CN113861186B - Isoxazole-based substituted benzamide derivative and application of anti-prostate cancer drug - Google Patents

Isoxazole-based substituted benzamide derivative and application of anti-prostate cancer drug Download PDF

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CN113861186B
CN113861186B CN202111060327.4A CN202111060327A CN113861186B CN 113861186 B CN113861186 B CN 113861186B CN 202111060327 A CN202111060327 A CN 202111060327A CN 113861186 B CN113861186 B CN 113861186B
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benzamide
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androgen
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CN113861186A (en
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周金明
张荣玉
黄坊娇
张若影
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Zhejiang Normal University CJNU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses an isoxazole-substituted benzamide derivative with a structure shown in a formula (I) and a structure shown in a formula (II) and application of an anti-prostate cancer drug, wherein the isoxazole-substituted benzamide derivative can effectively inhibit the activity of an androgen receptor, and further experiments prove that the compound can degrade Quan Changxiong hormone receptor and androgen receptor alternative spliceosome, is a novel androgen antagonist and can be applied to Yu Xiong hormone-dependent anti-prostate cancer drug treatment.

Description

Isoxazole-based substituted benzamide derivative and application of anti-prostate cancer drug
Technical Field
The invention relates to the field of medicines, in particular to a substituted benzamide derivative based on isoxazole, a preparation method thereof and application of an anti-prostate cancer medicine.
Background
Prostate Cancer (Prostate Cancer) is one of the common tumors threatening the health of men, and is a malignant tumor with the highest mortality rate among men in developed countries such as Europe and America. Androgen Deprivation Therapy (ADT) is a currently widely used therapeutic regimen for prostate cancer in the clinic. After a remission period of 18-24 months on average, the prostate cancer which was sensitive to endocrine therapy is changed into Castration Resistant Prostate Cancer (CRPC), and the traditional androgen deprivation therapy is no longer effective, so that the research on CRPC mechanism and therapy has become an important point and difficulty in the research on prostate cancer.
Androgen Receptor (AR) is a class of nuclear receptors comprising four major domains: nitrogen-terminal domain (NTD), DNA-binding domain (DBD), flexible Hinge region (Hinge), and ligand-binding domain (LBD). AR is very important for the development and progression of prostate cancer, while its signaling pathway remains active in most CRPC patients, and inhibition of AR signaling pathway is still of great significance for the treatment of CRPC. The current drugs clinically used in CRPC therapy are mainly second-generation AR antagonists, including Abiraterone, enzalutamide and aplutamide. Successful development of these drugs has facilitated treatment of CRPC patients and further clarified the key role of inhibiting androgen signaling pathway for treatment of CRPC.
Clinical treatment and basic studies have shown that CRPC develops resistance to both Enzalutamide and aplutamide. The method comprises the following steps: mutation of residue F876L at the AR Hormone Binding Pocket (HBP) can render CRPC resistant to Enzalutamide and aplutamide, making it an agonist from an antagonist. And two,: ARVs lacking ligand binding domains have androgen-independent transcriptional activity, and thus Enzalutamide, apalutamide and the like acting on HBP sites cannot inhibit transcriptional activity of ARVs. In addition, since Abiraterone functions by inhibiting the androgen synthesis pathway, the production of AR alternative spliceosomes is also a key factor in the development of drug resistance by Abiraterone. And thirdly,: activating the traditional NF- κb2 signaling pathway converts androgen-sensitive prostate cancer cells to androgen-insensitive, thereby developing resistance to anti-androgens. Fourth, it is: GR (Glucocorticoid Receptor) high expression acts as a bypass of the AR signaling pathway as a new mechanism for CRPC to develop resistance to Enzalutamide.
In recent years, protein-induced degradation small molecule technology mainly comprising proteolytic targeting chimeric molecules (PROTACs) has made a great breakthrough, and has become a new strategy for drug development. Compared with the traditional medicine which needs a large excess of medicine molecules by occupying binding sites, the protein-induced degradation small molecule can play a good role in inhibiting by only needing a catalytic amount, and the unique advantage which is not possessed by the conventional small molecule inhibitor is shown. This strategy was applied to AR antagonist development and made a breakthrough progress, and such molecules could selectively degrade AR, known as selective androgen receptor degradation molecules (SARDs). However, as a new technology, PROTACs have drawbacks, especially in terms of drug development. Firstly, the difunctional molecules have higher molecular weight, so that the drug properties cannot be guaranteed, and the water solubility, the oral absorption and the membrane permeability are poor, and the drug action and the drug substitution are poor. Second, the large molecular weight of the bifunctional molecule and the complexity of the chemical structure also lead to increased chemical synthesis difficulties and costs. Furthermore, since it is reported that the linker of the bifunctional SARDs acts on the LBD domain of AR, it is not able to degrade AR alternative spliceosome AR-V7 lacking the LBD domain, etc., and thus the drug resistance problem caused by expression of AR alternative spliceosome still cannot be overcome.
Disclosure of Invention
The invention aims to provide an isoxazole-substituted benzamide derivative based on the application of an anti-prostate cancer drug, and discovers and optimizes an isoxazole-substituted benzamide derivative androgen receptor degradation fraction and the application of the isoxazole-substituted benzamide derivative in resisting prostate cancer as a new generation androgen antagonist.
The structure of the isoxazole substituted benzamide derivative is shown as a formula (I) and a structural formula (II):
ring a is independently selected from: benzene, thiophene, furan, benzothiophene, benzofuran;
the C-ring is independently selected from: benzene, pyridine, biphenyl, naphthalene;
the D ring is independently selected from: pyrazole, indole, indoline, morpholine, cis-2, 6-dimethylmorpholine;
x is independently selected from: s atom and N atom;
y is independently selected from: s atom, O atom;
R 1 independently selected from: -F, -OCH 3 、-OCF 3 、-Br、-Cl、-CF 3 、-CH 3 、-CN；
R 2 Independently selected from: -OCH 3 、-CH 3 、-F、-OCF 3 、-CF 3 、-Cl、-NO 2 、-CN、-CHO、-CH 2 OH；
R 3 Independently selected from: h is formed;
R 4 independently selected from: H. -CH 3 、-OCH 3 、-OCF 3 、-F、-Cl；
R 5 Independently selected from: H. -F, -OCH 3 、-CH 3 ；
R 6 Independently selected from: H. -CH 3 ；
n 1 Independently selected from: 0-1;
n 2 independently selected from: 0-1;
n 3 independently selected from: 2-5;
n 4 independently selected from: 0-1;
n 5 independently selected from: 1-3.
