Thiadiazolidinone derivative as well as preparation method and application thereof

Abstract

The invention discloses a thiadiazolidinone compound and a preparation method and application thereof, the thiadiazolidinone derivative is a compound with a structure shown as a general formula (I) or pharmaceutically acceptable salt of the compound, and the invention further discloses application of the thiadiazolidinone derivative in medicine for treating PTPN2 / PTPN1 mediated diseases. The compound disclosed by the invention has obvious inhibitory activity on PTPN2 / PTPN1 phosphatase, has important influence on occurrence and development of tumors and immune response, can also be used in combination with an immunosuppressant to treat related immune diseases, can be developed into an anti-tumor drug with high activity, good selectivity and small toxic and side effects, and has the characteristics of strong plasticity and great future modification potential. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to thiadiazolidinone derivatives, and specifically to compounds represented by formula (I) or pharmaceutically acceptable salts thereof, drug combinations thereof, and uses thereof in treating PTPN1 / PTPN2-mediated diseases. Background Art

[0002] Protein phosphorylation is a universal and reversible post-translational modification process that can adapt to a variety of cellular regulatory mechanisms (Chrestia JF. et al., Pharnacol Res 190: 106712; 2023). Protein phosphokinase catalyzes phosphorylation by adding phosphate groups to amino acid residues to disrupt existing electrostatic interactions. Reversibly, dephosphorylation is the hydrolysis of phosphoamino acids catalyzed by phosphatases. An abnormal balance of phosphorylation and dephosphorylation can disrupt many cellular controls that regulate cell growth, metabolism, differentiation, and communication (Netto LES. et al., FEBS J289 (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 been shown to be effective in treating a variety of cancers, significantly improving treatment outcomes for populations with poor prognosis following conventional therapies. However, suboptimal clinical responses and the development of intrinsic or acquired resistance 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 that controls a variety of cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but is highly expressed in hematopoietic and placental cells (Mosinger, B.Jr.et al, Proc Natl 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 PTPN2 catalytic domain has 74% sequence homology with PTPN1 (also known as PTP1B) and has 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 that downregulates the insulin and leptin receptor signaling pathways (Kenner KA et al., J Biol Chem 271: 19810-19816, 1996). Animals lacking PTPN1 can improve glucose regulation and lipid profiles and resist weight gain when treated with a high-fat diet (Elchebly M. et al., Science 283: 1544-1548, 1999). Therefore, PTPN1 inhibitors are expected to be used to treat type II diabetes, obesity and metabolic syndrome.

[0006] Data from in vivo genetic screening for functional loss in a mouse B16F10 transplant tumor model using CRISPR / Cas9 genome editing technology showed that loss of the PTPN2 gene in tumor cells improved the response to the immunotherapy regimen of GM-CSF secretion vaccine (GVAX) plus PD-1 checkpoint blockade (Manguso RT et al., Nature 547: 413-418; 2017). Loss of PTPN2 sensitizes tumors to immunotherapy by enhancing IFNγ-mediated antigen presentation and growth inhibition. The same screening also 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, more and more studies have shown that PTPN2 has a carcinogenic effect. In pancreatic cancer, PTPN2 protein is specifically highly expressed and regulates the growth of tumor cells (Kuang W. et al., 13: 805311; 2022). These findings suggest that therapeutic strategies to enhance IFNγ sensing and signaling may play an important 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 a small molecule inhibitor with PTPN2 / PTPN1 inhibitory activity based on thiadiazolidinone as the parent core.

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

[0009] Technical solution: A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] Ring A is an aromatic heterocycle or C 3-11 Heterocycloalkane, independently and optionally replaced by one or more R 2 replace;

[0013] R 1 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, and:

[0014]

[0015] in:

[0016] m = 0-5;

[0017] n = 1-3;

[0018] o = 1-3;

[0019] R 3 are independently selected from CH and N;

[0020] R 4 are independently selected from CH, N and O, and when R 4 =0, R 5 does not exist;

[0021] When R 4 =N or CH, R 5 are independently selected from hydrogen, oxo, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-NH-C(=O)-, C3-C6 cycloalkyl-C(=O)- and C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Heterocycloalkyl-C(=O)- and C 3-6 Heterocycloalkyl-S(=O)2-;

[0022] R 2 are independently selected from hydrogen, halogen, oxo, phenyl, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, trifluoromethyl, trifluoromethoxy; or two R 2 forming a cycloalkyl or heterocycloalkyl group;

[0023] R 6 are independently selected from hydrogen, halogen, oxo, phenyl, hydroxy, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0024] R 10 are independently selected from C and N; when R 10 When N, R 7 Does not exist, R 8 , R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0025] When R 10 When C, R 7 , R 8 , R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0026] p=0-3.

[0027] The compound or its pharmaceutically acceptable salt:

[0028] Ring A is an aromatic heterocycle or C 3-11 Heterocycloalkane, independently and optionally replaced by one or more R 2 Substitution; the aromatic heterocycle is a 5- to 6-membered aromatic heterocycle containing N; the C 3-11 Heterocycloalkanes are C 3-11 Heterocycloalkanes;

[0029] R 1 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and:

[0030]

[0031] in:

[0032] m = 0, 1, 2, 3, 4 or 5;

[0033] n = 1, 2 or 3;

[0034] o = 1, 2 or 3;

[0035] p=1.

[0036] The compound or its pharmaceutically acceptable salt:

[0037] Ring A is:

[0038] Independently and arbitrarily represented by one or more R 2 replace;

[0039] in:

[0040] X and R 1 Connected,

[0041] U, V, W, X, and Y are each independently selected from CH or N;

[0042] h, i, j, k are independently selected from 1, 2, 3, 4, 5 or 6;

[0043] r, s are independently selected from 0, 1, 2, 3, 4 or 5;

[0044] t, z are independently selected from 1, 2, 3 or 4;

[0045] When ring A is When , i and h are not 2 at the same time;

[0046] The compound or its pharmaceutically acceptable salt:

[0047] Ring A is:

[0048] Independently and arbitrarily represented by one or more R 2 replace;

[0049] h, i are independently selected from 1, 2, 3, 4, 5 or 6;

[0050] r, s, q, t are independently selected from 0, 1, 2, 3, 4 or 5.

[0051] The compound or its pharmaceutically acceptable salt:

[0052] R1 is selected from hydrogen, C 1～4 Alkyl, (CH3)2-CH-(CH2) 0～4 -、

[0053] The compound or its pharmaceutically acceptable salt:

[0054] Ring A is:

[0055] R 1 for:

[0056] H.

