Protein tyrosine phosphatase degradation agent, use thereof, and method for preparing same

Abstract

Disclosed are a thiadiazolidinone derivative of formula (I), a method for preparing same, and use thereof. Such compounds have excellent PTPN2 and PTP1B degradation activity, wherein some preferred compounds have excellent PTPN2 degradation selectivity. Such compounds can promote the proliferation of T cells and enhance anti-tumor immunity, and thus possess good application prospects for treating cancers and other diseases related to tyrosine phosphatase.

Description

A protein tyrosine phosphatase degrading agent, its uses and preparation method

[0001] Priority of related applications

[0002] This application claims priority to Chinese invention patent filed on November 29, 2024, entitled "A protein tyrosine phosphatase degrading agent and its use and preparation method", application number: 2024117404754, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of biomedicine, specifically relating to a thiadiazolidinone derivative, its preparation method, and its application. Background Technology

[0004] Tyrosine-protein phosphatase (PTP) catalyzes the dephosphorylation of phosphorylated tyrosine residues in substrate proteins. In 1989, researchers discovered PTPN2 (also known as T cell PTP, TCPTP) and PTPN1 (also known as PTP1B) by screening human peripheral T cell cDNA libraries, with a similarity of over 70%. PTPN2 and PTP1B can dephosphorylate and inactivate a series of proteins related to T cell activation and hematopoiesis, including Src family kinases (c-Src, Fyn, Lck), Janus kinase (JAK), STAT-1, STAT-3, STAT-5, and STAT-6. PTPN2 and PTP1B are negative regulators of T cell receptor (TCR) and other cytokine-mediated signaling pathways; therefore, PTPN2 and PTP1B are potential immune checkpoints and key links in tumor cell immune evasion.

[0005] In 2020, Tiganis et al. reported that PTPN2 knockout could enhance anti-tumor immunity and the therapeutic effect of CAR-T cells on solid tumors. T cell-specific PTPN2 knockout p53 + / - The tumor incidence rate in mice (tumor-prone model animals) was significantly lower than that in the control group. This was achieved by knocking down PTPN2's CD8 receptor using siRNA. + HER2 CAR T cells can eliminate HER2-positive breast tumors in model animals (EMBO J, 39(2020)e103637.). In 2017, Sharpe et al. reported that knocking out PTPN2 using CRISPR-CAS9 technology can improve T cell exhaustion and enhance Tim-3. + CD8 +T cell killing power (Nature, 547(2017)413-418). Knocking out PTPN2 throughout the immune system can completely eliminate MC38 (colon cancer) and B16 (melanoma) tumor cells in experimental animals. In 2023, Zhu et al.'s study confirmed that the combination of small molecule PTPN2 inhibitors and PD-1 antagonists can increase the treatment of drug-resistant melanoma (Cancer Research Communications, 3(2023)119-129). Similarly, in 2022, Wiede et al. found that knocking out PTP1B can also promote T cell proliferation and enhance the anti-tumor immunity of CAR T cells. The above previous research results confirm that PTPN2 and PTP1B are potential targets for tumor immunotherapy (Cancer Discov. 2022 Mar 1; 12(3):752-773.). Degrading PTPN2 and PTP1B with small molecule degraders can increase the body's anti-tumor immunity and can be used in combination with other immunotherapies to treat solid tumors. On the other hand, PTP1B knockout in mice increases insulin receptor phosphorylation and enhances glucose metabolism, leading to a significant decrease in blood glucose and insulin concentrations. This indicates that PTP1B plays an important role in the insulin and leptin-mediated signaling pathways and is a potential target for diabetes treatment. In 2024, Hainaning and LaFleur used X-CHIME and CHIME technologies to knock out PTPN2 and PTP1B in the mouse immune system using bone marrow transplantation of transgenic hematopoietic cells. The results showed that knocking out PTPN2 or PTP1B alone did not affect mouse survival, while knocking out both PTPN2 and PTP1B simultaneously was lethal (Nat Immunol, 25(2024)178-188). The existing candidate drug targeting PTN2, ABBV-CLS-484 (AC484), is a dual-target drug for PTPN2 and PTP1B (Nature volume 622, pages 850–862). As can be seen from the above knockout experiments, dual-target drugs may have safety risks. PROTAC (proteolysis-targeting chimeras) is a drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade target proteins. A PROTAC is a chemical molecule with different ligands at both ends: one end binds to an E3 ubiquitin ligase, and the other end binds to an intracellular protein; these two ligands are linked by a linker group. This chemical molecule can bind to both E3 ubiquitin ligase and intracellular proteins, recruiting the target protein to the vicinity of the E3 ubiquitin ligase to achieve polyubiquitination of the target protein, which is then degraded by the proteasome. Summary of the Invention

[0006] One objective of this invention is to provide a compound of formula (I) that exhibits excellent PTPN2 and PTP1B degradation activity, wherein some preferred compounds possess excellent PTPN2 degradation selectivity. These compounds can promote T cell proliferation and enhance anti-tumor immunity, showing promising potential for treating cancer and other diseases related to tyrosine phosphatase.

[0007] A second objective of this invention is to provide a protein tyrosine phosphatase degrading agent containing the compound shown in formula (I) above.

[0008] A third objective of this invention is to provide a pharmaceutical composition containing the compound shown in formula (I) above.

[0009] The fourth objective of this invention is to provide an application of the compound shown in formula (I) and the above-described pharmaceutical composition, alone or in combination with other therapies, for the treatment of cancer and diabetes.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0011] The first aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, or isotopically labeled derivative:

[0012] Among them, R 1 R 2 Each is independently H, halogen, straight-chain or branched C1-C6 alkyl; X is CH or N atom;

[0013] Ring A is a saturated or unsaturated monocyclic ring, a saturated or unsaturated bicyclic ring, or a saturated or unsaturated tricyclic ring. The monocyclic, bicyclic, or tricyclic rings are substituted or unsubstituted five- to twelve-membered heterocyclic alkyl groups containing one to three heteroatoms selected from N, O, and S, or five- to twelve-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S. The substitution refers to the presence of 0 to 4 substituents R on ring A. A When multiple substituents R exist A At that time, each substituent R A Each group is independently selected from hydrogen, straight-chain or branched C1-C6 alkyl, carbonyl, halogen, amino, nitro, hydroxyl, carboxyl, amide, cyano, halogen-substituted C1-C6 alkyl, sulfonamide, sulfone, sulfoxide, C1-C6 alkyl-substituted acyl, and 0 substituents R. A This indicates that ring A may not contain the substituent R. A ;

[0014] The "linking group" is -(L1 ) n1 -(L 2 ) n2 -(L 3 ) n3 -(L 4 ) n4 -(L 5 ) n5 -, where the connector L 1 L 2 L 3 L 4 L 5 They are independently: -CH2-, -CHR L -、-CR L 2-, -O-, -S-, -NH-, -NR L -、 -N=、=N-、-CH2CH2O-、-CH=CH-、-CR L =CH-、-CR L =CR L -、-CH=CR L -、-C≡C-、C 3-8 Cycloalkylene groups, three to eight-membered heterocyclic alkylene groups containing one to three heteroatoms selected from N, O, and S, benzene rings, naphthene rings, five to eight-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S, C 4-8 cyclic ketone group, four- to eight-membered cyclic lactam group, -P(=O)R L -,-P(=O)OR L -、

[0015] n1, n2, n3, n4, and n5 are each independent integers selected from 0 to 20, and n1, n2, n3, n4, and n5 are not all 0 at the same time.

[0016] R L Each group is independently selected from halogens, -OH, -NH2, -SH, sulfonamides, sulfones, sulfoxides, carboxyl groups, and -C(=O)OC. 1- 6-alkyl-, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, -O(C) 1-8 alkyl), -S(C 1-8 alkyl), -NH(C) 1-8 alkyl), -N(C) 1- 8-alkyl)2, C 3-8Cycloalkyl, tri- to octa-cyclic heterocycloalkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, phenyl, naphthyl, penta- to octa-aryl groups containing 1 to 3 heteroatoms selected from N, O, and S, -O(C 3-8 cycloalkyl), -S(C 3-8 cycloalkyl), -NH(C 3-8 cycloalkyl), -N(C) 3-8 2, -O (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S), -S (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S), -NH (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S), -N (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S) 2, -N (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S) (C 3-8 cycloalkyl), -N (containing 1 to 3 heteroatoms selected from N, O and S, five to octa-aryl groups) (C 1-8 alkyl), -N(C) 1-8 Alkyl)(C 3-8 cycloalkyl).

[0017] Preferably, R 1 and R 2 Each is independently selected from H, halogens, straight-chain or branched C1-C4 alkyl groups.

[0018] Preferably, R 1 Selected from H, methyl, ethyl, n-propyl, and isopropyl.

[0019] Preferably, R 2 Selected from halogen atoms.

[0020] Preferably, the monocyclic ring A, along with the bicyclic or tricyclic ring, is a substituted or unsubstituted five- to eight-membered heterocyclic alkyl group containing one or two heteroatoms selected from N, O, and S, or a five- to eight-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S, wherein the substitution refers to the presence of 0 to 4 substituents R on the A ring. A When multiple substituents R exist A At that time, each substituent R A Each is independently selected from hydrogen, straight-chain or branched C1-C4 alkyl, carbonyl, or halogen.

[0021] Preferably, the A ring is selected from the following structures:

[0022] Among them, substituent R A As defined above.

[0023] Preferably, the "linking group" is -(L 1 ) n1-(L 2 ) n2 -(L 3 ) n3 -(L 4 ) n4 -(L 5 ) n5 -, where the connector L 1 L 2 L 3 L 4 L 5 They are independently: -CH2-, -CHR L -、-CR L 2-, -O-, -S-, -NH-, -NR L -、 -N=、=N-、-CH2CH2O-、-CH=CH-、-CR L =CH-、-CR L =CR L -、-CH=CR L -、-C≡C-、C 3-6 Cycloalkylene groups, three to six-membered heterocyclic alkylene groups containing one or two heteroatoms selected from N, O, and S, benzene rings, naphthene rings, five to six-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S, C 4-6 cyclic ketone group, four- to eight-membered cyclic lactam group, -P(=O)R L -,-P(=O)OR L -、

[0024] n1, n2, n3, n4 and n5 are each independent integers selected from 0 to 10, and n1, n2, n3, n4 and n5 are not all 0 at the same time;

[0025] R L Each group is independently selected from halogens, -OH, -NH2, -SH, sulfonamides, sulfones, sulfoxides, carboxyl groups, and -C(=O)OC. 1- 6-alkyl-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -O(C) 1-6 alkyl), -S(C 1-6 alkyl), -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2, C 3-6Cycloalkyl, tri- or hexacyclic heterocycloalkyl containing one or two heteroatoms selected from N, O, and S, phenyl, naphthyl, penta- or octacyclic heteroaryl containing one or two heteroatoms selected from N, O, and S, -O(C 3-6 cycloalkyl), -S(C 3-6 cycloalkyl), -NH(C 3-6 cycloalkyl), -N(C) 3-6 2, -O (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S), -S (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S), -NH (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S), -N (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S) 2, -N (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S) (C 3-6 cycloalkyl), -N (five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S) (C 1-6 alkyl), -N(C) 1-6 Alkyl)(C 3-6 cycloalkyl).

[0026] Preferably, the "linking group" - (L 1 ) n1 -(L 2 ) n2 -(L 3 ) n3 -(L 4 ) n4 -(L 5 ) n5 -The resulting combined structure is selected from the following structures:

[0027] Where R L For fluorine, chlorine, bromine, iodine, -OH, -NH2, sulfonamide, sulfone, sulfoxide, carboxylic acid, ester, C 1-8 Alkyl, C 2- 8-alkenyl, C 2-8 alkynyl group, -O(C) 1-8 alkyl), -NH(C) 1-8 alkyl), -N(C) 1-8 Alkyl)2, C 3-8 Cycloalkyl, tri- to octa-cyclic heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, phenyl, naphthyl, penta- to octa-cyclic heteroarylheteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, -O(C 3-8 cycloalkyl), -NH(C 3-8 cycloalkyl), -N(C) 3-82, -O (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S), -NH (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S), -N (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S), -N (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S) 2, -N (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S) (C 3-8 cycloalkyl), -N (five to eight-membered heteroaryl heteroaryl containing one to three heteroatoms selected from N, O and S) (C 1-8 alkyl), -N(C) 1-8 Alkyl)(C 3-8 cycloalkyl).

[0028] Preferably, the halogen is F, Cl, Br or I, and more preferably F, Cl or Br.

[0029] Preferably, the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, or isotopically labeled derivative is selected from the following structures:

[0030] A second aspect of the present invention is to provide a protein tyrosine phosphatase degrading agent comprising a compound provided according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, or isotope-labeled derivative.

[0031] A third aspect of the invention provides a pharmaceutical composition comprising a compound provided in the first aspect of the invention or a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, a prodrug thereof, a solvate thereof, an isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.

[0032] A fourth aspect of the invention is to provide the use of a compound provided in the first aspect of the invention or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, deuterated product, or composition provided in the third aspect of the invention in the preparation of a medicament for treating diseases associated with protein tyrosine phosphatase.

[0033] Preferably, the protein tyrosine phosphatase is PTPN2 or PTP1B.

[0034] Preferably, the disease associated with protein tyrosine phosphatase is cancer or diabetes.

[0035] Preferably, the cancer is selected from: melanoma, pancreatic cancer, lymphoma, breast cancer, colorectal cancer, blastoma, medulloblastoma, retinoblastoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, leukemia or lymphoid malignant tumor, myeloma, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, membranous adenocarcinoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, myeloma, esophageal cancer, biliary tract tumor, and head, neck and facial malignant tumors.

[0036] A fifth aspect of the invention is to provide a method for treating a disease associated with protein tyrosine phosphatase, the method comprising administering to a subject a therapeutically effective amount of a compound provided in the first aspect of the invention or a pharmaceutically acceptable salt thereof, ester thereof, isomer thereof, prodrug thereof, solvate thereof, deuterated thereof, or a composition provided in the third aspect of the invention.

[0037] Preferably, the disease associated with protein tyrosine phosphatase is cancer or diabetes.

[0038] Preferably, the cancer is selected from: melanoma, pancreatic cancer, lymphoma, breast cancer, colorectal cancer, blastoma, medulloblastoma, retinoblastoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, leukemia or lymphoid malignant tumor, myeloma, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, membranous adenocarcinoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, myeloma, esophageal cancer, biliary tract tumor, and head, neck and facial malignant tumors.

[0039] A sixth aspect of the present invention is the application of the compound provided in the first aspect or the pharmaceutical composition provided in the third aspect of the present invention in combination with CAR-T immunotherapy in cancer immunotherapy. CAR-T immunotherapy refers to chimeric antigen receptor T-cell immunotherapy, which is one of the more effective treatments for malignant tumors. Its basic principle is to utilize the patient's own immune cells to eliminate cancer cells, and it belongs to a type of cell therapy. Beneficial effects

[0040] The compounds of formula (I) according to the present invention can degrade protein tyrosine phosphatases, such as PTPN2, and can be used as anti-tumor immune enhancers for cancer treatment. The degradation activity and anti-tumor efficacy of the preferred embodiments are superior to existing small molecule modulators targeting PTPN2. Furthermore, some compounds of the present invention exhibit excellent PTPN2 degradation subtype selectivity, meaning that they degrade PTPN2 without affecting PTP1B, which can reduce off-target effects and has a significant advantage in avoiding off-target toxic side effects. Attached Figure Description

[0041] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0042] Figure 1 shows the experimental results of selective degradation of PTPN2 subtypes by some of the compounds according to the present invention.

