-yn-1-yl)piperazin-1-yl)but-2-yn-1-yl)oxy)phenyl)benzamide (compound 37)

[0139] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((4-(4-(prop-2-yn-1-yl)piperazin-1-yl)but-2-yn-1-yl)oxy)phenyl)benzamide to obtain compound 37, which showed a single point under TLC and blue fluorescence under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 8.04 – 7.98 (m, 2H), 7.86 (dd, J = 8.0, 1.6Hz, 1H), 7.69 (dd, J = 6.8, 2.2 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.34 – 7.28 (m,2H), 7.26 (t, J = 8.0 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.81 (ddd, J =7.9, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.20 (m, 1H), 4.77 (t, J = 2.5Hz, 2H), 4.05 (s, 2H), 3.76 (t, J = 2.5 Hz, 2H), 2.92 – 2.83 (m, 1H), 2.83 –2.72 (m, 8H), 2.63 – 2.52 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.14 – 2.04(m, 1H). MS (ESI) m / z calcd for C43H40N6O8 [M+H] + 768.2908; found 768.2901.

[0140] Example 38: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)prop-2-yn-1-yl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 38)

[0141] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(prop-2-yn-1-yl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 38, which showed a single point under TLC and blue fluorescence under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 8.08 – 7.95 (m, 2H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.69 (dd, J = 6.8, 2.2 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.31 (s, 2H), 7.25 (t, J= 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2Hz, 1H), 5.27 (s, 2H), 5.25 – 5.21 (m, 1H), 4.05 (s, 2H), 3.95 (t, J = 6.0Hz, 2H), 2.95 – 2.79 (m, 1H), 2.69 (ddd, J = 4.9, 2.9, 1.1 Hz, 4H), 2.64 –2.54 (m, 6H), 2.51 (t, MS (ESI) m / z calcdfor C43H44N6O8 [M+H] + 772.3221; found 772.3218.

[0142] Example 39: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxo)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)phenyl)benzamide (compound 39)

[0143] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)phenyl)benzamide to obtain compound 39. TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.7 Hz, 1H), 7.73 (p, J = 0.8 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.06 – 7.01(m, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.22 (m,1H), 4.71 (d, J = 1.0 Hz, 2H), 4.18 (t, J = 4.9 Hz, 2H), 4.07 (td, J = 6.2,0.9 Hz, 2H), 4.02 (t, J = 5.4 Hz, 2H), 3.86 (t, J = 4.9 Hz, 2H), 2.91 – 2.84(m, 1H), 2.61 – 2.52 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.13 – 2.05 (m,1H), 1.99 – 1.91 (m, 2H), 1.85 – 1.78 (m, 2H). MS (ESI) m / z calcd forC41H41N7O10 [M+H] + 791.2915; found 791.2911.

[0144] Example 40: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((5-((2-(2,6-dioxopiridin-3-yl)-1,3-dioxoisoindoline-5-yl)oxo)pentyl)oxo)phenyl)benzamide (compound 40)

[0145] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((5-hydroxypentyl)oxy)phenyl)benzamide to obtain compound 40. The TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7Hz, 1H), 7.41 – 7.36 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.06 –7.00 (m, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.21(m, 1H), 4.00 (td, J = 6.3, 2.2 Hz, 4H), 2.92 – 2.80 (m, 1H), 2.61 – 2.50 (m,2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.18 – 2.02 (m, 1H), 1.82 – 1.74 (m, 4H),1.62 – 1.53 (m, 2H). MS (ESI) m / z calcd for C37H36N4O9 [M+H] + 680.2482; found 680.2488.

[0146] Example 41: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((8-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)oxo)octyl)oxo)phenyl)benzamide (compound 41)

[0147] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((8-hydroxyoctyl)oxy)phenyl)benzamide to obtain compound 41. TLC detection showed a single point, and blue fluorescence was observed under UV light at 254 nm and 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7Hz, 1H), 7.41 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.06 –6.99 (m, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.22(m, 1H), 4.00 (t, J = 6.3 Hz, 4H), 2.91 – 2.84 (m, 1H), 2.62 – 2.52 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.13 – 2.04 (m, 1H), 1.77 (tt, J = 7.5, 6.3 Hz, 4H), 1.43 (dq, J = 7.8, 7.0 Hz, 4H), 1.32 – 1.26 (m, 4H). MS (ESI) m / z calcdfor C40H42N4O9 [M+H] + 722.2952; found 722.2954.

[0148] Example 42: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((12-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)dodecyl)oxy)phenyl)benzamide (compound 42)

[0149] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((12-hydroxydodecyl)oxy)phenyl)benzamide to obtain compound 42. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H),8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58(d, J = 2.7 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.31 (s, 2H), 7.24 (d, J = 7.9 Hz,1H), 7.07 – 6.99 (m, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H),5.25 – 5.21 (m, 1H), 4.00 (t, J = 6.3 Hz, 4H), 2.96 – 2.83 (m, 1H), 2.64 –2.51 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.12 – 2.01 (m, 1H), 1.77 (tt, J =7.5, 6.3 Hz, 4H), 1.43 (p, J = 7.3 Hz, 4H), 1.31 – 1.17 (m, 12H). MS (ESI) m / z calcd for C44H50N4O9 [M+H] + 778.3578; found 778.3571.

[0150] Example 43: Synthesis of 3-((12-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)dodecyl)oxy)-N-(2-((3,5-dimethylisooxazol-4-yl)methoxy)phenyl)benzamide (compound 43)

[0151] Following the synthesis of compound 1, intermediate 6 was replaced with N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-((12-hydroxydodecyl)oxy)benzamide to obtain compound 43. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H),8.56 (s, 1H), 7.92 – 7.84 (m, 3H), 7.64 – 7.53 (m, 3H), 7.50 – 7.33 (m, 3H),7.05 – 6.97 (m, 5H), 6.97 – 6.93 (m, 1H), 5.26 (s, 2H), 5.24 (t, J = 3.6 Hz, 1H), 4.00 (t, J = 6.3 Hz, 5H), 2.86 (d, J = 7.2 Hz, 1H), 2.62 – 2.51 (m, 2H),2.36 (s, 3H), 2.34 (s, 3H), 2.08 (d, J = 4.7 Hz, 1H), 1.77 (tt, J = 7.5, 6.3Hz, 5H), 1.43 (p, J = 7.2 Hz, 5H), 1.26 (s, 16H). MS (ESI) m / z calcd forC44H50N4O9 [M+H] + 778.3578; found 778.3576.

[0152] Example 44: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxo)ethoxy)ethoxy)phenyl)benzamide (compound 44).

[0153] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(2-(2-hydroxyethoxy)ethoxy)phenyl)benzamide to obtain compound 44. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H),8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.59(d, J = 2.8 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.33 – 7.28 (m, 2H), 7.25 (t, J =7.9 Hz, 1H), 7.07 – 7.01 (m, 2H), 6.85 (ddd, J = 7.9, 2.2, 1.3 Hz, 1H), 5.27(s, 2H), 5.25 – 5.21 (m, 1H), 4.13 (t, J = 5.0 Hz, 4H), 3.78 (t, J = 5.0 Hz, 4H), 2.92 – 2.81 (m, 1H), 2.62 – 2.50 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.18 – 2.01 (m, 1H). MS (ESI) m / z calcd for C36H34N4O10 [M+H] + 682.2275; found 682.2270.

[0154] Example 45: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxo)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)benzamide (compound 45)

[0155] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)phenyl)benzamide to obtain compound 45. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.86 (dd, J = 8.0,1.7 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.33 – 7.28 (m,2H), 7.25 (t, J = 7.9 Hz, 1H), 7.07 – 7.01 (m, 2H), 6.85 (ddd, J = 7.9, 2.2,1.3 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.18 (m, 1H), 4.13 (t, J = 4.9 Hz, 4H), 3.78 (t, J = 5.0 Hz, 4H), 3.70 (td, J = 4.6, 1.0 Hz, 4H), 3.66 (td, J = 4.5,1.0 Hz, 4H), 2.92 – 2.84 (m, 1H), 2.64 – 2.46 (m, 2H), 2.36 (s, 3H), 2.34 (s,3H), 2.13 – 2.03 (m, 1H). MS (ESI) m / z calcd for C40H42N4O12 [M+H] + 770.2799; found 770.2795.

[0156] Example 46: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(2-(2-(2-((2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)amino)ethoxy)ethoxy)ethoxy)phenyl)benzamide (compound 46)

[0157] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 46. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.7 Hz, 1H), 7.77 (d, J = 7.9Hz, 1H), 7.41 – 7.33 (m, 3H), 7.33 – 7.28 (m, 2H), 7.24 (d, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.94 (dd, J = 7.8, 2.1 Hz, 1H), 6.85 (ddd, J= 7.9, 2.2, 1.3 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.22 (m, 1H), 5.09 (t, J = 4.9Hz, 1H), 4.13 (t, J = 4.9 Hz, 2H), 3.78 (t, J = 5.0 Hz, 2H), 3.69 – 3.58 (m,6H), 3.42 (dt, J = 5.0, 4.2 Hz, 2H), 2.92 – 2.82 (m, 1H), 2.62 – 2.51 (m,2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.12 – 1.98 (m, 1H). MS (ESI) m / z calcd forC38H39N5O10 [M+H] + 725.2697; found 725.2691.

[0158] Example 47: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(2-(2-(2-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)benzamide (compound 47)

[0159] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenyl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 47. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.42 – 7.34 (m, 3H), 7.33 – 7.28 (m, 2H), 7.25 (t,J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.94 (dd, J = 7.8, 2.1 Hz,1H), 6.85 (ddd, J = 7.9, 2.2, 1.3 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.20 (m, 1H),5.09 (t, J = 4.9 Hz, 1H), 4.13 (t, J = 4.9 Hz, 2H), 3.78 (t, J = 5.0 Hz, 2H),3.72 – 3.59 (m, 10H), 3.42 (dt, J = 4.9, 4.1 Hz, 2H), 2.95 – 2.80 (m, 1H), 2.64 – 2.50 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.16 – 2.00 (m, 1H). MS(ESI) m / z calcd for C40H43N5O11 [M+H] + 769.2959; found 769.2954.

