AKR1C3 inhibitor with tricyclic structure and application of AKR1C3 inhibitor

Abstract

The invention discloses an aldehyde ketoreductase 1C3 selective inhibitor with a tricyclic structure and application of the aldehyde ketoreductase 1C3 selective inhibitor. The invention discloses a series of compounds with a structure as shown in a general formula I, and also discloses application of the compounds in cancer treatment. The inventor evaluates the efficacy of the compound represented by the general formula I in treatment of various cancers by taking an in-vitro anti-tumor cell experiment as a carrier, and finds that the compound has good in-vitro activity and can be used as a precursor substance for further development of a cancer treatment effect by inhibiting AKR1C3.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a class of AKR1C3 inhibitors with a tricyclic structure and their uses. Background Technology

[0002] Human aldehyde ketone reductase is a member of the oxidoreductase family, of which 16 families and 151 members have been identified to date. They are mainly found in the cytoplasm and have a molecular weight of approximately 34–37 kDa. Most...

[0003] The AKR family members belong to phase I metabolic enzymes. Due to their wide distribution in the body and diverse substrate sources, they play a role in various life activities (hormone metabolism and synthesis, drug metabolism, regulation of oxidative stress, and detoxification of carcinogens, etc.). AKR1C includes four subtypes: AKR1C1, AKR1C2, AKR1C3, and AKR1C4. Their amino acid sequences share a high degree of homology (84-98%), but they are distributed in different human tissues and perform various biochemical functions. AKR1C1 and AKR1C2 differ only in seven amino acid residues and are expressed in various tissues in the body, acting as steroid reductases for 3-keto, 17-keto, and 20-keto, regulating corresponding receptors and transactivation. AKR1C3 is mainly expressed in endocrine organs (prostate, breast, and adrenal glands, etc.) and plays a role in the de novo synthesis of adrenal and tumor steroids. AKR1C4 is liver-specific and participates in bile acid synthesis.

[0004] AKR1C3, also known as human 17β-hydroxysteroid type 5 dehydrogenase (17β-HSD5), is one of the four biological phenotypes of AKR1C with the most in-depth mechanistic research and the highest "drug-targetable" member, and is closely related to hormone metabolism in the body. First, as the active form of prostaglandin F synthase, AKR1C3 can catalyze the conversion of prostaglandin D2 to 9α,11β-PGF2α, and can also convert prostaglandin H to PGF2α[7]. In addition, AKR1C3 also has ketone steroid reduction activity, converting the weak androgen precursors Δ4-androsteneden 3,17-dione and 5α-androstane-3,17-dione into potent androgens testosterone and 5α-dihydrotestosterone, reducing the weak estrogen estrone to the potent estrogen 17β-estradiol, and converting the potent progesterone progesterone into the weak progesterone 20α-hydroxyprogesterone. These complex hormonal metabolic functions link AKR1C3 closely to hormone metabolism-related diseases, especially hormone-dependent tumors such as prostate cancer, castration-resistant prostate cancer, and breast cancer. Therefore, in-depth research and understanding of the biological functions and regulatory mechanisms of AKR1C3 are of great significance for the prevention and treatment of hormone metabolism-related diseases.

[0005] In addition, AKR1C3 is also associated with many non-hormone-dependent diseases. Studies have shown that AKR1C3 can affect multiple key signaling pathways in the human body, such as mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT), extracellular regulated protein kinase (ERK), nuclear factor kappa-B (NF-κB), and NF-E2-related factor 2 (Nrf2), participating in the regulation of normal physiological activities. Research has also found that AKR1C3 has nitroreductase function, which can participate in the metabolic activation process of antitumor prodrugs. Chemotherapy remains one of the main methods for treating tumors, but its drawbacks are also obvious, such as large dosage, severe side effects, and easy development of drug resistance. Many studies have shown that AKR1C3 is closely related to chemotherapy drug resistance, and inhibiting its expression or activity can effectively reverse chemotherapy resistance in tumor cells [17,18]. Therefore, the development of highly selective AKR1C3 inhibitors can point to a new strategic direction for research on reversing drug resistance. Several AKR1C3 inhibitors have been reported, but none have been successfully used in clinical practice. Therefore, developing highly effective and selective AKR1C3 inhibitors remains a challenge. Summary of the Invention

[0006] To address the aforementioned technical problems in the prior art, this invention provides a class of AKR1C3 inhibitors with a tricyclic structure and their uses.

[0007] The technical solution of this invention is as follows:

[0008] The first object of this invention is to provide a compound conforming to general formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] A is derived from C6 to C6 of any substitution of R1. 10 Aryl or 5- to 10-membered heteroaryl, wherein R1 is hydrogen, any substituted carboxyl, cyano, halogroup, trifluoromethyl, C1- to C6 alkyl, C1- to C6 alkoxy, C3- to C6 cycloalkyl, or C1- to C6 alkoxyacyl.

[0012] B is derived from C6 to C6 of R2 with arbitrary substitution. 10 Aryl or 5-6 heteroaryl, wherein R2 is hydrogen, nitro, cyano, halo, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, N,N-dimethylaminoformyl;

[0013] C is taken from C6 to C6 of any substitution of R3. 10Aryl or 5-10 heteroaryl; wherein R3 is hydrogen, or any substituted nitro, cyano, halogroup, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C1-C6 alkoxyacyl, Where W is taken from R4 is taken from n3 is taken from integers from 0 to 6;

[0014] X is taken from

[0015] Y is taken from R5, R6, and R7 are independently hydrogen or C1-C3 alkyl groups;

[0016] n1 is taken from integers from 0 to 5;

[0017] n2 is taken from integers from 0 to 4.

[0018] Furthermore, A is derived from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, furanyl, which are substituted with R1 in any way, wherein R1 is hydrogen, carboxyl, cyano, halogen, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, butoxy, methoxyacyl, ethoxyacyl, propoxyacyl, butoxyacyl;

[0019] B is derived from any substituted phenyl, pyridyl, oxazolyl, isoxazolyl, 3,5-dimethylisooxazol-4-yl, thiazolyl, furanyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, wherein R2 is hydrogen, nitro, cyano, fluoro, trifluoromethyl, N,N-dimethylaminoformyl, methyl, ethyl, methoxy, or ethoxy.

[0020] C is derived from phenyl, naphthyl, furanyl, quinolinyl, or isoquinolinyl, with R3 being any substitution. R3 is derived from hydrogen, and can be any substitution of nitro, cyano, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyacyl, ethoxyacyl, propoxyacyl, or butoxyacyl. Where W is taken from R4 is taken from n3 is taken from 0, 1, 2, 3, 4;

[0021] X is taken from

[0022] Y is taken from R5, R6, and R7 are independently hydrogen, methyl, or ethyl;

[0023] n1 is taken from 0, 1, 2, 3;

[0024] n2 is taken from 0, 1, 2.

[0025] Furthermore, the compound is selected from any one of the following compounds:

[0026]

[0027] Furthermore, pharmaceutically acceptable salts are selected from hydrochloride, maleate, and citrate.

[0028] A second object of the present invention is to provide the use of the aforementioned compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of cancer, preferably cancers associated with elevated aldehyde-ketone reductase levels; more preferably, cancers associated with elevated aldehyde-ketone reductase 1C3 levels. The aforementioned compounds or pharmaceutically acceptable salts thereof prevent and / or treat cancer by inhibiting aldehyde-ketone reductases, particularly aldehyde-ketone reductase 1C3.

[0029] A third object of the present invention is to provide the use of the aforementioned compounds or pharmaceutically acceptable salts thereof in the preparation of aldehyde-ketone reductase 1C3 inhibitors.

[0030] A fourth object of the present invention is to provide a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0031] Furthermore, the pharmaceutical composition also contains sorafenib.

[0032] A fifth object of the present invention is to provide the use of the aforementioned compounds or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments for the prevention and / or treatment of cancer, preferably cancers associated with elevated aldehyde-ketone reductase levels; more preferably, cancers associated with elevated aldehyde-ketone reductase 1C3 levels. The aforementioned pharmaceutical compositions prevent and / or treat cancer by inhibiting aldehyde-ketone reductases, particularly aldehyde-ketone reductase 1C3.

[0033] Furthermore, the aforementioned compounds or their pharmaceutically acceptable salts can reverse cancer cells' resistance to sorafenib, thereby effectively treating cancer.

[0034] In a particular embodiment, the cancer is liver cancer.

[0035] Furthermore, the aforementioned drug is in the form of tablets, capsules, powders, syrups, liquids, suspensions, or injections.

[0036] The technical solution of this invention has the following beneficial effects:

[0037] This invention provides a novel compound with a tricyclic structure as shown in Formula I. The efficacy of the compound shown in Formula I in treating various cancers was evaluated using in vitro antitumor cell experiments. It was found to have good in vitro activity and extremely high selectivity, and it can be used as a precursor for further development to exert cancer therapeutic effects by selectively inhibiting aldehyde-ketone reductase 1C3. Detailed Implementation

[0038] The present invention will be further explained below with reference to the embodiments, but the embodiments do not limit the present invention in any way.

