1, 2, 5-thiadiazole compound substituted by 4-position tetrahydronaphthalene or tetrahydroisoquinoline structure and application of 1, 2, 5-thiadiazole compound

Abstract

The invention discloses a 1, 2, 5-thiadiazole compound substituted by a 4-position tetrahydronaphthalene or tetrahydroisoquinoline structure and application of the 1, 2, 5-thiadiazole compound, and belongs to the field of medicines. The invention provides a 4-position tetrahydronaphthalene or tetrahydroisoquinoline structure substituted 1, 2, 5-thiadiazole compound with a structure shown as a formula (I) or a pharmaceutically acceptable salt thereof, and the compound has excellent protein tyrosine phosphatase inhibitory activity and can be used for preparing a medicine for preventing and treating diseases. A method of treatment of a disease or condition (e.g., cancer, type 2 diabetes, obesity, metabolic disease or any other disease, condition or condition) that is positively responsive to a protein tyrosine phosphatase (PTPN2 or PTPN1) inhibitor is provided.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to 1,2,5-thiadiazole compounds with 4-position tetrahydronaphthalene or tetrahydroisoquinoline-like structures substituted with these compounds and their applications. Background Technology

[0002] Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (e.g., PD-1 / PD-L1 and CTLA-4 blocking antibodies), have proven effective in treating a variety of cancers and have significantly improved outcomes in some conventionally resistant populations. However, incomplete clinical responses and the development of inherent or acquired resistance will continue to limit the patient population that may benefit from checkpoint blockade.

[0003] Type 2 non-receptor protein tyrosine phosphatase (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of a subfamily of phosphotyrosine-specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is widely expressed, but its expression is highest in hematopoietic cells and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503; 1992). In humans, PTPN2 expression is posttranscribedly controlled by the presence of two splicing variants: a 45 kDa form with a nuclear localization signal at the C-terminus upstream of the splice junction and a 48 kDa classical form with a C-terminal ER-retaining motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994). The 45 kDa isoform can passively infiltrate the cytoplasm under certain cellular stress conditions. Both isoforms possess an N-terminal phosphotyrosine phosphatase catalytic domain. PTPN2 negatively regulates signal transduction of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lck). As an important negative regulator of the JAK-STAT pathway, PTPN2 functions by directly regulating signal transduction through cytokine receptors (including IFNγ). The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also known as PTP1B) and exhibits similar enzyme kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003).

[0004] Data from in vivo loss-of-function gene screening using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model showed that deletion of the Ptpn2 gene in tumor cells improved the response to an immunotherapy regimen of GM-CSF secretory vaccine (GVAX) plus PD-1 checkpoint blockade (Manguso RT et al., Nature 547:413-418; 2017). Ptpn2 loss sensitized tumors to immunotherapy by enhancing IFNγ-mediated antigen presentation and growth inhibition. The same screening also showed that genes known to be involved in immune evasion (including PD-L1 and CD47) were depleted under immunotherapy selective pressure, while genes involved in IFNγ signaling pathways (including IFNGR, JAK1, and STAT1) were increased. These observations point to a hypothetical role for therapeutic strategies that enhance IFNγ sensing and signaling in improving the efficacy of cancer immunotherapy regimens.

[0005] Type 1 non-receptor protein tyrosine phosphatase (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), has been shown to play a crucial role in insulin and leptin signaling and is a major mechanism for downregulating both insulin and leptin receptor signaling pathways (Kenner KA et al., J Biol Chem 271:19810-19816, 1996). Animals lacking PTPN1 exhibit improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high-fat diet (Elchebly M. et al., Science 283:1544-1548, 1999). Therefore, PTPN1 inhibitors hold promise for the treatment of type 2 diabetes, obesity, and metabolic syndrome.

[0006] The latest protein tyrosine phosphatase inhibitor is ABB-CLS-484, with the following structure:

[0007]

[0008] However, the inhibitory activity of this inhibitor is still limited and needs further improvement. Summary of the Invention

[0009] This invention provides a 1,2,5-thiadiazole compound or a pharmaceutically acceptable salt thereof with a 4-position tetrahydronaphthalene or tetrahydroisoquinoline substituted structure, which can be used as an inhibitor of protein tyrosine phosphatase (PTPN2 or PTPN1) to treat related diseases.