[0160] Example 48: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((12-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)amino)dodecyl)oxo)phenyl)benzamide (compound 48)

[0161] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-((12-aminododecyl)oxy)phenyl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 48. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.42– 7.36 (m, 2H), 7.35 (d, J = 2.1 Hz, 1H), 7.33 – 7.28 (m, 2H), 7.26 (d, J =7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.95 (dd, J = 7.9, 2.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.32 (t, J = 4.7 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.21 (m, 1H), 4.00 (t, J = 6.3 Hz, 2H), 3.14 (td, J = 5.4, 4.6 Hz, 2H), 2.91 – 2.82 (m, 1H), 2.61 – 2.45 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.16 – 2.01 (m, 1H), 1.77 (tt, J = 7.4, 6.3 Hz, 2H), 1.59 (tt, J = 7.3, 5.3Hz, 2H), 1.43 (p, J = 7.3 Hz, 2H), 1.39 – 1.31 (m, 2H), 1.29 – 1.21 (m, 12H).MS (ESI) m / z calcd for C44H51N5O8 [M+H] + 777.3738; found 777.3731.

[0162] Example 49: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((12-((2-(2,6-dioxopiridin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)-12-oxododecyl)oxo)phenyl)benzamide (compound 49)

[0163] Following the synthesis of compound 1, intermediate 6 was replaced with 12-(3-(2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamido)phenoxy)dodecanoic acid to obtain compound 49. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm.1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 9.21 (s,1H), 8.89 (s, 1H), 7.92 – 7.82 (m, 2H), 7.63 (dd, J = 7.9, 2.2 Hz, 1H), 7.53(d, J = 2.1 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz,1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H),5.27 (s, 2H), 5.25 – 5.22 (m, 1H), 4.00 (t, J = 6.3 Hz, 2H), 2.93 – 2.83 (m,1H), 2.62 – 2.52 (m, 2H), 2.36 (s, 3H), 2.35 – 2.32 (m, 4H), 2.12 – 2.05 MS (ESI) m / z calcd for C44H49N5O9[M+H] + 791.3530; found 791.3532.

[0164] Example 50: Synthesis of 4-(4-(3-(2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoylamino)phenoxy)butyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carboxamide (Compound 50)

[0165] Following the synthesis of compound 1, intermediate 6 was replaced with 4-(4-(3-(2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamido)phenoxy)butyl)piperazine-1-carboxylic acid to obtain compound 50. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s,1H), 8.89 (s, 1H), 8.34 (s, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.86 (dd, J = 8.0,1.6 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 7.9, 2.0 Hz, 1H), 7.42 –7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 5.26 – 5.20 (m,1H), 3.95 (t, J = 6.0 Hz, 2H), 3.39 – 3.30 (m, 4H), 2.94 – 2.83 (m, 1H), 2.71– 2.64 (m, 4H), 2.62 – 2.52 (m, 2H), 2.50 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.11 – 2.01 (m, 1H), 1.81 – 1.67 (m, 2H), 1.64 – 1.55 (m, 2H).MS (ESI) m / z calcd for C41H43N7O9 [M+H] + 777.3122; found 777.3126.

[0166] Example 51: Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxo)propyl)piperazin-1-yl)butoxy)benzamide (compound 51)

[0167] Following the synthesis of compound 1, intermediate 6 was replaced with N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)benzamide to obtain compound 51. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.06(s, 1H), 8.56 (s, 1H), 7.91 – 7.85 (m, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.60(ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.47 – 7.36 (m, 2H), 7.03 – 6.98 (m, 3H), 6.97 – 6.93 (m, 1H), 6.79 (dd, J = 8.8, 2.2 Hz, 1H), 6.77 – 6.75 (m, 1H), 5.26 (s, 2H), 4.66 – 4.54 (m, 2H), 4.48 (dd, J = 13.5, 0.8 Hz, 1H), 4.05 (t,J = 6.6 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 2.79 – 2.61 (m, 7H), 2.59 – 2.46(m, 7H), 2.36 (s, 3H), 2.34 (s, 3H), 2.31 – 2.23 (m, 1H), 1.90 (p, J = 6.5Hz, 2H), 1.79 – 1.71 (m, 2H), 1.59 (s, 3H). MS (ESI) m / z calcd for C43H50N6O8[M+H] + 778.3690; found 778.3695.

[0168] Example 52: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxo)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 52)

[0169] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 52. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.06(s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (d, J = 8.8 Hz,1H), 7.42 – 7.34 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J= 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 6.82 – 6.73 (m,2H), 5.27 (s, 2H), 4.64 – 4.53 (m, 2H), 4.48 (dd, J = 13.4, 0.8 Hz, 1H), 4.05 (t, J = 6.6 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.75 – 2.62 (m, 7H), 2.57 –2.46 (m, 7H), 2.36 (s, MS(ESI) m / z calcd for C43H50N6O8 [M+H] + 778.3690; found 778.3694.

[0170] Example 53: Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxo)propyl)piperazin-1-yl)butoxy)phenyl)isonicotinamide (compound 53)

[0171] Following the synthesis of compound 1, intermediate 6 was replaced with 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)isonicotinamide to obtain compound 53. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.37(s, 1H), 9.06 (s, 1H), 8.47 – 8.32 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.68(d, J = 4.5 Hz, 1H), 7.36 (ddd, J = 8.0, 2.1, 1.2 Hz, 1H), 7.31 (d, J = 2.1Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 6.79(dd, J = 8.8, 2.2 Hz, 1H), 6.76 (dt, J = 2.0, 0.9 Hz, 1H), 5.36 (s, 2H), 4.63– 4.45 (m, 3H), 4.05 (t, J = 6.6 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.75 –2.63 (m, 7H), 2.55 – 2.44 (m, 7H), 2.36 (s, 3H), 2.34 (s, 3H), 2.28 (ddt, J =13.6, 8.1, 5.6 Hz, 1H), 1.90 (p, J = 6.6 Hz, 2H), 1.79 – 1.70 (m, 2H), 1.67 –1.55 (m, 3H). MS (ESI) m / z calcd for C42H49N7O8 [M+H] + 779.3643; found 779.3649.

[0172] Example 54: Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxo)propyl)piperazin-1-yl)butoxy)phenyl)isonicotinamide (compound 54)

[0173] Following the synthesis of compound 1, intermediate 6 was replaced with 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)nicotinamide to obtain compound 54. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.37(s, 1H), 9.06 (s, 1H), 8.46 – 8.28 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.68(d, J = 4.5 Hz, 1H), 7.36 (ddd, J = 8.0, 2.1, 1.2 Hz, 1H), 7.31 (d, J = 2.1Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 6.83– 6.72 (m, 2H), 5.36 (s, 2H), 4.62 – 4.46 (m, 3H), 4.05 (t, J = 6.6 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.76 – 2.60 (m, 7H), 2.56 – 2.46 (m, 7H), 2.36 (s,3H), 2.34 (s, MS (ESI) m / z calcd forC42H49N7O8 [M+H] + 779.3643; found 779.3641.

[0174] Example 55: Synthesis of ((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)amino)-3-oxopropyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 55)

[0175] Following the synthesis of compound 1, intermediate 6 was replaced with 3-(4-(4-(3-(2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamido)phenoxy)butyl)piperazin-1-yl)propionic acid to obtain compound 55. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.06(s, 1H), 9.00 (s, 1H), 8.89 (s, 1H), 7.98 – 7.71 (m, 2H), 7.48 – 7.44 (m,2H), 7.41 – 7.36 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J= 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 4.60(t, J = 5.8 Hz, 1H), 4.54 – 4.40 (m, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.84 (t,J = 5.8 Hz, 2H), 2.76 – 2.62 (m, 3H), 2.58 – 2.47 (m, 11H), 2.36 (s, 3H), 2.34 (s, 3H), 2.28 (ddt, J = 13.6, 8.1, 5.6 Hz, 1H), 1.82 – 1.67 (m, 2H),1.66 – 1.55 (m, 3H). MS (ESI) m / z calcd for C43H49N7O8 [M+H] + 791.3643; found 791.3647.

[0176] Example 56: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(3-(3-((2-(2,6-dioxopiridine-3-yl)-1-oxoisoindoline-5-yl)oxo)propyl)azacyclobutane-1-yl)butoxy)phenyl)benzamide (compound 56)

[0177] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(3-(3-hydroxypropyl)azacyclobutane-1-yl)butoxy)phenyl)benzamide to obtain compound 56. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d)δ 9.06 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.7 Hz, 1H), 7.76 (d, J =8.8 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 6.82 –6.75 (m, 2H), 5.27 (s, 2H), 4.63 – 4.57 (m, 1H), 4.57 – 4.44 (m, 2H), 3.95 (dt, J = 8.6, 6.2 Hz, 4H), 2.96 (dd, J = 10.2, 4.1 Hz, 2H), 2.73 – 2.63 (m,3H), 2.58 – 2.46 (m, 3H), 2.36 MS(ESI) m / z calcd for C42H47N5O8 [M+H] + 749.3425; found 749.3426.

[0178] Example 57: Synthesis of 2-((3,5-dimethylisoxazo-4-yl)methoxy)-N-(3-(4-(9-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxo)propyl)-3,9-diazaspiro(5,5)undecane-3-yl)butoxy)phenyl)benzamide (compound 57)

[0179] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(9-(3-hydroxypropyl)-3,9-diazaspiro[5.5]undecane-3-yl)butoxy)phenyl)benzamide to obtain compound 57. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz,1H), 6.79 (dd, J = 8.8, 2.2 Hz, 1H), 6.77 – 6.75 (m, 1H), 5.27 (s, 2H), 4.61(t, J = 5.9 Hz, 1H), 4.59 – 4.45 (m, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.95 (t,J = 6.0 Hz, 2H), 2.73 (t, J = 6.5 Hz, 2H), 1.88 (p, J = 6.5 Hz, 2H), 1.79 – 1.69 (m, 2H), 1.67 – 1.47(m, 11H). MS (ESI) m / z calcd for C48H58N6O8 [M+H] + 846.4316; found 846.4315.