[0039] Example 1

[0040] Synthesis of (1) tert-butyl (2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamate

[0041] N-Boc-2-aminophenol (1 g, 6.57 mmol) was dissolved in acetonitrile (20 mL) in a round-bottom flask, followed by the addition of potassium carbonate (1.36 g, 9.86 mmol) and 4-chloromethyl-3,5-dimethylisoxazole (0.96 g, 6.57 mmol). The reaction was carried out at 70 °C for 12 hours. After filtration, the filtrate was collected, and the solvent was removed under reduced pressure to obtain a white solid, 2-((3,5-dimethylisoxazole-4-yl)methoxy)benzoic acid (1.51 g, yield 87.8%). TLC detection showed a single spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR (500MHz, Chloroform-d) δ8.43-8.35(m,1H),7.06-6.96(m,2H),6.93(s,1H),6.96-6.88(m,1H),5.03(s,2H),2.28(d,J=10.1Hz,6H).

[0042] (2) Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)aniline

[0043] Dissolve 1 g (4.04 mmol) of tert-butyl (2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamate in 20 mL of DCM, add 1 mL of trifluoroacetic acid, and react overnight at room temperature. Then quench with saturated sodium bicarbonate, transfer the mixture to a separatory funnel, collect and combine the organic phases, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a yellow solid, 2-((3,5-dimethylisoxazol-4-yl)methoxy)aniline. 1H NMR(500MHz,Chloroform-d)δ6.85-6.75(m,2H),6.74-6.66(m,1H),5.03(s,1H),3.92(s,1H),2.29(s,2H).

[0044] (3) Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 1) 2-((3,5-dimethylisoxazol-4-yl)methoxy)aniline (0.5 g, 1.98 mmol) was dissolved in 20 mL of DMF, and HATU, DIEA, and benzoic acid were added sequentially. The reaction was carried out overnight at room temperature. The reaction was then quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a brown solid (2-(((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)amino)methyl)-4-nitrophenyl)methanol. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.74(dd,J=7.5,1.8Hz,1H),7.54-7.47 (m,1H),7.46-7.38(m,2H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2.29(s,3H).

[0045] Example 2

[0046] Synthesis of N-(3-((3,5-dimethylisoxazol-4-yl)methoxy)naphth-2-yl)benzamide (Example 2)

[0047] Following the synthesis method of Example 1, N-(3-((3,5-dimethylisoxazol-4-yl)methoxy)naphth-2-yl)benzamide (Example 2) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.61-7.54(m,1H),7.54-7.47(m,1H),7.46-7.38(m, 2H),7.42-7.33(m,1H),7.23-7.14(m,2H),6.64(d,J=2.1Hz,1H),6.57(d,J=2.1Hz,1H),5.13(s,2H),2.29(s,3H).

[0048] Example 3

[0049] Synthesis of N-(6-((3,5-dimethylisoxazol-4-yl)methoxy)quinoline-7-yl)benzamide (Example 3)

[0050] Following the synthesis method of Example 1, N-(6-((3,5-dimethylisoxazol-4-yl)methoxy)quinoline-7-yl)benzamide (Example 3) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.62(dd,J=4.1,1.7Hz,1H),8.02(dt,J=8.5,2.1Hz,1H),7.99-7.92( m,3H),7.54-7.47(m,1H),7.46-7.38(m,2H),7.26-7.21(m,1H),6.67(d,J=2.4Hz,1H),5.03(s,2H),2.29(s,3H).

[0051] Example 4

[0052] Synthesis of N-(3-((3,5-dimethylisoxazol-4-yl)methoxy)furan-2-yl)benzamide (Example 4)

[0053] Following the synthesis method of Example 1, N-(3-((3,5-dimethylisoxazol-4-yl)methoxy)furan-2-yl)benzamide (Example 4) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR (500MHz, Chloroform-d) δ 8.04-7.98 (m, 2H), 7.54-7.47 (m, 1H), 7.46-7.38 (m, 2H), 7.18 (s, 0H), 6.00 (d, J = 2.4Hz, 1H), 5.03 (s, 2H), 2.29 (s, 3H).

[0054] Example 5

[0055] Synthesis of N-(6-((3,5-dimethylisoxazol-4-yl)methoxy)isoquinoline-7-yl)benzamide (Example 5)

[0056] Following the synthesis method of Example 1, N-(6-((3,5-dimethylisoxazol-4-yl)methoxy)isoquinoline-7-yl)benzamide (Example 5) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ8.96(t,J=1.4Hz,1H),8.68(s,1H),8.19(dd,J=4.5,1.4Hz,1H),7.99-7.93(m,2H ),7.54-7.47(m,2H),7.46-7.38(m,2H),7.04(d,J=0.7Hz,1H),6.61(d,J=2.0Hz,1H),5.03(s,2H),2.29(s,3H).

[0057] Example 6

[0058] Synthesis of N-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyrimidin-4-yl)benzamide (Example 6)

[0059] Following the synthesis method of Example 1, N-(5-((3,5-dimethylisoxazol-4-yl)methoxy)pyrimidin-4-yl)benzamide (Example 6) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.76(s,1H),8.09(d,J=1.6Hz,1H),8.05-7.99(m,2H),7 .76(d,J=1.6Hz,1H),7.54-7.47(m,1H),7.46-7.38(m,2H),5.03(s,2H),2.29(s,3H).

[0060] Example 7

[0061] Synthesis of 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid (Example 7)

[0062] Following the synthesis method of Example 1, 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid (Example 7) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.43(d,J=2.2Hz,1H),7.99-7.93(m,3 H),7.54-7.47(m,1H),7.46-7.38(m,2H),7.14(s,0H),5.03(s,2H),2.29(s,3H).

[0063] Example 8

[0064] Synthesis of N-(5-cyano-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 8)

[0065] Following the synthesis method of Example 1, N-(5-cyano-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 8) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.28(d,J=2.1Hz,1H),7.99-7.93(m,2H),7.61(dd,J =8.5,2.1Hz,1H),7.54-7.47(m,1H),7.46-7.38(m,2H),7.15(s,0H),5.03(s,2H),2.29(s,3H).

[0066] Example 9

[0067] Synthesis of N-(5-chloro-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 9)

[0068] Following the synthesis method of Example 1, N-(5-chloro-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 9) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.54-7.47(m,2H),7. 46-7.38(m,2H),7.25-7.20(m,1H),6.99(d,J=8.7Hz,1H),5.03(s,2H),2.29(s,3H).

[0069] Example 10

[0070] Synthesis of N-(5-bromo-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 10)

[0071] Following the synthesis method of Example 1, N-(5-bromo-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 10) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.56(d,J=2.1Hz,1H),7.54-7.47 (m,1H),7.46-7.38(m,2H),7.26-7.21(m,1H),6.87(d,J=8.8Hz,1H),5.03(s,2H),2.29(s,3H).

[0072] Example 11

[0073] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-5-(trifluoromethyl)phenyl)benzamide (Example 11)

[0074] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-5-(trifluoromethyl)phenyl)benzamide (Example 11) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.82(d,J=2.1Hz,1H),7.62(dd,J=7.6 ,2.1Hz,1H),7.54-7.47(m,1H),7.46-7.38(m,2H),6.70(d,J=7.6Hz,1H),5.03(s,2H),2.29(s,3H).

[0075] Example 12

[0076] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-methylphenyl)benzamide (Example 12)

[0077] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-methylphenyl)benzamide (Example 12) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.57-7.47(m,2H),7.46-7. 38(m,2H),6.93(ddd,J=8.4,2.0,0.9Hz,1H),6.80-6.76(m,1H),5.03(s,1H),2.27(s,2H).

[0078] Example 13

[0079] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4,5-dimethylphenyl)benzamide (Example 13)

[0080] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4,5-dimethylphenyl)benzamide (Example 13) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR (500MHz, Chloroform-d) δ8.68(s,1H),7.99-7.93(m,2H),7.54-7.47(m,1H),7.46-7.38(m,2H),6.75(s,1H),5.03(s,1H),2.28(d,J=10.1Hz,4H).

[0081] Example 14

[0082] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-3,4,5-triethylphenyl)benzamide (Example 14)

[0083] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-3,4,5-triethylphenyl)benzamide (Example 14) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.54-7.47(m,1H),7.47-7.38(m,2H),5.03(s,2H),2.71(q d,J=7.4,0.8Hz,2H),2.63(q,J=7.6Hz,2H),2.29(s,3H),1.66(q,J=7.8Hz,2H),1.22(t,J=7.4Hz,3H),1.11-1.05(m,6H).

[0084] Example 15

[0085] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-5-ethylphenyl)benzamide (Example 15)

[0086] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-5-ethylphenyl)benzamide (Example 15) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.81(dt,J=2.0,0.9Hz,1H),7.54-7.47(m,1H),7.46-7.38(m,1H), 6.96(ddt,J=8.6,2.0,0.9Hz,1H),6.77(d,J=8.6Hz,1H),5.03(s,2H),2.74(qt,J=7.2,0.9Hz,2H),2.29(s,3H),1.31-1.25(m,3H).

