Thiadiazolidinone derivative, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a thiadiazolidinone compound, and a preparation method therefor and the use thereof. The thiadiazolidinone derivative of the present invention is a compound having a structure as represented by general formula (I), or a pharmaceutically acceptable salt thereof. Further disclosed in the present invention is the use of the thiadiazolidinone derivative in the treatment of PTPN2 / PTPN1-mediated diseases. The compound disclosed in the present invention has a significant inhibitory activity against PTPN2 / PTPN1 phosphatase and has a significant impact on the occurrence and development of tumors and immune responses. The compound can also be used in combination with an immunosuppressant to treat related immune diseases. The compound can be developed into an antitumor drug with high activity, good selectivity, and low toxicity or side effects, and has the characteristics of high plasticity and great potential for future modification.

Description

Thiadiazolidinone derivatives, and methods of making and using the same TECHNICAL FIELD

[0001] The present invention belongs to the field of medicinal chemistry, and relates to thiadiazolidinone derivatives, in particular to compounds as shown in formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical combinations thereof, and uses thereof in treating PTPN1 / PTPN2-mediated diseases. BACKGROUND

[0002] Protein phosphorylation is a ubiquitous 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 phosphorylation is catalyzed by phosphokinases, which disrupt existing electrostatic interactions by adding a phosphate group to an amino acid residue. Reversibly, dephosphorylation is the hydrolysis of the phosphoamino acid 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 J 289(18): 5480-504; 2022).

[0003] Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (e.g., PD-1 / PD-L1 and CTLA-4 blocking antibodies), have been shown to be effective in treating a variety of cancers, significantly improving the treatment of traditionally poor prognostic groups. However, suboptimal clinical responses and intrinsic or acquired resistance progression 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 protein tyrosine phosphatase 1 subfamily that controls a variety of cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but is more highly expressed in hematopoietic cells and placental cells (Mosinger, B. Jr. et al, Proc Natl Acad Sci USA 89:499-503; 1992). PTPN2 regulates the signaling of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lck). As a key negative regulator of the JAK-STAT pathway, PTPN2 directly modulates signaling through cytokine receptors, including IFNy. The catalytic domain of PTPN2 shares 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 for down-regulating the insulin and leptin receptor signaling pathways (Kenner K.A. et al., J Biol Chem 271:19810-19816, 1996). Animals lacking PTPN1 can improve glucose regulation and lipid profile and resist weight gain when treated with a high-fat diet (Elchebly M. et al., Science 283:1544-1548, 1999). Thus, PTPN1 inhibitors are expected to be useful for the treatment of type II diabetes, obesity, and metabolic syndrome.

[0006] Data from in vivo gene screening for loss-of-function in mouse B16F10 transplanted tumor models using CRISPR / Cas9 genome editing technology showed that loss of PTPN2 gene in tumor cells improved the response to an immunotherapy regimen of GM-CSF secreting vaccine (GVAX) plus PD-1 checkpoint blockade (Manguso R.T. et al., Nature 547:413-418; 2017). Loss of PTPN2 sensitized tumors to immunotherapy by enhancing IFNy-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 IFNy signaling pathway, including IFNGR, JAK1 and STAT1, were enriched. In recent years, more and more studies have shown that PTPN2 has 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 research results show that therapeutic strategies to enhance IFNy sensing and signaling can play an important role in improving the efficacy of cancer immunotherapy regimens. SUMMARY

[0007] The technical problem to be solved by the present application is to develop small molecule inhibitors with PTPN2 / PTPN1 inhibitory activity taking thiazolidinone as the parent nucleus.

[0008] The technical problem to be solved by the present application is to develop small molecule inhibitors with PTPN2 / PTPN1 inhibitory activity taking thiazolidinone as the parent nucleus.

[0009] Technical solution: A compound as shown in general formula (I) or a pharmaceutically acceptable salt thereof:

[0010] Wherein:

[0011] Ring A is an aromatic heterocycle or C 3-11 heterocycloalkane, independently and optionally substituted with one or more R 2 ;

[0012] R 1 selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, and:

[0013] Wherein:

[0014] m = 0-5;

[0015] n = 1-3;

[0016] o = 1-3;

[0017] R 3 independently selected from CH and N;

[0018] R 4 independently selected from CH, N and O, and when R 4 = O, R 5 is absent;

[0019] when R 4 = N or CH, R 5 is independently selected from hydrogen, oxo, C 1-6 alkyl-S(=O)2-, C 1-6 alkyl-NH-C(=O)-, C 3- C6cycloalkyl-C(=O)- and C 3-6 cycloalkyl-S(=O)2-, C 3-6 heterocycloalkyl-C(=O)- and C 3-6 heterocycloalkyl-S(=O)2-;

[0020] R 2 is independently selected from hydrogen, halogen, oxo, phenyl, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy; or two R 2 on the same atom form a cycloalkyl or heterocycloalkyl;

[0021] R 6 is independently selected from hydrogen, halogen, oxo, phenyl, hydroxy, cyano, C 1-6 alkyl and C 3-6 cycloalkyl;

[0022] R 10 is independently selected from C and N; when R 10 is N, R 7 is absent, R 8 , R 9 is independently selected from hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl and C 3-6 cycloalkyl;

[0023] when R 10 is C, R 7 , R 8 , R 9 is independently selected from hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl and C 3-6 cycloalkyl;

[0024] p = 0-3.