[0057] The compound or its pharmaceutically acceptable salt is selected from a compound or its pharmaceutically acceptable salt having any of the following structures:

[0058]

[0059] The preparation method of the compound represented by general formula (I):

[0060]

[0061]

[0062] Where A, R 1 The definition of is as above.

[0063] A pharmaceutical composition comprises the compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0064] Use of the compound or a pharmaceutically acceptable salt thereof in preparing a drug for treating diseases mediated by PTPN2 / PTPN1.

[0065] Unless otherwise specified, the terms used in the present invention generally have the following meanings.

[0066] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0067] The term "C 1-6 The term "alkyl" refers to a saturated straight chain or branched chain hydrocarbon group having 3 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

[0068] The term "C 3-6 The term "cycloalkyl" refers to a saturated cycloalkyl group having 3 to 6 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0069] The term "C 3-6 The term "heterocycloalkyl" refers to a saturated cycloalkyl group having 3 to 6 carbon atoms and having one or more non-C heteroatoms such as N, O, S, etc., including but not limited to aziridine, azetidinyl, aziridine, azohexyl, etc.

[0070] The term "aromatic heterocycle" refers to an aromatic ring having one or more non-C heteroatoms such as N, O, S, etc., including but not limited to pyrrole, pyrazine, thiophene, furan, pyrazole, etc.

[0071] The term "C 3-1 The term "heterocycloalkane" refers to cycloalkanes containing 3 to 8 carbon atoms and having one or more non-C heteroatoms such as N, O, S, as well as spirocyclic and polycyclic alkanes; it includes but is not limited to tetrahydropyrrole, piperidine, morpholine, piperazine, 2-azaspiro[3.3]heptane, 6-aza-spiro[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.

[0072] The term "-C(=O)-" refers to a carbonyl group, specifically a carbon-oxygen double bond.

[0073] The term "-S(=O)2-" represents a sulfonyl group.

[0074] The term "-S(=O)2NH-" represents a sulfonamide group.

[0075] The term "-C(=O)NH-" refers to an amide.

[0076] The term "-NHS(=O)2-" represents an aminosulfonyl group.

[0077] The term "-NH-C(=O)-" represents a carbamoyl group.

[0078] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the compounds disclosed in the present invention have significant activity against PTPN2 / PTPN1 phosphatase, and the synthesized compound IC 50 The value remains at the nM level, which can be used to have an important impact on the occurrence and development of tumors and immune responses. It 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 toxic side effects. It has the characteristics of a novel skeleton, strong plasticity, and great potential for future transformation. DETAILED DESCRIPTION

[0079] The following examples are provided to facilitate a better understanding of the present invention, but are not intended to limit the present invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are purchased from conventional biochemical reagent stores unless otherwise specified. The present application is described in detail below in conjunction with specific embodiments.

[0080] Example 1: Synthesis of Intermediate A1-1

[0081] 5-(2-(Benzyloxy)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0082]

[0083] The synthetic route is as follows:

[0084]

[0085] Step 1: Synthesis of intermediate A1-3

[0086] Add 5.04g sodium hydride (126mmol, 1.2eq) and 420mL tetrahydrofuran (4mL / mmol) to a 2L three-necked flask, install a constant pressure dropping funnel on the flask, replace the argon three times, and stir in an ice bath. Then, slowly add 25g of intermediate A1-2 (CAS: 147808-42-2, 105mmol, 1.0eq) in 420mL tetrahydrofuran (5mL / mmol) through the funnel, keeping the internal temperature below 5°C. After the addition is complete, slowly add 13.10mL (126mmol, 1.2eq) of benzyl alcohol to the solution with a syringe, keeping the internal temperature below 10°C. After the reaction is complete as monitored by TLC, move the solution to room temperature and stir for another 2.5h. Then add 1L of purified water to quench, and extract with 3×500mL 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 obtain 38.19 g of a red jelly, which was used directly in the next step without further purification. A small portion of the product was purified for analysis. 1 H NMR (400MHz, DMSO-d6) δ7.65 (t, J=1.8Hz, 1H), 7.61 (dd, J=9.4, 1.8Hz, 1H), 7.44-7.35 (m, 5H), 5.37 (s, 2H).

[0087] Step 2: Synthesis of intermediate A1-4

[0088] In a 2L flask, 38.19g of intermediate A1-3 (105mmol, 1.0eq), 525mL of methanol (5mL / mmol) and 525mL of tetrahydrofuran (5mL / mmol) were added, stirred, 28.08g of ammonium chloride (525mmol, 5.0eq) and 68.65g of zinc powder (1.05mol, 10.0eq) were added, argon was replaced three times, and stirred at room temperature overnight. After the reaction was completed by TLC monitoring, diatomaceous earth was used for suction filtration, the filtrate was concentrated under reduced pressure, 1L of purified water and 3×300mL of ethyl acetate were added for extraction, the organic phases were combined, washed with 3×400mL of saturated brine, and dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated under reduced pressure and dissolved in 500mL of ethyl acetate again, stirred in an ice bath, and 105mL of hydrogen chloride ethyl acetate solution (2.0M, 2.0eq) was added. 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 obtain intermediate A1-4 as a gray hydrochloride (31.46 g, intermediate A1-4 two-step yield 90.03%). A small portion of the product was neutralized and purified for analysis 1H NMR (400MHz, DMSO-d6) δ7.50 (d, J=6.7Hz, 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.

[0089] Step 3: Synthesis of intermediate A1-5

[0090] Add 31.46g of intermediate A1-4 (hydrochloride, 94.58mmol, 1.0eq), 31.456g of potassium iodide (94.58mmol, 1.0eq), 32.9mL of N, N-diisopropylethylamine (189mmol, 2.0eq), 380mL of N, N-dimethylformamide (4mL / mmol) and 13.4mL of methyl bromoacetate (141.87mmol, 1.5eq). Then heat the reaction to 65°C and stir for 16h. After the reaction is basically complete as monitored by TLC, quench the reaction with 500mL of purified water, extract with 3×300mL of ethyl acetate, combine the organic phases, wash with 3×400mL of saturated brine, dry with anhydrous sodium sulfate, and filter. The filtrate is concentrated in vacuo and purified on a silica gel column with petroleum ether / ethyl acetate = 20:1 to obtain a white solid, which is intermediate A1-5 (23.692g, 68.04%). 1 H NMR (400MHz, DMSO-d6) δ7.50-7.32 (m, 5H), 7.03-6.95 (m, 2H), 5.23 (td, J=6.9, 2 .7Hz, 1H), 5.17 (s, 2H), 4.04 (dd, J=7.0, 3.1Hz, 2H), 3.59 (s, 3H), MS (ESI) m / z (M 79 Br+H) + =368.