[0010] The present invention also provides a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof.

[0011] Furthermore, the present invention provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof.

[0012] Detailed plan content:

[0013] This invention provides a 1,2,5-thiadiazole compound or a pharmaceutically acceptable salt thereof with a 4-position tetrahydronaphthalene or tetrahydroisoquinoline substituted structure as shown in formula (I):

[0014]

[0015] Or its pharmaceutically acceptable salt.

[0016] In the formula,

[0017] X is selected from: O or S;

[0018] Z is selected from C(R7)(R8) and N(R9);

[0019] R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, deuterium, halogens (F, Cl, Br, I), hydroxyl groups, and C, respectively. 1-6 Straight-chain or branched alkyl groups, C 3-6 cycloalkyl, C 1-6 Alkoxy;

[0020] R7 is independently selected from hydrogen, deuterium, halogens (F, Cl, Br, I), hydroxyl groups, and C. 1-6 Straight-chain or branched alkyl groups, C 3-6 cycloalkyl;

[0021] R8 is independently selected from hydrogen, deuterium, halogens (F, Cl, Br, I), hydroxyl groups, and C. 1-6 Straight-chain or branched alkyl groups, C 3-6 cycloalkyl, C 1-6 Alkoxy, -NH2, -NH-C 1-8 Alkyl, -NH-C 3-6 cycloalkyl, -NH-C 1-6 Alkylene-C 3-6 cycloalkyl;

[0022] R9 is selected from free hydrogen and C. 1-6 alkyl;

[0023] Among them, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -NH2, -NH-C 1-8 Alkyl, -NH-C 3-6 cycloalkyl, -NH-C 1-6 Alkylene-C 3-6The cycloalkyl group may optionally be substituted on one or more available carbons by one or more halogen, hydroxyl, alkoxy, cyano, nitro, or oxo (=O) substituents.

[0024] In one embodiment of the present invention, the compound specifically includes:

[0025]

[0026] In one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt; wherein the inorganic salt is selected from sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar cationic salts, or selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, hydrogen sulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate or similar anionic salts.

[0027] The present invention also provides a pharmaceutical composition comprising the above-mentioned tetrahydronaphthalene, tetrahydroisoquinoline compounds or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or diluents.

[0028] A pharmaceutical composition comprising a compound as described in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

[0029] In one embodiment of the invention, the pharmaceutical composition further comprises an additional therapeutic agent.

[0030] In one embodiment of the invention, the additional therapeutic agent is an immunotherapeutic agent.

[0031] In one embodiment of the present invention, the immunotherapeutic agent is selected from the group consisting of: anti-PD 1 antibody, anti-PD L1 antibody and anti-CTLA 4 antibody.

[0032] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating protein tyrosine phosphatase-mediated diseases.

[0033] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating cancer.

[0034] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of type 2 diabetes, obesity or metabolic syndrome.

[0035] Beneficial effects:

[0036] The 1,2,5-thiadiazole compounds substituted at the 4-position with tetrahydronaphthalene or tetrahydroisoquinoline, or their pharmaceutically acceptable salts, can act as inhibitors of protein tyrosine phosphatase (PTPN2 or PTPN1). Compared with the positive control (ABB-CLS-484), their inhibitory activity is significantly improved. They can be used to treat and / or prevent diseases related to abnormal proliferation of cancer cells (such as pancreatic cancer, breast cancer, and other tumors), type 2 diabetes, obesity, and metabolic syndrome, and have great development and application prospects. Detailed Implementation

[0037] The following examples are illustrative and not limiting of the synthesis of compounds of general formula (I). All temperatures are in degrees Celsius. Unless otherwise stated, all evaporations were performed under reduced pressure. Unless otherwise stated, reagents were purchased from commercial suppliers and used without further purification. The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as elemental analysis and spectroscopic characterization, such as MS and NMR. Abbreviations used are conventional abbreviations in the art.

