Thiadiazolidinone derivative with PTPN2 / PTPN1 inhibitory activity, and preparation method therefor and use thereof

Abstract

A thiadiazolidinone compound with PTPN2 / PTPN1 inhibitory activity as represented by formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof in the preparation of a drug for treating PTPN2 / PTPN1-mediated diseases.

Description

Thiadiazolidinone derivatives with PTPN2 / PTPN1 inhibitory activity, and preparation method and application thereof TECHNICAL FIELD

[0001] The present application 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 in treating PTPN1 / PTPN2-mediated diseases. BACKGROUND

[0002] Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (such as PD-1 / PD-L1 and CTLA-4 blocking antibodies), have been proven effective in treating a variety of cancers, significantly improving the treatment of populations with poor prognosis for traditional therapies. However, the less-than-ideal clinical response and the progression of intrinsic or acquired resistance will continue to limit the further development of this therapy.

[0003] 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 phosphokinases catalyze phosphorylation, which disrupts existing electrostatic interactions by adding a phosphate group on amino acid residues. 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 J 289(18): 5480-504; 2022).

[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 class 1 subfamily 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 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 PTP1N), and has similar enzymatic kinetics (Romsicki Y. et al., Arch Biochem Biophys 414: 40-50; 2003).

[0005] Data from in vivo gene screening for loss-of-function in a mouse B16F10 transplanted tumor model 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 the IFNy signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. In recent years, more and more studies have shown that PTPN2 has oncogenic effects. 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 suggest that therapeutic strategies to enhance IFNy sensing and signaling can play an important role in improving the efficacy of cancer immunotherapy regimens.

[0006] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase 1B (PTP1B), plays a key role in insulin and leptin receptor signaling pathways and is a key protein for down-regulating 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). Therefore, PTPN1 inhibitors are expected to be useful for treating type II diabetes, obesity and metabolic syndrome. 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 a parent nucleus; and the technical problem to be solved by the present application is also to provide the use of the above thiazolidinone derivatives in the treatment of PTPN2 / PTPN1-mediated diseases.

[0008] Technical solution: A compound as shown in general formula (I) or a pharmaceutically acceptable salt thereof:

[0009] wherein:

[0010] Ring A is an aromatic ring or an aromatic heterocycle, independently and optionally substituted with one or more R 2 ;

[0011] R 1 is selected from hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, adamantyl and:

[0012] wherein:

[0013] m = 0-5;

[0014] n = 1-3;

[0015] o = 1-3;

[0016] R 3 is independently selected from CH and N;

[0017] R 4 is independently selected from CH, N and O, and when R 4 = O, R 5 is absent;

[0018] when R 4 = N or CH, R 5independently selected from hydrogen, oxo, C 1-6 alkyl-S(=0)2-, C 1-6 alkyl-NH-C(=0)-, C 3- C6cycloalkyl-C(=0)- and C 3-6 cycloalkyl-S(=0)2-, C 3-6 heterocycloalkyl-C(=0)- and C 3-6 heterocycloalkyl-S(=0)2-;

[0019] R 2 independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy;

[0020] R 6 independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl and C 3-6 cycloalkyl;

[0021] R 10 is independently selected from C and N; when R 10 is N, R 7 is absent, R 8 , R 9 independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl and C 3-6 cycloalkyl;

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

[0023] L is selected from -NR 8 -, -CH2-, -CH2-NH-, -S(=0)2-, -C(=0)NH-, -NHC(=0)-, -S(=0)2NH-, -NHS(=0)2- or -C(=0)-;

[0024] p = 0-3.

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

[0026] Ring A is an aromatic or heteroaromatic ring, independently and optionally substituted with one or more R 2 ; the aromatic ring is substituted or unsubstituted phenyl, the substitution being C 1-4haloalkyl-substituted; the aromatic heterocycle is a 5- to 6-membered aromatic heterocycle containing one or two of the atoms S, O, N, the substitution being C 1-4 alkyl-substituted;

[0027] R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, adamantyl 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] R 3 is independently selected from CH and N;

[0033] R 4 is independently selected from CH, N and O, and when R 4 = O, R 5 is absent;

[0034] when R 4 = N or CH, R 5 is independently selected from the group consisting of hydrogen, C 1-6 alkyl-S(=O)2-, C 1-6 alkyl-NH-C(=O)-, C 3-6 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-;

[0035] R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy;

[0036] R 6 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl and C 3-6 cycloalkyl;

[0037] 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 the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-6alkyl and C 3-6 cycloalkyl; when R 10 is C, R 7 , R 8 , R 9 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl and C 3-6 cycloalkyl;

[0038] L is selected from the group consisting of -NR a -, -CH2-, -CH2-NR b -, -S(=O)2-, -C(=O)NR c -, -C(=NH)NR d -, -NR c C(=O)-, -S(=O)2NR e -, -NR e S(=O)2- or -C(=O)-;

[0039] R a , R b , R c , R d , R e are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl;

[0040] p = 0, 1, 2 or 3.

[0041] the compound or a pharmaceutically acceptable salt thereof:

[0042] Ring A is selected from: independently and optionally substituted with one or more R 2 ;

[0043] wherein:

[0044] U = CH or N;

[0045] V = CH or N;

[0046] W = NH, O or S;

[0047] X = CH or N;

[0048] Y = CH or N;

[0049] h = 0, 1, 2 or 3;

[0050] i = 0, 1, 2 or 3;

[0051] Z, Z', are each independently selected from N and CH;

[0052] R2 independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, C 1-6 alkyl;

[0053] R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, adamantyl and:

[0054] wherein:

[0055] m = 0, 1, 2 or 3;

[0056] n = 1, 2 or 3;

[0057] o = 1, 2 or 3;

[0058] q = 0, 1, 2 or 3;

[0059] R 3 is independently selected from the group consisting of CH and N;

[0060] R 4 is independently selected from the group consisting of C, CH, N and O, and when R 4 = O, p = 0, i.e. R 5 is absent;

[0061] when R 4 = N or CH, t = 1, R 5 is independently selected from the group consisting of hydrogen, C 1-6 alkyl-S(=0)2-, C 3-6 cycloalkyl-C(=0)-, C 3-6 cycloalkyl-S(=0)2- and C 3-6 heterocycloalkyl-C(=0)-; when R 4 = C, t = 1-2, R 5 is independently selected from the group consisting of halogen, oxo and C 1-6 alkyl;

[0062] R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, trifluoromethyl;

[0063] R 6 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano and C 1-6 alkyl;

[0064] R 10 is independently selected from the group consisting of C and N; when R 10 is N, R 7 is absent, R 8 , R 9independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl and C 3-6 cycloalkyl; when R 10 is C, R 7 , R 8 , R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl and C 3-6 cycloalkyl;

[0065] L is selected from -NR a -, -CH2-, -CH2-NR b -, -S(=O)2-, -C(=O)NR c -, -C(=NH)NR d -, -NR c C(=O)-, -S(=O)2NR e -, -NR e S(=O)2- or -C(=O)-;

[0066] R a , R b , R c , R d , R e are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl;

[0067] p = 0, 1, 2 or 3.

[0068] the compound or a pharmaceutically acceptable salt thereof:

[0069] Ring A is selected from: independently and optionally substituted with one or more R 2 ;

[0070] wherein:

[0071] U = CH or N;

[0072] V = CH or N;

[0073] W = NH, O or S;

[0074] Z, Z' are each independently selected from N and CH;

[0075] h = 1-2;

[0076] i = 1-2;

[0077] R 1 is selected from hydrogen, (CH3)2-CH-(CH2) 0～4 -

[0078] the compound or a pharmaceutically acceptable salt thereof:

[0079] ring A is:

[0080] R 1 is: hydrogen,

[0081] 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:

[0082] a method for preparing the compound represented by the general formula (I):

[0083] when L is -NHC(=O)-,

[0084] A, R 1 , h, i are as defined above.

[0085] a method for preparing the compound represented by the general formula (V):

[0086] wherein A, R 1 are as defined above.

[0087] a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0088] use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a PTPN2 / PTPN1-mediated disease.

[0089] Unless otherwise specifically indicated, the terms in the present application have the following meanings:

[0090] The term "halogen" is fluorine, chlorine, bromine or iodine.

[0091] The term "C 1-6 alkyl" refers to saturated straight-chain and branched-chain hydrocarbon radicals having 3-6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like.

[0092] The term "C 3-6Heterocycloalkyl" refers to a saturated cyclic alkyl group having 1 or more N, O, S, etc. non-C heteroatoms and having 3-6 carbon atoms, including but not limited to aziridinyl, azetidinyl, azetidinyl, azetidinyl, etc.

[0093] The term "aromatic ring" refers to a ring system having aromaticity, including but not limited to benzene, pyrazole, thiophene, furan, thiazole, etc.

[0094] The term "aromatic ring" refers to a ring system having aromaticity, including but not limited to benzene, pyrazole, thiophene, furan, thiazole, etc.

[0095] The term "aromatic ring" refers to a ring system having aromaticity, including but not limited to benzene, pyrazole, thiophene, furan, thiazole, etc.

[0096] The term "aromatic ring" refers to a ring system having aromaticity, including but not limited to benzene, pyrazole, thiophene, furan, thiazole, etc.

[0097] The term "aromatic ring" refers to a ring system having aromaticity, including but not limited to benzene, pyrazole, thiophene, furan, thiazole, etc.

[0098] The term "aromatic ring" refers to a ring system having aromaticity, including but not limited to benzene, pyrazole, thiophene, furan, thiazole, etc.

[0099] The term "-C(=O)-" refers to a carbonyl group, specifically a carbon-oxygen double bond.

[0100] The term "-S(=O)2-" refers to a sulfonyl group.

[0101] The term "-S(=O)2NH-" refers to a sulfonamide group.

[0102] The term "-C(=O)NH-" refers to an amide group.

[0103] The term "-NHS(=O)2-" refers to an aminosulfonyl group.

[0104] The term "-NHC(=O)-" refers to a carbamoyl group.

[0105] The term "-NH-" refers to an imino group.

[0106] The term "-CH2-" refers to a methylene group.

[0107] Beneficial effects: Compared with the prior art, the present application has the following obvious 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

[0108] The following examples facilitate a 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; and in the following examples, the test materials are commercially available from conventional biochemical reagent stores unless otherwise specified. The present application will be described in detail below with specific examples.

[0109] Example 1: Synthesis of intermediate A1-1

[0110] 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

[0111] The synthetic route is as follows:

[0112] Step one: synthesis of intermediate A1-3

[0113] 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 argon was replaced for three times with stirring in an ice bath. Then 25g of intermediate A1-2 (CAS: 147808-42-2, 105mmol, 1.0eq) was slowly added to the flask through the funnel with 420mL of tetrahydrofuran (5mL / mmol) to keep the internal temperature below 5°C. After the addition was completed, 13.10mL (126mmol, 1.2eq) of benzyl alcohol was slowly added to the solution with the internal temperature 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 3×500mL of ethyl acetate was added for extraction. 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 A1-2 without further purification, and was directly used in the next step. 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).

[0114] Step two: synthesis of intermediate A1-4

[0115] 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, washed the combined organic phase 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) d 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.

[0116] Step three: synthesis of intermediate A1-5

[0117] 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.

[0118] Step four: synthesis of intermediate A1-6

[0119] Replace 23.692 g of intermediate A1-5 (64.34 mmol, 1.0 eq), 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 saturated 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.

[0120] Step five: synthesis of intermediate A1-7

[0121] Take a 100 mL three-necked flask, add 3 g of intermediate A1-6 (6.7 mmol, 1.0 eq) and dissolve with 30 mL (10 mL / g) of anhydrous tetrahydrofuran, replace with argon for five times. Under argon purging, add 402 mg of sodium hydride (10.05 mmol, 1.5 eq) in batches. Stir the reaction solution at room temperature for 20 minutes, then add 35 mL of 1.0 M aqueous HCl to quench, 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. Concentrate the filtrate under vacuum, and purify by full-automatic C18 reverse phase column chromatography (25 g, C18 silica gel), eluted with water / methanol = 1:1, to obtain intermediate A1-7 as a white solid (1.884 g, 67.65%). 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.

