Thiadiazolidine ketone derivatives, their preparation methods and applications

Abstract

This invention discloses a thiadiazolidinone compound, its preparation method, and its applications. The thiadiazolidinone derivative described in this invention is a compound with the structure shown in general formula (I) or a pharmaceutically acceptable salt thereof. This invention also discloses the application of the above-mentioned thiadiazolidinone derivative in drugs for treating PTPN2 / PTPN1-mediated diseases. The compound disclosed in this invention exhibits significant inhibitory activity against PTPN2 / PTPN1 phosphatases, has an important impact on tumor development and immune response, and can also be used in combination with immunosuppressants to treat related immune diseases. It can be developed into an antitumor drug with high activity, good selectivity, and low toxicity, and possesses strong plasticity and great potential for future modification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry and relates to thiadiazolidinone derivatives, specifically to compounds of formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical combinations thereof, and their use in the treatment of PTPN1 / PTPN2 mediated diseases. Background Technology

[0002] Protein phosphorylation is a ubiquitous and reversible post-translational modification process that can adapt to a variety of cellular regulatory mechanisms (Chrestia JF. et al., Pharmacol Res 190:106712; 2023). Protein phosphokinases catalyze phosphorylation, disrupting existing electrostatic interactions by adding a phosphate group to amino acid residues. Reversibly, dephosphorylation is the hydrolysis of phosphate-containing amino acids catalyzed by phosphatases. An abnormal balance between phosphorylation and dephosphorylation can disrupt many cellular regulations governing cell growth, metabolism, differentiation, and communication (Netto LES et al., FEBS J 289(18):5480-504; 2022).

[0003] Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (such as PD-1 / PD-L1 and CTLA-4 blocking antibodies), have proven effective in treating a variety of cancers, significantly improving outcomes in patients with poor prognoses from conventional therapies. However, unsatisfactory clinical responses and the progression of intrinsic or acquired resistance will continue to limit the further development of this therapy.

[0004] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phosphorylated tyrosine-specific phosphatases. It controls a variety of cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is universally expressed, but its expression is higher in hematopoietic cells and placental cells (Mosinger, B. Jr. et al.). ProcNatl Acad Sci USA 89:499-503; 1992). PTPN2 regulates signal transduction of non-receptor tyrosine kinases (such as JAK1, JAK3), receptor tyrosine kinases (such as INSR, EGFR, CSF1R, PDGFR), transcription factors (such as STAT1, STAT3, STAT5a / b), and Src family kinases (such as Fyn, Lck). As a key negative regulator of the JAK-STAT pathway, PTPN2 directly regulates signal transduction through cytokine receptors (including IFNγ). The catalytic domain of PTPN2 shares 74% sequence homology with PTPN1 (also known as PTP1B) and exhibits similar enzymatic kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003).

[0005] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase 1B (PTP1B), plays a key role in the insulin and leptin receptor signaling pathways and is a key protein in downregulating these pathways (Kenner KA et al.). , J Biol Chem 271: 19810-19816, 1996). Animals lacking PTPN1 showed improved glucose regulation and lipid profiles, and resisted weight gain during high-fat diet treatment (Elchebly M. et al., Science 283: 1544-1548, 1999). Therefore, PTPN1 inhibitors hold promise for the treatment of type II diabetes, obesity, and metabolic syndrome.

[0006] Data from in vivo gene screening for loss-of-function gene deletions in a mouse B16F10 transplanted tumor model using CRISPR / Cas9 genome editing technology showed that deletion of the PTPN2 gene in tumor cells improved the response to immunotherapy regimens of GM-CSF secreted vaccine (GVAX) plus PD-1 checkpoint blockade (Manguso RT et al., Nature PTPN2 deficiency sensitizes tumors to immunotherapy by enhancing IFNγ-mediated antigen presentation and growth inhibition. Similar screening showed that genes involved in immune evasion, including PD-L1 and CD47, were depleted under immunotherapy, while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. In recent years, increasing research has demonstrated the oncogenic role of PTPN2. In pancreatic cancer, PTPN2 protein is specifically highly expressed and regulates tumor cell growth (Kuang W. et al., 13:805311; 2022). These findings suggest that therapeutic strategies that enhance IFNγ sensing and signaling may play a crucial role in improving the efficacy of cancer immunotherapy regimens. Summary of the Invention

[0007] Purpose of the invention: The technical problem to be solved by the present invention is to develop small molecule inhibitors with PTPN2 / PTPN1 inhibitory activity based on thiadiazolidinone as the parent nucleus.

[0008] Another technical problem to be solved by the present invention is to provide the application of the above-mentioned thiadiazolidinone derivatives in drugs for treating PTPN2 / PTPN1 mediated diseases.

[0009] Technical solution: A compound as shown in general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is an aromatic heterocyclic ring or a C ring. 3-11 Heterocyclic alkanes, independently and arbitrarily separated by one or more R 2 replace; R 1 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl groups, and: , ; in: m = 0-5; n = 1-3; o = 1-3; R 3 Independently selected from CH and N; R 4 Independently selected from CH, N, and O, and when R 4 When = 0, R 5 It does not exist; When R 4 = N or CH, R 5 Independently selected from hydrogen, oxo, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-NH-C(=O)-, C 3- C6 cycloalkyl-C(=O)- and C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Heterocyclic alkyl-C(=O)- and C 3-6 Heterocyclic alkyl-S(=O)2-; R 2 Independently selected from hydrogen, halogen, oxo, phenyl, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, trifluoromethyl, trifluoromethoxy; or R on two identical atoms 2 Forming a cycloalkyl or heterocycloalkyl group; R 6 Independently selected from hydrogen, halogen, oxo, phenyl, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 cycloalkyl; R 10 Independently selected from C and N; when R 10 When R is N, 7 It does not exist, R 8 R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C1-6 Alkyl and C 3-6 cycloalkyl; When R 10 When it is C, R 7 R 8 R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 cycloalkyl; p = 0-3.

[0010] The compound or a pharmaceutically acceptable salt thereof: Ring A is an aromatic heterocyclic ring or a C ring. 3-11 Heterocyclic alkanes, independently and arbitrarily separated by one or more R 2 Substitution; the aromatic heterocycle is a 5-6 membered aromatic heterocycle containing N; the C 3-11 Heterocyclic alkanes are C atoms containing N. 3-11 Heterocyclic alkanes; R 1 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl groups and: , ; in: m = 0, 1, 2, 3, 4 or 5; n = 1, 2, or 3; o = 1, 2, or 3; p = 1.