[0043] Figure 2 illustrates the promoting effect of some compounds according to the present invention on tumor killing by T cell co-incubation.

[0044] Figure 3 shows the degradation effect of some compounds according to the present invention in experimental animal MC38 xenograft tumor tissue. Detailed Implementation

[0045] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0046] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0047] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0048] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0049] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0050] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0051] definition

[0052] Isotope-labeled derivatives:

[0053] This invention also includes isotopically labeled compounds of this invention, which are identical to those described herein unless one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 18 F and 36 Cl.

[0054] Certain isotopically labeled compounds of the present invention (e.g., those labeled with...) 3 H and 14 C-labeled compounds can be used to identify the distribution of compounds and / or matrix tissues. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detection. Furthermore, isotopes such as deuterium (i.e., 2The heavier isotope substitution of H) can provide certain therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred for use in certain conditions. The isotopically labeled compounds of the present invention can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents through a procedure similar to that disclosed in the processes and / or examples below.

[0055] The pharmaceutically acceptable salts described in this invention are: suitable salts of the compounds involved in this invention with organic acids, organic bases, inorganic acids, and inorganic bases, such as: hydrochloric acid, trifluoroacetic acid, sulfuric acid, acetic acid, phosphoric acid, citric acid, lactic acid, fumaric acid, maleic acid, methanesulfonic acid, nitric acid, hydrobromic acid, tartaric acid, ethanolamine, diethanolamine, N-ethylethanolamine, N-methylethanolamine, triethanolamine, diethylaminoethanol, 2-amino-2-methyl-n-propanol, dimethylaminoisopropanol, 2-amino-2-methylpropanediol, triisopropanolamine, ethylenediamine, 1,1-hexamethylenediamine, morpholine, piperidine, piperazine, cyclohexylamine, tributylamine, dodecylamine, dimethyldodecylamine; triethylamine benzylamine, dibenzylamine, N-methylpiperazine, 4-methylcyclohexylamine, N-methylmorpholine, methylamine, ethylamine, alkaline earth metals, alkali metals, aluminum, and transition metal salts. These salts can be prepared from the compounds shown in formula (I) using well-known salt-forming methods.

[0056] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0057] The compounds provided by this invention also include prodrug forms, representing compounds that are rapidly converted in vivo to the parent compound of the above formula, and are converted to the compounds of this invention by chemical or biochemical methods in vivo or in vitro environments, such as by hydrolysis in the blood.

[0058] The compounds of this invention can exist in both unsolvated and solvated forms, with solvation including hydrate forms. Generally, the solvated form is equivalent to the unsolvated form and is also covered within the scope of this invention.

[0059] The compounds of the present invention exist as geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, racemic mixtures thereof, and other mixtures, all of which are within the scope of the present invention.

[0060] The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0061] The term "diastereomer" refers to a stereoisomer of a molecule that has two or more chiral centers and is not a mirror image of the molecule.

[0062] The term "cis-trans isomer" refers to the configuration in which the double bonds or single bonds of cyclic carbon atoms in a molecule cannot rotate freely.

[0063] The stereoisomers of the compounds of this invention can be prepared by chiral synthesis or by chiral reagents or other conventional techniques.

[0064] Preferably, the amount of the compound used in the pharmaceutical composition is a therapeutically effective amount.

[0065] Preferably, the pharmaceutical composition further includes pharmaceutically acceptable excipients.

[0066] Pharmaceutical compositions can be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. Oral administration includes tablets, capsules (including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nano-suspensions, micron-suspensions, and spray-dried dispersants), syrups, and emulsions; sublingual administration; sublingual administration; parenteral administration, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or by infusion techniques (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasal administration, including administration to the nasal mucosa, such as by inhalation spray; topical administration, such as in the form of creams or ointments; or rectal administration, such as in the form of suppositories. They can be administered alone, but are usually administered with a pharmaceutical carrier selected according to the chosen route of administration and standard pharmaceutical practices.

[0067] The excipients described in this invention are selected from: lactose, microcrystalline cellulose, methylcellulose, sodium hydroxymethylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, dextrin, cellulose derivatives, polyvinyl alcohol, gelatin, polyethylene glycol, polyvinyl alcohol, brown sugar, distilled water, ethanol, starch paste, antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the subject, as well as aqueous and non-aqueous sterile suspending agents, which may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives; the pharmaceutical composition is suitable for gastrointestinal or non-gastrointestinal administration. As a general guideline, when used to indicate specific effects, the daily oral dose of each active ingredient is in the range of about 0.001 to about 5000 mg per day, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of the active ingredient; the most preferred intravenous dose during constant-rate infusion is in the range of about 0.01 to about 10 mg / kg / minute. The compounds of the present invention can be administered as a single daily dose, or the total daily dose can be administered in divided doses 2, 3, or 4 times daily.

[0068] The dosing regimen for the compounds used in this invention can, of course, be modified based on known factors, such as the pharmacodynamic characteristics of the specific agent and its mode and route of administration, the recipient's species, age, sex, health, medical condition and weight, the nature and severity of symptoms, the types of coexisting treatments, the frequency of treatment, the route of administration, the patient's renal and hepatic function, and the desired effect. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age and individual circumstances of the recipient, the condition or disease being treated, or its severity. Physicians, clinicians, or veterinarians with ordinary skills can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a condition or disease.

[0069] The pharmaceutical compositions of this invention can be used alone or in combination with other types of pharmaceutical preparations and / or treatment methods. The other types of pharmaceutical preparations are selected from: PD-1, PD-L1, CTLA-4, TIM-3, TGF-β and their receptors, antagonists of LAG3, or agonists of TLR4, TLR7, TLR8, TLR9, and STING, and cytotoxic chemotherapeutic drugs; the other types of treatment methods are selected from: radiotherapy and immunotherapy.

[0070] The application of the compounds provided in the first aspect of the present invention or the pharmaceutical compositions provided in the third aspect of the present invention in combination with immune checkpoint blockade therapy in cancer immunotherapy can degrade protein tyrosine phosphatases, such as PTPN2 and PTP1B, and can be used as an anti-tumor immune enhancer for the treatment of cancer and diabetes.

[0071] As used herein, the term “treatment” means the elimination, reduction, or improvement of a disease or condition and / or its associated symptoms. While not excluded, treating a disease or condition does not require the complete elimination of its associated symptoms. As used herein, the term “treatment” and similar terms can include “preventive treatment,” which refers to reducing the likelihood of the recurrence of a disease or condition or the relapse of a previously controlled disease or condition in subjects who are not at risk or are at risk of developing or being at risk of developing or experiencing a disease or condition or its recurrence. The term “treatment” and its synonyms are considered in relation to the administration of a therapeutically effective amount of the compound described herein to a subject who requires such treatment.

[0072] As used herein, the term "subject" (which may be alternatively referred to as "patient") means an animal, preferably a mammal, and most preferably a human, that has become the subject of treatment, observation, or experimentation. In any of the embodiments described herein, the subject may be a human.

[0073] The term "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 8 carbon atoms ("C"). 1–8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1–6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., halogens, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-8 Alkyl (e.g., unsubstituted C) 1-6 Alkyl group, such as -CH3). In some embodiments, the alkyl group is a substituted C. 1-8 Alkyl (e.g., substituted C) 1-6 Alkyl groups, such as -CF3).

[0074] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 8 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C"). 2–8 The alkenyl group ("alkenyl") can be located at the end of a long carbon chain or at any position permitted by the chemical structure therein. In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2- 6-Alkenyl). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C6”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). 2–4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-8 Alkenyl. In some embodiments, the alkenyl group is a substituted C. 2-8 Alkenyl. In alkenyl groups, the stereochemical C=C double bond is not specified (e.g., -CH=CHCH3 or...). It can be an (E)- or (Z)- double bond.

[0075] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 8 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds. 2–8 The alkynyl group (“C6”) can be located at the end of a long carbon chain or at any position permitted by the chemical structure therein. In some embodiments, the alkynyl group has 2 to 8 carbon atoms (“C6”). 2-8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. The one or more carbon-carbon triple bonds can be internal (e.g., in the 2-butynyl group) or terminal (e.g., in the 1-butynyl group). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkynyl groups include the C group mentioned above. 2-4The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Other examples of the alkynyl group include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of the alkynyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted by one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-8 Alkyne group. In some embodiments, the alkynyl group is a substituted C- group. 2-8 Alkyne group.

[0076] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 8 ring carbon atoms ("C"). 3-8 A group consisting of a carbocyclic group (“C”) and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 The carbocyclic group (“CCR”) has 3 to 6 cyclic carbon atoms in some embodiments. 3-6 The carbocyclic group (“CCR”) has 3 to 6 cyclic carbon atoms in some embodiments. 3-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group"). An example C 3-6 The carbocyclic group includes, but is not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example is C... 3-8 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3-6 Carbocyclic groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclic [2.2.1]heptyl (C7), bicyclic [2.2.2]octyl (C8), etc. As shown in the foregoing examples, in some embodiments, the carbocyclic group is a monocyclic (“monocyclic carbocyclic group”) or contains a fused ring, bridged ring, or spirocyclic structure, such as a bicyclic system, and may be saturated or may be partially unsaturated. “Cycloalkyl” also includes cyclic systems in which the cycloalkyl group as defined above is fused with one or more aryl or heteroaryl groups (where the connection point is on the carbocyclic ring), and in this case, the number of carbons continues to refer to the number of carbons in the carbocyclic system. Unless otherwise stated, each instance of a carbocyclic group is independently optionally substituted, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted by one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl is an unsubstituted C 3-8 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-8 Carbon cyclic group.

[0077] "Heterocyclic alkyl" or "heterocyclic group" refers to a group having a 5- to 12-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("five- to twelve-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the bonding point can be a carbon atom or a nitrogen atom, provided that the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic structures, such as bicyclic systems, and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the heterocycle as defined above is fused with one or more carbocyclic groups (where the bonding point is on the carbocyclic group or the heterocycle), or ring systems in which the heterocycle as defined above is fused with one or more aryl or heteroaryl groups (where the bonding point is on the heterocycle), and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise stated, each instance of a heterocyclic group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted by one or more substituents (“substituted heterocyclic group”).

[0078] "Aryl" refers to a group in a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups (wherein the group or linker is on the aryl ring), and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise stated, each instance of an aryl is optionally independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0079] "Heteroaryl" refers to a group having a 5-12 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) containing a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-12 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups (where the bonding point is on the heteroaryl ring), and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups (where the connection point is on an aryl ring or a heteroaryl ring), and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have the connection point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0080] "Heteroaryl" is a subset of alkyl and heteroaryl, and refers to an alkyl group that is optionally substituted by a heteroaryl group.

[0081] "Unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. The term "partially unsaturated" ring systems also aims to encompass rings with multiple unsaturated sites, but not to include aromatic groups (e.g., aryl or heteroaryl). Similarly, "saturated" means a group containing no double or triple bonds, i.e., entirely composed of single bonds.

[0082] The prefix "sub" is used to further refer to alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups that are divalent bridging groups, for example, alkylene, alkenylene, alkynylene, carbocyclic, heterocyclic, aryl, and heteroaryl.

[0083] Unless otherwise expressly stated, atoms, portions, or groups described herein may be unsubstituted or substituted, provided that valence permits. The term "optionally substituted" refers to both substituted and unsubstituted atoms.

[0084] In addition, unless otherwise stated, the synthetic reagents and solvents disclosed below were purchased from Bidex Pharmaceuticals and Adamas Reagents; HPLC measurements were performed using an Agilent Technoliges 1290 series; and 1H NMR was performed using a Bruker Ascend 500MHz or 600MHz NMR. Low-resolution and high-resolution mass spectrometry were performed using an Agilent 6125C MS and a Thermo Exactive Plus, respectively. The instruments and reagents used for bioactivity and efficacy evaluation are further described in the bioassay examples below.

[0085] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0086] Synthesis of intermediate S10

[0087] Synthesis of benzyl 2-(benzyloxy)-6-fluorobenzoate (S2):

[0088] 2-Fluoro-6-hydroxybenzoic acid (S1) (25.0 g, 160.3 mmol, 1.0 equivalent) and K2CO3 (66.3 g, 480.8 mmol, 3.0 equivalent) were dissolved in DMF (200.0 mL). Benzyl bromide (54.8 g, 320.6 mmol, 2.0 equivalent) was slowly added dropwise with stirring at room temperature. After 4 hours, the reaction mixture was poured into H2O (200.0 mL) and extracted with DCM (400.0 mL). The organic layer was washed with saturated NaCl solution (3 × 100.0 mL), dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to give a yellow oily S2 (48.5 g, 144.3 mmol, 90% yield), which could be used in the next step without further purification. LC-MS (ESI, m / z): calcd for C 21 H 18 FO3 + 337.1[M+H] +

[0089] Synthesis of 2-benzyloxy-6-fluorobenzoic acid (S3):

[0090] S2 (48.5 g, 144.3 mmol, 1.0 equiv.) was dissolved in 1,4-Dioxane (160.0 mL) and H2O (54.0 mL). NaOH (17.3 g, 432.9 mmol, 3.0 equiv.) was slowly added under stirring at room temperature, and the temperature was raised to 65 °C. After 12 hours, the reaction system gradually changed from turbid to clear. Most of the solvent was removed by concentration, and H2O (200.0 mL) was added to the residue. The aqueous layer was washed with DCM (2 × 100.0 mL). The aqueous layer was acidified with 6M HCl to pH < 4, and the layer changed from clear to white turbidity. The aqueous layer was then extracted with DCM (3 × 150.0 mL), and the organic layers were combined. The mixture was dried over anhydrous Na₂SO₄, filtered, concentrated, and dried to constant weight to obtain yellow crystalline S₃ (28.4 g, 115.4 mmol, yield 80%), which could be used in the next step without further purification. LC-MS (ESI, m / z): calcd for C 14 H 12 FO3 + 247.0 [M+H] +

[0091] Synthesis of (2-benzyloxy-6-fluorophenyl)-tert-butyl carbamate (S4):

[0092] S3 (28.4 g, 115.4 mmol, 1.0 equiv.) was dissolved in toluene (85.0 mL) and t-BuOH (85.0 mL), and TEA (24.0 mL, 173.1 mmol, 1.5 equiv.) was added. DPPA (32.3 mL, 150.0 mmol, 1.3 equiv.) was added dropwise under stirring at room temperature. After 2 hours, the temperature was raised to 100 °C. After 12 hours, the reaction system was cooled to room temperature, and a small amount of H2O (10.0 mL) was added to quench the reaction. Most of the toluene was removed by concentration. H2O (90.0 mL) was added to the residue, and the mixture was extracted with DCM (3 × 150.0 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was purified by a normal-phase preparative method using a rapid purification system (5% v / v EA / PE) to give S4 (28.5 g, 90.0 mmol, yield 78%) as a white solid. LC-MS (ESI, m / z): calcd for C 14 H 13 FNO3 + 262.1 [M-tert-butyl + H] +

