Furanamide compounds and uses thereof

Abstract

The application discloses a furan amide compound and application thereof, and belongs to the technical field of medicines.The structural general formula of the furan amide compound is shown as formula (I).The application provides a novel furan amide AR antagonist, the compound and the derivative thereof have obvious antagonistic activity on an androgen receptor, and exhibit good biological activity in in-vivo and in-vitro biological evaluation, the androgen receptor antagonistic activity is better than that of enzalutamide, the compound is effective in an AR F877L / T878A double-point mutant cell model resistant to enzalutamide, the activity is better than that of darolutamide, and the compound has good safety.Therefore, the compound can be applied to the treatment of diseases related to the androgen receptor as an androgen receptor antagonist, including but not limited to the treatment of prostate cancer, breast cancer, ovarian cancer and the like.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to furanamide compounds and their derivatives, and their use in the preparation of antitumor drugs, particularly their use as androgen receptor antagonists in the preparation of drugs for treating prostate cancer. Background Technology

[0002] Prostate cancer is the second most common cancer among men worldwide and the fifth leading cause of cancer death. In recent years, with population aging and changes in dietary habits, the incidence and mortality rates of prostate cancer in my country have been rising year by year. Therefore, prostate cancer has become a major "health killer" that seriously threatens human life.

[0003] Prostate cancer has a complex pathogenesis and is a multi-stage progressive disease. Based on disease progression, it can be classified into localized, locally advanced, and metastatic prostate cancer. Localized prostate cancer can be cured through surgery, radiotherapy, and other methods. For locally advanced and metastatic prostate cancer, the first-line treatment strategy is androgen deprivation therapy (ADT), which uses gonadotropin-releasing hormone agonists or antagonists and CYP17A1 inhibitors. Both normal prostate cells and cancer cells depend on androgens for growth. Surgical or medical castration can significantly reduce androgen levels in early-stage prostate cancer patients, thereby inhibiting the androgen-androgen receptor (AR)-dependent signaling pathway and ultimately suppressing the growth of prostate cancer cells. However, most patients who undergo ADT treatment typically progress to castration-resistant prostate cancer (CRPC) within two years, which has a poor prognosis, with a median survival of only 3-4 years, making it the most important factor contributing to death in prostate cancer patients.

[0004] Currently, a key strategy for treating CRPC in clinical practice is targeting the androgen receptor (AR). The AR belongs to the nuclear receptor superfamily and consists of four domains: an N-terminal domain, a DNA-binding domain, a flexible hinge region, and a C-terminal ligand-binding domain. The ligand-binding domain contains the ligand-binding pocket (LBP), which is the androgen-binding pocket. Two generations of AR antagonists are currently available clinically: first-generation drugs include flutamide, bicalutamide, and nilumid; second-generation drugs include enzalutamide, apalutamide, and dalostumamide. All of these second-generation AR antagonists target the AR's ligand-binding pocket (LBP), but prolonged use can lead to mutations and drug resistance. Most resistance mutations in the androgen receptor occur in the ligand-binding domain, particularly concentrated in the ligand-binding pocket, including F877L, T878A, H875Y, and W742C. These resistance mutations directly affect the binding of drugs to the ligand-binding pocket, reducing drug efficacy. At the same time, when drug resistance mutations occur, multidrug resistance often results, which severely limits the choice and effectiveness of clinical treatment.

[0005] Therefore, the search for and discovery of AR antagonists with novel structures and mechanisms can help overcome AR LBP mutation resistance and has important clinical value.

[0006] Inspired by gain-of-function mutations in androgen insensitivity syndrome, the inventors' team previously demonstrated through molecular dynamics simulations and small-angle X-ray scattering experiments that these mutations can disrupt AR dimerization, thereby blocking the AR signaling pathway. Further structural analysis of the AR dimerization interface revealed a novel binding pocket. Targeting this binding pocket, a lead molecule with certain AR transcriptional repressive activity was obtained through structure-based virtual screening and structural optimization (see patent document CN113444081B). Based on this, further structural optimization of the lead molecule is expected to yield novel compounds with further enhanced pharmacological activity. Summary of the Invention

[0007] The purpose of this invention is to provide a novel compound with androgen receptor antagonistic activity, which can be used in the preparation of drugs for treating androgen receptor-mediated diseases such as prostate cancer.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] This invention provides a furanamide compound, or a pharmaceutically acceptable salt thereof, said compound having a structure of the general formula shown in formula (I):

[0010]

[0011] Wherein, R1 and R2 are selected from hydrogen, halogen, nitro, cyano, hydroxyl, amino, C, respectively. 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy groups, C 1-3 alkylamine group, C 1-3 Dialkylamine group, C 3-6 Cycloalkylamine, C 1-3 Alkyl sulfone group;

[0012] R3 is selected from hydrogen, C 1-4 alkyl;

[0013] When X is O, Y and Z are selected from CH and N respectively, and at least one of Y and Z is N;

[0014] When X is S, Y is CH and Z is N;

[0015] When X is N, Y is N or CH, and Z is S;

[0016] L is selected from -CH2- and -CO-;

[0017] G is selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Fluoroalkyl groups, -NR4R5, -NH(CH2) n NR4R5, n = 1-3; R4 and R5 are independent and can be the same or different, selected from hydrogen, acetyl, hydroxyethyl, hydroxypropyl, methanesulfonyl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl; or NR4R5 is a 3-8 member cyclic amine or substituted cyclic amine, selected from morpholine, thiomorpholine, thiomorpholine dioxide, piperazine, pyrrolidine, piperidine, with substituents selected from hydrogen, halogen, amino, cyano, isopropyl, acetyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy groups, C 3-8 cycloalkyl, C 1-6 alkylamine group, C 1-6 Dialkylamine group.

[0018] Preferably, in the furanamide compound, R1 and R2 are selected from H, F, Cl, Br, NO2, CN, CH3, CF3, CF3CH2, OCH3, OCHF2, OCF3, OCH2CHF2, and OCH2CF3, respectively.

[0019] R3 is selected from H, CH3, and CH2CH3;

[0020]

[0021] L is selected from -CH2- and -CO-;

[0022] G is selected from H, F, CH3, CH2CH3, CF3, NH2, NHCH3, N(CH3)2, N(CH2CH3)2, OH, OCH3, OCH2CH3.

[0023] More preferably, the furanamide compounds have structural formulas as shown in any one of A-1 to A-57, B-1 to B-18, C-1 to C-18, D-1 to D-6, E-1 to E-6, F-1 to F-6, and G-1 to G-6.

[0024]

[0025]

[0026]

[0027]

[0028]

[0029] The present invention also provides derivatives of the aforementioned furanamide compounds, and pharmaceutically acceptable salts or mixtures thereof, tautomers, stereoisomers, solvates, metabolites, and prodrug molecules thereof.

[0030] Pharmaceutically acceptable salts include, but are not limited to, organic acid salts, inorganic acid salts, organic base salts, and inorganic base salts. Organic acid salts include, but are not limited to, oxalates, lactates, p-toluenesulfonates, maates, citrates, fumarates, camphorsulfonates, and methanesulfonates. Inorganic acid salts include, but are not limited to, nitrates, sulfates, hydrohalates, and phosphates. Organic base salts include, but are not limited to, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, triethylamine, and tert-butylamine. Inorganic base salts include, but are not limited to, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0031] The solvate is a complex with variable stoichiometry formed by a solute (the compound of formula (I) provided in this invention) and a solvent. Solvents include, but are not limited to, pharmaceutically acceptable solvents such as water, methanol, ethanol, and acetic acid.

[0032] This invention also provides polymorphs of the aforementioned furanamide compounds, their salts, or their solvates. The furanamide compounds, their salts, or their solvates can exhibit polymorphism, meaning they can produce different crystalline forms with different physical properties, such as density, stability, and solubility. Since different crystal forms and salt forms of drugs may affect their dissolution and absorption in vivo, this can, to some extent, affect the clinical efficacy and safety of the drugs. This invention, through the study of the polymorphism of compounds of formula (I), provides polymorphs that are easy to process and suitable for drug formulation.

[0033] This invention has revealed that the furanoamide compounds and their derivatives exhibit significant antagonistic activity against androgen receptors, demonstrating good biological activity in both in vitro and in vivo biological evaluations. Therefore, these compounds can be applied to the treatment of tumors associated with abnormal androgen receptor expression or mutations.

[0034] Specifically, the present invention provides the use of the aforementioned furanamide compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or prodrug molecules thereof, or polymorphs thereof, in the preparation of androgen receptor antagonists.