[0087] Example 16

[0088] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-6-propylphenyl)benzamide (Example 16)

[0089] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-6-propylphenyl)benzamide (Example 16) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ9.15(s,1H),7.99-7.93(m,2H),7.54-7.47(m,1H),7.46-7.38(m,2H),7.08(d,J=8.1Hz,1H),6.92(dq,J=8.1,0. 9Hz,1H),6.84(dd,J=8.3,1.2Hz,1H),5.03(s,2H),2.64(td,J=6.2,0.8Hz,2H),2.29(s,3H),1.66(qt,J=7.6,6.3Hz,2H),0.97(t,J=7.5Hz,3H).

[0090] Example 17

[0091] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-isopropylphenyl)benzamide (Example 17)

[0092] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-isopropylphenyl)benzamide (Example 17) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.59(d,J=7.9Hz,1H),7.54-7.47(m,1H),7.46-7.38(m, 1H),6.94(dd,J=1.9,0.9Hz,1H),6.89-6.83(m,1H),5.03(s,2H),2.90-2.78(m,1H),2.29(s,3H),1.24(d,J=6.6Hz,6H).

[0093] Example 18

[0094] Synthesis of N-(4-butyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 18)

[0095] Following the synthesis method of Example 1, N-(4-butyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 18) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.59(d,J=8.1H z,1H),7.54-7.47(m,1H),7.46-7.38(m,2H),6.95(ddt,J=8.0,1.7,0.9Hz,1H) ,6.82(dt,J=1.7,0.9Hz,1H),5.03(s,2H),2.37(tt,J=8.2,0.8Hz,2H),2.29(s ,3H),1.57(tt,J=8.3,6.6Hz,2H),1.32(h,J=7.0Hz,2H),1.04(t,J=7.2Hz,3H).

[0096] Example 19

[0097] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-isobutylphenyl)benzamide (Example 19)

[0098] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-isobutylphenyl)benzamide (Example 19) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.59(d,J=8.3Hz,1H),7.54-7.47(m,1H),7.46-7.38(m,1H),6.95(ddt,J=8.4,1.8, 0.9Hz,1H),6.82(dt,J=1.7,0.9Hz,1H),5.03(s,2H),2.34(dt,J=7.1,0.9 Hz, 2H), 2.29 (s, 3H), 1.85 (dp, J=14.0, 7.0Hz, 1H), 0.91 (d, J=6.9Hz, 6H).

[0099] Example 20

[0100] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-pentylphenyl)benzamide (Example 20)

[0101] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-pentylphenyl)benzamide (Example 20) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.59(d,J=8.1Hz,1H),7.54-7.47(m,1H),7.46-7.38(m,2H),6.95(ddt,J=8.0,1.7,0.9Hz ,1H),6.82(dt,J=1.7,0.9Hz,1H),5.03(s,2H),2.42(tt,J=7.7,0.9Hz,2H), 2.29(s,3H),1.56(p,J=7.5Hz,2H),1.40-1.24(m,4H),0.88(t,J=6.7Hz,3H).

[0102] Example 21

[0103] Synthesis of N-(4-cyclopropyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 21)

[0104] Following the synthesis method of Example 1, N-(4-cyclopropyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 21) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.59(d,J=8.6Hz,1H),7.54-7.47(m,1H),7.46-7.38(m,2H) ,6.96-6.92(m,1H),6.89-6.83(m,1H),5.03(s,2H),3.53-3.45(m,1H),2.29(s,3H),1.00-0.92(m,2H),0.68-0.60(m,2H).

[0105] Example 22

[0106] Synthesis of N-(4-cyclobutyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 22)

[0107] Following the synthesis method of Example 1, N-(4-cyclobutyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 22) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.59(d,J=8.6Hz,1H) ,7.54-7.47(m,1H),7.46-7.38(m,2H),6.96-6.92(m,1H),6.89-6.83(m,1H),5.03(s ,2H),3.28-3.20(m,1H),2.38(dtd,J=12.3,8.0,5.2Hz,2H),2.29(s,3H),2.12(dtd, J=12.3,8.0,5.1Hz,2H),1.63(dp,J=12.1,8.1Hz,1H),1.51(dp,J=12.1,8.1Hz,1H).

[0108] Example 23

[0109] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-methoxyphenyl)benzamide (Example 23)

[0110] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-methoxyphenyl)benzamide (Example 23) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.36(d,J=8.7Hz,1H),8.28(s,1H),7.99-7.93(m,2H),7.54-7.47(m,1H),7. 46-7.38(m,2H),6.66(d,J=2.3Hz,1H),6.53(dd,J=8.7,2.3Hz,1H),5.03(s,1H),3.83(s,2H),2.29(s,3H).

[0111] Example 24

[0112] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-ethoxyphenyl)benzamide (Example 24)

[0113] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-ethoxyphenyl)benzamide (Example 24) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.36(d,J=8.7Hz,1H),8.28(s,1H),7.99-7.93(m,2H),7.54-7.47(m,1H),7. 46-7.38(m,1H),6.68-6.61(m,2H),5.03(s,2H),4.09(q,J=6.8Hz,2H),2.29(s,3H),1.44(t,J=6.7Hz,3H).

[0114] Example 25

[0115] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-propoxyphenyl)benzamide (Example 25)

[0116] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-propoxyphenyl)benzamide (Example 25) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1HNMR(500MHz,Chloroform-d)δ8.36(d,J=8.7Hz,1H),8.28(s,1H),7.99-7.93(m,2H),7.54-7.47(m,1H),7.46-7.38(m,1H ),6.68-6.61(m,2H),5.03(s,1H),3.96(t,J=5.4Hz,2H),2.29(s,3H),1.83(qt,J=7.7,5.4Hz,2H),1.13(t,J=7.8Hz,3H).

[0117] Example 26

[0118] Synthesis of N-(4-butoxy-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 26)

[0119] Following the synthesis method of Example 1, N-(4-butoxy-2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 26) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.36(d,J=8.7Hz,1H),8.28(s,1H),7.99-7.93(m,2H),7.54-7.47(m,1H),7.46-7.38(m,1H),6.68- 6.61(m,2H),5.03(s,2H),4.00(t,J=6.4Hz,2H),2.29(s,3H),1.78(p,J=6.7Hz,2H),1.45(h,J=7.0Hz,2H),0.99(t,J=7.0Hz,3H).

[0120] Example 27

[0121] Synthesis of methyl 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (Example 27)

[0122] Following the synthesis method of Example 1, methyl 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (Example 27) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1HNMR(500MHz,Chloroform-d)δ8.68(s,1H),8.27(d,J=2.2Hz,1H),7.99-7.93(m,2H),7. 56-7.47(m,2H),7.46-7.38(m,2H),7.04(s,0H),5.03(s,2H),3.85(s,2H),2.29(s,3H).

[0123] Example 28

[0124] Synthesis of ethyl 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (Example 28)

[0125] Following the synthesis method of Example 1, ethyl 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (Example 28) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),8.27(d,J=2.2Hz,1H),7.99-7.93(m,2H),7.56-7.47(m,2H) ,7.46-7.38(m,2H),7.04(s,0H),5.03(s,2H),4.42(q,J=6.4Hz,2H),2.29(s,3H),1.40(t,J=6.4Hz,3H).

[0126] Example 29

[0127] Synthesis of propyl 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (Example 29)

[0128] Following the synthesis method of Example 1, propyl 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (Example 29) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ7.99-7.93(m,1H),7.56-7.47(m,1H),7.46-7.38(m,1H),5.03( s,1H),4.24(t,J=5.4Hz,1H),2.29(s,1H),1.93(qt,J=8.1,5.5Hz,1H),0.91(t,J=8.0Hz,1H).

[0129] Example 30

[0130] Synthesis of 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)butyl benzoate (Example 30)

[0131] Following the synthesis method of Example 1, butyl 3-benzamido-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (Example 30) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),8.27(d,J=2.2Hz,1H),7.99-7.93(m,2H),7.56-7.47(m,2H),7.46-7.38(m,2H),7. 04(s,0H),5.03(s,2H),4.20(t,J=6.4Hz,2H),2.29(s,3H),1.56(p,J=6.7Hz,2H),1.32(h,J=7.0Hz,2H),0.94(t,J=7.0Hz,3H).

[0132] Example 31

[0133] Synthesis of N-(2-(benzyloxy)phenyl)benzamide (Example 31)

[0134] Following the synthesis method of Example 1, N-(2-(benzyloxy)phenyl)benzamide (Example 31) was obtained. TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and no fluorescence under a UV lamp at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.74(dd,J=7.6,1.9Hz,1H),7.54-7.47(m,1H) ,7.46-7.34(m,5H),7.34-7.27(m,1H),7.04-6.93(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.19(t,J=0.9Hz,2H).

[0135] Example 32

[0136] Synthesis of N-(2-(pyridin-3-ylmethoxy)phenyl)benzamide (Example 32)

[0137] Following the synthesis method of Example 1, N-(2-(pyridin-3-ylmethoxy)phenyl)benzamide (Example 32) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.59(ddd,J=4.2,2.0,1.3Hz,1H),8.31(dq,J=2.1,1.0Hz,1H),7.99-7.94(m,2H),7.91(dd,J=7.7,4.3 Hz,1H),7.74(dd,J=7.6,1.8Hz,1H),7.55-7.47(m,2H),7.46-7.38(m,2H ),7.04-6.93(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(d,J=1.0Hz,2H).

