Bifunctional chimeric heterocyclic compounds and their use as androgen receptor degraders

Abstract

The present invention provides a compound of formula I, or an optical isomer thereof, or a solvate thereof, or a pharma- ceutically acceptable salt thereof, or a prodrug thereof, or a tautomer thereof, or a meso isomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a mixture thereof, or a metabolite thereof, or a metabolic precursor thereof, or an isotopically substituted form thereof. Wherein, TB is a target recognition / binding moiety, L is a linker moiety, and U is a ubiquitin protease recognition / binding moiety, and the three moieties are linked by a chemical bond. The compound of the present invention can significantly downregulate full-length and mutant androgen receptor (AR) proteins, and has good inhibitory activity against prostate cancer cell lines. The compound of formula I of the present invention can be used in the manufacture of proteolysis-inducing chimeric molecules targeting the regulation of androgen receptor and drugs for treating diseases related to the regulation of androgen receptor, and has good application prospects, especially in the manufacture of drugs for treating prostate cancer and breast cancer. [Formula 1] TIFF2024528143000896.tif18170I

Description

[Technical Field]

[0001] The present invention is in the field of drug synthesis, and specifically relates to bifunctional chimeric heterocyclic compounds and their uses. [Background technology]

[0002] With the global population growth and aging, the incidence of prostate cancer continues to increase. Currently, androgen deprivation therapy (ADT) is the primary treatment. The androgen receptor (AR) is a member of the nuclear receptor family and a ligand-dependent transcription factor. Dysregulation of the AR signaling pathway plays an important role in the development and progression of prostate cancer, and studies have shown that castration-resistant prostate cancer (CRPC) still relies on the role of the AR. The androgen receptor (AR) contains 918 amino acids and shares similar structure and function with other nuclear receptors. It consists of three key domains: the DNA-binding domain (DBD), the ligand-binding domain (LBD), and the N-terminal domain (NTD). The DBD and LBD are connected by a hinge region. The LBD, located at the carbon terminus of the AR, is the binding site between the AR and ligands, determining the specificity of the ligand-AR binding. Ligands bind to the LBD, thereby activating the AR. Currently, two transcriptional activation domains have been identified within the AR: activation function 1 (AF1) in the NTD domain and activation function 2 (AF2), a highly conserved hydrophobic pocket in the LBD domain. Before 2010, docetaxel-based chemotherapy was the only treatment that could extend the survival of patients with metastatic CRPC. Since 2011, the FDA has intermittently approved three AR signaling pathway inhibitors: abiraterone acetate and enzalutamide, approved in 2011 and 2012, respectively, for the treatment of metastatic castration-resistant prostate cancer, and apalutamide, approved in 2018 for the treatment of non-metastatic CRPC.

[0003] Although the second-generation AR signaling pathway inhibitors, abiraterone and enzalutamide, have shown some success in clinical treatment, clinical drug resistance has already emerged. Meanwhile, the F876L mutation in the ligand-binding domain is a missense mutation that causes drug resistance to enzalutamide, converting it from an antagonist to an agonist. Furthermore, AR splicing variants, particularly the AR-v7 mutation, which lacks the ligand-binding domain, are important mediators of the development of second-generation drug resistance. Therefore, novel AR signaling pathway inhibitors for the treatment of CRPC are urgently needed clinically.

[0004] Conventional small molecule inhibitors inhibit the function of target proteins by binding to them. However, the development of drug resistance is inevitable with long-term use of small molecule drugs. Furthermore, to achieve the desired effect, small molecule compounds must maintain a certain concentration within the cell, and relatively high concentrations of small molecules can cause off-target side effects. Therefore, finding small molecule compounds that can overcome these deficiencies is important for new drug development.

[0005] In recent years, proteolysis-inducing chimeric molecules (PROTACs) have attracted attention as small molecules capable of inducing the degradation of target proteins. PROTACs are bifunctional molecules that contain a small molecule compound capable of binding to a target protein of interest (POI), a linking group introduced at an appropriate position, and a small molecule compound capable of binding to an E3 ubiquitinase. PROTACs function as small molecule probes that simultaneously bind to the target protein and the E3 ubiquitinase, thereby promoting the ubiquitination of the target protein, allowing it to be recognized and degraded by the proteasome.

[0006] Over the past decade, it has been demonstrated that many tumor-related target proteins (including AR, ER, BRD4, ERRa, RIPK2, etc.) can be regulated and degraded using PROTACs. Furthermore, recent studies have demonstrated the catalytic properties of PROTACs, demonstrating that equivalent therapeutic effects can be achieved at lower chimeric molecule concentrations than those required for single inhibitors. Therefore, a novel tumor treatment strategy that uses PROTACs to induce protein degradation can regulate target protein levels through the intracellular ubiquitin-proteasome degradation system, thereby overcoming the shortcomings of traditional small molecule inhibitors.

[0007] However, current drug-resistant cancer treatment remains a major focus and challenge in cancer treatment. Existing drug therapies often result in drug resistance, leading to a lack of available drugs and increased mortality. While AR mutations (including point mutations and splicing mutations) are an important cause of drug resistance, few inhibitors have been reported to date that target the AR-v7 mutation, the main splicing mutation. Therefore, novel drugs are being developed to treat drug-resistant cancers by degrading AR-v7. Summary of the Invention

[0008] The present invention provides a compound of Formula I, its optical isomer, its solvate, its pharmaceutically acceptable salt, its prodrug, its tautomer, its meso form, its racemate, its enantiomer, its diastereomer, its mixture form, its metabolite, its metabolic precursor, or its isotopically substituted form. [ka] I TB is the target recognition and binding moiety, L is the linking moiety, and U is the ubiquitin protease recognition and binding moiety. The three moieties are linked via a chemical bond. The TB moiety above is the structure shown in formula IA. [ka] IA Here, A is none, an aromatic ring, an aromatic heterocycle, a non-aromatic heterocycle, a non-aromatic carbocycle, a bridged ring, a spirocycle, a fused heterocycle, or a fused aromatic heterocycle. The aromatic ring includes a benzene ring. The aromatic heterocycle includes a 5- to 6-membered aromatic heterocycle. The non-aromatic heterocycle includes a 3- to 7-membered non-aromatic heterocycle. The non-aromatic carbocycle includes a 3- to 7-membered non-aromatic carbocycle. The fused heterocycle includes a 5- to 6-membered heterocycle fused to a 5- to 6-membered heterocycle. The fused aromatic heterocycle includes a 5- to 6-membered heterocycle fused to a 5- to 6-membered aromatic heterocycle and a 5- to 6-membered aromatic heterocycle fused to a 5- to 6-membered aromatic heterocycle. where R 1 and R 2 are each independently none, hydrogen, halogen, cyano group, amino group, hydroxy group, C1-C6 alkoxy group, C1-C6 alkylamino group, C1-C6 alkylmercapto group, C1-C6 alkylsulfone group, C1-C6 alkylsulfoxide group, C1-C6 alkylcarbonyl group, C1-C6 alkylamino group, carbonyl group, -NR 3 R 4 , -CR a R 3 R 4 , -NR 3 -CO-R 4 , -CO-NR 3 R 4 , -NR 3 -SO2-R 4 , -SO2-NR 3 R 4 , -CO-R 3 , -SO-R 3 , -SO2-R 3 , -CR 3 =CH2, -OR 3 , -SR 3 R is selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted fused heterocyclyl group, a substituted or unsubstituted spiroheterocyclyl group, a substituted or unsubstituted aromatic heterocyclic group, and a substituted or unsubstituted phenyl group. 1 and R 2 can be linked to form a ring. The substituent of the substitution is R a , R 3 , R 4 and R a , R 3 , R 4 are each independently selected from hydrogen, halogen, a hydroxy group, an amino group, a cyano group, a C1-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkylsulfone group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocyclyl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted phenylacyl group, and a sulfonyl group. a , R 3 , R 4 Any two of these may be bonded to form a 3- to 8-membered ring. The substituents are selected from halogen, amino, hydroxy, and hydroxy-substituted C1-C6 alkyl groups. G 1 and G 2 are each independently linked via a chemical bond. 1 None, -(CH2) y -, -(CH2) m -CR g1 R g2 -, -(CH2) m -CO-, O, S, SO, SO2, NR g1 Selected from: G 2 None, -(CH2) n -CR g3 R g4 -, -(CH2) n -O-, O, S, SO, SO2, NR g2 where y, m, and n are integers from 0 to 3. g1 , R g2 , R g3 , and R g4 are each independently selected from hydrogen, a C1-C6 alkyl group, a halogen, and a hydroxy group. g1 , R g2 , R g3 , and R g4 can be linked to form a ring. G 1and G 2 When both are absent, X is directly linked to A via a chemical bond. X is -N-, -NR 5 -, -O-, -S-, -CO-, -SO-, -SO2-, -CONR 5 -, -NR 5 CO-, -CH-, -CHR 5 -, -CR 5 R 5’ - is selected from the group consisting of R 5 and R 5’ are each independently selected from H and a C1-C6 alkyl group. Rings B and C are each independently selected from the group consisting of a substituted or unsubstituted benzene ring, thiophene, pyridine, pyrimidine, a 5- or 6-membered aromatic heterocycle, a 3- or 8-membered naphthene ring, and a 3- or 8-membered heterocycle, and the substituents of the substitutions are halogen and cyano groups. B 1 and B 2 are each independently selected from hydrogen, halogen, and a C1-C6 alkyl group; or B 1 , B 2 and X are linked to form a ring. Z is -C-, -CO-, -CH-, -CH2-, -O-, -N-, -S-, -SO-, or -SO2-. T 1 and T 2 are each independently selected from none, hydrogen, a hydroxy group, an amino group, a substituted or unsubstituted C1-C6 alkyl group, a C1-C6 oxaalkyl group, a C1-C6 azaalkyl group, a C3-C6 cycloalkyl group, an acyl group, a C1-C6 alkoxy group, and a C1-C6 alkylamino group, or T 1 and T 2 can be bonded to each other to form a ring. The substituent of the substitution is a hydroxy group or an amino group. L 1 and L 2 are each independently selected from hydrogen, halogen, cyano, amino, hydroxy, and C1-C6 alkyl groups. The L moiety above is the structure shown in formula IL. [ka] IL Q, J, Y, W and V each independently represent none, -O-, -S-, -SO-, -SO2-, or -NR q1 -, -NR j1 -, -C≡C-, -C=C-, -NR q1 CO-, -NR j1 CO-, -CO-, -CONH-, -NR q11 SO2-, -CR q1 R q2 -, -CR y1 R y2 -, -CR w1 R w2 -, -CR v1 R v2 -, -CR j1 R j2 -, -[(OCH2CH2O)2] n5 -, -[(OCH2CH2O)3] n6 -, R c and R d a substituted or unsubstituted 3- to 7-membered cycloalkyl group, R c and R d a substituted or unsubstituted 3- to 7-membered heterocyclyl group, R c and R d a substituted or unsubstituted phenyl group, R c and R d a substituted or unsubstituted aromatic heterocyclic group, R c and R d The R is selected from substituted or unsubstituted fused aromatic heterocyclic groups. c and R d are each independently selected from hydrogen, halogen, and C1-C3 alkyl groups, or R c and R d can be bonded to each other to form a ring. R q1 , R q2 , R y1 , R y2 , R w1 , R w2 , R v1 , R v2 , R j1 and R j2are each independently selected from hydrogen, halogen-substituted or unsubstituted C1-C6 alkyl groups, C3-C6 cycloalkyl groups, C1-C6 oxaalkyl groups, C1-C6 azaalkyl groups, C3-C6 oxyheterocyclyl groups, and C3-C6 nitrogen heterocyclyl groups. R q1 and R q2 , R y1 and R y2 , R w1 and R w2 , R v1 and R v2 , R j1 and R j2 can be bonded to each other to form a ring. n1, n2, n3, n4, n5 and n6 are each independently selected from integers of 0 to 6. Q and J can be attached to either the TB moiety or the U moiety at will. The U moiety above is the structure shown in formula IU. [ka] IU Here, M is -O-, -S-, -CR m -, -NR m - is selected from R m is hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclyl group, and [ka] is selected from. R m1 is selected from hydrogen, a C1-C6 alkyl group, and a C3-C6 cycloalkyl group. X m -CR m2 R m3 -, -OR m2 -, -NR m2 R m3 - is selected from R m2 and R m3are each independently selected from hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclyl group, and a C1-C6 oxaalkyl group. m2 and R m3 can be linked to form a ring. E 1 and E 2 are each independently -CO-, -CS-, or -NR e1 -, -O-, -S-, -SO2-, -CH2-, -CD2-, -CR e2 R e3 -, [ka] is selected from. R e1 , R e2 and R e3 are each independently selected from a C1-C6 alkyl group, hydrogen, halogen, a hydroxy group, and an amino group. Y 1 , Y 2 and Y 3 are each independently selected from H, O, S, and a C1-C3 alkyl group. J and k are each independently selected from integers of 0 to 3, and J and k are not 0 at the same time. U 1 , U 2 , U 3 and U 4 are independently O, S, N, -CR g1 -, -CR g2 -, -CR g3 -, -CR g4 - is selected from R g1 , R g2 , R g3 and R g4 are each independently selected from hydrogen, halogen, a hydroxy group, an amino group, a sulfhydryl group, a sulfo group, a sulfoxide group, a nitro group, a cyano group, CF3, a heterocyclyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C2-C6 alkenyl group, and a C2-C6 alkynyl group.

[0009] Furthermore, in the above compound, G in the TB moiety 1 , G 2 and different atoms on A are linked via a chemical bond as shown in formula II-A, or G of the TB moiety 1 , G 2 and the same atoms on A are linked via a chemical bond as shown in formula II-B. [ka] II-A II-B

[0010] Furthermore, in the above compounds, A is an aromatic heterocycle, and G 1 and G 2 The TB portion of the compound has the structure shown in Formula III-A. [ka] III-A k 1 , k 2 , k 3 , k 4 , and k 5 are each independently selected from CH and N, but are not simultaneously CH.

[0011] Furthermore, among the above compounds, G 1 is -CH2-, and G 2 is —CH— or —CHCH—. The TB portion of the compound has the structure shown in formula IV-A or IV-B. [ka] IV-A IV-B k 1 , k 2 , k 3 and k 4 are each independently selected from CH and N, but are not simultaneously CH.

[0012] Furthermore, in the above compounds, A is an aromatic heterocycle, and G 2The TB portion of the compound has the structure shown in formula VA. [ka] VA where G 1 It's not a story, Alternatively, the TB portion of the compound has the structure shown in formula VB. [ka] VB

[0013] Furthermore, in the above compounds, A is a 6-membered aromatic heterocycle, and G 2 The TB portion of the compound has the structure shown in Formula VI-A. [ka] VI-A G 1 Not a story, z 1 , z 2 , z 3 , z 4 and z 5 are each independently selected from CH and N, but are not both CH or Alternatively, the TB portion of the compound has the structure shown in formula VI-B. [ka] VI-B where z 1 , z 2 , z 3 , z 4 and z 5 are each independently selected from CH and N, but are not simultaneously CH.

[0014] Furthermore, in the above compounds, A is a five-membered aromatic heterocycle, and G 2 This is the story. The TB portion of the compound has the structure shown in Formula VII-A. [ka] VII-A where G 1 Not a story, x 1 , x 2 , x 3 and x 4 are each independently selected from CH, N, O or S, but are not CH or Alternatively, the TB portion of the compound has the structure shown in Formula VII-B. [ka] VII-B where x 1 , x 2 , x 3 and x 4 are each independently selected from CH, N, O, or S, but are not simultaneously CH.

[0015] Furthermore, in the above compounds, A is a 6-membered aromatic heterocycle fused to a 5-membered aromatic heterocycle, and G 2 The TB portion of the compound has the structure shown in Formula VIII-A. [ka] VIII-A where p 1 , p 2 , p 3 , p 4 , p 5 , p 6 , p 7 and p 8 are each independently selected from CH, N, O, or S, and p 1 , p 2 , p 3 and p 4 At least one of the groups is not CH, and p 2 , p 3 , p 5 , p 6 , p 7 and p 8 At least one of them is not CH.

[0016] Furthermore, among the above compounds, A is absent and G 1 and G 2 is a story, R 1 is hydrogen and R 2 is nothing and X is -O-. The TB portion of the compound has the structure shown in formula IX-A. [ka] IX-A

[0017] Furthermore, the TB moiety of the above compound [ka] The moiety has the structure shown below, where X, X 1 , X 2 are each independently -N-, -NR 5 -, -O-, -S-, -CO-, -SO-, -SO2-, -CONR 5 -, -NR 5 CO-, -CH-, -CHR 5 -and-CR 5 R 5’ - is selected from the group consisting of R 5 and R 5’ are each independently selected from hydrogen and a C1-C6 alkyl group. [ka] [ka] [ka] [ka] [ka]

[0018] Furthermore, the TB moiety of the above compound [ka] The moiety has the structure shown below: [ka] or hydroxy group

[0019] Furthermore, R in the TB portion of the above compound 1 and R 2 are each independently selected from hydrogen, a trifluoromethyl group, or the following structure: [ka] q, r, s, and t are each independently selected from integers of 0 to 5; D 1 and D 2 are each independently -O-, -S-, -SO-, -SO2-, or -NR 6 -,-NCOR 6 -,-NSO2R 7 -, -CR 6 X 1 -and-CR 6 R 7 - is selected from R 6 and R 7 are each independently selected from hydrogen, halogen, a hydroxy group, an amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C6 alkylamino group, or R 6 and R 7 are bonded to form a ring. X 1 -OR 8 -, -NR 8 R 9 -,-NCOR 8 -,-NSO2R 9 -, -CR 8 R 9 -R 8 and R 9 are each independently selected from hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a C3-C6 cycloalkyl group, or R 8 and R 9can be bonded to each other to form a ring. The substituent of the substitution is a hydroxy group or an amino group.

[0020] Furthermore, R in the TB portion of the above compound 1 and R 2 are each independently selected from hydrogen, a trifluoromethyl group, or the following structure: Hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, amino, methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, cyclobutylamino, hydroxyethylamino, 1-hydroxymethylcyclopropylamino, N,N-dimethylamino, N,N-diethylamino, formyl, acetyl, propionyl, isopropionyl, cyclopropionyl, 1-hydroxymethyl, 1 -hydroxyethyl group, 1-hydroxypropyl group, 1-hydroxyisopropyl group, 1-hydroxycyclopropyl group, aminoacyl group, N-methylaminoacyl group, N-ethylaminoacyl group, N,N-dimethylacyl group, azetidine acyl group, tetrahydropyroyl acyl group, methoxyacyl group, ethoxyacyl group, azetidine group, tetrahydropyrrole group, piperidine group, morpholine group, piperazine group, N-methylpiperazine group, N-ethylpiperazine group, N-cyclopropylpiperazine group, 2-methylpiperazine group, 3-methylpiperazine group, 2,2-dimethylpiperazine group, 3,3-dimethylpiperazine group, 2,3-dimethylpiperazine group, [ka] [ka]

[0021] Furthermore, R in the TB portion of the above compound 1 and R 2are each independently selected from the following structures: hydrogen, fluorine, chlorine, bromine, iodine, a methyl group, an amide group, a substituted or unsubstituted 1,2-diazole group, a 1,3-diazole group, an N-methyl-1,2-diazole group, N 1 -1,2,3-triazole group, N 2 -1,2,3-triazole group, 1,3,4-triazole group, 1,2,4-triazole group, 1,2,5-triazole group, 1,2-oxazole group, 1,3-oxazole group, 1,2,3-oxadiazole group, 1,2,4-oxadiazole group, 1,3,5-oxadiazole group, 1,2-thioxazole group, 1,3-thioxazole group, 1,2,3-thiadiazole group, 1,2,4-thiadiazole group, 1,3,5-thiadiazole group, N 2 -4-fluoro-1,2,3-triazole group, N 2 -4-methyl-1,2,3-triazole group, 2-methyl-1,3,4-oxadiazole group, 5-methyl-1,2,4-oxadiazole group, 3-methyl-1,2,4-oxadiazole group, pyridine group, pyridazine group, pyrimidine group, pyrazine group, wherein the substituents are halogen, hydroxy group, amino group, C1-C6 alkoxy group, C1-C6 alkylamino group, cyano group, amido group, C1-C6 alkyl group, and C3-C6 cycloalkyl group.

[0022] Furthermore, R in the TB portion of the above compound 1 and R 2 are each independently selected from the following structures: Hydrogen, amino, methylamino, dimethylamino, methylthio, methylsulfonyl, 1,2,3-triazole, 1,2,4-triazole, pyridine, fluorine, iodine, 2-methyl-1,3,4-oxadiazole, cyano, 5-methyl-1,2,4-oxadiazole, 1-hydroxyethyl, 1-hydroxypropyl, acetyl, propionyl, cyclopropionyl, cyclobutyryl, isopropionyl, 1-hydroxyisopropyl, 1-hydroxyisobutyl, methoxyacyl, ethoxyacyl, 1-hydroxypropyl ... hydroxymethyl group, methoxy group, ethoxy group, cyclopropoxy group, aminoacyl group, N-methylaminoacyl group, 1-methyl-1,2-diazole group, 1,2-diazole group, 1,3-diazole group, 3-methyl-1,2,4-oxadiazole group, 1,2,4-oxadiazole group, 1,3,4-oxadiazole group, 3,5-dimethyl-1,2-oxazole group, tetrahydropyrrole group, 1,3,4-thiadiazole group, 3-methyl-1,2,4-thiadiazole group, hexahydropyridine group, carboxy group, 1,3-thiazole group, -NHCN, [ka] wherein R' is a methyl group, an ethyl group, or a cyclopropyl group, and R" is a hydrogen atom or a methyl group. R'" and R"" are each independently selected from a hydrogen atom, a methyl group, and an ethyl group, or R"'" and R"" combine to form a methyl-substituted or unsubstituted 4- to 6-membered heterocycle. Preferably, R 1 and R 2 teeth [ka] isn't it.

[0023] Furthermore, the TB moiety of the above compound [ka] The moiety has the structure shown below: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0024] Furthermore, the TB portion of the above compound [ka] The moiety is selected from any of the following structures: [ka] [ka] [ka] [ka]

[0025] Furthermore, the TB portion of the above compound [ka] The structure of the moiety is shown in formula IC. [ka] I C where M0 is -CR a R b - or -SO2-. T 1 and T 2 are each independently selected from -CH- or -N-. 1 and X 2 are each independently selected from hydrogen or halogen.

[0026] Furthermore, the TB portion of the above compound [ka] The moiety is selected from the following structures: [ka]

[0027] Additionally, the TB portion of the above compound is selected from the following structures: [ka] [ka] [ka] [ka]

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[0028] Furthermore, the L portion of the above compound has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0029] Furthermore, the L portion of the above compound is one of the following structures: [ka] [ka] [ka]

[0030] Additionally, the L portion of the above compound is the structure shown in formula XA. [ka] Formula XA n2 is 0 or 1. R y1 and R y2 are each independently selected from hydrogen or a C1-C3 alkyl group; R w1 and R w2are each independently selected from hydrogen or a halogen-substituted or unsubstituted C1-C3 alkyl group; Or R y1 and R y2 are linked to form a 3- or 4-membered saturated carbocyclic ring, or R w1 and R w2 are linked to form a 3- or 4-membered saturated carbocyclic ring, or R y2 and R w2 are linked to form a 3-4 membered saturated carbocyclic ring.

[0031] Furthermore, the above R y1 and R y2 are each independently selected from hydrogen or a methyl group; R w1 and R w2 are each independently selected from hydrogen, a methyl group, and a chlorine-substituted or unsubstituted propyl group; Or R y1 and R y2 are linked to form a three-membered saturated carbocyclic ring, or R w1 and R w2 are linked to form a 3- or 4-membered saturated carbocyclic ring, or R y2 and R w2 are linked to form a four-membered saturated carbocyclic ring.

[0032] Preferably, the L moiety is: [ka]

[0033] Additionally, the U portion of the above compound has the following structure: [ka] [ka] [ka] [ka]

[0034] Furthermore, the compound of formula IU above [ka] The moiety is selected from any of the following structures: [ka]

[0035] Preferably, U 1 , U 2 , U 3 and U 4 are all CH, or one is N or CX0 and the others are CH, where X0 is a halogen.

[0036] Furthermore, the compound of formula IU above [ka] The moiety has the following structure: [ka]

[0037] Preferably, R m is hydrogen or a methyl group.

[0038] Additionally, the U portion of the above compound has the following structure: [ka]

[0039] Furthermore, the compound is selected from any of the following compounds: [Table 1] [Table 2] [Table 3]

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

[0040] The present invention further provides a drug, which is a formulation prepared by adding a pharmaceutically acceptable excipient to the above-mentioned compound, its optical isomer, its solvate, its pharmaceutically acceptable salt, its prodrug, its tautomer, its meso form, its racemate, its enantiomer, its diastereomer, a mixture thereof, its metabolite, its metabolic precursor, or its isotopically substituted form as an active ingredient.

[0041] The present invention is the use of the above-mentioned compound, its optical isomer, its solvate, its pharmaceutically acceptable salt, its prodrug, its tautomer, its meso form, its racemate, its enantiomer, its diastereomer, its mixture form, its metabolite, its metabolic precursor, or its isotopically substituted form in the preparation of a chimeric molecule for proteolysis induction of the androgen receptor.

[0042] Furthermore, the above-mentioned proteolytically induced chimeric molecule can induce recognition and binding of the androgen receptor.

[0043] Furthermore, the proteolysis-inducing chimeric molecule described above is capable of degrading the androgen receptor.

[0044] Furthermore, the above androgen receptors include wild-type and mutant androgen receptors.

[0045] Furthermore, the above-mentioned mutant androgen receptor includes a splicing mutant androgen receptor and a point mutant androgen receptor, and is preferably a splicing mutant androgen receptor AR-v7.

[0046] Furthermore, the above-mentioned proteolysis-inducing chimeric molecules are drugs for treating related diseases controlled by the androgen receptor.

[0047] Furthermore, the disease is cancer, alopecia, acne or COVID-19.

[0048] Furthermore, the above cancers are cancers that are positive for androgen receptor expression.

[0049] Furthermore, the above cancers are drug-resistant cancers.

[0050] Preferably, the cancer is prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer or salivary gland cancer.

[0051] The experimental results demonstrate that the compounds of the present invention can target the degradation of AR and down-regulate the expression of AR, and in particular have significant degradation activity and inhibitory effect on AR-v7, an AR splicing mutation, and can effectively inhibit the proliferation of drug-resistant prostate cancer cells. They also exhibit good metabolic stability and oral pharmacokinetic properties, and have good application prospects in the manufacture of protein degraders targeting androgen receptors and in drugs for treating diseases related to the regulation of androgen receptors.

[0052] Regarding the definitions of terms used in the present invention, unless otherwise specified, the initial definition provided for a group or term in this specification applies to that group or term throughout the specification, and terms not specifically defined in this specification should be given the meaning that a person skilled in the art can give based on the disclosure and context.

[0053] In the present invention, "substitution" means that one, two or more hydrogen atoms in a molecule are replaced with other different atoms or molecules, and includes one, two or more substitutions on isotopic or heterotopic atoms in the molecule.

[0054] In the present invention, the minimum and maximum carbon atom content in the hydrocarbon group are represented by prefixes, for example, the C1-C6 alkyl group or C1-C6 alkyl group refers to C1, C2, C3, C4, C5, or C6 alkyl groups, i.e., linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, etc. Similarly, the C1-C6 alkoxy group refers to C1, C2, C3, C4, C5, or C6 alkoxy groups.

[0055] In the present invention, "solvate thereof" refers to the formation of a solvate of a compound with a solvent, wherein the solvent includes (but is not limited to) water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.

[0056] In the present invention, "pharmaceutically acceptable" means that a vector, carrier, diluent, adjuvant, and / or formed salt is chemically or physically compatible with other ingredients that normally constitute a drug dosage form and is physiologically compatible with a receptor.

[0057] In the present invention, the term "salt" refers to an acidic and / or basic salt formed by a compound or its stereoisomer with an inorganic and / or organic acid and / or base, including zwitterionic salts (internal salts) and quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can be obtained by mixing a compound or its stereoisomer with a certain amount of acid or base in an appropriate amount (e.g., equal equivalents). These salts can be produced by forming a precipitate in a solution and collecting it by filtration, or by evaporating the solvent, or by reacting in an aqueous medium and then lyophilizing it. In the present invention, the salt may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate salt of the compound.

[0058] In the present invention, "aromatic ring" refers to an all-carbon monocyclic ring or fused polycyclic ring having a conjugated π electron system, such as benzene or naphthalene. The aromatic ring may be fused with other ring structures (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be located on a carbon atom on the ring having a conjugated π electron system. "Monocyclic aromatic ring" refers to an all-carbon monocyclic ring having a conjugated π electron system. Similarly, "aryl group" refers to an all-carbon monocyclic group or fused polycyclic group having a conjugated π electron system, such as phenyl and naphthyl groups.

[0059] The term "heteroaromatic ring" refers to a monocyclic ring or fused polycyclic ring having a conjugated π-electron system containing one or more heteroatoms. The heteroaromatic ring contains at least one heteroatom selected from N, O, or S, with the remaining ring atoms being C, and furthermore has a completely conjugated π-electron system. Examples include furan, pyrrole, quinoline, thiophene, pyridine, pyrazole, N-alkylpyrrole, pyrimidine, pyrazine, imidazole, tetrazole, and thienopyridyl groups. The heteroaromatic ring may be fused to an aromatic ring, heterocyclic ring, or alkane ring. The term "monocyclic heteroaromatic ring" refers to a monocyclic ring having a conjugated π-electron system containing one or more heteroatoms. Similarly, the term "heteroaryl group" refers to a monocyclic or fused polycyclic ring having a conjugated π-electron system containing one or more heteroatoms.

[0060] "Halogen" is fluorine, chlorine, bromine or iodine. An "alkyl group" is a hydrocarbon group formed by removing one hydrogen atom from an alkane molecule, such as methyl -CH3, -CH3CH2, etc. The term "alkynyl group" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be linear or branched. When the number of carbon atoms is specified before the alkynyl group, for example, "C 2-6 "Alkynyl" means a straight or branched chain alkynyl group having 2 to 6 carbon atoms. The term "alkenyl group" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group may be linear or branched. When the number of carbon atoms is specified before the alkenyl group, for example, "C 2-6 "Alkenyl" means a straight or branched chain alkenyl group having 2 to 6 carbon atoms. "Cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon, and "cycloalkyl group" refers to a saturated or unsaturated cyclic hydrocarbon substituent, which may be monocyclic or polycyclic. For example, "3-8 membered cycloalkyl group" refers to a cycloalkyl group having 3 to 8 carbon atoms. A "heterocycle" refers to a saturated or unsaturated cyclic hydrocarbon, and a "heterocyclyl group" refers to a saturated or unsaturated cyclic hydrocarbon substituent, which may be monocyclic or polycyclic and has at least one heteroatom (including, but not limited to, O, S, or N). For example, a "3- to 8-membered heterocyclyl group" refers to a heterocyclyl group containing a total of 3 to 8 carbon atoms and heteroatoms. "Fused heterocyclyl" means a saturated or unsaturated polycyclic hydrocarbon, and "fused heterocyclyl group" means a saturated or unsaturated polycyclic hydrocarbon substituent and has at least one heteroatom (including, but not limited to, O, S, or N), and two rings in the polycyclic hydrocarbon share two adjacent carbon atoms or heteroatoms. The term "fused aromatic heterocycle" refers to a polycyclic structure in which at least one ring in the above-mentioned fused heterocyclyl is an aromatic ring, and the term "fused aromatic heterocyclic group" refers to a group in which at least one ring in the above-mentioned fused heterocyclyl group is an aromatic ring. A "spirocycle" means two multi-membered rings that share one carbon atom, and a "bridged ring" means two or more multi-membered rings that share two or more carbon atoms. A "spiroheterocyclyl group" is a polycyclic heterocyclyl group in which two rings share one carbon atom or heteroatom. The term "alkylmercapto group" refers to a group formed by bonding a straight-chain or branched-chain alkyl group or a cycloalkyl group to -S-. The term "alkylsulfone group" refers to a group formed by bonding a linear or branched alkyl group or a cycloalkyl group to -SO2-. The term "alkyl sulfoxide group" refers to a group formed by bonding a linear or branched alkyl group or a cycloalkyl group to -SO-. The term "alkylcarbonyl group" refers to a group formed by bonding a straight-chain or branched-chain alkyl group or a cycloalkyl group to -CO-.

[0061] An "alkylaminocarbonyl group" is a straight-chain or branched-chain alkyl group or a cycloalkyl group that is -NH-CO- or [ka] means a group formed by bonding to An "alkylamino group" is a group in which a straight-chain or branched-chain alkyl group or a cycloalkyl group is -NH- or [ka] means a group formed by bonding to

[0062] In the present invention, an isotopically substituted compound means a compound obtained after any one or more atoms in the compound are isotopically substituted. Isotopes refer to different nuclides of the same element that have the same number of protons but different numbers of neutrons, and are isotopes of each other. For example, hydrogen has three isotopes, such as H protium, D deuterium (also called heavy hydrogen), and T tritium (also called superheavy hydrogen), and unless otherwise specified, hydrogen in the present invention is H, and carbon has multiple isotopes, such as C, C, and C, and unless otherwise specified, C in the present invention is C. "Cbz" is a benzyloxycarbonyl protecting group. "Me" is a methyl group. Obviously, according to the above content of the present invention, many other modifications, substitutions or changes can be made based on ordinary technical knowledge and conventional means in the art without departing from the above basic technical idea of ​​the present invention.

[0063] The above content of the present invention will be described in more detail below with reference to specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0064] The raw materials and equipment used in the present invention are known products and can be obtained commercially.