[0035] This invention also provides the use of the aforementioned furanamide compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or prodrug molecules thereof, or polymorphs, in the preparation of medicaments for treating prostate cancer, breast cancer, and ovarian cancer. The prostate cancers include, but are not limited to, metastatic prostate cancer and castration-resistant prostate cancer. It is worth noting that the pharmaceutical use of these compounds is not limited to the preparation of drugs for the aforementioned tumors.

[0036] The therapeutic mechanism of the drug includes: its active ingredient, furanamide compounds, inhibits tumor cell proliferation by antagonizing androgen receptor activity; furthermore, furanamide compounds exert their antagonistic effect on androgen receptors by blocking the dimerization of androgen receptor ligand domains.

[0037] The present invention also provides a pharmaceutical composition for treating tumors associated with abnormal expression or mutation of androgen receptors, comprising a therapeutically effective amount of one or more of the aforementioned furanamide compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or prodrug molecules thereof, or polymorphs thereof, and a pharmaceutically acceptable carrier.

[0038] The carrier is a commonly used excipient, filler, disintegrant, diluent, surfactant, absorption enhancer, adsorbent, binder, lubricant, humectant, flavoring agent, sweetener, etc. in the pharmaceutical field. The pharmaceutical formulations of this invention can be prepared according to conventional methods in the pharmaceutical field, including but not limited to capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, or patches.

[0039] The compounds provided by this invention can be used in combination with existing antitumor drugs, including but not limited to microtubule degradation inhibitors (such as paclitaxel), mitotic inhibitors (such as vincristine, vindesine, etc.), antimetabolites (such as 5-fluorouracil, methotrexate, etc.), alkylating agents (cisplatin, carboplatin, etc.), intercalable antibiotics (mitomycin, etc.), topoisomerase inhibitors (such as etoposide and camptothecin), biological response modifiers (such as interferon), proteasome inhibitors (such as bortezomib), etc.

[0040] The beneficial effects of this invention are as follows:

[0041] This invention provides a novel class of furanamide-type androgen receptor antagonists. These compounds and their derivatives exhibit significant antagonistic activity against androgen receptors, demonstrating good biological activity in both in vivo and in vitro biological evaluations. Dozens of these compounds show superior activity compared to enzalutamide, and are effective in an enzalutamide-resistant AR F877L / T878A double-point mutant cell model, exhibiting activity superior to dalostumamide, and demonstrating good safety. Therefore, these compounds can be used as androgen receptor antagonists in the treatment of androgen receptor-related diseases, including but not limited to the treatment of prostate cancer, metastatic prostate cancer, castration-resistant prostate cancer, breast cancer, and ovarian cancer. Attached Figure Description

[0042] Figure 1 This is a synthetic route diagram for compounds A-1 to A-41.

[0043] Figure 2 This is the synthetic route diagram for compound A-1.

[0044] Figure 3 This is a synthetic route diagram for compounds A-42 to A-57.

[0045] Figure 4 This is the synthetic route diagram for compound A-42.

[0046] Figure 5 This is a synthetic route diagram for compounds B-1 to B-18.

[0047] Figure 6 This is the synthetic route diagram for compound B-1.

[0048] Figure 7 This is a synthetic route diagram for compounds C-1 to C-18.

[0049] Figure 8 This is the synthetic route diagram for compound C-1.

[0050] Figure 9 This is a synthetic route diagram for compounds D-1 to D-6.

[0051] Figure 10 This is the synthetic route diagram for compound D-1.

[0052] Figure 11 This is a synthetic route diagram for compounds E-1 to E-6, F-1 to F-6, and G-1 to G-6.

[0053] Figure 12 This is the synthetic route diagram for compound E-1. Detailed Implementation

[0054] The present invention will be further described below with reference to specific embodiments. These specific embodiments are for illustrative purposes only and should not be construed as limiting the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0055] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0056] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0057] Example 1: Preparation of target molecules A-1 to A-41

[0058] The synthetic routes for compounds A-1 to A-41 are as follows: Figure 1 As shown.

[0059] 1. Preparation of 2-methyl-N-(4-(pyrrolidone-1-ylmethyl)thiazolyl-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound A-1), the specific synthetic route is as follows: Figure 2 As shown, the method is as follows:

[0060] (a) Synthesis of 2-bromo-1-(3-trifluoromethylphenyl)ethyl-1-one (compound I-2-1)

[0061] m-Trifluoromethylacetophenone (I-1-1, 0.94 g, 5.0 mmol), N-bromosuccinimide (0.98 g, 5.5 mmol), and p-toluenesulfonic acid (0.43 g, 2.5 mmol) were dissolved in acetonitrile (20 mL), and the mixture was stirred at 60 °C for 1 h. The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated saline solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain a crude product, I-2-1, a pale yellow oily liquid, in 92% yield; ESI-MS: m / z = 267.0 [M+H]. + .

[0062] (b) Synthesis of ethyl 2-acetyl-4-oxo-4-(3-trifluoromethylphenyl)butyrate (compound I-3-1)

[0063] At 0°C, a THF (10 mL) solution of ethyl acetoacetate (439 mg, 4.2 mmol) was added dropwise to a 20 mL suspension of anhydrous THF of sodium hydride (60% w / w, 197 mg, 4.7 mmol). After stirring for half an hour, a THF (10 mL) solution of compound I-2-1 (1.25 g, 4.7 mmol) was added dropwise, and the mixture was then allowed to react overnight at room temperature. After quenching with an appropriate amount of water, an appropriate amount of ethyl acetate was added, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was subjected to column chromatography to give a pale yellow solid I-3-1, with a yield of 73%. 1 H NMR(500MHz,Chloroform-d)δ8.23(s,1H),8.17(d,J=8.0Hz,1H),7.85(d,J=8.0Hz,1H),7.63(t,J=8.0Hz,1H),4.30-4.20(m, 3H), 3.74 (dd, J=18.5, 8.0Hz, 1H), 3.52 (dd, J=18.5, 5.5Hz, 1H), 2.46 (s, 3H), 1.31 (t, J=7.0Hz, 3H); ESI-MS: m / z=317.1[M+H] + .

[0064] (c) Synthesis of ethyl 2-methyl-5-(3-trifluoromethylphenyl)furan-3-carboxylate (compound I-4-1)

[0065] Under N2 protection, compound I-3-1 (946 mg, 3.0 mmol) was dissolved in acetonitrile (20 mL), and trifluoromethanesulfonic acid (449 mg, 3.0 mmol) was added. The mixture was then heated to 85 °C and reacted for 1 h. A suitable amount of ethyl acetate was added to the system, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was subjected to column chromatography to give a pale yellow solid I-4-1, with a yield of 78%. 1 H NMR(500MHz,Chloroform-d)δ7.90-7.87(m,1H),7.83-7.78(m,1H),7.56-7.46(m,2H),6.99 (s,1H),4.33(q,J=7.0Hz,2H),2.67(s,3H),1.38(t,J=7.0Hz,3H); ESI-MS:m / z=299.1[M+H] + .

[0066] (d) Synthesis of 2-methyl-5-(3-trifluoromethylphenyl)furan-3-carboxylic acid (compound I-5-1)

[0067] Compound I-4-1 (600 mg, 2.22 mmol) was dissolved in ethanol and water (3:1, 20 mL), and sodium hydroxide (552 mg, 13.8 mmol) was added. The mixture was reacted overnight at room temperature. Part of the solvent was removed under reduced pressure, and the pH was adjusted to 3-4 by adding 2 mol / L dilute hydrochloric acid. The mixture was then filtered to obtain a white solid I-5-1, with a yield of 90%. 1 H NMR (500MHz, DMSO-d6) δ12.76(s,1H),8.06-7.96(m,2H),7.71-7.62(m,2H),7.37(s,1H),2.62(s,3H).ESI-MS: m / z=271.1[M+H] + .

[0068] (e) Synthesis of 4-(pyrrolidone-1-ylmethyl)thiazol-2-amine (compound I-7-1)

[0069] 2-Amino-4-chloromethylthiazolium hydrochloride I-6 (740 mg, 4.0 mmol) and tetrahydropyrrole (500 μL, 6.0 mmol) were dissolved in acetonitrile (10 mL), and then triethylamine (1.11 mL, 8.0 mmol) was added. The mixture was reacted overnight at room temperature. The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated saline solution. The solution was then dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid I-7-1 in 81% yield. 1 H NMR (500MHz, DMSO-d6) δ7.12(s,2H),6.77(s,1H),4.09(s,2H),3.30(s,4H),1.92-1.88(m,4H).ESI-MS:m / z=184.1[M+H] + .