The structure of the benzamide derivative modified by the ring A of the derivative is shown as a formula (III):
the ring A is benzene ring or benzene ring substituent and heterocycle or heterocycle substituent with 5-10 atoms, and the specific structure is shown in figure 1. The A ring structure of the phenylpropionamide derivative is shown in figure 1. The synthetic route of the A-ring modified benzamide derivative is shown in figure 2.
The structure of the benzamide derivative modified by the ring B of the derivative is shown as a formula (IV):
x is nitrogen atom, B ring is heterocyclic imidazole with 5 atoms, and the synthetic route is shown in figure 3. The synthetic route of the B-ring modified benzamide derivative is shown in figure 3.
The structure of the benzamide derivative modified by the derivative E (AB ring combination) is shown as a formula (V):
R 3 independently selected from: h is formed;
R 4 independently selected from: H. -CH 3 、-OCH 3 、-OCF 3 、-F、-Cl；
R 5 Independently selected from: H. -F, -OCH 3 、-CH 3 ；
R 6 Independently selected from: H. -CH 3 ；
Y is independently selected from: s, O.
The synthetic route of the E-ring modified benzamide derivative is shown in figure 4.
The structure of the benzamide derivative modified by the derivative C ring is shown as a formula (VI) and a formula (VII):
r is independently selected from: -OCH 3 、-CH 3 、-F、-OCF 3 、-CF 3 、-Cl、-NO 2 、-CN、-CHO、-CH 2 OH；
E is independently selected from: n.
The C-ring is independently selected from: biphenyl, naphthalene.
The synthetic route of the C-ring modified benzamide derivative is shown in figure 5.
The structure of the derivative D ring modified benzamide derivative is shown as a formula (VIII).
The D ring is independently selected from: pyrazole, indole, indoline, morpholine, cis-2, 6-dimethylmorpholine;
n 2 independently selected from: 0-1;
n 3 independently selected from: 1-2.
The synthetic route of the D-ring modified benzamide derivative is shown in figure 6.
The structure of the derivative chain optimized benzamide derivative is shown as a formula (IX)
n2 is independently selected from: 0-1;
n3 is independently selected from: 0-5;
n4 is independently selected from: 0-1;
the synthesis route of the chain modified benzamide derivative is shown in figure 7.
Use of isoxazole-based substituted benzamide derivatives for the preparation of androgen receptor antagonists and androgen receptor down-regulation.
The androgen receptor antagonist inhibits the activity of the AR-T877A mutant receptor. The androgen receptor antagonist inhibits the activity of the AR-F876L mutant receptor. The application of the androgen receptor antagonist in preparing medicines for treating androgen disorder diseases. The androgen dysregulation disease is a disease caused by androgen stimulation. The androgen dysregulation disease is prostatic hyperplasia or prostatic cancer. The androgen dyscrasia disease is male hypersexuality. The androgen disorder disease is female acne, female seborrheic dermatitis, female hirsutism and female alopecia.
The androgen receptor down-regulator promotes the degradation of androgen receptor proteins.
The application of the androgen receptor antagonist in preparing medicaments for treating the prostate cancer is characterized in that the androgen receptor antagonist is used as the androgen receptor antagonist and is used for treating the sensitive prostate cancer and the drug-resistant prostate cancer of the existing medicaments by the down-regulator. The androgen receptor antagonist is applied to the preparation of a compound drug (combined drug with the existing drug enzalutamide) for treating the prostate cancer.
Compared with the prior art, the invention has the following advantages:
the invention utilizes an AR protein degradation screening model constructed by a subject group and an AR dual-fluorescence reporting system screening to be synthesized and optimized, discovers that isoxazole substituted benzamide derivatives can effectively inhibit the activity of an androgen receptor, and further experiments prove that the compounds can degrade Quan Changxiong hormone receptor and androgen receptor alternative spliceosome, are novel androgen antagonists and can be applied to Yu Xiong hormone-dependent anti-prostate cancer drug treatment.
Drawings
FIG. 1 shows the A ring structure of a phenylpropionamide derivative;
FIG. 2 shows the synthetic route of ring A modified benzamide derivatives;
FIG. 3 shows the synthetic route of B-ring modified benzamide derivatives;
FIG. 4 shows the synthetic route of E-ring modified benzamide derivatives;
FIG. 5 shows the synthetic route for C-ring modified benzamide derivatives;
FIG. 6 shows the synthetic route for D-ring modified benzamide derivatives;
FIG. 7 is a synthetic route to chain modified benzamide derivatives;
FIG. 8 shows the result of a westen-blot of partial benzamide derivatives.
Detailed Description
The following examples are intended only to aid those skilled in the art in a better understanding of the present invention and are not intended to limit the present invention in any way.
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-phenylthiazol-2-yl) benzamide from example 1 (ZA 1)
Compound 1a and p-toluenesulfonic acid (TsOH, 0.1 eq) were dissolved in anhydrous dichloromethane, stirred at room temperature, N-bromosuccinimide (NBS, 1.0 eq) was added in portions, heated to reflux, and after 12h TLC detection the reaction was complete, the reaction liquid changed from pale yellow to brownish red. After cooling to room temperature, a proper amount of saturated saline is added for washing, dichloromethane extraction, anhydrous sodium sulfate drying and reduced pressure evaporation of the solvent are carried out, and the residue is separated by column chromatography to obtain a brownish red oily matter. Thiourea (1.2 eq) was dissolved in ethanol, stirred at room temperature, added with an ethanol solution of a reddish brown oil and heated to reflux. After 2h TLC showed complete reaction, the reaction was changed from pale yellow to dark yellow. After cooling, the solvent was evaporated under reduced pressure, washed with a suitable amount of saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue was separated by column chromatography to give 4a as a pale yellow solid in 63% yield.