[0180] Example 58: Synthesis of ((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxo)propyl)-(1,4'-bipiperidin)-1'-yl)butoxy)phenyl)benzamide (compound 58)

[0181] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-(4-(4-(3-hydroxypropyl)-[1,4′-bipiperidine]-1′-yl)butoxy)phenyl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 58. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz,1H), 6.83 – 6.74 (m, 2H), 5.27 (s, 2H), 4.61 (t, J = 5.9 Hz, 1H), 4.59 – 4.44(m, 2H), 3.96 (dt, J = 13.5, 6.1 Hz, 4H), 3.00 – 2.91 (m, 2H), 2.82 (ddd, J =12.1, 7.9, 5.1 Hz, 2H), 2.74 – 2.60 (m, 5H), 2.57 – 2.46 (m, 4H), 2.36 (s,3H), 2.34 (s, 3H), 2.28 (ddt, J = 13.6, 8.1, 5.6 Hz, 1H), 1.89 – 1.66 (m,8H), 1.65 – 1.49 (m, 8H), 1.49 – 1.38 (m, 2H). MS (ESI) m / z calcd forC49H60N6O8 [M+H] + 860.4473; found 860.4471.

[0182] Example 59: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 59)

[0183] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 59. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ9.06 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 – 7.36 (m,2H), 7.31 (s, 3H), 7.25 (t, J = 7.9 Hz, 1H), 7.19 (dt, J = 9.0, 0.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.95 (dd, J = 9.1, 2.1 Hz, 1H), 6.87 (ddd, J= 7.7, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 4.61 (t, J = 5.9 Hz, 1H), 4.53 – 4.38(m, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.43 (ddd, J = 12.4, 8.6, 5.9 Hz, 2H), 3.25 (ddd, J = 12.4, 8.6, 6.0 Hz, 2H), 2.81 – 2.73 (m, 2H), 2.67 (ddd, J =15.4, 8.1, 5.3 Hz, 1H), 2.61 (t, J = 4.5 Hz, 4H), 2.53 – 2.45 (m, 7H), 2.36(s, 3H), 2.34 (s, 3H), 2.27 (ddt, J = 13.6, 8.1, 5.6 Hz, 1H), 1.96 – 1.69 (m,6H), 1.68 – 1.49 (m, 4H). MS (ESI) m / z calcd for C46H55N7O7 [M+H] + 817.4163; found 817.4166.

[0184] Example 60: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxo)propyl)azacyclobutane-1-yl)-(1,4'-bipiperidine)-1'-yl)butoxy)phenyl)benzamide (compound 60)

[0185] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-(3-hydroxypropyl)azacyclobutane-1-yl)-[1,4′-bipiperidine]-1′-yl)butoxy)phenyl)benzamide to obtain compound 60. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR(500 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.31 (s, 2H), 7.25(t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1,1.2 Hz, 1H), 6.79 (dd, J = 8.8, 2.2 Hz, 1H), 6.77 – 6.76 (m, 1H), 5.27 (s,2H), 4.64 – 4.42 (m, 3H), 3.95 (dt, J = 8.7, 6.2 Hz, 4H), 2.98 (dd, J = 10.1,4.3 Hz, 2H), 2.88 – 2.61 (m, 11H), 2.58 – 2.45 (m, 4H), 2.43 (p, J = 4.8 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.31 – 2.23 (m, 1H), 1.96 (tp, J = 5.9, 4.3Hz, 1H), 1.92 – 1.79 (m, 4H), 1.78 – 1.68 (m, 4H), 1.66 – 1.51 (m, 9H). MS(ESI) m / z calcd for C52H65N7O8 [M+H] +915.4895; found 915.4899.

[0186] Example 61: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)ethynyl)piperidin-1-yl)but-2-yn-1-yl)oxo)phenyl)benzamide (compound 61)

[0187] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((4-(4-ethynylpiperidin-1-yl)but-2-yn-1-yl)oxy)phenyl)benzamide to obtain compound 61. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.89 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 8.0,1.7 Hz, 1H), 7.44 (dt, J = 2.0, 0.9 Hz, 1H), 7.41 (dd, J = 8.2, 2.2 Hz, 1H), 7.39 – 7.28 (m, 4H), 7.25 (s, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.81 (ddd,J = 7.9, 2.1, 1.2 Hz, 1H), 5.27 (s, 2H), 4.77 (t, J = 2.5 Hz, 2H), 4.69 –4.52 (m, 3H), 3.74 (t, J = 2.5 Hz, 2H), 2.91 (ddd, J = 11.0, 6.2, 3.5 Hz,2H), 2.73 – 2.57 (m, 4H), 2.50 (ddd, J = 15.2, 8.1, 5.3 Hz, 1H), 2.36 (s,3H), 2.34 (s, 3H), 2.28 (ddt, J = 13.6, 8.1, 5.6 Hz, 1H), 1.89 (dtd, J =11.9, 6.1, 3.4 Hz, 2H), 1.68 – 1.57 (m, 3H). MS (ESI) m / z calcd forC43H41N5O7 [M+H] +739.3006; found 739.3010.

[0188] Example 62: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)prop-2-yn-1-yl)piperazin-1-yl)but-2-yn-1-yl)oxo)phenyl)benzamide (compound 62)

[0189] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((4-(4-(4-(prop-2-yn-1-yl)piperazin-1-yl)but-2-yn-1-yl)oxy)phenyl)benzamide to obtain compound 62. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.89 (s, 1H), 8.00 (dt, J = 8.2, 0.9 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.41 (s, 6H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.81 (ddd, J = 7.9, 2.1, 1.2 Hz, 1H), 5.27 (s,2H), 4.77 (t, J = 2.5 Hz, 2H), 4.68 – 4.51 (m, 3H), 4.05 (s, 2H), 3.76 (t, J= 2.5 Hz, 2H), 2.83 – 2.73 (m, 8H), 2.70 – 2.65 (m, 1H), 2.50 (ddd, J = 15.2,8.1, 5.3 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.28 (ddt, J = 13.6, 8.1, 5.6Hz, 1H), 1.62 (ddt, J = 13.6, 8.1, 5.7 Hz, 1H). MS (ESI) m / z calcd forC43H42N6O7 [M+H] + 754.3115; found 754.3116.

[0190] Example 63: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)oxo)ethoxy)phenyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 63)

[0191] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 63. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.31 (s, 2H), 7.25 (t, J = 7.9Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.91 – 6.83 (m, 3H), 6.81 – 6.72 (m,4H), 5.27 (s, 2H), 4.65 – 4.58 (m, 1H), 4.53 (dd, J = 31.3, 0.7 Hz, 1H), 4.47– 4.43 (m, 2H), 4.36 (t, J = 4.9 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.29 –3.15 (m, 4H), 2.79 – 2.72 (m, 4H), 2.69 – 2.63 (m, 1H), 2.50 (ddd, J = 15.2,8.1, 5.3 Hz, 1H), 2.43 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.28(ddt, J = 13.6, 8.1, 5.6 Hz, 1H), 1.81 – 1.70 (m, 2H), 1.68 – 1.54 (m, 3H).MS (ESI) m / z calcd for C48H52N6O9 [M+H] + 856.3796; found 856.3799.

[0192] Example 64: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-((2-((2-(2,6-dioxopiridine-3-yl)-1-oxoisoindoline-5-yl)oxo)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)phenyl)benzamide (compound 64)

[0193] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazol-1-yl)butoxy)phenyl)benzamide to obtain compound 64. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.89 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.78 –7.70 (m, 2H), 7.42 – 7.36 (m, 2H), 7.31 (s, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 6.79 (dd, J = 8.8, 2.2 Hz, 1H), 6.76 (dt, J = 1.9, 0.8 Hz, 1H), 5.27 (s, 2H), 4.71 (d, J = 0.9 Hz, 2H), 4.61 (t, J = 5.9 Hz, 1H), 4.59 – 4.45 (m, 2H), 4.18 (t,J = 4.9 Hz, 2H), 4.07 (td, J = 6.2, 0.9 Hz, 2H), 4.02 (t, J = 5.4 Hz, 2H), 3.86 (t, J = 4.9 Hz, 2H), 2.67 (ddd, J = 15.4, 8.1, 5.3 Hz, 1H), 2.50 (ddd, J= 15.2, 8.1, 5.3 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.28 (ddt, J = 13.6,8.1, 5.6 Hz, 1H), 1.95 (ttd, J = 7.2, 6.3, 0.8 Hz, 2H), 1.82 (ttd, J = 7.7,5.4, 0.9 Hz, 2H), 1.62 (ddt, J = 13.6, 8.1, 5.7 Hz, 1H). MS (ESI) m / z calcdfor C41H43N7O9 [M+H] + 777.3122; found 777.3124.

[0194] Example 65: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((12-((2-(2,6-dioxopiridin-3-yl)-3-oxoisoindoline-5-yl)oxo)dodecyl)oxo)phenyl)benzamide (compound 65)

[0195] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((12-hydroxydodecyl)oxy)phenyl)benzamide to obtain compound 65. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H),8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42– 7.35 (m, 2H), 7.34 – 7.28 (m, 2H), 7.28 – 7.19 (m, 2H), 7.04 (dd, J = 7.9,1.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 6.83 (dd, J = 9.2, 2.7 Hz,1H), 5.27 (s, 2H), 4.69 – 4.40 (m, 3H), 4.00 (t, J = 6.3 Hz, 4H), 2.67 (ddd,J = 15.4, 8.1, 5.3 Hz, 1H), 2.50 (ddd, J = 15.2, 8.1, 5.3 Hz, 1H), 2.36 (s,3H), MS (ESI) m / z calcd forC44H52N4O8 [M+H] + 764.3785; found 764.3788.

[0196] Example 66: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-((12-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)amino)dodecyl)oxo)phenyl)benzamide (compound 66)

[0197] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-((12-aminododecyl)oxy)phenyl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 66. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.41– 7.36 (m, 2H), 7.35 (d, J = 2.1 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.26 (d, J =7.9 Hz, 1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.95 (dd, J = 7.9, 2.2 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.32 (t, J = 4.7 Hz, 1H), 5.27 (s, 2H), 5.25 – 5.23 (m, 1H), 4.00 (t, J = 6.3 Hz, 2H), 3.14 (td, J = 5.4, 4.6 Hz, 2H), 2.94 – 2.81 (m, 1H), 2.64 – 2.49 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H), 2.15 – 2.04 (m, 1H), 1.77 (tt, J = 7.4, 6.3 Hz, 2H), 1.59 (tt, J = 7.3, 5.3Hz, 2H), 1.46 – 1.39 (m, 2H), 1.39 – 1.32 (m, 2H), 1.31 – 1.18 (m, 12H). MS(ESI) m / z calcd for C44H51N5O8 [M+H] + 777.3738; found 777.3731.

