WO2025218831A2 - Thiadiazolidinone derivative with ptpn2/ptpn1 inhibitory activity, and preparation method therefor and use thereof - Google Patents

Abstract

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

Description

Thiadiazolidinone derivatives with PTPN2/PTPN1 inhibitory activity and preparation methods and applications thereof Technical Field

The present invention belongs to the field of medicinal chemistry and relates to thiadiazolidinone derivatives, specifically to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a drug combination thereof, and use thereof in treating PTPN1/PTPN2-mediated diseases.

Background Art

Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (such as PD-1/PD-L1 and CTLA-4 blocking antibodies), have been shown to be effective in treating a variety of cancers, significantly improving the treatment outcomes for patients with poor prognosis after conventional therapy. However, suboptimal clinical responses and the development of intrinsic or acquired resistance continue to limit the further development of this therapy.

Protein phosphorylation is a universal, reversible post-translational modification that can adapt to a variety of cellular regulatory mechanisms (Chrestia JF. et al., Pharmacol Res 190:106712; 2023). Protein phosphokinase catalyzes phosphorylation by adding phosphate groups to amino acid residues to disrupt existing electrostatic interactions. Reversibly, dephosphorylation is the hydrolysis of phosphoamino acids catalyzed by phosphatases. An abnormal balance between phosphorylation and dephosphorylation can disrupt many cellular regulatory mechanisms that regulate cell growth, metabolism, differentiation, and communication (Netto LES. et al., FEBS J 289(18):5480-504; 2022).

Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases. It controls a variety of cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is elevated in hematopoietic and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503; 1992). PTPN2 regulates signal transduction by 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 modulates signaling through cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 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).

Data from an in vivo loss-of-function genetic screen using CRISPR/Cas9 genome editing technology in a mouse B16F10 xenograft tumor model demonstrated that PTPN2 gene deletion in tumor cells enhanced response to immunotherapy with a GM-CSF-secreting vaccine (GVAX) plus PD-1 checkpoint blockade (Manguso R.T. et al., Nature 547:413-418; 2017). PTPN2 deletion sensitized tumors to immunotherapy by enhancing IFNγ-mediated antigen presentation and growth inhibition. The same screen also revealed that genes involved in immune evasion, including PD-L1 and CD47, were depleted in response to immunotherapy, while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. In recent years, increasing studies have demonstrated the oncogenic role of PTPN2. In pancreatic cancer, PTPN2 protein is specifically overexpressed and regulates tumor cell growth (Kuang W. et al., 13:805-311; 2022). These findings suggest that therapeutic strategies to enhance IFNγ sensing and signaling may play an important role in improving the efficacy of cancer immunotherapy regimens.

Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase 1B (PTP1B), plays a key role in insulin and leptin receptor signaling and is a key protein in downregulating insulin and leptin receptor signaling (Kenner K.A. et al., J Biol Chem 271:19810-19816; 1996). Animals lacking PTPN1 have improved glucose regulation and lipid profiles and are resistant to weight gain when fed a high-fat diet (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

Purpose of the invention: The technical problem to be solved by the present invention is to develop small molecule inhibitors with PTPN2/PTPN1 inhibitory activity based on thiadiazolidinone as the parent core; the technical problem to be solved by the present invention is to provide the use of the above-mentioned thiadiazolidinone derivatives in drugs for the treatment of PTPN2/PTPN1-mediated diseases.

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

in:

Ring A is an aromatic ring or an aromatic heterocyclic ring, independently and arbitrarily substituted by one or more R ² ;

^R1 is selected from hydrogen, halogen, _C1-6 alkyl, _C3-8 cycloalkyl, adamantyl and:

in:

m = 0-5;

n = 1-3;

o=1-3;

^R3 is independently selected from CH and N;

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

When R ⁴ ═N or CH, R ⁵ is independently selected from hydrogen, oxo, C _1-6 alkyl-S(═O) ₂ —, C _1-6 alkyl-NH-C(═O)-, C _3- C ₆ cycloalkyl-C(═O)-, C _3-6 cycloalkyl-S(═O) ₂ —, C _3-6 heterocycloalkyl-C(═O)-, and C _3-6 heterocycloalkyl-S(═O) ₂ —;

R ² is independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy;

R ⁶ is independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl;

R ¹⁰ is independently selected from C and N; when R ¹⁰ is N, R ⁷ is absent, and R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl;

When R ¹⁰ is C, R ⁷ , R ⁸ , and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl, and C _3-6 cycloalkyl;

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

p=0-3.

The compound or a pharmaceutically acceptable salt thereof:

Ring A is an aromatic ring or an aromatic heterocycle, independently and arbitrarily substituted by one or more ^R2 ; the aromatic ring is a substituted or unsubstituted phenyl group, wherein the substitution is a _C1-4 haloalkyl group; the aromatic heterocycle is a substituted or unsubstituted 5- to 6-membered aromatic heterocycle containing one or two atoms of S, O, and N, wherein the substitution is a _C1-4 alkyl group;

^R1 is selected from hydrogen, halogen, _C1-6 alkyl, _C3-8 cycloalkyl, adamantyl and:

in:

m = 0, 1, 2, 3, 4 or 5;

n = 1, 2, or 3;

o = 1, 2, or 3;

^R3 is independently selected from CH and N;

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

When R ⁴ ═N or CH, R ⁵ is independently selected from hydrogen, C _1-6 alkyl-S(═O) ₂ —, C _1-6 alkyl-NH-C(═O)-, C _3-6 cycloalkyl-C(═O)-, C _3-6 cycloalkyl-S(═O) ₂ —, C _3-6 heterocycloalkyl-C(═O)-, and C _3-6 heterocycloalkyl-S(═O) ₂ —;

R ² is independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy;

R ⁶ is independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl;

R ¹⁰ is independently selected from C and N; when R ¹⁰ is N, R ⁷ is absent, R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl; when R ¹⁰ is C, R ⁷ , R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl;

L is selected from ^-NRa- , _-CH2- , -CH2 _- ^NRb- , -S(=O) _2- , -C(=O) ^NRc- , -C(=NH)NRd-, -NRcC(= _O )-, -S(=O) ^{2NRe- , -NReS} ( ⁼ O) _2- , or -C(=O)-;

R ^a , R ^b , R ^c , R ^d , and R ^e are each independently selected from hydrogen, C _1-6 alkyl, and C _3-6 cycloalkyl;

p=0, 1, 2 or 3.

The compound or a pharmaceutically acceptable salt thereof:

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

in:

U＝CH or N;

V＝CH or N;

W＝NH, O or S;

X＝CH or N;

Y＝CH or N;

h = 0, 1, 2, or 3;

i = 0, 1, 2, or 3;

Z, Z', are independently selected from N and CH;

R ² is independently selected from hydrogen, halogen, trifluoromethyl, C _1-6 alkyl;

^R1 is selected from hydrogen, halogen, _C1-6 alkyl, _C3-8 cycloalkyl, adamantyl and:

in:

m = 0, 1, 2, or 3;

n = 1, 2, or 3;

o = 1, 2, or 3;

q = 0, 1, 2, or 3;

^R3 is independently selected from CH and N;

R ⁴ is independently selected from C, CH, N and O, and when R ⁴ ＝O, p＝0, that is, R ⁵ does not exist;

When R ⁴ =N or CH, t=1, R ⁵ is independently selected from hydrogen, C _1-6 alkyl-S(=O) ₂ -, C _3-6 cycloalkyl-C(=O)-, C _3-6 cycloalkyl-S(=O) ₂ - and C _3-6 heterocycloalkyl-C(=O)-; when R ⁴ =C, t=1-2, R ⁵ is independently selected from halogen, oxo and C _1-6 alkyl;

R ² is independently selected from hydrogen, halogen, hydroxy, C _1-6 alkyl, C _3-6 cycloalkyl, trifluoromethyl;

R ⁶ is independently selected from hydrogen, halogen, hydroxy, cyano and C _1-6 alkyl;

R ¹⁰ is independently selected from C and N; when R ¹⁰ is N, R ⁷ is absent, R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl; when R ¹⁰ is C, R ⁷ , R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, C _1-6 alkyl and C _3-6 cycloalkyl;

L is selected from ^-NRa- , _-CH2- , -CH2 _- ^NRb- , -S(=O) _2- , -C(=O) ^NRc- , -C(=NH)NRd-, -NRcC(= _O )-, -S(=O) ^{2NRe- , -NReS} ( ⁼ O) _2- , or -C(=O)-;

R ^a , R ^b , R ^c , R ^d , and R ^e are each independently selected from hydrogen, C _1-3 alkyl, and C _3-6 cycloalkyl;

p=0, 1, 2 or 3.

The compound or a pharmaceutically acceptable salt thereof:

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

in:

U＝CH or N;

V＝CH or N;

W＝NH, O or S;

Z, Z' are independently selected from N and CH;

h = 1-2;

i=1-2;

R ¹ is selected from hydrogen, (CH ₃ ) ₂ -CH-(CH ₂ ) _0-4 -,

The compound or a pharmaceutically acceptable salt thereof:

Ring A is:

^R1 is: hydrogen,

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

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

When L is -NHC(=O)-,

A, R ¹ , h, and i are as defined above.