3, 5-dimethyl-4-hydroxymethyl isoxazole was dissolved in anhydrous dichloromethane, stirred at room temperature, and phosphorus tribromide (PBr 3.2.0 eq) was added dropwise under nitrogen atmosphere at 0 ℃. After stirring for 4h from 0deg.C to room temperature, TLC was used to detect completion of the reaction, the reaction solution was changed from colorless transparent to pale yellow, saturated sodium bicarbonate solution was added to pH 7-8, extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was separated by column chromatography to give colorless transparent, irritating oil. 4-hydroxybenzoic acid (1.0 eq) and potassium hydroxide (KOH 2.5 eq) were dissolved in ethanol: the water is 9:1, stirring at room temperature, dropwise adding colorless transparent oily matter obtained by upper reaction of a compound into a reaction system, and heating and refluxing. After 12h TLC detection was complete. After cooling to room temperature, 6M HCl is added dropwise to the reaction system until the PH of the solution is 2-3, white solid is generated, the solution is filtered under reduced pressure and dried, and the obtained white solid is the compound 8, and the yield is 56%.
The compound 8 was dissolved in 1, 2-dichloroethane, stirred at room temperature, and 1.2eq HOBT, 1.5eq EDCI, 0.12eq DMAP and 3.0eq Et were added to the stirred mixture in this order 3 N, stirring at room temperature for one hour, adding compound 4, heating and refluxing, detecting the reaction completion by TLC after 24 hours, cooling to room temperature, adding distilled water for washing, extracting with dichloromethane three times, drying with saturated saline water, drying with anhydrous sodium sulfate, evaporating solvent under reduced pressure, separating and purifying the obtained residue by column chromatography and chromatography, and purifying by petroleum ether: the volume ratio of the ethyl acetate is 3:1, a mixed solvent ofRecrystallisation gives a white solid Z15 in 66% yield.
1 H NMR(600MHz,DMSO-d 6 )δ12.71(s,1H),8.19(d,J＝8.7Hz,2H),7.59(d,J＝3.0Hz,1H),7.56(s,1H),7.54(d,J＝4.9Hz,1H),7.20(d,J＝8.7Hz,2H),7.17–7.13(m,1H),5.07(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (3-fluorophenyl) thiazol-2-yl) benzamide (ZA 2)
The preparation method is the same as that of the compound ZA1, and 4b and 8 are used as raw materials to prepare white powdery solid ZA2, and the yield is 71%.
1 H NMR(600MHz,DMSO-d 6 )δ12.68(s,1H),8.19(d,J＝8.7Hz,2H),7.85(d,J＝10.2Hz,2H),7.79(d,J＝10.5Hz,1H),7.53(d,J＝7.1Hz,1H),7.21(d,J＝8.8Hz,3H),5.07(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (3-methoxyphenyl) thiazol-2-yl) benzamide (ZA 3)
The preparation method is the same as that of the compound ZA1, and 4c and 8 are used as raw materials to prepare white powdery solid ZA3, and the yield is 65%.
1 H NMR(400MHz,CDCl 3 )δ10.27(s,1H),7.89(d,J＝8.8Hz,2H),7.37-7.34(m,2H),7.29(d,J＝8.0Hz,1H),7.18(s,1H),6.96(d,J＝8.8Hz,2H),6.84(dd,J＝8.1,1.9Hz,1H),4.84(s,2H),3.84(s,3H),2.44(s,3H),2.31(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (4-fluorophenyl) thiazol-2-yl) benzamide (ZA 4)
The preparation method is the same as that of the compound ZA1, and 4d and 8 are used as raw materials to prepare white powdery solid ZA4, and the yield is 62%.
1 H NMR(400MHz,CDCl 3 )δ10.16(s,1H),7.91(d,J＝8.8Hz,2H),7.79–7.71(m,2H),7.12(s,1H),7.06(t,J＝8.7Hz,2H),6.99(d,J＝8.8Hz,2H),4.85(s,2H),2.44(s,3H),2.31(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (2-fluorophenyl) thiazol-2-yl) benzamide (ZA 5)
The preparation method is the same as that of the compound ZA1, and 4e and 8 are used as raw materials to prepare white powdery solid ZA5, and the yield is 64%.
1 H NMR(400MHz,CDCl 3 )δ10.76(s,1H),7.91(t,J＝7.7Hz,1H),7.84–7.77(m,2H),7.45(d,J＝2.1Hz,1H),7.25–7.18(m,1H),7.14–7.02(m,2H),6.93–6.86(m,2H),4.82(s,2H),2.44(s,3H),2.32(s,3H).
Synthesis of N- ([ 4,4' -bisthiazol ] -2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide from example 6 (ZA 6)
The preparation method is the same as that of the compound ZA1, and 4f and 8 are used as raw materials to prepare white powdery solid ZA6, and the yield is 58%.
1 H NMR(600MHz,DMSO-d 6 )δ12.74(s,1H),9.21(s,1H),8.19(d,J＝8.5Hz,2H),7.91(d,J＝1.8Hz,1H),7.65(s,1H),7.20(d,J＝8.6Hz,2H),5.12–5.03(m,2H),2.46(s,3H),2.26(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (4- (trifluoromethoxy) phenyl) thiazol-2-yl) benzamide (ZA 7)
The preparation method is the same as that of the compound ZA1, and 4g and 8g are used as raw materials to prepare white powdery solid ZA7, and the yield is 64%.
1 H NMR(600MHz,DMSO-d 6 )δ12.69(s,1H),8.16(d,J＝8.8Hz,2H),8.08(d,J＝8.7Hz,2H),7.77(s,1H),7.46(d,J＝8.3Hz,2H),7.18(d,J＝8.8Hz,2H),5.05(s,2H),2.44(s,3H),2.24(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (5-methylthiophene-2-yl) thiazol-2-yl) benzamide (ZA 8) from example 8
The preparation method is the same as that of the compound ZA1, and white powdery solid ZA8 is prepared by taking 4h and 8 as raw materials, and the yield is 45%.
1 H NMR(400MHz,DMSO-d6)δ12.64(s,1H),8.14(d,J＝8.9Hz,2H),7.40(s,1H),7.32(d,J＝3.5Hz,1H),7.16(d,J＝8.9Hz,2H),6.80(dd,J＝3.5,1.1Hz,1H),5.04(s,2H),2.46(d,J＝0.4Hz,3H),2.43(s,3H),2.23(s,3H).
