2,6-piperidinedione derivatives, processes for their preparation and use thereof

Abstract

The application provides a kind of 2,6-piperidinedione derivatives and preparation method and application thereof.The compound has the structure shown in the following formula I, formula II or formula III:2,6-piperidinedione derivatives described in the application can induce the degradation of GSPT1 protein, and have cytotoxic effect on cancer cells.Therefore, the compound and composition provided by the application can be used for preparing drugs for treating or preventing tumor formation, inflammation, viral infection, cell proliferative disorder, autoimmune disease, sepsis and other related diseases.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical technology, specifically relating to a 2,6-piperidinedione derivative, its preparation method, and its application. Background Technology

[0002] Normal protein expression and degradation are crucial for maintaining cellular homeostasis, and abnormal protein expression in the human body is closely related to the occurrence of various diseases. Traditional small molecule inhibitors inhibit the functional activity of target proteins by occupying their binding pockets; however, most proteins cannot be drugged due to the lack of binding pockets. Target protein degradation (TPD) technologies, most notably PROTAC (Protein Chimera) and molecular glue degraders, utilize the endogenous ubiquitin-proteasome system to induce the degradation of target proteins, thereby achieving therapeutic effects.

[0003] Ubiquitination is a common post-translational modification of proteins, widely involved in physiological processes such as transcriptional regulation, DNA damage repair, cell cycle, apoptosis, and vesicle transport by regulating protein stability, localization, activity, and interactions. The ubiquitin-proteasome system is a regulatory system present in all eukaryotic cells, and more than 80% of protein degradation in eukaryotes is mediated by the ubiquitin-proteasome pathway. The ubiquitin-proteasome system includes ubiquitin, ubiquitin activator (E1), ubiquitin conjugate (E2), ubiquitin-protein ligases (E3), the 26S proteasome, and ubiquitin dissociates (DUBs). Among them, E3 ubiquitin ligases perform substrate-specific recognition. Cullin-RING E3 ligases are currently the largest family of E3 ubiquitin ligases, composed of multi-subunit modules, capable of simultaneously binding to both target proteins and E2, transferring ubiquitin from E2 to the target. Cullin-RING E3 ligases consist of four main components: the Cullin protein, which acts as a scaffold protein; a ring finger protein that binds to E2; a substrate receptor that recognizes the target; and an adaptor protein that links the receptor to the Cullin protein. The substrate receptor is crucial for target-specific recognition. To date, target protein degradation technologies have only explored approximately 1% of E3 ubiquitin ligases, with Cereblon (CRBN) and Von Hippel Lindau (VHL) being the most widely studied substrate receptors for E3 ubiquitin ligases.

[0004] Since 2010, the mechanisms of action of immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, have been gradually elucidated. Studies have shown that IMiDs bind to CRBN and enhance the ubiquitination and degradation of cell survival-dependent proteins by the CRBN-CRL4 ubiquitin ligase through a molecular glue mechanism. Subsequently, a series of molecular glues based on modified CRBN ligands have been developed, a representative example being CC-885, an IMiD-like compound reported by Celgene in Nature in 2016. CC-885 mediates the recognition of the translation termination factor GSPT1 (G1 to S Phase Transition) by the CRBN-CRL4 ubiquitin ligase, thereby inducing the ubiquitination and degradation of GSPT1. GSPT1, also known as eRF3, is involved in the rapid occupancy of the A site on the ribosome when translation encounters a stop codon. Following eRF3 hydrolysis of GTP, eRF3 and GDP dissociate from the complex, while eRF1 rearranges into its active conformation, triggering ribosomal subunit dissociation and terminating protein translation. In addition, GSPT1 is involved in several other key cellular processes, such as cell cycle regulation, cytoskeleton organization, apoptosis, and transcription. Therefore, downregulation of GSPT1 levels can impair cell proliferation control and promote cell migration and scar formation. GSPT1 is implicated in the tumorigenesis of several different cancer types, including breast cancer, hepatocellular carcinoma, gastric cancer, and prostate cancer.

[0005] Abnormal expression of GSPT1 protein is associated with disease. Studies have found that targeted protein degraders can not only inhibit the activity of target proteins but also utilize the ubiquitin-proteasome system in the body to clear target proteins, thereby achieving therapeutic goals. Several IMiDs-like compounds have been reported as molecular glue degraders that can induce CRBN to recognize multiple novel substrates such as GSPT1, IKZF1, IKZF2, IKZF3, and CK1α, with indications covering solid tumors and hematological malignancies such as multiple myeloma, prostate cancer, lung cancer, myelodysplastic syndrome, osteosarcoma, and leukemia.

[0006] CN106660991A discloses an antiproliferative compound for treating, preventing, or controlling cancers such as leukemia, and provides methods for treating, preventing, or alleviating cancers including solid tumors and hematogenous tumors, as well as pharmaceutical compositions and dosage forms suitable for such methods.

[0007] CN113677664A discloses a tricyclic degradation product of Ikaros (IKZF1) and Aiolos (IKZF3). The compound disclosed in this application can be used as a CRBN binder to degrade Ikaros or Aiolos via the ubiquitin-proteasome pathway.

[0008] WO2022 / 152821A1 discloses a GSPT1 molecular glue degrader, the compound of which can induce GSPT1 ubiquitination degradation via CRBN. In in vivo experiments, this compound was able to inhibit the proliferation and survival of MYC-driven solid tumor cell lines.

[0009] However, only a few molecular gel degraders targeting GSPT1 have entered clinical trials. Therefore, there is an urgent need to develop novel, highly efficient compounds that can induce the degradation of the GSPT1 protein. Degraders targeting the GSPT1 protein may be beneficial for developing therapeutic strategies targeting diseases including cancer, inflammatory diseases, cell proliferation disorders, autoimmune diseases, sepsis, and viral infections. Summary of the Invention

[0010] To address the shortcomings of existing technologies, the present invention aims to provide a class of 2,6-piperidinedione derivatives that can regulate GSPT1 protein levels and / or function, exhibiting cytotoxic effects against cancer cells. This will provide a novel and promising class of drugs for the treatment of diseases including cancer, inflammatory diseases, cell proliferation disorders, autoimmune diseases, sepsis, and viral infections.

[0011] To achieve this objective, the present invention adopts the following technical solution:

[0012] In a first aspect, the present invention provides a 2,6-piperidinedione derivative having the structure shown in Formula I, Formula II, or Formula III:

[0013]

[0014] in,

[0015] X is selected from O or S;

[0016] R1 is selected from H, halogen, hydroxyl, substituted or unsubstituted C1-C5 (e.g., C1, C2, C3, C4, C5) alkyl, substituted or unsubstituted C1-C5 (e.g., C1, C2, C3, C4, C5) alkoxy, wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl;

[0017] R2 is selected from H, -SR a -OR a -SR b -OR b -N(R) a SO2R b -SO2N(R) a)R b -N(R) a COR b -CON(R) a )R b -、-N(R a CH2R b -NHCH(R) a )R b -N(R) a )R b -CH(R) a )R b -COR b -COOR b -OCOR b ;

[0018] R a The substituted group is selected from H, substituted or unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl, substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10) cycloalkyl, substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10) cycloalkenyl, and substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10) heterocyclic alkyl; the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl.

[0019] R b Selected from any one of the following groups (i), (ii), or (iii):

[0020] (i) substituted or unsubstituted C6-C20 (e.g., C6, C10, C12, C14, C16, C18, C20, etc.) aryl, substituted or unsubstituted C4-C20 (e.g., C4, C5, C6, C10, C12, C14, C16, C18, C20, etc.) heteroaryl; wherein the substituted group is selected from any one of halogen, hydroxyl, C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl, C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkoxy;

[0021] (ii) substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10) cycloalkyl, substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10) cycloalkenyl, substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10) heterocycloalkyl; wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl;

[0022] (iii) A substituted or unsubstituted C1-C5 (e.g., C1, C2, C3, C4, C5) alkyl, a substituted or unsubstituted C2-C10 (e.g., C2, C3, C4, C5, C6, C7, C8, C9, C10) alkenyl, or a substituted or unsubstituted C2-C10 (e.g., C2, C3, C4, C5, C6, C7, C8, C9, C10) alkynyl; wherein the substituted group is selected from any one of halogen, hydroxyl, C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkoxy;

[0023] R3, R4, R5, and R6 are each independently selected from H, halogen, hydroxyl, substituted or unsubstituted C1-C5 (e.g., C1, C2, C3, C4, C5) alkyl, substituted or unsubstituted C1-C5 (e.g., C1, C2, C3, C4, C5) alkoxy; the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl.

[0024] Z1 is selected from -N(SO2R) b (CH2) n CON(R c )-、-N(SO2R b (CH2) n CO-, -SO2N(R) b (CH2) n CON(R c )-、-SO2N(R b (CH2) n CO-、-CON(R b (CH2) n CON(R c )-、-CON(R b (CH2) n CO-, -N(COR) b (CH2) n CON(R c )-、-N(CORb (CH2) n CO-, -NH(CH2) n CON(R c -NH(CH2) n CO-, -O(CH2) n CON(R c )-、-O(CH2) n CO-, -S(CH2) n CON(R c )-、-S(CH2) n CO-, -(CH2) n CON(R c )-、-(CH2) n CO-, -CO-, -O-, -S-, -N- or single bonds, where n is 1-6;

[0025] R c Selected from H, substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10) cycloalkyl, substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10) cycloalkenyl, substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10) heterocycloalkyl, substituted or unsubstituted C6-C20 (e.g., C6, C10, C12), Aryl groups of C14, C16, C18, C20, etc.; substituted or unsubstituted C4-C20 heteroaryl groups of C4-C6 (e.g., C4, C6, C10, C12, C14, C16, C18, C20, etc.); substituted or unsubstituted C2-C10 alkenyl groups of C2-C9 (e.g., C2, C3, C4, C5, C6, C7, C8, C9, C10); wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups;

[0026] Z2 is selected from -O-, -NH-, -CH2-, and -NH(CH2). n CO-, -CO-, or single bonds;

[0027] L is selected from any one or a combination of at least two of the following groups: single bond, alkylene group, alkenyl group, alkyne group, ether group, thioether group, ester group, amino group, amide group, carbamate group, urea group, sulfone group, aryl group, heteroaryl group, carbonyl group, cycloalkyl group, heterocyclic group, spiroheterocyclic group, and bridged heterocyclic group;

[0028] E has the structure shown in Equation III, wherein For the location of the group connection:

[0029]

[0030] in,

[0031] T1 is selected from -O-, -S-, -CHTa-, -C(=O)-, -SO2-, -NTb-;

[0032] T a and T b Each is independently selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocyclic groups;

[0033] T2, T3, and T4 are each independently selected from O or S;

[0034] Y1, Y2, Y3, and Y4 are each independently selected from CH or N;

[0035] R7 and R8 are each independently selected from -H, hydroxyl, substituted or unsubstituted C1-C10 (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) alkyl, substituted or unsubstituted C3-C10 (e.g., C3, C4, C5, C6, C7, C8, C9, C10, etc.) cycloalkyl, substituted or unsubstituted C1-C10 (e.g., C1, C2, C3, ... C4, C5, C6, C7, C8, C9, C10, etc.) containing Ο heterocyclic alkyl groups; substituted or unsubstituted C1-C10 groups (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) containing Ν heterocyclic alkyl groups; substituted or unsubstituted C1-C10 groups (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, etc.) containing S heterocyclic alkyl groups. The substituted groups are selected from any one of halogens, hydroxyl groups, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups.

[0036] Alternatively, in the above-mentioned 2,6-piperidinedione derivatives, Y1, Y2, Y3, and Y4 are independently selected from CH;

[0037] Preferably, any one of the groups Y1, Y2, Y3, and Y4 is CH, and the group is attached to the CH.

[0038] Preferably, L is selected from any one of the following groups, wherein For the location of the group connection:

[0039]

[0040]

[0041] Wherein, n, m, and w are independently selected from integers between 0 and 8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, etc.), and when n, m, or w is 0, it indicates that the group does not exist here; p, q, u, and v are independently selected from 1 or 2; A, D, E, and G are independently selected from CH or N; U, M, and Z are independently selected from CH2, NH, and O;

[0042] Preferably, T1 is selected from -CH2- or -C(=O)-;

[0043] Alternatively, in the above-mentioned 2,6-piperidinedione derivatives, the 2,6-piperidinedione derivative has the structure shown in formula V, formula VI, or formula VII:

[0044]

[0045] The definitions of the groups R1, R2, R3, R4, R5, R6, R7, R8, X, Z1, Z2, L, Y1, Y2, Y3, Y4, T1, T2, T3, and T4 are the same as those in claim 1 or 2.

[0046] Preferably, the 2,6-piperidinedione derivative has the structure shown in formula V-a, formula VI-a, or formula VII-a:

[0047]

[0048] The definitions of the R1, R2, R3, R4, R5, R6, R7, R8, X, Z1, Z2, L, and T1 groups are the same as those described above.

[0049] Preferably, R1 is selected from H, halogen, hydroxyl, substituted or unsubstituted C1-C5 (e.g., C1, C2, C3, C4, C5) alkyl, and more preferably from H or unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl.

[0050] Preferably, R2 is H or -OR. a -N(R) a SO2R b -SO2N(R) a )R b -N(R) a COR b -CON(R) a )R b -, preferably H, -OR a -N(R) a SO2R b -N(R) a COR b ;

[0051] Preferably, the R a Selected from H, substituted or unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups, preferably H, unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups;

[0052] Preferably, the R b The group is selected from any group in group (i) or (iii) above, preferably a substituted or unsubstituted C1-C5 (e.g., C1, C2, C3, C4, C5) alkyl, a substituted or unsubstituted C6-C20 (e.g., C6, C10, C12, C14, C16, C18, C20, etc.) aryl, more preferably an unsubstituted C1-C5 (e.g., C1, C2, C3, C4, C5) alkyl, a substituted C6-C10 (e.g., C6, C10, C12, C14, C16, C18, C20, etc.) aryl; the substituted group is selected from any one of halogen, hydroxyl, C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkoxy;

[0053] Preferably, R3 and R5 are selected from H, halogens, substituted or unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups, and more preferably from H, halogens, or unsubstituted C1-C6 alkyl groups.

[0054] Preferably, R4 is selected from H, substituted or unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups, and more preferably unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups;

[0055] Preferably, R6 is selected from H, substituted or unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl, substituted or unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkoxy, and preferably unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkoxy;

[0056] Preferably, R7 and R8 are independently selected from H or C1-C10 (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10) alkyl groups;

[0057] Preferably, Z1 is selected from -O(CH2). n CON(R c )-、-(CH2) n CON(R c -NH(CH2) n CON(Rc )-、-O(CH2) n CO-, -N(SO2R) b (CH2) n CON(R c -, -CO-, or single bonds;

[0058] Preferably, the R b The group is selected from any group in group (i) or (iii) above, preferably a substituted or unsubstituted C1-C5 alkyl group, a substituted or unsubstituted C6-C20 (e.g., C6, C10, C12, C14, C16, C18, C20, etc.) aryl group, more preferably an unsubstituted C1-C5 (e.g., C1, C2, C3, C4, C5) alkyl group, a substituted C6-C10 (e.g., C6, C10, C12, C14, C16, C18, C20, etc.) aryl group; the substituted group is selected from any one of halogen, hydroxyl, C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkoxy group;

[0059] Preferably, T1 is selected from -CH2- or -C(=O)-;

[0060] Preferably, n is 1-3, R c Selected from H;

[0061] Preferably, the Z2 is selected from -NH(CH2). n CO-, -NH-, -CH2- or single bonds;

[0062] Preferably, n is 1-3;

[0063] Preferably, L is selected from any one of the following groups, wherein For the location of the group connection:

[0064]

[0065] Wherein, n, m, and w are independently selected from integers between 0 and 8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, etc.), and when n, m, or w is 0, it indicates that the group does not exist here; p, q, u, and v are independently selected from 1 or 2; A, D, E, and G are independently selected from CH or N; Z is independently selected from CH2, NH, and O;

[0066] Alternatively, in the above-mentioned 2,6-piperidinedione derivatives, the structure of the 2,6-piperidinedione derivative is as shown in formula V-b, formula VI-b, formula VII-1b, formula VII-2b, or formula VII-3b:

[0067]

[0068] Among them, R2, R3, R5, R6, R b X, Z1, Z2, L, and T1 have the same limiting range as described above;

[0069] Preferably, R2 is selected from H, -N(R a COR b -OR a ;

[0070] Preferably, the R a Selected from H, unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups;

[0071] Preferably, the R b The substituted group is selected from substituted C6-C12 (e.g., C6, C10, C12, C14, C16, C18, C20, etc.) aryl groups; the substituted group is selected from any one of halogen, hydroxyl, C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl, and C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkoxy groups.

[0072] Preferably, R6 is selected from -OR a ;

[0073] Preferably, the R a Selected from H, unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups;

[0074] Preferably, R3 and R5 are independently selected from H, halogens, and unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, C6) alkyl groups;

[0075] Preferably, Z1 is selected from -O(CH2). n CON(R c )-、-(CH2) n CON(R c -NH(CH2) n CON(R c )-、-O(CH2) n CO-, -CO-, or single bonds;

[0076] Preferably, T1 is selected from -CH2- or -C(=O)-;

[0077] Preferably, n is 1-3, R c Selected from H;

[0078] Preferably, the Z2 is selected from -NH(CH2). nCO-, -NH-, -CH2- or single bonds;

[0079] Preferably, n is 1-3;

[0080] Preferably, L is selected from any one of the following groups, wherein For the location of the group connection:

[0081]

[0082]

[0083] Wherein, n, m, and w are independently selected from integers between 0 and 8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, etc.), and when n, m, or w is 0, it indicates that the group does not exist here; p, q, u, and v are independently selected from 1 or 2; A, D, E, and G are independently selected from CH or N; Z is independently selected from CH2, NH, and O;

[0084] Alternatively, in the above-mentioned 2,6-piperidinedione derivatives, the 2,6-piperidinedione derivative is selected from any one of the structures shown in compounds 1-38 below:

[0085]

[0086]

[0087] In a second aspect, the present invention provides a pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound of the derivative as described in the first aspect above.

[0088] In a third aspect, the present invention provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients;

[0089] The active ingredient comprises at least one compound described in the first aspect above and / or at least one pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound described in the third aspect above.

[0090] In a fourth aspect, the present invention provides the use of the compound described in the first aspect, the pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate or deuterated compound described in the third aspect, or the pharmaceutical composition described in the third aspect, in the preparation of a formulation for degrading BET and / or GSPT1 protein.

[0091] In a fifth aspect, the present invention provides the use of the compounds described in the first aspect, the pharmaceutically acceptable salts, stereoisomers, N-oxides, prodrug molecules, solvates or deuterated compounds described in the third aspect, and the pharmaceutical compositions described in the fourth aspect in the preparation of medicaments for the prevention or treatment of cancer, cell proliferation disorders, inflammation, autoimmune diseases, sepsis, or viral infections.

[0092] Preferably, the cancer is selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia mixed spectrum leukemia, NUT-midline carcinoma, multiple myeloma, glioma, lung cancer, neuroblastoma, Burkitt lymphoma, cervical cancer, esophageal cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, or breast cancer. The inflammation or autoimmune disease is selected from inflammatory pelvic inflammatory disease, urethritis, pneumonia, meningitis, myocarditis, ulcerative colitis, organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune diseases, autoimmune alopecia, anemia, autoimmune hemolytic disease and systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's thyroiditis, or allergic dermatitis. The viral infection is selected from poliovirus, hepatitis A virus, rubella virus, Japanese encephalitis virus, hepatitis C virus, human papillomavirus, rabies virus, herpesvirus, Barr virus, or human immunodeficiency virus, novel coronavirus, or infection.

[0093] In this invention, exemplary cancers treated by the compounds applicable to this invention include, but are not limited to, leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, mixed leukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), multiple myeloma, polycythemia vera, cutaneous T-lymphocytoma, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Woldanström's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g.,Fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colonoma, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary gland carcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, and nephroblastoma are all mentioned. The cancers mentioned include: adrenal tumors, acoustic neuroma, acral melanoma, and acral sweat gland carcinoma. Adenoma, Acute eosinophilic leukemia, Acute red leukemia, Acute lymphoblastic leukemia, Acute megakaryocytic leukemia, Acute monocytic leukemia, Acute promyelocytic leukemia, Adenocarcinoma, Adenoid cystic carcinoma, Adipose tissue tumor, Adrenocortical carcinoma, Adult T-cell leukemia / lymphoma, AIDS-related lymphoma, Alveolar rhabdomyosarcoma, Alveolar soft sarcoma, Ameloblastic fibroma, Anaplastic large cell lymphoma, Undifferentiated thyroid carcinoma, Angiomyolipoma, Angiosarcoma, Astrocytoma, Atypical rod tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma Tumors, basal cell carcinoma, bile duct cancer, bladder cancer, germ cell tumors, bone tumors, brown tumors, Burkitt lymphoma, breast cancer, brain cancer, carcinoma in situ, chondroma, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colon cancer, small round cell tumors, diffuse B-cell lymphoma, neuroepithelial tumors, dysgerminoma, embryonal carcinoma, endocrine gland tumors, endodermal sinus tumors, esophageal cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular astrocytoma, thyroid cancer, gastrointestinal cancers, germ cell tumors, pregnancy Choriocarcinoma of pregnancy, giant cell fibroblastoma, giant cell tumor of bone, glioma, glioblastoma multiforme, glioma, granulosa cell tumor, androgenetic adenocarcinoma, gallbladder cancer, gastric cancer, hemangioblastoma, head and neck cancer, hemangiopericytoma, hepatoblastoma, cellular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, fatal midline carcinoma, leukemia, testicular interstitial cell tumor, liposarcoma, lung cancer, lymphangioma, lymphoepithelioma, lymphoma, acute lymphangiosarcoma, lymphocytic leukemia, chronic lymphocytic leukemia, liver cancer.Small cell lung cancer, non-small cell lung cancer, malt lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary breast carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic cell carcinoma, mixed Müllerian tumor, myxoma, multiple myeloma, muscle tissue tumor, mycosis myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neuroblastoma, neuroma, ocular cancer, eosinophilic, optic nerve sheath meningioma, tumor, oral cancer, osteosarcoma, ovarian cancer, papillary thyroid carcinoma, paraganglioma, pineal gland Cell tumors, pituitary cell tumors, precursor T-lymphoblastic lymphomas, primary central nervous system lymphomas, peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyosarcoma, rectal cancer, sarcoma, seminoma, trophoblastic tumors, skin cancer, small round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, spinal cord tumors, marginal zone lymphoma of the spleen, squamous cell carcinoma, synovial sarcoma, small intestinal cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, urogenital cancer, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer or vaginal cancer.