Preparation method of the compound represented by general formula (V):

wherein A and ^R1 are as defined above.

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

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

Unless otherwise specified, the terms in this invention generally have the following meanings:

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

The term "C _1-6 alkyl" refers to saturated straight and branched hydrocarbon groups having 3 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

The term " _C3-6 heterocycloalkyl" refers to a saturated cycloalkyl group having one or more non-C heteroatoms such as N, O, S and 3-6 carbon atoms, including but not limited to aziridine, azetidinyl, azepentyl, azetidinyl, oxetanyl, etc.

The term "aromatic ring" refers to a ring system having aromaticity, including but not limited to benzene ring, pyrazole, thiophene, furan, thiazole and the like.

The term "adamantyl" refers to

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

The term "partially saturated aromatic heterocycle" refers to an aromatic heterocycle in which a portion of double bonds are saturated with hydrogen atoms, including dihydropyrrole, tetrahydrobenzopyrazole and the like.

The term "saturated heterocycle" refers to a ring that is fully saturated and contains heteroatoms, including tetrahydropyrrole, acridine, and the like.

The term "heterocycloalkyl" refers to a cycloalkane having one or more non-C heteroatoms such as N, O, S, and includes but is not limited to tetrahydropyrrole, piperidine, morpholine, piperazine, pyrazine, N-methylpiperazine, N-ethylpiperazine, and the like.

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

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

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

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

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

The term "-NHC(=O)-" represents a carbamoyl group.

The term "-NH-" represents an imino group.

The term " _-CH2- " represents a methylene group.

Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the compounds disclosed in the present invention have significant activity against PTPN2/PTPN1 phosphatase, and the _IC50 value of the synthesized compounds remains at the nanomolar level. They can be used to have a significant impact on the occurrence and development of tumors and immune responses, and can also be used in combination with immunosuppressants to treat related immune diseases. They can be developed into anti-tumor drugs with high activity, good selectivity, and low toxic and side effects. They have the characteristics of novel skeleton, strong plasticity, and great potential for future transformation.

DETAILED DESCRIPTION

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

Example 1: Synthesis of Intermediate A1-1

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

The synthetic route is as follows:

Step 1: Synthesis of intermediate A1-3

To a 2L three-necked flask, add 5.04g of sodium hydride (126mmol, 1.2eq) and 420mL of tetrahydrofuran (4mL/mmol). A constant-pressure dropping funnel was installed on the flask, the atmosphere was replaced with argon three times, and the mixture was stirred in an ice bath. Then, a solution of 25g of intermediate A1-2 (CAS: 147808-42-2, 105mmol, 1.0eq) in 420mL of tetrahydrofuran (5mL/mmol) was slowly added via the funnel, maintaining the internal temperature below 5°C. After the addition was complete, 13.10mL (126mmol, 1.2eq) of benzyl alcohol was slowly added to the solution via syringe, maintaining the internal temperature below 10°C. After completion of the reaction as monitored by TLC, the solution was brought to room temperature and stirred for an additional 2.5h. The reaction was then quenched by the addition of 1L of purified water and extracted with 3×500mL of ethyl acetate. The combined organic layers were washed with 3 × 600 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to yield 38.19 g of a red gum, A1-2, which was used directly in the next step without further purification. A small portion of the product was purified for analysis. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.65 (t, J = 1.8 Hz, 1H), 7.61 (dd, J = 9.4, 1.8 Hz, 1H), 7.44–7.35 (m, 5H), 5.37 (s, 2H).

Step 2: Synthesis of Intermediate A1-4

To 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). Replace the atmosphere with argon three times and stir at room temperature overnight. After completion of the reaction, monitor by TLC, filter through Celite, concentrate the filtrate under reduced pressure, and extract with 1L of purified water and 3x300mL of ethyl acetate. Combine the organic phases, wash with 3x400mL of saturated brine, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, redissolve it in 500mL of ethyl acetate, stir in an ice bath, and add 105mL of 2.0M hydrogen chloride in ethyl acetate (2.0eq). The suspension was stirred in an ice bath for an additional 2 hours, then filtered, washed with 3×50 mL of glacial ethyl acetate, and dried in a forced air oven to yield Intermediate A1-4 as a gray hydrochloride salt (31.46 g, 90.03% yield of Intermediate A1-4 over two steps). A small portion of the product was neutralized and purified for analysis: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50 (d, J = 6.7 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.36–7.31 (m, 1H), 6.99–6.95 (m, 2H), 5.17 (s, 2H), 4.85 (s, 2H). MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 296.

Step 3: Synthesis of intermediate A1-5

31.46 g of Intermediate A1-4 (hydrochloride salt, 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 TLC indicated near-completion of the reaction, the reaction was quenched with 500 mL of purified water and extracted with 3 × 300 mL of ethyl acetate. The combined organic phases were washed with 3 × 400 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and purified on a silica gel column with petroleum ether/ethyl acetate = 20:1 to yield Intermediate A1-5 (23.692 g, 68.04%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )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.

Step 4: Synthesis of intermediate A1-6

A solution of 23.692 g of Intermediate A1-5 (64.34 mmol, 1.0 eq) and 74.334 g of aminosulfonyl chloride (643 mmol, 10.0 eq) in 129 mL of acetonitrile (2 mL/mmol) was replaced with argon three times and stirred in an ice bath. When the internal temperature reached 0°C, 89.43 mL of triethylamine (643 mmol, 10.0 eq) was slowly added via a constant pressure dropping funnel, maintaining the internal temperature below 20°C. The mixture was stirred at room temperature for an additional 2 hours. The mixture was 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 to dryness under reduced pressure and purified by column chromatography using petroleum ether/ethyl acetate = 5:1 to afford Intermediate A1-6 (12.922 g, 44.90%) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )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.

Step 5: Synthesis of intermediate A1-7

To a 100 mL three-necked flask, 3 g of Intermediate A1-6 (6.7 mmol, 1.0 eq) was added and dissolved in 30 mL (10 mL/g) of anhydrous tetrahydrofuran. The atmosphere was replaced with argon five times. Under an argon purge, 402 mg of sodium hydride (10.05 mmol, 1.5 eq) was added portionwise. The reaction mixture was stirred at room temperature for 20 minutes, then quenched with 35 mL of 1.0 M aqueous HCl and extracted with 3 × 75 mL of ethyl acetate. The combined organic phases were washed with 3 × 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and purified by automated C18 reverse-phase column chromatography (25 g, C18 silica gel) with a water/methanol ratio of 1:1 to afford Intermediate A1-7 as a white solid (1.884 g, 67.65%). ¹ H NMR (400MHz, DMSO-d ₆ ) 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.

Step 6: Synthesis of Intermediate A1-1

In a 10 mL sealed tube, add 415 mg of intermediate A1-7 (1.0 mmol, 1.0 eq), 295 mg of potassium acetate (3.0 mmol, 3.0 eq), 508 mg of pinacol diboron (2.0 mmol, 2.0 eq), 73 mg of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl ₂ , 0.1 mmol, 0.1 eq), and 5 mL of dioxane (5 mL/mmol). Replace the atmosphere with argon five times. The mixture was stirred at 105°C overnight. The reaction mixture was then filtered through celite, and the filtrate was concentrated in vacuo to afford a black oil, which was used directly in the next step without further purification. The MS (ESI) m/z of the corresponding boronic acid (M ⁷⁹ Br-H) ⁻ = 379.

Example 2: Synthesis of Compound 1-1

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

The synthetic route is as follows:

Step 1: Synthesis of Compound 1-3

To a solution of 414 mg of compound 1-2 (CAS: 7311-64-0, 2.0 mmol, 1.0 eq) dissolved in 5 mL of N,N-dimethylformamide, 1.05 mL of N,N-diisopropylethylamine (6.0 mmol, 3.0 eq) and 913 mg of HATU (2.4 mmol, 1.2 eq) were added. The mixture was stirred at room temperature for 1 hour, followed by the addition of 464 μL of isoamylamine (4.0 mmol, 2.0 eq) and stirring for an additional 2 hours. After TLC monitoring, the reaction was quenched with 10 mL of purified water and extracted with 3 × 10 mL of ethyl acetate. The combined organic phases were washed with 3 × 20 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was then filtered, concentrated under reduced pressure, and purified on a flash silica gel column eluting with petroleum ether/ethyl acetate (20:1) to afford compound 1-3 as a yellow oil (516 mg, 93.41%). MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 276.

Step 2: Synthesis of Compound 1-4

In a 10 mL sealed tube, 462 mg of IntA1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), 0.1 mmol, 0.1 eq), 276 mg of 1-3 (1.0 mmol, 1.0 eq), 0.5 mL of purified water (0.5 mL/mmol), and 5 mL of dioxane (5 mL/mmol) were combined. The atmosphere was replaced with argon five times and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water/methanol ratio of 7:3 as the eluent to afford 1-4 as a yellow solid (68 mg, 12.79%). This was used directly in the next step without further characterization.

