Thiadiazolidine ketone derivatives with PTPN2 / PTPN1 inhibitory activity, their preparation methods and applications

Abstract

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

Description

Technical Field

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

[0002] Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (such as PD-1 / PD-L1 and CTLA-4 blocking antibodies), have proven effective in treating a variety of cancers, significantly improving outcomes in patients with poor prognoses from conventional therapies. However, unsatisfactory clinical responses and the progression of intrinsic or acquired resistance will continue to limit the further development of this therapy.

[0003] Protein phosphorylation is a ubiquitous and reversible post-translational modification process that can be adapted to a variety of cellular regulatory mechanisms (Chrestia JF. et al., Pharmacol Res 190:106712; 2023). Protein phosphokinases catalyze phosphorylation, disrupting existing electrostatic interactions by adding phosphate groups to amino acid residues. Reversibly, dephosphorylation is the hydrolysis of phosphate amino acids catalyzed by phosphatases. An abnormal balance between phosphorylation and dephosphorylation can disrupt many cellular regulations governing cell growth, metabolism, differentiation, and communication (NettoLES. et al., FEBSJ 289(18):5480-504; 2022).

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

[0005] Data from in vivo gene screening using CRISPR / Cas9 genome editing technology in a mouse B16F10 transplanted tumor model showed that the deletion of the PTPN2 gene in tumor cells enhanced the response to immunotherapy regimens of GM-CSF secretory vaccine (GVAX) plus PD-1 checkpoint blockade (Manguso RT et al., Nature 547:413-418; 2017). The deletion of PTPN2 sensitized tumors to immunotherapy by enhancing IFNγ-mediated antigen presentation and growth inhibition. The same screening also showed that genes involved in immune evasion, including PD-L1 and CD47, were depleted under immunotherapy, while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. In recent years, increasing research has indicated that PTPN2 has oncogenic effects. In pancreatic cancer, PTPN2 protein is specifically highly expressed and regulates tumor cell growth (Kuang w. et al., 13:805311; 2022). These findings suggest that therapeutic strategies that enhance IFNγ sensing and signal transduction may 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 crucial role in the insulin and leptin receptor signaling pathways and is a key protein in downregulating these pathways (Kenner K.A. et al., J Biol Chem 271: 19810-19816; 1996). Animals lacking PTPN1 exhibit improved glucose regulation and lipid profiles and resist weight gain during high-fat diet therapy (Elchebly M. et al., Science 283: 1544-1548; 1999). Therefore, PTPN1 inhibitors hold promise for the treatment of type 2 diabetes, obesity, and metabolic syndrome. Summary of the Invention

[0007] Objective of the invention: The technical problem to be solved by the present invention is to develop small molecule inhibitors with PTPN2 / PTPN1 inhibitory activity based on thiadiazolidinone as the parent nucleus; another technical problem to be solved by the present invention is to provide the application of the above-mentioned thiadiazolidinone derivatives in drugs for treating PTPN2 / PTPN1 mediated diseases.

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

[0009]

[0010] in:

[0011] Ring A is an aromatic ring or an aromatic heterocyclic ring, independently and arbitrarily bounded by one or more R... 2 replace;

[0012] R 1 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-8 cycloalkyl, adamantyl, and:

[0013]

[0014] in:

[0015] m = 0 - 5;

[0016] n = 1 - 3;

[0017] o = 1 - 3;

[0018] R 3 Independently selected from CH and N;

[0019] R 4 Independently selected from CH, N, and O, and when R 4 When = 0, R 5 It does not exist;

[0020] When R 4 When =N or CH, R 5 Independently selected from hydrogen, oxo, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-NH-C(=O)-, C 3- C6 cycloalkyl-C(=O) and C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Heterocyclic alkyl-C(=O)- and C 3-6 Heterocyclic alkyl-S(=O)2-;

[0021] R 2 Independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, trifluoromethyl, trifluoromethoxy;

[0022] R 6 Independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 cycloalkyl;

[0023] R 10 Independently selected from C and N; when R 10 When R is N, 7 It does not exist, R 8 R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 cycloalkyl;

[0024] When R 10 When it is C, R 7 R 8 R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 cycloalkyl;

[0025] L is selected from -NR 8 -, -CH2-, -CH2-NH-, -S(=O)2-, -C(=O)NH-, -NHC(=O)-, -S(=O)2NH-, -NHS(=O)2- or -C(=O)-;

[0026] p = 0 - 3.

[0027] The compound or a pharmaceutically acceptable salt thereof:

[0028] Ring A is an aromatic ring or an aromatic heterocyclic ring, independently and arbitrarily bounded by one or more R... 2 Substitution; the aromatic ring is a substituted or unsubstituted phenyl group, and the substitution is C.1-4 Halogenated alkyl substitution; the aromatic heterocycle is a 5- to 6-membered aromatic heterocycle containing one or two of S, O, and N atoms, with or without substitution, and the substitution is C. 1-4 Alkyl substitution;

[0029] R 1 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-8 cycloalkyl, adamantyl, and:

[0030] in:

[0031] m = 0, 1, 2, 3, 4 or 5;

[0032] n = 1, 2, or 3;

[0033] o = 1, 2, or 3;

[0034] R 3 Independently selected from CH and N;

[0035] R 4 Independently selected from CH, N, and O, and when R 4 When = 0, R 5 It does not exist;

[0036] When R 4 When =N or CH, R 5 Independently selected from hydrogen and 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 Heterocyclic alkyl-C(=O)- and C 3-6 Heterocyclic alkyl-S(=O)2-;

[0037] R 2 Independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, trifluoromethyl, trifluoromethoxy;

[0038] R 6 Independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 cycloalkyl;

[0039] R 10 Independently selected from C and N; when R 10 When R is N, 7 It does not exist, R 8 R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C1-6 Alkyl and C 3-6 cycloalkyl; when R 10 When it is C, R 7 R 8 R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 cycloalkyl;

[0040] 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)-;

[0041] R a R b R c R d R e Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl;

[0042] p = 0, 1, 2 or 3.

[0043] The compound or a pharmaceutically acceptable salt thereof:

[0044] Ring A is selected from: Independently and arbitrarily controlled by one or more R 2 replace;

[0045] in:

[0046] U = CH or N;

[0047] V = CH or N;

[0048] W = NH, O, or S;

[0049] X = CH or N;

[0050] Y = CH or N;

[0051] h = 0, 1, 2 or 3;

[0052] i = 0, 1, 2 or 3;

[0053] Z and Z' are independently selected from N and CH, respectively;

[0054] R 2 Independently selected from hydrogen, halogen, trifluoromethyl, C 1-6 alkyl;

[0055] R 1 Selected from hydrogen, halogens, C 1-6 Alkyl, C 3-8 cycloalkyl, adamantyl, and:

[0056]

[0057] in:

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

[0059] n = 1, 2, or 3;

[0060] o = 1, 2, or 3;

[0061] q = 0, 1, 2 or 3;

[0062] R 3 Independently selected from CH and N;

[0063] R 4 Independently selected from C, CH, N, and O, and when R 4 When =0, p = 0, that is, R 5 It does not exist;

[0064] When R 4 When =N or CH, t=1, R 5 Independently selected from hydrogen and C 1-6 Alkyl-S(=O)2-, C 3-6 Cycloalkyl-C(=O)-, C 3-6 cycloalkyl-S(=O)2- and C 3-6 Heterocyclic alkyl-C(=O)-; when R 4 When C = , t = 1 - 2, R 5 Independently selected from halogens, oxidants, and C 1-6 alkyl;

[0065] R 2 Independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 3-6 cycloalkyl, trifluoromethyl;

[0066] R 6 Independently selected from hydrogen, halogen, hydroxyl, cyano, and C 1-6 alkyl;

[0067] R 10 Independently selected from C and N; when R 10 When R is N, 7 It does not exist, R8 R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl and C 3-6 cycloalkyl; when R 10 When it is C, R 7 R 8 R 9 Independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl and C 3-6 cycloalkyl;

[0068] 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)-;

[0069] R a R b R c R d R e Each is independently selected from hydrogen and C. 1-3 Alkyl, C 3-6 cycloalkyl;

[0070] p = 0, 1, 2 or 3.

[0071] The compound or a pharmaceutically acceptable salt thereof:

[0072] Ring A is selected from: Independently and arbitrarily controlled by one or more R 2 replace;

[0073] in:

[0074] U = CH or N;

[0075] V = CH or N;

[0076] W = NH, O, or S;

[0077] Z and Z' are independently selected from N and CH, respectively;

[0078] h = 1 - 2;

[0079] i = 1 - 2;

[0080] R 1Selected from hydrogen, (CH3)2-CH-(CH2) 0～4 -、

[0081]

[0082] The compound or a pharmaceutically acceptable salt thereof:

[0083] Ring A is:

[0084] R 1 For: hydrogen,

[0085]

[0086] The compound or a pharmaceutically acceptable salt thereof is selected from compounds or pharmaceutically acceptable salts of any of the following structures:

[0087]

[0088] The preparation method of the compound represented by general formula (I): when L is -NHC(=O)-,

[0089]

[0090] When L is -NH-

[0091]

[0092] When L is -NH-, A is hour,

[0093] A, R 1 The definitions of h and i are as described above.

[0094] Preparation method of compounds represented by general formula (V):

[0095]

[0096]

[0097] Where A, R 1 The definition is as described above.

[0098] A pharmaceutical composition comprising the said compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0099] The use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PTPN2 / PTPN1 mediated diseases.

[0100] Unless otherwise specified, the terms used in this invention generally have the following meanings:

[0101] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0102] Term "C" 1-6 "Alkyl" refers to saturated straight-chain and branched hydrocarbon groups with 3-6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

[0103] Term "C" 3-6 "Heterocyclic alkyl" refers to a saturated cycloalkyl group having one or more non-C heteroatoms such as N, O, and S and 3-6 carbon atoms, including but not limited to azirropropyl, azirrobutyl, azirropentyl, azirrohexyl, oxacyclobutyl, etc.

[0104] The term "aromatic ring" refers to a ring system that is aromatic, including but not limited to benzene rings, pyrazoles, thiophenes, furans, thiazoles, etc.

[0105] The term "adamantyl" refers to

[0106] The term "aromatic heterocycle" refers to an aryl group having one or more non-C heteroatoms such as N, O, and S. It includes, but is not limited to, pyrrole, pyrazine, thiophene, furan, pyrazole, and also includes bicyclic systems such as benzopyrazole.

[0107] The term "partially saturated aromatic heterocycle" refers to an aromatic heterocycle in which part of the double bond is saturated with hydrogen atoms, including dihydropyrrole, tetrahydrobenzopyrazole, etc.

[0108] The term "saturated heterocycle" refers to a fully saturated ring containing heteroatoms, including tetrahydropyrrole, acridine, etc.

[0109] The term "heterocyclic alkyl" refers to cycloalkanes having one or more non-C heteroatoms such as N, O, and S, including but not limited to tetrahydropyrrole, piperidine, morpholine, piperazine, pyrazine, N-methylpiperazine, and N-ethylpiperazine.

[0110] The term "-C(=O)-" represents a carbonyl group, specifically a carbon-oxygen double bond.

[0111] The term "-S(=O)2-" represents a sulfonyl group.

[0112] The term "-S(=O)2NH-" represents a sulfonamide group.

[0113] The term "-C(=O)NH-" represents an amide.

[0114] The term "-NHS(=O)2-" represents aminosulfonyl group.

[0115] The term "-NHC(=O)-" represents carbamoyl group.

[0116] The term "-NH-" represents imino.

[0117] The term "-CH2-" represents methylene.

[0118] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: The compounds disclosed in this invention have significant activity against PTPN2 / PTPN1 phosphatases, and the synthesized compounds have IC 50 With values ​​maintained at the nM level, it can be used to treat tumor development and immune response, and can also be used in combination with immunosuppressants to treat related immune diseases. It can be developed into an anti-tumor drug with high activity, good selectivity and low toxicity and side effects. It has the characteristics of novel skeleton, strong plasticity and great potential for future modification. Detailed Implementation

[0119] The following embodiments are provided to better understand the present invention, but do not limit the invention. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods; unless otherwise specified, the experimental materials used in the following embodiments were purchased from conventional biochemical reagent stores. The present application will now be described in detail with reference to specific embodiments.