[0065] Example 1: N-(4-((4-(2-(4-((8-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] Step 1: Synthesis of tert-butyl 4-(2-((8-bromooctyl)oxy)ethyl)piperazine-1-carboxylate, tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (2.3 g, 10 mmol) was dissolved in dry DMF (10 mL). Sodium hydride (800 mg, 20 mmol) was added in several portions under nitrogen gas protection in an ice-water bath for 0.5 h. 1,8-Dibromooctane (2.7 g, 10 mmol) was then added and the mixture was allowed to react at room temperature for 3 h. The reaction mixture was poured into water, extracted, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1.68 g of the product (40% yield). LC / MS (ESI+) calculation for C 19 H 37 BrN2O3([M+H] + ) m / z 421,found 421. Step 2: Synthesis of tert-butyl 4-(2-(8-(4-(2-(2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)ethyl)piperazine-1-carboxylate, Tert-butyl 4-(2-((8-bromooctyl)oxy)ethyl)piperazine-1-carboxylate (420 mg, 1 mmol) was dissolved in DMF (8 mL), and N-(4-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (413 mg, 1 mmol) and sodium bicarbonate (252 mg, 3 mmol) were added. The mixture was heated to 90°C and reacted for 15 h. The reaction mixture was poured into water and extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 600 mg of the product (80% yield). LC / MS (ESI+) calculation for C 40 H 59 N5O7S ([M+H] + ) m / z 754,found 754. Step 3: Synthesis of N-(4-(4-(2-(4-((8-(2-(piperazin-1-yl)ethoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonimide, tert-Butyl 4-(2-(8-(4-(2-(2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)ethyl)piperazine-1-carboxylate (754 mg, 1 mmol) was dissolved in 40 mL of dichloromethane and 10 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 x 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 653 mg of product. The yield was 99%. LC / MS (ESI+) calculation for C 35 H 51 N5O5S ([M+H] + ) m / z 654,found 654. Step 4: Synthesis of N-(4-((4-(2-(4-((8-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide, N-(4-(4-(2-(4-((8-(2-(piperazin-1-yl)ethoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonimide (653 mg, 1 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (276 mg, 1 mmol), and DIPEA (387 mg, 3 mmol) were added sequentially to 15 mL of DMSO, heated to 90 °C, and reacted for 36 h. The mixture was allowed to cool to room temperature, poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 455 mg of the product. The yield was 50%. 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 5.0 Hz, 1H), 8.15 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.20 - 7.11 (m, 3H), 7.10 - 6.99 (m, 3H), 6.88 - 6.79 (m, 2H), 6.77 - 6.67 (m, 2H), 5.05 (s, 2H), 4.94 (dd, J = 12.2, 5.2 Hz, 1H), 4.10 (p, J = 5.7, 5.2 Hz, 2H), 3.63 (t, J = 5.4 Hz, 2H), 3.48 (s, 6H), 3.41 (t, J = 6.6 Hz, 2H), 2.93 - 2.63 (m, 8H), 2.13 (ddd, J = 10.3, 5.0, 2.6 Hz, 1H), 1.72 (s, 2H), 1.65 - 1.40 (m, 9H). LC / MS (ESI+) calcd for C 48 H59 N7O9S([M+H] + ) m / z 910,found 910.

[0066] Example 2: N-(4-((4-(2-(4-((7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)heptyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] It was prepared using a method similar to that in Example 1. LC / MS (ESI+) calculation for C 47 H 57 N7O9S ([M+H] + ) m / z 896,found 896.

[0067] Example 3: N-(4-(4-(2-(4-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)butoxy)butoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a synthetic method similar to that in Example 1. 1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 5.1 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.23 - 7.10 (m, 3H), 7.10 - 6.99 (m, 2H), 6.87 - 6.79 (m, 2H), 6.76 (d, J = 2.1 Hz, 1H), 6.74 - 6.68 (m, 2H), 6.49 (dd, J = 8.3, 2.2 Hz, 1H), 5.06 (s, 2H), 4.95 - 4.90 (m, 1H), 4.12 (tt, J = 7.2, 3.2 Hz, 2H), 3.72 (s, 4H), 3.48 (s, 3H), 3.40 (dt, J = 9.5, 5.9 Hz, 4H), 2.92 - 2.70 (m, 4H), 2.63 (s, 6H), 2.44 (d, J = 8.4 Hz, 2H), 2.17 - 2.09 (m, 1H), 1.91 (t, J = 5.5 Hz, 4H), 1.79 (q, J = 8.3, 7.7 Hz, 2H), 1.62 (s, 10H). LC / MS (ESI+) calcd for C 49 H 59 N7O9S ([M+H] + ) m / z 922,found 922.

[0068] Example 4 Synthesis of N-(4-((4-(2-(4-(3-(3-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-)2,7-diazaspiro[3.5]nonan-7-yl)propoxy)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J = 5.0 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.21 - 7.09 (m, 3H), 7.08 - 7.00 (m, 2H), 6.86 - 6.79 (m, 2H), 6.77 (d, J = 2.1 Hz, 1H), 6.75 - 6.68 (m, 2H), 6.49 (dd, J = 8.3, 2.2 Hz, 1H), 5.08 (s, 2H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 4.23 - 4.11 (m, 2H), 3.73 (s, 3H), 3.52 - 3.34 (m, 6H), 2.92 - 2.69 (m, 4H), 2.63 (s, 6H), 2.18 - 2.08 (m, 2H), 2.01 - 1.89 (m, 6H), 1.82 (s, 2H), 1.62 (s, 6H). LC / MS (ESI+) calcd for C 47 H 55 N7O9S ([M+H] + ) m / z 894,found 894.

[0069] Example 5: N-(4-((4-(2-(4-((9-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azacyclobutan-3-yl)piperazin-1-yl)nonyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.18 (s, 1H), 8.68 (d, J = 5.1 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 6.93 (dd, J = 29.4, 8.4 Hz, 4H), 6.78 (s, 1H), 6.63 (d, J = 8.3 Hz, 3H), 5.14 (s, 2H), 5.05 (dd, J = 13.0, 5.5 Hz, 1H), 4.17 - 3.75 (m, 6H), 3.50 (s, 3H), 3.29 (t, J = 6.1 Hz, 5H), 2.94 - 2.80 (m, 1H), 2.22 (t, J = 7.3 Hz, 8H), 2.00 (d, J = 12.9 Hz, 1H), 1.59 (d, J = 36.0 Hz, 8H), 1.41 - 1.12 (m, 12H). LC / MS (ESI+) calcd for C 50 H 62 N8O8S ([M+H] + ) m / z 935,found 935.

[0070] Example 6 Synthesis of N-(4-((4-(2-(4-((6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl))piperazin-1-yl)methyl)piperidin-1-yl)hexyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 5.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H), 7.12 - 7.07 (m, 2H), 7.05 (dd, J = 8.8, 2.3 Hz, 3H), 6.85 - 6.79 (m, 2H), 6.78 - 6.68 (m, 2H), 5.07 (s, 2H), 4.99 - 4.89 (m, 1H), 4.63 (s, 2H), 4.07 (t, J = 7.5 Hz, 2H), 3.43 (d, J = 20.5 Hz, 6H), 3.25 (d, J = 11.7 Hz, 2H), 2.94 - 2.68 (m, 4H), 2.55 (t, J = 5.2 Hz, 6H), 2.35 - 2.20 (m, 6H), 2.17 - 2.09 (m, 2H), 1.87 (d, J = 11.9 Hz, 3H), 1.62 (s, 6H), 1.37 - 1.17 (m, 8H). LC / MS (ESI+) calcd for C 50 H 62 N8O8S([M+H] + ) m / z 935,found 935.

[0071] Example 7: N-(4-((4-(2-(4-((7-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)heptyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 5.0 Hz, 1H), 7.68 (dd, J = 8.5, 4.2 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.23 - 7.10 (m, 3H), 7.05 (dd, J = 7.7, 5.7 Hz, 3H), 6.91 - 6.78 (m, 2H), 6.78 - 6.64 (m, 2H), 5.05 (s, 2H), 4.94 (dd, J = 12.2, 5.3 Hz, 1H), 4.10 (q, J = 7.7 Hz, 2H), 3.57 - 3.32 (m, 11H), 2.94 - 2.47 (m, 12H), 2.13 (ddd, J = 11.9, 9.3, 5.6 Hz, 1H), 1.89 - 1.69 (m, 4H), 1.65-1.50 (m, 9H), 1.40-1.30 (m, 2H). LC / MS (ESI+) calcd for C 48 H 59 N7O9S ([M+H] + ) m / z 910,found 910.

[0072] Example 8: N-(4-((4-(2-(4-((6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butoxy)hexyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 5.1 Hz, 1H), 7.68 (dd, J = 8.5, 4.7 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.22 - 7.10 (m, 3H), 7.05 (dd, J = 7.7, 5.7 Hz, 3H), 6.93 - 6.78 (m, 2H), 6.76 - 6.62 (m, 2H), 5.06 (s, 2H), 4.94 (dd, J = 12.0, 5.5 Hz, 2H), 4.10 (t, J = 7.7 Hz, 2H), 3.56 - 3.32 (m, 13H), 2.94 - 2.58 (m, 10H), 2.18 - 2.02 (m, 2H), 1.76 (tq, J = 14.2, 6.6 Hz, 2H), 1.60 - 1.52 (m, 6H), 1.47 - 1.30 (m, 5H). LC / MS (ESI+) calcd for C 48 H 59 N7O9S([M+H] + ) m / z 910,found 910.

[0073] Example 9: N-(4-((4-(2-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] Step 1: Synthesis of N-(4-((4-(2-(4-((5-bromopentyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide, The compound N-(4-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (140 mg, 0.34 mmol) and 1,5-dibromopentane (85 mg, 0.37 mmol) were added to 4 mL of DMF, and K2CO3 (118 mg, 0.85 mmol) and KI (10 mg, 0.06 mmol) were further added. The mixture was stirred at 70 °C for 2 h, cooled to room temperature, and a small amount of water was added to the reaction mixture. The mixture was extracted three times with EA. The organic phases were combined, washed three times with saturated NaCl solution, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain the target compound (142 mg, 74% yield). LC / MS (ESI+) calculation for C 26 H 32 BrN3O4S + (M + H + ) m / z, 564.1; found, 564.1. Step 2: Synthesis of N-(4-((4-(2-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide The compound N-(4-((4-(2-(4-((5-bromopentyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (70 mg, 0.13 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (35 mg, 0.13 mmol) were added to 3 mL of DMF, and KCO (45 mg, 0.33 mmol) and KI (10 mg, 0.06 mmol) were further added. The mixture was stirred at 60 °C for 4 h, cooled to room temperature, a small amount of water was added to the reaction mixture, and the mixture was extracted three times with EA. The organic phases were combined, washed three times with saturated NaCl solution, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to give the target compound (29 mg, 30% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.16 (s, 1H), 8.67 (t, J = 4.0 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.32 (dd, J = 8.3, 2.3 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 7.13 - 7.07 (m, 2H), 7.01 - 6.94 (m, 2H), 6.93 - 6.86 (m, 2H), 6.67 - 6.60 (m, 2H), 5.18 - 5.08 (m, 3H), 4.16 (t, J = 6.4 Hz, 2H), 3.98 (dt, J = 18.0, 7.6 Hz, 2H), 3.52 (d, J = 5.6 Hz, 3H), 2.64 - 2.56 (m, 1H), 2.09 - 1.98 (m, 1H), 1.73 (ddt, J = 23.1, 15.8, 7.9 Hz, 4H), 1.54 (s, 6H), 1.44 (d, J = 7.5 Hz, 2H), 1.34 - 1.10 (m, 2H). LC / MS (ESI+) calcd for C 39 H 41 N5O9S (M + H + ) m / z, 756.2; found, 756.2.

[0074] Example 10: N-(4-((4-(2-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] It was prepared using a method similar to that in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.16 (s, 1H), 8.67 (d, J = 5.1 Hz, 1H), 7.55 (dd, J = 8.6, 7.1 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 7.13 - 7.05 (m, 3H), 7.03 - 6.94 (m, 3H), 6.92 - 6.85 (m, 2H), 6.67 - 6.61 (m, 2H), 6.57 (t, J = 6.0 Hz, 1H), 5.13 (s, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.01 (t, J = 7.4 Hz, 2H), 3.52 (s, 3H), 2.86 (ddd, J = 17.8, 13.8, 5.3 Hz, 1H), 2.56 (d, J = 17.6 Hz, 1H), 2.04 - 1.95 (m, 1H), 1.81 - 1.70 (m, 2H), 1.54 (s, 9H), 1.23 (s, 2H). LC / MS (ESI+) calcd for C 38 H 40 N6O8S (M + H + ) m / z, 741.2; found, 741.2.

[0075] Example 11: N-(4-((4-(2-(4-(3-(4-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azacyclobutan-3-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.18 (s, 1H), 8.67 (d, J = 5.1 Hz, 1H), 7.60 (dd, J = 17.1, 8.3 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.76 (s, 1H), 6.64 (d, J = 8.6 Hz, 3H), 5.12 (s, 2H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.16 - 3.92 (m, 5H), 3.65 (dd, J = 8.4, 5.6 Hz, 3H), 2.95 - 2.76 (m, 5H), 2.58 (dd, J = 10.8, 5.5 Hz, 3H), 2.29 (dd, J = 17.2, LC / MS (ESI+) calcd for C 51 H 63 N9O8S (M + H + ) m / z, 962.4; found, 962.4.

[0076] Example 12: N-(4-(2-(4-((1-((1-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azacyclobutan-3-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 4.9 Hz, 1H), 7.09 (dd, J = 15.7, 8.6 Hz, 5H), 6.87 (d, J = 9.0 Hz, 3H), 6.80 (d, J = 8.5 Hz, 2H), 6.64 (td, J = 12.9, 11.8, 6.2 Hz, 3H), 4.90 (s, 2H), 4.32 - 4.03 (m, 6H), 3.92 (t, J = 7.5 Hz, 3H), 2.96 (d, J = 3.1 Hz, 3H), 2.78 (dq, J = 17.8, 8.5, 7.9 Hz, 10H), 2.63 (d, J = 10.1 Hz, 4H), 2.16 - 2.03 (m, 9H), 1.99 (dt, J = 13.9, 7.0 Hz, 4H), 1.88 (s, 10H), 1.78 (d, J = 10.9 Hz, 4H). LC / MS (ESI+) calcd for C 55 H 69 N9O8S (M + H + ) m / z, 1016.5; found, 1016.5.

[0077] Example 13: N-(4-((4-(2-(4-((1-(4-(4-(4-)((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)butyl)pyrrolidin-3-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.18 (s, 1H), 8.69 (d, J = 5.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 7.15 - 7.08 (m, 3H), 6.98 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 2.1 Hz, 1H), 6.92 - 6.88 (m, 2H), 6.84 (dd, J = 8.4, 2.1 Hz, 1H), 6.66 - 6.61 (m, 2H), 5.15 (s, 2H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.05 - 3.94 (m, 2H), 3.53 (s, 3H), 3.16 (q, J = 6.1 Hz, 3H), 2.76 - 2.53 (m, 5H), 1.99 (tt, J = 9.9, 6.0 Hz, 2H), 1.70 - 1.37 (m, 19H), 1.23 (d, J = 3.5 Hz, 4H). LC / MS (ESI+) calcd for C 47 H 57 N7O9S (M + H + ) m / z, 896.4; found 896.4

[0078] Example 14: N-(4-(4-(2-(4-((1-(5-(4-)((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)pentyl)azacyclobutan-3-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.19 - 7.04 (m, 7H), 6.96 - 6.88 (m, 3H), 6.84 (dd, J = 8.4, 2.1 Hz, 1H), 6.70 (d, J = 8.7 Hz, 2H), 5.09 (s, 2H), 5.02 (dd, J = 12.9, 5.4 Hz, 1H), 4.70 (p, J = 5.7 Hz, 1H), 3.79 - 3.69 (m, 2H), 3.50 (s, 3H), 3.17 (d, J = 5.8 Hz, 4H), 3.00 - 2.79 (m, 5H), 2.44 (q, J = 5.8, 5.3 Hz, 3H), 1.98 (ddd, J = 11.5, 6.3, 3.7 Hz, 2H), 1.68 - 1.39 (m, 16H). LC / MS (ESI+) calcd for C 46 H 55 N7O9S (M + H + ) m / z, 882.4; found, 882.4

[0079] Example 15: N-(4-(4-(2-(4-((1-(5-(4-)((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)pentyl)piperidin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 5.1 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.10 (dt, J = 17.1, 7.4 Hz, 7H), 6.97 - 6.87 (m, 4H), 6.82 (t, J = 10.0 Hz, 3H), 5.04 (d, J = 6.7 Hz, 2H), 3.26 (s, 5H), 3.15 (d, J = 4.7 Hz, 4H), 2.89 (q, J = 7.2 Hz, 6H), 2.76 (dd, J = 22.8, 13.0 Hz, 4H), 2.54 (s, 6H), 2.35 (dt, J = 19.4, 8.7 Hz, 6H), 1.95 (dq, J = 23.8, 7.1 Hz, 5H), 1.46 (p, J = 7.0 Hz, 6H). LC / MS (ESI+) calcd for C 48 H 59 N7O9S (M + H + ) m / z, 910.4; found, 910.4

[0080] Example 16: N-(4-(4-(2-(4-((1-(3-(4-)((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)propyl)piperidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 5.1 Hz, 1H), 7.59 - 7.44 (m, 1H), 7.24 (d, J = 5.1 Hz, 1H), 7.10 (d, J = 8.4 Hz, 3H), 6.96 (t, J = 2.98 - 2.83 (m, 4H), 2.61 - 2.34 (m, 10H), 2.09 - 1.88 (m, 4H), 1.65 (t, J = 7.2 Hz, 2H), 1.56 (d, J = 16.9 Hz, 13H). LC / MS (ESI+) calcd for C 47 H 57 N7O9S (M + H + ) m / z,896.4; found 896.4

[0081] Example 17: N-(4-((4-(2-(4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] Step 1: Synthesis of tert-butyl (3-(3-(4-(2-(4-(2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propoxy)carbamate N-(4-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (206 mg, 0.5 mmol), 3-(3-((tert-butoxycarbonyl)amino)propoxy)propyl methanesulfonate (155 mg, 0.5 mmol), cesium carbonate (325 mg, 1.0 mmol), and sodium iodide (7.5 mg, 0.05 mmol) were added sequentially to 4 mL of DMF, heated to 60 °C, and reacted overnight. After complete reaction was monitored by TLC, the mixture was allowed to cool to room temperature, extracted with 4 mL of ethyl acetate, washed with saturated brine (3 × 4 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 125 mg of the target compound. The yield was 40%. The subsequent steps were carried out in a similar manner to that described in Example 1 to prepare the target compound. 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.47 (dd, J = 8.5, 7.1 Hz, 1H), 7.19 (d, J = 5.0 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.6 Hz, 1H), 6.83 (d, J = 8.9 Hz, 2H), 6.79 - 6.65 (m, 2H), 6.48 (s, 1H), 5.05 (s, 2H), 4.90 (dd, J = 12.1, 5.3 Hz, 1H), 4.28 - 4.17 (m, 2H), 3.56 - 3.46 (m, 5H), 3.40 (s, 2H), 3.11 (d, J = 37.0 Hz, 2H), 2.91 - 2.68 (m, 3H), 2.22 (t, J = 7.7 Hz, 1H), 2.07 (dd, J = 13.2, 6.1 Hz, 2H), 1.96 - 1.85 (m, 2H). LC / MS (ESI+) calcd for C 40 H 44 N6O9S ([M+H] +) m / z: 785.3; found 785.3.

[0082] Example 18: N-(4-((4-(2-(4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] N-(4-((4-(2-(4-(3-(3-aminopropoxy)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (41 mg, 0.075 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (18 mg, 0.075 mmol), and DIPEA (30 mg, 0.23 mmol) were added sequentially to 5 mL of DMSO, heated to 90 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 11 mg of the target compound. The yield was 18%. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 5.1 Hz, 1H), 8.06 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 5.1 Hz, 1H), 7.16 - 7.10 (m, 2H), 7.10 - 7.02 (m, 2H), 6.98 (d, J = 2.2 Hz, 1H), 6.85 - 6.79 (m, 2H), 6.79 - 6.74 (m, 1H), 6.74 - 6.68 (m, 2H), 5.06 (s, 2H), 4.91 (dd, J = 12.1, 5.3 Hz, 1H), 4.27 - 4.17 (m, 2H), 3.55 (dt, J = 8.3, 5.8 Hz, 4H), 3.51 (s, 3H), 3.34 (t, J = 6.1 Hz, 2H), 2.89 - 2.66 (m, 3H), 2.14 - 2.03 (m, 3H), 1.90 (q, J = 5.8 Hz, 3H), 1.62 (s, 6H). LC / MS (ESI+) calcd for C 40 H 44 N6O9S ([M+H] + ) m / z: 785.3; found 785.3.

[0083] Example 19: N-(4-((4-(2-(4-(3-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)propoxy)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 17. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.47 (dd, J = 8.5, 7.1 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 7.17 - 7.11 (m, 2H), 7.08 - 7.04 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.76 - 6.67 (m, 2H), 6.44 (s, 1H), 5.05 (s, 2H), 4.90 (dd, J = 12.0, 5.3 Hz, 1H), 4.27 - 4.13 (m, 2H), 3.57 - 3.44 (m, 11H), 3.37 (q, J = 6.3 Hz, 2H), 2.93 - 2.64 (m, 3H), 2.11 (dt, J = 10.4, 3.5 Hz, 1H), 2.01 (p, J = 6.3 Hz, 2H), 1.87 (dp, J = 18.4, 6.1 Hz, 5H), 1.61 (s, 6H). LC / MS (ESI+) calcd for C 43 H 50 NO 10 S ([M+H] + ) m / z: 843.3; found 843.3.

[0084] Example 20: N-(4-((4-(2-(4-(3-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propoxy)propoxy)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.0 Hz, 1H), 8.13 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 5.0 Hz, 1H), 7.16 - 7.11 (m, 2H), 7.09 - 7.02 (m, 2H), 6.93 (d, J = 2.1 Hz, 1H), 6.86 - 6.80 (m, 2H), 6.78 - 6.63 (m, 3H), 5.05 (s, 2H), 4.91 (dd, J = 12.1, 5.2 Hz, 1H), 4.20 (dd, J = 8.2, 6.3 Hz, 2H), 3.62 - 3.41 (m, 11H), 3.31 (t, J = 6.2 Hz, 2H), 2.94 - 2.69 (m, 3H), 2.15 - 2.07 (m, 1H), 2.07 - 1.98 (m, 2H), 1.87 (dp, J = 18.8, 6.1 Hz, 5H), 1.62 (s, 6H). LC / MS (ESI+) calcd for C 43 H 50 NO 10 S ( [M+H] + ) m / z: 843.3; found 843.3.

[0085] Example 21: N-(4-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.0 Hz, 1H), 8.01 (s, 1H), 7.48 (dd, J = 8.5, 7.1 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.07 (dd, J = 7.8, 3.5 Hz, 3H), 6.89 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.6 Hz, 2H), 6.26 (s, 1H), 5.05 (s, 2H), 4.93 - 4.87 (m, 1H), 4.14 - 4.05 (m, 2H), 3.53 - 3.36 (m, 7H), 3.30 (s, 2H), 2.89 - 2.73 (m, 3H), 2.11 (d, J = 5.3 Hz, 1H), 1.75 - 1.69 (m, 4H), 1.62 (s, 6H), 1.42 (d, J = 5.0 Hz, 2H), 1.32 (d, J = 6.4 Hz, 10H). LC / MS (ESI+) calcd for C 46 H 56 N6O9S ([M+H] + ) m / z: 869.4; found 869.4.

[0086] Example 22: N-(4-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.09 - 7.03 (m, 2H), 6.94 (d, J = 2.1 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.79 - 6.65 (m, 3H), 5.05 (s, 2H), 4.92 (dd, J = 12.0, 5.1 Hz, 1H), 4.13 - 4.02 (m, 2H), 3.63 (d, J = 6.7 Hz, 1H), 3.51 - 3.39 (m, 6H), 3.23 (t, J = 6.5 Hz, 2H), 2.89 - 2.67 (m, 3H), 2.15 - 2.08 (m, 1H), 1.73 (dd, J = LC / MS (ESI+) calcd for C 46 H 56 N6O9S ([M+H] + ) m / z: 869.4; found 869.4.

[0087] Example 23: N-(4-((4-(2-(4-((7-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)propoxy)heptyloxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 17. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.0 Hz, 1H), 8.08 (s, 1H), 7.48 (dd, J = 8.6, 7.1 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.16 - 7.11 (m, 2H), 7.11 - 7.02 (m, 3H), 6.91 (d, J = 8.5 Hz, 1H), 6.88 - 6.80 (m, 2H), 6.76 - 6.67 (m, 2H), 6.43 (s, 1H), 5.05 (s, 2H), 4.90 (dd, J = 12.1, 5.3 Hz, 1H), 4.15 - 4.05 (m, 2H), 3.75 (s, 1H), 3.56 - 3.48 (m, 5H), 3.48 (s, 3H), 3.38 (t, J = 6.7 Hz, 4H), 2.92 - 2.71 (m, 3H), 2.16 - 2.08 (m, LC / MS (ESI+) calcd for C 47 H 58 NO 10 S ( [M+H] + ) m / z: 899.4; found 899.4.

[0088] Example 24: N-(4-((4-(2-(4-((7-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propoxy)propoxy)heptyloxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.0 Hz, 1H), 8.09 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 7.16 - 7.10 (m, 2H), 7.10 - 7.02 (m, 2H), 6.94 (d, J = 1.9 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.71 (dd, J = 8.1, 6.0 Hz, 3H), 5.05 (s, 2H), 4.92 (dd, J = 12.0, 5.1 Hz, 1H), 4.14 - 4.03 (m, 2H), 3.57 (t, J = 5.4 Hz, 2H), 3.51 (dt, J = 8.6, 6.3 Hz, 4H), 3.40 (t, J = 6.6 Hz, 2H), 3.32 (t, J = 6.2 Hz, 2H), 2.91 - 2.70 (m, 3H), 2.11 (dd, J = 8.5, 6.0 Hz, 1H), 1.88 (dq, J = 18.9, 6.1 Hz, 4H), 1.62 (s, 6H), 1.56 (d, J = 6.6 Hz, 2H), 1.42 (d, J = 5.4 Hz, 2H), 1.32 - 1.26 (m, 6H).LC / MS (ESI+) calcd for C 47 H 58 NO 10 S ([M+H] + ) m / z: 899.4; found 899.4.

[0089] Example 25: N-(4-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide [ka] Step 1: Synthesis of N-methyl-N-(4-((4-(2-(4-(triphenylmethoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide N-(4-((4-(2-(4-(triphenylmethoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (328 mg, 1 mmol), iodomethane (142 mg, 1 mmol), and potassium carbonate (276 mg, 2 mmol) were added to 3 mL of DMF in this order and reacted overnight at room temperature. After monitoring the complete reaction by TLC, the mixture was extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 248 mg of the target compound. The yield was 73%. Step 2: Synthesis of N-(4-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide The compound N-methyl-N-(4-((4-(2-(4-(triphenylmethoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (248 mg, 0.73 mmol) was dissolved in 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was concentrated and purified using a chromatography column to obtain 136 mg of the target compound. The yield was 88%. The subsequent steps were carried out in a similar manner to that described in Example 1 to prepare the target compound. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.0 Hz, 1H), 7.99 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 7.18 - 7.06 (m, 4H), 6.95 (s, 1H), 6.87 - 6.75 (m, 4H), 6.75 - 6.68 (m, 1H), 5.07 (s, 2H), 4.92 (dd, J = 12.1, 5.2 Hz, 1H), 3.91 (t, J = 6.5 Hz, 2H), 3.54 (s, 3H), 3.49 (s, 3H), 3.44 (dt, J = 13.2, 6.3 Hz, 4H), 3.24 (t, J = 6.4 Hz, 2H), 2.88 - 2.67 (m, 3H), 2.12 (dd, J = 8.4, 5.9 Hz, 1H), 1.74 (dq, J = 13.8, 6.7 Hz, 8H), 1.63 (s, 6H), 1.42 (d, J = 5.0 Hz, 2H), 1.34 (s, 6H). LC / MS (ESI+) calcd for C 47 H 58 N6O9S ( [M+H] + ) m / z: 883.4; found 883.4.

[0090] Example 26: N-(4-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)acetamide [ka] The target compound was prepared using a method similar to that described in Example 1. 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 28.7 Hz, 2H), 7.59 (d, J = 7.7 Hz, 1H), 7.19 - 7.07 (m, 4H), 6.94 (s, 1H), 6.83 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 7.9 Hz, 1H), 5.08 (s, 2H), 4.93 (d, J = 11.2 Hz, 1H), 3.91 (t, J = 6.4 Hz, 2H), 3.45 (dt, J = 13.1, 6.0 Hz, 4H), 3.24 (s, 2H), 2.81 (dt, J = 44.5, 16.5 Hz, 3H), 2.47 (s, 3H), 2.11 (d, J = 10.9 Hz, 1H), 1.74 (dq, J = 13.5, 6.5 Hz, 8H), 1.63 (s, 6H), 1.34 (d, J = 6.1 Hz, 6H), 1.30 - 1.28 (m, 2H). LC / MS (ESI+) calcd for C 47 H 56 NO([M+H] + ) m / z: 833.4; found 833.4.

[0091] Example 27: 5-((4-((8-(4-(2-(4-((2-(1,1-dioxyisothiazolidin-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: 2-(4-((4-(2-(4-(triphenylmethoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)isothiazoline 1,1-dioxide 60% sodium hydride (80 mg, 2 mmol) was dissolved in 10 mL of DMF, and 1,1-dioxoisothiazole (242 mg, 2 mmol) was added in an ice bath. The mixture was stirred at room temperature for 10 min. 2-Chloro-4-((4-(2-(4-(triphenylmethoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidine (1.2 g, 2 mmol) was added, and the mixture was gradually heated to 70 °C and reacted overnight. After completion of the reaction was monitored by TLC, the reaction was quenched with saturated ammonium chloride in an ice bath. The mixture was extracted three times with 10 mL of ethyl acetate, washed with saturated brine (3 × 4 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 370 mg of the target compound. The yield was 27%. The subsequent steps were carried out in a similar manner to that described in Example 1 to prepare the target compound. 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 5.1 Hz, 1H), 7.17 - 7.06 (m, 4H), 6.94 (d, J = 2.0 Hz, 1H), 6.87 - 6.75 (m, 4H), 6.72 (dd, J = 8.4, 2.0 Hz, 1H), 5.06 (s, 2H), 4.92 (dd, J = 12.1, 5.2 Hz, 1H), 4.05 (t, J = 6.5 Hz, 2H), 3.91 (t, J = 6.5 Hz, 2H), 3.52 - 3.36 (m, 6H), 3.24 (t, J = 6.6 Hz, 2H), 2.91 - 2.68 (m, 3H), 2.50 (p, J = 7.0 Hz, 2H), 2.14 - 2.08 (m, 1H), 1.73 (dt, J = 14.3, 7.0 Hz, 6H), 1.62 (s, 6H), 1.58 (d, J = 6.8 Hz, 2H), 1.42 (dd, J = 6.6, 4.1 Hz, 2H), 1.34 (s, 6H). LC / MS (ESI+) calcd for C 48 H58 N6O9( [M+H] + ) m / z: 895.4; found 895.4.

[0092] Example 28: 5-((4-((8-(4-(2-(4-((2-aminopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of 4-((4-(2-(4-(triphenylmethoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-amine 2-Chloro-4-((4-(2-(4-(triphenylmethoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidine (1.8 g, 3 mmol) was dissolved in 5 mL of absolute ethanol, 2.5 mL of aqueous ammonia was added, and the mixture was allowed to react overnight in a sealed environment, gradually heated to 90°C. After monitoring for complete reaction by TLC, the mixture was extracted three times with 10 mL of ethyl acetate, washed with saturated brine (3 × 4 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 530 mg of the target compound. The yield was 31%. The subsequent steps were carried out in a similar manner to that described in Example 1 to prepare the target compound. 1H NMR (400 MHz, CDCl3) δ 8.65 - 8.03 (m, 2H), 7.59 (d, J = 7.3 Hz, 1H), 7.21 - 7.00 (m, 6H), 6.78 (td, J = 19.9, 18.3, 8.4 Hz, 7H), 4.94 (d, J = 21.6 Hz, 3H), 3.91 (t, J = 6.0 Hz, 2H), 3.45 (dt, J = 13.1, 6.1 Hz, 4H), 3.24 (s, 2H), 2.83 (dd, J = 36.7, 17.3 Hz, 3H), 1.81 - 1.69 (m, 6H), 1.62 (s, 6H), 1.49 - 1.40 (m, 4H), 1.33 (d, J = 8.6 Hz, 6H). LC / MS (ESI+) calcd for C 45 H 54 N6O7( [M+H] + ) m / z: 791.4; found 791.4.

