Sulfonamidoacetamide compound, preparation method therefor and use thereof

Abstract

Provided in the present invention are a sulfonamidoacetamide compound, a preparation method therefor and the use thereof. The structure of the sulfonamidoacetamide compound is shown as formula I. The sulfonamidoacetamide compound provided by the present invention can be used for the treatment of cancers, inflammations and autoimmune diseases. The compound can effectively reduce the level of GSPT1 and / or RORγ protein.

Description

sulfonamide acetamide compounds, their preparation methods and applications

[0001] Cross-references to related applications

[0002] This application claims the benefit of Chinese application number 2024106988780, filed on May 31, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of medicinal chemistry, specifically relating to sulfonamide acetamide compounds, their preparation methods and applications, and particularly to sulfonamide acetamide compounds, their preparation methods and applications. Background Technology

[0004] GSPT1 is a translation termination factor that mediates stop codon recognition and promotes the release of nascent peptides from ribosomes by binding to eRF1. GSPT1 is also involved in several other key cellular processes, such as cell cycle regulation, cytoskeleton organization, apoptosis, and transcription. Therefore, decreased GSPT1 levels can impair cell proliferation control and promote cell migration and scar formation. GSPT1 is involved in the oncogenic drivers of several different cancer types, including hematologic malignancies, breast cancer, hepatocellular carcinoma, gastric cancer, and prostate cancer. Several GSPT1 degrading agents are currently in clinical trials, and a GSPT1 molecular gel degrading agent has entered Phase I clinical trials for the treatment of acute myeloid leukemia and myelodysplastic syndromes.

[0005] Nuclear receptors are a class of transcription factors that bind to DNA, divided into seven subfamilies. ROR (retinoid receptor-associated orphan receptor) belongs to the thyroid hormone-like receptor subfamily of nuclear receptors, comprising RORα, RORβ, and RORγ. RORγ contains an N-terminal domain, a DNA-binding domain, a hinge region, and a ligand-binding domain. The ligand-binding domain of RORγ contains 12 α-helices and 3 β-sheets. The ligand-binding domain of RORγ binds to nuclear receptor coactivators, activating downstream genes. RORγ is highly expressed in the thymus and lymphoid tissues and is involved in immune cell differentiation and immune system regulation. Furthermore, RORγ is a key factor in hematologic malignancies.

[0006] Currently, there are quite a few small molecule inhibitors developed for RORγ, such as JTE-451, AUR-101, BI 730357, VTP-43742, BMS 986251, and ABBV-157. Among them, AUR-101 and BI 730357 have entered Phase II clinical trials for the treatment of psoriasis; XT-0528 has entered Phase I clinical trials for the treatment of solid tumors and malignant tumors.

[0007] In conclusion, developing compounds that can affect the functional activity of GSPT1 and / or RORγ proteins may be beneficial for developing therapeutic strategies targeting diseases such as cancer, inflammatory diseases, and autoimmune diseases. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the present invention aims to provide sulfonamide-based acetamide compounds, their preparation methods, and applications, particularly sulfonamide-based acetamide compounds, their preparation methods, and applications. The sulfonamide-based acetamide compounds provided by this invention can be used to treat cancer, inflammation, and autoimmune diseases. These compounds can effectively reduce GSPT1 and / or RORγ protein levels.

[0009] To achieve this objective, the present invention adopts the following technical solution:

[0010] In a first aspect, the present invention provides sulfonamide-based acetamide compounds, the structures of which are shown in Formula I:

[0011] Among them, R 1 R 2 and R 4 The substituted group is independently selected from any one of the following: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C12 heteroaryl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocyclic, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, and substituted or unsubstituted C2-C10 alkynyl.

[0012] R 3 The group is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, and substituted or unsubstituted C2-C10 alkynyl, wherein the substituted group is selected from halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkanes, and C1-C6 alkyl.

[0013] Y 1 Selected from single key, -R a OR b -、-R a SR b -、-R a N(R c )R b -、-R a OC(O)R b -、-R a OC(O)ORb -、-R a OC(O)N(R c )R b -、-R a C(O)R b -、-R a C(O)OR b -、-R a CON(R c )R b -、-R a S(O)R b -、-R a S(O)2R b -、-R a SO2N(R c )R b -、-R a N(R c )C(O)OR b -、-R a N(R c )C(O)R b -、-R a N(R c )C(O)N(R c )R b -、-R a N(R c )S(O)R b -、-R a N(R c )S(O)2R b -、-R a N(R c )S(O)2N(R d )R b - Any one of the following: substituted or unsubstituted C1-C10 alkylene, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkyne, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclic, substituted or unsubstituted C4-C13 fused cycloalkyl, substituted or unsubstituted C4-C13 fused heterocyclic, substituted or unsubstituted C5-C13 bridged cycloalkyl, substituted or unsubstituted C5-C13 bridged heterocyclic, substituted or unsubstituted C5-C13 spirocycloalkyl, substituted or unsubstituted C5-C13 spiroheterocyclic, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 heteroaryl, wherein the substituted group is selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkanes, and C1-C6 alkyl.

[0014] R a R bIndependently selected from single bonds, substituted or unsubstituted C1-C10 alkylene groups, substituted or unsubstituted C2-C10 alkenyl groups, substituted or unsubstituted C2-C10 ynynyl groups, substituted or unsubstituted C1-C8 alkoxy groups, substituted or unsubstituted C3-C10 cycloalkyl groups, substituted or unsubstituted C4-C10 heterocyclic groups, substituted or unsubstituted C4-C13 fused cycloalkyl groups, substituted or unsubstituted C4-C13 fused heterocyclic groups, substituted or unsubstituted... The substituted group is selected from any one of C5-C13 bridged cycloalkyl, substituted or unsubstituted C5-C13 bridged heterocyclic group, substituted or unsubstituted C5-C13 spirocycloalkyl, substituted or unsubstituted C5-C13 spiroheterocyclic group, substituted or unsubstituted C6-C12 aryl, and substituted or unsubstituted C6-C12 heteroaryl, wherein the substituted group is selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkanes, and C1-C6 alkyl.

[0015] R c R d Independently selected from any one of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclic, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 heteroaryl, or R c R d Together with the atoms attached to them, they form C3-C20 cycloalkyl or C4-C20 heteroaryl groups, wherein the substituted groups are selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkanes, and C1-C6 alkyl.

[0016] L is selected from any one or a combination of at least two of the following: single bond, substituted or unsubstituted C1-C10 alkylene group, substituted or unsubstituted C2-C10 alkenyl group, substituted or unsubstituted C2-C10 alkyne group, ether group, thioether group, ester group, amino group, amide group, carbamate group, urea group, sulfone group, substituted or unsubstituted C6-C12 aryl group, substituted or unsubstituted C6-C12 heteroaryl group, carbonyl group, substituted or unsubstituted C3-C10 cycloalkyl group, and substituted or unsubstituted C4-C10 heterocyclic group. The substituted group is selected from any one of the following: halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkanes, and C1-C6 alkyl groups.

[0017] Y 2 It is selected from any one of -O-, -NH-, -CH2-, -C(O)- or a single bond.

[0018] E has the structure shown in any one of Equations II-1 to II-4, wherein Indicates the location of the group connection:

[0019] Among them, Y 3 Selected from -O-, -S-, -CHR e -、-C(O)-、-SO2-、-N(R f Any one of them;

[0020] R e R f The group is independently selected from any one of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C8 heterocyclic groups, wherein the substituted group is selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkanes, and C1-C6 alkyl.

[0021] Y 4 Y 5 Y 6 Y 7 Independently selected from -CR g = or -N=.

[0022] R g It is selected from any one of H, halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkanes, and C1-C6 alkyl groups.

[0023] Y 8 Selected from CH or N.

[0024] T 1 T 2 T 3 Choose independently from O or S.

[0025] R 5 R 6 The group is independently selected from any one of H, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocyclic group, wherein the substituted group is selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkanes, and C1-C6 alkyl.

[0026] R 7 It is selected from any one of H, halogen, C1-C5 haloalkanes, C1-C6 alkoxy groups, and C1-C6 alkyl groups.

[0027] Y 9 Selected from -CH2-, -O-, -S-, -NR h -、-C(O)NR i - Any one of them.

[0028] Rh R i It is independently selected from any one of H, C1-C10 alkyl groups, and halogens.

[0029] Compounds with the aforementioned specific structures exhibit excellent anticancer effects. These compounds can be used to treat cancer, inflammation, and autoimmune diseases. They can effectively reduce GSPT1 and / or RORγ protein levels.

[0030] Preferably, the R 1 R 2 R 3 R 4 R 5 R 6 R 7 Y 1 Y 2 Having the same limiting range as above, Y 4 Y 5 Y 6 Y 7 It can be independently selected from either -CH= or -N=.

[0031] Preferably, the Y 4 Y 5 Y 6 Y 7 Selected independently from -CH=.

[0032] Preferably, the L is selected from any one of the following groups: Indicates the location of the group connection:

[0033] Where n and p are independently selected from integers from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, etc.

[0034] m and q are selected from integers from 0 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0035] When m and q are 0, it means that the group does not exist here; A, D, G, J, M, Q, W and Z are independently selected from -CH= or -N=.

[0036] Preferably, the Y 3 Selected from -CH2- or -C(O)-, preferably -C(O)-.

[0037] Preferably, the T 1 T 2 T 3 Selected from O.

[0038] Preferably, the sulfonamide acetamide compound has the structure shown in Formula III:

[0039] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 Y 1 Y 2 L has the same limiting range as described above.

[0040] Preferably, R 1 R 2 and R 4 The substituted group is independently selected from any one of substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C12 heteroaryl, and substituted or unsubstituted C1-C10 alkyl, wherein the substituted group is selected from any one of hydroxyl, halogen, cyano, C1-C5 haloalkanes, and C1-C6 alkyl.

[0041] Preferably, the R 3 It is selected from any one of H and C1-C10 alkyl groups.

[0042] Preferably, the R 5 R 6 It is independently selected from any one of H or C1-C10 alkyl groups.

[0043] Preferably, the R 7 It is selected from any one of H, halogen, or C1-C6 alkoxy groups.

[0044] Preferably, the Y 1 Selected from single key, -R a CON(R c )R b -、-R a N(R c )C(O)R b - Any one of them.

[0045] Preferably, the R a Selected from single-bonded, substituted or unsubstituted C1-C10 alkylene groups.

[0046] Preferably, the R b Selected from single bonds, substituted or unsubstituted C1-C10 alkylene groups, substituted or unsubstituted C3-C10 cycloalkyl groups, and substituted or unsubstituted C3-C10 heterocyclic groups.

[0047] Preferably, the R c Selected from H and C1-C10 alkyl groups.

[0048] Preferably, the Y 2 It is selected from any one of -NH-, -C(O)- or a single bond.

[0049] Preferably, the L is selected from any one of the following groups: Indicates the location of the group connection:

[0050] n and p are independently selected from integers from 1 to 10; m and q are selected from integers from 0 to 10, and m and q being 0 indicates that the group does not exist here; G, J, Q and Z are independently selected from -CH= or -N=.

[0051] Preferably, the sulfonamide acetamide compound has the structure shown in the following formula:

[0052] Among them, R 1 R 2 R 3 R 4 R 7 Y 1 Y 2 L has the same defined range as described above.

[0053] Preferably, the sulfonamide acetamide compound is selected from any one of the structures shown in Examples 1-58 below:

[0054] Secondly, the present invention provides a method for preparing the sulfonamide acetamide compound as described above, the method comprising Scheme 1 and Scheme 2:

[0055] Option 1:

[0056] R 1 R 2 R 3 R 4 Y 1 Y 2 L and E have the same scope of limitation as the first aspect mentioned above;

[0057] Where X a and X b Independently selected from halogens, hydroxyl groups, OTf, OTs, and OMs;

[0058] R 8 Selected from -R a C(O)O- t Bu, Ra It has the same scope of definition as the first aspect mentioned above; R 9 Selected from R 8 The deprotected group; X c Selected from primary amines and secondary amines;

[0059] Or R 8 Selected from -R a O-PG, -R a S-PG, -R a N(R c )-PG, where PG is a hydroxyl, thiol, or amino protecting group, including any one of TBDMS, TIPS, Boc, or Cbz; R a R c It has the same scope of definition as the first aspect mentioned above; R 9 Selected from R 8 The deprotected group; X c Selected from halogens, hydroxyl groups, OTf, OTs, and OMs;

[0060] Or R 8 Selected from -R a CHO, R a Having the same limiting scope as the first aspect mentioned above, X c Selected from primary amines and secondary amines;

[0061] The specific reaction steps are as follows: substrate 1-a and substrate 2-a undergo a nucleophilic substitution reaction to obtain 3-a; substrate 3-a and substrate 4-a undergo a nucleophilic substitution reaction to obtain 5-a; substrate 5-a is acylated and then undergoes a nucleophilic substitution reaction with substrate 6-a to obtain 7-a; substrate 7-a and substrate 8-a undergo a nucleophilic substitution reaction to obtain 9-a; substrate 9-a undergoes deprotection to obtain 10-a; substrate 10-a and substrate 11-a undergo a condensation reaction or a nucleophilic substitution reaction to obtain the compound shown in Formula I; or substrate 9-a and substrate 11-a undergo reductive ammoniation to obtain the compound shown in Formula I.

[0062] Option 2:

[0063] R 1 R 2 R 3 R 4 Y 1 Y 2 L and E have the same scope of limitation as the first aspect mentioned above.

[0064] Where X b R 8 R 9 X c It has the same scope of limitations as Scheme 1.

[0065] The specific reaction steps are as follows: substrate 6-a and substrate 8-a undergo a nucleophilic substitution reaction to obtain 12-a; substrate 5-a is acylated and then undergoes a nucleophilic substitution reaction with substrate 12-a to obtain 9-a; substrate 9-a undergoes deprotection to obtain 10-a; substrate 10-a and substrate 11-a undergo a condensation reaction or a nucleophilic substitution reaction to obtain the compound shown in Formula I; or substrate 9-a and substrate 11-a undergo reductive amination to obtain the compound shown in Formula I.

[0066] Thirdly, the present invention provides pharmaceutically acceptable salts of the sulfonamide acetamide compounds as described above.

[0067] Fourthly, the present invention provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients;

[0068] The active ingredient comprises at least one sulfonamide acetamide compound as described above and / or at least one pharmaceutically acceptable salt as described above.

[0069] Fifthly, the present invention also provides the use of the sulfonamide acetamide compounds, pharmaceutically acceptable salts, or pharmaceutical compositions as described above in the preparation of pharmaceutical formulations capable of effectively reducing GSPT1 and / or RORγ protein levels.

[0070] In a sixth aspect, the present invention also provides the use of the sulfonamide acetamide compounds, pharmaceutically acceptable salts, or pharmaceutical compositions as described above in the preparation of medicaments for the prevention or treatment of cancer, inflammation, and autoimmune diseases.

[0071] The cancers mentioned include any one of the following: acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, prostate cancer, breast cancer, pancreatic cancer, liver cancer, lung cancer, NUT midline carcinoma, multiple myeloma, glioma, neuroblastoma, Burkitt lymphoma, cervical cancer, esophageal cancer, nasopharyngeal carcinoma, ovarian cancer, or colorectal cancer.

[0072] The inflammation is selected from any one of the following: pharyngitis, prostatitis, vaginitis, cervicitis, frozen shoulder, pelvic inflammatory disease, urethritis, pneumonia, conjunctivitis, otitis media, meningitis, myocarditis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease, thyroiditis, or allergic dermatitis.

[0073] The autoimmune diseases mentioned are selected from any one of the following: rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelinating diseases, primary adrenal atrophy, chronic thyroiditis, juvenile diabetes mellitus, hyperthyroidism, chronic active hepatitis, pernicious anemia, atrophic gastritis, autoimmune glomerulonephritis, pulmonary-renal hemorrhage syndrome, autoimmune hemolysis, idiopathic thrombocytopenic purpura, or idiopathic leukopenia.

[0074] The various aspects and features of the present invention will be further described below.

[0075] The various terms and phrases used in this invention have their general meanings known to those skilled in the art. Nevertheless, this invention still aims to provide a more detailed explanation and interpretation of these terms and phrases. In the event of any inconsistency between the mentioned terms and their known meanings and those of the present invention, the meaning expressed in this invention shall prevail. Below are definitions of various terms used in this invention. These definitions apply to all terms used throughout this specification, unless otherwise specified in the specific context. The following provides definitions of various groups in the compounds of this invention, which, unless otherwise defined, are used consistently in the specification and claims.

[0076] As mentioned in this invention, the terms "halogen", "halogen", "halogen atom", etc., refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0077] As mentioned in this invention, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms, which can be a straight-chain alkyl group or a branched alkyl group. For example, when "C1-C6 alkyl" is mentioned, it refers to a straight-chain alkyl group or a branched alkyl group having 1-6 carbon atoms. Specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc., and similar groups.

[0078] As mentioned in this invention, the term "cycloalkyl" refers to a cyclic alkyl group having a specified number of cyclic carbon atoms. For example, when "C3-C10 cycloalkyl" is mentioned, it refers to a cycloalkyl group having 3-10 carbon atoms. Specific groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and similar groups.

[0079] As mentioned in this invention, the term "alkenyl" refers to an alkenyl group (a hydrocarbon group having one or more C=C double bonds) having a specified number of carbon atoms. It can be a straight-chain alkyl group or a branched alkenyl group. For example, when "C2-C6 alkenyl" is mentioned, it refers to a straight-chain alkyl group or a branched alkenyl group having 2-6 carbon atoms. Specific groups include vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 1,3-pentadienyl, 1-hexenyl, 2-hexenyl, etc., and similar groups.

[0080] As mentioned in this invention, the term "cycloalkenyl" refers to a cyclic alkenyl group (a hydrocarbon group having one or more C=C double bonds) having a specified number of carbon atoms. For example, "C3-C10 cycloalkenyl" refers to a cyclic alkenyl group having 3-10 carbon atoms. Specific groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and similar groups.

[0081] As mentioned in this invention, the term "alkynyl" refers to an alkynyl group (a hydrocarbon group having one or more C≡C triple bonds) having a specified number of carbon atoms. It can be a straight-chain alkyl or a branched alkynyl group. For example, when "C2-C6 alkynyl" is mentioned, it refers to a straight-chain alkyl or a branched alkynyl group having 2-6 carbon atoms. Specific groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-hexynyl, and similar groups.

[0082] As used in this invention, the term "heterocyclic group" refers to a non-aromatic heterocycle in which one or more of the ring-forming atoms are heteroatoms such as O, N, or S. Heterocyclic groups can include monocyclic or polycyclic ring systems (such as those having 2, 3, or 4 fused rings) and spirocyclic rings. Preferred examples of "heterocyclic" groups include, but are not limited to: azirropropyl, azirrobutyl, tetrahydrofuranyl, tetrahydrothiopheneyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, morpholinyl, thiomorpholinyl, piperazine, piperidinyl, and similar groups. Also included in the definition of heterocyclic groups are those portions having one or more aromatic rings fused to a non-aromatic heterocyclic ring (e.g., sharing a common bond), such as 2,3-dihydrobenzofuranyl, 1,3-benzodioxacyclopentenyl, benzo-1,4-dioxacyclohexyl, phthalimide, naphthalimide, and similar groups. Heterocyclic groups having one or more fused aromatic rings can be linked by either an aromatic or non-aromatic moiety.

[0083] As mentioned in this invention, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings), such as phenyl, naphthyl, anthracene, phenanthryl, indene, and similar groups.

[0084] As used in this invention, the term "heteroaryl" refers to an aromatic heterocycle having at least one heteroatom ring member such as O, N, or S. Heteroaryl groups include monocyclic or polycyclic ring systems (such as those having 2, 3, or 4 fused rings). Any N atom cyclic in the heterocyclic group can also be oxidized to form an N-oxide. Examples of preferred "heteroaryl" groups include, but are not limited to: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thiopheneyl, imidazoleyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrroleyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, indolyl, inzolyl, quinolinyl, isoquinolinyl, purineyl, carbazoleyl, benzimidazoleyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, and similar groups.

[0085] As mentioned in this invention, the term "single bond" refers to the direct connection between two groups attached to that position; for example, when Y 1 When it is a single bond, L is directly attached to amide N, and the structure shown in Formula I can be represented as: When Y 2 When it is a single bond, L and E are directly connected, and the structure shown in Equation I can be represented as: To give a more specific example, Y 2 In the case of single bonds, such as compounds 9, 10, and 11 provided in this invention.

[0086] As used herein, the term "compound" means, as is used herein, all stereoisomers, geometric isomers, tautomers, and isotopes.