[0025] the compound or a pharmaceutically acceptable salt thereof:

[0026] Ring A is an aromatic heterocycle or C 3-11 heterocycloalkane, independently and optionally substituted with one or more R 2 ; said aromatic heterocycle is a N-containing 5-6 membered aromatic heterocycle; said C 3-11 heterocycloalkane is a N-containing C 3-11 heterocycloalkane;

[0027] R 1 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, and:

[0028] wherein:

[0029] m = 0, 1, 2, 3, 4 or 5;

[0030] n = 1, 2 or 3;

[0031] o = 1, 2 or 3;

[0032] p = 1.

[0033] said compound or a pharmaceutically acceptable salt thereof:

[0034] Ring A is: independently and optionally substituted with one or more R 2 ;

[0035] wherein:

[0036] X is attached to R 1 ,

[0037] U, V, W, X, Y are each independently selected from CH or N;

[0038] h, i, j, k are each independently selected from 1, 2, 3, 4, 5 or 6;

[0039] r, s are each independently selected from 0, 1, 2, 3, 4 or 5;

[0040] t, z are each independently selected from 1, 2, 3 or 4;

[0041] wherein when Ring A is , i and h are not both 2;

[0042] said compound or a pharmaceutically acceptable salt thereof:

[0043] Ring A is: independently and optionally substituted with one or more R 2 ;

[0044] h, i are each independently selected from 1, 2, 3, 4, 5 or 6;

[0045] r, s, q, t are each independently selected from 0, 1, 2, 3, 4 or 5.

[0046] the compound or a pharmaceutically acceptable salt thereof:

[0047] R1is selected from hydrogen, C 1～4 alkyl, (CH3)2-CH-(CH2) 0～4 -,

[0048] the compound or a pharmaceutically acceptable salt thereof:

[0049] ring A is:

[0050] R 1 is: H.

[0051] the compound or a pharmaceutically acceptable salt thereof, is selected from a compound or a pharmaceutically acceptable salt thereof of any one of the following structures:

[0052] a method for preparing a compound represented by general formula (I):

[0053] wherein A, R 1 are defined as above.

[0054] a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0055] use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a PTPN2 / PTPN1-mediated disease.

[0056] Unless otherwise indicated, the terms in the present application have the following meanings.

[0057] The term "halogen" is fluorine, chlorine, bromine or iodine.

[0058] The term "C 1-6 alkyl" refers to saturated straight chain and branched chain hydrocarbon groups having 3-6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the like.

[0059] The term "C3-6 Cycloalkyl" refers to saturated cyclic alkyl groups having 3-6 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0060] The term "C 3-6 Heterocycloalkyl" refers to saturated cyclic alkyl groups having 1 or more N, O, S, and the like non-C heteroatoms and having 3-6 carbon atoms, including but not limited to aziridinyl, azetidinyl, azacyclopentyl, azacyclohexyl, and the like.

[0061] The term "Aromatic heterocycle" refers to aromatic rings having 1 or more N, O, S, and the like non-C heteroatoms, including but not limited to pyrrole, pyrazine, thiophene, furan, pyrazole, and the like.

[0062] The term "C 3-11 Heterocycloalkane" refers to cyclic, spiro, and polycyclic alkane having 3-8 carbon atoms and having 1 or more N, O, S, and the like non-C heteroatoms; including but 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, and the like.

[0063] The term "-C(=O)-" represents a carbonyl group, specifically a carbon-oxygen double bond.

[0064] The term "-S(=O)2-" represents a sulfonyl group.

[0065] The term "-S(=O)2NH-" represents a sulfonamide group.

[0066] The term "-C(=O)NH-" represents an amide.

[0067] The term "-NHS(=O)2-" represents an aminosulfonyl group.

[0068] The term "-NH-C(=O)-" represents a carbamoyl group.

[0069] Beneficial effects: Compared with the prior art, the present application has the following remarkable advantages: the compounds disclosed by the present application have significant activity on PTPN2 / PTPN1 phosphatase, the synthesized compounds have IC 50The value is maintained at nM level, which can be used to have important influence on the development of tumor and immune response, can be combined with immunosuppressants to treat related immune diseases, and can be developed into anti-tumor drugs with high activity, good selectivity and small side effects, and has the characteristics of novel skeleton, strong plasticity and great potential for future modification. DETAILED DESCRIPTION

[0070] The following examples facilitate better understanding of the present application, but do not limit the present application. In the following examples, the experimental methods are conventional methods unless otherwise specified. In the following examples, the test materials used are commercially available from conventional biochemical reagent stores unless otherwise specified. The present application will be described in detail below in combination with specific examples.