[0011] The compound or a pharmaceutically acceptable salt thereof: Ring A is: , , , , , , , , , , Independently and arbitrarily controlled by one or more R 2 replace; in: X and R 1 Connected, U, V, W, X, Y are each independently selected from CH or N; h, i, j, k are each independently selected from 1, 2, 3, 4, 5, or 6; r and s are independently selected from 0, 1, 2, 3, 4 or 5 respectively; t and z are each independently selected from 1, 2, 3, or 4; Where ring A is At that time, i and h are not both 2; The compound or a pharmaceutically acceptable salt thereof: Ring A is: , , , , , , , , , , Independently and arbitrarily controlled by one or more R 2 replace; h and i are each independently selected from 1, 2, 3, 4, 5 or 6; r, s, q, t are each independently selected from 0, 1, 2, 3, 4, or 5.

[0012] The compound or a pharmaceutically acceptable salt thereof: R1 is selected from hydrogen, C 1~4 Alkyl group, (CH3)2-CH-(CH2) 0~4 -、 , , , , , , , , , , , , ; The compound or a pharmaceutically acceptable salt thereof: Ring A is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; R 1 for: , , , , , , , , , , , , , , , ; , , , , H.

[0013] The compound or a pharmaceutically acceptable salt thereof is selected from compounds or pharmaceutically acceptable salts of any of the following structures: .

[0014] Preparation method of the compound represented by general formula (I):

[0015] or,

[0016] or,

[0017] or,

[0018] Where A, R 1 The definition is as described above.

[0019] A pharmaceutical composition comprising the said compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0020] The use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PTPN2 / PTPN1 mediated diseases.

[0021] Unless otherwise specified, the terms used in this invention generally have the following meanings.

[0022] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0023] Term "C" 1-6 "Alkyl" refers to saturated straight-chain and branched hydrocarbon groups with 3-6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

[0024] Term "C" 3-6 "Cycloalkyl" refers to saturated cycloalkyl groups having 3-6 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0025] Term "C" 3-6 "Heterocyclic alkyl" refers to a saturated cycloalkyl group having one or more non-C heteroatoms such as N, O, and S and 3-6 carbon atoms, including but not limited to azirropropyl, azirrobutyl, azirropentyl, and azirrohexyl.

[0026] The term "aromatic heterocycle" refers to an aromatic ring having one or more non-C heteroatoms such as N, O, and S, including but not limited to pyrrole, pyrazine, thiophene, furan, and pyrazole.

[0027] Term "C" 3-11 "Heterocyclic alkanes" refers to cycloalkanes containing 3-8 carbon atoms, as well as spirocyclic and polycyclic alkanes, which have one or more non-C heteroatoms such as N, O, and S; including but not limited to tetrahydropyrrole, piperidine, morpholine, piperazine, 2-azaspiro[3.3]heptane, 6-azaspiro[3.4]octane, 7-azabicyclo[3.3.0]octane, 3-azaspiro[5.5]undecane, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.5]decane, 8-azaspiro[4.5]decane, 2-azaspiro[5.5]undecane, 6-azaspiro[3.5]nonane, etc.

[0028] The term "-C(=O)-" represents a carbonyl group, specifically a carbon-oxygen double bond.

[0029] The term "-S(=O)2-" represents a sulfonyl group.

[0030] The term "-S(=O)2NH-" represents a sulfonamide group.

[0031] The term "-C(=O)NH-" indicates an amide.

[0032] The term "-NHS(=O)2-" represents aminosulfonyl group.

[0033] The term "-NH-C(=O)-" represents carbamoyl group.

[0034] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: The compounds disclosed in this invention have significant activity against PTPN2 / PTPN1 phosphatases, and the synthesized compounds have IC 50 With values ​​maintained at the nM level, it can be used to treat tumor development and immune response, and can also be used in combination with immunosuppressants to treat related immune diseases. It can be developed into an anti-tumor drug with high activity, good selectivity and low toxicity and side effects. It has the characteristics of novel skeleton, strong plasticity and great potential for future modification. Detailed Implementation

[0035] The following embodiments are provided to better understand the present invention, but do not limit the invention. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods. Unless otherwise specified, the experimental materials used in the following embodiments were purchased from conventional biochemical reagent stores. The present application will now be described in detail with reference to specific embodiments.

[0036] Example 1: Synthesis of intermediate A1-1 5-(2-(benzyloxy)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0037] The synthesis route is as follows:

[0038] Step 1: Synthesis of intermediate A1-3 Add 5.04 g sodium hydride (126 mmol, 1.2 eq) and 420 mL tetrahydrofuran (4 mL / mmol) to a 2 L three-necked flask. Attach a constant-pressure dropping funnel to the flask, purge three times with argon, and stir in an ice bath. Then, slowly add 420 mL of a tetrahydrofuran (5 mL / mmol) solution of 25 g intermediate A1-2 (CAS: 147808-42-2, 105 mmol, 1.0 eq) through the funnel, maintaining the internal temperature below 5 °C. After the addition is complete, slowly add 13.10 mL (126 mmol, 1.2 eq) of benzyl alcohol to the solution using a syringe, maintaining the internal temperature below 10 °C. After the reaction is complete as monitored by TLC, transfer the solution to room temperature and stir for another 2.5 h. Then quench with 1 L of purified water and extract with 3 × 500 mL ethyl acetate. The organic layers were combined and washed with 3 × 600 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 38.19 g of a red gel-like substance, which was used directly in the next step without further purification. A small portion of the product was purified for analysis.

[0039] 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (t, J = 1.8 Hz, 1H), 7.61 (dd, J =9.4, 1.8 Hz, 1H), 7.44-7.35 (m, 5H), 5.37 (s, 2H). Step 2: Synthesis of intermediate A1-4 In a 2 L flask, add 38.19 g of intermediate A1-3 (105 mmol, 1.0 eq), 525 mL of methanol (5 mL / mmol), and 525 mL of tetrahydrofuran (5 mL / mmol). Stir, then add 28.08 g of ammonium chloride (525 mmol, 5.0 eq) and 68.65 g of zinc powder (1.05 mol, 10.0 eq). Purge three times with argon and stir overnight at room temperature. After the reaction is complete as monitored by TLC, filter with diatomaceous earth. Concentrate the filtrate under reduced pressure, extract with 1 L of purified water and 3 × 300 mL of ethyl acetate, combine the organic phases, wash with 3 × 400 mL of saturated brine, and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, redissolve in 500 mL of ethyl acetate, stir in an ice bath, and add 105 mL of ethyl hydrochloride solution (2.0 M, 2.0 eq). The suspension was stirred in an ice bath for another 2 hours, then filtered, washed with 3 × 50 mL of glacial ethyl acetate, and dried in a forced-air drying oven to give intermediate A1-4 as a gray hydrochloride (31.46 g, two-step yield of intermediate A1-4 90.03%). A small portion of the product was neutralized and purified for analysis.