[0070] (f) Preparation of 2-methyl-N-(4-(pyrrolidone-1-ylmethyl)thiazolyl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-1)

[0071] Compound I-5-1 (270 mg, 1.0 mmol), compound I-7-1 (183 mg, 1.0 mmol), EDCI (382 mg, 2.0 mmol), and 4-PPY (15 mg, 0.1 mmol) were dissolved in DCM (10 mL) and refluxed with stirring overnight. The solvent was removed under reduced pressure, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid A-1 in 76% yield. 1H NMR(500MHz,DMSO-d6)δ12.26(s,1H),7.94-7.87(m,3H),7.76-7.69(m,2H), 7.11(s,1H),3.82(s,2H),2.70(s,7H),1.76(s,4H).ESI-MS:m / z=436.1[M+H] + .

[0072] 2. Preparation of N-(4-((3,3-difluoropyrrolidone-1-yl)methyl)thiazolyl)-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-2)

[0073] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with 3,3-difluoropyrrole to give a white solid in 68% yield; 1 H NMR(500MHz,DMSO-d6)δ12.26(s,1H),7.94-7.85(m,3H),7.76-7.68(m,2H),7.06(s,1H),3.69(s, 2H),2.97(s,2H),2.77(s,2H),2.70(s,3H),2.25(tt,J=14.8,6.9Hz,2H).ESI-MS:m / z=471.2[M+H] + .

[0074] 3. Preparation of N-(4-((3-hydroxypyrrolidone-1-yl)methyl)thiazolyl)-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-3)

[0075] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with 3-hydroxypyrrole to give a white solid in 61% yield; 1 H NMR(500MHz,DMSO-d6)δ12.26(s,1H),8.04-7.81(m,3H),7.77-7.62(m,2H),7.13(s,1H),4.91(s,1H), 4.25(s,1H),3.84(s,2H),3.06-2.55(m,7H),2.06-1.95(m,1H),1.63(s,1H).ESI-MS: m / z=452.1[M+H] + .

[0076] 4. Preparation of N-(4-((dimethylamino)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-4)

[0077] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with dimethylamino to give a white solid in 56% yield; 1 HNMR(500MHz,DMSO-d6)δ12.28(s,1H),(t,J=1.9Hz,1H),8.07–7.89(m,3H),7.67–7.5 6(m,2H),7.02(s,1H),3.62(s,2H),2.73(s,6H),2.61(s,3H).ESI-MS:m / z=410.1[M+H] + .

[0078] 5. Preparation of N-(4-((diethylamino)methyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-5)

[0079] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with diethylamino to give a white solid in 63% yield; 1 HNMR(500MHz,DMSO-d6)δ12.23(s,1H),7.94-7.86(m,3H),7.76-7.67(m,2H),7.04( s,1H),3.66(s,2H),2.70(s,3H),2.57(s,4H),1.03(s,6H).ESI-MS:m / z=438.1[M+H] + .

[0080] 6. Preparation of 2-methyl-N-(4-methylthiazo-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-6)

[0081] Following the synthesis of compound A-1, 4-(pyrrolidone-1-ylmethyl)thiazol-2-amine (I-7-1) was replaced with 4-methylthiazol-2-amine to give a white solid in 83% yield; 1 H NMR(500MHz,DMSO-d6)δ12.17(s,1H),7.93-7.82(m,3H),7.75-7.66(m,2H),6.8 1(d,J=1.2Hz,1H),2.70(s,3H),2.31(d,J=1.1Hz,3H).ESI-MS:m / z=367.1[M+H] + .

[0082] 7. Preparation of 2-methyl-N-(4-(piperidin-1-ylmethyl)thiazo-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-7)

[0083] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with piperidine, yielding a white solid in 52% yield; 1 H NMR(500MHz,DMSO-d6)δ12.26(s,1H),7.93-7.86(m,3H),7.75-7.68(m,2H),6.98(s,1H),3.4 8(s,2H),2.70(s,3H),2.40(s,4H),1.50(m,4H),1.42-1.34(m,2H).ESI-MS:m / z=450.1[M+H] + .

[0084] 8. Preparation of N-(4-((4,4-difluoropiperidin-1-yl)methyl)thiazolyl)-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-8)

[0085] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with 4,4-difluoropiperidine to give a white solid in 78% yield; 1 H NMR(500MHz,DMSO-d6)δ12.28(s,1H),7.95-7.85(m,3H),7.76-7.67(m,2H),7.05(s,1H),3.60(s,2H),2.70(s,3H),2.56(t,J=5.7Hz,4H),2.01 -1.91(m,4H).ESI-MS:m / z=486.1[M+H] + .

[0086] 9. Preparation of N-(4-((4,4-difluoropiperidin-1-yl)methyl)thiazolyl-2-yl)-5-(3-methoxyphenyl)-2-methylfuran-3-carboxamide (Compound A-9)

[0087] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-methoxyacetophenone, and tetrahydropyrrole was replaced with 4,4-difluoropiperidine, yielding a white solid in 76% yield; ESI-MS: m / z = 448.1 [M+H] + .

[0088] 10. Preparation of N-(4-((4,4-difluoropiperidin-1-yl)methyl)thiazolyl)-2-methyl-5-(3-(trifluoromethoxy)phenyl)furan-3-carboxamide (Compound A-10)

[0089] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-trifluoromethoxyacetophenone, and tetrahydropyrrole was replaced with 4,4-difluoropiperidine, yielding a white solid in 65% yield; ESI-MS: m / z = 502.1 [M+H]+ .

[0090] 11. Preparation of 5-(3-(difluoromethoxy)phenyl)-N-(4-((4,4-difluoropiperidin-1-yl)methyl)thiazolyl)-2-methylfuran-3-carboxamide (Compound A-11)

[0091] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-difluoromethoxyacetophenone, and tetrahydropyrrole was replaced with 4,4-difluoropiperidine, yielding a white solid in 60% yield; ESI-MS: m / z = 484.1 [M+H] + .

[0092] 12. Preparation of 5-(3-cyanophenyl)-N-(4-((4,4-difluoropiperidin-1-yl)methyl)thiazolyl)-2-methylfuran-3-carboxamide (Compound A-12)

[0093] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-cyanoacetophenone, and tetrahydropyrrole was replaced with 4,4-difluoropiperidine, yielding a white solid in 79% yield; ESI-MS: m / z = 443.1 [M+H] + .

[0094] 13. Preparation of 2-methyl-5-(3-(trifluoromethyl)phenyl)-N-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)thiazo-2-yl)furan-3-carboxamide (Compound A-13)

[0095] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with p-trifluoromethylpiperidine, yielding a white solid in 66% yield; 1 H NMR (500MHz, DMSO-d6) δ12.27(s,1H),7.97-7.84(m,3H),7.77-7.66(m,2H),7.02(s,1H),3.53(s,2H),2.95(d,J=11.2Hz,2H) ,2.70(s,3H),2.32-2.19(m,1H),2.09-1.97(m,2H),1.84-1.73(m,2H),1.45(qd,J=12.4,4.0Hz,2H).ESI-MS:m / z=518.1[M+H] + .

[0096] 14. Preparation of N-(4-((4-(dimethylamino)piperidin-1-yl)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-14)

[0097] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with p-dimethylaminopiperidine to give a white solid in 52% yield; 1 H NMR(500MHz,DMSO-d6)δ12.25(s,1H),7.94-7.86(m,3H),7.72-7.69(m,2H),6.98(s,1H),3.48(s,2H),2.92-2.86(m,2H),2.70(s,3H),2.19( s,6H),2.09(s,1H),1.98(td,J=11.6,2.3Hz,2H),1.72(d,J=11.9Hz,2H),1.63(p,J=6.0Hz,1H),1.42-1.38(m,1H).ESI-MS:m / z=493.2[M+H] + .

[0098] 15. Preparation of N-(4-((4-methoxypiperidin-1-yl)methyl)thiazolyl-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-15)

[0099] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with p-methoxypiperidine to give a white solid in 77% yield; 1 H NMR(500MHz,DMSO-d6)δ12.27(s,1H),7.93-7.86(m,3H),7.76-7.69(m,2H),7.00(s,1H),3.50(s,2H),3.21(s, 3H),3.16(s,1H),2.70(s,5H),2.15(s,2H),1.82(d,J=10.5Hz,2H),1.47-1.35(m,2H).ESI-MS:m / z=480.1[M+H] + .

[0100] 16. Preparation of N-(4-((4-hydroxypiperidin-1-yl)methyl)thiazolyl)-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-16)

[0101] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with p-hydroxypiperidine, yielding a white solid in 60% yield; 1HNMR(500MHz,DMSO-d6)δ12.26(s,1H),7.95-7.85(m,3H),7.76-7.68(m,2H),7.07-6.91(m,1H),4.55(s,1H),3.4 7(d,J=22.2Hz,3H),2.70(s,5H),2.11(s,2H),1.71(d,J=11.6Hz,2H),1.45-1.35(m,2H).ESI-MS:m / z=466.1[M+H] + .