[0198] Example 67: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(2-(2-(2-(2-(2,6-dioxopiridine-3-yl)-1-oxoisoindoline-5-yl)oxo)ethoxy)ethoxy)ethoxy)phenyl)benzamide (compound 67)

[0199] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)phenyl)benzamide to obtain compound 67. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.89 (s, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (d, J =8.8 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.33 – 7.28 (m, 2H), 7.25 (t, J = 7.9 Hz,1H), 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.87 – 6.81 (m, 1H), 6.82 – 6.73 (m,2H), 5.27 (s, 2H), 4.61 (t, J = 5.9 Hz, 1H), 4.59 – 4.42 (m, 2H), 4.13 (t, J= 4.9 Hz, 4H), 3.78 (t, J = 5.0 Hz, 4H), 3.72 – 3.68 (m, 4H), 3.66 (td, J =4.5, 1.0 Hz, 4H), 2.74 – 2.61 (m, 1H), 2.54 – 2.46 (m, 1H), 2.36 (s, 3H),2.34 (s, 3H), 2.30 – 2.22 (m, 1H), 1.66 – 1.57 (m, 1H). MS (ESI) m / z calcdfor C40H44N4O11 [M+H] + 756.3007; found 756.3005.

[0200] Example 68: Synthesis of 5-(3-(4-(4-(3-(((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)amino)methyl)phenoxy)butyl)piperazin-1-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 68)

[0201] Following the synthesis of compound 1, intermediate 6 was replaced with 3-(4-(4-(3-(((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)amino)methyl)phenoxy)butyl)piperazin-1-yl)propanol to obtain compound 68. The TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1 H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.21 (d, J= 16.0 Hz, 1H), 7.12 (ddq, J = 8.0, 1.9, 0.9 Hz, 1H), 7.02 (dd, J = 7.9, 2.7Hz, 1H), 6.95 – 6.78 (m, 4H), 6.76 – 6.67 (m, 2H), 5.54 (t, J = 5.5 Hz, 1H), 5.28 – 5.21 (m, 2H), 4.50 (dt, J = 5.5, 0.8 Hz, 2H), 4.08 – 3.96 (m, 3H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 5H), 2.63 – 2.48 (m, 7H), 2.36 (s, 3H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 2H), 1.79 – 1.70 (m, 2H), 1.59(ttd, J = 7.9, 6.0, 0.9 Hz, 2H). MS (ESI) m / z calcd for C43H50N6O8 [M+H] + 778.3690; found 778.3691.

[0202] Example 69: Synthesis of N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)-2-(benzyloxy)benzamide (compound 69)

[0203] Following the synthesis of compound 1, intermediate 6 was replaced with 2-(benzyloxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 69. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 7.93 – 7.84 (m, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.43 – 7.22 (m, 5H), 7.07 – 7.00 (m, 1H), 6.87 (ddd, J =7.7, 2.1, 1.2 Hz, 1H), 5.26 – 5.21 (m, 1H), 5.05 (t, J = 0.9 Hz, 1H), 4.05(t, J = 6.6 Hz, 1H), 3.95 (t, J = 6.0 Hz, 1H), 2.92 – 2.83 (m, 1H), 2.75 –2.66 (m, 3H), 2.63 MS (ESI) m / z calcd forC 44 H 47 N5O8 [M+H] + 773.3425; found 773.3430.

[0204] Example 70: Synthesis of N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)-2-((pyridin-4-yl)methoxy)benzamide (compound 70)

[0205] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)-2-(pyridin-4-ylmethoxy)benzamide to obtain compound 70. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H),8.89 (s, 1H), 8.60 – 8.55 (m, 1H), 7.93 – 7.84 (m, 1H), 7.58 (d, J = 2.7 Hz,1H), 7.42 – 7.35 (m, 1H), 7.35 (dt, J = 4.6, 0.9 Hz, 1H), 7.33 – 7.28 (m,1H), 7.25 (t, J = 7.9 Hz, 1H), 7.07 – 7.00 (m, 1H), 6.87 (ddd, J = 7.7, 2.1,1.2 Hz, 1H), 5.26 – 5.21 (m, 1H), 5.14 (t, J = 0.8 Hz, 1H), 4.05 (t, J = 6.6Hz, 1H), 3.95 (t, J = 6.0 Hz, 1H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 3H), 2.63 – MS (ESI) m / z calcd forC 43 H 46 N6O8 [M+H] + 774.3377; found 774.3379.

[0206] Example 71: Synthesis of 2-(((3,5-dimethylisoxazol-4-yl)methyl)amino)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 71)

[0207] Following the synthesis of compound 1, intermediate 6 was replaced with 2-(((3,5-dimethylisoxazol-4-yl)methyl)amino)N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 71. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d)δ 9.51 (s, 1H), 8.90 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.88 – 7.80 (m, 1H),7.58 (d, J = 2.7 Hz, 1H), 7.38 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 7.35 – 7.22(m, 3H), 7.17 – 7.09 (m, 1H), 7.02 (dd, J = 7.9, 2.7 Hz, 1H), 6.91 – 6.84 (m,2H), 5.26 – 5.21 (m, 1H), 4.67 (d, J = 8.2 Hz, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 5H), 2.63 –2.48 (m, 6H), 2.50 (s, 1H), 2.30 (s, 3H), 2.13 – 2.04 (m, 1H), 1.90 (p, J =6.6 Hz, 2H), 1.79 – 1.70 (m, 2H), 1.64 – 1.54 (m, 2H). MS (ESI) m / z calcd forC 43 H 49 N7O8 [M+H] + 791.3643; found 791.3642.

[0208] Example 72: Synthesis of 2-(((3,5-dimethylisoxazol-4-yl)methyl)amino)-N-(4-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)pyridin-2-yl)benzamide (compound 72)

[0209] Following the synthesis of compound 1, intermediate 6 was replaced with 2-(((3,5-dimethylisoxazol-4-yl)methyl)amino)-N-(4-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)pyridin-2-yl)benzamide to obtain compound 72. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.50 (d, J = 11.5 Hz, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.90 (d,J = 7.9 Hz, 1H), 7.88 – 7.81 (m, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.33 – 7.23(m, 1H), 7.17 – 7.09 (m, 1H), 7.02 (dd, J = 7.9, 2.7 Hz, 1H), 6.95 (d, J =2.2 Hz, 1H), 6.88 (t, J = 8.2 Hz, 1H), 6.65 (dd, J = 5.2, 2.1 Hz, 1H), 5.26 –5.21 (m, 1H), 4.67 (d, J = 8.2 Hz, 2H), 4.08 – 3.96 (m, 3H), 2.92 – 2.83 (m,1H), 2.75 – 2.66 (m, 5H), 2.63 – 2.51 (m, 2H), 2.53 (s, 1H), 2.54 – 2.48 (m,4H), 2.30 (s, 3H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 2H), 1.75 (ttd,J = 7.8, 6.0, 0.7 Hz, 2H), 1.64 – 1.54 (m, 2H). MS (ESI) m / z calcd for C 42 H 48 N8O8 [M+H] + 792.3595; found 792.3593.

[0210] Example 73: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)pyridin-2-yl)benzamide (compound 73)

[0211] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)pyridin-2-yl)benzamide to obtain compound 73. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H), 7.42 –7.35 (m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 2H), 6.57 (dd, J = 7.6,1.2 Hz, 1H), 5.29 – 5.21 (m, 3H), 4.25 (t, J = 6.9 Hz, 2H), 4.05 (t, J = 6.6Hz, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 6H), 2.63 – 2.48 (m, 7H), 2.50 (s, 1H), 2.36 (s, 3H), 2.13 – 2.04 (m, 1H), 1.94 – 1.79 (m, 4H), 1.60 (tt, J= 7.8, 5.9 Hz, 2H). MS (ESI) m / z calcd for C42H47N7O9 [M+H] + 793.3435; found 793.3431.

[0212] Example 74: Synthesis of N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)-2-((furan-3-yl)methoxy)benzamide (compound 74)

[0213] Following the synthesis of compound 1, intermediate 6 was replaced with 2-(furan-3-ylmethoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 74. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89(s, 1H), 7.93 – 7.84 (m, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.46 (dq, J = 1.7,0.8 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.34 – 7.22 (m, 1H), 7.07 – 7.00 (m, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 6.41 (dq, J = 1.7, 0.9 Hz, 1H), 5.26 –5.21 (m, 1H), 5.10 (t, J = 0.8 Hz, 1H), 4.05 (t, J = 6.6 Hz, 1H), 3.95 (t, J= 6.0 Hz, 1H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 3H), 2.63 – 2.47 (m, 4H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 1H), 1.79 – 1.70 (m, 1H), 1.64 –1.54 (m, 1H). MS (ESI) m / z calcd for C42H45N5O9 [M+H] + 763.3217; found 763.3216.

[0214] Example 75: Synthesis of 2-((1H-imidazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 75)

[0215] Referring to the synthesis of compound 1, intermediate 6 was replaced with 2-((1H-imidazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 75. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.93 – 7.84 (m, 2H), 7.68 (dd, J = 6.0, 1.6 Hz, 1H), 7.58 (d, J= 2.7 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.34 – 7.28 (m, 2H), 7.28 – 7.22 (m, 2H), 7.07 – 7.00 (m, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.38 (d, J = 1.0Hz, 2H), 5.26 – 5.21 (m, 1H), 4.46 (dd, J = 5.9, 4.9 Hz, 1H), 4.05 (t, J =6.6 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m,6H), 2.63 MS (ESI) m / z calcdfor C41H45N7O8 [M+H] + 763.3330; found 763.3334.

[0216] Example 76: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 76)

[0217] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 76. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 7.93– 7.84 (m, 1H), 7.57 (dd, J = 9.3, 1.9 Hz, 1H), 7.07 – 7.00 (m, 1H), 6.90 –6.84 (m, 1H), 5.29 – 5.21 (m, 1H), 4.05 (t, J = 6.6 Hz, 1H), 3.98 (t, J = 6.0Hz, 1H), 2.75 – 2.66 (m, 2H), 2.63 – 2.50 (m, 2H), 2.53 – 2.48 (m, 1H), 2.36(s, 1H), 1.90 (p, J = 6.6 Hz, 1H), 1.79 – 1.70 (m, 1H), 1.59 (ttd, J = 7.9,6.0, 0.9 Hz, 1H). MS (ESI) m / z calcd for C43H48N6O9 [M+H] + 792.3483; found 792.3481.