[0094] In this invention, the cell proliferation disorder includes: benign soft tissue tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine tumors, nasal polyps, pituitary tumors, prolactinomas, seborrheic keratosis, gastric polyps, thyroid nodules, hepatic hemangiomas, vocal cord nodules, polyps, cysts, pilonidal disease, dermatofibromas, Pilar cysts, or pyogenic granulomas.

[0095] In this invention, the inflammatory diseases include: inflammatory pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune diseases, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, and more. Scleroderma, scleroderma, vasculitis, autoimmune hemolytic anemia and thrombocytopenia, pulmonary hemorrhage and nephritis syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, allergic dermatitis, degenerative joint disease, Guillain-Barré syndrome, mycosis fungoides, or acute inflammatory reactions.

[0096] In this invention, the viral infection includes: poliovirus, hepatitis A virus, rubella virus, Japanese encephalitis virus, hepatitis C virus, human papillomavirus, rabies virus, herpesvirus, Barr virus or human immunodeficiency virus, novel coronavirus or infection.

[0097]

Terminology Explanation

[0098] The various aspects and features of the present invention will be further described below.

[0099] 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.

[0100] As mentioned in this invention, the terms “halogen,” “halogen,” “halogen atom,” “halogenated,” etc., refer to fluorine, chlorine, bromine, or iodine, and in particular to fluorine, chlorine, or bromine.

[0101] 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-C20 alkyl" is mentioned, it refers to a straight-chain alkyl group or a branched alkyl group having 1-20 carbon atoms. Specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc., and similar groups.

[0102] 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.

[0103] 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-C20 alkenyl" is mentioned, it refers to a straight-chain alkyl group or a branched alkenyl group having 2-20 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.

[0104] 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.

[0105] 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 group or a branched alkynyl group. For example, when "C2-C20 alkynyl" is mentioned, it refers to a straight-chain alkyl group or a branched alkynyl group having 2-20 carbon atoms. Specific groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-hexynyl, etc., and similar groups.

[0106] As used in this invention, the term "heterocyclic alkyl" 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 (e.g., having 2, 3, or 4 fused rings) and spirocyclic rings. Preferred examples of "heterocyclic alkyl" 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 alkyl groups are those moieties having one or more aromatic rings fused to a non-aromatic heterocyclic alkyl ring (e.g., having a shared bond), such as 2,3-dihydrobenzofuranyl, 1,3-benzodioxacyclopentenyl, benzo-1,4-dioxacyclohexyl, phthalimide, naphthalimide, and similar groups. Heterocyclic alkyl groups having one or more fused aromatic rings can be linked by either an aromatic or non-aromatic moieties.

[0107] 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.

[0108] 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.

[0109] As mentioned in this invention, the term "single bond" refers to the direct connection between two groups attached to that position; for example, when Z1 is a single bond and L is directly attached to the benzene ring, the structure of Formula I can be represented as: When Z2 is a single bond, L is directly connected to E, and the structure described in Equation I can be expressed as:

[0110] As used herein, the term "compound" means, as is used herein, all stereoisomers, geometric isomers, tautomers, and isotopes.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] Pharmaceutically acceptable salts of the compounds shown in Formulas I, II, and III 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 Formulas I, II, and III 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 Formulas I, II, and III include lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc; bases that form pharmaceutically acceptable salts with the compounds shown in Formulas I, II, and III include choline, diethanolamine, and morpholine.

[0118] As mentioned in this invention, the term "prodrug" refers to derivatives of compounds shown in Formulas I, II, and III that are converted in vivo (e.g., hydrolyzed, reduced, or oxidized) into compounds shown in Formula I through in vivo metabolism. For example, compounds containing hydroxyl groups, as shown in Formulas I, II, and III, 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, hydroxyethyl sulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0119] Compared with the prior art, the present invention has the following beneficial effects:

[0120] (1) This invention provides a class of novel compounds and their pharmaceutically acceptable salts, stereoisomers, tautomers, N-oxides or their prodrug molecules, which can effectively induce the degradation of GSPT1;

[0121] (2) The compounds and compositions provided by the present invention can be used to prepare drugs for treating or preventing diseases such as tumor formation, inflammation, viral infection, cell proliferation disorder, autoimmune diseases, and sepsis. Attached Figure Description

[0122] Figure 1 As shown, the compounds of the present invention in Examples 2, 18, 20, 1, 4, 6 and 7 significantly induced the degradation of GSPT1 protein after 6 hours of treatment with 22Rv1 cells at 500 nM.

[0123] Figure 2 As shown, the compounds of the present invention in Examples 2, 18, 20, 1, 4, 6 and 7, when treated with MV4;11 cells at 500 nM for 6 hours, significantly induced the degradation of GSPT1 protein.

[0124] Figure 3 As shown, the compounds of the present invention in Examples 8, 9, 10, 13, 15, 16 and 22 significantly induced the degradation of GSPT1 protein after treating MOLM-16 cells with 500 nM for 6 hours. Detailed Implementation

[0125] 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.

[0126] Example 1

[0127] 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0128] The synthetic route of Example 1 is shown below:

[0129]

[0130] (a)2-(2,6-dioxadiazine-3-yl)-4-fluoroisoindoline-1,3-dione (1-1)

[0131] 3-Fluorophthalic anhydride (25.00 g, 150.50 mmol), 3-amino-2,6-piperidin-diketone hydrochloride (24.78 g, 150.50 mmol), and sodium acetate (14.80 g, 180.60 mmol) were dissolved in acetic acid solution and heated under reflux at 120 °C overnight. The reaction was monitored by TLC. After the reaction was complete, ice water was added until a solid was formed, and the mixture was filtered. The filter cake was washed several times with water, transferred to a wedge flask, and a small amount of methanol was added. The mixture was then concentrated under reduced pressure at 80 °C. The target product, 1-1, was obtained as a grayish-white solid (38.00 g, 91% yield).

[0132] 1 H NMR(500MHz,DMSO-d6)δ11.16(s,1H),7.99-7.93(m,1H),7.80(d,J=7.3Hz,1H),7.75(t,J=8.9Hz,1H), 5.17(dd,J=13.0,5.4Hz,1H),2.94-2.84(m,1H),2.66-2.52(m,2H),2.10-2.03(m,1H).MS(ESI)m / z[MH] - Theoretical value: 275.05; Actual value: 275.1.

[0133] (b)(5-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)tert-butyl carbamate (1-2)

[0134] Compound 1-1 (3.00 g, 10.86 mmol) was dissolved in ultra-dry DMF, and mono-BOC-pentanediamine (2.00 g, 9.89 mmol) and DIPEA (8.61 mL, 49.43 mmol) were added. The mixture was stirred at 100 °C for 2 h, and the reaction was monitored by TLC. After the reaction was complete, ethyl acetate and water were added to the reaction system for two extractions. The organic layers were combined and extracted once with saturated brine. The organic layers were separated and combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 100:1, v / v) to give the target product 1-2, a yellow viscous solid (3.37 g, yield 67%).

[0135] 1H NMR(400MHz,Chloroform-d6)δ8.93(s,1H),7.44(t,J=8.4Hz,1H),7.03(d,J=7.1Hz, 1H),6.83(d,J=8.8Hz,1H),6.21(s,1H),4.93-4.87(m,1H),4.71(s,1H),3.26-3.18(m ,2H),3.12-3.02(m,2H),2.84-2.77(m,1H),2.77-2.70(m,2H),2.10-2.04(m,1H),1.6 7-1.60(m,2H),1.52-1.45(m,2H),1.40(s,9H),1.39-1.37(m,2H).MS(ESI)m / z[M+Na] + Theoretical value: 481.21; Actual value: 481.4.

[0136] (c) 4-((5-aminopentyl)amino)-2-(2,6-dioxadiazine-3-yl)isoindoline-1,3-dione trifluoroacetate (1-3)

[0137] Compounds 1-2 (0.78 g, 1.70 mmol) were dissolved in dichloromethane (5.00 mL), and trifluoroacetic acid (0.20 mL) was added. The reaction was stirred at room temperature and monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 15:1, v / v) to obtain the target product 1-3, a yellow solid (0.61 g, yield 76%).

[0138] 1 H NMR(500MHz,DMSO-d6)δ11.12(s,1H),7.67(s,3H),7.60(t,J=7.8Hz,1H),7 .11(d,J=8.6Hz,1H),7.05(d,J=7.0Hz,1H),6.56(t,J=5.8Hz,1H),5.06(dd, J=12.8,5.4Hz,1H),3.32(d,m,2H),2.94-2.86(m,1H),2.84-2.76(m,2H),2. 64-2.55(m,2H),2.03(m,1H),1.60(m,4H),1.39(m,2H).HRMS(ESI)m / z[M+H] + Theoretical value: 359.1714; Actual value: 359.1673.

[0139] (d)N-(4-fluoro-2-hydroxyphenyl)-2,5-dimethoxybenzenesulfonamide (1-4)

[0140] 2-Amino-5-fluorophenol (1.50 g, 11.80 mmol) and 2,5-dimethoxybenzenesulfonyl chloride (3.07 g, 12.98 mmol) were dissolved in 20 mL of dichloromethane, and pyridine (2.85 mL, 35.37 mmol) was added. The mixture was reacted at room temperature for 4 h. After the reaction was completed, water was added for extraction. The organic layer was extracted with dilute hydrochloric acid aqueous solution and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration of the organic layer under reduced pressure, the crude product was purified and separated by silica gel column chromatography (PE:EA = 3:1, v / v) to obtain the target product 1-4, a reddish-brown viscous solid (2.39 g, yield 62%).

[0141] 1 H NMR(500MHz,DMSO-d6)δ10.19(s,1H),8.57(s,1H),7.18-7.13(m,3H),7.11(t ,J=7.7Hz,1H),6.59-6.48(m,2H),3.82(s,3H),3.70(s,3H).MS(ESI)m / z[MH] - Theoretical value: 326.05; Actual value: 326.2.

[0142] (e)2-(2-((2,5-dimethoxyphenyl)sulfonylamino)-5-fluorophenoxy)tert-butyl acetate (1-5)

[0143] Compounds 1-4 (1.50 g, 4.58 mmol) were dissolved in 6.00 mL of ultradry DMF, and KHCO3 (0.69 g, 6.87 mmol) was added and stirred thoroughly in an ice bath. Tert-butyl bromobutyrate (0.94 mL, 4.82 mmol) was dissolved in 4 mL of ultradry DMF and added dropwise to the reaction system. The mixture was stirred at 40 °C for 4 h. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the organic layer was extracted with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1, v / v) to obtain the target product 1-5 as a white solid (0.32 g, yield 16%).

[0144] 1 H NMR(500MHz,DMSO-d6)δ8.58(s,1H),7.31-7.24(m,1H),7.20-7.10(m,3H),6.85(dd,J=10.6,2.7Hz,1H ),6.75(td,J=8.6,2.5Hz,1H),4.64(s,2H),3.81(s,3H),3.70(s,3H),1.42(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 464.12; Actual value: 464.2.

[0145] (f)2-(2-((2,5-dimethoxyphenyl)sulfonylamino)-5-fluorophenoxy)acetic acid (1-6)

[0146] Compounds 1-5 (0.32 g, 0.73 mmol) were dissolved in 1.00 mL of dichloromethane, and 0.50 mL of trifluoroacetic acid was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 40:1, v / v) to obtain the target product 1-6 as a white solid (0.19 g, 66%).

[0147] 1 H NMR (500MHz, DMSO-d6) δ13.14(s,1H),8.67(s,1H),7.28(dd,J=9.0,6.2Hz,1H),7.18-7.10(m,3H),6.88(d d,J=10.5,2.7Hz,1H),6.74(td,J=8.7,2.7Hz,1H),4.64(s,2H),3.81(s,3H),3.70(s,3H).MS(ESI)m / z[MH] - Theoretical value: 384.06; Actual value: 384.2.

[0148] (g)2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 1)

[0149] Compounds 1-6 (0.06 g, 0.16 mmol) and HATU (0.07 g, 0.19 mmol) were dissolved in DMF, and DIPEA (0.26 mL, 1.48 mmol) was added. The mixture was stirred at room temperature for 10 min. Then, 1-3 (0.053 g, 0.15 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic layer was extracted with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM:MeOH = 100:1, v / v) to give compound 1 as a yellow solid (0.06 g, yield 56%).

[0150] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.36(s,1H),8.16(t,J=5.7Hz,1H),7.58(t,J=8.1Hz,1H),7.29(t,J=7.3Hz,1H), 7.15-7.10(m,2H),7.08(t,J=6.7Hz,2H),7.03(d,J=6.7Hz,1H),6.89(d,J=10.4Hz,1H),6.76(t,J=8.8Hz,1H),6.52(t,J =6.3Hz,1H),5.05(dd,J=11.7,4.7Hz,1H),4.32(s,2H),3.67(s,3H),3.65(s,3H),3.33-3.25(m,2H),3.17-3.14(m,2H) ,2.89(t,J=16.9Hz,1H),2.63-2.52(m,2H),2.04-2.00(m,1H),1.61-1.55(m,2H),1.49-1.43(m,2H),1.34-1.30(m,2H); 13 C NMR (101MHz, DMSO) δ173.35, 170.64, 169.46, 167.82, 167.11, 160.53 (d, J = 242.0Hz), 152.40, 151 .64(d,J=10.8Hz),151.08,146.89,136.81,132.70,128.19,126.58(d,J=9.6Hz),122.80(d,J=2.6 Hz),120.18,117.67,115.20,114.41,110.92,109.53,107.93(d,J=22.4Hz),101.73(d,J=27.4Hz ),68.09,56.68,56.18,49.04,42.27,38.59,31.48,29.40,28.87,24.17,22.65.MS(ESI)m / z[M+H] + Theoretical values: 726.22 and 727.23; Actual values: 726.4 and 727.4;

[0151] Example 2

[0152] 2-(2-((5-bromo-2-methoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0153]

[0154] The synthesis method follows the same route as in Example 1, with the following differences:

[0155] In step (d), an equimolar amount of 5-bromo-2-methoxybenzenesulfonyl chloride raw material is replaced with 2,5-dimethoxybenzenesulfonyl chloride raw material to obtain the intermediate 5-bromo-N-(4-fluoro-2-hydroxyphenyl)-2-methoxybenzenesulfonamide (2-1).

[0156] 1 H NMR(500MHz,DMSO-d6)δ7.74(dd,J=8.9,2.6Hz,1H),7.66(d,J=2.5Hz,1H),7.19(d,J=8 .9Hz,1H),7.08(dd,J=8.4,6.4Hz,1H),6.54-6.50(m,2H),3.86(s,3H).MS(ESI)m / z[MH] - Theoretical values: 373.95 and 375.95; Actual values: 374.2 and 376.2.

[0157] In step (e), equimolar amounts of raw materials 1-5 are replaced with raw material 2-1 to obtain the intermediate ((5-bromo-2-methoxyphenyl)sulfonyl)(2-(2-(tert-butoxy)-2-carbonylethoxy)-4-fluoro)amide (2-2).

[0158] 1 H NMR (500MHz, DMSO-d6) δ8.98(s,1H),7.75(dd,J=8.8,2.2Hz,1H),7.67(d,J=2.2Hz,1H),7.25(dd,J=8.7,6.4Hz,1H),7.18(d,J= 8.9Hz,1H),6.82(dd,J=10.6,2.3Hz,1H),6.77(td,J=8.5,2.4Hz,1H),4.59(s,2H),3.86(s,3H),1.40(s,9H)..MS(ESI)m / z[MH] - Theoretical values: 488.02 and 490.02; Actual values: 488.01 and 489.98.

[0159] In step (f), raw materials 1-6 are replaced with an equimolar amount of raw material 2-2 to obtain intermediate 2-(2-((5-bromo-2-methoxyphenyl)sulfonamide)-5-fluorophenoxy)acetic acid (2-3).

[0160] 1H NMR (500MHz, DMSO-d6) δ9.04(s,1H),7.75(dd,J=8.7,1.9Hz,1H),7.67(d,J=1.9Hz,1H),7.27(dd,J=8.5,6.4Hz,1H),7.1 7(d,J=8.9Hz,1H),6.86(dd,J=10.7,1.8Hz,1H),6.77(td,J=8.7,2.2Hz,1H),4.60(s,2H),3.85(s,3H).MS(ESI)m / z[MH] - Theoretical values: 431.96 and 433.95; Actual values: 431.92 and 433.93;

[0161] In step (g), raw materials 1-6 were replaced with equimolar amounts of raw materials 2-3 to obtain 2-(2-((5-bromo-2-methoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 2), which was a yellow solid with a yield of 41%.

[0162] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.60(s,1H),8.12(t,J=5.9Hz,1H),7.74(dd,J=8.8,2.5Hz,1H),7.69(d,J=2.6Hz,1H),7.59(t, J=7.8Hz,1H),7.31(dd,J=8.8,6.2Hz,1H),7.13(d,J=8.8Hz,1H),7.09(d,J=8.6Hz,1H),7.04(d,J=7.0Hz,1H),6.93(dd,J=10.7,2.8H z,1H),6.80(td,J=8.5,2.7Hz,1H),6.54(t,J=5.9Hz,1H),5.07(dd,J=12.9,5.4Hz,1H),4.35(s,2H),3.68(s,3H),3.31-3.24(m,2H), 3.18-3.12(m,2H),2.95-2.84(m,1H),2.65-2.53(m,2H),2.09-2.00(m,1H),1.63-1.55(m,2H),1.50-1.42(m,2H),1.36-1.29(m,2H); 13C NMR (101MHz, DMSO-d6) δ173.36, 170.65, 169.48, 167.83, 167.05, 160.86 (d, J = 242.9Hz), 156. 47,152.03(d,J=10.9Hz),146.91,137.74,136.82,132.72,131.82,129.78,127.52(d,J=10.0 Hz), 122.43, 117.68, 115.65, 111.13, 110.94, 109.56, 108.03 (d, J = 22.7Hz), 101.73 (d, J = 27. 2Hz),68.05,56.77,49.06,42.30,38.67,31.50,29.44,28.90,24.20,22.67; MS(ESI)m / z[MH] - Theoretical values: 774.12 and 776.12; Actual values: 774.13 and 776.17; HPLC analysis: MeOH-H2O (85:15), 7.66 min, 95.13% purity.

[0163] Example 3

[0164] N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-(5-fluoro-2-phenylsulfonylamino)phenoxy)acetamide

[0165]

[0166] The synthesis method follows the same route as in Example 1, with the following differences:

[0167] In step (d), an equimolar amount of benzenesulfonyl chloride raw material is replaced with 2,5-dimethoxybenzenesulfonyl chloride raw material to obtain the intermediate N-(4-fluoro-2-hydroxyphenyl)benzenesulfonamide (3-1).

[0168] 1 H NMR (500MHz, DMSO-d6) δ9.95(s,1H),9.33(s,1H),7.69(d,J=7.7Hz,2H),7.60(t,J=7.4Hz,1H),7.51(t ,J=7.6Hz,2H),7.07(dd,J=8.9,6.5Hz,1H),6.54(td,J=8.6,2.9Hz,1H),6.50(dd,J=10.2,2.7Hz,1H).

[0169] In step (e), raw materials 1-5 are replaced with an equimolar amount of raw material 3-1 to obtain intermediate 2-(5-fluoro-2-(benzenesulfonamide)phenoxy)tert-butyl acetate (3-2).

[0170] 1 H NMR(500MHz,DMSO-d6)δ8.98(s,1H),7.75(dd,J=8.8,2.2Hz,1H),7.67(d,J=2.2Hz,1H),7.25(dd,J=8.7,6.4Hz,1H),7 .18(d,J=8.9Hz,1H),6.82(dd,J=10.6,2.3Hz,1H),6.77(td,J=8.5,2.4Hz,1H),4.59(s,2H),3.86(s,3H),1.40(s,9H).

[0171] In step (f), raw materials 1-6 are replaced with an equimolar amount of raw material 3-2 to obtain intermediate 2-(5-fluoro-2-(benzenesulfonyl)phenoxy)acetic acid (3-3).

[0172] 1 H NMR(500MHz,Chloroform-d6)δ9.52(s,1H),7.71(d,J=8.1Hz,2H),7.59(t,J=7.3Hz,1H),7.49(t,J=7.6Hz ,2H),7.22(dd,J=8.8,6.3Hz,1H),6.80(dd,J=10.7,2.7Hz,1H),6.75(td,J=8.5,2.6Hz,1H),4.38(s,2H).

[0173] In step (g), raw materials 1-6 were replaced with an equimolar amount of raw material 3-3 to obtain N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)-2-(5-fluoro-2-phenylsulfonylamino)phenoxy)acetamide (Example 3), which was a yellow solid with a yield of 49%.

[0174] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.70(s,1H),8.11(t,J=6.1Hz,1H),7.59-7.50(m,4H),7.42( d,J=7.9Hz,2H),7.34(d,J=8.1Hz,1H),7.10(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),6.84(m,2H),6 .55(t,J=5.9Hz,1H),5.05(dd,J=13.1,5.2Hz,1H),3.90(s,2H),3.21-3.16(m,4H),2.92-2.83(m,1 H),2.62-2.51(m,2H),2.06-1.98(m,1H),1.67-1.62(m,2H),1.58-1.52(m,2H),1.45-1.37(m,2H); 13 C NMR(101MHz,DMSO-d6)δ173.37,170.66,169.48,167.84,166.65,161.37(d,J=243.5Hz),15 2.26(d,J=11.1Hz),146.93,139.93,136.83,133.22,132.72,129.35(d,J=10.3Hz),129.18, 127.06,121.77(d,J=2.8Hz),117.70,110.95,109.56,108.30(d,J=22.4Hz),101.87(d,J=2 7.1Hz),67.68,49.06,42.33,38.59,31.49,29.68,28.97,24.36,22.67; HRMS(ESI)m / z[M+H] + Theoretical value: 666.2028; Actual value: 666.2020; HPLC analysis: MeOH-H2O (90:10), 6.69 min, 99.24% purity.