[0087] The compounds of this invention can be asymmetric, for example, having one or more stereocenters. Unless otherwise specified, all stereoisomers can be enantiomers and diastereomers. Compounds of this invention containing asymmetrically substituted carbon atoms can be isolated into optically pure or racemic forms. The optically pure form can be prepared by resolving the racemic mixture or by using a chiral synthon or a chiral reagent.

[0088] The compounds of this invention may also include tautomer forms. New tautomer forms are generated by the exchange of single bonds and adjacent double bonds along with proton migration.

[0089] The compounds of this invention may also include all isotopic forms of atoms present in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

[0090] As used in this invention, the term "pharmaceutical composition" can also refer to a "composition" that can be used in subjects, particularly mammals, to treat and / or prevent the diseases or conditions described in this invention.

[0091] As used in this invention, the term "disease and / or symptom" refers to a physical state of the subject that is related to the disease and / or symptom described in this invention. For example, the disease and / or symptom described in this invention can refer to either a physical state or a disease state. In this document, no distinction is made between physical state and disease state, or the two may refer to each other.

[0092] As mentioned in this invention, the term "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic substance that has pharmaceutical value, such as a salt formed as an intermediate during chiral resolution, although such intermediate salt cannot be directly given to the subject, but can play a role in obtaining the end product of this invention.

[0093] Pharmaceutically acceptable salts of the compounds shown in Formula I can be formed in two forms: one is a salt formed with an acid; the other is a salt formed with a base or alkali metal. Acids that form pharmaceutically acceptable salts with the compounds shown in Formula I include inorganic acids and organic acids. Suitable inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids include aliphatic, cyclic aliphatic, aromatic, heterocyclic carboxylic acids, and sulfonic acid organic acids, examples of which include, but are not limited to, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkyl sulfonic acid, and aromatic sulfonic acid. Alkali metals that form pharmaceutically acceptable salts with the compounds shown in Formula I include lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc; bases that form pharmaceutically acceptable salts with the compounds shown in Formula I include choline, diethanolamine, and morpholine.

[0094] As mentioned in this invention, the term "prodrug" refers to derivatives of compounds of Formula I that are converted in vivo (e.g., hydrolyzed, reduced, or oxidized) into compounds of Formula I through in vivo metabolism. For example, compounds of Formula I containing hydroxyl groups can be reacted with acids to prepare the corresponding esters, which are prodrugs that can be used to hydrolyze the parent drug in vivo. Suitable acids for preparing "prodrugs" include, but are not limited to: acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, oxalic acid, salicylic acid, succinic acid, fumaric acid, maleic acid, methylene-bis-β-hydroxynaphthyl acid, gentian acid, hydroxyethylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0095] Compared with the prior art, the present invention has the following beneficial effects:

[0096] This invention provides an arylimidazolylisoxazole compound that, by selecting specific functional groups, exhibits excellent anticancer effects. This class of compounds can be used to treat cancer, inflammation, and autoimmune diseases. These compounds can effectively reduce GSPT1 and / or RORγ protein levels. Attached Figure Description

[0097] Figure 1 shows the cell proliferation inhibition curves of compound 15 against MV4-11 cells (left) and (right);

[0098] Figure 2 shows the cell proliferation inhibition curves of compound 53 against MV4-11 cells (left) and (right);

[0099] Figure 3 shows the reduction of GSPT1 protein levels in MV4-11 cells by different compounds.

[0100] Figure 4 shows the reduction of GSPT1 and / or RORγ protein levels in MV4-11 cells at different concentrations of compound 15. Detailed Implementation

[0101] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0102] Unless otherwise stated, temperatures are in Celsius. All reagents purchased are ready for use without further purification, unless otherwise stated.

[0103] Unless otherwise specified, the following reactions shall be carried out under positive pressure of anhydrous solvent, nitrogen or argon or using a drying tube; the reaction flask shall be sealed with a rubber stopper to allow for the addition of substrate and reagents via syringe; glassware shall be heated and dried before use.

[0104] Solvents used in NMR data include CDCl3 and DMSO-d6, with tetramethylsilane (0.00 ppm) or residual solvent peaks as references (CDCl3: 7.26 ppm, DMSO-d6: 2.50 ppm). When indicating peak diversity, the following abbreviations are used to represent different peak types: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet), td (triple doublet). The given coupling constants are in Hertz (Hz).

[0105] The abbreviations are shown in the table below:

[0106] Intermediate preparation:

[0107] The synthesis method of the intermediates used in the following preparation examples is as follows:

[0108] Intermediate 1: N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine

[0109] Step 1: Synthesis of N-(3,4-dichlorophenyl)-4-methylbenzenesulfonamide

[0110] Take compound m-3,4-dichloroaniline (162.01 g, 20.00 g, 123.449 mmol, 1 eq), dissolve it in pyridine (79.10 g, 39.7 mL, 493.797 mmol, 4 eq, 0.983 g / mL), and stir in an ice bath. Separately, take compound 4-methylbenzenesulfonyl chloride (190.64 g, 28.24 g, 148.139 mmol, 1.2 eq), dissolve it in pyridine (79.10 g, 39.7 mL, 493.797 mmol, 4 eq, 0.983 g / mL), and slowly add it dropwise to the system. Remove from the ice bath, heat to 80 °C, and reflux for 4 hours. After the reaction was completed, the product was diluted with a large amount of ethyl acetate and extracted three times with 1M dilute hydrochloric acid, twice with water, and once with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, the product was subjected to column chromatography (petroleum ether: dichloromethane = 2:1, then replaced with dichloromethane) to obtain N-(3,4-dichlorophenyl)-4-methylbenzenesulfonamide (316.20, 36.10 g, 114.168 mmol, 92%). 1 HNMR(500MHz,DMSO-d6)δ10.64(s,1H),7.66(d,J=8.2Hz,2H),7.50(d,J=8.8Hz,1 H),7.37(d,J=8.0Hz,2H),7.27(d,J=2.4Hz,1H),7.11–7.05(m,1H),2.34(s,3H).

[0111] Step 2: Synthesis of N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycine tert-butyl ester

[0112] The double-necked flask was dried. Sodium hydride (24 g, 2.28 g, 56.926 mmol, 1.2 eq) was taken, and after evacuation, 20 mL of anhydrous DMF was added. The mixture was stirred in an ice bath. Separately, N-(3,4-dichlorophenyl)-4-methylbenzenesulfonamide (316.20 g, 15.00 g, 47.438 mmol, 1 eq) was taken, and after evacuation, 15 mL of anhydrous DMF was added to dissolve it. This solution was then slowly added dropwise to the system, and the mixture was stirred in an ice bath for 30 minutes. Tert-butyl bromoacetate (195.05 g, 8.30 mL, 56.926 mmol, 1.2 eq, 1.338 g / mL) was slowly added dropwise to the system. The remaining tert-butyl bromoacetate in the dropping funnel was rinsed with 15 mL of anhydrous DMF. The ice bath was removed, and the mixture was refluxed at 90 °C for 4 hours. After the reaction was complete, saturated ammonium chloride aqueous solution was added dropwise under ice bath conditions to quench the reaction. Add a large amount of ethyl acetate, extract five times with saturated sodium chloride aqueous solution, dry to anhydrous sodium sulfate, and evaporate to dryness. Column chromatography (petroleum ether: dichloromethane gradient elution) yielded the compound N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycine tert-butyl ester (430.34 g, 17.00 g, 39.504 mmol, 83%). 1 HNMR(500MHz,DMSO-d6)δ7.64(d,J=8.7Hz,1H),7.56(d,J=8.1Hz,2H),7.45(s,1H), 7.40(d,J=7.8Hz,2H),7.18(d,J=8.7Hz,1H),4.43(s,2H),2.39(s,3H),1.33(s,9H).

[0113] Step 3: Synthesis of N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycine

[0114] The compound N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycine tert-butyl ester (429.45 g, 5.00 g, 11.643 mmol, 1 eq) was dissolved in 15 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was evaporated to dryness, and methanol was added to form a suspension. The suspension was filtered, and the filter cake was washed with methanol to give the product N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycine (372.99 g, 3.30 g, 8.847 mmol, 76%). 1 H NMR(500MHz,DMSO-d6)δ7.62(d,J=8.7Hz,1H),7.55(d,J=7.6Hz,2H),7.46(s ,1H),7.40(d,J=7.7Hz,2H),7.19(d,J=8.7Hz,1H),4.45(s,2H),2.39(s,3H).

[0115] Step 4: Synthesis of N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl chloride

[0116] The double-necked flask was dried. Compound N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycine (372.99 g, 13.40 g, 35.926 mmol, 1 eq) was taken, the atmosphere was evacuated, and 67 mL of redistilled dichloromethane was added. The mixture was stirred in an ice bath. Thionyl chloride (118.97 g, 26.06 mL, 359.259 mmol, 10 eq, 1.64 g / mL) was added dropwise to the system. The ice bath was removed, and the mixture was heated to 42 °C and stirred overnight. After the reaction was complete, the mixture was evaporated to dryness to obtain the crude product N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl chloride (390.96 g, 14.00 g, 35.809 mmol, 99%). The crude product was directly added to the next reaction without characterization.

[0117] Step 5: Synthesis of N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)acetamide

[0118] The double-necked flask was dried. Compound p-aminobenzonitrile (118.14 g, 6.04 g, 51.126 mmol, 1 eq) was taken, and after evacuation, 30 mL of dichloromethane and triethylamine (101.19 g, 8.5 mL, 30.694 mmol, 1.2 eq, 0.728 g / mL) were added vial. The mixture was stirred at room temperature for 10 minutes, then stirred in an ice bath. Separately, N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl chloride (390.96 g, 20.00 g, 51.126 mmol, 1 eq) was dissolved in 30 mL of dichloromethane and added dropwise to the mixture. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with a large amount of dichloromethane, extracted three times with water, dried over anhydrous sodium sulfate, and then evaporated to dryness. The product was dissolved in dichloromethane, and a large amount of white solid precipitated out. After filtration, the filter cake was washed with methanol to obtain the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)acetamide (473.04 g, 18.40 g, 38.897 mmol, 76%). 1 H NMR (500MHz, DMSO-d6) δ10.54(s,1H),7.77(d,J=8.2Hz,2H),7.70(d,J=8.1Hz,2H),7.63(d,J=8.6Hz,1H), 7.56(d,J=7.6Hz,2H),7.52(s,1H),7.43(d,J=7.6Hz,2H),7.21(d,J=8.3Hz,1H),4.56(s,2H),2.40(s,3H).

[0119] Step 6: Synthesis of N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine tert-butyl ester

[0120] Compound N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)acetamide (473.04 g, 10.00 g, 21.140 mmol, 1 eq) was dissolved in 46 mL of DMF and stirred at room temperature. Potassium carbonate (138.21 g, 5.84 g, 42.280 mmol, 2 eq) was added, and the mixture was stirred at room temperature for 15 minutes, followed by stirring in an ice bath. Tert-butyl bromoacetate (195.05 g, 12.3 mL, 84.560 mmol, 4 eq, 1.338 g / mL) was slowly added dropwise to the system, and the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was completed, the product was diluted with a large amount of ethyl acetate, extracted five times with saturated sodium chloride water, dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography (petroleum ether: dichloromethane = 10:1) to give N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine tert-butyl ester (587.1 g, 5.25 g, 8.942 mmol, 42%). 1 HNMR (500MHz, DMSO-d6) δ7.97(d,J=6.9Hz,2H),7.58(d,J=8.6Hz,3H),7.46(d,J=6.0Hz,2H),7.39(d,J=2. 0Hz, 1H), 7.34 (d, J = 7.8Hz, 2H), 7.13 (d, J = 8.3Hz, 1H), 4.42 (s, 2H), 4.26 (s, 2H), 2.37 (s, 3H), 1.36 (s, 9H).

[0121] Step 7: Synthesis of N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine

[0122] Compound N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine tert-butyl ester (587.10, 6.90 g, 11.753 mmol, 1 eq) was dissolved in 14 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added with stirring. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the sample was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 50:1) to give the product N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine (532.39, 9.10 g, 17.093 mmol, 73%). 1H NMR(500MHz,DMSO-d6)δ7.95(d,J=5.3Hz,2H),7.57(d,J=8.6Hz,3H),7.46(br,2H) ,7.40–7.32(m,3H),7.13(d,J=8.3Hz,1H),4.42(s,2H),4.33(s,2H),2.37(s,3H).

[0123] Intermediate 2: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetic acid

[0124] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione

[0125] Compounds 3-hydroxyphthalic anhydride (164.12 g, 10.00 g, 60.931 mmol, 1 eq) and 3-amino-2,6-piperidinidone hydrochloride (164.59 g, 10.03 g, 60.931 mmol, 1 eq) were added to 120 mL of toluene. Triethylamine (101.19 g, 9.32 mL, 67.024 mmol, 0.728 g / mL) was added with stirring at room temperature. The mixture was heated to 115 °C and refluxed overnight. After the reaction was confirmed to be complete, the product was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol system, gradient elution) to give 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione (274.23 g, 14.60 g, 53.240 mmol, 87%). 1 H NMR(500MHz,DMSO-d6)δ11.08(s,1H),10.43(br,1H),7.68–7.62(m,1H),7.33–7.27(m,2H ),5.07(dd,J=12.8,5.4Hz,1H),2.93–2.84(m,1H),2.62–2.51(m,2H),2.05–1.98(m,1H).

[0126] Step 2: Synthesis of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetate

[0127] Take compound 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione (272.7 g, 14.60 g, 53.539 mmol, 1 eq) and potassium carbonate (138.2 g, 11.10 g, 80.308 mmol, 1.5 eq), dissolve them in 53 mL of DMF, stir at room temperature for 15 minutes, stir in an ice bath, add tert-butyl bromoacetate (195.05 g, 7.80 mL, 53.539 mmol, 1 eq, 1.338 g / mL), remove from ice bath, and stir at room temperature for 2 hours. After the reaction was detected as complete, the product was diluted with a large amount of ethyl acetate, extracted once with water, extracted twice with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography (dichloromethane:methanol system, gradient elution) to obtain the product 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)tert-butyl acetate (388.38 g, 10.91 g, 28.091 mmol, 52%). 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),7.83–7.77(m,1H),7.48(d,J=7.2Hz,1H),7.38(d,J=8.6Hz,1H),5.10 (dd,J=12.8,5.4Hz,1H),4.97(s,2H),2.95–2.84(m,1H),2.65–2.51(m,2H),2.08–2.00(m,1H),1.43(s,9H).

[0128] Step 3: Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetic acid

[0129] 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetic acid tert-butyl ester (388.38 g, 3.00 g, 7.724 mmol, 1 eq) was dissolved in 10 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the product 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetic acid (332.27 g, 2.57 g, 7.724 mmol, greater than 99%) was obtained by evaporation to dryness. 1H NMR (500MHz, DMSO-d6) δ13.26(br,1H),11.11(s,1H),7.79(t,J=7.9Hz,1H),7.47(d,J=7.2Hz,1H),7.39(d,J=8 .5Hz,1H),5.10(dd,J=12.6,5.4Hz,1H),4.99(s,2H),2.94–2.84(m,1H),2.61–2.52(m,2H),2.09–2.00(m,1H).

[0130] Intermediate 3: 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione

[0131] Take compound 3-fluorophthalic anhydride (166.11 g, 10.00 g, 60.201 mmol, 1 eq), add 142 mL of acetic acid, and add 3-amino-2,6-piperidinedione hydrochloride (164.59 g, 9.91 g, 60.201 mmol, 1 eq) and sodium acetate (82.03 g, 5.92 g, 72.241 mmol, 1.2 eq) under stirring at room temperature. Heat to 120 °C and reflux overnight. After the reaction is complete, evaporate to dryness, add water and stir for 1 hour, filter, and the filter cake is the product 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (276.05 g, 13.90 g, 50.353 mmol, 83%). 1 H NMR (500MHz, DMSO-d6) δ11.15(s,1H),7.98–7.92(m,1H),7.79(d,J=7.3Hz,1H),7.73(t,J=8.9 Hz,1H),5.16(dd,J=12.9,5.4Hz,1H),2.94–2.84(m,1H),2.65–2.51(m,2H),2.12–2.03(m,1H).

[0132] Intermediate 4: 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

[0133] Take 3-bromophthalic anhydride (225.93 g, 10.00 g, 44.261 mmol, 1 eq), add 140 mL of acetic acid, and add 3-amino-2,6-piperidinedione hydrochloride (164.59 g, 8.01 g, 48.688 mmol, 1.1 eq) and sodium acetate (82.03 g, 4.36 g, 53.114 mmol, 1.2 eq) with stirring at room temperature. Heat to 140 °C and reflux overnight. After the reaction is complete, filter the mixture. The filter cake is the product 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (335.97 g, 13.40 g, 39.884 mmol, 90%). 1 H NMR (500MHz, DMSO-d6) δ11.14(s,1H),8.06(d,J=8.0Hz,1H),7.93(d,J=7.3Hz,1H),7.78(t,J=7. 7Hz, 1H), 5.16 (dd, J = 12.9, 5.4Hz, 1H), 2.93–2.84 (m, 1H), 2.65–2.51 (m, 2H), 2.10–2.03 (m, 1H).

[0134] Intermediate 5: 3-(4-iodo-1-oxoisoindol-2-yl)piperidin-2,6-dione

[0135] Step 1: Synthesis of methyl 3-iodo-2-methylbenzoate

[0136] 3-Iodo-2-methylbenzoic acid (261.95 g, 10.00 g, 38.175 mmol, 1 eq) was dissolved in 60 mL of methanol. Concentrated sulfuric acid (98.08 g, 6.14 mL, 114.526 mmol, 3 eq, 1.83 g / mL) was added with stirring at room temperature, and the mixture was heated to 65 °C and reacted for 8 hours. After confirming the reaction was complete, the solution was evaporated to dryness. A large amount of ethyl acetate was added, and the mixture was extracted three times with water. The extract was dried over anhydrous sodium sulfate and evaporated to dryness again to give methyl 3-iodo-2-methylbenzoate (275.96 g, 10.53 g, 38.175 mmol, >99%). 1 H NMR (500MHz, DMSO-d6) δ 8.05 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 3.83 (s, 3H), 2.54 (s, 3H).

[0137] Step 2: Synthesis of methyl 2-(bromomethyl)-3-iodobenzoate

[0138] Methyl 3-iodo-2-methylbenzoate (275.96 g, 10.53 g, 38.175 mmol, 1 eq) was dissolved in 100 mL of 1,2-dichloroethane. While stirring, N-bromosuccinimide (177.98 g, 7.47 g, 41.993 mmol, 1.1 eq) and azobisisobutyronitrile (164.21 g, 0.75 g, 4.581 mmol, 0.12 eq) were added. The mixture was heated to 80 °C and reacted for 4 hours. After confirming the reaction was complete, the product was evaporated to dryness, diluted with a large amount of ethyl acetate, and extracted once with saturated sodium sulfite aqueous solution and twice with water. The extract was dried over anhydrous sodium sulfate and evaporated to dryness. Column chromatography (petroleum ether) yielded the product methyl 2-(bromomethyl)-3-iodobenzoate (353.88 g, 9.40 g, 26.563 mmol, 70%). 1 H NMR (500MHz, DMSO-d6) δ8.14(d,J=7.8Hz,1H),7.84(d,J=7.7Hz,1H),7.20(t,J=7.7Hz,1H),5.03(s,2H),3.87(s,3H).

[0139] Step 3: Synthesis of 3-(4-iodo-1-oxoisoindol-2-yl)piperidine-2,6-dione

[0140] Methyl 2-(bromomethyl)-3-iodobenzoate (353.88 g, 9.40 g, 26.563 mmol, 1 eq) and 3-amino-2,6-piperidinidone hydrochloride (164.59 g, 5.33 g, 32.406 mmol, 1.22 eq) were dissolved in 100 mL of acetonitrile. Triethylamine (101.19 g, 4.91 mL, 35.328 mmol, 1.33 eq, 0.728 g / mL) was added, and the mixture was heated to 80 °C and reacted overnight. After the reaction was complete, the mixture was filtered, and the filter cake contained the product 3-(4-iodo-1-oxoisoindol-2-yl)piperidinidone-2,6-dione (369.98 g, 5.20 g, 14.055 mmol, 53%). 1 HNMR (500MHz, DMSO-d6) δ11.00(s,1H),8.04(d,J=7.6Hz,1H),7.77(d,J=7.4Hz,1H),7.35(t,J=7.6Hz,1H),5.14(dd,J=13.3,5.1H z,1H),4.29(d,J=17.4Hz,1H),4.14(d,J=17.4Hz,1H),2.95–2.86(m,1H),2.64–2.57(m,1H),2.48–2.43(m,1H),2.04–1.99(m,1H).