[0093] Example 29: N-(4-((4-(2-(4-(3-(4-((1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] Step 1: Synthesis of tert-butyl 4-(3-bromopropyl)piperazine-1-carboxylate Piperazine-1-tert-butylformate (1.8 g, 10 mmol), 1,3-dibromopropane (1.0 g, 5 mmol), and potassium carbonate (2.76 g, 20 mmol) were added sequentially to 20 mL of DMF and reacted overnight at room temperature. After monitoring the complete reaction by TLC, the mixture was extracted with 20 mL of ethyl acetate, washed with saturated brine (3 × 20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 870 mg of the target compound in a 57% yield. Step 2: Synthesis of tert-butyl 4-(3-(4-(2-(4-(4-((2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)piperazine-1-carboxylate N-(4-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (413 mg, 1 mmol), tert-butyl 4-(3-bromopropyl)piperazine-1-carboxylate (306 mg, 1 mmol), potassium carbonate (276 mg, 2 mmol), and sodium iodide (7.5 mg, 0.05 mmol) were added sequentially to 4 mL of DMF, heated to 60 °C, and reacted overnight. After complete reaction was monitored by TLC, the mixture was allowed to cool to room temperature, extracted with 4 mL of ethyl acetate, washed with saturated brine (3 × 4 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 539 mg of the target compound. The yield was 84%. Step 3: Synthesis of N-(4-((4-(2-(4-(3-(piperazin-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide The compound tert-butyl 4-(3-(4-(2-(4-(4-((2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)piperazine-1-carboxylate (539 mg, 0.84 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After completion of the reaction was monitored by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 385 mg of the desired compound in an 85% yield. Step 4: Synthesis of tert-butyl (3-(4-(3-(4-(4-(2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)piperazin-1-yl)methyl)piperidin-1-yl)propyl)carbamate The compound N-(4-((4-(2-(4-(3-(piperazin-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (385 mg, 0.7 mmol) was dissolved in 10 mL of dichloromethane, and tert-butyl (3-(4-formylpiperidin-1-yl)propyl)carbamate (190 mg, 0.7 mmol) and glacial acetic acid (4 mg, 0.07 mmol) were added, followed by stirring at room temperature for 10 min. Sodium triacetylborohydride (190 mg, 1.4 mmol) was added, and the mixture was stirred at room temperature overnight. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated ammonium chloride solution in an ice bath. The mixture was extracted with dichloromethane (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 190 mg of the target compound. The yield was 34%. Step 5: Synthesis of N-(4-((4-(2-(4-(3-(3-aminopropyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide The compound (3-(4-(3-(4-(4-(2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)piperazin-1-yl)methyl)piperidin-1-yl)propyl) tert-butyl carbamate (190 mg, 0.24 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After completion of the reaction was confirmed by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 124 mg of the target compound. The yield was 74%. Step 6: Synthesis of N-(4-((4-(2-(4-(3-(4-((1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide N-(4-((4-(2-(4-(3-(3-aminopropyl)piperidin-4-yl)methyl)piperazin-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (124 mg, 0.18 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (50 mg, 0.18 mmol), and DIPEA (70 mg, 0.54 mmol) were added sequentially to 5 mL of DMSO, heated to 90 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 18 mg of the target compound. The yield was 11%. 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 5.1 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 7.10 (dd, J = 25.5, 8.3 Hz, 4H), 6.92 (s, 1H), 6.80 (dd, J = 21.6, 8.4 Hz, 4H), 6.55 (s, 1H), 5.01 (s, 2H), 4.96 - 4.88 (m, 1H), 4.17 (d, J = 8.6 Hz, 2H), 3.48 (s, 3H), 3.34 (s, 2H), 3.20 (s, 2H), 2.92 - 2.67 (m, 5H), 2.46 (s, 8H), 2.15 (d, J = 34.5 Hz, 6H), 1.99 (s, 4H), 1.84 (d, J = 13.3 Hz, 2H), 1.62 (s, 6H), 1.42 (d, J = 5.5 Hz, 4H). LC / MS (ESI+) calcd for C 50 H 63 N9O8S( [M+H] + ) m / z: 950.5; found 950.5.

[0094] Example 30: N-(4-((4-(2-(4-((8-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that of Example 29. 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 8.54 (d, J = 5.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.15 - 7.01 (m, 4H), 6.95 (s, 1H), 6.87 - 6.76 (m, 2H), 6.76 - 6.66 (m, 2H), 6.46 (dd, J = 8.3, 2.1 Hz, 1H), 5.05 (s, 2H), 4.92 (dd, J = 12.0, 5.3 Hz, 1H), 4.18 - 3.95 (m, 6H), 3.48 (s, 7H), 2.90 - 2.67 (m, 3H), 2.62 - 2.42 (m, 2H), 2.16 - 2.05 (m, 1H), 1.70 (d, J = 7.5 Hz, 2H), 1.61 (s, 6H), 1.43 - 1.30 (m, 4H). LC / MS (ESI+) calcd for C 47 H 55 N7O8S ( [M+H] + ) m / z: 878.4; found 878.4.

[0095] Example 31: N-(6-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrazin-2-yl)methanesulfonamide [ka] Step 1: Synthesis of 2-chloro-6-(chloromethyl)pyrazine 2-Chloro-6-methylpyrazine (6 g, 50 mmol) was dissolved in 100 mL of carbon tetrachloride, NCS (6.65 g, 51 mmol) and BPO (1.21 g, 5 mmol) were added, and the mixture was refluxed for 24 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by chromatography to obtain 2.8 g of the desired compound. The yield was 35%. Step 2: Synthesis of tert-butyl (4-((8-(4-(2-(4-((6-chloropyrazin-2-yl)methoxy)phenyl)propyl-2-yl)phenoxy)octyl)oxy)butylcarbamate tert-Butyl (3-((8-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)octyl)oxy)propyl)carbamate (1.05 g, 2 mmol), 2-chloro-4-(chloromethyl)pyrimidine (320 mg, 2 mmol), and potassium carbonate (552 mg, 4 mmol) were added to 10 mL of DMF in this order and reacted overnight at room temperature. After monitoring the complete reaction by TLC, the mixture was extracted with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 400 mg of the target compound. The yield was 31%. Step 3: Synthesis of tert-butyl (4-((8-(4-(2-(4-((6-(methylsulfamido)pyrazin-2-yl)methoxy)phenyl)propyl-2-yl)phenoxy)octyl)oxy)carbamate The compound (4-((8-(4-(2-(4-((6-chloropyrazin-2-yl)methoxy)phenyl)propyl-2-yl)phenoxy)octyl)oxy)butylcarbamate (400 mg, 0.61 mmol), methylsulfonamide (115 mg, 1.22 mmol), Pd2(dba)3 (55 mg, 0.061 mmol), XantPhos (69 mg, 0.12 mmol), and cesium carbonate (590 mg, 1.8 mmol) were added to 5 mL of dioxane. The reaction mixture was purged with helium and incubated at 110 °C overnight. After completion of the reaction was monitored by TLC, the reaction mixture was filtered through diatomaceous earth, concentrated, and purified by chromatography to obtain 150 mg of the desired compound in a 35% yield. Step 4: Synthesis of N-(6-((4-(2-(4-((8-(4-aminobutoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrazin-2-yl)methylsulfonamide The compound (4-((8-(4-(2-(4-((6-(methylsulfamido)pyrazin-2-yl)methoxy)phenyl)propyl-2-yl)phenoxy)octyl)oxy) tert-butyl carbamate (150 mg, 0.21 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After completion of the reaction was monitored by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 77 mg of the desired compound. The yield was 60%. Step 5: Synthesis of N-(6-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrazin-2-yl)methanesulfonamide N-(6-((4-(2-(4-((8-(4-aminobutoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrazin-2-yl)methylsulfonamide (77 mg, 0.12 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (33 mg, 0.12 mmol), and DIPEA (60 mg, 0.45 mmol) were added to 5 mL of DMSO in this order, heated to 90°C, and reacted overnight. The mixture was then allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 x 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 8 mg of the target compound. The yield was 8%. LC / MS (ESI+) calculation for C 46 H 56 N6O9S( [M+H] + ) m / z: 869.4; found 869.4.

[0096] Example 32: N-(2-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-4-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 31. LC / MS (ESI+) calculation for C 46 H 56 N6O9S ( [M+H] + ) m / z: 869.4; found 869.4.

[0097] Example 33: N-(6-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyridin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 31. LC / MS (ESI+) calculation for C 47 H 57 N5O9S ( [M+H] + ) m / z: 868.4; found 868.4.

[0098] Example 34: N-(4-((4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] Step 1: Synthesis of tert-butyl 4-(4-(2-(4-((2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidine-1-carboxylate The compound N-(4-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (200 mg, 0.48 mmol) and tert-butyl 4-(p-tolyloxy)piperidine-1-carboxylate (189 mg, 0.53 mmol) were added to 10 mL of DMF, and CsCO (235 mg, 0.72 mmol) and KI (9 mg, 0.05 mmol) were further added, followed by stirring at 70°C for 2 h. After cooling to room temperature, a small amount of water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated NaCl solution, dried over anhydrous sodium sulfate, spun dry, and purified by column chromatography to obtain the compound tert-butyl 4-(4-(2-(4-((2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidine-1-carboxylate (134 mg, 0.22 mmol). The yield was 47%. LC / MS (ESI+) calculation for C31 H 40 N4O6S ( [M+H] + ) m / z 596.74; found 597.2. Step 2: Synthesis of N-(4-((4-(2-(4-(piperidin-4-oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide Compound tert-butyl 4-(4-(2-(4-((2-(methylsulfamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidine-1-carboxylate (134 mg, 0.22 mmol) was added to 2 mL of 1,4-dioxane and stirred in an ice bath. 2 mL of 4 M hydrochloric acid in dioxane was further added and stirred at room temperature for 15 min. The reaction mixture was adjusted to basicity with saturated NaHCO3 solution and extracted three times with DCM. The organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and spin-dried to obtain compound N-(4-((4-(2-(4-(piperidin-4-oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (96 mg, 0.19 mmol). The yield was 88%. LC / MS (ESI+) calculation for C 26 H 32 N4O4S ( [M+H] + ) m / z 496.63; found 497.1. Step 3: Synthesis of N-(4-((4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide N-(4-((4-(2-(4-(piperidin-4-oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (48 mg, 0.09 mmol) was dissolved in 5 mL of DMSO, and DIPEA (36 mg, 0.28 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (28 mg, 0.10 mmol) were added sequentially. The mixture was heated to 90°C under N gas protection and reacted overnight. The mixture was cooled to room temperature, quenched by adding water, extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, spin-dried, and purified by prep-TLC to obtain compound N-(4-((4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (16 mg, 0.02 mmol). The yield was 24%. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.44 (d, J = 4.9 Hz, 1H), 8.26 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.16 - 7.07 (m, 5H), 6.98 (d, J = 8.2 Hz, 1H), 6.92 - 6.88 (m, 3H), 5.07 (dd, J = 12.9, 5.3 Hz, 1H), 5.00 (s, 2H), 4.60 (s, 1H), 3.79 (s, 2H), 3.14 (s, 3H), 2.88 (s, 2H), 2.04 - 1.96 (m, 3H), 1.66 (d, J = 7.8 Hz, 3H), 1.58 (d, J = 2.6 Hz, 6H), 1.42 - 1.31 (m, 2H). LC / MS (ESI+) calcd for C 39 H 40 N6O8S ([M+H] + ) m / z 752.84; found 753.2.

[0099] Example 35: N-(4-((4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that of Example 34. 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.26 (s, 1H), 7.72 - 7.66 (m, 1H), 7.36 (d, J = 4.5 Hz, 1H), 7.12 (t, J = 9.4 Hz, 5H), 7.00 (d, J = 5.4 Hz, 1H), 6.90 (t, J = 7.7 Hz, 3H), 5.10 (dd, J = 13.0, 5.3 Hz, 1H), 5.03 (s, 2H), 4.56 (s, 1H), 3.20 (s, 3H), 2.60 (s, 2H), 2.06 (s, 3H), 1.81 (s, 3H), 1.58 (s, 6H), 1.45 - 1.29 (m, 2H). LC / MS (ESI+) calcd for C 39 H 40 N6O8S ( [M+H] + ) m / z 752.84; found 753.2.

[0100] Example 36: N-(4-((4-(2-(4-((1-(4-(4-(4-)((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)butyl)piperidin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 34. LC / MS (ESI+) calculation for C 47 H 57 N7O9S1( [M+H] + ) m / z 896.07; found 896.8.

[0101] Example 37: N-(4-((4-(2-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 34. LC / MS (ESI+) calculation for C 37 H 39 N6O8S + ([M+H] + ) m / z: 727.2; found 727.2. 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 5.0 Hz, 1H), 7.14 (dd, J = 15.0, 8.6 Hz, 4H), 6.96 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 17.2, 8.6 Hz, 4H), 6.75 (d, J = 8.1 Hz, 1H), 5.16 - 5.03 (m, 2H), 4.92 (dd, J = 12.0, 5.3 Hz, 1H), 4.14 - 4.02 (m, 2H), 3.60 - 3.47 (m, 2H), 3.46 (s, 2H), 2.91 (d, J = 14.6 Hz, 1H), 2.81 - 2.69 (m, 2H), 2.63 (s, 3H), 2.12 (s, 3H), 1.64 (d, J = 2.4Hz, 6H).

[0102] Example 38: N-(4-((4-(2-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 34. LC / MS (ESI+) calculation for C 39 H 43 N6O8S + ([M+H] + ) m / z: 755.3; found 755.2. 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.14 (dd, J = 11.7, 8.5 Hz, 4H), 6.97 (s, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.6 Hz, 1H), 5.09 (s, 2H), 4.93 (dd, J = 12.0, 5.2 Hz, 1H), 3.96 (t, J = 6.1 Hz, 2H), 3.45 (s, 3H), 3.27 (t, J = 6.8 Hz, 2H), 2.94 - 2.85 (m, 1H), 2.82 - 2.70 (m, 2H), 2.22 (t, J = 7.7 Hz, 1H), 2.12 (d, J = 7.0 Hz, 1H), 2.01 (d, J = 7.0 Hz, 1H), 1.83 (t, J = 6.9 Hz, 2H), 1.73 (s, 2H), 1.63 (s, 6H)

[0103] Example 39: N-(4-((4-(2-(4-((1r,4r)-4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonyl-7-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)pyrimidin-2-yl)methanesulfonamide [ka] Step 1: Synthesis of N-(4-((4-(2-(4-((1r,4r)-4-((tert-butyldimethylsilyloxy)methyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide. In a 25 mL recovery flask, compound N-(4-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (300.0 mg, 0.7 mmol), Cs2CO3 (354.0 mg, 1.1 mmol), and KI (12.0 mg, 0.07 mmol) were added to 4 mL of DMF. The mixture was heated to 70 °C and stirred overnight. After cooling to room temperature, ethyl acetate and water were added for extraction. The organic layer was washed with saturated brine, dried, spun dry, and purified using a large preparative plate. Compound N-(4-((4-(2-(4-((1r,4r)-4-((tert-butyldimethylsilyloxy)methyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (100.0 mg, 0.15 mmol) was obtained. The yield was 21%. Step 2: N-(4-((4-(2-(4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide. In a 25 mL recovery flask, compound N-(4-((4-(2-(4-((1r,4r)-4-((tert-butyldimethylsilyloxy)methyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (100.0 mg, 0.15 mmol) was added to 2 mL of THF, and 0.3 mL of TBAF (1 M, 0.3 mmol) was added. The mixture was stirred at room temperature overnight. Ethyl acetate and water were added for extraction, and the organic layer was washed with saturated brine, dried, spin-dried, and purified using a large preparative plate. Compound N-(4-((4-(2-(4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (40.0 mg, 0.07 mmol) was obtained. The yield was 49%. Step 3: Synthesis of N-(4-((4-(2-(4-((1r,4r)-4-formylcyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide. In a 25 mL recovery flask, compound N-(4-((4-(2-(4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (40.0 mg, 0.07 mmol) was added to 2 mL of dichloromethane, and PCC (32.0 mg, 0.14 mmol) was added. The mixture was stirred at room temperature for 2 h, extracted with dichloromethane and water, and the organic layer was washed with saturated brine, dried, spin-dried, and purified using a large preparative plate. Compound N-(4-((4-(2-(4-((1r,4r)-4-formylcyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (25.0 mg, 0.04 mmol) was obtained in a 63% yield. Step 4: Synthesis of N-(4-((4-(2-(4-((1r,4r)-4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonyl-7-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)pyrimidin-2-yl)methanesulfonamide. In a 25 mL recovery flask, the compound N-(4-((4-(2-(4-((1r,4r)-4-formylcyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (25.0 mg, 0.04 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindole-1,3-dione (22.0 mg, 0.04 mmol), and sodium borohydride acetate (29.0 mg, 0.12 mmol) were added to 2 mL of dichloromethane, and acetic acid (3.0 mg, 0.08 mmol) was added. The mixture was stirred overnight at room temperature, extracted with dichloromethane and saturated sodium carbonate, and the organic layer was washed with saturated brine, dried, spin-dried, and purified using a large preparative plate. Compound N-(4-((4-(2-(4-((1r,4r)-4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonyl-7-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)pyrimidin-2-yl)methanesulfonamide (20 mg, 0.02 mmol) was obtained. The yield was 43%. LC / MS (ESI+) calculation for C 55 H 69 N8O8S + ([M1 / 2+H] + ) m / z: 501.3; found 501.4. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.1 Hz, 1H), 7.61 (dd, J = 17.1, 8.0 Hz, 1H), 7.10 (dd, J = 15.2, 8.0 Hz, 5H), 6.90 (d, J = 8.5 Hz, 2H), 6.84 - 6.71 (m, 3H), 6.63 (t, J = 8.1 Hz, 1H), 5.07 (s, 3H), 3.77 - 3.67 (m, 6H), 3.29 (s, 3H), 2.89 (dd, J = 22.1, 9.3 Hz, 5H), 2.64 - 2.52 (m, 2H), 2.37 - 2.25 (m, 4H), 2.13 (dd, J = 20.8, 6.7 Hz, 5H), 1.97 (dd, J = 22.6, 10.7 Hz, 4H), 1.84 - 1.73 (m, 7H), 1.57 (s, 6H), 1.18 - 0.99 (m, 6H), 0.86 (d, J= 11.1 Hz, 2H).

[0104] Example 40: N-(4-((4-(2-(4-((1-(3-(3-)((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propoxy)propyl)piperidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 39. LC / MS (ESI+) calculation for C 46 H 56 N7O9S + ( [M+H] + ) m / z: 882.4; found 882.3.

[0105] Example 41: N-(4-((4-(2-(4-((1-(4-(4-)((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)butyl)piperidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 39. LC / MS (ESI+) calculation for C 48 H 60 N7O9S + ([M+H] + ) m / z: 910.4; found 910.3

[0106] Example 42: N-(4-(2-(4-(4-((1-((1r,4r)-4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonyl-7-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 39. LC / MS (ESI+) calculation for C 55 H 69 N8O8S + ([M1 / 2+H] + ) m / z: 501.2; found 501.4. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 5.1 Hz, 1H), 7.61 (dd, J = 17.2, 8.3 Hz, 1H), 7.11 (dt, J = 14.4, 7.8 Hz, 6H), 6.90 (d, J = 8.5 Hz, 2H), 6.83 - 6.75 (m, 3H), 6.64 (d, J = 8.3 Hz, 1H), 5.11 - 5.00 (m, 3H), 3.74 (q, J = 6.9, 6.3 Hz, 6H), 2.89 (dd, J = 20.7, 8.9 Hz, 5H), 2.61 - 2.52 (m, 2H), 2.37 - 2.20 (m, 5H), 2.09 (dd, J = 20.2, 6.7 Hz, 4H), 2.03 - 1.86 (m, 5H), 1.74 (t, J = 11.1 Hz, 10H), 1.57 (s, 6H), 1.41 (d, J = 18.3Hz, 4H).

[0107] Example 43: N-(4-((4-(2-(4-((1r,4r)-4-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] In a 25 mL recovery flask, the compound N-(4-((4-(2-(4-((1r,4r)-4-formylcyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (14.0 mg, 26.0 μmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (11.0 mg, 26.0 μmol) were added to 2 mL of dichloromethane, and a catalytic amount of acetic acid was added. The mixture was stirred at room temperature overnight. The mixture was spin-dried in vacuo and purified using a preparative silica gel plate. A yellow solid, N-(4-((4-(2-(4-((1r,4r)-4-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxyisoquinolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (11 mg, 11.4 μmol) was obtained. The yield was 44%. LC / MS (ESI+) calculation for C 52 H 65 N8O8S + ([M+H] + ) m / z: 961.5; found 961.5. 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.54 (d, J = 5.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.14 - 7.05 (m, 6H), 6.95 - 6.88 (m, 3H), 6.84 (d, J = 9.2 Hz, 1H), 6.79 (d, J = 8.3 Hz, 2H), 5.03 (d, J = 16.1 Hz, 3H), 3.74 (d, J = 5.8 Hz, 2H), 3.26 (s, 3H), 3.23 - 3.11 (m, 8H), 2.95 - 2.82 (m, 5H), 2.57 (s, 2H), 2.31 (d, J = 8.4 Hz, 3H), 1.95 (dt, J = 23.1, 9.0 Hz, 5H), 1.79 - 1.62 (m, 6H), 1.56 (s, 6H), 1.50 - 1.45 (m, 4H).

[0108] Example 44: N-(4-(4-(2-(4-((8-(4-)((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)ethanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 39. LC / MS (ESI+) calculation for C 47 H 59 N6O9S + ([M1 / 2+H] + ) m / z: 442.2; found 442.1. 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.8 Hz, 1H), 8.09 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.15 (dd, J = 10.6, 6.7 Hz, 3H), 7.07 (d, J = 8.1 Hz, 2H), 6.99 (s, 1H), 6.83 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.4 Hz, 3H), 5.04 (s, 2H), 4.98 - 4.88 (m, 1H), 4.09 - 4.01 (m, 2H), 3.77 (q, J = 7.2 Hz, 2H), 3.45 (dt, J = 13.0, 6.2 Hz, 4H), 3.24 (s, 2H), 2.94 - 2.74 (m, 3H), 2.11 (d, J = 8.8 Hz, 1H), 1.72 (d, J = 24.2 Hz, 6H), 1.62 (s, 6H), 1.57 (s, 2H), 1.34 (d, J = 7.3 Hz, 11H)

[0109] Example 45: N-(4-((4-(2-(4-((1-((1r,4r)-4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 39. LC / MS (ESI+) calculation for C 52 H 64 N8O8S + ([M1 / 2+H] + ) m / z: 481.3; found 481.3. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.1 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.15 (d, J = 8.7 Hz, 2H), 7.07 - 7.03 (m, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 5.10 (s, 2H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 4.04 (d, J = 6.9 Hz, 2H), 3.59 (s, 13H), 3.29 (s, 4H), 3.00 (q, J = 7.3 Hz, 1H), 2.91 - 2.81 (m, 2H), 2.80 - 2.72 (m, 2H), 2.65 (d, J = 6.5 Hz, 2H), 1.91 - 1.81 (m, 8H), 1.62 (s, 6H),1.12 - 0.81 (m, 8H)

[0110] Example 46: N-(4-((4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azacyclobutan-3-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 34. LC / MS (ESI+) calculation for C 37 H 36 N6O8S ( [M+H] + ) m / z: 724.2; found 723.3. 1H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.90 (dd, J = 7.4, 1.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.22 (dd, J = 7.5, 1.6 Hz, 1H), 7.16 (ddd, J = 7.7, 6.3, 1.4 Hz, 5H), 6.93 - 6.81 (m, 4H), 5.50 (t, J = 7.0 Hz, 1H), 5.22 - 5.06 (m, 2H), 4.73 (p, J = 7.0 Hz, 1H), 4.09 (dd, J = 12.4, 7.1 Hz, 2H), 3.97 (dd, J = 12.5, 7.1 Hz, 2H), 3.08 (s, 3H), 2.67 - 2.52 (m, 2H), 2.25 - 2.04 (m, 2H), 1.62 (s, 6H).

[0111] Example 47: Synthesis of N-(4-((4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azacyclobutan-3-yl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 34. LC / MS (ESI+) calculation for C 37 H 36 N6O8S ( [M+H] + ) m / z: 724.2; found 723.3. 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 1.4 Hz, 1H), 7.21 - 7.11 (m, 6H), 6.93 - 6.83 (m, 4H), 5.45 (t, J = 7.0 Hz, 1H), 5.22 - 5.08 (m, 2H), 4.73 (p, J = 7.0 Hz, 1H), 4.09 - 3.87 (m, 4H), 3.08 (s, 3H), 2.68 - 2.55 (m, 2H), 2.24 - 2.02 (m, 2H), 1.62 (s, 6H).

[0112] Example 48: N-(4-((4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azacyclobutan-3-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 34. LC / MS (ESI+) Calcd for C 38 H 36 N6O8S (M+H + ) m / z, 738.3;found 738.3.

[0113] Example 49: N-(4-((4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azacyclobutan-3-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 34. LC / MS (ESI+) Calcd for C 38 H36 N6O8S (M+H + ) m / z, 738.3;found 738.3.

[0114] Example 50: N-(4-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino))butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)cyclopropanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 34. LC / MS (ESI+) calculation for C 48 H 58 N6O9S + ([M+H] + ) m / z: 894.4; found 894.3. 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.8 Hz, 1H), 8.09 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.15 (dd, J = 10.6, 6.7 Hz, 3H), 7.05 (d, J = 8.1 Hz, 2H), 6.99 (s, 1H), 6.81 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.4 Hz, 3H), 5.04 (s, 2H), 4.98 - 4.88 (m, 1H), 4.09 - 4.01 (m, 2H), 3.77 (q, J = 7.2 Hz, 2H), 3.45 (dt, J = 13.0, 6.2 Hz, 4H), 3.24 (s, 2H), 2.94 - 2.74 (m, 3H), 2.11 (d, J = 8.8 Hz, 1H), 1.72 (d, J = 24.2 Hz, 6H), 1.62 (s, 6H), 1.57 (s, 2H), 1.43 (d, J = 7.3 Hz, 11H)

[0115] Example 51: N-(5-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino))butoxy)octyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared and obtained using a method similar to that of Example 34. LC / MS (ESI+) calculation for C 46 H 56 N6O9S + ([M+H] + ) m / z: 868.4; found 868.3. 1 H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 4.8 Hz, 1H), 8.08 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.15 (dd, J = 10.6, 6.7 Hz, 3H), 7.07 (d, J = 8.1 Hz, 2H), 6.99 (s, 1H), 6.83 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.4 Hz, 3H), 5.04 (s, 2H), 4.98 - 4.88 (m, 1H), 4.09 - 4.01 (m, 2H), 3.45 (dt, J = 13.0, 6.2 Hz, 4H), 3.24 (s, 2H), 2.94 - 2.74 (m, 3H), 2.11 (d, J = 8.8 Hz, 1H), 1.72 (d, J = 24.2 Hz, 6H), 1.62 (s, 6H), 1.57 (s, 2H), 1.34 (d, J = 7.3Hz, 11H)

[0116] Example 52: N-(4-((4-(2-(4-((5-(3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methoxy)propoxy)pentyl)oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide [ka] The target compound was prepared using a method similar to that of Example 29. 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.0 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 5.0 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.09 - 7.02 (m, 2H), 6.93 (d, J = 2.2 Hz, 1H), 6.89 - 6.79 (m, 2H), 6.78 - 6.68 (m, 2H), 6.66 (dd, J = 8.5, 2.3 Hz, 1H), 5.05 (s, 2H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 4.14 - 4.04 (m, 2H), 3.57 - 3.44 (m, 10H), 3.44 - 3.36 (m, 4H), 3.21 (dd, J = 10.2, 6.7 Hz, 1H), 2.92 - 2.60 (m, 4H), 2.21 - 2.08 (m, 2H), 1.92 - 1.69 (m, 6H), 1.40 (dq, J = 10.0, 7.1 Hz, 2H). LC / MS (ESI+) calcd for C 47 H 56 NO 10 S ( [M+H] + ) m / z: 897.4; found 897.4.

[0117] Example 53: N-(4-((4-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide [ka] Step 1: Synthesis of ethyl 2-((tert-butoxycarbonyl)amino)methanesulfonate N-Boc-ethanolamine (2000 mg, 12.41 mmol) was weighed and placed in a single-neck round-bottom flask. Dichloromethane (30 mL) was added and stirred at room temperature to dissolve and clarify the mixture. Triethylamine (3767 mg, 37.23 mmol) was then added. After completion, the mixture was transferred to an ice-water bath, cooled, and stirred. After 15 min, 10 mL of a dichloromethane solution containing methanesulfonyl chloride (1706 mg, 14.89 mmol) was added dropwise to the mixture. The mixture was then stirred at room temperature. After 4 h, the reaction was monitored for completion by TLC. The reaction was then terminated and extracted with dichloromethane and water. The organic phase was washed with saturated ammonium chloride, then with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product, which was purified by column chromatography to yield the desired product (2100 mg, 71%) as an off-white solid. Step 2: Synthesis of tert-butyl (2-(4-(2-(4-((2-(methylsulfonamino)pyrimidin-4-yl)methoxy)phenyl)isopropyl-2-yl)phenoxy)ethyl)carbamate N-(4-((4-(2-(4-hydroxyphenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamino (230 mg, 0.56 mmol), ethyl 2-((tert-butoxycarbonyl)amino)methanesulfonate (90 mg, 0.84 mmol), potassium iodide (93 mg, 0.56 mmol), and cesium carbonate (274 mg, 0.84 mmol) were added to 6 mL of DMF, and the system was then evacuated and argon gas was introduced three times. After completion, the system was heated to 60°C and the reaction was stirred. The next day, after TLC monitoring confirmed that the raw material had been consumed, the mixture was stopped from heating, cooled to room temperature, and extracted with ethyl acetate and water. The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a crude product. This was separated and purified by prep-TLC to obtain the desired product (115 mg, 37%) as an off-white solid. LC / MS (ESI + ) calcd for C 28 H 36 N4O6S ([M-55] + ) m / z, 556.2; found, 501.1. Step 3: Synthesis of N-(4-((4-(2-(4-(2-aminoethoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide The compound tert-butyl (2-(4-(2-(4-((2-(methylsulfonamino)pyrimidin-4-yl)methoxy)phenyl)isopropyl-2-yl)phenoxy)ethyl)carbamate (115 mg, 0.21 mmol) was dissolved in 1 mL of 1,4-dioxane and then transferred to an ice-water bath to cool and stir. After 10 min, a solution of hydrogen chloride in dioxane (2 mL) was added. After completion, the system was allowed to cool to room temperature and react. After 30 min, TLC monitoring confirmed the completion of the reaction. The solvent was removed by rotary evaporation, and the remaining dioxane was removed by several rotations using dichloromethane to obtain the hydrochloride salt of the desired product as an off-white solid, which was used directly in the next reaction without further purification. Step 4: Synthesis of compound N-(4-((4-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide N-(4-((4-(2-(4-(2-aminoethoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide hydrochloride (0.21 mmol) from the previous step, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (88 mg, 0.32 mmol), and sodium bicarbonate (62 mg, 0.74 mmol) were added to 5 mL of dry dimethyl sulfoxide. The system was then evacuated and then argon gas was introduced, which was repeated three times. Upon completion, the system was transferred to a 100 °C oil bath and the reaction was stirred. After 4.5 h, TLC showed essentially complete consumption of the starting material. The mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic layer was washed successively with saturated ammonium chloride, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was then purified by prep-TLC to obtain the desired product (16 mg, 10%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 8.63 (d, J = 5.0 Hz, 1H), 7.96 (s, 1H), 7.50 (dd, J = 8.4, 7.1 Hz, 1H), 7.27 (d, J = 5.0 Hz, 1H),7.20 - 7.03 (m, 6H), 6.86 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 5.13 (s, 2H), 4.87 (dd, J = 12.1, 5.3 Hz, 1H), 4.33 (t, J = 6.6 Hz, 2H), 3.68 (t, J = 6.5 Hz, 2H), 3.53 (s, 3H), 3.11 (br, 1H), 2.89 - 2.62 (m, 4H), 2.09 (ddd, J = 8.3, 6.5, 3.8 Hz, 1H), 1.63 (s, 6H).LC / MS (ESI + ) calcd for C 36 H 36 N6O8S ([M+H] + ) m / z, 712.2; found, 713.2.

[0118] Example 54: N-(4-((4-(2-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)butoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide [ka] It was prepared using a method similar to that of Example 53. 1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 5.0 Hz, 1H), 8.06 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 7.17 - 7.11 (m, 2H), 7.09 - 7.03 (m, 2H), 6.96 (d, J = 1.9 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.73 (td, J = 7.7, 6.7, 2.1 Hz, 3H), 5.05 (s, 2H), 4.92 (dd, J = 12.2, 5.3 Hz, 1H), 4.19 - 4.07 (m, 2H), 3.53 - 3.36 (m, 7H), 3.22 (t, J = 6.8 Hz, 2H), 2.92 - 2.66 (m, 3H), 2.15 - 2.08 (m, 1H), 1.90 - 1.80 (m, 3H), 1.75 (dt, J = 13.5, 6.6 Hz, 3H), 1.67 (dt, J = 14.9, 6.7 Hz, 4H), 1.62 (s, 6H). LC / MS (ESI + ) calcd for C 42 H 48 N6O9S ([M+H] + ) m / z, 812.3; found, 813.3.

[0119] Example 55: N-(4-((4-(2-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butoxy)butoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide [ka] It was prepared using a method similar to that of Example 53. 1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 5.0 Hz, 1H), 8.11 (s, 1H), 7.47 (dd, J = 8.5, 7.2 Hz, 1H), 7.19 (d, J = 5.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.10 - 7.02 (m, 3H), 6.87 (d, J = 8.6 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 5.05 (s, 2H), 4.91 (dd, J = 12.0, 5.3 Hz, 1H), 4.20 - 4.07 (m, 2H), 3.55 - 3.39 (m, 7H), 3.28 (t, J = 6.6 Hz, 2H), 2.92 - 2.66 (m, 3H), 2.11 (dt, J = 9.8, 3.3 Hz, 1H), 2.01 (dd, J = 11.9, 6.2 Hz, 1H), 1.82 (dt, J = 14.9, 7.8 Hz, 3H), 1.76 - 1.63 (m, 6H), 1.62 (s, 6H). LC / MS (ESI + ) calcd for C 42 H 48 N6O9S ([M+H] + ) m / z, 812.3; found, 813.3.