[0138] Example 33

[0139] Synthesis of N-(2-(oxazol-4-ylmethoxy)phenyl)benzamide (Example 33)

[0140] Following the synthesis method of Example 1, N-(2-(oxazol-4-ylmethoxy)phenyl)benzamide (Example 33) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR (500MHz, Chloroform-d) δ7.99-7.93(m,1H),7.79-7.71(m,1H),7.54-7.47(m,0H),7.46-7.38(m,1H),7.04-6.89(m,2H),5.15(d,J=1.0Hz,1H).

[0141] Example 34

[0142] Synthesis of N-(2-(isoxazo-4-ylmethoxy)phenyl)benzamide (Example 34)

[0143] Following the synthesis method of Example 1, N-(2-(isoxazo-4-ylmethoxy)phenyl)benzamide (Example 34) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.70-8.64(m,2H),8.49(dt,J=1.9,0.9Hz,1H),7.99-7.93(m,2H),7.74(dd,J=7.6,1.8 Hz,1H),7.54-7.47(m,1H),7.46-7.38(m,2H),7.04-6.93(m,2H),6.92(dd,J=7.6,1.7Hz,1H),5.03(d,J=1.0Hz,2H).

[0144] Example 35

[0145] Synthesis of N-(2-(thiophene-3-ylmethoxy)phenyl)benzamide (Example 35)

[0146] Following the synthesis method of Example 1, N-(2-(thiophene-3-ylmethoxy)phenyl)benzamide (Example 35) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.74(dd,J=7.6,1.8Hz,1H),7.54-7.47(m,1H),7.46-7.38(m ,2H),7.23(dd,J=5.1,1.7Hz,1H),7.17-7.13(m,1H),7.04-6.93(m,3H),6.92(dd,J=7.7,1.7Hz,1H),5.08(t,J=0.9Hz,2H).

[0147] Example 36

[0148] Synthesis of N-(2-((1,2,4-oxadiazol-3-yl)methoxy)phenyl)benzamide (Example 36)

[0149] Following the synthesis method of Example 1, N-(2-((1,2,4-oxadiazol-3-yl)methoxy)phenyl)benzamide (Example 36) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.74(dd,J=7.6,1.8Hz,1H),7.5 4-7.47(m,1H),7.46-7.38(m,2H),7.04-6.93(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.05(s,2H).

[0150] Example 37

[0151] Synthesis of N-(2-((1,2,5-oxadiazol-3-yl)methoxy)phenyl)benzamide (Example 37)

[0152] Following the synthesis method of Example 1, N-(2-((1,2,5-oxadiazol-3-yl)methoxy)phenyl)benzamide (Example 37) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm.1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.74(dd,J=7.6,1.8Hz,1H),7.5 4-7.47(m,1H),7.46-7.38(m,2H),7.04-6.93(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.15(s,2H).

[0153] Example 38

[0154] Synthesis of N-(2-((3-nitrobenzyl)oxy)phenyl)benzamide (Example 38)

[0155] Following the synthesis method of Example 1, N-(2-((3-nitrobenzyl)oxy)phenyl)benzamide (Example 38) was obtained. TLC detection showed a single point, a dark spot under a UV lamp at 254 nm, and no fluorescence under a UV lamp at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.14-8.07(m,2H),7.99-7.93(m,2H),7.77-7.70(m,2H),7.58(dd,J=8.7,7 .9Hz,1H),7.54-7.47(m,1H),7.46-7.38(m,2H),7.04-6.93(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(t,J=0.8Hz,2H).

[0156] Example 39

[0157] Synthesis of N-(2-((3-cyanobenzyl)oxy)phenyl)benzamide (Example 39)

[0158] Following the synthesis method of Example 1, N-(2-((3-cyanobenzyl)oxy)phenyl)benzamide (Example 39) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.91(m,3H),7.84(t,J=6.7Hz,1H),7.74(dd,J=7.6,1.8Hz,1H),7.62 (ddq,J=6.7,2.0,1.0Hz,1H),7.54-7.38(m,3H),7.04-6.93(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(d,J=1.0Hz,2H).

[0159] Example 40

[0160] Synthesis of N-(2-((3-fluorobenzyl)oxy)phenyl)benzamide (Example 40)

[0161] Following the synthesis method of Example 1, N-(2-((3-fluorobenzyl)oxy)phenyl)benzamide (Example 40) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.74(dd,J=7.6,1.8Hz,1H),7.54-7.47(m,1H),7.46-7 .39(m,1H),7.35(td,J=7.7,5.0Hz,1H),7.11(ddq,J=7.5,1.9,1.0Hz,1H),7.07-6.88(m,5H),5.03(d,J=1.0Hz,2H).

[0162] Example 41

[0163] Synthesis of N-(2-((3,5-difluorobenzyl)oxy)phenyl)benzamide (Example 41)

[0164] Following the synthesis method of Example 1, N-(2-((3,5-difluorobenzyl)oxy)phenyl)benzamide (Example 41) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ7.99-7.93(m,1H),7.74(dd,J=7.6,1.8Hz,0H),7.54-7.47(m,0H), 7.46-7.38(m,1H),7.04-6.89(m,2H),6.69(ddt,J=12.2,1.8,0.9Hz,1H),5.03(t,J=0.9Hz,1H).

[0165] Example 42

[0166] Synthesis of N-(2-((3-(trifluoromethyl)benzyl)oxy)phenyl)benzamide (Example 42)

[0167] Following the synthesis method of Example 1, N-(2-((3-(trifluoromethyl)benzyl)oxy)phenyl)benzamide (Example 42) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.74(dd,J=7.5,1.8Hz,1H),7.54-7.47(m,1H) ,7.47-7.37(m,5H),7.29-7.22(m,1H),7.04-6.93(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.21(d,J=1.0Hz,2H).

[0168] Example 43

[0169] Synthesis of 3-((2-benzamidophenoxy)methyl)-N,N-dimethylbenzamide (Example 43)

[0170] Following the synthesis method of Example 1, 3-((2-benzamidophenoxy)methyl)-N,N-dimethylbenzamide (Example 43) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,3H),7.77-7.71(m,2H),7.59(ddq,J=7.9,2.0,1.0Hz,1H),7.54-7.47(m, 1H),7.46-7.38(m,2H),7.30(d,J=8.2Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(d,J=0.9Hz,2H),3.03(s,5H).

[0171] Example 44

[0172] Synthesis of N-(2-((5-methylpyridin-2-yl)methoxy)phenyl)benzamide (Example 44)

[0173] Following the synthesis method of Example 1, N-(2-((5-methylpyridin-2-yl)methoxy)phenyl)benzamide (Example 44) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.32(d,J=2.3Hz,1H),7.99-7.93(m,2H),7.80-7.71(m,2H),7.54-7.47(m,1H),7.4 6-7.38(m,2H),7.04-6.93(m,2H),6.92(dd,J=7.6,1.7Hz,1H),6.77(dt,J=8.0,1.0Hz,1H),5.29(d,J=1.0Hz,2H),2.34(s,3H).

[0174] Example 45

[0175] Synthesis of N-(2-((3,5-diethylpyridin-2-yl)methoxy)phenyl)benzamide (Example 45)

[0176] Following the synthesis method of Example 1, N-(2-((3,5-diethylpyridin-2-yl)methoxy)phenyl)benzamide (Example 45) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.72-8.66(m,1H),7.99-7.93(m,1H),7.80-7.71(m,1H),7.54-7.47(m,0H),7.46-7.38(m,1 H),7.04-6.89(m,1H),5.48(s,1H),2.77(qt,J=7.7,0.9Hz,1H),2.63(qd,J=7.9,0.9Hz,1H),1.25(dt,J=19.7,7.8Hz,3H).

[0177] Example 46

[0178] Synthesis of N-(2-((3-methoxybenzyl)oxy)phenyl)benzamide (Example 46)

[0179] Following the synthesis method of Example 1, N-(2-((3-methoxybenzyl)oxy)phenyl)benzamide (Example 46) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ7.99-7.93(m,1H),7.74(dd,J=7.6,1.8Hz,0H),7.54-7.47(m,0H),7. 46-7.38(m,1H),7.05-6.87(m,3H),6.83(td,J=2.1,1.0Hz,0H),5.03(t,J=0.9Hz,1H),3.75(s,1H).

[0180] Example 47

[0181] Synthesis of N-(2-((3-ethoxybenzyl)oxy)phenyl)benzamide (Example 47)

[0182] Following the synthesis method of Example 1, N-(2-((3-ethoxybenzyl)oxy)phenyl)benzamide (Example 47) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.74(dd,J=7.6,1.8Hz ,1H),7.54-7.47(m,1H),7.46-7.38(m,2H),7.26(d,J=15.9Hz,1H),7.01(dddd,J=9. 1,4.8,2.1,1.1Hz,3H),7.01-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),6.83(tt,J=2 .1,0.8Hz,1H),5.03(t,J=0.9Hz,2H),4.14(q,J=6.6Hz,2H),1.44(d,J=13.4Hz,2H).

[0183] Example 48

[0184] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2-naphthoamide (Example 48)

[0185] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-2-naphthylcarboxamide (Example 48) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.40(t,J=1.8Hz,1H),8.08-8.00(m,2H),7.97(dd,J=8.4,0.6Hz,1H),7.77-7 .68(m,3H),7.60(ddd,J=8.4,6.7,1.4Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2.29(s,3H).