[0120] Example 1: Synthesis of intermediate A1-1

[0121] 5-(2-(benzyloxy)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0122]

[0123] The synthesis route is as follows:

[0124]

[0125] Step 1: Synthesis of intermediate A1-3

[0126] Add 5.04 g sodium hydride (126 mmol, 1.2 eq) and 420 mL tetrahydrofuran (4 mL / mmol) to a 2 L three-necked flask. Attach a constant-pressure dropping funnel to the flask, purge three times with argon, and stir in an ice bath. Then, slowly add 420 mL of a tetrahydrofuran (5 mL / mmol) solution of 25 g intermediate A1-2 (CAS: 147808-42-2, 105 mmol, 1.0 eq) through the funnel, maintaining the internal temperature below 5 °C. After the addition is complete, slowly add 13.10 mL (126 mmol, 1.2 eq) of benzyl alcohol to the solution using a syringe, maintaining the internal temperature below 10 °C. After the reaction is complete as monitored by TLC, transfer the solution to room temperature and stir for another 2.5 h. Then quench with 1 L of purified water and extract with 3 × 500 mL ethyl acetate. After combining the organic layers, the mixture was washed with 3 × 600 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 38.19 g of a red gel-like substance, which was A1-2. No further purification was required; it was used directly in the next step. A small portion of the product was purified for analysis. 1 H NMR (400MHz, DMSO-d6) δ7.65 (t, J=1.8Hz, 1H), 7.61 (dd, J=9.4, 1.8Hz, 1H), 7.44-7.35 (m, 5H), 5.37 (s, 2H).

[0127] Step 2: Synthesis of intermediate A1-4

[0128] In a 2L flask, add 38.19g of intermediate A1-3 (105mmol, 1.0eq), 525mL of methanol (5mL / mmol), and 525mL of tetrahydrofuran (5mL / mmol). Stir, then add 28.08g of ammonium chloride (525mmol, 5.0eq) and 68.65g of zinc powder (1.05mol, 10.0eq). Purge three times with argon and stir overnight at room temperature. After the reaction is complete as monitored by TLC, filter through diatomaceous earth. Concentrate the filtrate under reduced pressure, extract with 1L of purified water and 3×300mL of ethyl acetate, combine the organic phases, wash with 3×400mL of saturated brine, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, redissolve in 500mL of ethyl acetate, stir in an ice bath, and add 105mL of ethyl hydrochloride solution (2.0M, 2.0eq). The suspension was stirred in an ice bath for another 2 hours, then filtered, washed with 3 × 50 mL of glacial ethyl acetate, and dried in a forced-air drying oven to give intermediate A1-4 as a gray hydrochloride (31.46 g, two-step yield of intermediate A1-4 90.03%). A small portion of the product was neutralized and purified for analysis. 1H NMR (400MHz, DMSO-d6) δ7.50 (d, J=6.7Hz, 2H), 7.40 (t, J=7.4Hz, 2H), 7.36-7.31 (m, 1H), 6.99-6.95 (m, 2H), 5.17 (s, 2H), 4.85 (s, 2H).MS (ESI) m / z (M 79 Br+H) + =296.

[0129] Step 3: Synthesis of intermediate A1-5

[0130] 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) were added. The reaction was then heated to 65 °C and stirred for 16 h. After the reaction was monitored by TLC to be nearly complete, the reaction was quenched with 500 mL of purified water, extracted with 3 × 300 mL of ethyl acetate, and the organic phases were combined, washed with 3 × 400 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, purified by silica gel column chromatography, and eluted with petroleum ether / ethyl acetate at a ratio of 20:1 to give a white solid, which was intermediate A1-5 (23.692 g, 68.04%). 1 H NMR (400MHz, DMSO-d6) δ7.50-7.32 (m, 5H), 7.03-6.95 (m, 2H), 5.23 (td, J=6.9, 2 .7Hz, 1H), 5.17 (s, 2H), 4.04 (dd, J=7.0, 3.1Hz, 2H), 3.59 (s, 3H), MS (ESI) m / z (M 79 Br+H) + =368.

[0131] Step 4: Synthesis of intermediate A1-6

[0132] A solution of 23.692 g intermediate A1-5 (64.34 mmol, 1.0 eq) and 74.334 g aminosulfonyl chloride (643 mmol, 10.0 eq) in 129 mL of acetonitrile (2 mL / mmol) was purged three times with argon gas and stirred in an ice bath. When the internal temperature reached 0 °C, 89.43 mL of triethylamine (643 mmol, 10.0 eq) was slowly added through a constant-pressure dropping funnel to maintain the internal temperature below 20 °C. The mixture was stirred at room temperature for another 2 hours, then extracted with 150 mL of purified water and 3 × 150 mL of ethyl acetate. The organic phases were combined, washed with 3 × 200 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, purified by column chromatography, and eluted with petroleum ether / ethyl acetate at a ratio of 5:1 to obtain a white solid, which was intermediate A1-6 (12.922 g, 44.90%). 1 H NMR (400MHz, DMSO-d6) δ7.55-7.48(m, 2H), 7.45-7.32(m, 3H), 7.25-7.17(m, 2H), 7.05(s, 2H), 5.20(s, 2H), 4.42-4.19(m, 2H), 3.57(s, 3H), MS(ESI)m / z(M 79 Br+H) + =446.

[0133] Step 5: Synthesis of intermediate A1-7

[0134] Take a 100 mL three-necked flask, add 3 g of intermediate A1-6 (6.7 mmol, 1.0 eq), dissolve in 30 mL (10 mL / g) of anhydrous tetrahydrofuran, and purge five times with argon. Under argon purging, add 402 mg of sodium hydride (10.05 mmol, 1.5 eq) in portions. Stir the reaction solution at room temperature for 20 minutes, then quench with 35 mL of 1.0 M HCl aqueous solution, and extract with 3 × 75 mL of ethyl acetate. Combine the organic phases, wash with 3 × 50 mL of saturated brine, dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate under vacuum, purify by automated C18 reversed-phase column chromatography (25 g, C18 silica gel), eluting with water / methanol = 1:1, to obtain intermediate A1-7 as a white solid (1.884 g, 67.65%). 1 H NMR (400MHz, DMSO-d6) δ7.51-7.47 (m, 2H), 7.39-7.28 (m, 3H), 7.19 (dd, J=8.0, 1.7Hz, 2H), 5.20 (s, 2H), 3.95 (s, 2H), MS (ESI) m / z (M 79 Br-H) - =413.

[0135] Step Six: Synthesis of Intermediate A1-1

[0136] In a 10 mL sealed tube, add 415 mg of intermediate A1-7 (1.0 mmol, 1.0 eq), 295 mg of potassium acetate (3.0 mmol, 3.0 eq), 508 mg of pinacol diboronate (2.0 mmol, 2.0 eq), 73 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 0.1 mmol, 0.1 eq), and 5 mL of dioxane (5 mL / mmol). Purge with argon five times. The mixture was stirred overnight at 105°C. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to obtain a black oily substance, which was used directly in the next step without further purification. The MS (ESI) m / z (M) values ​​of the corresponding boric acid were also calculated. 79 Br-H)-=379.

[0137] Example 2: Synthesis of Compound 1-1

[0138] 3-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylthiophene-2-carboxamide

[0139]

[0140] The synthesis route is as follows:

[0141] Step 1: Synthesis of compounds 1-3

[0142] In a 5 mL solution of N,N-dimethylformamide containing 414 mg of compound 1-2 (CAS: 7311-64-0, 2.0 mmol, 1.0 eq), 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. The mixture was stirred at room temperature for 1 h, followed by the addition of 464 μL of isoamylamine (4.0 mmol, 2.0 eq), and stirring for another 2 h. After the reaction was complete as monitored by TLC, 10 mL of purified water was added to quench the reaction, and the mixture was extracted with 3 × 10 mL of ethyl acetate. The organic phases were combined, washed with 3 × 20 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was then filtered, and the filtrate was concentrated under reduced pressure and purified by rapid silica gel column elution with petroleum ether / ethyl acetate (20:1) to give compounds 1-3 as a yellow oil (516 mg, 93.41%). MS (ESI) m / z (M 79 Br+H) + =276.

[0143] Step 2: Synthesis of compounds 1-4

[0144] In a 10 mL sealed tube, 462 mg IntA1-1 (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), 276 mg 1-3 (1.0 mmol, 1.0 eq), 0.5 mL purified water (0.5 mL / mmol), and 5 mL dioxane (5 mL / mmol) were mixed. The mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated C18 reversed-phase column chromatography (25 g C18 silica gel) with water / methanol elution at a 7:3 ratio to give 1-4 as a yellow solid (68 mg, 12.79%). No characterization was required, and it was used directly in the next reaction.

[0145] Step 3: Synthesis of Compound 1-1

[0146] A solution of 1.3 mL of boron trichloride dichloromethane (1.0 M, 1.3 mmol / mmol) was slowly added along the side of a flask 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, maintaining the internal temperature below -70 °C. The resulting solution was stirred at -78 °C for 5 minutes, 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. The mixture was quenched with 2.6 mL of methanol, and then allowed to warm naturally to room temperature. The solution was concentrated under reduced pressure to form an oil, which was further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) eluting with water / methanol at a ratio of 4:1 to give compound 1-1 as a yellow solid (13 mg, 26.09%). 1 H NMR (400MHz, DMSO-d6) δ8.03 (s, 1H), 7.67 (dd, J=5.0, 3.0Hz, 1H), 7.19 (d, J=5.1Hz, 1H), 6.81-6.70 (m, 2H), 3.98 (s, 2H ), 2.00 (q, J=7.2Hz, 2H), 1.48 (dd, J=13.9, 7.0Hz, 2H), 1.33 (d, J=5.1Hz, 1H), 0.85 (d, J=6.5Hz, 6H), MS (ESI) m / z (M+H) + =442.

[0147] Example 3: Synthesis of Compound 2-1

[0148] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylthiophene-3-carboxamide

[0149]

[0150] The compound can be prepared by using the method described in Example 2 and replacing 1-2 with 5-bromothiophene-3-carboxylic acid (CAS: 100523-84-0). 1 H NMR (400MHz, DMSO-d6) δ8.03 (s, 1H), 7.67 (dd, J=5.0, 3.0Hz, 1H), 7.19 (d, J=5.1Hz, 1H), 6.81-6.70 (m, 2H), 3.98 (s, 2H ), 2.00 (q, J=7.2Hz, 2H), 1.48 (dd, J=13.9, 7.0Hz, 2H), 1.33 (d, J=5.1Hz, 1H), 0.85 (d, J=6.5Hz, 6H), MS (ESI) m / z (M+H) + =442.

[0151] Example 4: Synthesis of Compound 3-1

[0152] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylthiophene-2-carboxamide

[0153]

[0154] The compound can be prepared by using the method described in Example 2 and replacing 1-2 with 2-bromothiophene-5-carboxylic acid (CAS: 7311-63-9). 1 H NMR (400MHz, DMSO-d6) δ10.74 (s, 1H), 8.54 (t, J=5.8Hz, 1H), 7.74 (d, J=4.0Hz, 1H), 7.55 (d, J=4.0Hz, 1H), 7.17 (dd, J=10.8, 2.0Hz , 1H), 7.02 (s, 1H), 3.26 (q, J=6.1Hz, 2H), 1.62 (hept, J=6.6Hz, 1H), 1.42 (q, J=7.0Hz, 2H), 0.91 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =442.