[0120] Example 56: N-(4-((4-(2-(4-(((1r,4r)-4-(((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)oxy)methyl)cyclohexyl)methoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide [ka] Step 1: Synthesis of (((1r,4r)-4-(((5-bromopentyl)oxy)methyl)cyclohexyl)methoxy)(tert-butyl)dimethylsilane ((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methanol (1082 mg, 4.19 mmol) was weighed and added to a single-neck round-bottom flask, and DMF (10 mL) was added. The mixture was stirred at room temperature to dissolve and clarify. The mixture was then transferred to an ice-water bath, cooled, and stirred. After 15 min, sodium hydride (201 mg, 5.03 mmol) was added to the mixture, and the mixture was kept in an ice-water bath for 10 min. 2 mL of a DMF solution of 1,5-dibromopentane (1060 mg, 4.61 mmol) was added to the mixture. After completion, the mixture was stirred at room temperature. After 3 h, the disappearance of the starting material was monitored by TLC. In an ice-water bath, saturated ammonium chloride solution was added to the system to quench the reaction, and then ethyl acetate and water were added to complete the extraction operation. The organic phase was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a crude product, which was separated and purified by column chromatography to obtain the target product (512 mg, 30%) as a colorless, transparent oily liquid. Step 2: Synthesis of 2-(5-(((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methoxy)pentyl)isoindoline-1,3-dione (((1r,4r)-4-(((5-bromopentyl)oxy)methyl)cyclohexyl)methoxy)(tert-butyl)dimethylsilane (500 mg, 1.23 mmol) was weighed and placed in a single-neck round-bottom flask. DMF (12 mL) was added and stirred at room temperature to dissolve and clarify the mixture. Potassium iodide (204 mg, 1.23 mmol) and potassium phthalimide (228 mg, 1.23 mmol) were added to the mixture, and the mixture was evacuated and argon gas was introduced into the mixture, repeating this procedure three times. The mixture was then left overnight in an 80°C oil bath. The next day, the completion of the reaction was monitored by TLC. After the heating was stopped, the mixture was cooled to room temperature, and ethyl acetate and water were added for extraction. The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was then purified by column chromatography to obtain the target product (428 mg, 74%) as an off-white solid. LC / MS (ESI + ) calcd for C 27 H 43 NO4Si ([M+H] + ) m / z, 473.3; found, 474.3. Step 3: Synthesis of 2-(5-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)pentyl)isoindoline-1,3-dione 2-(5-(((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methoxy)pentyl)isoindoline-1,3-dione (428 mg, 0.90 mmol) was added to 10 mL of THF and stirred at room temperature to dissolve and clarify. TBAF.HO (706 mg, 2.70 mmol) was added to the system, and the system was stirred overnight at room temperature while evacuating and introducing argon gas. This procedure was repeated three times. The next day, the completion of the reaction was monitored by TLC. The system was extracted with ethyl acetate and water. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to remove the solvent to obtain the crude product. This crude product was purified by prep-TLC to obtain the desired product (140 mg, 43%) as an off-white solid. Step 4: Synthesis of methyl ((1r,4r)-4-(((5-(1,3-dioxoisoindolin-2-yl)pentyl)oxy)methyl)cyclohexyl)methanesulfonate 2-(5-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)pentyl)isoindoline-1,3-dione (140 mg, 0.39 mmol) was weighed and dissolved in 5 mL of dichloromethane. Triethylamine (52 mg, 0.51 mmol) and DMAP (5 mg, 0.04 mmol) were added to the mixture, which was then transferred to an ice-water bath for cooling and stirring. After 15 min, methanesulfonyl chloride (49 mg, 0.43 mmol) was added. Upon completion, the mixture was stirred at room temperature. After 2.5 h, TLC showed that the starting material had disappeared. Dichloromethane and water were added to the mixture to complete the extraction, which was then dried over anhydrous sodium sulfate and rotary evaporated to remove the solvent, yielding the desired product (171 mg) as an off-white solid. This was used directly in the next reaction without further purification. Step 5: Synthesis of N-(4-((4-(2-(4-(((1r,4r)-4-(((5-(1,3-dioxopiperidin-2-yl)pentyl)oxy)methyl)cyclohexyl)methoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide Methyl ((1r,4r)-4-(((5-(1,3-dioxoisoindolin-2-yl)pentyl)oxy)methyl)cyclohexyl)methanesulfonate (171 mg, 0.39 mmol), N-(4-((4-(2-(4-hydroxyphenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (128 mg, 0.31 mmol), potassium carbonate (108 mg, 0.78 mmol), and potassium iodide (98 mg, 0.59 mmol) were added to 5 mL of DMF. The system was evacuated and then re-introduced with argon gas three times. The system was then transferred to a 75 °C oil bath and stirred overnight. After 17 h, the reaction was monitored for completion by TLC. The mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was purified by prep-TLC to obtain the desired product (78 mg, 33%) as an off-white solid. LC / MS (ESI + ) calcd for C 42 H 50 N4O7S ([M+H] + ) m / z, 754.3; found, 755.3. Step 6: Synthesis of N-(4-((4-(2-(4-(((1r,4r)-4-(((5-aminopentyl)oxy)methyl)cyclohexyl)methoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide N-(4-((4-(2-(4-(((1r,4r)-4-(((5-(1,3-dioxopiperidin-2-yl)pentyl)oxy)methyl)cyclohexyl)methoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (78 mg, 0.10 mmol) was dissolved in 5 mL of ethanol, and then hydrazine hydrate (54 mg, 1.00 mmol) was added. The reaction mixture was refluxed in an oil bath at 85° C. After 2 h, TLC showed that the raw material had been completely consumed. The mixture was cooled to room temperature, and suction filtered. The filter cake was eluted with small portions of ethanol several times. The filtrates were combined and rotary evaporated to remove the solvent, yielding a crude product. Dichloromethane was added to the mixture, which was then stirred in an ice-water bath. After 30 min, the mixture was subjected to suction filtration, and the filter cake was eluted with small amounts of dichloromethane several times. The filtrates were combined and rotary evaporated to remove the solvent, yielding the desired product (58 mg, 89%) as an off-white solid. Step 7: Synthesis of N-(4-((4-(2-(4-(((1r,4r)-4-(((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)oxy)methyl)cyclohexyl)methoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide N-(4-((4-(2-(4-(((1r,4r)-4-(((5-aminopentyl)oxy)methyl)cyclohexyl)methoxy)phenyl)isopropyl-2-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide (58 mg, 0.09 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (30 mg, 0.11 mmol), and DIPEA (233 mg, 1.80 mmol) were added to 8 mL of dry dimethyl sulfoxide. The system was then evacuated and then argon gas was introduced, which was repeated three times. Upon completion, the system was transferred to a 90°C oil bath and the reaction was stirred. The next day, TLC showed essentially complete consumption of the starting material. The mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic layer was washed successively with saturated ammonium chloride, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was then purified by prep-TLC to obtain the target product (15 mg, 18%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J = 4.0 Hz, 1H), 8.07 (s, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.14 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.96 (s, 1H), 6.84 (d, J = 8.3 Hz, 2H), 6.73 (d, J = 8.3 Hz, 3H), 5.05 (s, 2H), 4.93 (dd, J = 11.7, 5.1 Hz, 1H), 4.01 (d, J = 6.6 Hz, 2H), 3.50 (s, 3H), 3.41 (t, J = 5.6 Hz, 2H), 3.21 (d, J = 6.0 Hz, 4H), 2.98 - 2.61 (m, 4H), 2.28 - 2.19 (m, 1H), 2.17 - 2.08 (m, 2H), 2.01 (dd, J = 11.8, 7.2 Hz, 1H), 1.78 (t, J = 13.0 Hz, 6H), 1.71 - 1.65 (m, 2H),1.63 (s, 6H), 1.53 - 1.44 (m, 3H), 1.10 - 0.96 (m, 3H).LC / MS (ESI + ) calcd for C 47 H 56 N6O9S ([M+H] + ) m / z, 880.4; found, 881.2.

[0121] Example 57: N-(4-((4-(3-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)pentyl-3-yl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide [ka] The target compound was prepared and obtained using a method similar to that in Example 1. LC / MS (ESI + ) calcd for C48 H 60 N6O9S([M+H] + ) m / z, 896.4; found, 897.2.

[0122] Example 58: N-(4-((4-(1-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyl)oxy)phenyl)cyclobutyl)phenoxy)methyl)pyrimidin-2-yl)methylsulfonamide [ka] It was prepared using a method similar to that in Example 1. 1 H NMR (400 MHz, Chloroform-d) δ 8.62 (d, J = 15.1 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.25 - 7.10 (m, 6H), 6.94 (s, 1H), 6.82 (dd, J = 19.3, 8.6 Hz, 4H), 6.71 (d, J = 8.0 Hz, 1H), 5.38 - 5.32 (m, 1H), 5.07 (s, 2H), 4.92 (dd, J = 12.0, 5.1 Hz, 1H), 3.89 (t, J = 6.4 Hz, 2H), 3.56 - 3.31 (m, 7H), 3.24 (p, J = 6.1 Hz, 2H), 2.94 - 2.55 (m, 8H), 2.27 - 2.18 (m, 1H), 2.16 - 2.07 (m, 1H), 2.02 (dt, J = 11.8, 6.2 Hz, 2H), 1.94 (dt, J = 14.8, 7.5 Hz, 3H), 1.78 - 1.56 (m, 12H). LC / MS (ESI + ) calcd for C 47 H 56 N6O9S ([M+H] + ) m / z, 879.4; found, 880.3.

[0123] Example 59: 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(2-(4-(2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl (3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)propyl)carbamate Bisphenol A (11.4 g, 50 mmol), 3-((tert-butoxycarbonyl)amino)propyl methanesulfonate (12.6 g, 50 mmol), and cesium carbonate (32.5 g, 100 mmol) were added sequentially to 200 mL of DMF, heated to 60 °C, and reacted overnight. After complete reaction was monitored by TLC, the mixture was cooled to room temperature, extracted with 200 mL of ethyl acetate, washed with saturated brine (3 × 100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 11.1 g of the target compound. The yield was 58%. Step 2: Synthesis of tert-butyl (3-(4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)carbamate tert-Butyl (3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)propyl)carbamate (3.85 g, 10 mmol), 2-chloro-4-(chloromethyl)pyrimidine (1.62 g, 10 mmol), and potassium carbonate (2.76 g, 20 mmol) were added to 30 mL of DMF in this order and reacted overnight at room temperature. After monitoring the complete reaction by TLC, the mixture was extracted with 20 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 4.05 g of the target compound. The yield was 79%. Step 3: Synthesis of tert-butyl (3-(4-(2-(4-((2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)carbamate tert-Butyl (3-(4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)carbamate (102 mg, 0.2 mmol), morpholine (35 mg, 0.4 mmol), and potassium carbonate (56 mg, 0.4 mmol) were added to 1 mL of DMF in this order, heated to 60°C, and reacted overnight. After complete reaction was monitored by TLC, the mixture was allowed to cool to room temperature, extracted with 1 mL of ethyl acetate, washed with saturated brine (3 × 1 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 88 mg of the target compound. The yield was 78%. Step 4: Synthesis of (3-(4-(2-(4-((2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-1-amine The compound (3-(4-(2-(4-((2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl) tert-butyl carbamate (88 mg, 0.16 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 52 mg of the target compound. The yield was 70%. Step 5: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(2-(4-(2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione (3-(4-(2-(4-((2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-1-amine (52 mg, 0.11 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (33 mg, 0.12 mmol), and DIPEA (43 mg, 0.33 mmol) were added sequentially to 5 mL of DMSO, heated to 130 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to give 6 mg of the final product. The yield was 7.6%. 1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.14 (s, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.11 (dd, J = 18.1, 7.6 Hz, 5H), 6.92 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.2 Hz, 4H), 6.77 (s, 1H), 6.46 (d, J = 5.9 Hz, 1H), 4.94 (s, 2H), 4.90 (d, J = 4.5 Hz, 1H), 4.07 (t, J = 5.6 Hz, 2H), 3.80 (d, J = 17.9 Hz, 8H), 3.50 (d, J = 6.2 Hz, 2H), 3.00 - 2.62 (m, 3H), 2.18 - 2.03 (m, 3H), 1.63 (s, 6H). LC / MS (ESI+) calcd for C 40 H 42 N6O7( [M+H] + ) m / z: 719.3; found 719.3.

[0124] Example 60: 2-(2,6-dioxopiperidin-3-yl)-4-((3-(4-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 59. 1 H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.29 (d, J = 5.0 Hz, 1H), 7.46 (dd, J = 8.5, 7.1 Hz, 1H), 7.16 - 7.10 (m, 4H), 7.08 (d, J = 7.1 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.86 - 6.79 (m, 4H), 6.71 (d, J = 5.0 Hz, 1H), 6.45 (t, J = 5.8 Hz, 1H), 4.92 (s, 2H), 4.91 - 4.87 (m, 1H), 4.06 (t, J = 5.6 Hz, 2H), 3.89 (t, J = 4.9 Hz, 4H), 3.50 (q, J = 6.3 Hz, 2H), 2.91 - 2.71 (m, 3H), 2.55 (t, J = 5.2 Hz, 4H), 2.38 (s, 3H), 2.14 - 2.09 (m, 3H), 1.62 (s, 6H). LC / MS (ESI+) calcd for C 41 H 45 N7O6( [M+H] + ) m / z: 732.4; found 732.4.

[0125] Example 61: 5-((4-((8-(4-(2-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of 4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenol Bisphenol A (2.28 g, 10 mmol), 2-chloro-4-(chloromethyl)pyrimidine (0.81 g, 5 mmol), and potassium carbonate (1.38 g, 10 mmol) were added sequentially to 20 mL of DMF and reacted overnight at room temperature. After monitoring the complete reaction by TLC, the mixture was extracted with 20 mL of ethyl acetate, washed with saturated brine (3 × 20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 0.65 g of the target compound in a 36% yield. Step 2: Synthesis of 4-(2-(4-((2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenol 4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenol (650 mg, 1.8 mmol), 2-oxa-6-azaspiro[3.3]heptane (200 mg, 2 mmol), and DIPEA (702 mg, 5.4 mmol) were added sequentially to 10 mL of DMSO and reacted at 80 °C overnight. After monitoring for complete reaction by TLC, the mixture was extracted with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 680 mg of the target compound. The yield was 90%. The subsequent steps were carried out in a similar manner to Example 59 to prepare the target compound. 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.12 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.18 - 7.08 (m, 4H), 6.95 (d, J = 2.1 Hz, 1H), 6.88 (s, 1H), 6.85 - 6.75 (m, 4H), 6.71 (dd, J = 8.3, 2.1 Hz, 1H), 4.97 (s, 2H), 4.95 - 4.84 (m, 5H), 4.40 (s, 4H), 3.91 (t, J = 6.5 Hz, 2H), 3.44 (dt, J = 13.2, 6.3 Hz, 4H), 3.24 (t, J = 6.6 Hz, 2H), 2.88 - 2.70 (m, 3H), 2.22 (t, J = 7.6 Hz, 1H), 1.72 (d, J = 7.5 Hz, 4H), 1.62 (s, 6H), 1.42 (d, J = 5.2 Hz, 4H), 1.34 (d, J = 5.5 Hz, 8H). LC / MS (ESI+) calcd for C 50 H 60 N6O8( [M+H] + ) m / z: 873.5; found 873.5.

[0126] Example 62: 5-((3-(3-((7-(4-(2-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)heptyl)oxy)propoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 59. 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.13 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.17 - 7.08 (m, 4H), 6.95 (d, J = 2.1 Hz, 1H), 6.90 (s, 1H), 6.86 - 6.75 (m, 4H), 6.71 (dd, J = 8.3, 2.2 Hz, 1H), 4.97 (s, 2H), 4.95 - 4.78 (m, 5H), 4.43 (s, 4H), 3.91 (t, J = 6.5 Hz, 2H), 3.58 (t, J = 5.5 Hz, 2H), 3.52 (dt, J = 8.4, 6.3 Hz, 4H), 3.41 (t, J = 6.7 Hz, 2H), 3.33 (t, J = 6.3 Hz, 2H), 2.92 - 2.72 (m, 3H), 2.22 (t, J = 7.6 Hz, 1H), 1.92 - 1.85 (m, 4H), 1.62 (s, 6H), 1.44 - 1.40 (m, 4H), 1.30 - 1.28 (m, 6H). LC / MS (ESI+) calcd for C 51 H 62 N6O9( [M+H] + ) m / z: 903.5; found 903.5.

[0127] Example 63: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((8-(4-(2-(2-(3-methylazacyclobutan-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 59. 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.10 (d, J = 11.7 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.11 (td, J = 16.2, 7.5 Hz, 4H), 6.94 (s, 2H), 6.86 - 6.68 (m, 5H), 5.07 - 4.86 (m, 3H), 4.50 (s, 2H), 3.91 (t, J = 6.6 Hz, 3H), 3.61 - 3.17 (m, 7H), 2.94 - 2.74 (m, 3H), 2.38 - 2.17 (m, 1H), 2.11 (t, J = LC / MS (ESI+) calcd for C 49 H 60 N6O7( [M+H] + ) m / z: 845.5; found 845.5.

[0128] Example 64: 2-(2,6-dioxopiperidin-3-yl)-5-((4-((8-(4-(2-(2-hydroxyethyl)(methyl)amino)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 59. 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.07 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 7.10 (t, J = 8.3 Hz, 4H), 6.95 (d, J = 2.1 Hz, 1H), 6.83 - 6.77 (m, 4H), 6.72 (dd, J = 8.3, 2.2 Hz, 1H), 5.06 (s, 2H), 4.92 (dd, J = 12.0, 5.2 Hz, 1H), 4.02 (d, J = 26.4 Hz, 4H), 3.91 (t, J = 6.5 Hz, 2H), 3.45 (dd, J = 11.8, 6.3 Hz, 4H), 3.37 (s, 3H), 3.24 (t, J = 6.6 Hz, 2H), 2.91 - 2.72 (m, 3H), 2.11 (dd, J = 12.2, 5.8 Hz, 1H), 1.73 (dq, J = 21.8, 7.0 Hz, 8H), 1.63 (s, 6H), 1.43 (d, J = 3.9 Hz, 2H), 1.34 (d, J = 5.4 Hz, 6H). LC / MS (ESI+) calcd for C 48 H 60 N6O8( [M+H] + ) m / z: 849.5; found 849.5.

[0129] Example 65: 5-((4-((8-(4-(2-(4-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)-5,8-dihydropyridine[3,4-d]pyrimidin-7(6H)-yl)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl 2-chloro-5,8-dihydropyridine[3,4-d]pyrimidine-7(6H)-carboxylate 2,4-Dichloro-5,8-dihydropyridine[3,4-d]pyrimidine-7(6H)-tert-butyl carboxylate (13 g, 42 mmol) was dissolved in 150 mL of absolute ethanol. Zinc powder (3.2 g, 50 mmol) and 30 mL of aqueous ammonia were added sequentially to the reaction mixture. The mixture was incubated at 80 °C overnight. After completion of the reaction was monitored by TLC, the mixture was filtered through diatomaceous earth, added with 100 mL of water, extracted twice with 100 mL of ethyl acetate, washed with 0.5 N hydrochloric acid (2 × 50 mL), saturated sodium bicarbonate solution (2 × 50 mL), and saturated brine (2 × 50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 9 g of the desired compound in 80% yield. Step 2: Synthesis of tert-butyl 2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)-5,8-dihydropyridine[3,4-d]pyrimidine-7(6H)-carboxylate tert-Butyl 2-chloro-5,8-dihydropyridine[3,4-d]pyrimidine-7(6H)-carboxylate (1 g, 3.7 mmol), 2-oxa-6-azaspiro[3.3]heptane (380 mg, 3.7 mmol), and DIPEA (1.3 g, 10 mmol) were added sequentially to 10 mL of DMSO and reacted at 80 °C overnight. After monitoring for complete reaction by TLC, the mixture was extracted with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 1.1 g of the desired compound in 90% yield. Step 3: Synthesis of 6-(5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-2-yl)-2-oxa-6-azaspiro[3.3]heptane The compound tert-butyl 2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)-5,8-dihydropyridine[3,4-d]pyrimidine-7(6H)-carboxylate (1.1 g, 3.3 mmol) was dissolved in 10 mL of dichloromethane and 5 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 800 mg of the desired compound. The yield was 99%. Step 4: Synthesis of 6-(7-(4-(2-(4-(4-methoxybenzyl)oxy)phenyl)propan-2-yl)phenyl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-2-yl)-2-oxo-6-azaspiro[3.3]heptane The compound 6-(5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (400 mg, 1.7 mmol), 4-(2-(4-((4-methoxybenzyl)oxy)phenyl)propan-2-yl)phenyl triflate (816 mg, 1.7 mmol), Pd(dba)2 (96 mg, 0.17 mmol), XPhos (161 mg, 0.34 mmol), and cesium carbonate (1.1 g, 3.4 mmol) were added to 10 mL of dioxane. The reaction mixture was purged with helium and incubated at 110 °C overnight. After monitoring for completeness by TLC, the reaction mixture was filtered through diatomaceous earth, concentrated, and purified by chromatography to obtain 700 mg of the desired compound. The yield was 73%. Step 5: Synthesis of 4-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)-5,8-dihydropyridine[3,4-d]pyrimidin-7(6H)-yl)phenyl)propan-2-yl)phenol The compound 6-(7-(4-(2-(4-(4-methoxybenzyl)oxy)phenyl)propan-2-yl)phenyl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-2-yl)-2-oxo-6-azaspiro[3.3]heptane (700 mg, 1.2 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was concentrated and purified using a chromatography column to obtain 190 mg of the target compound. The yield was 36%. The subsequent steps were carried out in a similar manner to Example 59 to prepare the target compound. 1 H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.20 - 7.07 (m, 4H), 6.97 (d, J = 19.3 Hz, 2H), 6.88 - 6.64 (m, 5H), 4.86 (s, 2H), 4.56 (s, 2H), 4.40 (s, 2H), 3.91 (d, J = 6.8 Hz, 2H), 3.85 (s, 2H), 3.76 (s, 2H), 3.57 (s, 2H), 3.44 (dd, J = 12.4, 6.0 Hz, 4H), 3.24 (s, 2H), 2.94 - 2.70 (m, 5H), 2.22 (t, J = LC / MS (ESI+) calcd for C 52 H 63 N7O7( [M+H] + ) m / z: 898.5; found 898.5.

[0130] Example 66: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl (3-(4-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)carbamate Tert-butyl (3-(4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)carbamate (511 mg, 1 mmol) and sodium methyl mercaptide (144 mg, 2 mmol) were added to 4 mL of DMF in this order, and the mixture was allowed to react overnight at room temperature. After monitoring the reaction was complete by TLC, the mixture was extracted with 4 mL of ethyl acetate, washed with saturated brine (3 × 4 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 400 mg of the target compound. The yield was 76%. Step 2: Synthesis of 3-(4-(2-(4-(2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-1-amine The compound (3-(4-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl) tert-butyl carbamate (150 mg, 0.28 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 104 mg of the target compound. The yield was 88%. Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione 3-(4-(2-(4-(2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-1-amine (104 mg, 0.24 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (66 mg, 0.24 mmol), and DIPEA (94 mg, 0.72 mmol) were added sequentially to 5 mL of DMSO, heated to 90 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 70 mg of the target compound. The yield was 43%. LC / MS (ESI+) calculation for C 37 H 37 N5O6S( [M+H] + ) m / z: 680.3; found 680.3.

[0131] Example 67: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-(4-(2-(methylsulfonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] 2-(2,6-Dioxopiperidin-3-yl)-5-((3-(4-(2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione (50 mg, 0.07 mmol) was dissolved in 5 mL of dichloromethane, and metachloroperbenzoic acid (24 mg, 0.14 mmol) was added in an ice-salt bath. The reaction was continued for 1 h in an ice-salt bath. The reaction was monitored by TLC for completeness, and the reaction was quenched with saturated sodium sulfite while maintaining an ice-salt bath. The mixture was extracted with 5 mL of dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography column to obtain 7 mg of compound 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-(4-(2-(methylsulfonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione. The yield was 14%. 1 H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 7.83 (d, J = 5.1 Hz, 1H), 7.21 - 7.11 (m, 4H), 6.97 (d, J = 2.1 Hz, 1H), 6.89 - 6.77 (m, 4H), 6.73 (dd, J = 8.3, 2.1 Hz, 1H), 5.26 (s, 2H), 4.93 (dd, J = 11.9, 5.2 Hz, 1H), 4.09 (t, J = 5.5 Hz, 2H), 3.46 (t, J = 6.5 Hz, 2H), 3.38 (s, 3H), 2.91 - 2.77 (m, 3H), 2.13 (t, J = 6.4 Hz, 3H), 1.64 (s, 6H). LC / MS (ESI+) calcd for C 37 H 37 N5O8S( [M+H] + ) m / z: 712.2; found 712.2.

[0132] Example 68: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-((2-methoxypyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 66. 1 H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 5.0 Hz, 1H), 8.07 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.19 (dd, J = 5.0, 0.8 Hz, 1H), 7.17 - 7.11 (m, 4H), 6.97 (d, J = 2.2 Hz, 1H), 6.87 - 6.79 (m, 4H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 5.06 (d, J = 0.7 Hz, 2H), 4.94 (d, J = 5.3 Hz, 1H), 4.13 - 4.05 (m, 2H), 4.02 (s, 3H), 3.46 (q, J = 6.2 Hz, 2H), 2.94 - 2.70 (m, 3H), 2.16 - 2.07 (m, 3H), 1.63 (s, 6H). LC / MS (ESI+) calcd for C 37 H 37 N5O7( [M+H] + ) m / z: 664.3; found 664.3.

[0133] Example 69: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-((2-ethoxypyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 66. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.08 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.15 (dd, J = 8.7, 2.3 Hz, 5H), 6.97 (d, J = 1.8 Hz, 1H), 6.83 (dd, J = 11.6, 8.6 Hz, 4H), 6.78 - 6.71 (m, 1H), 5.05 (s, 2H), 4.93 (dd, J = 12.1, 5.2 Hz, 1H), 4.44 (q, J = 7.0 Hz, 2H), 4.09 (t, J = 5.4 Hz, 2H), 3.46 (t, J = LC / MS (ESI+) calcd for C 38 H 39 N5O7( [M+H] + ) m / z: 678.3; found 678.3.

[0134] Example 70: 5-((3-(4-(2-(4-((2-cyclopropoxypyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 66. 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.07 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H), 7.15 (dd, J = 8.7, 2.1 Hz, 4H), 6.98 (d, J = 2.0 Hz, 1H), 6.91 - 6.77 (m, 4H), 6.78 - 6.70 (m, 1H), 5.06 (s, 2H), 4.93 (dd, J = 12.0, 5.2 Hz, 1H), 4.36 (d, J = 3.6 Hz, 1H), 4.09 (t, J = 5.4 Hz, 2H), 3.46 (t, J LC / MS (ESI+) calcd for C 39 H 39 N5O7( [M+H] + ) m / z: 690.3; found 690.3.

[0135] Example 71: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-((2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 61. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 5.0 Hz, 1H), 8.13 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.21 - 7.05 (m, 4H), 6.97 (d, J = 2.1 Hz, 1H), 6.89 - 6.78 (m, 4H), 6.78 - 6.71 (m, 2H), 4.98 - 4.89 (m, 3H), 4.08 (t, J = 5.5 Hz, 2H), 3.97 - 3.63 (m, 8H), 3.45 (d, J = 7.5 Hz, 2H), 2.92 - 2.66 (m, 3H), 2.13 (p, J = 7.6, 7.0 Hz, 3H), 1.63 (s, 6H). LC / MS (ESI+) calcd for C 40 H 42 N6O7( [M+H] + ) m / z: 719.3; found 719.3.

[0136] Example 72: 2-((2,6-dioxopiperidin-3-yl)-5-(3-(4-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 61. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 5.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.17 - 7.08 (m, 4H), 6.96 (d, J = 2.2 Hz, 1H), 6.81 (t, J = 8.6 Hz, 4H), 6.74 - 6.66 (m, 2H), 4.91 (s, 2H), 4.89 (d, J = 5.7 Hz, 1H), 4.07 (t, J = 5.5 Hz, 2H), 3.85 (t, J = 5.0 Hz, 4H), 3.43 (q, J = 6.2 Hz, 2H), 2.94 - 2.67 (m, LC / MS (ESI+) calcd for C 41 H 45 N7O6( [M+H] + ) m / z: 732.4; found 732.4.

[0137] Example 73: 5-((3-(4-(2-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 61. 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.10 (s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.14 (s, 4H), 6.98 (s, 1H), 6.82 (s, 4H), 6.76 (s, 1H), 4.94 (d, J = 29.0 Hz, 7H), 4.64 - 4.18 (m, 4H), 4.09 (s, 2H), 3.47 (s, 2H), 2.96 - 2.69 (m, 3H), 2.13 (s, 3H), 1.64 (s, 6H). LC / MS (ESI+) calcd for C 41 H 42 N6O7( [M+H] + ) m / z: 731.3; found 731.3.

[0138] Example 74: 5-((3-(4-(2-(4-((2-aminopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 61. 1 H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.30 (s, 1H), 7.55 (dd, J = 27.3, 8.3 Hz, 1H), 7.20 - 7.02 (m, 4H), 6.99 - 6.86 (m, 2H), 6.87 - 6.67 (m, 5H), 5.05 - 4.84 (m, 3H), 4.15 - 3.98 (m, 2H), 3.48 (dt, J = 19.3, 6.7 Hz, 2H), 2.95 - 2.67 (m, 3H), 2.16 - 2.05 (m, 3H), 1.62 (d, J = 2.7 Hz, 6H). LC / MS (ESI+) calcd for C 36 H 36 N6O6( [M+H] +) m / z: 649.3; found 649.3.

[0139] Example 75: 5-(((1r,3r)-3-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate Tert-butyl ((1r,3r)-3-(4-(2-(4-hydroxyphenyl)propyl-2-yl)phenoxy)cyclobutyl)carbamate (400 mg, 1 mmol), 2-chloro-4-(chloromethyl)pyrimidine (162 mg, 1 mmol), and potassium carbonate (276 mg, 2 mmol) were added to 5 mL of DMF in this order and reacted overnight at room temperature. After monitoring the reaction was complete by TLC, the mixture was extracted with 20 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 180 mg of the desired compound. The yield was 34%. Step 2: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate Tert-butyl ((1r,3r)-3-(4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (180 mg, 0.34 mmol), 2-oxa-6-azaspiro[3.3]heptane (35 mg, 0.34 mmol), and DIPEA (90 mg, 0.7 mmol) were added to 2 mL of DMSO in this order and reacted at 80 °C overnight. After monitoring for complete reaction by TLC, the mixture was extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 120 mg of the target compound. The yield was 60%. Step 3: Synthesis of (1r,3r)-3-(4-(2-(4-((2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine The compound ((1r,3r)-3-(4-(2-(4-((2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl) tert-butyl carbamate (120 mg, 0.2 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After completion of the reaction was monitored by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 60 mg of the target compound. The yield was 62%. Step 4: Synthesis of 5-(((1r,3r)-3-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1r,3r)-3-(4-(2-(4-((2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine (60 mg, 0.12 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (30 mg, 0.12 mmol), and DIPEA (52 mg, 0.4 mmol) were added sequentially to 5 mL of DMSO, heated to 90 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 20 mg of the target compound. The yield was 22%. 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.39 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.12 (dd, J = 8.5, 4.9 Hz, 4H), 6.96 - 6.77 (m, 4H), 6.69 (t, J = 8.6 Hz, 3H), 4.90 (d, J = 34.4 Hz, 7H), 4.49 (p, J = 7.0 Hz, 1H), 4.31 (s, 4H), 3.74 (q, J = 7.4 Hz, 1H), 3.10 (dt, J = 13.1, 6.8 Hz, 2H), 2.94 - 2.64 (m, 3H), 2.08 (p, J = 7.7, 7.3 Hz, 3H), 1.62 (s, 6H). LC / MS (ESI+) calcd for C 42 H 42 N6O7( [M+H] + ) m / z: 743.3; found 743.3.

[0140] Example 76: 5-(((1s,3s)-3-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 75. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.33 (d, J = 4.9 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 6.4 Hz, 1H), 7.15 - 7.03 (m, 4H), 6.89 (dd, J = 9.2, 2.3 Hz, 3H), 6.82 (dd, J = 8.3, 2.1 Hz, 1H), 6.76 (dd, J = 9.8, 3.5 Hz, 3H), 5.04 (dd, J = 13.0, 5.3 Hz, 1H), 4.95 (s, 2H), 4.71 (s, 4H), 4.48 (p, J = 7.1 Hz, 1H), 4.19 (s, 4H), 3.77 (q, J = 7.4 Hz, 1H), 3.14 - 2.98 (m, 2H), 2.87 (ddd, J = 17.3, 14.0, 5.4 Hz, 1H), 2.68 - 2.51 (m, 2H), 2.02 (d, J = 7.7 Hz, 1H), 1.95 (d, J = 9.9 Hz, 2H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 42 H 42 N6O7( [M+H] + ) m / z: 743.3; found 743.3.

[0141] Example 77: 5-((3-(4-(2-(4-((2-(2-oxy-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 61.1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.33 (d, J = 4.9 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 5.5 Hz, 1H), 7.16 - 7.06 (m, 4H), 6.98 (d, J = 2.1 Hz, 1H), 6.94 - 6.76 (m, 5H), 6.65 (d, J = 5.0 Hz, 1H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (s, 2H), 4.34 (s, 4H), 4.07 - 3.98 (m, 2H), 3.74 - 3.61 (m, 4H), 3.32 (d, J = 9.2 Hz, 2H), 2.87 (ddd, J = 17.4, 14.0, 5.4 Hz, 1H), 2.63 - 2.51 (m, 2H), 2.03 - 1.94 (m, 3H), 1.83 - 1.72 (m, 4H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 43 H 46 N6O7( [M+H] + ) m / z: 759.4; found 759.4.

[0142] Example 78: 5-((3-(4-(2-(4-((2-(2-oxy-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 75. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 5.5 Hz, 1H), 7.62 (dd, J = 8.2, 2.2 Hz, 1H), 7.13 (dd, J = 8.9, 5.8 Hz, 4H), 6.89 (dd, J = 9.5, 2.0 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.76 - 6.66 (m, 4H), 4.97 - 4.88 (m, 3H), 4.86 (s, 1H), 4.50 (s, 4H), 4.21 (s, 1H), 3.78 (t, J = 5.5 Hz, 4H), 3.18 - 3.05 (m, 1H), 2.92 - 2.64 (m, 4H), 2.40 (dd, J = 12.2, 6.3 Hz, 1H), 2.16 - 2.06 (m, 2H), 1.91 (t, J = 5.5 Hz, 4H), 1.63 (s, 6H). LC / MS (ESI+) calcd for C 44 H 46 N6O7( [M+H] + ) m / z: 771.4; found 771.4.