Synthesis of N- (4- (5-bromothiophen-2-yl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide from example 9 (ZA 9)
The preparation method is the same as that of the compound ZA1, and 4i and 8 are used as raw materials to prepare white powdery solid ZA9, and the yield is 58%.
1 H NMR(600MHz,DMSO-d 6 )δ12.81(s,1H),8.25(d,J＝8.8Hz,2H),7.71(s,1H),7.51(d,J＝3.9Hz,1H),7.35(d,J＝3.9Hz,1H),7.27(d,J＝8.8Hz,2H),5.14(s,2H),2.54(s,3H),2.34(s,3H).
Synthesis of N- (4- (5-chlorothien-2-yl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide from example 10 (ZA 10)
The preparation method is the same as that of the compound ZA1, and 4j and 8 are used as raw materials to prepare white powdery solid ZA10, and the yield is 53%.
1 H NMR(600MHz,DMSO-d 6 )δ12.74(s,1H),8.18(d,J＝8.8Hz,2H),7.63(s,1H),7.47(d,J＝3.9Hz,1H),7.19(d,J＝8.8Hz,2H),7.18(d,J＝3.9Hz,1H),5.07(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (furan-2-yl) thiazol-2-yl) benzamide (ZA 11) from example 11
The preparation method is the same as that of the compound ZA1, and 4k and 8 are used as raw materials to prepare white powdery solid ZA11, and the yield is 68%.
1 H NMR(600MHz,DMSO-d 6 )δ12.75(s,1H),8.18(d,J＝8.9Hz,2H),7.78(d,J＝1.0Hz,1H),7.43(s,1H),7.20(d,J＝8.9Hz,2H),6.77(d,J＝3.2Hz,1H),6.64(dd,J＝3.3,1.8Hz,1H),5.07(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (4- (trifluoromethyl) phenyl) thiazol-2-yl) benzamide from example 12 (ZA 12)
The preparation method is the same as that of the compound ZA1, and 4l and 8 are used as raw materials to prepare white powdery solid ZA12, and the yield is 49%.
1 H NMR(400MHz,DMSO-d 6 )δ12.76(s,1H),8.21(t,J＝7.4Hz,4H),7.96(s,1H),7.86(d,J＝8.1Hz,2H),7.21(d,J＝8.6Hz,2H),5.08(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of N- (4- (3-cyanophenyl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide from example 13 (ZA 13)
The preparation method is the same as that of the compound ZA1, and white powdery solid ZA13 is prepared by taking 4m and 8 as raw materials, and the yield is 62%.
1 H NMR(400MHz,DMSO-d 6 )δ12.71(s,1H),8.43(s,1H),8.32(d,J＝8.0Hz,1H),8.19(d,J＝8.8Hz,2H),7.96(s,1H),7.84(d,J＝7.7Hz,1H),7.71(t,J＝7.8Hz,1H),7.21(d,J＝8.8Hz,2H),5.08(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of N- (4- (3-cyanophenyl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide from example 14 (ZA 14)
The preparation method is the same as that of the compound ZA1, and 4n and 8 are used as raw materials to prepare white powdery solid ZA14, and the yield is 57%.
1 H NMR(600MHz,DMSO-d 6 )δ12.79(s,1H),8.20(d,J＝8.8Hz,2H),8.00(d,J＝7.9Hz,1H),7.90(d,J＝5.8Hz,2H),7.79(s,1H),7.48–7.36(m,2H),7.21(d,J＝8.9Hz,2H),5.08(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (3- (trifluoromethyl) phenyl) thiazol-2-yl) benzamide from example 15 (ZA 15)
The preparation method is the same as that of the compound ZA1, and white powdery solid ZA15 is prepared by taking 4o and 8 as raw materials, and the yield is 60%.
1 H NMR(400MHz,DMSO-d6)δ12.68(s,1H),8.36(s,1H),8.28(t,J＝3.7Hz,1H),8.20(d,J＝8.8Hz,2H),7.94(s,1H),7.70(t,J＝6.4Hz,2H),7.20(d,J＝8.9Hz,2H),5.06(s,2H),2.46(s,3H),2.26(s,3H).
Synthesis of N- (4- (benzofuran-2-yl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide from example 16 (ZA 16)
The preparation method is the same as that of the compound ZA1, and 4p and 8 are used as raw materials to prepare white powdery solid ZA16, and the yield is 66%.
1 H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.23(d,J＝8.8Hz,2H),7.78(s,1H),7.76(d,J＝7.8Hz,1H),7.69(d,J＝8.1Hz,1H),7.40(dd,J＝11.2,4.2Hz,1H),7.34(t,J＝7.4Hz,1H),7.24(d,J＝9.1Hz,3H),5.10(s,2H),2.49(s,3H),2.29(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (thiophen-2-yl) -1H-imidazol-2-yl) benzamide from example 17 (ZB 1)
2-Acetylthiophene and TsOH (0.1 eq) were dissolved in dichloromethane, and NBS (1.0 eq) was added in portions with stirring at room temperature, and heated under reflux, after 12h the reaction was complete by TLC, the reaction solution turned from pale yellow to brownish red. After cooling to room temperature, a proper amount of saturated saline is added for washing, dichloromethane extraction, anhydrous sodium sulfate drying and reduced pressure evaporation of the solvent are carried out, and the residue is separated by column chromatography to obtain a brownish red oily substance 2. The oily substance 2 was dissolved in DMF, 3a (1-acetylguanidine, 3.0 eq) was added to the stirred solution, and the temperature was raised to 60℃and stirred. After 12h TLC detection was complete, the reaction was light yellow to reddish brown. After cooling, DMF was washed with a large amount of saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was separated by column chromatography to give a pale yellow solid. The pale yellow solid thus separated was dissolved in methanol, 8M HCl was added to the stirred mixture, and the mixture was heated under reflux. After 4h TLC detection was complete, cooled to room temperature, 6M NaOH adjusted solution pH 10, ethyl acetate extraction, anhydrous sodium sulfate drying, evaporation of solvent under reduced pressure, column chromatography separation of the residue afforded 4' a as a pale yellow solid, yield 37%.
The preparation method is the same as that of the compound ZA1, and 4' a and 8 are used as raw materials to prepare white powdery solid ZB1, and the yield is 47%.