[0186] Example 49

[0187] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)quinoline-3-carboxamide (Example 49)

[0188] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)quinoline-3-carboxamide (Example 49) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ9.80(d,J=1.8Hz,1H),9.68(t,J=2.0Hz,1H),8.58(s,1H),8.44-8.38(m,1H),8.24-8.18(m,1H),7.92-7.84( m,1H),7.79(td,J=7.6,1.3Hz,1H),7.74(dd,J=7.5,1.8Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2.29(s,3H).

[0189] Example 50

[0190] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)isoquinoline-6-carboxamide (Example 50)

[0191] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)isoquinoline-6-carboxamide (Example 50) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1HNMR(500MHz,Chloroform-d)δ9.32-9.28(m,1H),8.70-8.64(m,2H),8.47(ddd,J=5.1,3.4,1.9Hz,2H),8.42(dd,J=8.8,1.5Hz,1H) ,7.88(dd,J=4.4,2.1Hz,1H),7.74(dd,J=7.5,1.8Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2.29(s,3H).

[0192] Example 51

[0193] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)furan-3-carboxamide (Example 51)

[0194] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)furan-3-carboxamide (Example 51) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.63(dd,J=1.6,0.9Hz,1H),8.58(s,1H),7.74(dd,J=7.5,1.8Hz,1H),7.49(t ,J=1.7Hz,1H),7.39-7.35(m,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2.29(s,3H).

[0195] Example 52

[0196] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-nitrobenzamide (Example 52)

[0197] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-nitrobenzamide (Example 52) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1HNMR(500MHz,Chloroform-d)δ8.98(t,J=2.2Hz,1H),8.68(s,1H),8.53(ddd,J=8.0,2.2,1.2Hz,1H),8.46(ddd,J=8.8,2.1,1.1Hz,1H),7 .85(dd,J=8.9,8.1Hz,1H),7.74(dd,J=7.5,1.8Hz,1H),7.04-6.96(m,2H),6.94(ddd,J=20.6,7.8,1.6Hz,2H),5.03(s,2H),2.27(s,3H).

[0198] Example 53

[0199] Synthesis of 3-cyano-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 53)

[0200] Following the synthesis method of Example 1, 3-cyano-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 53) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),8.50(t,J=2.1Hz,1H),8.26(ddd,J=6.6,2.1,1.1Hz,1H),8.05(ddd,J=7.1,2.2,1.1Hz,1 H),7.74(dd,J=7.5,1.8Hz,1H),7.65-7.59(m,1H),7.04-6.96(m,1H),6.94(ddd,J=20.6,7.8,1.6Hz,2H),5.03(s,2H),2.27(s,3H).

[0201] Example 54

[0202] Synthesis of 3-chloro-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 54)

[0203] Following the synthesis method of Example 1, 3-chloro-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 54) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.97-7.93(m,1H),7.93-7.86(m,1H),7.74(dd,J=7.5,1.8 Hz,1H),7.72-7.64(m,2H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2.29(s,3H).

[0204] Example 55

[0205] Synthesis of 3-bromo-N-(2-((3,5-dimethylisoxazo-4-yl)methoxy)phenyl)benzamide (Example 55)

[0206] Following the synthesis method of Example 1, 3-bromo-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 55) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.14(t,J=2.1Hz,1H),7.96(ddd,J=8.1,2.2,1.2Hz,1H),7.77-7 .70(m,2H),7.50(t,J=8.1Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2.27(s,3H).

[0207] Example 56

[0208] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-methylbenzamide (Example 56)

[0209] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-methylbenzamide (Example 56) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ7.87-7.79(m,1H),7.74(dd,J=7.6,1.8Hz,0H),7.49-7.41(m,1H),7.04-6.89(m,2H),5.03(s,1H),2.28(d,J=10.1Hz,3H).

[0210] Example 57

[0211] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3,5-dimethylbenzamide (Example 57)

[0212] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3,5-dimethylbenzamide (Example 57) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.74(dd,J=8.7,2.0Hz,4H),7.20-7.16(m,1H), 7.04-6.96(m,2H),6.94(ddd,J=20.6,7.8,1.6Hz,2H),5.03(s,2H),2.28(d,J=10.1Hz,8H).

[0213] Example 58

[0214] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-ethylbenzamide (Example 58)

[0215] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-ethylbenzamide (Example 58) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.89(ddd,J=8.2,2.2,1.2Hz,1H), 7.74(dd,J=7.5,1.8Hz,1H),7.58(tt,J=2.1,0.9Hz,1H),7.43(ddq,J=7.9,2.0 ,1.0Hz,1H),7.31(d,J=16.1Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz ,1H),5.03(s,2H),2.68(qt,J=7.1,0.9Hz,2H),2.29(s,3H),1.31-1.25(m,3H).

[0216] Example 59

[0217] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-propylbenzamide (Example 59)

[0218] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-propylbenzamide (Example 59) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.89(ddd,J=8.2,2.2,1.2Hz,1H),7.74(d d,J=7.5,1.8Hz,1H),7.58(tt,J=2.1,0.9Hz,1H),7.43(ddq,J=7.9,2.0,1.0Hz,1H),7 .31(d,J=16.1Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2. 58(tt,J=6.4,0.9Hz,2H),2.29(s,3H),1.65(qt,J=7.4,6.3Hz,2H),1.00-0.94(m,3H).

[0219] Example 60

[0220] Synthesis of 3-Butyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 60)

[0221] Following the synthesis method of Example 1, 3-butyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 60) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.89(ddd,J=8.2,2.2,1.2Hz,1H),7.74(dd,J=7 .5,1.8Hz,1H),7.58(tt,J=2.1,0.9Hz,1H),7.43(ddq,J=7.9,2.0,1.0Hz,1H),7.31(d,J=16. 1Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2.49(tt,J=8.2,0.9Hz ,2H),2.29(s,3H),1.57(tt,J=8.3,6.6Hz,2H),1.32(h,J=7.0Hz,2H),1.04(t,J=7.2Hz,3H).

[0222] Example 61

[0223] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-methoxybenzamide (Example 61)

[0224] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-methoxybenzamide (Example 61) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,2H),7.74(dd,J=7.5,1.8Hz,2H),7.59(ddd,J=8.1,2.1,1.0Hz,2H),7.44(t,J=8.1Hz,2H),7.32(d,J= 3.9Hz,1H),7.18(ddd,J=8.0,1.8,1.0Hz,2H),7.04-6.96(m,3H),6.94(ddd,J=20.6,7.8,1.6Hz,3H),5.03(s,3H),3.77(s,5H),2.29(s,6H).

[0225] Example 62

[0226] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-ethoxybenzamide (Example 62)

[0227] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-ethoxybenzamide (Example 62) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,0H),7.74(dd,J=7.5,1.8Hz,1H),7.62-7.52(m,1H) ,7.09-6.89(m,3H),5.03(s,1H),3.93(q,J=6.7Hz,1H),2.29(s,2H),1.44(t,J=6.7Hz,2H).

[0228] Example 63

[0229] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-propoxybenzamide (Example 63)

[0230] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-propoxybenzamide (Example 63) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ7.62-7.52(m,1H),7.09-6.89(m,1H),5.03(s,1H),3. 96(t,J=5.4Hz,1H),2.29(s,1H),1.83(qt,J=7.7,5.4Hz,1H),1.13(t,J=7.8Hz,1H).

[0231] Example 64

[0232] Synthesis of 3-butoxy-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 64)

[0233] Following the synthesis method of Example 1, 3-butoxy-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 64) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.74(dd,J=7.5,1.8Hz,1H),7.59(ddd,J=8.1,2.1,0.9Hz,1H),7.54(t,J=2.0Hz,1H),7. 09-6.89(m,4H),5.03(s,1H),4.00(t,J=6.4Hz,2H),2.29(s,3H),1.78(p,J=6.7Hz,2H),1.45(h,J=7.0Hz,2H),0.99(t,J=7.0Hz,3H).

[0234] Example 65

[0235] Synthesis of 3-cyclopropyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 65)

[0236] Following the synthesis method of Example 1, 3-cyclopropyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 65) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1HNMR(500MHz,Chloroform-d)δ8.68(s,1H),8.00(td,J=2.2,0.8Hz,1H),7.89(ddd, J=7.9,2.1,1.1Hz,1H),7.74(dd,J=7.5,1.8Hz,1H),7.47(ddt,J=8.1,2.0,0.9Hz,1 H),7.27(d,J=8.0Hz,1H),7.04-6.93(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2 H),3.49(qd,J=5.6,4.7Hz,1H),2.29(s,3H),1.00-0.92(m,2H),0.68-0.60(m,2H).

[0237] Example 66

[0238] Synthesis of 3-cyclobutyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 66)

[0239] Following the synthesis method of Example 1, 3-cyclobutyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 66) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),8.00(td,J=2.2,0.8Hz,1H),7.89(ddd,J=7.9,2.1,1.1Hz,1 H),7.74(dd,J=7.5,1.8Hz,1H),7.47(ddt,J=8.1,2.0,0.9Hz,1H),7.27(d,J=8.0Hz,1H),7.04-6.93(m,2 H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),3.28-3.20(m,1H),2.38(dtd,J=12.3,8.0,5.2Hz,2H),2.2 9(s,3H),2.12(dtd,J=12.3,8.0,5.1Hz,2H),1.63(dp,J=12.1,8.1Hz,1H),1.51(dp,J=12.1,8.1Hz,1H).