[0175] Example 4

[0176] N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-(5-fluoro-2-((2-methoxyphenyl)sulfonylamino)phenoxy)acetamide

[0177]

[0178] The synthesis method follows the same route as in Example 1, with the following differences:

[0179] In step (d), an equimolar amount of 2-methoxybenzenesulfonyl chloride raw material is replaced with 2,5-dimethoxybenzenesulfonyl chloride raw material to obtain the intermediate N-(4-fluoro-2-hydroxyphenyl)-2-methoxybenzenesulfonamide (4-1).

[0180] 1 H NMR (500MHz, DMSO-d6) δ10.13(s,1H),8.50(s,1H),7.61(d,J=7.8Hz,1H),7.57(t,J=7.9Hz,1H),7.19(d,J= 8.4Hz,1H),7.09(t,J=7.6Hz,1H),6.98(t,J=7.6Hz,1H),6.53-6.48(m,2H),3.88(s,3H).MS(ESI)m / z[M+H] + Theoretical value: 298.05; Actual value: 298.1.

[0181] In step (e), raw materials 1-5 are replaced with an equimolar amount of raw material 4-1 to obtain intermediate 2-(5-fluoro-2-((2-methoxyphenyl)sulfonamido)phenoxy)tert-butyl acetate (4-2).

[0182] 1 H NMR (500MHz, DMSO-d6) δ8.53(s,1H),7.65(d,J=7.7Hz,1H),7.57(t,J=7.9Hz,1H),7.26(dd,J=8.8,6.4Hz,1H),7.18(d,J=8.3Hz,1H),6 .99(t,J=7.5Hz,1H),6.83(dd,J=10.5,2.5Hz,1H),6.72(td,J=8.7,2.5Hz,1H),4.62(s,2H),3.87(s,3H),1.41(s,9H).MS(ESI)m / z[MH] - Theoretical value: 410.11; Actual value: 410.3. In step (f), raw materials 1-6 are replaced with an equimolar amount of raw material 4-2 to obtain intermediate 2-(5-fluoro-2-((2-methoxyphenyl)sulfonamido)phenoxy)acetic acid (4-3).

[0183] 1H NMR (500MHz, DMSO-d6) δ8.75(s,1H),7.64(d,J=7.7Hz,1H),7.57(t,J=7.9Hz,1H),7.27(dd,J=8.9,6.1Hz,1H),7.17(d,J=8.5Hz, 1H),6.99(t,J=7.6Hz,1H),6.86(dd,J=10.5,2.8Hz,1H),6.72(td,J=8.6,2.6Hz,1H),4.60(s,2H),3.86(s,3H).MS(ESI)m / z[MH] - Theoretical value: 354.04; Actual value: 354.2.

[0184] In step (g), raw materials 1-6 were replaced with equimolar amounts of raw materials 4-3 to obtain N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)-2-(5-fluoro-2-((2-methoxyphenyl)sulfonylamino)phenoxy)acetamide (Example 4), which was a yellow solid with a yield of 48%.

[0185] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.32(s,1H),8.19(t,J=6.0Hz,1H),7.63-7.53(m,3H),7.28(t,J=7.5Hz,1H),7.13( d,J=8.3Hz,1H),7.09(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.96(t,J=7.5Hz,1H),6.88(dd,J=10.7,2.8Hz,1H),6.74(t, J=8.7Hz,1H),6.53(t,J=6.1Hz,1H),5.05(dd,J=12.7,5.4Hz,1H),4.32(s,2H),3.73(s,3H),3.30-3.24(m,2H),3.18-3.12 (m,2H),2.92-2.84(m,1H),2.62-2.53(m,2H),2.06-1.99(m,1H),1.63-1.54(m,2H),1.50-1.43(m,2H),1.34-1.30(m,2H); 13C NMR (126MHz, DMSO-d6) δ173.26, 170.55, 169.44, 167.78, 167.17, 160.45 (d, J = 242.3Hz), 157.08, 151.64(d,J=10.6Hz),146.90,136.78,135.40,132.67,130.15,127.54,126.45(d,J=10.0Hz),12 2.89(d,J=3.0Hz),120.23,117.64,113.07,110.91,109.55,107.90(d,J=22.3Hz),101.71(d,J=2 7.2Hz),68.11,56.35,49.05,42.29,38.61,31.45,29.35,28.86,24.14,22.64; MS(ESI)m / z[M+H] + Theoretical values: 696.21 and 697.22; Actual values: 696.4 and 697.4; HPLC analysis: MeOH-H2O (90:10), 6.75 min, 96.94% purity.

[0186] Example 5

[0187] N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-(5-fluoro-2-((3-methoxyphenyl)sulfonylamino)phenoxy)acetamide

[0188]

[0189] The synthesis method follows the same route as in Example 1, with the following differences:

[0190] In step (d), an equimolar amount of 3-methoxybenzenesulfonyl chloride raw material is replaced with 2,5-dimethoxybenzenesulfonyl chloride raw material to obtain the intermediate N-(4-fluoro-2-hydroxyphenyl)-3-methoxybenzenesulfonamide (5-1).

[0191] 1 H NMR(500MHz,DMSO-d6)δ10.05(s,1H),9.31(s,1H),7.42(t,J=8.0Hz,1H),7.29-7.20(m,2H ),7.16(dd,J=8.3,2.4Hz,1H),7.08(dd,J=8.7,6.5Hz,1H),6.59-6.48(m,2H),3.76(s,3H).

[0192] In step (e), raw materials 1-5 are replaced with an equimolar amount of raw material 5-1 to obtain intermediate 2-(5-fluoro-2-((3-methoxyphenyl)sulfonamido)phenoxy)tert-butyl acetate (5-2).

[0193] 1 H NMR(500MHz,DMSO-d6)δ9.46(s,1H),7.42(t,J=7.9Hz,1H),7.28(d,J=7.8Hz,1H ),7.24-7.15(m,3H),6.81-6.72(m,2H),4.43(s,2H),3.76(s,3H),1.40(s,9H).

[0194] In step (f), raw materials 1-6 are replaced with an equimolar amount of raw material 5-2 to obtain intermediate 2-(5-fluoro-2-((3-methoxyphenyl)sulfonamido)phenoxy)acetic acid (5-3).

[0195] 1 H NMR(500MHz, DMSO-d6)δ7.40(t,J=8.0Hz,1H),7.27(d,J=7.8Hz,1H),7.25-7.19(m,2H),7.14(dd,J= 8.2, 2.5Hz, 1H), 6.83 (dd, J=10.5, 2.8Hz, 1H), 6.76 (td, J=8.6, 2.6Hz, 1H), 4.33 (s, 2H), 3.75 (s, 3H).

[0196] In step (g), raw materials 1-6 were replaced with an equimolar amount of raw materials 5-3 to obtain N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)-2-(5-fluoro-2-((3-methoxyphenyl)sulfonylamino)phenoxy)acetamide (Example 5), which was a yellow solid with a yield of 52%.

[0197] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.70(s,1H),8.09(t,J=6.1Hz,1H),7.58(t,J=7.8Hz,1H),7.34(t,J=7.9Hz,2H),7.13(d, J=8.4Hz,1H),7.10(d,J=8.6Hz,1H),7.06(d,J=7.8Hz,1H),7.03(d,J=7.0Hz,1H),6.99(s,1H),6.90(dd,J=10.4,1.2Hz,1H),6.8 4(td,J=8.6,2.5Hz,1H),6.55(t,J=6.1Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),3.96(s,2H),3.68(s,3H),3.32-3.28(m,2H),3.20 -3.15(m,2H),2.93-2.83(m,1H),2.62-2.52(m,2H),2.06-2.00(m,1H),1.66-1.60(m,2H),1.56-1.49(m,2H),1.42-1.35(m,2H); 13 C NMR (101MHz, DMSO-d6) δ173.38, 170.66, 169.48, 167.84, 166.69, 161.29 (d, J = 243.8Hz), 159. 52,152.37(d,J=10.6Hz),146.92,141.28,136.83,132.71,130.42,129.10(d,J=10.4Hz),122. 06,119.08,118.53,117.71,112.39,110.94,109.54,108.26(d,J=22.3Hz),101.90(d,J=27.3H z),67.79,55.96,49.05,42.31,38.60,31.49,29.54,28.95,24.32,22.66; HRMS(ESI)m / z[M+H] + Theoretical value: 696.2135; Actual value: 696.2126; HPLC analysis: MeOH-H2O (90:10), 6.71 min, 96.73% purity.

[0198] Example 6

[0199] 2-(2-((5-bromo-2-methoxyphenyl)sulfonamide)-5-tolyloxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0200]

[0201] The synthesis method follows the same route as in Example 1, with the following differences:

[0202] In step (d), 2,5-dimethoxybenzenesulfonyl chloride is replaced with an equimolar amount of 5-bromo-2-methoxybenzenesulfonyl chloride, and 2-amino-5-fluorophenol is replaced with an equimolar amount of 6-amino-m-cresol, to obtain the intermediate 5-bromo-N-(2-hydroxy-4-methylphenyl)-2-methoxybenzenesulfonamide (6-1).

[0203] 1 H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.67(s,1H),7.75(dd,J=8.9,2.6Hz,1H),7.66(d,J=2.5Hz,1H),7.19(d,J= 8.9Hz,1H),6.99(d,J=8.1Hz,1H),6.55(d,J=1.9Hz,1H),6.50(dd,J=8.2,1.9Hz,1H),3.89(s,3H),2.13(s,3H).

[0204] In step (e), equimolar amounts of raw materials 1-5 are replaced with raw material 6-1 to obtain intermediate 2-(2-((5-bromo-2-methoxyphenyl)sulfonamido)-5-methylphenoxy)tert-butyl acetate (6-2).

[0205] 1 H NMR (500MHz, DMSO-d6) δ8.71(s,1H),7.75(dd,J=9.1,2.6Hz,1H),7.68(d,J=2.6Hz,1H),7.16(dd,J=11 .7,8.5Hz,2H),6.72(d,J=8.2Hz,1H),6.69(s,1H),4.56(s,2H),3.88(s,3H),2.19(s,3H),1.42(s,9H).

[0206] In step (f), raw materials 1-6 are replaced with an equimolar amount of raw material 6-2 to obtain intermediate 2-(2-((5-bromo-2-methoxyphenyl)sulfonamido)-5-methylphenoxy)acetic acid (6-3).

[0207] 1H NMR (500MHz, DMSO-d6) δ8.83(s,1H),7.75(dd,J=8.8,2.6Hz,1H),7.67(d,J=2.5Hz,1H),7. 17(d,J=2.0Hz,1H),7.16(s,1H),6.75-6.71(m,2H),4.58(s,2H),3.87(s,3H),2.19(s,3H).

[0208] In step (g), raw materials 1-6 were replaced with equimolar amounts of raw materials 6-3 to obtain 2-(2-((5-bromo-2-methoxyphenyl)sulfonamide)-5-tolyloxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 6), which was a yellow solid with a yield of 42%.

[0209] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.45(s,1H),8.14(t,J=5.9Hz,1H),7.72(dd,J=8.9,2.6Hz,1H),7.67(d,J=2.5Hz,1H),7. 58(t,J=7.8Hz,1H),7.17(d,J=8.0Hz,1H),7.13(d,J=8.9Hz,1H),7.07(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.78(s,1H),6.73 (d,J=8.1Hz,1H),6.52(t,J=6.0Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.32(s,2H),3.72(s,3H),3.28-3.22(m,2H),3.15(s,2H) ,2.93-2.84(m,1H),2.62-2.53(m,2H),2.21(s,3H),2.05-1.99(m,1H),1.60-1.54(m,2H),1.49-1.43(m,2H),1.33-1.28(m,2H); 13C NMR(126MHz,DMSO-d6)δ173.20,170.50,169.40,167.73,167.54,156.41,150.3 9,146.85,137.55,136.71,136.69,132.64,131.71,129.74,125.42,123.39,12 2.29,117.58,115.61,114.08,111.01,110.85,109.52,67.80,56.75,55.33,49 .01,42.25,38.57,31.42,29.32,28.84,24.10,22.60,21.24; MS(ESI)m / z[M+H] + Theoretical values: 770.15 and 772.15; Actual values: 770.4 and 772.4; HPLC analysis: MeOH-H2O (90:10), 7.05 min, 97.96% purity.

[0210] Example 7

[0211] 2-(2-((5-bromo-2-methoxyphenyl)sulfonamide)phenoxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0212]

[0213] The synthesis method follows the same route as in Example 1, with the following differences:

[0214] In step (d), 2,5-dimethoxybenzenesulfonyl chloride is replaced with an equimolar amount of 5-bromo-2-methoxybenzenesulfonyl chloride, and 2-amino-5-fluorophenol is replaced with an equimolar amount of 2-aminophenol, to obtain the intermediate 5-bromo-N-(2-hydroxyphenyl)-2-methoxybenzenesulfonamide (7-1).

[0215] 1 H NMR (500MHz, DMSO-d6) δ9.69(s,1H),8.74(s,1H),7.75(dd,J=8.8,2.6Hz,1H),7.70(d,J=2.5Hz,1H),7.19(d,J=8.8Hz,1H),7.14(dd,J =7.9,1.6Hz,1H),6.93(td,J=7.7,1.7Hz,1H),6.75(dd,J=8.1,1.5Hz,1H),6.70(td,J=7.6,1.4Hz,1H),3.87(s,3H).MS(ESI)m / z[M+K] +Theoretical value: 395.93; Actual value: 395.5.

[0216] In step (e), equimolar amounts of raw materials 1-5 are replaced with raw material 7-1 to obtain intermediate 2-(2-((5-bromo-2-methoxyphenyl)sulfonamide)phenoxy)tert-butyl acetate (7-2).

[0217] 1 H NMR (500MHz, DMSO-d6) δ8.81(s,1H),7.75(dd,J=8.9,2.5Hz,1H),7.72(d,J=2.5Hz,1H),7.29(dd,J=8.1,1.7Hz,1H),7.18(d,J=8.9 Hz,1H),7.08-7.03(m,1H),6.91(t,J=7.7Hz,1H),6.87(d,J=8.2Hz,1H),4.60(s,2H),3.87(s,3H),1.42(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 496.02; Actual value: 496.1.

[0218] In step (f), raw materials 1-6 are replaced with an equimolar amount of raw material 7-2 to obtain intermediate 2-(2-((5-bromo-2-methoxyphenyl)sulfonamido)phenoxy)acetic acid (7-3).

[0219] 1 H NMR (500MHz, DMSO-d6) δ8.91(s,1H),7.76(dd,J=9.1,2.4Hz,1H),7.72(d,J=2.5Hz,1H),7.30(dd,J=8.3,1 .7Hz,1H),7.17(d,J=8.9Hz,1H),7.05(td,J=7.8,1.7Hz,1H),6.94-6.89(m,2H),4.62(s,2H),3.86(s,3H).

[0220] In step (g), raw materials 1-6 were replaced with equimolar amounts of raw materials 7-3 to obtain 2-(2-((5-bromo-2-methoxyphenyl)sulfonamide)phenoxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 7), which was a yellow solid with a yield of 47%.

[0221] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.56(s,1H),8.17(t,J=5.9Hz,1H),7.75-7.68(m,2H),7.58(t,J=7.9,7 .4Hz,1H),7.32(dd,J=7.9,1.7Hz,1H),7.14-7.06(m,3H),7.03(d,J=7.0Hz,1H),6.97-6.90(m,2H),6.52(t,J= 5.9Hz,1H),5.05(dd,J=12.8,5.5Hz,1H),4.34(s,2H),3.69(s,3H),3.29-3.24(m,2H),3.19-3.12(m,2H),2.9 3-2.84(m,1H),2.62-2.55(m,2H),2.05-1.99(m,1H),1.61-1.54(m,2H),1.49-1.43(m,2H),1.33-1.29(m,2H); 13 C NMR(126MHz,DMSO-d6)δ173.20,170.50,169.40,167.73,167.47,156.40,150 .35,146.85,137.62,136.72,132.64,131.73,129.73,126.84,126.21,125.20 ,121.88,117.60,115.64,113.44,111.04,110.85,109.52,67.93,56.73,55. 33,49.01,42.25,38.57,31.42,29.33,28.83,24.11,22.60; MS(ESI)m / z[M+H] + Theoretical values: 758.13 and 756.13; Actual values: 758.4 and 756.4; HPLC analysis: MeOH-H2O (90:10), 6.95 min, 98.47% purity.

[0222] Example 8

[0223] 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propyl)acetamide

[0224]

[0225] The synthesis method follows the same route as in Example 1, with the following differences:

[0226] In step (b), the mono-BOC-pentanediamine raw material is replaced with an equimolar amount of N-tert-butoxycarbonyl-1,3-propanediamine raw material to obtain (3-((2-(2,6-dioxadiidine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propyl)tert-butyl carbamate (8-1).

[0227] 1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),7.58(dd,J=8.6,7.1Hz,1H),7.09(d,J=8.6Hz, 1H),7.03(d,J=7.0Hz,1H),6.93(t,J=5.5Hz,1H),6.67(t,J=6.4,5.8Hz,1H),5.06(d d,J=12.7,5.4Hz,1H),3.33-3.29(m,2H),3.03-2.97(m,2H),2.93-2.85(m,1H),2.63 -2.54(m,2H),2.06-2.01(m,1H),1.69-1.63(m,2H),1.38(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 453.16; Actual value: 453.17.

[0228] In step (c), raw material 1-2 is replaced with an equimolar amount of raw material 8-1 to obtain 4-((3-aminopropyl)amino)-2-(2,6-dioxadiazine-3-yl)isoindoline-1,3-dione trifluoroacetate (8-2).

[0229] 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),7.73(s,3H),7.61(dd,J=8.6,7.1Hz,1H),7.15(d,J=8.6Hz,1H),7.06(d,J=7.0Hz,1H),6.76(t,J=6.3Hz,1H ),5.06(dd,J=12.8,5.4Hz,1H),3.44-3.40(m,4H),2.93-2.84(m,3H),2. 62-2.53(m,2H),2.07-2.01(m,1H),1.88-1.80(m,2H).MS(ESI)m / z[M+H] + Theoretical value: 331.14; Actual value: 331.06.

[0230] In step (g), raw materials 1-3 were replaced with an equimolar amount of raw material 8-2 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propyl)acetamide (Example 8), which was a yellow solid with a yield of 46%.

[0231] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.36(s,1H),8.28(t,J=5.9Hz,1H),7.57(dd,J=8.5,7.1Hz,1H),7.30( dd,J=8.9,6.2Hz,1H),7.15-7.09(m,2H),7.09-7.02(m,3H),6.91(dd,J=10.8,2.7Hz,1H),6.76(td,J=8.6,2 .7Hz,1H),6.69(t,J=6.2Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.34(s,2H),3.66(s,3H),3.64(s,3H),3.31- 3.28(m,2H),3.26-3.22(m,2H),2.93-2.85(m,1H),2.62-2.53(m,2H),2.06-2.00(m,1H),1.75-1.68(m,2H); 13 C NMR(126MHz,DMSO-d6)δ173.29,170.59,169.33,167.79,167.47,160.49(d,J=242.5Hz),1 52.41,151.56(d,J=10.5Hz),151.07,146.73,136.74,132.75,128.21,126.49(d,J=10.1H z),122.80,120.18,117.56,115.21,114.46,110.95,109.71,107.94(d,J=22.3Hz),101.7 0(d,J=27.1Hz),68.08,56.70,56.18,49.04,36.36,31.46,29.34,22.64; MS(ESI)m / z[M+H] + Theoretical value: 698.19; Actual value: 698.25; HPLC analysis: MeOH-H2O (90:10), 6.75 min, 98.36% purity.

[0232] Example 9

[0233] 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)acetamide

[0234]

[0235] The synthesis method follows the same route as in Example 1, with the following differences:

[0236] In step (b), the mono-BOC-pentanediamine raw material is replaced with an equimolar amount of N-tert-butoxycarbonyl-1,4-butanediamine raw material to obtain (4-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)carbamate tert-butyl ester (9-1).

[0237] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),7.58(t,J=7.8Hz,1H),7.11(d,J=8.6Hz,1H),7. 03(d,J=7.1Hz,1H),6.84(t,J=5.9Hz,1H),6.56(t,J=6.0Hz,1H),5.05(dd,J=12.8,5.4 Hz,1H),3.33-3.28(m,2H),2.98-2.92(m,2H),2.92-2.84(m,1H),2.62-2.53(m,2H),2. 08-2.01(m,1H),1.58-1.51(m,2H),1.51-1.42(m,2H),1.37(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 467.19; Actual value: 467.15.

[0238] In step (c), raw materials 1-2 are replaced with an equimolar amount of raw material 9-1 to obtain 4-((4-aminobutyl)amino)-2-(2,6-dioxadiazine-3-yl)isoindoline-1,3-dione trifluoroacetate (9-2).

[0239] 1H NMR (500MHz, DMSO-d6) δ11.11(s,1H),7.70(s,3H),7.60(dd,J=8.6,7.0Hz,1H),7.13(d,J=8.6Hz,1H),7.05(d,J=7.1Hz,1H),6 .62(t,J=6.0Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),2.95-2.81(m,3H),2.64-2.51(m,4H),2.08-2.00(m,1H).MS(ESI)m / z[M+H] + Theoretical value: 345.16; Actual value: 345.09.

[0240] In step (g), raw materials 1-3 were replaced with an equimolar amount of raw material 9-2 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)acetamide (Example 9), which was a yellow solid with a yield of 39%.