[0091] Step 4: Synthesis of intermediate A1-6

[0092] A solution of 23.692 g of intermediate A1-5 (64.34 mmol, 1.0 equiv) and 74.334 g of aminosulfonyl chloride (643 mmol, 10.0 eq) in 129 mL of acetonitrile (2 mL / mmol) was replaced with argon three times 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 keep the internal temperature below 20°C. Stir for another 2 hours at room temperature, add 150 mL of purified water and 3×150 mL of ethyl acetate for extraction, combine the organic phases, wash with 3×200 mL of brine, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure and purified by column chromatography, and eluted with petroleum ether / ethyl acetate = 5:1 to obtain a white solid, which is intermediate A1-6 (12.922 g, 44.90%). 1 H NMR (400MHz, DMSO-d6) δ7.55-7.48(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.

[0093] Step 5: Synthesis of intermediate A1-7

[0094] Take a 100mL single-mouth bottle, add 7.156g of intermediate A1-6 (16mmol, 1.0eq), 4.322g of sodium methoxide (80mmol, 5.0eq), dissolve with 72mL of methanol, reflux and stir in a 65℃ oil bath for 1h, and move to room temperature to cool naturally after TLC monitoring. Then add 4.0M HCl to adjust pH=1, and extract with 3×75mL of ethyl acetate, combine the organic phases, wash with 3×50mL of saturated brine, dry with anhydrous sodium sulfate, and filter. The filtrate is concentrated in vacuo to obtain a reddish brown oil, then add a minimum amount of DCM to pulp and filter and air dry to obtain intermediate A1-7 as a white solid (4.018g, 60.48%). 1 H NMR (400MHz, DMSO-d6) δ7.51-7.47 (m, 2H), 7.39-7.28 (m, 3H), 7.19 (dd, J=8.0, 1.7Hz, 2H), 5.20 (s, 2H), 3.95 (s, 2H), MS (ESI) m / z (M 79 Br-H)-=413.

[0095] Step 6: Synthesis of intermediate A1-1

[0096] 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 biboronic acid pinacol ester (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). Replace with argon 5 times and stir at 105°C overnight. Then filter the reaction mixture through diatomaceous earth, and concentrate the filtrate in vacuo to obtain a black oil, which is used directly in the next step without further purification. The MS (ESI) of the corresponding boronic acid is m / z 379 (M 79 Br-H)-.

[0097] Example 2: Synthesis of Compound 1-1

[0098] 5-(2-Fluoro-6-hydroxy-4-(1-isopentyl-1H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0099]

[0100] The synthetic route is as follows:

[0101]

[0102] Step 1: Synthesis of Compound 1-3

[0103] In a 10 mL sealed tube, 415 mg of intermediate A1-7 (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), 264 mg of 1-2 (CAS: 777063-41-9, 1.0 mmol, 1.0 eq), 0.5 mL of purified water (0.5 mL / mmol), and 5 mL of dioxane (5 mL / mmol) were mixed. The argon gas was replaced 5 times and stirred at 100 ° C overnight. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by fully automatic C18 reverse phase column chromatography (25 g C18 silica gel), eluted with water / methanol = 7:3 to obtain compound 1-3 as a yellow solid (165 mg, 34.92%), which was used directly in the next step without further purification. MS (ESI) m / z (M+H) + =473.

[0104] Step 2: Synthesis of compound 1-1

[0105] 10 mg 10% Pd / C (0.1 m / m) was added to a suspension of 165 mg compound 1-3 (0.35 mmol, 1.0 eq) and 132 mg ammonium formate (2.1 mmol, 6.0 eq) in 1.8 mL methanol (5 mL / mmol) and 1.8 mL tetrahydrofuran (5 mL / mmol). The suspension was refluxed at 65° C. for 2 h, and the filtrate after filtration was concentrated under reduced pressure and further purified by C18 reverse phase column chromatography (10 g, C18 silica gel), eluting with water / methanol = 4:1 to obtain compound 1-1 as a white solid (66 mg, 49.31%). 1 H NMR (400MHz, DMSO-d6) δ10.16 (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, 6.5Hz, 1H), 0.90 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =383.

[0106] Example 3: Synthesis of Compound 2-1

[0107] 5-(4-(1-cyclopentyl-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0108]

[0109] This compound was prepared using the method described in Example 2 and substituting 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS: 1233526-60-7) for compound 1-2. 1 H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 6.95 (d, J = 11.8Hz, 1H), 6.90 (s, 1H), 4.68 (p, J = 7.1Hz, 1H), 3.96 (s , 2H), 2.09 (dq, J=12.9, 7.2Hz, 2H), 1.94 (dq, J=13.9, 6.6Hz, 2H), 1.85-1.74 (m, J=4.8Hz, 2H), 1.69-1.59 (m, 2H).MS (ESI) m / z (M+H) + =381.

[0110] Example 4: Synthesis of Compound 3-1

[0111] 5-(2-Fluoro-6-hydroxy-4-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0112]

[0113] The compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 1-[2-(1-pyrrolidine)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS: 1000802-52-7). 1 HNMR (400MHz, DMSO-d6) δ9.41 (s, 1H), 8.27 (d, J=5.0Hz, 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.

[0114] Example 5: Synthesis of Compound 4-1

[0115] 5-(2-Fluoro-6-hydroxy-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0116]

[0117] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 1-(tetrahydropyran-4-yl)-1H-pyrazole-4-boronic acid pinacol ester (CAS: 1040377-03-4). 1 H NMR (400MHz, DMSO-d6) δ8.16 (s, 1H), 7.77 (s, 1H), 6.71 (s, 1H), 6.62 (s, 1H), 4.38 (td, J = 11.3, 1 0.5, 5.0Hz, 1H), 3.97 (d, J=22.0Hz, 4H), 3.46 (s, 2H), 1.95 (d, J=21.3Hz, 4H).MS (ESI) m / z (M+H) + =397.

[0118] Example 6: Synthesis of Compound 5-1

[0119] 5-(2-Fluoro-6-hydroxy-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0120]

[0121] This compound was prepared using the method described in Example 2 and substituting 1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]boronic acid naphthalene ester (CAS: 1082503-77-2) for compound 1-2. 1 H NMR (400MHz, DMSO-d6) δ9.37 (s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 6.94 (d, J=11.6Hz, 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.