[0093] Synthesis of (6-benzyloxy-3-bromo-2-fluorophenyl)-tert-butyl carbamate (S5):

[0094] S4 (5.0 g, 15.8 mmol, 1.0 equiv.) was dissolved in DMF (40.0 mL). NBS (3.4 g, 19.0 mmol, 1.2 equiv.) was slowly added under stirring in an ice bath. The reaction mixture was stirred in an ice bath for 2 hours, then the ice bath was removed. After 24 hours, the reaction mixture was poured into H2O (50.0 mL) and extracted with EA (3 × 100.0 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to obtain a brownish-red powder, S5 (5.1 g, 12.8 mmol, yield 81%), which could be used in the next step without further purification. LC-MS (ESI, m / z): calcd for C 14 H 12 BrFNO3 + 362.0 [M-tert-butyl + Na] +

[0095] Synthesis of [(6-benzyloxy-3-bromo-2-fluorophenyl)-tert-butoxycarbonylamino]-methyl acetate (S6):

[0096] S5 (5.1 g, 12.8 mmol, 1.0 equiv.) was dissolved in DMF (50.0 mL), and K2CO3 (3.5 g, 25.6 mmol, 2.0 equiv.) was added. Methyl 2-bromoacetate (1.8 mL, 19.2 mmol, 1.5 equiv.) was added under stirring at 60 °C. The reaction mixture was monitored by LC-MS every 2 hours, and an equimolar amount of unreacted methyl bromoacetate was added as needed until the reaction was complete. The reaction mixture was cooled to room temperature, and the reaction was quenched with H2O (100.0 mL). Extraction was performed using DCM (3 × 100.0 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to obtain a brownish-red solid, S6 (5.1 g, 11.0 mmol, yield 86%), which could be used in the next step without further purification. LC-MS (ESI, m / z): calcd for C 17 H 16 BrFNO5 + 412.2[M-tert-butyl+H] +

[0097] Synthesis of (6-benzyloxy-3-bromo-2-fluoroaniline)-methyl acetate (S7):

[0098] S6 (5.1 g, 11.0 mmol, 1.0 equiv.) was dissolved in DCM (20.0 mL), and TFA (10.0 mL) was added dropwise under stirring at room temperature. After 1 hour, the reaction was quenched by slowly adding saturated NaHCO3 solution (120.0 mL), allowed to stand, and the organic layer was collected. The aqueous layer was then extracted with DCM (3 × 30.0 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Purification was performed using a normal-phase preparative method (10% v / v EA / PE) via a rapid purification system to give a yellow oily S7 (3.0 g, 8.3 mmol, yield 75%). LC-MS (ESI, m / z): calcd for C 16 H 16 BrFNO3 + 368.2 [M+H] +

[0099] Synthesis of methyl 2-{[6-(benzyloxy)-3-bromo-2-fluorophenyl](tert-butoxycarbonylaminosulfonamide)amino}acetate (S8):

[0100] Chlorosulfonyl isocyanate (1.0 mL, 11.6 mmol, 1.4 equiv.) was dissolved in DCM (8.0 mL), and t-BuOH (1.1 mL, 11.6 mmol, 1.4 equiv.) was added dropwise under ice bath stirring. After 30 minutes, a solution of S7 (3.0 g, 8.3 mmol, 1.0 equiv.) and TEA (2.3 mL, 16.5 mmol, 2.0 equiv.) in DCM (8.0 mL) was slowly added dropwise through a dropping funnel. After 2 hours, the reaction was quenched by adding H2O (15.0 mL), allowed to stand, and the organic layer was collected. The aqueous layer was then extracted with DCM (2 × 10.0 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to give a yellow oily substance S8, which could be used for the next step without further purification. LC-MS (ESI, m / z): calcd for C 17 H 17 BrFN2O7S + 491.0 [M-tert-butyl+H] +

[0101] Synthesis of methyl 2-{[6-(benzyloxy)-3-bromo-2-fluorophenyl](aminosulfonamide)amino}acetate (S9):

[0102] S8 was dissolved in DCM (20.0 mL), and TFA (10.0 mL) was added dropwise under stirring at room temperature. After 1 hour, the reaction was quenched by slowly adding saturated NaHCO3 solution (110.0 mL), allowed to stand, and the organic layer was collected. The aqueous layer was then extracted with DCM (3 × 50.0 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Purification was performed using a normal-phase preparative method (15% v / v EA / PE) via a rapid purification system to give a yellow oily S9 (2.7 g, 6.1 mmol, two-step yield 74%). LC-MS (ESI, m / z): calcd for C 16 H 17 BrFN2O5S + 448.2 [M+H] +

[0103] 5-[6-(benzyloxy)-3-bromo-2-fluorophenyl]-2-[(benzyloxy)methyl]-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (S10):

[0104] S9 (2.7 g, 6.1 mmol, 1.0 equiv.) was dissolved in THF (30.5 mL), and t-BuOK solution (6.7 mL, 6.7 mmol, 1.1 equiv.) (1.0 mol / L in THF) was added dropwise under stirring at room temperature. After 3 hours, BOMCl (1.2 mL, 9.2 mmol, 1.5 equiv.) was added dropwise to the reaction system. After 5 hours, the reaction was quenched by adding H2O (40.0 mL), and extracted with DCM (3 × 50.0 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The solution was purified by a normal-phase preparative method (20% v / v EA / PE) using a rapid purification system to give S10 (2.8 g, 5.2 mmol, yield 85%) as a yellow solid. LC-MS (ESI, m / z): calcd for C 23 H 19 BrFN2O5S - 534.3 [MH] -

[0105] Synthesis of intermediate K11

[0106] Synthesis of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (K2):

[0107] 5-Bromo-1,3-difluoro-2-nitrobenzene (K1) (25.0 g, 105.5 mmol, 1.0 equiv.) was dissolved in MeOH (250.0 mL), and KOH (65.1 g, 116.0 mmol, 1.1 equiv.) was added with stirring at room temperature. The mixture was then heated to 90 °C. After 4 hours, the reaction mixture was cooled to room temperature, and the reaction was quenched with H2O (1000.0 mL). The mixture was then extracted with EA (3 × 250.0 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to give K2 (26.0 g, 104.4 mmol, 99% yield), which could be used in the next step without further purification. LC-MS (ESI, m / z): calcd for C7H6BrFNO3 + 249.3 [M+H] +

[0108] Synthesis of 1-fluoro-3-methoxy-5-methyl-2-nitrobenzene (K3):

[0109] K₂ (26.0 g, 104.4 mmol, 1.0 equiv.) was dissolved in 1,4-Dioxane (450.0 mL) and H₂O (45.0 mL). Methylboric acid (8.1 g, 135.7 mmol, 1.3 equiv.), Cs₂CO₃ (129.2 g, 396.7 mmol, 3.8 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.6 g, 10.4 mmol, 0.1 equiv.) were added under stirring at room temperature. The mixture was heated to 100 °C under nitrogen protection. After 16 hours, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and rinsed with EA (50.0 mL). The filtrate was added to H₂O (300.0 mL) and extracted with EA (3 × 150.0 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. K3 (17.2 g, 92.9 mmol, 89% yield) was purified by normal-phase preparative method using a rapid purification system (15% v / v EA / PE). LC-MS (ESI, m / z): calcd for C8H9FNO3 + 185.9 [M+H] +

[0110] Synthesis of 3-fluoro-2-iodo-5-methoxy-1-methyl-4-nitrobenzene (K4):

[0111] K3 (17.2 g, 92.9 mmol, 1.0 equiv.) was dissolved in ACN (170.0 mL), and NIS (62.7 g, 278.7 mmol, 3.0 equiv.) and TFA (2.0 mL) were added under stirring at room temperature. The mixture was then heated to 80 °C. After 16 hours, the reaction mixture was cooled to room temperature, and the reaction was quenched by adding saturated sodium thiosulfate solution (220.0 mL) dropwise under stirring. Extraction was performed by adding EA (3 × 200.0 mL). The combined organic layers were washed with saturated NaCl solution (200.0 mL), dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to give K4 (35.2 g, 113.3 mmol, yield 122%), which could be used for the next step without further purification. LC-MS (ESI, m / z): calcd for C8H6FINO3 - 309.8 [MH] -

[0112] Synthesis of 3-fluoro-4-iodo-5-methyl-2-nitrophenol (K5):

[0113] K4 (10.0 g, 32.2 mmol, 1.0 equiv.) was dissolved in DCM (95.0 mL), and then BBr3 (96.6 mL, 96.6 mmol, 3.0 equiv.) (1.0 mol / L in DCM) was added dropwise under stirring at 0 °C, and the mixture was heated to room temperature. After 30 minutes, DCM (100.0 mL) was added for dilution, and the reaction was quenched with H2O (200.0 mL). The mixture was allowed to stand, and the organic layer was collected. The aqueous layer was extracted again with DCM (3 × 50.0 mL), and the combined organic layers were washed with saturated NaCl solution (2 × 100.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was purified by a normal-phase preparative method (10% v / v EA / PE) using a rapid purification system to give K5 (8.3 g, 28.0 mmol, yield 87%). LC-MS (ESI, m / z): calcd for C7H4FINO3 - 295.8 [MH] -

[0114] Synthesis of 1-(benzyloxy)-3-fluoro-4-iodo-5-methyl-2-nitrotoluene (K6):

[0115] K5 (8.3 g, 28.0 mmol, 1.0 equiv.) was dissolved in DMF (76.0 mL). K2CO3 (4.6 g, 33.6 mmol, 1.2 equiv.) and benzyl bromide (3.3 mL, 28.0 mmol, 1.0 equiv.) were added under stirring at room temperature, and the mixture was heated to 60 °C. After 1 hour, the reaction mixture was cooled to room temperature, diluted with H2O (100.0 mL), and extracted with EA (3 × 100.0 mL). The combined organic layers were washed with saturated NaCl solution (2 × 50.0 mL), dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to give K6 (7.3 g, 18.8 mmol, yield 67%), which could be used in the next step without further purification.

[0116] Synthesis of 6-(benzyloxy)-2-fluoro-3-iodo-4-methylaniline (K7):

[0117] K6 (7.3 g, 18.8 mmol, 1.0 equivalent) was dissolved in EtOH (60.0 mL) and H2O (20.0 mL). NH4Cl (10.1 g, 188.0 mmol, 10.0 equivalent) and iron powder (5.3 g, 94.0 mmol, 5.0 equivalent) were added sequentially with stirring at room temperature, and the mixture was heated to 80 °C. After 1 hour, the reaction mixture was cooled to room temperature, diluted with H2O (40.0 mL), and extracted with EA (3 × 100.0 mL). The combined organic layers were washed with saturated NaCl solution (2 × 50.0 mL), dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to give K7 (6.0 g, 16.9 mmol, 90% yield), which could be used in the next step without further purification. LC-MS (ESI, m / z): calcd for C 14 H 14 FINO + 357.8 [M+H] +

[0118] Synthesis of methyl 2-{[6-(benzyloxy)-2-fluoro-3-iodo-4-methylphenyl]amino}acetate (K8):

[0119] K7 (6.0 g, 16.9 mmol, 1.0 equiv.) was dissolved in DMF (60.0 mL). K2CO3 (5.8 g, 42.3 mmol, 2.5 equiv.) and methyl 2-bromoacetate (6.4 mL, 67.6 mmol, 4.0 equiv.) were added under stirring at room temperature, and the mixture was heated to 60 °C. After 16 hours, the reaction mixture was cooled to room temperature, and the reaction was quenched with H2O (100.0 mL). Extraction was performed with EA (3 × 100.0 mL), and the organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Purification was performed using a normal-phase preparative method (5% v / v EA / PE) via a rapid purification system to obtain K8 (4.0 g, 9.3 mmol, yield 55%). LC-MS (ESI, m / z): calcd for C 17 H 18 FINO3 + 429.9 [M+H] +

[0120] Synthesis of methyl 2-{[6-(benzyloxy)-2-fluoro-3-iodo-4-methylphenyl](tert-butoxycarbonylaminosulfonamide)amino}acetate (K9):

[0121] Chlorosulfonyl isocyanate (1.2 mL, 14.0 mmol, 1.5 equiv.) was dissolved in DCM (18.8 mL), and t-BuOH (1.6 mL, 16.7 mmol, 1.8 equiv.) was added dropwise under ice bath stirring. After 30 minutes, a solution of K8 (4.0 g, 9.3 mmol, 1.0 equiv.) and TEA (2.6 mL, 18.6 mmol, 2.0 equiv.) in DCM (18.6 mL) was slowly added dropwise through a dropping funnel, and the mixture was heated to room temperature. After 1 hour, the reaction was quenched by adding H2O (40.0 mL), allowed to stand, and the organic layer was collected. The aqueous layer was then extracted with DCM (3 × 20.0 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to obtain K9, which could be used for the next step without further purification. LC-MS (ESI, m / z): calcd for C 18 H 19 FIN2O7S + 553.0 [M-tert-butyl+H] +

[0122] Synthesis of methyl 2-{[6-(benzyloxy)-2-fluoro-3-iodo-4-methylphenyl](aminosulfonamide)amino}acetate (K10):

[0123] K9 was dissolved in DCM (20.0 mL), and TFA (10.0 mL) was added dropwise under stirring at room temperature. After 1 hour, the reaction was quenched by slowly adding saturated NaHCO3 solution (110.0 mL), allowed to stand, and the organic layer was collected. The aqueous layer was then extracted with DCM (3 × 50.0 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. K10 was purified by a normal-phase preparative method using a rapid purification system (20% v / v EA / PE) to give K10 (2.8 g, 5.6 mmol, 60% yield in two steps). LC-MS (ESI, m / z): calcd for C 17 H 19 FIN₂O₅S + 509.2 [M + H] +

[0124] 5-[6-(benzyloxy)-2-fluoro-3-iodo-4-methylphenyl]-2-[(benzyloxy)methyl]-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (K11):

[0125] K10 (2.8 g, 5.6 mmol, 1.0 equiv.) was dissolved in THF (30.0 mL), and t-BuOK solution (5.6 mL, 5.6 mmol, 1.0 equiv.) (1.0 mol / L in THF) was added dropwise under stirring at room temperature. After 20 minutes, BOMCl (1.1 mL, 8.4 mmol, 1.5 equiv.) was added dropwise to the reaction system. After 5 hours, the reaction was quenched by adding H2O (40.0 mL), and extracted with DCM (3 × 50.0 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. K11 (2.6 g, 4.4 mmol, 78% yield) was obtained by a normal-phase preparative purification method using a rapid purification system (10% v / v MeOH / DCM). LC-MS (ESI, m / z): calcd for C 24 H 21 FIN2O5S - 595.6 [MH] -

[0126] 5-[6-(benzyloxy)-2-fluoro-3-(pyrrolidine-3-ethynyl)phenyl]-2-[(benzyloxy)methyl]-1λ 6 Synthesis of 2,5-thiadiazol-3-one-1,1-dioxide (S11):