[0155] Example 5: Synthesis of Compound 4-1

[0156] 5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylfuran-2-carboxamide

[0157]

[0158] The synthesis route is as follows:

[0159]

[0160] Step 1: Synthesis of Compound 4-3

[0161] In a 5 mL solution of 382 mg of compound 4-2 (2.0 mmol, 1.0 eq) in 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. The mixture was stirred at room temperature for 1 h, then 464 μL of isoamylamine (4.0 mmol, 2.0 eq) was added, and the mixture was stirred for another 2 h. The mixture was then quenched with 10 mL of purified water, extracted with 3 × 10 mL of ethyl acetate, and the organic phases were combined, washed with 3 × 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, purified by rapid silica gel column chromatography, and eluted with petroleum ether / ethyl acetate at a ratio of 20:1 to give a yellow oily substance, which was compound 4-3 (472 mg, 90.08%). MS (ESI) m / z (M 79 Br+H) + =260.

[0162] Step 2: Synthesis of Compound 4-4

[0163] In a 10 mL sealed tube, 462 mg of intermediate A1-1 (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), 260 mg of compound 4-3 (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 reaction mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated C18 reversed-phase column chromatography (25 g, C18 silica gel) with water / methanol = 7:3 elution to give compound 4-4 as a yellow solid (102 mg), which was used directly in the next step without further characterization.

[0164] Step 3: Synthesis of Compound 4-1

[0165] 10 mg of 10% Pd / C (0.1 m / m) was added to a suspension of 102 mg compound 4-4 (0.2 mmol, 1.0 eq) and 76 mg ammonium formate (1.2 mmol, 6.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol). The reaction mixture was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) eluting with water / methanol at a ratio of 4:1 to give compound 4-1 as a white solid (41 mg, 48.71%). 1 H NMR (400MHz, DMSO-d6) δ9.55 (s, 1H), 8.49 (t, J=6.0Hz, 1H), 7.32 (dd, J=11.3, 2.0Hz, 1H), 7.23-7.20 (m, 1H), 7.11 (d, J=3.6Hz, 1H), 7.08 (d, J=3.5H z, 1H), 3.99 (s, 2H), 3.27 (dt, J=8.6, 6.1Hz, 2H), 1.61 (dp, J=13.4, 6.7Hz, 1H), 1.43 (dt, J=8.6, 6.9Hz, 2H), 0.91 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =426.

[0166] Example 6: Synthesis of Compound 5-1

[0167] 5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylfuran-3-carboxamide

[0168]

[0169] The compound can be prepared using the method described in Example 5, with 2-bromofuran-4-carboxylic acid (CAS: 58832-36-3) instead of 4-2. 1 H NMR (400MHz, DMSO-d6) δ9.79 (s, 1H), 8.21 (d, J = 0.9Hz, 1H), 8.16 (t, J = 5.6Hz, 1H), 7.25 (d, J = 1.0Hz, 1H), 7.01 (d, J = 2.0Hz, 1H), 6.99 (s, 1 H), 3.97 (s, 2H), 3.26-3.21 (m, 2H), 2.04-1.95 (m, 1H), 1.65-1.58 (m, 1H), 1.40 (q, J=6.9Hz, 2H), 0.90 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =426.

[0170] Example 7: Synthesis of Compound 6-1

[0171] 5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylthiazolyl-2-carboxamide

[0172]

[0173] The compound can be prepared by using the method described in Example 5 and replacing 4-2 with 5-bromothiazol-2-carboxylic acid (CAS: 957346-62-2). 1 H NMR (400MHz, DMSO-d6) δ10.01 (s, 1H), 8.91 (t, J=6.0Hz, 1H), 8.37 (s, 1H), 7.237.10 (m, 2H), 4.00 (s, 2H), 3.29 (q, J=6.1Hz, 2H), 1.59 (dt, J=13.1, 6.5Hz, 1H), 1.43 (q, J=7.1Hz, 2H), 0.90 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =443.

[0174] Example 8: Synthesis of Compound 7-1

[0175] 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylthiazolyl-5-carboxamide

[0176]

[0177] The compound can be prepared by using the method described in Example 5 and replacing 5-bromofuran-2-carboxylic acid with 2-bromothiazol-5-carboxylic acid (CAS: 54045-76-0). 1 H NMR (400MHz, DMSO-d6) δ10.29 (s, 1H), 8.81 (t, J=5.7Hz, 1H), 8.47 (s, 1H), 7.34 (s, 1H), 7.26 (dd, J=10.6, 1.9Hz, 1H), 4.02 ( s, 2H), 3.27 (d, J=7.0Hz, 2H), 1.62 (dt, J=12.5, 6.3Hz, 1H), 1.43 (q, J=6.9Hz, 2H), 0.91 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =443.

[0178] Example 9: Synthesis of Compound 8-1

[0179] 5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentyl-4-methyl-1H-pyrazole-3-carboxamide

[0180]

[0181] The compound can be prepared by 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 (400MHz, DMSO-d6) δ9.92 (s, 1H), 8.02 (t, J = 5.8Hz, 1H), 6.89 (d, J = 11.1Hz, 2H), 4.05 (s, 2H), 3.28-3.23 (m, 2H), 2.34 (s, 3H), 1.59 (dd, J=14.2, 7.1Hz, 1H), 1.25 (d, J=8.1Hz, 2H), 0.90 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =440.

[0182] Example 10: Synthesis of Compound 9-1

[0183] 4-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentyl-1-methyl-1H-imidazol-2-carboxamide

[0184]

[0185] The synthesis route is as follows:

[0186] Step 1: Synthesis of Compound 9-3

[0187] Take a 50 mL single-necked flask, add 876 mg of 9-2 (4.0 mmol, 1.0 eq), 7 mL of isoamylamine (60 mmol, 15.0 eq), and 16 mL of methanol, and reflux at 50 °C with stirring for 24 h. TLC showed the reaction was complete. Extract with 3 × 50 mL of ethyl acetate, combine the organic phases, wash with 3 × 100 mL of saturated brine, and dry to anhydrous sodium sulfate. Then filter, prepare slurry from the filtrate, and purify by rapid silica gel column chromatography to give 700 mg of a yellow oily liquid, yield 63.84%. MS (ESI) m / z (M 79 Br+H) + =274.

[0188] Step 2: Synthesis of Compound 9-4

[0189] In a 10 mL sealed tube, 462 mg of intermediate A1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 0.1 mmol, 0.1 eq), 274 mg of compound 9-3 (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 reaction mixture was purged five times with argon and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated C18 reversed-phase column chromatography (25 g, C18 silica gel) with water / methanol = 7:3 elution to give compound 9-4 as a yellow solid (140 mg), which could be used directly for the next step without further purification. MS (ESI) m / z (M+H) + =530.

[0190] Step 3: Synthesis of Compound 9-1

[0191] 10 mg of 10% Pd / C (0.1 m / m) was added to a suspension of 106 mg compound 9-4 (0.2 mmol, 1.0 eq) and 76 mg ammonium formate (1.2 mmol, 6.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol). The reaction mixture was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) with water / methanol elution of 4:1 to give compound 9-1 as a white solid (58 mg, 66.06%). 1 H NMR (400MHz, DMSO-d6) δ9.55 (s, 1H), 8.49 (t, J=6.0Hz, 1H), 7.32 (dd, J=11.3, 2.0Hz, 1H), 7.23-7.20 (m, 1H), 7.11 (d, J=3.6Hz, 1H), 7.08 (d, J=3.5H z, 1H), 3.99 (s, 2H), 3.27 (dt, J=8.6, 6.1Hz, 2H), 1.61 (dp, J=13.4, 6.7Hz, 1H), 1.43 (dt, J=8.6, 6.9Hz, 2H), 0.91 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =440.

[0192] Example 11: Synthesis of Compound 10-1

[0193] 4′-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-3′-fluoro-5′-hydroxy-N-isopentyl-[1,1′-biphenyl]-3-carboxamide

[0194]

[0195] The compound can be prepared by using the method described in Example 5 and replacing 4-2 with 3-bromobenzoic acid (CAS: 585-76-2). 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H), 7.77 (dd, J=28.3, 7.8Hz, 2H), 7.51 (t, J=7.6Hz, 1H), 6.92 (s, 2H), 4.04 (s, 2H), 3.30 (s, 2H), 1.62 (q, J=5.9Hz, 1H), 1.44 (q, J=6.9Hz, 2H), 0.91 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =436.

[0196] Example 12: Synthesis of Compound 11-1

[0197] 4′-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-3′-fluoro-5′-hydroxy-N-isopentyl-4-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide

[0198]

[0199] The compound can be prepared by using the method described in Example 5 and replacing 4-2 with 2-bromo-5-trifluoromethylbenzoic acid (CAS: 1483-56-3). 1 H NMR (400MHz, DMSO-d6) δ8.40 (s, 1H), 8.32 (t, J=6.0Hz, 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=5.9Hz, 2H), 1.41 (t, J=6.7Hz, 1H), 1.24-1.19 (m, 2H), 0.82 (d, J=6.5Hz, 6H), MS (ESI) m / z (M+H) + =504.

[0200] Example 13: Synthesis of Compound 12-1

[0201] 4′-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-3′-fluoro-5′-hydroxy-N-isopentyl-[1,1′-biphenyl]-4-carboxamide

[0202]

[0203] The compound can be prepared by using the method described in Example 5 and replacing 4-2 with 4-bromobenzoic acid (CAS: 586-76-5). 1 H NMR (400MHz, DMSO-d6) δ8.47 (t, J=5.6Hz, 1H), 7.88 (d, J=8.5Hz, 2H), 7.67 (d, J=8.5Hz, 2H), 6.88 (d, J=23.9Hz, 2H), 4.04 (s, 2H), 3.31-3.26 (m, 2H), 1.62 (dq, J=13.5, 6.8Hz, 1H), 1.43 (q, J=6.8Hz, 2H), 0.91 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =436.

[0204] Example 14: Synthesis of Compound 13-1

[0205] 4′-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-3′-fluoro-5′-hydroxy-N-isopentyl-[1,1′-biphenyl]-2-carboxamide

[0206]

[0207] The compound can be prepared by using the method described in Example 5 and replacing 4-2 with 2-bromobenzoic acid (CAS: 88-65-3). 1 H NMR (400MHz, DMSO-d6) δ8.09 (t, J=5.9Hz, 1H), 7.52-7.32 (m, 6H), 6.73-6.70 (m, 1H), 6.65 (dd, J=11.1, 2.0Hz, 1H), 3.98 ( s, 2H), 3.13-3.08 (m, 2H), 1.46-1.41 (m, 1H), 1.17 (dd, J=14.2, 7.1Hz, 2H), 0.82 (dd, J=6.6, 2.2Hz, 6H), MS (ESI) m / z (M+H) + =436.

[0208] Example 15: Synthesis of Compound 14-1

[0209] 5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-N-(1-(methanesulfonyl)piperidin-4-yl)furan-2-carboxamide

[0210]

[0211] The compound can be prepared using the method described in Example 5, with 1-methanesulfonyl-4-aminopiperidine (CAS: 402927-97-3) replacing isopentylamine. 1 H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 8.38 (d, J = 8.1Hz, 1H), 7.32 (dd, J = 11.2, 1.9Hz, 1H), 7.26-7.20 (m, 1H), 7.18 (d, J=3.6Hz, 1H), 7.10 (d, J=3.5Hz, 1H), 3. 99(s, 2H), 3.95-3.88(m, 1H), 3.60(d, J=12.1Hz, 2H), 2.89(s, 3H), 2.87-2.71( m, 2H), 1.91 (d, J=10.3Hz, 2H), 1.65 (qd, J=12.1, 4.8Hz, 2H), MS (ESI) m / z (M+H) + =517.

[0212] Example 16: Synthesis of Compound 15-1

[0213] N-(2-cyclohexylethyl)-5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

[0214]

[0215] The compound can be prepared using the method described in Example 5, with cyclohexylethylamine (CAS: 4442-85-7) instead of isopentylamine. 1 H NMR (400MHz, DMSO-d6) δ8.49 (t, J=5.8Hz, 1H), 7.32 (dd, J=11.3, 2.0Hz, 1H), 7.22 (t, J=1.6Hz, 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, 6.5Hz, 2H), 1.29 (ddt, J=10.6, 7.0, 3. 6Hz, 1H), 1.24-1.10 (m, 3H), 0.91 (qd, J=10.5, 9.4, 5.8Hz, 2H), MS (ESI) m / z (M+H) + =466.