[0071] Example 1: Synthesis of intermediate A1-1

[0072] 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

[0073] The synthetic route is as follows:

[0074] Step one: synthesis of intermediate A1-3

[0075] A 2L three-necked flask was added with 5.04g of sodium hydride (126mmol, 1.2eq), 420mL of tetrahydrofuran (4mL / mmol), a constant pressure dropping funnel was installed on the flask, and it was replaced with argon for three times and stirred in an ice bath. Then 25g of intermediate A1-2 (CAS: 147808-42-2, 105mmol, 1.0eq) was slowly added into 420mL of tetrahydrofuran (5mL / mmol) solution through the funnel, and the internal temperature was kept below 5°C. After the addition was completed, 13.10mL (126mmol, 1.2eq) of benzyl alcohol was slowly added into the solution with a syringe, and the internal temperature was kept below 10°C. After TLC monitoring showed that the reaction was complete, the solution was moved to room temperature and stirred for another 2.5h. Then 1L of purified water was added to quench, and extracted with 3×500mL of ethyl acetate. The organic layers were combined and washed with 3×600mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 38.19g of red gum, which was used directly in the next step without further purification. A small amount of the product was purified for analysis. 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).

[0076] Step two: synthesis of intermediate A1-4

[0077] Into a 2 L flask was added 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), stirred, added 28.08 g of ammonium chloride (525 mmol, 5.0 eq) and 68.65 g of zinc powder (1.05 mol, 10.0 eq), replaced with argon three times, stirred at room temperature overnight. After monitoring the completion of the reaction by TLC, filtered with celite, concentrated the filtrate under reduced pressure, added 1 L of purified water and extracted with 3 x 300 mL of ethyl acetate, combined the organic phase, washed with 3 x 400 mL of saturated brine, dried with anhydrous sodium sulfate. Filtered, concentrated the filtrate under reduced pressure, then dissolved in 500 mL of ethyl acetate, stirred in an ice bath, added 105 mL of hydrogen chloride ethyl acetate solution (2.0 M, 2.0 eq). The suspension was stirred in an ice bath for another 2 hours, then filtered, washed with 3 x 50 mL of ice ethyl acetate, dried in a blast drying oven, to obtain intermediate A1-4 as a gray hydrochloride salt (31.46 g, two-step yield of intermediate A1-4 90.03%). A small part of the product was neutralized and purified for analysis 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 6.7 Hz, 2H), 7.40 (t, J = 7.4 Hz, 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.

[0078] Step three: synthesis of intermediate A1-5

[0079] 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). Then heat the reaction to 65°C, stir for 16 h, and after TLC monitoring of the reaction is substantially complete, quench the reaction with 500 mL of purified water, extract with 3x300 mL of ethyl acetate, combine the organic phases, wash with 3x400 mL of saturated brine, dry over anhydrous sodium sulfate, and filter under suction. Concentrate the filtrate under vacuum, purify on a silica gel column eluting with petroleum ether / ethyl acetate = 20:1 to obtain white solid, which is intermediate A1-5 (23.692 g, 68.04%). 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.

[0080] Step four: synthesis of intermediate A1-6

[0081] Replace 23.692 g of intermediate A1-5 (64.34 mmol, 1.0 equiv), 74.334 g of aminosulfonyl chloride (643 mmol, 10.0 eq) in 129 mL of acetonitrile (2 mL / mmol) with argon three times, and stir in an ice bath. When the internal temperature reaches 0°C, slowly add 89.43 mL of triethylamine (643 mmol, 10.0 eq) through a constant pressure dropping funnel, keeping the internal temperature below 20°C. Stir for another 2 h at room temperature, add 150 mL of purified water and extract with 3x150 mL of ethyl acetate, combine the organic phases, wash with 3x200 mL of brine, dry over anhydrous sodium sulfate, and filter under suction. Concentrate the filtrate under reduced pressure, purify by column chromatography eluting with petroleum ether / ethyl acetate = 5:1 to obtain white solid, which is intermediate A1-6 (12.922 g, 44.90%). 1 H 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 (M79 Br + H) + = 446.

[0082] Step five: synthesis of intermediate A1-7

[0083] Take a 100 mL single mouth bottle, add 7.156 g of intermediate A1-6 (16 mmol, 1.0 eq), 4.322 g of sodium methoxide (80 mmol, 5.0 eq), dissolve with 72 mL of methanol, stir at 65 °C oil bath reflux for 1 h, monitor the reaction end by TLC, then move to room temperature and cool naturally, then add 4.0 M HC1 to adjust pH = 1, and extract with 3 x 75 mL of ethyl acetate, wash the combined organic phase with 3 x 50 mL of saturated brine, dry over anhydrous sodium sulfate, and filter under suction. The filtrate was concentrated under vacuum to give a red-brown oil, then add a minimum amount of DCM to pulp and filter under suction to dry air to give intermediate A1-7 as a white solid (4.018 g, 60.48%). 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.