[0122] Example 7: Synthesis of Compound 6-1

[0123] 5-(4-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0124]

[0125] The compound can be prepared using the method described in Example 2 and replacing compound 1-2 with N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethylamine (CAS: 1086111-20-7). 1 H NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 6.96 (dd, J=11.4, 2.0Hz, 1H), 6.90 (s, 1H) ), 4.53 (s, 2H), 3.96 (s, 2H), 3.60 (s, 2H), 3.17 (d, J = 4.6Hz, 4H), 1.17 (t, J = 7.1Hz, 6H).MS (ESI) m / z (M+H) + =412.

[0126] Example 8: Synthesis of Compound 7-1

[0127] 5-(4-(1-cyclohexyl-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0128]

[0129] The compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 1-cyclohexyl-pyrazole-4-boronic acid pinacol ester (CAS: 1175275-00-9). 1 H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 6.94 (dd, J=11. 5, 1.9Hz, 1H), 6.90-6.88 (m, 1H), 4.11 (td, J=7.7, 3.8Hz, 1H), 3.96 (s, 2H), 2.0 4(dd, J=12.1, 3.6Hz, 2H), 1.75(dtd, J=36.9, 12.5, 11.3, 5.7Hz, 5H), 1.40(dtd , J=12.8, 9.4, 4.6Hz, 2H), 1.23 (ddd, J=16.3, 8.2, 3.6Hz, 1H).MS (ESI) m / z (M+H) + =395.

[0130] Example 9: Synthesis of Compound 8-1

[0131] 5-(4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0132]

[0133] The compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo(1,2-B)pyrazole (CAS: 1314138-13-0). 1 H NMR (400MHz, DMSO-d6) δ7.82 (s, 1H), 6.72 (s, 2H), 4.08 (t, J=7.4Hz, 2H), 3.9 6 (s, 2H), 3.03 (t, J=7.4Hz, 2H), 2.61 (p, J=7.2, 6.5Hz, 2H).MS (ESI) m / z (M+H) + =353.

[0134] Example 10: Synthesis of Compound 9-1

[0135] 5-(4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0136]

[0137] The compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 1-cyclopropylpyrazole-4-boronic acid pinacol ester (CAS: 1151802-22-0). 1 H NMR (400MHz, DMSO-d6) δ10.17 (s, 1H), 8.26 (s, 1H), 7.83 (d, J=0.9Hz, 1H), 7.01 (dd, J=11.2, 1.9Hz, 1H), 6.92-6.87 (m, 1 H), 4.31 (d, J=7.4Hz, 2H), 3.75 (tt, J=7.5, 3.9Hz, 1H), 1.08 (dq, J=5.8, 3.8Hz, 2H), 1.02-0.95 (m, 2H).MS (ESI) m / z (M+H) + =353.

[0138] Example 11: Synthesis of Compound 10-1

[0139] 5-(4-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0140]

[0141] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propylamine (CAS: 847818-72-8). 1 H NMR (400MHz, DMSO-d6) δ9.58-9.09 (m, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 7.06-6.73 (m, 2H), 4.13 (t, J=7.0Hz, 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.

[0142] Example 12: Synthesis of Compound 11-1

[0143] 5-(4-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0144]

[0145] This compound was prepared using the method described in Example 2 and substituting 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS: 1000801-75-1) for compound 1-2. 1 H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 8.21 (s, 1H), 7.84 (s, 1H), 6.94 (d, J = 11.9Hz, 1H), 6.89 (s, 1H), 3. 97 (d, J=5.1Hz, 4H), 1.32-1.21 (m, 1H), 0.55 (d, J=8.1Hz, 2H), 0.39 (t, J=5.2Hz, 2H).MS (ESI) m / z (M+H) + =367.

[0146] Example 13: Synthesis of Compound 12-1

[0147] 5-(2-Fluoro-6-hydroxy-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0148]

[0149] This compound was prepared using the method described in Example 2 and substituting 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS: 1000801-75-1) for compound 1-2. 1 H NMR (400MHz, DMSO-d6) δ7.93 (s, 1H), 7.70 (s, 1H), 6.80-6.71 (m, 2H), 4.09 (t, J=6.1Hz, 2H), 3.97 (s , 2H), 2.91 (t, J=6.3Hz, 2H), 2.01-1.96 (m, 2H), 1.83 (qd, J=9.5, 7.8, 4.4Hz, 2H).MS (ESI) m / z (M+H) + =367.

[0150] Example 14: Synthesis of Compound 13-1

[0151] 2-(2-Fluoro-6-hydroxy-4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)isothiazolidin-4-one 1,1-dioxide

[0152]

[0153] The synthetic route is as follows:

[0154]

[0155] Step 1: Synthesis of 13-3

[0156] In a 100mL single-mouth bottle, 462mg of intermediate A1-1 (1.0mmol, 1.0eq), 415mg of potassium carbonate (3.0mmol, 3.0eq), 116mg of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 0.1mmol, 0.1eq), 198mg of 40-2 (CAS: 55405-67-9, 1.0mmol, 1.0eq), 2mL of purified water (2mL / mmol), and 12mL of dioxane (12mL / mmol) were mixed. The argon gas was replaced 5 times and stirred at 100°C overnight. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by fully automatic column chromatography, eluting with dichloromethane / methanol = 1:10 to obtain compound 13-3, which was used directly in the next step without further purification. MS (ESI) m / z (M+H) + =454.

[0157] Step 2: Synthesis of 13-1

[0158] In a 50mL single-mouth bottle, 170mg 13-3, 109mg pentamethylbenzene (0.74mmol, 2.0eq), 3.7mL DCM (10mL / mmol) were mixed, placed in -80℃ and stirred for 0.5h, 3.7mL boron trichloride (1.0M in DCM, 3.7mmol, 10.0eq) was slowly dripped into the reaction bottle. After 4h of reaction, methanol was quenched. Sand was made and purified with a 25g reverse phase C18 column, and the product was eluted with 30% MeOH / H2O. 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 9.19 (d, J=7.0Hz, 1H), 8.89-8.57 (m, 2H), 7.66 (s, 1H), 7.50 (d, J=11.6Hz, 1H), 7.16 (dd, J=6.9, 4.0Hz, 1H), 4.31 (s, 2H).MS (ESI) m / z (M+H) + =364.