[0241] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.36(s,1H),8.21(t,J=5.9Hz,1H),7.58(t,J=7.8Hz,1H),7.30(dd,J =8.9,6.2Hz,1H),7.14-7.04(m,4H),7.03(d,J=7.0Hz,1H),6.89(dd,J=10.6,2.7Hz,1H),6.75(td,J=8.5,2. 7Hz,1H),6.55(t,J=5.7Hz,1H),5.06(dd,J=12.7,5.4Hz,1H),4.32(s,2H),3.67(s,3H),3.64(s,3H),3.33- 3.29(m,2H),3.21-3.15(m,2H),2.93-2.84(m,1H),2.62-2.53(m,2H),2.06-2.00(m,1H),1.59-1.47(m,4H); 13CNMR(126MHz,DMSO-d6)δ173.29,170.59,169.43,167.79,167.17,160.48(d,J=242.4Hz),152.40 ,151.59(d,J=10.8Hz),151.08,146.87,136.77,132.68,128.19,126.48(d,J=10.1Hz),122.82(d ,J=3.4Hz),120.20,117.66,115.21,114.43,110.92,109.54,107.93(d,J=22.4Hz),101.74(d,J= 27.2Hz),68.10,56.69,56.19,49.04,41.98,38.42,31.46,27.09,26.66,22.63; MS(ESI)m / z[M+H] + Theoretical value: 712.21; Actual value: 712.26; HPLC analysis: MeOH-H2O (90:10), 6.79 min, 98.35% purity.

[0242] Example 10

[0243] N-(2-(2-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-2-carbonylethoxy)-4-fluorophenyl)-2,5-dimethoxyphenylsulfonamide

[0244]

[0245] The synthesis method follows the same route as in Example 1, with the following differences:

[0246] In step (b), the mono-BOC-pentanediamine feedstock was replaced with an equimolar amount of 2-BOC-octahydropyrrolo[3,4-C]pyrrole feedstock to obtain 5-(2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (10-1).

[0247] 1H NMR(500MHz,DMSO-d6)δ11.07(s,1H),7.59(dd,J=8.6,6.9Hz,1H),7.18(d,J =6.9Hz,1H),7.13(d,J=8.6Hz,1H),5.07(dd,J=12.8,5.5Hz,1H),3.81-3.70( m,2H),3.57-3.48(m,4H),3.21-3.13(m,2H),3.04-2.94(m,2H),2.93-2.83( m,1H),2.62-2.52(m,2H),2.05-1.98(m,1H),1.40(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 491.19; Actual value: 491.18.

[0248] In step (c), raw materials 1-2 are replaced with an equimolar amount of raw material 10-1 to obtain 2-(2-(2,6-dioxadiazin-3-yl)-4-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)isoindoline-1,3-dione trifluoroacetate (10-2).

[0249] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.88(s,2H),7.69(dd,J=8.5,7.1Hz,1H),7.32(d,J=7.0Hz,1H),7.21(d,J=8.5Hz,1H),5.11(dd,J=12.8, 5.5Hz,1H),3.75-3.66(m,2H),3.57-3.46(m,4H),3.13-3.05(m,4H),2. 98-2.84(m,3H),2.64-2.53(m,2H),2.07-1.99(m,1H).MS(ESI)m / z[M+H] + Theoretical value: 369.16; Actual value: 369.09.

[0250] In step (g), equimolar amounts of raw materials 1-3 were replaced with 10-2 raw materials to obtain N-(2-(2-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-2-carbonylethoxy)-4-fluorophenyl)-2,5-dimethoxyphenylsulfonamide (Example 10), which was a yellow solid with a yield of 53%.

[0251] 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),9.15(s,1H),7.60(dd,J=8.6,7.0Hz,1H),7.26(dd,J=9.0,6.1Hz,1H), 7.18(dd,J=7.1,1.9Hz,1H),7.17-7.09(m,4H),6.93(dd,J=10.4,2.8Hz,1H),6.77(td,J=8.6,2.8Hz,1H),5.0 7(dd,J=12.7,5.4Hz,1H),4.76(s,2H),3.83-3.78(m,2H),3.77(s,3H),3.69(s,3H),3.68-3.61(m,2H),3.58 -3.50(m,4H),3.11-3.06(m,1H),3.02-2.95(m,1H),2.92-2.84(m,1H),2.62-2.55(m,2H),2.04-1.98(m,1H); 13 C NMR(126MHz,DMSO-d6)δ173.29,170.50,167.52,167.09,166.74,160.02(d,J=241.9Hz),152.37,152 .32(d,J=11.8Hz),151.06,146.33,135.48,134.39,128.11,124.82(d,J=10.3Hz),124.54,122.29,1 20.30,114.79,114.37,112.52(d,J=5.5Hz),111.34(d,J=6.1Hz),108.87(d,J=23.2Hz),104.70(dd, J=26.3,5.5Hz),69.50,56.73,56.22,55.35,55.28,55.15,50.16,49.26,48.78,42.40,31.43,22.60;

[0252] Example 11

[0253] N-(2-(2-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-carbonylethoxy)-4-fluorophenyl)-2,5-dimethoxyphenylsulfonamide

[0254]

[0255] The synthesis method follows the same route as in Example 1, with the following differences:

[0256] In step (b), the mono-BOC-pentanediamine feedstock was replaced with an equimolar amount of 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane feedstock to obtain 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (11-1).

[0257] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),7.69(t,J=7.8Hz,1H),7.33(t,J=7.0Hz,2H),5.09(dd,J=12.7,5.4Hz,1H),3.70-3.54(m,4 H),3.28-3.15(m,4H),2.94-2.82(m,1H),2.64-2.53(m,2H),2.09-1.99(m,1H),1.93-1.79(m,4H),1.39(s,9H).MS(ESI)m / z[M+H] + Theoretical value: 483.22; Actual value: 483.21.

[0258] In step (c), raw material 1-2 is replaced with an equimolar amount of raw material 11-1 to obtain 2-(2,6-dioxadiazin-3-yl)-4-(2,7-diazaspiro[3.5]nonane-7-yl)isoindoline-1,3-dione (11-2).

[0259] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.72(s,2H),7.70(t,J=7.8Hz,1H),7.35(dd,J=10.1,7.8Hz,2H),5.10(dd,J=12.8,5.4Hz,1H) ,3.88-3.83(m,4H),3.29-3.16(m,4H),2.95-2.80(m,1H),2.63-2.53(m,2H),2.08-2.00(m,1H),2.00-1.87(m,4H).MS(ESI)m / z[M+H] + Theoretical value: 383.17; Actual value: 383.13.

[0260] In step (g), equimolar amounts of raw materials 11-2 were replaced with raw materials 1-3 to obtain N-(2-(2-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-carbonylethoxy)-4-fluorophenyl)-2,5-dimethoxyphenylsulfonamide (Example 11), which was a yellow solid with a yield of 46%.

[0261] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.04(s,1H),7.69(t,J=7.6Hz,1H),7.35(d,J=7.8Hz,2H),7 .20(dd,J=8.9,6.2Hz,1H),7.19-7.12(m,3H),6.92(dd,J=10.4,2.8Hz,1H),6.77(td,J=8.6,2.8Hz ,1H),5.10(dd,J=12.7,5.5Hz,1H),4.61(s,2H),3.93(s,2H),3.79(s,3H),3.70(s,2H),3.70(s,3 H),3.29-3.17(m,4H),2.93-2.83(m,1H),2.63-2.55(m,2H),2.06-2.01(m,1H),1.93-1.84(m,4H); 13 C NMR (126MHz, DMSO-d6) δ173.28, 170.50, 167.82, 167.56, 166.81, 160.26 (d, J = 242.4Hz), 152.54 (d ,J=10.8Hz),152.43,151.00,150.36,136.26,134.15,128.37,125.55(d,J=10.0Hz),124.50,123.9 1(d,J=2.8Hz),120.27,117.07,115.15,114.79,114.49,108.59(d,J=22.6Hz),103.70(d,J=26.3H z),67.99,59.65,58.22,56.78,56.22,49.28,48.40,35.23,34.35,31.44,22.55; MS(ESI)m / z[M+H] + Theoretical value: 750.22; Actual value: 750.28; HPLC analysis: MeOH-H2O (90:10), 6.77 min, 98.06% purity.

[0262] Example 12

[0263] N-(2-(2-(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-2,8-diazaspiro[4.5]decane-2-yl)-2-carbonylethoxy)-4-fluorophenyl)-2,5-dimethoxyphenylsulfonamide

[0264]

[0265] The synthesis method follows the same route as in Example 1, with the following differences:

[0266] In step (b), the mono-BOC-pentanediamine feedstock was replaced with an equimolar amount of 2-BOC-2,8-diazaspiro[4.5]decane feedstock to obtain 8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (12-1).

[0267] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),7.69(dd,J=8.4,7.1Hz,1H),7.42-7.29(m,2H),5.09(dd,J=12.7,5.4Hz,1H),3.33-3.28(m,4H),3.27-3.18( m,2H),3.16(s,2H),2.93-2.82(m,1H),2.63-2.53(m,2H),2.06-1.98(m, 1H),1.80-1.72(m,2H),1.71-1.61(m,4H),1.41(s,9H).MS(ESI)m / z[M+H] + Theoretical value: 497.24; Actual value: 497.21.

[0268] In step (c), raw material 1-2 is replaced with an equimolar amount of raw material 12-1 to obtain 2-(2,6-dioxadiazin-3-yl)-4-(2,8-diazaspiro[4.5]decane-8-yl)isoindoline-1,3-dione trifluoroacetate (12-2).

[0269] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.95-8.76(m,2H),7.71(t,J=7.8Hz,1H),7.36(d,J=7.8Hz,2H),5.09(dd,J=12.8,5.5Hz,1H),3.36-3.2 4(m,6H),3.13-3.03(m,2H),2.94-2.84(m,1H),2.65-2.55(m,2H),2.0 8-2.01(m,1H),1.92-1.85(m,2H),1.83-1.66(m,4H).MS(ESI)m / z[M+H] + Theoretical value: 397.19; Actual value: 397.14.

[0270] In step (g), equimolar amounts of raw materials 1-3 were replaced with raw materials 12-2 to obtain N-(2-(2-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-carbonylethoxy)-4-fluorophenyl)-2,5-dimethoxyphenylsulfonamide (Example 12), which was a yellow solid with a yield of 43%.

[0271] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.22(d,J=15.9Hz,1H),7.70(ddd,J=8.4,7.1,3.2Hz,1H),7.39-7.33(m,2H),7 .27(dd,J=8.9,6.1Hz,1H),7.18-7.11(m,3H),6.95(dd,J=10.2,2.8Hz,1H),6.78(td,J=8.6,2.8Hz,1H),5.10(dd,J=1 2.7,5.5Hz,1H),4.77(d,J=6.6Hz,2H),3.78(d,J=4.4Hz,3H),3.70(s,3H),3.52-3.44(m,4H),3.33-3.18(m,4H),2.9 3-2.84(m,1H),2.63-2.54(m,2H),2.07-2.01(m,1H),1.86(t,J=7.1Hz,1H),1.77(t,J=7.2Hz,1H),1.73-1.66(m,4H); 13C NMR (126MHz, DMSO-d6) δ173.29,170.51,167.58,166.82,166.69(d,J=5.6Hz),160.00(dd,J=242.2,6.4Hz),152.38,152.33(dd,J=16.6,10 .7Hz),151.07,150.47(d,J=4.5Hz),136.25,134.15(d,J=5.4Hz),128.14(d,J=11.0Hz),124.95-124.34(m,3×C),120.32(d,J=4.2Hz),116 .93,115.05,114.78(d,J=3.5Hz),114.40,108.94(dd,J=22.3,5.4Hz),104.83(dd,J=25.5,10.7Hz),69.56(d,J=23.3Hz),56.71,56.23,54 .90(d,J=138.2Hz),49.28,48.82,48.75,43.86(d,J=164.5Hz),41.15,38.64,35.13(d,J=260.2Hz),34.43,31.43,22.56; MS(ESI)m / z[M+H] + Theoretical value: 764.24; Actual value: 764.31; HPLC analysis: MeOH-H2O (90:10), 6.85 min, 97.59% purity.

[0272] Example 13

[0273] 2-(2-((2,5-dimethoxyphenyl)sulfonamide-5-fluorophenoxy)-N-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)methyl)acetamide

[0274]

[0275] The synthesis method follows the same route as in Example 1, with the following differences:

[0276] In step (b), the mono-BOC-pentanediamine raw material is replaced with an equimolar amount of 4-Boc-aminomethylpiperidine raw material to obtain ((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)methyl)tert-butyl carbamate (13-1)

[0277] 1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),7.68(dd,J=8.4,7.1Hz,1H),7.33(dd,J =7.8,4.7Hz,2H),6.92(t,J=6.1Hz,1H),5.09(dd,J=12.7,5.4Hz,1H),3.76-3. 62(m,2H),2.93-2.80(m,5H),2.62-2.52(m,2H),2.07-1.96(m,1H),1.79-1.6 4(m,2H),1.61-1.51(m,1H),1.39(s,9H),1.36-1.28(m,2H).MS(ESI)m / z[M+H] + Theoretical value: 471.22; Actual value: 471.22.

[0278] In step (c), raw material 1-2 is replaced with an equimolar amount of raw material 13-1 to obtain 4-(4-(aminomethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (13-2).

[0279] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),7.80(s,3H),7.70(t,J=7.7Hz,1H),7.35(d,J=7.7Hz,2H),5.09(dd,J=12.7,5.5Hz,1H),3. 75-3.70(m,2H),2.92-2.79(m,5H),2.63-2.54(m,2H),2.07-2.00(m,1H),1.88-1.75(m,3H),1.48-1.38(m,2H).MS(ESI)m / z[M+H] + Theoretical value: 371.17; Actual value: 371.13.

[0280] In step (g), raw materials 1-3 were replaced with an equimolar amount of raw material 13-2 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamide-5-fluorophenoxy)-N-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)methyl)acetamide (Example 13), which was a yellow solid with a yield of 41%.

[0281] 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.37(s,1H),8.22(t,J=6.2Hz,1H),7.68(t,J=7.7Hz,1H),7.33(d, J=7.8Hz,2H),7.29(dd,J=8.9,6.3Hz,1H),7.15-7.08(m,3H),6.91(dd,J=10.7,2.8Hz,1H),6.77(td,J=8 .5,2.7Hz,1H),5.09(dd,J=12.7,5.4Hz,1H),4.37(s,2H),3.70-3.66(m,8H),3.14-3.09(m,2H),2.91-2. 79(m,3H),2.63-2.55(m,2H),2.06-2.00(m,1H),1.73-1.67(m,2H),1.65-1.58(m,1H),1.38-1.31(m,2H); 13 C NMR (126MHz, DMSO-d6) δ173.29, 170.52, 167.59, 167.44, 166.78, 160.53 (d, J = 242.2Hz), 152.41, 151.73 (d,J=10.5Hz),151.09,150.59,136.22,134.16,128.27,126.61(d,J=10.4Hz),124.41,122.89(d,J=2.1 Hz), 120.23, 116.87, 115.13, 114.94, 114.48, 107.97 (d, J = 22.5 Hz), 101.82 (d, J = 26.8 Hz), 68.17, 56.73, 56.19, 51.29, 49.27, 44.20, 35.90, 31.44, 30.12, 22.55; HPLC analysis: MeOH-H2O (90:10), 6.88 min, 97.52% purity.

[0282] Example 14

[0283] N-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)piperidin-1-yl)-2-carbonylethoxy)-4-fluorophenyl)-2,5-dimethoxyphenylsulfonamide

[0284]

[0285] The synthesis method follows the same route as in Example 1, with the following differences:

[0286] In step (b), the mono-BOC-pentanediamine raw material is replaced with an equimolar amount of 1-Boc-4-aminopiperidine raw material to obtain 4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (14-1).

[0287] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),7.60(dd,J=8.6,7.1Hz,1H),7.22(d,J=8.6H z,1H),7.06(d,J=7.1Hz,1H),6.27(d,J=8.4Hz,1H),5.06(dd,J=12.8,5.4Hz,1H), 3.95-3.86(m,2H),3.81-3.73(m,1H),2.98-2.83(m,3H),2.62-2.54(m,2H),2.06- 2.00(m,1H),1.96-1.90(m,2H),1.41(s,9H),1.41-1.36(m,2H).MS(ESI)m / z[M+Na] + Theoretical value: 479.19; Actual value: 479.18.

[0288] In step (c), raw material 1-2 is replaced with an equimolar amount of raw material 14-1 to obtain 2-(2,6-dioxadiazin-3-yl)-4-(piperidin-4-amino)isoindoline-1,3-dione trifluoroacetate (14-2).

[0289] 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),8.47(s,2H),7.63(dd,J=8.6,7.1Hz,1H),7.24(d ,J=8.5Hz,1H),7.11(d,J=7.1Hz,1H),6.30(d,J=8.2Hz,1H),5.07(dd,J=12.8,5.5Hz,1 H),3.95-3.79(m,1H),3.09-3.00(m,2H),2.95-2.85(m,1H),2.67-2.53(m,2H),2.50-2 .45(m,2H),2.17-2.08(m,2H),2.08-2.00(m,1H),1.76-1.60(m,2H).MS(ESI)m / z[M+H] + Theoretical value: 357.16; Actual value: 357.11.

[0290] In step (g), equimolar amounts of raw materials 1-3 were replaced with raw materials 14-2 to obtain N-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)piperidin-1-yl)-2-carbonylethoxy)-4-fluorophenyl)-2,5-dimethoxyphenylsulfonamide (Example 14), which was a yellow solid with a yield of 33%.

[0291] 1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.08(s,1H),7.62(t,J=7.9Hz,1H),7.30-7.24(m,2H),7.18-7.11(m,3H),7.0 8(d,J=7.1Hz,1H),6.94(dd,J=10.3,2.1Hz,1H),6.77(td,J=8.7,2.8Hz,1H),6.28(d,J=8.3Hz,1H),5.06(dd,J=12.9 ,5.4Hz,1H),4.90(s,2H),4.31-4.23(m,1H),3.88-3.83(m,1H),3.79(s,3H),3.70(s,3H),3.70-3.65(m,1H),3.17( 13C NMR(126MHz,DMSO-d6)δ173.29,170.54,169.55,167.69,166.35,159.99(d,J=242.2Hz) ,152.40,152.19(d,J=10.4Hz),151.04,145.77,136.87,132.72,128.05,124.63-124.25 (m),120.36,118.27,114.82,114.42,111.44,109.90,108.73(d,J=21.6Hz),104.40(d,J =25.5Hz),69.09,56.76,56.51,56.23,49.07,48.76,42.99,32.15,31.66,31.44,22.61; 13C NMR (126MHz, DMSO) δ173.29, 170.54, 169.55, 167.69, 166.35, 159.99 (d, J = 242.2Hz), 152.40 ,152.19(d,J=10.4Hz),151.04,145.77,136.87,132.72,128.05,124.63-124.25(m,2×C),120 .36,118.27,114.82,114.42,111.44,109.90,108.73(d,J=21.6Hz),104.40(d,J=25.5Hz),69 .09,56.76,56.23,49.07,48.76,42.99,40.72,32.15,31.66,31.44,22.61; MS(ESI)m / z[M+H] + Theoretical value: 724.21; Actual value: 724.25; HPLC analysis: MeOH-H2O (90:10), 6.78 min, 98.95% purity.

[0292] Example 15

[0293] 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexyl)acetamide

[0294]

[0295] The synthesis method follows the same route as in Example 1, with the following differences:

[0296] In step (b), the mono-BOC-pentanediamine raw material is replaced with an equimolar amount of N-tert-butoxycarbonyl-1,6-hexanediamine raw material to obtain (6-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexyl)tert-butyl carbamate (15-1).

[0297] 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),7.58(dd,J=8.6,7.1Hz,1H),7.09(d,J=8.6Hz,1H) ,7.03(d,J=7.0Hz,1H),6.76(t,J=5.2Hz,1H),6.54(t,J=6.0Hz,1H),5.05(dd,J=12.8,5 .4Hz,1H),3.32-3.26(m,2H),2.94-2.83(m,3H),2.62-2.53(m,2H),2.08-1.98(m,1H),1 .61-1.52(m,2H),1.41-1.38(m,2H),1.37(s,9H),1.36-1.29(m,4H).MS(ESI)m / z[M+Na] + Theoretical value: 495.22; Actual value: 495.21.

[0298] In step (c), raw material 1-2 is replaced with an equimolar amount of raw material 15-1 to obtain 4-((6-aminohexyl)amino)-2-(2,6-dioxadiazine-3-yl)isoindoline-1,3-dione trifluoroacetate (15-2).

[0299] 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),7.66(s,3H),7.59(t,J=7.8Hz,1H),7.10(d ,J=8.6Hz,1H),7.04(d,J=7.0Hz,1H),6.55(t,J=6.0Hz,1H),5.05(dd,J=12.8,5.4 Hz,1H),3.35-3.27(m,4H),2.93-2.84(m,1H),2.78(t,J=7.6Hz,2H),2.63-2.54( m,2H),2.07-2.00(m,1H),1.63-1.48(m,4H),1.37-1.35(m,2H).MS(ESI)m / z[M+H] + Theoretical value: 373.19; Actual value: 373.13.

[0300] In step (g), equimolar amounts of raw materials 1-3 were replaced with raw material 15-2 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexyl)acetamide (Example 15), which was a yellow solid with a yield of 46%.

[0301] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.36(s,1H),8.13(t,J=5.8Hz,1H),7.58(dd,J=8.6,7.1Hz,1H),7.28(dd,J=8.9,6.2 Hz,1H),7.15-7.05(m,4H),7.02(d,J=7.0Hz,1H),6.88(dd,J=10.7,2.8Hz,1H),6.75(td,J=8.5,2.7Hz,1H),6.53(t,J=6.0H z,1H),5.05(dd,J=12.8,5.4Hz,1H),4.32(s,2H),3.67(s,3H),3.65(s,3H),3.31-3.27(m,2H),3.16-3.10(m,2H),2.93-2.8 2(m,1H),2.62-2.52(m,2H),2.07-2.00(m,1H),1.59-1.51(m,2H),1.45-1.39(m,2H),1.37-1.31(m,2H),1.30-1.26(m,2H); 13 C NMR (126MHz, DMSO-d6) δ173.29,170.58,169.47,167.80,167.09,160.53(d,J=242.4Hz),152.41,151 .70(d,J=10.3Hz),151.07,146.92,136.76,132.68,128.24,126.59(d,J=10.1Hz),122.81(d,J=3.1H z),120.16,117.65,115.19,114.43,110.88,109.52,107.91(d,J=22.3Hz),101.71(d,J=27.1Hz),68 .09,56.69,56.17,49.04,42.26,38.66,31.46,29.59,29.12,26.57,26.53,22.64; MS(ESI)m / z[M+H] + Theoretical value: 740.24; Actual value: 740.28; HPLC analysis: MeOH-H2O (90:10), 6.96 min, 98.25% purity.