Step 3: Synthesis of compound 1-1

To a -78°C 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) was slowly added 1.3 mL of boron trichloride in dichloromethane (1.0 M, 1.3 mmol, 10.0 eq) along the side of the flask, maintaining the internal temperature below -70°C. The resulting solution was stirred at -78°C for 5 minutes, after which the cooling bath was removed and the reaction mixture was allowed to warm to an internal temperature of 0°C and then cooled back to -78°C. The mixture was quenched by the addition of 2.6 mL of methanol, which was then allowed to warm to room temperature and concentrated under reduced pressure to form an oil. This oil was further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) using a water/methanol ratio of 4:1 as the eluent to afford compound 1-1 as a yellow solid (13 mg, 26.09%). ¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 3: Synthesis of Compound 2-1

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

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

Example 4: Synthesis of Compound 3-1

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

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

Example 5: Synthesis of Compound 4-1

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

The synthetic route is as follows:

Step 1: Synthesis of compound 4-3

To a solution of 382 mg of compound 4-2 (2.0 mmol, 1.0 eq) in 5 mL of N,N-dimethylformamide, 1.05 mL of N,N-diisopropylethylamine (6.0 mmol, 3.0 eq) and 913 mg of HATU (2.4 mmol, 1.2 eq) were added with stirring. The mixture was stirred at room temperature for 1 h, and 464 μL of isopentylamine (4.0 mmol, 2.0 eq) was added. The mixture was stirred for an additional 2 h, quenched with 10 mL of purified water, and extracted with 3 × 10 mL of ethyl acetate. The combined organic phases were washed with 3 × 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and purified on a flash silica gel column using petroleum ether/ethyl acetate = 20:1 to obtain compound 4-3 (472 mg, 90.08%) as a yellow oil. MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 260.

Step 2: Synthesis of compound 4-4

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(PPh ₃ ) 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 replaced with argon five times and stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g, C18 silica gel) with water/methanol = 7:3 as the eluent to afford compound 4-4 as a yellow solid (102 mg), which was used directly in the next step without characterization.

Step 3: Synthesis of compound 4-1

To a suspension of 102 mg of compound 4-4 (0.2 mmol, 1.0 eq) and 76 mg of ammonium formate (1.2 mmol, 6.0 eq) in 1 mL of methanol (5 mL/mmol) and 1 mL of tetrahydrofuran (5 mL/mmol) was added 10 mg of 10% Pd/C (0.1 m/m). The reaction mixture was refluxed at 65°C for 2 h. The filtered filtrate was concentrated under reduced pressure and further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) with water/methanol = 4:1 as the eluent to afford compound 4-1 as a white solid (41 mg, 48.71%). ¹ H NMR (400 MHz, DMSO-d ₆ )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＝3.5Hz,1H),3.9 9(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.

Example 6: Synthesis of Compound 5-1

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

This compound was prepared using the method described in Example 5 and replacing 4-2 with 2-bromofuran-4-carboxylic acid (CAS: 58832-36-3). ¹ H NMR (400 MHz, DMSO-d ₆ )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,1H),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.

Example 7: Synthesis of Compound 6-1

5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylthiazole-2-carboxamide

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

Example 8: Synthesis of Compound 7-1

2-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylthiazole-5-carboxamide

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

Example 9: Synthesis of Compound 8-1

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

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

Example 10: Synthesis of Compound 9-1

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

The synthetic route is as follows:

Step 1: Synthesis of compound 9-3

To a 50ml single-necked flask, add 876mg of 9-2 (4.0mmol, 1.0eq), 7ml of isoamylamine (60mmol, 15.0eq), and 16ml of methanol. Stir under reflux at 50°C for 24h. TLC indicated completion of the reaction. Extraction was performed with 3x50mL of ethyl acetate. The combined organic phases were washed with 3x100mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was then filtered, sanded, and purified by flash silica gel column chromatography to yield 700mg of a yellow oily liquid in a 63.84% yield. MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 274.

Step 2: Synthesis of compound 9-4

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(PPh ₃ ) 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 replaced with argon five times and stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g, C18 silica gel) with water/methanol = 7:3 as the eluent to afford compound 9-4 as a yellow solid (140 mg). This was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 530.

Step 3: Synthesis of compound 9-1

To a suspension of 106 mg of compound 9-4 (0.2 mmol, 1.0 eq) and 76 mg of ammonium formate (1.2 mmol, 6.0 eq) in 1 mL of methanol (5 mL/mmol) and 1 mL of tetrahydrofuran (5 mL/mmol) was added 10 mg of 10% Pd/C (0.1 m/m). The reaction mixture was refluxed at 65°C for 2 h. The filtered filtrate was concentrated under reduced pressure and further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) with water/methanol = 4:1 as the eluent to afford compound 9-1 as a white solid (58 mg, 66.06%). ¹ H NMR (400 MHz, DMSO-d ₆ )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＝3.5Hz,1H),3.9 9(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.

Example 11: Synthesis of Compound 10-1

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

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

Example 12: Synthesis of Compound 11-1

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

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

Example 13: Synthesis of Compound 12-1

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

This compound was prepared using the method described in Example 5, substituting 4-bromobenzoic acid (CAS: 586-76-5) for 4-2. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (t, J = 5.6 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 23.9 Hz, 2H), 4.04 (s, 2H), 3.31–3.26 (m, 2H), 1.62 (dq, J = 13.5, 6.8 Hz, 1H), 1.43 (q, J = 6.8 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). MS (ESI) m/z (M+H) ⁺ = 436.

Example 14: Synthesis of Compound 13-1

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

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

Example 15: Synthesis of Compound 14-1

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

This compound was prepared using the method described in Example 5, substituting 1-methanesulfonyl-4-aminopiperidine (CAS: 402927-97-3) for isoamylamine. ¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 16: Synthesis of Compound 15-1

N-(2-Cyclohexylethyl)-5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

This compound was prepared using the method described in Example 5, substituting cyclohexylethylamine (CAS: 4442-85-7) for isoamylamine. ¹ H NMR (400 MHz, DMSO-d ₆ )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),1.7 0–1.55(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.

Example 17: Synthesis of Compound 16-1

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

This compound was prepared using the method described in Example 5, substituting 1-methanesulfonylpiperazine (CAS: 55276-43-2) for isoamylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.18–7.13 (m, 3H), 7.11–7.08 (m, 1H), 3.99 (s, 2H), 3.84 (s, 4H), 3.24 (t, J = 5.3 Hz, 4H), 2.92 (s, 3H). MS (ESI) m/z (M+H) ⁺ = 503.

Example 18: Synthesis of Compound 17-1

5-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N-(3-hydroxy-3-methylbutyl)furan-2-carboxamide

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

Example 19: Synthesis of Compound 18-1

5-(4-(5-(Azolidin-1-carbonyl)furan-2-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

This compound was prepared using the method described in Example 5, substituting heptamethylimine (CAS: 1121-92-2) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) 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.

Example 20: Synthesis of Compound 19-1

N-(Adamantane-1-yl)-5-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

This compound was prepared using the method described in Example 5, substituting adamantane (CAS: 768-94-5) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 7.53 (s, 1H), 7.30 (dd, J = 11.1, 2.1 Hz, 1H), 7.15 (d, J = 3.5 Hz, 1H), 7.07 (d, J = 3.6 Hz, 1H), 4.01 (s, 2H), 2.10–2.05 (m, 9H), 1.67 (d, J = 2.6 Hz, 6H). MS (ESI) m/z (M+H) ⁺ = 490.

Example 21: Synthesis of Compound 20-1

N-Cycloheptyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

This compound was prepared using the method described in Example 5, substituting cycloheptylamine (CAS: 5452-35-7) for isoamylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.34 (dd, J = 11.1, 2.1 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.11–7.08 (m, 1H), 4.05 (s, 2H), 3.94 (tt, J = 9.5, 4.8 Hz, 1H), 1.91–1.79 (m, 2H), 1.77–1.27 (m, 10H). MS (ESI) m/z (M+H) ⁺ = 452.

Example 22: Synthesis of Compound 21-1

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

This compound was prepared using the method described in Example 5, substituting ethylamine (CAS: 75-04-7) for isoamylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (t, J = 5.8 Hz, 1H), 7.33 (dd, J = 11.3, 2.0 Hz, 1H), 7.23 (t, J = 1.5 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 7.09 (d, J = 3.6 Hz, 1H), 3.99 (s, 2H), 3.29 (dd, J = 7.3, 5.9 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) ⁺ = 384.

Example 23: Synthesis of Compound 22-1

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

This compound was prepared using the method described in Example 5, substituting isopropylamine (CAS: 75-31-0) for isoamylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 11.1 Hz, 1H), 7.24 (s, 1H), 7.11 (dd, J = 25.2, 3.6 Hz, 2H), 4.11 (q, J = 6.9 Hz, 1H), 4.01 (s, 2H), 1.19 (d, J = 6.5 Hz, 6H). MS (ESI) m/z (M+H) ⁺ = 398.