[0216] Example 17: Synthesis of Compound 16-1

[0217] 5-(2-fluoro-6-hydroxy-4-(5-(4-(methanesulfonyl)piperazine-1-carbonyl)furan-2-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0218]

[0219] The compound can be prepared by using the method described in Example 5 and replacing isopentylamine with 1-methanesulfonylpiperazine (CAS: 55276-43-2). 1 H NMR (400MHz, DMSO-d6) δ7.18-7.13 (m, 3H), 7.11-7.08 (m, 1H), 3.99 (s, 2H), 3.84 (s, 4H), 3.24 (t, J=5.3Hz, 4H), 2.92 (s, 3H).MS (ESI) m / z (M+H) + =503.

[0220] Example 18: Synthesis of Compound 17-1

[0221] 5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-(3-hydroxy-3-methylbutyl)furan-2-carboxamide

[0222]

[0223] The compound can be prepared using the method described in Example 5, with 4-amino-2-methyl-but-2-ol (CAS: 26734-08-7) instead of isopentylamine. 1 H NMR (400MHz, DMSO-d6) δ9.58 (s, 1H), 8.48 (t, J=5.8Hz, 1H), 7.30 (dd, J=11.3, 2.0Hz, 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=6.6Hz, 2H), 1.68-1.60 (m, 2H), 1.14 (s, 6H), MS (ESI) m / z (M+H) + =442.

[0224] Example 19: Synthesis of Compound 18-1

[0225] 5-(4-(5-(azoalkyl-1-carbonyl)furan-2-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0226]

[0227] This compound was prepared using the method described in Example 5, with heptamethylimine (CAS: 1121-92-2) substituted for isopentylamine. ¹H 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.

[0228] Example 20: Synthesis of Compound 19-1

[0229] N-(adamantane-1-yl)-5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

[0230]

[0231] The compound can be prepared by using the method described in Example 5 and replacing isopentylamine with adamantane (CAS: 768-94-5). 1 H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 7.53 (s, 1H), 7.30 (dd, J=11.1, 2.1Hz, 1H), 7.15 (d, J=3.5Hz, 1 H), 7.07 (d, J=3.6Hz, 1H), 4.01 (s, 2H), 2.10-2.05 (m, 9H), 1.67 (d, J=2.6Hz, 6H).MS (ESI) m / z (M+H) + =490.

[0232] Example 21: Synthesis of Compound 20-1

[0233] N-Cycloheptyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

[0234]

[0235] The compound can be prepared using the method described in Example 5, with cycloheptylamine (CAS: 5452-35-7) instead of isopentylamine. 1H NMR (400MHz, DMSO-d6) δ9.79 (s, 1H), 8.30 (d, J = 8.3Hz, 1H), 7.34 (dd, J = 11.1, 2.1Hz, 1H), 7.23 (s, 1H), 7.15 (d, J = 3.6Hz, 1 H), 7.11-7.08 (m, 1H), 4.05 (s, 2H), 3.94 (tt, J=9.5, 4.8Hz, 1H), 1.91-1.79 (m, 2H), 1.77-1.27 (m, 10H).MS (ESI) m / z (M+H) + =452.

[0236] Example 22: Synthesis of compound 21-1

[0237] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-ethylfuran-2-carboxamide

[0238]

[0239] The compound can be prepared using the method described in Example 5, with ethylamine (CAS: 75-04-7) instead of isopentylamine. 1 H NMR (400MHz, DMSO-d6) δ8.58 (t, J=5.8Hz, 1H), 7.33 (dd, J=11.3, 2.0Hz, 1H), 7.23 (t, J=1.5Hz, 1H), 7.13 (d, J=3.6 Hz, 1H), 7.09 (d, J=3.6Hz, 1H), 3.99 (s, 2H), 3.29 (dd, J=7.3, 5.9Hz, 2H), 1.14 (t, J=7.2Hz, 3H), MS (ESI) m / z (M+H) + =384.

[0240] Example 23: Synthesis of Compound 22-1

[0241] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopropylfuran-2-carboxamide

[0242]

[0243] The compound can be prepared using the method described in Example 5, with isopropylamine (CAS: 75-31-0) instead of isopentylamine. 1H NMR (400MHz, DMSO-d6) δ8.26 (d, J=7.8Hz, 1H), 7.33 (d, J=11.1Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J =25.2, 3.6Hz, 2H), 4.11 (q, J = 6.9Hz, 1H), 4.01 (s, 2H), 1.19 (d, J = 6.5Hz, 6H), MS (ESI) m / z (M+H) + =398.

[0244] Example 24: Synthesis of Compound 23-1

[0245] N-Cyclopentyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

[0246]

[0247] The compound can be prepared by using the method described in Example 5 and replacing isopentylamine with isopropylamine (CAS: 1003-03-8). 1 H NMR (400MHz, DMSO-d6) δ8.22 (d, J=7.7Hz, 1H), 7.08 (d, J=3.5Hz, 1H), 6.84 (d, J=3.5Hz, 1H), 6.80 (s, 1H), 6.68 (d, J=10.3Hz, 1H), 4.2 1 (q, J=7.4Hz, 1H), 4.09 (s, 2H), 1.92-1.86 (m, 2H), 1.71 (dq, J=8.0, 2.7Hz, 2H), 1.55 (ddq, J=7.5, 5.3, 2.9Hz, 4H), MS (ESI) m / z (M+H) + =424.

[0248] Example 25: Synthesis of Compound 24-1

[0249] N-(cyclopentylmethyl)-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

[0250]

[0251] The compound can be prepared using the method described in Example 5, with cyclopentaneethylamine (CAS: 6053-81-2) instead of isopentylamine. 1H NMR (400MHz, DMSO-d6) δ8.52 (t, J=5.9Hz, 1H), 7.32 (d, J=11.4Hz, 1H), 7.22 (s, 1H), 7.15-7.06 (m, 2H), 3.9 9(s, 2H), 3.31-3.20(m, 2H), 1.80(d, J=5.5Hz, 3H), 1.68-1.39(m, 6H), 1.14-1.05(m, 2H).MS(ESI)m / z(M+H) + =452.

[0252] Example 26: Synthesis of Compound 25-1

[0253] N-Cyclohexyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

[0254]

[0255] The compound can be prepared by using the method described in Example 5 and replacing isopentylamine with cyclohexylamine (CAS: 108-91-8). 1 H NMR (400MHz, DMSO-d6) δ9.62 (s, 1H), 8.24 (d, J=8.1Hz, 1H), 7.34 (dd, J=11.3, 2.0Hz, 1H), 7.27-7.19 (m, 1H), 7.15 (d, J =3.5Hz, 1H), 7.08 (d, J = 3.5Hz, 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.

[0256] Example 27: Synthesis of Compound 26-1

[0257] The synthesis route is as follows:

[0258] Step 1: Synthesis of Compound 26-3

[0259] Take a 50 mL three-necked flask, add 240 mg sodium hydride (6.0 mmol, 3.0 eq) and 2 mL DMF, purge with argon five times, and cool to 0 °C in an ice bath. Take another sample vial, add 520 mg 4-3 (2.0 mmol, 1.0 eq) and dissolve in 4 mL DMF. Then slowly inject this solution into the three-necked flask using a syringe, stir in an ice bath for 0.5 h, and then move to room temperature and stir for 1 h. Immediately afterwards, put the three-necked flask back into the ice bath, slowly inject 1 mL of the prepared iodomethane (300 μL, 4.8 mmol, 2.4 eq) DMF solution using a syringe, stir in an ice bath for 0.5 h, and then move to room temperature and stir for 2 h. After the reaction is complete as monitored by TLC, slowly add 15 mL of purified water to quench the reaction, then add 20 mL of ethyl acetate for extraction. After separation, extract the aqueous phase again with 15 mL of ethyl acetate. Combine the organic phases, wash five times with saturated brine, and dry with anhydrous sodium sulfate. The solution was then filtered, concentrated under reduced pressure, and purified by rapid silica gel column chromatography. The product 26-3 was eluted with 4% ethyl acetate / petroleum ether as a yellow oil (151 mg, 55.08%). MS (ESI) m / z (M 79 Br+H) + =274.

[0260] Step 2: Synthesis of Compound 26-4

[0261] The compound was prepared using the method described in Example 5, with 26-3 replacing 4-3. MS(ESI) m / z(M+H) + =530.

[0262] Step 3: Synthesis of Compound 26-1

[0263] The compound can be prepared by using the method described in Example 5, with 26-4 replacing 4-4. 1 H NMR (400MHz, DMSO-d6) δ9.82 (s, 1H), 7.11 (dd, J=12.4, 5.5Hz, 4H), 3.99 (s, 2H), 3.31 (d, J=4.6Hz, 2H), 2.00 (q, J=6.8, 6.3Hz, 1H), 1.57 (p, J=6.3Hz, 2H), 1.24 (s, 3H), 0.90 (s, 6H).MS (ESI) m / z (M+H) + =440.

[0264] Example 28: Synthesis of Compound 27-1

[0265] 5-(2-fluoro-6-hydroxy-4-(5-(isopentylamino)methyl)furan-2-yl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0266]

[0267] The synthesis route is as follows:

[0268]

[0269] Step 1: Synthesis of Compound 27-3

[0270] In 136 mL of 1,2-dichloroethane solution containing 6.8 g of compound 27-2 (CAS: 1899-24-7, 40.0 mmol, 2.0 eq), 10.44 mL of DIPEA (60 mmol, 3.0 eq) and 7 mL of isoamylamine (60 mmol, 3.0 eq) were added. The mixture was purged with argon three times and stirred at room temperature for 2 h. Then, 3.03 g of sodium borohydride (80 mmol, 4.0 eq) was added, and the mixture was purged with argon three times again. The mixture was stirred at room temperature for 4-5 h. After the reaction was complete as monitored by TLC, 50 mL of methanol was added to quench the reaction. The mixture was then concentrated under reduced pressure and purified by rapid silica gel column elution with petroleum ether / ethyl acetate (20:1) to give compound 27-3 (2.5 g, 25.41%). MS (ESI) m / z (M 79 Br+H) + =246.

[0271] Step 2: Synthesis of Compound 27-4

[0272] In a 10 mL sealed tube, 462 mg IntA1-1 (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), 246 mg 27-4 (1.0 mmol, 1.0 eq), 0.5 mL purified water (0.5 mL / mmol), and 5 mL dioxane (5 mL / mmol) were mixed. The mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated C18 reversed-phase column chromatography (25 g C18 silica gel) with a water / methanol ratio of 7:3 to obtain an oily liquid of 27-4 (302 mg, 60.28%), which could be used directly for the next reaction without further purification. MS (ESI) m / z (M+H) + =502.

[0273] Step 3: Synthesis of Compound 27-1

[0274] 50 mg of 10% Pd / C (0.1 m / m) was added 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). The reaction mixture was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) with water / methanol elution of 4:1 to give compound 27-1 as an off-white solid (72 mg, 29.2%). 1 H NMR (400MHz, DMSO-d6) δ7.06 (dd, J=11.1, 2.0Hz, 1H), 7.04-7.01 (m, 1H), 6.97 (d, J=3.4Hz, 1H), 6.56 (d, J=3.3Hz, 1H), 4.05 ( s, 2H), 3.98 (s, 2H), 2.78 (t, J=7.8Hz, 2H), 1.66-1.59 (m, 1H), 1.42 (q, J=7.2Hz, 2H), 0.88 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =412.

[0275] Example 29: Synthesis of Compound 28-1

[0276] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

[0277]

[0278] The synthesis route is as follows:

[0279]

[0280] Step 1: Synthesis of Compound 28-3

[0281] In a 7.5 mL THF solution containing 573 mg of compound 4-2 (3.0 mmol, 1.0 eq), 535 mg of CDI (3.3 mmol, 1.1 eq) and 4.5 mL of ammonia were added. The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, it was directly concentrated under reduced pressure and purified by rapid 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.