1 H NMR(600MHz,DMSO-d 6 )δ11.98(s,1H),11.60(s,1H),8.13(d,J＝8.5Hz,2H),7.36(d,J＝4.1Hz,1H),7.32(s,1H),7.26(s,1H),7.17(d,J＝8.5Hz,2H),7.07(s,1H),5.06(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of N- (benzo [ d ] oxazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide from example 18 (ZE 1)
The preparation method is the same as that of the compound ZA1, and 9a and 8 are used as raw materials to prepare white powdery solid ZE1, and the yield is 37%.
1 H NMR(600MHz,DMSO-d 6 )δ12.06(s,1H),8.10(d,J＝8.4Hz,2H),7.67(d,J＝7.7Hz,1H),7.63(d,J＝7.1Hz,1H),7.36(dd,J＝13.6,7.6Hz,2H),7.19(d,J＝8.6Hz,2H),5.07(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (5-fluorobenzo [ d ] thiazol-2-yl) benzamide (ZE 2)
The preparation method is the same as that of the compound ZA1, and 9b and 8 are used as raw materials to prepare white powdery solid ZE2, and the yield is 55%.
1 H NMR(600MHz,DMSO-d 6 )δ12.86(s,1H),8.17(d,J＝8.8Hz,2H),8.05(dd,J＝8.5,5.5Hz,1H),7.61(d,J＝9.6Hz,1H),7.23(td,J＝9.2,2.4Hz,1H),7.19(d,J＝8.8Hz,2H),5.05(s,2H),2.44(s,3H),2.23(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (5-methoxybenzo [ d ] thiazol-2-yl) benzamide (ZE 3) example 20
The preparation method is the same as that of the compound ZA1, and 9c and 8 are used as raw materials to prepare white powdery solid ZE3, and the yield is 58%.
1 H NMR(600MHz,DMSO-d 6 )δ12.75(s,1H),8.19(d,J＝8.7Hz,2H),7.90(d,J＝8.7Hz,1H),7.32(s,1H),7.21(d,J＝8.8Hz,2H),7.01(dd,J＝8.7,2.3Hz,1H),5.08(s,2H),3.87(s,3H),2.47(s,3H),2.27(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (6- (trifluoromethoxy) benzo [ d ] thiazol-2-yl) benzamide (ZE 4)
The preparation method is the same as that of the compound ZA1, and 9d and 8 are used as raw materials to prepare white powdery solid ZE4, and the yield is 43%.
1 H NMR(600MHz,DMSO-d 6 ) Delta 12.88 (s, 1H), 8.24-8.13 (m, 3H), 7.87 (d, J=8.7 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 2H), 5.06 (s, 2H), 2.44 (s, 3H), 2.24 (s, 3H) & lt, example 22 & gt 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (6-fluorobenzo [ d ]]Synthesis of thiazol-2-yl) benzamide (ZE 5)
The preparation method is the same as that of the compound ZA1, and 9e and 8 are used as raw materials to prepare white powdery solid ZE5, and the yield is 38%.
1 H NMR(600MHz,DMSO-d 6 )δ12.78(s,1H),8.17(d,J＝8.8Hz,2H),7.93(dd,J＝8.6,2.5Hz,1H),7.79(dd,J＝8.7,4.7Hz,1H),7.32(td,J＝9.1,2.6Hz,1H),7.19(d,J＝8.8Hz,2H),5.05(s,2H),2.44(s,3H),2.24(s,3H).
Synthesis of N- (6-chlorobenzo [ d ] thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide from example 23 (ZE 6)
The preparation method is the same as that of the compound ZA1, and 9f and 8 are used as raw materials to prepare white powdery solid ZE6, and the yield is 63%.
1 H NMR(600MHz,DMSO-d 6 )δ12.84(s,1H),8.17(d,J＝8.5Hz,3H),7.77(d,J＝8.6Hz,1H),7.49(dd,J＝8.6,2.1Hz,1H),7.19(d,J＝8.8Hz,2H),5.05(s,2H),2.44(s,3H),2.24(s,3H).
Synthesis of N- (5, 6-Dibenzo [ d ] thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide from example 24 (ZE 7)
The preparation method is the same as that of the compound ZA1, 9g and 8g are used as raw materials, and white powdery solid ZE7 is prepared, and the yield is 54%.
1 H NMR(600MHz,DMSO-d 6 )δ12.63(s,1H),8.15(d,J＝8.8Hz,2H),7.74(s,1H),7.57(s,1H),7.17(d,J＝8.8Hz,2H),5.04(s,2H),2.43(s,3H),2.34(d,J＝6.8Hz,6H),2.23(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-methoxy-N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide from example 25 (ZC 1)
The preparation method is the same as that of the compound ZA1, 8a and 4 are used as raw materials, and white powdery solid ZC1 is prepared with the yield of 36%.
1 H NMR(600MHz,DMSO-d 6 )δ12.74(s,1H),7.83(d,J＝3.9Hz,2H),7.59(d,J＝3.5Hz,1H),7.56-7.3(m,2H),7.28(d,J＝7.8Hz,1H),7.18–7.12(m,1H),5.04(d,J＝1.3Hz,2H),3.90(s,3H),2.45(s,3H),2.26(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-methyl-N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide from example 26 (ZC 2)
The preparation method is the same as that of the compound ZC2, 8b and 4 are used as raw materials, and white powdery solid ZC2 is prepared, and the yield is 62%.
1 H NMR(400MHz,DMSO-d 6 )δ12.59(s,1H),8.13–7.95(m,2H),7.54(s,1H),7.49(s,2H),7.29–7.00(m,2H),5.03(s,2H),2.43(s,3H),2.25(s,3H),2.19(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-fluoro-N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide from example 27 (ZC 3)
The preparation method is the same as that of the compound Za1, 8c and 4 are used as raw materials, and white powdery solid ZC3 is prepared, and the yield is 63%.
1 H NMR(600MHz,DMSO-d 6 )δ12.80(s,1H),8.11–8.04(m,2H),7.62–7.56(m,2H),7.55(d,J＝4.9Hz,1H),7.51(t,J＝8.4Hz,1H),7.17-7.15(m,1H),5.17(s,2H),2.47(s,3H),2.27(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) -3- (trifluoromethyl) benzamide (ZC 4)
The preparation method is the same as that of the compound ZA1, 8d and 4 are used as raw materials, and white powdery solid ZC4 is prepared, and the yield is 65%.