[0127] S10 (500.00 mg, 0.94 mmol, 1.00 equiv.) was dissolved in DMF (3.00 mL). Under stirring at room temperature, palladium dichloride bis(triphenylphosphine) chloride (33.00 mg, 0.05 mmol, 0.05 equiv.), CuI (8.93 mg, 0.05 mmol, 0.05 equiv.), and TEA (0.39 mL, 2.82 mmol, 3.00 equiv.) were added. The reaction system was heated to 65 °C under argon protection, and a DMF (1.00 mL) solution of 1-Boc-3-ynylpyrrolidine (220.00 mg, 1.13 mmol, 1.20 equiv.) was slowly added dropwise over 90 minutes using a dropping funnel. After 5 hours, the reaction system was cooled to room temperature, and the reaction was quenched by adding H2O (10.00 mL). Extraction was performed with EA (3 × 10.00 mL), and the combined organic layers were washed with saturated NH4Cl solution (2 × 10.00 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification was carried out using a normal-phase preparative method (25% v / v PE / EA) via a rapid purification system to give a yellow oil (204.15 mg, 0.31 mmol, yield 33%). LC-MS (ESI, m / z): 672.3 [M + Na] +

[0128] The yellow oily substance from the previous step was dissolved in DCM (4.00 mL), and TFA (2.00 mL) was added dropwise under stirring at room temperature. After 15 minutes, the reaction was quenched by slowly adding saturated NaHCO3 solution (20.00 mL), allowed to stand, and the organic layer was collected. The aqueous layer was then extracted again with DCM (3 × 20.00 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to give S11 (161.68 mg, 0.29 mmol, yield 95%), which could be used in the next step without further purification. LC-MS (ESI, m / z): 550.2 [M+H] +

[0129] Synthesis of 5-[6-(benzyloxy)-2-fluoro-4-methyl-3-(pyrrolidine-3-ethynyl)phenyl]-2-[(benzyloxy)methyl]-1,2,5-thiadiazol-3-one-1,1-dioxide (K12):

[0130] Following the synthesis method for S11, K12 (225.95 mg, 0.40 mmol, two-step yield 48%) was synthesized from K11 (500.00 mg, 0.84 mmol, 1.00 equiv.). LC-MS (ESI, m / z): 564.5 [M+H] +

[0131] 5-[6-(benzyloxy)-2-fluoro-3-(piperidin-4-ethynyl)phenyl]-2-[(benzyloxy)methyl]-1λ 6 Synthesis of 2,5-thiadiazol-3-one-1,1-dioxide (S12):

[0132] Following the synthesis method of S11, S12 (180.16 mg, 0.32 mmol, two-step yield 34%) was synthesized from S10 (500.00 mg, 0.94 mmol, 1.00 equiv.). LC-MS (ESI, m / z): 564.1 [M+H] +

[0133] Synthesis of 2-(4-(4-(benzyloxy))-3-(5-((benzyloxy)methyl)-1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluorophenyl)ethynyl)-1H-pyrazol-1-yl)acetaldehyde (S13):

[0134] 4-Ethyrynpyrazole (100.00 mg, 1.09 mmol, 1.00 equiv.) was dissolved in ACN (2.00 mL). K₂CO₃ (450.68 mg, 3.26 mmol, 3.00 equiv.) and 3-bromo-1,1-diethoxypropane (251.79 mg, 1.20 mmol, 1.10 equiv.) were added under stirring at room temperature, and the mixture was heated to 60 °C. After 5 hours, the reaction mixture was cooled to room temperature, and the reaction was quenched by adding H₂O (0.50 mL). The mixture was concentrated and purified using a normal-phase preparative method (10% v / v PE / EA) via a rapid purification system to obtain a transparent, colorless oil (215.36 mg, 0.97 mmol, yield 89%).

[0135] S10 (200.00 mg, 0.37 mmol, 1.00 equiv.) was dissolved in DMF (2.00 mL). Under stirring at room temperature, palladium dichloride bis(triphenylphosphine) chloride (12.99 mg, 0.02 mmol, 0.05 equiv.), CuI (3.81 mg, 0.02 mmol, 0.05 equiv.), and TEA (0.15 mL, 1.11 mmol, 3.00 equiv.) were added. The reaction system was heated to 80 °C under argon protection. Over 90 minutes, a DMF (1.00 mL) solution of the colorless oily substance (98.57 mg, 0.44 mmol, 1.20 equiv.) prepared in the first step was slowly added dropwise using a dropping funnel. After 5 hours, the reaction system was cooled to room temperature, and the reaction was quenched by adding H2O (10.00 mL). Extraction was performed with EA (3 × 10.00 mL), and the combined organic layers were washed with saturated NH4Cl solution (2 × 10.00 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification was carried out using a normal-phase preparative method with a rapid purification system (25% v / v PE / EA) to give a yellow oil (77.62 mg, 0.11 mmol, yield 31%). LC-MS (ESI, m / z): 675.2 [MH] -

[0136] The yellow oily substance from the previous step was dissolved in 4M HCl in 1,4-Dioxane (2.00 mL) and reacted with stirring at room temperature. After 15 minutes, the reaction was quenched by slowly adding saturated NaHCO3 solution (10.00 mL), allowed to stand, and the organic layer was collected. The aqueous layer was then extracted with DCM (3 × 20.00 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to give S13 (51.76 mg, 0.09 mmol, yield 80%), which could be used in the next step without further purification. LC-MS (ESI, m / z): 587.6 [MH] -

[0137] Example 1

[0138] 5-(4-((3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (GBA-01-17)

[0139] S11 (50.00 mg, 0.15 mmol, 1.00 equivalent) was dissolved in NMP (3.00 mL). 17a (57.08 mg, 0.15 mmol, 1.00 equivalent) was added with stirring at room temperature, followed by the addition of NaBH(OAc)3 (38.16 mg, 0.18 mmol, 1.20 equivalent) in three portions. After 30 minutes, the reaction was quenched by dropwise addition of H2O, and the mixture was extracted with EA (3 × 10.00 mL). The combined organic layers were washed with saturated NaCl solution (2 × 10.00 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a yellow-green solid (99.36 mg, 0.11 mmol, yield 72%), which could be used in the next step without further purification. LC-MS (ESI, m / z): calcd for C 48 H 47 F2N6O9S + 921.2[M+H] +

[0140] Compound 17a was prepared according to a synthetic method reported in known literature (WO2022143856).

[0141] The yellow-green solid obtained in the previous step (99.36 mg, 0.11 mmol, 1.00 equiv.) was dissolved in DCM (2.00 mL), and PMB (64.68 mg, 0.44 mmol, 4.00 equiv.) was added. The reaction mixture was protected with argon and cooled to -78 °C. BCl3 solution (0.88 mL, 0.88 mmol, 8.00 equiv.) (1.0 mol / L in DCM) was added dropwise with stirring. After 15 minutes, the reaction was quenched dropwise with 20% v / v EtOH / DCM at -78 °C. The mixture was promptly concentrated and purified using a reverse-phase preparative method with a Biotage Isolera One chromatograph (10%–100% v / v ACN / H2O with 0.1% TFA) to obtain GBA-01-17 (25.78 mg, 0.04 mmol, yield 33%). 1H NMR (500MHz, DMSO-d6) δ11.11(s,1H),10.20(s,1H),7.73(d,J=11.2Hz,1H),7.48( d,J=7.3Hz,1H),7.24(t,J=8.2Hz,1H),6.70(d,J=8.7Hz,1H),5.11(dd,J=12.9,5.5 Hz,1H),4.01(s,2H),3.65(d,J=11.9Hz,4H),3.19(d,J=34.5Hz,4H),2.91(q,J=20. 9,16.6Hz,4H),2.74(s,1H),2.20–1.79(m,6H),1.45–1.12(m,3H).HRMS(ESI)calcd for C 33 H 33 F2N6O8S + 711.2043[M+H] + ,found 711.2036.

[0142] Example 2

[0143] 4-(4-((3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GBA-01-18)

[0144] Following the synthesis method of Example 1, GBA-01-18 was synthesized using S11 and 18a as raw materials (two-step yield 26%). 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.67(s,1H),7.72–7.66(m,1H),7.39– 7.26(m,3H),6.73(d,J=8.7Hz,1H),5.12–5.07(m,1H),4.20(s,2H),3.66–3. 44(m,5H),3.28–3.10(m,2H),3.07–2.83(m,4H),2.66–2.53(m,3H),2.47–2. 14(m,1H),2.07–1.68(m,6H),1.45(q,J=12.7,12.3Hz,1H).HRMS(ESI)calcd for C 33 H 34 FN6O8S + 693.2137[M+H] + ,found693.2133.

[0145] Compound 18a was prepared according to a synthetic method reported in known literature (10.1016 / j.ejmech.2022.114544).

[0146] Example 3

[0147] 4-(4-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GBA-01-19)

[0148] S11 (50.00 mg, 0.15 mmol, 1.00 equivalent) was dissolved in DMF (3.00 mL). 19a (60.00 mg, 0.15 mmol, 1.00 equivalent), DIPEA (104.31 mL, 0.60 mmol, 4.00 equivalent), and PyBop (85.80 mg, 0.17 mmol, 1.10 equivalent) were added under stirring at room temperature. The reaction was quenched dropwise with H2O after 15 minutes, and the mixture was extracted with EA (3 × 10.00 mL). The combined organic layers were washed with saturated NaCl solution (2 × 10.00 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a yellow-green solid (111.72 mg, 0.12 mmol, 80% yield). No further purification was required for the next step. LC-MS (ESI, m / z): calcd for C 48 H 47 FN7O 10 S + 931.9[M+H] +

[0149] Among them, compounds 19a and 21a were prepared by synthetic methods reported in known literature (WO2021207291).

[0150] The yellow-green solid obtained in the previous step (111.72 mg, 0.12 mmol, 1.00 equiv.) was dissolved in DCM (2.00 mL), and PMB (70.56 mg, 0.48 mmol, 4.00 equiv.) was added. The reaction mixture was protected with argon and cooled to -78 °C. BCl3 solution (0.96 mL, 0.96 mmol, 8.00 equiv.) (1.0 mol / L in DCM) was added dropwise with stirring. After 15 minutes, the reaction was quenched dropwise with 20% v / v EtOH / DCM at -78 °C. The mixture was promptly concentrated and purified using a reverse-phase preparative method with a Biotage Isolera One chromatograph (10%–100% v / v ACN / H2O with 0.1% TFA) to obtain GBA-01-19 (32.88 mg, 0.05 mmol, yield 38%).

[0151] 1 H NMR(500MHz,DMSO-d6)δ11.11(s,1H),10.06(d,J=4.5Hz,1H),7.80–7.75(m,1H) ,7.49–7.40(m,2H),7.21(t,J=8.3Hz,1H),6.70–6.64(m,1H),5.11(dd,J=12.8, 5.5Hz,1H),3.96(s,2H),3.90–3.42(m,11H),3.14–3.07(m,1H),2.94–2.85(m,1 H),2.65–2.53(m,2H),2.35–1.93(m,4H),1.18(t,J=7.3Hz,2H).HRMS(ESI)calcd for C 33 H 33 FN7O9S + 722.2039[M+H] + ,found 722.2031.

[0152] Example 4

[0153] 3-(5-(1-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)-1H-pyrazol-1-yl)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (GBA-01-20)

[0154] Following the synthesis method of Example 1, GBA-01-20 was synthesized using S13 and 20a as raw materials (two-step yield 22%).1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),10.29(s,1H),9.50(s,1H),8.25(s,1H),7.84(s ,1H),7.31(t,J=8.3Hz,1H),7.15–6.82(m,3H),6.73(d,J=8.7Hz,1H),5.36(dd,J=12.9 ,5.4Hz,1H),4.63(t,J=6.3Hz,2H),4.06(s,2H),3.69–3.62(m,3H),3.34(s,3H),3.19– 3.07(m,2H),2.97–2.56(m,4H),2.15–1.72(m,5H),1.43–1.06(m,1H).HRMS(ESI)calcd for C 33 H 34 FN8O7S + 705.2250[M+H] + ,found 725.2244.

[0155] Among them, compounds 20a, 22a, and 33a were prepared by synthetic methods reported in known literature (WO2021127586).

[0156] Example 5

[0157] 4-(4-(2-(4-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GBA-01-21)

[0158] Following the synthesis method of Example 1, GBA-01-21 was synthesized using S13 and 21a as raw materials (two-step yield 24%). 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),10.21(s,1H),8.23(s,1H),7.83(s,1H),7.77(t,J=7.8Hz,1H),7 .44(dd,J=20.5,7.7Hz,2H),7.30(t,J=8.3Hz,1H),6.72(d,J=8.6Hz,1H),5.11(dd,J=12.8,5.5Hz,1H) ,4.61(t,J=6.2Hz,2H),4.03(s,2H),3.87–3.46(m,8H),2.89(ddd,J=17.0,13.9,5.4Hz,1H),2.67–2.5 2(m,2H),2.09–1.98(m,1H),1.81–1.42(m,1H),1.34–1.14(m,1H),1.10–0.78(m,1H).HRMS(ESI)calcd for C 32 H 30 FN8O8S + 705.1886[M+H] + ,found 705.1883.

[0159] Example 6

[0160] 3-(5-(1-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)-2-oxoethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (GBA-01-22)

[0161] Following the synthesis method of Example 3, GBA-01-22 was synthesized using S11 and 22a as raw materials (two-step yield 35%). 1H NMR (500MHz, DMSO-d6) δ11.10 (s, 1H), 10.07 (d, J = 7.5Hz, 1H), 9.58 (s, 1H), 7.24–7.19 (m, 1H), 7.11–7. 04(m,2H),6.94(d,J=8.3Hz,1H),6.68(dd,J=8.8,3.4Hz,1H),5.36(dd,J=12.9,5.5Hz,1H),3.97(s,2H) ,3.65–3.47(m,6H),3.14(d,J=10.0Hz,2H),2.96–2.83(m,2H),2.76–2.60(m,3H),2.40–2.15(m,2H),2 .14–1.92(m,6H),1.76(s,1H),1.26(dd,J=14.0,6.4Hz,2H),1.17–1.04(m,1H).LC-MS(ESI,m / z):calcd for C 34 H 37 FN7O8S + 722.6[M+H] +

[0162] Example 7

[0163] 3-(6-(1-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)-2-oxoethyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (GBA-01-23)

[0164] Following the synthesis method of Example 3, GBA-01-23 was synthesized using S11 and 23a as raw materials (two-step yield 35%). 1H NMR (500MHz, DMSO-d6) δ11.14(s,1H),10.14(s,1H),9.70(s,1H),8.53(d,J=8.4Hz,1H),8.14(d,J=6.9Hz,1H) ,7.90(t,J=7.6Hz,1H),7.37(d,J=7.5Hz,1H),7.26–7.11(m,2H),6.68(dd,J=8.7,4.5Hz,1H),5.46(dd,J=13. 1,5.4Hz,1H),4.42–4.21(m,2H),4.00(s,2H),3.86–3.46(m,9H),3.06–2.89(m,1H),2.84–2.64(m,2H),2.41– 2.15(m,3H),2.14–2.06(m,3H),1.98(ddd,J=15.8,11.2,8.1Hz,1H),1.25(d,J=12.2Hz,1H).HRMS(ESI)calcd for C 37 H 36 FN6O8S + 743.2294[M+H] + ,found 743.2287.