[0302] Example 16

[0303] 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)benzyl)acetamide

[0304]

[0305] The synthesis method follows the same route as in Example 1, with the following differences:

[0306] In step (b), the mono-BOC-pentanediamine feedstock is replaced with an equimolar amount of 1-(N-Boc-aminomethyl)-4-(aminomethyl)benzene feedstock to obtain (4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)benzyl)tert-butyl carbamate (16-1)

[0307] 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),7.50(t,J=7.8Hz,1H),7.33(dd,J=21.7,7 .0Hz,3H),7.19(d,J=7.7Hz,3H),7.02(d,J=7.1Hz,1H),6.95(d,J=8.6Hz,1H),5. 07(dd,J=12.7,5.4Hz,1H),4.53(d,J=6.3Hz,2H),4.09(d,J=6.2Hz,2H),2.93-2. 85(m,1H),2.63-2.55(m,2H),2.09-2.00(m,1H),1.38(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 515.19; Actual value: 515.19.

[0308] In step (c), raw material 1-2 is replaced with an equimolar amount of raw material 16-1 to obtain 4-((4-(aminomethyl)benzyl)amino)-2-(2,6-dioxadiazine-3-yl)isoindoline-1,3-dione trifluoroacetate (16-2).

[0309] 1 H NMR(500MHz,DMSO-d6)δ11.12(s,1H),8.13(s,3H),7.50(t,J=7.8Hz,1H),7 .47-7.38(m,4H),7.27(t,J=6.3Hz,1H),7.03(d,J=7.1Hz,1H),6.94(d,J=8 .6Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.58(d,J=6.3Hz,2H),4.01(s,2H) ,2.97-2.85(m,1H),2.64-2.54(m,2H),2.10-2.00(m,1H).MS(ESI)m / z[M+H] +Theoretical value: 393.16; Actual value: 393.13.

[0310] In step (g), equimolar amounts of raw materials 1-3 were replaced with raw materials 16-2 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)benzyl)acetamide (Example 16), which was a yellow solid with a yield of 38%.

[0311] 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),9.39(s,1H),8.75(t,J=5.5Hz,1H),7.50(t,J=7.8Hz,1H),7 .36-7.29(m,3H),7.24-7.18(m,3H),7.15-7.10(m,2H),7.07-7.00(m,2H),6.98-6.89(m,2H),6.7 6(td,J=8.5,2.7Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.54(d,J=6.3Hz,2H),4.39(s,2H),4.35(d ,J=6.1Hz,2H),3.66(s,3H),3.59(s,3H),2.93-2.85(m,1H),2.62-2.55(m,2H),2.07-2.00(m,1H); 13 C NMR (126MHz, DMSO-d6) δ173.28, 170.56, 169.26, 167.76, 167.41, 160.40 (d, J = 242.2Hz), 152.40, 151.34 (d,J=10.6Hz),151.08,146.53,138.29,138.06,136.53,132.66,128.18,127.81(2×C),127.48(2×C),126 .21(d,J=10.2Hz),122.83(d,J=2.7Hz),120.19,118.15,115.22,114.47,111.25,110.09,107.93(d,J=2 2.2Hz),101.74(d,J=27.1Hz),68.13,56.69,56.18,49.07,45.70,41.85,31.46,22.63; MS(ESI)m / z[M+H] + Theoretical value: 760.21; Actual value: 760.28; HPLC analysis: MeOH-H2O (90:10), 6.81 min, 99.72% purity.

[0312] Example 17

[0313] 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethyl)acetamide

[0314]

[0315] The synthesis method follows the same route as in Example 1, with the following differences:

[0316] In step (b), the mono-BOC-pentanediamine raw material is replaced with an equimolar amount of [2-(2-aminoethoxy)ethyl]tert-butyl carbamate raw material to obtain (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethyl)tert-butyl carbamate (17-1)

[0317] 1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),7.59(dd,J=8.6,7.1Hz,1H),7.16(d,J=8.6Hz ,1H),7.05(d,J=7.0Hz,1H),6.76(t,J=5.9Hz,1H),6.61(t,J=5.9Hz,1H),5.06(dd, J=12.8,5.5Hz,1H),3.61-3.59(m,2H),3.43-3.42(m,4H),3.14-3.03(m,2H),2.94- 2.81(m,1H),2.62-2.54(m,2H),2.06-1.99(m,1H),1.36(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 483.19; Actual value: 483.16.

[0318] In step (c), raw materials 1-2 are replaced with an equimolar amount of raw material 17-1 to obtain 4-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxadiazine-3-yl)isoindoline-1,3-dione trifluoroacetate (17-2).

[0319] 1H NMR(500MHz,DMSO-d6)δ11.11(s,1H),7.80(s,3H),7.61(dd,J=8.5,7.1Hz,1H ),7.17(d,J=8.6Hz,1H),7.07(d,J=7.0Hz,1H),6.64(t,J=5.9Hz,1H),5.05(d d,J=12.9,5.4Hz,1H),3.67-3.64(m,2H),3.53-3.51(m,4H),3.05-2.96(m,2H ),2.94-2.85(m,1H),2.65-2.55(m,2H),2.08-2.00(m,1H).MS(ESI)m / z[M+H] + Theoretical value: 361.15; Actual value: 361.09.

[0320] In step (g), raw materials 1-3 were replaced with an equimolar amount of raw material 17-2 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethyl)acetamide (Example 17), which was a yellow solid with a yield of 47%.

[0321] 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),9.41(s,1H),8.36(t,J=5.9Hz,1H),7.58(dd,J=8.6,7.1Hz,1H),7 .31(dd,J=8.9,6.2Hz,1H),7.15-7.10(m,3H),7.08-7.03(m,2H),6.90(dd,J=10.7,2.8Hz,1H),6.75(td, J=8.5,2.7Hz,1H),6.60(t,J=5.8Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.32(s,2H),3.67(s,3H),3.65(s ,3H),3.61(t,J=5.5Hz,2H),3.49-3.45(m,6H),2.91-2.84(m,1H),2.61-2.55(m,2H),2.04-1.99(m,1H); 13C NMR (126MHz, DMSO-d6) δ173.24, 170.54, 169.45, 167.75, 167.48, 160.38 (d, J = 242.3Hz), 152.38, 151.41(d,J=10.5Hz),151.07,146.85,136.73,132.56,128.08,126.12(d,J=10.2Hz),122.85(d, J=3.1Hz),120.20,117.88,115.27,114.40,111.20,109.76,107.94(d,J=22.4Hz),101.80(d,J=2 7.3Hz),69.30,69.19,68.15,56.67,56.18,49.06,42.09,38.74,31.45,22.61; MS(ESI)m / z[M+H] + Theoretical value: 728.20; Actual value: 728.25; HPLC analysis: MeOH-H2O (90:10), 6.91 min, 99.20% purity.

[0322] Example 18

[0323] 2-((3-bromo-N-(4-fluoro-2-hydroxyphenyl)phenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0324]

[0325] The synthetic route of Example 18 is shown below:

[0326]

[0327] (a) 3-Bromo-N-(4-fluoro-2-hydroxyphenyl)benzenesulfonamide (18-1)

[0328] 2-Amino-5-fluorophenol (1.50 g, 11.80 mmol) and 3-bromo-benzenesulfonyl chloride (1.79 mL, 12.39 mmol) were dissolved in 20.00 mL of dichloromethane. Pyridine (2.85 mL, 35.40 mmol) was added, and the mixture was reacted at room temperature for 4 h. After the reaction was completed, the mixture was extracted with water. The organic layer was extracted with dilute hydrochloric acid aqueous solution and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, dissolved in a small amount of dichloromethane, and then a suitable amount of petroleum ether was added to precipitate a solid. The solid was filtered under reduced pressure to obtain the target product 18-1 (1.65 g, yield 41%).

[0329] 1H NMR(500MHz,DMSO-d6)δ9.83(s,1H),7.87-7.80(m,2H),7.64(d,J=7.9Hz,1H),7.48(t,J=7.9Hz,1H),7 .10(dd,J=8.8,6.4Hz,1H),6.58(td,J=8.6,2.8Hz,1H),6.52(dd,J=10.3,2.8Hz,1H).MS(ESI)m / z[MH] - Theoretical values: 343.94 and 345.94; Actual values: 344.1 and 346.1.

[0330] (b) N-((3-bromophenyl)sulfonyl)-N-(4-fluoro-2-hydroxyphenyl)glycine tert-butyl ester (18-2)

[0331] Compound 18-1 (1.50 g, 4.35 mmol) was dissolved in 6.00 mL of ultradry DMF, and KHCO3 (0.65 g, 6.523 mmol) was added and stirred thoroughly in an ice bath. Tert-butyl bromobutyrate (0.66 mL, 4.566 mmol) was dissolved in 4 mL of ultradry DMF and added dropwise to the reaction system. The mixture was stirred at 40 °C for 4 h. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the organic layer was extracted with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1, v / v) to obtain the target product 18-2 as a white solid (1.60 g, 80% yield).

[0332] 1 H NMR (500MHz, DMSO-d6) δ10.29(s,1H),7.88(d,J=8.6Hz,1H),7.82(s,1H),7.66(d,J=8.1Hz,1H),7.52(t,J=8.0Hz,1H),7.2 7(dd,J=8.8,6.6Hz,1H),6.66(t,J=8.7Hz,1H),6.58(dd,J=10.4,2.8Hz,1H),4.29(s,2H),1.35(s,9H).MS(ESI)m / z[M+Na] + Theoretical values: 482.00 and 484.00; Actual values: 482.1 and 484.1.

[0333] (c)N-((3-bromophenyl)sulfonyl)-N-(4-fluoro-2-hydroxyphenyl)glycine (18-3)

[0334] Compound 18-2 (0.30 g, 0.65 mmol) was dissolved in 2.00 mL of dichloromethane, and 1.00 mL of trifluoroacetic acid was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 30:1, v / v) to obtain a white solid as the target product 18-3 (0.14 g, 54%).

[0335] 1 H NMR (500MHz, DMSO-d6) δ12.92(s,1H),10.32(s,1H),7.88(d,J=8.0Hz,1H),7.81(s,1H),7.65(d,J=7.9Hz,1H),7.51(t,J=7.9 Hz,1H),7.26(dd,J=8.8,6.5Hz,1H),6.64(td,J=8.6,2.9Hz,1H),6.57(dd,J=10.4,2.9Hz,1H),4.32(s,2H).MS(ESI)m / z[MH] - Theoretical values: 401.94 and 403.94; Actual values: 402.1 and 404.1.

[0336] (d)N-((3-bromophenyl)sulfonyl)-N-(4-fluoro-2-hydroxyphenyl)glycyl chloride (18-4)

[0337] Compound 18-3 (0.08 g, 0.19 mmol) was dissolved in 1.00 mL of thionyl chloride and reacted overnight at 40 °C under nitrogen protection. After the reaction was complete, the solvent was evaporated under reduced pressure, and the product was used directly in the next reaction.

[0338] (e) 2-((3-bromo-N-(4-fluoro-2-hydroxyphenyl)phenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 18)

[0339] Compounds 1-3 (0.06 g, 0.17 mmol) were dissolved in 6.00 mL of dichloromethane, and triethylamine (0.03 mL, 0.21 mmol) was added. The mixture was stirred thoroughly at room temperature and then placed in an ice bath. Compound 18-4 (0.07 g, 0.17 mmol) was dissolved in 6.00 mL of dichloromethane and added to the reaction system. The mixture was stirred in an ice bath for 1 h. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic layer was extracted with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM:MeOH = 150:1, v / v) to give compound 18 as a yellow solid (0.04 g, yield 31%).

[0340] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),10.89(s,1H),8.28(t,J=6.0Hz,1H),7.91(d,J=8.1Hz,1H),7.80(s,1H),7 .63(d,J=7.9Hz,1H),7.59-7.52(m,2H),7.07(t,J=7.2Hz,2H),7.02(d,J=7.0Hz,1H),6.66-6.58(m,2H),6.53(t ,J=5.5Hz,1H),5.05(dd,J=12.5,5.2Hz,1H),4.24(s,2H),3.27(q,J=6.9Hz,2H),3.10(q,J=6.6Hz,2H),2.92-2. 85(m,1H),2.62-2.54(m,2H),2.04-1.99(m,8.0Hz,1H),1.60-1.54(m,2H),1.47-1.41(m,2H),1.33-1.39(m,2H); 13 C NMR(101MHz,DMSO-d6)δ173.36,170.65,169.46,169.40,167.84,163.09(d,J=245.5Hz),15 7.27(d,J=12.8Hz),146.90,141.65,136.80,136.48,133.55(d,J=11.0Hz),132.72,131.83, 130.10,126.90,122.90,122.45,117.68,110.91,109.54,106.43(d,J=22.9Hz),104.29(d,J =24.7Hz),53.83,49.05,42.30,39.21,31.50,29.01,28.80,24.02,22.67; MS(ESI)m / z[M+H] + Theoretical values: 744.11 and 746.11; Actual values: 744.3, 746.3; HPLC analysis: MeOH-H2O (90:10), 6.78 min, 96.82% purity.

[0341] Example 19

[0342] 2-((4-chloro-N-(4-fluoro-2-hydroxyphenyl)phenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0343]

[0344] The synthesis method is the same as the synthesis route in Example 18, except that:

[0345] In step (a), the 3-bromo-benzenesulfonyl chloride raw material was replaced with an equimolar amount of 4-chlorobenzenesulfonyl chloride raw material to obtain 4-chloro-N-(4-fluoro-2-hydroxyphenyl)benzenesulfonamide (19-1).

[0346] 1 H NMR (500MHz, DMSO-d6) δ9.75-9.62(m,2H),7.67(d,J=8.3Hz,2H),7.60(d,J=8. 2Hz, 2H), 7.10 (t, J = 7.6Hz, 1H), 6.57 (t, J = 8.8Hz, 1H), 6.51 (d, J = 10.3Hz, 1H).

[0347] In step (b), 18-1 is replaced with an equimolar amount of 19-1 to obtain N-((4-chlorophenyl)sulfonyl)-N-(4-fluoro-2-hydroxyphenyl)glycine tert-butyl ester (19-2).

[0348] 1 H NMR (500MHz, DMSO-d6) δ10.22(s,1H),7.67(d,J=8.3Hz,2H),7.62(d,J=8.3Hz,2H),7.28(dd, J=8.8,6.6Hz,1H),6.69-6.62(m,1H),6.56(dd,J=10.8,2.2Hz,1H),4.25(s,2H),1.35(s,9H).

[0349] In step (c), 18-2 is replaced with an equimolar amount of 19-2 to obtain N-((4-chlorophenyl)sulfonyl)-N-(4-fluoro-2-hydroxyphenyl)glycine (19-3).

[0350] 1 H NMR (500MHz, DMSO-d6) δ10.22(s,1H),7.67(d,J=8.3Hz,2H),7.62(d,J=8.3Hz,2H),7.28(dd, J=8.8,6.6Hz,1H),6.69-6.62(m,1H),6.56(dd,J=10.8,2.2Hz,1H),4.25(s,2H),1.35(s,9H).

[0351] In step (d), raw material 18-3 is replaced with an equimolar amount of raw material 19-3 to obtain N-((4-chlorophenyl)sulfonyl)-N-(4-fluoro-2-hydroxyphenyl)glycyl chloride (19-4).

[0352] In step (e), equimolar amounts of raw material 19-4 were replaced with raw material 18-4 to obtain 2-((4-chloro-N-(4-fluoro-2-hydroxyphenyl)phenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 19), which was a yellow solid with a yield of 36%.

[0353] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),10.86(s,1H),8.27(t,J=5.9Hz,1H),7.66(s,4H),7.57(t,J =7.8Hz,1H),7.07(t,J=8.1Hz,2H),7.02(d,J=6.9Hz,1H),6.63-6.58(m,2H),6.52(t,J=6.3Hz,1H) ,5.05(dd,J=12.9,5.4Hz,1H),4.21(s,2H),3.28-3.24(m,2H),3.12-3.08(m,2H),2.92-2.84(m,1 H),2.61-2.52(m,2H),2.06-2.00(m,1H),1.59-1.54(m,2H),1.46-1.42(m,2H),1.32-1.28(m,2H); 13 C NMR(101MHz,DMSO-d6)δ173.37,170.65,169.46,167.85,163.06(d,J=245.1Hz),157.27( d,J=12.8Hz),146.91,138.60,138.55,136.81,133.50(d,J=11.2Hz),132.71,129.79,129 .75,122.98(d,J=3.0Hz),117.68,110.93,109.54,106.47(d,J=22.8Hz),104.29(d,J=24. 8Hz),53.83,49.05,42.31,39.21,31.50,29.01,28.81,24.02,22.67; HRMS(ESI)m / z[M+H] + Theoretical value: 700.1639; Actual value: 700.1634; HPLC analysis: MeOH-H2O (90:10), 6.86 min, 94.91% purity.

[0354] Example 20

[0355] 2-((2,6-dichloro-N-(4-fluoro-2-hydroxyphenyl)phenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0356]

[0357] The synthesis method follows the same synthetic route as in Example 18. The difference is:

[0358] In step (a), the 3-bromo-benzenesulfonyl chloride raw material is replaced with an equimolar amount of 2,6-dichlorobenzenesulfonyl chloride raw material to obtain 2,6-dichloro-N-(4-fluoro-2-hydroxyphenyl)benzenesulfonamide (20-1).

[0359] 1 H NMR(500MHz,DMSO-d6)δ10.17(s,1H),9.56(s,1H),7.58(d,J=7.9Hz,2H),7.5 2(t,J=8.0Hz,1H),7.07(t,J=7.6Hz,1H),6.59-6.50(m,2H).MS(ESI)m / z[MH] - Theoretical value: 333.95; Actual value: 334.1.

[0360] In step (b), 18-1 raw material is replaced with an equimolar amount of 20-1 raw material to obtain N-((4-chlorophenyl)sulfonyl)-N-(4-fluoro-2-hydroxyphenyl)glycine tert-butyl ester (20-2).

[0361] 1 H NMR(500MHz,DMSO-d6)δ10.30(s,1H),7.62-7.49(m,4H),7.43(dd,J=8.8,6.6Hz,1H),6.66(td ,J=8.7,2.8Hz,1H),6.51(dd,J=10.4,2.6Hz,1H),4.49(s,2H),1.38(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 472.02; Actual value: 472.1.

[0362] In step (c), 18-2 is replaced with an equimolar amount of 20-2 to obtain N-((4-chlorophenyl)sulfonyl)-N-(4-fluoro-2-hydroxyphenyl)glycine (20-3).

[0363] 1H NMR (500MHz, DMSO-d6) δ12.91(s,1H),10.73(s,1H),7.57(d,J=7.8Hz,2H),7.53-7.50(dd,J=9.0,6.9Hz,1H) ,7.38-7.27(m,1H),6.61(td,J=8.5,2.8Hz,1H),6.51(dd,J=10.4,2.8Hz,1H),4.49(s,2H).MS(ESI)m / z[M+H] + Theoretical value: 391.96; Actual value: 392.1.

[0364] In step (d), 18-3 raw material is replaced with an equimolar amount of 20-3 raw material to obtain N-((4-chlorophenyl)sulfonyl)-N-(4-fluoro-2-hydroxyphenyl)glycyl chloride (20-4).

[0365] In step (e), equimolar amounts of 20-4 raw material are replaced with 18-4 raw material to obtain 2-((2,6-dichloro-N-(4-fluoro-2-hydroxyphenyl)phenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 20), which is a yellow solid with a yield of 30%.

[0366] 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),10.92(s,1H),8.27(t,J=5.7Hz,1H),7.61-7.54(m, 4H),7.08(t,J=9.4Hz,2H),7.02(d,J=7.0Hz,1H),6.61-6.52(m,3H),5.05(dd,J=12.7,5.4 Hz,1H),4.50(s,2H),3.26(q,J=6.9Hz,2H),3.10(q,J=6.7Hz,2H),2.93-2.84(m,1H),2.62 -2.53(m,2H),2.05-2.02(m,1H),1.60-1.54(m,2H),1.47-1.41(m,2H),1.32-1.28(m,2H); 13C NMR(101MHz,DMSO-d6)δ173.37,170.65,169.50,169.46,167.85,163.31(d,J=245.5Hz),15 7.77(d,J=12.8Hz),146.91,136.81,135.61,135.30,134.44(d,J=10.3Hz),134.39,132.72, 132.26,121.35(d,J=2.4Hz),117.70,110.92,109.54,106.41(d,J=22.5Hz),104.09(d,J=2 4.5Hz),54.69,49.05,42.30,39.24,31.50,29.01,28.80,24.05,22.67; HRMS(ESI)m / z[M+H] + Theoretical value: 734.1249; Actual value: 734.1242; HPLC analysis: MeOH-H2O (90:10), 6.77 min, 97.00% purity.

[0367] Example 21

[0368] 2-((5-bromo-N-(2-hydroxy-4-tolyl)-2-methoxyphenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0369]

[0370] The synthesis method is the same as the synthesis route in Example 18, except that:

[0371] In step (b), 18-1 is replaced with an equimolar amount of 6-1 to obtain N-((5-bromo-2-methoxyphenyl)sulfonyl)-N-(2-hydroxy-4-methylphenyl)glycine tert-butyl ester (21-1).

[0372] 1 H NMR(500MHz,DMSO-d6)δ9.49(s,1H),7.76(dd,J=7.1,2.5Hz,1H),7.54(d,J=2.6Hz,1H),7.24(d,J=8.9 Hz,1H),7.13(d,J=7.9Hz,1H),6.58-6.54(m,2H),4.39(s,2H),3.91(s,3H),2.17(s,3H),1.37(s,10H).