[0282] Step 2: Synthesis of Compound 28-4

[0283] In a 10 mL sealed tube, 462 mg IntA1-1 (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), and 5 mL dioxane (5 mL / mmol) were mixed. The mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated C18 reversed-phase column chromatography (25 g C18 silica gel) with water / methanol at a ratio of 7:3 to obtain 28-4 as an oily liquid (280 mg, 62.92%), which could be used directly for the next reaction without further purification. MS (ESI) m / z (M+H) + =446.

[0284] Step 3: Synthesis of Compound 28-1

[0285] 50 mg of 10% Pd / C (0.1 m / m) was added to a suspension of 280 mg of compound 28-4 (0.63 mmol, 1.0 eq) and 483 mg of ammonium formate (7.6 mmol, 12.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol). The reaction mixture was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) with water / methanol elution of 4:1 to give compound 28-1 as an off-white solid (80 mg, 35.77%). 1 H NMR (400MHz, DMSO-d6) δ8.02 (s, 1H), 7.47 (s, 1H), 7.32 (dd, J=11.2, 1.9Hz, 1H), 7.21 (t, J=1.5Hz, 1H), 7.167.09 (m, 2H), 4.00 (s, 2H).MS (ESI) m / z (M+H) + =356.

[0286] Example 30: Synthesis of Compound 29-1

[0287] N-Benzyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

[0288]

[0289] The compound can be prepared using the method described in Example 5, with benzylamine (CAS: 100-46-9) instead of isopentylamine.1 H NMR (400MHz, DMSO-d6) δ9.15 (t, J=6.2Hz, 1H), 7.34 (d, J=5.3Hz, 5H), 7.28-7.22 (m, 2H), 7.20 (d, J=3.6Hz, 1H), 7.12 (d, J=3.6Hz, 1H), 4.48 (d, J=6.1Hz, 2H), 4.00 (s, 2H), MS (ESI) m / z (M+H) + =446.

[0290] Example 31: Synthesis of Compound 30-1

[0291] 5-(2-fluoro-6-hydroxy-4-(5-(isopentyl(methyl)amino)methyl)furan-2-yl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0292]

[0293] The synthesis route is as follows:

[0294]

[0295] Step 1: Synthesis of Compound 30-3

[0296] In a reaction flask containing 492 mg of compound 27-3 (2.0 mmol, 1.0 eq), 2 mL of formic acid, 866 mg of paraformaldehyde, and 750 μL of water (41.6 mmol, 20.8 eq) were added. The mixture was refluxed at 105 °C and stirred overnight. After the reaction was complete as monitored by TLC, the mixture was directly concentrated under reduced pressure and purified by rapid silica gel column elution with petroleum ether / ethyl acetate (20:1) to give compound 30-3 (191 mg, 36.73%). MS (ESI) m / z (M+H) + =261.

[0297] Step 2: Synthesis of Compound 30-4

[0298] In a 10 mL sealed tube, 462 mg IntA1-1 (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), 191 mg 30-3 (0.7 mmol, 0.7 eq), 0.5 mL purified water (0.5 mL / mmol), and 5 mL dioxane (5 mL / mmol) were mixed. The mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated C18 reversed-phase column chromatography (25 g C18 silica gel) with water / methanol at a ratio of 7:3 to give 30-4 as an oily liquid (220 mg, 42.72%). No further purification was required, and it was used directly in the next reaction. MS (ESI) m / z (M+H) + =516.

[0299] Step 3: Synthesis of Compound 30-1

[0300] 50 mg of 10% Pd / C (0.1 m / m) was added 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). The reaction mixture was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) with water / methanol elution of 4:1 to give compound 30-1 as an off-white solid (34 mg, 19.95%). 1 H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 7.11 (dd, J=11.1, 1.9Hz, 1H), 7.07 (t, J=2.7Hz, 2H), 6.84 (d, J=3.4Hz, 1H), 4.47 (d, J=1 4.5Hz, 2H), 3.98 (s, 2H), 3.08 (d, J=29.4Hz, 2H), 2.77 (s, 3H), 1.60 (q, J=7.9Hz, 3H), 0.90 (d, J=5.8Hz, 6H).MS (ESI) m / z (M+H) + =426.

[0301] Example 32: Synthesis of compound 31-1

[0302] 5-(4-(1,1-dioxy-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylfuran-2-carboxylaminoamide

[0303]

[0304] The synthesis route is as follows:

[0305]

[0306] Step 1: Synthesis of Compound 31-3

[0307] Take a 50 mL pre-dried three-necked flask, heat it with an electric heating gun, and purge it with argon five times. Then, inject 688 mg of 31-2 (4.0 mmol, 1.0 eq) dissolved in 10 mL of anhydrous ethanol into the reaction flask using a syringe, and stir in an ice bath. After the internal temperature reaches 5 °C, slowly inject 2.85 mL of acetyl chloride (40 mmol, 10.0 eq) using a syringe. The reaction is exothermic, with the highest temperature reaching 40 °C. After the addition is complete, the internal temperature reaches 25 °C, and the mixture is stirred overnight at room temperature. A large amount of white solid precipitates. After TLC detection confirms the reaction is complete, transfer the reaction solution to a single-necked flask with anhydrous ethanol, and then concentrate it to dryness under reduced pressure. The resulting white and yellow mixed solid is slurried with 10 mL of anhydrous tetrahydrofuran for 1 h, then filtered. The filter cake is washed with 10 mL of anhydrous tetrahydrofuran and dried by forced air to obtain 1.03 g of white solid, which is Pinner salt 31-3, with a crude product yield of 103.89%, and is directly used in the next reaction.

[0308] Step 2: Synthesis of Compound 31-4

[0309] Take a 25 mL single-necked flask, add the white solid 31-3 obtained in the previous step, then add 10 mL of anhydrous ethanol, purge with argon five times, and stir in an ice bath. Then inject 4.2 mL of isoamylamine (36 mmol, 9.0 eq) using a syringe, transfer to room temperature and stir overnight. After the reaction is complete as detected by TLC, concentrate the reaction solution under reduced pressure, add 10 mL of ethyl acetate and stir for 1 h, then filter. Dry the solid by blast drying to obtain 31-4, a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.46 (s, 2H), 7.82 (d, J=3.8Hz, 1H), 6.99 (d, J=3.8Hz, 1H), 3.43-3.36 (m, 2H), 1.65 (dp, J=13.1, 6.6Hz, 1H), 1.551.48 (m, 2H), 0.92 (d, J=6.5Hz, 6H).MS (ESI) m / z (M 79 Br+H) + =259.

[0310] Step 3: Synthesis of Compound 31-5

[0311] The compound was prepared using the method described in Example 5, with 31-4 replacing 4-3. MS(ESI) m / z(M+H)+ =515.

[0312] Step 4: Synthesis of Compound 31-1

[0313] The compound can be prepared by using the method described in Example 5, with 31-5 replacing 4-4. 1 H NMR (400MHz, DMSO-d6) δ7.27 (dd, J=11.3, 1.9Hz, 1H), 7.18 (d, J=1.4Hz, 1H), 7.06 (t, J=5.4Hz, 2H), 6.68 (s, 1H), 5.33 (t, J=4. 6Hz, 1H), 3.98 (s, 2H), 3.22 (s, 2H), 1.68 (dt, J=13.4, 6.5Hz, 1H), 1.50-1.45 (m, 2H), 0.92 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =425.

[0314] Example 33: Synthesis of Compound 32-1

[0315] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentyl-1H-pyrrole-2-carboxamide

[0316]

[0317] The synthesis route is as follows:

[0318]

[0319] Step 1: Synthesis of Compound 32-3

[0320] In a single-necked flask, 654 mg of compound 32-2 (1.0 mmol, 1.0 eq) was added, along with 501 mg of lithium hydroxide monohydrate (6.0 mmol, 3.0 eq), 6.6 mL of methanol (10 mL / g), and 1.32 mL of water (2 mL / g). The mixture was refluxed at 75 °C with stirring overnight. After the reaction was monitored by TLC until complete, 30 mL of purified water was added to quench the reaction. The mixture was then extracted with 30 mL of ethyl acetate and 3 × 30 mL of water. The aqueous phases were combined, and the pH was adjusted to 1 with 6N hydrochloric acid. The mixture was then extracted with 3 × 30 mL of ethyl acetate and the organic phases were combined. The mixture was washed with 3 × 30 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was then filtered, and 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.

[0321] Step 2: Synthesis of Compound 32-4

[0322] In a 5 mL solution of N,N-dimethylformamide containing 380 mg of compound 32-3 (2.0 mmol, 1.0 eq), 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. The mixture was stirred at room temperature for 1 h, followed by the addition of 464 μL of isoamylamine (4.0 mmol, 2.0 eq), and stirring for another 2 h. After the reaction was complete as monitored by TLC, 10 mL of purified water was added to quench the reaction, followed by extraction with 3 × 10 mL of ethyl acetate. The organic phases were combined, washed with 3 × 20 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was then filtered, and the filtrate was concentrated under reduced pressure and purified by rapid silica gel column elution with petroleum ether / ethyl acetate (20:1) to give compound 32-4 as an oil (300 mg, 57.91%). MS (ESI) m / z (M 79 Br+H) + =259.

[0323] Step 3: Synthesis of Compound 32-5

[0324] In a 10 mL sealed tube, 462 mg IntA1-1 (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), and 5 mL dioxane (5 mL / mmol) were mixed. The mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated C18 reversed-phase column chromatography (25 g C18 silica gel) with a water / methanol ratio of 7:3 to give 32-5 as a solid (100 mg, 19.41%). No further purification was required, and it was used directly in the next reaction. MS (ESI) m / z (M+H) + =515.

[0325] Step 4: Synthesis of Compound 32-1

[0326] 10 mg of 10% Pd / C (0.1 m / m) was added to a suspension of 100 mg of compound 32-5 (0.19 mmol, 1.0 eq) and 73 mg of ammonium formate (1.14 mmol, 6.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol). The reaction mixture was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) elution with water / methanol = 4:1 to give compound 35-1 as a white solid (35 mg, 43.3%). 1 H NMR (400MHz, DMSO-d6) δ11.67 (s, 1H), 8.01 (t, J=5.7Hz, 1H), 7.21 (dd, J=11.9, 2.0Hz, 1H), 7.09-7.05 (m, 1H), 6.80 (d, J=3.8Hz, 1H), 6.54 (d, J=4.1H z, 1H), 3.97 (s, 2H), 3.26 (dt, J=7.7, 6.1Hz, 2H), 1.63 (dt, J=13.3, 6.7Hz, 1H), 1.41 (dt, J=8.1, 6.8Hz, 2H), 0.91 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =425.

[0327] Example 34: Synthesis of compound 33-1

[0328] N-(5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-1H-pyrazole-3-yl)-4-methylpentanamide

[0329]

[0330] The compound can be prepared by using the method described in Example 33 and replacing 32-2 with ethyl 5-bromo-1H-pyrazole-3-carboxylate (CAS: 1392208-46-6). 1 H NMR (400MHz, DMSO-d6) δ13.63 (d, J=16.5Hz, 1H), 9.70 (s, 1H), 7.20 (d, J=18.1Hz, 1H), 7.10 (s, 1H), 6.99 (d, J=14 .6Hz, 1H), 3.99 (s, 2H), 3.27 (s, 2H), 1.61 (s, 1H), 1.42 (d, J=7.6Hz, 2H), 0.91 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =426.

[0331] Example 35: Synthesis of Compound 34-1

[0332] N-Cyclohexyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-1H-pyrazole-3-carboxyl 9-ammonia

[0333]

[0334] The compound can be prepared by using the method described in Example 34 and replacing isopentylamine with cyclohexylamine (CAS: 108-91-8). 1 H NMR (400MHz, DMSO-d6) δ13.62 (s, 1H), 9.73 (s, 1H), 8.04 (dd, J=164.5, 7.9Hz, 1H), 7.14 (dd, J=54.0, 29.8Hz, 3H), 4.00 (s, 2H), 3.81-3.70 (m, 1H), 1.83-1.09 (m, 10H), MS (ESI) m / z (M+H) + =438.