Example 24: Synthesis of Compound 23-1

N-Cyclopentyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

This compound was prepared using the method described in Example 5, substituting isopropylamine (CAS: 1003-03-8) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H), 6.84 (d, J = 3.5 Hz, 1H), 6.80 (s, 1H), 6.68 (d, J = 10.3 Hz, 1H), 4.21 (q, J = 7.4 Hz, 1H), 4.09 (s, 2H), 1.92–1.86 (m, 2H), 1.71 (dq, J = 8.0, 2.7 Hz, 2H), 1.55 (ddq, J = 7.5, 5.3, 2.9 Hz, 4H). MS (ESI) m/z (M+H) ⁺ = 424.

Example 25: Synthesis of Compound 24-1

N-(Cyclopentylmethyl)-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

This compound was prepared using the method described in Example 5, substituting cyclopentaneethylamine (CAS: 6053-81-2) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (t, J = 5.9 Hz, 1H), 7.32 (d, J = 11.4 Hz, 1H), 7.22 (s, 1H), 7.15–7.06 (m, 2H), 3.99 (s, 2H), 3.31–3.20 (m, 2H), 1.80 (d, J = 5.5 Hz, 3H), 1.68–1.39 (m, 6H), 1.14–1.05 (m, 2H). MS (ESI) m/z (M+H) ⁺ = 452.

Example 26: Synthesis of Compound 25-1

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

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

Example 27: Synthesis of Compound 26-1

The synthetic route is as follows:

Step 1: Synthesis of compound 26-3

To a 50 mL three-necked flask, add 240 mg of sodium hydride (6.0 mmol, 3.0 eq) and 2 mL of DMF. The atmosphere was replaced with argon five times, and the mixture was cooled to 0°C in an ice bath. In another sample vial, add 520 mg of compound 4-3 (2.0 mmol, 1.0 eq) and dissolve it in 4 mL of DMF. This solution was then slowly pipetted into the three-necked flask using a syringe, stirred in an ice bath for 0.5 h, and then moved to room temperature and stirred for 1 h. The three-necked flask was then placed in an ice bath again, and a solution of iodomethane (300 μL, 4.8 mmol, 2.4 eq) in 1 mL of DMF was slowly pipetted into the flask using a syringe. Stirred in an ice bath for 0.5 h, and then moved to room temperature and stirred for 2 h. After TLC monitoring, the reaction was quenched by slowly adding 15 mL of purified water, followed by extraction with 20 mL of ethyl acetate. After separation, the aqueous phase was extracted thoroughly with 15 mL of ethyl acetate. The combined organic phases were washed five times with saturated brine and dried over anhydrous sodium sulfate. The product 26-3 was then filtered, and the filtrate was concentrated to dryness under reduced pressure and purified by flash 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.

Step 2: Synthesis of compound 26-4

This compound was prepared using the method described in Example 5, substituting 26-3 for 4-3. MS (ESI) m/z (M+H) ⁺ = 530.

Step 3: Synthesis of compound 26-1

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

Example 28: Synthesis of Compound 27-1

5-(2-Fluoro-6-hydroxy-4-(5-(isopentylamino)methyl)furan-2-yl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

The synthetic route is as follows:

Step 1: Synthesis of compound 27-3

To a solution of 6.8 g of compound 27-2 (CAS: 1899-24-7, 40.0 mmol, 2.0 eq) dissolved in 136 mL of 1,2-dichloroethane was added 10.44 mL of DIPEA (60 mmol, 3.0 eq) and 7 mL of isopentylamine (60 mmol, 3.0 eq). The mixture was purged with argon three times and stirred at room temperature for 2 hours. After that, 3.03 g of sodium borohydride (80 mmol, 4.0 eq) was added and purged with argon three times again. The mixture was stirred at room temperature for 4-5 hours. After TLC, the reaction was quenched with 50 mL of methanol and concentrated under reduced pressure. The reaction was then purified by flash silica gel column elution with petroleum ether/ethyl acetate (20:1) to yield compound 27-3 (2.5 g, 25.41%). MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 246.

Step 2: Synthesis of compound 27-4

In a 10 mL sealed tube, 462 mg of IntA1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), 0.1 mmol, 0.1 eq), 246 mg of 27-4 (1.0 mmol, 1.0 eq), 0.5 mL of purified water (0.5 mL/mmol), and 5 mL of dioxane (5 mL/mmol) were combined. The atmosphere was replaced with argon five times and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water/methanol ratio of 7:3 as the eluent to afford 27-4 as an oily liquid (302 mg, 60.28%). This was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 502.

Step 3: Synthesis of compound 27-1

To a suspension of 302 mg of compound 27-4 (0.60 mmol, 1.0 eq) and 457 mg of ammonium formate (7.2 mmol, 12.0 eq) in 1 mL of methanol (5 mL/mmol) and 1 mL of tetrahydrofuran (5 mL/mmol) was added 50 mg of 10% Pd/C (0.1 m/m). The reaction solution was refluxed at 65°C for 2 h. The filtered filtrate was concentrated under reduced pressure and further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) with water/methanol = 4:1 as the eluent to afford compound 27-1 as an off-white solid (72 mg, 29.2%). ¹ H NMR (400MHz, DMSO-d ₆ )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),3.9 8(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.

Example 29: Synthesis of Compound 28-1

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

The synthetic route is as follows:

Step 1: Synthesis of compound 28-3

To a solution of 573 mg of compound 4-2 (3.0 mmol, 1.0 eq) dissolved in 7.5 mL of THF was added 535 mg of CDI (3.3 mmol, 1.1 eq) and 4.5 mL of aqueous ammonia. The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by flash silica gel column elution using petroleum ether/ethyl acetate (20:1) to obtain compound 28-3 (320 mg, 56.14%). MS (ESI) m/z (M+H) ⁺ = 191.

Step 2: Synthesis of compound 28-4

In a 10 mL sealed tube, 462 mg of IntA1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), 0.1 mmol, 0.1 eq), 190 mg of 28-3 (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 combined. The atmosphere was replaced with argon five times and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water/methanol ratio of 7:3 as the eluent to afford 28-4 as an oily liquid (280 mg, 62.92%). This was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 446.

Step 3: Synthesis of compound 28-1

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) was added 50 mg of 10% Pd/C (0.1 m/m). The reaction mixture was refluxed at 65°C for 2 h. The filtered filtrate was concentrated under reduced pressure and further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) with water/methanol = 4:1 as the eluent to afford compound 28-1 as an off-white solid (80 mg, 35.77%). ¹ H NMR (400MHz, DMSO-d ₆ )δ8.02(s,1H),7.47(s,1H),7.32(dd,J＝11.2,1.9Hz,1H),7.21(t,J＝1.5Hz,1H),7.16–7.09(m,2H),4.00(s,2H).MS(ESI)m/z(M+H) ⁺ ＝356.

Example 30: Synthesis of Compound 29-1

N-Benzyl-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)furan-2-carboxamide

This compound was prepared using the method described in Example 5, substituting benzylamine (CAS: 100-46-9) for isoamylamine. ^1H NMR (400 MHz, DMSO-d6) δ 9.15 (t, J = 6.2 Hz, 1H), 7.34 (d, J = 5.3 Hz, 5H), 7.28–7.22 (m, 2H), 7.20 (d, J = 3.6 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 4.48 (d, J = 6.1 Hz, 2H), 4.00 (s, 2H). MS (ESI) m/z (M+H) ⁺ = 446.

Example 31: Synthesis of Compound 30-1

5-(2-Fluoro-6-hydroxy-4-(5-(isopentyl(methyl)amino)methyl)furan-2-yl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

The synthetic route is as follows:

Step 1: Synthesis of compound 30-3

To 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 stirred and refluxed at 105°C overnight. After completion of the reaction, the mixture was concentrated under reduced pressure and purified using a flash silica gel column eluting with petroleum ether/ethyl acetate (20:1) to obtain compound 30-3 (191 mg, 36.73%). MS (ESI) m/z (M+H) ⁺ = 261.

Step 2: Synthesis of compound 30-4

In a 10 mL sealed tube, 462 mg of IntA1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakistriphenylphosphine palladium (Pd(PPh ₃ ) ₄ ), 0.1 mmol, 0.1 eq), 191 mg of 30-3 (0.7 mmol, 0.7 eq), 0.5 mL of purified water (0.5 mL/mmol), and 5 mL of dioxane (5 mL/mmol) were combined. The atmosphere was replaced with argon five times and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water/methanol ratio of 7:3 as the eluent to afford 30-4 as an oily liquid (220 mg, 42.72%). This was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 516.

Step 3: Synthesis of compound 30-1

To a suspension of 220 mg of compound 30-4 (0.40 mmol, 1.0 eq) and 305 mg of ammonium formate (4.8 mmol, 12.0 eq) in 1 mL of methanol (5 mL/mmol) and 1 mL of tetrahydrofuran (5 mL/mmol) was added 50 mg of 10% Pd/C (0.1 m/m). The reaction mixture was refluxed at 65°C for 2 h. The filtered filtrate was concentrated under reduced pressure and further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) with water/methanol = 4:1 as the eluent to afford compound 30-1 as an off-white solid (34 mg, 19.95%). ¹ H NMR (400MHz, DMSO-d ₆ )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＝14.5Hz,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.