[0143] Example 79: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-((2-(7-methyl-2,7-diazaspiro[4.4]nonyl-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of 3-aminocyclobutan-1-ol trifluoroacetate The compound 3-hydroxycyclobutylamine-1-tert-butoxycarbonylamino (3.6 g, 20 mmol) was dissolved in 40 mL of dichloromethane, and 20 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 1 h. After monitoring the complete reaction by TLC, the reaction mixture was concentrated to give 4.1 g of the crude target compound. Step 2: Synthesis of 2-(3-hydroxycyclobutyl)isoindoline-1,3-dione The crude product, 3-aminocyclobutan-1-ol trifluoroacetate (4.1 g), phthalic anhydride (3 g, 20 mmol), and triethylamine (10 g, 100 mmol) were added to 50 mL of toluene in that order and reacted at 100°C overnight. After complete reaction was monitored by TLC, the reaction mixture was concentrated, 50 mL of water was added, extracted with ethyl acetate (2 x 50 mL), washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 3 g of the target compound. The overall yield for the two steps was 69%. Step 3: Synthesis of 2-(3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione The compound 2-(3-hydroxycyclobutyl)isoindoline-1,3-dione (3 g, 13.8 mmol), bisphenol A (3.1 g, 13.8 mmol), and triphenylphosphine (4 g, 15 mmol) were dissolved in 50 mL of tetrahydrofuran, and DIAD (3 g, 15 mmol) was added in an ice bath. The mixture was stirred for 0.5 h while maintaining the ice bath, and then reacted overnight at 65 °C. After monitoring the complete reaction by TLC, the reaction solvent was concentrated and purified using a chromatography column to obtain 12 g of the crude target compound. Step 4: Synthesis of 2-(3-(4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione The crude product, 2-(3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione, 2-chloro-4-(chloromethyl)pyrimidine (2.2 g, 13.8 mmol), and potassium carbonate (4.1 g, 30 mmol) were added sequentially to 100 mL of DMF and reacted overnight at room temperature. After completion of the reaction was monitored by TLC, the mixture was extracted with 100 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 3.1 g of the target compound. The overall yield of the two steps was 41%. Step 5: Synthesis of tert-butyl 7-(4-(2-(4-(4-(3-(1,3-dioxoisoindolin-2-yl)cyclobutoxy)phenyl)propan-2-yl)phenoxy)pyrimidin-2-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate 2-(3-(4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione (500 mg, 0.9 mmol), tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (226 mg, 1 mmol), and DIPEA (260 mg, 2 mmol) were added sequentially to 10 mL of DMSO and reacted at 80 °C overnight. After monitoring for complete reaction by TLC, the mixture was extracted with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 488 mg of the target compound. The yield was 73%. Step 6: Synthesis of 2-(3-(4-(2-(4-((2-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione tert-Butyl 7-(4-(2-(4-(4-(3-(1,3-dioxoisoindolin-2-yl)cyclobutoxy)phenyl)propan-2-yl)phenoxy)pyrimidin-2-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (288 mg, 0.38 mmol) was dissolved in 2 mL of dichloromethane and 1 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After completion of the reaction was monitored by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 204 mg of the target compound. The yield was 83%. Step 7: Synthesis of 2-(3-(4-(2-(4-((2-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione The compound 2-(3-(4-(2-(4-((2-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione (204 mg, 0.32 mmol) was dissolved in 5 mL of dichloromethane, and paraformaldehyde (270 mg, 3 mmol) and glacial acetic acid (2 mg, 0.03 mmol) were added. The mixture was stirred at room temperature for 10 min. Sodium triacetylborohydride (135 mg, 0.64 mmol) was added and the mixture was stirred at room temperature overnight. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated ammonium chloride solution in an ice bath. The mixture was extracted with dichloromethane (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 140 mg of the target compound. The yield was 66%. Step 8: Synthesis of 3-(4-(2-(4-((2-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine The compound 2-(3-(4-(2-(4-((2-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione (140 mg, 0.21 mmol) was dissolved in 5 mL of absolute ethanol, and hydrazine hydrate (32 mg, 1 mmol) was added and stirred at 80°C for 2 h. After monitoring the complete reaction by TLC, the reaction mixture was concentrated and purified using a chromatography column to obtain 92 mg of the target compound. The yield was 83%. Step 9: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-((2-(7-methyl-2,7-diazaspiro[4.4]nonyl-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione 3-(4-(2-(4-((2-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine (92 mg, 0.17 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (50 mg, 0.17 mmol), and DIPEA (70 mg, 0.5 mmol) were added sequentially to 5 mL of DMSO, heated to 90 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 15 mg of the target compound. The yield was 11%. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 5.0 Hz, 1H), 7.62 (dd, J = 8.3, 2.2 Hz, 1H), 7.12 (dt, J = 8.7, 1.9 Hz, 4H), 6.90 (dd, J = 9.7, 2.2 Hz, 1H), 6.87 - 6.79 (m, 2H), 6.75 - 6.63 (m, 4H), 4.93 (s, 2H), 4.91 (s, 2H), 3.68 - 3.50 (m, 4H), 3.20 - 3.05 (m, 1H), 2.91 - 2.61 (m, 7H), 2.46 (s, 3H), 2.38 (dd, J = 13.4, 6.3 Hz, 1H), 2.15 - 1.94 (m, 8H), 1.62 (s, 6H). LC / MS (ESI+) calcd for C 45 H 49 N7O6( [M+H] + ) m / z: 784.4; found 784.4.

[0144] Example 80: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] Prepared using a method similar to that of Example 79. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 5.0 Hz, 1H), 7.65 - 7.40 (m, 2H), 7.11 (t, J = 8.6 Hz, 4H), 6.94 - 6.65 (m, 6H), 5.03 (dd, J = 13.0, 5.4 Hz, 1H), 4.95 (s, 2H), 4.56 - 4.39 (m, 1H), 3.82 - 3.52 (m, 5H), 3.10 - 2.71 (m, 8H), 2.69 - 2.51 (m, 2H), 2.42 (s, 2H), 1.96 (q, J = 20.1, 15.4 Hz, 3H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 43 H 45 N7O6( [M+H] + ) m / z: 756.4; found 756.4.

[0145] Example 81: 5-(((1r,3r)-3-(4-(2-(4-((2-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 79. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.35 (d, J = 5.0 Hz, 1H), 7.57 (dd, J = 12.2, 6.9 Hz, 2H), 7.11 (t, J = 8.6 Hz, 4H), 6.94 - 6.68 (m, 6H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (s, 2H), 4.88 - 4.80 (m, 1H), 4.16 (d, J = 24.8 Hz, 1H), 3.52 (dd, J = 27.8, 10.2 Hz, 4H), 3.30 - 3.10 (m, 6H), 2.88 (dd, J = 22.4, 9.5 Hz, 1H), 2.70 - 2.53 (m, 2H), 2.47 - 2.31 (m, 3H), 1.98 (dqt, J = 20.4, 13.1, 7.3 Hz, 5H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 44 H 47 N7O6( [M+H] + ) m / z: 770.4; found 770.4.

[0146] Example 82: 5-(((1r,3r)-3-(4-(2-(4-((2-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 79. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 5.4 Hz, 1H), 7.66 - 7.39 (m, 2H), 7.10 (d, J = 8.4 Hz, 4H), 6.96 - 6.61 (m, 7H), 4.94 (s, 2H), 4.84 (d, J = 8.2 Hz, 1H), 4.47 (s, 1H), 4.15 (d, J = 29.4 Hz, 8H), 2.88 (dd, J = 20.5, 11.3 Hz, 2H), 2.63 (d, J = 30.5 Hz, 2H), 1.98 (s, 3H), 1.56 (s, 6H).LC / MS (ESI+) calcd for C 42 H 43 N7O6( [M+H] + ) m / z: 742.3; found 742.3.

[0147] Example 83: 5-(((1r,3r)-3-(4-(2-(4-((2-(2,6-diazaspiro[3.4]octyl-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 79. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 7.63 (t, J = 5.6 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.10 (t, J = 8.1 Hz, 4H), 6.93 - 6.83 (m, 3H), 6.84 - 6.67 (m, 4H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (d, J = 4.1 Hz, 2H), 4.89 (s, 1H), 4.13 (dp, J = 12.6, 5.5 Hz, 1H), 4.03 - 3.85 (m, 4H), 3.49 (q, J = 8.5, 7.7 Hz, 4H), 2.87 (ddd, J = 17.5, 14.0, 5.4 Hz, 1H), 2.64 - 2.51 (m, 2H), 2.43 (dt, J = 10.7, 6.2 Hz, 3H), 2.23 (t, J = 6.9 Hz, 2H), 2.13 - 1.89 (m, 2H), 1.56 (d, J = 5.6 Hz, 6H). LC / MS (ESI+) calcd for C 43 H 45 N7O6( [M+H] + ) m / z: 756.4; found 756.4.

[0148] Example 84: 5-(((1s,3s)-3-(4-(2-(4-((2-(2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 79. 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.34 (d, J = 4.9 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 6.6 Hz, 1H), 7.10 (t, J = 8.7 Hz, 4H), 6.90 - 6.87 (m, 2H), 6.82 (dd, J = 8.5, 2.1 Hz, 1H), 6.76 (dd, J = 9.5, 2.8 Hz, 2H), 6.67 (d, J = 4.9 Hz, 1H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (s, 2H), 4.48 (p, J = 6.9 Hz, 1H), 3.95 - 3.44 (m, 9H), 3.13 - 2.98 (m, 2H), 2.87 (ddd, J = 18.1, 14.0, 5.6 Hz, 1H), 2.65 - 2.51 (m, 2H), 1.97 (td, J = 11.5, 11.0, 4.1 Hz, 3H), 1.77 (t, J = 5.7 Hz, 4H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 44 H 47 N7O6( [M+H] + ) m / z: 770.4; found 770.4.

[0149] Example 85: 5-(((1s,3s)-3-(4-(2-(4-((2-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 79. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 5.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 6.6 Hz, 1H), 7.10 (t, J = 8.6 Hz, 4H), 6.94 - 6.85 (m, 3H), 6.82 (dd, J = 8.5, 2.1 Hz, 1H), 6.74 (dd, J = 13.4, 6.7 Hz, 3H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (s, 2H), 4.48 (p, J = 7.1 Hz, 1H), 3.78 (s, 4H), 3.10 - 2.99 (m, 2H), 2.95 - 2.79 (m, 5H), 2.69 - 2.51 (m, 2H), 1.96 (p, J = 9.7, 8.9 Hz, 3H), 1.82 (d, J = 5.7 Hz, 4H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 44 H 47 N7O6( [M+H] + ) m / z: 770.4; found 770.4.

[0150] Example 86: 5-(((1s,3s)-3-(4-(2-(4-((2-(2,6-diazaspiro[3.3]-((2-(2,6-heptan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 79. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.35 (d, J = 5.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 6.5 Hz, 1H), 7.10 (t, J = 8.6 Hz, 4H), 6.96 - 6.67 (m, 7H), 5.03 (dd, J = 12.8, 5.4 Hz, 1H), 4.95 (s, 2H), 4.48 (p, J = 6.9 Hz, 1H), 4.18 (d, J = 17.4 Hz, 8H), 3.78 (p, J = 7.7 Hz, 1H), 3.04 (ddd, LC / MS (ESI+) calcd for C 42 H 43 N7O6( [M+H] + ) m / z: 742.3; found 742.3.

[0151] Example 87: 5-(((1s,3s)-3-(4-(2-(4-((2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 76. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 6.4 Hz, 1H), 7.17 - 7.05 (m, 4H), 6.96 - 6.85 (m, 3H), 6.82 (dd, J = 8.4, 2.1 Hz, 1H), 6.79 - 6.69 (m, 2H), 6.67 (d, J = 5.0 Hz, 1H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.95 (s, 2H), 4.48 (p, J = 7.1 Hz, 1H), 3.86 - 3.74 (m, 3H), 3.58 - 3.42 (m, 6H), 3.18 - 3.00 (m, 2H), 2.92 - 2.81 (m, 1H), 2.69 - 2.52 (m, 2H), 2.00 - 1.83 (m, 7H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 44 H 46 N6O7( [M+H] + ) m / z: 771.4; found 771.4.

[0152] Example 88: 5-(((1s,3s)-3-(4-(2-(4-((2-(6-oxa-2-azaspiro[3.4]octyl-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 76. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 6.4 Hz, 1H), 7.10 (t, J = 8.5 Hz, 4H), 6.94 - 6.85 (m, 3H), 6.79 - 6.69 (m, 3H), 5.04 (dd, J = 12.9, 5.3 Hz, 1H), 4.95 (s, 2H), 4.48 (p, J = 7.0 Hz, 1H), 4.00 (s, 4H), 3.85 - 3.66 (m, 5H), 3.09 - 3.00 (m, 2H), 2.87 (ddd, J = 17.4, 14.0, 5.4 Hz, 1H), 2.63 - 2.51 (m, 2H), 2.14 (t, J = 6.9 Hz, 2H), 2.04 - 1.94 (m, 3H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 43 H 44 N6O7( [M+H] + ) m / z: 757.3; found 757.3.

[0153] Example 89: 5-(((1s,3s)-3-(4-(2-(4-((2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 76. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 6.4 Hz, 1H), 7.10 (t, J = 8.4 Hz, 4H), 6.93 - 6.85 (m, 3H), 6.82 (dd, J = 8.4, 2.1 Hz, 1H), 6.79 - 6.73 (m, 2H), 6.72 (d, J = 5.0 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (s, 2H), 4.48 (p, J = 7.0 Hz, 1H), 3.78 (s, 5H), 3.54 (t, J = 5.2 Hz, 4H), 3.10 - 3.01 (m, 2H), 2.87 (ddd, J = 17.4, 14.1, 5.5 Hz, 1H), 2.57 (dd, J = LC / MS (ESI+) calcd for C 44 H 46 N6O7( [M+H] + ) m / z: 771.4; found 771.4.

[0154] Example 90: 5-(((1s,3s)-3-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 76. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.59 (d, J = 10.2 Hz, 1H), 7.20 (dd, J = 6.8, 2.5 Hz, 1H), 7.14 - 7.07 (m, 4H), 7.05 (d, J = 7.2 Hz, 1H), 6.93 - 6.83 (m, 2H), 6.81 - 6.71 (m, 3H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.95 (s, 2H), 4.71 (s, 4H), 4.45 (p, J = 7.0 Hz, 1H), 4.19 (s, 4H), 3.85 (p, J = 7.5 Hz, 1H), 3.07 - 2.82 (m, 3H), 2.64 - 2.51 (m, 2H), 2.13 (q, J = 9.1 Hz, 2H), 2.06 - 1.99 (m, 1H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 42 H 41 FN6O7( [M+H] + ) m / z: 761.3; found 761.3.

[0155] Example 91: 3-(5-(((1s,3s)-3-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Step 1: Synthesis of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione Methyl 4-bromo-2-(bromomethyl)benzoate (3 g, 10 mmol), 3-amino-2,6-piperidinedione hydrochloride (1.65 g, 10 mmol), and DIPEA (2.6 g, 20 mmol) were dissolved in 30 mL of acetonitrile and reacted at 60 °C overnight. The mixture was allowed to cool to room temperature and then stirred in an ice bath for 1 h. The precipitated solid was filtered and washed with a small amount of cold acetonitrile to give 1.8 g of the desired compound. The yield was 56%. Step 2: Synthesis of 3-(5-(((1s,3s)-3-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione The compound (1s,3s)-3-(4-(2-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine (73 mg, 0.15 mmol), 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (48 mg, 0.15 mmol), (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (12 mg, 0.015 mmol), and cesium carbonate (100 mg, 0.3 mmol) were added to 2 mL of dioxane, and the reaction system was purged with a helium atmosphere and reacted at 110 °C overnight. After monitoring the reaction for completeness by TLC, the reaction mixture was filtered through diatomaceous earth, concentrated, and purified using a chromatography column to obtain 8 mg of the target compound. The yield was 7%. LC / MS (ESI+) calculation for C 42 H 44 N6O6([M+H] + ) m / z: 729.3; found 729.3.

[0156] Example 92: 3-(6-(((1s,3s)-3-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Step 1: Synthesis of methyl 5-bromo-2-(bromomethyl)benzoate Methyl 5-bromo-2-methylbenzoate (2.2 g, 10 mmol) was dissolved in 20 mL of carbon tetrachloride, NBS (1.8 g, 10 mmol) and BPO (242 mg, 1 mmol) were added, and the mixture was refluxed for 24 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by chromatography to obtain 2.4 g of the target compound. The yield was 80%. The subsequent steps were carried out in a similar manner to Example 91 to prepare the target compound. LC / MS (ESI+) calculation for C 42 H 44 N6O6([M+H] + ) m / z: 729.3; found 729.3.

[0157] Example 93: 3-(5-((1r,3r)-3-(4-(2-(4-((6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] 5-((1r,3r)-3-(4-(2-(4-((6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-ylphenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (35 mg, 0.05 mmol) was dissolved in 2 mL of glacial acetic acid, zinc powder (64 mg, 1 mmol) was added, and the reaction was carried out at 60°C for 2 h. Complete consumption of the starting material was monitored by TLC. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the resulting solution was purified with concentrated glacial acetic acid. The reaction was made weakly basic by adding saturated sodium bicarbonate, and extracted by adding 5 mL of ethyl acetate several times. The organic phases were combined and washed with saturated brine. The organic phase was dried and concentrated. The obtained solution was dissolved in 2 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid and triethylsilane (12 mg, 0.1 mmol) were added. The mixture was stirred at room temperature overnight, and the reaction was stopped upon monitoring by LC-MS that the hydroxy compound had been completely consumed. Most of the dichloromethane and trifluoroacetic acid were directly concentrated, saturated sodium bicarbonate was added to make the system weakly basic, and 5 mL of ethyl acetate was added several times to extract and dry the organic phases. The combined organic phases were concentrated and separated and purified using a chromatography column to obtain 11 mg of the compound 3-(5-((1r,3r)-3-(4-(2-(4-((6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. The yield was 32%. 1 H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.78 (m, 3H), 7.07 (m, 7H), 6.85 (m, 2H), 6.59 (m, 2H), 5.00 (m, 1H), 4.76 (s, 1H), 4.11 (m, 4H), 2.47 (m, 8H), 1.56 (s, 6H). LC / MS (ESI+) calcd for C 39 H 37 N7O5( [M+H]+ ) m / z: 684.3; found 684.3.

[0158] Example 94: 3-(6-(((1r,3r)-3-(4-(2-(4-((6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] The target compound was obtained during the preparation of Example 93. 1 H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.76 (s, 2H), 7.61 (t, J = 6.4 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.10 (dd, J = 8.6, 4.5 Hz, 2H), 7.06 - 6.87 (m, 4H), 6.82 (dd, J = 8.4, 4.4 Hz, 2H), 6.57 (dd, J = 8.6, 4.5 Hz, 2H), 5.08 - 4.96 (m, 1H), 4.83 (s, 1H), 4.38 - 3.93 (m, 4H), 2.69 (d, J = 14.2 Hz, 3H), 2.57 (s, 2H), 2.11 (d, J = 64.6 Hz, 3H), 1.53 (s, 6H). LC / MS (ESI+) calcd for C 39 H 37 N7O5( [M+H] + ) m / z: 684.3; found 684.3.

[0159] Example 95: 2-(2,6-dioxopiperidin-3-yl)-5-(((1r,3r)-3-(4-(2-(4-((5-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of 3-(4-(2-(4-((1r,3r)-3-(1,3-dioxoisoindolin-2-yl)cyclobutoxy)phenyl)propan-2-yl)phenoxy)-5-fluoropicolinonitrile 60% sodium hydride (88 mg, 2.2 mmol) was dissolved in 10 mL of DMF, and 2-((1r,3r)-3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione (854 mg, 2 mmol) was added in an ice bath. The mixture was stirred at room temperature for 10 min, and 3,5-difluoropicolinonitrile (280 mg, 2 mmol) was added. The mixture was gradually warmed to room temperature and allowed to react for 2 h. After monitoring complete reaction by TLC, the reaction was quenched with saturated ammonium chloride in an ice bath, extracted three times with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to give 470 mg of the desired compound in 43% yield. Step 2: Synthesis of 3-(4-(2-(4-((1r,3r)-3-aminocyclobutoxy)phenyl)propan-2-yl)phenoxy)-5-fluoropicolinic acid hydrochloride The compound 3-(4-(2-(4-((1r,3r)-3-(1,3-dioxoisoindolin-2-yl)cyclobutoxy)phenyl)propan-2-yl)phenoxy)-5-fluoropicolinonitrile (460 mg, 0.84 mmol) was dissolved in 5 mL of methanol, and concentrated hydrochloric acid (1 mL, 12 mmol) was added and reacted at 90°C overnight. After monitoring the complete reaction by TLC, the solvent was directly concentrated to give 380 mg of the target compound. The yield was 95%. Step 3: Synthesis of 3-(4-(2-(4-((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)-5-fluoropicolinic acid The compound 3-(4-(2-(4-((1r,3r)-3-aminocyclobutoxy)phenyl)propan-2-yl)phenoxy)-5-fluoropicolinic acid hydrochloride (380 mg, 0.8 mmol) was dissolved in 10 mL of methanol, 3 mL of aqueous sodium bicarbonate solution (2 M) was added, and the mixture was stirred at room temperature for 10 min. Boc anhydride (218 mg, 1 mmol) was then added. After the reaction was complete by TLC, saturated sodium bicarbonate solution was added to the reaction mixture to quench the reaction, and the mixture was stirred for 10 min. The mixture was extracted with ethyl acetate (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 190 mg of the target compound. The yield was 44%. Step 4: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((2-(2-acetohydrazido-1-carbonyl)-5-fluoropyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate The compound 3-(4-(2-(4-((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)-5-fluoropicolinic acid (190 mg, 0.35 mmol) was dissolved in 2 mL of dichloromethane, and DIPEA (90 mg, 0.7 mmol) and HATU (133 mg, 0.35 mmol) were added. The mixture was stirred at room temperature for 10 min. Then, acetohydrazide (51 mg, 0.7 mmol) was added, and the mixture was allowed to react at room temperature for 6 h. After the reaction was complete by TLC, the reaction was quenched by adding saturated ammonium chloride solution to the mixture in an ice bath. The mixture was extracted with dichloromethane, washed with saturated brine, and the organic phase was concentrated and purified using a chromatography column to obtain 138 mg of the target compound. The yield was 67%. Step 5: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((5-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate The compound ((1r,3r)-3-(4-(2-(4-((2-(2-acetohydrazide-1-carbonyl)-5-fluoropyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl) tert-butyl carbamate (138 mg, 0.23 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (50 mg, 0.46 mmol) was added, and p-toluenesulfonyl chloride (88 mg, 0.46 mmol) was added, and the reaction was carried out at room temperature overnight. After monitoring the complete reaction by TLC, the reaction system was concentrated and separated and purified using a chromatography column to obtain 110 mg of the target compound. The yield was 83%. Step 6: (1r,3r)-3-(4-(2-(4-((5-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine Tert-butyl ((1r,3r)-3-(4-(2-(4-((5-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (110 mg, 0.19 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 42 mg of the target compound. The yield was 46%. Step 7: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(((1r,3r)-3-(4-(2-(4-((5-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (1r,3r)-3-(4-(2-(4-((5-fluoro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine (42 mg, 0.09 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (25 mg, 0.09 mmol), and DIPEA (40 mg, 0.3 mmol) were added sequentially to 10 mL of DMSO, heated to 90 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 12 mg of the target compound. The yield was 18%. 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.09 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.03 (t, J = 8.7 Hz, 3H), 6.88 (s, 1H), 6.71 (d, J = 8.1 Hz, 3H), 4.92 (dd, J = 11.9, 5.1 Hz, 1H), 4.87 (s, 1H), 4.22 (s, 1H), 2.93 - 2.68 (m, 5H), 2.65 (s, 3H), 2.42 (d, J = 11.0 Hz, 2H), 2.16 - 2.07 (m, 1H), 1.67 (s, 6H). LC / MS (ESI+) calcd for C 40 H 35 FN6O7( [M+H] + ) m / z: 731.3; found 731.3.

[0160] Example 96: 2-(2,6-dioxopiperidin-3-yl)-5-(((1r,3r)-3-(4-(2-(4-((5-(5-methyl-1,3,4-oxadiazol-2-yl)oxazol-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of ethyl 2-(4-(2-(4-((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)oxazole-5-carboxylate 60% sodium hydride (44 mg, 1.1 mmol) was dissolved in 5 mL of DMF, and 2-((1r,3r)-3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)cyclobutyl)isoindoline-1,3-dione (427 mg, 1 mmol) was added in an ice bath. The mixture was stirred at room temperature for 10 min, and then ethyl 2-bromooxazole-5-carboxylate (218 mg, 1 mmol) was added. The mixture was gradually warmed to room temperature and allowed to react for 2 h. After monitoring the complete reaction by TLC, the reaction was quenched with saturated ammonium chloride in an ice bath, extracted three times with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to give 402 mg of the desired compound in 75% yield. Step 2: Synthesis of 2-(4-(2-(4-((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)oxazole-5-carboxylic acid The compound 2-(4-(2-(4-((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)oxazole-5-carboxylate (402 mg, 0.75 mmol) was dissolved in 4 mL of acetonitrile, 2 mL of water was added, triethylamine (150 mg, 1.5 mmol), and lithium bromide (258 mg, 3 mmol) were added, and the mixture was reacted at 90°C overnight. After monitoring the complete reaction by TLC, 0.5 N hydrochloric acid was added to adjust the pH to less than 7, followed by extraction with ethyl acetate. The organic phases were combined, dried, concentrated, and purified using a chromatography column to obtain 146 mg of the target compound. The yield was 38%. Step 3: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((5-(2-acetohydrazido-1-carbonyl)oxazol-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate The compound 2-(4-(2-(4-((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)oxazole-5-carboxylic acid (146 mg, 0.29 mmol) was dissolved in 2 mL of dichloromethane, and DIPEA (80 mg, 0.6 mmol) and HATU (114 mg, 0.3 mmol) were added. The mixture was stirred at room temperature for 10 min. Then, acetohydrazide (45 mg, 0.6 mmol) was added, and the mixture was allowed to react at room temperature for 6 h. After the reaction was confirmed to be complete by TLC, the reaction was quenched by adding saturated ammonium chloride solution to the mixture in an ice bath. The mixture was extracted with dichloromethane, washed with saturated brine, and the organic phase was concentrated and purified by chromatography to obtain 112 mg of the target compound. The yield was 68%. Step 4: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((5-(5-methyl-1,3,4-oxadiazol-2-yl)oxazol-2-yl)oxy)phenyl)propyl-2-yl)phenoxy)cyclobutyl)carbamate The compound ((1r,3r)-3-(4-(2-(4-((5-(2-acetohydrazide-1-carbonyl)oxazol-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl) tert-butyl carbamate (112 mg, 0.2 mmol) was dissolved in 5 mL of dichloromethane, and triethylamine (40 mg, 0.4 mmol) and p-toluenesulfonyl chloride (76 mg, 0.4 mmol) were added. The mixture was allowed to react at room temperature overnight. After monitoring the complete reaction by TLC, the reaction mixture was concentrated and purified using a chromatography column to obtain 108 mg of the target compound. The yield was 98%. Step 5: Synthesis of (1r,3r)-3-(4-(2-(4-((5-(5-methyl-1,3,4-oxadiazol-2-yl)oxazol-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine-1-amine Tert-butyl ((1r,3r)-3-(4-(2-(4-((5-(5-methyl-1,3,4-oxadiazol-2-yl)oxazol-2-yl)oxy)phenyl)propyl-2-yl)phenoxy)cyclobutyl)carbamate (108 mg, 0.19 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 32 mg of the target compound. The yield was 38%. Step 6: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(((1r,3r)-3-(4-(2-(4-((5-(5-methyl-1,3,4-oxadiazol-2-yl)oxazol-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (1r,3r)-3-(4-(2-(4-((5-(5-methyl-1,3,4-oxadiazol-2-yl)oxazol-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine-1-amine (32 mg, 0.07 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (20 mg, 0.07 mmol), and DIPEA (40 mg, 0.3 mmol) were added sequentially to 10 mL of DMSO, heated to 90 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 3 mg of the target compound. The yield was 6%. 1 H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 3H), 7.24 (s, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.90 (s, 1H), 6.71 (d, J = 8.6 Hz, 3H), 4.95 - 4.86 (m, 2H), 4.25 (s, 1H), 2.91 (s, 1H), 2.74 (d, J = 18.8 Hz, 3H), 2.56 (s, 3H), 2.41 (s, 2H), 2.12 (d, J = 9.2 Hz, 2H), 1.67 (s, 6H). LC / MS (ESI+) calcd for C 38 H 34 N6O8( [M+H] + ) m / z: 703.3; found 703.3.

[0161] Example 97: 5-(4-(2-(4-((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)pyrimidine-2-formonitrile [ka] Step 1: Synthesis of 5-(4-(2-(4-((1r,3r)-3-aminocyclobutoxy)phenyl)propan-2-yl)phenoxy)pyrimidine-2-formonitrile Tert-butyl ((1r,3r)-3-(4-(2-(4-((2-cyanopyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (100 mg, 0.2 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 52 mg of the target compound. The yield was 65%. Step 2: Synthesis of 5-(4-(2-(4-((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)pyrimidine-2-formonitrile 5-(4-(2-(4-((1r,3r)-3-aminocyclobutoxy)phenyl)propan-2-yl)phenoxy)pyrimidine-2-formonitrile (52 mg, 0.13 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (38 mg, 0.13 mmol), and DIPEA (52 mg, 0.4 mmol) were added sequentially to 10 mL of DMSO, heated to 90°C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 x 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 20 mg of the target compound. The yield was 23%. LC / MS (ESI+) calculation for C 37 H 32 N6O6( [M+H] +) m / z: 657.3; found 657.3.

[0162] Example 98: 6-(4-(2-(4-((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)pyridazine-3-formonitrile [ka] Step 1: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((6-cyanopyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate tert-Butyl ((1r,3r)-3-(4-(2-(4-hydroxyphenyl)propyl-2-phenoxy)cyclobutyl)carbamate (200 mg, 0.5 mmol), 6-chloropyridine-3-formonitrile (70 mg, 0.5 mmol), and cesium carbonate (326 mg, 1 mmol) were added to 5 mL of DMF in this order and reacted overnight at room temperature. After monitoring the complete reaction by TLC, the mixture was extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 162 mg of the target compound. The yield was 65%. The subsequent steps were carried out in a similar manner to Example 97 to prepare the target compound. LC / MS (ESI+) calculation for C 37 H 32 N6O6( [M+H] + ) m / z: 657.3; found 657.3.

[0163] Example 99: 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(1-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)ethyl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl ((1r,3r)-3-(4-(1-(4-((2-cyanopyrimidin-5-yl)oxy)phenyl)ethyl)phenoxy)cyclobutyl)carbamate The compound ((1r,3r)-3-(4-(1-(4-hydroxyphenyl)ethyl)phenoxy)cyclobutyl) tert-butyl carbamate (383 mg, 1 mmol), 5-fluoropyrimidine-2-formonitrile (123 mg, 1 mmol), cuprous iodide (19 mg, 0.1 mmol), 2-picolinic acid (24 mg, 0.2 mmol), and potassium phosphate (424 mg, 2 mmol) were placed in a 25 mL round-bottom flask, 5 mL of dimethyl sulfoxide was added, the system was purged with argon gas, and the reaction was carried out at 90 °C overnight. After monitoring the reaction completion by TLC, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, added 5 mL of water, and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, concentrated, and purified by chromatography to obtain 340 mg of the desired compound. The yield was 70%. Step 2: Synthesis of tert-butyl ((1r,3r)-3-(4-(1-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)ethyl)phenoxy)cyclobutyl)carbamate The compound ((1r,3r)-3-(4-(1-(4-((2-cyanopyrimidin-5-yl)oxy)phenyl)ethyl)phenoxy)cyclobutyl)carbamate (340 mg, 0.7 mmol) was dissolved in 10 mL of absolute ethanol, and hydroxylamine (46 mg, 1.4 mmol) was added. The reaction was carried out at 70 °C for 2 h. After TLC showed complete consumption of the starting material, the absolute ethanol was directly concentrated. Ethyl acetate was added, the mixture was washed with water and saturated brine, and the organic phases were combined and concentrated. The resulting mixture was dissolved in 5 mL of pyridine, and acetyl chloride (109 mg, 1.4 mmol) was added in an ice bath. The mixture was then reacted at 100 °C for 3 h. After TLC showed complete reaction, most of the pyridine was concentrated, the mixture was washed with 0.5 N hydrochloric acid, extracted with ethyl acetate, washed with water, and washed with saturated brine. The organic phases were combined, dried, concentrated, and purified using a chromatography column to obtain 115 mg of the target compound. The yield was 30%. Step 3: Synthesis of (1r,3r)-3-(4-(1-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)ethyl)phenoxy)cyclobutan-1-amine Tert-butyl ((1r,3r)-3-(4-(1-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)ethyl)phenoxy)cyclobutyl)carbamate (115 mg, 0.21 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 33 mg of the target compound. The yield was 36%. Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(1-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)ethyl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (1r,3r)-3-(4-(1-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)ethyl)phenoxy)cyclobutan-1-amine (33 mg, 0.074 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (22 mg, 0.074 mmol), and DIPEA (40 mg, 0.3 mmol) were added sequentially to 10 mL of DMSO, heated to 90 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 15 mg of the target compound. The yield was 29%. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.73 (s, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 5.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 2H), 7.21 - 7.14 (m, 4H), 6.85 (s, 1H), 6.83 - 6.71 (m, 3H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.91 - 4.81 (m, 1H), 4.15 (d, J = 8.4 Hz, 2H), 2.94 - 2.80 (m, 1H), 2.69 (s, 3H), 2.63 - 2.51 (m, 3H), 2.47 - 2.39 (m, 2H), 2.19 - 1.86 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H). LC / MS (ESI+) calcd for C 38 H 33 N7O7( [M+H] +) m / z: 700.3; found 700.3.