[0040] 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 6.7 Hz, 2H), 7.40 (t, J = 7.4Hz, 2H), 7.36-7.31 (m, 1H), 6.99-6.95 (m, 2H), 5.17 (s, 2H), 4.85 (s, 2H); MS(ESI) m / z (M 79 Br+H) + =296. Step 3: Synthesis of intermediate A1-5 Add 31.46 g of intermediate A1-4 (hydrochloride, 94.58 mmol, 1.0 eq), 31.456 g of potassium iodide (94.58 mmol, 1.0 eq), 32.9 mL of N,N-diisopropylethylamine (189 mmol, 2.0 eq), 380 mL of N,N-dimethylformamide (4 mL / mmol), and 13.4 mL of methyl bromoacetate (141.87 mmol, 1.5 eq). The reaction was then heated to 65 °C and stirred for 16 h. After the reaction was monitored by TLC to be nearly complete, the reaction was quenched with 500 mL of purified water, extracted with 3 × 300 mL of ethyl acetate, and the organic phases were combined, washed with 3 × 400 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, purified by silica gel column chromatography, and eluted with petroleum ether / ethyl acetate at a ratio of 20:1 to obtain a white solid, which was intermediate A1-5 (23.692 g, 68.04%).

[0041] 1 H NMR (400 MHz, DMSO-d6) δ 7.50-7.32 (m, 5H), 7.03-6.95 (m, 2H), 5.23(td, J = 6.9, 2.7 Hz, 1H), 5.17 (s, 2H), 4.04 (dd, J = 7.0, 3.1 Hz, 2H), 3.59(s, 3H), MS (ESI) m / z (M 79 Br+H) + =368. Step 4: Synthesis of intermediate A1-6 A solution of 23.692 g intermediate A1-5 (64.34 mmol, 1.0 equiv) and 74.334 g aminosulfonyl chloride (643 mmol, 10.0 eq) in 129 mL of acetonitrile (2 mL / mmol) was purged three times with argon and stirred in an ice bath. When the internal temperature reached 0 °C, 89.43 mL of triethylamine (643 mmol, 10.0 eq) was slowly added through a constant-pressure dropping funnel to maintain the internal temperature below 20 °C. The mixture was stirred at room temperature for another 2 hours, then extracted with 150 mL of purified water and 3 × 150 mL of ethyl acetate. The organic phases were combined, washed with 3 × 200 mL of brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, purified by column chromatography, and eluted with petroleum ether / ethyl acetate at a ratio of 5:1 to give a white solid, which was intermediate A1-6 (12.922 g, 44.90%).

[0042] 1H NMR (400 MHz, DMSO-d6) δ 7.55-7.48 (m, 2H), 7.45 – 7.32 (m, 3H), 7.25-7.17 (m, 2H), 7.05 (s, 2H), 5.20 (s, 2H), 4.42-4.19 (m, 2H), 3.57 (s,3H), MS (ESI) m / z (M 79 Br+H) + =446. Step 5: Synthesis of intermediate A1-7 Take a 100 mL single-necked flask, add 7.156 g of intermediate A1-6 (16 mmol, 1.0 eq) and 4.322 g of sodium methoxide (80 mmol, 5.0 eq), dissolve in 72 mL of methanol, reflux in an oil bath at 65 °C with stirring for 1 h. After the reaction is completed by TLC monitoring, transfer to room temperature and allow to cool naturally. Then add 4.0 M HCl to adjust the pH to 1, and extract with 3 × 75 mL of ethyl acetate. Combine the organic phases, wash with 3 × 50 mL of saturated brine, dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate under vacuum to obtain a reddish-brown oily substance. Then add a minimum amount of DCM, slurry, filter, and dry with a forced air to obtain intermediate A1-7 as a white solid (4.018 g, 60.48%).

[0043] 1 H NMR (400 MHz, DMSO-d6) δ 7.51-7.47 (m, 2H), 7.39-7.28 (m, 3H), 7.19(dd, J = 8.0, 1.7 Hz, 2H), 5.20 (s, 2H), 3.95 (s, 2H), MS (ESI) m / z (M 79 Br-H) - =413. Step Six: Synthesis of Intermediate A1-1 In a 10 mL sealed tube, add 415 mg of intermediate A1-7 (1.0 mmol, 1.0 eq), 295 mg of potassium acetate (3.0 mmol, 3.0 eq), 508 mg of pinacol diboronate (2.0 mmol, 2.0 eq), 73 mg of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 0.1 mmol, 0.1 eq), and 5 mL of dioxane (5 mL / mmol). Purge with argon five times and stir overnight at 105 °C. Then filter the reaction mixture through diatomaceous earth, and concentrate the filtrate under vacuum to obtain a black oily substance, which can be used directly in the next step without further purification. The MS (ESI) m / z of the corresponding boric acid is 379 (M). 79 Br-H) - . Example 2: Synthesis of Compound 1-1 5-(2-fluoro-6-hydroxy-4-(1-isopentyl-1H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0044] The synthesis route is as follows:

[0045] Step 1: Synthesis of compounds 1-3 In a 10 mL sealed tube, mix 415 mg intermediate A1-7 (1.0 mmol, 1.0 eq), 415 mg potassium carbonate (3.0 mmol, 3.0 eq), 116 mg tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 0.1 mmol, 0.1 eq), 264 mg 1-2 (CAS:777063-41-9, 1.0 mmol, 1.0 eq), 0.5 mL purified water (0.5 mL / mmol), and 5 mL dioxane (5 mL / mmol). Purify five times with argon and stir overnight at 100 °C. Filter the reaction mixture through diatomaceous earth, concentrate the filtrate under reduced pressure, and purify by automated C18 reversed-phase column chromatography (25 g C18 silica gel) with water / methanol = 7:3 elution to give compounds 1-3 as a yellow solid (165 mg, 34.92%), which can be used directly in the next step without further purification. MS (ESI) m / z (M+H) + =473. Step 2: Synthesis of Compound 1-1 10 mg of 10% Pd / C (0.1 m / m) was added to a suspension of 165 mg of compound 1-3 (0.35 mmol, 1.0 eq) and 132 mg of ammonium formate (2.1 mmol, 6.0 eq) in 1.8 mL of methanol (5 mL / mmol) and 1.8 mL of tetrahydrofuran (5 mL / mmol). The suspension was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) with water / methanol elution of 4:1 to give compound 1-1 as a white solid (66 mg, 49.31%).