[0122] Step six: synthesis of intermediate A1-1

[0123] 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, and stir at 105°C overnight. Then filter the reaction mixture through diatomite, concentrate the filtrate under vacuum to obtain a black oil, which is directly used in the next step without further purification. MS (ESI) m / z (M 105°C overnight. Then filter the reaction mixture through diatomite, concentrate the filtrate under vacuum to obtain a black oil, which is directly used in the next step without further purification. MS (ESI) m / z (M 79 Br-H) - = 379.

[0124] Example 2: synthesis of compound 1-1

[0125] 3-(4-(1,1 -dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-N-isopenty lthiophene-2-carboxamide

[0126] The synthetic route is as follows:

[0127] Step one: synthesis of compound 1-3

[0128] In a 10 mL sealed tube, mix 462 mg of IntA1-1 (accounting for 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), 276 mg of 1-3 (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. Filter the reaction mixture through celite, concentrate the filtrate under reduced pressure, purify by full-automatic C18 reverse phase column chromatography (25 g C18 silica gel), elute with water / methanol = 7:3, to get 1-4 as yellow solid (68 mg, 12.79%), without characterization, directly used in the next step reaction. 79 Br+H) + = 276.

[0129] Step two: synthesis of compound 1-4

[0130] In a 10 mL sealed tube, mix 462 mg of IntA1-1 (accounting for 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), 276 mg of 1-3 (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. Filter the reaction mixture through celite, concentrate the filtrate under reduced pressure, purify by full-automatic C18 reverse phase column chromatography (25 g C18 silica gel), elute with water / methanol = 7:3, to get 1-4 as yellow solid (68 mg, 12.79%), without characterization, directly used in the next step reaction.

[0131] Step three: synthesis of compound 1-1

[0132] To a solution of 60 mg of compound 1-4 (0.13 mmol, 1.0 eq) and 38 mg of pentamethylbenzene (0.26 mmol, 2.0 eq) in 1.3 mL of dichloromethane (10 mL / mmol) at -78 °C, 1.3 mL of boron trichloride dichloromethane (1.0 M, 1.3 mmol, 10.0 eq) was added slowly along the side of the flask, keeping the internal temperature below -70 °C. The resulting solution was stirred at -78 °C for 5 min, then the cooling bath was removed and the reaction mixture was allowed to warm naturally to an internal temperature of 0 °C, then cooled back to -78 °C again. Quench with 2.6 mL of methanol, then the solution was allowed to warm naturally to room temperature and concentrated under reduced pressure to form an oil, which was further purified by C18 reverse phase column chromatography (10 g, C18 silica gel) eluted with water / methanol = 4:1 to give compound 1-1 as a yellow solid (13 mg, 26.09%). 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.67 (dd, J = 5.0, 3.0 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 6.81 - 6.70 (m, 2H), 3.98 (s, 2H), 2.00 (q, J = 7.2 Hz, 2H), 1.48 (dd, J = 13.9, 7.0 Hz, 2H), 1.33 (d, J = 5.1 Hz, 1H), 0.85 (d, J = 6.5 Hz, 6H), MS (ESI) m / z (M+H) + = 442.

[0133] Example 3: Synthesis of compound 2-1

[0134] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentylthiophene-3-carboxamide

[0135] This compound can be prepared using the method described in Example 2 and replacing 1-2 with 5-bromothiophene-3-carboxylic acid (CAS: 100523-84-0). 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.67 (dd, J = 5.0, 3.0 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 6.81 - 6.70 (m, 2H), 3.98 (s, 2H), 2.00 (q, J = 7.2 Hz, 2H), 1.48 (dd, J = 13.9, 7.0 Hz, 2H), 1.33 (d, J = 5.1 Hz, 1H), 0.85 (d, J = 6.5 Hz, 6H), MS (ESI) m / z (M+H) + = 442.

[0136] Example 4: Synthesis of compound 3-1

[0137] 5-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentylthiophene-2-carboxamide

[0138] This compound can be prepared using the method described in Example 2 and replacing 1-2 with 2-bromothiophene-5-carboxylic acid (CAS: 7311-63-9). 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.54 (t, J = 5.8 Hz, 1H), 7.74 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.17 (dd, J = 10.8, 2.0 Hz, 1H), 7.02 (s, 1H), 3.26 (q, J = 6.1 Hz, 2H), 1.62 (hept, J = 6.6 Hz, 1H), 1.42 (q, J = 7.0 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 442.

[0139] Example 5: Synthesis of compound 4-1

[0140] 5-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentylthiophene-2-carboxamide

[0141] The synthetic route is as follows:

[0142] Step one: Synthesis of compound 4-3

[0143] To a solution of 382 mg of compound 4-2 (2.0 mmol, 1.0 eq) in 5 mL of N,N- dimethylformamide, 1.05 mL of N,N-diisopropylethylamine (6.0 mmol, 3.0 eq) and 913 mg of HATU (2.4 mmol, 1.2 eq) were added with stirring. Stirring at room temperature for 1 h, 464 μL of isoamylamine (4.0 mmol, 2.0 eq) was added, and stirring was continued for 2 h, 10 mL of purified water was added to quench, 3x10 mL of ethyl acetate was extracted, the organic phase was combined, 3x20 mL of saturated brine was washed, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under vacuum, and purified on a flash silica gel column with petroleum ether / ethyl acetate = 20:1 as eluent to give compound 4-3 (472 mg, 90.08%) as a yellow oil. MS (ESI) m / z (M+H)79 Br + H) + = 260.

[0144] Step two: synthesis of compound 4-4

[0145] In a 10 mL sealed tube, mix 462 mg of intermediate Al-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), 260 mg of compound 4-3 (1.0 mmol, 1.0 eq), 0.5 mL of purified water (0.5 mL / mmol), 5 mL of dioxane (5 mL / mmol). Replace the reaction solution with argon for 5 times, stir at 100 °C overnight. Filter the reaction mixture through celite, concentrate the filtrate under reduced pressure, and purify by full-automatic C18 reverse phase column chromatography (25 g, C18 silica gel) eluted with water / methanol = 7:3 to give compound 4-4 as a yellow solid (102 mg), which is used directly in the next step without further purification.

[0146] Step three: synthesis of compound 4-1

[0147] In a suspension of 102 mg of compound 4-4 (0.2 mmol, 1.0 eq) and 76 mg of ammonium formate (1.2 mmol, 6.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol), add 10 mg of 10% Pd / C (0.1 m / m). Reflux the reaction solution at 65 °C for 2 h, concentrate the filtrate after filtration under reduced pressure, and further purify by C18 reverse phase column chromatography (10 g, C18 silica gel) eluted with water / methanol = 4:1 to give compound 4-1 as a white solid (41 mg, 48.71%). 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.49 (t, J = 6.0 Hz, 1H), 7.32 (dd, J = 11.3, 2.0 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.11 (d, J = 3.6 Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H), 3.99 (s, 2H), 3.27 (dt, J = 8.6, 6.1 Hz, 2H), 1.61 (dp, J = 13.4, 6.7 Hz, 1H), 1.43 (dt, J = 8.6, 6.9 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M+H) + = 426.

[0148] Example 6: synthesis of compound 5-1

[0149] 5-(4-(1,1 -dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentylfuran-3-carboxamide

[0150] This compound can be prepared using the method described in Example 5 and replacing 4-2 with 2-bromofuran-4-carboxylic acid (CAS: 58832-36-3). 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1 H), 8.21 (d, J = 0.9 Hz, 1 H), 8.16 (t, J = 5.6 Hz, 1 H), 7.25 (d, J = 1.0 Hz, 1 H), 7.01 (d, J = 2.0 Hz, 1 H), 6.99 (s, 1 H), 3.97 (s, 2H), 3.26 - 3.21 (m, 2H), 2.04 - 1.95 (m, 1 H), 1.65 - 1.58 (m, 1 H), 1.40 (q, J = 6.9 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M+H) + = 426.

[0151] Example 7: Synthesis of compound 6-1

[0152] 5-(4-(1,1 -dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentylfuran-3-carboxamide

[0153] This compound can be prepared using the method described in Example 5 and replacing 4-2 with 5-bromothiazole-2-carboxylic acid (CAS: 957346-62-2). 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1 H), 8.91 (t, J = 6.0 Hz, 1 H), 8.37 (s, 1 H), 7.23 - 7.10 (m, 2H), 4.00 (s, 2H), 3.29 (q, J = 6.1 Hz, 2H), 1.59 (dt, J = 13.1, 6.5 Hz, 1 H), 1.43 (q, J = 7.1 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M+H) + = 443.

[0154] Example 8: Synthesis of compound 7-1

[0155] 2-(4-(1,1 -dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentylfuran-3-carboxamide

[0156] This compound can be prepared using the method described in Example 5 and replacing 5-bromo furan-2-carboxylic acid with 2-bromothiazole-5-carboxylic acid (CAS: 54045-76-0). 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.81 (t, J = 5.7 Hz, 1H), 8.47 (s, 1H), 7.34 (s, 1H), 7.26 (dd, J = 10.6, 1.9 Hz, 1H), 4.02 (s, 2H), 3.27 (d, J = 7.0 Hz, 2H), 1.62 (dt, J = 12.5, 6.3 Hz, 1H), 1.43 (q, J = 6.9 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M+H) + = 443.

[0157] Example 9: Synthesis of compound 8-1

[0158] 5-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentyl-4-methyl-1H-pyrazole-3-carboxamide

[0159] This compound can be prepared using the method described in Example 5 and replacing 4-2 with 3-bromo-4-methyl-1H-pyrazole-5-carboxylic acid (CAS: 929554-40-5). 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.02 (t, J = 5.8 Hz, 1H), 6.89 (d, J = 11.1 Hz, 2H), 4.05 (s, 2H), 3.28 - 3.23 (m, 2H), 2.34 (s, 3H), 1.59 (dd, J = 14.2, 7.1 Hz, 1H), 1.25 (d, J = 8.1 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 440.

[0160] Example 10: Synthesis of compound 9-1

[0161] 5-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentyl-4-methyl-1H-pyrazole-3-carboxamide

[0162] The synthesis route is as follows:

[0163] Step one: synthesis of compound 9-3

[0164] A 50 mL single neck flask was charged with 876 mg of 9-2 (4.0 mmol, 1.0 eq), 7 mL of isoamylamine (60 mmol, 15.0 eq), 16 mL of methanol, and stirred at 50 °C for 24 h. TLC showed the reaction was complete, extracted with 3 x 50 mL of ethyl acetate, combined organic phase, washed with 3 x 100 mL of saturated brine, dried over anhydrous sodium sulfate. Then filtered, concentrated and purified by flash silica gel column chromatography to give 700 mg of yellow oil liquid, 63.84% yield. MS (ESI) m / z (M 79 Br+H) + = 274.

[0165] Step two: synthesis of compound 9-4

[0166] A 10 mL sealed tube was charged with 462 mg of intermediate Al-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), 274 mg of compound 9-3 (1.0 mmol, 1.0 eq), 0.5 mL of purified water (0.5 mL / mmol), 5 mL of dioxane (5 mL / mmol). The reaction was purged with argon for 5 times, stirred at 100 °C overnight. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, purified by full automatic C18 reverse phase column chromatography (25 g, C18 silica gel) eluted with water / methanol = 7:3 to give compound 9-4 as yellow solid (140 mg), which was used in the next step without further purification. MS (ESI) m / z (M+H) + = 530.