[0165] Compounds 23a and 43a were prepared according to the synthetic method reported in known literature (WO2021127586).

[0166] Example 8

[0167] 4-(6-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)-2-azaspiro[3.3]heptane-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GBA-01-30)

[0168] Following the synthesis method of Example 1, GBA-01-30 was synthesized using S11 and 30a as raw materials (two-step yield 24%). 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),10.16(s,1H),7.64–7.54(m,1H),7.24(t,J=8.3Hz,1H),7.14( d,J=7.0Hz,1H),6.80(dd,J=8.6,5.6Hz,1H),6.70(d,J=8.7Hz,1H),5.05(dd,J=12.8,5.5Hz,1H),4. 21(d,J=26.5Hz,3H),3.99(s,2H),3.94–3.47(m,5H),3.12(d,J=70.4Hz,2H),2.88(ddd,J=17.5,13. 9,5.4Hz,1H),2.67–2.53(m,3H),2.47–2.11(m,3H),2.10–1.90(m,2H),1.24(s,1H).HRMS(ESI)calcd for C 33 H 32 FN6O8S + 691.1981[M+H] + ,found691.1976.

[0169] Compound 30a was prepared according to a synthetic method reported in known literature (WO2022251224).

[0170] Example 9

[0171] 3-(6-(1-(3-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-carbonyl)cyclobutyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (GBA-01-31)

[0172] 43a (100.00 mg, 0.28 mmol, 1.00 equiv.) was dissolved in NMP (4.00 mL), and 3-oxocyclobutanecarboxylic acid (31.40 mg, 0.28 mmol, 1.00 equiv.) was added under stirring at room temperature, followed by the addition of NaBH(OAc)3 (71.23 mg, 0.34 mmol, 1.20 equiv.) in three portions. After 30 minutes, the reaction was quenched by dropwise addition of H2O, and the mixture was extracted with EA (3 × 20.00 mL). The combined organic layers were washed with saturated NaCl solution (2 × 20.00 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 31a (110.64 mg, 0.24 mmol, yield 87%), which could be used in the next step without further purification. LC-MS (ESI, m / z): calcd for C 26 H 28 N3O5 + 462.5 [M+H] +

[0173] Following the synthesis method of Example 3, GBA-01-31 was synthesized using K12 and 31a as raw materials (two-step yield 34%). 1 H NMR(500MHz,DMSO-d6)δ11.14(s,1H),8.55–8.46(m,1H),8.13(d,J=6.9Hz,1H), 7.89(t,J=7.7Hz,1H),7.34(t,J=6.5Hz,1H),7.15(d,J=7.4Hz,1H),6.63(s,1H) ,5.46(dd,J=13.1,5.4Hz,1H),4.10(d,J=4.0Hz,2H),3.81–3.64(m,5H),3.13–2 .53(m,11H),2.27(s,3H),2.26–1.75(m,8H),1.40–1.17(m,3H).HRMS(ESI)calcd for C 41 H 42 FN6O8S + 797.2763[M+H] + ,found 797.2757.

[0174] Example 10

[0175] 5-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonane-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (GBA-01-32)

[0176] Following the synthesis method of Example 1, GBA-01-32 was synthesized using S11 and 32a as raw materials (two-step yield 19%). 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),10.33(d,J=57.2Hz,2H),7.66(d,J=8.5Hz,1H),7.34(d,J=2.3Hz,1H),7.25(t, J=8.4Hz,2H),6.71(d,J=8.7Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.06–4.02(m,2H),3.99–3.82(m,2H),3.72–3.60(m ,2H),3.18(d,J=11.3Hz,1H),3.09–3.02(m,1H),2.89(ddd,J=16.6,13.6,5.4Hz,1H),2.65–2.54(m,2H),2.47–2.33( m,1H),2.23(tdd,J=20.3,13.2,8.1Hz,3H),2.07–1.75(m,5H),1.67–1.60(m,4H),1.37–1.07(m,2H).HRMS(ESI)calcd for C 35 H 36 FN6O8S + 719.2294[M+H] + ,found 719.2291.

[0177] Compound 32a was prepared according to a synthetic method reported in known literature (10.1021 / acs.jmedchem.3c01789).

[0178] Example 11

[0179] 3-(5-(1-(3-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-carbonyl)cyclobutyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (GBA-01-33)

[0180] Following the synthesis method of Example 3, GBA-01-33 was synthesized using S11 and 33a as raw materials (two-step yield 33%). 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.45(s,1H),7.34–7.19(m,1H),7.13–7.00(m,2H),6.91(d,J=8.0Hz,1H ),6.72(d,J=8.5Hz,1H),5.36(dd,J=12.9,5.4Hz,1H),4.25–4.20(m,2H),4.03(d,J=7.1Hz,1H),3.80–3.74(m, 1H),3.67–3.57(m,2H),3.54–3.37(m,4H),3.26(d,J=18.4Hz,1H),3.07(t,J=9.2Hz,1H),2.99–2.74(m,4H),2 .73–2.52(m,3H),2.47–2.15(m,4H),2.09–1.95(m,4H),1.94–1.76(m,3H),1.26–1.15(m,1H).HRMS(ESI)calcd for C 37 H 41 FN7O8S + 762.2716[M+H] + ,found 762.2712.

[0181] Example 12

[0182] 6-(3-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-carbonyl)cyclobutyl)-2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (GBA-01-34)

[0183] Following the synthesis method of Example 3, GBA-01-34 was synthesized using S11 and 34a as raw materials (two-step yield 24%). 1 H NMR (500MHz, DMSO-d6) δ11.15(s,1H),7.97(d,J=9.3Hz,2H),7.24(t,J=8.2Hz,1H),6.70(dd,J=8.7,2.9Hz,1H),5.18(dd,J=12 .8,5.4Hz,1H),4.20–4.02(m,3H),3.55–3.29(m,9H),3.19–2.85(m,2H),2.75–2.52(m,5H),2.37–1.85(m,4H).HRMS(ESI)calcd for C 34 H 32FN6O9S + 719.1930[M+H] + ,found 719.1929.

[0184] Compound 34a was prepared according to a synthetic method reported in known literature (WO2022187588).

[0185] Example 13

[0186] 3-(6-(1-(2-(4-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (GBA-01-40)

[0187] Following the synthesis method of Example 3, GBA-01-40 was synthesized using S12 and 23a as raw materials (two-step yield 33%). 1 H NMR (500MHz, DMSO-d6) δ11.14(s,1H),9.99(s,1H),9.54(s,1H),8.54(d,J=8.4Hz,1H),8.14(d,J=6.8Hz,1H),7.90(t,J=7.8Hz ,1H),7.37(d,J=7.5Hz,1H),7.17(dd,J=23.0,7.7Hz,2H),6.67(d,J=8.7Hz,1H),5.47(d,J=12.8Hz,1H),5.33(t,J=5.1Hz,1H), 4.45(d,J=48.3Hz,2H),3.96(s,2H),3.61(d,J=32.3Hz,4H),3.42(d,J=9.5Hz,2H),3.06–2.94(m,2H),2.81–2.65(m,2H),2.23 (s,2H),2.10(d,J=5.5Hz,2H),2.02–1.91(m,4H),1.77–1.71(m,1H),1.60(d,J=9.7Hz,1H),1.49–1.42(m,1H).HRMS(ESI)calcd for C 38 H 38 FN6O8S + 757.2450[M+H] + ,found 757.2446.

[0188] Example 14

[0189] 3-(6-(1-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-yl)-2-oxoethyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (GBA-01-41)

[0190] Following the synthesis method of Example 3, GBA-01-41 was synthesized using K12 and 23a as raw materials (two-step yield 29%). 1 H NMR (500MHz, DMSO-d6) δ11.15(s,1H),9.95(s,1H),9.71(s,1H),8.54(d,J=8.3Hz,1H),8.14(d,J=6.9Hz,1H),7.90(t,J=7 .6Hz,1H),7.37(d,J=7.5Hz,1H),7.15(d,J=7.4Hz,1H),6.61(d,J=4.1Hz,1H),5.47(dd,J=13.0,5.4Hz,1H),4.45–4.22(m ,2H),3.98(d,J=4.3Hz,2H),3.87–3.44(m,10H),2.97(ddd,J=17.4,13.3,5.4Hz,1H),2.81–2.71(m,1H),2.71–2.64(m,1H ),2.44–2.30(m,1H),2.29(d,J=4.9Hz,3H),2.22(d,J=13.7Hz,2H),2.13–2.06(m,3H),2.04–1.91(m,1H).HRMS(ESI)calcd for C 38 H 38 FN6O8S + 757.2450[M+H] + ,found757.2443.

[0191] Example 15

[0192] 3-(6-(1-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-yl)acetyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (GBA-01-43)

[0193] K12 (100.00 mg, 0.18 mmol, 1.0 equiv.) was dissolved in DMF (2.00 mL). TEA (0.12 mL, 0.89 mmol, 5.00 equiv.) and tert-butyl 2-bromoacetate (42.12 mg, 0.22 mmol, 1.20 equiv.) were added under stirring at room temperature, and the mixture was heated to 60 °C. After 5 hours, the reaction mixture was cooled to room temperature, and the reaction was quenched with H2O (10.0 mL). Extraction was performed with EA (3 × 10.0 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to give a yellowish-brown oil (109.67 mg, 0.16 mmol, 90% yield). No further purification was required, and TE could be used for the next step. LC-MS (ESI, m / z): calcd for C 36 H 41 FN3O7S + 678.2 [M+H] +

[0194] The yellow oily substance from the previous step was dissolved in DCM (2.00 mL), and TFA (1.00 mL) was added dropwise under stirring at room temperature. After 15 minutes, the reaction was quenched by slowly adding saturated NaHCO3 solution (10.00 mL), allowed to stand, and the organic layer was collected. The aqueous layer was then extracted again with DCM (3 × 10.00 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to obtain a brownish-red oily K13, which could be used in the next step without further purification. LC-MS (ESI, m / z): calcd for C 32 H 33 FN3O7S + 622.5 [M+H] +

[0195] Following the synthesis method of Example 3, GBA-01-43 was synthesized using K13 and 43a as raw materials (two-step yield 35%). 1H NMR (600MHz, DMSO-d6) δ11.13(s,1H),10.39–9.93(m,2H),8.52(d,J=8.3Hz,1H),8.13(d,J=7.0Hz,1H),7.89(t,J=7.7Hz,1H),7 .34(d,J=7.3Hz,1H),7.12(d,J=7.6Hz,1H),6.63(s,1H),5.76(s,1H),5.45(dd,J=13.2,5.4Hz,1H),4.62–4.41(m,3H),4.09(s,2 H),3.79–3.65(m,4H),3.26(d,J=12.9Hz,3H),2.99–2.91(m,2H),2.79–2.71(m,1H),2.69–2.62(m,1H),2.46–2.38(m,1H),2.31 (s,3H),2.15(ddd,J=64.4,11.9,5.8Hz,2H),1.96(d,J=12.8Hz,2H),1.79(d,J=27.8Hz,1H),1.68–1.59(m,1H).HRMS(ESI)calcd for C 38 H 38 FN6O8S + 757.2450[M+H] + ,found 757.2448.

[0196] Example 16

[0197] The synthesis of intermediate 25M1 of 3-(5-(1-(3-((3-((3-(1-1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)methyl)cyclobutyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (GBA-01-25) was carried out with reference to the synthetic method of similar compounds in literature CN116253730, and was prepared by nucleophilic substitution of 4-hydroxypiperidine and difluorothalidomide and desmartin oxidation. Then, following the synthetic method of Example 1, GBA-01-25 was synthesized from S11 and 25M1 as starting materials (two-step yield 29%). 1H NMR(500MHz,DMSO-d6)δ11.11(s,1H),10.09(s,1H),7.82–7.70(m,1H),7.52(d,J=7.3Hz ,1H),7.22(t,J=8.2Hz,1H),6.69(d,J=8.7Hz,1H),5.11(dd,J=12.9,5.4Hz,1H),3.95(s, 2H),3.78–3.68(m,3H),3.65–3.55(brs,2H),3.50–3.40(brs,2H),3.00–2.81(m,4H),2.6 7–2.55(m,2H),2.15–2.02(m,3H),2.08–1.95(m,2H),1.81–1.62(m,2H).LC-MS:calc.for C 32 H 30 F2N6O8S2 + 696.2 [M+H] + Found 696.7.

[0198] Example 17

[0199] 3-(6-(1-(3-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-carbonyl)cyclobutyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (GBA-01-26) was synthesized from S12 and 31a using the method described in Example 3 (two-step yield 33%). 1 H NMR(500MHz,DMSO-d6)δ11.14(s,1H),8.84(s,1H),8.60–8.43(m,1H),8.14(d,J=7.0Hz,1H),7.9 0(t,J=7.6Hz,1H),7.38–7.02(m,4H),6.69(d,J=8.7Hz,1H),5.50–5.43(m,1H),4.02(s,2H),3.66 -3.57(m,6H),3.53–3.46(brs,4H),3.16-3.10(m,4H),3.10–3.01(m,2H),2.78–2.62(m,2H),2.17–2.00(m,4H).HRMS(ESI,m / z): calcd for C 40 H 40 FN6O8S + 783.2607[M+H] +Found 783.2611.

[0200] Example 18

[0201] 3-(6-(4-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)cyclohexyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (GBA-01-27)

[0202] First, 300 mg of raw material 27a was reacted with an equivalent amount of 1,4-dioxa-spiro[4,5]dec-7-en-8-boronate pinacol ester, 5% Pd(dppf)Cl2, and two equivalents of cesium carbonate in a water-dioxane mixed solution under reflux to obtain 350 mg of crude product 27b. Then, it was deprotected by 10% palladium on carbon at atmospheric pressure and HCl dioxane solution (4N). Finally, 258 mg of intermediate 27c was obtained by reversed-phase column chromatography. LC-MS: calc.for C 22 H 21 N2O4 + 377.1[M+H] + Found 377.5.

[0203] Following the synthesis method of Example 1, GBA-01-27 was synthesized using S12 and 27c as raw materials (two-step yield 35%). 1 H NMR(500MHz,DMSO-d6)δ11.13(s,1H),10.08(s,1H),8.51-8.35(m,1H),8. 16-8.03m,1H),7.92-7.80(m,1H),7.66–7.41(m,2H),7.37–7.19(m,2H),7 .17–6.95(m,2H),6.75–6.65(m,2H),5.49–4.99(m,2H),4.08–3.79(m,4H) ,3.02–2.61(m,4H),2.19–2.06(m,4H),1.86–1.62(m,3H).HRMS(ESI)calcd for C 36 H 35 FN5O7S + 700.2236[M+H] + ,found 700.2233.