[0373] In step (c), 18-2 is replaced with an equimolar amount of 21-2 to obtain N-((5-bromo-2-methoxyphenyl)sulfonyl)-N-(2-hydroxy-4-methylphenyl)glycine (21-3).

[0374] 1 H NMR (500MHz, DMSO-d6) δ9.48(s,1H),7.76(dd,J=8.9,2.6Hz,1H),7.54(d,J=2.6Hz,1H),7.23(d,J=8.9 Hz,1H),7.13(d,J=7.9Hz,1H),6.58-6.54(m,2H),4.39(s,2H),3.91(s,3H),2.17(s,3H),1.37(s,9H).

[0375] In step (d), raw material 18-3 is replaced with an equimolar amount of raw material 21-3 to obtain N-((5-bromo-2-methoxyphenyl)sulfonyl)-N-(2-hydroxy-4-methylphenyl)glycyl chloride (21-4).

[0376] In step (e), equimolar amounts of raw material 21-4 are replaced with raw material 18-4 to obtain 2-((5-bromo-N-(2-hydroxy-4-tolyl)-2-methoxyphenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 21), which is a yellow solid with a yield of 39%.

[0377] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),10.54(s,1H),8.33(t,J=5.7Hz,1H),7.82(dd,J=8.9,2.6Hz,1H),7.58(dd,J=8.6,7.1Hz,1H), 7.54(d,J=2.5Hz,1H),7.29(d,J=9.0Hz,1H),7.09(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),6.64(s,1H),6.59(d,J=8.0Hz,1H),6.54(t ,J=6.0Hz,1H),6.43(dd,J=8.1,2.0Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),4.37(s,2H),4.01(s,3H),3.30-3.24(m,2H),3.16-3.10(m ,2H),2.92-2.84(m,1H),2.62-2.53(m,2H),2.16(s,3H),2.06-1.99(m,1H),1.61-1.54(m,2H),1.50-1.43(m,2H),1.36-1.28(m,2H); 13 C NMR(126MHz,DMSO-d6)δ173.29,170.73,170.57,169.43,167.80,156.52,155.89,14 6.91,140.59,137.89,136.79,132.73,132.68,130.58,129.88,123.77,120.40,118. 05, 117.68, 116.01, 111.27, 110.88, 109.53, 57.10, 55.30, 49.03, 42.28, 39.24, 31.46, 28.99, 28.79, 24.05, 22.63, 21.25; HPLC analysis: MeOH-H2O (90:10), 7.11 min, 99.76% purity.

[0378] Example 22

[0379] 2-((5-bromo-N-(2-hydroxyphenyl)-2-methoxyphenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0380]

[0381] The synthesis method is the same as the synthesis route in Example 18, except that:

[0382] In step (b), 18-1 is replaced with an equimolar amount of 7-1 to obtain N-((5-bromo-2-methoxyphenyl)sulfonyl)-N-(2-hydroxyphenyl)glycine tert-butyl ester (22-1).

[0383] 1 H NMR(500MHz,DMSO-d6)δ9.49(s,1H),7.76(dd,J=7.1,2.5Hz,1H),7.54(d,J=2.6Hz,1H),7.24(d,J=8.9Hz,1H),7 .13(d,J=7.9Hz,1H),6.58-6.54(m,2H),4.39(s,2H),3.91(s,3H),2.17(s,3H),1.37(s,10H).MS(ESI)m / z[M+Na] + Theoretical value: 496.02; Actual value: 496.1.

[0384] In step (c), 18-2 is replaced with an equimolar amount of 22-2 to obtain N-((5-bromo-2-methoxyphenyl)sulfonyl)-N-(2-hydroxyphenyl)glycine (22-3).

[0385] 1 H NMR (500MHz, DMSO-d6) δ9.48(s,1H),7.76(dd,J=8.9,2.6Hz,1H),7.54(d,J=2.6Hz,1H),7.23(d,J=8.9 Hz,1H),7.13(d,J=7.9Hz,1H),6.58-6.54(m,2H),4.39(s,2H),3.91(s,3H),2.17(s,3H),1.37(s,9H).

[0386] In step (d), raw material 18-3 is replaced with an equimolar amount of raw material 22-2 to obtain N-((5-bromo-2-methoxyphenyl)sulfonyl)-N-(2-hydroxyphenyl)glycyl chloride (22-3).

[0387] In step (e), equimolar amounts of raw material 22-3 were replaced with raw material 18-4 to obtain 2-((5-bromo-N-(2-hydroxyphenyl)-2-methoxyphenyl)sulfonamide)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 22), which was a yellow solid with a yield of 36.00%.

[0388] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),10.67(s,1H),8.34(t,J=5.6Hz,1H),7.82(dd,J=8.9,2.6Hz,1H),7.58(dd,J=8.6,7.1Hz,1H),7.55(d,J= 2.6Hz,1H),7.30(d,J=8.9Hz,1H),7.14(ddd,J=8.7,7.3,1.7Hz,1H),7.09(d,J=8.6Hz,1H),7.02(d,J=7.0Hz,1H),6.83(dd,J=8.2,1.4Hz,1H),6 .76(dd,J=7.9,1.7Hz,1H),6.64(td,J=7.6,1.5Hz,1H),6.54(t,J=5.9Hz,1H),5.05(dd,J=12.8,5.5Hz,1H),4.39(s,2H),4.00(s,3H),3.29-3. 25(m,2H),3.16-3.10(m,2H),2.92-2.84(m,1H),2.62-2.54(m,2H),2.0 6-2.00(m,1H),1.61-1.56(m,2H),1.48-1.43(m,2H),1.34-1.30(m,2H); 13 C NMR(126MHz,DMSO-d6)δ173.30,170.62,170.57,169.43,167.81,156.55,156.21,14 6.90,137.92,136.77,132.72,132.67,131.13,130.73,129.79,126.37,119.56,117. 67, 117.63, 116.01, 111.24, 110.88, 109.52, 57.08, 55.12, 49.03, 42.28, 39.25, 31.46, 28.98, 28.79, 26.82, 24.05, 22.64; HPLC analysis: MeOH-H2O (90:10), 7.00 min, 99.06% purity.

[0389] Example 23

[0390] 2-((5-acetamido-3-methylbenzo[d]isoxazol-6-yl)oxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide

[0391]

[0392] The synthetic route for compound 23 is shown below:

[0393]

[0394] (a) N-(2,4-dimethoxyphenyl)acetamide (23-1)

[0395] 2,4-Dimethoxyaniline (30.00 g, 195.85 mmol) and triethylamine (53.57 mL, 254.60 mmol) were dissolved in 100.00 mL of dichloromethane. Acetic anhydride (27.77 mL, 292.77 mmol) was added dropwise under an ice-water bath, and the reaction was stirred at room temperature under nitrogen protection. After the reaction was complete, the mixture was extracted with dichloromethane and water. The organic layer was extracted with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine, respectively, and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and then subjected to silica gel column chromatography (PE:EA = 5:1, v / v) to give the target product 23-1 as a white solid (27.02 g, yield 71%).

[0396] 1 H NMR(500MHz,DMSO-d6)δ9.11(s,1H),7.69(s,1H),6.94(d,J=6.5Hz,1H),6.6 1(d,J=8.1Hz,1H),3.78(s,3H),3.68(s,3H),2.09(s,3H).MS(ESI)m / z[M+H] + Theoretical value: 196.10; Actual value: 196.1.

[0397] (b) N-(5-acetyl-4-hydroxy-2-methoxyphenyl)acetamide (23-2)

[0398] Compound 23-1 (3.00 g, 15.385 mmol) was dissolved in 50 mL of dichloromethane. Aluminum trichloride (8.70 g, 65.23 mmol) was slowly added in portions under ice bath conditions, followed by dropwise addition of acetyl chloride (3.26 mL, 48.92 mmol). The reaction mixture was stirred at 43 °C. After the reaction was complete, the reaction solution was slowly quenched in ice water for 2 h. The mixture was then extracted with dichloromethane and water. The organic layer was extracted with saturated brine and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, a small amount of dichloromethane was added, followed by the addition of a suitable amount of petroleum ether. A solid precipitated was obtained, filtered under reduced pressure, and the filter cake was dried to give a pale yellow solid as the target product 23-2 (1.00 g, yield 29%).

[0399] 1H NMR (500MHz, DMSO-d6) δ11.96(s,1H),9.42(s,1H),7.88(s,1H),7.34(s,1H),3.88(s,3H),2.61(s,3H),2.17(s,3H).

[0400] (c)(E)N-(4-hydroxy-5-(1-(hydroxyimino)ethyl)-2-methoxyphenyl)acetamide (23-3)

[0401] Compound 23-2 (10.00 g, 44.80 mmol) was dissolved in 100.00 mL of anhydrous ethanol-water solution (3:1, v / v), and sodium acetate (5.88 g, 71.68 mmol) and hydroxylamine hydrochloride (4.98 g, 71.68 mmol) were added. The mixture was refluxed at 80 °C for 70 min, and the reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure. The extract was obtained with ethyl acetate and water, and the organic layer was extracted with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, a light yellow solid 23-3 (6.93 g, 64% yield) was obtained.

[0402] 1 H NMR (500MHz, DMSO-d6) δ11.38(s,1H),11.18(s,1H),9.17(s,1H),7.71(s,1H),7.01(s,1H),3.82(s,3H),2.26(s,3H),2.11(s,3H).

[0403] (d)N-(6-methoxy-3-methylbenzo[d]isoxazole-5-yl)acetamide (23-4)

[0404] Dissolve 23-3 (0.70 g, 2.94 mmol) in 6.00 mL of 1,4-dioxane. After stirring and clarifying at room temperature, place the solution in an oil bath and gradually heat to 100 °C. When the temperature reaches 40 °C, add N,N-dimethylformamide dimethyl acetal (1.80 mL, 13.55 mmol) in portions. React at 100 °C for 7 min. Concentrate under reduced pressure to remove most of the solvent, extract with ethyl acetate and water, extract the organic layer with saturated brine, and dry to anhydrous sodium sulfate. Concentrate the crude product under reduced pressure and then perform silica gel column chromatography (PE:EA = 10:1, v / v) to obtain the target product 23-4 (0.30 g, yield 47%).

[0405] 1 H NMR (500MHz, Chloroform-d6) δ8.71(s,1H),8.06(s,1H),6.93(s,1H),3.99(s,3H),2.54(s,3H),2.28(s,3H).

[0406] (e)N-(6-hydroxy-3-methylbenzo[d]isoxazole-5-yl)acetamide (23-5)

[0407] Dissolve 23-4 (0.29 g, 1.32 mmol) in 6.00 mL of dichloromethane, and dissolve BBr3 in 6.00 mL of dichloromethane. Add the solutions slowly to the reaction mixture under ice bath conditions and allow the reaction to proceed at room temperature for 5 h under argon protection. After the reaction is complete, quench the reaction by slowly adding methanol and ammonium chloride solution, and adjust the pH to 7 with sodium hydroxide solution. Extract with ethyl acetate and water, then extract the organic layer with saturated brine and dry with anhydrous sodium sulfate. Concentrate under reduced pressure, add a small amount of ethyl acetate, and then add an appropriate amount of petroleum ether. A brown solid precipitates, which is filtered under reduced pressure. The filter cake is washed with a small amount of dichloromethane and dried to obtain the target product 23-5 (0.20 g, 74% yield).

[0408] 1 H NMR (500MHz, DMSO-d6) δ10.36(s,1H),9.34(s,1H),8.37(s,1H),7.08(s,1H),2.45(s,3H),2.18(s,3H).

[0409] (f) 2-((5-acetamido-3-methylbenzo[d]isoxazol-6-yl)oxy)tert-butyl acetate (23-6)

[0410] Compound 23-5 (0.15 g, 0.73 mmol) was dissolved in 2.00 mL of ultra-dry DMF, and KHCO3 (0.11 g, 1.09 mmol) was added and stirred thoroughly in an ice bath. Tert-butyl bromobutyrate (0.112 mL, 1.06 mmol) was dissolved in 2 mL of ultra-dry DMF and added dropwise to the reaction system. The mixture was stirred at 40 °C for 4 h. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the organic layer was extracted with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1, v / v) to obtain the target product 23-6 as a white solid (0.15 g, yield 66%).

[0411] 1 H NMR (500MHz, DMSO-d6) δ9.43(s,1H),8.45(s,1H),7.38(s,1H),4.85(s,2H),2.48(s,3H),2.20(s,3H),1.44(s,9H).

[0412] (g)2-((5-acetamido-3-methylbenzo[d]isoxazol-6-yl)oxy)acetic acid (23-6)

[0413] Compound 23-6 (0.15 g, 0.48 mmol) was dissolved in 2.00 mL of dichloromethane, and 1.00 mL of trifluoroacetic acid was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 20:1, v / v) to obtain a white solid as the target product 23-7 (0.12 g, 99%).

[0414] 1 H NMR (500MHz, DMSO-d6) δ9.60(s,1H),8.45(s,1H),7.43(s,1H),4.85(s,2H),2.48(s,3H),2.20(s,3H).

[0415] (h)2-((5-acetamido-3-methylbenzo[d]isoxazol-6-yl)oxy)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)acetamide (Example 23)

[0416] Compounds 23-7 (0.02 g, 0.08 mmol) and 1-3 (0.03 g, 0.09 mmol) were dissolved in ultradry DMF, and PyBop (0.047 g, 0.09 mmol) and DIPEA (0.13 mL, 0.76 mmol) were added. The mixture was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the organic layer was extracted with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (DCM:MeOH = 70:1, v / v) to give compound 23 as a yellow solid (0.04 mg, yield 85%).

[0417] 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.71(s,1H),8.37(s,1H),8.36(s,1H),7.58(t,J=7.9Hz,1H), 7.45(s,1H),7.07(d,J=8.6Hz,1H),7.02(d,J=7.1Hz,1H),6.52(t,J=6.0Hz,1H),5.05(dd,J=12.9,5. 3Hz,1H),4.64(s,2H),3.27-3.23(m,2H),3.22-3.18(m,2H),2.92-2.84(m,1H),2.61-2.54(m,2H),2 .49(s,3H),2.19(s,3H),2.02-1.99(m,1H),1.60-1.55(m,2H),1.54-1.49(m,2H),1.35-1.30(m,2H); 13 C NMR (126MHz, DMSO-d6) δ173.31,170.59,169.65,169.46,167.88,167.81,158.27,155.42,146.90,145.67,136.79,132.69,131.75,117.63 ,116.86,110.93,109.54,104.60,101.48,69.40,49.05,42.27,38.66,31.46,29.19,28.83,24.70,24.10,22.64,10.03; MS(ESI)m / z[M+H] + Theoretical value: 605.24; Actual value: 605.32; HPLC analysis: MeOH-H2O (90:10), 6.71 min, 96.86% purity.

[0418] Example 24

[0419] N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-((3-methylbenzo[d]isoxazol-6-yl)oxy)acetamide

[0420]

[0421] The synthesis method is the same as the synthesis steps (c), (d), (e), (f), (g), and (h) of Example 23, except that:

[0422] In step (c), the 23-2 raw material is replaced with an equimolar amount of 1-(2-hydroxy-4-methoxyphenyl)ethyl ketone to obtain (E)-1-(2-hydroxy-4-methoxyphenyl)ethyl-1-one oxime (24-1).

[0423] 1 H NMR (500MHz, DMSO-d6) δ11.88(s,1H),11.32(s,1H),7.41(d,J=8.8Hz,1H),6.48(d,J=8.7Hz,1H),6.43(s,1H),3.75(s,3H),2.23(s,3H).

[0424] In step (d), raw material 23-3 is replaced with an equimolar amount of raw material 24-1 to obtain 6-methoxy-3-methylbenzo[d]isoxazole (24-2).

[0425] 1 H NMR (500MHz, DMSO-d6) δ7.70(d,J=8.6Hz,1H),7.25(s,1H),6.98(d,J=8.7Hz,1H),3.87(s,3H),2.50(s,3H).

[0426] In step (e), 23-4 is replaced with an equimolar amount of 24-2 to obtain 3-methylbenzo[d]isoxazole-6-ol (24-3).

[0427] 1 H NMR (500MHz, DMSO-d6) δ10.31(s,1H),7.61(d,J=8.4Hz,1H),6.91(s,1H),6.84(d,J=8.5Hz,1H),2.46(s,3H).

[0428] In step (f), 23-5 is replaced with an equimolar amount of 24-3 to obtain 2-((3-methylbenzo[d]isoxazol-6-yl)oxy)tert-butyl acetate (24-4).

[0429] 1 H NMR (500MHz, Chloroform-d6) δ7.63(d,J=8.7Hz,1H),7.04(s,1H),6.99(d,J=8.5Hz,1H),4.56(s,2H),2.72(s,3H),1.49(s,9H).

[0430] In step (g), 23-6 is replaced with an equimolar amount of 24-4 to obtain 2-((3-methylbenzo[d]isoxazol-6-yl)oxy)acetic acid (24-5).

[0431] 1 H NMR (500MHz, DMSO-d6) δ13.04(s,1H),7.53(d,J=8.6Hz,1H),7.27(s,1H),6.93(d,J=8.6Hz,1H),4.74(s,2H),2.57(s,3H).

[0432] In step (h), raw material 23-7 is replaced with an equimolar amount of raw material 24-5 to obtain N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)-2-((3-methylbenzo[d]isoxazol-6-yl)oxy)acetamide (Example 24)

[0433] Example 24 is a yellow solid with a yield of 50%.

[0434] 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),8.19(t,J=5.4Hz,1H),7.74(d,J=8.6Hz,1H),7.58(t,J=7.8H z,1H),7.22(s,1H),7.07(t,J=9.2Hz,2H),7.03(d,J=7.1Hz,1H),6.53(t,J=5.4Hz,1H),5.05(dd,J =12.8,5.4Hz,1H),4.60(s,2H),3.26(q,J=6.7Hz,2H),3.16(q,J=6.7Hz,2H),2.93-2.84(m,1H),2. 62-2.55(m,2H),2.05-2.00(m,1H),1.57(q,J=7.4Hz,2H),1.49(q,J=7.4Hz,2H),1.34-1.31(m,2H); 13 C NMR (126MHz, DMSO-d6) δ173.29,170.57,169.45,167.80,167.39,164.15,160.74,155.29,146.90,136.78,132.68,122.84,117.6 6,116.22,114.54,110.89,109.53,94.36,67.91,49.03,42.26,38.66,31.45,29.22,28.83,24.10,22.62,9.93; MS(ESI)m / z[M+H] + Theoretical value: 548.21; Actual value: 548.30; HPLC analysis: MeOH-H2O (70:30), 6.32 min, 98.01% purity.

[0435] Example 25

[0436] N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-((6-methoxy-3-methylbenzo[d]isoxazole-5-yl)amino)acetamide

[0437]

[0438] The synthetic route for compound 25 is shown below:

[0439]

[0440] (a) 6-Methoxy-3-methylbenzo[d]isoxazole-5-amine (25-1)

[0441] 24-4 (1.04 g, 4.72 mmol) was dissolved in 15.00 mL of hydrochloric acid (3 mol / L) and refluxed at 90 °C for 3 h. The reaction was monitored by TLC. After the reaction was complete, sodium hydroxide solution (3 mol / L) was added to adjust the pH to neutral (7-9), precipitating the solid. The precipitate was filtered under reduced pressure, washed with a small amount of water, and dried to give a brownish-yellow solid 25-1 (0.75 g, yield 89%).

[0442] 1 H NMR(500MHz,DMSO-d6)δ7.04(s,1H),6.71(s,1H),5.55(s,2H),3.85(s,3H),2.40(s,3H).MS(ESI)m / z[M+H] + Theoretical value: 179.08; Actual value: 179.04.

[0443] (b) (6-methoxy-3-methylbenzo[d]isoxazole-5-yl)tert-butyl acetate (25-2)

[0444] The synthesis method is the same as step (f) of Example 23, except that raw material 23-5 is replaced with an equimolar amount of raw material 25-1.

[0445] 1 H NMR(500MHz,DMSO-d6)δ7.09(s,1H),6.54(s,1H),5.92(t,J=6.1Hz,1H),3.9 3(d,J=6.1Hz,2H),3.89(s,3H),2.42(s,3H),1.43(s,9H).MS(ESI)m / z[M+H] + Theoretical value: 293.15; Actual value: 293.10.

[0446] (c) (6-methoxy-3-methylbenzo[d]isoxazole-5-yl)acetic acid (25-3)

[0447] The synthesis method is the same as step (g) of Example 23, except that raw material 23-6 is replaced with an equimolar amount of raw material 25-2.

[0448] 1 H NMR(500MHz,DMSO-d6)δ7.09(s,1H),6.57(s,1H),5.86(s,1H),3.95(s,2H),3.90(s,3H),2.42(s,3H).MS(ESI)m / z[M+H] + Theoretical value: 237.09; Actual value: 237.04.

[0449] (d)N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)-2-((6-methoxy-3-methylbenzo[d]isoxazole-5-yl)amino)acetamide (Example 25)

[0450] The synthesis method follows the steps (h) of Example 23, except that starting material 23-7 is replaced with an equimolar amount of starting material 25-3. Example 25 yielded a yellow solid with a yield of 78%.

[0451] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),8.03(t,J=5.8Hz,1H),7.58(t,J=7.9Hz,1H),7.09(s,1H),7.06(d,J= 8.4Hz,1H),7.02(d,J=7.0Hz,1H),6.52(t,J=6.3Hz,1H),6.44(s,1H),5.99(t,J=5.6Hz,1H),5.05(dd,J=12. 9,5.4Hz,1H),3.90(s,3H),3.76(d,J=5.3Hz,2H),3.27-3.21(m,2H),3.15-3.09(m,2H),2.92-2.83(m,1H), 2.62-2.55(m,2H),2.42(s,3H),2.05-2.00(m,1H),1.59-1.52(m,2H),1.49-1.42(m,2H),1.35-1.29(m,2H); 13C NMR(126MHz,DMSO-d6)δ173.33,170.59,169.45,169.40,167.82,160.09,154.88,146.89,145.34,141.85,136.80,132.65,117.65,1 10.91,110.27,109.50,99.93,88.42,56.49,49.03,46.53,42.26,38.85,31.43,29.18,28.80,24.07,22.63,9.99; MS(ESI)m / z[M+H] + Theoretical value: 577.24; Actual value: 577.32; HPLC analysis: MeOH-H2O (90:10), 6.81 min, 98.16% purity.