1 H NMR(400MHz,DMSO-d 6 )δ12.97(s,1H),8.50(d,J＝11.4Hz,2H),7.63-7.59(m,3H),7.55(d,J＝5.0Hz,1H),7.17-7.15(m,1H),5.24(s,2H),2.49(s,3H),2.26(s,3H).
Synthesis of 6- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) nicotinamide (ZC 5) from example 29
The preparation method is the same as that of the compound ZC5, 8e and 4 are used as raw materials, and white powdery solid ZC5 is prepared, and the yield is 57%.
1 H NMR(600MHz,DMSO-d 6 )δ12.64(s,1H),8.79(d,J＝2.5Hz,1H),8.14(dd,J＝9.6,2.6Hz,1H),7.58(d,J＝3.5Hz,1H),7.55(d,J＝1.2Hz,1H),7.54(d,J＝5.0Hz,1H),7.17–7.12(m,1H),6.53(d,J＝9.5Hz,1H),5.00(s,2H),2.47(s,3H),2.23(s,3H).
Synthesis of 3-chloro-4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide from example 30 (ZC 6)
The preparation method is the same as that of the compound ZA1, 8f and 4 are used as raw materials, and white powdery solid ZC6 is prepared, and the yield is 59%.
1 H NMR(600MHz,DMSO-d 6 )δ12.78(s,1H),8.28(d,J＝2.2Hz,1H),8.17(dd,J＝8.7,2.2Hz,1H),7.56(d,J＝3.5Hz,1H),7.55(s,1H),7.52(d,J＝5.0Hz,1H),7.46(d,J＝8.8Hz,1H),7.13(dd,J＝5.0,3.7Hz,1H),5.16(s,2H),2.46(s,3H),2.27(s,3H).
Synthesis of 4'- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) - [1,1' -biphenyl ] -4-carboxamide (ZC 7) in example 31
The preparation method is the same as that of the compound ZA1, 8g and 4 are used as raw materials, and white powdery solid ZC7 is prepared, and the yield is 68%.
1 H NMR(600MHz,DMSO-d 6 )δ12.85(s,1H),8.21(d,J＝8.1Hz,2H),7.83(d,J＝8.1Hz,2H),7.76(d,J＝8.4Hz,2H),7.57(d,J＝2.7Hz,1H),7.56(s,1H),7.52(d,J＝4.9Hz,1H),7.14(t,J＝8.4Hz,3H),4.99(s,2H),2.44(s,3H),2.24(s,3H).
Synthesis of 6- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) -2-naphthamide (ZC 8) from example 32
The preparation method is the same as that of the compound Z15, 8h and 4 are used as raw materials, and white powdery solid ZC8 is prepared, and the yield is 56%.
1 H NMR(600MHz,DMSO-d 6 )δ12.87(s,1H),8.78(s,1H),8.13(d,J＝8.6Hz,1H),8.01(d,J＝9.0Hz,1H),7.95(d,J＝8.6Hz,1H),7.57(dd,J＝7.0,4.0Hz,3H),7.52(d,J＝5.0Hz,1H),7.33(dd,J＝8.9,2.2Hz,1H),7.16–7.11(m,1H),5.11(s,2H),2.47(s,3H),2.26(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-formyl-N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide from example 33 (ZC 9)
The preparation method is the same as that of the compound ZA1, 8i and 4 are used as raw materials, and white powdery solid ZC9 is prepared, and the yield is 66%.
1 H NMR(600MHz,DMSO-d 6 )δ12.95(s,1H),10.34(s,1H),8.56(d,J＝2.3Hz,1H),8.49(dd,J＝8.8,2.3Hz,1H),7.58(dd,J＝9.1,5.4Hz,3H),7.55(d,J＝4.9Hz,1H),7.20–7.13(m,1H),5.26(s,2H),2.50(s,3H),2.30(s,3H).
Synthesis of 3-cyano-4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide from example 34 (ZC 10)
The preparation method is the same as that of the compound Z15, 8j and 4 are used as raw materials, and white powdery solid ZC10 is prepared, and the yield is 53%.
1 H NMR(600MHz,DMSO-d 6 )δ12.84(s,1H),8.56(d,J＝2.2Hz,1H),8.44(dd,J＝8.9,2.2Hz,1H),7.57(t,J＝4.5Hz,3H),7.52(d,J＝4.7Hz,1H),7.16–7.10(m,1H),5.25(s,2H),2.47(s,3H),2.28(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-nitro-N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide from example 35 (ZC 11)
The preparation method is the same as that of the compound ZA1, 8k and 4 are used as raw materials, and white powdery solid ZC11 is prepared, and the yield is 57%.
1 H NMR(400MHz,DMSO-d 6 )δ12.96(s,1H),8.71(d,J＝2.3Hz,1H),8.46(dd,J＝8.9,2.3Hz,1H),7.68(d,J＝9.0Hz,1H),7.59–7.54(m,2H),7.52(dd,J＝5.0,1.1Hz,1H),7.13(dd,J＝5.0,3.6Hz,1H),5.26(s,2H),2.45(s,3H),2.25(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3- (hydroxymethyl) -N- (4- (thiophen-2-yl) t-thiazol-2-yl) benzamide from example 36 (ZC 12)
ZC12 is obtained by reducing ZC9 with sodium borohydride.
1 H NMR(600MHz,DMSO-d 6 )δ12.67(s,1H),8.19(d,J＝1.8Hz,1H),8.15(dd,J＝8.6,2.1Hz,1H),7.55(d,J＝3.4Hz,1H),7.51(d,J＝4.0Hz,2H),7.24(d,J＝8.6Hz,1H),7.15–7.09(m,1H),5.19(t,J＝5.4Hz,1H),5.06(s,2H),4.51(d,J＝5.4Hz,2H),2.44(s,3H),2.25(s,3H).