[0159] Example 15: Synthesis of Compound 14-1

[0160] 5-(2-Fluoro-6-hydroxy-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0161]

[0162] The synthetic route is as follows:

[0163]

[0164] Step 1: Synthesis of intermediate 14-3

[0165] Referring to the method of step 1 in Example 14, the common intermediate 13-3 of Example 14 and Example 15 was obtained.

[0166] Step 2: Synthesis of 14-1

[0167] Referring to the method of step 2 in Example 1, 1-3 is replaced by 13-3 to prepare 14-1. 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 1H), 7.45 (s, 1H), 6.73 (d, J = 11.8Hz, 2H), 6.17 (d, J = 3.1Hz, 1H) , 4.01 (t, J=6.1Hz, 2H), 3.95 (s, 2H), 3.24-3.20 (m, 2H), 2.00 (p, J=5.9Hz, 2H).MS (ESI) m / z (M+H) + =368.

[0168] Example 16: Synthesis of Compound 15-1

[0169] 5-(2-Fluoro-6-hydroxy-4-(1H-indolazol-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0170]

[0171] This compound was prepared using the method described in Example 14 and substituting 3-bromoindazole (CAS: 40598-94-5) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ13.33 (s, 1H), 9.79 (s, 1H), 8.04 (d, J = 8.2Hz, 1H), 7.60 (d, J = 8.4Hz, 1H ), 7.45-7.39 (m, 1H), 7.36 (t, J=1.5Hz, 1H), 7.26-7.21 (m, 2H), 4.03 (s, 2H).MS (ESI) m / z (M+H)+ =363.

[0172] Example 17: Synthesis of Compound 16-1

[0173] 5-(2-Fluoro-6-hydroxy-4-(1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0174]

[0175] This compound was prepared using the method described in Example 14 and substituting 3-bromo-1H-pyrazolo[4,3-B]pyridine (CAS: 633328-33-3) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ13.93 (s, 1H), 8.58 (d, J = 4.4Hz, 1H), 8.54 (d, J = 8.2Hz, 1H), 7.40 (s, 1 H), 7.30 (dd, J=8.2, 4.5Hz, 1H), 7.26 (dd, J=11.0, 2.0Hz, 1H), 4.04 (s, 2H).MS (ESI) m / z (M+H) + =364.

[0176] Example 18: Synthesis of Compound 17-1

[0177] 5-(2-Fluoro-6-hydroxy-4-(imidazo[1,2-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0178]

[0179] This compound was prepared using the method described in Example 14 and substituting 3-bromoimidazole[1,2-A]pyrimidine (CAS: 4926-47-0) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ10.13 (s, 1H), 8.79 (d, J = 6.9Hz, 1H), 8.21 (s, 1H), 7.91 (d, J = 8.9Hz, 1H), 7.77 (dd, J = 9.1, 6.8H z, 1H), 7.34 (td, J=6.9, 1.2Hz, 1H), 7.11 (dd, J=10.6, 2.0Hz, 1H), 7.03 (t, J=1.6Hz, 1H), 4.07 (s, 2H).MS (ESI) m / z (M+H) + =363.

[0180] Example 19: Synthesis of Compound 18-1

[0181] 5-(2-Fluoro-6-hydroxy-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

[0182]

[0183] This compound was prepared using the method described in Example 15 and substituting 3-bromoimidazole[1,2-A]pyrimidine (CAS: 4926-47-0) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 7.73 (s, 1H), 6.95 (dd, J=10.7, 2.0Hz, 1H), 6.87 (t, J=1.5Hz, 1H), 4.10 (t, J=5.6Hz, 2H), 4.00 (s, 2H), 3.02 (t, J=6.1Hz, 2H), 1.93 (ddd, J=13.6, 8.4, 4.9Hz, 4H).MS (ESI) m / z (M+H) + =367.

[0184] Example 20: Synthesis of Compound 19-1

[0185] 5-(2-Fluoro-6-hydroxy-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0186]

[0187] This compound was prepared using the method described in Example 15 and substituting 2-bromoimidazole [1,2-a] pyridine (CAS: 112581-95-0) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ9.18 (s, 1H), 7.31 (d, J = 6.2Hz, 1H), 6.59 (d, J = 12.4Hz, 2H), 3.58 (d, J = 5.9 Hz, 2H), 3.53 (s, 2H), 2.43 (t, J=6.0Hz, 2H), 1.47 (dd, J=21.1, 7.3Hz, 4H). MS (ESI) m / z (M+H)+=367.

[0188] Example 21: Synthesis of Compound 20-1

[0189] 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-thiadiazolidin-3-one 1,1-dioxide

[0190]

[0191] This compound was prepared using the method described in Example 15 and substituting 3-bromo-[1,2,4]thiazolo[4,3-A]pyridine (CAS: 4922-68-3) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ10.08 (s, 1H), 7.19 (d, J=51.1Hz, 1H), 7.08-7.00 (m, 2H), 4.08 (t , J=5.7Hz, 2H), 4.03 (s, 2H), 2.90 (t, J=6.2Hz, 2H), 1.92-1.81 (m, 4H).MS (ESI) m / z (M+H) + =368.

[0192] Example 22: Synthesis of Compound 21-1

[0193] 5-(2-Fluoro-6-hydroxy-4-(pyrazolo[1,5-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0194]

[0195] This compound was prepared using the method described in Example 14 and substituting 3-bromopyrazolo[1,5-A]pyridine (CAS: 5910-12-3) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 8.79-8.74 (m, 1H), 8.39 (s, 1H), 7.95 (dt, J=9.0, 1.2Hz, 1H), 7.40 (ddd, J= 9.0, 6.7, 1.1Hz, 1H), 7.09 (d, J=9.8Hz, 2H), 7.00 (td, J=6.8, 1.3Hz, 1H), 4.36 (d, J=2.2Hz, 2H).MS (ESI) m / z (M+H) + =363.

[0196] Example 23: Synthesis of Compound 22-1

[0197] 5-(2-Fluoro-6-hydroxy-4-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0198]

[0199] This compound can be prepared using the method described in Example 14 and substituting 3-bromo-6,7,8,9-tetrahydro-5H-imidazole[1,2-a]cycloheximide (CAS: 701298-97-7) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ9.89 (s, 1H), 7.11 (s, 1H), 6.73-6.66 (m, 2H), 4.09-4.0 1(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.