[0335] Example 36: Synthesis of Compound 35-1

[0336] N-(2-Cyclopentylethyl)-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-1H-pyrazole-3-carboxamide

[0337]

[0338] The compound can be prepared by using the method described in Example 34 and replacing isopentylamine with cyclopentaneethylamine (CAS: 684221-26-9). 1 H NMR (400MHz, DMSO-d6) δ13.62 (s, 1H), 8.31 (d, J = 120.5Hz, 1H), 7.06 (d, J = 33.7Hz, 3H) , 3.99 (s, 2H), 3.26 (d, J=7.1Hz, 2H), 1.90-1.38 (m, 9H), 1.10 (s, 2H), MS (ESI) m / z (M+H) + =452.

[0339] Example 37: Synthesis of Compound 36-1

[0340] N-Cycloheptyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-1H-pyrazole-3-carboxamide

[0341]

[0342] The compound can be prepared using the method described in Example 34, with cycloheptaneamine (CAS: 5452-35-7) instead of isopentylamine. 1 H NMR (400MHz, DMSO-d6) δ13.61 (s, 1H), 9.47 (s, 1H), 8.14 (s, 1H), 7.11 (s, 3H), 4.01 (s, 2H), 1.95-1.20 (m, 13H), MS (ESI) m / z (M+H) + =452.

[0343] Example 38: Synthesis of Compound 37-1

[0344] N-Cyclooctyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-1H-pyrazole-3-carboxamide

[0345]

[0346] The compound can be prepared using the method described in Example 34, with cyclooctylamine (CAS: 5452-37-9) instead of isopentylamine. 1 H NMR (400MHz, DMSO-d6) δ13.62 (s, 1H), 8.06 (d, J=161.4Hz, 1H), 7.07 (d, J=33.5Hz, 2H), 3.99 (s, 2H), 1.82-1.18 (m, 15H), MS (ESI) m / z (M+H) + =466.

[0347] Example 39: Synthesis of Compound 38-1

[0348] N-Cycloheptyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxamide

[0349]

[0350] The compound can be prepared using the method described in Example 9, with cycloheptaneamine (CAS: 5452-35-7) instead of isopentylamine. 1 H NMR (400MHz, DMSO-d) 6)δ13.29 (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=9.8Hz, 2H), 1.64-1.42 (m, 10H), MS (ESI) m / z (M+H) + =466.

[0351] Example 40: Synthesis of Compound 39-1

[0352] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentyl-1H-imidazol-2-formyl 9-ammonia

[0353]

[0354] The compound can be prepared by using the method described in Example 33 and replacing 32-2 with ethyl 5-bromoimidazole-2-carboxylate (CAS: 944900-49-6). 1 H NMR (400MHz, DMSO-d6) δ8.36 (t, J=6.1Hz, 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=7.3Hz, 2H), 0.91(d, J=6.6Hz, 6H), MS(ESI)m / z(M+H) + =426.

[0355] Example 41: Synthesis of Compound 40-1

[0356] N-Cycloheptyl-4-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolyl-2-yl)-3-fluoro-5-hydroxyphenyl)-1H-imidazol-2-carboxamide

[0357]

[0358] The compound can be prepared using the method described in Example 40, with cycloheptaneamine (CAS: 5452-35-7) instead of isopentylamine. 1 H NMR (400MHz, DMSO-d) 6)δ9.27 (s, 1H), 8.08 (d, J = 8.1Hz, 1H), 7.77 (s, 1H), 7.19 (d, J = 17.3Hz, 2H), 3.9 5(d, J=16.6Hz, 3H), 1.49 (td, J=116.1, 112.0, 49.5Hz, 12H), MS (ESI) m / z (M+H) + =452.

[0359] Example 42: Synthesis of compound 41-1

[0360] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentyl-1H-1,2,4-triazol-3-carboxamide

[0361]

[0362] The compound can be prepared by using the method described in Example 33 and replacing it with methyl 5-bromo-4H-[1,2,4]thiazole-3-carboxylic acid (CAS: 704911-47-7). 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 7.40 (s, 1H), 7.29 (d, J=10.6Hz, 1H), 4.02 (s, 2H), 2.79 (dd, J=9.4, 6.4 Hz, 1H), 1.60 (dp, J=13.4, 6.5Hz, 2H), 1.44 (dt, J=11.2, 5.8Hz, 2H), 0.91 (d, J=6.7Hz, 6H), MS (ESI) m / z (M+H) + =427.

[0363] Example 43: Synthesis of Compound 42-1

[0364] 5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentyl-1-methyl-1H-pyrazole-3-carboxamide

[0365]

[0366] The compound can be prepared by using the method described in Example 33 and replacing it with methyl 1-methyl-5-bromo-3-pyrazolium carboxylate (CAS: 1222174-92-6). 1H NMR (400MHz, DMSO-d6) δ8.14 (t, J=6.0Hz, 1H), 6.95 (dd, J=10.7, 2.0Hz, 1H), 6.86 (t, J=1.6Hz, 1H), 6.74 (s, 1H), 4.02 (s, 2H), 3.92 (s, 3H), 3.25 (dt, J=7.7, 6.2Hz, 2H), 1.58 (dq, J=13.2, 6.6Hz, 1H), 1.40 (q, J=6.8Hz, 2H), 0.89 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =440.

[0367] Example 44: Synthesis of compound 43-1

[0368] 5-(2-fluoro-6-hydroxy-4-(3-(isopentylamino)-1H-pyrazol-5-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0369]

[0370] The synthesis route is as follows:

[0371]

[0372] Step 1: Synthesis of Compound 43-3

[0373] In 5 mL of DCE solution containing 324 mg of compound 43-2 (2.0 mmol, 1.0 eq), 258 μL of isovaleraldehyde, 119 μL of acetic acid, and 848 mg of sodium triacetoxyborohydride were added. The mixture was purged with argon three times and 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. The mixture was concentrated under reduced pressure and purified by rapid silica gel column elution with petroleum ether / ethyl acetate (20:1) to give compound 43-3 (209 mg, 45.20%). MS (ESI) m / z (M 79 Br+H) + =232.

[0374] Step 2: Synthesis of compound 43-4

[0375] In a 10 mL sealed tube, 462 mg IntA1-1 (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), 209 mg 43-3 (0.9 mmol, 0.9 eq), 0.5 mL purified water (0.5 mL / mmol), and 5 mL dioxane (5 mL / mmol) were mixed. The mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated C18 reversed-phase column chromatography (25 g C18 silica gel) with water / methanol at a ratio of 7:3 to give 43-4 as a black solid (182 mg, 37.32%). No further purification was required, and it was used directly in the next reaction. MS (ESI) m / z (M+H) + =488.

[0376] Step 3: Synthesis of Compound 43-1

[0377] A 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 along the side of a flask at -78 °C to maintain the internal temperature below -70 °C. The resulting solution was stirred at -78 °C for 5 minutes, then the cooling bath was removed, and the reaction mixture was allowed to warm naturally to an internal temperature of 0 °C, and then cooled back to -78 °C. The mixture was quenched with 2.6 mL of methanol, and then allowed to warm naturally to room temperature. The solution was concentrated under reduced pressure to form an oil, which was further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) eluting with water / methanol at a ratio of 4:1 to give compound 43-1 as a yellow solid (20 mg, 13.60%). 1 H 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.

[0378] Example 45: Synthesis of Compound 44-1

[0379] N-(5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)-1H-pyrazole-3-yl)-4-methylpentanamide

[0380]

[0381] The synthesis route is as follows:

[0382]

[0383] Step 1: Synthesis of Compound 44-3

[0384] In 8 mL of THF solution containing 323 mg of compound 44-2 (2.0 mmol, 1.0 eq), 546 μL of isohexanoyl chloride was added. 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. The mixture was concentrated under reduced pressure and purified by rapid silica gel column elution with petroleum ether / ethyl acetate (20:1) to give compound 44-3 (220 mg, 42.30%). MS (ESI) m / z (M 79 Br+H) + =260.

[0385] Step 2: Synthesis of compound 44-4

[0386] In a 10 mL sealed tube, 462 mg IntA1-1 (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), 220 mg 44-3 (0.8 mmol, 0.8 eq), 0.5 mL purified water (0.5 mL / mmol), and 5 mL dioxane (5 mL / mmol) were mixed. The mixture was purged with argon five times and stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by automated C18 reversed-phase column chromatography (25 g C18 silica gel) with water / methanol at a ratio of 7:3 to give 44-4 as a black solid (300 mg, 58.36%). No further purification was required, and it was used directly in the next reaction. MS (ESI) m / z (M+H) + =516.

[0387] Step 3: Synthesis of Compound 44-1

[0388] 50 mg of 10% Pd / C (0.1 m / m) was added to a suspension of 300 mg of compound 44-4 (0.58 mmol, 1.0 eq) and 445 mg of ammonium formate (7.0 mmol, 12.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol). The reaction mixture was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) with water / methanol elution of 4:1 to give compound 44-1 as a solid (60 mg, 24.34%). 1 H NMR (400MHz, DMSO-d6) δ12.81 (s, 1H), 10.40 (s, 1H), 9.71 (s, 1H), 7.05 (d, J = 11.0Hz, 1H), 6.92 (d, J = 58.6Hz, 2 H), 3.98 (s, 2H), 2.31 (t, J=7.4Hz, 2H), 1.51 (tt, J=14.2, 6.8Hz, 3H), 0.89 (d, J=6.3Hz, 6H), MS (ESI) m / z (M+H) + =426.

[0389] Example 47: Synthesis of Compound 45-1

[0390]

[0391] Step 1: Synthesis of Compound 45-3

[0392] Take a 50 mL three-necked flask, add 240 mg sodium hydride (6.0 mmol, 1.2 eq) and 10 mL DMF, purge with argon five times, and cool to 0 °C in an ice bath. Take another sample vial, add 1.095 mg 45-2 (5.0 mmol, 1.0 eq) and dissolve in 10 mL DMF. Then slowly inject this solution into the three-necked flask using a syringe, stir in an ice bath for 0.5 h, and then move to room temperature and stir for 1 h. Immediately afterwards, put the three-necked flask back into the ice bath, slowly inject a 5 mL DMF solution of prepared SEM-Cl (1.325 mL, 7.5 mmol, 1.5 eq) using a syringe, stir in an ice bath for 0.5 h, and then move to room temperature and stir for 2 h. After the reaction is complete as monitored by TLC, slowly add 40 mL of purified water to quench the reaction, then add 20 mL of ethyl acetate for extraction. After separation, extract the aqueous phase again with 40 mL of ethyl acetate. Combine the organic phases, wash five times with saturated brine, and dry with anhydrous sodium sulfate. The solution was then filtered, concentrated under reduced pressure, and purified by rapid silica gel column chromatography. The product 45-3 was eluted with 1% ethyl acetate / petroleum ether as a yellow oily substance (1.102 g, 63.10%). 1H NMR (400MHz, DMSO-d6) δ7.11 (s, 1H), 5.71 (s, 2H), 4.32 (q, J=7.1Hz, 2H), 3.58-3. 52 (m, 2H), 1.30 (t, J=7.1Hz, 3H), 0.84-0.76 (m, 2H), -0.07 (s, 10H).MS (ESI) m / z (M 79 Br+H) + =349.

[0393] Step 2: Synthesis of Compound 45-4

[0394] Take a single-necked flask containing 1.102 g of 26-3 (3.15 mmol, 1.0 eq), dissolve it in 16 mL of anhydrous ethanol, then add isoamylamine (3.3 mL, 28.4 mmol, 9.0 eq), and stir overnight at 70 °C. After the reaction is complete as monitored by TLC, concentrate the solution under reduced pressure, add 20 mL of 0.5 N hydrochloric acid aqueous solution, then add 20 mL of ethyl acetate for extraction. After separation, extract the aqueous phase again with 30 mL of ethyl acetate. Combine the organic phases, wash with 3 × 20 mL of 0.5 N hydrochloric acid aqueous solution, then wash 5 times with saturated brine, and dry with anhydrous sodium sulfate. Then filter, concentrate the filtrate under reduced pressure to obtain 1.2 g of brown oily substance, which is 45-3, and use it directly in the next reaction. MS (ESI) m / z (M 79 Br+Na) + =412.