Synthesis of 4- ((1H-pyrazol-1-yl) methoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide (ZD 1) example 37
The commercially available compound 1-pyrazole methanol (5 a) was dissolved in thionyl chloride and heated to reflux. After 4h TLC detection was complete, evaporated under reduced pressureSolvent, residue 6a was obtained. Compound 14 and cesium carbonate (Cs 2 CO 3 2.5 eq) was dissolved in DMF and stirred at room temperature, and compound 6a was added to the reaction system and stirred with heating at 70 ℃. After 12h TLC detection was complete. After cooling to room temperature, DMF was washed with a large amount of saturated brine, extracted with ethyl acetate, the solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography to give a white solid. The solid obtained by separation and sodium hydroxide (4 eq) were dissolved in methanol: water = 9:1, heating and refluxing, and detecting the reaction to be complete by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise thereto, the pH of the solution was adjusted to 4-6, and a white solid was precipitated. Vacuum filtering and drying to obtain white solid compound 15a.
The preparation method is the same as that of the compound Z15, and 15a and 4 are used as raw materials to prepare white powdery solid ZD1, and the yield is 46%.
1 H NMR(600MHz,DMSO-d 6 )δ12.73(s,1H),8.19–8.14(m,2H),8.09(d,J＝2.3Hz,1H),7.64(d,J＝1.5Hz,1H),7.59(dd,J＝3.5,1.0Hz,1H),7.57(s,1H),7.55(dd,J＝5.0,0.9Hz,1H),7.31(d,J＝8.9Hz,2H),7.16(dd,J＝5.0,3.6Hz,1H),6.42–6.38(m,1H),6.24(s,2H)
Synthesis of 4- ((1H-indol-1-yl) methyl) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide (ZD 2) from example 38
Indole and cesium carbonate (Cs) 2 CO 3 2.5 eq) was dissolved in DMF and stirred at room temperature, and compound 14a was added to the reaction system and stirred with heating at 70 ℃. After 12h TLC detection was complete. After cooling to room temperature, DMF was washed with a large amount of saturated brine, extracted with ethyl acetate, the solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography to give a white solid. The solid obtained by separation and sodium hydroxide (4 eq) were dissolved in methanol: water = 9:1, heating and refluxing, and detecting the reaction to be complete by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise thereto, the pH of the solution was adjusted to 4-6, and a white solid was precipitated. Vacuum filtering and drying to obtain a white solid compound 15c.
The preparation method is the same as that of the compound ZA1, and 15c and 4 are used as raw materials to prepare white powdery solid ZD2, and the yield is 76%.
1 H NMR(600MHz,DMSO-d 6 )δ12.82(s,1H),8.09(d,J＝8.2Hz,2H),7.62(d,J＝7.8Hz,1H),7.59(dd,J＝5.6,3.4Hz,2H),7.57(s,1H),7.54(d,J＝5.0Hz,1H),7.48(d,J＝8.2Hz,1H),7.34(d,J＝8.2Hz,2H),7.15(d,J＝3.7Hz,1H),7.14(t,J＝5.3Hz,1H),7.07(t,J＝7.4Hz,1H),6.56(d,J＝2.9Hz,1H),5.58(s,2H).
Synthesis of 4- (indol-1-ylmethyl) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide from example 39 (ZD 3)
The preparation method is the same as that of the compound ZD2, and the yield is 64%.
1 H NMR(600MHz,DMSO-d 6 )δ12.84(s,1H),8.16(d,J＝8.0Hz,2H),7.63–7.57(m,2H),7.57–7.50(m,3H),7.20–7.13(m,1H),7.10(d,J＝7.0Hz,1H),7.02(t,J＝7.6Hz,1H),6.63(t,J＝7.3Hz,1H),6.60(d,J＝7.8Hz,1H),4.39(s,2H),3.34(t,J＝8.3Hz,2H),2.96(t,J＝8.2Hz,2H).
EXAMPLE 40 Synthesis of 4- (2- (1H-indol-1-yl) ethoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide (ZD 4)
Indole and cesium carbonate (Cs) 2 CO 3 2.5 eq) was dissolved in DMF and stirred at room temperature, 2-bromoethanol was added to the reaction system and heated at 70 ℃. After 12h TLC detection was complete. After cooling to room temperature, DMF was washed with a large amount of saturated brine, extracted with ethyl acetate, the solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography to give a white solid. The solid obtained by separation and sodium hydroxide (4 eq) were dissolved in methanol: water = 9:1, heating and refluxing, and detecting the reaction to be complete by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise thereto, the pH of the solution was adjusted to 4-6, and a white solid was precipitated. Vacuum filtering and drying to obtain white solid compound 16 with a yield of 85%.
Compound 16 was dissolved in toluene, stirred at room temperature, and to the stirred mixture was added N-methylimidazole (nmi 1.5 eq), p-toluenesulfonyl chloride (TsCl 1.5 eq) and triethylamine (1.5 eq) in this order, stirred at room temperature, and after 1h the reaction was complete by TLC. Methanol was added and the solvent was evaporated under reduced pressure, and the residue was chromatographed on column to give 17 as a white solid. Compound 16 and cesium carbonate (Cs 2 CO 3 2.5 eq) was dissolved in DMF and stirred at room temperature to the reaction systemMethyl paraben (compound 14) was added and heated to 70 ℃ with stirring. After 12h TLC detection was complete. After cooling to room temperature, DMF was washed with a large amount of saturated brine, extracted with ethyl acetate, the solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography to give a white solid. The solid obtained by separation and sodium hydroxide (4 eq) were dissolved in methanol: water = 9:1, heating and refluxing, and detecting the reaction to be complete by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise thereto, the pH of the solution was adjusted to 4-6, and a white solid was precipitated. Vacuum filtering and drying to obtain white solid compound 15e with a yield of 81%.
The preparation method is the same as that of the compound ZA1, and 15e and 4 are used as raw materials to prepare white powdery solid ZD4, and the yield is 73%.
1 H NMR(400MHz,DMSO-d 6 )δ12.64(s,1H),8.09(d,J＝8.9Hz,2H),7.58(d,J＝8.3Hz,1H),7.55(d,J＝3.4Hz,1H),7.53(d,J＝10.2Hz,2H),7.50(s,1H),7.45(d,J＝3.1Hz,1H),7.16(t,J＝7.7Hz,1H),7.12(dd,J＝5.0,3.7Hz,1H),7.03(dd,J＝8.0,4.2Hz,3H),6.46(d,J＝2.9Hz,1H),4.61(t,J＝5.1Hz,2H),4.41(t,J＝5.2Hz,2H).