[0167] Step three: synthesis of compound 9-1

[0168] A 10 mL sealed tube was charged with 462 mg of intermediate Al-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), 274 mg of compound 9-3 (1.0 mmol, 1.0 eq), 0.5 mL of purified water (0.5 mL / mmol), 5 mL of dioxane (5 mL / mmol). The reaction was purged with argon for 5 times, stirred at 100 °C overnight. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, purified by full automatic C18 reverse phase column chromatography (25 g, C18 silica gel) eluted with water / methanol = 7:3 to give compound 9-4 as yellow solid (140 mg), which was used in the next step without further purification. MS (ESI) m / z (M+H) 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.49 (t, J = 6.0 Hz, 1H), 7.32 (dd, J = 11.3, 2.0 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.11 (d, J = 3.6 Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H), 3.99 (s, 2H), 3.27 (dt, J = 8.6, 6.1 Hz, 2H), 1.61 (dp, J = 13.4, 6.7 Hz, 1H), 1.43 (dt, J = 8.6, 6.9 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 440.

[0169] Example 11: Synthesis of compound 10-1

[0170] 4'-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3'-fluoro-5'-hydroxy-N- isopentyl-[1,1'-biphenyl]-3-carboxamide

[0171] This compound can be prepared using the method described in Example 5 and replacing 4-2 with 3-bromobenzoic acid (CAS: 585-76-2). 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.77 (dd, J = 28.3, 7.8 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 6.92 (s, 2H), 4.04 (s, 2H), 3.30 (s, 2H), 1.62 (q, J = 5.9 Hz, 1H), 1.44 (q, J = 6.9 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 436.

[0172] Example 12: Synthesis of compound 11-1

[0173] 4'-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3'-fluoro-5'-hydroxy-N- isopentyl-4-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0174] This compound can be prepared using the method described in Example 5 and replacing 4-2 with 2-bromo-5-trifluoromethylbenzoic acid (CAS: 1483-56-3). 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.32 (t, J = 6.0 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.69 - 7.62 (m, 2H), 6.77 - 6.69 (m, 2H), 4.02 (s, 2H), 3.13 (d, J = 5.9 Hz, 2H), 1.41 (t, J = 6.7 Hz, 1H), 1.24 - 1.19 (m, 2H), 0.82 (d, J = 6.5 Hz, 6H), MS (ESI) m / z (M+H) + = 504.

[0175] Example 13: Synthesis of compound 12-1

[0176] 4'-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3'-fluoro-5'-hydroxy-N- isopentyl-[1,1'-biphenyl]-4-carboxamide

[0177] This compound can be prepared using the method described in Example 5 and substituting 4-2 with 4-bromobenzoic acid (CAS: 586-76-5). 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.32 (t, J = 6.0 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.69 - 7.62 (m, 2H), 6.77 - 6.69 (m, 2H), 4.02 (s, 2H), 3.13 (d, J = 5.9 Hz, 2H), 1.41 (t, J = 6.7 Hz, 1H), 1.24 - 1.19 (m, 2H), 0.82 (d, J = 6.5 Hz, 6H), MS (ESI) m / z (M+H) + = 436.

[0178] Example 14: Synthesis of compound 13-1

[0179] 4'-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3'-fluoro-5'-hydroxy-N- isopentyl-[1,1'-biphenyl]-2-carboxamide

[0180] This compound can be prepared using the method described in Example 5 and substituting 4-2 with 2-bromobenzoic acid (CAS: 88-65-3). 1H NMR (400 MHz, DMSO-d6) δ 8.09 (t, J = 5.9 Hz, 1H), 7.52 - 7.32 (m, 6H), 6.73 - 6.70 (m, 1H), 6.65 (dd, J = 11.1, 2.0 Hz, 1H), 3.98 (s, 2H), 3.13 - 3.08 (m, 2H), 1.46 - 1.41 (m, 1H), 1.17 (dd, J = 14.2, 7.1 Hz, 2H), 0.82 (dd, J = 6.6, 2.2 Hz, 6H), MS (ESI) m / z (M+H) + = 436.

[0181] Example 15: Synthesis of compound 14-1

[0182] 5-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N-(1- (methylsulfonyl)piperidin-4-yl)furan-2-carboxamide

[0183] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with 1-methylsulfonyl-4-aminopiperidine (CAS: 402927-97-3). 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 11.2, 1.9 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.18 (d, J = 3.6 Hz, 1H), 7.10 (d, J = 3.5 Hz, 1H), 3.99 (s, 2H), 3.95 - 3.88 (m, 1H), 3.60 (d, J = 12.1 Hz, 2H), 2.89 (s, 3H), 2.87 - 2.71 (m, 2H), 1.91 (d, J = 10.3 Hz, 2H), 1.65 (qd, J = 12.1, 4.8 Hz, 2H), MS (ESI) m / z (M+H) + = 517.

[0184] Example 16: Synthesis of compound 15-1

[0185] N-(2-cyclohexylethyl)-5-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)furan-2-carboxamide

[0186] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with cyclohexylethylamine (CAS: 4442-85-7). 1H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J = 5.8 Hz, 1H), 7.32 (dd, J = 11.3, 2.0 Hz, 1H), 7.22 (t, J = 1.6 Hz, 1H), 7.14 - 7.03 (m, 2H), 3.99 (s, 2H), 3.30 - 3.24 (m, 2H), 1.77 - 1.69 (m, 2H), 1.70 - 1.55 (m, 3H), 1.43 (dt, J = 8.6, 6.5 Hz, 2H), 1.29 (ddt, J = 10.6, 7.0, 3.6 Hz, 1H), 1.24 - 1.10 (m, 3H), 0.91 (qd, J = 10.5, 9.4, 5.8 Hz, 2H), MS (ESI) m / z (M+H) + = 466.

[0187] Example 17: Synthesis of compound 16-1

[0188] 5-(2-Fluoro-6-hydroxy-4-(5-(4-(methylsulfonyl)piperazine-l-carbonyl)furan-2-yl)phenyl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0189] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with 1-methanesulfonylpiperazine (CAS: 55276-43-2). 1 H NMR (400 MHz, DMSO-d6) δ 7.18 - 7.13 (m, 3H), 7.11 - 7.08 (m, 1H), 3.99 (s, 2H), 3.84 (s, 4H), 3.24 (t, J = 5.3 Hz, 4H), 2.92 (s, 3H). MS (ESI) m / z (M+H) + = 503.

[0190] Example 18: Synthesis of compound 17-1

[0191] 5-(4-(l,l-Dioxo-4-oxo-l,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N-(3- hydroxy-3-methylbutyl)furan-2-carboxamide

[0192] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with 4-amino-2-methyl-butan-2-ol (CAS: 26734-08-7). 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.48 (t, J = 5.8 Hz, 1H), 7.30 (dd, J = 11.3, 2.0 Hz, 1H), 7.22 - 7.19 (m, 1H), 7.11 - 7.07 (m, 2H), 4.38 (s, 1H), 3.98 (s, 2H), 3.09 (d, J = 6.6 Hz, 2H), 1.68 - 1.60 (m, 2H), 1.14 (s, 6H), MS (ESI) m / z (M+H) + = 442.

[0193] Example 19: Synthesis of compound 18-1

[0194] 5-(4-(5-(azomethine-1-carbonyl)furan-2-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide

[0195] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with heptamethylenimine (CAS: 1121-92-2). 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.17 - 7.03 (m, 4H), 3.99 (s, 2H), 3.74 (d, J = 5.3 Hz, 2H), 3.61 - 3.51 (m, 2H), 1.83 - 1.60 (m, 6H), 1.51 (s, 4H). MS (ESI) m / z (M+H) + = 452.

[0196] Example 20: Synthesis of compound 19-1

[0197] N-(adamantan-1-yl)-5-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)furan-2-carboxamide

[0198] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with adamantanamine (CAS: 768-94-5). 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.53 (s, 1H), 7.30 (dd, J = 11.1, 2.1 Hz, 1H), 7.15 (d, J = 3.5 Hz, 1H), 7.07 (d, J = 3.6 Hz, 1H), 4.01 (s, 2H), 2.10 - 2.05 (m, 9H), 1.67 (d, J = 2.6 Hz, 6H). MS (ESI) m / z (M+H)+ = 490.

[0199] Example 21: Synthesis of compound 20-1

[0200] N-cycloheptyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)furan-2-carboxamide

[0201] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with cycloheptanamine (CAS: 5452-35-7). 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.34 (dd, J = 11.1, 2.1 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.11 - 7.08 (m, 1H), 4.05 (s, 2H), 3.94 (tt, J = 9.5, 4.8 Hz, 1H), 1.91 - 1.79 (m, 2H), 1.77 - 1.27 (m, 10H). MS (ESI) m / z (M+H) + = 452.

[0202] Example 22: Synthesis of compound 21-1

[0203] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- ethylfuran-2-carboxamide

[0204] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with ethylamine (CAS: 75-04-7), 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (t, J = 5.8 Hz, 1H), 7.33 (dd, J = 11.3, 2.0 Hz, 1H), 7.23 (t, J = 1.5 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 7.09 (d, J = 3.6 Hz, 1H), 3.99 (s, 2H), 3.29 (dd, J = 7.3, 5.9 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H), MS (ESI) m / z (M+H) + = 384.

[0205] Example 23: Synthesis of compound 22-1

[0206] 5-(4-(1,1 -dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopropylfuran-2-carboxamide

[0207] This compound can be prepared using the method described in Example 5 and replacing isoamylamine (CAS: 123-72-8) with isopropylamine (CAS: 75-31 -0). 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 1 1.1 Hz, 1 H), 7.24 (s, 1 H), 7.1 1 (dd, J = 25.2, 3.6 Hz, 2H), 4.1 1 (q, J = 6.9 Hz, 1 H), 4.01 (s, 2H), 1.19 (d, J = 6.5 Hz, 6H), MS (ESI) m / z (M+H) + = 398.

[0208] Example 24: Synthesis of compound 23-1

[0209] N-cyclopentyl-5-(4-(1,1 -dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)furan-2-carboxamide

[0210] This compound can be prepared using the method described in Example 5 and replacing isoamylamine (CAS: 123-72-8) with isopropylamine (CAS: 1003-03-8). 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 7.7 Hz, 1 H), 7.08 (d, J = 3.5 Hz, 1 H), 6.84 (d, J = 3.5 Hz, 1 H), 6.80 (s, 1 H), 6.68 (d, J = 10.3 Hz, 1 H), 4.21 (q, J = 7.4 Hz, 1 H), 4.09 (s, 2H), 1.92 - 1.86 (m, 2H), 1.71 (dq, J = 8.0, 2.7 Hz, 2H), 1.55 (ddq, J = 7.5, 5.3, 2.9 Hz, 4H), MS (ESI) m / z (M+H) + = 424.

[0211] Example 25: Synthesis of compound 24-1

[0212] N-(cyclopentylmethyl)-5-(4-(1,1 -dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)furan-2-carboxamide

[0213] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with cyclopentaneethylamine (CAS: 6053-81-2). 1 HNMR (400 MHz, DMSO-d6) δ 8.52 (t, J = 5.9 Hz, 1H), 7.32 (d, J = 11.4 Hz, 1H), 7.22 (s, 1H), 7.15 - 7.06 (m, 2H), 3.99 (s, 2H), 3.31 - 3.20 (m, 2H), 1.80 (d, J = 5.5 Hz, 3H), 1.68 - 1.39 (m, 6H), 1.14 - 1.05 (m, 2H). MS (ESI) m / z (M+H) + = 452.

[0214] Example 26: Synthesis of compound 25-1

[0215] N-cyclohexyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)furan-2-carboxamide

[0216] This compound can be prepared using the method described in Example 5 and replacing isoamylamine with cyclohexylamine (CAS: 108-91-8). 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.34 (dd, J = 11.3, 2.0 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.15 (d, J = 3.5 Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H), 3.99 (s, 2H), 3.77 (s, 1H), 1.85 - 1.60 (m, 4H), 1.40 - 1.16 (m, 6H). MS (ESI) m / z (M+H) + = 438.