[0200] Example 24: Synthesis of Compound 23-1

[0201] 5-(4-(3-cyclopropyl-4H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0202]

[0203] This compound was prepared using the method described in Example 15 and substituting 4-bromo-5-cyclopropylpyrazole (CAS: 957345-28-7) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ9.39 (s, 1H), 7.27-7.17 (m, 1H), 7.15-7.04 (m, 1H), 6.97-6.87 (m , 2H), 3.97 (d, J=6.1Hz, 2H), 1.98 (d, J=7.6Hz, 1H), 0.97-0.78 (m, 4H).MS (ESI) m / z (M+H) + =353

[0204] Example 25: Synthesis of Compound 24-1

[0205] 5-(2-Fluoro-6-hydroxy-4-(3-methyl-4H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0206]

[0207] This compound was prepared using the method described in Example 14 and substituting 4-bromo-3-methylpyrazole (CAS: 13808-64-5) for compound 13-2. 1 H NMR (400MHz, DMSO-d6) δ12.67 (s, 1H), 9.39 (s, 1H), 7.71 (s, 1H), 6.76 (d, J=10.0Hz, 2H), 3.97 (s, 2H), 2.36 (s, 3H).MS (ESI) m / z (M+H) + =327

[0208] Example 26: Synthesis of Compound 25-1

[0209] 5-(2-Fluoro-6-hydroxy-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0210]

[0211] The synthetic route is as follows:

[0212]

[0213] Step 1: Synthesis of intermediate 25-3

[0214] In a 100mL single-mouth bottle, 462mg of intermediate A1-1 (1.0mmol, 1.0eq), 415mg of potassium carbonate (3.0mmol, 3.0eq), 116mg of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 0.1mmol, 0.1eq), 302mg of 25-2 (CAS: 1196154-25-2, 1.0mmol, 1.0eq), 2mL of purified water (2mL / mmol), and 12mL of dioxane (12mL / mmol) were mixed. The argon gas was replaced 5 times and stirred at 100°C overnight. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by fully automatic column chromatography, eluting with dichloromethane / methanol = 10:1 to obtain compound 25-3, which was used directly in the next step without further purification. MS (ESI) m / z (M+H) + =558.

[0215] Steps 2 to 3: Synthesis of 25-1

[0216] The method of step 2 of Example 14 was used to obtain 25-3. DCM and TFA were directly added without purification, and stirred at room temperature for 4 hours, then concentrated under reduced pressure, and eluted with water / methanol: 3:1 by fully automatic reverse phase column chromatography (25 g reverse phase C18 column). 25-1 was obtained. 1HNMR (400MHz, DMSO-d6) δ9.45 (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=22.1Hz, 2H), 3.70 (s, 2H).MS (ESI) m / z (M+H) + =368.

[0217] Example 27: Synthesis of Compound 26-1

[0218] 5-(2-Fluoro-6-hydroxy-4-(5-isopentyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0219]

[0220] The synthetic route is as follows:

[0221]

[0222] Take 73mg 25-1 (0.2mmol, 1.0eq), add 1.4mL DCM to dissolve, add 105μL DIPEA (0.6mmol, 3.0eq), then add 43μL isovaleraldehyde (0.4mmol, 2.0eq), replace with argon 5 times, and stir at room temperature for 1h. Then add 38mg sodium cyanoborohydride (0.6mmol, 3.0eq), replace with argon 5 times, and stir at room temperature. After the reaction is completed by LC-MS monitoring, add 3mL methanol to quench the reaction, concentrate under reduced pressure to make sand, and purify with reverse phase C18 column, 40% MeOH / H2O eluted product 26-1 as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.53 (s, 1H), 8.22 (s, 1H), 7.80 (d, J=6.8Hz, 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, 3.9Hz, 2H), 3.14 (tt, J=7.3, 3.7Hz, 2H), 1.63 (dt, J=13.2, 6.6Hz, 1H), 1.54-1.43 (m, 2H), 1.23 (s, 2H), 0.91 (d, J=6.5Hz, 6H).MS (ESI)

[0223] m / z(M+H) + =438.

[0224] Example 28: Synthesis of Compound 27-1

[0225] 5-(2-Fluoro-6-hydroxy-4-(1-isopentylpyrrolidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0226]

[0227] The synthetic route is as follows:

[0228]

[0229] Step 1: Synthesis of intermediate 27-3

[0230] Take a 10mL sealed tube, add 207mg IntA1-7 (0.5mmol, 1.0eq), 221mg 27-2 (CAS: 212127-83-8, 0.75mmol, 1.5eq), 159mg sodium carbonate (1.5mmol, 3.0eq), 73mg Pd(dppf)Cl2 (1.0mmol, 0.2eq), add 3.5mL dioxane and 0.35mL purified water to dissolve, replace argon 5 times and stir at 80℃ for 4h. After LC-MS monitoring, the reaction is complete, cool to room temperature, filter with 0.1mmol small test reaction solution and filter with diatomaceous earth, sand the filtrate and purify with reverse phase C18 column, the product is eluted with 40% MeOH / H2O as a light brown solid, 295mg, yield 97.64%. MS (ESI) m / z (M+H) + =504.

[0231] Step 2 to Step 4: Synthesis of 27-1

[0232] Take a single-mouth bottle 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 and stir in a 65°C oil bath for 4 h, filter after the reaction is complete under TLC monitoring, concentrate the filtrate under reduced pressure to dryness, then add 6 mL DCM to dissolve, then add 1.4 mL trifluoroacetic acid (18.75 mmol, 32 eq), stir at room temperature for 30 min, after the reaction is completed under TLC monitoring, concentrate under reduced pressure to dryness, 2×6 mL toluene, 2×6 mL DCM to dryness. Then add 6 mL DCM to dissolve, add DIPEA to adjust pH=8, then add 126 μL isovaleraldehyde (1.17 mmol, 2.0 eq), replace with argon 5 times, and stir at room temperature for 1 h. Then add 110 mg sodium cyanoborohydride, replace with argon 5 times, and stir at room temperature. After the reaction was completed as monitored by LC-MS, 6 mL of methanol was added to quench the reaction, the mixture was concentrated to dryness under reduced pressure and purified using a reverse phase C18 column. The product was eluted with 40% MeOH / H2O as a white solid to give 34 mg. The three-step yield was 15.06%. 1 H NMR(400 MHz, DMSO-d6) δ9.80 (s, 1H), 9.58 (d, J = 25.4Hz, 1H), 6.76 (d, J = 11.5Hz, 1H), 6.69 (s, 1H), 3.98 (d, J = 5.6Hz, 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, 6.6Hz, 1H), 1.57-1.50 (m, 2H), 0.91 (d, J=6.5Hz, 6H).MS (ESI) m / z (M+H) + =386.