[0218] Example 77: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(2-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 77)

[0219] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(2-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 77. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.86 (s, 1H), 7.93 – 7.84 (m, 3H), 7.58 (d, J = 2.7 Hz, 1H), 7.39(td, J = 7.9, 1.6 Hz, 1H), 7.34 – 7.27 (m, 1H), 7.07 – 6.97 (m, 4H), 6.97 –6.90 (m, 1H), 5.29 – 5.21 (m, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.97 (t, J = 6.0Hz, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 5H), 2.63 – 2.51 (m, 2H), 2.53(s, 1H), 2.54 – 2.48 (m, 4H), 2.36 (s, 3H), 2.13 – 2.04 (m, 1H), 1.90 (p, J =6.6 Hz, 2H), 1.80 (ddt, J = 8.3, 7.6, 5.8 Hz, 2H), 1.63 – 1.54 (m, 2H). MS(ESI) m / z calcd for C43H48N6O9 [M+H] + 792.3483; found 792.3482.

[0220] Example 78: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)pyridin-2-yl)benzamide (compound 78)

[0221] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)pyridin-2-yl)benzamide to obtain compound 78. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 9.17 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.93 – 7.84 (m, 2H), 7.58 (d, J = 2.7 Hz, 1H), 7.39 (td, J = 7.8, 1.6 Hz, 1H), 7.34 – 7.27 (m,1H), 7.07 – 7.00 (m, 2H), 6.95 (d, J = 2.2 Hz, 1H), 6.65 (dd, J = 5.2, 2.1Hz, 1H), 5.29 – 5.21 (m, 2H), 4.08 – 3.96 (m, 3H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 5H), 2.63 – 2.48 (m, 7H), 2.36 (s, 3H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 2H), 1.75 (ttd, J = 7.8, 6.0, 0.7 Hz, 2H), 1.64 – 1.54 (m,2H). MS (ESI) m / z calcd for C42H47N7O9 [M+H] + 793.3435; found 793.3431.

[0222] Example 79: Synthesis of N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)-2-((pyridin-3-yl)methoxy)benzamide (compound 79)

[0223] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)-2-(pyridin-3-ylmethoxy)benzamide to obtain compound 79. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 8.55 – 8.49 (m,1H), 7.93 – 7.84 (m, 1H), 7.71 (dtt, J = 7.7, 1.9, 0.9 Hz, 1H), 7.60 – 7.52(m, 1H), 7.42 – 7.35 (m, 1H), 7.34 – 7.22 (m, 1H), 7.07 – 7.00 (m, 1H), 6.87(ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.26 – 5.21 (m, 2H), 4.05 (t, J = 6.6 Hz,1H), 3.95 (t, J = 6.0 Hz, 1H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 3H), 2.63 – 2.47 (m, 4H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 1H), 1.79 – 1.70(m, 1H), 1.64 – 1.54 (m, 1H). MS (ESI) m / z calcd for C43H46N6O8 [M+H] + 774.3377; found 774.3379.

[0224] Example 80: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-1,4-diazacycloheptane-1-yl)butoxy)phenyl)benzamide (compound 80)

[0225] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)-1,4-diazaheptacyclic-1-yl)butoxy)phenyl)benzamide to obtain compound 80. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.89 (s, 1H), 7.93 – 7.84 (m, 1H), 7.58 (d, J =2.7 Hz, 1H), 7.42 – 7.35 (m, 1H), 7.34 – 7.22 (m, 1H), 7.07 – 7.00 (m, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.29 – 5.21 (m, 2H), 4.05 (t, J = 6.6Hz, 1H), 3.95 (t, J = 6.0 Hz, 1H), 2.92 – 2.83 (m, 1H), MS (ESI) m / z calcd for C44H50N6O9 [M+H] + 806.3639; found 806.3631.

[0226] Example 81: Synthesis of 2-(2-(3,5-dimethylisoxazol-4-yl)ethoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 81)

[0227] Following the synthesis of compound 1, intermediate 6 was replaced with 2-(2-(3,5-dimethylisoxazol-4-yl)ethoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 81. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 8.90 (s, 1H), 7.93 – 7.84 (m, 2H), 7.58 (d, J = 2.7 Hz, 1H),7.42 – 7.35 (m, 2H), 7.34 – 7.22 (m, 2H), 7.02 (ddd, J = 7.9, 1.9, 0.7 Hz, 2H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.26 – 5.21 (m, 1H), 4.20 (t, J =5.9 Hz, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.14 (t, J =6.0 Hz, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 6H), 2.63 – 2.53 (m, 2H), 2.56 – 2.48 (m, 6H), 2.30 (s, 2H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz,2H), 1.79 – 1.70 (m, 2H), 1.64 – 1.54 (m, 2H). MS (ESI) m / z calcd forC44H50N6O9 [M+H] + 806.3639; found 806.3634.

[0228] Example 82: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)benzyl)benzamide (compound 82)

[0229] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)benzyl)benzamide to obtain compound 82. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 8.00– 7.93 (m, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.39 (td, J = 7.9, 1.6 Hz, 1H), 7.32 – 7.21 (m, 1H), 7.19 – 7.13 (m, 1H), 7.07 – 7.00 (m, 1H), 6.92 (ddd, J =8.1, 2.2, 1.3 Hz, 1H), 6.85 (tt, J = 2.0, 0.9 Hz, 1H), 5.29 – 5.21 (m, 1H), 4.48 (dt, J = 5.7, 0.9 Hz, 1H), 4.08 – 3.96 (m, 2H), 2.75 – 2.66 (m, 2H), 2.63 – 2.48 (m, 3H), 2.36 (s, 1H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz,1H), 1.79 – 1.70 (m, 1H), 1.59 (ttd, J = 7.9, 6.0, 0.9 Hz, 1H). MS (ESI) m / zcalcd for C44H50N6O9 [M+H] + 806.3639; found 806.3634.

[0230] Example 83: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenethyl)benzamide (compound 83)

[0231] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenethyl)benzamide to obtain compound 83. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 7.96 (dd, J = 8.0, 1.6 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.58(d, J = 2.8 Hz, 1H), 7.54 (t, J = 4.9 Hz, 1H), 7.39 (td, J = 7.9, 1.6 Hz,1H), 7.28 (td, J = 7.8, 1.2 Hz, 1H), 7.20 (d, J = 15.9 Hz, 1H), 7.07 – 7.00(m, 2H), 6.89 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 6.84 (ddq, J = 7.9, 2.0, 0.9Hz, 1H), 6.65 (tt, J = 2.2, 0.9 Hz, 1H), 5.29 – 5.21 (m, 2H), 4.08 – 3.96 (m,4H), 3.50 (q, J = 5.1 Hz, 2H), 2.92 – 2.83 (m, 3H), 2.75 – 2.66 (m, 6H), 2.63 – 2.48 (m, 8H), 2.36 (s, 3H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 2H),1.79 – 1.70 (m, 2H), 1.59 (ttd, J = 7.9, 6.0, 0.9 Hz, 2H). MS (ESI) m / z calcdfor C45H52N6O9 [M+H] + 820.3796; found 820.3791.

[0232] Example 84: Synthesis of (S)-2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 84)

[0233] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 84. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 7.93 – 7.84 (m, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 –7.35 (m, 1H), 7.34 – 7.22 (m, 1H), 7.07 – 7.00 (m, 1H), 6.87 (ddd, J = 7.7,2.1, 1.2 Hz, 1H), 5.27 (s, 1H), 5.19 – 5.13 (m, 1H), 4.05 (t, J = 6.6 Hz,1H), 3.95 (t, J = 6.0 Hz, 1H), 2.75 – 2.65 (m, 4H), 2.63 – 2.48 (m, 4H), 2.36 (s, 2H), 2.13 – 2.05 (m, 1H), 1.90 (p, J = 6.6 Hz, 1H), 1.79 – 1.70 (m, 1H),1.64 – 1.54 (m, 1H). MS (ESI) m / z calcd for C43H48N6O9 [M+H] + 792.3483; found 792.3482.

[0234] Example 85: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)phenyl)butoxy)pyridin-2-yl)benzamide (compound 85)

[0235] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-hydroxypropyl)phenyl)butoxy)pyridin-2-yl)benzamide to obtain compound 85. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H), 7.42 – 7.35(m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 2H), 6.80 (dt, J = 8.1, 0.9 Hz,2H), 6.69 (dt, J = 8.1, 0.9 Hz, 2H), 6.57 (dd, J = 7.6, 1.2 Hz, 1H), 5.29 –5.21 (m, 2H), 4.28 (t, J = 6.8 Hz, 2H), 4.09 – 4.03 (m, 2H), 2.92 – 2.83 (m,1H), 2.74 (tt, J = 8.4, 0.9 Hz, 2H), 2.65 – 2.52 (m, 4H), 2.36 (s, 3H), 2.13– 2.04 (m, 1H), 1.94 (tt, J = 8.3, 6.2 Hz, 2H), 1.90 – 1.80 (m, 2H), 1.71 –1.61 (m, 2H). MS (ESI) m / z calcd for C44H43N5O9 [M+H] + 785.3061; found 785.3065.

[0236] Example 86: Synthesis of (S)-2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 86)

[0237] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-hydroxypropyl)phenyl)butoxy)pyridin-2-yl)benzamide to obtain compound 86. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 8.89 (s, 1H), 7.93 – 7.84 (m, 2H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 –7.35 (m, 2H), 7.34 – 7.22 3.95 (t, J = 6.0 Hz, 2H), 2.75 – 2.65 (m, 7H), 2.62 – 2.48 (m, 8H), 2.36 (s, 3H), 2.13 – 2.05 (m, 1H), 1.90 (p, J = 6.6 Hz, 2H), 1.79 – 1.70 (m, 2H),1.64 – 1.54 (m, 2H). MS (ESI) m / z calcd for C44H43N5O9 [M+H] + 785.3061; found 785.3064.