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

[0218] The synthesis route is as follows:

[0219] Step one: Synthesis of compound 26-3

[0220] Take a 50 mL three-necked flask, add 240 mg sodium hydride (6.0 mmol, 3.0 eq), 2 mL DMF, replace with argon for 5 times, cool to 0 °C in ice bath. Take another sample flask, add 520 mg 4-3 (2.0 mmol, 1.0 eq), dissolve in 4 mL DMF. Then slowly inject the solution into the three-necked flask with a syringe, stir in ice bath for 0.5 h, then move to room temperature for 1 h. Next, inject the prepared iodomethane (300 μL, 4.8 mmol, 2.4 eq) in 1 mL DMF solution into the three-necked flask with a syringe in ice bath, stir for 0.5 h, then move to room temperature for 2 h. After TLC monitoring reaction is complete, slowly add 15 mL purified water to quench the reaction, then add 20 mL ethyl acetate for extraction, separate the liquid, then use 15 mL ethyl acetate to extract the water phase again until clean, combine the organic phase, wash with saturated brine for 5 times, dry with anhydrous sodium sulfate. Then filter under reduced pressure, concentrate the filtrate to dryness, then purify with flash silica gel column chromatography, elute the product 26-3 as a yellow oil (151 mg, 55.08%) with 4% ethyl acetate / petroleum ether, MS (ESI) m / z (M+H) 79 Br+H) + = 274.

[0221] Step two: synthesis of compound 26-4

[0222] This compound can be prepared using the method described in Example 5 and replacing 4-3 with 26-3. MS (ESI) m / z (M+H) + = 530.

[0223] Step three: synthesis of compound 26-1

[0224] This compound can be prepared using the method described in Example 5 and replacing 4-4 with 26-4. 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.11 (dd, J = 12.4, 5.5 Hz, 4H), 3.99 (s, 2H), 3.31 (d, J = 4.6 Hz, 2H), 2.00 (q, J = 6.8, 6.3 Hz, 1H), 1.57 (p, J = 6.3 Hz, 2H), 1.24 (s, 3H), 0.90 (s, 6H). MS (ESI) m / z (M+H) + = 440.

[0225] Example 28: synthesis of compound 27-1

[0226] 5-(2-Fluoro-6-hydroxy-4-(5-(isopentylamino)methyl)furan-2-yl)phenyl)-1,2,5-thiadiazolidine-3-ketone-1,1-dioxide

[0227] The synthetic route is as follows:

[0228] Step one: synthesis of compound 27-3

[0229] In a solution of 6.8 g of compound 27-2 (CAS: 1899-24-7, 40.0 mmol, 2.0 eq) in 136 mL of 1,2-dichloroethane, 10.44 mL of DIPEA (60 mmol, 3.0 eq), 7 mL of isoamylamine (60 mmol, 3.0 eq) were added, and the solution was protected by argon gas for three times. After stirring at room temperature for 2 h, 3.03 g of sodium borohydride (80 mmol, 4.0 eq) was added, and the solution was protected by argon gas for three times again. After stirring at room temperature for 4-5 h, TLC monitoring showed that the reaction was complete. Then 50 mL of methanol was added to quench the reaction, and the solution was directly concentrated under reduced pressure. Purification was performed by flash silica gel column elution with petroleum ether / ethyl acetate = 20:1 to obtain compound 27-3 (2.5 g, 25.41%). MS (ESI) m / z (M+H) 79 Br+H) + = 246.

[0230] Step two: synthesis of compound 27-4

[0231] In a 10 mL sealed tube, 462 mg of IntA1-1 (calculated as 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), 246 mg of 27-4 (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 solution was replaced by argon gas for five times, and stirred at 100°C overnight. The reaction mixture was filtered through diatomite, and the filtrate was concentrated under reduced pressure. Purification was performed by full-automatic C18 reverse phase column chromatography (25 g C18 silica gel) eluted with water / methanol = 7:3 to obtain 27-4 as an oily liquid (302 mg, 60.28%). Without further purification, it was directly used in the next reaction. MS (ESI) m / z (M+H) + = 502.

[0232] Step three: synthesis of compound 27-1

[0233] To a suspension of 302 mg of compound 27-4 (0.60 mmol, 1.0 eq) and 457 mg of ammonium formate (7.2 mmol, 12.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol) was added 50 mg of 10% Pd / C (0.1 m / m). The reaction was refluxed at 65 °C for 2 h, the filtrate after filtration was concentrated under reduced pressure, further purified by C18 reverse phase column chromatography (10 g, C18 silica gel), eluted with water / methanol = 4:1 to give compound 27-1 as a white solid (72 mg, 29.2%). 1 H NMR (400 MHz, DMSO-d6) δ 7.06 (dd, J = 11.1, 2.0 Hz, 1H), 7.04 - 7.01 (m, 1H), 6.97 (d, J = 3.4 Hz, 1H), 6.56 (d, J = 3.3 Hz, 1H), 4.05 (s, 2H), 3.98 (s, 2H), 2.78 (t, J = 7.8 Hz, 2H), 1.66 - 1.59 (m, 1H), 1.42 (q, J = 7.2 Hz, 2H), 0.88 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 412.

[0234] Example 29: Synthesis of compound 28-1

[0235] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2- carboxamide

[0236] The synthetic route is as follows:

[0237] Step one: Synthesis of compound 28-3

[0238] To a solution of 573 mg of compound 4-2 (3.0 mmol, 1.0 eq) in 7.5 mL of THF was added 535 mg of CDI (3.3 mmol, 1.1 eq), 4.5 mL of ammonia water, stirred at room temperature overnight, after TLC monitoring the reaction was complete, directly concentrated under reduced pressure, purified by flash silica gel column elution with petroleum ether / ethyl acetate = 20:1 to give compound 28-3 (320 mg, 56.14%). MS (ESI) m / z (M+H) + = 191.

[0239] Step two: Synthesis of compound 28-4

[0240] In a 10 mL sealed tube, mix 462 mg IntAl-1 (counted as 1.0 mmol, 1.0 eq), 415 mg potassium carbonate (3.0 mmol, 3.0 eq), 116 mg tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), 0.1 mmol, 0.1 eq), 190 mg 28-3 (1.0 mmol, 1.0 eq), 0.5 mL purified water (0.5 mL / mmol), 5 mL dioxane (5 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 C18 reverse phase column chromatography (25 g C18 silica gel), elute with water / methanol = 7:3, to get 28-4 as an oily liquid (280 mg, 62.92 %), no further purification, directly used in the next step reaction. MS (ESI) m / z (M+H) + = 446.

[0241] Step three: synthesis of compound 28-1

[0242] In a suspension of 280 mg compound 28-4 (0.63 mmol, 1.0 eq) and 483 mg ammonium formate (7.6 mmol, 12.0 eq) in 1 mL methanol (5 mL / mmol) and 1 mL tetrahydrofuran (5 mL / mmol), add 50 mg 10% Pd / C (0.1 m / m). Reflux the reaction at 65 °C for 2 h, concentrate the filtrate after filtration under reduced pressure, further purify by C18 reverse phase column chromatography (10 g, C18 silica gel), elute with water / methanol = 4:1, to get compound 28-1 as a white solid (80 mg, 35.77 %). 1 H NMR (400 MHz, DMSO-d6) d 8.02 (s, 1H), 7.47 (s, 1H), 7.32 (dd, J = 11.2, 1.9 Hz, 1H), 7.21 (t, J = 1.5 Hz, 1H), 7.16 - 7.09 (m, 2H), 4.00 (s, 2H). MS (ESI) m / z (M+H) + = 356.

[0243] Example 30: synthesis of compound 29-1

[0244] N-benzyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)furan-2-carboxamide

[0245] This compound can be prepared using the method described in example 5 and replacing isoamylamine with benzylamine (CAS: 100-46-9). 1H NMR (400 MHz, DMSO-d6) δ 9.15 (t, J = 6.2 Hz, 1H), 7.34 (d, J = 5.3 Hz, 5H), 7.28 - 7.22 (m, 2H), 7.20 (d, J = 3.6 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 4.48 (d, J = 6.1 Hz, 2H), 4.00 (s, 2H), MS (ESI) m / z (M+H) + = 446.

[0246] Example 31: Synthesis of compound 30-1

[0247] 5-(2-Fluoro-6-hydroxy-4-(5-(isopenty(l)methyl)amino)methyl)furan-2-yl)phenyl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0248] The synthetic route is as follows:

[0249] Step one: Synthesis of compound 30-3

[0250] In a 10 mL sealed tube, mix 462 mg of IntA1-1 (calculated as 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), 191 mg of 30-3 (0.7 mmol, 0.7 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. Filter the reaction mixture through celite, concentrate the filtrate under reduced pressure, purify by full-automatic C18 reverse phase column chromatography (25 g C18 silica gel), elute with water / methanol = 7:3, get 30-4 as an oily liquid (220 mg, 42.72%), no further purification is needed, directly used in the next step reaction. MS (ESI) m / z (M+H) + = 261.

[0251] Step two: Synthesis of compound 30-4

[0252] In a 10 mL sealed tube, mix 462 mg of IntA1-1 (calculated as 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), 191 mg of 30-3 (0.7 mmol, 0.7 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. Filter the reaction mixture through celite, concentrate the filtrate under reduced pressure, purify by full-automatic C18 reverse phase column chromatography (25 g C18 silica gel), elute with water / methanol = 7:3, get 30-4 as an oily liquid (220 mg, 42.72%), no further purification is needed, directly used in the next step reaction. MS (ESI) m / z (M+H)+ = 516.

[0253] Step three: synthesis of compound 30-1

[0254] To a suspension of 220 mg of compound 30-4 (0.40 mmol, 1.0 eq) and 305 mg of ammonium formate (4.8 mmol, 12.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol) was added 50 mg of 10% Pd / C (0.1 m / m). The reaction was refluxed at 65 °C for 2 h, the filtrate after filtration was concentrated under reduced pressure, further purified by C18 reverse phase column chromatography (10 g, C18 silica gel), eluted with water / methanol = 4:1 to give compound 30-1 as a white solid (34 mg, 19.95%). 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.11 (dd, J = 11.1, 1.9 Hz, 1H), 7.07 (t, J = 2.7 Hz, 2H), 6.84 (d, J = 3.4 Hz, 1H), 4.47 (d, J = 14.5 Hz, 2H), 3.98 (s, 2H), 3.08 (d, J = 29.4 Hz, 2H), 2.77 (s, 3H), 1.60 (q, J = 7.9 Hz, 3H), 0.90 (d, J = 5.8 Hz, 6H). MS (ESI) m / z (M+H) + = 426.

[0255] Example 32: synthesis of compound 31-1

[0256] 5-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-n- isopentylfuran-2-carboxamidine

[0257] The synthetic route is as follows:

[0258] Step one: synthesis of compound 31-3

[0259] Into a 50 mL three-necked flask, purged with argon, 688 mg of 31-2 (4.0 mmol, 1.0 eq) was dissolved in 10 mL of anhydrous ethanol, and stirred in an ice-bath. After the internal temperature reached 5 °C, 2.85 mL of acetyl chloride (40 mmol, 10.0 eq) was added slowly by syringe. The exothermic reaction heated up to 40 °C. After the dropping was completed, the internal temperature reached 25 °C, and the mixture was stirred at room temperature overnight. A large amount of white solid precipitated. After TLC indicated the reaction was complete, the reaction mixture was transferred to a single-necked flask with anhydrous ethanol, and then concentrated to dryness under reduced pressure. The resulting white and yellow mixed solid was slurried with 10 mL of anhydrous tetrahydrofuran for 1 h, and then filtered under suction. The filter cake was washed with 10 mL of anhydrous tetrahydrofuran, and then dried by air blowing to give 1.03 g of white solid, which was pinner salt 31-3. The crude yield was 103.89%, and the product was used directly in the next step.

[0260] Step Two: Synthesis of compound 31-4

[0261] Into a 25 mL single-necked flask, 31-3 from the previous step was added, and then 10 mL of anhydrous ethanol was added. The mixture was stirred in an ice-bath after purging with argon for 5 times. Then 4.2 mL of isoamylamine (36 mmol, 9.0 eq) was added by syringe. The mixture was stirred at room temperature overnight. After TLC indicated the reaction was complete, the reaction mixture was concentrated to dryness under reduced pressure. The residue was slurried with 10 mL of ethyl acetate for 1 h, and then filtered under suction. The solid was dried by air blowing to give 31-4 as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 2H), 7.82 (d, J = 3.8 Hz, 1H), 6.99 (d, J = 3.8 Hz, 1H), 3.43 - 3.36 (m, 2H), 1.65 (dp, J = 13.1, 6.6 Hz, 1H), 1.55 - 1.48 (m, 2H), 0.92 (d, J = 6.5 Hz, 6H). MS (ESI) m / z (M 79 Br+H) + = 259.