[0102] 17. Preparation of N-(4-((4-hydroxypiperidin-1-yl)methyl)thiazolyl-2-yl)-5-(3-methoxyphenyl)-2-methylfuran-3-carboxamide (Compound A-17)

[0103] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-methoxyacetophenone, and tetrahydropyrrole was replaced with 4-hydroxypiperidine, yielding a white solid in 68% yield; ESI-MS: m / z = 428.1 [M+H] + .

[0104] 18. Preparation of N-(4-((4-hydroxypiperidin-1-yl)methyl)thiazolyl)-2-yl)-2-methyl-5-(3-(trifluoromethoxy)phenyl)furan-3-carboxamide (Compound A-18)

[0105] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-trifluoromethoxyacetophenone, and tetrahydropyrrole was replaced with 4-hydroxypiperidine, yielding a white solid in 61% yield; ESI-MS: m / z = 482.1 [M+H] + .

[0106] 19. Preparation of 5-(3-(difluoromethoxy)phenyl)-N-(4-((4-hydroxypiperidin-1-yl)methyl)thiazolyl)-2-methylfuran-3-carboxamide (A-19)

[0107] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-difluoromethoxyacetophenone, and tetrahydropyrrole was replaced with 4-hydroxypiperidine, yielding a white solid in 58% yield; ESI-MS: m / z = 464.1 [M+H] + .

[0108] 20. Preparation of N-(4-((3-hydroxypiperidin-1-yl)methyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-20)

[0109] Following the synthesis of compound A-1, replacing tetrahydropyrrole with 3-hydroxypiperidine yielded a white solid in 66% yield; ESI-MS: m / z = 466.1 [M+H] + .

[0110] 21. Preparation of N-(4-((2-hydroxypiperidin-1-yl)methyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-21)

[0111] Following the synthesis of compound A-1, replacing tetrahydropyrrole with 2-hydroxypiperidine yielded a white solid in 60% yield; ESI-MS: m / z = 466.1 [M+H] + .

[0112] 22. Preparation of N-(4-((4-(hydroxymethyl)piperidin-1-yl)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-22)

[0113] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with p-hydroxymethylpiperidine, yielding a white solid in 71% yield; 1 H NMR(500MHz,DMSO-d6)δ12.27(s,1H),7.96-7.84(m,3H),7.76-7.67(m,2H),6.99(s,1H),4.41(s,1H),3.50(s,2H),3.24(d,J=6.2Hz,2H) ,2.86(d,J=27.8Hz,2H),2.70(s,3H),1.97(s,2H),1.64(d,J=12.5Hz,2H),1.37-1.30(m,1H),1.21-1.08(m,2H).ESI-MS:m / z=480.1[M+H] + .

[0114] 23. Preparation of N-(4-((4-(2-hydroxypropyl-2-yl)piperidin-1-yl)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-23)

[0115] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with 2-(4-piperidinyl)-2-propanol to give a white solid in 66% yield; 1H NMR(500MHz,DMSO-d6)δ12.27(s,1H),7.98–7.81(m,3H),7.76-7.69(m,2H),7.04(s,1H),4.07(s,1H),3.75-3.41(m,2H),3.00 (s,2H),2.70(s,3H),2.08(d,J=94.7Hz,2H),1.65(d,J=19.2Hz,2H),1.38-1.27(m,3H),1.02(s,6H).ESI-MS:m / z=508.1[M+H] + .

[0116] 24. Preparation of 2-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)thiazo-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-24)

[0117] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with 4-methylpiperazine to give a white solid in 72% yield; 1 HNMR(500MHz,DMSO-d6)δ12.27(s,1H),8.00-7.82(m,3H),7.77-7.66(m,2H),7.00( s,1H),3.50(s,2H),2.70(s,3H),2.44(s,8H),2.17(s,3H).ESI-MS:m / z=465.1[M+H] + .

[0118] 25. Preparation of N-(4-((4-ethylpiperazin-1-yl)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-25)

[0119] The preparation of target compound A-25 was based on the synthesis of compound A-1, except that tetrahydropyrrole was replaced with 4-ethylpiperazine, yielding a white solid in 74% yield. 1 H NMR(500MHz,DMSO-d6)δ12.27(s,1H),7.95-7.85(m,3H),7.75-7.69(m,2H),7.00(s,1H),3. 50(s,2H),2.70(s,3H),2.50-2.14(m,10H),0.98(t,J=7.2Hz,3H).ESI-MS:m / z=479.1[M+H] + .

[0120] 26. Preparation of N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-26)

[0121] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with N-hydroxyethylpiperazine to give a white solid in 64% yield; 1 H NMR(500MHz,DMSO-d6)δ12.26(s,1H),7.98-7.85(m,3H),7.76-7.69(m,2H),7.00(s,1H),4. 40(s,1H),3.50(d,J=9.2Hz,4H),2.70(s,3H),2.50-2.15(m,11H).ESI-MS:m / z=495.1[M+H] + .

[0122] 27. Preparation of N-(4-((4-acetylpiperazin-1-yl)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-27)

[0123] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with 4-acetylpiperazine to give a white solid in 73% yield; 1 HNMR(500MHz,DMSO-d6)δ12.29(s,1H),7.94-7.87(m,3H),7.76-7.67(m,2H),7.05(s,1H) ,3.55(s,6H),2.70(s,3H),2.41(d,J=22.0Hz,4H),1.98(s,3H).ESI-MS:m / z=493.1[M+H] + .

[0124] 28. Preparation of 2-methyl-N-(4-(morpholinomethyl)thiazolyl-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-28)

[0125] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with morpholine to give a white solid in 81% yield; 1H NMR(500MHz,Chloroform-d)δ9.75(s,1H),7.89-7.85(m,1H),7.77(dt,J=7.2,1.9Hz,1H),7.58-7.51(m,2H),6.86(s,1 H),6.82(s,1H),3.72(t,J=4.7Hz,4H),3.55-3.51(m,2H),2.77(s,3H),2.47(t,J=4.4Hz,4H).ESI-MS:m / z=452.1[M+H] + .

[0126] 29. Preparation of 2-methyl-N-(4-(morpholinomethyl)thiazolyl-2-yl)-5-(3-(trifluoromethoxy)phenyl)furan-3-carboxamide (Compound A-29)

[0127] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-trifluoromethoxyacetophenone, and tetrahydropyrrole was replaced with morpholine, yielding a white solid in 76% yield; 1 H NMR(500MHz,DMSO-d6)δ12.29(s,1H),7.82(s,1H),7.67-7.60(m,2H),7.54-7.49(m,1H),7.34(m,1H),7.0 3(s,1H),3.58(t,J=4.6Hz,4H),3.51(s,2H),2.69(s,3H),2.42(t,J=4.6Hz,4H).ESI-MS:m / z=468.1[M+H] + .

[0128] 30. Preparation of 5-(3-(difluoromethoxy)phenyl)-2-methyl-N-(4-(morpholinomethyl)thiazo-2-yl)furan-3-carboxamide (Compound A-30)

[0129] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-difluoromethoxyacetophenone, and tetrahydropyrrole was replaced with morpholine, yielding a white solid in 80% yield; 1 H NMR (500MHz, DMSO-d6) δ12.30(s,1H),7.78(s,1H),7.56-7.48(m,2H),7.37(t,J=2.0Hz,1H),7.33(s,1H),7.15(m, 1H),7.02(s,1H),3.58(t,J=4.6Hz,4H),3.51(s,2H),2.69(s,3H),2.42(t,J=4.6Hz,4H).ESI-MS:m / z=450.1[M+H] + .

[0130] 31. Preparation of 5-(3-methoxyphenyl)-2-methyl-N-(4-(morpholinomethyl)thiazo-2-yl)furan-3-carboxamide (Compound A-31)

[0131] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-methoxyacetophenone, and tetrahydropyrrole was replaced with morpholine, yielding a white solid in 69% yield; ESI-MS: m / z = 414.1 [M+H] + .

[0132] 32. Preparation of 5-(3-cyanophenyl)-2-methyl-N-(4-(morpholinomethyl)thiazo-2-yl)furan-3-carboxamide (Compound A-32)

[0133] Following the synthesis of compound A-1, m-trifluoromethylacetophenone was replaced with m-cyanoacetophenone, and tetrahydropyrrole was replaced with morpholine, yielding a white solid in 62% yield; ESI-MS: m / z = 409.1 [M+H] + .