[0240] Example 67

[0241] Synthesis of 3-cyclopentyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 67)

[0242] Following the synthesis method of Example 1, 3-cyclopentyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 67) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),8.00(td,J=2.2,0.8Hz,1H),7.89(ddd,J=7.9,2.1,1.1Hz,1H),7.74(dd,J=7.5,1.8Hz,1H),7.47(ddt,J=8.1 ,2.0,0.9Hz,1H),7.27(d,J=8.0Hz,1H),7.04-6.89(m,3H),5.03(s,1H),2.8 3-2.75(m,1H),2.28(d,J=10.1Hz,5H),2.06-1.94(m,2H),1.84-1.56(m,5H).

[0243] Example 68

[0244] Synthesis of 3-cyclohexyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 68)

[0245] Following the synthesis method of Example 1, 3-cyclohexyl-N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 68) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR (500MHz, Chloroform-d) δ8.68 (s, 1H), 8.00 (td, J=2.2, 0.8Hz, 1H), 7.89 (ddd, J=7. 9,2.1,1.1Hz,1H),7.74(dd,J=7.5,1.8Hz,1H),7.47(ddt,J=8.1,2.0,0.9Hz,1H),7.27(d ,J=8.0Hz,1H),7.04-6.93(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),2.76-2.68(m ,1H),2.29(s,3H),2.27(s,3H),2.27-2.18(m,2H),1.70-1.58(m,2H),1.58-1.40(m,6H).

[0246] Example 69

[0247] Synthesis of methyl 3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamoyl)benzoate (Example 69)

[0248] Following the synthesis method of Example 1, methyl 3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamoyl)benzoate (Example 69) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.60(t,J=2.1Hz,1H),8.16(ddd,J=8.0,2.2,1.2Hz,1H),8.10(ddd,J=8.0,2.0 ,1.1Hz,1H),7.74(dd,J=7.5,1.8Hz,1H),7.63(t,J=8.1Hz,1H),7.04-6.89(m,2H),5.03(s,1H),3.85(s,2H),2.29(s,2H).

[0249] Example 70

[0250] Synthesis of ethyl 3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamoyl)benzoate (Example 70)

[0251] Following the synthesis method of Example 1, ethyl 3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamoyl)benzoate (Example 70) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.60(t,J=2.1Hz,1H),8.16(ddd,J=8.0,2.2,1.2Hz,1H),8.10(ddd,J=8.0,2.0,1.1Hz,1H),7.74(dd,J=7.5,1.8H z,1H),7.63(t,J=8.1Hz,1H),7.04-6.96(m,2H),6.94(ddd,J=20.6,7.8,1.6H z,2H),5.03(s,2H),4.42(q,J=6.4Hz,2H),2.27(s,3H),1.40(t,J=6.4Hz,3H).

[0252] Example 71

[0253] Synthesis of propyl 3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamoyl)benzoate (Example 71)

[0254] Following the synthesis method of Example 1, propyl 3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamoyl)benzoate (Example 71) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.60(t,J=2.1Hz,1H),8.16(ddd,J=8.0, 2.2,1.2Hz,1H),8.10(ddd,J=8.0,2.0,1.1Hz,1H),7.74(dd,J=7.5,1.8Hz,1H),7.6 3(t,J=8.1Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),4.2 4(t,J=5.4Hz,2H),2.27(s,3H),1.93(qt,J=8.1,5.5Hz,2H),0.91(t,J=8.0Hz,3H).

[0255] Example 72

[0256] Synthesis of 3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamoyl)butyl benzoate (Example 72)

[0257] Following the synthesis method of Example 1, 3-((2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)carbamoyl)butyl benzoate (Example 72) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.60(t,J=2.1Hz,1H),8.16(ddd,J=8.0,2.2 ,1.2Hz,1H),8.10(ddd,J=8.0,2.0,1.1Hz,1H),7.74(dd,J=7.5,1.8Hz,1H),7.63(t,J=8 .1Hz,1H),7.04-6.94(m,2H),6.92(dd,J=7.7,1.7Hz,1H),5.03(s,2H),4.20(t,J=6.4H z,2H),2.29(s,3H),1.56(p,J=6.7Hz,2H),1.32(h,J=7.0Hz,2H),0.94(t,J=7.0Hz,3H).

[0258] Example 73

[0259] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(4-methylpiperazin-1-yl)benzamide (Example 73)

[0260] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(4-methylpiperazin-1-yl)benzamide (Example 73) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.74(dd,J=7.5,1.8Hz,1H),7.22(d d,J=8.2,7.5Hz,1H),7.11(ddd,J=8.2,2.2,1.2Hz,1H),7.04-6.89(m,2H),6.86 (ddd,J=7.3,2.1,1.2Hz,1H),5.03(s,1H),3.67(ddd,J=11.2,5.6,3.9Hz,1H),3 .43(ddd,J=11.2,5.8,3.8Hz,1H),3.23-3.13(m,3H),3.03(s,2H),2.29(s,2H).

[0261] Example 74

[0262] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-morpholinylbenzamide (Example 74)

[0263] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-morpholinobenzamide (Example 74) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ8.68(s,1H),7.74(dd,J=7.5,1.8Hz,1H),7.22(dd,J=8.2,7.5Hz,1H),7.11(ddd,J=8.2,2.2,1.2Hz,1H),7.04-6. 96(m,1H),6.94(ddd,J=20.6,7.8,1.6Hz,1H),6.86(ddd,J=7.3,2.1,1.2 Hz,1H),5.03(s,1H),3.89-3.83(m,3H),3.19-3.13(m,3H),2.29(s,2H).

[0264] Example 75

[0265] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(morpholinomethyl)benzamide (Example 75)

[0266] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(morpholinomethyl)benzamide (Example 75) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.96(dtd,J=6.6,2.1,1.2Hz,1H),7.74(dd,J=7.6,1.9Hz,1H),7.50(ddq,J=8.2,2.0,1.0 Hz,1H),7.32-7.26(m,1H),7.04-6.89(m,2H),5.03(s,1H),3.73-3.67(m,3H),3.49(t,J=0.8Hz,1H),2.48-2.42(m,3H),2.29(s,2H).

[0267] Example 76

[0268] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-((4-methylpiperazin-1-yl)methyl)benzamide (Example 76)

[0269] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-((4-methylpiperazin-1-yl)methyl)benzamide (Example 76) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR (500MHz, Chloroform-d) δ7.96 (dtd, J=4.7, 2.1, 1.2Hz, 1H), 7.74 (dd, J=7.6, 1.9Hz, 0H), 7.50 (ddq, J=8.2, 2.0, 1.0Hz ,1H),7.04-6.89(m,1H),5.03(s,1H),3.49(t,J=0.8Hz,1H),2.74-2.68(m,2H),2.44-2.38(m,2H),2.28(d,J=10.1Hz,3H).

[0270] Example 77

[0271] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(morpholinylmethoxy)benzamide (Example 77)

[0272] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(morpholinylmethoxy)benzamide (Example 77) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.74(dd,J=7.5,1.8Hz,1H),7.59(ddd,J=8.1,2.1,1.0Hz,1H),7.44(t,J=8.1Hz,1H), 7.13(ddd,J=8.1,1.7,0.9Hz,1H),7.04-6.89(m,2H),5.02(d,J=10.1Hz,3H),3.72-3.66(m,3H),2.49-2.43(m,3H),2.29(s,2H).

[0273] Example 78

[0274] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-((morpholinomethyl)amino)benzamide (Example 78)

[0275] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-((morpholinomethyl)amino)benzamide (Example 78) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.74(dd,J=7.6,1.9Hz,1H),7.33-7.25(m,1H),7.19(ddd,J=8.1,2.2,1.3Hz,1H),7.04-6.96(m,1H),6.94(ddd, J=20.6,7.8,1.6Hz,1H),6.79(ddd,J=8.1,2.2,1.2Hz,1H),5.03(s,1H),4.13 (d,J=3.5Hz,1H),3.63-3.57(m,3H),2.47(dd,J=4.8,4.0Hz,3H),2.29(s,2H).

[0276] Example 79

[0277] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(2-morpholinylethoxy)benzamide (Example 79)

[0278] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(2-morpholinylethoxy)benzamide (Example 79) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ7.74(dd,J=7.5,1.8Hz,0H),7.62-7.52(m,1H),7.09-6.89(m,2H),5.03( s,1H),4.11-4.05(m,1H),3.72(t,J=4.7Hz,2H),2.68(t,J=5.9Hz,1H),2.54-2.42(m,2H),2.29(s,2H).

[0279] Example 80

[0280] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(3-morpholinylpropoxy)benzamide (Example 80)

[0281] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(3-morpholinylpropoxy)benzamide (Example 80) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ7.74(dd,J=7.6,1.9Hz,0H),7.62-7.52(m,1H),7.09-6.89(m,2H),5.03(s,1H),4.08 (t,J=6.5Hz,1H),3.77-3.71(m,2H),2.85(t,J=6.5Hz,1H),2.51-2.45(m,2H),2.29(s,2H),1.84(p,J=6.6Hz,1H).