[0262] Step Three: Synthesis of compound 31-5

[0263] This compound was prepared using the procedure described in Example 5, substituting 31-4 for 4-3. MS (ESI) m / z (M+H) + = 515.

[0264] Step Four: Synthesis of compound 31-1

[0265] This compound was prepared using the procedure described in Example 5, substituting 31-5 for 4-4. 1H NMR (400 MHz, DMSO-d6) δ 7.27 (dd, J = 11.3, 1.9 Hz, 1H), 7.18 (d, J = 1.4 Hz, 1H), 7.06 (t, J = 5.4 Hz, 2H), 6.68 (s, 1H), 5.33 (t, J = 4.6 Hz, 1H), 3.98 (s, 2H), 3.22 (s, 2H), 1.68 (dt, J = 13.4, 6.5 Hz, 1H), 1.50 - 1.45 (m, 2H), 0.92 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M+H) + = 425.

[0266] Example 33: Synthesis of compound 32-1

[0267] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentyl-1H-pyrrole-2-carboxamide

[0268] The synthetic route is as follows:

[0269] Step one: Synthesis of compound 32-3

[0270] Take a single mouth bottle, add compound 654 mg 32-2 (1.0 mmol, 1.0 eq), add 501 mg lithium hydroxide monohydrate (6.0 mmol, 3.0 eq), 6.6 mL methanol (10 mL / g), 1.32 mL water (2 mL / g), 75 °C under reflux stirring overnight. After monitoring the reaction complete by TLC, add 30 mL purified water to quench, 30 mL ethyl acetate, 3x30 mL water extraction, combined aqueous phase, using 6N hydrochloric acid to adjust pH = 1, 3x30 mL ethyl acetate extraction, combined organic phase, 3x30 mL saturated brine washing, anhydrous sodium sulfate drying. Then suction filtration, the filtrate was concentrated under reduced pressure to give compound 32-3 as a yellow oil (500 mg, 87.71%). MS (ESI) m / z (M 79 Br+H) + = 189.

[0271] Step two: Synthesis of compound 32-4

[0272] In a 10 mL sealed tube, mix 462 mg IntA1-1 (calculated as 1.0 mmol, 1.0 eq), 415 mg potassium carbonate (3.0 mmol, 3.0 eq), 116 mg tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), 0.1 mmol, 0.1 eq), 260 mg 32-4 (1.0 mmol, 1.0 eq), 0.5 mL purified water (0.5 mL / mmol), 5 mL dioxane (5 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 C18 reverse phase column chromatography (25 g C18 silica gel), elute with water / methanol = 7:3, to get 32-5 as a solid (100 mg, 19.41%), use directly in the next step without further purification. MS (ESI) m / z (M+H) 79 Br+H) + = 259.

[0273] Step three: synthesis of compound 32-5

[0274] In a 10 mL sealed tube, mix 462 mg IntA1-1 (calculated as 1.0 mmol, 1.0 eq), 415 mg potassium carbonate (3.0 mmol, 3.0 eq), 116 mg tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), 0.1 mmol, 0.1 eq), 260 mg 32-4 (1.0 mmol, 1.0 eq), 0.5 mL purified water (0.5 mL / mmol), 5 mL dioxane (5 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 C18 reverse phase column chromatography (25 g C18 silica gel), elute with water / methanol = 7:3, to get 32-5 as a solid (100 mg, 19.41%), use directly in the next step without further purification. MS (ESI) m / z (M+H) + = 515.

[0275] Step four: synthesis of compound 32-1

[0276] In a 10 mL sealed tube, mix 462 mg IntA1-1 (calculated as 1.0 mmol, 1.0 eq), 415 mg potassium carbonate (3.0 mmol, 3.0 eq), 116 mg tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), 0.1 mmol, 0.1 eq), 260 mg 32-4 (1.0 mmol, 1.0 eq), 0.5 mL purified water (0.5 mL / mmol), 5 mL dioxane (5 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 C18 reverse phase column chromatography (25 g C18 silica gel), elute with water / methanol = 7:3, to get 32-5 as a solid (100 mg, 19.41%), use directly in the next step without further purification. MS (ESI) m / z (M+H) 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.01 (t, J = 5.7 Hz, 1H), 7.21 (dd, J = 11.9, 2.0 Hz, 1H), 7.09 - 7.05 (m, 1H), 6.80 (d, J = 3.8 Hz, 1H), 6.54 (d, J = 4.1 Hz, 1H), 3.97 (s, 2H), 3.26 (dt, J = 7.7, 6.1 Hz, 2H), 1.63 (dt, J = 13.3, 6.7 Hz, 1H), 1.41 (dt, J = 8.1, 6.8 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M+H) + = 425.

[0277] Example 34: Synthesis of compound 33-1

[0278] N-(5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-1H-pyrazol-3-yl)-4-methylpentanamide

[0279] This compound can be prepared using the method described in Example 33 and replacing 32-2 with 5-bromo-1H-pyrazole-3-carboxylic acid ethyl ester (CAS: 1392208-46-6). 1 H NMR (400 MHz, DMSO-d6) δ 13.63 (d, J = 16.5 Hz, 1H), 9.70 (s, 1H), 7.20 (d, J = 18.1 Hz, 1H), 7.10 (s, 1H), 6.99 (d, J = 14.6 Hz, 1H), 3.99 (s, 2H), 3.27 (s, 2H), 1.61 (s, 1H), 1.42 (d, J = 7.6 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 426.

[0280] Example 35: Synthesis of compound 34-1

[0281] N-cyclohexyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-1H-pyrazole-3-carboxamide

[0282] This compound can be prepared using the method described in Example 34 and replacing isoamylamine with cyclohexylamine (CAS: 108-91-8). 1HNMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H), 9.73 (s, 1H), 8.04 (dd, J = 164.5, 7.9 Hz, 1H), 7.14 (dd, J = 54.0, 29.8 Hz, 3H), 4.00 (s, 2H), 3.81 - 3.70 (m, 1H), 1.83 - 1.09 (m, 10H), MS (ESI) m / z (M+H) + = 438.

[0283] Example 36: Synthesis of compound 35-1

[0284] N-(2-cyclopentylethyl)-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-1H-pyrazole-3-carboxamide

[0285] This compound can be prepared using the method described in Example 34 and replacing isoamylamine with cyclopentaneethylamine (CAS: 684221-26-9). 1 H NMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H), 9.73 (s, 1H), 8.04 (dd, J = 164.5, 7.9 Hz, 1H), 7.14 (dd, J = 54.0, 29.8 Hz, 3H), 4.00 (s, 2H), 3.81 - 3.70 (m, 1H), 1.83 - 1.09 (m, 10H), MS (ESI) m / z (M+H) + = 452.

[0286] Example 37: Synthesis of compound 36-1

[0287] N-(2-cyclopentylethyl)-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-1H-pyrazole-3-carboxamide

[0288] This compound can be prepared using the method described in Example 34 and replacing isoamylamine with cyclopentaneethylamine (CAS: 684221-26-9). 1 H NMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H), 9.73 (s, 1H), 8.04 (dd, J = 164.5, 7.9 Hz, 1H), 7.14 (dd, J = 54.0, 29.8 Hz, 3H), 4.00 (s, 2H), 3.81 - 3.70 (m, 1H), 1.83 - 1.09 (m, 10H), MS (ESI) m / z (M+H) + = 452.

[0289] Example 38: Synthesis of compound 37-1

[0290] N-cyclooctyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-1 H-pyrazole-3-carboxamide

[0291] This compound can be prepared by following the procedure described in Example 34 and replacing isoamylamine (CAS: 123-42-2) with cyclooctylamine (CAS: 5452-37-9). 1 HNMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H), 8.06 (d, J = 161.4 Hz, 1H), 7.07 (d, J = 33.5 Hz, 2H), 3.99 (s, 2H), 1.82 - 1.18 (m, 15H), MS (ESI) m / z (M+H) + = 466.

[0292] Example 39: Synthesis of compound 38-1

[0293] N-cycloheptyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-4-methyl-1 H-pyrazole-3-carboxamide

[0294] This compound can be prepared by following the procedure described in Example 9 and replacing isoamylamine (CAS: 123-42-2) with cycloheptaneamine (CAS: 5452-35-7). 1 HNMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 7.72 (s, 1H), 6.92 - 6.85 (m, 2H), 4.00 (s, 2H), 3.93 (td, J = 8.8, 4.4 Hz, 1H), 2.33 (s, 3H), 1.82 (d, J = 9.8 Hz, 2H), 1.64 - 1.42 (m, 10H), MS (ESI) m / z (M+H) + = 466.

[0295] Example 40: Synthesis of compound 39-1

[0296] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isoamyl-1 H-imidazole-2-carboxamide

[0297] This compound can be prepared by following the procedure described in Example 33 and replacing 32-2 with 5-bromoimidazole-2-carboxylic acid ethyl ester (CAS: 944900-49-6). 1H NMR (400 MHz, DMSO-d6) δ 8.36 (t, J = 6.1 Hz, 1H), 7.78 (s, 1H), 7.23 - 7.16 (m, 2H), 3.97 (s, 2H), 3.28 (s, 2H), 1.63 - 1.57 (m, 1H), 1.44 (d, J = 7.3 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 426.

[0298] Example 41: Synthesis of compound 40-1

[0299] N-cycloheptyl-4-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-1H-imidazole-2-carboxamide

[0300] This compound can be prepared using the method described in Example 40 and replacing isoamylamine (CAS: 123-52-0) with cycloheptanamine (CAS: 5452-35-7). 1 HNMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.19 (d, J = 17.3 Hz, 2H), 3.95 (d, J = 16.6 Hz, 3H), 1.49 (td, J = 116.1, 112.0, 49.5 Hz, 12H), MS (ESI) m / z (M+H) + = 452.

[0301] Example 42: Synthesis of compound 41-1

[0302] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isoamyl-1H-1,2,4-triazole-3-carboxamide

[0303] This compound can be prepared using the method described in Example 33 and replacing 5-bromo-4H-[1,2,4]thiazole-3-carboxylic acid methyl ester (CAS: 704911-47-7) with 5-bromo-4H-[1,2,4]thiazole-3-carboxylic acid methyl ester (CAS: 704911-47-7). 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.40 (s, 1H), 7.29 (d, J = 10.6 Hz, 1H), 4.02 (s, 2H), 2.79 (dd, J = 9.4, 6.4 Hz, 1H), 1.60 (dp, J = 13.4, 6.5 Hz, 2H), 1.44 (dt, J = 11.2, 5.8 Hz, 2H), 0.91 (d, J = 6.7 Hz, 6H), MS (ESI) m / z (M+H) + = 427.

[0304] Example 43: Synthesis of compound 42-1

[0305] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N- isopentyl-1-methyl-1H-pyrazole-3-carboxamide

[0306] This compound can be prepared using the method described in Example 33 and replacing 1-methyl-5-bromo-3-pyrazolecarboxylic acid methyl ester (CAS: 1222174-92-6). 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.40 (s, 1H), 7.29 (d, J = 10.6 Hz, 1H), 4.02 (s, 2H), 2.79 (dd, J = 9.4, 6.4 Hz, 1H), 1.60 (dp, J = 13.4, 6.5 Hz, 2H), 1.44 (dt, J = 11.2, 5.8 Hz, 2H), 0.91 (d, J = 6.7 Hz, 6H), MS (ESI) m / z (M+H) + = 440.