[0141] Intermediate 6: 3-(4-bromo-1-oxoisoindol-2-yl)piperidin-2,6-dione

[0142] The synthesis method is the same as that described in steps 2-3 of intermediate 5, with a yield of 45%. The NMR characterization results of the product are as follows: 1 H NMR (500MHz, DMSO-d6) δ11.01(s,1H),7.87(d,J=7.9Hz,1H),7.77(d,J=7.5Hz,1H),7.51(t,J=7.7Hz,1H),5.14(dd,J=13.3,5.0Hz ,1H),4.42(d,J=17.6Hz,1H),4.26(d,J=17.6Hz,1H),2.95–2.86(m,1H),2.63–2.56(m,1H),2.48–2.42(m,1H),2.06–1.99(m,1H).

[0143] Intermediate 7: 2-(3-(2,6-dioxadiazine-3-yl)phenoxy)acetic acid

[0144] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol

[0145] Prepare a reflux tube and a two-necked flask. Take 2,6-bis(benzyloxy)-3-bromopyridine (369.04, 1.00 g, 2.710 mmol, 1 eq), 3-hydroxyphenylboronic acid (137.93, 0.75 g, 5.419 mmol, 2 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (810.59, 0.022 g, 0.0271 mmol, 0.01 eq), and potassium phosphate (212.27, 1.27 g, 5.961 mmol, 2.2 eq). Vacuum the solution for 15 minutes. Separately, prepare a two-necked flask. Take 15 mL of ultra-dry 1,4-dioxane and 2.5 mL of water (in a 6:1 ratio). Vacuum the solution for 15 minutes and add it to the system. Heat the solution to 100 °C and react for 16 hours. After the reaction was detected as complete, the product was diluted with a large amount of ethyl acetate, extracted twice with water, and once with saturated brine. The product was dried over anhydrous sodium sulfate and then evaporated to dryness. Column chromatography (petroleum ether:ethyl acetate = 6:1) yielded the product 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (383.45 g, 0.91 g, 2.373 mmol, 88%). 1H NMR(500MHz,DMSO-d6)δ9.40(s,1H),7.68(d,J=8.1Hz,1H),7.46–7.27(m,10H),7.17(t,J=7.8 Hz,1H),6.99–6.92(m,2H),6.73–6.67(m,1H),6.52(d,J=8.1Hz,1H),5.40(s,2H),5.36(s,2H).

[0146] Step 2: Synthesis of 2-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)tert-butyl acetate

[0147] Compound 3-(2,6-bis(benzyloxy)pyridin-3-yl)phenol (383.45, 0.91 g, 2.373 mmol, 1 eq) was added to 4 mL of DMF, followed by potassium carbonate (138.2, 0.49 g, 3.560 mmol, 1.5 eq). The mixture was stirred in an ice bath for 10 minutes, and then tert-butyl bromoacetate (195.05, 0.34 mL, 2.373 mmol, 1.338 g / mL) was added dropwise. The mixture was then removed from the ice bath and stirred at room temperature for 3 hours. The reaction was then checked for completeness, diluted with a large amount of ethyl acetate, and extracted twice with water and once with saturated brine. The extract was dried over anhydrous sodium sulfate and evaporated to dryness. Column chromatography (petroleum ether:ethyl acetate = 20:1) yielded the product 2-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)tert-butyl acetate (497.59, 1.12 g, 2.251 mmol, 95%). 1 H NMR(500MHz,DMSO-d6)δ7.75(d,J=8.1Hz,1H),7.50–7.25(m,11H),7.15(d,J=7.8Hz,1H),7.12–7.05(m,1H ),6.82(dd,J=8.2,2.0Hz,1H),6.55(d,J=8.1Hz,1H),5.41(s,2H),5.37(s,2H),4.61(s,2H),1.41(s,9H).

[0148] Step 3: Synthesis of tert-butyl 2-(3-(2,6-dioxadiazine-3-yl)phenoxy)acetate

[0149] Compound 2-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)tert-butyl acetate (497.59 g, 1.12 g, 2.251 mmol, 1 eq) was added to 10 mL of anhydrous ethanol, followed by palladium on carbon (10%, 166.93 g, 0.11 g, 0.671 mmol). The mixture was evacuated three times with a hydrogen balloon and stirred overnight at room temperature. After confirming the reaction was complete, a large amount of ethyl acetate was added, and the mixture was filtered. The filtrate was evaporated to dryness. Column chromatography (dichloromethane:methanol = 80:1) yielded the product 2-(3-(2,6-dioxadiazin-3-yl)phenoxy)tert-butyl acetate (319.36 g, 0.70 g, 2.192 mmol, 97%). 1 HNMR(500MHz,DMSO-d6)δ10.83(s,1H),7.29–7.19(m,1H),6.84–6.75(m,3H),4.62(s,2H),3.82(dd,J=11 .4,4.9Hz,1H),2.68–2.61(m,1H),2.49–2.43(m,1H),2.24–2.13(m,1H),2.05–1.99(m,1H),1.42(s,9H).

[0150] Step 4: Synthesis of 2-(3-(2,6-dioxadiazine-3-yl)phenoxy)acetic acid

[0151] Compound 2-(3-(2,6-dioxadiazin-3-yl)phenoxy)acetic acid (319.36 g, 0.70 g, 2.192 mmol, 1 eq) was dissolved in 5 mL of dichloromethane and stirred at room temperature. 1 mL of trifluoroacetic acid was added, and the mixture was allowed to react at room temperature for 2 hours. The reaction was checked for completeness by rotary evaporation. Upon addition of dichloromethane, a white solid appeared. This solid was filtered, and the filter cake yielded the product 2-(3-(2,6-dioxadiazin-3-yl)phenoxy)acetic acid (263.08 g, 0.49 g, 1.862 mmol, 85%). 1 H NMR(500MHz,DMSO-d6)δ10.82(s,1H),7.24(dd,J=9.0,7.5Hz,1H),6.84–6.78(m,3H),4.65(s,2H),3.8 2(dd,J=11.5,4.9Hz,1H),2.67–2.62(m,1H),2.49–2.43(m,1H),2.24–2.15(m,1H),2.05–1.99(m,1H).

[0152] Intermediate 8: 3-(3'-(2-aminoethyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0153] Step 1: Synthesis of tert-butyl (3-bromophenylethyl)carbamate

[0154] 3-Bromophenylethylamine (199.00 g, 5.00 g, 25.126 mmol, 1 eq) was mixed with 20 mL of dichloromethane, sodium bicarbonate (84.01 g, 3.17 g, 37.688 mmol, 1.5 eq), and di-tert-butyl dicarbonate (218.12 g, 8.65 mL, 37.688 mmol, 1.5 eq, 0.95 g / mL). The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was diluted with a large amount of dichloromethane, extracted three times with water, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography (petroleum ether:ethyl acetate = 8:1) yielded the product (3-bromophenylethyl) tert-butyl carbamate (299.05 g, 6.00 g, 20.064 mmol, 80%). 1 H NMR(500MHz,DMSO-d6)δ7.40–7.36(m,2H),7.24(t,J=7.9Hz,1H),7.19(d,J=7.5Hz,1 H), 6.87 (t, J = 5.7Hz, 1H), 3.14 (q, J = 6.7Hz, 2H), 2.69 (t, J = 7.0Hz, 2H), 1.35 (s, 9H).

[0155] Step 2: Synthesis of tert-butyl (3-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)phenethyl)carbamate

[0156] Prepare a double-necked flask and a reflux tube. Take (3-bromophenylethyl) tert-butyl carbamate (299.05, 1.00 g, 3.344 mmol, 1 eq), neopentyl glycol diboronate (225.89, 1.89 g, 8.360 mmol, 2.5 eq), tris(dibenzylacetone)palladium (915.72, 0.009 g, 0.0100 mmol, 0.003 eq), phosphorylated adamantane (292.31, 0.009 g, 0.030 mmol, 0.009 eq), and potassium acetate (98.14, 0.82 g, 8.360 mmol, 2.5 eq). Vacuum for 1 hour, add 10 mL of ultra-dry 1,4-dioxane, change the gas, raise the temperature to 80 °C, and react for 24 hours. After the reaction was detected as complete, the mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product (3-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)phenethyl)carbamate tert-butyl ester (333.24 g, 1.11 g, 3.344 mmol, >99%). The crude product was directly added to the next reaction without further characterization.

[0157] Step 3: Synthesis of tert-butyl (2-(3'-bromo-[1,1'-biphenyl]-3-yl)ethyl)carbamate

[0158] Prepare a reflux tube and a double-necked flask. Take the compound (3-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)phenethyl) tert-butyl carbamate (333.24 g, 1.11 g, 3.345 mmol, 1 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (810.59 g, 0.027 g, 0.033 mmol, 0.01 eq), and potassium phosphate (212.27 g, 1.56 g, 7.357 mmol, 2.2 eq). Vacuum for 1 hour. In a separate two-necked flask, add 1-bromo-3-iodobenzene (281.85 g, 0.85 mL, 6.688 mmol, 2 eq, 2.219 g / mL), 12 mL of ultra-dry 1,4-dioxane, and 2 mL of water (6:1 ratio). Vacuum for 40 minutes, add the mixture to the system, evaporate, and heat to 60 °C. React overnight. To confirm completion of the reaction, evaporate to dryness, dilute with a large amount of ethyl acetate, extract three times with saturated brine, dry to anhydrous sodium sulfate, and evaporate to dryness again. Column chromatography (petroleum ether:ethyl acetate system, 40:1 → 10:1) yields (2-(3'-bromo-[1,1'-biphenyl]-3-yl)ethyl)tert-butyl carbamate (375.08 g, 0.60 g, 1.600 mmol, 48%). 1 HNMR(500MHz,DMSO-d6)δ7.84(s,1H),7.67(d,J=7.7Hz,1H),7.55(d,J=8.1Hz,1H),7.52–7.46(m,2H),7.44–7.3 5(m,2H),7.22(d,J=7.5Hz,1H),6.90(t,J=5.0Hz,1H),3.20(q,J=6.7Hz,2H),2.77(t,J=7.1Hz,2H),1.34(s,9H).

[0159] Step 4: Synthesis of tert-butyl (2-(3'-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)-[1,1'-biphenyl]-3-yl)ethyl)carbamate

[0160] Prepare a double-necked flask and a reflux tube. Take the following compounds: (2-(3'-bromo-[1,1'-biphenyl]-3-yl)ethyl)tert-butyl carbamate (375.08, 0.60 g, 1.600 mmol, 1 eq), neopentyl glycol diboronate (225.89, 0.90 g, 3.999 mmol, 2.5 eq), tris(dibenzylideneacetone)dipalladium (915.72, 0.004 g, 0.005 mmol, 0.003 eq), adamantane phosphorothione (292.31, 0.004 g, 0.014 mmol, 0.009 eq), and potassium acetate (98.14, 0.39 g, 3.999 mmol, 2.5 eq). After evacuation for 1 hour, add 6 mL of ultra-dry 1,4-dioxane. After evacuation, heat to 80 °C and react for 24 hours. After the reaction was detected as complete, the product was diluted with ethyl acetate, filtered, and the filtrate was evaporated to dryness. The product was then diluted with petroleum ether, filtered, and the filtrate was evaporated to dryness to give the crude product (2-(3'-(5,5-dimethyl-1,3,2-dioxaborane-2-yl)-[1,1'-biphenyl]-3-yl)ethyl)tert-butyl carbamate (409.24 g, 0.65 g, 1.600 mmol, >99%). The crude product was directly added to the next reaction without further characterization.

[0161] Step 5: Synthesis of tert-butyl (2-(3'-(2,6-bis(benzyloxy)pyridin-3-yl)-[1,1'-biphenyl]-3-yl)ethyl)carbamate

[0162] Prepare a reflux tube and a two-necked flask. Take the following compounds: 2,6-bis(benzyloxy)-3-bromopyridine (369.04, 0.88 g, 2.399 mmol, 1.5 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (810.59, 0.013 g, 0.016 mmol, 0.01 eq), and potassium phosphate (212.27, 0.75 g, 3.519 mmol, 2.2 eq). Vacuum for 1 hour. In a separate two-necked flask, add compound (2-(3'-(2,6-bis(benzyloxy)pyridin-3-yl)-[1,1'-biphenyl]-3-yl)ethyl)tert-butyl carbamate (409.24 g, 0.65 g, 1.600 mmol, 1 eq), 7.8 mL of ultra-dry 1,4-dioxane, and 1.3 mL of water (6:1 ratio). Vacuum for 40 minutes, then add the mixture to the system. Vacuum evacuate, heat to 80 °C, and incubate overnight. Once the reaction is complete, dilute with a large amount of ethyl acetate, extract three times with saturated brine, dry to anhydrous sodium sulfate, and evaporate to dryness. Column chromatography (petroleum ether: ethyl acetate system, 20:1→15:1) yielded the product (2-(3'-(2,6-bis(benzyloxy)pyridin-3-yl)-[1,1'-biphenyl]-3-yl)ethyl)tert-butyl carbamate (586.28 g, 0.30 g, 0.512 mmol, 32%). 1HNMR(500MHz,DMSO-d6)δ7.85(d,J=8.1Hz,1H),7.81(t,J=1.9Hz,1H),7.57–7.51(m,2H),7.49–7.45(m,4H),7.42–7.31(m,10H),7.18(d, J=7.4Hz,1H),6.89(t,J=5.2Hz,1H),6.58(d,J=8.1Hz,1H),5.42–5.40(m,4H),3.18(q,J=6.6Hz,2H),2.75(t,J=7.2Hz,2H),1.33(s,9H).

[0163] Step 6: Synthesis of tert-butyl (2-(3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-3-yl)ethyl)carbamate

[0164] Take compound (2-(3'-(2,6-bis(benzyloxy)pyridin-3-yl)-[1,1'-biphenyl]-3-yl)ethyl)tert-butyl carbamate (586.28, 0.30 g, 0.512 mmol, 1 eq), add 5 mL of methanol, add palladium on carbon (5%, 166.93, 0.068 g, 0.409 mmol, 0.8 eq), purge with a hydrogen balloon 3 times, and react overnight at room temperature. To confirm the completion of the reaction, dilute with a large amount of ethyl acetate, filter, and evaporate the filtrate to dryness. Column chromatography (dichloromethane:methanol = 80:1) gives product (2-(3'-(2,6-dioxopiridine-3-yl)-[1,1'-biphenyl]-3-yl)ethyl)tert-butyl carbamate (408.2, 0.21 g, 0.512 mmol, >99%). 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.56–7.35(m,6H),7.23–7.17(m,2H),6.89(t,J=5.2Hz,1H),3.94(dd,J=11.7,4.9Hz,1H),3 .21–3.16(m,2H),2.76(t,J=7.4Hz,2H),2.73–2.65(m,1H),2.58–2.52(m,1H),2.35–2.25(m,1H),2.13–2.05(m,1H),1.35(s,9H).

[0165] Step 7: Synthesis of 3-(3'-(2-aminoethyl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0166] Compound (2-(3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-3-yl)ethyl)tert-butyl carbamate (408.20, 0.21 g, 0.512 mmol, 1 eq) was added to 5 mL of dichloromethane, stirred at room temperature, and then 1 mL of trifluoroacetic acid was added. The reaction was allowed to proceed for 2 hours at room temperature. The reaction was then checked for completeness and the solution was evaporated to dryness. Column chromatography (dichloromethane:methanol = 8:1) yielded the product 3-(3'-(2-aminoethyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (308.15, 0.16 g, 0.512 mmol, >99%). 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),7.94(br,2H),7.58–7.51(m,4H),7.46–7.40(m,2H),7.29–7.21(m,2H),3.94(dd,J=11.2,4 .0Hz,1H),3.15–3.09(m,2H),2.94(t,J=7.0Hz,2H),2.75–2.66(m,1H),2.58–2.54(m,1H),2.34–2.24(m,1H),2.13–2.04(m,1H).

[0167] Example 1: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)amino)ethyl)amino)-2-oxoethyl)acetamide

[0168] Step 1: Synthesis of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethyl)carbamate

[0169] Prepare a double-necked flask and a reflux tube. Take intermediate 3 (276.05 g, 1.00 g, 3.622 mmol, 1 eq), evacuate the gas, add 6 mL of ultra-dry DMF and DIPEA (129.24 g, 1.26 mL, 7.245 mmol, 2 eq, 0.742 g / mL), place in an ice bath and stir. Add mono-Boc-ethylenediamine (160.21 g, 0.63 mL, 3.985 mmol, 1.1 eq, 1.012 g / mL), heat to 90 °C, and react overnight. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted five times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol system, gradient elution) was performed to obtain the product (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethyl)tert-butyl carbamate (416.43 g, 0.39 g, 0.936 mmol, 26%).1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),7.58(t,J=7.8Hz,1H),7.14(d,J=8.6Hz,1H),7.06–6.95(m,2H),6.71(t,J=5.8Hz,1H),5.05(dd ,J=12.7,5.4Hz,1H),3.40–3.36(m,2H),3.12(q,J=6.2Hz,2H),2.93–2.83(m,1H),2.65–2.52(m,2H),2.05–1.97(m,1H),1.36(s,9H).

[0170] Step 2: Synthesis of 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

[0171] Compound (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)amino)ethyl)tert-butyl carbamate (416.43, 0.20 g, 0.480 mmol, 1 eq) was dissolved in 5 mL of dichloromethane, and 1.5 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was evaporated to dryness, methanol was added, and the mixture was filtered. The filter cake contained the product 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (316.32, 0.092 g, 0.291 mmol, 60%). 1 HNMR(500MHz,DMSO-d6)δ11.11(s,1H),7.81(br,2H),7.62(t,J=7.8Hz,1H),7.18(d,J=8.6Hz,1H),7.09(d,J=7.0Hz,1H),6.83(t,J=6.3 Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),3.57(q,J=5.9Hz,2H),3.03–2.97(m,2H),2.94–2.85(m,1H),2.64–2.53(m,2H),2.07–1.99(m,1H).

[0172] Step 3: Synthesis of N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)amino)ethyl)amino)-2-oxoethyl)acetamide

[0173] Prepare a double-necked flask. Take intermediate 1 (531.04 g, 0.15 g, 0.291 mmol, 1 eq), add 2 mL of ultra-dry DMF, HATU (380.23 g, 0.17 g, 0.436 mmol, 1.5 eq), and DIPEA (129.24 g, 0.15 mL, 0.872 mmol, 3 eq, 0.742 g / mL), evacuate the flask, and stir at room temperature for 10 minutes. Separately, take compound 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (316.32 g, 0.092 g, 0.291 mmol, 1 eq), dissolve it in 2 mL of ultra-dry DMF, add it to the system, and react at room temperature for 2 hours. After the reaction is complete, add a large amount of ethyl acetate, extract five times with saturated sodium chloride aqueous solution, dry to anhydrous sodium sulfate, and evaporate to dryness. Column chromatography (dichloromethane:methanol system, gradient elution) yielded the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethyl)amino)-2-oxoethyl)acetamide (829.15, 0.08 g, 0.096 mmol, 33%). 1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),8.26(br,1H),7.90(br,2H),7.73–7.55(m,3H),7. 54–7.44(m,3H),7.41(s,1H),7.33(d,J=7.6Hz,2H),7.17–7.08(m,2H),7.01(d,J=6.9Hz ,1H),6.70(t,J=5.5Hz,1H),5.05(dd,J=12.7,5.3Hz,1H),4.39(br,2H),4.22(br,2H),3 .33–3.19(m,4H),2.93–2.84(m,1H),2.65–2.55(m,2H),2.35(s,3H),2.04–1.99(m,1H).

[0174] Example 2: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)amino)propyl)amino)-2-oxoethyl)acetamide

[0175] The synthesis method was the same as that described in Example 1, with a yield of 17%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),8.10(br,1H),7.99–7.83(m,2H),7.73–7.50(m,4H),7.50–7. 41(m,2H),7.39(s,1H),7.33(d,J=7.8Hz,2H),7.12(d,J=7.8Hz,1H),7.07–6.94(m,2H),6.61(t,J= 5.7Hz,1H),5.04(dd,J=12.8,5.4Hz,1H),4.39(br,2H),4.26(br,2H),3.28–3.23(m,2H),3.18–3.1 1(m,2H),2.93–2.82(m,1H),2.65–2.52(m,2H),2.34(s,3H),2.05–1.98(m,1H),1.72–1.60(m,2H).