[0084] Step six: synthesis of intermediate A1-1

[0085] 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 diboron (2.0 mmol, 2.0 eq), 73 mg of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2, 0.1 mmol, 0.1 eq), 5 mL of dioxane (5 mL / mmol). Replace with argon for 5 times, stir at 105 °C overnight. Then filter the reaction mixture through diatomite, concentrate the filtrate under vacuum to give a black oil, which is used directly for the next step without further purification. MS (ESI) m / z 379 (M 79 Br-H) - .

[0086] Example 2: synthesis of compound 1-1

[0087] 5-(2-fluoro-6-hydroxy-4-(1-isopentyl-1H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0088] The synthetic route is as follows:

[0089] Step one: synthesis of compound 1-3

[0090] In a 10 mL sealed tube, mix 415 mg of intermediate Al-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), 5 mL of dioxane (5 mL / mmol). Replace with argon for 5 times, stir at 100 °C overnight. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and purified by full-automatic C18 reverse phase column chromatography (25 g C18 silica gel) eluted with water / methanol = 7:3 to give 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.

[0091] Step two: synthesis of compound 1-1

[0092] In a 10 mL sealed tube, mix 415 mg of intermediate Al-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), 5 mL of dioxane (5 mL / mmol). Replace with argon for 5 times, stir at 100 °C overnight. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and purified by full-automatic C18 reverse phase column chromatography (25 g C18 silica gel) eluted with water / methanol = 7:3 to give 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) 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.

[0093] Example 3: synthesis of compound 2-1

[0094] 5-(4-(1-cyclopentyl-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0095] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS: 1233526-60-7). 1 H 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), 3.96 (s, 2H), 2.09 (dq, J = 12.9, 7.2 Hz, 2H), 1.94 (dq, J = 13.9, 6.6 Hz, 2H), 1.85 - 1.74 (m, J = 4.8 Hz, 2H), 1.69 - 1.59 (m, 2H). MS (ESI) m / z (M+H) + = 381.

[0096] Example 4: Synthesis of compound 3-1

[0097] 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

[0098] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 1-[2-(1-pyrrolidin)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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.

[0099] Example 5: Synthesis of compound 4-1

[0100] 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

[0101] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-boronic acid pinacol ester (CAS: 1040377-03-4). 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (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 = 21.3 Hz, 4H). MS (ESI) m / z (M+H) + = 397.

[0102] Example 6: Synthesis of compound 5-1

[0103] 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

[0104] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]boronic acid pinacol ester (CAS: 1082503-77-2). 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (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.

[0105] Example 7: Synthesis of compound 6-1

[0106] 5-(4-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide

[0107] This 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-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)ethanamine (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.

[0108] Example 8: Synthesis of compound 7-1

[0109] 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

[0110] This 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 (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) + = 395.

[0111] Example 9: Synthesis of compound 8-1

[0112] 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

[0113] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H- pyrrolo(l,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, 6.5 Hz, 2H). MS (ESI) m / z (M+H) + = 353.

[0114] Example 10: Synthesis of compound 9-1

[0115] 5-(4-(l-cyclopropyl-lH-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide

[0116] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with l-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.

[0117] Example 11: Synthesis of compound 10-1

[0118] 5-(4-(l-(3-(dimethylamino)propyl)-lH-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-l,2,5- thiadiazolidin-3-one 1,1-dioxide

[0119] 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-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)propan-l -amine (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.

[0120] Example 12: Synthesis of compound 11-1

[0121] 5-(4-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-l,2,5- thiadiazolidin-3-one 1,1-dioxide

[0122] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with l-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (CAS: 1000801-75-1). 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) + = 367.

[0123] Example 13: Synthesis of compound 12-1

[0124] 5-(2-fluoro-6-hydroxy-4-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-3-yl)phenyl)-l,2,5- thiadiazolidin-3-one 1,1-dioxide

[0125] This compound can be prepared using the method described in Example 2 and replacing compound 1-2 with 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (CAS: 1000801-75-1). 1 H NMR (400 MHz, DMSO-d6) d 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.

[0126] Example 14: Synthesis of compound 13-1

[0127] 2-(2-fluoro-6-hydroxy-4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)isothiazolidin-4-one 1,1-dioxide

[0128] The synthetic route is as follows:

[0129] Step one: Synthesis of 13-3

[0130] In a 100 mL single neck flask, mix 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), 12 mL of dioxane (12 mL / mmol). Replace with argon for 5 times, stir at 100 °C overnight. Filter the reaction mixture through celite, concentrate the filtrate under reduced pressure, purify by full-automatic column chromatography, elute with dichloromethane / methanol = 1:10 to obtain compound 13-3, which is used directly in the next step without further purification. MS (ESI) m / z (M+H) + = 454.