[0134] 33. Preparation of N-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-33)

[0135] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with (2S,6R)-2,6-dimethylmorpholine to give a white solid in 70% yield; 1 H NMR(500MHz,DMSO-d6)δ12.27(s,1H),7.94-7.86(m,3H),7.75-7.69(m,2H),7.02(s,1H),3.61-3 .43(m,4H),2.70(s,5H),1.71(t,J=10.4Hz,2H),1.04(d,J=6.3Hz,6H).ESI-MS:m / z=480.1[M+H] + .

[0136] 34. Preparation of 2-methyl-N-(4-(thiomorpholinemethyl)thiazolyl-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-34)

[0137] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with thiomorpholine to give a white solid in 82% yield; 1HNMR(500MHz,DMSO-d6)δ12.28(s,1H),7.93-7.87(m,3H),7.75-7.69(m,2H),7.02(s,1H) ,3.54(s,2H),2.69(d,J=4.8Hz,7H),2.61(dd,J=5.9,3.9Hz,4H).ESI-MS:m / z=468.1[M+H] + .

[0138] 35. Preparation of N-(4-((1,1-dioxothiomorpholino)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-35)

[0139] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with thiomorpholine-1,1-dioxide to give a white solid in 74% yield; 1 H NMR(500MHz,DMSO-d6)δ12.29(s,1H),7.97-7.86(m,3H),7.77-7.68(m,2H),7.12(s,1H) ,3.75(s,2H),3.13(d,J=5.9Hz,4H),2.98(s,4H),2.70(s,3H).ESI-MS:m / z=500.1[M+H] + .

[0140] 36. Preparation of N-(4-(((2-hydroxyethyl)amino)methyl)thiazolyl-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-36)

[0141] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with 2-aminoethanol to give a white solid in 63% yield; 1 HNMR(500MHz,DMSO-d6)δ7.90(dd,J=17.0,6.6Hz,3H),7.77-7.65(m,2H),7.03(s,1H), 4.62(s,1H),3.81(s,2H),3.52(t,J=5.6Hz,2H),2.70(s,5H).ESI-MS:m / z=426.1[M+H] + .

[0142] 37. Preparation of N-(4-(((2-hydroxyethyl)(methyl)amino)methyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-37)

[0143] Following the synthesis of compound A-1, replacing tetrahydropyrrole with 2-methylaminoethanol yielded a white solid in 68% yield; ESI-MS: m / z = 440.1 [M+H] + .

[0144] 38. Preparation of (R)-N-(4-(((1-hydroxypropyl-2-yl)amino)methyl)thiazolyl-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-38)

[0145] Following the synthesis of compound A-1, replacing tetrahydropyrrole with (R)-2-aminopropane-1-ol yielded a white solid in 60% yield; ESI-MS: m / z = 440.1 [M+H] + .

[0146] 39. Preparation of N-(4-(((3-hydroxypropyl)amino)methyl)thiazolyl-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-39)

[0147] Following the synthesis of compound A-1, tetrahydropyrrole was replaced with 3-amino-1-propanol to give a white solid in 56% yield. 1 H NMR(500MHz,DMSO-d6)δ7.91(dd,J=19.0,7.5Hz,3H),7.76-7.69(m,2H),7.28(s,1H),4.06(s,2H),3 .49(t,J=6.1Hz,2H),2.95(t,J=7.6Hz,2H),2.70(s,3H),1.78-1.69(m,2H).ESI-MS:m / z=440.1[M+H] + .

[0148] 40. Preparation of 2-methyl-N-(4-(((2-morpholinoethyl)amino)methyl)thiazolyl-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-40)

[0149] Following the synthesis of compound A-1, replacing tetrahydropyrrole with N-(2-aminoethyl)morpholine yielded a white solid in 68% yield; ESI-MS: m / z = 495.1 [M+H] + .

[0150] 41. Preparation of N-(4-(hydroxymethyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-41)

[0151] Referring to the synthesis of compound A-1, 4-(pyrrolidone-1-ylmethyl)thiazol-2-amine (I-7-1) was replaced with 2-amino-4-hydroxymethylthiazolium to give a white solid in 70% yield; 1 H NMR(500MHz,DMSO-d6)δ8.09-8.03(m,2H),7.69-7.64(m,2H),7.45(s,1H),7.0 4(s,2H),6.64(s,1H),5.11-5.02(m,2H),2.65(s,3H).ESI-MS:m / z=383.1[M+H] + .

[0152] Example 2: General method for preparing target molecules A-42 to A-57

[0153] The synthetic routes for compounds A-42 to A-57 are as follows: Figure 3 As shown.

[0154] 1. Preparation of compound A-42, the synthetic route is as follows: Figure 4 As shown, the method is as follows:

[0155] (a) Synthesis of (2-aminothiazo-4-yl)(3,3-difluoropyrrolidone-1-yl)methyl ketone (I-7-a-1)

[0156] 2-Aminothiazol-4-carboxylic acid (I-6-a, 720 mg, 5.0 mmol), 3,3-difluoropyrrolidine (710 μL, 7.5 mmol), and HATU (3.80 g, 10.0 mmol) were dissolved in DMF (15 mL), and then DIPEA (2.6 mL, 15.0 mmol) was added dropwise to the reaction mixture. The mixture was stirred overnight at room temperature. A suitable amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid 1-7-a-1 in 88% yield; ESI-MS: m / z = 234.0 [M+H]. + .

[0157] (b) Preparation of N-(4-(3,3-difluoropyrrolidine-1-carbonyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-42)

[0158] Compound I-5-1 (270 mg, 1.0 mmol), compound I-7-a-1 (233 mg, 1.0 mmol), EDCI (382 mg, 2.0 mmol), and 4-PPY (15 mg, 0.1 mmol) were dissolved in DCM (10 mL) and refluxed with stirring overnight. The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated saline solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid A-42 in 78% yield; ESI-MS: m / z = 486.1 [M+H] + .

[0159] 2. Preparation of N-(4-(4,4-difluoropiperidin-1-carbonyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-43)

[0160] Following the synthesis of compound A-42, replacing 3,3-difluoropyrrolidine with 4,4-difluoropiperidine yielded a white solid in 81% yield; ESI-MS: m / z = 500.1 [M+H] + .

[0161] 3. Preparation of N-(4-(4-hydroxypiperidin-1-carbonyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-44)

[0162] Following the synthesis of compound A-42, replacing 3,3-difluoropyrrolidine with 4-hydroxypiperidine yielded a white solid in 76% yield; ESI-MS: m / z = 480.1 [M+H] + .

[0163] 4. Preparation of N-(4-(4-(hydroxymethyl)piperidin-1-carbonyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-45)

[0164] Following the synthesis of compound A-42, replacing 3,3-difluoropyrrolidine with p-hydroxymethylpiperidine yielded a white solid in 70% yield; ESI-MS: m / z = 494.1 [M+H] + .

[0165] 5. Preparation of 2-methyl-N-(4-(4-methylpiperazin-1-carbonyl)thiazolyl-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-46)

[0166] Following the synthesis of compound A-42, replacing 3,3-difluoropyrrolidine with 4-methylpiperazine yielded a white solid in 79% yield; ESI-MS: m / z = 479.1 [M+H] + .

[0167] 6. Preparation of 2-methyl-N-(4-(morpholin-4-carbonyl)thiazolyl-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-47)

[0168] Referring to the synthesis of compound A-42, 3,3-difluoropyrrolidine was replaced with morpholine to give a white solid in 87% yield; 1 H NMR (500MHz, DMSO-d6) δ12.40(s,1H),7.96-7.87(m,3H),7.76-7.70(m,2H),7.67(s,1H),2.71(s,3H).ESI-MS: m / z=466.1[M+H] + .

[0169] 7. Preparation of 2-methyl-N-(4-(morpholin-4-carbonyl)thiazolyl-2-yl)-5-(3-(trifluoromethoxy)phenyl)furan-3-carboxamide (Compound A-48)

[0170] Following the synthesis of compound A-42, 3,3-difluoropyrrolidine was replaced with morpholine, and trifluoromethylacetophenone was replaced with trifluoromethoxyacetophenone, yielding a white solid in 80% yield; ESI-MS: m / z = 482.1 [M+H] + .

[0171] 8. Preparation of 5-(3-(difluoromethoxy)phenyl)-2-methyl-N-(4-(morpholin-4-carbonyl)thiazo-2-yl)furan-3-carboxamide (Compound A-49)

[0172] Following the synthesis of compound A-42, 3,3-difluoropyrrolidine was replaced with morpholine, and trifluoromethylacetophenone was replaced with difluoromethoxyacetophenone, yielding a white solid in 71% yield; ESI-MS: m / z = 464.1 [M+H] + .