[0452] Example 26

[0453] N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-((4-fluoro-2-methoxyphenyl)amino)acetamide

[0454]

[0455] The synthesis method is the same as the synthesis steps (f), (g), and (h) of Example 23, except that:

[0456] In step (f), the 23-5 raw material is replaced with an equimolar amount of 4-fluoro-2-methoxyaniline raw material to obtain (4-fluoro-2-methoxyphenyl) tert-butyl acetate (26-1), and the crude product is directly fed into the next step.

[0457] In step (g), 23-6 raw material is replaced with an equimolar amount of 26-1 raw material to obtain (4-fluoro-2-methoxyphenyl)acetic acid (26-2).

[0458] 1 H NMR (500MHz, DMSO-d6) δ6.79(dd,J=10.8,2.3Hz,1H),6.59(td,J=8.5,2.1Hz,1H),6.37(dd,J=8.3,6.0Hz,1H),3.82(s,3H),3.81(s,2H).MS(ESI)m / z[MH] - Theoretical value: 198.06; Actual value: 198.01.

[0459] In step (h), raw material 23-7 is replaced with an equimolar amount of raw material 26-2 to obtain N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)-2-((4-fluoro-2-methoxyphenyl)amino)acetamide (Example 26)

[0460] Compound 26 is a yellow solid with a yield of 69.00%.

[0461] 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),7.91(t,J=5.9Hz,1H),7.58(t,J=8.0Hz,1H),7.08(d,J=8.6Hz,1H),7.03(d,J=6. 9Hz,1H),6.78(dd,J=10.6,2.4Hz,1H),6.59(td,J=8.8,2.6Hz,1H),6.53(t,J=6.0Hz,1H),6.28(dd,J=8.6,5.9Hz,1H),5 .15(t,J=5.7Hz,1H),5.05(dd,J=12.8,5.3Hz,1H),3.81(s,3H),3.61(d,J=5.6Hz,2H),3.29-3.22(m,2H),3.13-3.07(m ,2H),2.93-2.83(m,1H),2.62-2.52(m,2H),2.06-2.00(m,1H),1.60-1.52(m,2H),1.47-1.40(m,2H),1.33-1.27(m,2H); 13 C NMR(126MHz,DMSO-d6)δ173.31,170.57,170.19,169.45,167.81,155.10(d,J=23 2.3Hz),147.60(d,J=9.5Hz),146.90,136.78,134.75,132.66,117.66,110.90,1 09.50,109.42(d,J=9.2Hz),106.22(d,J=21.6Hz),99.32(d,J=27.1Hz),56.23,4 9.03,47.49,42.28,38.75,31.44,29.23,28.81,24.07,22.63; MS(ESI)m / z[M+H] + Theoretical value: 540.23; Actual value: 540.28; HPLC analysis: MeOH-H2O (90:10), 6.80 min, 98.41% purity.

[0462] Example 27

[0463] N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-(3-fluorophenoxy)acetamide

[0464]

[0465] The synthesis method is the same as the synthesis steps (f), (g), and (h) of Example 23, except that:

[0466] In step (f), 23-5 raw material was replaced with an equimolar amount of 3-fluorophenol raw material to obtain 2-(3-fluorophenoxy) tert-butyl acetate (27-1).

[0467] 1 H NMR(500MHz,DMSO-d6)δ7.32(q,J=7.5Hz,1H),6.83-6.75(m,3H),4.70(s,2H),1.43(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 249.09; Actual value: 249.02

[0468] In step (g), 23-6 raw material is replaced with an equimolar amount of 27-1 raw material to obtain (2-(3-fluorophenoxy)acetic acid (27-2).

[0469] 1 H NMR(500MHz,DMSO-d6)δ13.07(s,1H),7.32(q,J=7.8Hz,1H),6.85-6.76(m,3H),4.72(s,2H).MS(ESI)m / z[MH] - Theoretical value: 169.03; Actual value: 168.98.

[0470] In step (h), raw material 23-7 is replaced with an equimolar amount of raw material 27-2 to obtain N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)-2-(3-fluorophenoxy)acetamide (Example 27)

[0471] Compound 27 is a yellow solid with a yield of 59%.

[0472] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),8.11(t,J=6.1Hz,1H),7.59(t,J=7.8Hz,1H),7.36-7.30(m ,1H),7.09(d,J=8.6Hz,1H),7.03(d,J=7.1Hz,1H),6.85-6.78(m,3H),6.54(t,J=5.4Hz,1H),5.05 (dd,J=12.8,5.4Hz,1H),4.49(s,2H),3.30-3.28(m,2H),3.16-3.13(m,2H),2.90-2.87(m,1H),2 .62-2.59(m,2H),2.03-2.01(m,1H),1.60-1.56(m,2H),1.51-1.47(m,2H),1.35-1.32(m,2H); 13C NMR(126MHz,DMSO-d6)δ173.29,170.57,169.45,167.80,167.57,160.50(d,J =224.3Hz),146.91,136.79,132.68,131.18(d,J=10.4Hz),117.67,111.50(d ,J=2.2Hz),110.89,109.53,108.28(d,J=21.6Hz),102.91(d,J=25.0Hz),67. 69,49.03,42.28,38.62,31.45,29.22,28.82,24.08,22.63; MS(ESI)m / z[M+H] + Theoretical value: 511.20; Actual value: 511.26; HPLC analysis: MeOH-H2O (90:10), 6.86 min, 99.04% purity.

[0473] Example 28

[0474] N-(5-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-phenoxyacetamide

[0475]

[0476] The synthesis method is the same as the synthesis steps (f), (g), and (h) of Example 23, except that:

[0477] In step (f), 23-5 raw material is replaced with an equimolar amount of phenol raw material to obtain tert-butyl 2-phenoxyacetic acid (28-1).

[0478] 1H NMR(500MHz,DMSO-d6)δ7.30(t,J=7.4Hz,2H),6.96(t,J=7.3Hz,1H),6.90(d,J=7.9Hz,2H),4.65(s,2H),1.43(s,9H).MS(ESI)m / z[M+Na] + Theoretical value: 231.10; Actual value: 231.0

[0479] In step (g), 23-6 raw material is replaced with an equimolar amount of 28-1 raw material to obtain 2-phenoxyacetic acid (28-2).

[0480] 1 H NMR(500MHz,DMSO-d6)δ13.01(s,1H),7.30(t,J=7.1Hz,2H),6.96(t,J=7.3Hz,1H),6.91(d,J=7.9Hz,2H),4.67(s,2H).MS(ESI)m / z[MH] - Theoretical value: 151.04; Actual value: 151.01.

[0481] In step (h), raw material 23-7 was replaced with an equimolar amount of raw material 28-2 to obtain N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)-2-phenoxyacetamide (Example 28).

[0482] Compound 28 is a yellow solid with a yield of 85%.

[0483] 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),8.08(t,J=6.0Hz,1H),7.59(t,J=7.9Hz,1H),7.30(t,J=7. 1Hz,2H),7.09(d,J=8.6Hz,1H),7.03(d,J=7.1Hz,1H),6.99-6.94(m,3H),6.53(t,J=6.0Hz,1H),5 .05(dd,J=12.7,5.4Hz,1H),4.46(s,2H),3.29-3.26(m,2H),3.17-3.12(m,2H),2.93-2.84(m,1H ),2.62-2.54(m,2H),2.06-2.00(m,1H),1.62-1.54(m,2H),1.52-1.45(m,2H),1.34-1.29(m,2H); 13C NMR(126MHz,DMSO-d6)δ173.30,170.58,169.45,167.99,167.81,158.21,146.92,136.79,132.69,129.95,121.65, 117.68,115.20,110.90,109.53,67.47,49.04,42.29,38.61,31.46,29.25,28.83,24.09,22.64.MS(ESI)m / z[M+H] + Theoretical value: 493.21; Actual value: 493.15; HPLC analysis: MeOH-H2O (90:10), 6.78 min, 97.20% purity.

[0484] Example 29

[0485] 2-(2-((2,5-dimethoxyphenyl)sulfonamido)-5-fluorophenoxy)-N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)phenyl)acetamide

[0486]

[0487] The synthesis method followed the synthetic route of Example 1 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamido)-5-fluorophenoxy)-N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)phenyl)acetamide (29).

[0488] 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),9.37(s,1H),8.75(t,J=5.5Hz,1H),7.47(t,J=7.8Hz,1H ),7.36-7.29(m,3H),7.25-7.18(m,3H),7.15-7.10(m,2H),7.07-7.00(m,2H),6.98-6.89(m,2H ),6.77(td,J=8.5,2.7Hz,1H),5.07(dd,J=12.7,5.4Hz,1H),4.56(d,J=6.3Hz,2H),4.37(d,J= 6.1Hz,2H),3.67(s,3H),3.56(s,3H),2.95-2.85(m,1H),2.63-2.55(m,2H),2.07-2.00(m,1H); 13C NMR (126MHz, DMSO-d6) δ172.28,171.56,169.06,167.74,167.40,160.43(d,J=242.2Hz),153.40,151.37(d,J=10.6Hz),1 51.09,146.73,138.09,138.06,136.50,132.56,128.08,127.81(2×C),127.48(2×C),126.21(d,J=10.2Hz),122.83(d,J=2 .7Hz), 120.19, 118.15, 115.22, 114.49, 111.26, 110.05, 107.94 (d, J = 22.2Hz), 101.84 (d, J = 27.1Hz), 68.23, 56.71, 56.58, 49.17, 45.68, 31.41, 22.62; MS (ESI) m / z [M+H]+ theoretical value: 746.74; actual value: 746.68; HPLC analysis: MeOH-H2O (90:10), 6.81 min, 99.72% purity.

[0489] Example 30

[0490] 2-(2-((2,5-dimethoxyphenyl)sulfonamido)-5-fluorophenoxy)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide

[0491]

[0492] The synthesis method followed the synthetic route of Example 1 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamido)-5-fluorophenoxy)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide (30).

[0493] 1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),9.56(s,1H),8.41(t,J=5.9Hz,1H),7.59(dd,J=8.6,7.1Hz,1H),7 .32(dd,J=8.9,6.2Hz,1H),7.14-7.10(m,3H),7.11-7.03(m,2H),6.92(dd,J=10.7,2.8Hz,1H),6.76(td ,J=8.5,2.7Hz,1H),6.66(t,J=5.8Hz,1H),5.04(dd,J=12.8,5.4Hz,1H),4.32(s,2H),3.67(s,3H),3.65 (s,3H),3.61-3.54(m,4H),3.49-3.40(m,8H),2.91-2.84(m,1H),2.61-2.55(m,2H),2.04-1.99(m,1H); 13 C NMR (126MHz, DMSO-d6) δ173.24, 170.54, 169.45, 167.75, 167.48, 160.38 (d, J = 242.3Hz), 152.38, 151.41 (d ,J=10.5Hz),151.07,146.85,136.73,132.56,128.08,126.12(d,J=10.2Hz),122.85(d,J=3.1Hz),120.20,1 17.88, 115.27, 114.40, 111.20, 109.76, 107.94 (d, J = 22.4 Hz), 101.80 (d, J = 27.3 Hz), 71.11, 69.30, 69.19, 68.15, 68.01, 56.67, 56.18, 49.06, 42.09, 38.74, 31.45, 22.61; MS(ESI) m / z [M+H]+ theoretical value: 772.77; actual value: 772.65.

[0494] Example 31

[0495] N-(2-(2-(4-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazin-1-yl)-2-oxoethoxy)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide

[0496]

[0497] The synthesis method followed the synthetic route of Example 1 to obtain N-(2-(2-(4-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)piperazin-1-yl)-2-oxoethoxy)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide (31).

[0498] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.04(s,1H),7.60(t,J=8.0Hz,1H),7.26(t,J=7 .9Hz,1H),7.18–7.08(m,4H),7.05(d,J=7.0Hz,1H),6.92(d,J=10.1Hz,1H),6.85–6.73 (m,2H),5.07(dd,J=13.1,5.5Hz,1H),4.88(s,2H),3.78(s,3H),3.70(s,3H),3.50–3. 38(m,6H),2.92–2.82(m,1H),2.65–2.54(m,4H),2.49–2.42(m,4H),2.06–1.99(m,1H). 13 C NMR (101MHz, DMSO) δ173.58,170.80,169.57,168.03,166.62,160.19(d,J=241.9Hz),152.50,152.33(d,J=1 0.7Hz),151.16,146.91,137.03,132.72,128.12,124.96(d,J=9.8Hz),124.43(d,J=2.7Hz),120.50,118.22 ,114.94,114.53,111.28,109.85,108.84(d,J=22.1Hz),104.30(d,J=26.3Hz),68.99,56.87,56.37,56.15,55.52,52.96,52.55,49.18,44.54,42.10,40.00,31.61,22.78.MS(ESI)m / z[M+H]+ Theoretical value: 753.24; Actual value: 753.37.

[0499] Example 32

[0500] 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)ethyl)acetamide

[0501]

[0502] The synthesis method followed the synthetic route of Example 1 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamide)-5-fluorophenoxy)-N-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)ethyl)acetamide (32).

[0503] 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.36(s,1H),8.14(t,J=5.8Hz,1H),7.69(t,J=8.0Hz,1H),7.36–7.2 5(m,3H),7.18–7.07(m,3H),6.89(dd,J=10.7,2.8Hz,1H),6.76(td,J=8.5,2.8Hz,1H),5.09(dd,J=12.6,5 .4Hz,1H),4.36(s,2H),3.68(s,6H),3.68–3.61(m,2H),3.28–3.13(m,2H),2.93–2.83(m,1H),2.83–2.72( m,2H),2.62–2.54(m,2H),2.05–1.99(m,1H),1.81–1.72(m,2H),1.72–1.60(m,1H),1.41–1.34(m,4H).13C NMR (101MHz, DMSO) δ173.35,170.57,167.62,167.16,166.80,160.57(d,J=242.6Hz),152.40,151.74(d, J=10.8Hz),151.09,150.65,136.27,134.18,128.23,126.72(d,J=10.2Hz),124.39,122.79(d,J=2.8Hz), 120.19, 116.84, 115.15, 114.92, 114.47, 107.98 (d, J = 22.3 Hz), 101.70 (d, J = 27.0 Hz), 68.08, 56.75, 56.21, 51.59, 49.27, 36.32, 36.28, 32.79, 32.21, 31.48, 22.58. MS(ESI) m / z [M+H]+ Theoretical value: 752.24; Actual value: 752.45.

[0504] Example 33

[0505] N-(2-(2-(4-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)piperidin-1-yl)-2-oxoethoxy)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide

[0506]

[0507] The synthesis method followed the synthetic route of Example 1 to obtain N-(2-(2-(4-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)piperidin-1-yl)-2-oxoethoxy)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide (33).

[0508] 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.09(s,1H),7.59(t,J=7.8Hz,1H),7.30–7.23(m,1H),7.18–7.08(m,4H),7.04(d ,J=7.0Hz,1H),6.93(dd,J=10.2,2.7Hz,1H),6.77(t,J=8.4Hz,1H),6.55(t,J=6.3Hz,1H),5.06(dd,J=12.8,5.5Hz,1H), 4.86(s,2H),4.31(d,J=13.0Hz,1H),3.77(s,3H),3.70(s,3H),3.65(d,J=13.5Hz,1H),3.00–2.85(m,2H),2.65–2.52(m ,4H),2.06–2.00(m,1H),1.80–1.71(m,2H),1.65–1.58(m,1H),1.57–1.49(m,2H),1.20–1.11(m,1H),1.07–0.98(m,1H). 13C NMR (126MHz, DMSO) δ173.28, 170.57, 169.40, 167.78, 166.12, 159.94 (d, J = 242.0Hz), 152.38, 152.16 (d, J = 10.6H z),151.01,146.81,136.78,132.69,128.04,124.56(d,J=3.2Hz),124.42(d,J=10.0Hz),120.32,117.65,114.80, 114.39, 110.93, 109.62, 108.73 (d, J = 22.5 Hz), 104.46 (d, J = 26.1 Hz), 69.21, 56.71 (d, J = 4.1 Hz), 56.22 (d, J = 3.8 Hz), 49.04, 44.38, 42.02, 35.53, 33.38, 32.40, 31.74, 31.46, 22.64. MS(ESI) m / z [M+H]+ Theoretical value: 752.24; Actual value: 752.42.

[0509] Example 34

[0510] N-(2-(2-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)piperidin-1-yl)-2-oxoethoxy)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide

[0511]

[0512] The synthesis method followed the synthetic route of Example 1 to obtain N-(2-(2-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)piperidin-1-yl)-2-oxoethoxy)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide (34).

[0513] 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.10(s,1H),7.59(dd,J=8.6,7.1Hz,1H),7.26(dd,J=9.0,6.2Hz,1H),7.20–7.09(m,4 H),7.04(d,J=7.0Hz,1H),6.92(dd,J=10.4,2.9Hz,1H),6.76(td,J=8.6,2.8Hz,1H),6.66(t,J=6.2Hz,1H),5.06(dd,J=12.8 ,5.4Hz,1H),4.92–4.81(m,2H),4.34(d,J=13.0Hz,1H),3.76(s,3H),3.70(s,3H),3.67(s,1H),3.28–3.20(m,2H),3.00–2.8 5(m,2H),2.64–2.54(m,3H),2.07–1.99(m,1H),1.91–1.80(m,1H),1.78–1.69(m,2H),1.23–1.13(m,1H),1.12–1.02(m,1H). 13 C NMR (126MHz, DMSO) δ173.27, 170.55, 169.45, 167.75, 166.18, 159.94 (d, J = 241.7Hz), 152.38, 152.17 (d, J = 10.7H z),151.01,147.05,136.73,132.67,128.04,124.55(d,J=3.1Hz),124.45(d,J=10.0Hz),120.33,117.87,114.80, 114.38, 110.97, 109.58, 108.74 (d, J = 22.3 Hz), 104.46 (d, J = 26.3 Hz), 69.21, 56.71 (d, J = 4.0 Hz), 56.22 (d, J = 3.9 Hz), 49.05, 47.41, 44.11, 41.75, 35.77, 31.46, 30.17, 29.54, 22.64; MS(ESI) m / z [M+H]+ theoretical value: 738.22; actual value: 738.39.

[0514] Example 35

[0515] 2-(2-((2,5-dimethoxyphenyl)sulfonamido)-5-fluorophenoxy)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)cyclohexyl)acetamide

[0516]

[0517] The synthesis method followed the synthetic route of Example 1 to obtain 2-(2-((2,5-dimethoxyphenyl)sulfonamido)-5-fluorophenoxy)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)cyclohexyl)acetamide (35).

[0518] 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),9.15(s,1H),7.60(dd,J=8.6,7.0Hz,1H),7.26(dd,J=9.0,6.1Hz,1H), 7.18(dd,J=7.1,1.9Hz,1H),7.17–7.09(m,4H),6.93(dd,J=10.4,2.8Hz,1H),6.77(td,J=8.6,2.8Hz,1H),5.0 7(dd,J=12.7,5.4Hz,1H),4.76(s,2H),3.83–3.78(m,2H),3.77(s,3H),3.69(s,3H),3.68–3.61(m,2H),3.58 –3.50(m,4H),3.11–3.06(m,1H),3.02–2.95(m,1H),2.92–2.84(m,1H),2.62–2.55(m,2H),2.04–1.98(m,1H). 13 C NMR (126MHz, DMSO-d6) δ173.29,170.50,167.52,167.09,166.74,160.02(d,J=241.9Hz),152.37,152.32(d,J=1 1.8Hz),151.06,146.33,135.48,134.39,128.11,124.82(d,J=10.3Hz),124.54,122.29,120.30,114.79,114.37 ,112.52(d,J=5.5Hz),111.34(d,J=6.1Hz),108.87(d,J=23.2Hz),104.70(dd,J=26.3,5.5Hz),69.50,56.73,56.22,55.35,55.28,55.15,50.16,49.26,48.78,42.40,31.43,22.60.MS(ESI)m / z[M+H]+ Theoretical value: 736.21; Actual value: 736.34.

[0519] Example 36

[0520] N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-carbonyl)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide

[0521]

[0522] The synthetic route of Example 36 is shown below:

[0523]

[0524] (a) 2-((2,5-dimethoxyphenyl)sulfonamido)-5-fluorobenzoic acid (36-1)

[0525] 2-Amino-5-fluorobenzoic acid (1.00 g, 6.446 mmol) and 2,5-dimethoxybenzenesulfonyl chloride (1.60 g, 6.769 mmol) were dissolved in 20 mL of dichloromethane, and pyridine (1.60 mL, 20 mmol) was added. The mixture was reacted at room temperature for 4 h. After the reaction was completed, water was added for extraction. The organic layer was extracted with dilute hydrochloric acid aqueous solution and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration of the organic layer under reduced pressure, the crude product was purified and separated by silica gel column chromatography to obtain the target product 36-1 (0.93 g, yield 41%).

[0526] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 11.12 (s, 1H), 7.63 (dd, J = 9.1, 2.9Hz, 1H), 7.55 (dd, J = 9.3, 4.7Hz, 1H), 7.39 (td, J = 8.5, 2.9Hz, 1H), 7.35 (d, J = 2.9Hz, 1H), 7.19 (dd, J = 9.2, 3.0Hz, 1H), 7.11 (d, J = 9.1Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H). MS (ESI) m / z [M–H] – Theoretical value: 354.04; Actual value: 353.98.

[0527] (b) 4-((4-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-4-yl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (36-2)

[0528] Compound 1-1 (0.80 g, 2.90 mmol) was dissolved in ultradry DMSO, and tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (0.82 g, 2.90 mmol) and DIPEA (2.52 mL, 14.48 mmol) were added. The mixture was stirred at 100 °C for 2 h, and the reaction was monitored by TLC. After the reaction was complete, ethyl acetate and water were added to the reaction system for two extractions. The organic layers were combined and extracted once with saturated brine. The organic layers were separated and combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target product 36-2, a yellow viscous solid (1.20 g, yield 77%).