[0238] Example 87: Synthesis of N-(6-(4-(3-chloro-5-(3-((2-(2,6-dioxopiridin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)pyridin-2-yl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisooxazol-4-yl)methoxy)benzamide (compound 87)

[0239] Following the synthesis of compound 1, intermediate 6 was replaced with N-(6-(4-(3-chloro-5-(3-hydroxypropyl)pyridin-2-yl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 87. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 8.04 (dt, J = 1.8, 0.9 Hz, 1H), 7.93 – 7.84 (m, 1H), 7.60 –7.53 (m, 1H), 7.42 – 7.35 (m, 1H), 7.07 – 7.00 (m, 1H), 6.57 (dd, J = 7.6,1.2 Hz, 1H), 5.29 – 5.21 (m, 1H), 4.28 (t, J = 6.7 Hz, 1H), 4.06 (t, J = 6.2Hz, 1H), 2.92 – 2.81 (m, 2H), 2.63 – 2.52 (m, 1H), 2.36 (s, 1H), 2.13 – 2.03(m, 1H), 1.98 – 1.84 (m, 2H). MS (ESI) m / z calcd for C43H41ClN6O9 [M+H] + 820.2624; found 820.2624.

[0240] Example 88: Synthesis of N-(6-(4-(2-cyano-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)phenyl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide (compound 88)

[0241] Following the synthesis of compound 1, intermediate 6 was replaced with N-(6-(4-(2-cyano-4-(3-hydroxypropyl)phenyl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 88. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H),7.42 – 7.35 (m, 2H), 7.34 – 7.23 (m, 2H), 7.10 – 7.00 (m, 3H), 6.97 (dt, J =7.3, 0.8 Hz, 1H), 6.57 (dd, J = 7.6, 1.2 Hz, 1H), 5.29 – 5.21 (m, 2H), 4.28(t, J = 6.8 Hz, 2H), 4.09 – 4.03 (m, 2H), 2.92 – 2.83 (m, 1H), 2.76 – 2.67(m, 4H), 2.63 – 2.52 (m, 2H), 2.36 (s, 3H), 2.13 – 2.04 (m, 1H), 2.01 – 1.83(m, 4H), 1.77 – 1.67 (m, 2H). MS (ESI) m / z calcd for C45H42N6O9 [M+H] + 810.3013; found 810.3019.

[0242] Example 89: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-2-methylphenyl)butoxy)pyridin-2-yl)benzamide (compound 89)

[0243] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-hydroxypropyl)-2-methylphenyl)butoxy)pyridin-2-yl)benzamide to obtain compound 89. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d)δ 9.51 (s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H), 7.42– 7.35 (m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 2H), 6.96 – 6.88 (m,2H), 6.87 (dd, J = 1.9, 1.0 Hz, 1H), 6.57 (dd, J = 7.6, 1.2 Hz, 1H), 5.29 –5.21 (m, 2H), 4.28 (t, J = 6.8 Hz, 2H), 4.06 (t, J = 6.1 Hz, 2H), 2.92 – 2.83(m, 1H), 2.66 (dddd, J = 8.9, 8.0, 1.9, 0.9 Hz, 4H), 2.62 – 2.52 (m, 2H), 2.35 (d, J = 9.7 Hz, 6H), 2.13 – 2.04 (m, 1H), 1.96 (tt, J = 8.3, 6.2 Hz,2H), 1.92 – 1.83 (m, 2H), 1.71 – 1.61 (m, 2H). MS (ESI) m / z calcd forC45H45N5O9 [M+H] + 799.3217; found 799.3215.

[0244] Example 90: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)pyridin-2-yl)butoxy)pyridin-2-yl)benzamide (compound 90)

[0245] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(5-(3-hydroxypropyl)pyridin-2-yl)butoxy)pyridin-2-yl)benzamide to obtain compound 90. The TLC detection showed a single spot, a dark spot under a UV lamp at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 9.19 (s, 1H), 8.48 (dt, J = 1.8, 0.8 Hz, 1H), 7.93 – 7.84 (m,3H), 7.60 – 7.53 (m, 3H), 7.42 – 7.35 (m, 3H), 7.34 – 7.25 (m, 2H), 7.07 –6.98 (m, 4H), 6.57 (dd, J = 7.6, 1.2 Hz, 1H), 5.29 – 5.21 (m, 3H), 4.28 (t, J= 6.7 Hz, 3H), 4.06 (t, J = 6.2 Hz, 3H), 2.92 – 2.80 (m, 3H), 2.82 – 2.74 (m,3H), 2.63 – 2.52 (m, 3H), 2.36 (s, 4H), 2.13 – 2.00 (m, 4H), 1.97 – 1.87 (m,3H), 1.86 – 1.76 (m, 3H). MS (ESI) m / z calcd for C43H42N6O9 [M+H] + 786.3013; found 786.3019.

[0246] Example 91: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(5-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-4-methylpyridin-2-yl)butoxy)pyridin-2-yl)benzamide (compound 91)

[0247] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(5-(3-hydroxypropyl)-4-methylpyridin-2-yl)butoxy)pyridin-2-yl)benzamide to obtain compound 91. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 9.19 (s, 1H), 8.09 (d, J = 1.0 Hz, 1H), 7.93 –7.84 (m, 2H), 7.60 – 7.53 (m, 2H), 7.42 – 7.35 (m, 2H), 7.34 – 7.27 (m, 1H),7.07 – 7.00 (m, 2H), 6.92 (d, J = 0.8 Hz, 1H), 6.57 (dd, J = 7.6, 1.2 Hz,1H), 5.29 – 5.21 (m, 2H), 4.28 (t, J = 6.7 Hz, 2H), 4.07 (t, J = 6.1 Hz, 2H), 2.92 – 2.78 (m, 2H), 2.80 – 2.73 (m, 2H), 2.63 – 2.52 (m, 2H), 2.35 (d, J =9.7 Hz, 6H), 2.13 – 2.00 (m, 3H), 1.92 (ttd, J = 7.5, 6.5, 1.0 Hz, 2H), 1.87– 1.77 (m, 2H). MS (ESI) m / z calcd for C44H44N6O9 [M+H] + 800.3170; found 800.3175.

[0248] Example 92: Synthesis of N-(6-(4-(3-cyano-5-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)pyridin-2-yl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide (compound 92)

[0249] Following the synthesis of compound 1, intermediate 6 was replaced with N-(6-(4-(3-cyano-5-(3-hydroxypropyl)pyridin-2-yl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 92. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 9.19 (s, 1H), 8.12 (dt, J = 1.6, 0.8 Hz, 1H), 7.93 – 7.84 (m, 2H), 7.78 (dt, J = 1.8, 0.9 Hz, 1H), 7.60 – 7.53 (m, 2H), 7.42 – 7.35 (m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 2H), 6.57 (dd, J =7.6, 1.2 Hz, 1H), 5.29 – 5.21 (m, 2H), 4.28 (t, J = 6.6 Hz, MS (ESI) m / z calcd for C44H41N7O9 [M+H] + 811.2966; found 811.2964.

[0250] Example 93: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-2-ethylphenyl)butoxy)pyridin-2-yl)benzamide (compound 93)

[0251] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(2-ethyl-4-(3-hydroxypropyl)phenyl)butoxy)pyridin-2-yl)benzamide to obtain compound 93. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d)δ 9.51 (s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H), 7.42– 7.35 (m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 2H), 6.87 (ddt, J = 8.2,1.8, 0.9 Hz, 1H), 6.64 (dp, J = 1.8, 0.9 Hz, 1H), 6.57 (dd, J = 7.6, 1.2 Hz,1H), 6.35 (dt, J = 8.4, 0.8 Hz, 1H), 5.29 – 5.21 (m, 2H), 4.28 (t, J = 6.8Hz, 2H), 4.06 (t, J = 6.1 Hz, 2H), 2.92 – 2.83 (m, 1H), 2.71 – 2.49 (m, 6H), 2.36 (s, 2H), 2.13 – 2.04 (m, 1H), 2.01 – 1.83 (m, 3H), 1.71 – 1.61 (m, 2H),1.16 – 1.10 (m, 2H). MS (ESI) m / z calcd for C46H47N5O9 [M+H] + 813.3374; found 813.3376.

[0252] Example 94: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-2-methoxyphenyl)butoxy)pyridin-2-yl)benzamide (compound 94)

[0253] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-hydroxypropyl)-2-methoxyphenyl)butoxy)pyridin-2-yl)benzamide to obtain compound 94. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H),7.42 – 7.35 (m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 3H), 6.82 (ddt, J =8.2, 1.8, 0.9 Hz, 1H), 6.62 – 6.54 (m, 2H), 5.29 – 5.21 (m, 2H), 4.28 (t, J =6.8 Hz, 2H), 4.06 (t, J = 6.1 Hz, 2H), 3.77 (s, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 4H), 2.63 – 2.52 (m, 2H), 2.36 (s, 3H), 2.13 – 2.04 (m, 1H), 1.96 (tt, J = 8.3, 6.2 Hz, 2H), 1.92 – 1.83 (m, 2H), 1.70 (pd, J = 7.6, 0.7Hz, 2H). MS (ESI) m / z calcd for C45H45N5O10 [M+H] + 815.3166; found 815.3164.

[0254] Example 95: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-2-ethoxyphenyl)butoxy)pyridin-2-yl)benzamide (compound 95)

[0255] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(2-ethoxy-4-(3-hydroxypropyl)phenyl)butoxy)pyridin-2-yl)benzamide to obtain compound 95. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H),7.42 – 7.35 (m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 3H), 6.83 (ddt, J =8.2, 1.8, 0.9 Hz, 1H), 6.60 – 6.52 (m, 2H), 5.29 – 5.21 (m, 2H), 4.28 (t, J =6.8 Hz, 2H), 4.07 (dt, J = 13.0, 6.2 Hz, 4H), 2.92 – 2.83 (m, 1H), 2.77 –2.66 (m, 4H), 2.63 – 2.52 (m, 2H), 2.36 (s, 3H), 2.13 – 2.04 (m, 1H), 1.96(tt, J = 8.3, 6.2 Hz, 2H), 1.92 – 1.83 (m, 2H), 1.70 (pd, J = 7.6, 0.7 Hz,2H), 1.43 (t, J = 6.2 Hz, 3H). MS (ESI) m / z calcd for C46H47N5O10 [M+H] + 829.3323; found 829.3324.