[0176] Example 3: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)amino)butyl)amino)-2-oxoethyl)acetamide

[0177] The synthesis method was the same as that described in Example 1, with a yield of 17%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),8.00(br,1H),7.95–7.86(m,2H),7.70–7.52(m,4H),7.51–7.42(m, 2H),7.39(s,1H),7.33(d,J=7.9Hz,2H),7.12(d,J=7.8Hz,1H),7.07(d,J=8.6Hz,1H),7.01(d,J=7.0Hz,1H ),6.51(t,J=5.8Hz,1H),5.04(dd,J=12.7,5.4Hz,1H),4.38(br,2H),4.25(br,2H),3.29–3.25(m,2H),3. 13–3.06(m,2H),2.92–2.83(m,1H),2.66–2.52(m,2H),2.35(s,3H),2.07–1.98(m,1H),1.53–1.42(m,4H).

[0178] Example 4: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)amino)ethoxy)ethyl)amino)-2-oxoethyl)acetamide

[0179] The synthesis method was the same as that described in Example 1, with a yield of 11%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),8.07(br,1H),7.95–7.86(m,2H),7.66–7.54(m,4H),7.50–7. 43(m,2H),7.40(s,1H),7.34(d,J=7.9Hz,2H),7.14–7.10(m,2H),7.03(d,J=7.0Hz,1H),6.58(t,J=6 .0Hz,1H),5.04(dd,J=12.7,5.6Hz,1H),4.39(br,2H),4.26(br,2H),3.58(t,J=5.3Hz,2H),3.44–3. 43(m,4H),3.25–3.23(m,2H),2.88–2.84(m,1H),2.64–2.61(m,2H),2.36(s,3H),2.00–1.98(m,1H).

[0180] Example 5: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamido)propyl)amino)-2-oxoethyl)acetamide

[0181] Step 1: Synthesis of tert-butyl carbamate (3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamamido)propyl)carbamate

[0182] Prepare a double-necked flask. Take intermediate 2 (332.27 g, 0.50 g, 1.505 mmol, 1 eq), HATU (380.23 g, 0.57 g, 1.505 mmol, 1 eq), add 4 mL of ultradry DMF, and DIPEA (129.24 g, 0.79 mL, 4.514 mmol, 3 eq, 0.742 g / mL). Vacuum the mixture and stir at room temperature for 30 minutes. Add N-tert-butoxycarbonyl-1,3-propanediamine (174.24 g, 0.29 mL, 1.655 mmol, 1.1 eq, 0.998 g / mL). React overnight at room temperature. Once the reaction is complete, add a large amount of ethyl acetate, extract five times with saturated sodium chloride aqueous solution, dry to anhydrous sodium sulfate, and evaporate to dryness. Column chromatography (dichloromethane:methanol = 50:1) yielded the product (3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamyl)propyl)tert-butyl carbamate (488.50, 0.14 g, 0.282 mmol, 19%). 1 HNMR (500MHz, DMSO-d6) δ11.11(s,1H),7.96(t,J=5.5Hz,1H),7.81(t,J=7. 9Hz,1H),7.50(d,J=7.3Hz,1H),7.39(d,J=8.5Hz,1H),6.78(t,J=5.2Hz,1H) ,5.12(dd,J=12.8,5.4Hz,1H),4.77(s,2H),3.16–3.09(m,2H),2.94–2.85(m ,3H),2.63–2.54(m,2H),2.07–2.01(m,1H),1.57–1.50(m,2H),1.36(s,9H).

[0183] Step 2: Synthesis of N-(3-aminopropyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamide

[0184] Compound (3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetamyl)propyl)tert-butyl carbamate (488.50, 0.11 g, 0.282 mmol, 1 eq) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was evaporated to dryness. Column chromatography (dichloromethane:methanol = 50:1 → 10:1) yielded the product N-(3-aminopropyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetamide (388.38, 0.045 g, 0.116 mmol, 51%). 1H NMR (500MHz, DMSO-d6) δ11.12(s,1H),8.14(t,J=5.2Hz,1H),7.82(t,J=7.9Hz,1H),7.73(br,2H),7.51(d,J=7.1Hz,1H),7.40(d,J=8.5Hz,1H),5.11(dd ,J=12.8,5.2Hz,1H),4.80(s,2H),3.22(q,J=6.3Hz,2H),2.94–2.85(m,1H), 2.83–2.73(m,2H),2.66–2.54(m,2H),2.09–1.99(m,1H),1.78–1.64(m,2H).

[0185] Step 3: Synthesis of N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamamido)propyl)amino)-2-oxoethyl)acetamide

[0186] Prepare a double-necked flask. Take intermediate 1 (531.04 g, 0.062 g, 0.117 mmol, 1 eq), HATU (380.23 g, 0.063 g, 0.167 mmol, 1.5 eq), add 3 mL of ultra-dry DMF, and DIPEA (129.24 g, 0.058 mL, 0.334 mmol, 3 eq, 0.742 g / mL). After evacuating the gas, stir at room temperature for 30 minutes. Separately, take N-(3-aminopropyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamide (388.38 g, 0.045 g, 0.117 mmol, 1.05 eq), dissolve it in 1 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted five times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 50:1) was performed to give the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamido)propyl)amino)-2-oxoethyl)acetamide (901.17, 0.04 g, 0.044 mmol, 38%). 1H NMR(500MHz,CD3OD_SPE)δ7.82(d,J=7.5Hz,2H),7.77(t,J=7.9Hz,1H),7.61(br,2H),7.5 0(d,J=7.3Hz,1H),7.46–7.35(m,4H),7.35–7.21(m,3H),6.98(d,J=7.9Hz,1H),5.11(dd, J=12.5,5.5Hz,1H),4.75(s,2H),4.43–4.23(m,4H),3.30–3.26(m,2H),3.26–3.20(m,2H) ,2.90–2.82(m,1H),2.77–2.66(m,2H),2.38(s,3H),2.17–2.10(m,1H),1.76–1.68(m,2H).

[0187] Example 6: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamido)butyl)amino)-2-oxoethyl)acetamide

[0188] The synthesis method was the same as that described in Example 5, with a yield of 14%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),8.07–7.84(m,4H),7.79(t,J=7.6Hz,1H),7 .72–7.53(m,3H),7.52–7.43(m,3H),7.42–7.32(m,4H),7.13(d,J=8.2Hz,1H),5. 11(dd,J=12.4,5.1Hz,1H),4.76(s,2H),4.58–4.11(m,4H),3.14–3.03(m,4H),2. 93–2.85(m,1H),2.64–2.57(m,2H),2.36(s,3H),2.03–1.98(m,1H),1.37(s,4H).

[0189] Example 7: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamido)ethoxy)ethyl)amino)-2-oxoethyl)acetamide

[0190] The synthesis method was the same as that described in Example 5, with a yield of 50%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,CD3OD_SPE)δ7.82–7.75(m,3H),7.58(br,2H),7.51(d,J=7.3Hz,1H),7.42– 7.36(m,4H),7.30–7.23(m,3H),6.97(d,J=6.6Hz,1H),5.14(dd,J=12.5,5.5Hz,1H),4.7 6(s,2H),4.32(br,4H),3.59(t,J=5.1Hz,2H),3.54(t,J=5.3Hz,2H),3.51–3.48(m,2H), 3.45–3.39(m,2H),2.91–2.83(m,1H),2.76–2.69(m,2H),2.38(s,3H),2.16–2.11(m,1H).

[0191] Example 8: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetamide)hexyl)amino)-2-oxoethyl)acetamide

[0192] The synthesis method was the same as that described in Example 5, with a yield of 50%. The NMR characterization results of the product are as follows: 1 H NMR(400MHz, CDCl3)δ9.37(s,1H),7.81–7.74(m,3H),7.60–7.53(m,4H), 7.49–7.43(m,2H),7.33–7.30(m,1H),7.26–7.15(m,4H),7.01–6.94(m,1H ),6.82(br,1H),5.06–4.98(m,1H),4.68(s,2H),4.37–4.17(m,4H),3.36 (m,4H),2.93–2.78(m,3H),2.42(s,3H),2.19(br,1H),1.61–1.36(m,8H).

[0193] Example 9: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0194] Step 1: Synthesis of tert-butyl carbamate (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)prop-2-yn-1-yl)carbamate

[0195] Prepare a double-necked flask and take intermediate 4 (335.97 g, 1.50 g, 4.465 mmol, 1 eq), N-Boc-aminopropyne (155.19 g, 2.08 g, 13.394 mmol, 3 eq), Pd(PPh3)2Cl2 (701.90 g, 0.31 g, 0.446 mmol, 0.1 eq), and cuprous iodide (190.45 g, 0.085 g, 0.446 mmol, 0.1 eq). Vacuum the mixture for 15 minutes, add 15 mL of ultra-dry DMF and triethylamine (101.19 g, 9.31 mL, 66.970 mmol, 15 eq, 0.728 g / mL), evacuate the mixture, raise the temperature to 80 °C, and react for 12 hours. After the reaction was completed, the product was evaporated to dryness at 80 °C and subjected to column chromatography (dichloromethane:methanol = 80:1) to obtain the product (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)prop-2-yn-1-yl)carbamate tert-butyl ester (411.41, 1.20 g, 2.917 mmol, 65%). 1 H NMR(500MHz,DMSO-d6)δ11.13(s,1H),7.90(d,J=6.6Hz,1H),7.88–7.81(m,2H),7.41(t,J=4.7Hz,1H),5.13(dd, J=12.8,5.4Hz,1H),4.07(d,J=5.4Hz,2H),2.93–2.84(m,1H),2.65–2.55(m,2H),2.09–2.02(m,1H),1.40(s,9H).

[0196] Step 2: Synthesis of 4-(3-aminopropyl-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

[0197] Compound (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)prop-2-yn-1-yl) tert-butyl carbamate (411.41, 0.40 g, 0.972 mmol, 1 eq) was dissolved in 5 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was evaporated to dryness. Column chromatography (dichloromethane:methanol = 50:1 → 10:1) yielded the product 4-(3-aminopropyl-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol-1,3-dione (311.30, 0.29 g, 0.932 mmol, 96%). 1HNMR(500MHz,DMSO-d6)δ11.15(br,1H),7.96(d,J=6.8Hz,1H),7.93–7.86(m,2H),5.15(dd ,J=12.9,5.4Hz,1H),4.01(s,2H),2.93–2.85(m,1H),2.65–2.52(m,2H),2.10–2.03(m,1H).

[0198] Step 3: Synthesis of N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0199] Prepare a double-necked flask. Take intermediate 1 (531.04 g, 0.15 g, 0.282 mmol, 1 eq), HATU (380.23 g, 0.16 g, 0.424 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, and DIPEA (129.24 g, 0.15 mL, 0.847 mmol, 3 eq, 0.742 g / mL). Vacuum the flask and stir at room temperature for 30 minutes. Separately, take 4-(3-aminopropyl-1-yn-1-yl)-2-(2,6-dioxopiridin-3-yl)isoindole-1,3-dione (311.3 g, 0.092 g, 0.296 mmol, 1.05 eq), dissolve it in 1 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted five times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 60:1) was performed to give the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide (824.12, 0.10 g, 0.120 mmol, 42%). 1H NMR(500MHz,DMSO-d6)δ11.13(s,1H),8.67(br,1H),7.95–7.89(m,3H),7.8 6–7.80(m,2H),7.72–7.56(m,3H),7.47(br,2H),7.40(s,1H),7.33(d,J=8. 0Hz,2H),7.14(d,J=8.5Hz,1H),5.13(dd,J=12.8,5.4Hz,1H),4.45–4.22(m ,6H),2.91–2.86(m,1H),2.64–2.58(m,2H),2.35(s,3H),2.08–2.03(m,1H).

[0200] Example 10: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)propyl)amino)-2-oxoethyl)acetamide

[0201] Step 1: Synthesis of tert-butyl (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)propyl)carbamate

[0202] Compound (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)propyl-2-yn-1-yl) tert-butyl carbamate (411.41, 0.80 g, 1.944 mmol, 1 eq) was dissolved in 10 mL of methanol. Palladium on carbon (10%, 106.42, 0.083 g, 0.778 mmol, 0.4 eq) was added with stirring at room temperature. Hydrogen was purged, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to give product (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)propyl) tert-butyl carbamate (415.45, 0.74 g, 1.781 mmol, 92%). 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),7.80–7.73(m,2H),7.70(d,J=6.9Hz,1H),6.91–6.80(m,1H),5.12(dd,J=12.7,5.4Hz,1H),3 .01(t,J=7.5Hz,2H),2.98–2.93(m,2H),2.92–2.84(m,1H),2.63–2.53(m,2H),2.09–2.02(m,1H),1.78–1.67(m,2H),1.37(s,9H).

[0203] Step 2: Synthesis of 4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0204] Compound (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)propyl)tert-butyl carbamate (415.45 g, 0.12 g, 0.289 mmol, 1 eq) was dissolved in 3 mL of dichloromethane. 1 mL of trifluoroacetic acid was added with stirring at room temperature, and the mixture was stirred for 2 hours at room temperature. After the reaction was complete, the solution was evaporated to dryness, and then filtered through dichloromethane. The filter cake was the product 4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (315.33 g, 0.091 g, 0.289 mmol, >99%).

[0205] Step 3: Synthesis of N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)propyl)amino)-2-oxoethyl)acetamide

[0206] Prepare a double-necked flask. Take intermediate 1 (531.04 g, 0.14 g, 0.264 mmol, 1 eq), HATU (380.23 g, 0.15 g, 0.395 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, and DIPEA (129.24 g, 0.14 mL, 0.791 mmol, 3 eq, 0.742 g / mL). Vacuum the flask and stir at room temperature for 30 minutes. Separately, take 4-(3-aminopropyl)-2-(2,6-dioxopiridin-3-yl)isoindoline-1,3-dione (315.33 g, 0.091 g, 0.290 mmol, 1.1 eq), dissolve it in 1 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted five times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 50:1) was performed to give the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)propyl)amino)-2-oxoethyl)acetamide (828.15, 0.12 g, 0.142 mmol, 54%). 1H NMR(500MHz,DMSO-d6)δ11.11(s,1H),8.06(br,1H),7.92(br,2H),7.76–7.72(m,2H),7.67–7.61 (m,2H),7.55(d,J=8.7Hz,2H),7.47(br,2H),7.39(s,1H),7.32(d,J=8.0Hz,2H),7.12(d,J=7.6Hz ,1H),5.12(dd,J=12.8,5.4Hz,1H),4.40(br,2H),4.25(br,2H),3.15–3.06(m,2H),2.96(t,J=7.4 Hz,2H),2.92–2.85(m,1H),2.64–2.54(m,2H),2.34(s,3H),2.09–2.01(m,1H),1.77–1.67(m,2H).

[0207] Example 11: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)but-3-yn-1-yl)amino)-2-oxoethyl)acetamide

[0208] The synthesis method was the same as that described in Example 9, with a yield of 45%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.13(s,1H),8.24(br,1H),7.97–7.83(m,3H),7.83–7.77 (m,2H),7.73–7.52(m,3H),7.47(br,2H),7.40(s,1H),7.34(d,J=8.0Hz,2H),7.13 (d,J=8.8Hz,1H),5.13(dd,J=12.8,5.4Hz,1H),4.38(br,2H),4.30(br,2H),3.37– 3.34(m,2H),2.91–2.84(m,1H),2.65–2.55(m,4H),2.36(s,3H),2.06–2.00(m,1H).

[0209] Example 12: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)butyl)amino)-2-oxoethyl)acetamide

[0210] The synthesis method was the same as that described in Example 10, with a yield of 63%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),8.08–7.88(m,3H),7.78–7.72(m,2H),7.71–7.53(m,4H) ),7.47(br,2H),7.39(s,1H),7.34(d,J=7.7Hz,2H),7.12(d,J=7.9Hz,1H),5.12(dd,J=12.7, 5.4Hz,1H),4.39(br,2H),4.24(br,2H),3.15–3.06(m,2H),3.04–2.96(m,2H),2.92–2.84(m, 1H),2.66–2.54(m,1H),2.36(s,3H),2.05–1.97(m,1H),1.60–1.51(m,2H),1.46–1.38(m,2H).

[0211] Example 13: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)pent-4-yn-1-yl)amino)-2-oxoethyl)acetamide

[0212] The synthesis method was the same as that described in Example 9, with a yield of 49%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.13(s,1H),8.10(br,1H),7.97–7.89(m,2H),7.87–7.80(m,3 H),7.73–7.55(m,3H),7.47(br,2H),7.40(s,1H),7.34(d,J=7.9Hz,2H),7.13(d,J=8.2 Hz,1H),5.14(dd,J=12.8,5.4Hz,1H),4.39(br,2H),4.26(br,2H),3.27–3.21(m,2H),2 .92–2.85(m,1H),2.63–2.54(m,4H),2.35(s,3H),2.07–2.02(m,1H),1.73–1.66(m,2H).

[0213] Example 14: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)pentyl)amino)-2-oxoethyl)acetamide

[0214] The synthesis method was the same as that described in Example 10, with a yield of 52%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),8.06–7.87(m,3H),7.78–7.73(m,2H),7.69–7.54(m,4H),7. 47(br,2H),7.40(s,1H),7.34(d,J=7.7Hz,2H),7.13(d,J=7.7Hz,1H),5.12(dd,J=12.7,5.4Hz,1H ),4.39(br,2H),4.24(br,2H),3.10–3.02(m,2H),3.01–2.95(m,2H),2.92–2.84(m,1H),2.62–2.5 4(m,2H),2.35(s,3H),2.07–2.01(m,1H),1.62–1.53(m,2H),1.43–1.36(m,2H),1.31–1.26(m,2H).

[0215] Example 15: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0216] The synthesis method was the same as that described in Example 9, with a yield of 32%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ11.00(s,1H),8.62(br,1H),7.93(br,2H),7.75(d,J=7.6Hz,1H ),7.64(d,J=7.6Hz,2H),7.62–7.51(m,3H),7.45(br,2H),7.39(s,1H),7.32(d,J=8.0Hz ,2H),7.12(d,J=8.5Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.50–4.25(m,6H),4.20(d,J= 4.4Hz,2H),2.95–2.86(m,1H),2.61–2.57(m,1H),2.43–2.33(m,4H),2.01–1.98(m,1H).

[0217] Example 16: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)propyl)amino)-2-oxoethyl)acetamide

[0218] The synthesis method was the same as that described in Example 10, with a yield of 23%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.06(br,1H),7.96–7.88(m,2H),7.66–7.52 (m,4H),7.48–7.40(m,4H),7.38(s,1H),7.31(d,J=7.8Hz,2H),7.11(d,J=8.0Hz,1H ),5.12(dd,J=13.4,5.0Hz,1H),4.50–4.20(m,6H),3.14–3.08(m,2H),2.95–2.88( m,1H),2.62–2.57(m,3H),2.40–2.33(m,4H),2.01–1.98(m,1H),1.74–1.67(m,2H).

[0219] Example 17: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)piperazin-1-yl)-2-oxoethyl)acetamide

[0220] The synthesis method was the same as that described in Example 1, with a yield of 64%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),7.95(br,2H),7.73(t,J=7.8Hz,1H),7.69 –7.55(m,3H),7.48(br,2H),7.42–7.39(m,2H),7.36–7.33(m,3H),7.17–7.13(m, 1H),5.11(dd,J=12.7,5.5Hz,1H),4.62(br,2H),4.42(br,2H),3.62(br,4H),3.2 6(br,4H),2.92–2.84(m,1H),2.61–2.54(m,2H),2.36(s,3H),2.05–2.01(m,1H).

[0221] Example 18: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)piperidin-4-yl)amino)-2-oxoethyl)acetamide

[0222] The synthesis method was the same as that described in Example 1, with a yield of 62%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.08(s,1H),8.19–7.86(m,3H),7.76–7.54(m,4H),7.48(br,2H),7. 41(s,1H),7.37–7.32(m,4H),7.14(d,J=8.0Hz,1H),5.09(dd,J=12.7,5.4Hz,1H),4.40(br,2 H),4.27(br,2H),3.77(s,1H),3.63(d,J=11.3Hz,2H),3.03–2.94(m,2H),2.93–2.84(m,1H), 2.64–2.54(m,2H),2.36(s,3H),2.06–2.00(m,1H),1.82(d,J=8.9Hz,2H),1.64–1.53(m,2H).

[0223] Example 19: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)piperidin-4-yl)methyl)amino)-2-oxoethyl)acetamide

[0224] The synthesis method was the same as that described in Example 1, with a yield of 48%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.08(s,1H),8.20–7.86(m,3H),7.81–7.53(m,4H),7.47(br,2H), 7.40(s,1H),7.37–7.29(m,4H),7.13(d,J=7.8Hz,1H),5.08(dd,J=12.7,5.4Hz,1H),4.40(b r,2H),4.28(br,2H),3.71–3.59(m,2H),3.02(br,2H),2.92–2.76(m,3H),2.64–2.53(m,2H ),2.35(s,3H),2.06–2.00(m,1H),1.64(d,J=11.3Hz,2H),1.54(br,1H),1.30–1.24(m,2H).