[0307] Example 44: Synthesis of compound 43-1

[0308] 5-(2-fluoro-6-hydroxy-4-(3-(isopentylamino)-1H-pyrazol-5-yl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide

[0309] The synthesis route is as follows:

[0310] Step one: Synthesis of compound 43-3

[0311] 324 mg of compound 43-2 (2.0 mmol, 1.0 eq) dissolved in 5 mL of DCE was added with 258 μL of isovaleraldehyde, 119 μL of acetic acid, and 848 mg of sodium triacetoxyborohydride. The mixture was purged with argon three times and stirred at room temperature for 4-5 hours. After the reaction was complete as monitored by TLC, 10 ml of methanol was added to stop the reaction. The mixture was concentrated under reduced pressure and purified by flash silica gel column elution with petroleum ether / ethyl acetate = 20:1 to obtain compound 43-3 (209 mg, 45.20%). MS (ESI) m / z (M 79 Br+H) + =232.

[0312] Step 2: Synthesis of compound 43-4

[0313] In a 10 mL sealed tube, 462 mg of IntA1-1 (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), 209 mg of 43-3 (0.9 mmol, 0.9 eq), 0.5 mL of purified water (0.5 mL / mmol), and 5 mL of dioxane (5 mL / mmol) were combined. The atmosphere was replaced with argon five times and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water / methanol ratio of 7:3 to afford 43-4 as a black solid (182 mg, 37.32%). This was used directly in the next step without further purification. MS (ESI) m / z (M+H) + =488.

[0314] Step 3: Synthesis of compound 43-1

[0315] To a -78°C solution of 182 mg of compound 43-4 (0.37 mmol, 1.0 eq) and 109 mg of pentamethylbenzene (0.74 mmol, 2.0 eq) in 4 mL of dichloromethane (10 mL / mmol) was slowly added 4 mL of boron trichloride in dichloromethane (1.0 M, 1.3 mmol, 10.0 eq) along the side of the flask, maintaining the internal temperature below -70°C. The resulting solution was stirred at -78°C for 5 minutes, after which the cooling bath was removed and the reaction mixture was allowed to warm to an internal temperature of 0°C and then cooled back to -78°C. The mixture was quenched by the addition of 2.6 mL of methanol, which was then allowed to warm to room temperature and concentrated under reduced pressure to form an oil. This oil was further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) using a water / methanol ratio of 4:1 as the eluent to afford compound 43-1 as a yellow solid (20 mg, 13.60%). 1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),7.07(d,J=11.9Hz,2H),5.99(s,1H),4.13(s,2H) ,3.10(s,2H),1.44(dd,J=19.6,11.8Hz,3H),0.91(d,J=6.6Hz,6H).MS(ESI)m / z(M+H) + =398.

[0316] Example 45: Synthesis of Compound 44-1

[0317] N-(5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-1H-pyrazol-3-yl)-4-methylpentanamide

[0318] The synthetic route is as follows:

[0319] Step 1: Synthesis of compound 44-3

[0320] 546 μL of isohexanoyl chloride was added to 8 mL of THF solution containing 323 mg of compound 44-2 (2.0 mmol, 1.0 eq), and the mixture was stirred at room temperature for 4-5 h. After the reaction was complete as monitored by TLC, 10 ml of methanol was added to stop the reaction, and the mixture was concentrated under reduced pressure. The mixture was purified by eluting with a flash silica gel column using petroleum ether / ethyl acetate = 20:1 to obtain compound 44-3 (220 mg, 42.30%). MS (ESI) m / z (M 79 Br+H) + =260.

[0321] Step 2: Synthesis of compound 44-4

[0322] In a 10 mL sealed tube, 462 mg of IntA1-1 (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), 220 mg of 44-3 (0.8 mmol, 0.8 eq), 0.5 mL of purified water (0.5 mL / mmol), and 5 mL of dioxane (5 mL / mmol) were combined. The atmosphere was replaced with argon five times and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water / methanol ratio of 7:3 to afford 44-4 as a black solid (300 mg, 58.36%). This was used directly in the next step without further purification. MS (ESI) m / z (M+H) += 516.

[0323] Step three: synthesis of compound 44-1

[0324] To a suspension of 300 mg compound 44-4 (0.58 mmol, 1.0 eq) and 445 mg ammonium formate (7.0 mmol, 12.0 eq) in 1 mL methanol (5 mL / mmol) and 1 mL tetrahydrofuran (5 mL / mmol) was added 50 mg 10% Pd / C (0.1 m / m). The reaction was refluxed at 65 °C for 2 h, the filtrate was concentrated under reduced pressure, and further purified by C18 reverse phase column chromatography (10 g, C18 silica gel) eluted with water / methanol = 4:1 to give compound 44-1 as a solid (60 mg, 24.34%). 1 H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.40 (s, 1H), 9.71 (s, 1H), 7.05 (d, J = 11.0 Hz, 1H), 6.92 (d, J = 58.6 Hz, 2H), 3.98 (s, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.51 (tt, J = 14.2, 6.8 Hz, 3H), 0.89 (d, J = 6.3 Hz, 6H), MS (ESI) m / z (M+H) + = 426.

[0325] Example 47: synthesis of compound 45-1

[0326] Step one: synthesis of compound 45-3

[0327] Take a 50 mL three-necked bottle, add 240 mg sodium hydride (6.0 mmol, 1.2 eq), 10 mL DMF, replace with argon for 5 times, cool to 0 °C in ice bath. Take another sample bottle, add 1.095 mg 45-2 (5.0 mmol, 1.0 eq), dissolve in 10 mL DMF. Then slowly inject the solution into the three-necked bottle with a syringe, stir in ice bath for 0.5 h, then move to room temperature for 1 h. Next, the three-necked bottle is again cooled in an ice bath, and a prepared solution of SEM-Cl (1.325 mL, 7.5 mmol, 1.5 eq) in 5 mL DMF is slowly injected into the three-necked bottle with a syringe, stirred in an ice bath for 0.5 h, then moved to room temperature for 2 h. After monitoring the reaction to completion by TLC, the reaction is quenched by slowly adding 40 mL purified water, then 20 mL ethyl acetate is added for extraction, the aqueous phase is further extracted with 40 mL ethyl acetate until clean, the combined organic phase is washed with saturated brine for 5 times, and dried over anhydrous sodium sulfate. Then filter under suction, and the filtrate is concentrated under reduced pressure, then purified by flash silica gel column chromatography, eluted with 1% ethyl acetate / petroleum ether to give product 45-3 as a yellow oil (1.102 g, 63.10%),1 H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 1H), 5.71 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.58 - 3.52 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.84 - 0.76 (m, 2H), -0.07 (s, 10H). MS (ESI) m / z (M 79 Br + H) + = 349.

[0328] Step two: synthesis of compound 45-4

[0329] A single neck flask containing 1.102 g of 26-3 (3.15 mmol, 1.0 eq) was charged with 16 mL of anhydrous ethanol to dissolve, then isopentylamine (3.3 mL, 28.4 mmol, 9.0 eq) was added, and stirred at 70 °C overnight. After TLC monitoring the reaction was complete, the reaction was concentrated under reduced pressure, 20 mL of 0.5 N aqueous hydrochloric acid was added, then 20 mL of ethyl acetate was added to extract, after separation, the aqueous phase was extracted with 30 mL of ethyl acetate to be clean, and the combined organic phase was washed with 3 x 20 mL of 0.5 N aqueous hydrochloric acid, then washed with saturated brine 5 times, and dried over anhydrous sodium sulfate. Then suction filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 1.2 g of brown oil, which was 45-3 and was used directly in the next step. MS (ESI) m / z (M 79 Br + Na) + = 412.

[0330] Step three: synthesis of compound 45-5

[0331] This compound was prepared using the method described in Example 26 and replacing 4-3 with 45-4. MS (ESI) m / z (M 79 Br + H) + = 404.

[0332] Step four: synthesis of compound 45-6

[0333] A single neck flask containing 202 mg of 45-5 was charged with 2 mL of DCM to dissolve, then 2 mL of TFA was added, and stirred at room temperature for 2 h. After TLC monitoring the reaction was complete, the reaction was concentrated under reduced pressure, and the obtained oil was purified by flash silica gel column chromatography, and eluted with 20% ethyl acetate / petroleum ether to obtain 80 mg of the product as a colorless oil, with a yield of 58.4%.

[0334] Step five: synthesis of compound 45-7

[0335] This compound was prepared using the method described in Example 5 and replacing 4-3 with 45-6. MS (ESI) m / z (M + H) += 530.

[0336] Step six: synthesis of compound 45-1

[0337] This compound can be prepared using the procedure described in example 5 and substituting 45-7 for 4-4. 1 H NMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H), 9.48 (s, 1H), 7.27 - 7.06 (m, 3H), 6.94 (s, 1H), 3.99 (s, 2H), 3.47 (s, 2H), 2.97 (s, 3H), 1.57 (q, J = 7.3, 6.8 Hz, 1H), 1.46 (t, J = 7.3 Hz, 2H), 1.21 - 0.86 (m, 6H), MS (ESI) m / z (M+H) + = 440.

[0338] Example 47: synthesis of compound 46-1

[0339] 5-(2-Fluoro-6-hydroxy-4-(6-(isopentylamino)pyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3- one 1,1-dioxide

[0340] Step one: synthesis of compound 46-3

[0341] In a solution of 205 μL compound 46-2 (CAS: 766-11-0, 2.0 mmol, 1.0 eq) in 6 mL DMSO, 817 mg potassium carbonate (6.0 mmol, 3.0 eq), 348 μL isopentylamine (3 mmol, 1.5 eq) were added, stirred at 90 °C for 4 h. TLC monitoring reaction complete, 10 mL purified water was added, 3 x 10 mL ethyl acetate was extracted, combined organic phase, 3 x 20 mL saturated brine was washed, dried over anhydrous sodium sulfate. Then suction filtered, the filtrate was concentrated under reduced pressure to get an oil (421 mg, 86.98 %). MS (ESI) m / z (M 79 Br+H) + = 243.

[0342] Step two: synthesis of compound 46-4

[0343] In a 10 mL sealed tube, mix 462 mg IntAl-1 (counted as 1.0 mmol, 1.0 eq), 415 mg potassium carbonate (3.0 mmol, 3.0 eq), 116 mg tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), 0.1 mmol, 0.1 eq), 218 mg 46-3 (0.9 mmol, 0.9 eq), 0.5 mL purified water (0.5 mL / mmol), 5 mL dioxane (5 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 C18 reverse phase column chromatography (25 g C18 silica gel), elute with water / methanol = 7:3, to get 46-4 as an oily liquid (230 mg, 46.18%), no further purification, directly used in the next step reaction. MS (ESI) m / z (M+H) + = 499.

[0344] Step three: synthesis of compound 46-1

[0345] In a suspension of 230 mg compound 46-4 (0.46 mmol, 1.0 eq) and 351 mg ammonium formate (5.52 mmol, 12.0 eq) in 1 mL methanol (5 mL / mmol) and 1 mL tetrahydrofuran (5 mL / mmol), add 50 mg 10% Pd / C (0.1 m / m). Reflux the reaction at 65 °C for 2 h, filter the filtrate under reduced pressure, further purify by C18 reverse phase column chromatography (10 g, C18 silica gel), elute with water / methanol = 4:1, to get compound 46-1 as a white solid (50 mg, 26.6%). 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.16 (s, 1H), 7.02 (d, J = 11.3 Hz, 1H), 6.92 (s, 2H), 4.02 (d, J = 2.5 Hz, 2H), 1.69 (dt, J = 13.4, 6.7 Hz, 1H), 1.49 (q, J = 7.2 Hz, 2H), 1.23 (s, 2H), 0.92 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 409.

[0346] Example 48: synthesis of compound 47-1

[0347] 5-(4-(6-(4,4-difluoropiperidin-l-yl)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-l,2,5- thiadiazolidin-3-one 1,1-dioxide

[0348] This compound can be prepared using the method described in Example 47 and replacing isoamylamine with 4,4-difluoropiperidine (CAS: 144230-52-4). 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.43 (d, J = 2.6 Hz, 1H), 7.84 (dd, J = 8.9, 2.6 Hz, 1H), 7.12 - 6.85 (m, 3H), 3.99 (s, 2H), 3.75 (t, J = 5.7 Hz, 4H), 2.00 (tt, J = 13.7, 5.5 Hz, 4H), MS (ESI) m / z (M+H) + = 443.