Example 32: Synthesis of Compound 31-1

5-(4-(1,1-dioxy-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentylfuran-2-carboxamidoamide

The synthetic route is as follows:

Step 1: Synthesis of compound 31-3

A 50 mL, pre-dried, three-necked flask was heated with an electric hot plate and replaced with argon five times. Then, 688 mg of 31-2 (4.0 mmol, 1.0 eq) dissolved in 10 mL of anhydrous ethanol was syringed into the reaction flask and stirred in an ice bath. After the internal temperature reached 5°C, 2.85 mL of acetyl chloride (40 mmol, 10.0 eq) was slowly syringed in. A vigorous exotherm, reaching a peak temperature of 40°C, was achieved. After addition, the internal temperature reached 25°C and the reaction mixture was stirred at room temperature overnight. A large amount of white solid precipitated. After TLC analysis of the reaction, the reaction mixture was transferred to a single-necked flask with anhydrous ethanol and concentrated to dryness under reduced pressure. The resulting white and yellow solid was slurried with 10 mL of anhydrous tetrahydrofuran for 1 h, then filtered with suction. The filter cake was washed with 10 mL of anhydrous tetrahydrofuran and air-dried to yield 1.03 g of a white solid, the pinner salt 31-3, in a crude yield of 103.89%, which was used directly in the next reaction.

Step 2: Synthesis of compound 31-4

To a 25 mL single-necked flask, add the white solid 31-3 obtained in the previous step, followed by 10 mL of anhydrous ethanol. The atmosphere was replaced with argon five times, and the mixture was stirred in an ice bath. 4.2 mL of isopentylamine (36 mmol, 9.0 eq) was then injected via syringe, and the mixture was stirred at room temperature overnight. After TLC confirmed the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, stirred with 10 mL of ethyl acetate for 1 hour, and then filtered and air-dried to obtain 31-4 as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )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),1.55–1.48(m,2H),0.92(d,J＝6.5Hz,6H).MS(ESI)m/z(M ^79Br +H) ⁺ =259.

Step 3: Synthesis of compound 31-5

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

Step 4: Synthesis of compound 31-1

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

Example 33: Synthesis of Compound 32-1

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

The synthetic route is as follows:

Step 1: Synthesis of compound 32-3

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 stirred under reflux at 75°C overnight. After TLC monitoring, the reaction was quenched with 30 mL of purified water, followed by extraction with 30 mL of ethyl acetate and 3 × 30 mL of water. The aqueous phases were combined, the pH adjusted to 1 with 6N hydrochloric acid, and the organic phases were combined, washed with 3 × 30 mL of saturated brine, and dried over anhydrous sodium sulfate. The filtrate was then filtered and concentrated under reduced pressure to yield compound 32-3 as a yellow oil (500 mg, 87.71%). MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 189.

Step 2: Synthesis of compound 32-4

To a solution of 380 mg of compound 32-3 (2.0 mmol, 1.0 eq) dissolved in 5 mL of N,N-dimethylformamide was added 1.05 mL of N,N-diisopropylethylamine (6.0 mmol, 3.0 eq) and 913 mg of HATU (2.4 mmol, 1.2 eq). The mixture was stirred at room temperature for 1 hour, followed by the addition of 464 μL of isoamylamine (4.0 mmol, 2.0 eq) and stirring for an additional 2 hours. After TLC monitoring of the reaction, 10 mL of purified water was added for quenching, followed by extraction with 3 × 10 mL of ethyl acetate. The combined organic phases were washed with 3 × 20 mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was then filtered, concentrated under reduced pressure, and purified on a flash silica gel column eluting with petroleum ether/ethyl acetate (20:1) to afford compound 32-4 as an oil (300 mg, 57.91%). MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 259.

Step 3: Synthesis of compound 32-5

In a 10 mL sealed tube, 462 mg of IntA1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakistriphenylphosphine palladium (Pd(PPh ₃ ) ₄ ), 0.1 mmol, 0.1 eq), 260 mg of 32-4 (1.0 mmol, 1.0 eq), 0.5 mL of purified water (0.5 mL/mmol), and 5 mL of dioxane (5 mL/mmol) were combined. The atmosphere was replaced with argon five times, and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water/methanol ratio of 7:3 to afford 32-5 as a solid (100 mg, 19.41%), which was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 515.

Step 4: Synthesis of compound 32-1

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) was added 10 mg of 10% Pd/C (0.1 m/m). The reaction mixture was refluxed at 65°C for 2 h. The filtered filtrate was concentrated under reduced pressure and further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) with water/methanol = 4:1 as the eluent to afford compound 35-1 as a white solid (35 mg, 43.3%). ¹ H NMR (400MHz, DMSO-d ₆ )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＝4.1Hz,1H),3.9 7(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.

Example 34: Synthesis of Compound 33-1

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

This compound was prepared using the method described in Example 33, substituting ethyl 5-bromo-1H-pyrazole-3-carboxylate (CAS: 1392208-46-6) for 32-2. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.63 (d, J = 16.5 Hz, 1H), 9.70 (s, 1H), 7.20 (d, J = 18.1 Hz, 1H), 7.10 (s, 1H), 6.99 (d, J = 14.6 Hz, 1H), 3.99 (s, 2H), 3.27 (s, 2H), 1.61 (s, 1H), 1.42 (d, J = 7.6 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). MS (ESI) m/z (M+H) ⁺ = 426.

Example 35: Synthesis of Compound 34-1

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

This compound was prepared using the method described in Example 34, substituting cyclohexylamine (CAS: 108-91-8) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.62 (s, 1H), 9.73 (s, 1H), 8.04 (dd, J = 164.5, 7.9 Hz, 1H), 7.14 (dd, J = 54.0, 29.8 Hz, 3H), 4.00 (s, 2H), 3.81–3.70 (m, 1H), 1.83–1.09 (m, 10H). MS (ESI) m/z (M+H) ⁺ = 438.

Example 36: Synthesis of Compound 35-1

N-(2-Cyclopentylethyl)-5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-1H-pyrazole-3-carboxamide

This compound was prepared using the method described in Example 34, substituting cyclopentaneethylamine (CAS: 684221-26-9) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.62 (s, 1H), 8.31 (d, J = 120.5 Hz, 1H), 7.06 (d, J = 33.7 Hz, 3H), 3.99 (s, 2H), 3.26 (d, J = 7.1 Hz, 2H), 1.90–1.38 (m, 9H), 1.10 (s, 2H). MS (ESI) m/z (M+H) ⁺ = 452.

Example 37: Synthesis of Compound 36-1

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

This compound was prepared using the method described in Example 34, substituting cycloheptylamine (CAS: 5452-35-7) for isoamylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.61 (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.

Example 38: Synthesis of Compound 37-1

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

This compound was prepared using the method described in Example 34, substituting cyclooctylamine (CAS: 5452-37-9) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.62 (s, 1H), 8.06 (d, J = 161.4 Hz, 1H), 7.07 (d, J = 33.5 Hz, 2H), 3.99 (s, 2H), 1.82–1.18 (m, 15H). MS (ESI) m/z (M+H) ⁺ = 466.

Example 39: Synthesis of Compound 38-1

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

This compound was prepared using the method described in Example 9, substituting cycloheptylamine (CAS: 5452-35-7) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.29 (s, 1H), 7.72 (s, 1H), 6.92–6.85 (m, 2H), 4.00 (s, 2H), 3.93 (td, J = 8.8, 4.4 Hz, 1H), 2.33 (s, 3H), 1.82 (d, J = 9.8 Hz, 2H), 1.64–1.42 (m, 10H). MS (ESI) m/z (M+H) ⁺ = 466.

Example 40: Synthesis of Compound 39-1

5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentyl-1H-imidazole-2-carboxamide

This compound was prepared using the method described in Example 33, substituting ethyl 5-bromoimidazole-2-carboxylate (CAS: 944900-49-6) for 32-2. ^1H NMR (400 MHz, DMSO-d6) δ 8.36 (t, J = 6.1 Hz, 1H), 7.78 (s, 1H), 7.23–7.16 (m, 2H), 3.97 (s, 2H), 3.28 (s, 2H), 1.63–1.57 (m, 1H), 1.44 (d, J = 7.3 Hz, 2H), 0.91 (d, J = 6.6 Hz, 6H). MS (ESI) m/z (M+H) ⁺ = 426.

Example 41: Synthesis of Compound 40-1

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

This compound was prepared using the method described in Example 40, substituting cycloheptylamine (CAS: 5452-35-7) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.19 (d, J = 17.3 Hz, 2H), 3.95 (d, J = 16.6 Hz, 3H), 1.49 (td, J = 116.1, 112.0, 49.5 Hz, 12H). MS (ESI) m/z (M+H) ⁺ = 452.