[0225] Example 20: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)piperidin-4-yl)ethyl)amino)-2-oxoethyl)acetamide

[0226] The synthesis method was the same as that described in Example 1, with a yield of 62%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.08(s,1H),8.10–7.86(m,3H),7.75–7.54(m,4H),7.48(br,2H),7.40 (s,1H),7.36–7.28(m,4H),7.14(d,J=8.2Hz,1H),5.08(dd,J=12.7,5.5Hz,1H),4.41(br,2H),4. 27(br,2H),3.65(d,J=11.5Hz,2H),3.71–3.60(m,2H),2.91–2.84(m,1H),2.76(t,J=11.1Hz,2H ),2.61–2.54(m,2H),2.36(s,3H),2.07–2.00(m,1H),1.72(d,J=11.2Hz,2H),1.39–1.25(m,5H).

[0227] Example 21: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethyl)piperazin-1-yl)-2-oxoethyl)acetamide

[0228] The synthesis method was the same as that described in Example 1, with a yield of 55%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.08(s,1H),7.94(br,2H),7.66–7.53(m,4H),7.48(br,2 H),7.41(br,1H),7.35(d,J=6.6Hz,2H),7.15–7.09(m,2H),7.03(d,J=7.0Hz,1H),6 .80(br,1H),5.06(dd,J=12.7,5.4Hz,1H),4.55(br,2H),4.40(br,2H),3.48–3.36( m,8H),2.91–2.84(m,1H),2.60–2.53(m,4H),2.42–2.36(m,5H),2.04–1.98(m,1H).

[0229] Example 22: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)-2,13-dioxo-6,9-dioxa-3,12-diazatetradecyl)acetamide

[0230] The synthesis method was the same as that described in Example 5, with a yield of 54%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ11.11(s,1H),8.21–7.97(m,2H),7.97–7.84(m,2H),7.83–7.76(m,1H),7.75–7.53(m ,3H),7.52–7.43(m,3H),7.41–7.37(m,2H),7.34(d,J=7.7Hz,2H),7.13(d,J=8.6Hz,1H),5.11(dd,J=12.7,5 .4Hz,1H),4.78(s,2H),4.39(br,2H),4.26(br,2H),3.49(br,4H),3.44(t,J=5.7Hz,2H),3.38–3.37(m,2H), 3.31–3.29(m,2H),3.23–3.17(m,2H),2.93–2.85(m,1H),2.61–2.56(m,2H),2.36(s,3H),2.06–2.00(m,1H).

[0231] Example 23: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)-2,16-dioxo-6,9,12-trioxa-3,15-diazaheptadecyl)acetamide

[0232] The synthesis method was the same as that described in Example 5, with a yield of 54%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),8.16–7.97(m,2H),7.97–7.86(m,2H),7.83–7.78(m,1H),7.73–7.5 2(m,3H),7.51–7.42(m,3H),7.39(d,J=8.5Hz,2H),7.34(d,J=7.7Hz,2H),7.13(d,J=7.4Hz,1H),5.11(dd ,J=12.8,5.4Hz,1H),4.78(s,2H),4.39(br,2H),4.25(br,2H),3.51–3.43(m,10H),3.37–3.35(m,2H),3. 31–3.29(m,2H),3.24–3.16(m,2H),2.93–2.84(m,1H),2.64–2.55(m,2H),2.36(s,3H),2.06–2.01(m,1H).

[0233] Example 24: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)-2,19-dioxo-6,9,12,15-tetraoxa-3,18-diazaeicosyl)acetamide

[0234] The synthesis method was the same as that described in Example 5, with a yield of 50%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),8.15–7.97(m,2H),7.96–7.84(m,2H),7.83–7.78(m,1H),7.75–7.5 3(m,3H),7.53–7.43(m,3H),7.39(d,J=8.5Hz,2H),7.34(d,J=7.6Hz,2H),7.13(d,J=8.5Hz,1H),5.11(dd ,J=12.8,5.4Hz,1H),4.78(s,2H),4.39(br,2H),4.25(br,2H),3.50–3.44(m,14H),3.37–3.35(m,2H),3. 31–3.28(m,2H),3.23–3.17(m,2H),2.93–2.85(m,1H),2.62–2.57(m,2H),2.36(s,3H),2.06–2.01(m,1H).

[0235] Example 25: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)but-3-yn-1-yl)amino)-2-oxoethyl)acetamide

[0236] The synthesis method was the same as that described in Example 9, with a yield of 60%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.28(br,1H),7.85(br,2H),7.71(d,J=7.5H z,1H),7.61–7.55(m,3H),7.54–7.41(m,4H),7.39(s,1H),7.33(d,J=7.9Hz,2H),7 .12(d,J=8.6Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.47–4.25(m,6H),3.32–3.25( m,2H),2.94–2.87(m,1H),2.61–2.57(m,3H),2.43–2.35(m,4H),2.01–1.98(m,1H).

[0237] Example 26: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0238] The synthesis method was the same as that described in Example 9, with a yield of 61%. The NMR characterization results of the product are as follows: 1 H NMR (500MHz, DMSO-d6) δ10.99 (s, 1H), 8.63 (br, 1H), 7.98–7.91 (m, 2H), 7.71 (d, J = 7. 8Hz,1H),7.70–7.54(m,4H),7.53–7.43(m,3H),7.41(s,1H),7.33(d,J=8.1Hz,2H),7 .14(d,J=8.8Hz,1H),5.11(dd,J=13.3,5.0Hz,1H),4.52–4.24(m,6H),4.19(d,J=4.8 Hz,2H),2.95–2.86(m,1H),2.63–2.58(m,1H),2.40–2.34(m,4H),2.03–1.99(m,1H).

[0239] Example 27: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)but-3-yn-1-yl)amino)-2-oxoethyl)acetamide

[0240] The synthesis method was the same as that described in Example 9, with a yield of 64%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.27(br,1H),7.88(br,2H),7.67(d,J=7.8Hz ,1H),7.65–7.54(m,4H),7.48(d,J=7.8Hz,3H),7.40(s,1H),7.33(d,J=7.9Hz,2H), 7.13(d,J=8.7Hz,1H),5.11(dd,J=13.3,4.9Hz,1H),4.47–4.26(m,6H),3.31–3.27( m,2H),2.94–2.88(m,1H),2.62–2.57(m,3H),2.41–2.35(m,4H),2.02–1.99(m,1H).

[0241] Example 28: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)pent-4-yn-1-yl)amino)-2-oxoethyl)acetamide

[0242] The synthesis method was the same as that described in Example 9, with a yield of 59%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.09(br,1H),7.96–7.88(m,2H),7.68(d,J=7.9Hz, 1H),7.65–7.53(m,4H),7.49(d,J=7.8Hz,3H),7.40(s,1H),7.34(d,J=7.8Hz,2H),7.13(d ,J=8.3Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.48–4.23(m,6H),3.23–3.18(m,2H),2.93– 2.87(m,1H),2.64–2.56(m,1H),2.44–2.35(m,6H),2.02–1.98(m,1H),1.70–1.64(m,2H).

[0243] Example 29: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0244] The synthesis method was the same as that described in Example 9, with a yield of 48%. The NMR characterization results of the product are as follows:1 H NMR(500MHz,DMSO-d6)δ11.00(s,1H),8.61(br,1H),7.97–7.89(m,2H),7.76–7.59( m,5H),7.57(d,J=8.7Hz,1H),7.47(br,2H),7.41(s,1H),7.33(d,J=8.0Hz,2H),7.1 4(d,J=8.6Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.54–4.25(m,6H),4.18(d,J=4.6H z,2H),2.95–2.87(m,1H),2.63–2.58(m,1H),2.43–2.34(m,4H),2.03–1.98(m,1H).

[0245] Example 30: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)but-3-yn-1-yl)amino)-2-oxoethyl)acetamide

[0246] The synthesis method was the same as that described in Example 9, with a yield of 60%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.00(s,1H),8.29(br,1H),7.86(br,2H),7.72–7. 56(m,6H),7.47(br,2H),7.40(s,1H),7.34(d,J=8.0Hz,2H),7.13(d,J=8.6H z,1H),5.11(dd,J=13.3,5.1Hz,1H),4.52–4.19(m,6H),3.33–3.28(m,2H), 2.95–2.87(m,1H),2.62–2.55(m,3H),2.44–2.35(m,4H),2.04–1.99(m,1H).

[0247] Example 31: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((5-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)pent-4-yn-1-yl)amino)-2-oxoethyl)acetamide

[0248] The synthesis method was the same as that described in Example 9, with a yield of 59%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.08(br,1H),7.96–7.88(m,2H),7.66–7.5 5(m,6H),7.48(br,2H),7.40(s,1H),7.34(d,J=7.8Hz,2H),7.13(d,J=6.7Hz,1H), 5.11(dd,J=13.3,5.0Hz,1H),4.49–4.23(m,6H),3.22–3.20(m,2H),2.94–2.87(m ,1H),2.62–2.60(m,1H),2.41–2.35(m,6H),2.03–1.99(m,1H),1.70–1.64(m,2H).

[0249] Example 32: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0250] The synthesis method was the same as that described in Example 9, with a yield of 44%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ10.99(s,1H),8.63(br,1H),7.99–7.85(m,2H),7.73–7 .53(m,5H),7.53–7.43(m,3H),7.41(s,1H),7.33(d,J=8.0Hz,2H),7.14(d,J=6 .9Hz,1H),5.02(dd,J=13.2,5.1Hz,1H),4.67–4.24(m,6H),4.20(d,J=4.5Hz,2 H),2.92–2.83(m,1H),2.65–2.58(m,1H),2.46–2.34(m,4H),2.03–1.97(m,1H).

[0251] Example 33: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-4-yl)but-3-yn-1-yl)amino)-2-oxoethyl)acetamide

[0252] The synthesis method was the same as that described in Example 9, with a yield of 60%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.31(br,1H),7.83(br,2H),7.69–7.5 1(m,5H),7.51–7.42(m,3H),7.40(s,1H),7.33(d,J=8.0Hz,2H),7.13(d,J=8. 6Hz,1H),5.03(dd,J=13.2,5.1Hz,1H),4.70–4.18(m,6H),3.32–3.16(m,2H) ,2.89–2.81(m,1H),2.60–2.55(m,3H),2.43–2.35(m,4H),2.02–1.96(m,1H).

[0253] Example 34: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((5-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-4-yl)pent-4-yn-1-yl)amino)-2-oxoethyl)acetamide

[0254] The synthesis method was the same as that described in Example 9, with a yield of 55%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ10.98(s,1H),8.12(br,1H),7.91(br,2H),7.81–7.53(m, 5H),7.52–7.43(m,3H),7.40(s,1H),7.34(d,J=7.5Hz,2H),7.13(d,J=7.6Hz,1H), 5.07(dd,J=13.2,4.9Hz,1H),4.62–4.08(m,6H),3.31–3.27(m,2H),2.93–2.84(m ,1H),2.63–2.58(m,1H),2.46–2.34(m,6H),2.01–1.97(m,1H),1.74–1.63(m,2H).

[0255] Example 35: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)acetamide

[0256] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0257] Prepare a double-necked flask and take the following compounds: 3-(4-iodo-1-oxoisoindol-2-yl)piperidin-2,6-dione (369.98 g, 1.50 g, 4.054 mmol, 1 eq), Pd(OAc)2 (224.51 g, 0.09 g, 0.405 mmol, 0.1 eq), and bis(adamantane-1-yl)(butyl)phosphine hydroiodate (358.54 g, 0.29 g, 0.811 mmol, 0.1 eq). 0.2 eq), cesium carbonate (325.82, 3.96 g, 12.163 mmol, 3 eq), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (309.21, 1.50 g, 4.865 mmol, 1.2 eq), purged with gas; prepare a separate two-necked flask, take 16 mL of 1,4-dioxane and 4 mL of water, purged with gas and add to the system, heat to 40 °C, and stir for 3 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted five times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 80:1 → 60:1 → 50:1) was performed to give the product 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (425.49 g, 0.60 g, 1.410 mmol, 35%). 1 HNMR(500MHz,DMSO-d6)δ10.99(s,1H),7.65(d,J=7.2Hz,1H),7.57(d,J=7.1Hz,1 H),7.53(t,J=7.5Hz,1H),6.02(br,1H),5.14(dd,J=13.4,5.0Hz,1H),4.56(d,J= 17.5Hz,1H),4.38(d,J=17.5Hz,1H),4.00(br,2H),3.55(t,J=5.9Hz,2H),2.98–2 .86(m,1H),2.66–2.55(m,2H),2.48–2.45(m,2H),2.01–1.97(m,1H),1.43(s,9H).

[0258] Step 2: Synthesis of 3-(1-oxo-4-(1,2,3,6-tetrahydropyridin-4-yl)isoindol-2-yl)piperidin-2,6-dione

[0259] Compound 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (425.49 g, 0.17 g, 0.400 mmol, 1 eq) was dissolved in 3 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 8:1 → 3:1) to give the product 3-(1-oxo-4-(1,2,3,6-tetrahydropyridine-4-yl)isoindol-2-yl)piperidin-2,6-dione (325.37 g, 0.10 g, 0.307 mmol, 77%). 1 HNMR(500MHz,DMSO-d6)δ11.03(s,1H),8.84(br,1H),7.70(d,J=6.9Hz,1H),7.66–7.51(m,2H),6.04(br,1H),5.17(dd,J=13.3,5.1Hz,1H),4.57( d,J=17.3Hz,1H),4.38(d,J=17.3Hz,1H),3.76(s,2H),3.32(br,2H),2.9 8–2.89(m,1H),2.69–2.59(m,3H),2.43–2.36(m,1H),2.06–1.99(m,1H).

[0260] Step 3: Synthesis of N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)acetamide

[0261] Prepare a double-necked flask. Take intermediate 1 (531.04 g, 0.12 g, 0.226 mmol, 1 eq), HATU (380.23 g, 0.13 g, 0.339 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, and DIPEA (129.24 g, 0.12 mL, 0.678 mmol, 3 eq, 0.742 g / mL). Vacuum the flask and stir at room temperature for 30 minutes. Separately, take 3-(1-oxo-4-(1,2,3,6-tetrahydropyridin-4-yl)isoindol-2-yl)piperidin-2,6-dione (325.37 g, 0.10 g, 0.294 mmol, 1.3 eq), dissolve it in 1 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted five times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 60:1) was performed to give the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)acetamide (838.17, 0.11 g, 0.131 mmol, 58%). 1 H NMR (500MHz, DMSO-d6) δ10.98 (s, 1H), 7.94 (br, 2H), 7.66 (d, J = 7.0Hz, 2H), 7.61–7.51 (m, 4H), 7. 48(br,2H),7.41(s,1H),7.33(d,J=7.8Hz,2H),7.14(d,J=8.4Hz,1H),6.03(d,J=24.4Hz,1H),5. 13(dd,J=13.3,4.8Hz,1H),4.77–4.33(m,6H),4.12(d,J=18.6Hz,2H),3.65(d,J=28.9Hz,2H),2. 95–2.87(m,1H),2.67–2.54(m,3H),2.46–2.42(m,1H),2.35(d,J=6.7Hz,3H),2.01–1.97(m,1H).

[0262] Example 36: N-(4-cyanophenyl)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-2-((4-methyl-N-(3-(trifluoromethyl)phenyl)phenyl)sulfonamido)acetamide

[0263] Step 1: Synthesis of N-(4-cyanophenyl)-N-(N-p-toluenesulfonyl-N-(3-(trifluoromethyl)phenyl)glycyl)glycine

[0264] The synthesis method is the same as that described for intermediate 1, with a yield of 86%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz, CDCl3)δ7.77(d,J=8.3Hz,2H),7.54–7.49(m,3H),7.45(d,J=8.2Hz,2H),7.4 1–7.37(m,2H),7.30(s,1H),7.20(d,J=8.1Hz,2H),4.41(s,2H),4.27(s,2H),2.38(s,3H).

[0265] Step 2: Synthesis of tert-butyl (3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)carbamate

[0266] Prepare a double-necked flask and take the following compounds: 3-(4-iodo-1-oxoisoindol-2-yl)piperidine-2,6-dione (369.98, 3.00 g, 8.108 mmol, 1 eq), N-Boc-aminopropyne (155.19, 2.53 g, 16.217 mmol, 2 eq), Pd(PPh3)2Cl2 (701.90, 0.28 g, 0.405 mmol, 0.05 eq), and cuprous iodide (190.45, 0.15 g, 0.811 mmol, 0.1 eq). Vacuum the mixture for 20 minutes, add 30 mL of ultra-dry DMF and triethylamine (101.19, 16.90 mL, 121.628 mmol, 15 eq, 0.728 g / mL), evacuate the mixture, raise the temperature to 80 °C, and react for 12 hours. After the reaction was completed, the sample was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 50:1) to obtain the product (3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)carbamate tert-butyl ester (397.16 g, 1.70 g, 4.280 mmol, 53%). 1 H NMR(500MHz,DMSO-d6)δ11.02(s,1H),7.74(d,J=7.5Hz,1H),7.66(d,J=7.2Hz, 1H),7.55(t,J=7.6Hz,1H),7.44–7.36(m,1H),5.17(dd,J=13.3,5.1Hz,1H),4. 45(d,J=17.7Hz,1H),4.30(d,J=17.7Hz,1H),4.02(d,J=5.4Hz,2H),2.97–2.90 (m,1H),2.65–2.57(m,1H),2.43–2.34(m,1H),2.08–2.00(m,1H),1.40(s,9H).

[0267] Step 3: Synthesis of 3-(4-(3-aminopropyl-1-yn-1-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione

[0268] Compound (3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)tert-butyl carbamate (397.16, 1.00 g, 2.518 mmol, 1 eq) was dissolved in 10 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 10:1 → 8:1) to give the product 3-(4-(3-aminopropyl-1-yn-1-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (297.31, 0.73 g, 2.455 mmol, 97%). 1 H NMR (500MHz, DMSO-d6) δ11.06(s,1H),8.37(br,2H),7.82(d,J=7.5Hz,1H),7.71(d,J=7.2Hz,1H),7.60(t,J=7.6Hz,1H),5.21(dd,J=13.3,5.1Hz ,1H),4.49(d,J=17.8Hz,1H),4.35(d,J=17.8Hz,1H),4.06(br,2H),3.0 0–2.91(m,1H),2.67–2.59(m,1H),2.38–2.30(m,1H),2.10–2.03(m,1H).

[0269] Step 4: Synthesis of N-(4-cyanophenyl)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-2-((4-methyl-N-(3-(trifluoromethyl)phenyl)phenyl)sulfonamido)acetamide

[0270] Prepare a double-necked flask. Take N-(4-cyanophenyl)-N-(N-p-toluenesulfonyl-N-(3-(trifluoromethyl)phenyl)glycyl)glycine (531.11, 0.15 g, 0.282 mmol, 1 eq), HATU (380.23, 0.16 g, 0.424 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, DIPEA (129.24, 0.15 mL, 0.847 mmol, 3 eq, 0.742 g / mL), evacuate the flask, and stir at room temperature for 30 minutes. Separately, take 3-(4-(3-aminopropyl-1-yn-1-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (297.31, 0.11 g, 0.367 mmol, 1.3 eq), dissolve it in 2 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted five times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 60:1) was performed to give the product N-(4-cyanophenyl)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-2-((4-methyl-N-(3-(trifluoromethyl)phenyl)phenyl)sulfonamido)acetamide (810.21, 0.14 g, 0.173 mmol, 61%). 1 H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.62(br,1H),7.92(br,2H),7.75(d,J =7.5Hz,1H),7.67–7.60(m,3H),7.59–7.48(m,3H),7.48–7.36(m,4H),7.31(d ,J=7.8Hz,2H),5.14(dd,J=13.1,4.6Hz,1H),4.59–4.26(m,6H),4.20(br,2H) ,2.96–2.86(m,1H),2.64–2.57(m,1H),2.46–2.32(m,4H),2.03–1.98(m,1H).

[0271] Example 37: N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-N-(4-fluorophenyl)-2-((4-methyl-N-(3-(trifluoromethyl)phenyl)phenyl)sulfonamido)acetamide

[0272] The synthesis method was the same as that described in Example 36, with a yield of 69%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.54(br,1H),7.75(d,J=7.4Hz,1H),7.66–7.59(m,2H),7.58–7.47(m,5H),7.47–7.36(m,3H),7.36– 7.24(m,4H),5.14(dd,J=13.2,4.8Hz,1H),4.48–4.17(m,8H),2.97–2.86(m,1H),2.64–2.56(m,1H),2.46–2.31(m,4H),2.04–1.97(m,1H).