[0256] Example 96: Synthesis of N-(6-(4-(2-chloro-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)phenyl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisooxazol-4-yl)methoxy)benzamide (compound 96)

[0257] Following the synthesis of compound 1, intermediate 6 was replaced with N-(6-(4-(2-chloro-4-(3-hydroxypropyl)phenyl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 96. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d)δ 9.51 (s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H), 7.42– 7.35 (m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 3H), 7.00 (dt, J = 8.4,0.9 Hz, 1H), 6.90 (ddt, J = 8.3, 1.9, 0.8 Hz, 1H), 6.57 (dd, J = 7.6, 1.2 Hz,1H), 5.29 – 5.21 (m, 3H), 4.28 (t, J = 6.8 Hz, 2H), 4.09 – 4.03 (m, 2H), 2.92– 2.83 (m, 1H), 2.79 – 2.70 (m, 4H), 2.63 – 2.52 (m, 2H), 2.36 (s, 3H), 2.13– 2.04 (m, 1H), 1.96 (tt, J = 8.3, 6.2 Hz, 2H), 1.88 (dddd, J = 14.1, 7.5,6.6, 0.7 Hz, 2H), 1.75 (pd, J = 7.8, 1.0 Hz, 2H). MS (ESI) m / z calcd forC44H42ClN5O9 [M+H] + 819.2671; found 819.2674.

[0258] Example 97: Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)-2-fluorophenyl)butoxy)pyridin-2-yl)benzamide (compound 97)

[0259] Following the synthesis of compound 1, intermediate 6 was replaced with 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(6-(4-(2-fluoro-4-(3-hydroxypropyl)phenyl)butoxy)pyridin-2-yl)benzamide to obtain compound 97. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H), 7.42 –7.35 (m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 2H), 6.85 (ddt, J = 7.8,4.7, 0.9 Hz, 1H), 6.77 (dq, J = 7.8, 1.0 Hz, 1H), 6.60 – 6.53 (m, 2H), 5.29 –5.21 (m, 2H), 4.28 (t, J = 6.8 Hz, 2H), 4.06 (t, J = 6.1 Hz, 2H), 2.92 – 2.83(m, 1H), 2.75 – 2.66 (m, 4H), 2.63 – 2.52 (m, 2H), 2.36 (s, 3H), 2.13 – 2.04(m, 1H), 2.01 – 1.83 (m, 4H), 1.77 – 1.66 (m, 2H). MS (ESI) m / z calcd forC44H42FN5O9 [M+H] + 803.2967; found 803.2964.

[0260] Example 98: Synthesis of N-(6-(4-(2-bromo-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)phenyl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide (compound 98)

[0261] Following the synthesis of compound 1, intermediate 6 was replaced with N-(6-(4-(2-bromo-4-(3-hydroxypropyl)phenyl)butoxy)pyridin-2-yl)-2-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide to obtain compound 98. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d)δ 9.51 (s, 1H), 9.19 (s, 1H), 7.93 – 7.84 (m, 2H), 7.60 – 7.53 (m, 2H), 7.42– 7.35 (m, 2H), 7.34 – 7.27 (m, 1H), 7.07 – 7.00 (m, 3H), 6.85 – 6.75 (m,2H), 6.57 (dd, J = 7.6, 1.2 Hz, 1H), 5.29 – 5.21 (m, 2H), 4.28 (t, J = 6.8Hz, 2H), 4.09 – 4.03 (m, 2H), 2.92 – 2.83 (m, 1H), 2.80 – 2.69 (m, 4H), 2.63– 2.52 (m, 2H), 2.36 (s, 3H), 2.13 – 2.04 (m, 1H), 2.01 – 1.83 (m, 4H), 1.71(pd, J = 7.7, 0.9 Hz, 2H). MS (ESI) m / z calcd for C44H42BrN5O9 [M+H] + 863.2166; found 863.2168.

[0262] Example 99: Synthesis of 5-(3-(4-(4-(3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)benzyl)amino)phenoxy)butyl)piperazin-1-yl)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 99)

[0263] Following the synthesis of compound 1, intermediate 6 was replaced with 3-(4-(4-(3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)benzyl)amino)phenoxy)butyl)piperazin-1-yl)propanol to obtain compound 99. TLC detection showed a single point, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51(s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.33 (ddd, J =7.9, 1.7, 0.8 Hz, 1H), 7.16 – 7.00 (m, 3H), 6.93 – 6.83 (m, 2H), 6.71 (ddd, J= 7.9, 2.1, 1.3 Hz, 1H), 6.29 – 6.22 (m, 2H), 6.12 (t, J = 5.4 Hz, 1H), 5.28– 5.21 (m, 2H), 4.49 (dd, J = 5.4, 0.8 Hz, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 6H), 2.63 –2.53 (m, 2H), 2.56 – MS (ESI) m / zcalcd for C43H50N6O8 [M+H] + 778.3690; found 778.3694.

[0264] Example 100: Synthesis of N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)-2-((thiophen-3-yl)methoxy)benzamide (compound 100)

[0265] Following the synthesis of compound 1, intermediate 6 was replaced with N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)-2-(thiophen-3-ylmethoxy)benzamide to obtain compound 100. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 9.51 (s, 1H),8.89 (s, 1H), 7.93 – 7.84 (m, 2H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 – 7.35 (m,2H), 7.34 – 7.29 (m, 2H), 7.31 – 7.22 (m, 2H), 7.07 – 7.00 (m, 3H), 6.87(ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.26 – 5.21 (m, 1H), 5.14 (t, J = 0.8 Hz, 2H), 4.05 (t, J = 6.6 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 6H), 2.63 – 2.53 (m, 2H), 2.56 – 2.48 (m, 6H), 2.13 – 2.04(m, 1H), 1.90 (p, J = 6.6 Hz, 2H), 1.79 – 1.70 (m, 2H), 1.64 – 1.54 (m, 2H).MS (ESI) m / z calcd for C42H45N5O8S [M+H] + 779.2989; found 779.2981.

[0266] Example 101: Synthesis of 2-((1H-pyrrolo-3-yl)methoxy)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 101)

[0267] Referring to the synthesis of compound 1, intermediate 6 was replaced with 2-((1H-pyrrolo-3-yl)methoxy)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 101. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ 7.93 –7.84 (m, 1H), 7.66 (t, J = 6.6 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 – 7.35(m, 1H), 7.34 – 7.22 (m, 1H), 7.07 – 7.00 (m, 1H), 6.93 – 6.84 (m, 1H), 6.75(ddd, J = 6.6, 3.4, 1.7 Hz, 1H), 5.93 (ddt, J = 3.5, 1.8, 0.9 Hz, 1H), 5.29(t, J = 0.9 Hz, 1H), 5.26 – 5.21 (m, 1H), 4.05 (t, J = 6.6 Hz, 1H), 3.95 (t,J = 6.0 Hz, 1H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 3H), 2.63 – 2.47 (m,4H), 2.13 – 2.04 (m, 1H), 1.90 (p, J = 6.6 Hz, 1H), 1.79 – 1.70 (m, 1H), 1.64– 1.54 (m, 1H). MS (ESI) m / z calcd for C42H46N6O8 [M+H] + 762.3377; found 762.3374.

[0268] Example 102: Synthesis of 2-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-N-(3-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)phenyl)benzamide (compound 102)

[0269] Following the synthesis of compound 1, intermediate 6 was replaced with 2-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-N-(3-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)phenyl)benzamide to obtain compound 102. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d) δ9.51 (s, 1H), 8.43 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.72 (dd, J = 7.8, 1.8Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.42 – 7.23 (m, 6H), 7.02 (dd, J = 7.9,2.7 Hz, 1H), 6.87 (ddd, J = 7.7, 2.1, 1.2 Hz, 1H), 5.26 – 5.21 (m, 1H), 4.05(t, J = 6.6 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.25 (ddt, J = 8.5, 7.8, 1.0Hz, 2H), 3.20 – 3.13 (m, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 6H), 2.63– 2.53 (m, 2H), 2.56 – MS (ESI) m / zcalcd for C44H50N6O8 [M+H] + 790.3690; found 790.3695.

[0270] Example 103: Synthesis of 2-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-N-(4-(4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)piperazin-1-yl)butoxy)pyridin-2-yl)benzamide (compound 103)

[0271] Following the synthesis of compound 1, intermediate 6 was replaced with 2-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-N-(4-(4-(4-(4-(3-hydroxypropyl)piperazin-1-yl)butoxy)pyridin-2-yl)benzamide to obtain compound 103. TLC detection showed a single spot, a dark spot under UV light at 254 nm, and blue fluorescence at 365 nm. 1H NMR (500 MHz, Chloroform-d)δ 9.51 (s, 1H), 9.40 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.74 (dd, J = 7.9, 1.7 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 7.41 – 7.28(m, 3H), 7.02 (dd, J = 7.9, 2.7 Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.65 (dd,J = 5.2, 2.1 Hz, 1H), 5.26 – 5.21 (m, 1H), 4.05 (t, J = 6.6 Hz, 2H), 3.99 (t,J = 6.0 Hz, 2H), 3.27 – 3.20 (m, 2H), 3.20 – 3.13 (m, 2H), 2.92 – 2.83 (m,1H), 2.75 – 2.66 (m, 6H), 2.63 – 2.48 (m, 8H), 2.30 (s, 2H), 2.13 – 2.04 (m,1H), 1.90 (p, J = 6.6 Hz, 2H), 1.75 (ttd, J = 7.8, 6.0, 0.7 Hz, 2H), 1.64 –1.54 (m, 2H). MS (ESI) m / z calcd for C43H49N7O8 [M+H] + 791.3643; found 791.3462.

[0272] Table 1. Structural formulas of compounds synthesized in Examples 1-103

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284] The following are the test results of the compounds of this invention inhibiting the activity of four proteins in the AKR1C subfamily:

[0285] Experimental materials and methods:

[0286] Aldehyde reductases possess a universal catalytic function, reducing the carbonyl group of a substrate to a hydroxyl group, with NAD(P)H as the coenzyme. They can also reversely oxidize the hydroxyl group of 17β-hydroxysteroids to a carbonyl group. Therefore, a widely accepted assay system from the literature was chosen. Aldehyde reductases can use S-tetrahydronaphthol (S-tetralol) as a substrate in NADP... + With the participation of [a specific enzyme], it is oxidized to generate NAD(P)H. NAD(P)H can be detected at an excitation wavelength of 340 nm and an emission wavelength of 460 nm. The fluorescence value, i.e. the amount of NAD(P)H generated, can reflect the catalytic ability of the enzyme.

[0287] (1) Prepare 0.1 M phosphate buffer (pH = 7.0): accurately weigh 2.19 g of disodium hydrogen phosphate dodecahydrate and 6.84 g of sodium dihydrogen phosphate dihydrate, and make up to 500 mL with deionized water. Adjust the pH of the solution to 7 precisely.