[0038] Example 1: Synthesis of (R)-4-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide

[0039]

[0040] Synthesis of intermediate a-2: methyl 2-(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxolane]-7-yl)-2-oxoacetate

[0041] At 0°C, AlCl3 (1.12 g, 3.6 mmol) was suspended in CH2Cl2 (20 mL) in a three-necked round-bottom flask equipped with a cooling system. Methyl chlorooxyacetate (0.40 mL, 3.6 mmol) was added dropwise over approximately 10–15 minutes. After 10 minutes, the suspension was stirred until it turned into a pale yellow solution. 8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane] (α-1,592.8 mg, 1.9 mmol) was added dropwise to the reaction mixture over approximately 10 minutes. The reaction mixture was kept at 0°C. The solution was stirred at room temperature for 2 hours. Three times the volume of H2O was carefully added to the reaction mixture. The mixture was extracted with EtOAc (5 × 30 mL). The organic layer was collected. The organic layer was washed with a saturated NaCl solution (2 × 30 mL). The organic layer was dried with Na2SO4. The organic layer was concentrated under vacuum. Column chromatography yielded the title compound (818.7 mg, 57%). MS (ESI+) m / z 399.19 [M+H]+.

[0042] Synthesis of intermediate a-3: 1,1-dioxide of 14-(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxolane]-7-yl)-1,2,5-thiadiazol-3(2H)-one

[0043] CH3ONa (30 wt%, in 20 mL CH3OH) was slowly added to a solution of thioamide (916.0 mg, 10 mmol) in 25 mL dry CH3OH. The mixture was stirred at room temperature for 30 minutes. Intermediate a-2 (798.0 mg, 2.0 mmol) was added to the mixture. The resulting mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was dissolved in Et2O, stirred at room temperature for 10 minutes, and filtered. The organic layer was concentrated under vacuum. Column chromatography gave the title compound (685.3 mg, 77%). MS (ESI+) m / z 445.09 [M+H]+.

[0044] Synthesis of intermediate a-4: 4-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide

[0045] Intermediate a-3 (267.0 mg, 0.6 mmol) was suspended in formic acid (1.3 mL, 30.7 mmol, 88%), rapidly forming a yellow suspension. After 15 minutes, the reaction mixture was diluted with brine (10 mL) by slow addition. The aqueous solution of the mixture was extracted with a 2:1 mixture of ethyl acetate and acetonitrile (3 × 10 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over sodium sulfate, and filtered. The solution was concentrated under vacuum and column chromatography gave the title compound (1.92 g, 80% yield). MS (ESI+) m / z 401.05 [M+H]+.

[0046] Intermediate a-5: 4-(1-fluoro-7-(isopentylamino)-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphthalene-2-

[0047] 1,1-dioxide of 1,2,5-thiadiazole-3(2H)-one

[0048] Sodium cyanoborohydride (145.0 mg, 2.3 mmol) was added to a solution of intermediate a-4 (770.0 mg, 1.92 mmol) and isopentylamine (251.0 mg, 2.88 mmol) in acetonitrile (19.2 mL) at room temperature. After 18 hours, the reaction mixture was diluted with acetonitrile (10 mL), quenched with ammonium hydroxide (0.436 mL, 23 mmol), and then water (2 mL) was added. Celite (5 g) was then added, and the mixture was concentrated under vacuum. The residue was purified by reversed-phase chromatography to give the title compound (498.4 mg, 55% yield). MS (ESI+) m / z 472.20 [M+H]+.

[0049] Intermediate a-6: (R)-4-(1-fluoro-7-(isopentylamino)-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide

[0050] Intermediate a-5 (204.7 mg, 0.434 mmol) was resolved by SFC. Column: Daicel Chiralpak AD-HSFC (20 mm ID * 250 mmL, 5 μm); flow rate: 38 mL / min; A(CO2):B(MeOH(0.1% NH3)) = 70:30; column temperature: 30 °C, yielding the title compound (43.0 mg, 41.9% yield). ESI-MS m / z: 472.21 [M+H]+.

[0051] Preparation of (R)-4-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide (Example 1):

[0052] Hydrogen chloride solution (0.316 mL, 1.27 mmol, 4 M dioxane solution) was added to the suspension of intermediate a-6 (120.0 mg, 0.25 mmol) in acetonitrile (2.5 mL). After 2 hours, the reaction mixture was diluted with acetonitrile (3 mL), quenched with ammonium hydroxide (0.030 mL, 1.42 mmol), and then diluted with water (1.0 mL). Celite (2 g) was added and the resulting suspension was concentrated. The crude residue was dry-loaded onto a 150 g C18 column and purified by reversed-phase liquid chromatography to give the title compound (72.8 mg, 70% yield). ESI-MS m / z: 384.17 [M+H]+.