[0173] 9. Preparation of N-(4-(4-acetylpiperazin-1-carbonyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-50)

[0174] Following the synthesis of compound A-42, 3,3-difluoropyrrolidine was replaced with acetylpiperazine to give a white solid in 75% yield; 1H NMR(500MHz,DMSO-d6)δ12.43(s,1H),7.95-7.88(m,3H),7.75-7.69(m,2H), 7.67(s,1H),3.51(s,4H),2.71(s,3H),2.04(s,3H).ESI-MS:m / z=507.1[M+H] + .

[0175] 10. Preparation of N-(4-(4-(2-hydroxyethyl)piperazin-1-carbonyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-51)

[0176] Following the synthesis of compound A-42, replacing 3,3-difluoropyrrolidine with N-hydroxyethylpiperazine yielded a white solid in 62% yield; ESI-MS: m / z = 509.1 [M+H] + .

[0177] 11. Preparation of N-(4-(4-(dimethylamino)piperidin-1-carbonyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-52)

[0178] The preparation of target compound A-52 was performed following the synthesis of compound A-42, with 3,3-difluoropyrrolidine replaced by 4-dimethylaminopiperidine, yielding a white solid in 54% yield; ESI-MS: m / z = 507.1 [M+H] + .

[0179] 12. Preparation of 2-methyl-N-(4-(thiomorpholine-4-carbonyl)thiazolyl-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-53)

[0180] Following the synthesis of compound A-42, replacing 3,3-difluoropyrrolidine with thiomorpholine yielded a white solid in 68% yield; ESI-MS: m / z = 482.1 [M+H] + .

[0181] 13. Preparation of N-(4-(1,1-dioxothiomorpholine-4-carbonyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (Compound A-54)

[0182] Referring to the synthesis of compound A-42, 3,3-difluoropyrrolidine was replaced with thiomorpholine 1,1-dioxide to give a white solid in 80% yield; 1H NMR(500MHz,DMSO-d6)δ12.40(s,1H),7.96-7.91(m,2H),7.86(s,1H),7.77(s,1H),7.75-7.7 0(m,2H),4.03(d,J=7.1Hz,4H),3.28(t,J=5.3Hz,4H),2.71(s,3H).ESI-MS:m / z=514.1[M+H] + .

[0183] 14. Preparation of N-(2-hydroxyethyl)-2-(2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamido)thiazole-4-carboxamide (Compound A-55)

[0184] Following the synthesis of compound A-42, replacing 3,3-difluoropyrrolidine with 2-aminoethanol yielded a white solid in 66% yield; ESI-MS: m / z = 440.1 [M+H] + .

[0185] 15. Preparation of N-(2-hydroxyethyl)-N-methyl-2-(2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamido)thiazole-4-carboxamide (Compound A-56)

[0186] Following the synthesis of compound A-42, replacing 3,3-difluoropyrrolidine with 2-methylaminoethanol yielded a white solid in 60% yield; ESI-MS: m / z = 454.1 [M+H] + .

[0187] 16. Preparation of 2-(2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamido)-N-(methanesulfonyl)thiazole-4-carboxamide (Compound A-57)

[0188] Following the synthesis of compound A-42, 3,3-difluoropyrrolidine was replaced with methanesulfonamide, yielding a white solid in 72% yield; ESI-MS: m / z = 474.0 [M+H] + .

[0189] Example 3: General method for preparing target molecules B-1 to B-18

[0190] The synthetic routes for compounds B-1 to B-18 are as follows: Figure 5 As shown.

[0191] 1. Preparation of compound B-1, the synthetic route is as follows: Figure 6 As shown.

[0192] (a) Synthesis of 5-bromofuran-3-carboxylic acid (compound II-2)

[0193] 3-Furfuric acid (II-1, 200 mg, 1.79 mmol), pyridine bromide (0.63 g, 1.97 mmol), and glacial acetic acid (3 mL) were added to a reaction flask and reacted overnight at 50 °C. The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated saline solution. The organic layers were combined and dried over anhydrous Na₂SO₄. The mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid II-2 in 70% yield; ESI-MS: m / z = 191.0 [M+H]. + .

[0194] (b) Synthesis of 5-(3-(trifluoromethyl)phenyl)furan-3-carboxylic acid (compound II-3)

[0195] Under N2 protection, a mixed solvent of DME (15 mL) and water (3 mL) was added to a double-necked flask containing m-trifluoromethylphenylboronic acid (340 mg, 1.79 mmol), compound II-2 (340 mg, 1.79 mmol), sodium carbonate (450 mg, 5.39 mmol), and tetra(triphenylphosphine)palladium (105 mg, 0.08 mmol). The mixture was heated to 90 °C and reacted for 2 h. After cooling to room temperature, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, the organic layers were combined, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid II-3 in 65% yield. 1 H NMR(500MHz,Chloroform-d)δ8.17(d,J=1.0Hz,1H),7.96-7.93(m,1H),7.88-7 .84(m,1H),7.61-7.53(m,2H),7.10(d,J=1.0Hz,1H); ESI-MS:m / z=257.0[M+H] + .

[0196] (c) Preparation of N-(4-((diethylamino)methyl)thiazolyl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound B-1)

[0197] Compound II-3 (256 mg, 1.0 mmol), 4-((diethylamino)methyl)thiazol-2-amine (II-4, 185 mg, 1.0 mmol), EDCI (382 mg, 2.0 mmol), and 4-PPY (15 mg, 0.1 mmol) were dissolved in DCM (10 mL) and refluxed with stirring overnight (compound II-4 was prepared from compound I-6 and diethylamino using the same synthetic method as compound I-7-1). The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid B-1 in 72% yield; ESI-MS: m / z = 424.1 [M+H]. + .

[0198] 2. Preparation of target molecules B-2 to B-18

[0199] Referring to the synthesis of compound B-1, compounds B-2 to B-15 were prepared using compounds II-3 and 2-amino-4-chloromethylthiazolium hydrochloride (I-6) as raw materials, respectively, by substituting 3,3-difluoropyrrolidine, 3-hydroxypyrrolidine, piperidine, 4,4-difluoropiperidine, 4-hydroxypiperidine, 4-hydroxymethylpiperidine, 4-methylpiperazine, 4-acetylpiperazine, N-hydroxyethylpiperazine, 4-dimethylaminopiperidine, morpholine, (2S,6R)-2,6-dimethylmorpholine, thiomorpholine, and thiomorpholine dioxide for diethylamino.

[0200] Referring to the synthesis of compound B-1, compounds B-16 to B-18 were prepared by using compound II-3 and 2-aminothiazolyl-4-carboxylic acid (I-6-a) as raw materials and replacing diethylamino with 4-hydroxypiperidine, morpholine and thiomorpholine, respectively.

[0201] The chemical structures and ESI-MS results of the above compounds are shown in Table 1.

[0202] Table 1. Chemical structures of representative B-series target molecules

[0203]

[0204]

[0205] Example 4: General method for preparing target molecules C-1 to C-18

[0206] The synthetic routes for compounds C-1 to C-18 are as follows: Figure 7 As shown.

[0207] 1. Preparation of compound C-1, the synthetic route is as follows: Figure 8 As shown, the method is as follows:

[0208] (a) 5-Amino-1,3,4-Thiadiazole-2-carboxylic acid (compound III-2)

[0209] Ethyl 2-amino-1,3,4-thiadiazole-5-carboxylate (III-1, 865 mg, 5.0 mmol) was dissolved in ethanol (20 mL), and then an aqueous solution of sodium hydroxide (5 M, 10 mL, 50 mmol) was added. The mixture was stirred overnight at room temperature. Part of the solvent was removed under reduced pressure, and the pH was adjusted to 3-4 with 2 mol / L dilute hydrochloric acid. The mixture was filtered to obtain a white solid, III-2, in 93% yield; ESI-MS: m / z = 146.0 [M+H]. + .

[0210] (b) 5-Amino-1,3,4-thiadiazol-2-yl-(3,3-difluoropyrrolidone-1-yl)methyl ketone (compound III-3-1)

[0211] Compound III-2 (580 mg, 4.0 mmol), 3,3-difluoropyrrolidine (570 μL, 6.0 mmol), and HATU (3.04 g, 8.0 mmol) were dissolved in DMF (20 mL), and then DIPEA (2.08 mL, 12.0 mmol) was added dropwise to the reaction mixture. The mixture was stirred overnight at room temperature. A suitable amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was subjected to column chromatography to give a white solid III-3 in 78% yield; ESI-MS: m / z = 235.0 [M+H]. + .