[0282] Example 81

[0283] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(4-morpholinylbutoxy)benzamide (Example 81)

[0284] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-(4-morpholinylbutoxy)benzamide (Example 81) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ7.74(dd,J=7.6,1.9Hz,0H),7.62-7.52(m,1H),7.09-6.89(m,2H),5.03(s,1H),3.92(t,J=6 .0Hz,1H),3.77-3.71(m,2H),2.51-2.45(m,2H),2.38(t,J=6.0Hz,1H),2.29(s,2H),1.77-1.67(m,1H),1.63-1.53(m,1H).

[0285] Example 82

[0286] Synthesis of N-benzyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)aniline (Example 82)

[0287] Following the synthesis method of Example 1, N-benzyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)aniline (Example 82) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ7.36-7.24(m,4H),6.90-6.81(m,2H),6.69-6.61( m,2H),5.03(s,2H),4.12(dt,J=5.4,0.9Hz,2H),4.03-3.97(m,1H),2.29(s,3H).

[0288] Example 83

[0289] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)benzyl)aniline (Example 83)

[0290] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)benzyl)aniline (Example 83) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ7.35(ddd,J=8.0,1.8,0.9Hz,1H),7.16-7.08(m,2H),7.02(td,J=7.7,1.8Hz,1H),6.95(dd,J=8.0,1.3Hz,1H),6.87( td,J=7.7,1.3Hz,1H),6.77(tt,J=7.0,1.2Hz,1H),6.57-6.51(m,2H),5.0 3(s,2H),4.31(dd,J=5.4,0.9Hz,2H),4.06(t,J=5.5Hz,1H),2.29(s,3H).

[0291] Example 84

[0292] Synthesis of N-benzyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-methylaniline (Example 84)

[0293] Following the synthesis method of Example 1, N-benzyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-methylaniline (Example 84) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ7.32-7.21(m,2H),6.87(dd,J=7.3,1.5Hz,1H),6.81(td,J=7.5,1.2Hz,1H),6.66 (dd,J=8.3,1.2Hz,1H),6.58(ddd,J=8.2,7.5,1.5Hz,1H),5.03(s,1H),4.59(s,1H),2.92(s,2H),2.29(s,2H).

[0294] Example 85

[0295] Synthesis of N-benzyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-ethylaniline (Example 85)

[0296] Following the synthesis method of Example 1, N-benzyl-2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-ethylaniline (Example 85) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ7.37-7.21(m,3H),6.87(dd,J=7.3,1.5Hz,1H),6.81(td,J=7.5,1.2Hz,1H),6.66(dd,J=8.3,1.2Hz,1 H),6.58(ddd,J=8.2,7.5,1.5Hz,1H),5.03(s,1H),4.73(d,J=0.9Hz,1H),3.77(q,J=7.2Hz,1H),2.29(s,2H),1.31(t,J=7.2Hz,2H).

[0297] Example 86

[0298] Synthesis of 5-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-3-phenyl-1,2,4-oxadiazole (Example 86)

[0299] Following the synthesis method of Example 1, 5-(2-((3,5-dimethylisooxazol-4-yl)methoxy)phenyl)-3-phenyl-1,2,4-oxadiazole (Example 86) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR(500MHz,Chloroform-d)δ7.87(dt,J=9.0,1.2Hz,2H),7.59-7.45(m,4H),7.31-7.25(m,1 H),7.10(ddd,J=9.9,7.4,1.2Hz,1H),6.99(dd,J=7.9,1.2Hz,1H),5.03(s,2H),2.29(s,3H).

[0300] Example 87

[0301] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-methylbenzamide (Example 87)

[0302] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-methylbenzamide (Example 87) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ7.50(tt,J=7.7,1.6Hz,1H),7.39(ddd,J=7.3,5.0,1.5Hz,2 H),7.17-7.00(m,2H),6.94(dd,J=8.0,1.4Hz,1H),5.03(s,1H),3.62(s,2H),2.29(s,2H).

[0303] Example 88

[0304] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-ethylbenzamide (Example 88)

[0305] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)-N-ethylbenzamide (Example 88) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 HNMR(500MHz,Chloroform-d)δ7.50(tt,J=7.7,1.6Hz,1H),7.38(dd,J=7.2,1.6Hz,1H),7.30(dt,J=8.4,1.6Hz,2H),7 .17-7.00(m,4H),6.94(dd,J=8.0,1.4Hz,1H),5.03(s,2H),3.95(q,J=7.5Hz,2H),2.29(s,3H),1.13(t,J=7.5Hz,3H).

[0306] Example 89

[0307] Synthesis of N-(2-((3,5-dimethylisoxazol-4-yl)oxy)phenyl)benzamide (Example 89)

[0308] Following the synthesis method of Example 1, N-(2-((3,5-dimethylisoxazol-4-yl)oxy)phenyl)benzamide (Example 89) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.70(s,1H),8.42(dd,J=7.9,1.4Hz,1H),7.99-7.93(m,2H),7.54-7.47(m,1H),7.4 6-7.38(m,2H),7.04(td,J=8.0,1.4Hz,1H),6.97(td,J=8.0,1.5Hz,1H),6.71(dd,J=7.9,1.4Hz,1H),2.61(s,2H).

[0309] Example 90

[0310] The synthesis of N-(2-(2-(3,5-dimethylisoxazol-4-yl)ethoxy)phenyl)benzamide (Example 90) was carried out according to the synthesis method of Example 1. N-(2-(2-(3,5-dimethylisoxazol-4-yl)ethoxy)phenyl)benzamide (Example 90) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),7.99-7.93(m,2H),7.74(dd,J=7.8,1.6Hz,1H),7.54-7.47( m,1H),7.46-7.38(m,1H),7.05-6.90(m,3H),3.99(t,J=5.9Hz,2H),3.06(t,J=6.0Hz,2H),2.29(s,2H).

[0311] Example 91

[0312] Synthesis of N-(2-(3-(3,5-dimethylisoxazol-4-yl)propoxy)phenyl)benzamide (Example 91)

[0313] Following the synthesis method of Example 1, N-(2-(3-(3,5-dimethylisoxazol-4-yl)propoxy)phenyl)benzamide (Example 91) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm.1 H NMR(500MHz,Chloroform-d)δ7.99-7.93(m,1H),7.74(dd,J=7.8,1.6Hz,0H),7.54-7.47(m,0H),7.46-7.38(m,1 H),7.05-6.90(m,1H),3.99(t,J=6.1Hz,1H),2.64(t,J=11.0Hz,1H),2.29(s,1H),2.05(tt,J=11.0,6.1Hz,1H).

[0314] Example 92

[0315] Synthesis of N-(3-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 92)

[0316] Following the synthesis method of Example 1, N-(3-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)benzamide (Example 92) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ9.06(s,1H),7.99-7.93(m,2H),7.57(t,J=2.2Hz,1H),7.54-7.42(m,2H) ,7.45-7.38(m,2H),7.26(d,J=8.0Hz,1H),6.72(ddd,J=7.7,2.1,1.2Hz,1H),5.03(s,2H),2.29(s,3H).

[0317] Example 93

[0318] Synthesis of N-benzyl-1-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)methylamine (Example 93)

[0319] Following the synthesis method of Example 1, N-benzyl-1-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)methylamine (Example 93) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1H NMR (500MHz, Chloroform-d) δ8.78 (p, J=5.8Hz, 1H), 7.36-7.23 (m, 2H), 7.15 (ddt, J=7.9, 1.8, 0.9Hz, 1H), 7.02 (td, J= 7.7,1.8Hz,1H),6.97-6.85(m,1H),5.03(s,1H),3.92(dt,J=5.6,0.8Hz,1H),3.79(dd,J=5.8,0.9Hz,1H),2.29(s,2H).

[0320] Example 94

[0321] Synthesis of N-(3-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)propyl)aniline (Example 94)

[0322] Following the synthesis method of Example 1, N-(3-(2-((3,5-dimethylisoxazol-4-yl)methoxy)phenyl)propyl)aniline (Example 94) was obtained. TLC detection showed a single point, a dark spot under UV light at 254 nm, and no fluorescence under UV light at 365 nm. 1 H NMR(500MHz,Chloroform-d)δ7.21-7.12(m,2H),6.94-6.87(m,1H),6.77(tt,J=6.9,1.2Hz,0H),6.50-6.44(m,1H),5.03(s,1 H),4.04(t,J=4.6Hz,0H),3.27(td,J=5.5,4.6Hz,1H),2.64(td,J=7.7,0.8Hz,1H),2.29(s,1H),1.97(tt,J=7.8,5.5Hz,1H).

[0323] The structural formulas of the compounds synthesized in Examples 1-94

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338] Experimental Example 1: Inhibitory effect of the compounds shown in Examples 1-94 on aldehyde-ketone reductase

[0339] The expression of four proteins from the AKR1C subfamily in various cancers is associated with tumor progression and prognosis. Below are the test results of the compounds of this invention inhibiting the activity of these four proteins:

[0340] Experimental materials and methods:

[0341] Aldehyde reductases possess universal catalytic functions, reducing the carbonyl group of a substrate to a hydroxyl group, with NAD(P)H as the coenzyme. They can also reversely oxidize the hydroxyl group of 17β-hydroxysteroids to a carbonyl group. Therefore, a widely accepted assay system from the literature was chosen. Aldehyde reductases can use S-tetrahydronaphthol (S-tetralol) as a substrate in NADP... + With the participation of [a specific enzyme], it is oxidized to generate NAD(P)H. NAD(P)H can be detected at an excitation wavelength of 340 nm and an emission wavelength of 460 nm. The fluorescence value, i.e. the amount of NAD(P)H generated, can reflect the catalytic ability of the enzyme.