[0395] Step 3: Synthesis of Compound 45-5

[0396] The compound was prepared by using the method described in Example 26, with 45-4 replacing 4-3. MS(ESI)m / z(M 79 Br+H) + =404.

[0397] Step 4: Synthesis of Compound 45-6

[0398] Take a single-necked flask containing 202 mg of 45-5, add 2 mL of DCM to dissolve it, then add 2 mL of TFA, stir at room temperature for 2 h, monitor the reaction for completeness by TLC, and then concentrate the reaction solution under reduced pressure. The resulting oily substance is then purified by rapid silica gel column chromatography. 80 mg of the product was eluted with 20% ethyl acetate / petroleum ether as a colorless oily substance, with a yield of 58.4%.

[0399] Step 5: Synthesis of Compound 45-7

[0400] The compound was prepared using the method described in Example 5, with 45-6 replacing 4-3. MS(ESI) m / z(M+H) + =530.

[0401] Step Six: Synthesis of Compound 45-1

[0402] The compound can be prepared by using the method described in Example 5, with 45-7 replacing 4-4. 1 H NMR (400MHz, DMSO-d6) δ13.62 (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, 6.8Hz, 1H), 1.46 (t, J=7.3Hz, 2H), 1.21-0.86 (m, 6H), MS (ESI) m / z (M+H) + =440.

[0403] Example 47: Synthesis of Compound 46-1

[0404] 5-(2-fluoro-6-hydroxy-4-(6-(isopentylamino)pyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0405]

[0406] Step 1: Synthesis of Compound 46-3

[0407] In a 6 mL DMSO solution containing 205 μL of compound 46-2 (CAS: 766-11-0, 2.0 mmol, 1.0 eq), 817 mg of potassium carbonate (6.0 mmol, 3.0 eq) and 348 μL of isoamylamine (3 mmol, 1.5 eq) were added, and the mixture was stirred at 90 °C for 4 h. After the reaction was complete as monitored by TLC, 10 mL of purified water was added, and the mixture was extracted with 3 × 10 mL of ethyl acetate. The organic phases were combined, washed with 3 × 20 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to give an oil (421 mg, 86.98%). MS (ESI) m / z (M 79 Br+H) + =243.

[0408] Step 2: Synthesis of Compound 46-4

[0409] In a 10 mL sealed tube, mix 462 mg IntA1-1 (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), and 5 mL dioxane (5 mL / mmol). Purify five times with argon and stir overnight at 100 °C. Filter the reaction mixture through diatomaceous earth, concentrate the filtrate under reduced pressure, and purify by automated C18 reversed-phase column chromatography (25 g C18 silica gel), eluting with water / methanol at a 7:3 ratio to obtain 46-4 as an oily liquid (230 mg, 46.18%). No further purification is required; it can be used directly in the next reaction. MS (ESI) m / z (M+H) + =499.

[0410] Step 3: Synthesis of Compound 46-1

[0411] 50 mg of 10% Pd / C (0.1 m / m) was added to a suspension of 230 mg of compound 46-4 (0.46 mmol, 1.0 eq) and 351 mg of ammonium formate (5.52 mmol, 12.0 eq) in 1 mL of methanol (5 mL / mmol) and 1 mL of tetrahydrofuran (5 mL / mmol). The reaction mixture was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) with water / methanol elution of 4:1 to give compound 46-1 as a white solid (50 mg, 26.6%). 1 H NMR (400MHz, DMSO-d6) δ9.75 (s, 1H), 8.16 (s, 1H), 7.02 (d, J = 11.3Hz, 1H), 6.92 (s, 2H), 4.02 (d, J = 2.5Hz, 2H ), 1.69 (dt, J=13.4, 6.7Hz, 1H), 1.49 (q, J=7.2Hz, 2H), 1.23 (s, 2H), 0.92 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =409.

[0412] Example 48: Synthesis of Compound 47-1

[0413] 5-(4-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0414]

[0415] The compound can be prepared by using the method described in Example 47 and replacing isopentylamine with 4,4-difluoropiperidine (CAS: 144230-52-4). 1 H NMR (400MHz, DMSO-d6) δ9.57 (s, 1H), 8.43 (d, J=2.6Hz, 1H), 7.84 (dd, J=8.9, 2.6Hz, 1H), 7.12-6 .85 (m, 3H), 3.99 (s, 2H), 3.75 (t, J=5.7Hz, 4H), 2.00 (tt, J=13.7, 5.5Hz, 4H), MS (ESI) m / z (M+H) + =443.

[0416] Example 49: Synthesis of Compound 48-1

[0417] 5-(4-(6-(cycloheptylamino)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0418]

[0419] The compound can be prepared using the method described in Example 47, with cycloheptaneamine (CAS: 5452-35-7) instead of isopentylamine. 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 8.25 (d, J=2.5Hz, 1H), 7.63 (dd, J=8.8, 2.6Hz, 1H), 6.92-6.83 (m, 2H), 6.71 (d, J =7.9Hz, 1H), 6.52 (d, J = 8.8Hz, 1H), 3.97 (s, 2H), 1.90 (dt, J = 10.5, 4.5Hz, 2H), 1.66-1.45 (m, 11H), MS (ESI) m / z (M+H) + =435.

[0420] Example 50: Synthesis of Compound 49-1

[0421] 5-(4-(6-(cyclooctylamino)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0422]

[0423] The compound can be prepared using the method described in Example 47, with cyclooctylamine (CAS: 5452-37-9) instead of isopentylamine. 1H NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 8.25 (d, J=2.6Hz, 1H), 7.62 (dd, J=8.8, 2.6Hz, 1H), 6.97-6.83 (m , 2H), 6.67 (d, J=7.9Hz, 1H), 6.51 (d, J=8.8Hz, 1H), 3.97 (s, 2H), 1.85-1.44 (m, 15H), MS (ESI) m / z (M+H) + =449.

[0424] Example 51: Synthesis of Compound 50-1

[0425] 5-(4-(6-(cyclohexylamino)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0426]

[0427] The compound can be prepared by using the method described in Example 47 and replacing isopentylamine with cyclohexylamine (CAS: 108-91-8). 1 H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 8.25 (d, J=2.6Hz, 1H), 7.62 (dd, J=8.8, 2.6Hz, 1H), 6.906.83 (m, 2H), 6.62 (d, J=7.8Hz, 1H), 6.51 (d, J=8.8Hz, 1H), 3.97 (s, 2H), 1.92 (dd, J=12.7, 4.3Hz, 2H), 1.76-1.70 (m, 2H), 1.60 (d, J=12.4Hz, 1H), 1.36-1.13 (m, 6H), MS (ESI) m / z (M+H) + =421.

[0428] Example 52: Synthesis of Compound 51-1

[0429] 5-(2-fluoro-6-hydroxy-4-(6-(isopentylamino)-5-methylpyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0430]

[0431] The 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 (400MHz, DMSO-d6) δ9.76 (s, 1H), 8.02 (d, J = 13.2Hz, 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, 7.2Hz, 1H), 1.54 (d, J=7.3Hz, 2H), 0.94 (d, J=6.6Hz, 6H).

[0432] Example 53: Synthesis of Compound 52-1

[0433] 5-(4-(6-(cyclohexylamino)-5-methylpyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0434]

[0435] The compound can be prepared by using the method described in Example 47, with cyclohexylamine (CAS: 108-91-8) instead of isopentylamine and 2-fluoro-3-methyl-5-bromopyridine (CAS: 29312-98-9) instead of 46-2. 1 H NMR (400MHz, DMSO-d6) δ8.07 (d, J=2.4Hz, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 6.36 (s, 1H), 5.47 (d, J=7.7Hz, 1H), 4 .06 (s, 2H), 3.92 (d, J=9.3Hz, 1H), 2.07 (s, 3H), 1.54 (d, J=2.2Hz, 8H), 1.30 (d, J=9.0Hz, 2H), MS (ESI) m / z (M+H) + =435.

[0436] Example 54: Synthesis of Compound 53-1

[0437] 5-(2-fluoro-6-hydroxy-4-(2-(isopentylamino)pyrimidin-5-yl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0438]

[0439] The 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 (400MHz, DMSO-d6) δ10.44 (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 .8Hz, 2H), 1.63 (dq, J=13.3, 6.7Hz, 1H), 1.44 (dt, J=8.7, 6.9Hz, 2H), 0.90 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =410.

[0440] Example 55: Synthesis of Compound 54-1

[0441] 5-(2-fluoro-6-hydroxy-4-(6-(isopentylamino)-2-methylpyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0442]

[0443] The compound can be prepared using the method described in Example 47, with 5-bromo-2-fluoro-6-methylpyridine (CAS: 375368-83-5) as a substitute. 1 H NMR (400MHz, DMSO-d6) δ9.89 (s, 1H), 7.77 (d, J = 9.1Hz, 1H), 6.92 (d, J = 9.0Hz, 1H), 6.76 (dd, J = 10.7, 2.0Hz, 1H), 6.68 (d, J = 1.8Hz, 1 H), 4.06 (q, J=2.6Hz, 2H), 2.45 (s, 3H), 1.69 (dt, J=13.4, 6.7Hz, 1H), 1.51 (q, J=7.1Hz, 2H), 0.95 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =423.

[0444] Example 56: Synthesis of Compound 55-1

[0445] 5-(3,3′-difluoro-5-hydroxy-4′-(isopentylamino)-[1,1′-biphenyl]-4-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0446]

[0447] Step 1: Synthesis of Compound 55-3

[0448] In 5 mL of DCE solution containing 380 mg of compound 55-2 (CAS: 367-24-8, 2.0 mmol, 1.0 eq), 119 μL of acetic acid (2.08 mmol, 1.04 eq), 258 μL of isovaleraldehyde (2.4 mmol, 1.2 eq), and 848 mg of sodium triacetoxyborohydride (4 mmol, 2 eq) were added. The mixture was purged three times with argon gas and stirred at room temperature for 4 h. After the reaction was complete as monitored by TLC, 10 mL of methanol was added to quench the reaction, followed by direct concentration under reduced pressure. Purification was achieved by rapid silica gel column elution with petroleum ether / ethyl acetate (20:1) to give compound 55-3 (208 mg, 40.07%). MS (ESI) m / z (M+H) + =262.

[0449] Step 2: Synthesis of Compound 55-4

[0450] In a 10 mL sealed tube, mix 462 mg IntA1-1 (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), 208 mg 55-3 (0.8 mmol, 0.9 eq), 0.5 mL purified water (0.5 mL / mmol), and 5 mL dioxane (5 mL / mmol). Purify five times with argon and stir overnight at 100 °C. Filter the reaction mixture through diatomaceous earth, concentrate the filtrate under reduced pressure, and purify by automated C18 reversed-phase column chromatography (25 g C18 silica gel), eluting with water / methanol at a 7:3 ratio to obtain 55-4 as an oily liquid (280 mg, 54.16%). No further purification is required; it can be used directly in the next reaction. MS (ESI) m / z (M+H) + =517.

[0451] Step 3: Synthesis of Compound 55-1

[0452] 50 mg of 10% Pd / C (0.1 m / m) was added to 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). The reaction mixture was refluxed at 65 °C for 2 h. The filtrate was concentrated under reduced pressure and further purified by C18 reversed-phase column chromatography (10 g, C18 silica gel) with water / methanol elution of 4:1 to give compound 55-1 as a yellow solid (52 mg, 21.74%). 1H NMR (400MHz, DMSO-d6) δ9.76 (s, 1H), 7.04 (d, J = 51.1Hz, 2H), 6.85 (s, 1H), 6.60 (d, J = 2.2Hz, 1H), 6.45 (s, 1H), 3.96 (s, 2H), 3. 11 (t, J=7.4Hz, 2H), 2.21 (s, 3H), 1.71 (dq, J=13.3, 6.7Hz, 1H), 1.51 (q, J=7.2Hz, 2H), 0.94 (d, J=6.6Hz, 6H), MS (ESI) m / z (M+H) + =426.