[0212] (c) 5-((3,3-difluoropyrrolidone-1-yl)methyl)-1,3,4-thiadiazole-2-amine (compound III-4-1)

[0213] Compound III-3-1 (468 mg, 2.0 mmol) was dissolved in 10 mL of THF at 0 °C, followed by the slow addition of BH3-THF (1 M, 20 mL, 20.0 mmol). The reaction was allowed to proceed for 30 min after the addition was complete, then heated to 60 °C for 3 h. After cooling to room temperature, 2 M HCl was added, and the mixture was heated to 70 °C for 2 h. After cooling to room temperature, a suitable amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was then subjected to column chromatography to give a white solid, III-4-1, in 60% yield; ESI-MS: m / z = 221.0 [M+H]. + .

[0214] (d) N-(5-((3,3-difluoropyrrolidone-1-yl)methyl)-1,3,4-thiadiazol-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound C-1)

[0215] Compound III-4-1 (220 mg, 1.0 mmol), compound I-5-1 (270 mg, 1.0 mmol), EDCI (382 mg, 2.0 mmol), and 4-PPY (15 mg, 0.1 mmol) were dissolved in DCM (10 mL) and refluxed with stirring overnight. The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated saline solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was subjected to column chromatography to give a white solid C-1 in 66% yield; ESI-MS: m / z = 473.1 [M+H]. + .

[0216] 2. Preparation of target molecules C-2 to C-18

[0217] Using compound III-2 as a starting material, 3-hydroxypyrrolidine, 4,4-difluoropiperidine, p-trifluoromethylpiperidine, 4-methoxypiperidine, 4-hydroxypiperidine, 4-hydroxymethylpiperidine, 4-methylpiperazine, N-hydroxyethylpiperazine, 4-acetylpiperazine, morpholine, (2S,6R)-2,6-dimethylmorpholine, thiomorpholine, thiomorpholine dioxide, and 4-dimethylaminopiperidine were used to replace 3,3-difluoropyrrolidine. The mixture was then subjected to a condensation reaction under HATU conditions, followed by reduction with BH3-THF, and finally condensed with compound I-5-1 under EDCI conditions to prepare compounds C-2 to C-15.

[0218] Using compound III-2 as a raw material, morpholine, thiomorpholine, and 4-hydroxypiperidine were used to replace 3,3-difluoropyrrolidine, respectively. The mixture was then subjected to a condensation reaction under HATU conditions, and finally condensed with compound I-5-1 under EDCI conditions to prepare compounds C-16 to C-18.

[0219] The chemical structures and ESI-MS results of the above compounds are shown in Table 2.

[0220] Table 2. Chemical structures of representative C-series target molecules

[0221]

[0222] Example 5: General method for preparing target molecules D-1 to D-6

[0223] The synthetic routes for compounds D-1 to D-6 are as follows: Figure 9 As shown.

[0224] 1. The synthesis of compound D-1, the synthetic route is as follows: Figure 10 As shown, the method is as follows:

[0225] (a) 5-((3,3-difluoropyrrolidone-1-yl)methyl)thiazol-2-amine (compound IV-2-1)

[0226] 2-Amino-5-aldehydethiazole (IV-1, 640 mg, 5.0 mmol) and 3,3-difluoropyrrolidine (710 μL, 7.5 mmol) were dissolved in DCM (20 mL), and then 2 drops of AcOH were added. The mixture was stirred at room temperature for 30 min. Subsequently, NaBH(OEt)3 (1.6 g, 7.5 mmol) was added in portions, and the mixture was stirred at room temperature for 4 h. The solution was quenched with an appropriate amount of water, extracted with DCM, and the organic layer was washed with saturated saline solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid IV-2-1 in 78% yield; ESI-MS: m / z = 220.1 [M+H]. + .

[0227] (b) N-(5-((3,3-difluoropyrrolidone-1-yl)methyl)thiazolyl)-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound D-1)

[0228] Compound IV-2-1 (219 mg, 1.0 mmol), compound I-5-1 (270 mg, 1.0 mmol), EDCI (382 mg, 2.0 mmol), and 4-PPY (15 mg, 0.1 mmol) were dissolved in DCM (10 mL) and refluxed with stirring overnight. The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid D-1 in 69% yield; ESI-MS: m / z = 472.1 [M+H] + .

[0229] 2. Preparation of N-(5-((4,4-difluoropiperidin-1-yl)methyl)thiazolyl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound D-2)

[0230] The preparation of target compound D-2 followed the synthesis of compound D-1, except that 3,3-difluoropyrrolidine was replaced with 4,4-difluoropiperidine, yielding a white solid in 84% yield; ESI-MS: m / z = 486.1 [M+H] + .

[0231] 3. Preparation of 2-methyl-N-(5-(morpholinomethyl)thiazo-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound D-3)

[0232] The preparation of target compound D-3 was the same as that of compound D-1, except that 3,3-difluoropyrrolidine was replaced with morpholine, yielding a white solid in 80% yield; 1 H NMR(500MHz,Chloroform-d)δ11.39(s,1H),7.85(d,J=1.8Hz,1H),7.76(dt,J=7.6,1.6Hz,1H),7.58-7.48( m,2H),7.15(s,1H),7.01(s,1H),3.68(t,J=4.6Hz,4H),3.62(s,2H),2.79(s,3H).ESI-MS:m / z=452.1[M+H] + .

[0233] 4. Preparation of 2-methyl-N-(5-(thiomorpholinemethyl)thiazolyl-2-yl)-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound D-4)

[0234] The preparation of target compound D-4 followed the synthesis of compound D-1, except that 3,3-difluoropyrrolidine was replaced with thiomorpholine, yielding a white solid in 77% yield; ESI-MS: m / z = 468.1 [M+H] + .

[0235] 5. Preparation of N-(5-((4-hydroxypiperidin-1-yl)methyl)thiazolyl)-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound D-5)

[0236] The preparation of target compound D-5 followed the synthesis of compound D-1, except that 3,3-difluoropyrrolidine was replaced with 4-hydroxypiperidine, yielding a white solid in 59% yield; ESI-MS: m / z = 466.1 [M+H] + .

[0237] 6. Preparation of N-(5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)thiazo-2-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound D-6)

[0238] The preparation of target compound D-6 was based on the synthesis of compound D-1, except that 3,3-difluoropyrrolidine was replaced with N-hydroxyethylpiperidine, yielding a white solid in 62% yield; ESI-MS: m / z = 495.2 [M+H] + .

[0239] Example 6: General method for preparing target molecules E-1~E-6, F-1~F-6, G-1~G-6

[0240] The synthetic routes for compounds E-1 to E-6, F-1 to F-6, and G-1 to G-6 are as follows: Figure 11 As shown.

[0241] 1. Preparation of compound E-1, the synthetic route is as follows: Figure 12 As shown, the method is as follows:

[0242] (a) Ethyl 5-(2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamido)isoxazole-3-carboxylate (compound V-2)

[0243] Ethyl 5-aminoisoxazole-3-carboxylate (V-1, 312 mg, 2.0 mmol), compound I-5-1 (520 mg, 2.0 mmol), EDCI (764 mg, 4.0 mmol), and 4-PPY (30 mg, 0.2 mmol) were dissolved in DCM (20 mL) and refluxed with stirring overnight. The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid V-2 in 87% yield. 1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),7.98-7.89(m,2H),7.77-7.69(m,3H),6.67(s,1 H),4.37(q,J=7.1Hz,2H),2.68(s,3H),1.33(t,J=7.1Hz,3H).ESI-MS:m / z=409.1[M+H] + .

[0244] (b) N-(3-(hydroxymethyl)isoxazol-5-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound V-3)

[0245] Compound V-2 (120 mg, 0.3 mmol) was dissolved in 5 mL of THF at -20 °C, followed by the slow addition of a 1 M, 0.6 mL, 0.6 mmol solution of LiAlH4 in THF. The reaction was continued at -20 °C for 30 min. Subsequently, 1 mL of water was slowly added dropwise to the reaction mixture, followed by 1 mL of a 15% NaOH aqueous solution. Anhydrous Na2SO4 was then added, and the mixture was filtered through diatomaceous earth. Part of the solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated saline solution. The solution was then dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid V-3 in 50% yield. 1 H NMR(500MHz,DMSO-d6)δ11.61(s,1H),7.97-7.89(m,2H),7.77-7.66(m,3H),6.41(s,1 H),5.47(t,J=6.2Hz,1H),4.47(d,J=6.1Hz,2H),2.68(s,3H).ESI-MS:m / z=367.1[M+H] + .