[0046] 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 6.75 (s, 1H), 6.72 -6.58 (m, 1H), 4.17- 4.05 (m, 2H), 4.01 (s, 2H), 1.75-1.60 (m, 2H), 1.48 (dp, J = 13.1, 6.5 Hz, 1H), 0.90 (d, J = 6.6 Hz, 6H), MS(ESI) m / z (M+H) + =383. Example 3: Synthesis of Compound 2-1 5-(4-(1-cyclopentyl-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0047] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole (CAS: 1233526-60-7). 1H NMR(400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 6.95 (d, J =11.8 Hz, 1H), 6.90 (s, 1H), 4.68 (p, J = 7.1 Hz, 1H), MS (ESI) m / z(M+H) + =381. Example 4: Synthesis of Compound 3-1 5-(2-fluoro-6-hydroxy-4-(1-(2-(pyrrolidone-1-yl)ethyl)-1H-pyrazole-4-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0048] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with 1-[2-(1-pyrrolidine)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole (CAS: 1000802-52-7). 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.27 (d, J = 5.0 Hz, 1H), 7.98 (s,1H), 6.99 – 6.87 (m, 2H), 4.47 (s, 2H), 3.96 (s, 2H), 3.59 (s, 2H), 1.97 –1.75 (m, 4H), 1.24 (s, 4H).MS (ESI) m / z (M+H) + =410. Example 5: Synthesis of Compound 4-1 5-(2-fluoro-6-hydroxy-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0049] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with 1-(tetrahydropyran-4-yl)-1H-pyrazole-4-boronic acid pinacol ester (CAS: 1040377-03-4). 1 H NMR (400 MHz, DMSO-d6) δ8.16 (s, 1H), 7.77 (s, 1H), 6.71 (s, 1H), 6.62 (s, 1H), 4.38 (td, J = 11.3,10.5, 5.0 Hz, 1H), 3.97 (d, J = 22.0 Hz, 4H), 3.46 (s, 2H), 1.95 (d, J = 21.3Hz, 4H). MS (ESI) m / z (M+H) + =397. Example 6: Synthesis of Compound 5-1 5-(2-fluoro-6-hydroxy-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0050] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with 1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]boronic acid terephthalate (CAS: 1082503-77-2). 1 H NMR (400 MHz, DMSO-d6) δ9.37 (s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 6.94 (d, J = 11.6 Hz, 1H), 6.88 (s,1H), 4.75 (s, 1H), 4.01 (s, 2H), 3.96 (s, 2H), 1.08 (s, 6H). MS (ESI) m / z (M+H) + =385. Example 7: Synthesis of Compound 6-1 5-(4-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0051] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazol-1-yl)ethylamine (CAS: 1086111-20-7). 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 6.96 (dd, J = 11.4, 2.0 Hz, 1H), 6.90 (s, 1H), 4.53 (s, 2H), 3.96 (s, 2H), 3.60 (s, 2H), 3.17 (d, J = 4.6 Hz, 4H), 1.17 (t, J = 7.1 Hz, 6H). MS (ESI) m / z (M+H) + =412. Example 8: Synthesis of Compound 7-1 5-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0052] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with 1-cyclohexyl-pyrazole-4-boronic acid pinacol ester (CAS: 1175275-00-9). 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 6.94 (dd, J = 11.5, 1.9 Hz, 1H), 6.90 – 6.88 (m,1H), 4.11 (td, J = 7.7, 3.8 Hz, 1H), 3.96 (s, 2H), 2.04 (dd, J = 12.1, 3.6Hz, 2H), 1.75 (dtd, J = 36.9, 12.5, 11.3, 5.7 Hz, 5H), 1.40 (dtd, J = 12.8,9.4, 4.6 Hz, 2H), 1.23 (ddd, J = 16.3, 8.2, 3.6 Hz, 1H).MS (ESI) m / z (M+H) + =395. Example 9: Synthesis of Compound 8-1 5-(4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0053] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5,6-dihydro-4H-pyrrolo(1,2-B)pyrazole (CAS: 1314138-13-0). 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 6.72 (s, 2H), 4.08 (t, J =7.4 Hz, 2H), 3.96 (s, 2H), 3.03 (t, J = 7.4 Hz, 2H), 2.61 (p, J = 7.2, 6.5Hz, 2H). MS (ESI) m / z (M+H) + =353. Example 10: Synthesis of Compound 9-1 5-(4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0054] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with 1-cyclopropylpyrazole-4-boronic acid pinacol ester (CAS: 1151802-22-0). 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.26 (s, 1H), 7.83 (d, J = 0.9 Hz, 1H), 7.01 (dd, J = 11.2, 1.9 Hz, 1H), 6.92– 6.87 (m, 1H), 4.31 (d, J = 7.4 Hz, 2H), 3.75 (tt, J = 7.5, 3.9 Hz, 1H), 1.08 (dq, J = 5.8, 3.8 Hz, 2H), 1.02 – 0.95 (m, 2H). MS (ESI) m / z (M+H) + =353. Example 11: Synthesis of Compound 10-1 5-(4-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0055] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazol-1-yl)propylamine (CAS: 847818-72-8). 1 H NMR (400 MHz, DMSO-d6) δ 9.58 – 9.09 (m, 1H), 8.17 (s, 1H), 7.85 (s,1H), 7.06 – 6.73 (m, 2H), 4.13 (t, J = 7.0 Hz, 2H), 3.96 (s, 2H), 2.37 (s,2H), 2.26 (s, 6H), 2.07 – 1.91 (m, 2H).MS (ESI) m / z(M+H) + =398. Example 12: Synthesis of Compound 11-1 5-(4-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0056] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole (CAS: 1000801-75-1). 1 H NMR(400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.21 (s, 1H), 7.84 (s, 1H), 6.94 (d, J =11.9 Hz, 1H), 6.89 (s, 1H), 3.97 (d, J = 5.1 Hz, 4H), 1.32 – 1.21 (m, 1H), 0.55 (d, J = 8.1 Hz, 2H), 0.39 (t, J = 5.2 Hz, 2H). MS (ESI) m / z(M+H) + =367. Example 13: Synthesis of Compound 12-1 5-(2-fluoro-6-hydroxy-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0057] The compound can be prepared by using the method described in Example 2 and replacing compounds 1-2 with 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole (CAS: 1000801-75-1). 1 H NMR(400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.70 (s, 1H), 6.80 – 6.71 (m, 2H), 4.09(t, J = 6.1 Hz, 2H), 3.97 (s, 2H), 2.91 (t, J = 6.3 Hz, 2H), 2.01 – 1.96 (m,2H), 1.83 (qd, J = 9.5, 7.8, 4.4 Hz, 2H). MS (ESI) m / z(M+H) + =367. Example 14: Synthesis of Compound 13-1 2-(2-fluoro-6-hydroxy-4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)isothiazolidin-4-one 1,1-dioxide