[0131] Step two: Synthesis of 13-1

[0132] In a 50 mL single neck flask, mix 170 mg of 13-3, 109 mg of pentamethylbenzene (0.74 mmol, 2.0 eq), 3.7 mL of DCM (10 mL / mmol), put into -80 °C stirring for 0.5 h, take 3.7 mL of boron trichloride (1.0 M in DCM, 3.7 mmol, 10.0 eq) slowly drop into the reaction bottle. After 4 h of reaction, quench with methanol. Prepare sand and purify with 25 g of reversed phase C18 column, elute the product 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.

[0133] Example 15: Synthesis of compound 14-1

[0134] 5-(2-fluoro-6-hydroxy-4-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidin-3-yl)phenyl)- 1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0135] The synthetic route is as follows:

[0136] Step one: Synthesis of intermediate 14-3

[0137] Refer to the method of step one in Example 14 to obtain the common intermediate 13-3 of Example 14 and Example 15.

[0138] Step two: Synthesis of 14-1

[0139] Refer to the method of step two in Example 1, replace 1-3 with 13-3 to prepare 14-1. 1 H NMR (400 MHz, 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.

[0140] Example 16: Synthesis of compound 15-1

[0141] 5-(2-fluoro-6-hydroxy-4-(lH-indolyl)phenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide

[0142] This compound can be prepared 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.

[0143] Example 17: Synthesis of compound 16-1

[0144] 5-(2-fluoro-6-hydroxy-4-(lH-indolyl)phenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide

[0145] This compound can be prepared using the method described in Example 14 and replacing compound 13-2 with 3-bromo-lH-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.

[0146] Example 18: Synthesis of compound 17-1

[0147] 5-(2-fluoro-6-hydroxy-4-(lH-indolyl)phenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide

[0148] This compound can be prepared using the method described in Example 14 and replacing compound 13-2 with 3-bromoimidazo[l,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, 6.8 Hz, 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.

[0149] Example 19: Synthesis of compound 18-1

[0150] 5-(2-Fluoro-6-hydroxy-4-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-3-yl)phenyl)- 1,2,5-thiadiazolidine-3-ketone 1,1-dioxide

[0151] This compound can be prepared using the method described in Example 15 and replacing compound 13-2 with 3-bromoimidazo[l,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.

[0152] Example 20: Synthesis of compound 19-1

[0153] 5-(2-Fluoro-6-hydroxy-4-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl)phenyl)- 1,2,5-thiadiazolidine-3-ketone 1,1-dioxide

[0154] This compound can be prepared using the method described in Example 15 and replacing compound 13-2 with 2-bromoimidazo[l,2-A]pyridine (CAS: 112581-95-0). 1H 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.

[0155] Example 21: Synthesis of compound 20-1

[0156] 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

[0157] This compound can be prepared using the method described in Example 15 and replacing compound 13-2 with 3-bromo-[1,2,4]thiazolo[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.

[0158] Example 22: Synthesis of compound 21-1

[0159] 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

[0160] This compound can be prepared using the method described in Example 14 and replacing compound 13-2 with 3-bromopyrazolo[1,5-A]pyridine (CAS: 5910-12-3). 1H 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.

[0161] Example 23: Synthesis of compound 22-1

[0162] 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

[0163] This compound can be prepared using the method described in Example 14 and replacing compound 13-2 with 3-bromo-6,7,8,9-tetrahydro-5H-imidazo[1,2-A]cycloheximine (CAS: 701298-97-7). 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (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.

[0164] Example 24: Synthesis of compound 23-1

[0165] 5-(4-(3-Cyclopropyl-4H-pyrazol-4-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide

[0166] This compound can be prepared using the method described in Example 15 and replacing compound 13-2 with 4-bromo-5-cyclopropylpyrazole (CAS: 957345-28-7). 1H 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

[0167] Example 25: Synthesis of compound 24-1

[0168] 5-(2-Fluoro-6-hydroxy-4-(3-methyl-4H-pyrazol-4-yl)phenyl)-1,2,5-thiadiazolidine-3- one 1,1-dioxide

[0169] This compound can be prepared using the method described in Example 14 and replacing compound 13-2 with 4-bromo-3-methylpyrazole (CAS: 13808-64-5). 1 H 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

[0170] Example 26: Synthesis of compound 25-1

[0171] 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

[0172] The synthesis route is as follows:

[0173] Step one: Synthesis of intermediate 25-3

[0174] In a 100 mL single neck flask, mix 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), 12 mL of dioxane (12 mL / mmol). Replace with argon for 5 times, stir at 100 °C overnight. Filter the reaction mixture through celite, concentrate the filtrate under reduced pressure, purify by full-automatic column chromatography, elute with dichloromethane / methanol = 10:1 to get compound 25-3, which is used for next step without further purification. MS (ESI) m / z (M+H) + = 558.