[0233] Example 29: Synthesis of Compound 28-1

[0234] 5-(2-Fluoro-6-hydroxy-4-(1-isopentylazetidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0235]

[0236] The synthetic route is as follows:

[0237]

[0238] Step 1: Synthesis of intermediate 28-3

[0239] Take a 50mL single-mouth bottle, add 415mg IntA1-7 (1.0mmol, 1.0eq), 111mg TBAI (0.3mmol, 0.3eq), 196mg zinc powder (3.0mmol, 3.0eq), 40mg Ni(dtbbpy)Cl2 (0.1mmol, 0.1eq), 208μL 27-2 (2.0mmol, 2.0eq). Add 10mL DMA to dissolve, replace argon 5 times and stir at 60℃ for 12h. After LC-MS monitoring, the reaction is complete, cool to room temperature, filter and filter with diatomaceous earth, add 30mL purified water to the filtrate, extract and separate with 30mL EA, extract the aqueous phase with 5×30mL EA, combine the organic phases, wash with 5×80mL saturated brine, and dry with anhydrous sodium sulfate. Then, the filtrate was filtered, sanded and purified by 25g reverse phase C18 column. The product was eluted with 60% MeOH / H2O as a nearly colorless oil, 50 mg, yield 10.17%. MS (ESI) m / z (MH) - = 490.

[0240] Step 2 to Step 4: Synthesis of 28-1

[0241] Referring to the synthesis steps of 27-1, 27-3 was replaced by 28-3, and 32 mg of light yellow solid was obtained with 100 mg of 28-3. The three-step yield was 42.34%. 1 H NMR (400MHz, DMSO-d6) δ9.86 (s, 1H), 9.55 (s, 1H), 6.86 (d, J=11.1Hz, 1H), 6.69 (s, 1H), 4.35 (s, 2H), 4.09 (s, 2H), 3.95 (s, 2H), 3.22 (t, J=8 .1Hz, 2H), 3.14 (d, J=7.1Hz, 1H), 1.59 (dq, J=13.1, 6.6Hz, 1H), 1.35 (dd, J=10.1, 5.9Hz, 2H), 0.90 (d, J=6.6Hz, 6H). MS (ESI) m / z (MH) -= 370.

[0242] Example 30: Synthesis of Compound 29-6

[0243]

[0244] 5-(2-Fluoro-6-hydroxy-4-(2-azapyridine[3.3]heptane-6-yl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide trifluoroacetate

[0245] The synthetic route is as follows:

[0246]

[0247] Step 1: Synthesis of intermediate 29-3

[0248] Take a 100mL three-necked flask, add a three-way argon balloon, a constant pressure dropping funnel, a thermometer, connect to vacuum and heat with a hair dryer, then add argon from the balloon, repeat 4 times until the bottle is dry and full of argon. Then use a syringe to inject 10mL of 0.5mmol / mL 29-2 / anhydrous DCM solution (5.0mmol, 1.0eq) into the three-necked flask, stir and cool in a cold trap. When the internal temperature reaches -78°C, use a syringe to slowly inject 10mL of 1.0M LiHMDS / THF solution (10.0mmol, 2.0eq), control the internal temperature not to exceed -65°C, and then keep warm and stir for 1h. Then use a syringe to inject 15mL of 0.5mmol / mL PhN(Tf)2 / anhydrous DCM solution (7.5mmol, 1.5eq) into the constant pressure dropping funnel and slowly add it dropwise to the three-necked flask. Control the internal temperature not to exceed -65°C. After the dropwise addition, the mixture was moved to room temperature and stirred overnight. The next day, TLC was monitored and potassium permanganate was used to develop the color. A new spot with a polarity slightly greater than PhNHTf was observed, which was the product. 40 mL of saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and then 60 mL of ethyl acetate was added for extraction. The liquid was separated, and the aqueous phase was extracted cleanly 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. Then, the filtrate was filtered, the filtrate was sanded and purified with a silica gel column. 400 mg of the product was eluted as a yellow oil with a ratio of 30:1 petroleum ether / ethyl acetate, and the yield was 23.3%. 1 H NMR (400MHz, DMSO-d6) δ5.83 (s, 1H), 4.13-3.90 (m, 4H), 3.13 (s, 2H), 1.38 (s, 9H).MS (ESI) m / z (M-Boc+H) + =244.

[0249] Step 2: Synthesis of intermediate 29-4

[0250] Take a 10mL sealed tube, add 0.5mmol IntA1-1 (1.0eq), 343mg 29-3 (1.0mmol, 2.0eq), 159mg sodium carbonate (1.5mmol, 3.0eq), 37mg Pd(dppf)Cl2 (0.05mmol, 0.1eq), add 2.5mL dioxane and 0.25mL purified water to dissolve, replace argon 5 times and stir at 80℃ for 12h. After LC-MS monitoring, the reaction is complete, cool to room temperature, filter and filter with diatomaceous earth, the filtrate is sanded and purified by reverse phase C18 column, the product is eluted with 40% MeOH / H2O as a light yellow solid, 104mg, yield 39.28%. MS (ESI) m / z (M+H) +=530.

[0251] Step 3: Synthesis of 29-6

[0252] A single-mouth bottle containing 100 mg of 29-4 (0.19 mmol, 1.0 eq) was added, 72 mg of ammonium formate (1.13 mmol, 6.0 eq), 1 mL of methanol, 1 mL of tetrahydrofuran, and 10 mg of 10% Pd / C. The mixture was refluxed and stirred in an oil bath at 65°C for 2 h. After the reaction was completed as monitored by TLC, it was filtered off with suction. The filtrate was concentrated to dryness under reduced pressure and 2 mL of DCM was added to dissolve it. Subsequently, 0.5 mL of trifluoroacetic acid was added and stirred at room temperature for 30 min. After the reaction was completed as monitored by TLC, it was concentrated to dryness under reduced pressure. 3 mL of methyl tert-butyl ether was added and slurried for 1 h. The resulting white slurry was filtered off with suction and rinsed with 3 mL of methyl tert-butyl ether. The filter cake was dried with air to obtain the product 29-6 as a white solid (38 mg, two-step reaction yield 44.19%). 1 H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 8.50 (s, 2H), 6.56 (dd, J=11.4, 2.0Hz, 1H), 6.52-6.49 (m, 1H), 4.08 (t, J=5.9Hz, 2H), 3.92 (s, 2H), 3.88 (t, J=5.8Hz, 2H), 3.26 (q, J=8.5Hz, 1H), 2.56 (ddd, J=9.8, 8.3, 2.9Hz, 2H), 2.25 (td, J=9.6, 2.9Hz, 2H).MS (ESI) m / z (M+H) + =342.