[0288] (2) Preparation of substrate stock solution: Accurately weigh an appropriate amount of S-tetralol, dissolve the substrate in DMSO to prepare a 10 -1 Mother liquor of M.

[0289] (3) Preparation of coenzyme solution: Accurately weigh NADP + 14.4 mg was added to 0.1 M phosphate buffer and brought to a final volume of 9.68 mL to prepare a 2 mM stock solution.

[0290] (4) Preparation of compound stock solution: Accurately weigh a small amount of the compound to be tested, dissolve the compound in DMSO and prepare a solution of 10... -1 Mother liquor with concentration M.

[0291] (5) Diluting the compound stock solution: The previously prepared 100 mM compound stock solution was diluted stepwise to prepare a 10 mM solution. -4 M-10 -9 M Six concentrations were tested, with three replicates for each concentration, resulting in a final experimental concentration of 10. -5 M-10 -10 M.

[0292] (6) A 96-well microplate was used, with 200 μL of reaction solution in each well. The blank group contained 0.1 M potassium phosphate buffer, 0.2 mM substrate solution, and 0.1 mM coenzyme solution. For the test group, each compound at each concentration was prepared in triplicate, with each well containing the corresponding concentration of the compound, 0.1 M potassium phosphate buffer, 0.2 mM substrate solution, 0.1 mM coenzyme solution, and the corresponding concentration of AKR1C protein. The control group contained 0.1 M potassium phosphate buffer, 0.2 mM substrate solution, 0.1 mM coenzyme solution, and the corresponding concentration of AKR1C protein. The protein concentrations of AKR1C1-4, determined by the Km value, were 34, 42, 71, and 72 nM, respectively. After mixing all reactants, the mixture was incubated at 37 °C for 15 minutes, and the fluorescence intensity was detected using a fluorescence microplate reader at an excitation wavelength of 340 nm and an emission wavelength of 460 nm. The data were processed and analyzed using GraphPad Prism. TM The (USA) software calculates the corresponding IC using a nonlinear decay analysis model. 50 value.

[0293] Table 2. Inhibitory activity of Examples 1-103 against AKR1C1-AKR1C4, µM a

[0294]

[0295] a All experiments were repeated in triplicate, and the results were averaged.

[0296] The following are the pharmacodynamic tests and results of the compounds of this invention:

[0297] Experimental materials: HepG2 (human liver cancer cells) cells were purchased from the Cell Culture Center of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (Shanghai, China). Dulbecco modified Eagle medium (DMEM) was purchased from Jiangsu Kaiji Biotechnology Co., Ltd. (Nanjing, China). Fetal bovine serum (FBS) was purchased from Gibco (Invitrogen Corp., USA). Trypsin was purchased from Solarbio (Beijing, China). Unless otherwise specified, all media were supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. The CCK-8 kit was purchased from Solarbio (Beijing, China).

[0298] Experimental Methods: HepG2 cells were cultured in high-glucose DMEM medium containing 10% FBS. Culture conditions were 37°C, 5% CO2, and saturated humidity. When the cell density reached 80%–90%, cells were digested at 37°C for 3 minutes with a 0.25% trypsin solution containing 0.01% EDTA. After observing the cells becoming rounded under a microscope, complete culture medium was added to terminate the digestion. The cells were centrifuged at 1000 rpm for 5 minutes. The digestion solution was discarded, and fresh culture medium was added. Adherent cells were pipetted and thoroughly mixed. Cells were then transferred to new culture flasks according to the required cell volume, and an appropriate amount of culture medium was added and mixed thoroughly before continuing culture. A certain amount of cells was then taken and diluted to the required concentration using complete culture medium.

[0299] (1) Disperse HepG2 cells in a complete medium containing 10% FBS at a concentration of 1.5-2 × 10⁻⁶ cells / mL. 4 Cells were seeded at a density of 100 μL / mL in 96-well plates. The 96-well plates containing cells were placed in an incubator and incubated at 37 °C and 5% CO2 for 18 h until the cells adhered.

[0300] (2) The test compound was serially diluted to the target concentration using complete culture medium. The original culture medium was discarded, and the cells were treated with blank complete culture medium or the specified concentration of the test compound at 37 °C and 5% CO2 for 72 h. Three replicates were set up for each concentration.

[0301] (3) After 72 h, discard the original culture medium, add incomplete culture medium containing 10% CCK-8 solution to each well under light-protected conditions, incubate at 37 ℃ for 1-4 h, and detect the OD value of each well at 450 nm wavelength using an ELISA reader.

[0302] (4) Data processing: Cell viability = (A 测试 - A 空白 ) / (A 阴性 - A 空白 ) × 100%. Where A 空白For blank absorption of 96-well plate.

[0303] Experimental Results: As shown in the figure, treatment with S16-2001 alone in the concentration range of 0.1–1000 nM had no significant effect on the survival rate of MCF-7 / ADR cells, with cell viability remaining above approximately 95%. However, when S16-2001 was combined with DOX, cell viability decreased significantly, and this decrease increased with increasing DOX concentration. At 5 μM DOX, the combination of S16-2001 and 0.1 nM significantly reduced cell viability to approximately 70%, and further decreased to approximately 30–40% at 10–1000 nM. At 10 μM DOX, the combination of S16-2001 and concentrations above 10 nM almost completely inhibited cell survival, with cell viability less than 10%. The results of the differential analysis showed that the combined group had extremely significant differences compared with DOX treatment alone (****, p<0.0001), suggesting that S16-2001 can significantly enhance the killing effect of DOX on MCF-7 / ADR cells and effectively reverse their multidrug resistance.

[0304] The following are the degradation experiments and results of the target protein of the compound of this invention:

[0305] Experimental materials: H460 cells were purchased from the Cell Culture Center of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (Shanghai, China). Dulbecco modified Eagle medium (DMEM) was purchased from Jiangsu Kaiji Biotechnology Co., Ltd. (Nanjing, China), fetal bovine serum (FBS) was purchased from Gibco (Invitrogen Corp., USA), and trypsin was purchased from Solarbio (Beijing, China). Unless otherwise specified, all media were supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin.

[0306] Experimental methods: H460 cells were cultured in high-glucose DMEM medium containing 10% FBS at 37 °C, 5% CO2, and saturated humidity. When the cells reached 80% confluence, the medium was discarded, and the cells were digested with a digestion solution containing 0.25% trypsin at 37 °C for 2–3 min. The cells were gently dispersed by pipetting, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in fresh medium and cultured for a longer period.

[0307] (1) H460 cells were fed at a concentration of 1×10 6 The cells were seeded at a density of cells per well in 6-well plates, and then allowed to adhere and be processed to the desired experimental conditions.

[0308] (2) Discard the culture medium, gently wash the cells twice with pre-cooled PBS buffer, add an appropriate amount of RIPA lysis buffer (containing PMSF inhibitor) to each well, and lyse on ice for 30 min. Centrifuge the lysis buffer at 12000 rpm for 15 min, collect the supernatant and determine the protein concentration.

[0309] (3) Take an equal amount of protein (30–50 μg), add 5×SDS protein loading buffer, and heat in a 95 °C metal bath for 5 min to denature. After separation by 10% SDS-PAGE gel electrophoresis, the protein sample is transferred to a PVDF membrane.

[0310] (4) The PVDF membrane was blocked in 5% skim milk powder TBST solution at room temperature for 1 h, and then the primary antibody was added and incubated overnight at 4 °C with shaking.

[0311] (5) The next day, wash with TBST 3 times for 10 min each time, add the corresponding HRP-labeled secondary antibody (1:5000 dilution), and incubate at room temperature for 1 h.

[0312] (6) Wash three more times with TBST, 10 min each time. Develop color with ECL chemiluminescent reagent, and detect and record the band signals using a gel imaging system.

[0313] Experimental Results: As shown in Figure (A), S16-2001 reduced the protein level of AKR1C3 in HepG2 cells in a concentration-dependent manner. When the treatment concentration increased from 10... 5 As the concentration of AKR1C3 protein gradually decreased from nM to 0.01 nM, it exhibited a significant downregulation within the 10–1 nM range. The expression level of the internal control protein α-Tubulin remained stable, indicating consistent sample loading. Further analysis using grayscale values ​​to calculate the drug degradation curve (Figure B) showed that the DC value of S16-2001... 50 The value was 3.11 nM, indicating that it has high degradation activity against AKR1C3 protein.

Claims

1. A class of compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, (I) The structural formula of AM is shown in equation (II): in, Ring A is selected from a benzene ring, an unsubstituted or substituted 5-6 membered heteroaromatic ring containing 1-2 heteroatoms independently selected from O, N, and S, wherein the substituents of the 5-6 membered heteroaromatic ring are 1-2 carbon atoms. 1-3 Alkyl group; ring B is selected from benzene ring or pyridine ring, and ring C is selected from benzene ring or pyridine ring; Y is selected from -O-, -NH-, or -CH2-; W1 and W2 are independently selected from -NH-, -C(O)-, and -CH2-; m and n are independently selected from any integer from 1 to 3; The structural formula of CM is shown in equation (II): Where Z is selected from -CH 2- Or -C(O)-; This indicates that the bond can be stereospecific or non-stereospecific; L comprises a chemical structure represented by formula (III) or formula (IV): Where Q and V are each independently a bond, O, NH, ; R1, R2, and R3 are independently selected from C. 1-5 Saturated alkylene chains, or C with arbitrary substitution of D group 3-7 Saturated heterocycles, phenyl, C 5-7 Heterocyclic aromatic rings or spiro-[jk] heterocyclic groups, wherein the D group is selected from C 1-3 Alkyl, C 2-4 Alkyl, halogen, cyano; m1 and m2 are each independently chosen from 1 to 3; where j and k are each independently integers from 2 to 6; R4 is taken from m3 is any integer from 1 to 5.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Ring A is selected from: 。 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Excerpt Selected from: 。 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Excerpt Selected from:

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The structure of AM is shown in any of the following structures:

6. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, R1, R2, R3, and R4 are independently selected from: 。 7. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, L consists of a chemical structure represented by any of the following structures:

8. A pharmaceutical composition, characterized in that, It comprises a compound as described in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of a compound as described in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of an AKR1C3 inhibitor.

10. The use of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 9 in the preparation of an antitumor drug, wherein the tumor is an AKR1C3-associated tumor.

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