[0175] Step two to three: synthesis of 25-1

[0176] Apply the method of step two of Example 14 to get 25-3, which is directly used for next step without purification. After stirring at room temperature for 4 h after adding DCM and TFA, concentrate under reduced pressure, purify by full-automatic reverse phase column chromatography (25 g reverse phase C18 column) eluting with water / methanol: 3:1. 25-1 can be obtained 1 H NMR (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.

[0177] Example 27: synthesis of compound 26-1

[0178] 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

[0179] The synthetic route is as follows:

[0180] Take 73 mg of 25-1 (0.2 mmol, 1.0 eq), dissolve in 1.4 mL of DCM, add 105 μL of DIPEA (0.6 mmol, 3.0 eq), then add 43 μL of isovaleraldehyde (0.4 mmol, 2.0 eq), replace with argon for 5 times, stir at room temperature for 1 h. Then add 38 mg of sodium cyanoborohydride (0.6 mmol, 3.0 eq), replace with argon for 5 times, stir at room temperature. After the reaction is completed by LC-MS monitoring, add 3 mL of methanol to quench the reaction, concentrate under reduced pressure, and purify with a reverse phase C18 column, eluting the product 26-1 as a white solid with 40% MeOH / H2O. 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.

[0181] Example 28: Synthesis of compound 27-1

[0182] 5-(2-Fluoro-6-hydroxy-4-(1-isopentylpyrrolidin-3-yl)phenyl)-1,2,5-thiadiazolidine-3- one 1,1-dioxide

[0183] The synthetic route is as follows:

[0184] Step one: synthesis of intermediate 27-3

[0185] Take a 10 mL vial, 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), 73 mg Pd(dppf)Cl2 (1.0 mmol, 0.2 eq), dissolve in 3.5 mL dioxane and 0.35 mL purified water, replace with argon for 5 times, stir at 80 °C for 4 h. After monitoring the reaction complete by LC-MS, cool to room temperature, filter together with 0.1 mmol small test reaction solution and filter with diatomite, concentrate the filtrate and purify with reverse phase C18 column, elute the product with 40% MeOH / H2O as a light brown solid, yield 295 mg, 97.64% yield. MS (ESI) m / z (M+H) + = 504.

[0186] Step two to step four: synthesis of 27-1

[0187] Take a single-port 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, then add 147 mg 10% Pd / C, stir at 65 °C oil bath reflux for 4 h, filter after monitoring the reaction complete by TLC, concentrate the filtrate under reduced pressure, then dissolve in 6 mL DCM, then add 1.4 mL trifluoroacetic acid (18.75 mmol, 32 eq), stir at room temperature for 30 min, concentrate under reduced pressure after monitoring the reaction complete by TLC, 2 x 6 mL toluene, 2 x 6 mL DCM to dry. Then dissolve in 6 mL DCM, adjust pH = 8 by adding DIPEA, then add 126 μL isovaleraldehyde (1.17 mmol, 2.0 eq), replace with argon for 5 times, stir at room temperature for 1 h. Then add 110 mg sodium cyanoborohydride, replace with argon for 5 times, stir at room temperature. After monitoring the reaction complete by LC-MS, quench the reaction by adding 6 mL methanol, concentrate under reduced pressure, purify with reverse phase C18 column, elute the product with 40% MeOH / H2O as a white solid, yield 34 mg, 15.06% yield for three steps. 1H 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.

[0188] Example 29: Synthesis of compound 28-1

[0189] 5-(2-fluoro-6-hydroxy-4-(1-isopentylazetidin-3-yl)phenyl)-1,2,5-thiadiazolidine-3- one 1,1-dioxide

[0190] The synthetic route is as follows:

[0191] Step one: synthesis of intermediate 28-3

[0192] Take a 50 mL single-necked flask, 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), 208 μL 27-2 (2.0 mmol, 2.0 eq). Dissolve in 10 mL DMA, replace with argon for 5 times, then stir at 60 °C for 12 h. After monitoring the reaction is complete by LC-MS, cool to room temperature, suction filter and filter with diatomite, add 30 mL purified water to the filtrate, separate the liquid by 30 mL EA extraction, extract the water phase with 5x30 mL EA until clean, combine the organic phase, wash with 5x80 mL saturated brine, dry with anhydrous sodium sulfate. Then suction filter, concentrate the filtrate and purify with 25 g reversed-phase C18 column, elute the product with 60% MeOH / H2O as a nearly colorless oil, 50 mg, 10.17% yield. MS (ESI) m / z (M-H) - = 490.