[0204] Example 19

[0205] 3-(5-(1-(3-((3-((3-(1-1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)methyl)cyclobutyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (GBA-01-36): 500 mg of raw material 20a is dissolved in 5 mL with 2 equivalents of 3-hydroxycyclohexanone. In the DCE, 2 equivalents of sodium triacetoxyborohydride were added, and the reaction was completed in about three hours. Then, 10 times the amount of dichloromethane was added, and the mixture was extracted three times with water. The dichloromethane layer was dried and concentrated to obtain the crude product 36b. 36b was dissolved in 5 mL of DMSO, and then 1.5 equivalents of Desmartin oxidant were added. Monitoring showed that the reaction was complete. The reaction solution was separated by a C18 reversed-phase column (acetonitrile / water = 10-100%) and concentrated to obtain 250 mg of compound 36c. LC-MS: calc. for C 23 H 29 N4O4 + 425.2[M+H] + Found 425.3.

[0206] Finally, following the synthesis method of Example 1, GBA-01-36 was synthesized using S12 and 36c as raw materials (two-step yield 36%). 1 H NMR (600MHz, DMSO-d6) δ11.10(s,1H),10.13(s,1H),7.23(t,J=8.3Hz,1H),7.11–7.01(m,2H),6.93(d,J=7.9Hz,1H),6.70(d,J=8.3Hz,1H),6.54(s, 1H),5.50–5.24(m,1H),3.97(s,2H),3.59–3.41(m,2H),3.28–3.13(m,2H) ,3.03–2.83(m,3H),2.76–2.60(m,2H),2.28–1.91(m,8H).HRMS(ESI)calcd for C 37 H 43 FN7O7S + 748.2923[M+H] + ,found748.2924.

[0207] Example 20

[0208] 3-(6-(1-(3-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2-fluoro-4-hydroxyphenyl)ethynyl)pyrrolidine-1-yl)methyl)cyclobutyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (GBA-01-29)

[0209] Following the synthetic method of 31a, 29a was synthesized from 23e and 3-(hydroxymethyl)-cyclobutanone (yield 81%). LC-MS (ESI, m / z): 448.6 [M+H] +

[0210] 29a (305.2 mg, 0.68 mmol, 1.0 equiv.) was dissolved in DMSO (3.0 mL), and Dysmart reagent (434.2 mg, 1.0 mmol, 1.5 equiv.) was added under stirring at room temperature. After 5 hours, the reaction mixture was cooled to room temperature, and the reaction was quenched with H2O (15.00 mL). The mixture was extracted with EA (3 × 15.00 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Purification was performed using a normal-phase preparative method (15% v / v PE / EA) via a rapid purification system to give 29b (267.1 mg, 0.6 mmol, yield 88%). LC-MS (ESI, m / z): 444.2 [MH] -

[0211] Following the synthesis method of GBA-01-17, GBA-01-29 was synthesized using S11 and 29b as raw materials (two-step yield 24%). 1 H NMR(600MHz,DMSO-d6)δ11.14(s,1H),8.52(d,J=8.4Hz,1H),8.18–8.10(m,1H),7.90(t,J =7.6Hz,1H),7.53–7.21(m,2H),7.19–7.11(m,1H),7.08–6.71(m,1H),5.52–5.38(m,1H),4 .25(s,2H),3.95–3.68(m,2H),3.69–3.57(m,3H),3.55–3.41(m,6H),3.06–2.73(m,3H),2. 71–2.58(m,2H),2.32–2.25(m,2H),2.22–2.14(m,1H),2.14–2.04(m,3H).HRMS(ESI)calcd for:C 40 H 42 FN6O7S +769.2814[M+H] + ,found 769.2814.

[0212] Example 21

[0213] 3-(6-(1-((2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-yl)ethyl)sulfonyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (GBA-01-53)

[0214] 50 mg of compound 23e was dissolved in 2 mL of dimethylacetamide, followed by the addition of 0.2 mL of DIPEA, and then 35 μL of chloroethylsulfonyl chloride. After the formation of the corresponding vinylsulfonamide derivative was detected, 95 mg of 3-ethynyltetrahydropyrrole was added. After reacting for 1 hour, the concentrated reaction solution was subjected to column chromatography (C18 reversed-phase column separation: acetonitrile / water = 10-100%) to obtain 35 mg of compound 53a. LC-MS: calc. for C 29 H 33 N4O5S + 549.2 [M+H] + Found 549.1.35 mg of compound 53a and 41 mg of K12 were dissolved in 3 mL of THF, and 0.3 mL of DIPEA was added. After bubbling with argon, 5% equivalent of Pd(PPh3)4 and 2% equivalent of cuprous iodide were added, and the reaction was carried out overnight at 50 °C. The resulting reaction solution was extracted with EA (3 × 15.00 mL) and 15 mL of water. The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product obtained from the Sonogashira reaction was dissolved in 5 mL of dichloromethane, and 50 mg of pentamethylbenzene was added. The mixture was cooled to -78 °C, and then 1.5 mL of 1 M BCl3 DCM solution was added. The reaction was carried out for half an hour, and then quenched with 0.5 mL of ethanol in a cold bath. The resulting reaction liquid was concentrated and then subjected to column chromatography (C18 reversed-phase column separation: acetonitrile / water = 10-100%) to obtain 3 mg of GBA-01-53. 1HNMR(600MHz,DMSO-d6)δ11.13(s,1H),8.51–8.37(m,1H),8.19–8.04(m,1H), 7.93–7.82(m,1H),7.73–7.53(m,1H),7.54–7.34(m,1H),7.16–7.05(m,1H),5. 45(d,J=12.5Hz,1H),5.14–4.93(m,2H),4.27(d,J=7.4Hz,2H),3.96–3.71(m, 8H),3.08–2.88(m,5H),2.79–2.61(m,5H),2.11–1.79(m,5H).LC-MS:calc.for C 38 H 40 FN6O9S2 + 807.2[M+H] + Found 807.4.

[0215] Example 22

[0216] Synthesis of 5-(4-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione GBA-01-62:

[0217] Intermediate C2 was synthesized following a similar method described in CN116253730, via nucleophilic substitution of 4-hydroxypiperidine and difluthalidomide followed by desmartin oxidation. Then, following the synthetic method described in GBA-01-17, it was synthesized from 65 mg of PTPN2 ligand building block S11 and 83 mg of C2, yielding 25 mg of TFA salt as a bright yellow powder. The two-step yield was approximately 30%. 1 H NMR(600MHz,DMSO-d6)δ11.12(s,1H),10.65–10.50(m,1H),10.09(s,1H),7 .76(d,J=10.9Hz,1H),7.51(d,J=7.2Hz,1H),6.63(s,1H),5.16–5.08(m,1H) ,4.03(s,2H),3.94(t,J=8.9Hz,1H),3.80–3.60(m,4H),3.32–3.16(m,1H), 3.01–2.81(m,3H),2.70–2.53(m,2H),2.44–2.09(m,6H),2.10–1.74(m,3H).13 C NMR(151MHz,DMSO-d6)δ173.26,172.00,170.38,167.12,166.65,162.83(d,J=4.7Hz ),161.17,158.68,157.63(d,J=4.3Hz),157.00,145.27,141.78,129.17,124.21,114 .76,113.48,112.59,112.00,102.23,95.52,75.32,61.48,57.33,55.71,51.44,50. 61,49.56,48.61,31.98,31.42,30.66,28.83,28.35,28.11,22.52,20.62.LCMS[M+H] + Found 711.2

[0218] Example 23

[0219] Synthesis of 3-(6-(1-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-yl)ethyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione GBA-01-63:

[0220] Step 1: 80 mg (0.22 mmol) of CRBN ligand 1H was dissolved in 3 mL of acetonitrile, then 1.5 eq. acetal (56 mg (0.33 mmol)) and 2 eq. 61 mg potassium carbonate were added. The mixture was stirred overnight at 50 °C. After cooling and filtration, the mixture was subjected to reversed-phase column chromatography (acetonitrile / water 0.1% TFA = 10%-100%) to obtain 65 mg (0.14 mmol) of 2-H. LCMS [M+H] +

[0221] Found 452.2, yield 65%.

[0222] Step 2: 65 mg of compound 2H was dissolved in 4 mL of dioxane hydrochloride solution (4 M) and reacted for 3 hours. After rotary evaporation to dryness, the solution was slurried with 3 mL of MTBE, and the precipitate was collected and dried to obtain 39 mg of aldehyde (0.09 mmol). LCMS [M+H] + found406.2.

[0223] Step 3: The aldehyde intermediate (39 mg, 0.09 mmol) from Step 2 and compound S11 (43 mg, 0.1 mmol) were dissolved in HFIP / DCE (1:1, 3 mL). 100 mg of activated molecular sieve was added and stirred at room temperature for half an hour. NaB(OAc)3H (111 mg, 0.5 mmol, 5 equiv.) was added in five portions. After 2 hours, the mixture was filtered and concentrated to obtain a yellow-green solid (20 mg), which could be used for the next step of debenzylation without further purification. Following the general synthetic method for debenzylation, GBA-01-63, 5 mg was synthesized, with an overall yield of 7% for both steps. 1 H NMR (600MHz, DMSO-d6) δ11.14(s,1H),9.92(s,1H),8.50(d,J=8.4Hz,1H),8. 13(d,J=6.9Hz,1H),7.90(t,J=7.5Hz,1H),7.35(t,J=7.5Hz,1H),7.15(d,J=7 .5Hz,1H),6.61(s,1H),5.46(dd,J=13.0,5.5Hz,1H),3.95(s,2H),3.76–3.5 5(m,4H),3.25–3.05(m,3H),3.02–2.53(m,6H),2.32–1.40(m,6H).LCMS[M+H] + Found 743.1

[0224] Example 24

[0225] Synthesis of 3-(6-(4-(2-(3-((4-(benzyloxy)-3-(5-(((benzyloxy)methyl)-1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-6-methylphenyl)ethynyl)pyrrolidine-1-yl)-2-oxoethyl)piperazin-1-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione GBA-01-64:

[0226] Steps 1-2 (Buchwald coupling): Approximately 0.45 mmol of 160 mg of 23e and 180 mg of piperazine fragment (two equivalents) were dissolved in 1,4-dioxane. 300 mg of cesium carbonate (2 eq.) was added, and oxygen was removed by sonication. Then, 40 mg each of 10% of two pre-catalysts (used in combination) – tBuXphos Pd G3 and ruphos Pd G3 – were added. The mixture was refluxed overnight. The resulting product was combined with the products from the previous two reactions, filtered, and evaporated to dryness. The product obtained by reversed-phase column chromatography (acetonitrile / water 0.1% TFA = 10%-100%) was dissolved in 2 mL of trifluoroacetic acid and reacted for one hour. Evaporation was then carried out to dryness to obtain 80 mg of compound C5. (The combined processing of the three reactions yielded a two-step yield of 14% based on a total feed amount of 480 mg). LCMS [M+H] + Found 423.2

[0227] Steps 3-4: Dissolve 0.19 mmol (80 mg) of compound C5 and 0.1 mmol (55 mg) of PTPN2 target S11 in 2 mL of DMF. Add 0.3 mL of DIPEA, 76 mg (1 eq.) of HATU, and 60 mg (2 eq.) of HOBt. React for five minutes, and monitor the reaction [M+H] using LCMS. + Found 968.4 was completely converted, and after rotary evaporation, it was subjected to reversed-phase column chromatography (acetonitrile / water 0.1% TFA = 10%-100%) to obtain 30 mg of the product. Then, it was subjected to the aforementioned general debenzylation step and the same reversed-phase column chromatography method to obtain 8 mg of GBA-01-64 (overall yield of the two steps is about 6%). 1 H NMR (600MHz, DMSO-d6) δ11.12(s,1H),10.10(s,1H),9.82(d,J=5.4Hz,1H),8.31(d,J=8.2Hz,1H ),8.11(d,J=7.0Hz,1H),7.86(td,J=7.6,3.0Hz,1H),7.06(s,2H),6.59(d,J=3.3Hz,1H),5.48–5 .40(m,1H),5.32(t,J=4.9Hz,1H),4.57–4.20(m,2H),3.92(s,2H),3.85–3.60(m,4H),3.59–3.4 2(m,6H),2.98–2.80(m,3H),2.77–2.62(m,2H),2.35–2.23(m,4H),2.12–1.95(m,4H).LCMS[M+H] + Found 758.17

[0228] Synthetic routes for Examples 25 and 26:

[0229] Example 25

[0230] Synthesis of 3-(6-(1-(3-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-yl)-3-oxopropyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione GBA-01-68

[0231] Steps 1 and 2: Preparation of intermediates 2-TB and 3-2CH: 2-TB: 90 mg (0.25 mmol) of CRBN ligand 23e was dissolved in 3 mL of acetonitrile, followed by the addition of 2 eq. 105 mg of tert-butyl ester building blocks and 3 eq. 103 mg of potassium carbonate. The reaction was carried out overnight at 40 °C. After cooling and filtration, 93 mg of 2TB was obtained by reversed-phase column chromatography (acetonitrile / water 0.1% TFA = 15%-100%). LC-MS [M+H]+ found 492.3, yield 76%. 3-2CH: 93 mg of 2-TB was dissolved in 3 mL of TFA and reacted for half an hour. The solution was directly evaporated to dryness to obtain 83 mg of 3-2CH (complete deconversion of BOC).

[0232] Steps 3 and 4: Amide condensation and debenzylation: 43 mg 0.1 mmol 3-2CH and 55 mg PTPN2 ligand S11 were dissolved in 2 mL DMF, 0.2 mL DIPEA and 76 mg 2 eq. HATU were added, and the reaction was carried out for 5 minutes. LCMS monitoring showed that [M+H]+ found 981.3% was completely converted. After drying, the product was obtained by reversed-phase column chromatography (acetonitrile / water 0.1% TFA = 10%-100%). 25 mg of the product was then obtained by the aforementioned general debenzylation step and the same reversed-phase column chromatography method to obtain 8 mg of GBA-01-68 (total yield of the two steps is approximately 10%). 1H NMR(600MHz,DMSO-d6)δ11.14(s,1H),9.82(s,1H),9.14(s,1H),8.62–8.0 5(m,3H),7.90(t,J=7.7Hz,1H),7.55–7.01(m,2H),6.59(d,J=3.3Hz,1H),5 .50–5.43(m,1H),4.01–3.79(m,2H),3.74–3.42(m,4H),3.27–3.02(m,2H), 3.03–2.53(m,6H),2.33–2.23(m,2H),2.15–2.05(m,2H).LCMS[M+H]+found 771.3

[0233] Example 26

[0234] Synthesis of 3-(6-(1-(4-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-yl)-4-oxobutyl)piperidin-4-yl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione GBA-01-69

[0235] Step 1: 90 mg (0.25 mmol) of 2-BN:CRBN ligand 23e was dissolved in 3 mL of acetonitrile, followed by the addition of 2 eq. 105 mg of tert-butyl ester building blocks and 3 eq. 103 mg of potassium carbonate. The reaction was carried out overnight at 40 °C. After cooling and filtration, 95 mg of 2-BN was obtained by reversed-phase column chromatography (acetonitrile / water 0.1% TFA = 15%–100%). LC-MS [M+H] + Found 540.3. Yield 70%

[0236] Step 2: 3-3CH: Dissolve 95 mg of 2-BN in 10 mL of ethanol, add 40 mg of 10% Pd(OH)2 / C, react under a hydrogen atmosphere for 18 hours, filter, and then directly evaporate to dryness to obtain 76 mg of 3-3CH (complete debenzylation).