[0164] Example 100: 5-((1r,3r)-3-(4-(2-(4-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] 5-(((1s,3s)-3-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (70 mg, 0.09 mmol) was dissolved in 2 mL of DMF, potassium carbonate (28 mg, 0.2 mmol) was added, and iodomethane (15 mg, 0.1 mmol) was added in an ice bath. The reaction was allowed to proceed at room temperature for 1 h. After the reaction was complete by TLC, the mixture was extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography. mg of the compound 5-((1r,3r)-3-(4-(2-(4-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was obtained. The yield was 59%. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 5.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.12 - 7.08 (m, 4H), 6.92 - 6.86 (m, 3H), 6.82 (dd, J = 8.3, 2.0 Hz, 1H), 6.80 - 6.72 (m, 3H), 5.10 (dd, J = 13.0, 5.3 Hz, 1H), 4.95 (s, 2H), 4.71 (s, 4H), 4.49 (t, J = 6.9 Hz, 1H), 4.19 (s, 4H), 3.77 (d, J = 7.2 Hz, 1H), 3.08 - 3.02 (m, 2H), 3.00 (s, 3H), 2.92 (d, J = 12.5 Hz, 1H), 2.54 (d, J = 5.3 Hz, 2H), 2.02 - 1.94 (m, 3H), 1.57 (s, 6H). LC / MS (ESI+) calcd for C 43 H 44 N6O7( [M+H] + ) m / z: 757.3; found 757.3.

[0165] Example 101: (S)-3-(5-((1r,3S)-3-(4-(2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-1-oxoindolin-2-yl)piperidine-2,6-dione [ka] Step 1: Synthesis of (S)-5-amino-4-((benzyloxy)carbonyl)amino)-5-oxopentanoic acid tert-butyl ester (S)-2-((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (10 g, 30 mmol) was dissolved in 100 mL of dioxane, and di-tert-butyl dicarbonate (10.4 g, 48 mmol) and pyridine (4.5 g, 60 mmol) were added sequentially to the reaction mixture. The reaction mixture was purged with helium and reacted at 0 °C for 0.5 h. While maintaining the temperature at 0 °C, ammonium bicarbonate (7.1 g, 90 mmol) was added and the reaction mixture was reacted at room temperature overnight. After monitoring the reaction for completeness by TLC, the reaction was quenched by the addition of water, extracted twice with 100 mL of ethyl acetate, washed with 0.5 N hydrochloric acid (2 × 50 mL), saturated sodium bicarbonate solution (2 × 50 mL), and saturated brine (2 × 50 mL), dried over anhydrous sodium sulfate, concentrated, and slurried in ethyl acetate to give 8.2 g of the desired compound. The yield was 83%. Step 2: Synthesis of (S)-tert-butyl 4,5-diamino-5-oxopentanoate (S)-tert-Butyl 5-amino-4-((benzyloxy)carbonyl)amino)-5-oxopentanoate (8.1 g, 24 mmol) was dissolved in 150 mL of methanol, 800 mg of 10% palladium on carbon was added, the reaction mixture was purged with hydrogen gas using a hydrogen balloon, and the mixture was stirred overnight at room temperature. After monitoring the reaction for completeness by TLC, the reaction mixture was concentrated and purified using a chromatography column to obtain 4.7 g of the desired compound. The yield was 97%. Step 3: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate The compound ((1r,3r)-3-(4-(2-(4-((2-cyanopyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (2 g, 4 mmol) was dissolved in 30 mL of absolute ethanol, and hydroxylamine (270 mg, 8 mmol) was added. The reaction was carried out at 70 °C for 2 h. After TLC showed complete consumption of the starting material, the absolute ethanol was directly concentrated. Ethyl acetate was added, the mixture was washed with water and saturated brine, and the organic phases were combined and concentrated. The resulting mixture was dissolved in 20 mL of pyridine, and acetyl chloride (630 mg, 8 mmol) was added in an ice bath. The mixture was then reacted at 100 °C for 3 h. After TLC showed complete reaction, most of the pyridine was concentrated, the mixture was washed with 0.5 N hydrochloric acid, extracted with ethyl acetate, washed with water, and washed with saturated brine. The organic phases were combined, dried, concentrated, and purified using a chromatography column to obtain 1.4 g of the target compound. The yield was 63%. Step 4: Synthesis of (1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine-1-amine Tert-butyl ((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (1.4 g, 2.5 mmol) was dissolved in 20 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added in an ice bath. The mixture was then stirred at room temperature for 0.5 h. After completion of the reaction was monitored by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 1.02 g of the target compound. The yield was 88%. Step 5: Synthesis of 5-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isobenzofuran-1(3H)-one The compound (1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine-1-amine (300 mg, 0.65 mmol), 5-bromophthalide (152 mg, 0.71 mmol), (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (54 mg, 0.065 mmol), and cesium carbonate (425 mg, 1.3 mmol) were added to 5 mL of dioxane, and the reaction system was purged with a helium atmosphere and reacted at 110 °C overnight. After monitoring the reaction for completeness by TLC, the reaction mixture was filtered through diatomaceous earth, concentrated, and purified by chromatography to give 79 mg of the target compound in a yield of 21%. Step 6: Synthesis of 2-(hydroxymethyl)-4-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)benzoic acid 5-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isobenzofuran-1(3H)-one (79 mg, 0.13 mmol) was added to 1 mL of THF, 1 mL of methanol was added, and 5 N sodium hydroxide solution (0.2 mL, 1 mmol) was added. The mixture was heated to 40 °C and reacted for 0.5 h. After monitoring the complete reaction by TLC, the mixture was allowed to cool to room temperature, and the pH was adjusted to acidic with 0.5 N dilute hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated brine (3 × 4 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 70 mg of the target compound. The yield was 89%. Step 7: Synthesis of methyl 2-(hydroxymethyl)-4-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)benzoate The compound 2-(hydroxymethyl)-4-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)benzoic acid (70 mg, 0.11 mmol) was dissolved in 1 mL of dichloromethane, and trimethylsilylated diazomethane (0.5 mL, 0.5 mmol) was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the solvent was directly concentrated and the mixture was purified by chromatography to obtain 55 mg of the target compound. The yield was 80%. Step 8: Synthesis of methyl 2-(bromomethyl)-4-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)benzoate The compound 2-(hydroxymethyl)-4-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)methyl benzoate (55 mg, 0.09 mmol) was dissolved in 1 mL of dichloromethane, triphenylphosphine (47 mg, 0.18 mmol) was added, and carbon tetrabromide (60 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for 0.5 h. After monitoring the complete reaction by TLC, the solvent was directly concentrated and the mixture was purified by chromatography to obtain 27 mg of the target compound. The yield was 44%. Step 9: tert-butyl (S)-5-amino-4-(5-((1r,3S)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-1-oxoindolin-2-yl)-5-oxoglutarate Methyl 2-(bromomethyl)-4-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)benzoate (27 mg, 0.04 mmol) was dissolved in 1 mL of acetonitrile, and tert-butyl (S)-4,5-diamino-5-oxopentanoate (8 mg, 0.04 mmol) and DIPEA (10 mg, 0.08 mmol) were added. The mixture was heated to 90 °C and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 18 mg of the target compound. The yield was 56%. Step 10: Synthesis of (S)-3-(5-((1r,3S)-3-(4-(2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-1-oxoindolin-2-yl)piperidine-2,6-dione Methyl 2-((((S)-1-amino-5-(tert-butoxy)-1,5-dioxopentyl-2-yl)amino)-4-((1r,3S)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)amino)benzoate (18 mg, 0.02 mmol) was dissolved in 1 mL of acetonitrile, p-toluenesulfonic acid (17 mg, 0.1 mmol) was added, and the mixture was heated to 80 °C overnight. After TLC showed complete consumption of the starting material, the mixture was cooled to room temperature and quenched by adding water. The mixture was extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 2 mg of the compound. The yield was 14%. LC / MS (ESI+) calcd for C 39 H 37 N7O6( [M+H] + ) m / z: 700.3; found 700.3;98% ee from chiral SFC analysis.

[0166] Example 102: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] (1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylamine-1-amine (100 mg, 0.22 mmol), 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (65 mg, 0.22 mmol), and DIPEA (86 mg, 0.66 mmol) were added in this order to 10 mL of DMSO, and the mixture was heated to 90° C. and allowed to react overnight. The mixture was cooled to room temperature, extracted with 5 mL of ethyl acetate, washed with saturated brine (3 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 21 mg of the compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((1r,3r)-3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione. The yield was 13%. 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.74 (s, 2H), 7.62 (d, J = 10.2 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.28 - 7.24 (m, 1H), 7.18 - 7.12 (m, 4H), 6.92 (d, J = 7.1 Hz, 1H), 6.80 - 6.74 (m, 2H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.88 (s, 1H), 4.23 (d, J = 5.3 Hz, 1H), 2.92 - 2.82 (m, 1H), 2.69 (s, 3H), 2.63 - 2.52 (m, 5H), 2.00 (d, J = 7.3 Hz, 2H), 1.63 (s, 6H). LC / MS (ESI+) calcd for C 39 H 34 FN7O7( [M+H] + ) m / z: 732.3; found 732.3.

[0167] Example 103: 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(1-(4-((6-(1-hydroxyethyl)pyridazin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl ((1r,3r)-3-(4-(1-(4-((6-cyanopyridin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)carbamate Tert-butyl ((1r,3r)-3-(4-(1-(4-hydroxyphenyl)cyclopentyl)phenoxy)cyclobutyl)carbamate (423 mg, 1 mmol), 6-chloropyridine-3-formonitrile (140 mg, 1 mmol), and cesium carbonate (652 mg, 2 mmol) were added to 10 mL of DMF in this order and reacted overnight at room temperature. After monitoring the reaction for completeness by TLC, the mixture was extracted with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified using a chromatography column to obtain 484 mg of the target compound. The yield was 92%. Step 2: Synthesis of tert-butyl ((1r,3r)-3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)carbamate The compound ((1r,3r)-3-(4-(1-(4-((6-cyanopyridin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)carbamate tert-butyl (484 mg, 0.92 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and methylmagnesium bromide (5 mL, 5 mmol) was added in an ice bath. The mixture was stirred at room temperature for 0.5 h. After complete reaction was monitored by TLC, 0.5 N hydrochloric acid was added and the mixture was stirred at room temperature for 10 min. The mixture was extracted with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 450 mg of the target compound. The yield was 90%. Step 3: Synthesis of tert-butyl ((1r,3r)-3-(4-(1-(4-((6-(1-hydroxyethyl)pyridazin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)carbamate The compound ((1r,3r)-3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl) tert-butyl carbamate (450 mg, 0.8 mmol) was dissolved in 10 mL of methanol, and sodium borohydride (152 mg, 4 mmol) was added in an ice bath. The mixture was stirred at room temperature for 3 h. After monitoring the complete reaction by TLC, the reaction was quenched by adding saturated ammonium chloride solution. The mixture was extracted with 10 mL of ethyl acetate, washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 380 mg of the target compound. The yield was 85%. Step 4: Synthesis of 1-(6-(4-(1-(4-((1r,3r)-3-aminocyclobutoxy)phenyl)cyclopentyl)phenoxy)pyridazin-3-yl)ethan-1-ol Tert-butyl ((1r,3r)-3-(4-(1-(4-((6-(1-hydroxyethyl)pyridazin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)carbamate (380 mg, 0.7 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added in an ice bath. The mixture was then stirred at room temperature for 0.5 h. After completion of the reaction was monitored by TLC, the reaction mixture was poured into saturated sodium bicarbonate solution in an ice bath to make the mixture basic. The mixture was extracted with dichloromethane / methanol (10:1) (3 × 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 276 mg of the target compound. The yield was 88%. Step 5: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(1-(4-((6-(1-hydroxyethyl)pyridazin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione 1-(6-(4-(1-(4-((1r,3r)-3-aminocyclobutoxy)phenyl)cyclopentyl)phenoxy)pyridazin-3-yl)ethan-1-ol (276 mg, 0.62 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (171 mg, 0.62 mmol), and DIPEA (390 mg, 3 mmol) were added sequentially to 30 mL of DMSO, heated to 90 °C, and reacted overnight. The mixture was allowed to cool to room temperature, extracted with 30 mL of ethyl acetate, washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 114 mg of the target compound. The yield was 26%. 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 5.4 Hz, 1H), 7.43 - 7.31 (m, 3H), 7.29 - 7.19 (m, 2H), 7.11 - 7.03 (m, 2H), 6.86 (s, 1H), 6.76 (dd, J = 19.0, 8.6 Hz, 3H), 5.59 (d, J = 4.7 Hz, 1H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.95 - 4.79 (m, 2H), 4.13 (d, J = 4.7 Hz, 1H), 2.87 (ddd, J = 17.3, 14.0, 5.5 Hz, 1H), 2.61 - 2.51 (m, 3H), 2.42 (q, J = 6.6 Hz, 2H), 2.27 (s, 4H), 2.04 - 1.95 (m, 1H), 1.62 (s, 4H), 1.39 (d, J = 6.5 Hz, 3H). LC / MS (ESI+) calcd for C 40 H 39 N5O7( [M+H] + ) m / z: 702.3; found 702.3.

[0168] Example 104: 5-((1r,3r)-3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] 2-(2,6-Dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(1-(4-((6-(1-hydroxyethyl)pyridazin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (60 mg, 0.085 mmol) was dissolved in 2 mL of dichloromethane, and Dess-Martin oxidant (106 mg, 0.25 mmol) was added. The reaction was allowed to proceed at room temperature for 3 h, and the completion of the reaction was monitored by TLC. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified using a chromatography column to obtain 34 mg of the compound 5-((1r,3r)-3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. The yield was 57%. 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.55 (dt, J = 14.5, 6.8 Hz, 3H), 7.47 - 7.35 (m, 2H), 7.35 - 7.22 (m, 2H), 7.24 - 7.09 (m, 2H), 6.86 (s, 1H), 6.77 (dd, J = 15.2, 8.8 Hz, 3H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.93 - 4.78 (m, 1H), 4.13 (d, J = 5.1 Hz, 1H), 2.86 (d, J = 12.1 Hz, 1H), 2.67 (s, 3H), 2.62 - 2.51 (m, 3H), 2.43 (p, J = 6.0 Hz, 2H), 2.28 (s, 4H), 2.05 - 1.92 (m, 1H), 1.63 (s, 4H). LC / MS (ESI+) calcd for C 40 H 37 N5O7( [M+H] + ) m / z: 700.3; found 700.3.

[0169] Example 105: 2-(2,6-dioxopiperidin-3-yl)-5-(1r,3r)-3-(4-(4-(6-(1-hydroxyethyl)pyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 103. 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.57 (s, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 5.4 Hz, 1H), 7.43 - 7.31 (m, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.07 - 6.95 (m, 2H), 6.85 (s, 1H), 6.78 (t, J = 8.8 Hz, 3H), 5.22 (d, J = 5.5 Hz, 1H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.86 (s, 1H), 4.79 (q, J = 6.3 Hz, 1H), 4.13 (s, 1H), 3.58 (t, J = 5.0 Hz, 4H), 2.96 - 2.80 (m, 1H), 2.54 (s, 4H), 2.39 (d, J = 31.0 Hz, 6H), 1.99 (d, J = 12.3 Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H). LC / MS (ESI+) calcd for C 40 H 39 NO ([M+H] + ) m / z: 718.3; found 718.3.

[0170] Example 106: 5-((1r,3r)-3-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 105. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.69 (s, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 5.4 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.30 - 7.23 (m, 2H), 7.18 - 7.11 (m, 2H), 6.86 (s, 1H), 6.77 (d, J = 8.9 Hz, 3H), 5.03 (dd, J = 13.0, 5.4 Hz, 1H), 4.91 - 4.80 (m, 1H), 4.18 - 4.09 (m, 1H), 3.59 (d, J = 5.3 Hz, 4H), 3.17 (d, J = 5.2 Hz, 1H), 2.96 - 2.79 (m, 1H), 2.64 (s, 3H), 2.60 - 2.53 (m, 2H), 2.43 (d, J = 5.5 Hz, 2H), 2.37 (d, J = 5.9 Hz, 4H), 2.00 (d, J = 7.8 Hz, 2H). LC / MS (ESI+) calcd for C 40 H 37 NO ([M+H] + ) m / z: 716.3; found 716.3.

[0171] Example 107: 5-(3-(4-(2-(2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of N-Boc-3-methanesulfonyloxypiperidine N-Boc-3-hydroxypiperidine (1.00 g, 5 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (2.01 g, 20 mmol) was added, and methanesulfonyl chloride (851 mg, 7.5 mmol) was added in an ice-water bath. The mixture was warmed to room temperature and reacted for 2 h. After monitoring the completion of the reaction of the raw materials by TLC, the mixture was quenched by adding saturated aqueous ammonium chloride solution and extracted with 10 mL of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to dryness, yielding 1.50 g of the product, N-Boc-3-methanesulfonyloxypiperidine crude product. Step 2: Synthesis of tert-butyl 3-(4-(2-(4-((2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidine-1-carboxylate N-Boc-3-methanesulfonyloxypiperidine (350 mg crude product, 0.78 mmol) and 4-(2-(4-((2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenol (100 mg, 0.26 mmol) were dissolved in 5 mL of DMF, and CsCO (167 mg, 0.51 mmol) was added. The mixture was allowed to react overnight at 100 °C. Water was added to quench the reaction, and the mixture was extracted with 10 mL of ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by prep-TLC to give compound tert-butyl 3-(4-(2-(4-((2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidine-1-carboxylate (50 mg). The yield was 34%. LC / MS (ESI+) calculation for C 34 H 43 N3O5( [M+H] + ) m / z 574.3; found 574.3. Step 3: Synthesis of 2-(1-ethoxyvinyl)-4-((4-(2-(4-(piperidin-3-oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidine Tert-butyl 3-(4-(2-(4-((2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidine-1-carboxylate (50 mg, 0.08 mmol) was dissolved in 4 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added dropwise in an ice bath. After the addition, the reaction was stirred in an ice bath for 1 h. After monitoring the complete reaction by TLC, the pH was adjusted to basic with saturated aqueous sodium carbonate, extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give compound 2-(1-ethoxyvinyl)-4-((4-(2-(4-(piperidin-3-oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidine (40 mg). The yield was 95%. LC / MS (ESI+) calculation for C 29 H 35 N3O3( [M+H] + ) m / z 474.3; found 474.3. Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(2-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidin-1-yl)isoindoline-1,3-dione 2-(1-Ethoxyvinyl)-4-((4-(2-(4-(piperidin-3-oxy)phenyl)propan-2-yl)phenoxy)methyl)pyrimidine (40 mg, 0.085 mmol) was dissolved in 5 mL of DMSO, and 3 drops of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (30 mg, 0.11 mmol) were added, followed by reaction at 90°C overnight. The mixture was quenched with water, extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, spin-dried, and purified by prep-TLC to give the compound 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(2-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidin-1-yl)isoindole-1,3-dione (34 mg). The yield was 54%. LC / MS (ESI+) calculation for C 42 H 43 N5O7( [M+H] + ) m / z 730.3; found 730.3. Step 5: Synthesis of 5-(3-(4-(2-(2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(2-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidin-1-yl)isoindole-1,3-dione (34 mg, 0.046 mmol) was dissolved in 2 mL of acetone, and 2 mL of 2N aqueous HCl was added. The reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, 10 The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by prep-TLC to obtain the product 5-(3-(4-(2-(2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (8 mg, yellow solid). The yield was 25%. 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.01 (d, J = 5.1 Hz, 1H), 7.77 (d, J = 5.1 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 5.4, 2.3 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.17 - 7.12 (m, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.82 (dd, J = 8.9, 2.4 Hz, 2H), 5.26 (s, 2H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.48 (s, 1H), 3.83 (d, J = 13.3 Hz, 1H), 3.60 (s, 1H), 3.56 - 3.40 (m, 2H), 2.95 - 2.81 (m, 1H), 2.67 (s, 3H), 2.63 - 2.52 (m, 2H), 2.00 (dd, J = 14.9, 7.1 Hz, 3H), 1.83 (s, 1H), 1.72 (d, J = 8.8 Hz, 1H), 1.58 (s, 6H). LC / MS (ESI+) calculation for C 40 H 39 NO([M+H] + ) m / z: 702.3; found 702.3.

[0172] Example 108: Synthesis of 5-(4-((4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 107. 1 H NMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 5.1 Hz, 1H), 8.12 (s, 1H), 7.71 (dd, J = 22.0, 6.8 Hz, 2H), 7.30 (s, 1H), 7.20 - 7.03 (m, 4H), 6.83 (dd, J = 27.9, 8.4 Hz, 4H), 5.25 (s, 2H), 4.94 (dd, J = 12.2, 5.3 Hz, 1H), 4.00 (d, J = 13.0 Hz, 2H), 3.82 (d, J = 6.2 Hz, 2H), 3.03 (t, J = 12.8 Hz, 2H), 2.79 LC / MS (ESI+) calcd for C 41 H 41 NO([M+H] + ) m / z 716,found 716.

[0173] Example 109: Synthesis of 5-((2-(4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 107. 1 H NMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 5.1 Hz, 1H), 8.13 (s, 1H), 7.74 (d, J = 5.1 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.16 (dd, J = 8.8, 3.1 Hz, 4H), 7.03 (d, J = 2.2 Hz, 1H), 6.92 - 6.75 (m, 5H), 5.25 (s, 2H), 4.93 (dd, J = 12.1, 5.2 Hz, 1H), 4.23 - 4.12 (m, 2H), 3.63 (t, J = 5.1 Hz, 2H), 2.94 - 2.65 (m, 6H), 2.17 - 2.08 (m, 1H), 1.64 (s, 6H). LC / MS (ESI+) calcd for C 37 H 35 NO([M+H] + ) m / z 662,found 662.

[0174] Example 110: Synthesis of 5-(((trans)-3-(4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 107. 1H NMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 5.1 Hz, 1H), 8.08 (s, 1H), 7.74 (dt, J = 5.1, 0.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.21 - 7.09 (m, 4H), 6.91 - 6.82 (m, 3H), 6.69 (dq, J = 7.1, 3.2, 2.6 Hz, 3H), 5.25 (d, J = 0.8 Hz, 2H), 4.93 (dd, J = 12.2, 5.2 Hz, 1H), 4.85 (td, J = 6.9, 3.5 Hz, 1H), 4.22 (td, J = 7.8, 3.9 Hz, 1H), 2.94 - 2.74 (m, 6H), 2.73 - 2.67 (m, 2H), 2.40 (dt, J = 12.9, 6.1 Hz, 2H), 2.12 (ddd, J = 13.2, 5.8, 2.9 Hz, 1H), 1.64 (s, 6H). LC / MS (ESI+) calcd for C 39 H 37 NO([M+H] + ) m / z 688,found 688.

[0175] Example 111: Synthesis of 5-(((trans)-3-(4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 107. 1H NMR (400 MHz, Chloroform-d) δ 9.01 - 8.85 (m, 1H), 8.19 (s, 1H), 7.80 - 7.72 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.22 - 7.07 (m, 5H), 6.88 (td, J = 6.0, 2.8 Hz, 3H), 6.71 (d, J = 8.5 Hz, 2H), 5.25 (s, 2H), 4.94 (dd, J = 12.0, 5.2 Hz, 1H), 4.74 (d, J = 6.7 Hz, 1H), 4.61 (p, J = 7.8 Hz, 1H), 3.06 (s, 3H), 2.95 - 2.51 (m, 10H), 2.19 - 2.08 (m, 1H), 1.65 (s, 6H). LC / MS (ESI+) calcd for C 40 H 39 NO([M+H] + ) m / z 702,found 702.

[0176] Example 112: Synthesis of 5-((3-((4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 59. 1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 5.3 Hz, 2H), 7.60 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 8.4 Hz, 4H), 6.96 - 6.76 (m, 6H), 6.68 (td, J = 8.5, 2.1 Hz, 1H), 4.91 (d, J = 34.5 Hz, 8H), 4.32 (s, 4H), 3.93 (t, J = 8.7 Hz, 2H), 2.95 - 2.42 (m, 6H), 2.16 - 2.10 (m, 1H), 1.91 - 1.77 (m, 2H), 1.64 (d, J = 4.8 Hz, 6H). LC / MS (ESI+) calcd for C 43 H 44 N6O7([M+H] + ) m / z 757,found 757.

[0177] Example 113: Synthesis of 5-(3-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] 4-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl methanesulfonate (554 mg, 1 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (274 mg, 1 mmol), and sodium bicarbonate (252 mg, 3 mmol) were added sequentially to 15 mL of DMF, heated to 75 °C, and reacted for 16 h. The mixture was allowed to cool to room temperature, poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to obtain 439 mg of product. The yield was 60%. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = 8.3, 2.3 Hz, 1H), 7.09 (dd, J = 8.9, 2.5 Hz, 4H), 6.94 - 6.80 (m, 4H), 6.74 (d, J = 5.0 Hz, 1H), 5.11 (dd, J = 12.9, 5.4 Hz, 1H), 4.94 (s, 2H), 4.71 (s, 4H), 4.32 (t, J = 6.2 Hz, 2H), 4.19 (s, 4H), 4.10 (t, J = 6.2 Hz, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.64 - 2.54 (m, 1H), 2.20 (q, J = 6.2 Hz, 2H), 2.10 - 1.99 (m, 1H), 1.56 (s, 6H). LC / MS (ESI+) calcd for C 41 H 41 NO([M+H] + ) m / z 732, found 732.

[0178] Example 114: Synthesis of N-(2-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)ethyl)-2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-formamide [ka] A similar method was used to obtain the target compound. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.12 (t, J = 5.4 Hz, 1H), 8.45 - 8.27 (m, 3H), 8.03 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 8.5 Hz, 5H), 6.87 (dd, J = 8.6, 6.1 Hz, 4H), 6.74 (d, J = 5.0 Hz, 1H), 5.19 (dd, J = 12.8, 5.3 Hz, 1H), 4.94 (s, 2H), 4.71 (s, 4H), 4.15 (d, J = 29.8 Hz, 6H), 3.66 (q, J = 5.7 Hz, 2H), 2.89 (ddd, J = 17.0, 14.1, 5.2 Hz, 1H), 2.59 (td, J = 15.6, 14.9, 4.1 Hz, 2H), 2.08 (ddt, J = 12.3, 7.1, 4.3 Hz, 1H), 1.56 (s, 6H). LC / MS (ESI+) calcd for C 41 H 40 NO([M+H] + ) m / z 745, found 745.

[0179] Example 115: Synthesis of 5-(((trans)-3-(4-(2-(4-((2-(cyclopropanecarbonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of (1r,3r)-3-(4-(2-(4-((2-cyanopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate, 4-(Chloromethyl)pyrimidine-2-carbonitrile (153 mg, 1 mmol) and tert-butyl ((1r,3r)-3-(4-(2-(4-hydroxyphenyl)propyl-2-phenoxy)cyclobutyl)carbamate (397 mg, 1 mmol) were dissolved in DMF (8 mL), potassium carbonate (276 mg, 2 mmol) was added, and the reaction was allowed to proceed at room temperature for 15 h. The reaction mixture was poured into water and extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give 413 mg of the product (80% yield). LC / MS (ESI+) calculation for C 30 H 34 N4O4([M+H] + ) m / z 515, found 515. Step 2: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-(2-(cyclopropanecarbonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate, (1r,3r)-3-(4-(2-(4-((2-cyanopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (514 mg, 1 mmol) was dissolved in dry THF (10 mL). A THF solution of cyclopropylmagnesium bromide (10 mL, 5 mmol) was added in an ice-water bath under nitrogen gas protection, and the mixture was allowed to react in an ice-water bath for 10 min. The reaction mixture was poured into cold 0.5 N dilute hydrochloric acid, extracted, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give 398 mg of the product (70% yield). LC / MS (ESI+) calculation for C 33 H 39 N3O5([M+H] + ) m / z 558, found 558. Step 3: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-(2-(cyclopropyl(hydroxy)methyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate, tert-Butyl ((1r,3r)-3-(4-(2-(4-(2-(cyclopropanecarbonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (557 mg, 1 mmol) was dissolved in 15 mL of methanol, and sodium borohydride (114 mg, 3 mmol) was added in several portions in an ice-water bath. After the addition was complete, the reaction was allowed to proceed for 0.5 h. The reaction mixture was poured into water and extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give 502 mg of the product (yield: 90%). LC / MS (ESI+) calculation for C 33 H 41 N3O5([M+H] + ) m / z 560, found 560. Subsequent steps were carried out in a manner similar to that described in Example 107 to prepare 5-((1r,3r)-3-(4-(2-(2-(cyclopropyl(hydroxy)methyl)pyrimidin-4-ylmethoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione. LC / MS (ESI+) calculation for C 41 H 41 NO([M+H] + ) m / z 716,found 716. Step 6: Synthesis of 5-((1r,3r)-3-(4-(2-(4-(2-(cyclopropanecarbonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopyridin-3-yl)isoindoline-1,3-dione, 5-((1r,3r)-3-(4-(2-(2-(cyclopropyl(hydroxy)methyl)pyrimidin-4-ylmethoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (715 mg, 1 mmol) was dissolved in 30 mL of DCM and added with Dess-Martin oxidant (640 mg, 1.5 mmol) in several portions over an ice-water bath. The mixture was allowed to warm to room temperature and react for 16 h. The mixture was poured into saturated aqueous sodium sulfite, filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to give 356 mg of product in a 50% yield. LC / MS (ESI+) calculation for C 41 H 39 NO([M+H] + ) m / z 714,found 714.

[0180] Example 116: Synthesis of 5-(((trans)-3-(4-(2-(4-((6-(cyclopropyl(hydroxy)methyl)pyridin-2-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that described in Example 115. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.81 (t, J = 7.7 Hz, 1H), 7.56 (dd, J = 25.0, 6.9 Hz, 2H), 7.39 (dd, J = 20.2, 7.7 Hz, 2H), 7.11 (dd, J = 8.7, 4.8 Hz, 4H), 6.99 - 6.64 (m, 6H), 5.32 (d, J = 4.7 Hz, 1H), 5.18 - 4.98 (m, 3H), 4.86 (p, J = 6.1 Hz, 1H), 4.15 (dt, J = 9.8, 4.7Hz, 2H), 2.88 (ddd, J = 17.5, 14.2, 5.5 Hz, 1H), 2.64 - 2.51 (m, 3H), 2.42 (dq, J = 12.5, 8.1, 6.3 Hz, 3H), 2.06 - 1.91 (m, 1H), 1.57 (s, 6H), 1.18 - 1.07 (m, 1H), 0.37 (t, J = 7.5 Hz, 4H). LC / MS (ESI+) calcd for C 42 H 42 N4O7([M+H] + ) m / z 715,found 715.

[0181] Example 117: Synthesis of 5-(((trans)-3-(4-(2-(4-((6-(cyclopropanecarbonyl)pyridin-2-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] 5-(((trans)-3-(4-(2-(4-((6-(cyclopropyl(hydroxy)methyl)pyridin-2-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (714 mg, 1 mmol) was dissolved in 30 mL of DCM and added with Dess-Martin oxidant (640 mg, 1.5 mmol) in several portions in an ice-water bath. The mixture was allowed to warm to room temperature and react for 16 h. The mixture was poured into saturated aqueous sodium sulfite, filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to give 356 mg of product in a 50% yield. LC / MS (ESI+) calculation for C 42 H 40 N4O7([M+H] + ) m / z 713,found 713.

[0182] Example 118: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(((trans)-3-(4-(2-(4-((2-(1-hydroxyethyl)pyrimidin-5-yl))oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((2-cyanopyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate, tert-Butyl ((1r,3r)-3-(4-(2-(4-hydroxyphenyl)propyl-2-phenoxy)cyclobutyl)carbamate (397 mg, 1 mmol), 2-cyano-5-bromopyrimidine (183 mg, 1 mmol), CuI (26 mg, 0.2 mmol), dipicolinic acid (33 mg, 0.2 mmol), and potassium phosphate (424 mg, 2 mmol) were dissolved in DMSO (8 mL). The atmosphere was purged with nitrogen gas three times, heated to 90 °C, and reacted for 5 h. The reaction solution was poured into water and extracted. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give 400 mg of the product (80% yield). LC / MS (ESI+) calculation for C 29 H 32 N4O4([M+H] + ) m / z 501,found 501. Step 2: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate, tert-Butyl ((1r,3r)-3-(4-(2-(4-((2-cyanopyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (500 mg, 1 mmol) was dissolved in THF (10 mL). A solution of methylmagnesium bromide in THF (10 mL, 5 mmol) was added to the solution in an ice-water bath under nitrogen gas protection, and the mixture was allowed to react for 10 min in an ice-water bath. The reaction mixture was poured into cold 0.5 N dilute hydrochloric acid, extracted, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give 360 ​​mg of the product (70% yield). LC / MS (ESI+) calculation for C 30 H 35 N3O5([M+H] + ) m / z 518, found 518. Step 3: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-(2-(1-hydroxyethyl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate, tert-Butyl ((1r,3r)-3-(4-(2-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (517 mg, 1 mmol) was dissolved in 15 mL of methanol, and sodium borohydride (114 mg, 3 mmol) was added in several portions in an ice-water bath. After the addition was complete, the reaction was allowed to proceed for 0.5 h. The reaction mixture was poured into water and extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give 470 mg of the product (yield: 90%). LC / MS (ESI+) calculation for C 30 H 37 N3O5([M+H] + ) m / z 520, found 520. The subsequent steps 4 and 5 were carried out in a similar manner to the last two steps of Example 1 to prepare the target compound in 25% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 2H), 8.30 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.18 - 7.09 (m, 2H), 6.99 - 6.92 (m, 2H), 6.88 (d, J = 2.1 Hz, 1H), 6.77 - 6.65 (m, 3H), 5.02 - 4.82 (m, 3H), 4.21 (td, J = 7.7, 3.9 Hz, 1H), 2.93 - 2.65 (m, 5H), 2.40 (dt, J = 13.8, 5.9 Hz, 2H), 2.11 (td, J = 9.3, 8.6, 5.4 Hz, 1H), 1.67 (s, 6H), 1.57 (d, J = 6.6 Hz, 3H). LC / MS (ESI+) calcd for C 38 H37 NO([M+H] + ) m / z 676, found 676.