[0453] Example 57: Synthesis of Compound 56-1

[0454] 5-(2-fluoro-6-hydroxy-4-(3-(isopentylamino)azayn-1-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0455]

[0456] The synthesis route is as follows:

[0457]

[0458] Step 1: Synthesis of intermediate 56-3

[0459] In a 50 mL single-necked flask, 415 mg IntA1-7 (1.0 mmol, 1.0 eq), 29 mg 56-23-N-tert-butoxycarbonylaminocyclobutylamine (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), and 92 mg Pd2(DBA)3 (0.1 mmol, 0.1 eq) were mixed and 10 mL Dioxane (10 mL / mmol) was added. After purging with argon five times, the mixture was stirred at 80 °C for 12 h. After the reaction was monitored by LC-MS to be complete, the mixture was cooled to room temperature, filtered with diatomaceous earth as a filter aid, and the filtrate was prepared into sand and subjected to fully automated column chromatography. Elution with 10% MeOH / DCM yielded 380 mg 56-3, with a yield of 75.10%. MS (ESI) m / z (M-Boc+H) + =407.

[0460] Steps two through four: Synthesis of 56-1

[0461] Take a single-necked flask containing 380 mg 56-3 (0.75 mmol, 1.0 eq), add 286 mg ammonium formate (4.50 mmol, 6.0 eq), 3.75 mL methanol, 3.75 mL tetrahydrofuran, and then add 190 mg 10% Pd / C. Reflux in an oil bath at 65 °C with stirring for 4 h. After the reaction is complete as monitored by TLC, filter the solution. Concentrate the filtrate to dryness under reduced pressure, then dissolve it in 7.5 mL DCM. Next, add 1.9 mL trifluoroacetic acid, stir at room temperature for 30 min, and after the reaction is complete as monitored by TLC, concentrate to dryness under reduced pressure. Add 2 × 10 mL toluene and 2 × 10 mL DCM to remove the residue. Then, redissolve the residue in 8 mL DCM, adjust the pH to 8 with DIPEA, and then add 162 μL isovaleraldehyde (1.5 mmol, 2.0 eq). Purge with argon five times and stir at room temperature for 1 h. Subsequently, 141 mg of sodium cyanoborohydride (2.25 mmol, 3.0 eq) was added, followed by purging with argon five times and stirring at room temperature. After the reaction was monitored by LC-MS, 10 mL of methanol was added to quench the reaction, and the product was concentrated under reduced pressure to obtain sintered sand and purified by reverse-phase C18 column. The product was eluted with 40% MeOH / H2O as a white solid, yielding 40 mg. The three-step yield was 13.80%. 1 H NMR (400MHz, DMSO-d6) δ5.72 (dd, J=12.3, 2.5Hz, 1H), 5.705.64 (m, 1H), 3.93 (t, J=7.2Hz, 2H), 3.83 (s, 2H), 1. 99 (q, J=7.0, 6.5Hz, 2H), 1.64-1.57 (m, 1H), 1.52-1.34 (m, 2H), 0.84 (d, J=6.6Hz, 6H). MS (ESI) m / z (MH)-= 385.

[0462] Example 58: Synthesis of Compound 57-1

[0463] (R)-5-(2-fluoro-6-hydroxy-4-(3-(isopentylamino)pyrrolidin-1-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0464]

[0465] The compound can be prepared by using the method described in Example 57 and replacing 56-2 with (R)-3-tert-butoxycarbonylaminopyrrolidine (CAS: 122536-77-0). 1H NMR (400MHz, DMSO-d6) δ8.96 (s, 1H), 8.59 (s, 2H), 5.97 (d, J=13.3Hz, 1H), 5.89 (s, 1H), 3.89 (d, J=20.5Hz, 3H), 3.65-3.49 (m, 2H), 3.26-3.11 (m, 2H ), 2.99 (t, J = 8.0Hz, 2H), 2.24 (dt, J = 89.1, 9.7Hz, 2H), 1.65 (p, J = 6.9Hz, 1H), 1.48 (q, J = 7.6Hz, 2H), 0.91 (d, J = 6.5Hz, 6H). MS (ESI) m / z (MH) - = 399.

[0466] Example 59: Synthesis of Compound 58-1

[0467] 3-(4-(1,1-dioxy-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylpyrazolo[1,5-a]pyridine-5-carboxamide

[0468]

[0469] 58-1 can be prepared by replacing 4-2 with 3-bromopyrazole[1,5-A]pyridine-5-carboxylic acid (CAS: 876379-79-2) according to the synthesis method of Example 5. 1 H NMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 7.98 (t, J=5.6Hz, 1H), 7.72 (s, 1H), 6 .76 (d, J=10.8Hz, 2H), 4.264.18 (m, 1H), 4.03 (dt, J=11.9, 6.0Hz, 1H), 3.97 (s, 2H), 3.262.86 (m, 5H), 2.67 (s, 1H), 2.182.01 (m, 2H), 1.58 (dt, J=13.4, 6.7Hz, 1H), 1.32 (q, J=7.2Hz, 2H), 0.87 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =480.

[0470] Example 60: Synthesis of Compound 59-1

[0471] 3-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide

[0472]

[0473] Partial synthetic routes are as follows:

[0474]

[0475] Step 1: Synthesis of intermediate 59-3

[0476] Take a 250 mL single-necked flask, add 840 mg of pyrazolo[1,5-a]pyridine-2-carboxylic acid (CAS: 63237-88-7, 5 mmol, 1.0 eq), 980 mg of NBS (5.5 mmol, 1.1 eq), and 50 mL of DMF (10 mL / mmol). Stir at room temperature for 4 h, then extract with water and ethyl acetate. Retain the ethyl acetate layer, wash three times with saturated NaCl solution, and evaporate to dryness to obtain 923 mg of 94-3 yellow solid. MS (ESI) m / z (M 79 Br+H) + =245.

[0477] Steps two to four: Synthesis of 59-1

[0478] The compound can be prepared by using the method described in Example 5 and replacing compound 4-2 with 59-3. 1 H NMR (400MHz, DMSO-d6) δ6.65 (d, J=11.1Hz, 2H), 4.12 (t, J=6.1Hz, 2H), 3.97 (s, 2H), 3.19 (q, J=6.6Hz, 2H), 2.74 (t, J=6.3Hz, 2H), 2.00 (d, J=3.5Hz, 2H), 1.78 (s, 2H), 1.56 (dt, J=13.4, 6.7Hz, 1H), 1.36 (q, J=7.1Hz, 2H), 0.87 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =480

[0479] Example 61: Synthesis of Compound 60-1

[0480] 5-(2-fluoro-6-hydroxy-4-(2-(isopentylamino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0481]

[0482] Partial synthetic routes are as follows:

[0483]

[0484] Step 1: Synthesis of Intermediate 60-3

[0485] Take a 50 mL three-necked flask, add 735 mg 59-3 (3.0 mmol, 1.0 eq), 970 μL DPPA (1.4 mmol, 1.5 eq), 1 mL TEA (7.2 mmol, 2.4 eq), and 12 mL THF (4 mL / mmol), purge with argon five times, stir at room temperature for 4 h, then add 735 μL water (5 mL / g), reflux at 60 °C and stir for 4 h, then perform automated column chromatography, eluting with 25% petroleum ether / ethyl acetate, and concentrate under reduced pressure to obtain 60-3. MS (ESI) m / z (M 79 Br+H) + =216.

[0486] Step 2: Synthesis of intermediate 60-4

[0487] Take a 25 mL single-necked flask and add 310 mg 60-3 (1.43 mmol, 1.0 eq), 162 μL isovaleraldehyde (1.5 mmol, 1.05 eq), 85 μL acetic acid (1.5 mmol, 1.04 eq), and 455 mg sodium triacetoxyborohydride (2.14 mmol, 1.5 eq) to 4.65 mL of LDCE (15 mL / g). Stir at room temperature for 4 h, then perform automated column chromatography, eluting with 10% petroleum ether / ethyl acetate. Concentrate under reduced pressure to obtain 60-4. MS (ESI) m / z (M 79 Br+H) + =286.

[0488] Steps three and four: Synthesis of 60-1

[0489] Compound 60-1 can be prepared by using the method described in Example 5 and replacing compound 4-4 with 60-4. 1 HNMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 6.70-6.58 (m, 2H), 3.95 (s, 2H), 3.85 (t, J=6.1Hz, 2H), 2.69 (t, J=6.2Hz, 2H), 1.92 (td, J=7.9, 6.9, 4.2Hz , 2H), 1.70 (q, J=5.8Hz, 2H), 1.62 (dq, J=13.3, 6.7Hz, 1H), 1.44 (q, J=7.0Hz, 2H), 1.15 (d, J=6.7Hz, 2H), 0.88 (d, J=6.6Hz, 6H).MS (ESI) m / z (M+H) + =452.

[0490] Example 62: Synthesis of compound 61-1

[0491] 5-(3-fluoro-5-hydroxy-4′-(isopentamineamino)-2′,5′-dimethyl-[1,1′-biphenyl]-4-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0492]

[0493] Compound 61-1 can be prepared by 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 (400MHz, DMSO-d6) δ9.76 (s, 1H), 7.04 (d, J=51.1Hz, 2H), 6.85 (s, 1H), 6.60 (d, J=2.2Hz, 1H), 6.45 (s, 1H), 4.15 (s, 2H), 3.11 (t, J =7.4Hz, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 1.70 (dt, J = 13.3, 6.7Hz, 1H), 1.51 (q, J = 7.2Hz, 2H), 0.94 (d, J = 6.6Hz, 6H).MS (ESI) m / z (M+H) + =436.

[0494] II. Biological Evaluation

[0495] (1). PTPN2 / PTPN1 enzyme activity assay method

[0496] Compound activity was determined in vitro using unlabeled full-length human PTPN2 / PTPN1 protein via an enzymatic method. The PTPN2 / PTPN1 enzyme was diluted to a final concentration of 0.5 nM in experimental buffer (50 mM HEPES, pH 7.2, 100 mM NaCl, 1 mM EDTA, 0.005% Tween-20, and 5 mM TCEP) and added to black 384-well plates (Greiner, 781900). Compounds were then added using a Tecan D300e dispenser. After incubation at room temperature for 10 minutes, DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 5 μM. After incubation at room temperature for 30 minutes, the plates were transferred to a SpectraMax plate reader (Molecular Devices) to measure fluorescence intensity (ex 358, em 455). Each plate included a 100% inhibition control (enzyme-free) and a 0% inhibition control (DMSO), from which the percentage inhibition of the tested compound was calculated. IC50 was determined from % inhibition rate data using four-parameter curve fitting. 50 value.

[0497] IC obtained 50The values ​​are shown in Table 1. A represents compounds with activity below 10 nM, B represents compounds with activity between 10 and 100 nM, C represents compounds with activity between 100 nM and 1 μM, and D represents compounds with activity above 1 μM.

[0498] Table 1 IC50 values ​​of the compounds in the examples against PTPN1 / PTPN2 phosphatases 50 Measured values

[0499]

[0500] (2). Rat pharmacokinetic tests of some compounds of the present invention

[0501] Experimental methods: Compounds 4-1, 40-1, and 51-1 were administered intravenously at 1 mg / kg and orally at 10 mg / kg, respectively. Rat plasma was collected at specified time points. An LC-MS / MS method was established to determine the concentrations of compounds 501-43 and 502-74 in rat plasma. Plasma drug concentration-time curves were plotted using Graphpad Prism software, and pharmacokinetic parameters were calculated using WinNonlin software. The pharmacokinetic parameters of the compounds of this invention are as follows:

[0502] Table 2 Results of pharmacokinetic assays of the compounds in rats

[0503] Example number <![CDATA[AUC o-t (mg / mL)]]> F(％) 4-1 293.01±1.11 2.36 40-1 230.51±162.82 9.20 51-1 133.44±66.59 6.06

[0504] As shown in Table 2, introducing basic groups into the molecule to neutralize nitrogen atoms and increasing the proportion of SP3 carbon atoms can significantly improve the bioavailability of the compounds. Among them, the imidazole derivative 40-1 has better AUC and bioavailability.

Claims

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

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

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