[0237] Steps 3 and 4: Amide condensation and debenzylation: 45 mg 0.1 mmol 3-3CH and 55 mg PTPN2 ligand S11 were dissolved in 2 mL DMF, 0.2 mL DIPEA and 76 mg 2 eq. HATU were added, and the reaction was carried out for 5 minutes. LCMS monitoring showed that [M+H]+ found 995.3, indicating complete conversion. After drying, the product was obtained by reversed-phase column chromatography (acetonitrile / water 0.1% TFA = 10%-100%), yielding 23 mg of the product. This product was then subjected to the aforementioned general debenzylation step and the same reversed-phase column chromatography method to obtain 6 mg of GBA-01-69 (total yield of the two steps is approximately 7%). 1 H NMR(600MHz,DMSO-d6)δ11.15(s,1H),10.01(s,1H),9.82(s,1H),9.35(s,1H),8.60–8.3 1(m,1H),8.23–8.07(m,1H),7.97–7.80(m,1H),7.53–7.28(m,1H),7.23–7.05(m,1H),6. 61(s,1H),5.55–5.43(m,1H),4.21–3.77(m,4H),3.74–3.59(m,5H),3.59–3.47(m,4H),3 .29–3.13(m,3H),3.04–2.60(m,4H),2.48–2.37(m,2H),2.28(s,3H),2.17–1.88(m,6H).13 C NMR(151MHz,DMSO-d6)δ172.75,170.83,170.17,169.54,169.36,166.77,162.05,160.39,157 .94,156.68,141.55,134.81,132.29,129.93,129.13,128.86,127.46,126.86,125.76,124.79 ,124.58,124.28,120.74,112.92,110.68,101.99,97.49(d,J=73.7Hz),73.43,56.15,54.63,5 2.23,51.34,49.84,48.40,44.88,33.67,32.45,31.18,30.31,28.74,22.26,20.03.LCMS[M+H] + Found 785.3

[0238] Example 27

[0239] Synthesis of 1-(5-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-formyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione GBA-01-66:

[0240] Following the synthesis method of Example 1, GBA-01-66 was synthesized using S11 and 66a as raw materials (two-step yield 30%). 1 H NMR (600MHz, DMSO-d6) δ10.34(s,1H),7.60–7.48(m,2H),7.17(d,J=8.7Hz,1H),6.65(d,J=13.1Hz,1H),4.38(s,2H),3.86(s,4H),3.68 –3.50(m,5H),3.39(dt,J=39.8,6.7Hz,1H),2.74–2.67(m,2H),2.28(d,J=37.7Hz,4H),2.09–1.96(m,1H),1.29–1.23(m,1H).LCMS[M+H] + Found 600.2

[0241] Example 28

[0242] Synthesis of 1-(5-(4-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-yl)-2-oxoethyl)piperazine-1-formyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione GBA-01-67

[0243] 67a (50.00 mg, 0.2 mmol, 1.00 equiv.) was dissolved in DMF (3.00 mL). Boc-piperazine (38.00 mg, 0.2 mmol, 1.00 equiv.), DIPEA (104.31 mL, 0.60 mmol, 4.00 equiv.), and PyBop (85.80 mg, 0.17 mmol, 1.10 equiv.) were added under stirring at room temperature. The reaction was quenched dropwise with H₂O after 15 minutes, and the mixture was extracted with EA (3 × 10.00 mL). The combined organic layers were washed with saturated NaCl solution (2 × 10.00 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give a yellow-green solid 67b (66.90 mg, 0.16 mmol, 80% yield), which could be used for the next step without further purification.

[0244] The yellow oily substance from the previous step was dissolved in DCM (2.00 mL), and TFA (1.00 mL) was added dropwise under stirring at room temperature. After 15 minutes, the reaction was quenched by slowly adding saturated NaHCO3 solution (10.00 mL), allowed to stand, and the organic layer was collected. The aqueous layer was then extracted again with DCM (3 × 10.00 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered, concentrated, and dried to constant weight to obtain a yellow oily substance, 67C, which can be used in the next step without further purification. LCMS[M+H] + Found 319.3

[0245] Following the two-step synthesis method of intermediate K13, intermediate 67d was obtained from 67C and tert-butyl bromoacetate as starting materials (two-step yield 81%) LCMS[M+H). + Found 377.1

[0246] Following the synthesis method of Example 1, GBA-01-67 was synthesized using S11 and 67d as raw materials (two-step yield 37%). 1H NMR (600MHz, DMSO-d6) δ10.37(s,1H),7.47(dd,J=8.5,2.2Hz,1H),7.42(d,J=2.2Hz,1H),7.21(d,J=8.5Hz,1H),6.64(d,J=4.3Hz,1H),4.33–4.20(m, 6H),3.87(s,3H),3.76(ddd,J=25.1,10.5,6.9Hz,2H),3.64–3.37(m,10H) ,3.18(s,1H),2.70(t,J=6.7Hz,2H),2.34–2.23(m,4H),2.12–1.95(m,1H).

[0247] LCMS[M+H] + Found 726.2

[0248] Example 29

[0249] Synthesis of 3-((4-(1-(2-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-yl)-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidin-2,6-dione GBA-01-72

[0250] Following the synthesis method of Example 1, GBA-01-72 was synthesized using S11 and 72a as raw materials (two-step yield 37%). 1 H NMR (600MHz, DMSO-d6) δ10.78(s,1H),10.17(s,1H),9.57(s,1H),6.97(d,J=8.0Hz,1H),6.64( dd,J=17.4,5.4Hz,2H),4.31–4.14(m,3H),4.10(s,2H),3.83–3.77(m,2H),3.75–3.68(m,4H),3 .55(d,J=11.4Hz,5H),3.10(s,2H),2.74(ddd,J=17.5,12.2,5.4Hz,1H),2.67–2.55(m,2H),2.2 8(d,J=3.9Hz,3H),2.12–2.08(m,1H),1.94(q,J=8.3,5.0Hz,3H),1.90–1.80(m,1H).LCMS[M+H] + Found 681.2

[0251] Example 30

[0252] Synthesis of 3-((4-(1-(3-(3-((3-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2-fluoro-4-hydroxy-6-methylphenyl)ethynyl)pyrrolidine-1-formyl)cyclobutyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidin-2,6-dione GBA-01-75

[0253] Following the synthetic method described for 31a, 76b was synthesized from 76a and 3-oxocyclobutane carboxylic acid (72% yield). LC-MS (ESI, m / z): 404.2 [M+H] +

[0254] Following the synthesis method of Example 1, GBA-01-75 was synthesized using S11 and 76b as raw materials (two-step yield 30%). 1 H NMR(500MHz,DMSO-d6)δ10.80(s,1H),10.19(s,1H),9.43(s,1H),6.95(t,J=8.8Hz,1H), 6.62(s,1H),6.52–6.43(m,2H),4.33(dd,J=11.6,4.8Hz,1H),4.11(d,J=3.9Hz,2H),3.4 5–3.31(m,6H),3.22(d,J=12.8Hz,2H),2.94–2.85(m,3H),2.78–2.64(m,2H),2.60–2.54 (m,2H),2.45–2.37(m,2H),2.27(s,3H),2.12–1.99(m,2H),1.96–1.75(m,7H).LCMS[M+H] + Found 739.3.

[0255] Test Example 1: Evaluation of protein tyrosine phosphatase degradation activity

[0256] Jurkat cells were seeded at 5 × 10⁶ cells. 6Cells were treated with specified concentrations of the drug (0.1 nmol / L, 1 nmol / L, 10 nmol / L, 100 nmol / L, 1 μmol / L, 10 μmol / L) for 24 h in 12-well plates with 10 cells / well. Cells were then collected in 1.5 mL EP tubes and centrifuged at 3500 rpm for 3 min. The cell pellet was washed once with 1×PBS, and the protein sample was diluted in 2×Laemmli sample buffer containing 10% β-mercaptoethanol (2×Laemmli sample buffer to protein volume ratio 1:1) and incubated in a metal bath at 95 °C for 10 min. Protein lysates were then separated on a 10% SDS-PAGE gel. Proteins were transferred to a 0.45 μm NC membrane using the eblot L1 rapid transfer system and blocked with 5% bovine serum albumin solution at room temperature for 1 h. Primary incubation was then performed overnight at 4 °C. Primary antibodies were TCPTP rabbit monoclonal antibody (CST, number 58935S, 1:1000), PTP1B rabbit monoclonal antibody (CST, number 5311S, 1:1000), and GAPDH rabbit monoclonal antibody (CST, number 5174S, 1:10000). The membrane was washed three times with 1×TBST and then incubated at 25°C for 1 hour at a 1:10000 dilution with secondary antibody Goat Anti-Rabbit IgG (H&L)-HRP Conjugated (BE0101 easybio) (Jackson, 111-035-003) at 25°C. The membrane was washed three times with 1×TBST, ECL chemiluminescence buffer was added, and Western blot images were obtained using a contact non-destructive quantitative imaging system. Image lab software was used to process the images and calculate the grayscale values. The experimental results are shown in Table 1 and Figure 1 below.

[0257] Table 1. PTPN2 degradation rate in Jurkat cells after treatment (with DMSO as control)

[0258] Degradation rates are categorized into five levels: A, B, C, D, and E, with 80-100% classified as A, 60-80% as B, 40-60% as C, and 20-40% as D.

[0259] 0-20% is E, DC 50 It is divided into three levels: A, B, and C. >10nM is C, 1-10nM is B, and <1nM is A.

[0260] As shown in Figure 1 (experimental results of the subtype-selective degradation of PTPN2 by the compounds), some of the compounds of the present invention also have the subtype-selective characteristic of PTPN2, that is, they degrade PTPN2 without affecting PTP1B, which can reduce off-target effects and has significant advantages in avoiding potential toxic side effects caused by off-target effects.

[0261] Test Example 2: Co-incubation anti-proliferative test of the compound's promoting effect on T cell killing.

[0262] 1. OT-I mice were euthanized by dislocation, and the spleen was removed under sterile conditions. The spleen cells were then separated by grinding with a 0.45-micron sieve to prepare a single-cell suspension of spleen cells. Subsequently, the spleen cells were lysed with erythrocyte lysis buffer at room temperature for 5 min, and then centrifuged to obtain mouse spleen cells.

[0263] 2. After washing the cells once with PBS, resuspend the cells in 1 mL of complete culture medium (RPMI 1640 medium containing 10% FBS, 10 ng / mL IL-2, 50 μmol / L β-mercaptoethanol, 1% penicillin and 1% streptomycin).

[0264] 3. Add 1 / 10 of the cell suspension to 10 mL of complete culture medium, and add 10 ng / mL of OVA. 257-264 The peptide was placed in a 37°C incubator and cultured normally for 2.5 days.

[0265] 4.2.5 days later, replace with fresh complete culture medium and continue culturing for 2 days to obtain mature CTLs (Cytotoxic T lymphocytes).

[0266] 5. CTLs and B16-F10 target cells overexpressing OVA (mCherry) were separately introduced into the target cells. + The inoculum was inoculated into a 96-well plate with a round bottom at a ratio of 1:4, with a total volume of 180 μL.

[0267] 6. Dilute the 10 mM compound in DMSO at a ratio of 1:5. Further dilute the compound / DMSO solution in complete culture medium at a ratio of 1:20. Add 20 μL of the diluted solution to the cell suspension. The final compound concentration is 5 μmol / L, and the final DMSO concentration is 0.2%.

[0268] 7. The 96-well plate was then placed in a saturated humidity incubator at 37°C with 5% CO2 for further incubation.

[0269] 8. After culturing for 20-24 hours, the remaining tumor cells (mCherry) were detected by flow cytometry. + The number of cells is used to calculate the target cell killing ability of CTLs.

[0270] T cells are the main force of adaptive immunity, including CD4+. + T cells and CD8 + T cells. Among them, CD8... +As the primary effector T cells, T cells can directly kill target cells by binding to FasL on the surface of tumor cells, and can also indirectly kill target cells by releasing cytokines such as Granzyme B and IFNγ. The targeted killing ability of cytotoxic T cells (CTLs) plays an important role in anti-tumor immunity.

[0271] In this experiment, known PTPN2 regulators AC484 (Nature 2023, 622, 850–862) and PVD-06 (J.Med.Chem.2023, 66, 15269-15287) were selected as positive control drugs.

[0272] As shown in Figure 2, the compounds GBA-01-23, GBA-01-31, GBA-01-41 and GBA-01-43 of the present invention can promote the tumor-targeting killing ability of T cells. Therefore, the compounds involved in the present invention are expected to be used in tumor immunotherapy and can play a synergistic role when used in combination with CAR-T therapy.

[0273] Test Example 3: Compound Inhibits the Proliferation of B16-F10 Melanoma Cells

[0274] 1. Take B16-F10 mouse melanoma cells in the logarithmic growth phase and seed them in 96-well transparent plates at a density of 500 cells per well, with a total volume of 80 μL.

[0275] 2. Place the cells in a 37°C, 5% CO2 saturated humidity incubator overnight to allow them to adhere to the incubator wall.

[0276] 3. On the second day, mouse IFNγ was diluted to 50 ng / mL with complete culture medium (RPMI 1640 medium containing 10% FBS, 1% penicillin, and 1% streptomycin) for subsequent compound dilutions. The control group received complete culture medium without mouse IFNγ.

[0277] 4. Dilute the 10 mM compound in DMSO at eight 5-fold serial dilutions. Further dilute the compound / DMSO solutions 1:200 in either IFNγ-containing or IFNγ-free complete medium. Add 20 μL of each dilution to 80 μL of cells. The final DMSO concentration is 0.1%.

[0278] 5. Return the 96-well cell plate to the incubator and continue culturing for 3 days. Then, read the plate at 450 nm and 650 nm using the Cell Counting Kit-8 method.

[0279] 6. Calculate the percentage (%Activity) of the test substance's activity against tumor cell proliferation using the following formula. Where OD... Sample Indicates the absorbance value of the drug delivery well (OD) 450 –OD 650 ), OD DMSO The absorbance (OD) of the DMSO control well is indicated. 450 –OD 650 ), OD Blank The absorbance (OD) of the control wells of the culture medium is indicated. 450 –OD 650 The logarithm of concentration was plotted against the percentage of activity (%Activity). A nonlinear regression curve was used to fit the curve, and the IC50 value was calculated using GraphPad Prism8 software with the parameters set as log(inhibitor) vs normalized response – Variable slope. %Activity = (OD Sample -OD Blank ) / (OD DMSO -OD Blank )*100

[0280] The specific test results are shown in Table 2. IFNγ is mainly a cytokine produced by immune cells such as T cells or NK cells. The regulation of IFNγ signaling affects tumor growth; weakening IFNγ signal transduction promotes tumor growth, while enhancing IFNγ signal transduction inhibits tumor growth. Since PTPN2 is a negative regulator of IFNγ signaling, an effective PTPN2 degrader should promote tumor growth arrest in the presence of IFNγ. As shown in Table 2, the proliferation of B16F10 melanocytes treated with the compound and IFNγ for 72 hours was significantly inhibited.