[0193] Step two to step four: synthesis of 28-1

[0194] Referring to the synthesis steps of 27-1, replace 27-3 with 28-3, 100 mg 28-3 to get 32 mg light yellow solid, three-step yield 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, 6.6 Hz, 1H), 1.35 (dd, J = 10.1, 5.9 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M-H) - = 370.

[0195] Example 30: Synthesis of compound 29-6

[0196] 5-(2-Fluoro-6-hydroxy-4-(2-azapentalen[3.3]heptan-6-yl)phenyl)-1,2,5-thiadiazol-3-one-1,1-dioxide trifluoroacetate salt

[0197] The synthesis route is as follows:

[0198] Step one: Synthesis of intermediate 29-3

[0199] A 100 mL three-necked flask was charged with a three-way argon balloon, constant pressure dropping funnel, thermometer, vacuum adapter, and heated with an electric hair dryer. The flask was then flushed with argon four times until dry and filled with argon. Then, 10 mL of 0.5 mmol / mL 29-2 in anhydrous DCM (5.0 mmol, 1.0 eq) was injected into the flask with a syringe. The flask was cooled with stirring in a cold bath. When the internal temperature reached -78°C, 10 mL of 1.0 M LiHMDS in THF (10.0 mmol, 2.0 eq) was slowly injected into the flask with a syringe. The internal temperature was controlled to be no more than -65°C. Then, the flask was stirred for 1 h. Next, 15 mL of 0.5 mmol / mL PhN(Tf)2 in anhydrous DCM (7.5 mmol, 1.5 eq) was injected into the constant pressure dropping funnel and slowly added into the flask. The internal temperature was controlled to be no more than -65°C. After the addition was completed, the flask was removed from the cold bath and stirred at room temperature overnight. The next day, TLC monitoring and potassium permanganate color observation showed that a new spot with slightly higher polarity than PhNHTf was the product. The reaction was quenched by adding 40 mL of saturated ammonium chloride solution. Then, 60 mL of ethyl acetate was added to extract the product. The aqueous phase was extracted with 2 x 40 mL of ethyl acetate. The organic phases were combined and washed with 3 x 100 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. Then, the organic phase was filtered and concentrated. The residue was purified by silica gel column chromatography with 30:1 petroleum ether / ethyl acetate to give 400 mg of the product as a yellow oil in 23.3% yield. 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.

[0200] Step two: synthesis of intermediate 29-4

[0201] A 10 mL sealed tube was charged with 0.5 mmol of IntA1-1 (1.0 eq), 343 mg of 29-3 (1.0 mmol, 2.0 eq), 159 mg of sodium carbonate (1.5 mmol, 3.0 eq), 37 mg of Pd(dppf)Cl2(0.05 mmol, 0.1 eq), 2.5 mL of dioxane, and 0.25 mL of purified water. After the tube was flushed with argon five times, it was stirred at 80°C for 12 h. After the reaction was completed by LC-MS monitoring, the tube was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by reverse phase C18 column chromatography with 40% MeOH / H2O to give 104 mg of the product as a light yellow solid in 39.28% yield. MS (ESI) m / z (M+H) + = 530.

[0202] Step three: synthesis of 29-6

[0203] A single neck flask was charged with 100 mg of 29-4 (0.19 mmol, 1.0 eq), to which was added 72 mg of ammonium formate (1.13 mmol, 6.0 eq), 1 mL of methanol, 1 mL of tetrahydrofuran, followed by 10 mg of 10% Pd / C, and stirred at reflux in an oil bath at 65 °C for 2 h. After the reaction was complete as monitored by TLC, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2 mL of DCM, followed by the addition of 0.5 mL of trifluoroacetic acid, and stirred at room temperature for 30 min. After the reaction was complete as monitored by TLC, the reaction mixture was concentrated under reduced pressure. The residue was slurried in 3 mL of methyl tert-butyl ether for 1 h. The resulting white slurry was filtered, and the filter cake was washed with 3 mL of methyl tert-butyl ether. The filter cake was dried under a stream of air to give the product 29-6 as a white solid (38 mg, 44.19% yield over two steps). 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 = 8.5 Hz, 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.

[0204] Example 30: Synthesis of compound 29-1

[0205] 5-(2-Fluoro-6-hydroxy-4-(2-isopentyl-2-azaspiro[3.3]heptan-6-yl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide

[0206] Following the procedure for the synthesis of 26-1, replacing 25-1 with 29-6, 38 mg of 25-6 gave 22 mg of 29-1 as a light yellow solid, in 28.81% yield over three steps. 1H 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.

[0207] Example 31: Synthesis of compound 30-6

[0208] 5-(2-fluoro-6-hydroxy-4-(6-isopentyl-6-azaspiro[3.4]octan-2-yl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide

[0209] This compound was prepared according to the synthetic steps of Example 29-6, replacing 29-2 with 6-Boc-2-oxo-6-azaspiro[3.4]octane (CAS: 203661-71-6). MS (ESI) m / z (M-H) - = 354.