[0183] Example 119: Synthesis of 5-(((trans)-3-(4-(2-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] 2-(2,6-Dioxopiperidin-3-yl)-5-(((trans)-3-(4-(2-(4-((2-(1-hydroxyethyl)pyrimidin-5-yl))oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isodihydroindoline-1,3-dione (675 mg, 1 mmol) was dissolved in 30 mL of DCM and added with Dess-Martin oxidant (640 mg, 1.5 mmol) in several portions in an ice-water bath. The mixture was allowed to warm to room temperature and react for 16 h. The mixture was poured into saturated aqueous sodium sulfite, filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography to give 510 mg of product in an 80% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 2H), 8.15 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.20 - 7.08 (m, 2H), 7.05 - 6.97 (m, 2H), 6.90 (d, J = 2.1 Hz, 1H), 6.72 (dd, J = 8.8, 2.5 Hz, 3H), 4.99 - 4.82 (m, 2H), 4.22 (td, J = 7.8, 4.0 Hz, 1H), 2.93 - 2.66 (m, 8H), 2.42 (dt, J = 12.9, 6.2 Hz, 2H), 2.16 - 2.08 (m, 1H), 1.68 (s, 6H). LC / MS (ESI+) calcd for C 38 H 35 NO([M+H] + ) m / z 674,found 674.

[0184] Example 120: 3-(7-(((trans)-3-(4-(2-(4-((6-(5-methyl-1,3,4-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl))oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-4-oxoquinazoline-3(tetrahydro)-yl)piperidine-2,6-dione [ka] Step 1: Synthesis of 2-amino-N-(2,6-dioxopiperidin-3-yl)-4-fluorobenzamide 2-Amino-4-fluorobenzoic acid (155 mg, 1 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (166 mg, 1 mmol) was dissolved in 6 mL of DMF, and DIEA (387 mg, 3 mmol) and HATU (380 mg, 1 mmol) were added. The reaction was allowed to proceed with stirring at room temperature for 2 h. The reaction mixture was poured into water, extracted, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then scalded to give 160 mg of the product. The yield was 60%. LC / MS (ESI+) calculation for C 12 H 12 FN3O3([M+H] + ) m / z 266, found 266. Step 2: Synthesis of 3-(7-fluoro-4-oxazoquinazolin-3(4H)-yl)piperidine-2,6-dione 2-Amino-N-(2,6-dioxopiperidin-3-yl)-4-fluorobenzamide (265 mg, 1 mmol) and TsOH (172 mg, 1 mmol) were dissolved in 5 mL of trimethyl orthoformate and heated to 120°C for 2 h. After cooling, EA and methanol were added to form a slurry, yielding 138 mg of product in a 50% yield. LC / MS (ESI+) calculation for C 13 H 10 FN3O3([M+H] + ) m / z 276,found 276. The subsequent steps were carried out in a similar manner to Example 116 to prepare the target compound. 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.21 - 8.10 (m, 2H), 7.82 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 8.8, 2.9 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.22 - 7.05 (m, 5H), 6.78 (t, J = 9.6 Hz, 3H), 6.44 (d, J = 2.2 Hz, 1H), 5.33 (s, 1H), 4.88 (h, J = 6.0, 5.5 Hz, 1H), 4.06 (dd, J = 26.5, 6.5 Hz, 1H), 2.81 (q, J = 14.3 Hz, 1H), 2.59 (s, 5H), 2.53 (d, J = 7.6 Hz, 2H), 2.45 (q, J = 5.7 Hz, 2H), 2.17 - 2.02 (m, 1H), 1.63 (s, 6H). LC / MS (ESI+) calcd for C 40 H 37 N7O6([M+H] + ) m / z 712,found 712.

[0185] Example 122: Synthesis of 5-(((trans)-3-(4-(4-((5-(dihydro-1,2,3-triazol-2-yl)pyrimidin-2-yl)oxy)phenoxy)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 228. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.23 (s, 2H), 8.23 ​​(s, 2H), 7.67 - 7.50 (m, 2H), 7.33 - 7.20 (m, 2H), 7.06 - 6.81 (m, 8H), 5.04 (dd, J = 13.0, 5.4 Hz, 1H), 4.96 - 4.82 (m, 1H), 4.17 (s, 1H), 2.93 - 2.80 (m, 1H), 2.57 (d, J = 17.3 Hz, 3H), 2.46 (d, J = 5.9 Hz, 2H), 1.99 (s, 2H).LC / MS (ESI+) calcd for C 35 H 28 N8O7([M+H] + ) m / z 673, found 673.

[0186] Example 123: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(((trans)-3-(4-(2-(4-((6-(1-hydroxyethyl)pyridin-3-yl))oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 118. The yield was 25%. 1H NMR (400 MHz, Chloroform-d) δ 8.33 - 8.20 (m, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.6, 2.7 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.18 - 7.10 (m, 2H), 6.96 - 6.86 (m, 3H), 6.77 - 6.66 (m, 3H), 5.00 - 4.81 (m, 4H), 4.22 (s, 1H), 2.93 - 2.65 (m, 5H), 2.47 - 2.34 (m, 2H), 2.14 - 2.10 (m, 1H), 1.66 (s, 6H), 1.53 (d, J = 6.5 Hz, 3H). LC / MS (ESI+) calcd for C 39 H 38 N4O7([M+H] + ) m / z 675,found 675.

[0187] Example 124: Synthesis of 5-((((trans)-3-(4-(2-(4-((6-acetylpyridin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-oxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared according to a method similar to that of Example 119. The yield was 80%. LC / MS (ESI+) calculation for C 39 H 36 N4O7([M+H] + ) m / z 673, found 673.

[0188] Example 125: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(((trans)-3-(4-(2-(4-((6-(1-hydroxyethyl)pyridazin-3-yl))oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 118. The yield was 25%. 1 H NMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 7.60 (t, J = 8.9 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 7.12 (dd, J = 28.8, 8.3 Hz, 4H), 6.93 - 6.85 (m, 1H), 6.70 (dd, J = 8.3, 4.7 Hz, 3H), 5.10 (d, J = 6.6 Hz, 1H), 4.99 - 4.80 (m, 2H), 4.21 (s, 1H), 2.99 (s, 2H), 2.91 - 2.75 (m, 2H), 2.69 (td, J = 9.4, 6.8, LC / MS (ESI+) calcd for C 38 H 37 NO([M+H] + ) m / z 676, found 676.

[0189] Example 126: Synthesis of 5-(((trans)-3-(4-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 119. The yield was 80%. 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.56 (td, J = 10.9, 6.9 Hz, 3H), 7.37 - 7.27 (m, 2H), 7.22 - 7.13 (m, 4H), 6.90 - 6.71 (m, 4H), 5.03 (dd, J = 12.9, 5.4 Hz, 1H), 4.88 (p, J = 6.1 Hz, 1H), 4.15 (d, J = 5.0 Hz, 1H), 2.89 (s, 2H), 2.73 (d, J = 0.6 Hz, 2H), 2.68 (s, LC / MS (ESI+) calcd for C 38 H 35 N5O7([M+H]+) m / z 674,found 674.

[0190] Example 127: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(((cis)-3-(4-(2-(4-((2-(1-hydroxyethyl)pyrimidin-5-yl))oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 118. The yield was 25%. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.58 (s, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 6.4 Hz, 1H), 7.32 - 7.20 (m, 2H), 7.19 - 7.09 (m, 2H), 7.07 - 6.97 (m, 2H), 6.90 (d, J = 2.0 Hz, 1H), 6.86 - 6.73 (m, 3H), 5.24 (d, J = 5.5 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.86 - 4.73 (m, 1H), 4.57 - 4.41 (m, 1H), 3.86 - 3.67 (m, 1H), 3.00 (s, 3H), 2.94 - 2.81 (m, 1H), 2.63 - 2.52 (m, 1H), 2.08 - 1.87 (m, 3H), 1.61 (s, 6H), 1.41 (d, J = 6.6 Hz, 3H). LC / MS (ESI+) calcd for C 38 H 37 NO([M+H] + ) m / z 676,found 676.

[0191] Example 128: Synthesis of 5-(((cis)-3-(4-(2-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 119. The yield was 80%. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.70 (s, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 6.4 Hz, 1H), 7.37 - 7.25 (m, 2H), 7.22 - 7.08 (m, 4H), 6.95 - 6.73 (m, 4H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.50 (t, J = 6.9 Hz, 1H), 3.78 (d, J = 7.3 Hz, 1H), 3.13 - 2.98 (m, 2H), 2.95 - 2.77 (m, 1H), 2.69 - 2.51 (m, 5H), 2.04 - 1.88 (m, 3H), 1.63 (s, 6H). LC / MS (ESI+) calcd for C 38 H 35 NO([M+H] + ) m / z 674, found 674.

[0192] Example 129: 2-(2,6-dioxopiperidin-3-yl)-5-((cis)-3-(4-(2-(4-((5-(1-hydroxyethyl)pyrazin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 118. The yield was 25%. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.41 (d, J = 1.4 Hz, 1H), 8.29 - 8.19 (m, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 6.5 Hz, 1H), 7.33 - 7.22 (m, 2H), 7.21 - 7.12 (m, 2H), 7.12 - 7.04 (m, 2H), 6.95 - 6.74 (m, 4H), 5.49 (d, J = 4.7 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.79 (dd, J = 6.5, 4.7 Hz, 1H), 4.50 (t, J = 6.9 Hz, 1H), 3.78 (d, J = 7.2 Hz, 1H), 3.14 - 2.97 (m, 2H), 2.95 - 2.81 (m, 1H), 2.63 - 2.52 (m, 1H), 2.06 - 1.88 (m, 3H), 1.63 (s, 6H), 1.44 - 1.33 (m, 3H). LC / MS (ESI+) calcd for C 38 H 37 NO([M+H] + ) m / z 676, found 676.

[0193] Example 130: Synthesis of 5-((cis)-3-(4-(2-(4-((5-acetylpyrazin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 119. The yield was 80%. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.65 (d, J = 25.9 Hz, 2H), 7.59 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 6.4 Hz, 1H), 7.37 - 7.05 (m, 6H), 6.98 - 6.72 (m, 4H), 5.04 (dd, J = 13.2, 5.2 Hz, 1H), 4.60 - 4.39 (m, 1H), 3.78 (s, 1H), 3.06 (s, 2H), 2.88 (t, J = 14.5 Hz, 1H), 2.57 (d, J = 18.9 Hz, 4H), 1.96 (d, J = 16.5 Hz, 4H), 1.64 (s, 6H). LC / MS (ESI+) calcd for C 38 H 35 NO([M+H] + ) m / z 674, found 674.

[0194] Example 131: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((trans)-3-(4-(3-(4-((2-(1-hydroxyethyl)pyrimidin-5-yl)oxy)phenyl)pentan-3-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 118. The yield was 25%. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.56 (s, 2H), 7.56 (dd, J = 20.9, 6.8 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.09 - 6.96 (m, 4H), 6.90 - 6.71 (m, 4H), 5.24 (d, J = 5.5 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.93 - 4.71 (m, 2H), 4.14 (d, J = 5.7 Hz, 1H), 2.87 (td, J = 17.2, 15.4, 5.3 Hz, 1H), 2.63 - 2.51 (m, 3H), 2.41 (t, J = 6.1 Hz, 3H), 2.01 (dq, J = 13.7, 6.0, 5.4 Hz, 5H), 1.40 (d, J = 6.5 Hz, 3H), 0.56 (t, J = 7.1 Hz, 6H). LC / MS (ESI+) calcd for C 40 H 41 NO([M+H] + ) m / z 704, found 704.

[0195] Example 132: 5-((trans)-3-(4-(3-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)pentan-3-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopyridin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 119. The yield was 80%. 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.68 (s, 2H), 7.56 (dd, J = 20.5, 6.8 Hz, 2H), 7.33 - 7.01 (m, 6H), 6.95 - 6.65 (m, 4H), 5.03 (dd, J = 13.1, 5.5 Hz, 1H), 4.94 - 4.83 (m, 1H), 4.14 (s, 1H), 2.97 - 2.79 (m, 1H), 2.64 (s, 3H), 2.43 (q, J = 7.3, 6.2 Hz, 2H), 2.03 (td, J = 14.9, 14.0, LC / MS (ESI+) calcd for C 40 H 39 NO([M+H] + ) m / z 702, found 702.

[0196] Example 133: 2-(2,6-dioxopiperidin-3-yl)-5-((cis)-3-(4-(3-(4-((2-(1-hydroxyethyl)pyrimidin-5-yl)oxy)phenyl)pentan-3-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 118. The yield was 25%. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.56 (s, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 6.4 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.10 - 6.99 (m, 4H), 6.90 (d, J = 2.0 Hz, 1H), 6.85 - 6.75 (m, 3H), 5.24 (d, J = 5.5 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.87 - 4.72 (m, 1H), 4.50 (p, J = 7.0 Hz, 1H), 3.78 (p, J = 7.5 Hz, 1H), 3.13 - 2.96 (m, 2H), 2.87 (ddd, J = 17.2, 14.0, 5.4 Hz, 1H), 2.63 - 2.51 (m, 2H), 2.11 - 1.85 (m, 7H), 1.40 (d, J = 6.5 Hz, 3H), 0.56 (t, J = 7.2 Hz, 6H). LC / MS (ESI+) calcd for C 40 H 41 NO([M+H] + ) m / z 704, found 704.

[0197] Example 134: 2-(2,6-dioxopiperidin-3-yl)-5-((trans)-3-(4-(1-(4-((2-(1-hydroxyethyl)pyrimidin-5-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 118. The yield was 25%. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.56 (s, 2H), 7.56 (dd, J = 21.7, 6.9 Hz, 2H), 7.39 - 7.28 (m, 2H), 7.27 - 7.17 (m, 2H), 7.04 - 6.93 (m, 2H), 6.90 - 6.67 (m, 4H), 5.24 (d, J = 5.5 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.90 - 4.72 (m, 2H), 4.13 (d, J = 5.1 Hz, 1H), 2.88 (ddd, J = 19.5, 15.3, 5.5 Hz, 1H), 2.57 (d, J = 17.6 Hz, 3H), 2.42 (q, J = 6.1 Hz, 2H), 2.23 (s, 4H), 1.99 (q, J = 4.9, 4.2 Hz, 1H), 1.60 (t, J = 3.8 Hz, 4H), 1.40 (d, J = 6.6 Hz, 3H). LC / MS (ESI+) calcd for C 40 H 39 NO([M+H] + ) m / z 702, found 702.

[0198] Example 135: 5-((trans)-3-(4-(1-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)cyclopentyl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared according to a similar method to Example 119. The yield was 80%. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.68 (s, 2H), 7.56 (dd, J = 19.9, 6.8 Hz, 2H), 7.45 - 7.33 (m, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.16 - 7.06 (m, 2H), 6.91 - 6.67 (m, 4H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.84 (dd, J = 8.9, 3.8 Hz, 1H), 4.12 (s, 1H), 2.96 - 2.78 (m, 1H), 2.64 (s, 3H), 2.59 LC / MS (ESI+) calcd for C 40 H 37 NO([M+H] + ) m / z 700, found 700.

[0199] Example 136: 5-((4-((8-(4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl (4-((8-(4-(2-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butylcarbamate Tert-butyl (4-((8-(4-(4-hydroxyphenyl)propyl-2-phenoxy)octyl)oxy)carbamate (264 mg, 0.50 mmol) was dissolved in 5 mL of DMF, and cesium carbonate (325 mg, 1.0 mmol) and (2-(1-ethoxyvinyl)pyrimidin-4-yl)methanesulfonate (129 mg, 0.5 mmol) were added. The mixture was allowed to react at room temperature for 2 hours, and then 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted, and the aqueous layer was separated into 10 mL. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin layer chromatography to obtain 172 mg of the product, tert-butyl (4-((8-(4-(2-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butylcarbamate. The yield was 50%. LC / MS (ESI+) calculation for C 41 H 59 N3O6([M+H] + ) m / e 690.4,found 690.4. Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((8-(4-(2-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)isoindoline-1,3-dione Tert-butyl (4-((8-(4-(2-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butylcarbamate (170 mg, 0.24 mmol) was dissolved in 4 mL of dichloromethane, 1 mL of trifluoroacetic acid was added dropwise in an ice-water bath, and the mixture was allowed to react for 1 hour while keeping the temperature high. The pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain 130 mg of a solid product. 65 mg was dissolved in 5 mL of DMSO, and 5 drops of N,N-diisopropylethylamine and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (48 mg, 0.16 mmol) were added dropwise. The mixture was reacted at 90 ° C overnight, cooled, extracted with dichloromethane / water, dried, concentrated to dryness, and purified by thin layer chromatography to obtain 23 mg of the product 2-(2,6-dioxopiperidin-3-yl)-5-(4-((8-(4-(2-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)isoindoline-1,3-dione. The yield was 25%. LC / MS (ESI+) calculation for C 49 H 59 NO([M+H] + ) m / e 845.4,found 845.4. Step 3: Synthesis of 5-((4-((8-(4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 2-(2,6-Dioxopiperidin-3-yl)-5-(4-((8-(4-(2-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)isoindoline-1,3-dione (23 mg, 0.027 mmol) was dissolved in 4 mL of acetone, 2 mL of 2N aqueous HCl solution was added, and the mixture was reacted at room temperature for 1.5 h. 15 mL of ethyl acetate and 12 mL of water were added, stirred, and extracted. The aqueous layer was then separated into 10 mL of acetone and 2 mL of 2N aqueous HCl solution. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin layer chromatography to obtain 10 mg of the product, 5-((4-((8-(4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)octyl)oxy)butyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. The yield was 45%. LC / MS (ESI+) calculation for C 47 H 55 NO([M+H] + ) m / e 818.4,found 818.4, 1H NMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 5.0 Hz, 1H), 8.00 (s, 1H), 7.74 (d, J = 4.8 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.14 - 7.09 (m, 2H), 6.99 (s, 1H), 6.86 (d, J = 8.5 Hz, 2H), 6.82 - 6.74 (m, 3H), 5.25 (s, 2H), 4.92 (dd, J = 12.0, 5.2 Hz, 1H), 3.91 (t, J = 6.5 Hz, 2H), 3.45 (dt, J = 13.3, 6.2 Hz, 4H), 3.25 (t, J = 6.5 Hz, 2H), 2.80 (s, 5H), 2.13 (d, J = 5.9 Hz, 2H), 2.01 (d, J = 4.6 Hz, 2H), 1.74 (dd, J = 13.7, 6.4 Hz, 6H), 1.63 (s, 6H), 1.46 - 1.41 (m, 2H), 1.26 (s, 6H).

[0200] Example 137: 5-((4-(2-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-N-methyl-1,2,4-oxadiazole-3-formamide [ka] Step 1: Synthesis of tert-butyl (3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)propyl)carbamate Bisphenol A (17.1 g, 75 mmol) was dissolved in 100 mL of DMF. Anhydrous cesium carbonate (24.4 g, 75 mmol) was added with stirring. N-Boc-3-aminopropyl bromide (11.9 g, 50 mmol) was dissolved in 30 mL of DMF and added dropwise to the reaction mixture. After the addition was complete, the mixture was reacted at 60 °C for 5 h. The mixture was then cooled to room temperature, and 150 mL of ethyl acetate and 120 mL of water were added. The mixture was stirred and extracted. The aqueous layer was back-extracted once more with 100 mL of ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The product was purified by column chromatography to give 12.2 g of tert-butyl (3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)propyl)carbamate in 63% yield. LC / MS (ESI+) calculation for C 23 H 31 NO4([M+H] + ) m / e 386.2,found 386.2. Step 2: Synthesis of ethyl 5-((4-(2-(4-(3-((tert-butoxycarbonyl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-1,2,4-oxadiazole-3-carboxylate Tert-butyl (3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)propyl)carbamate (1930 mg, 5.0 mmol) was dissolved in 15 mL of DMF, anhydrous potassium carbonate (1.38 g, 10 mmol) was added, and ethyl 5-(chloromethyl)-1,2,4-oxadiazole-3-carboxylate (953 mg, 5.0 mmol) was added. The mixture was stirred overnight at room temperature, and then 35 mL of ethyl acetate and 30 mL of water were added and extracted. The organic layer was back-extracted once with 25 mL of ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by column chromatography to obtain 1.55 g of the product, 5-((4-(2-(4-(3-((tert-butoxycarbonyl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-1,2,4-oxadiazole-3-carboxylate. The yield was 57%. LC / MS (ESI+) calculation for C 29 H 37 N3O7([M+H] + ) m / e 540.2,found 540.2 . Step 3: Synthesis of tert-butyl (3-(4-(2-(4-((3-(methylcarbamoyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)carbamate Ethyl 5-((4-(2-(4-(3-((tert-butoxycarbonyl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-1,2,4-oxadiazole-3-carboxylate (225 mg, 0.42 mmol) was dissolved in 2 mL of methanol, and 1 mL of 7 mmol / L methylamine alcohol solution was added. The mixture was reacted in a sealed tube at 100°C for 3 h, cooled to room temperature, and purified by thin-layer chromatography to obtain 120 mg of tert-butyl (3-(4-(2-(4-((3-(methylcarbamoyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)carbamate. The yield was 54%. LC / MS (ESI+) calculation for C 28 H 36 N4O6([M+H] + ) m / e 525.3,found 525.3 . Step 4: Synthesis of 5-((4-(2-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-N-methyl-1,2,4-oxadiazole-3-formamide Tert-butyl (3-(4-(2-(4-((3-(methylcarbamoyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)carbamate (120 mg, 0.24 mmol) was dissolved in 4 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added dropwise in an ice-water bath. The mixture was allowed to react for 1 hour while keeping the temperature constant. The pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with a 10:1 mixture of dichloromethane and methanol. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to dryness. Dissolved in 5 mL of dimethyl sulfoxide, 5 drops of N,N-diisopropylethylamine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (70 mg, 0.25 mmol) were added, and the mixture was reacted at 95°C overnight. The mixture was cooled, extracted with dichloromethane / water, dried, concentrated to dryness, and purified by thin layer chromatography to obtain the product 5-((4-(2-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-N-methyl-1,2,4-oxadiazole-3-formamide 29 mg. The yield was 18%. LC / MS (ESI+) calculation for C 36 H 36 NO([M+H] + ) m / e 681.3,found681.3; 1H NMR (400 MHz, Chloroform-d) δ 8.13 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.20 - 7.10 (m, 4H), 7.06 (s, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.90 - 6.85 (m, 2H), 6.84 - 6.79 (m, 2H), 6.75 (dd, J = 8.3, 2.2 Hz, 1H), 5.31 (s, 2H), 5.01 (s, 1H), 4.93 (dd, J = 12.1, 5.2 Hz, 1H), 4.09 (t, J = 5.5 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 3.04 (d, J = 5.1 Hz, 3H), 2.93 - 2.68 (m, 4H), 2.15 - 2.11 (m, 2H), 1.64 (s, 6H).

[0201] Example 138: 5-((4-(2-(4-((8-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)octyloxy)phenyl)propan-2-yl)phenoxy)methyl)-1,2,4-oxadiazole-3-formamide [ka] The target compound was prepared using a method similar to that of Example 137. LC / MS (ESI+) calculation for C 44 H 52 N6O9([M+H] + ) m / e 809.4,found 809.4; 1H NMR (400 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 4.9 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 6.81 - 6.71 (m, 3H), 5.96 (s, 1H), 5.33 (s, 2H), 4.96 - 4.90 (m, 1H), 3.91 (t, J = 6.5 Hz, 2H), 3.45 (dt, J = 13.1, 6.1 Hz, 4H), 3.30 - 3.22 (m, 2H), 2.94 - 2.68 (m, 4H), 1.78 - 1.71 (m, 6H), 1.63 (s, 6H), 1.59 (d, J = 7.9 Hz, 2H), 1.46 - 1.41 (m, 2H), 1.26 (t, J = 4.7 Hz, 6H).

[0202] Example 139: 5-((3-(4-(2-(4-((3-(azacyclobutane-1-carbonyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 137. LC / MS (ESI+) calculation for C 38 H 38 NO([M+H] + ) m / e 706.3,found 706.3. 1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.19 - 7.10 (m, 4H), 6.98 (d, J = 2.2 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.84 - 6.78 (m, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 5.32 (s, 2H), 5.02 - 4.89 (m, 2H), 4.60 - 4.53 (m, 2H), 4.29 - 4.23 (m, 2H), 4.09 (t, J = 5.5 Hz, 2H), 3.46 (q, J = 7.2, 5.9 Hz, 2H), 2.93 - 2.69 (m, 3H), 2.46 - 2.35 (m, 2H), 2.18 - 2.07 (m, 3H), 1.63 (s, 6H).

[0203] Example 140: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-((3-(pyrrolidine-1-carbonyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 137. LC / MS (ESI+) calculation for C 39 H 40 NO([M+H] + ) m / e 721.3,found 721.3. 1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.19 - 7.10 (m, 4H), 6.98 (d, J = 2.2 Hz, 1H), 6.92 - 6.87 (m, 2H), 6.84 - 6.79 (m, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 5.33 (s, 2H), 4.97 - 4.89 (m, 1H), 4.41 (s, 1H), 4.09 (t, J = 5.5 Hz, 2H), 3.77 (t, J = 6.5 Hz, 2H), 3.69 (t, J = 6.6 Hz, 2H), 3.51 - 3.42 (m, 2H), 2.93 - 2.69 (m, 3H), 2.17 - 2.08 (m, 3H), 1.98 (dtd, J = 9.6, 7.0, 5.2 Hz, 4H), 1.64 (s, 6H).

[0204] Example 141: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(2-(4-((3-(4-methylpiperazine-1-carbonyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 137. LC / MS (ESI+) calculation for C 40 H 43 N7O8([M+H] + ) m / e 750.3,found 750.3. 1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.15 (dd, J = 8.8, 6.9 Hz, 4H), 6.98 (d, J = 2.2 Hz, 1H), 6.92 - 6.85 (m, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 5.33 (s, 2H), 4.99 (s, 1H), 4.92 (dd, J = 12.1, 5.2 Hz, 1H), 4.09 (t, J = 5.5 Hz, 2H), 3.88 (s, 2H), 3.72 (s, 2H), 3.46 (q, J = 6.3 Hz, 2H), 2.91 - 2.72 (m, 3H), 2.54 (s, 3H), 2.39 (s, 3H), 2.12 (dt, J = 10.1, 4.8 Hz, 4H), 1.64 (s, 6H).

[0205] Example 142: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-((3-(morpholine-4-carbonyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)propan-2-yl)phenoxy)propyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 137. LC / MS (ESI+) calculation for C 39 H 40 N6O9([M+H] + ) m / e 737.3,found737.3. 1H NMR (400 MHz, Chloroform-d) δ 8.13 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.20 - 7.10 (m, 4H), 6.98 (d, J = 2.1 Hz, 1H), 6.92 - 6.86 (m, 2H), 6.84 - 6.79 (m, 2H), 6.75 (dd, J = 8.3, 2.1 Hz, 1H), 5.33 (s, 2H), 4.97 - 4.88 (m, 1H), 4.09 (t, J = 5.5 Hz, 2H), 3.86 - 3.76 (m, 4H), 3.74 - 3.65 (m, 4H), 3.46 (t, J = 6.4 Hz, 2H), 2.92 - 2.70 (m, 4H), 2.17 - 2.07 (m, 2H), 1.64 (s, 6H).

[0206] Example 143: 5-((4-(2-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propoxy)phenyl)propan-2-yl)phenoxy)methyl)-1,2,4-oxadiazole-3-formamide [ka] The target compound was prepared using a method similar to that of Example 137. LC / MS (ESI+) calculation for C 35 H 36 NO([M+H] + ) m / e 666.2,found 666.2. 1H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.15 (dd, J = 8.7, 6.6 Hz, 4H), 6.98 (d, J = 2.0 Hz, 1H), 6.92 - 6.85 (m, 3H), 6.82 (d, J = 8.8 Hz, 2H), 6.76 - 6.72 (m, 1H), 5.33 (s, 2H), 4.93 (dd, J = 11.9, 5.2 Hz, 1H), 4.09 (t, J = 5.5 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 2.93 - 2.73 (m, 4H), 2.14 (d, J = 7.4 Hz, 2H), 1.29 - 1.23 (m, 6H).

[0207] Example 144: 5-((R)-2-((4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of (R)-tert-butyl 2-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate Boc-D-prolinol (1.05 g, 5.0 mmol) was dissolved in 15 mL of dichloromethane, triethylamine (1.01 g, 10.0 mmol) was added, and methanesulfonyl chloride (684 mg, 6.0 mmol) was added in an ice-water bath. The mixture was warmed to room temperature and reacted at room temperature overnight. The mixture was washed with a saturated aqueous ammonium chloride solution and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to dryness to obtain the product, 1.22 g of tert-butyl (R)-2-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate. Step 2: Synthesis of (R)-tert-butyl 2-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrrolidine-1-carboxylate Bisphenol A (514 mg, 2.25 mmol) was dissolved in 6 mL of DMF, and anhydrous cesium carbonate (975 mg, 3.0 mmol) and (R)-tert-butyl 2-((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (420 mg, 1.5 mmol) were added. The mixture was incubated at 60 °C for 5 h, cooled to room temperature, and then 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted. The aqueous layer was back-extracted once more with 10 mL of ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin-layer chromatography to give 200 mg of the product, (R)-tert-butyl 2-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrrolidine-1-carboxylate. The yield was 33%. LC / MS (ESI+) calculation for C 25 H 33 NO4([M+H] + ) m / e 412.2 ,found 412.2. Step 3: Synthesis of tert-butyl (R)-2-((4-(2-(4-((2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidine-1-carboxylate (R)-tert-butyl 2-((4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)methyl)pyrrolidine-1-carboxylate (112 mg, 0.27 mmol) was dissolved in 5 mL of DMF, and anhydrous cesium carbonate (176 mg, 0.54 mmol) and methyl (2-(1-ethoxyvinyl)pyrimidin-4-yl)methanesulfonate (70 mg, 0.27 mmol) were added. The mixture was reacted at 60°C for 4 hours, cooled to room temperature, and 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted. The aqueous layer was separated into 10 mL of ethyl acetate and 10 mL of water. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin layer chromatography to obtain 110 mg of the product, tert-butyl (R)-2-((4-(2-(4-((2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidine-1-carboxylate. The yield was 71%. LC / MS (ESI+) calculation for C 34 H 43 N3O5([M+H] + ) m / e 574.3,found 574.3. Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((R)-2-((4-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)isoindoline-1,3-dione (R)-tert-Butyl 2-((4-(2-(4-((2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidine-1-carboxylate (110 mg, 0.19 mmol) was dissolved in 4 mL of dichloromethane, 1 mL of trifluoroacetic acid was added dropwise in an ice-water bath, and the mixture was allowed to react for 1 hour while keeping the temperature high. The pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Dissolved in 5 mL of DMSO, 5 drops of N,N-diisopropylethylamine and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (70 mg, 0.25 mmol) were added, and the mixture was reacted at 90 ° C overnight. The mixture was cooled, extracted with dichloromethane / water, dried, concentrated to dryness, and purified by thin layer chromatography to obtain 50 mg of the product, 2-(2,6-dioxopiperidin-3-yl)-5-((R)-2-((4-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)isoindoline-1,3-dione. The yield was 36%. LC / MS (ESI+) calculation for C 42 H 43 NO([M+H] + ) m / e 730.3,found 730.3. Step 5: Synthesis of 5-((R)-2-((4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 2-(2,6-Dioxopiperidin-3-yl)-5-((R)-2-((4-(2-(1-ethoxyvinyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)isoindoline-1,3-dione (50 mg, 0.069 mmol) was dissolved in 4 mL of acetone, 2 mL of 2N aqueous HCl was added, and the mixture was reacted at room temperature for 1.5 h. 15 mL of ethyl acetate and 12 mL of water were added, stirred, and extracted. The aqueous layer was then separated into 10 mL of acetone and 2 mL of 2N aqueous HCl was added. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin layer chromatography to obtain 20 mg of the product, 5-((R)-2-((4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. The yield was 42%. LC / MS (ESI+) calculation for C 40 H 39 NO([M+H] + ) m / e 702.8,found 702.8; 1H NMR (400 MHz, Chloroform-d) δ 8.91 (d, J = 5.1 Hz, 1H), 8.08 (d, J = 14.0 Hz, 1H), 7.73 (dd, J = 5.1, 1.1 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.20 - 7.06 (m, 5H), 6.89 - 6.80 (m, 3H), 6.79 - 6.73 (m, 2H), 5.24 (s, 2H), 4.94 (dd, J = 12.2, 5.2 Hz, 1H), 4.29 (s, 1H), 4.01 (dd, J = 9.2, 3.8 Hz, 1H), 3.84 (t, J = 8.4 Hz, 1H), 3.59 (t, J = 8.6 Hz, 1H), 3.34 (q, J = 8.6, 6.6 Hz, 1H), 2.93 - 2.83 (m, 1H), 2.80 (s, 3H), 2.79 - 2.59 (m, 2H), 2.28 - 2.08 (m, 5H), 1.63 (s, 6H).

[0208] Example 145: 5-((S)-2-((4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 144. LC / MS (ESI+) calculation for C 40 H 39 NO([M+H] + ) m / e 702.8,found 702.8. 1H NMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 14.6 Hz, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.20 - 7.03 (m, 5H), 6.84 (t, J = 9.9 Hz, 3H), 6.77 (d, J = 8.5 Hz, 2H), 5.24 (s, 2H), 4.94 (dd, J = 12.3, 5.2 Hz, 1H), 4.29 (s, 1H), 4.01 (dd, J = 9.3, 3.6 Hz, 1H), 3.84 (t, J = 8.4 Hz, 1H), 3.59 (s, 1H), 3.34 (s, 1H), 2.93 - 2.69 (m, 6H), 2.27 - 2.09 (m, 5H), 1.63 (s, 6H).

[0209] Example 146: 5-((1r,4r)-4-((4-(2-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)cyclohexyl)amino)-2-(2,6-dioxopyridin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 144. LC / MS (ESI+) calculation for C 42 H 43 NO([M+H] + ) m / e 730.3,found 730.3. 1H NMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 15.3, 8.6 Hz, 4H), 6.96 (s, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1H), 5.35 (t, J = 4.9 Hz, 2H), 5.25 (s, 2H), 4.93 (dd, J = 12.1, 5.5 Hz, 1H), 4.31 (t, J = 6.7 Hz, 1H), 3.78 (d, J = 6.1 Hz, 2H), 3.39 (s, 1H), 2.81 (s, 4H), 2.27 - 2.15 (m, 3H), 2.01 (d, J = 6.5 Hz, 4H), 1.42 (d, J = 6.6 Hz, 1H), 1.26 (s, 6H), 0.87 (d, J = 7.0 Hz, 2H).