[0273] Example 38: N-(4-cyanophenyl)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-2-((4-methyl-N-(4-(trifluoromethyl)phenyl)phenyl)sulfonamido)acetamide

[0274] The synthesis method was the same as that described in Example 36, with a yield of 35%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz, DMSO-d6)δ11.01(s,1H),8.62(br,1H),7.93(br,2H),7.75(d,J=7.4Hz,1H),7.68–7.60(m,4H),7.60–7.39(m,4H),7.38–7.29(m,4 H),5.15(dd,J=13.3,5.1Hz,1H),4.56–4.26(m,6H),4.20(br,2H),2.95 –2.87(m,1H),2.60–2.57(m,1H),2.45–2.32(m,4H),2.03–1.99(m,1H).

[0275] Example 39: N-(4-cyanophenyl)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-2-((4-fluoro-N-(p-tolyl)phenyl)sulfonamido)acetamide

[0276] The synthesis method was the same as that described in Example 36, with a yield of 25%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.61(br,1H),7.95–7.88(m,2H),7.76(d,J=7.5Hz,1 H),7.66–7.59(m,4H),7.55(t,J=7.6Hz,2H),7.34(t,J=8.7Hz,2H),7.08(d,J=8.2Hz,2H),6 .98(d,J=7.7Hz,2H),5.15(dd,J=13.3,5.1Hz,1H),4.47–4.28(m,6H),4.20(d,J=5.0Hz,2H ),2.95–2.88(m,1H),2.64–2.58(m,1H),2.43–2.37(m,1H),2.25(s,3H),2.02–1.99(m,1H).

[0277] Example 40: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-fluorophenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0278] Step 1: Synthesis of (4-cyanophenyl)glycine tert-butyl ester

[0279] Prepare a double-necked flask, take p-aminobenzonitrile (118.14, 10.00 g, 84.645 mmol, 1 eq) and tetrabutylammonium iodide (369.37, 6.25 g, 16.929 mmol, 0.2 eq), purge the gas, add 50 mL of ultra-dry tetrahydrofuran and DIPEA (129.24, 15.48 mL, 88.878 mmol, 1.05 eq, 0.742 g / mL), purge the gas, stir at room temperature for 10 minutes, add tert-butyl bromoacetate (195.05, 12.96 mL, 88.878 mmol, 1.05 eq, 1.338 g / mL), heat to 65 °C, and react for 16 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted twice with water and once with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (petroleum ether: ethyl acetate = 8:1) was performed to give the product (4-cyanophenyl)glycine tert-butyl ester (232.12 g, 15.00 g, 64.622 mmol, 76%). 1 H NMR (500MHz, DMSO-d6) δ7.46 (d, J = 8.8 Hz, 2H), 6.94 (t, J = 6.2 Hz, 1H), 6.62 (d, J = 8.7 Hz, 2H), 3.87 (d, J = 6.3 Hz, 2H), 1.41 (s, 9H).

[0280] Step 2: Synthesis of N-(3,4-dichlorophenyl)-N-((4-fluorophenyl)sulfonyl)glycyl chloride

[0281] The synthesis method was the same as that described in steps 1-4 of intermediate 1, with a yield of 25%. The crude product was directly fed into the next reaction without characterization.

[0282] Step 3: Synthesis of N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N(((4-fluorophenyl)sulfonyl)glycine)tert-butyl ester

[0283] Prepare a double-necked flask. Take (4-cyanophenyl)glycine tert-butyl ester (232.12, 1.23 g, 5.317 mmol, 1 eq), add 8 mL of dichloromethane and triethylamine (101.19, 0.89 mL, 6.381 mmol, 1.2 eq, 0.728 g / mL), evacuate the gas, and stir at room temperature for 10 minutes. Separately, dissolve N-(3,4-dichlorophenyl)-N-((4-fluorophenyl)sulfonyl)glycyl chloride (394.94, 2.52 eq, 6.381 mmol, 1.2 eq) in 8 mL of dichloromethane, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of dichloromethane was added, and the mixture was extracted three times with water. After drying with anhydrous sodium sulfate, column chromatography (petroleum ether: ethyl acetate = 6:1 → 4:1) was performed to obtain the product N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N(((4-fluorophenyl)sulfonyl)glycine)tert-butyl glycine (591.08 g, 1.90 g, 3.214 mmol, 50%). 1 H NMR(500MHz,DMSO-d6)δ8.03–7.89(m,2H),7.66(br,2H),7.63–7.51(m,3H),7.43(d,J=2.1Hz ,1H),7.39(t,J=8.3Hz,2H),7.16(d,J=7.1Hz,1H),4.44(br,2H),4.26(br,2H),1.35(s,9H).

[0284] Step 4: Synthesis of N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N-((4-fluorophenyl)sulfonyl)glycine)glycine

[0285] Compound N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N(((4-fluorophenyl)sulfonyl)glycine)tert-butyl glycine (591.08, 1.90 g, 3.214 mmol, 1 eq) was dissolved in 8 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 100:1, methanol system was changed) to give product N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N-((4-fluorophenyl)sulfonyl)glycine)glycine (535.02, 1.40 g, 2.617 mmol, 81%). 1 H NMR(500MHz,DMSO-d6)δ7.92(br,2H),7.70(br,2H),7.66–7.50(m,3H),7.45(s ,1H),7.40(t,J=8.4Hz,2H),7.18(d,J=8.0Hz,1H),4.46(br,2H),4.24(s,2H).

[0286] Step 5: Synthesis of N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-fluorophenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0287] Prepare a two-necked flask. Take N-(4-cyanophenyl)-N-(N-(3,4-dichlorophenyl)-N-((4-fluorophenyl)sulfonyl)glycine)glycine (535.02, 0.15 g, 0.280 mmol, 1 eq), HATU (380.23, 0.16 g, 0.420 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, and DIPEA (129.24, 0.15 g (0.841 mmol, 3 eq, 0.742 g / mL) was added to the mixture under evacuation and stirred at room temperature for 30 minutes. Separately, 3-(4-(3-aminopropyl-1-yn-1-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (297.31 g, 0.11 g, 0.364 mmol, 1.3 eq) was dissolved in 3 mL of ultra-dry DMF and added to the mixture. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted once with water and twice with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 80:1 → 60:1) was performed to give the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-fluorophenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide (814.12, 0.13 g, 0.160 mmol, 57%). 1 H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.62(br,1H),7.93(br,2H),7.76(d,J=7.6H z,1H),7.70–7.62(m,4H),7.62–7.50(m,3H),7.43(s,1H),7.37(t,J=8.6Hz,2H),7 .18–7.13(m,1H),5.15(dd,J=13.2,5.0Hz,1H),4.49–4.26(m,6H),4.21(d,J=4.4H z,2H),2.95–2.88(m,1H),2.61–2.57(m,1H),2.43–2.37(m,1H),2.02–1.98(m,1H).

[0288] Example 41: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-(trifluoromethyl)phenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0289] The synthesis method was the same as that described in Example 40, with a yield of 59%. The NMR characterization results of the product are as follows:1 H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.62(br,1H),8.00–7.88(m,4H),7.84–7 .74(m,3H),7.73–7.57(m,4H),7.54(t,J=7.6Hz,1H),7.47(s,1H),7.19(d,J=8 .3Hz,1H),5.15(dd,J=13.2,5.0Hz,1H),4.54–4.25(m,6H),4.21(d,J=3.6Hz,2 H),2.95–2.88(m,1H),2.61–2.57(m,1H),2.44–2.36(m,1H),2.03–1.98(m,1H).

[0290] Example 42: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole-4-yl)amino)-2-oxoethyl)acetamide

[0291] Prepare a double-necked flask. Take intermediate 1 (531.04, 0.15 g, 0.282 mmol, 1 eq), HATU (380.23, 0.16 g, 0.424 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, and DIPEA (129.24, 0.15 mL, 0.847 mmol, 3 eq, 0.742 g / mL). Vacuum the flask and stir at room temperature for 30 minutes. Separately, take lenalidomide (259.10, 0.10 g, 0.367 mmol, 1.3 eq), dissolve it in 3 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted three times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 80:1 → 50:1 → 30:1) was performed to give the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)-2-oxoethyl)acetamide (772.19 g, 0.055 g, 0.071 mmol, 25%). 1H NMR(500MHz,DMSO-d6)δ11.02(s,1H),10.02(br,1H),8.05–7.88(m,2H),7.84(d,J=7.4Hz ,1H),7.82–7.59(m,2H),7.58(d,J=8.7Hz,1H),7.55–7.43(m,4H),7.40(s,1H),7.31(d,J =8.0Hz,2H),7.14(d,J=8.0Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.73–4.37(m,4H),4.36 –4.27(m,2H),2.95–2.87(m,1H),2.62–2.57(m,1H),2.35–2.26(m,4H),2.05–1.99(m,1H).

[0292] Example 43: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)propionamide

[0293] The synthesis method was the same as that described in Example 40, with a yield of 26%. The NMR characterization results of the product are as follows: 1 HNMR(500MHz,DMSO-d6)δ10.99(s,1H),8.62(s,1H),8.10–7.93(m,2H),7.88–7.77(m,2H),7.76(d,J= 7.6Hz,1H),7.66(d,J=7.6Hz,1H),7.60–7.52(m,3H),7.42(d,J=6.7Hz,2H),7.34–7.29(m,2H),7.18( d,J=8.4Hz,1H),5.14(dd,J=13.2,4.9Hz,1H),4.92–4.79(m,1H),4.49–4.42(m,1H),4.36–4.22(m,5H ),2.95–2.86(m,1H),2.64–2.56(m,1H),2.44–2.33(m,4H),2.01–1.98(m,1H),0.91(d,J=5.5Hz,3H).

[0294] Example 44: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)ethyl)amino)-2-oxoethyl)acetamide

[0295] Step 1: Synthesis of tert-butyl carbamate (2-(2-(3-(2,6-dioxopyrimidin-3-yl)phenoxy)acetamido)carbamate

[0296] Prepare a double-necked flask, take intermediate 7 (263.25, 0.10 g, 0.380 mmol, 1 eq), HATU (380.23, 0.22 g, 0.570 mmol, 1.5 eq), add 5 mL of ultra-dry DMF, DIPEA (129.24, 0.20 mL, 1.140 mmol, 3 eq, 0.742 g / mL), evacuate the gas, stir at room temperature for 30 minutes, add mono-Boc-ethylenediamine (160.22, 0.08 mL, 0.494 mmol, 1.3 eq, 1.012 g / mL), stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted three times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, dichloromethane was added, and the mixture was filtered. The filter cake was the product (2-(2-(3-(2,6-dioxopyrimidin-3-yl)phenoxy)acetamido)carbamate tert-butyl ester (405.45g, 0.12g, 0.296mmol, 78%). 1 H NMR(500MHz,DMSO-d6)δ10.84(s,1H),8.13(t,J=5.5Hz,1H),7.28–7.23(m,1H),6.90–6.81(m,4H),4.43(s,2H),3.83(dd,J=11.3,4.9Hz,1 H), 3.16 (q, J = 6.1Hz, 2H), 3.02 (q, J = 6.1Hz, 2H), 2.66–2.62 (m, 1H), 2.48–2.45 (m, 1H), 2.22–2.14 (m, 1H), 2.06–2.00 (m, 1H), 1.37 (s, 9H).

[0297] Step 2: Synthesis of N-(2-aminoethyl)-2-(3-(2,6-dioxopyrimidin-3-yl)phenoxy)acetamide

[0298] Compound (2-(2-(2-(3-(2,6-dioxonil-3-yl)phenoxy)acetamyl)carbamate tert-butyl ester (405.45, 0.12 g, 0.296 mmol, 1 eq) was dissolved in 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 6:1 → 2:1) to give the product N-(2-aminoethyl)-2-(3-(2,6-dioxonil-3-yl)phenoxy)acetamide (305.33, 0.09 g, 0.296 mmol, >99%). 1H NMR (500MHz, DMSO-d6) δ8.28(t,J=5.6Hz,1H),7.26(t,J=7.8Hz,1H),6.91–6.82(m,3H),4.47(s,2H),3.84(dd,J=11.4,4.9H z,1H),3.32–3.30(m,2H),2.84(t,J=6.3Hz,2H),2.70–2.62(m,1H),2.49–2.44(m,1H),2.23–2.13(m,1H),2.07–2.00(m,1H).

[0299] Step 3: Synthesis of N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamamido)ethyl)amino)-2-oxoethyl)acetamide

[0300] Prepare a double-necked flask. Take intermediate 1 (531.04 g, 0.10 g, 0.188 mmol, 1 eq), HATU (380.23 g, 0.11 g, 0.282 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, DIPEA (129.24 g, 0.10 mL, 0.565 mmol, 3 eq, 0.742 g / mL), evacuate the flask, and stir at room temperature for 30 minutes. Separately, take N-(2-aminoethyl)-2-(3-(2,6-dioxopyrimidin-3-yl)phenoxy)acetamide (305.33 g, 0.07 g, 0.245 mmol, 1.3 eq), dissolve it in 2 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted three times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 50:1) was performed to give the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)ethyl)amino)-2-oxoethyl)acetamide (818.17, 0.03 g, 0.037 mmol, 19%). 1H NMR(500MHz,DMSO-d6)δ10.83(s,1H),8.26–8.01(m,2H),7.90(br,2H),7.78–7.52(m,3H), 7.46(br,2H),7.40(s,1H),7.34(d,J=7.9Hz,2H),7.28–7.21(m,1H),7.13(d,J=7.9Hz,1H) ,6.91–6.79(m,3H),4.41(br,4H),4.22(br,2H),3.82(dd,J=11.3,4.9Hz,1H),3.17(br,4H ),2.68–2.61(m,1H),2.48–2.43(m,1H),2.36(s,3H),2.22–2.13(m,1H),2.06–1.99(m,1H).

[0301] Example 45: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)propyl)amino)-2-oxoethyl)acetamide

[0302] The synthesis method was the same as that described in Example 44, with a yield of 27%. The NMR characterization results of the product are as follows: 1 HNMR(500MHz,DMSO-d6)δ10.82(s,1H),8.08(t,J=5.7Hz,1H),8.07–7.75(m,3H),7.74–7.50(m,3H) ,7.47(br,2H),7.40(s,1H),7.34(d,J=7.9Hz,2H),7.26–7.22(m,1H),7.13(d,J=7.5Hz,1H),6.86– 6.81(m,3H),4.43(br,4H),4.24(br,2H),3.82(dd,J=11.3,5.0Hz,1H),3.11–3.02(m,4H),2.66–2. 61(m,1H),2.47–2.44(m,1H),2.36(s,3H),2.21–2.13(m,1H),2.04–1.99(m,1H),1.56–1.49(m,2H).

[0303] Example 46: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((4-(2-(3-(2,6-dioxopiperidin-3-yl)phenoxy)acetamido)butyl)amino)-2-oxoethyl)acetamide

[0304] The synthesis method was the same as that described in Example 44, with a yield of 36%. The NMR characterization results of the product are as follows: 1 HNMR(500MHz,DMSO-d6)δ10.83(s,1H),8.07(t,J=5.8Hz,1H),8.05–7.79(m,3H),7.78–7.51(m,3H),7.46 (br,2H),7.39(s,1H),7.34(d,J=7.8Hz,2H),7.27–7.22(m,1H),7.12(d,J=8.8Hz,1H),6.85–6.81(m,3H) ,4.43(br,4H),4.23(br,2H),3.82(dd,J=11.3,4.9Hz,1H),3.10(q,J=6.4Hz,2H),3.06–3.00(m,2H),2.6 6–2.62(m,1H),2.47–2.45(m,1H),2.36(s,3H),2.20–2.14(m,1H),2.05–2.01(m,1H),1.39–1.31(m,4H).

[0305] Example 47: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-3-yl)ethyl)amino)-2-oxoethyl)acetamide

[0306] Prepare a double-necked flask. Take intermediate 1 (531.04, 0.15 g, 0.282 mmol, 1 eq), HATU (380.23, 0.16 g, 0.424 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, and DIPEA (129.24, 0.15 mL, 0.847 mmol, 3 eq, 0.742 g / mL). Vacuum the mixture and stir at room temperature for 30 minutes. Separately, take compound intermediate 8 (308.15, 0.11 g, 0.367 mmol, 1.3 eq), dissolve it in 2 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted once with water and twice with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 80:1) was performed to give the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((2-(3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-3-yl)ethyl)amino)-2-oxoethyl)acetamide (821.18, 0.14 g, 0.170 mmol, 60%). 1HNMR(500MHz,DMSO-d6)δ10.86(s,1H),8.13(br,1H),7.87(br,2H),7.68–7.52(m, 4H),7.51–7.44(m,5H),7.42–7.39(m,2H),7.36–7.32(m,3H),7.21(d,J=7.6Hz,1H ),7.15–7.11(m,2H),4.58–4.10(m,4H),3.93(dd,J=11.8,4.8Hz,1H),3.35–3.31( m,2H),2.77–2.67(m,3H),2.55–2.53(m,1H),2.35–2.25(m,4H),2.10–2.04(m,1H).

[0307] Example 48: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(((3'-(2,6-dioxoperidin-3-yl)-[1,1'-biphenyl]-3-yl)methyl)amino)-2-oxoethyl)acetamide

[0308] The synthesis method was the same as that described in Example 47, with a yield of 40%. The NMR characterization results of the product are as follows: 1 HNMR(500MHz,DMSO-d6)δ10.86(s,1H),8.57(br,1H),7.90(br,2H),7.65(br,2H), 7.57–7.43(m,7H),7.42–7.36(m,3H),7.32(d,J=8.0Hz,2H),7.23(d,J=7.6Hz,1H), 7.17(d,J=7.5Hz,1H),7.14–7.09(m,1H),4.60–4.23(m,6H),3.94(dd,J=11.8,4.9H z,1H),2.73–2.65(m,1H),2.56–2.52(m,1H),2.36–2.25(m,4H),2.12–2.05(m,1H).

[0309] Example 49: N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-2-((4-fluoro-N-(3-(trifluoromethyl)phenyl)phenyl)sulfonamido)-N-(4-fluorophenyl)acetamide

[0310] The synthesis method was the same as that described in Example 40, with a yield of 30%. The NMR characterization results of the product are as follows: 1HNMR(500MHz,DMSO-d6)δ11.01(s,1H),8.58–8.51(m,1H),7.75(d,J=7.5Hz,1H),7.66–7 .59(m,4H),7.57–7.51(m,5H),7.48(d,J=7.9Hz,1H),7.35(t,J=8.4Hz,2H),7.30(t,J=8. 4Hz,2H),5.15(dd,J=13.2,4.9Hz,1H),4.45(d,J=17.7Hz,1H),4.37–4.28(m,3H),4.24– 4.18(m,4H),2.95–2.88(m,1H),2.61–2.57(m,1H),2.45–2.39(m,1H),2.03–1.99(m,1H).

[0311] Example 50: N-(4-cyanophenyl)-2-(N-(3,4-dichlorophenyl)ethylsulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0312] The synthesis method was the same as that described in Example 40, with a yield of 30%. The NMR characterization results of the product are as follows: 1 HNMR(500MHz,DMSO-d6)δ11.01(s,1H),8.62(br,1H),7.97–7.89(m,2H),7.75(d,J=7. 5Hz,1H),7.73–7.57(m,5H),7.55(t,J=7.5Hz,1H),7.42(d,J=8.0Hz,1H),5.15(dd,J=1 3.2,5.0Hz,1H),4.48–4.26(m,6H),4.19(d,J=3.5Hz,2H),3.24–3.17(m,2H),2.95–2. 88(m,1H),2.61–2.57(m,1H),2.43–2.39(m,1H),2.02–1.99(m,1H),1.18–1.13(m,3H).

[0313] Example 51: N-(4-cyanophenyl)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-2-((N-ethyl-4-methylphenyl)sulfonamido)acetamide

[0314] The synthesis method was the same as that described in Example 40, with a yield of 30%. The NMR characterization results of the product are as follows: 1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),8.64(br,1H),7.94(d,J=8.4Hz,2H),7.76(d,J=7.5Hz,1H),7.75–7 .62(m,3H),7.60(d,J=7.0Hz,2H),7.55(t,J=7.6Hz,1H),7.32(d,J=8.1Hz,2H),5.15(dd,J=13.3,5.1Hz, 1H),4.45(d,J=17.8Hz,1H),4.32(d,J=17.7Hz,3H),4.22(d,J=5.1Hz,2H),3.92(br,2H),3.14(q,J=7.0H z,2H),2.95–2.87(m,1H),2.61–2.56(m,1H),2.43–2.33(m,4H),2.04–1.99(m,1H),0.92(t,J=7.0Hz,3H).