Example 42: Synthesis of Compound 41-1

5-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxyphenyl)-N-isopentyl-1H-1,2,4-triazole-3-carboxamide

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

Example 43: Synthesis of Compound 42-1

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

This compound was prepared using the procedure described in Example 33, substituting methyl 1-methyl-5-bromo-3-pyrazolecarboxylate (CAS: 1222174-92-6). ¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 44: Synthesis of Compound 43-1

5-(2-Fluoro-6-hydroxy-4-(3-(isopentylamino)-1H-pyrazol-5-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

The synthetic route is as follows:

Step 1: Synthesis of compound 43-3

To a solution of 324 mg of compound 43-2 (2.0 mmol, 1.0 eq) dissolved in 5 mL of DCE, 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 hours. After completion of the reaction as monitored by TLC, 10 mL of methanol was added to terminate the reaction. The mixture was concentrated under reduced pressure and purified by flash silica gel column elution using petroleum ether/ethyl acetate (20:1) to obtain compound 43-3 (209 mg, 45.20%). MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 232.

Step 2: Synthesis of compound 43-4

In a 10 mL sealed tube, 462 mg of IntA1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), 0.1 mmol, 0.1 eq), 209 mg of 43-3 (0.9 mmol, 0.9 eq), 0.5 mL of purified water (0.5 mL/mmol), and 5 mL of dioxane (5 mL/mmol) were combined. The atmosphere was replaced with argon five times and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water/methanol ratio of 7:3 to afford 43-4 as a black solid (182 mg, 37.32%). This was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 488.

Step 3: Synthesis of compound 43-1

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

Example 45: Synthesis of Compound 44-1

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

The synthetic route is as follows:

Step 1: Synthesis of compound 44-3

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

Step 2: Synthesis of compound 44-4

In a 10 mL sealed tube, 462 mg of IntA1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), 0.1 mmol, 0.1 eq), 220 mg of 44-3 (0.8 mmol, 0.8 eq), 0.5 mL of purified water (0.5 mL/mmol), and 5 mL of dioxane (5 mL/mmol) were combined. The atmosphere was replaced with argon five times, and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water/methanol ratio of 7:3 to afford 44-4 as a black solid (300 mg, 58.36%). This was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 516.

Step 3: Synthesis of compound 44-1

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) was added 50 mg of 10% Pd/C (0.1 m/m). The reaction mixture was refluxed at 65°C for 2 h. The filtered filtrate was concentrated under reduced pressure and further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) with water/methanol = 4:1 as the eluent to afford compound 44-1 as a solid (60 mg, 24.34%). ¹ H NMR (400MHz, DMSO-d ₆ )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,2H),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.

Example 47: Synthesis of Compound 45-1

Step 1: Synthesis of compound 45-3

To a 50 mL three-necked flask, add 240 mg of sodium hydride (6.0 mmol, 1.2 eq) and 10 mL of DMF. The atmosphere was replaced with argon five times, and the mixture was cooled to 0°C in an ice bath. In another sample vial, add 1.095 mg of 45-2 (5.0 mmol, 1.0 eq) and dissolve it in 10 mL of DMF. This solution was then slowly syringed into the three-necked flask, stirred in an ice bath for 0.5 h, then moved to room temperature and stirred for 1 h. The three-necked flask was then placed in an ice bath again, and a 5 mL DMF solution of SEM-Cl (1.325 mL, 7.5 mmol, 1.5 eq) was slowly syringed into the flask. Stirred in an ice bath for 0.5 h, then moved to room temperature and stirred for 2 h. After TLC monitoring, the reaction was quenched by slowly adding 40 mL of purified water, followed by extraction with 20 mL of ethyl acetate. After separation, the aqueous phase was extracted thoroughly with 40 mL of ethyl acetate. The combined organic phases were washed five times with saturated brine and dried over anhydrous sodium sulfate. The product 45-3 was then filtered, and the filtrate was concentrated to dryness under reduced pressure and purified by flash silica gel column chromatography. Elution with 1% ethyl acetate/petroleum ether afforded the product 45-3 as a yellow oil (1.102 g, 63.10%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.11 (s, 1H), 5.71 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.58–3.52 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.84–0.76 (m, 2H), −0.07 (s, 10H). MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 349.

Step 2: Synthesis of compound 45-4

A single-necked flask containing 1.102 g of 26-3 (3.15 mmol, 1.0 eq) was dissolved in 16 mL of anhydrous ethanol, followed by the addition of isopentylamine (3.3 mL, 28.4 mmol, 9.0 eq) and stirred overnight at 70°C. After TLC monitoring, the reaction was concentrated to dryness under reduced pressure, followed by the addition of 20 mL of 0.5 N aqueous hydrochloric acid and extraction with 20 mL of ethyl acetate. After separation, the aqueous phase was extracted thoroughly with 30 mL of ethyl acetate. The combined organic phases were washed with 3 × 20 mL of 0.5 N aqueous hydrochloric acid, then washed five times with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was then filtered and concentrated to dryness under reduced pressure to yield 1.2 g of a brown oil, 45-3, which was used directly in the next reaction. MS (ESI) m/z (M ⁷⁹ Br+Na) ⁺ = 412.

Step 3: Synthesis of compound 45-5

This compound was prepared using the method described in Example 26, substituting 45-4 for 4-3. MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 404.

Step 4: Synthesis of compound 45-6

Take a single-necked bottle containing 202 mg of 45-5, add 2 mL of DCM to dissolve, then add 2 mL of TFA, stir at room temperature for 2 h, and after the reaction is completed by monitoring by TLC, concentrate the reaction solution under reduced pressure to dryness. The obtained oil is then purified by flash silica gel column chromatography, and 80 mg of the product is eluted as a colorless oil with 20% ethyl acetate/petroleum ether. The yield is 58.4%.

Step 5: Synthesis of compound 45-7

This compound was prepared using the method described in Example 5, substituting 45-6 for 4-3. MS (ESI) m/z (M+H) ⁺ = 530.

Step 6: Synthesis of compound 45-1

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

Example 47: Synthesis of Compound 46-1

5-(2-Fluoro-6-hydroxy-4-(6-(isopentylamino)pyridin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

Step 1: Synthesis of compound 46-3

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

Step 2: Synthesis of compound 46-4

In a 10 mL sealed tube, 462 mg of IntA1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakistriphenylphosphine palladium (Pd(PPh ₃ ) ₄ ), 0.1 mmol, 0.1 eq), 218 mg of 46-3 (0.9 mmol, 0.9 eq), 0.5 mL of purified water (0.5 mL/mmol), and 5 mL of dioxane (5 mL/mmol) were combined. The atmosphere was replaced with argon five times, and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water/methanol ratio of 7:3 as the eluent to afford 46-4 as an oily liquid (230 mg, 46.18%). This was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 499.

Step 3: Synthesis of compound 46-1

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) was added 50 mg of 10% Pd/C (0.1 m/m). The reaction solution was refluxed at 65°C for 2 h. The filtered filtrate was concentrated under reduced pressure and further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) with water/methanol = 4:1 as the eluent to afford compound 46-1 as a white solid (50 mg, 26.6%). ¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 48: Synthesis of Compound 47-1

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

This compound was prepared using the method described in Example 47, substituting 4,4-difluoropiperidine (CAS: 144230-52-4) for isoamylamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.43 (d, J = 2.6 Hz, 1H), 7.84 (dd, J = 8.9, 2.6 Hz, 1H), 7.12–6.85 (m, 3H), 3.99 (s, 2H), 3.75 (t, J = 5.7 Hz, 4H), 2.00 (tt, J = 13.7, 5.5 Hz, 4H). MS (ESI) m/z (M+H) ⁺ = 443.

Example 49: Synthesis of Compound 48-1

5-(4-(6-(cycloheptylamino)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

This compound was prepared using the method described in Example 47, substituting cycloheptylamine (CAS: 5452-35-7) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.63 (dd, J = 8.8, 2.6 Hz, 1H), 6.92–6.83 (m, 2H), 6.71 (d, J = 7.9 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 3.97 (s, 2H), 1.90 (dt, J = 10.5, 4.5 Hz, 2H), 1.66–1.45 (m, 11H). MS (ESI) m/z (M+H) ⁺ = 435.

Example 50: Synthesis of Compound 49-1

5-(4-(6-(cyclooctylamino)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

This compound was prepared using the method described in Example 47, substituting cyclooctylamine (CAS: 5452-37-9) for isoamylamine. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.62 (dd, J = 8.8, 2.6 Hz, 1H), 6.97–6.83 (m, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 3.97 (s, 2H), 1.85–1.44 (m, 15H). MS (ESI) m/z (M+H) ⁺ = 449.

Example 51: Synthesis of Compound 50-1

5-(4-(6-(cyclohexylamino)pyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

This compound was prepared using the method described in Example 47, substituting cyclohexylamine (CAS: 108-91-8) for isoamylamine. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.43(s,1H),8.25(d,J＝2.6Hz,1H),7.62(dd,J＝8.8,2.6Hz,1H),6.90–6.83(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.