[0529] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 11.11 (s, 1H), 7.70 (t, J = 7.5Hz, 1H), 7.40–7.28 (m, 2H), 5.16–5.05 (m, 1H), 4.02–3.81 (m, 2H), 3.31–3.26 (m, 4H), 2.93–2.82 (m, 1H), 2.82–2.52 (m, 8H), 2.24–2.14 (m, 2H), 2.06–1.98 (m, 1H), 1.76–1.63 (m, 3H), 1.39 (s, 9H), 1.03–0.89 (m, 2H). MS (ESI) m / z [M+H]+ Theoretical value: 540.28; Actual value: 540.36.

[0530] (c)2-(2,6-dioxadipinidin-3-yl)-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (36-3)

[0531] Compound 36-2 (1.20 g, 2.225 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the product was concentrated under reduced pressure. The crude product was used directly in the next reaction without further processing. MS (ESI) m / z [M+H]+ theoretical value: 440.23; actual value: 440.29.

[0532] (d)N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperazin-1-yl)methyl)piperidin-1-carbonyl)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide (36)

[0533] Compound 36-1 (0.035 g, 0.098 mmol) and HATU (0.05 g, 0.13 mmol) were dissolved in DMF, and DIPEA (0.153 mL, 0.88 mmol) was added. The mixture was stirred at room temperature for 10 min. Then, 36-3 (0.043 g, 0.098 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic layer was extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain compound 36 as a yellow solid (0.04 g, 53% yield).

[0534] 1 H NMR (500MHz, DMSO-d6) δ11.12(s,1H),9.10(s,1H),7.71(t,J=7.8Hz,1H),7.41–7.32(m,2H),7.25–7.18( m,4H),7.17–7.10(m,2H),5.10(dd,J=12.8,5.5Hz,1H),4.52–4.30(m,1H),3.85(s,3H),3.71(s,3H),3.35 –3.27(m,6H),2.91–2.84(m,1H),2.82–2.67(m,2H),2.63–2.53(m,5H),2.29–2.14(m,2H),2.05–2.00(m,1H),1.87–1.76(m,2H),1.64–1.56(m,1H),1.16–1.05(m,2H). MS(ESI) m / z[M+H]+ Theoretical value: 777.27; Actual value: 777.46.

[0535] Example 37

[0536] N-(2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)piperidin-1-yl)methyl)piperidin-1-carbonyl)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide

[0537]

[0538] The synthetic route of Example 37 is shown below:

[0539]

[0540] (a) 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (37-1)

[0541] Compound 1-1 (4.00 g, 14.48 mmol) was dissolved in ultradry DMSO, and 1-Boc-4-aminopiperidine (2.90 g, 14.48 mmol) and DIPEA (12.63 mL, 72.51 mmol) were added. The mixture was stirred at 100 °C for 2 h, and the reaction was monitored by TLC. After the reaction was complete, ethyl acetate and water were added to the reaction system for two extractions. The organic layers were combined and extracted once with saturated brine. The organic layers were separated and combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target product 37-2, a yellow viscous solid (3.20 g, yield 48%).

[0542] 1 H NMR (500MHz, DMSO-d6) δ11.12(s,1H),7.60(t,J=7.8Hz,1H),7.22(d,J=8.6Hz,1H),7.0 6(d,J=7.0Hz,1H),6.27(d,J=8.4Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.01–3.82(m,2H ), 3.82–3.67(m,1H), 3.02–2.80(m,3H), 2.63–2.53(m,2H), 2.08–1.98(m,1H), 1.98–1.86(m,2H), 1.41(s,10H), 1.40–1.33(m,2H). MS(ESI) m / z[M+H]+ Theoretical value: 479.19; Actual value: 479.24.

[0543] (b) 2-(2,6-dioxadipinidin-3-yl)-4-(4-(piperidin-4-ylamino)isoindoline-1,3-dione (37-2)

[0544] Compound 37-1 (2.0 g, 4.38 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (4 mL) was added. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was used directly in the next reaction without further processing. MS (ESI) m / z [M+H]+ theoretical value: 357.16; actual value: 357.16.

[0545] (c)4-((4-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)piperidin-1-yl)methyl)piperidin)-1-carboxylic acid tert-butyl ester (37-3)

[0546] 37-2 (0.30 g, 0.84 mmol) was dissolved in a mixture of 1,2-dichloroethane and methanol. Sodium acetate (0.30 g, 1.684 mmol) was added while stirring. After stirring for 15 min, acetic acid (0.07 g, 1.18 mmol) and 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (0.22 g, 1.01 mmol) were added, and the mixture was stirred at room temperature for 2 h. Sodium cyanoborohydride (0.16 g, 2.53 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with water and ethyl acetate. The organic layers were extracted with dilute hydrochloric acid aqueous solution and saturated brine, respectively, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography to obtain the target product 37-3 (0.25 g, 54% yield).

[0547] 1 H NMR(500MHz,DMSO-d6)δ11.12(s,1H),7.61(t,J=7.1,6.5Hz,1H),7.27–7.13(m,1 H),7.13–7.03(m,1H),6.32–6.20(m,1H),5.06(dd,J=13.0,5.4Hz,1H),4.02–3.8 5(m,2H),3.67–3.43(m,3H),2.93–2.84(m,1H),2.84–2.52(m,8H),2.21–1.91(m,6H),1.73–1.62(m,3H),1.40(s,9H).MS(ESI)m / z[M+H]+ Theoretical value: 554.30; Actual value: 554.40.

[0548] (d)2-(2,6-dioxadipinidin-3-yl)-4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)amino)isoindoline-1,3-dione(37-4)

[0549] Compound 37-3 (0.25 g, 0.45 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the product was concentrated under reduced pressure. The crude product was used directly in the next reaction without further processing. MS (ESI) m / z [M+H]+ theoretical value: 454.25; actual value: 454.30.

[0550] (e)N-(2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)piperidin-1-yl)methyl)piperidin-1-carbonyl)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide(37)

[0551] Compound 36-1 (0.04 g, 0.11 mmol) and HATU (0.06 g, 0.15 mmol) were dissolved in DMF, and DIPEA (0.153 mL, 0.88 mmol) was added. The mixture was stirred at room temperature for 10 min. Then, 37-4 (0.05 g, 0.12 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic layer was extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography to obtain compound 37 as a yellow solid (0.03 g, 35% yield).

[0552] 1 H NMR(500MHz,DMSO-d6)δ11.12(s,1H),9.08(s,1H),7.60(t,J=7.9Hz,1H),7.25–7.17(m,5H),7.16–7.10(m,2H),7.06 (d,J=7.0Hz,1H),6.26(d,J=8.1Hz,1H),5.06(dd,J=12.6,5.4Hz,1H),4.50–4.34(m,1H),3.84(s,3H),3.71(s,3H),3 .65–3.55(m,1H),3.52–3.45(m,1H),2.93–2.83(m,1H),2.82–2.65(m,4H),2.62–2.55(m,2H),2.24–2.09(m,3H),2.07–1.92(m,4H),1.89–1.67(m,2H),1.64–1.42(m,3H),1.14–1.00(m,2H).MS(ESI) m / z[M+H]+ Theoretical value: 791.29; Actual value: 791.45.

[0553] Example 38

[0554] N-(2-(4-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)piperidin-1-yl)ethyl)piperidin-1-carbonyl)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide

[0555]

[0556] The synthesis method followed the synthetic route of Example 37 to obtain N-(2-(4-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)piperidin-1-yl)ethyl)piperidin-1-carbonyl)-4-fluorophenyl)-2,5-dimethoxybenzenesulfonamide (38).

[0557] 1 H NMR (500MHz, DMSO-d6) δ11.13(s,1H),9.12(s,1H),7.60(t,J=7.8Hz,1H),7.32–7.10(m,7H),7.06(d,J=7.0Hz,1 H),6.27(d,J=8.1Hz,1H),5.06(dd,J=12.8,5.5Hz,1H),4.46–4.32(m,1H),3.84(s,3H),3.71(s,3H),3.67–3.59 (m,1H),3.33–3.23(m,2H),2.95–2.55(m,7H),2.46–2.19(m,3H),2.06–2.01(m,1H),2.01–1.92(m,2H),1.79–1.69(m,1H),1.60–1.47(m,4H),1.46–1.40(m,2H),1.18–1.05(m,2H).MS(ESI)m / z[M+H]+ Theoretical value: 805.30; Actual value: 805.49.

[0558] Test Example 1

[0559] Cell proliferation inhibition assay (CellTiter-Glo)

[0560] Experimental objective: To evaluate the antitumor cell proliferation activity of compounds 1-38 of this invention and compound CC-90009 (see CN106660991A) in the prior art using CellTiter-Glo assay reagent. The structure of CC-90009 is as follows:

[0561]

[0562] Experimental Methods: Seed 500-1500 cells / 20 μl in 384 or 96-well plates and incubate overnight in a constant temperature incubator. Dilute the compound to the specified concentration with the corresponding cell culture medium (+10% FBS), and add 10 μl of the diluted compound to each well. Continue incubation for 72-120 h. Then add 25 μL of CellTiter-Glo reagent to each well and measure the fluorescence signal using a PerkinElmer microplate reader.

[0563] Western blotting assay

[0564] Experimental objective: To evaluate the GSPT1 degradation activity induced by compounds 1-38 of this invention and compound CC-90009 (see CN106660991A) in the prior art using Western blotting detection method.

[0565] Experimental Methods: Cells treated with 500 nM of the drug in the example for 6 hours were collected. After thorough lysis, the supernatant was collected and separated by 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 the protein molecular weight. The corresponding GSPT1 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 3-6 times with 1×TBST, followed by incubation with the corresponding secondary antibody dilution buffer at room temperature for 1-2 hours. After incubation, the membrane was washed 3-6 times with 1×TBST for 10 minutes each time. Finally, chemiluminescence and development were performed.

[0566] The experimental results are shown in Table 1 below:

[0567] Table 1:

[0568]

[0569]

[0570] Note: a The antitumor cell proliferation activity of compounds 1-38 of this invention was evaluated using CellTiter-Glo assay reagents, where A ≤ 0.01 μM indicates strong activity; 0.1 ≥ B > 0.01 μM indicates good activity; 1 ≥ C > 0.1 μM indicates moderate activity; D > 1 μM indicates weak activity; NT indicates "not test", meaning this item was not tested.

[0571] b The degradation activity of compounds 1-38 of this invention inducing GSPT1 was evaluated using Western blotting. Here, + represents 0-25%, weak degradation rate; ++ represents 25-50%, moderate degradation rate; +++ represents 50-75%, good degradation rate; ++++ represents 75-100%, strong degradation rate; NT indicates "nottest," meaning this item was not tested.

[0572] According to the results in Table 1, some compounds of the present invention have strong anti-proliferation inhibitory activity against a variety of tumor cells, and some compounds have GSPT1 degradation-inducing activity in a variety of tumor cells.

[0573] Test Example 2

[0574] Western blot assay

[0575] The experimental results of GSPT1 degradation induced by representative compounds are as follows: Figure 1-3 As shown:

[0576] like Figure 1As shown, the compounds of the present invention in Examples 2, 18, 20, 1, 4, 6 and 7 significantly induced the degradation of GSPT1 protein after treating 22Rv1 cells with 500 nM for 6 hours.

[0577] like Figure 2 As shown, the compounds of the present invention in Examples 2, 18, 20, 1, 4, 6 and 7, when treated with MV4;11 cells at 500 nM for 6 hours, significantly induced the degradation of GSPT1 protein.

[0578] like Figure 3 As shown, the compounds of the present invention in Examples 8, 9, 10, 13, 15, 16 and 22 significantly induced the degradation of GSPT1 protein after treating MOLM-16 cells with 500 nM for 6 hours.

[0579] The applicant declares that this invention illustrates the arylimidazolyl isoxazole 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.

[0580] 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.

[0581] 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 2,6-piperidinedione derivative, characterized in that, The 2,6-piperidinidone derivative has a structure as shown in Formula I, Formula II or Formula III: in, X is selected from O or S; R1 is selected from H, halogen, hydroxyl, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl; R2 is selected from H, -SR a , -OR a , -SR b , -OR b , -N(R a )SO2R b , -SO2N(R a )R b , -N(R a )COR b , -CON(R a )R b -, -N(R a )CH2R b , -NHCH(R a )R b , -N(R a )R b , -CH(R a )R b , -COR b , -COOR b , -OCOR b ; R a The group is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl, and substituted or unsubstituted C3-C10 heterocyclic alkyl; the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl. R b Selected from any of the following groups (i), (ii), or (iii): (i) substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C4-C20 heteroaryl; wherein the substituted group is selected from any one of halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy; (ii) substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C3-C10 heterocycloalkyl; wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl; (iii) substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl; wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl; R3, R4, R5 and R6 are each independently selected from H, halogen, hydroxyl, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, wherein the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl; Z1 is selected from -N(SO2R b )(CH2) n CON(R c )-, -N(SO2R b )(CH2) n CO-, -SO2N(R b )(CH2) n CON(R c )-, -SO2N(R b )(CH2) n CO-, -CON(R b )(CH2) n CON(R c )-, -CON(R b )(CH2) n CO-, -N(COR b )(CH2) n CON(R c )-, -N(COR b )(CH2) n CO-, -NH(CH2) n CON(R c )-, -NH(CH2) n CO-, -O(CH2) n CON(R c )-, -O(CH2) n CO-, -S(CH2) n CON(R c )-, -S(CH2) n CO-, -(CH2) n CON(R c )-, -(CH2) n CO-, -CO-, -O-, -S-, -N- or a single bond, and n is 1 - 6; R c The substituted group is selected from H, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkenyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C4-C20 heteroaryl, and substituted or unsubstituted C2-C10 alkenyl; the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl. Z2 is selected from -O-, -NH-, -CH2-, and -NH(CH2). n CO-, -CO-, or single bonds; L is selected from any one or a combination of at least two of the following groups: single bond, alkylene group, alkenyl group, alkyne group, ether group, thioether group, ester group, amino group, amide group, carbamate group, urea group, sulfone group, aryl group, heteroaryl group, carbonyl group, cycloalkyl group, heterocyclic group, spiroheterocyclic group, and bridged heterocyclic group; E has the structure shown in Formula IV, where For the location of the group connection: in, T1 is selected from -O-, -S-, -CHT a -, -C(=O)-, -SO2-, -NTb-; T a and T b Each is independently selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocyclic groups; T2, T3, and T4 are each independently selected from O or S; Y1, Y2, Y3, and Y4 are each independently selected from CH or N; R7 and R8 are each independently selected from H, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 heterocyclic alkyl, substituted or unsubstituted C1-C10 heterocyclic alkyl, substituted or unsubstituted C1-C10 heterocyclic alkyl; the substituted group is selected from any one of halogen, hydroxyl, and C1-C6 alkyl.

2. The 2,6-piperidinedione derivative according to claim 1, characterized in that, Y1, Y2, Y3, and Y4 are independently selected from CH or N; Preferably, any one of the groups Y1, Y2, Y3, and Y4 is CH, and the group is attached to the CH. Preferably, L is selected from any one of the following groups, wherein For the location of the group connection: Wherein, n, m, and w are independently selected from integers between 0 and 8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, etc.), and when n, m, or w is 0, it indicates that the group does not exist here; p, q, u, and v are independently selected from 1 or 2; A, D, E, and G are independently selected from CH or N; U, M, and Z are independently selected from CH2, NH, and O; Preferably, T1 is selected from -CH2- or -C(=O)-.

3. The 2,6-piperidinedione derivative according to claim 1 or 2, characterized in that, The 2,6-piperidinedione derivative has the structure shown in formula V, formula VI or formula VII: The definitions of the groups R1, R2, R3, R4, R5, R6, R7, R8, X, Z1, Z2, L, Y1, Y2, Y3, Y4, T1, T2, T3, and T4 are the same as those in claim 1 or 2. Preferably, the 2,6-piperidinedione derivative has the structure shown in formula V-a, formula VI-a, or formula VII-a: The definitions of the R1, R2, R3, R4, R5, R6, R7, R8, X, Z1, Z2, L, and T1 groups are the same as those in claim 1 or 2. Preferably, R1 is selected from H, halogen, hydroxyl, substituted or unsubstituted C1-C5 alkyl, and more preferably from H or unsubstituted C1-C6 alkyl; Preferably, R2 is H or -OR. a -N(R) a SO2R b -SO2N(R) a )R b -N(R) a )COR b -CON(R) a )R b -, preferably H, -OR a -N(R) a SO2R b -N(R) a )COR b ; Preferably, the R a Selected from H, substituted or unsubstituted C1-C6 alkyl groups, preferably H or unsubstituted C1-C6 alkyl groups; Preferably, the R b The group is selected from any group in group (i) or (iii) above, preferably a substituted or unsubstituted C1-C5 alkyl group, a substituted or unsubstituted C6-C20 aryl group, and more preferably an unsubstituted C1-C5 alkyl group or a substituted C6-C10 aryl group; the substituted group is selected from any one of halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy groups; Preferably, R3 and R5 are selected from H, halogens, substituted or unsubstituted C1-C6 alkyl groups, and more preferably from H, halogens, or unsubstituted C1-C6 alkyl groups. Preferably, R4 is selected from H, substituted or unsubstituted C1-C6 alkyl groups, and more preferably unsubstituted C1-C6 alkyl groups; Preferably, R6 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and preferably unsubstituted C1-C6 alkoxy; Preferably, R7 and R8 are independently selected from H or C1-C10 alkyl groups; Preferably, Z1 is selected from -O(CH2). n CON(R c )-、-(CH2) n CON(R c -NH(CH2) n CON(R c )-、-O(CH2) n CO-, -N(SO2R) b (CH2) n CON(R c -, -CO-, or single bonds; Preferably, the R b The group is selected from any group in group (i) or (iii) above, preferably a substituted or unsubstituted C1-C5 alkyl group, a substituted or unsubstituted C6-C20 aryl group, and more preferably an unsubstituted C1-C5 alkyl group or a substituted C6-C10 aryl group; the substituted group is selected from any one of halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy groups; Preferably, T1 is selected from -CH2- or -C(=O)-; Preferably, n is 1-3, R c Selected from H; Preferably, the Z2 is selected from -NH(CH2). n CO-, -NH-, -CH2- or single bonds; Preferably, n is 1-3; Preferably, L is selected from any one of the following groups, wherein For the location of the group connection: Wherein, n, m and w are independently selected from integers between 0 and 8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, etc.), and when n, m or w is 0, it indicates that the group does not exist here; p, q, u, v are independently selected from 1 or 2; A, D, E, G are independently selected from CH or N; Z is independently selected from CH2, NH, O.

4. The 2,6-piperidinedione derivative according to any one of claims 1-3, characterized in that, The structures of the 2,6-piperidinedione derivatives are shown in formulas V-b, VI-b, VII-1b, VII-2b, or VII-3b: Among them, R2, R3, R5, R6, R b X, Z1, Z2, L, and T1 have the same scope as claim 3; Preferably, R2 is selected from H, -N(R a )COR b -OR a ; Preferably, the R a Selected from H, unsubstituted C1-C6 alkyl groups; Preferably, the R b Selected from substituted C6-C12 aryl groups; the substituted group is selected from any one of halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy groups. Preferably, R6 is selected from -OR a ; Preferably, the R a Selected from H, unsubstituted C1-C6 alkyl groups; Preferably, R3 and R5 are independently selected from H, halogens, and unsubstituted C1-C6 alkyl groups; Preferably, Z1 is selected from -O(CH2). n CON(R c )-、-(CH2) n CON(R c -NH(CH2) n CON(R c )-、-O(CH2) n CO-, -CO-, or single bonds; Preferably, T1 is selected from -CH2- or -C(=O)-; Preferably, n is 1-3, R c Selected from H; Preferably, the Z2 is selected from -NH(CH2). n CO-, -NH-, -CH2- or single bonds; Preferably, n is 1-3; Preferably, L is selected from any one of the following groups, wherein For the location of the group connection: Wherein, n, m and w are independently selected from integers between 0 and 8 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, etc.), and when n, m or w is 0, it indicates that the group does not exist here; p, q, u, v are independently selected from 1 or 2; A, D, E, G are independently selected from CH or N; Z is independently selected from CH2, NH, O.

5. The 2,6-piperidinedione derivative according to any one of claims 1-4, characterized in that, The 2,6-piperidinidone derivative is selected from any one of the structures shown in compounds 1-38 below:

6. A pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound of a 2,6-piperidinedione derivative as described in any one of claims 1-5.

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition includes an active ingredient and pharmaceutically acceptable excipients; The active ingredient comprises at least one 2,6-piperidinedione derivative as described in any one of claims 1-5 and / or at least one pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound as described in claim 7.

8. The use of a 2,6-piperidinedione derivative as described in any one of claims 1-5, a pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound as described in claim 7, or a pharmaceutical composition as described in claim 8, in the preparation of a formulation for degrading GSPT1 protein.

9. The use of a 2,6-piperidinedione derivative as described in any one of claims 1-5, a pharmaceutically acceptable salt, stereoisomer, N-oxide, prodrug molecule, solvate, or deuterated compound as described in claim 7, or a pharmaceutical composition as described in claim 7, in the preparation of a medicament for the prevention or treatment of cancer, cell proliferation disorders, inflammation, autoimmune diseases, sepsis, or viral infections; The cancers mentioned include any one of the following: acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia mixed spectrum leukemia, NUT midline carcinoma, multiple myeloma, glioma, lung cancer, neuroblastoma, Burkitt lymphoma, cervical cancer, esophageal cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, or breast cancer; 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. The autoimmune diseases mentioned are selected from any one of the following: rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelinating diseases, primary adrenal cortical atrophy, chronic thyroiditis, juvenile diabetes mellitus, hyperthyroidism, chronic nonspecific ulcerative colitis, chronic active hepatitis, pernicious anemia, atrophic gastritis, autoimmune glomerulonephritis, pulmonary-renal hemorrhage syndrome, autoimmune hemolysis, idiopathic thrombocytopenic purpura, or idiopathic leukopenia.

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