[0210] Example 147: 5-((4-(4-(2-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of 4-(2-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenol 4-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenol (1.76 g, 5.0 mmol) was dissolved in 13 mL of DMSO, DIEA (1.95 g, 15 mmol) was added, and 2-oxo-6-azaspiro[3.3]heptane hemioxalate (865 mg, 3.0 mmol) was added. The mixture was reacted at 90°C overnight, cooled to room temperature, and 30 mL of ethyl acetate and 25 mL of water were added. The mixture was stirred and extracted. The aqueous layer was back-extracted once more with 25 mL of ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. 10 mL of ethyl acetate was added to the mixture. The mixture was slurried for 1 min, filtered, and the filter cake was dried to obtain 1.7 g of the product, 4-(2-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenol. The yield was 81%. LC / MS (ESI+) calculation for C 25 H 27 N3O3([M+H] + ) m / e 418.2,found 418.2. Step 2: tert-butyl 4-(4-(2-(4-((2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidine-1-carboxylate 4-(2-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenol (100 mg, 0.23 mmol) was dissolved in 5 mL of DMF, and anhydrous cesium carbonate (325 mg, 1.0 mmol) and 1-N-Boc-4-bromopiperidine (132 mg, 0.5 mmol) were added, followed by reaction at 80°C overnight. The mixture was cooled to room temperature, and 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted. The aqueous layer was back-extracted once more with 10 mL of ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by thin-layer chromatography to obtain 50 mg of the product, tert-butyl 4-(4-(2-(4-((2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidine-1-carboxylate. The yield was 35%. LC / MS (ESI+) calculation for C 35 H 44 N4O5([M+H] + ) m / e 601.3,found 601.3. Step 3: 5-((4-(4-(2-(4-((2-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione tert-Butyl 4-(4-(2-(4-((2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidine-1-carboxylate (50 mg, 0.083 mmol) was dissolved in 4 mL of dichloromethane, 1 mL of trifluoroacetic acid was added in an ice-water bath, the mixture was kept warm for 1 h, the pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The mixture was dissolved in 5 mL of acetonitrile, and 3 drops of N,N-diisopropylethylamine and 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (30 mg, 0.09 mmol) were added. The mixture was allowed to react at 40°C overnight, cooled, extracted with dichloromethane / water, dried, concentrated to dryness, and purified by thin layer chromatography to obtain the product 5-((4-(4-(2-(4-((2-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)piperidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (12 mg). The yield was 18%. LC / MS (ESI+) calculation for C 44 H 46 N6O7([M+H] + ) m / e 771.3,found 771.3; 1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 5.1 Hz, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.88 (d, J = 4.6 Hz, 1H), 7.17 - 7.06 (m, 4H), 6.86 - 6.74 (m, 5H), 4.99 (dd, J = 12.3, 5.2 Hz, 1H), 4.94 (s, 2H), 4.86 (s, 4H), 4.41 (s, 1H), 4.29 (s, 4H), 3.84 (s, 1H), 2.97 - 2.68 (m, 5H), 2.54 (s, 1H), 2.17 (dt, J = 10.6, 6.6 Hz, 2H), 1.94 (s, 3H), 1.62 (s, 6H), 1.26 (s, 2H).

[0211] Example 148: 5-((3-(4-(2-(4-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)azetidin-1-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 147. LC / MS (ESI+) calculation for C 42 H 42 N6O7([M+H] + ) m / e 743.3,found 743.3. 1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 5.0 Hz, 1H), 8.27 (s, 1H), 7.88 (s, 3H), 7.12 (dd, J = 8.8, 2.1 Hz, 4H), 6.86 - 6.78 (m, 3H), 6.68 - 6.61 (m, 2H), 4.98 (dd, J = 12.2, 5.3 Hz, 1H), 4.94 (s, 2H), 4.89 (d, J = 6.3 Hz, 1H), 4.86 (s, 4H), 4.29 (s, 4H), 4.11 (s, 1H), 4.04 (s, 2H), 3.40 (s, 2H), 2.96 - 2.69 (m, 4H), 2.19 - 2.11 (m, 1H), 1.61 (s, 6H).

[0212] Example 149: 5-((R)-1-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-methylbutan-2-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl (R)-(1-(4-(2-(4-((2-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-methylbutan-2-yl)carbamate 4-(2-(4-((2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenol (140 mg, 0.34 mmol) was dissolved in 5 mL of DMF, and cesium carbonate (330 mg, 1.02 mmol) and (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutyl methanesulfonate (191 mg, 0.68 mmol) were added. The mixture was reacted at 100°C overnight, cooled to room temperature, and 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted. The aqueous layer was separated and 10 mL of ethyl acetate was added. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by thin layer chromatography to obtain 150 mg of the product, (R)-(1-(4-(2-(4-((2-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-methylbutan-2-yl)tert-butylcarbamate. The yield was 73%. LC / MS (ESI+) calculation for C 35 H 46 N4O5([M+H] + ) m / e 603.3,found 603.3. Step 2: Synthesis of 5-((R)-1-(4-(2-(4-((2-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-methylbutan-2-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (R)-(1-(4-(2-(4-((2-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-methylbutan-2-yl)tert-butylcarbamate (80 mg, 0.13 mmol) was dissolved in 4 mL of dichloromethane, 1 mL of trifluoroacetic acid was added dropwise in an ice-water bath, and the mixture was allowed to react for 1 h. The pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to dryness to obtain 60 mg of the product. The product was dissolved in 5 mL of DMSO and 3 drops of N,N-diisopropylethylamine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (40 mg, 0.15 mmol). The mixture was added with 5-((R)-1-(4-(2-(4-((2-(2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-methylbutan-2-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3 mg). The yield was 3%. LC / MS (ESI+) calculation for C 43 H 46 N6O7([M+H] + ) m / e 759.3,found 759.3; 1H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 8.15 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 4H), 7.03 (s, 1H), 6.98 (s, 1H), 6.82 - 6.75 (m, 5H), 5.02 (s, 2H), 4.93 (s, 1H), 4.87 (s, 4H), 4.56 (s, 4H), 4.05 (s, 2H), 3.63 (s, 1H), 2.89 - 2.76 (m, 3H), 2.13 (s, 1H), 1.62 (s, 6H), 1.06 (dd, J = 6.7, 3.3 Hz, 6H).

[0213] Example 150: 5-((S)-1-(4-(2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)-3-methylbutan-2-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 149. LC / MS (ESI+) calculation for C 43 H 46 N6O7([M+H] + ) m / e 759.3,found 759.3.

[0214] Example 151: 5-((1-(4-(2-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-2-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 149. LC / MS (ESI+) calculation for C 41 H 42 N6O7([M+H] + ) m / e 731.3,found 731.3. 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 4.7 Hz, 1H), 8.11 (d, J = 14.2 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 8.5 Hz, 4H), 7.02 (d, J = 2.1 Hz, 1H), 6.91 (s, 1H), 6.80 (t, J = 8.9 Hz, 5H), 4.99 (s, 2H), 4.96 - 4.91 (m, 1H), 4.86 (s, 4H), 4.45 (s, 4H), 4.02 (s, 2H), 3.97 (d, J = 5.3 Hz, 1H), 2.94 - 2.66 (m, 4H), 2.12 (d, J = 5.3 Hz, 1H), 1.63 (s, 6H), 1.41 (d, J = 6.0 Hz, 3H).

[0215] Example 152: 5-((1R)-2-(4-(2-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclohexyl)amino)-2-(2,6-dioxopyridin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 149. LC / MS (ESI+) calculation for C 44 H 46 N6O7([M+H] + ) m / e 771.3,found 771.3.

[0216] Example 153: 5-(((1s,4s)-4-(4-(2-(4-((2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenoxy)cyclohexyl)amino)-2-(2,6-dioxopyridin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 149. LC / MS (ESI+) calculation for C 44 H 46 N6O7([M+H] + ) m / e 771.3,found 771.3. 1 H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 5.0 Hz, 1H), 8.08 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.18 - 7.09 (m, 4H), 6.97 (d, J = 2.2 Hz, 1H), 6.86 - 6.77 (m, 5H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 4.94 (s, 2H), 4.94 - 4.89 (m, 1H), 4.86 (s, 4H), 4.51 (d, J = 11.9 Hz, 2H), 4.30 (s, 4H), 3.50 (s, 1H), 2.93 - 2.68 (m, 3H), 2.16 - 2.06 (m, 2H), 2.01 (d, J = 5.5 Hz, 1H), 1.89 (s, 2H), 1.72 (d, J = 9.8 Hz, 4H), 1.26 (s, 6H).

[0217] Example 154: 5-((1-(4-(2-(4-(4-((2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)phenyl)azacyclobutan-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 149. LC / MS (ESI+) calculation for C 41 H 41 N7O6([M+H] + ) m / e 728.3,found728.3; 1 H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 5.1 Hz, 1H), 8.13 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.17 - 7.07 (m, 4H), 6.92 (d, J = 2.1 Hz, 1H), 6.86 - 6.79 (m, 3H), 6.75 (dd, J = 8.3, 2.2 Hz, 1H), 6.46 - 6.38 (m, 2H), 5.02 (d, J = 6.5 Hz, 1H), 4.94 (s, 2H), 4.92 (d, J = 5.4 Hz, 1H), 4.86 (s, 4H), 4.45 (q, J = 5.7 Hz, 1H), 4.31 (s, 6H), 3.68 (dd, J = 7.6, 4.6 Hz, 2H), 2.92 - 2.69 (m, 3H), 2.15 - 2.08 (m, 1H), 1.62 (s, 6H).

[0218] Example 155: 5-((1s,3s)-3-(4-(2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxapyridin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of 6-(2-chloropyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane 2,4-Dichloropyrimidine (1.19 g, 8.0 mmol) was dissolved in 20 mL of toluene, 2-oxo-6-azaspiro[3.3]heptane hemioxalate (577 mg, 2.0 mmol) was added, and N,N-diisopropylethylamine (1.03 g, 8.0 mmol) was added. The mixture was reacted at room temperature for 3 h, concentrated under reduced pressure to dryness, and purified by thin-layer chromatography to obtain 490 mg of 6-(2-chloropyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane in 58% yield. LC / MS (ESI+) calculation for C9H 10 ClNO ([M+H] + ) m / e 212.0,found 212.0. Step 2: Synthesis of tert-butyl ((1s,3s)-3-(4-(2-(4-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate Tert-butyl ((1s,3s)-3-(4-(2-(4-hydroxyphenyl)propyl-2-phenoxy)cyclobutyl)carbamate (90 mg, 0.23 mmol) was dissolved in 5 mL of DMF, and anhydrous potassium carbonate (64 mg, 0.46 mmol) and 6-(2-chloropyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane (72 mg, 0.34 mmol) were added. The mixture was reacted at 100°C overnight, cooled to room temperature, and 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted. The aqueous layer was then separated and 10 mL of ethyl acetate was added. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin layer chromatography to obtain 75 mg of the product ((1s,3s)-3-(4-(2-(4-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)tert-butylcarbamate. The yield was 57%. LC / MS (ESI+) calculation for C 33 H40 N4O5([M+H] + ) m / e 573.3,found 573.3. Step 3: Synthesis of 5-((1s,3s)-3-(4-(2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxapyridin-3-yl)isoindoline-1,3-dione Tert-butyl ((1s,3s)-3-(4-(2-(4-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (75 mg, 0.13 mmol) was dissolved in 4 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added in an ice-water bath, and the mixture was allowed to react for 1 h while keeping the temperature constant. The pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Dissolved in 5 mL of DMSO, 5 drops of N,N-diisopropylethylamine, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (45 mg, 0.16 mmol) was added, and the mixture was reacted at 93 ° C overnight. The mixture was cooled, extracted with dichloromethane / water, dried, concentrated to dryness, and purified by thin layer chromatography to obtain the product 5-((1s,3s)-3-(4-(2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxapyridin-3-yl)isoindoline-1,3-dione (10 mg). The yield was 16%. LC / MS (ESI+) calculation for C 41 H 40 N6O7([M+H] + ) m / e 729.3,found 729.3; 1H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.24 - 7.20 (m, 2H), 7.18 - 7.14 (m, 2H), 7.07 - 7.04 (m, 2H), 6.92 (d, J = 2.2 Hz, 1H), 6.74 - 6.70 (m, 3H), 5.92 (d, J = 5.9 Hz, 1H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 4.85 (s, 4H), 4.51 (t, J = 6.8 Hz, 1H), 4.26 (s, 4H), 3.77 (t, J = 8.3 Hz, 1H), 3.17 - 3.08 (m, 2H), 2.95 - 2.68 (m, 4H), 2.17 - 2.04 (m, 3H), 1.66 (d, J = 2.8 Hz, 6H).

[0219] Example 156: 5-((1r,3r)-3-(4-(2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxapyridin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 155. LC / MS (ESI+) calculation for C 41 H 40 N6O7([M+H] + ) m / e 729.3,found 729.3.

[0220] Example 157: 2-(2,6-dioxopiperidin-3-yl)-5-((1s,3s)-3-(4-(4-((5-fluoro-4-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 155. LC / MS (ESI+) calculation for C 41 H 39 FN6O7([M+H] + ) m / e 747.3,found 747.3. 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.76 (d, J = 3.6 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.24 - 7.19 (m, 2H), 7.19 - 7.13 (m, 2H), 7.06 - 7.01 (m, 2H), 6.92 (d, J = 2.2 Hz, 1H), 6.72 (dd, J = 9.0, 2.5 Hz, 3H), 4.93 (dd, J = 12.1, 5.2 Hz, 1H), 4.85 (s, 4H), 4.77 (s, 1H), 4.51 (t, J = 6.8 Hz, 1H), 4.43 (s, 4H), 3.77 (s, 1H), 3.18 - 3.07 (m, 2H), 2.93 - 2.66 (m, 3H), 2.16 - 2.03 (m, 3H), 1.66 (s, 6H).

[0221] Example 158: 2-(2,6-dioxopiperidin-3-yl)-5-((1s,3s)-3-(4-(4-((5-fluoro-2-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 155. LC / MS (ESI+) calculation for C 41 H 39 FN6O7([M+H] + ) m / e 747.3,found 747.3. 1 H NMR (400 MHz, Chloroform-d) δ 8.12 - 8.04 (m, 2H), 7.62 (d, J = 8.2 Hz, 1H), 7.24 (s, 2H), 7.18 - 7.11 (m, 2H), 7.08 (t, J = 6.5 Hz, 2H), 6.92 (d, J = 2.1 Hz, 1H), 6.77 - 6.69 (m, 3H), 4.93 (dd, J = 12.0, 5.3 Hz, 1H), 4.79 (s, 4H), 4.54 (q, J = 7.0 Hz, 1H), 4.12 (s, 4H), 3.79 (d, J = 9.4 Hz, 2H), 3.19 - 3.08 (m, 2H), 2.93 - 2.71 (m, 3H), 2.11 (dd, J = 10.4, 4.7 Hz, 3H), 1.69 (s, 6H).

[0222] Example 159: 5-((1s,3s)-3-(4-(2-(4-((6-(2-oxy-6-azaspiro[3.3]heptan-6-yl)pyrazin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopyridin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 155. LC / MS (ESI+) calculation for C 41 H 40 N6O7([M+H] + ) m / e729.3,found 729.3. 1H NMR (400 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 2.1 Hz, 2H), 7.25 - 7.20 (m, 2H), 7.17 - 7.12 (m, 2H), 7.05 - 6.99 (m, 2H), 6.92 (d, J = 2.1 Hz, 1H), 6.76 - 6.70 (m, 3H), 4.93 (dd, J = 12.1, 5.2 Hz, 1H), 4.84 (s, 4H), 4.77 (d, J = 6.0 Hz, 1H), 4.53 (t, J = 6.8 Hz, 1H), 4.19 (s, 4H), 3.78 (d, J = 6.8 Hz, 1H), 3.18 - 3.09 (m, 2H), 2.93 - 2.70 (m, 3H), 2.16 - 2.04 (m, 3H), 1.67 (s, 6H).

[0223] Example 160: 5-((1r,3r)-3-(4-(2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,5-triazin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 155. LC / MS (ESI+) calculation for C 40 H 39 N7O7([M+H] + ) m / e 730.3,found 730.3. 1H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.07 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.26 - 7.23 (m, 2H), 7.18 - 7.13 (m, 2H), 7.07 - 7.02 (m, 2H), 6.89 (d, J = 2.1 Hz, 1H), 6.73 - 6.67 (m, 3H), 4.96 - 4.90 (m, 1H), 4.89 - 4.86 (m, 1H), 4.85 (d, J = 2.5 Hz, 5H), 4.33 (d, J = 21.5 Hz, 4H), 4.22 (d, J = 6.9 Hz, 1H), 2.92 - 2.74 (m, 3H), 2.70 (dd, J = 13.2, 5.9 Hz, 2H), 2.40 (dt, J= 13.6, 6.3 Hz, 2H), 2.16 - 2.08 (m, 1H), 1.67 (s, 6H).

[0224] Example 161: 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(2-(4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of methyl 2-(4-(2-(4-((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)pyrimidine-4-carboxylate Tert-butyl ((1r,3r)-3-(4-(2-(4-hydroxyphenyl)propyl-2-phenoxy)cyclobutyl)carbamate (200 mg, 0.5 mmol) was dissolved in 5 mL of DMF, anhydrous potassium carbonate (138 mg, 1.0 mmol) was added, and methyl 2-chloropyrimidine-4-carboxylate (86 mg, 0.5 mmol) was added with stirring. The mixture was allowed to react at room temperature overnight, and 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted, and the aqueous layer was back-extracted once more with 10 mL of ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. The product was purified by thin-layer chromatography to give methyl 2-(4-(2-(4-((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)pyrimidine-4-carboxylate 190 mg was obtained in a yield of 71%. LC / MS (ESI+) calculation for C 30 H 35 N3O6([M+H] + ) m / e 534.2,found 534.2. Step 2: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate Methyl 2-(4-(2-(4-((1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutoxy)phenyl)propan-2-yl)phenoxy)pyrimidine-4-carboxylate (190 mg, 0.35 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, cooled in an ice-water bath under argon gas protection, and 0.6 mL of 3N MeMgBr solution was added dropwise. After the addition was complete, the mixture was kept warm for 1.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution, and 15 mL of dichloromethane and 10 mL of water were added, stirred, and extracted. The aqueous layer was then separated into 10 The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin layer chromatography to obtain 60 mg of the product ((1r,3r)-3-(4-(2-(4-((4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate. The yield was 32%. LC / MS (ESI+) calculation for C 31 H 39 N3O5([M+H] + ) m / e 534.2,found 534.2. Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(2-(4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione Tert-butyl ((1r,3r)-3-(4-(2-(4-((4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (60 mg, 0.11 mmol) was dissolved in 4 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added in an ice-water bath, and the mixture was allowed to react for 1 hour while keeping the temperature constant. The pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Dissolved in 5 mL of DMSO, 5 drops of N,N-diisopropylethylamine and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (45 mg, 0.16 mmol) were added, and the mixture was reacted at 93 ° C overnight. The mixture was cooled, extracted with dichloromethane / water, dried, concentrated to dryness, and purified by thin layer chromatography to obtain the product 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(2-(4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (12 mg). The yield was 16%. LC / MS (ESI+) calculation for C 39 H 39 NO([M+H] + ) m / e 690.2,found 690.2; 1H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J = 5.1 Hz, 1H), 8.06 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 3.1 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.14 - 7.06 (m, 3H), 6.90 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 9.5, 2.4 Hz, 3H), 4.93 (dd, J = 12.2, 5.2 Hz, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.27 - 4.19 (m, 1H), 2.94 - 2.65 (m, 6H), 2.41 (dt, J = 12.9, 6.1 Hz, 2H), 2.15 - 2.08 (m, 1H), 1.68 (s, 6H), 1.53 (s, 6H).

[0225] Example 162: 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(2-(4-((6-(2-hydroxypropan-2-yl)pyrazin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 161. LC / MS (ESI+) calculation for C 39 H 39 NO([M+H] + ) m / e 690.2,found 690.2. 1H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.27 (s, 1H), 7.25 (d, J = 3.1 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.07 - 7.02 (m, 2H), 6.90 (d, J = 2.1 Hz, 1H), 6.75 - 6.68 (m, 3H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 4.90 - 4.83 (m, 1H), 4.77 (s, 1H), 4.23 (d, J = 4.6 Hz, 1H), 2.94 - 2.74 (m, 3H), 2.74 - 2.66 (m, 2H), 2.41 (dt, J = 12.9, 6.0 Hz, 2H), 2.16 - 2.09 (m, 1H), 1.68 (s, 6H), 1.54 (s, 6H).

[0226] Example 163: 5-((1r,3r)-3-(4-(2-(2-(4-((1H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-ylphenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((2-bromopyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate Tert-butyl ((1r,3r)-3-(4-(2-(4-hydroxyphenyl)propyl-2-phenoxy)cyclobutyl)carbamate (200 mg, 0.5 mmol) was dissolved in 5 mL of DMF, and anhydrous cesium carbonate (325 mg, 1.0 mmol) was added. 4-Fluoro-2-bromopyridine (106 mg, 0.6 mmol) was added with stirring. The mixture was reacted at 80°C for 4 hours, cooled to room temperature, and 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted. The aqueous layer was then separated into 10 mL of ethyl acetate and 10 mL of water. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin-layer chromatography to obtain 240 mg of the product ((1r,3r)-3-(4-(2-(4-((2-bromopyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate. The yield was 87%. LC / MS (ESI+) calculation for C 29 H 33 BrN2O4([M+H] + ) m / e 553.1,found 553.1. Step 2: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((2-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylcarbamate, tert-butyl ((1r,3r)-3-(4-(2-(4-(2-(1H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylcarbamate [ka] Pd2(dba)3 (19 mg, 0.02 mmol) and the ligand (26 mg, 0.055 mmol) were added to a single-neck round-bottom flask, and 1 mL of toluene was added. The mixture was stirred under argon gas protection at 120 °C for 3 min to prepare a precatalyst, followed by cooling to room temperature. ((1r,3r)-3-(4-(2-(4-((2-bromopyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate tert-butyl (125 mg, 0.22 mmol) was dissolved in 3 mL of toluene, and anhydrous potassium phosphate and 2H-triazazole were added. The precatalyst was added under argon gas protection and reacted at 120 °C overnight under argon gas protection. The mixture was cooled to room temperature, and 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted, and the aqueous layer was separated into 10 mL. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin layer chromatography to give 65 mg of the product ((1r,3r)-3-(4-(2-(4-(2-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)tert-butyl cyclobutylcarbamate and 45 mg of the product ((1r,3r)-3-(4-(2-(4-(2-(1H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)tert-butyl cyclobutylcarbamate, for an overall yield of 90%. LC / MS (ESI+) calculation for C 31 H 35 NO([M+H] + ) m / e 542.2,found 542.2. Step 3: Synthesis of 5-(((1r,3r)-3-(4-(2-(4-((2-(1H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-ylphenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Tert-butyl ((1r,3r)-3-(4-(2-(4-(2-(1H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylcarbamate (45 mg, 0.083 mmol) was dissolved in 4 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added in an ice-water bath, and the mixture was allowed to react for 1 hour while keeping the temperature constant. The pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Dissolved in 5 mL of DMSO, 5 drops of N,N-diisopropylethylamine and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (30 mg, 0.11 mmol) were added, and the mixture was reacted at 93°C overnight. The mixture was cooled, extracted with dichloromethane / water, dried, concentrated to dryness, and purified by thin layer chromatography to obtain 20 mg of the product 5-(((1r,3r)-3-(4-(2-(4-((2-(1H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-ylphenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. The yield was 17%. LC / MS (ESI+) calculation for C 39 H 35 N7O6([M+H] + ) m / e 698.2, 1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.34 (d, J = 5.7 Hz, 1H), 8.04 (s, 1H), 7.81 (s, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.06 - 7.00 (m, 2H), 6.93 (dd, J = 5.8, 2.3 Hz, 1H), 6.91 (s, 1H), 6.73 (t, J = 8.1 Hz, 3H), 4.93 (dd, J = 12.2, 5.2 Hz, 1H), 4.88 (s, 1H), 4.24 (s, 1H), 2.94 - 2.66 (m, 5H), 2.42 (s, 2H), 2.17 - 2.08 (m, 1H), 1.70 (s, 6H).

[0227] Example 164: 5-(((1r,3r)-3-(4-(2-(4-((2-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-ylphenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] Tert-butyl ((1r,3r)-3-(4-(2-(4-(2-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutylcarbamate (65 mg, 0.12 mmol) was dissolved in 4 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added in an ice-water bath, and the mixture was allowed to react for 1 hour while keeping the temperature constant. The pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Dissolved in 5 mL of DMSO, 5 drops of N,N-diisopropylethylamine and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (40 mg, 0.14 mmol) were added, and the mixture was reacted at 93° C. overnight. The mixture was cooled, extracted with dichloromethane / water, dried, concentrated to dryness, and purified by thin layer chromatography to obtain 20 mg of the product 5-(((1r,3r)-3-(4-(2-(4-((2-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)oxy)phenyl)propan-2-ylphenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. The yield was 24%. LC / MS (ESI+) calculation for C 39 H 35 N7O6([M+H] + ) m / e 698.2, 1H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 5.7 Hz, 1H), 8.06 (s, 1H), 7.88 (d, J = 1.3 Hz, 2H), 7.66 - 7.59 (m, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 1.8 Hz, 1H), 6.88 - 6.83 (m, 1H), 6.77 - 6.67 (m, 3H), 4.95 - 4.91 (m, 1H), 4.88 (s, 1H), 4.25 (s, 1H), 2.94 - 2.65 (m, 5H), 2.48 - 2.36 (m, 2H), 2.12 (dd, J = 14.2, 6.7 Hz, 1H), 1.70 (s, 6H).

[0228] Example 165: 5-(((1r,3r)-3-(4-(2-((4-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)oxy)phenyl)propan-2-ylphenoxy)cyclobutyl)amino)-2-(2,6-dioxopyridin-3-yl)isoindole-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 164. LC / MS (ESI+) calculation for C 39 H 35 N7O6([M+H] + ) m / e 698.2,found 698.2. 1H NMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 2.7 Hz, 1H), 8.35 (dd, J = 8.9, 2.8 Hz, 1H), 8.07 (s, 1H), 7.83 (s, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.26 (s, 1H), 7.20 - 7.15 (m, 2H), 7.09 - 7.04 (m, 2H), 7.01 (d, J = 8.9 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.71 (dq, J = 10.4, 2.7, 2.2 Hz, 3H), 4.93 (dd, J = 12.1, 5.2 Hz, 1H), 4.90 - 4.83 (m, 1H), 4.22 (td, J = 7.7, 3.8 Hz, 1H), 2.98 - 2.57 (m, 6H), 2.40 (dt, J = 12.8, 6.3 Hz, 2H), 2.12 (ddd, J = 10.4, 5.0, 2.7 Hz, 1H), 1.68 (s, 6H).

[0229] Example 166: 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(2-(4-(4-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] Step 1: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((4-cyanopyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate Tert-butyl ((1r,3r)-3-(4-(2-(4-hydroxyphenyl)propyl-2-phenoxy)cyclobutyl)carbamate (320 mg, 0.8 mmol) was dissolved in 5 mL of DMF, and anhydrous potassium carbonate (221 mg, 1.6 mmol) was added. 2-Fluoro-4-cyanopyrimidine (140 mg, 1.0 mmol) was added with stirring, and the mixture was reacted at 66°C for 5 hours. The mixture was cooled to room temperature, and 15 mL of ethyl acetate and 12 mL of water were added. The mixture was stirred and extracted. The aqueous layer was then separated into 10 mL of ethyl acetate and 10 mL of water. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by thin-layer chromatography to obtain 390 mg of the product ((1r,3r)-3-(4-(2-(4-((4-cyanopyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate. The yield was 97%. LC / MS (ESI+) calculation for C 29 H 32 N4O4([M+H] + ) m / e 501.2,found 501.2. Step 2: Synthesis of tert-butyl ((1r,3r)-3-(4-(2-(4-((4-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate tert-Butyl ((1r,3r)-3-(4-(2-(4-((4-cyanopyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (390 mg, 0.78 mmol) was dissolved in 5 mL of ethanol, and 50% aqueous hydroxylamine solution (106 mg, 1.6 mmol) was added. The mixture was refluxed for 1 h, cooled to room temperature, filtered, and the filter cake was eluted with a small amount of ethyl acetate and dried to give the white solid product. The mixture was dissolved in 3 mL of pyridine, cooled in an ice-water bath, and added dropwise with acetyl chloride (173 mg, 2.2 mmol). After the addition was complete, the mixture was stirred for 10 min, the ice-water bath was removed, and the mixture was heated to 105°C and reacted overnight. The mixture was then concentrated under reduced pressure to dryness and purified by thin-layer chromatography to obtain 235 mg of the product, tert-butyl ((1r,3r)-3-(4-(2-(4-((4-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate. The yield was 54%. LC / MS (ESI+) calculation for C 31 H 35 N5O5([M+H] + ) m / e 558.2,found 558.2. Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(2-(4-(4-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione Tert-butyl ((1r,3r)-3-(4-(2-(4-((4-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)carbamate (230 mg, 0.42 mmol) was dissolved in 4 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added in an ice-water bath, and the mixture was allowed to react for 1 hour while keeping the temperature constant. The pH was adjusted to basic with saturated aqueous sodium carbonate, and the mixture was extracted with dichloromethane / methanol = 10:1, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Dissolved in 5 mL of DMSO, 8 drops of N,N-diisopropylethylamine and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (152 mg, 0.55 mmol) were added, and the mixture was reacted at 93 ° C overnight. The mixture was cooled, extracted with dichloromethane / water, dried, concentrated to dryness, and purified by thin layer chromatography to obtain 60 mg of the product, 2-(2,6-dioxopiperidin-3-yl)-5-((1r,3r)-3-(4-(2-(4-(4-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione. The yield was 20%. LC / MS (ESI+) calculation for C 39 H 35 N7O7([M+H] + ) m / e 714.2,found 714.2; 1H NMR (400 MHz, Chloroform-d) δ 8.69 (d, J = 4.8 Hz, 1H), 8.01 (s, 1H), 7.74 (d, J = 4.7 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.16 (dd, J = 16.4, 8.4 Hz, 4H), 6.90 (s, 1H), 6.71 (d, J = 8.2 Hz, 3H), 4.93 (dd, J = 12.0, 5.2 Hz, 1H), 4.87 (s, 1H), 4.24 (s, 1H), 2.93 - 2.72 (m, 5H), 2.72 (s, 3H), 2.41 (d, J = 10.1 Hz, 2H), 2.16 - 2.08 (m, 1H), 1.69 (s, 6H).

[0230] Example 167: 2-(2,6-dioxopyridin-3-yl)-5-(((1r,3r)-3-(4-(2-((4-(2-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-4-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to that of Example 166. LC / MS (ESI+) calculation for C 40 H 35 N6O7([M+H] + ) m / e 713.2,found 713.2. 1H NMR (400 MHz, Chloroform-d) δ 8.62 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 4.9 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.71 (dd, J = 11.6, 7.5 Hz, 3H), 4.93 (dd, J = 12.2, 5.3 Hz, 1H), 4.88 (s, 1H), 4.22 (d, J = 4.9 Hz, 1H), 2.95 - 2.69 (m, 5H), 2.68 (s, 3H), 2.41 (dt, J = 12.8, 6.0 Hz, 2H), 2.17 - 2.08 (m, 1H), 1.69 (s, 6H).

[0231] Example 168: 5-(((1r,3r)-3-(4-(2-(4-((4-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)oxy)phenyl)propan-2-ylphenoxy)cyclobutyl)amino)-2-(2,6-dioxopyridin-3-yl)isoindoline-1,3-dione [ka] The target compound was prepared using a method similar to ...

Claims

1. A compound selected from any of the following compounds, its optical isomer, its solvate, its pharmaceutically acceptable salt, its tautomer, its meso form, its racemate, its enantiomer, its diastereomer, or its isotopically substituted form: 【Chemical 1】 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】

2. A drug characterized in that it is a formulation prepared by adding a pharmaceutically acceptable excipient to the compound according to claim 1, its optical isomer, its solvate, its pharmaceutically acceptable salt, its tautomer, its meso form, its racemate, its enantiomer, its diastereomer, or its isotopically substituted form as an active ingredient.

3. Use of the compound of claim 1, its optical isomer, its solvate, its pharmaceutically acceptable salt, its tautomer, its meso form, its racemate, its enantiomer, its diastereomer, or its isotopically substituted form in the preparation of a chimeric molecule for the proteolysis induction of the androgen receptor.

4. The use according to claim 3, characterized in that the proteolysis-inducing chimeric molecule is capable of inducing recognition and binding to the androgen receptor.

5. The use according to claim 3, characterized in that the proteolysis-inducing chimeric molecule is capable of degrading the androgen receptor.

6. The use according to claim 3, characterized in that the androgen receptor includes wild-type and mutant androgen receptors.

7. The use according to claim 6, characterized in that the mutant androgen receptor includes a splicing mutant androgen receptor and a point mutant androgen receptor.

8. The use according to claim 7, characterized in that the mutant androgen receptor is a splicing mutant androgen receptor AR-v7.

9. The use according to claim 3, wherein the proteolysis-inducing chimeric molecule is a drug for treating a related disease controlled by the androgen receptor.

10. 10. The use according to claim 9, wherein the disease is cancer, alopecia, acne or COVID-19.

11. The use according to claim 10, characterized in that the cancer is an androgen receptor positive cancer.

12. The use according to claim 10, wherein the cancer is a drug-resistant cancer.

13. 12. The use according to claim 11, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer or salivary gland cancer.

14. 13. The use according to claim 12, wherein the cancer is prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer or salivary gland cancer.

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