[0210] Example 32: Synthesis of compound 30-1

[0211] 5-(2-fluoro-6-hydroxy-4-(6-isopentyl-6-azaspiro[3.4]octan-2-yl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide

[0212] This compound was prepared according to the synthetic steps of Example 29-1, replacing 29-6 with 30-6. 1 H 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 (M-H) - = 424.

[0213] Example 32: Synthesis of compound 31-1

[0214] 5-(2-fluoro-6-hydroxy-4-((3aR,6aS)-2-isopentyldihydrocyclopenta[c]pyrrol-5-yl)phenyl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0215] This compound was prepared according to the procedure for the synthesis of Reference 29-1, replacing 29-2 with cis-5-oxohexahydrocyclopenta[C]pyrrole-2(lH)-carboxylic acid tert-butyl ester (CAS: 146231-54-1). 1 H NMR (400 MHz, DMSO-d6) d 9.47 (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 (M-H) - = 424.

[0216] II. Biological evaluation

[0217] (1). PTPN2 / PTPN1 enzyme activity assay test method

[0218] Compound activity was measured by in vitro enzymatic assay using unlabelled full-length human PTPN2 / PTPN1 protein. PTPN2 / PTPN1 enzyme was diluted to a final concentration of 0.5 nM in assay 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 a 10 min incubation at room temperature, DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 5 mM. After a 30 min incubation at room temperature, plates were transferred to a SpectraMax plate reader (Molecular Devices) and fluorescence intensity (ex 358, em 455) was measured. Each plate included 100% inhibition controls (no enzyme) and 0% inhibition controls (DMSO) from which % inhibition of test compounds was calculated. IC 50 values were determined from % inhibition data using a four parameter curve fit.

[0219] IC50 50 Values are shown in Table 1, A represents the activity of the compound is below 20 nM, B represents the activity of the compound is between 20-100 nM, C represents the activity of the compound is between 100 nM-1 μM, D represents the activity of the compound is above 1 μM.

[0220] Table 1 IC50 of example compounds against PTPN1 / PTPN2 phosphatase inhibitory activity 50 Measured values

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: Ring A is an aromatic heterocycle or C 3-11 heterocycloalkane, independently and optionally substituted with one or more R 2 substituents; R 1 selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, and: wherein: m＝0-5； n＝1-3； o＝1-3； R 3 is independently selected from CH and N; R 4 is independently selected from CH, N and O, and when R 4 = O, R 5 is absent; 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)-, 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-; R 2 independently selected from hydrogen, halogen, oxo, phenyl, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy; or two R 2 form a cycloalkyl or heterocycloalkyl; R 6 independently selected from hydrogen, halogen, oxo, phenyl, hydroxyl, cyano, C 1-6 alkyl, and C 3-6 cycloalkyl; R 10 is independently selected from C and N; when R 10 is N, R 7 is absent, R 8 , R 9 is independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl and C 3-6 cycloalkyl; R is C, R is independently selected from hydrogen, halogen, hydroxyl, cyano, C 10 alkyl and C 7 cycloalkyl; R is C, R is independently selected from hydrogen, halogen, hydroxyl, cyano, C 8 alkyl and C 9 cycloalkyl; R is C, R is independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl and C 3-6 cycloalkyl; R is C, R is independently selected from hydrogen, halogen, hydroxyl, cyano, C < p＝0-3。 2.The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein: Ring A is an aromatic heterocycle or C 3-11 heterocycloalkane, independently and optionally substituted with one or more R 2 ; the aromatic heterocycle is a N-containing 5-6 membered aromatic heterocycle; the C 3-11 heterocycloalkane is a N-containing C 3-11 heterocycloalkane; R 1 selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, and: wherein: m = 0, 1, 2, 3, 4 or 5; n = 1, 2 or 3; o = 1, 2 or 3; p＝1。 3.The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein: Ring A is: independently and optionally substituted by one or more R 2 substituted; wherein: X is connected to R 1 connected, U, V, W, X, Y are 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; wherein when ring A is when i and h are not 2 at the same time; 4.The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein: Ring A is: independently and optionally substituted by one or more R 2 substituted; 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 or pharmaceutically acceptable salt thereof according to claim 1, wherein: R1is selected from hydrogen, C 1～4 alkyl, (CH3)2-CH-(CH2) 0～4 -, 6.The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein: Ring A is: R 1 is: H。 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: a compound selected from any one of the following structures:

8. A process for the preparation of a compound of formula (I) ###0002### (I) characterized in that: wherein A, R 1 are as defined in any one of claims 1-4. 9.A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5, and one or more pharmaceutically acceptable carriers. 10.Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5 in the preparation of a medicament for treating a PTPN2 / PTPN1-mediated disease.

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