[0315] Example 52: 2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-N-ethylacetamide

[0316] Step 1: Synthesis of ethylglycine tert-butyl ester

[0317] Ethylamine (45.08 g, 14.27 mL, 256.344 mmol, 10 eq, 0.81 g / mL) was dissolved in 25 mL of tetrahydrofuran and stirred at room temperature. Separately, tert-butyl bromoacetate (195.05 g, 5.00 mL, 25.634 mmol, 1 eq, 1.338 g / mL) was dissolved in 5 mL of tetrahydrofuran and added dropwise to the mixture. The mixture was stirred overnight at room temperature. After the reaction was complete, the solution was evaporated to dryness, and a large amount of dichloromethane was added. The solution was extracted twice with 0.1 M sodium hydroxide aqueous solution to give the product tert-butyl ethyl glycine (159.13 g, 1.08 g, 6.787 mmol, 26%). 1 HNMR (500MHz, CDCl3) δ3.26 (s, 2H), 2.61 (q, J = 7.1Hz, 2H), 1.43 (s, 9H), 1.08 (t, J = 7.1Hz, 3H).

[0318] Step 2: Synthesis of N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)-N-ethylglycine tert-butyl ester

[0319] Prepare a double-necked flask. Take compound ethyl glycine tert-butyl ester (159.13, 0.68 g, 4.263 mmol, 1 eq), add 6 mL of dichloromethane and triethylamine (101.19, 0.71 mL, 5.116 mmol, 1.2 eq, 0.728 g / mL), evacuate the gas, and stir at room temperature for 10 minutes. Separately, dissolve compound N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl chloride (390.96, 2.00 g, 5.116 mmol, 1.2 eq) in 6 mL of dichloromethane, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of dichloromethane was added, and the mixture was extracted three times with water. The extract was dried over anhydrous sodium sulfate and subjected to column chromatography (petroleum ether:ethyl acetate = 4:1) to give the product N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)-N-ethylglycine tert-butyl ester (514.11, 1.56 g, 3.034 mmol, 59%). The product was a rotational isomer in a 5:6 ratio. 1 H NMR(500MHz,DMSO-d6)δ7.63–7.54(m,33H),7.49(s,6H),7.43–7.36(m,27H),7 .20(d,J=8.5Hz,6H),7.16(d,J=8.4Hz,5H),4.73(s,12H),4.51(s,10H),4.16( s,10H),3.85(s,12H),3.41–3.37(m,12H),3.24(q,J=6.5Hz,10H),2.39(s,33H ), 1.42 (s, 45H), 1.33 (s, 54H), 1.10 (t, J = 6.9Hz, 18H), 0.93 (t, J = 6.9Hz, 15H).

[0320] Step 3: Synthesis of N-(N-(3,4-dichlorophenyl)-N-toluenesulfonylglycyl)-N-ethylglycine

[0321] Compound N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)-N-ethylglycine tert-butyl ester (4514.11, 1.56 g, 3.034 mmol, 1 eq) was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 20:1) to give the product N-(N-(3,4-dichlorophenyl)-N-toluenesulfonylglycyl)-N-ethylglycine (458.05, 1.39 g, 3.034 mmol, >99%). The product was a rotational isomer in a ratio of 5:6. 1HNMR(500MHz,DMSO-d6)δ7.63–7.54(m,33H),7.46–7.35(m,33H),7.21–7.12(m,11H),4.71(s,12H),4.55(s,10H),4.16(s,10H ), 3.89 (s, 12H), 3.37 (q, J = 6.4Hz, 12H), 3.23 ( q, J = 6.5Hz, 10H), 2.38 ( s, 33H), 1.10 ( t, J = 6.8Hz, 18H), 0.92 ( t, J = 6.9Hz, 15H).

[0322] Step 4: Synthesis of 2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-N-ethylacetamide

[0323] Prepare a double-necked flask. Take N-(N-(3,4-dichlorophenyl)-N-toluenesulfonylglycyl)-N-ethylglycine (458.05, 0.15 g, 0.327 mmol, 1 eq), HATU (380.23, 0.19 g, 0.491 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, DIPEA (129.24, 0.17 mL, 0.982 mmol, 3 eq, 0.742 g / mL), evacuate the flask, and stir at room temperature for 10 minutes. Separately, take 3-(4-(3-aminopropyl-1-yn-1-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (297.31, 0.13 g, 0.426 mmol, 1.3 eq), dissolve it in 2 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted three times with saturated sodium chloride aqueous solution. The extract was dried over anhydrous sodium sulfate and subjected to column chromatography (dichloromethane:methanol = 80:1 → 50:1 → 30:1) to give the product 2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-N-ethylacetamide (737.15 g, 0.09 g, 0.122 mmol, 37%). The product was a rotational isomer in a 1:1 ratio. 1H NMR (500MHz, DMSO-d6) δ11.02(s,2H),8.73(t,J=4.6Hz,1H),8.40(t,J=4.9Hz,1H),7.75(d,J=6.9Hz,2H),7.65(d,J=7.2Hz,2H),7.61–7.5 2(m,8H),7.46(s,1H),7.44(s,1H),7.39–7.32(m,4H),7.18(d,J=8.3Hz,1H),7.14(d,J=8.7Hz,1H),5.15(dd,J=13.1,4.6Hz,2H),4.73(s, 2H),4.64(s,2H),4.45(d,J=17.8Hz,2H),4.31(d,J=17.5Hz,2H),4.24(d,J=4.7Hz,2H),4.17(d,J=4.9Hz,2H),4.06(s,2H),3.87(s,2H),3 .28–3.16(m,4H),2.96–2.86(m,2H),2.65–2.57(m,2H),2.44–2.34(m,8H),2.04–1.99(m,2H),1.11(t,J=6.8Hz,3H),0.91(t,J=6.9Hz,3H).

[0324] Example 53: 2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-N-((R)-2-hydroxypropyl)acetamide

[0325] Step 1: Synthesis of (R)-2-((tert-butyldiphenylsilyl)oxy)prop-1-amine

[0326] Prepare a two-necked flask. Dissolve (R)-(-)-1-amino-2-propanol (75.07 mg, 1.00 mL, 13.321 mmol, 1 eq, 0.954 g / mL) in 10 mL of dichloromethane. Add triethylamine (101.19 mg, 3.70 mL, 26.642 mmol, 2 eq, 0.728 g / mL), purge with a water pump, and stir in an ice bath. Separately, dissolve tert-butyldiphenylchlorosilane (274.09 mg, 3.45 mL, 13.321 mmol, 1 eq, 1.057 g / mL) in 10 mL of dichloromethane and add it dropwise to the system. Stir overnight at room temperature. After the reaction is complete, quench with saturated ammonium chloride aqueous solution. Add a large amount of dichloromethane, extract three times with water, dry with anhydrous sodium sulfate, and perform column chromatography (dichloromethane:methanol = 100:1 → 5:1) to give the product (R)-2-((tert-butyldiphenylsilyl)oxy)prop-1-amine (313.19 g, 1.69 g, 5.396 mmol, 40%). 1 H NMR (400MHz, CDCl3) δ7.68 (d, J = 6.6Hz, 4H), 7.45–7.36 (m, 6H), 3.87–3.78 (m, 1H), 2.71–2.58 (m, 2H), 1.09–1.04 (m, 12H).

[0327] Step 2: Synthesis of (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)glycine tert-butyl ester

[0328] Compound (R)-2-((tert-butyldiphenylsilyl)oxy)propyl-1-amine (313.19 g, 1.28 g, 4.101 mmol, 2 eq) was dissolved in 12 mL of DMF. DIPEA (129.24 g, 0.71 mL, 4.101 mmol, 2 eq, 0.742 g / mL) and tert-butyl bromoacetate (195.05 g, 0.40 mL, 2.051 mmol, 1 eq, 1.338 g / mL) were added with stirring at room temperature. The mixture was then heated to 50 °C and reacted for 16 hours. Upon completion of the reaction, a large amount of ethyl acetate was added, and the mixture was extracted three times with water. The extract was dried over anhydrous sodium sulfate and subjected to column chromatography (petroleum ether:ethyl acetate = 4:1) to give product (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)glycine tert-butyl ester (427.25 g, 0.85 g, 1.989 mmol, 97%). 1 H NMR (400MHz, Chloroform-d) δ7.73–7.66(m,4H),7.43–7.33(m,6H),4.01–3.94(m,1H),3.23(s,2H),2.72–2.52(m,2H),1.46(s,9H),1.06(br,12H).

[0329] Step 3: Synthesis of (R)-N-(2-((tert-butyldiphenylsilyl)oxy)propyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine tert-butyl ester

[0330] Prepare a double-necked flask. Take compound (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)glycine tert-butyl ester (427.25, 1.00 g, 2.345 mmol, 1 eq), add 5 mL of dichloromethane and triethylamine (101.19, 0.39 mL, 2.814 mmol, 1.2 eq, 0.728 g / mL), evacuate the flask, and stir at room temperature for 10 minutes. Separately, dissolve compound N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl chloride (390.96, 1.10 g, 2.814 mmol, 1.2 eq) in 5 mL of dichloromethane, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of dichloromethane was added, and the mixture was extracted three times with water. After drying with anhydrous sodium sulfate, column chromatography (petroleum ether:ethyl acetate = 6:1) yielded the product (R)-N-(2-((tert-butyldiphenylsilyl)oxy)propyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine tert-butyl ester (782.24 g, 1.81 g, 2.314 mmol, 82%). The product was a rotational isomer in a 5:6 ratio. 1 H NMR (400MHz, DMSO-d6) δ7.60–7.55(m,33H),7.55–7.50(m,44H),7.48–7.42(m,33H),7.41–7.35(m,66H),7.13(d d,J=8.7,2.3Hz,5H),7.07(dd,J=8.7,2.3Hz,6H),4.86(d,J=17.4Hz,6H),4.59–4.43(m,16H),4.11(s,10H),3.98 –3.92(m,6H),3.89(q,J=5.9Hz,5H),3.82(d,J=16.8Hz,6H),3.62(d,J=16.9Hz,6H),3.50–3.41(m,12H),3.24–3. 19(m,10H),2.38(s,33H),1.37(s,45H),1.30(s,54H),0.96–0.93(m,60H),0.89(s,54H),0.82(d,J=6.0Hz,18H).

[0331] Step 4: Synthesis of (R)-N-(2-((tert-butyldiphenylsilyl)oxy)propyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine

[0332] Compound (R)-N-(2-((tert-butyldiphenylsilyl)oxy)propyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine tert-butyl ester (782.24 g, 1.68 g, 2.148 mmol, 1 eq) was dissolved in 26 mL of methanol and 26 mL of tetrahydrofuran and stirred at room temperature. Lithium hydroxide (23.95 g, 2.47 g, 103.132 mmol, 48 eq) was dissolved in 26 mL of water and added to the system. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the product was evaporated to dryness, a large amount of ethyl acetate was added, and the product was extracted three times with water. The product was then evaporated to dryness to obtain the product (R)-N-(2-((tert-butyldiphenylsilyl)oxy)propyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine (726.18 g, 1.27 g, 1.749 mmol, 81%). 1 H NMR(400MHz,DMSO-d6)δ7.74–7.23(m,16H),7.20–7.12(m,1H),4.55(s,2H),3.95–3.86(m,1H) ),3.71–3.59(m,2H),3.25–3.20(m,1H),3.13–3.03(m,1H),2.37(s,3H),1.01–0.74(m,12H).

[0333] Step 5: Synthesis of N-((R)-2-((tert-butyldiphenylsilyl)oxy)propyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide

[0334] Prepare a double-necked flask and take compound (R)-N-(2-((tert-butyldiphenylsilyl)oxy)propyl)-N-(N-(3,4-dichlorophenyl)-N-p-toluenesulfonylglycyl)glycine (726.18, 0.30 g, 0.413 mmol, 1 eq), HATU (380.23, 0.24 g, 0.620 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, and DIPEA (12 9.24, 0.22 mL, 1.239 mmol, 3 eq, 0.742 g / mL), evacuated, stirred at room temperature for 15 minutes; separately, 3-(4-(3-aminopropyl-1-yn-1-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (297.31, 0.16 g, 0.537 mmol, 1.3 eq), dissolved in 2 mL of ultra-dry DMF, added to the system, stirred at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted three times with saturated sodium chloride aqueous solution. The extract was dried over anhydrous sodium sulfate and subjected to column chromatography (dichloromethane:methanol = 80:1 → 50:1) to give the product N-((R)-2-((tert-butyldiphenylsilyl)oxy)propyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide (1005.28, 0.16 g, 0.159 mmol, 38%). The product was a rotational isomer in a 1:1 ratio. 1H NMR(400MHz,DMSO-d6)δ11.02(s,2H),8.73(t,J=4.8Hz,1H),8.44–8.38(m,1 H),7.77–7.74(m,2H),7.65(d,J=7.5Hz,2H),7.60–7.53(m,10H),7.51–7.48 (m,4H),7.45–7.38(m,12H),7.36–7.31(m,8H),7.12–7.08(m,1H),7.07–7.0 4(m,1H),5.14(dd,J=13.4,4.7Hz,2H),4.89(d,J=17.6Hz,1H),4.68–4.50(m, 3H),4.49–4.42(m,2H),4.36–4.29(m,2H),4.24(d,J=4.8Hz,2H),4.18–4.11 (m,3H),4.06–3.90(m,4H),3.76–3.69(m,1H),3.50–3.44(m,2H),3.24–3.20( m,1H),3.13–3.07(m,1H),2.96–2.86(m,2H),2.60–2.54(m,2H),2.41–2.34( m,8H),2.03–1.99(m,2H),0.91(br,12H),0.86(s,9H),0.78(d,J=6.1Hz,3H).

[0335] Step 6: Synthesis of 2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-N-((R)-2-hydroxypropyl)acetamide

[0336] Prepare a double-necked flask. Dissolve compound N-((R)-2-((tert-butyldiphenylsilyl)oxy)propyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)acetamide (1005.28, 0.16 g, 0.159 mmol, 1 eq) in 5 mL of ultra-dry tetrahydrofuran. Vacuum the flask, add 1 M tetrabutylammonium fluoride solution (297.31, 0.06 mL, 0.207 mmol, 1.3 eq) with stirring at room temperature, and stir overnight at room temperature. After the reaction was completed, the solution was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 60:1 → 30:1 → 20:1) to give the product 2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-N-((R)-2-hydroxypropyl)acetamide (767.16, 0.02 g, 0.026 mmol, 16%). The product was a rotational isomer in a ratio of 5:12. 1H NMR (500MHz, DMSO-d6) δ11.00(s,17H),8.76(t,J=5.2Hz,5H),8.49(t,J=5.3Hz,12H),7. 75(d,J=7.6Hz,17H),7.67–7.64(m,17H),7.59–7.54(m,56H),7.53–7.51(m,12H),7.43–7 .41(m,17H),7.37–7.32(m,34H),7.17–7.13(m,17H),5.16–5.12(m,29H),4.84–4.82(m, 17H),4.73(d,J=4.4Hz,5H),4.66(dd,J=17.1,3.8Hz,5H),4.60(dd,J=17.2,3.4Hz,5H),4 .49–4.43(m,17H),4.34(d,J=5.2Hz,12H),4.30(d,J=5.2Hz,5H),4.25–4.17(m,51H),3. 96(dd,J=16.4,5.5Hz,12H),3.87(dd,J=16.5,6.9Hz,12H),3.83–3.76(m,12H),3.73–3.6 6(m,5H),3.33–3.27(m,34H),2.94–2.88(m,17H),2.60–2.56(m,17H),2.44–2.39(m,17H) ,2.37–2.34(m,51H),2.02–1.99(m,17H),1.06(d,J=6.2Hz,36H),0.92(d,J=6.1Hz,15H).

[0337] Example 54: 2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)amino)-2-oxoethyl)-N-((S)-2-hydroxypropyl)acetamide

[0338] The synthesis method was the same as that described in Example 53, with a yield of 42%. The NMR characterization results of the product are as follows: the product is a rotational isomer with a ratio of 1:2. 1H NMR(500MHz,DMSO-d6)δ11.02(s,3H),8.77(br,1H),8.51(br,2H),7.75(d,J=7.2Hz,3H),7.68–7.63(m,3H),7.60–7.51(m,12H),7.42(br,3H),7 .39–7.31(m,6H),7.18–7.11(m,3H),5.18–5.10(m,5H),4.83(br,3H),4. 75(d,J=3.5Hz,1H),4.66(d,J=14.1Hz,1H),4.60(d,J=18.7Hz,1H),4.47 (s,1H),4.44(s,2H),4.35–4.28(m,3H),4.27–4.12(m,9H),3.96(dd,J=15.5,4.8Hz,2H),3.87(dd,J=16.0,7.3Hz,2H),3.79(br,2H),3.69(br,1 H),3.30–3.24(m,6H),2.94–2.88(m,3H),2.66–2.59(m,3H),2.42–2.34( m,12H),2.03–1.99(m,3H),1.05(d,J=5.4Hz,6H),0.92(d,J=5.8Hz,3H).

[0339] Example 55: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)ethynyl)piperidin-1-yl)-2-oxoethyl)acetamide

[0340] Step 1: Synthesis of 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester

[0341] Prepare a two-necked flask. Take 1-tert-butyloxycarbonylpiperidin-4-carboxaldehyde (213.14 g, 0.50 g, 2.346 mmol, 1 eq) and potassium carbonate (138.21 g, 0.65 g, 4.692 mmol, 2 eq). Add 5 mL of methanol, purge, and add (1-diazo-2-oxopropyl)phosphonate dimethyl ester (192.11 g, 0.60 g, 2.815 mmol, 1.2 eq) with stirring at room temperature. Stir for 16 hours at room temperature. After the reaction is complete, add a large amount of ethyl acetate, extract once with water, and extract twice with saturated sodium chloride solution. Dry the product on anhydrous sodium sulfate and evaporate to dryness to obtain tert-butyl 4-ethynylpiperidin-1-carboxylic acid (209.14 g, 0.49 g, 2.346 mmol, >99%). 1H NMR(500MHz,Chloroform-d)δ3.73–3.64(m,2H),3.21–3.14(m,2H),2.61–2.54(m,1H),2.15–2.04(m,1H),1.77(br,2H),1.61–1.54(m,2H),1.44(s,9H).

[0342] Step 2: Synthesis of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)ethynyl)piperidine-1-carboxylate

[0343] Prepare a double-necked flask and take the following compounds: 3-(4-iodo-1-oxoisoindol-2-yl)piperidin-2,6-dione (369.98, 0.55 g, 1.486 mmol, 1 eq), tert-butyl 4-ethynylpiperidin-1-carboxylic acid (209.14, 0.47 g, 2.230 mmol, 1.5 eq), Pd(PPh3)2Cl2 (701.90, 0.05 g, 0.074 mmol, 0.05 eq), and cuprous iodide (190.45, 0.03 g, 0.149 mmol, 0.1 eq). Vacuum for 30 minutes, add 5 mL of ultra-dry DMF and triethylamine (101.19, 3.10 mL, 22.298 mmol, 15 eq, 0.728 g / mL), evacuate the flask, raise the temperature to 80 °C, and react overnight. After the reaction was completed, the sample was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 20:1) to obtain the product 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)ethynyl)piperidin-1-carboxylic acid tert-butyl ester (451.21, 0.51 g, 1.130 mmol, 76%). 1 HNMR(500MHz,DMSO-d6)δ11.01(s,1H),7.71(d,J=7.6Hz,1H),7.64(d,J=7.5Hz,1H),7. 52(t,J=7.6Hz,1H),5.12(dd,J=13.3,5.1Hz,1H),4.45(d,J=17.8Hz,1H),4.31(d,J=17. 8Hz,1H),3.69–3.61(m,2H),3.20–3.10(m,2H),2.94–2.87(m,2H),2.64–2.57(m,1H),2 .48–2.43(m,1H),2.03–1.98(m,1H),1.87–1.80(m,2H),1.59–1.50(m,2H),1.39(s,9H).

[0344] Step 3: Synthesis of 3-(1-oxo-4-(piperidin-4-ylethynyl)isoindol-2-yl)piperidin-2,6-dione

[0345] Compound 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)ethynyl)piperidin-1-carboxylic acid tert-butyl ester (451.21, 0.20 g, 0.443 mmol, 1 eq) was dissolved in 3 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was evaporated to dryness and subjected to column chromatography (dichloromethane:methanol = 20:1) to give the product 3-(1-oxo-4-(piperidin-4-ylethynyl)isoindol-2-yl)piperidin-2,6-dione (351.16, 0.16 g, 0.443 mmol, >99%). 1 H NMR(500MHz,DMSO-d6)δ11.02(s,1H),8.85–8.77(m,1H),7.74(d,J=7.4Hz,1H),7 .67(d,J=7.4Hz,1H),7.54(t,J=7.5Hz,1H),5.14(dd,J=12.9,4.0Hz,1H),4.47(d, J=17.7Hz,1H),4.32(d,J=17.7Hz,1H),3.24(br,2H),3.06(br,3H),2.98–2.86(m ,1H),2.64–2.57(m,1H),2.48–2.39(m,1H),2.11–1.99(m,3H),1.87–1.77(m,2H).