[0053] 1 H NMR (400MHz, DMSO-d6) δppm 9.18 (s, 1H), 8.33 (br s,2H),6.51(s,1H),3.47-3.32(m,1H),3.10(m,1H),3.08(m,2H),2.80(m,1H),2.75(m,1H ),2.56-2.45(m,1H),2.25-2.13(m,1H),1.65(m,2H),1.52(m,2H),0.97(d,J=6.6Hz,6H).

[0054] Examples 2-7 were obtained by operating in a manner similar to that of Example 1 (see Table 1).

[0055] Table 1

[0056]

[0057]

[0058] Example 8: (R)-5-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-thione 1,1-dioxide

[0059]

[0060] Compound 1 (38.0 mg, 0.1 mmol) was added to toluene (5.0 mL) with phosphorus pentasulfide (16.0 mg, 0.07 mmol). After reacting at 60 °C for 2 hours, the mixture was concentrated under vacuum and purified by reversed-phase liquid chromatography to give the title compound (68.0 mg, 70% yield). ESI-MS m / z: 400.19 [M+H] + .

[0061] 1 H NMR (400MHz, DMSO-d6) δppm 10.06 (s, 1H), 8.31 (br s,2H),6.55(s,1H),3.45-3.37(m,1H),3.12(dd,J=16.0,5.6Hz,1H),3.13(td,J=7.0,2.1Hz,2H),2.83(dt,J=17 .2,4.7H,1H),2.75(m,1H),2.56-2.50(m,1H),2.2-2.13(m,1H),1.69(m,2H),1.50(m,2H),0.90(d,J=6.6Hz,6H).

[0062] Example 9: (R)-4-(7-((2-cyclopentylethyl)amino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazole-3(2H)-thione 1,1-dioxide

[0063]

[0064] Example 9 was obtained by operating on a similar basis to Example 8. ESI-MS m / z: 426.13 [M+H] + .

[0065] 1 H NMR (400MHz, DMSO-d6) δppm; 1H NMR (400MHz, DMSO-d6) δppm 10.27 (br s, 1H), 8.36 (br s,2H),6.43(s,1H),3.46-3.37(m,1H),3.08(dd,J=16.0,5.0Hz,1H),3.02(dd,J=9.6,6.0Hz,2H),2.89 -2.62(m,2H),2.61-2.51(m,1H),2.20(dd,J=11.6,5.2Hz,1H),1.90-1.51(m,10H),1.20-1.12(m,2H).

[0066] Example 10: Phosphatase Activity Assay

[0067] Evaluation of the selectivity and efficacy of small molecule PTPN2 inhibitors (test compounds)

[0068] The selectivity and potency of an analyte compound (e.g., the compound shown in Formula I) against one or more protein tyrosine phosphatases (PTPs), and particularly against PTPN2, can be evaluated in various ways. One or more PTP enzymes include mycobacterial protein tyrosine phosphatase A (mPTPA), mycobacterial protein tyrosine phosphatase B (mPTPB), PTPN1 (i.e., PTP1B), PTPN2 (i.e., TC-PTP), SHP-1, SHP-2, FAP-1, Meg2, HePTP, Laforin, VHX, VHR, LMWPTP, Cdc14A, LAR, CD45, PTPRG, fragments thereof, variants thereof, and combinations thereof. The selectivity and potency of the analyte compound are evaluated using a PTP activity inhibition assay. The assay is performed using a buffer containing 50 mM Bis-Tris (pH 6.3), 2 mM EDTA, and 5 mM N,N'-dimethyl-N,N'-bis(mercaptoacetyl)hydrazine (DMH). The assay was performed using a phosphorylated substrate, such as 10 mM fluorescein diphosphate (FDP) stored at -20 °C. Alternatively, or additionally, 10 mM DiFMUP was used as the phosphorylated substrate. Each PTP enzyme was diluted in an enzyme dilution buffer containing 50 mM Bis-Tris (pH 6.3), 2 mM EDTA, 5 mM MDH, 20% (v / v) glycerol, and 0.01% (v / v) Triton X-100.