[0246] (c) N-(3-(bromomethyl)isoxazol-5-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound V-4)

[0247] Under N2 conditions, compounds V-3 (366 mg, 1.0 mmol), PPh3 (446 mg, 1.7 mmol), and CBr4 (564 mg, 1.7 mmol) were dissolved in DCM (15 mL), and then 2,6-dimethylpyridine (31 μL, 0.4 mmol) was added. The mixture was reacted at room temperature for 1 h. After adding an appropriate amount of water, the mixture was extracted with DCM. The organic layer was washed with saturated saline solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid V-4 in 41% yield. 1 H NMR(500MHz, DMSO-d6)δ12.30(d,J=4.4Hz,1H),7.96-7.90(m,2H),7.77-7.68(m,3H),6.48(s,1H),4.84(s,2H),2.68(s,3H).ESI-MS:m / z=429.0[M+H] + .

[0248] (d) Synthesis of N-(3-((4,4-difluoropiperidin-1-yl)methyl)isoxazol-5-yl)-2-methyl-5-(3-(trifluoromethyl)phenyl)furan-3-carboxamide (compound E-1)

[0249] Compound V-4 (428 mg, 1.0 mmol) and 4,4-difluoropiperidine (157 μL, 1.5 mmol) were dissolved in acetonitrile (10 mL), and then DIPEA (350 μL, 2.0 mmol) was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution. The solution was then dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was subjected to column chromatography to give a white solid E-1 in 83% yield. 1 H NMR(500MHz,Chloroform-d)δ7.93(d,J=1.5Hz,1H),7.71(dt,J=7.3,1.9Hz,1H),7.48-7.33(m,2H),6.91(s,1H),5. 69(s,1H),3.62(s,2H),2.70(ddd,J=12.3,5.8,4.9Hz,2H),2.62-2.52(m,5H),2.03(m,4H).ESI-MS:m / z=470.1[M+H] + .

[0250] 2. Preparation of target molecules E-2~E-6, F-1~F-6, G-1~G-6

[0251] Using compound V-4 as a raw material, compounds E-2 to E-6 were prepared by replacing 4,4-difluoropiperidine with p-hydroxypiperidine, morpholine, 4-methylpiperazine, N-hydroxyethylpiperazine, and thiomorpholine, respectively.

[0252] Compounds F-1 to F-6 were prepared by replacing 5-aminoisoxazole-3-carboxylic acid ethyl ester (V-1) with 2-aminoxazole-4-carboxylic acid ethyl ester, followed by condensation under EDCI conditions, reduction with LiAlH4, bromination with CBr4, and finally nucleophilic substitution reactions with 3,3-difluoropyrrolidine, 4,4-difluoropiperidine, 4-hydroxypiperidine, N-hydroxyethylpiperidine, morpholine, and thiomorpholine.

[0253] The compounds G-1 to G-6 were prepared by replacing 5-aminoisoxazole-3-carboxylic acid ethyl ester (V-1) with 5-amino-1,2,4-oxadiazole-3-carboxylic acid ethyl ester, followed by condensation under EDCI conditions, reduction with LiAlH4, bromination with CBr4, and finally nucleophilic substitution reactions with 3-hydroxypyrrolidine, 4-hydroxypiperidine, N-hydroxyethylpiperidine, morpholine, thiomorpholine, and 4,4-difluoropiperidine.

[0254] The chemical structures and ESI-MS results of the above compounds are shown in Table 3.

[0255] Table 3. Chemical structures of representative E, F, and G series target molecules

[0256]

[0257] Example 7: Experiment evaluating the activity of antagonistic androgen receptor transcription factors

[0258] Detection Principle: Androgen receptors, as transcription factors, require binding to androgen response elements to exert their transcriptional activity. In androgen-dependent prostate cancer cells (LNCaP), the promoter ARR2PB, which exhibits a strong response to the androgen receptor (AR), was stably transfected and linked to enhanced green fluorescent protein (eGFP) to construct a stable LNCaP-ARR2PB-eGFP expression model. After treatment with a concentration gradient of the compound, the fluorescence intensity directly reflects the transcriptional activity of AR, thus indicating the strength of the compound's antagonistic ability against the androgen receptor.

[0259] Detection procedure: LNCaP-ARR2PB-eGFP cells were cultured in 10% fetal bovine serum (FBS) RPMI-1640 medium until 80% confluence. They were then passaged and cultured for another 4-5 days in androgen-free 5% FBS RPMI-1640 medium. Then, they were incubated at 3.5 × 10⁻⁶ cells / day. 4 Cells were seeded at a density of 1 cell per well into 96-well plates. After 24 hours of cell adhesion, each well was given 5 nM dihydrotestosterone (DHT) and a gradient of the test compound (Examples 1-6). After incubation for another 72 hours, the fluorescence intensity (excitation light 485 nm, emission light 530 nm) was detected by a multi-functional microplate reader.

[0260] Detection results: As shown in Table 4, most compounds exhibited strong AR transcriptional repression activity, and the activity of several compounds was higher than that of enzalutamide.

[0261] Table 4. AR transcriptional repressive activity of representative compounds

[0262] serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> A1 0.975 A2 0.025 A3 0.454 A5 0.871 A6 1.135 A7 0.213 A8 0.068 A13 0.660 A14 6.598 A15 0.288 A16 0.231 A22 1.631 A23 1.874 A25 0.279 A26 0.248 A27 0.054 A28 0.058 A29 0.035 A30 0.014 A33 0.046 A34 0.020 A35 0.006 A47 0.087 C11 96.12 D3 4.080 F5 32.08 Enzalutamide 0.159

[0263] Example 8: Detection of the activity of the compound against AR F877L / T878A

[0264] Detection Principle: A drug-resistant cell model based on a dual-luciferase reporter system is employed. Transient co-transfection of an AR expression plasmid with the F877L / T878A double mutation and a luciferase expression plasmid dependent on an AR strong promoter allows luciferase activity to directly reflect the transcription factor activity of the AR mutant. Adding the test compound to this system and detecting changes in luciferase activity allows for the assessment of the test compound's activity against AR F877L / T878A.

[0265] Detection Method: 10,000 PC3 cells were added to each well of a 96-well plate with a white background and cultured at 37°C for 24 hours. Transfection was then performed according to the transfection reagent instructions. Co-transfected plasmids included a nuclear receptor expression plasmid, a firefly luciferase expression plasmid dependent on the AR strong promoter, and a Renilla plasmid expressing Renina luciferase. 24 hours after transfection, the culture medium containing the transfection reagent was aspirated, and fresh phenol red-free 1640 medium was added. Then, 2 nM DHT and a concentration gradient of the test compound were added to each well, and a control group was set up. 24 hours after administration, fluorescence values ​​were detected according to the dual-luciferase reporter system instructions, and the compound effect was calculated. IC50 50 The values ​​were obtained by fitting using Graphpad Prism 8.0.2 software.

[0266] Detection results: As shown in Table 5, multiple compounds showed antagonistic activity against the ARF877L / T878A resistant cell model.

[0267] Table 5. Activities of representative compounds against the AR F877L / T878A resistance model

[0268] serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> A2 0.380 A7 0.334 A8 1.435 A15 0.804 A27 0.063 A28 1.450 A29 0.092 A30 0.258 A33 0.323 A34 0.124 A35 0.284 A47 1.423 Enzalutamide Excited Darolulamide 1.219

[0269] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A furanamide compound or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula of the compound is shown in any one of the following: A-1 to A-3, A-5 to A-8, A-13 to A-16, A-22 to A-23, A-25 to A-30, A-33 to A-35, A-47, C-11, D-3, and F-5.

2. The furanamide compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, The pharmaceutically acceptable salts are organic acid salts, inorganic acid salts, organic base salts, and inorganic base salts; the organic acid salts are oxalate, lactate, p-toluenesulfonate, malate, citrate, fumarate, camphorsulfonate, and methanesulfonate; the inorganic acid salts are nitrates, sulfates, hydrohalates, and phosphates; the organic base salts are sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, triethylamine, and tert-butylamine; and the inorganic base salts are sodium hydroxide, potassium hydroxide, and lithium hydroxide.

3. The use of the furanamide compound or a pharmaceutically acceptable salt thereof as described in claim 1 or 2 in the preparation of androgen receptor antagonists.

4. The use of the furanamide compound or a pharmaceutically acceptable salt thereof as described in claim 1 or 2 in the preparation of medicaments for treating prostate cancer, breast cancer, and ovarian cancer.

5. A pharmaceutical composition, characterized in that, It contains a therapeutically effective amount of one or more furanamide compounds as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition is formulated in the form of capsules, powders, tablets, granules, pills, injections, syrups, or oral liquids.

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