[0346] Step 4: Synthesis of N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)ethynyl)piperidin-1-yl)-2-oxoethyl)acetamide

[0347] Prepare a double-necked flask. Take intermediate 1 (531.04 g, 0.15 g, 0.282 mmol, 1 eq), HATU (380.23 g, 0.16 g, 0.424 mmol, 1.5 eq), add 4 mL of ultra-dry DMF, and DIPEA (129.24 g, 0.15 mL, 0.847 mmol, 3 eq, 0.742 g / mL). Vacuum the flask and stir at room temperature for 15 minutes. Separately, take compound 3-(1-oxo-4-(piperidin-4-ylethynyl)isoindol-2-yl)piperidin-2,6-dione (351.16 g, 0.13 g, 0.367 mmol, 1.3 eq), dissolve it in 2 mL of ultra-dry DMF, add it to the system, and stir at room temperature for 2 hours. After the reaction was completed, a large amount of ethyl acetate was added, and the mixture was extracted once with water and three times with saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, column chromatography (dichloromethane:methanol = 80:1 → 50:1) was performed to give the product N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)ethynyl)piperidin-1-yl)-2-oxoethyl)acetamide (864.19 g, 0.07 g, 0.081 mmol, 29%). 1 HNMR(500MHz,DMSO-d6)δ11.00(s,1H),7.94(br,2H),7.72(d,J=7.5Hz,1H),7.69–7.62(m,2H),7.58(d,J=8 .7Hz,1H),7.56–7.50(m,2H),7.46(br,2H),7.40(s,1H),7.34(d,J=6.7Hz,2H),7.13(d,J=7.9Hz,1H),5.13 (dd,J=13.2,4.9Hz,1H),4.59–4.28(m,6H),3.92–3.80(m,1H),3.68–3.60(m,1H),3.28–3.18(m,2H),3.00– 2.87(m,2H),2.62–2.57(m,1H),2.45–2.34(m,4H),2.03–1.99(m,1H),1.91–1.81(m,2H),1.65–1.51(m,2H).

[0348] Example 56: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)prop-2-yn-1-yl)piperidin-1-yl)-2-oxoethyl)acetamide

[0349] The synthesis method was the same as that described in Example 55, with a yield of 36%. The NMR characterization results of the product are as follows: 1 H NMR (500MHz, DMSO-d6) δ11.02(s,1H),7.94(br,2H),7.72(d,J=7.6Hz,1H),7.67–7.61(m,2H),7.59(d,J=8.6Hz, 1H),7.57–7.50(m,2H),7.47(br,2H),7.41(s,1H),7.35(d,J=5.9Hz,2H),7.14(d,J=7.8Hz,1H),5.14(dd,J=13. 2,5.0Hz,1H),4.55–4.29(m,6H),3.83–3.75(m,1H),3.56–3.48(m,1H),3.36–3.30(m,1H),3.04–2.87(m,2H),2. 62–2.58(m,1H),2.47–2.36(m,6H),2.03–2.00(m,1H),1.87–1.77(m,3H),1.33–1.27(m,1H),1.14–1.07(m,1H).

[0350] Example 57: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)-[4,4'-dipiperidin]-1-yl)-2-oxoethyl)acetamide

[0351] The synthesis method was the same as that described in Example 1, with a yield of 36%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),7.94(br,2H),7.69–7.60(m,2H),7.58(d,J=8.6Hz,1H),7.47(b r,2H),7.41(s,1H),7.40–7.24(m,5H),7.14(d,J=8.4Hz,1H),5.08(dd,J=12.7,5.4Hz,1H),4.52(br, 2H),4.37(br,2H),3.83–3.69(m,3H),3.36–3.28(m,1H),2.93–2.87(m,1H),2.84–2.77(m,2H),2.64– 2.53(m,2H),2.36(s,3H),2.04–1.99(m,1H),1.81–1.67(m,4H),1.49–1.27(m,4H),1.14–0.97(m,2H).

[0352] Example 58: N-(4-cyanophenyl)-2-((N-(3,4-dichlorophenyl)-4-methylphenyl)sulfonamido)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)acetamide

[0353] The synthesis method was the same as that described in Example 1, with a yield of 51%. The NMR characterization results of the product are as follows: 1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),7.94(br,2H),7.70(t,J=7.7Hz,1H),7.65–7.57(m,2H),7.47(br,2H),7.4 1(s,1H),7.39–7.28(m,5H),7.14(d,J=8.6Hz,1H),5.09(dd,J=12.7,5.5Hz,1H),4.51(br,2H),4.46–4.21(m,3H ),3.80–3.70(m,1H),3.35–3.32(m,2H),3.31–3.26(m,4H),3.03–2.93(m,1H),2.90–2.83(m,1H),2.61–2.52(m, 5H),2.37(s,3H),2.21–2.15(m,2H),2.05–2.00(m,1H),1.82–1.70(m,3H),1.07–0.97(m,1H),0.96–0.87(m,1H).

[0354] The structures of the above embodiments 1-58 are as shown in the invention summary section.

[0355] Bioactivity test

[0356] Assay of the inhibitory activity of the compound on cancer cell proliferation

[0357] In this application, Cell Titer-Glo reagent was used to determine the inhibitory effect of the compound on cancer cell proliferation. MV4-11, 22Rv1, MOLM-16, HL-60, KG-1, Kasumi-1, LNCaP, C4-2B, H466, H1975, and MM1S cells were placed in their respective cell culture media containing 10% FBS and cultured at 37°C in a 5% CO2 incubator. The compound was diluted to the specified concentration with culture medium (+10% FBS), and 10 μL of the diluted compound was added to each well of the plate. The plates were then cultured for 72-120 h. For testing: 25 μL of Cell Titer-Glo reagent (Promega) was added, and the fluorescence signal was measured using a PerkinElmer EnVision microplate reader. The half-maximal inhibitory concentration (IC50) was calculated using GraphPadPrism 7 software. 50 )value.

[0358] The test results of the inhibitory effects of Examples 1-58 on the proliferation of MV4-11 and 22Rv1 cells are shown in Table 1 below:

[0359] Table 1 Note: IC 50 >30μM, weak activity; 30μM>IC 50 >10μM, moderate activity; IC 50 <10μM, with strong activity.

[0360] Based on the results in the table above, compounds of the present invention in Examples 1, 3, 6, 9-11, 15-17, 25, 34-40, 42-44, 49-50, and 52-54 exhibited strong anti-proliferation inhibitory activity against MV4-11 cells, while Example 45 showed moderate anti-proliferation inhibitory activity against MV4-11 cells. Compounds of the present invention in Examples 1, 9-11, 15-17, 35-40, 42-44, 47-50, and 52-54 exhibited strong anti-proliferation inhibitory activity against 22Rv1 cells, while Examples 45 and 46 showed moderate anti-proliferation inhibitory activity against 22Rv1 cells. The proliferation inhibition curves of Examples 15 and 53 on MV4-11 and 22Rv1 cells are shown in Figures 1 and 2, respectively.

[0361] In addition, Examples 15 and 53 were selected to test the inhibitory effects of MOLM-16, HL-60, KG-1, Kasumi-1, LNCaP, C4-2B, H466, H1975, and MM1S cell proliferation. The test results are shown in Table 2 below:

[0362] Table 2 Note: IC 50 >30μM, weak activity; 30μM>IC50 >10μM, moderate activity; IC 50 <10μM, high activity. NT, not tested.

[0363] According to the results in the table above, the compounds of the present invention in Examples 15 and 53 exhibit strong anti-proliferation inhibitory activity against MOLM-16, HL-60, KG-1, Kasumi-1, LNCaP, C4-2B, H466, H1975 and MM1S cells.

[0364] Western blot assay

[0365] In this application, Western blotting was used to determine the effect of the compound on the target protein level. Total protein sample collection: Cells treated with the drug were collected, thoroughly lysed, and the supernatant was used for SDS-PAGE electrophoresis. The proteins on the SDS-PAGE gel were then transferred to a membrane. After complete transfer, the membrane was blocked in 5% skim milk. After blocking, the membrane was cut according to protein molecular weight. The corresponding primary antibody was diluted to an appropriate concentration with blocking buffer and incubated overnight at 4°C with the PVDF membrane. After primary antibody incubation, the membrane was washed 6 times with 1×TBST, followed by incubation with the corresponding secondary antibody dilution buffer at room temperature for 2 hours. After incubation, the membrane was washed 6 times with 1×TBST for 10 minutes each time. Finally, chemiluminescence and development were performed.

[0366] The experimental results are shown in Figure 3-4:

[0367] As shown in Figure 3, Examples 15, 17, 35, 38, 36, 37 and 40 of the present invention can significantly reduce the level of GSPT1 protein in cells.

[0368] As shown in Figure 4, the reduction of intracellular GSPT1 protein levels in Example 15 of the present invention is concentration-dependent. Treatment of MV4-11 cells with 0.33 μM of Example 15 for 48 hours significantly reduced GSPT1 protein levels, and treatment of MV4-11 cells with 1 μM of Example 15 for 48 hours significantly reduced RORγ protein levels.

[0369] The applicant declares that this invention illustrates the sulfonamide-based acetamide compounds, their preparation methods, and applications through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of this invention.

[0370] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0371] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A sulfonamide-acetamide compound, characterized in that, The sulfonamide-based acetamides have a structure as shown in Formula I: wherein R 1 , R 2 and R 4 are independently selected from any of substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C12 heteroaryl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, said substituted groups being selected from any of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 halogenated hydrocarbon, C1-C6 alkyl; R 3 is selected from any one of H, substituted or unsubstituted C1-C10alkyl, substituted or unsubstituted C2-10alkenyl, substituted or unsubstituted C2-C10alkynyl, the substituted groups being selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5haloalkane, C1-C6alkyl; Y 1 selected from a single bond, -R a OR b -, -R a SR b -, -R a N(R c )R b -, -R a OC(O)R b -, -R a OC(O)OR b -, -R a OC(O)N(R c )R b -, -R a C(O)R b -, -R a C(O)OR b -, -R a CON(R c )R b -, -R a S(O)R b -, -R a S(O)2R b -, -R a SO2N(R c )R b -, -R a N(R c )C(O)OR b -, -R a N(R c )C(O)R b -, -R a N(R c )C(O)N(R c )R b -, -R a N(R c )S(O)R b -, -R a N(R c )S(O)2R b -, -R a N(R c )S(O)2N(R d )R b - any of substituted or unsubstituted C1-C10 alkylene, substituted or unsubstituted C2-C10 alkenylene, substituted or unsubstituted C2-C10 alkynylene, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, substituted or unsubstituted C4-C13 fused cycloalkyl, substituted or unsubstituted C4-C13 fused heterocyclyl, substituted or unsubstituted C5-C13 bridged cycloalkyl, substituted or unsubstituted C5-C13 bridged heterocyclyl, substituted or unsubstituted C5-C13 spirocycloalkyl, substituted or unsubstituted C5-C13 spiroheterocyclyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 heteroaryl, the substituted groups being selected from any of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 halogenated hydrocarbon, C1-C6 alkyl; R a , R b are independently selected from any one of a single bond, substituted or unsubstituted C1-C10 alkylene, substituted or unsubstituted C2-C10 alkenylene, substituted or unsubstituted C2-C10 alkynylene, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, substituted or unsubstituted C4-C13 fused cycloalkyl, substituted or unsubstituted C4-C13 fused heterocyclyl, substituted or unsubstituted C5-C13 bridged cycloalkyl, substituted or unsubstituted C5-C13 bridged heterocyclyl, substituted or unsubstituted C5-C13 spirocycloalkyl, substituted or unsubstituted C5-C13 spiroheterocyclyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 heteroaryl, the substituted groups being selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 halogenated hydrocarbon, C1-C6 alkyl; R c , R d is independently selected from any of H, substituted or unsubstituted C1-C10alkyl, substituted or unsubstituted C2-C10alkenyl, substituted or unsubstituted C2-C10alkynyl, substituted or unsubstituted C1-C10alkoxy, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C4-C10heterocyclyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl, or R c , R d and the atom to which they are attached together form a C3-C20cycloalkyl or C4-C20heteroaryl, said substituted groups are selected from any of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5halogenated hydrocarbon, C1-C6alkyl; L is selected from any one or a combination of at least two of the following: single bond, substituted or unsubstituted C1-C10 alkylene group, substituted or unsubstituted C2-C10 alkenyl group, substituted or unsubstituted C2-C10 alkyne group, ether group, thioether group, ester group, amino group, amide group, carbamate group, urea group, sulfone group, substituted or unsubstituted C6-C12 aryl group, substituted or unsubstituted C6-C12 heteroaryl group, carbonyl group, substituted or unsubstituted C3-C10 cycloalkyl group, and substituted or unsubstituted C4-C10 heterocyclic group; wherein the substituted group is selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 haloalkanes, and C1-C6 alkyl groups. Y 2 is selected from any one of -0-, -NH-, -CH2-, -C(O)- or a single bond; E has the structure of any one of Formulae II-1 to II-4, wherein indicates the position of the group attachment: wherein Y is selected from -O-, -S-, -CHR 3 is selected from -O-, -S-, -CHR e -, -C(O)-, -SO2-, -N(R f )-; R e , R f are independently selected from any one of H, substituted or unsubstituted C1-C10alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocyclyl, the substituted groups being selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5halogenated hydrocarbon, C1-C6alkyl; Y 4 , Y 5 , Y 6 , Y 7 are independently selected from -CR g = or -N=; R g any one of H, halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5halogenated hydrocarbon, C1-C6alkyl; Y 8 is selected from CH or N; T 1 , T 2 , T 3 is independently selected from O or S; R 5 , R 6 is independently selected from any one of H, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocyclyl, the substituted groups being selected from any one of halogen, amino, nitro, carboxyl, cyano, hydroxyl, C1-C5 halogenated hydrocarbon, C1-C6 alkyl; R 7 is selected from any one of H, halogen, C1-C5halogenated hydrocarbon, C1-C6alkoxy, C1-C6alkyl; Y 9 is selected from any one of -CH2-, -O-, -S-, -NR h -, -C(O)NR i - R h , R i is independently selected from any one of H, C1-C10 alkyl, halogen.

2. The sulfonamidyl acetamides according to claim 1, characterized in that, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y 1 , Y 2 have the same scope of limitation as recited in claim 1, said Y 4 , Y 5 , Y 6 , Y 7 are independently selected from any one of -CH= and -N=. Preferably, said Y 4 , Y 5 , Y 6 , Y 7 is independently selected from -CH=; Preferably, said L is selected from any one of the following groups, indicates the position of the group attachment: Where n and p are independently selected from integers from 1 to 10; m and q are selected from integers from 0 to 10, and m and q being 0 indicates that the group does not exist here; A, D, G, J, M, Q, W and Z are independently selected from -CH= or -N=; Preferably, said Y 3 is selected from -CH2- or -C(O)-, preferably -C(O)-; Preferably, said T 1 , T 2 , T 3 is selected from O.

3. The sulfonamide acetamide compound according to claim 1 or 2, characterized in that, The sulfonamide-based acetamides have the following formula III: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y 1 , Y 2 , L has the same defined range as in claim 1 or 2; Preferably, said R 1 , R 2 and R 4 are independently selected from any one of substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C12 heteroaryl, substituted or unsubstituted C1-C10 alkyl, said substituted groups being selected from any one of hydroxy, halogen, cyano, C1-C5 halogenated hydrocarbon, C1-C6 alkyl; Preferably, said R 3 is selected from any one of H, C1-C10 alkyl; Preferably, said R 5 , R 6 are independently selected from any one of H or C1-C10 alkyl; Preferably, said R 7 is selected from any one of H, halogen or Ci-C6alkoxy; Preferably, the Y 1 Selected from single key, -R a C(O)R b -、-R a CON(R c )R b -、-R a N(R c )C(O)R b - Any one of them; Preferably, said R a selected from a single bond, substituted or unsubstituted C1-C10alkylene; Preferably, said R b is selected from a single bond, substituted or unsubstituted C1-C10alkylene, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C3-C10heterocyclyl; Preferably, said R c selected from H, C1-C10 alkyl; Preferably, said Y is selected from -NH-, -C(O)- or a single bond. 2 is selected from -NH-, -C(O)- or a single bond; Preferably, said L is selected from any one of the following groups, indicates the position of the group attachment: n and p are independently selected from integers from 1 to 10; m and q are selected from integers from 0 to 10, and m and q being 0 indicates that the group does not exist here; G, J, Q and Z are independently selected from -CH= or -N=.

4. The sulfonamide acetamide compound according to any one of claims 1-3, characterized in that, The sulfonamide-based acetamides have the following formula: wherein R 1 , R 2 , R 3 , R 4 , R 7 , Y 1 , Y 2 , L has the same defined range as in claims 1-3.

5. The sulfonamide acetamide compound according to any one of claims 1-4, characterized in that, The sulfonamide-based acetamides are selected from any one of the structures shown in Examples 1-58:

6. A method for preparing a sulfonamidoacetamide compound according to any one of claims 1 to 5, characterized by, The preparation method includes scheme 1 and scheme 2: Scheme 1: R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , L, E have the same defined range as in any of claims 1-5; wherein X a and X b are independently selected from halogen, hydroxyl, OTf, OTs, OMs; R 8 selected from -R a C(O)O- t Bu, R a having the same scope of definition as in any of claims 1-5; R 9 selected from R 8 after deprotection; X c selected from primary amines, secondary amines; or R 8 selected from -R a O-PG, -R a S-PG, -R a N(R c )-PG, PG is a hydroxyl, thiol or amino protecting group, including any one of TBDMS, TIPS, Boc or Cbz; R a , R c have the same defined range as any one of claims 1-5; R 9 selected from R 8 after deprotection; X c selected from halogen, hydroxyl, OTf, OTs, OMs; or R 8 selected from -R a CHO, R a having the same range of limitations as any of claims 1-5, X c selected from primary amines, secondary amines; The specific reaction steps are as follows: Substrate 1-a and substrate 2-a undergo a nucleophilic substitution reaction to obtain 3-a; substrate 3-a and substrate 4-a undergo a nucleophilic substitution reaction to obtain 5-a; substrate 5-a is acylated and then undergoes a nucleophilic substitution reaction with substrate 6-a to obtain 7-a; substrate 7-a and substrate 8-a undergo a nucleophilic substitution reaction to obtain 9-a; substrate 9-a undergoes deprotection to obtain 10-a; substrate 10-a and substrate 11-a undergo a condensation reaction or a nucleophilic substitution reaction to obtain the compound shown in Formula I; or substrate 9-a and substrate 11-a undergo reductive amination to obtain the compound shown in Formula I. Option 2: R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , L, E have the same defined range as in any of claims 1-5; wherein X b , R 8 , R 9 , X c have the same defined ranges as in Scheme 1 ; The specific reaction steps are as follows: substrate 6-a and substrate 8-a undergo a nucleophilic substitution reaction to obtain 12-a; substrate 5-a is acylated and then undergoes a nucleophilic substitution reaction with substrate 12-a to obtain 9-a; substrate 9-a undergoes deprotection to obtain 10-a; substrate 10-a and substrate 11-a undergo a condensation reaction or a nucleophilic substitution reaction to obtain the compound shown in Formula I; or substrate 9-a and substrate 11-a undergo reductive ammoniation to obtain the compound shown in Formula I.

7. A pharmaceutically acceptable salt of a sulfonamide acetamide compound according to any one of claims 1-5.

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises an active ingredient and pharmaceutically acceptable excipients; The active ingredient comprises at least one sulfonamide acetamide compound as described in any one of claims 1-5 and / or at least one pharmaceutically acceptable salt as described in claim 7.

9. The use of a sulfonamide acetamide compound according to any one of claims 1-5, a pharmaceutically acceptable salt according to claim 7, or a pharmaceutical composition according to claim 8 in the preparation of a pharmaceutical formulation capable of effectively reducing GSPT1 and / or RORγ protein levels.

10. The use of a sulfonamide acetamide compound according to any one of claims 1-5, a pharmaceutically acceptable salt according to claim 7, or a pharmaceutical composition according to claim 8 in the preparation of a medicament for the prevention or treatment of cancer, inflammation, or autoimmune diseases.

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