[0069] The assay was performed at room temperature in a 96-well plate. 170 μL of the reaction mixture containing 10 μM FDP or DiFMUP was added to each well. 10 μL of either (i) the analyte compound (e.g., a PTPN2 inhibitor) dissolved in DMSO at one of 10 concentrations obtained from serial dilutions, or (ii) a control, was added to each well. The reaction was initiated by adding 20 μL of PTP enzyme (e.g., PTPN2) diluted in enzyme dilution buffer. The phosphatase activity of PTP enzymes was evaluated using the following method: A Gemini™ XPS microplate spectrophotometer (Molecular) was used, with excitation at 440 nm and emission at 530 nm (cutoff filter at 525 nm) for FMP, and excitation at 360 nm and emission at 450 nm (cutoff filter at 435 nm) for DiFMU. The appearance of fluorescent products (e.g., fluorescein monophosphate (FMP) obtained from FDP, or 6,8-difluoro-7-hydroxyl-1-4-coumarin (DiFMU)) was continuously monitored for approximately 15 to 30 minutes. The rate of FMP or DiFMU formation (e.g., initial rate) was plotted against the concentration of the analyte compound, and the data were fitted (e.g., using a 4-parameter equation) to determine the inflection point of the fit as the IC50 of the analyte compound for the specific enzyme. 50 .

[0070] Table 2 IC50 values ​​of the test compounds relative to PTPN2 and PTPN1 50 value

[0071] Test compound <![CDATA[PTPN2 IC 50 (nM)]]> <![CDATA[PTPN1 IC 50 (nM)]]> Example 1 0.92 1.92 Example 2 1.37 3.07 Example 3 1.26 2.42 Example 4 1.32 2.09 Example 5 1.04 1.99 Example 6 1.63 2.89 Example 7 1.15 2.83 Example 8 1.42 2.67 Example 9 1.27 2.81 ABB-CLS-484 1.64 3.88

[0072] The protein tyrosine phosphatase (PTPN2 or PTPN1) inhibition rate of the example compounds and the control compound ABB-CLS-484 in this series was tested. The experimental results are shown in Table 2. Under the same batch testing conditions, example compounds 1-9 all showed better inhibitory activity than the control compound ABB-CLS-484, demonstrating better drug potential.

[0073] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug thereof: In the formula, X is selected from O or S; Z is selected from C(R7)(R8) and N(R9); R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, deuterium, halogen, hydroxyl, and C, respectively. 1-6 Straight-chain or branched alkyl groups, C 3-6 cycloalkyl, C 1-6 Alkoxy; R7 is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-6 Straight-chain or branched alkyl groups, C 3-6 cycloalkyl; R8 is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-6 Straight-chain or branched alkyl groups, C 3-6 cycloalkyl, C 1-6 Alkoxy, -NH2, -NH-C 1-8 Alkyl, -NH-C 3-6 cycloalkyl, -NH-C 1-6 Alkylene-C3-6 cycloalkyl; R9 is selected from hydrogen and C. 1-6 alkyl; in, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -NH2, -NH-C 1-8 Alkyl, -NH-C 3-6 cycloalkyl, -NH-C 1-6 Alkylene-C 3-6 The cycloalkyl group may optionally be substituted on one or more available carbons by one or more halogen, hydroxyl, alkoxy, cyano, nitro, or oxo groups.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, characterized in that, The compounds specifically include:

3. The compound according to claim 1 or 2, or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, characterized in that, The pharmaceutically acceptable salt is an inorganic or organic salt; wherein the inorganic salt is selected from sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar cationic salts, or selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, hydrogen sulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from organic amino salts, formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.

4. A pharmaceutical composition comprising a compound as described in any one of claims 1-3 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, prodrug, and pharmaceutical excipient.

5. The pharmaceutical composition according to claim 4, characterized in that, It also includes additional treatments.

6. The pharmaceutical composition according to claim 5, characterized in that, The additional treatment agent is an immunotherapy agent.

7. The pharmaceutical composition of claim 6, wherein the immunotherapeutic agent is selected from the group consisting of: anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA4 antibody.

8. Use of the compound of any one of claims 1-3 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug in the preparation of a medicament for treating protein tyrosine phosphatase-mediated diseases.

9. Use of the compound of any one of claims 1-3 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug in the preparation of a medicament for treating cancer.

10. Use of the compound of any one of claims 1-3 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug in the preparation of a medicament for the treatment of type 2 diabetes, obesity, or metabolic syndrome.

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