[0253] Example 30: Synthesis of Compound 29-1

[0254] 5-(2-Fluoro-6-hydroxy-4-(2-isopentyl-2-azaspiro[3.3]heptane-6-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0255]

[0256] Referring to the synthesis steps of 26-1, 25-1 was replaced by 29-6, and 22 mg of light yellow solid 29-1 was obtained with 38 mg of 25-6. The three-step yield was 28.81%. 1H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 9.46 (s, 1H), 6.62-6.48 (m, 2H), 4.18 (s, 2H), 3.97 (t, J=7.0Hz, 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=6.7Hz, 1H), 1.30 (dq, J=10.3, 5.3, 3.3Hz, 2H), 0.88 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =412.

[0257] Example 31: Synthesis of Compound 30-6

[0258] 5-(2-Fluoro-6-hydroxy-4-(6-azaspiro[3.4]octan-2-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide trifluoroacetate

[0259]

[0260] Referring to the synthesis steps of 29-6, the 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.

[0261] Example 32: Synthesis of Compound 30-1

[0262] 5-(2-Fluoro-6-hydroxy-4-(6-isopentyl-6-aza[3.4]octan-2-yl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

[0263]

[0264] The compound can be prepared by referring to the synthetic steps of 29-1 and replacing 29-6 with 30-6. 1H NMR (400MHz, DMSO-d6) δ9.45 (s, 1H), 9.32 (d, J = 9.0Hz, 1H), 6.63-6.53 (m, 2H), 3.93 (s, 2H), 3.53 (d, J = 12.6Hz, 2H), 3.42 (q, J = 8.9Hz, 1 H), 3.10 (s, 4H), 2.27 (d, J = 53.0Hz, 6H), 1.62 (tt, J = 13.5, 6.5Hz, 1H), 1.53-1.44 (m, 2H), 0.91 (t, J = 6.4Hz, 6H). MS (ESI) m / z (MH) - = 424.

[0265] Example 32: Synthesis of Compound 31-1

[0266] 5-(2-Fluoro-6-hydroxy-4-((3aR,6aS)-2-isopentyldihydrocyclopenta[c]pyrrol-5-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0267]

[0268] The compound can be prepared by referring to the synthesis steps of 29-1, replacing 29-2 with cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester (CAS: 146231-54-1). 1 H NMR (400MHz, DMSO-d6) δ9.47 (d, J=57.7Hz, 1H), 9.27 (d, J=8.3Hz, 1H), 6.66 (d, J=14.5Hz, 2H), 3.94 (s, 2H), 3.76 (s, 1H), 3.50 (d, J= 9.1Hz, 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.

[0269] 2. Biological Evaluation

[0270] (1). PTPN2 / PTPN1 enzyme activity analysis test method

[0271] The activity of the compound was determined by in vitro enzymatic assay using unlabeled full-length human PTPN2 / PTPN1 protein. The PTPN2 / PTPN1 enzyme was diluted to a final concentration of 0.5 nM in an 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 a black 384-well plate (Greiner, 781900). Compounds were subsequently added using a Tecan D300e dispenser. After incubation at room temperature for 10 minutes, DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 5 μM. After incubation at room temperature for 30 minutes, the plate was transferred to a SpectraMax plate reader (Molecular Devices) and the fluorescence intensity (ex 358, em 455) was measured. Each plate included a 100% inhibition control (no enzyme) and a 0% inhibition control (DMSO), from which the inhibition rate of the test compound was calculated. IC was determined from % inhibition data using a four-parameter curve fit 50 value.

[0272] IC 50 The values ​​are shown in Table 1 , where A represents a compound with an activity below 20 nM, B represents a compound with an activity between 20 and 100 nM, C represents a compound with an activity between 100 nM and 1 μM, and D represents a compound with an activity above 1 μM.

[0273] Table 1 IC of the inhibitory activity of the example compounds on PTPN1 / PTPN2 phosphatase 50 Measurements

[0274]

[0275]

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is an aromatic heterocycle or C 3-11 Heterocycloalkane, independently and optionally replaced by one or more R 2 replace; R 1 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, and: in: m＝0-5； n＝1-3； o＝1-3； R 3 are independently selected from CH and N; R 4 are independently selected from CH, N and O, and when R 4 =0, R 5 does not exist; When R 4 =N or CH, R 5 are 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 Heterocycloalkyl-C(=O)- and C 3-6 Heterocycloalkyl-S(=O)2-; R 2 are independently selected from hydrogen, halogen, oxo, phenyl, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, trifluoromethyl, trifluoromethoxy; or two R 2 forming a cycloalkyl or heterocycloalkyl group; R 6 are independently selected from hydrogen, halogen, oxo, phenyl, hydroxy, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl; R 10 are independently selected from C and N; when R 10 When N, R 7 Does not exist, R 8 , R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl; When R 10 When C, R 7 , R 8 , R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl; p＝0-3。 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is an aromatic heterocycle or C 3-11 Heterocycloalkane, independently and optionally replaced by one or more R 2 Substitution; the aromatic heterocycle is a 5-6 membered aromatic heterocycle containing N; the C 3-11 Heterocycloalkanes are C 3-11 Heterocycloalkanes; R 1 Selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and: in: m = 0, 1, 2, 3, 4 or 5; n = 1, 2 or 3; o = 1, 2 or 3; p＝1。 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is: Independently and arbitrarily represented by one or more R 2 replace; in: X and R 1 Connected, U, V, W, X, and Y are each independently selected from CH or N; h, i, j, k are independently selected from 1, 2, 3, 4, 5 or 6; r, s are independently selected from 0, 1, 2, 3, 4 or 5; t, z are independently selected from 1, 2, 3 or 4; When ring A is , i and h are not 2 at the same time.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is: Independently and arbitrarily represented by one or more R 2 replace; h, i are independently selected from 1, 2, 3, 4, 5 or 6; r, s, q, t are independently selected from 0, 1, 2, 3, 4 or 5.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, C 1～4 Alkyl, (CH3)2-CH-(CH2) 0～4 -、 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is: R 1 for:

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: A compound selected from any of the following structures or a pharmaceutically acceptable salt thereof:

8. A method for preparing a compound represented by general formula (I), characterized in that: Where A, R 1 The definition as described in any one of claims 1-4.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

10. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease mediated by PTPN2 / PTPN1.

Images