[0058] The synthesis route is as follows:

[0059] Step 1: Synthesis of 13-3 In a 100 mL single-necked flask, 462 mg of intermediate A1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 0.1 mmol, 0.1 eq), 198 mg of 40-2 (CAS: 55405-67-9, 1.0 mmol, 1.0 eq), 2 mL of purified water (2 mL / mmol), and 12 mL of dioxane (12 mL / mmol) were mixed. The mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated column chromatography using dichloromethane / methanol at a ratio of 1:10 to give compound 13-3, which was used directly in the next step without further purification. MS (ESI) m / z (M+H) + =454. Step 2: Synthesis of 13-1 In a 50 mL single-necked flask, 170 mg of 13-3, 109 mg of pentamethylbenzene (0.74 mmol, 2.0 eq), and 3.7 mL of DCM (10 mL / mmol) were mixed and stirred at -80 °C for 0.5 h. Then, 3.7 mL of boron trichloride (1.0 M in DCM, 3.7 mmol, 10.0 eq) was slowly added dropwise to the reaction flask. After 4 h of reaction, the reaction was quenched with methanol. The product was prepared as a granule and purified using a 25 g reverse-phase C18 column, eluting with 30% MeOH / H2O. 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.19 (d, J = 7.0 Hz, 1H), 8.89-8.57 (m, 2H), 7.66 (s, 1H), 7.50 (d, J = 11.6 Hz,1H), 7.16 (dd, J = 6.9, 4.0 Hz, 1H), 4.31 (s, 2H).MS (ESI) m / z (M+H) + =364. Example 15: Synthesis of Compound 14-1 5-(2-fluoro-6-hydroxy-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0060] The synthesis route is as follows:

[0061] Step 1: Synthesis of Intermediate 14-3 The common intermediate 13-3 of Examples 14 and 15 was obtained by referring to the method in step one of Example 14.

[0062] Step 2: Synthesis of 14-1 Following the method in step two of Example 1, replace 1-3 with 13-3 to prepare 14-1. 1 H NMR (400MHz, DMSO-d6) δ 9.12 (s, 1H), 7.45 (s, 1H), 6.73 (d, J = 11.8 Hz, 2H), 6.17(d, J = 3.1 Hz, 1H), 4.01 (t, J = 6.1 Hz, 2H), 3.95 (s, 2H), 3.24 – 3.20 (m,2H), 2.00 (p, J = 5.9 Hz, 2H).MS (ESI) m / z (M+H) + =368. Example 16: Synthesis of Compound 15-1 5-(2-fluoro-6-hydroxy-4-(1H-indoleazol-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0063] The compound can be prepared by using the method described in Example 14 and replacing compound 13-2 with 3-bromoindazole (CAS: 40598-94-5). 1 H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.79 (s, 1H), 8.04(d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.36 (t,J = 1.5 Hz, 1H), 7.26 – 7.21 (m, 2H), 4.03 (s, 2H).MS (ESI) m / z (M+H) + =363. Example 17: Synthesis of Compound 16-1 5-(2-fluoro-6-hydroxy-4-(1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0064] The compound can be prepared by using the method described in Example 14 and replacing compound 13-2 with 3-bromo-1H-pyrazolo[4,3-B]pyridine (CAS: 633328-33-3). 1 H NMR (400 MHz, DMSO-d6) δ 13.93 (s, 1H), 8.58 (d, J = 4.4 Hz, 1H), 8.54 (d, J = 8.2 Hz, 1H), 7.40 (s, 1H), 7.30 (dd, J= 8.2, 4.5 Hz, 1H), 7.26 (dd, J = 11.0, 2.0 Hz, 1H), 4.04 (s, 2H).MS (ESI) m / z (M+H) + =364. Example 18: Synthesis of Compound 17-1 5-(2-fluoro-6-hydroxy-4-(imidazol[1,2-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0065] The compound can be prepared by using the method described in Example 14 and replacing compound 13-2 with 3-bromoimidazole[1,2-A]pyrimidine (CAS: 4926-47-0). 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.79 (d, J= 6.9 Hz, 1H), 8.21 (s, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.77 (dd, J = 9.1, 6.8Hz, 1H), 7.34 (td, J = 6.9, 1.2 Hz, 1H), 7.11 (dd, J = 10.6, 2.0 Hz, 1H), 7.03 (t, J = 1.6 Hz, 1H), 4.07 (s, 2H).MS (ESI) m / z (M+H) + =363. Example 19: Synthesis of Compound 18-1 5-(2-fluoro-6-hydroxy-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0066] The compound can be prepared by using the method described in Example 15 and replacing compound 13-2 with 3-bromoimidazole[1,2-A]pyrimidine (CAS: 4926-47-0). 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.73 (s,1H), 6.95 (dd, J = 10.7, 2.0 Hz, 1H), 6.87 (t, J = 1.5 Hz, 1H), 4.10 (t, J =5.6 Hz, 2H), 4.00 (s, 2H), 3.02 (t, J = 6.1 Hz, 2H), 1.93 (ddd, J = 13.6,8.4, 4.9 Hz, 4H).MS (ESI) m / z (M+H) + =367. Example 20: Synthesis of Compound 19-1 5-(2-fluoro-6-hydroxy-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0067] The compound can be prepared by using the method described in Example 15 and replacing compound 13-2 with 2-bromoimidazole[1,2-A]pyridine (CAS: 112581-95-0). 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.31 (d,J = 6.2 Hz, 1H), 6.59 (d, J = 12.4 Hz, 2H), 3.58 (d, J = 5.9 Hz, 2H), 3.53(s, 2H), 2.43 (t, J = 6.0 Hz, 2H), 1.47 (dd, J = 21.1, 7.3 Hz, 4H).MS (ESI)m / z (M+H) + =367. Example 21: Synthesis of Compound 20-1 5-(2-fluoro-6-hydroxy-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0068] The compound can be prepared by using the method described in Example 15 and replacing compound 13-2 with 3-bromo-[1,2,4]thiazo[4,3-A]pyridine (CAS: 4922-68-3). 1 H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.19 (d, J = 51.1 Hz, 1H), 7.08- 7.00 (m, 2H), 4.08 (t, J = 5.7 Hz, 2H), 4.03(s, 2H), 2.90 (t, J = 6.2 Hz, 2H), 1.92-1.81 (m, 4H).MS (ESI) m / z (M+H) + =368. Example 22: Synthesis of compound 21-1 5-(2-fluoro-6-hydroxy-4-(pyrazolo[1,5-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0069] The compound can be prepared by using the method described in Example 14 and replacing compound 13-2 with 3-bromopyrazolo[1,5-A]pyridine (CAS: 5910-12-3). 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.79 –8.74 (m, 1H), 8.39 (s, 1H), 7.95 (dt, J = 9.0, 1.2 Hz, 1H), 7.40 (ddd, J =9.0, 6.7, 1.1 Hz, 1H), 7.09 (d, J = 9.8 Hz, 2H), 7.00 (td, J = 6.8, 1.3 Hz,1H), 4.36 (d, J = 2.2 Hz, 2H). MS (ESI) m / z (M+H) + =363. Example 23: Synthesis of Compound 22-1 5-(2-fluoro-6-hydroxy-4-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azapine-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0070] The compound can be prepared by using the method described in Example 14 and replacing compound 13-2 with 3-bromo-6,7,8,9-tetrahydro-5H-imidazolium[1,2-A]cycloheximine (CAS: 701298-97-7). 1 H NMR (400 MHz, DMSO-d6) δ9.89 (s, 1H), 7.11 (s, 1H), 6.73 – 6.66 (m, 2H), 4.09 – 4.01 (m, 2H), 4.00(s, 2H), 2.98 – 2.93 (m, 2H), 1.87 – 1.64 (m, 6H).MS (ESI) m / z (M+H) + =381. Example 24: Synthesis of compound 23-1 5-(4-(3-cyclopropyl-4H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0071] The compound can be prepared by using the method described in Example 15 and replacing compound 13-2 with 4-bromo-5-cyclopropylpyrazole (CAS: 957345-28-7). 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.27 – 7.17(m, 1H), 7.15 – 7.04 (m, 1H), 6.97 – 6.87 (m, 2H), 3.97 (d, J = 6.1 Hz, 2H), 1.98 (d, J = 7.6 Hz, 1H), 0.97 – 0.78 (m, 4H).MS (ESI) m / z (M+H) + =353 Example 25: Synthesis of Compound 24-1 5-(2-fluoro-6-hydroxy-4-(3-methyl-4H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0072] The compound can be prepared by using the method described in Example 14 and replacing compound 13-2 with 4-bromo-3-methylpyrazole (CAS: 13808-64-5). 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.39 (s,1H), 7.71 (s, 1H), 6.76 (d, J = 10.0 Hz, 2H), 3.97 (s, 2H), 2.36 (s, 3H).MS(ESI) m / z (M+H) + =327 Example 26: Synthesis of Compound 25-1 5-(2-fluoro-6-hydroxy-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0073] The synthesis route is as follows:

[0074] Step 1: Synthesis of Intermediate 25-3 In a 100 mL single-necked flask, 462 mg of intermediate A1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 0.1 mmol, 0.1 eq), 302 mg of 25-2 (CAS: 1196154-25-2, 1.0 mmol, 1.0 eq), 2 mL of purified water (2 mL / mmol), and 12 mL of dioxane (12 mL / mmol) were mixed. The mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated column chromatography using dichloromethane / methanol at a ratio of 10:1 to give compound 25-3, which was used directly in the next step without further purification. MS (ESI) m / z (M+H) + =558. Steps two and three: Synthesis of 25-1 Using the method in step two of Example 14 to obtain 25-3, without purification, DCM and TFA were directly added, and the mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, it was eluted by fully automated reversed-phase column chromatography (25 g reversed-phase C18 column) with a water / methanol ratio of 3:1. This yielded 25-1. 1HNMR (400 MHz, DMSO-d6) δ 9.45 (s, 2H), 7.92 (s, 1H), 6.83 – 6.77 (m, 1H), 6.71 (s, 1H), 4.65 (s, 2H), 4.37 (s, 2H), 4.03 (d, J = 22.1 Hz, 2H), 3.70 (s,2H).MS (ESI) m / z (M+H) + =368. Example 27: Synthesis of Compound 26-1 5-(2-fluoro-6-hydroxy-4-(5-isopentyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0075] The synthesis route is as follows:

[0076] 73 mg of 25-1 (0.2 mmol, 1.0 eq) was dissolved in 1.4 mL of DCM, followed by the addition of 105 μL of DIPEA (0.6 mmol, 3.0 eq), and then 43 μL of isovaleraldehyde (0.4 mmol, 2.0 eq). The mixture was purged with argon five times and stirred at room temperature for 1 h. Subsequently, 38 mg of sodium cyanoborohydride (0.6 mmol, 3.0 eq) was added, and the mixture was purged with argon five times and stirred at room temperature. After the reaction was monitored by LC-MS, 3 mL of methanol was added to quench the reaction. The product was concentrated under reduced pressure, dried to a fine powder, and purified using a reverse-phase C18 column. The product 26-1 was eluted with 40% MeOH / H2O as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.22(s, 1H), 7.80 (d, J = 6.8 Hz, 1H), 6.78 – 6.73 (m, 1H), 6.70 – 6.67 (m, 1H), 4.20 (s, 2H), 3.97 (s, 2H), 3.63 (pd, J = 6.6, 3.9 Hz, 2H), 3.14 (tt, J =7.3, 3.7 Hz, 2H), 1.63 (dt, J = 13.2, 6.6 Hz, 1H), 1.54 – 1.43 (m, 2H), 1.23(s, 2H), 0.91 (d, J = 6.5 Hz, 6H).MS (ESI) m / z(M+H)+ =438. Example 28: Synthesis of Compound 27-1 5-(2-fluoro-6-hydroxy-4-(1-isopentylpyrrolidine-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0077] The synthesis route is as follows:

[0078] Step 1: Synthesis of intermediate 27-3 Take a 10 mL sealed tube, add 207 mg IntA1-7 (0.5 mmol, 1.0 eq), 221 mg 27-2 (CAS: 212127-83-8, 0.75 mmol, 1.5 eq), 159 mg sodium carbonate (1.5 mmol, 3.0 eq), and 73 mg Pd(dppf)Cl2 (1.0 mmol, 0.2 eq). Dissolve in 3.5 mL dioxane and 0.35 mL purified water. After purging with argon five times, stir at 80 °C for 4 h. After the reaction is complete as monitored by LC-MS, cool to room temperature and filter together with 0.1 mmol of the small-scale reaction solution using diatomaceous earth as a filter aid. Prepare sand from the filtrate and purify using a reverse-phase C18 column. The product, a light brown solid, is eluted with 40% MeOH / H2O, yielding 295 mg, with a yield of 97.64%. MS (ESI) m / z(M+H) + =504. Steps two through four: Synthesis of 27-1 Take a single-necked flask containing 295 mg 27-2 (0.59 mmol, 1.0 eq), add 223 mg ammonium formate (3.52 mmol, 6.0 eq), 3 mL methanol, 3 mL tetrahydrofuran, and then add 147 mg 10% Pd / C. Reflux in an oil bath at 65 °C with stirring for 4 h. After the reaction is complete as monitored by TLC, filter the solution. Concentrate the filtrate to dryness under reduced pressure, then dissolve it in 6 mL DCM. Next, add 1.4 mL trifluoroacetic acid (18.75 mmol, 32 eq), and stir at room temperature for 30 min. After the reaction is complete as monitored by TLC, concentrate to dryness under reduced pressure, then add 2 × 6 mL toluene and 2 × 6 mL DCM to remove the residue. Redissolve the residue in 6 mL DCM, adjust the pH to 8 with DIPEA, and then add 126 μL isovaleraldehyde (1.17 mmol, 2.0 eq). Purge with argon five times and stir at room temperature for 1 h. 110 mg of sodium cyanoborohydride was then added, followed by purging with argon five times and stirring at room temperature. After the reaction was completed as monitored by LC-MS, 6 mL of methanol was added to quench the reaction, and the product was concentrated under reduced pressure to obtain sintered sand and purified by reverse-phase C18 column. The product was eluted with 40% MeOH / H2O to obtain a white solid, yielding 34 mg, with a three-step yield of 15.06%. 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.58 (d, J = 25.4 Hz, 1H), 6.76 (d, J = 11.5 Hz, 1H), 6.69 (s, 1H), 3.98 (d, J = 5.6 Hz, 2H), 3.89– 3.40 (m, 4H), 3.27 – 3.12 (m, 3H), 2.41 – 1.96 (m, 2H), 1.63 (dq, J = 13.1,6.6 Hz, 1H), 1.57 – 1.50 (m, 2H), 0.91 (d, J = 6.5 Hz, 6H).MS (ESI) m / z(M+H) + =386. Example 29: Synthesis of Compound 28-1 5-(2-fluoro-6-hydroxy-4-(1-isopentylazonobutane-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0079] The synthesis route is as follows:

[0080] Step 1: Synthesis of intermediate 28-3 Take a 50 mL single-necked flask and add 415 mg IntA1-7 (1.0 mmol, 1.0 eq), 111 mg TBAI (0.3 mmol, 0.3 eq), 196 mg zinc powder (3.0 mmol, 3.0 eq), 40 mg Ni(dtbbpy)Cl2 (0.1 mmol, 0.1 eq), and 208 μL 27-2 (2.0 mmol, 2.0 eq). Add 10 mL DMA to dissolve, purge with argon five times, and stir at 60 °C for 12 h. After the reaction is complete as monitored by LC-MS, cool to room temperature, filter with diatomaceous earth as the filter aid, add 30 mL purified water to the filtrate, extract and separate the phase with 30 mL EA, extract the aqueous phase again with 5 × 30 mL EA, combine the organic phases, wash with 5 × 80 mL saturated brine, and dry with anhydrous sodium sulfate. The solution was then filtered, and the filtrate was prepared into sand and purified using a 25 g reverse-phase C18 column. The product, an almost colorless oil, was eluted with 60% MeOH / H2O, yielding 50 mg, with a yield of 10.17%. MS (ESI) m / z (MH) - =490. Steps two through four: Synthesis of 28-1 Following the synthesis steps of 27-1, 27-3 was replaced with 28-3, and 100 mg of 28-3 yielded 32 mg of pale yellow solid, with a three-step yield of 42.34%. 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.55 (s, 1H), 6.86 (d, J = 11.1 Hz, 1H), 6.69 (s, 1H), 4.35 (s, 2H), 4.09 (s, 2H), 3.95 (s, 2H), 3.22 (t, J = 8.1 Hz, 2H), 3.14 (d, J = 7.1 Hz, 1H), 1.59 (dq, J = 13.1, 6.6Hz, 1H), 1.35 (dd, J = 10.1, 5.9 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H).MS (ESI)m / z(MH) - =370. Example 30: Synthesis of Compound 29-6

[0081] 5-(2-fluoro-6-hydroxy-4-(2-azapyrheptan[3.3]heptane-6-yl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide trifluoroacetate The synthesis route is as follows:

[0082] Step 1: Synthesis of intermediate 29-3 Take a 100 mL three-necked flask, attach a three-way argon balloon, a constant-pressure dropping funnel, and a thermometer. Vacuum the flask and heat it with a hairdryer. Then, introduce argon gas into the balloon, repeating this process four times until the flask is dry and filled with argon. Next, inject 10 mL of 0.5 mmol / mL 29-2 / anhydrous DCM solution (5.0 mmol, 1.0 eq) into the three-necked flask using a syringe, and cool it by stirring in a cold trap. When the internal temperature reaches -78 °C, slowly inject 10 mL of 1.0 M LiHMDS / THF solution (10.0 mmol, 2.0 eq) using a syringe, controlling the internal temperature to not exceed -65 °C, and then maintain the temperature and stir for 1 hour. Then, inject 15 mL of 0.5 mmol / mL PhN(Tf)2 / anhydrous DCM solution (7.5 mmol, 1.5 eq) into the constant-pressure dropping funnel using a syringe and slowly add it dropwise into the three-necked flask. The internal temperature should be controlled to not exceed -65 °C. After the addition is complete, the mixture should be transferred to room temperature and stirred overnight. The next day, TLC monitoring and colorimetric analysis with potassium permanganate were used to observe a new spot with a polarity slightly greater than PhNHTf, which is the product. The reaction was quenched by adding 40 mL of saturated ammonium chloride solution, followed by extraction with 60 mL of ethyl acetate. The aqueous phase was separated, and the aqueous phase was extracted again with 2 × 40 mL of ethyl acetate. The organic phases were combined, washed with 3 × 100 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was then filtered, and the filtrate was prepared into a slurry and purified by silica gel column chromatography. 400 mg of the product, a yellow oil, was eluted with a 30:1 petroleum ether / ethyl acetate solution, yielding a yield of 23.3%. 1 H NMR (400 MHz, DMSO-d6) δ 5.83 (s, 1H), 4.13 – 3.90 (m, 4H), 3.13 (s, 2H), 1.38 (s, 9H).MS(ESI) m / z(M-Boc+H) + =244. Step 2: Synthesis of intermediate 29-4 Take a 10 mL sealed tube, add 0.5 mmol IntA1-1 (1.0 eq), 343 mg 29-3 (1.0 mmol, 2.0 eq), 159 mg sodium carbonate (1.5 mmol, 3.0 eq), and 37 mg Pd(dppf)Cl2 (0.05 mmol, 0.1 eq), dissolve in 2.5 mL dioxane and 0.25 mL purified water, purge with argon five times, and stir at 80 °C for 12 h. After the reaction is complete as monitored by LC-MS, cool to room temperature, filter with diatomaceous earth as the filter aid, prepare sand from the filtrate, and purify using a reverse-phase C18 column. The product, a pale yellow solid, is eluted with 40% MeOH / H2O, yielding 104 mg, a yield of 39.28%. MS (ESI) m / z (M+H) + =530. Step 3: Synthesis of 29-6 Take a single-necked flask containing 100 mg 29-4 (0.19 mmol, 1.0 eq), add 72 mg ammonium formate (1.13 mmol, 6.0 eq), 1 mL methanol, 1 mL tetrahydrofuran, and then add 10 mg 10% Pd / C. Reflux and stir in an oil bath at 65 ℃ for 2 h. After the reaction is complete as monitored by TLC, filter. Concentrate the filtrate under reduced pressure to dryness, add 2 mL DCM to dissolve it, then add 0.5 mL trifluoroacetic acid. Stir at room temperature for 30 min. After the reaction is complete as monitored by TLC, concentrate under reduced pressure to dryness, add 3 mL methyl tert-butyl ether and stir for 1 h. Filter the resulting white slurry and wash with 3 mL methyl tert-butyl ether. Dry the filter cake by forced air to obtain product 29-6, a white solid (38 mg, two-step reaction yield 44.19%). 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s,1H), 8.50 (s, 2H), 6.56 (dd, J = 11.4, 2.0 Hz, 1H), 6.52 – 6.49 (m, 1H), 4.08(t, J = 5.9 Hz, 2H), 3.92 (s, 2H), 3.88 (t, J = 5.8 Hz, 2H), 3.26 (q, J = 8.5Hz, 1H), 2.56 (ddd, J = 9.8, 8.3, 2.9 Hz, 2H), 2.25 (td, J = 9.6, 2.9 Hz, 2H).MS (ESI) m / z(M+H) + =342. Example 30: Synthesis of Compound 29-1 5-(2-fluoro-6-hydroxy-4-(2-isopentyl-2-azaspiro[3.3]heptane-6-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0083] Following the synthesis steps of 26-1, 25-1 was replaced with 29-6. 38 mg of 25-6 yielded 22 mg of pale yellow solid, which is 29-1. The three-step yield was 28.81%. 1 H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.46 (s,1H), 6.62 – 6.48 (m, 2H), 4.18 (s, 2H), 3.97 (t, J = 7.0 Hz, 4H), 3.32 – 3.27(m, 1H), 3.16 – 3.06 (m, 2H), 2.69 – 2.52 (m, 2H), 2.32 – 2.20 (m, 2H), 1.58(hept, J = 6.7 Hz, 1H), 1.30 (dq, J = 10.3, 5.3, 3.3 Hz, 2H), 0.88 (d, J =6.6 Hz, 6H).MS (ESI) m / z(M+H) + =412. Example 31: Synthesis of compound 30-6 5-(2-fluoro-6-hydroxy-4-(6-azaspiro[3.4]octane-2-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide trifluoroacetate

[0084] Following the synthetic steps in 29-6, this compound can be prepared by replacing 29-2 with 6-Boc-2-oxo-6-azaspiro[3.4]octane (CAS: 203661-71-6). MS (ESI) m / z (MH) - =354. Example 32: Synthesis of Compound 30-1 5-(2-fluoro-6-hydroxy-4-(6-isopentyl-6-aza[3,4]octane-2-yl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0085] The compound can be prepared by replacing 29-6 with 30-6, following the synthesis steps in 29-1. 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.32 (d, J = 9.0 Hz, 1H), 6.63 – 6.53 (m, 2H), 3.93(s, 2H), 3.53 (d, J = 12.6 Hz, 2H), 3.42 (q, J = 8.9 Hz, 1H), 3.10 (s, 4H), 2.27 (d, J = 53.0 Hz, 6H), 1.62 (tt, J = 13.5, 6.5 Hz, 1H), 1.53 – 1.44 (m,2H), 0.91 (t, J = 6.4 Hz, 6H).MS (ESI)m / z(MH) - =424. Example 33: Synthesis of compound 31-1 5-(2-fluoro-6-hydroxy-4-((3aR,6aS)-2-isopentyldihydrocyclopentano[c]pyrrolo-5-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0086] The compound can be prepared by replacing 29-2 with cis-5-oxohexahydrocyclopentadienyl[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester (CAS: 146231-54-1) according to the synthesis steps of 29-1. 1 H NMR (400 MHz, DMSO-d6) δ9.47 (d, J = 57.7 Hz, 1H), 9.27 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 14.5 Hz,2H), 3.94 (s, 2H), 3.76 (s, 1H), 3.50 (d, J = 9.1 Hz, 2H), 3.23 – 3.03 (m,4H), 2.92 (s, 2H), 2.82 (s, 1H), 2.21 (s, 2H), 1.62 – 1.47 (m, 4H), 1.10 –0.75 (m, 6H).MS (ESI) m / z(MH) - =424. II. Biological Evaluation (1). PTPN2 / PTPN1 enzyme activity assay method Compound activity was determined in vitro using unlabeled full-length human PTPN2 / PTPN1 protein via an enzymatic method. The PTPN2 / PTPN1 enzyme was diluted to a final concentration of 0.5 nM in experimental buffer (50 mM HEPES, pH 7.2, 100 mM NaCl, 1 mM EDTA, 0.005% Tween-20, and 5 mM TCEP) and added to black 384-well plates (Greiner, 781900). Compounds were then added using a Tecan D300e dispenser. After incubation at room temperature for 10 min, DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 5 μM. After incubation at room temperature for 30 min, the plate was transferred to a SpectraMax plate reader (Molecular Devices) to measure fluorescence intensity (ex 358, em 455). Each plate included a 100% inhibition control (enzyme-free) and a 0% inhibition control (DMSO), from which the inhibition rate (%) of the test compound was calculated. IC50 was determined from the % inhibition rate data using four-parameter curve fitting. 50 Value. The obtained IC 50 The values ​​are shown in Table 1. A represents compounds with activity below 20 nM, B represents compounds with activity between 20 and 100 nM, C represents compounds with activity between 100 nM and 1 μM, and D represents compounds with activity above 1 μM.

[0087] Table 1 IC50 values ​​of the compounds in the examples against PTPN1 / PTPN2 phosphatases 50 Measured values .

Claims

1. A compound or a pharmaceutically acceptable salt thereof, having the following structural formula: 。 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PTPN2 / PTPN1 mediated diseases.

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