[0349] Example 49: Synthesis of compound 48-1

[0350] 5-(4-(6-(Cycloheptylamino)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3- one 1,1-dioxide

[0351] This compound can be prepared using the method described in Example 47 and replacing isoamylamine with cycloheptanamine (CAS: 5452-35-7). 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.43 (d, J = 2.6 Hz, 1H), 7.84 (dd, J = 8.9, 2.6 Hz, 1H), 7.12 - 6.85 (m, 3H), 3.99 (s, 2H), 3.75 (t, J = 5.7 Hz, 4H), 2.00 (tt, J = 13.7, 5.5 Hz, 4H), MS (ESI) m / z (M+H) + = 435.

[0352] Example 50: Synthesis of compound 49-1

[0353] 5-(4-(6-(Cycloheptylamino)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3- one 1,1-dioxide

[0354] This compound can be prepared using the method described in Example 47 and replacing isoamylamine with cyclooctylamine (CAS: 5452-37-9). 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.62 (dd, J = 8.8, 2.6 Hz, 1H), 6.97 - 6.83 (m, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 3.97 (s, 2H), 1.85 - 1.44 (m, 15H), MS (ESI) m / z (M+H) + = 449.

[0355] Example 51: Synthesis of compound 50-1

[0356] 5-(4-(6-(Cyclohexylamino)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3- one 1,1-dioxide

[0357] This compound can be prepared by using the method described in Example 47 and replacing isoamylamine (CAS: 123-52-0) with cyclohexylamine (CAS: 108-91-8). 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.62 (dd, J = 8.8, 2.6 Hz, 1H), 6.90 - 6.83 (m, 2H), 6.62 (d, J = 7.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 3.97 (s, 2H), 1.92 (dd, J = 12.7, 4.3 Hz, 2H), 1.76 - 1.70 (m, 2H), 1.60 (d, J = 12.4 Hz, 1H), 1.36 - 1.13 (m, 6H), MS (ESI) m / z (M+H) + = 421.

[0358] Example 52: Synthesis of compound 51-1

[0359] 5-(2-Fluoro-6-hydroxy-4-(6-(iso-pentylamino)-5-methylpyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3- one 1,1-dioxide

[0360] This compound can be prepared by using the method described in Example 47 and replacing 46-2 with 2-fluoro-3-methyl-5-bromopyridine (CAS: 29312-98-9). 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.02 (d, J = 13.2 Hz, 2H), 7.65 (s, 1H), 7.05 (s, 1H), 6.97 (s, 1H), 4.05 (s, 2H), 2.23 (s, 3H), 1.68 (dt, J = 14.0, 7.2 Hz, 1H), 1.54 (d, J = 7.3 Hz, 2H), 0.94 (d, J = 6.6 Hz, 6H).

[0361] Example 53: Synthesis of compound 52-1

[0362] 5-(4-(6-(Cyclohexylamino)-5-methylpyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide

[0363] This compound can be prepared by using the method described in Example 47 and replacing isopentylamine (CAS: 110-97-4) with cyclohexylamine (CAS: 108-91-8), 2-fluoro-3-methyl-5-bromopyridine (CAS: 29312-98-9) with 46-2. 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 2.4 Hz, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 6.36 (s, 1H), 5.47 (d, J = 7.7 Hz, 1H), 4.06 (s, 2H), 3.92 (d, J = 9.3 Hz, 1H), 2.07 (s, 3H), 1.54 (d, J = 2.2 Hz, 8H), 1.30 (d, J = 9.0 Hz, 2H), MS (ESI) m / z (M+H) + = 435.

[0364] Example 54: Synthesis of compound 53-1

[0365] 5-(2-Fluoro-6-hydroxy-4-(2-(isopentylamino)pyrimidin-5-yl)phenyl)-1,2,5-thiadia- zolidin-3-one 1,1-dioxide

[0366] This compound can be prepared by using the method described in Example 47 and replacing 46-2 with 5-bromo-2-fluoropyrimidine (CAS: 62802-38-4). 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.58 (s, 2H), 7.51 (s, 1H), 7.10 - 6.91 (m, 2H), 4.37 (s, 2H), 3.33 (d, J = 14.8 Hz, 2H), 1.63 (dq, J = 13.3, 6.7 Hz, 1H), 1.44 (dt, J = 8.7, 6.9 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 410.

[0367] Example 55: Synthesis of compound 54-1

[0368] 5-(2-Fluoro-6-hydroxy-4-(6-(isopentylamino)-2-methylpyridin-3-yl)phenyl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0369] This compound can be prepared using the method described in Example 47 and substituting 5-bromo-2-fluoro-6-methylpyridine (CAS: 375368-83-5). 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.77 (d, J = 9.1 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 6.76 (dd, J = 10.7, 2.0 Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H), 4.06 (q, J = 2.6 Hz, 2H), 2.45 (s, 3H), 1.69 (dt, J = 13.4, 6.7 Hz, 1H), 1.51 (q, J = 7.1 Hz, 2H), 0.95 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 423.

[0370] Example 56: Synthesis of compound 55-1

[0371] 5-(3,3'-Difluoro-5-hydroxy-4'-(isopentylamino)-[1,1'-biphenyl]-4-yl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide

[0372] Step one: Synthesis of compound 55-3

[0373] In a solution of 380 mg of compound 55-2 (CAS: 367-24-8, 2.0 mmol, 1.0 eq) in 5 mL of DCE, 119 μL of acetic acid (2.08 mmol, 1.04 eq), 258 μL of isovaleraldehyde (2.4 mmol, 1.2 eq), 848 mg of sodium triacetoxyborohydride (4 mmol, 2 eq) were added, and the reaction was stirred at room temperature for 4 h under argon protection. After TLC monitoring showed that the reaction was complete, 10 mL of methanol was added to quench the reaction, and the reaction was directly concentrated under reduced pressure. Purification was performed by flash silica gel column chromatography using petroleum ether / ethyl acetate = 20:1 to obtain compound 55-3 (208 mg, 40.07%). + = 262.

[0374] Step two: synthesis of compound 55-4

[0375] In a 10 mL sealed tube, 462 mg of IntA1-1 (calculated as 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), 208 mg of 55-3 (0.8 mmol, 0.9 eq), 0.5 mL of purified water (0.5 mL / mmol), and 5 mL of dioxane (5 mL / mmol) were mixed. The reaction was stirred at 100°C overnight after being replaced with argon for 5 times. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Purification was performed by full-automatic C18 reverse phase column chromatography (25 g C18 silica gel) using water / methanol = 7:3 as the eluent to obtain 55-4 as an oily liquid (280 mg, 54.16%), which was used directly in the next step without further purification. MS (ESI) m / z (M+H) + = 517.

[0376] Step three: synthesis of compound 55-1

[0377] In a suspension of 280 mg of compound 55-4 (0.54 mmol, 1.0 eq) and 412 mg of ammonium formate (6.48 mmol, 12.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol), 50 mg of 10% Pd / C (0.1 m / m) was added. The reaction was refluxed at 65°C for 2 h, and the filtrate was concentrated under reduced pressure. Purification was performed by C18 reverse phase column chromatography (10 g, C18 silica gel) using water / methanol = 4:1 as the eluent to obtain compound 55-1 as a yellow solid (52 mg, 21.74%). 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 7.04 (d, J = 51.1 Hz, 2H), 6.85 (s, 1H), 6.60 (d, J = 2.2 Hz, 1H), 6.45 (s, 1H), 3.96 (s, 2H), 3.11 (t, J = 7.4 Hz, 2H), 2.21 (s, 3H), 1.71 (dq, J = 13.3, 6.7 Hz, 1H), 1.51 (q, J = 7.2 Hz, 2H), 0.94 (d, J = 6.6 Hz, 6H), MS (ESI) m / z (M+H) + = 426.

[0378] Example 57: Synthesis of compound 56-1

[0379] 5-(2-fluoro-6-hydroxy-4-(3-(isopentylamino)azavinyl-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0380] The synthesis route is as follows:

[0381] Step one: Synthesis of intermediate 56-3

[0382] In a 50 mL single neck flask, mix 415 mg IntA1-7 (1.0 mmol, 1.0 eq), 29 mg 56-2 3-N-tert-butoxycarbonylaminocyclobutane amine (CAS: 91188-13-5, 1.1 mmol, 1.1 eq), 978 mg Cs2CO3(3.0 mmol, 3.0 eq), 1.07 g Brettphos (2.0 mmol, 2.0 eq), 92 mg Pd2(DBA)3(0.1 mmol, 0.1 eq) into 10 mL Dioxane (10 mL / mmol), replace with argon for 5 times, then stir at 80 °C for 12 h. After monitoring the reaction is complete by LC-MS, cool to room temperature, suction filter and filter with diatomite, concentrate the filtrate and purify by full-automatic column chromatography, elute with 10% MeOH / DCM to get 380 mg 56-3, yield 75.10%, MS (ESI) m / z (M-Boc+H) + = 407.

[0383] Step two to step four: Synthesis of 56-1

[0384] A single neck flask was charged with 380 mg of 56-3 (0.75 mmol, 1.0 eq), to which was added 286 mg of ammonium formate (4.50 mmol, 6.0 eq), 3.75 mL of methanol, 3.75 mL of tetrahydrofuran, followed by 190 mg of 10% Pd / C, and stirred at reflux in a 65 °C oil bath for 4 h. After the reaction was complete as monitored by TLC, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 7.5 mL of DCM, followed by 1.9 mL of trifluoroacetic acid, and stirred at room temperature for 30 min. After the reaction was complete as monitored by TLC, the reaction was concentrated under reduced pressure, and the residue was dissolved in 2 x 10 mL of toluene and 2 x 10 mL of DCM. The residue was then dissolved in 8 mL of DCM, adjusted to pH = 8 with DIPEA, followed by 162 μL of isovaleraldehyde (1.5 mmol, 2.0 eq), and stirred at room temperature for 1 h. The reaction was then stirred at room temperature for 1 h after being purged with argon for 5 times, followed by 141 mg of sodium cyanoborohydride (2.25 mmol, 3.0 eq), and stirred at room temperature for 1 h. After the reaction was complete as monitored by LC-MS, the reaction was quenched with 10 mL of methanol, and concentrated under reduced pressure. The residue was purified by reverse phase C18 column eluted with 40% MeOH / H2O to give 40 mg of the product as a white solid in 13.80% yield over three steps. 1 H NMR (400 MHz, DMSO-d6) δ 5.72 (dd, J = 12.3, 2.5 Hz, 1H), 5.70 - 5.64 (m, 1H), 3.93 (t, J = 7.2 Hz, 2H), 3.83 (s, 2H), 1.99 (q, J = 7.0, 6.5 Hz, 2H), 1.64 - 1.57 (m, 1H), 1.52 - 1.34 (m, 2H), 0.84 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M-H) - = 385.

[0385] Example 58: Synthesis of compound 57-1

[0386] (R)-5-(2-fluoro-6-hydroxy-4-(3-(isopentylamino)pyrrolidin-1-yl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide

[0387] This compound was prepared using the method described in Example 57 and replacing (R)-3-tert-butoxycarbonylaminopyrrolidine (CAS: 122536-77-0) for 56-2. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.59 (s, 2H), 5.97 (d, J = 13.3 Hz, 1H), 5.89 (s, 1H), 3.89 (d, J = 20.5 Hz, 3H), 3.65 - 3.49 (m, 2H), 3.26 - 3.11 (m, 2H), 2.99 (t, J = 8.0 Hz, 2H), 2.24 (dt, J = 89.1, 9.7 Hz, 2H), 1.65 (p, J = 6.9 Hz, 1H), 1.48 (q, J = 7.6 Hz, 2H), 0.91 (d, J = 6.5 Hz, 6H). MS (ESI) m / z (M-H) - = 399.