[0281] Test Example 4: Compound Inhibits the Proliferation of HT-29 Human Colon Cancer Cells

[0282] Experimental steps:

[0283] 1. HT29 human colon cancer cells in the logarithmic growth phase were seeded at a density of 1500 cells per well in 96-well transparent plates, with a total volume of 80 μL.

[0284] 2. Place the cells in a 37°C, 5% CO2 saturated humidity incubator overnight to allow them to adhere to the incubator wall.

[0285] 3. On the second day, Human IFNγ (hereinafter referred to as IFNγ) was diluted to 50 ng / ml with complete medium (McCoy's 5A medium with 10% FBS) for subsequent compound dilutions. The control group was complete medium without IFNγ.

[0286] 4. Dilute the 10 mM compound to eight concentration points using DMSO in a 5-fold serial dilution. Further dilute these compound / DMSO solutions 200-fold in complete culture medium, with or without IFNγ. Then, add 20 μL of each 200-fold dilution to 80 μL of cell suspension. The final IFNγ concentration is 10 ng / mL, and the final DMSO concentration is 1‰.

[0287] 5. Return the 96-well cell plate to the incubator and continue culturing for 3 days. Then, read the plate at 450 nm and 650 nm using the Cell Counting Kit-8 method.

[0288] 6. Calculate the percentage (%Activity) of the test substance's activity against tumor cell proliferation using the following formula. Where OD... Sample Indicates the absorbance value of the drug delivery well (OD) 450 –OD 650 ), OD DMSO The absorbance (OD) of the DMSO control well is indicated. 450 –OD 650 ), OD Blank The absorbance (OD) of the control wells of the culture medium is indicated. 450 –OD 650 The logarithm of the concentration was plotted against the percentage of activity (%Activity). A nonlinear regression curve was used to fit the curve, and the IC50 value was calculated using the GraphPad Prism8 software with the parameters set as log(inhibitor) vs normalized response – Variable slope.

[0289] %Activity=(OD Sample -OD Blank ) / (OD DMSO -OD Blank )*100

[0290] The specific test results are shown in Table 2.

[0291] Table 2. Evaluation of the inhibitory activity of the compounds on the proliferation of B16F10 and HT29

[0292] Test Example 5: In vivo degradation effect - animal experiment

[0293] Experimental steps:

[0294] 1. Select 6-8 week old female C57BL / 6 mice. On day 0, administer 5×10⁻⁶ doses to the right lower abdomen of the mice. 6MC38 cells were seeded at a density of 100 μL / animal (PBS:Matrix gel = 1:1). Tumor volume was measured starting on day 6 post-seedling and continued until the tumor volume exceeded 500 mmHg. 3 The criteria for determination are as follows: the longest diameter (length) and the largest vertical diameter (width) are recorded manually, and the tumor volume is calculated using the formula: (length × width²) / 2.

[0295] 2. Mice were randomly divided into a solvent group and a drug administration group. Each mouse was injected via tail vein with 25 mg / kg or 50 mg / kg of the corresponding compound, depending on its body weight. The compound solvent was 7.5% DMSO + 30% PEG-400 + 62.5% physiological saline.

[0296] 3. Twenty-four hours after administration, the mice were euthanized by dislocation, and the tumor tissue was collected on ice and placed in cryopreservation tubes.

[0297] 4. Take a portion of tumor tissue into a 1.5 mL EP tube, add 300 μL of RIPA lysis buffer (1 mM PMSF needs to be added to the RIPA lysis buffer) and 2 grinding beads, homogenize the tissue for 30 minutes, and then centrifuge at 12000 rpm for 30 minutes.

[0298] 5. Take 2 μL of tissue lysis supernatant and add it to 18 μL of ultrapure water. Add 200 μL of BCA quantitative working solution and incubate at 37°C for 30 minutes. Read the absorbance value at 562 nM and calculate the protein concentration according to the standard curve.

[0299] 6. Dilute the protein sample (4×) in 4× Laemmli sample buffer containing 10% β-mercaptoethanol.

[0300] The volume ratio of Laemmli sample buffer to protein was 3:1, and the sample was in a metal bath at 100°C for 10 minutes.

[0301] 7. Protein lysates were then separated on a 10% SDS-PAGE gel. Proteins were transferred to a 0.45 μm NC membrane using an eblot L1 rapid transfer system and blocked with 5% bovine serum albumin solution at room temperature for 1 h. The membrane was then incubated overnight at 4°C with a primary antibody. The antibodies used were TCPTP rabbit monoclonal antibody (CST, 58935S, 1:1000), PTP1B rabbit monoclonal antibody (CST, 5311S, 1:1000), and GAPDH rabbit monoclonal antibody (CST, 5174S, 1:10000). The membrane was washed three times with 1×TBST and then incubated at 25°C at a 1:10000 dilution for 1 h with the secondary antibody Goat Anti-Rabbit IgG (H&L)-HRP Conjugated (BE0101 easybio) (Jackson, 111-035-003).

[0302] 8. Wash the membrane three times with 1×TBST, add ECL luminescent solution, and obtain protein blot images using a contact non-destructive quantitative imaging system.

[0303] As shown in Figure 3, compounds GBA-01-31, GBA-01-41, and GBA-01-69 can significantly reduce the levels of PTPN2 and PTP1B proteins in MC38 xenograft tissues of experimental animals.

[0304] The above experimental results illustrate the application of the compounds of the preferred embodiments of this invention in the treatment of tumors. It is a well-known fact in the art that IFNγ can regulate anti-tumor immunity in various solid tumors and hematological malignancies. The compounds involved in this invention can promote the anti-tumor immunity of IFNγ and have superior efficacy compared to the existing candidate drug AC484 (Nature volume 622, pages 850–862), and are expected to be used for the treatment of various cancers, not limited to the cancers involved in this embodiment. The compounds of this invention, with their effects of promoting T cell proliferation and enhancing the anti-tumor immunity of IFNγ, are expected to be used to treat cancer and other diseases related to tyrosine phosphatase.

[0305] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, or isotopically labeled derivative: in, R 1 R 2 Each is independently H, halogen, straight-chain or branched C1-C6 alkyl; X is CH or N atom; Ring A is a saturated or unsaturated monocyclic ring, a saturated or unsaturated bicyclic ring, or a saturated or unsaturated tricyclic ring. The monocyclic, bicyclic, or tricyclic rings are substituted or unsubstituted five- to twelve-membered heterocyclic alkyl groups containing one to three heteroatoms selected from N, O, and S, or five- to twelve-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S. The substitution refers to the presence of 0 to 4 substituents R on ring A. A When multiple substituents R exist A At that time, each substituent R A Each group is independently selected from hydrogen, straight-chain or branched C1-C6 alkyl, carbonyl, halogen, amino, nitro, hydroxyl, carboxyl, amide, cyano, halogen-substituted C1-C6 alkyl, sulfonamide, sulfone, sulfoxide, C1-C6 alkyl-substituted acyl, and 0 substituents R. A This indicates that ring A may not contain the substituent R. A ; The "linking group" is -(L 1 ) n1 -(L 2 ) n2 -(L 3 ) n3 -(L 4 ) n4 -(L 5 ) n5 -, where the connector L 1 L 2 L 3 L 4 L 5 They are independently: -CH2-, -CHR L -、-CR L 2-, -O-, -S-, -NH-, -NR L -、 -N=、=N-、-CH2CH2O-、-CH=CH-、-CR L =CH-、-CR L =CR L -、-CH=CR L -、-C≡C-、C 3-8 Cycloalkylene groups, three to eight-membered heterocyclic alkylene groups containing one to three heteroatoms selected from N, O, and S, benzene rings, naphthene rings, five to eight-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S, C 4-8 cyclic ketone group, four- to eight-membered cyclic lactam group, -P(=O)R L -,-P(=O)OR L -、 n1, n2, n3, n4, and n5 are each independent integers selected from 0 to 20, and n1, n2, n3, n4, and n5 are not all 0 at the same time. R L Each group is independently selected from halogens, -OH, -NH2, -SH, sulfonamides, sulfones, sulfoxides, carboxyl groups, and -C(=O)OC. 1- 6-alkyl-, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, -O(C) 1-8 alkyl), -S(C 1-8 alkyl), -NH(C) 1-8 alkyl), -N(C) 1- 8-alkyl)2, C 3-8 Cycloalkyl, tri- to octa-cyclic heterocycloalkyl groups containing 1 to 3 heteroatoms selected from N, O, and S, phenyl, naphthyl, penta- to octa-aryl groups containing 1 to 3 heteroatoms selected from N, O, and S, -O(C 3-8 cycloalkyl), -S(C 3-8 cycloalkyl), -NH(C 3-8 cycloalkyl), -N(C) 3-8 2, -O (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S), -S (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S), -NH (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S), -N (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S) 2, -N (a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S) (C 3-8 cycloalkyl), -N (containing 1 to 3 heteroatoms selected from N, O and S, five to octa-aryl groups) (C 1-8 alkyl), -N(C) 1-8 Alkyl)(C 3-8 cycloalkyl).

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, isotope-labeled derivative, characterized in that, Preferably, R 1 and R 2 Each is independently selected from H, halogens, straight-chain or branched C1-C4 alkyl groups; Preferably, R 1 Selected from H, methyl, ethyl, n-propyl, and isopropyl; Preferably, R 2 Selected from halogen atoms; Preferably, the monocyclic ring A, along with the bicyclic or tricyclic ring, is a substituted or unsubstituted five- to eight-membered heterocyclic alkyl group containing one or two heteroatoms selected from N, O, and S, or a five- to eight-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S, wherein the substitution refers to the presence of 0 to 4 substituents R on the A ring. A When multiple substituents R exist A At that time, each substituent R A Each is independently selected from hydrogen, straight-chain or branched C1-C4 alkyl, carbonyl, or halogen groups; Preferably, the A ring is selected from the following structures: Among them, substituent R A As defined above; Preferably, the "linking group" is -(L 1 ) n1 -(L 2 ) n2 -(L 3 ) n3 -(L 4 ) n4 -(L 5 ) n5 -, where the connector L 1 L 2 L 3 L 4 L 5 They are independently: -CH2-, -CHR L -、-CR L 2-, -O-, -S-, -NH-, -NR L -、 -N=、=N-、-CH2CH2O-、-CH=CH-、-CR L =CH-、-CR L =CR L -、-CH=CR L -、-C≡C-、C 3-6 Cycloalkylene groups, three to six-membered heterocyclic alkylene groups containing one or two heteroatoms selected from N, O, and S, benzene rings, naphthene rings, five to six-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S, C 4-6 cyclic ketone group, four- to eight-membered cyclic lactam group, -P(=O)R L -,-P(=O)OR L -、 n1, n2, n3, n4 and n5 are each independent integers selected from 0 to 10, and n1, n2, n3, n4 and n5 are not all 0 at the same time; R L Each group is independently selected from halogens, -OH, -NH2, -SH, sulfonamides, sulfones, sulfoxides, carboxyl groups, and -C(=O)OC. 1- 6-alkyl-, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -O(C) 1-6 alkyl), -S(C 1-6 alkyl), -NH(C) 1-6 alkyl), -N(C) 1- 6-alkyl)2, C 3-6 Cycloalkyl, tri- or hexacyclic heterocycloalkyl containing one or two heteroatoms selected from N, O, and S, phenyl, naphthyl, penta- or octacyclic heteroaryl containing one or two heteroatoms selected from N, O, and S, -O(C 3-6 cycloalkyl), -S(C 3-6 cycloalkyl), -NH(C 3-6 cycloalkyl), -N(C) 3-6 2, -O (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S), -S (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S), -NH (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S), -N (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S) 2, -N (a five- to six-membered heteroaryl group containing one or two heteroatoms selected from N, O, and S) (C 3-6 cycloalkyl), -N (five- to six-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S) (C 1-6 alkyl), -N(C) 1-6 Alkyl)(C 3-6 cycloalkyl); Preferably, the "linking group" - (L 1 ) n1 -(L 2 ) n2 -(L 3 ) n3 -(L 4 ) n4 -(L 5 ) n5 -The resulting combined structure is selected from the following structures: Where R L For fluorine, chlorine, bromine, iodine, -OH, -NH2, sulfonamide, sulfone, sulfoxide, carboxylic acid, ester, C 1-8 Alkyl, C 2- 8-alkenyl, C 2-8 alkynyl group, -O(C) 1-8 alkyl), -NH(C) 1-8 alkyl), -N(C) 1-8 Alkyl)2, C 3-8 Cycloalkyl, tri- to octa-cyclic heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, phenyl, naphthyl, penta- to octa-cyclic heteroarylheteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, -O(C 3-8 cycloalkyl), -NH(C 3-8 cycloalkyl), -N(C) 3-8 2, -O (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S), -NH (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S), -N (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S), -N (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S) 2, -N (five to eight-membered heteroaryl-heteroaryl containing 1 to 3 heteroatoms selected from N, O and S) (C 3-8 cycloalkyl), -N (five to eight-membered heteroaryl heteroaryl containing one to three heteroatoms selected from N, O and S) (C 1-8 alkyl), -N(C) 1-8 Alkyl)(C 3-8 cycloalkyl); Preferably, the halogen is F, Cl, Br or I, and more preferably F, Cl or Br.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, isotope-labeled derivative, characterized in that, It is selected from the following structure:

4. A protein tyrosine phosphatase degrading agent, said protein tyrosine phosphatase degrading agent comprising a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, or isotope-labeled derivative.

5. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, an ester thereof, an isomer thereof, a prodrug thereof, a solvate thereof, an isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.

6. The use of the compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, isotopically labeled derivative, or composition according to claim 5 in the preparation of a medicament for treating diseases associated with protein tyrosine phosphatase; Preferably, the protein tyrosine phosphatase is PTPN2 or PTP1B; Preferably, the disease associated with protein tyrosine phosphatase is cancer or diabetes; Preferably, the cancer is selected from: melanoma, pancreatic cancer, lymphoma, breast cancer, colorectal cancer, blastoma, medulloblastoma, retinoblastoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, leukemia or lymphoid malignant tumor, myeloma, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, membranous adenocarcinoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, myeloma, esophageal cancer, biliary tract tumor, and head, neck and facial malignant tumors.

7. A method for treating a disease associated with protein tyrosine phosphatase, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, isotopically labeled derivative, or composition according to claim 5. Preferably, the disease associated with protein tyrosine phosphatase is cancer or diabetes; Preferably, the cancer is selected from: melanoma, pancreatic cancer, lymphoma, breast cancer, colorectal cancer, blastoma, medulloblastoma, retinoblastoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, leukemia or lymphoid malignant tumor, myeloma, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, membranous adenocarcinoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, myeloma, esophageal cancer, biliary tract tumor, and head, neck and facial malignant tumors.

8. The use of the compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, its ester, its isomer, prodrug, solvate, isotopically labeled derivative, or composition according to claim 5 in combination with PD-1 / PD-L1 blockade therapy or CAR-T immunotherapy in the treatment of cancer.

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