[0342] (1) Prepare 0.1M phosphate buffer (pH=7.0): Accurately weigh 2.19g of disodium hydrogen phosphate dodecahydrate and 6.84g of sodium dihydrogen phosphate dihydrate, and make up to 500mL with deionized water. Precisely adjust the pH of the solution to 7.

[0343] (2) Preparation of substrate stock solution: Accurately weigh an appropriate amount of S-tetralol, dissolve the substrate in DMSO to prepare a 10-fold stock solution. -1 Mother liquor of M.

[0344] (3) Preparation of coenzyme solution: Accurately weigh NADP + 14.4 mg was added to 0.1 M phosphate buffer and brought to a final volume of 9.68 mL to prepare a 2 mM stock solution.

[0345] (4) Preparation of compound stock solution: Accurately weigh a small amount of the compound to be tested, dissolve the compound in DMSO and prepare a 10% stock solution. -1 Mother liquor with concentration M.

[0346] (5) Diluting the compound stock solution: The previously prepared 100mM compound stock solution was diluted stepwise to prepare a 10mM solution. -4 M-10 -9 M has 6 concentrations, with three replicates for each concentration, resulting in a final experimental concentration of 10. -5 M-10 -10 M.

[0347] (6) A 96-well microplate was used, with 200 μL of reaction solution in each well. The blank group contained 0.1 M potassium phosphate buffer, 0.2 mM substrate solution, and 0.1 mM coenzyme solution. For the test group, each compound and each concentration was prepared in triplicate, with each well containing the corresponding concentration of the compound, 0.1 M potassium phosphate buffer, 0.2 mM substrate solution, 0.1 mM coenzyme solution, and the corresponding concentration of AKR1C protein. The control group contained 0.1 M potassium phosphate buffer, 0.2 mM substrate solution, 0.1 mM coenzyme solution, and the corresponding concentration of AKR1C protein. The protein concentrations of AKR1C1-4, determined by the Km value, were 34, 42, 71, and 72 nM, respectively. After mixing all reactants, the mixture was incubated at 37°C for 15 minutes, and the fluorescence intensity was detected using a fluorescence microplate reader at an excitation wavelength of 340 nm and an emission wavelength of 460 nm. The data were processed and analyzed using GraphPad Prism. TM The (USA) software calculates the corresponding IC using a nonlinear decay analysis model. 50 value.

[0348] Experimental results: Inhibitory activity of Examples 1-94 against AKR1C1-AKR1C4 a

[0349]

[0350]

[0351]

[0352]

[0353] a All tests were expressed as the mean±SEM of three independent experiments.

[0354] It can be seen that the compound described in this invention has a significant inhibitory effect on aldehyde-ketone reductase 1C3 and can be used for the treatment of cancers related to aldehyde-ketone reductase, especially those associated with elevated aldehyde-ketone reductase 1C3.

[0355] Further testing of the in vivo antitumor activity of the selected compounds in reversing sorafenib resistance in cancer cells was conducted using a xenograft tumor model:

[0356] Drugs and reagents: The test compound was synthesized by the applicant. Sorafenib was purchased from Jiangsu Aikon Co., Ltd., BALB / c nude mice were provided by Jiangsu Huachuang Xinno Pharmaceutical Technology Co., Ltd., and the human drug-resistant liver cancer HepG2 / Sora model was constructed by the applicant and the drug resistance coefficient was determined.

[0357] Experimental methods: Human drug-resistant hepatocellular carcinoma HepG2 / Sora cells in logarithmic growth phase were prepared into 2×10⁻⁶ cells under aseptic conditions. 8 Cell suspension of 0.1 ml was subcutaneously injected into the left axilla of nude mice. The diameter of the xenograft tumor in the nude mice was measured with calipers. The tumor was allowed to grow to 100–200 mm. 3 The animals were then randomly divided into groups. Each treatment group received its first dose on the day of separation (D0). In Example 59, the dose volume was 0.2 ml / 20 g, administered once every 3 days. The combination therapy group (Example 59 + sorafenib) received a dose volume of 0.2 ml / 20 g, administered once every 3 days. Sorafenib, the positive control drug, was administered intraperitoneally, once every 3 days, with a dose volume of 0.2 ml / 20 g. Tumor diameter and body weight were measured every 3 days during the experiment to dynamically observe the antitumor effect of the test substances. The experimental animals were sacrificed on day 21 (D21) after separation, and the tumor was surgically removed and weighed.

[0358] Results and Discussion:

[0359] In Example 59, after administering the drug intravenously at a dose of 10 mg / kg every 3 days for a total of 7 administrations, the tumor inhibition rate against HepG2 / Sora human drug-resistant liver cancer xenografts in nude mice reached 26.61%.

[0360] In the positive control group, sorafenib was administered intravenously at a dose of 10 mg / kg every 3 days for a total of 7 doses. The tumor inhibition rate against HepG2 / Sora human hepatocellular carcinoma xenografts in nude mice reached 58.87%.

[0361] The combined administration group was administered 10 mg / kg intravenously once every 3 days for a total of 7 times. After this, the tumor inhibition rate of HepG2 / Sora human hepatocellular carcinoma xenografts in nude mice reached 91.94%. Compared with the blank group, the positive drug sorafenib group, and the Example 59 group, it showed a highly significant tumor inhibition effect (P < 0.01). That is, when the compound of the present invention is used in combination with the positive drug sorafenib, it can reverse the resistance of cancer cells to sorafenib and has a synergistic effect.

[0362] At the end of the experiment, there was no significant difference in body weight compared with the blank group, the positive drug sorafenib group, and the Example 59 group (P>0.05).

[0363] 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. Compounds conforming to general formula I or their pharmaceutically acceptable salts: in: A is derived from C6 to C6 of any substitution of R1. 10 Aryl or 5- to 10-membered heteroaryl, wherein R1 is hydrogen, any substituted carboxyl, cyano, halogroup, trifluoromethyl, C1- to C6 alkyl, C1- to C6 alkoxy, C3- to C6 cycloalkyl, or C1- to C6 alkoxyacyl. B is derived from C6 to C6 of R2 with arbitrary substitution. 10 Aryl or 5-6 heteroaryl, wherein R2 is hydrogen, nitro, cyano, halo, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, N,N-dimethylaminoformyl; C is taken from C6 to C6 of any substitution of R3. 10 Aryl or 5-10 heteroaryl; wherein R3 is hydrogen, or any substituted nitro, cyano, halogroup, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C1-C6 alkoxyacyl, Where W is taken from R4 is taken from n3 is taken from integers from 0 to 6; X is taken from Y is taken from R5, R6, and R7 are independently hydrogen or C1-C3 alkyl groups; n1 is taken from integers from 0 to 5; n2 is taken from integers from 0 to 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: A is derived from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, or furanyl, in any form of substitution for R1, wherein R1 is hydrogen, or in any form of substitution for carboxyl, cyano, halogen, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, butoxy, methoxyacyl, ethoxyacyl, propoxyacyl, or butoxyacyl. B is derived from any substituted phenyl, pyridyl, oxazolyl, isoxazolyl, 3,5-dimethylisooxazol-4-yl, thiazolyl, furanyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, wherein R2 is hydrogen, nitro, cyano, fluoro, trifluoromethyl, N,N-dimethylaminoformyl, methyl, ethyl, methoxy, or ethoxy. C is derived from phenyl, naphthyl, furanyl, quinolinyl, or isoquinolinyl, with R3 being any substitution. R3 is derived from hydrogen, and can be any substitution of nitro, cyano, chloro, bromo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyacyl, ethoxyacyl, propoxyacyl, or butoxyacyl. Where W is taken from R4 is taken from n3 is taken from 0, 1, 2, 3, 4; X is taken from Y is taken from R5, R6, and R7 are independently hydrogen, methyl, or ethyl; n1 is taken from 0, 1, 2, 3; n2 is taken from 0, 1, 2.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from any one of the following compounds:

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Pharmaceutically acceptable salts are selected from hydrochloride, maleate, and citrate.

5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an aldehyde-ketone reductase 1C3 inhibitor.

6. A pharmaceutical composition, characterized in that, It contains the compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition also contains sorafenib.

8. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 6 in the preparation of a medicament for the prevention and / or treatment of cancer, preferably, wherein the cancer is associated with elevated aldehyde reductase; more preferably, wherein the cancer is associated with elevated aldehyde reductase 1C3.

9. The application according to claim 8, characterized in that, The compound of claim 1 or a pharmaceutically acceptable salt thereof can reverse cancer cells’ resistance to sorafenib.

10. The application according to claim 5 or 8, characterized in that, The drugs mentioned are tablets, capsules, powders, syrups, liquids, suspensions, and injections.

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