[0388] Example 59: Synthesis of compound 58-1

[0389] 3-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-N-isopentylpyrazolo[1,5-a]pyridine-5-carboxamide

[0390] 58-1 can be prepared by replacing 4-2 with 3-bromopyrazolo[1,5-A]pyridine-5- carboxylic acid (CAS: 876379-79-2) according to the synthetic procedure of Example 5. 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.98 (t, J = 5.6 Hz, 1H), 7.72 (s, 1H), 6.76 (d, J = 10.8 Hz, 2H), 4.26 - 4.18 (m, 1H), 4.03 (dt, J = 11.9, 6.0 Hz, 1H), 3.97 (s, 2H), 3.26 - 2.86 (m, 5H), 2.67 (s, 1H), 2.18 - 2.01 (m, 2H), 1.58 (dt, J = 13.4, 6.7 Hz, 1H), 1.32 (q, J = 7.2 Hz, 2H), 0.87 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M+H) + = 480.

[0391] Example 60: Synthesis of compound 59-1

[0392] 3-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- hydroxyphenyl)-N-isopentyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2- carboxamide

[0393] A partial synthesis route is as follows:

[0394] Step one: synthesis of intermediate 59-3

[0395] Into a 250 mL single neck flask, 840 mg of pyrazolo[l,5-a]pyridine-2-carboxylic acid (CAS: 63237-88-7, 5 mmol, 1.0 eq), 980 mg of NBS (5.5 mmol, 1.1 eq) were added into 50 mL of DMF (10 mL / mmol) and stirred at room temperature for 4 h. The reaction mixture was extracted with water and ethyl acetate. The ethyl acetate layer was retained and washed with saturated NaCl solution for 3 times and spin dried to give 94-3 as yellow solid 923 mg. MS (ESI) m / z (M+H) 288.0. 79 Br+H) + = 245.

[0396] Step two to four: synthesis of 59-1

[0397] This compound was prepared using the procedure described in Example 5 and substituting compound 59-3 for compound 4-2. 1 H NMR (400 MHz, DMSO-d6) δ 6.65 (d, J = 11.1 Hz, 2H), 4.12 (t, J = 6.1 Hz, 2H), 3.97 (s, 2H), 3.19 (q, J = 6.6 Hz, 2H), 2.74 (t, J = 6.3 Hz, 2H), 2.00 (d, J = 3.5 Hz, 2H), 1.78 (s, 2H), 1.56 (dt, J = 13.4, 6.7 Hz, 1H), 1.36 (q, J = 7.1 Hz, 2H), 0.87 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M+H) + = 480

[0398] Example 61: synthesis of compound 60-1

[0399] 5-(2-fluoro-6-hydroxy-4-(2-(isopentylamino)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyridin-3-yl)phenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide

[0400] The partial synthesis route is as follows:

[0401] Step one: synthesis of intermediate 60-3

[0402] Into a 50 mL three-necked flask, charge 735 mg of 59-3 (3.0 mmol, 1.0 eq), 970 μL of DPPA (1.4 mmol, 1.5 eq), 1 mL of TEA (7.2 mmol, 2.4 eq), 12 mL of THF (4 mL / mmol), replace with argon for 5 times, stir at room temperature for 4 h, then add 735 μL of water (5 mL / g), stir at 60 °C for 4 h, prepare sand full-automatic column chromatography, elute with 25% petroleum ether / ethyl acetate, concentrate under reduced pressure to give 60-3. MS (ESI) m / z (M 79 Br + H) + = 216.

[0403] Step two: synthesis of intermediate 60-4

[0404] Into a 25 mL single-necked flask, charge 310 mg of 60-3 (1.43 mmol, 1.0 eq), 162 μL of isovaleraldehyde (1.5 mmol, 1.05 eq), 85 μL of acetic acid (1.5 mmol, 1.04 eq), 455 mg of sodium triacetoxyborohydride (2.14 mmol, 1.5 eq), add 4.65 mL of DCE (15 mL / g), stir at room temperature for 4 h, prepare sand full-automatic column chromatography, elute with 10% petroleum ether / ethyl acetate, concentrate under reduced pressure to give 60-4. MS (ESI) m / z (M 79 Br + H) + = 286.

[0405] Steps three to four: synthesis of 60-1

[0406] This compound 60-1 can be prepared using the method described in Example 5 and replacing compound 4-4 with 60-4. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 6.70 - 6.58 (m, 2H), 3.95 (s, 2H), 3.85 (t, J = 6.1 Hz, 2H), 2.69 (t, J = 6.2 Hz, 2H), 1.92 (td, J = 7.9, 6.9, 4.2 Hz, 2H), 1.70 (q, J = 5.8 Hz, 2H), 1.62 (dq, J = 13.3, 6.7 Hz, 1H), 1.44 (q, J = 7.0 Hz, 2H), 1.15 (d, J = 6.7 Hz, 2H), 0.88 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M + H) + = 452.

[0407] Example 62: synthesis of compound 61-1

[0408] 5-(3-fluoro-5-hydroxy-4'-(isopentylamino)-2',5'-dimethyl-[1,1'-biphenyl]-4-yl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0409] This compound 61-1 can be prepared using the method described in Example 56 and replacing compound 55-2 with 4-bromo-2,5-dimethylaniline (CAS: 30273-40-6). 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 7.04 (d, J = 51.1 Hz, 2H), 6.85 (s, 1H), 6.60 (d, J = 2.2 Hz, 1H), 6.45 (s, 1H), 4.15 (s, 2H), 3.11 (t, J = 7.4 Hz, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 1.70 (dt, J = 13.3, 6.7 Hz, 1H), 1.51 (q, J = 7.2 Hz, 2H), 0.94 (d, J = 6.6 Hz, 6H). MS (ESI) m / z (M+H) + = 436.

[0410] II. Biological Evaluation

[0411] (1). PTPN2 / PTPN1 enzyme activity assay test method

[0412] 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 µM. 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 four parameter curve fitting.

[0413] IC 50The values are shown in Table 1, A represents that the activity of the compound is below 10 nM, B represents that the activity of the compound is between 10-100 nM, C represents that the activity of the compound is between 100 nM-1 μM, and D represents that the activity of the compound is above 1 μM.

[0414] Table 1 IC of example compounds for PTPN1 / PTPN2 phosphatase inhibitory activity 50 Measurement value

[0415] (2). Rat pharmacokinetic test of some compounds of the present application

[0416] Experimental method: Compound 4-1, 40-1, 51-1 is respectively administered at 1 mg / kg by intravenous injection, 10 mg / kg by gavage, and the rat plasma is collected at the specified time; LC-MS / MS method is established to determine the concentration of compounds 501-43, 502-74 in rat plasma, the plasma drug concentration-time curve is drawn by using Graphpad Prism software, and the pharmacokinetic parameters are calculated by using WinNonlin software. The pharmacokinetic parameters of the compounds of the present application are as follows:

[0417] Table 2 Test results of rat in vivo pharmacokinetics of compounds

[0418] According to Table 2, the introduction of basic groups and nitrogen atoms in the molecule and the increase of the proportion of SP3 carbon atoms can significantly improve the bioavailability of the compounds. Among them, imidazole derivative 40-1 has better AUC and bioavailability.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: Ring A is an aromatic or heteroaromatic ring, independently and optionally substituted with one or more R 2 substituents; R 1 selected from hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, adamantyl, 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; R 4 = N or CH, R 5 is independently selected from the group consisting of hydrogen, oxo, C 1-6 alkyl-S(=0)2-, C 1-6 alkyl-NH-C(=0)-, C3-C6cycloalkyl-C(=0)- and C 3-6 cycloalkyl-S(=0)2-, C 3-6 heterocycloalkyl-C(=0)- and C 3-6 heterocycloalkyl-S(=0)2-; R 2 independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy; R 6 independently selected from hydrogen, halogen, 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; When R 10 When C, R 7 , R 8 , R 9 independently selected from hydrogen, halogen, hydroxy, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl; L is selected from -NR 8 -CH2-, -CH2-NH-, -S(=0)2-, -C(=0)NH-, -NHC(=0)-, -S(=0)2NH-, -NHS(=0)2-, or -C(=0)-; p＝0-3。 2.The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Ring A is an aromatic or heteroaromatic ring, independently and optionally substituted with one or more R 2 substituted; said aromatic ring is substituted or unsubstituted phenyl, said substitution is C 1-4 haloalkyl; said heteroaromatic ring is a 5-6 membered heteroaromatic ring containing one or two of S, O, N atoms, said substitution is C 1-4 alkyl; R 1 selected from hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, adamantyl, and: wherein: m = 0, 1, 2, 3, 4 or 5; n = 1, 2 or 3; o = 1, 2 or 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; R 4 = N or CH, R 5 is independently selected from the group consisting of hydrogen, C 1-6 alkyl-S(=O)2-, C 1-6 alkyl-NH-C(=O)-, C 3-6 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, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy; R 6 independently selected from hydrogen, halogen, 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; when R 10 is C, R 7 , R 8 , R 9 is independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl and C 3-6 cycloalkyl; L is selected from -NR a -CH2-, -CH2-NR b -CH2-, -CH2-NR c -CH2-, -CH2-NR d -CH2-, -CH2-NR c -CH2-, -CH2-NR e -CH2-, -CH2-NR e -CH2-, -CH2-NR R a , R b , R c , R d , R e are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl; p = 0, 1, 2 or 3. 3.The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Ring A is selected from: independently and optionally substituted by one or more R 2 substituted; wherein: U = CH or N; V = CH or N; W = NH, O or S; X = CH or N; Y = CH or N; h = 0, 1, 2 or 3; i = 0, 1, 2 or 3; Z, Z' are independently selected from N and CH; R 2 independently selected from hydrogen, halogen, trifluoromethyl, C 1-6 alkyl; R 1 selected from hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, adamantyl, and: wherein: m = 0, 1, 2 or 3; n = 1, 2 or 3; o = 1, 2 or 3; q = 0, 1, 2 or 3; R 3 is independently selected from CH and N; R 4 is independently selected from C, CH, N and O, and when R 4 = O, p = 0, i.e. R 5 is absent; When R 4 =N or CH, t=1, R 5 are independently selected from hydrogen, C 1-6 Alkyl-S(=O)2-, C 3-6 Cycloalkyl-C(=O)-, C 3-6 Cycloalkyl-S(=O)2- and C 3-6 Heterocycloalkyl-C(=O)-; when R 4 =C, t = 1-2, R 5 Independently selected from halogen, oxo and C 1-6 alkyl; R 2 independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, trifluoromethyl; R 6 independently selected from hydrogen, halogen, hydroxyl, cyano, and C 1-6 alkyl; 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; when R 10 is C, R 7 , R 8 , R 9 is independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl and C 3-6 cycloalkyl; L is selected from -NR a -CH2-, -CH2-NR b -CH2-, -CH2-NR c -CH2-, -CH2-NR d -CH2-, -CH2-NR c -CH2-, -CH2-NR -S(=O)2NR e - and -NR e S(=O)2- or -C(=O)-; R a , R b , R c , R d , R e are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl; p = 0, 1, 2 or 3. 4.The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Ring A is selected from: independently and optionally substituted by one or more R 2 substituted; wherein: U = CH or N; V = CH or N; W = NH, O or S; Z, Z' are independently selected from N and CH; h＝1-2； i＝1-2； R 1 selected from hydrogen, (CH3)2-CH-(CH2) 0～4 -、 5.The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Ring A is: R 1 For: hydrogen, 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: a compound selected from any one of the following structures: 7.A method for preparing the compound of general formula (I) according to claim 1, characterized in that: when L is -NHC(=O)-, when L is -NH-, R1is -CH2- and R2is -CH2-, When L is -NH-, A is Time, A, R 1 , h, i are as defined in any one of claims 1 to 4.

8. A process for the preparation of a compound of formula (V) ###0009### (V) characterized in that: wherein A, R 1 are as defined in any one of claims 1-5. 9.A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6, and one or more pharmaceutically acceptable carriers. 10.Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6 in the preparation of a medicament for treating PTPN2 / PTPN1-mediated diseases.

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