Example 52: Synthesis of Compound 51-1

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

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

Example 53: Synthesis of Compound 52-1

5-(4-(6-(cyclohexylamino)-5-methylpyridin-3-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

This compound was prepared using the method described in Example 47, substituting cyclohexylamine (CAS: 108-91-8) for isoamylamine and 2-fluoro-3-methyl-5-bromopyridine (CAS: 29312-98-9) for 46-2. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (d, J = 2.4 Hz, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 6.36 (s, 1H), 5.47 (d, J = 7.7 Hz, 1H), 4.06 (s, 2H), 3.92 (d, J = 9.3 Hz, 1H), 2.07 (s, 3H), 1.54 (d, J = 2.2 Hz, 8H), 1.30 (d, J = 9.0 Hz, 2H). MS (ESI) m/z (M+H) ⁺ = 435.

Example 54: Synthesis of Compound 53-1

5-(2-Fluoro-6-hydroxy-4-(2-(isopentylamino)pyrimidin-5-yl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide

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

Example 55: Synthesis of Compound 54-1

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

This compound was prepared using the procedure described in Example 47, substituting 5-bromo-2-fluoro-6-methylpyridine (CAS: 375368-83-5). ¹ H NMR (400MHz, DMSO-d ₆ )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,1H),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.

Example 56: Synthesis of Compound 55-1

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

Step 1: Synthesis of compound 55-3

To a solution of 380 mg of compound 55-2 (CAS: 367-24-8, 2.0 mmol, 1.0 eq) dissolved in 5 mL of DCE, 119 μL of acetic acid (2.08 mmol, 1.04 eq), 258 μL of isovaleraldehyde (2.4 mmol, 1.2 eq), and 848 mg of sodium triacetoxyborohydride (4 mmol, 2 eq) were added. The mixture was purged with argon three times and stirred at room temperature for 4 h. After TLC, the reaction was quenched with 10 mL of methanol, and the mixture was concentrated under reduced pressure. The product was then purified by flash silica gel column elution using petroleum ether/ethyl acetate (20:1) to afford compound 55-3 (208 mg, 40.07%). MS (ESI) m/z (M+H) ⁺ = 262.

Step 2: Synthesis of compound 55-4

In a 10 mL sealed tube, 462 mg of IntA1-1 (1.0 mmol, 1.0 eq), 415 mg of potassium carbonate (3.0 mmol, 3.0 eq), 116 mg of tetrakistriphenylphosphine palladium (Pd(PPh ₃ ) ₄ ), 0.1 mmol, 0.1 eq), 208 mg of 55-3 (0.8 mmol, 0.9 eq), 0.5 mL of purified water (0.5 mL/mmol), and 5 mL of dioxane (5 mL/mmol) were combined. The atmosphere was replaced with argon five times and the mixture was stirred at 100°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by automated C18 reverse-phase column chromatography (25 g of C18 silica gel) with a water/methanol ratio of 7:3 to afford 55-4 as an oily liquid (280 mg, 54.16%). This was used directly in the next step without further purification. MS (ESI) m/z (M+H) ⁺ = 517.

Step 3: Synthesis of compound 55-1

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) was added 50 mg of 10% Pd/C (0.1 m/m). The reaction mixture was refluxed at 65°C for 2 h. The filtered filtrate was concentrated under reduced pressure and further purified by C18 reverse-phase column chromatography (10 g, C18 silica gel) with water/methanol = 4:1 as the eluent to afford compound 55-1 as a yellow solid (52 mg, 21.74%). ¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 57: Synthesis of Compound 56-1

5-(2-Fluoro-6-hydroxy-4-(3-(isopentylamino)azepine-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

The synthetic route is as follows:

Step 1: Synthesis of intermediate 56-3

In a 50 mL single-necked bottle, 415 mg of IntA1-7 (1.0 mmol, 1.0 eq), 29 mg of 56-2 3-N-tert-butyloxycarbonylaminocyclobutylamine (CAS: 91188-13-5, 1.1 mmol, 1.1 eq), 978 mg of Cs ₂ CO ₃ (3.0 mmol, 3.0 eq), 1.07 g of Brettphos (2.0 mmol, 2.0 eq), and 92 mg of Pd ₂ (DBA) ₃ (0.1 mmol, 0.1 eq) were mixed, and 10 mL of Dioxane (10 mL/mmol) was added. The atmosphere was replaced with argon five times, and the mixture was stirred at 80°C for 12 h. After completion of the reaction as monitored by LC-MS, the mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was sanded and subjected to automatic column chromatography. Elution with 10% MeOH/DCM afforded 380 mg of 56-3 in a yield of 75.10%. MS (ESI) m/z (M-Boc+H) ⁺ = 407.

Step 2 to Step 4: Synthesis of 56-1

To a single-necked flask containing 380 mg of 56-3 (0.75 mmol, 1.0 eq), 286 mg of ammonium formate (4.50 mmol, 6.0 eq), 3.75 mL of methanol, and 3.75 mL of tetrahydrofuran were added, followed by 190 mg of 10% Pd/C. The mixture was refluxed in an oil bath at 65°C and stirred for 4 h. After completion of the reaction as monitored by TLC, the filtrate was filtered and concentrated to dryness under reduced pressure. 7.5 mL of DCM was added for dissolution, followed by 1.9 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 30 min. After completion of the reaction as monitored by TLC, the mixture was concentrated to dryness under reduced pressure, and then 2 × 10 mL of toluene and 2 × 10 mL of DCM were added for dryness. 8 mL of DCM was then added for reconstitution, and DIPEA was added to adjust the pH to 8. 162 μL of isovaleraldehyde (1.5 mmol, 2.0 eq) was added. The atmosphere was replaced with argon five times, and the mixture was stirred at room temperature for 1 h. 141 mg of sodium cyanoborohydride (2.25 mmol, 3.0 eq) was then added, and the atmosphere was replaced with argon five times, followed by stirring at room temperature. After completion of the reaction, as monitored by LC-MS, 10 mL of methanol was added to quench the reaction, concentrated under reduced pressure to dryness, and purified on a reverse-phase C18 column. The product was eluted with 40% MeOH/ _H₂O as a white solid, yielding 40 mg, for a three-step yield of 13.80%. ¹ H NMR (400MHz, DMSO-d ₆ )δ5.72(dd,J＝12.3,2.5Hz,1H),5.70–5.64(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.

Example 58: Synthesis of Compound 57-1

(R)-5-(2-Fluoro-6-hydroxy-4-(3-(isopentylamino)pyrrolidin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

This compound was prepared using the method described in Example 57, substituting (R)-3-tert-butoxycarbonylaminopyrrolidine (CAS: 122536-77-0) for 56-2. ¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 59: Synthesis of Compound 58-1

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

Referring to the synthetic method of Example 5, 58-1 can be prepared by replacing 4-2 with 3-bromopyrazolo[1,5-A]pyridine-5-carboxylic acid (CAS: 876379-79-2). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.52(s,1H),7.98(t,J＝5.6Hz,1H),7.72(s,1H),6.76(d,J＝10.8Hz,2H),4.26–4.18(m,1H),4.03(dt,J＝11.9,6.0Hz,1H),3.97(s,2H),3.2 6–2.86(m,5H),2.67(s,1H),2.18–2.01(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.

Example 60: Synthesis of Compound 59-1

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

Some of the synthetic routes are as follows:

Step 1: Synthesis of intermediate 59-3

In a 250 mL single-necked bottle, 840 mg of pyrazolo[1,5-a]pyridine-2-carboxylic acid (CAS: 63237-88-7, 5 mmol, 1.0 eq) and 980 mg of NBS (5.5 mmol, 1.1 eq) were added to 50 mL of DMF (10 mL/mmol). The mixture was stirred at room temperature for 4 hours, followed by extraction with water and ethyl acetate. The ethyl acetate layer was retained, rinsed three times with saturated NaCl solution, and then dried to yield 923 mg of 94-3 as a yellow solid. MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 245.

Steps 2 to 4: Synthesis of 59-1

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

Example 61: Synthesis of Compound 60-1

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

Some of the synthetic routes are as follows:

Step 1: Synthesis of intermediate 60-3

In a 50 mL three-necked flask, 735 mg of 59-3 (3.0 mmol, 1.0 eq), 970 μL of DPPA (1.4 mmol, 1.5 eq), 1 mL of TEA (7.2 mmol, 2.4 eq), and 12 mL of THF (4 mL/mmol) were placed under argon exchange five times. After stirring at room temperature for 4 h, 735 μL of water (5 mL/g) was added. The mixture was refluxed at 60°C and stirred for 4 h. The mixture was then purified by automated sand column chromatography using 25% petroleum ether/ethyl acetate as the eluent. The mixture was concentrated under reduced pressure to yield 60-3. MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 216.

Step 2: Synthesis of intermediate 60-4

In a 25 mL single-necked bottle, 310 mg of 60-3 (1.43 mmol, 1.0 eq), 162 μL of isovaleraldehyde (1.5 mmol, 1.05 eq), 85 μL of acetic acid (1.5 mmol, 1.04 eq), and 455 mg of sodium triacetoxyborohydride (2.14 mmol, 1.5 eq) were added to 4.65 mL of DCE (15 mL/g). The mixture was stirred at room temperature for 4 h, then subjected to sand-making automated column chromatography using 10% petroleum ether/ethyl acetate as the eluent. The mixture was concentrated under reduced pressure to yield 60-4. MS (ESI) m/z (M ⁷⁹ Br+H) ⁺ = 286.

Steps 3 to 4: Synthesis of 60-1

Compound 60-1 can be prepared using the method described in Example 5 and substituting 60-4 for compound 4-4. ¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 62: Synthesis of Compound 61-1

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

Compound 61-1 can be prepared using the method described in Example 56 and replacing compound 55-2 with 4-bromo-2,5-dimethylaniline (CAS: 30273-40-6). ¹ H NMR (400MHz, DMSO-d ₆ )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.

2. Biological Evaluation

(1) PTPN2/PTPN1 enzyme activity analysis test method

Compound activity was determined by an in vitro enzymatic assay using unlabeled full-length human PTPN2/PTPN1 protein. PTPN2/PTPN1 enzyme was diluted to a final concentration of 0.5 nM in assay buffer (50 mM HEPES, pH 7.2, 100 mM NaCl, 1 mM EDTA, 0.005% Tween-20, and 5 mM TCEP) and added to a black 384-well plate (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 plate was transferred to a SpectraMax plate reader (Molecular Devices) and fluorescence intensity was measured (ex 358, em 455). Each plate included a 100% inhibition control (no enzyme) and a 0% inhibition control (DMSO), from which the % inhibition of the test compound was calculated. _IC50 values were determined from the % inhibition data using a four-parameter curve fit.

The obtained _IC50 values are shown in Table 1, where A represents compound activity below 10 nM, B represents compound activity between 10-100 nM, C represents compound activity between 100 nM-1 μM, and D represents compound activity above 1 μM.

Table 1 _IC50 values of the inhibitory activity of the example compounds on PTPN1/PTPN2 phosphatase

(2) Pharmacokinetic test of some compounds of the present invention in rats

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 the prescribed 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 the present invention are as follows:

Table 2 Pharmacokinetic test results of compounds in rats

As shown in Table 2, introducing basic groups into the molecule to neutralize nitrogen atoms and increase 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 (10)

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
in: Ring A is an aromatic ring or an aromatic heterocyclic ring, independently and arbitrarily substituted by one or more R ² ; ^R1 is selected from hydrogen, halogen, _C1-6 alkyl, _C3-8 cycloalkyl, adamantyl and:
in: m = 0-5; n = 1-3; o=1-3; ^R3 is independently selected from CH and N; R ⁴ is independently selected from CH, N and O, and when R ⁴ ＝O, R ⁵ is absent; When R ⁴ ═N or CH, R ⁵ is independently selected from hydrogen, oxo, C _1-6 alkyl-S(═O) ₂ —, C _1-6 alkyl-NH-C(═O)-, C ₃ -C ₆ cycloalkyl-C(═O)-, C _3-6 cycloalkyl-S(═O) ₂ —, C _3-6 heterocycloalkyl-C(═O)-, and C _3-6 heterocycloalkyl-S(═O) ₂ —; R ² is independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy; R ⁶ is independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl; R ¹⁰ is independently selected from C and N; when R ¹⁰ is N, R ⁷ is absent, and R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl; When R ¹⁰ is C, R ⁷ , R ⁸ , and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl, and C _3-6 cycloalkyl; L is selected from -NR ⁸ -, -CH ₂ -, -CH ₂ -NH-, -S(=O) ₂ -, -C(=O)NH-, -NHC(=O)-, -S(=O) ₂ NH-, -NHS(=O) ₂ -, or -C(=O)-; p=0-3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is an aromatic ring or an aromatic heterocycle, independently and arbitrarily substituted by one or more ^R2 ; the aromatic ring is a substituted or unsubstituted phenyl group, wherein the substitution is a _C1-4 haloalkyl group; the aromatic heterocycle is a substituted or unsubstituted 5- to 6-membered aromatic heterocycle containing one or two atoms of S, O, and N, wherein the substitution is a _C1-4 alkyl group; ^R1 is selected from hydrogen, halogen, _C1-6 alkyl, _C3-8 cycloalkyl, adamantyl and: in: m = 0, 1, 2, 3, 4 or 5; n = 1, 2, or 3; o = 1, 2, or 3; ^R3 is independently selected from CH and N; R ⁴ is independently selected from CH, N and O, and when R ⁴ ＝O, R ⁵ is absent; When R ⁴ ═N or CH, R ⁵ is independently selected from hydrogen, C _1-6 alkyl-S(═O) ₂ —, C _1-6 alkyl-NH-C(═O)-, C _3-6 cycloalkyl-C(═O)-, C _3-6 cycloalkyl-S(═O) ₂ —, C _3-6 heterocycloalkyl-C(═O)-, and C _3-6 heterocycloalkyl-S(═O) ₂ —; R ² is independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, trifluoromethyl, trifluoromethoxy; R ⁶ is independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl; R ¹⁰ is independently selected from C and N; when R ¹⁰ is N, R ⁷ is absent, R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl; when R ¹⁰ is C, R ⁷ , R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl; L is selected from ^-NRa- , _-CH2- , -CH2 _- ^NRb- , -S(=O) _2- , -C(=O) ^NRc- , -C(=NH)NRd-, -NRcC(= _O )-, -S(=O) ^{2NRe- , -NReS} ( ⁼ O) _2- , or -C(=O)-; R ^a , R ^b , R ^c , R ^d , and R ^e are each independently selected from hydrogen, C _1-6 alkyl, and C _3-6 cycloalkyl; p=0, 1, 2 or 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from: is independently and optionally substituted with one or more R ² ; in: U＝CH or N; V＝CH or N; W＝NH, O or S; X＝CH or N; Y＝CH or N; h = 0, 1, 2, or 3; i = 0, 1, 2, or 3; Z, Z', are independently selected from N and CH; R ² is independently selected from hydrogen, halogen, trifluoromethyl, C _1-6 alkyl; ^R1 is selected from hydrogen, halogen, _C1-6 alkyl, _C3-8 cycloalkyl, adamantyl and:
in: m = 0, 1, 2, or 3; n = 1, 2, or 3; o = 1, 2, or 3; q = 0, 1, 2, or 3; ^R3 is independently selected from CH and N; R ⁴ is independently selected from C, CH, N and O, and when R ⁴ ＝O, p＝0, that is, R ⁵ does not exist; When R ⁴ =N or CH, t=1, R ⁵ is independently selected from hydrogen, C _1-6 alkyl-S(=O) ₂ -, C _3-6 cycloalkyl-C(=O)-, C _3-6 cycloalkyl-S(=O) ₂ - and C _3-6 heterocycloalkyl-C(=O)-; when R ⁴ =C, t=1-2, R ⁵ is independently selected from halogen, oxo and C _1-6 alkyl; R ² is independently selected from hydrogen, halogen, hydroxy, C _1-6 alkyl, C _3-6 cycloalkyl, trifluoromethyl; R ⁶ is independently selected from hydrogen, halogen, hydroxy, cyano and C _1-6 alkyl; R ¹⁰ is independently selected from C and N; when R ¹⁰ is N, R ⁷ is absent, R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, cyano, C _1-6 alkyl and C _3-6 cycloalkyl; when R ¹⁰ is C, R ⁷ , R ⁸ and R ⁹ are independently selected from hydrogen, halogen, hydroxy, C _1-6 alkyl and C _3-6 cycloalkyl; L is selected from ^-NRa- , _-CH2- , -CH2 _- ^NRb- , -S(=O) _2- , -C(=O) ^NRc- , -C(=NH) ^NRd- , ^-NRcC (=O)-, -S(＝O) ₂ NR ^e -, -NR ^e S(＝O) ₂ -or -C(＝O)-; R ^a , R ^b , R ^c , R ^d , and R ^e are each independently selected from hydrogen, C _1-3 alkyl, and C _3-6 cycloalkyl; p=0, 1, 2 or 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from: is independently and optionally substituted with one or more R ² ; in: U＝CH or N; V＝CH or N; W＝NH, O or S; Z, Z' are independently selected from N and CH; h = 1-2; i=1-2; R ¹ is selected from hydrogen, (CH ₃ ) ₂ -CH-(CH ₂ ) _0-4 -, The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is: ^R1 is: hydrogen, The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is a compound or a pharmaceutically acceptable salt thereof selected from any of the following structures:
A method for preparing the compound represented by general formula (I) according to claim 1, characterized in that: When L is -NHC(=O)-,
When L is -NH-,
When L is -NH-, A is hour,
A, R ¹ , h, and i are as defined in any one of claims 1-4. A method for preparing a compound represented by general formula (V), characterized in that:
wherein A and R ¹ are as defined in any one of claims 1-5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PTPN2/PTPN1-mediated diseases.