EXAMPLE 41 Synthesis of 4- (2- (indol-1-yl) ethoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide (ZD 5)
The preparation method is the same as that of the compound ZD4, and the yield is 63%.
1 H NMR(600MHz,DMSO-d 6 )δ12.66(s,1H),8.13(d,J＝8.9Hz,2H),7.55(dd,J＝3.5,1.0Hz,1H),7.53(s,1H),7.51(dd,J＝5.0,1.0Hz,1H),7.14–7.12(m,1H),7.11(d,J＝8.8Hz,2H),7.04(d,J＝7.1Hz,1H),7.00(t,J＝7.7Hz,1H),6.62–6.55(m,2H),4.30(t,J＝5.6Hz,2H),3.51–3.43(m,4H),2.90(t,J＝8.4Hz,2H).
Synthesis of 4- (((5-methylisoxazol-4-yl) methoxy) methyl) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide from example 42 (ZLN 1)
Compound 5 was dissolved with anhydrous THF, stirred at room temperature, sodium hydride (NaH 1.5 eq) was added under nitrogen atmosphere and stirred for 1h, after which tetrabutylammonium iodide (TBAI 0.12 eq) and compound 6 were added to the stirred mixture in sequence. After 12h TLC detection was complete. The remaining sodium hydride was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was chromatographed on column to give a pale yellow solid. The solid obtained by separation and sodium hydroxide (4 eq) were dissolved in methanol: water = 9:1, heating and refluxing, and detecting the reaction to be complete by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise thereto, the pH of the solution was adjusted to 4-6, and a white solid was precipitated. Vacuum filtering and drying to obtain white solid compound 8'e with a yield of 37%.
The preparation method is the same as that of the compound ZA1, 8'e and 4 are used as raw materials, and white powdery solid ZLN1 is prepared, and the yield is 66%.
1 H NMR(600MHz,DMSO-d 6 )δ12.83(s,1H),8.12(d,J＝8.1Hz,2H),7.56(d,J＝3.4Hz,1H),7.55(s,1H),7.52(d,J＝5.0Hz,1H),7.49(d,J＝8.1Hz,2H),7.15–7.11(m,1H),4.57(s,2H),4.38(s,2H),2.37(s,3H),2.21(s,3H).
Synthesis of 4- (2- ((3, 5-dimethylisoxazol-4-yl) methoxy) ethoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide (ZLN 2)
Compound 14 and potassium carbonate (K) 2 CO 3 2.5 eq) was dissolved in DMF and stirred at room temperature, and the compound 17a was added to the reaction system and heated at 70 ℃. After 12h TLC detection was complete. After cooling to room temperature, DMF was washed with a large amount of saturated brine, extracted with ethyl acetate, the solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography to give a white solid 18a in 85% yield.
The preparation method is the same as 8'e, and the white powdery solid 8' a is prepared by taking 18a and 6 as raw materials, and the yield is 49%.
The preparation method is the same as that of the compound Z15, 8' a and 4 are used as raw materials, and white powdery solid ZLN3 is prepared, and the yield is 54%.
1 H NMR(600MHz,DMSO-d 6 )δ12.66(s,1H),8.13(d,J＝8.7Hz,2H),7.56(d,J＝3.2Hz,1H),7.53(s,1H),7.51(d,J＝4.9Hz,1H),7.16–7.10(m,1H),7.08(d,J＝8.8Hz,2H),4.38(s,2H),4.25–4.18(m,2H),3.77–3.68(m,2H),2.37(s,3H),2.19(s,3H).
EXAMPLE 44 Synthesis of 4- (3- ((3, 5-dimethylisoxazol-4-yl) methoxy) propoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide (ZLN 3)
The preparation method is the same as that of the compound ZLN2, 8' b and 4 are used as raw materials, and white powdery solid ZLN3 is prepared, and the yield is 67%.
1 H NMR(600MHz,DMSO-d 6 )δ12.69(s,1H),8.15(d,J＝8.7Hz,2H),7.59(d,J＝2.7Hz,1H),7.57–7.49(m,2H),7.15(dd,J＝4.6,3.8Hz,1H),7.08(d,J＝8.7Hz,2H),4.32(s,2H),4.15(t,J＝6.1Hz,2H),3.56(t,J＝6.1Hz,2H),2.37(s,3H),2.18(s,3H),2.08–1.95(m,2H).
EXAMPLE 45 Synthesis of 4- (4- ((3, 5-dimethylisoxazol-4-yl) methoxy) butoxy) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide (ZLN 4)
The preparation method is the same as that of the compound ZLN2, 8'c and 4 are used as raw materials, and white powdery solid ZLN4 is prepared, and the yield is 46%.
1 H NMR(600MHz,DMSO-d 6 )δ12.69(s,1H),8.15(d,J＝8.7Hz,2H),7.59(d,J＝3.2Hz,1H),7.56(s,1H),7.54(d,J＝5.0Hz,1H),7.08(d,J＝8.8Hz,2H),4.30(s,2H),4.11(t,J＝6.4Hz,2H),3.46(t,J＝6.3Hz,2H),2.38(s,3H),2.21(d,J＝5.6Hz,3H),1.88–1.77(m,2H),1.70(dt,J＝12.9,6.3Hz,3H).
Synthesis of 4- (((5- ((3, 5-dimethylisoxazol-4-yl) methoxy) pentyl) oxy) -N- (4- (thiophen-2-yl) thiazol-ol-2-yl) benzamide (ZLL 5) from example 46
The preparation method is the same as that of the compound ZLN2, 8'd and 4 are used as raw materials to prepare white powdery solid ZLN5, and the yield is 42%.
1 H NMR(600MHz,DMSO-d 6 )δ12.64(s,1H),8.12(d,J＝8.8Hz,2H),7.55(d,J＝3.4Hz,1H),7.52(s,1H),7.51(d,J＝5.0Hz,1H),7.12(dd,J＝4.9,3.7Hz,1H),7.05(d,J＝8.8Hz,2H),4.26(s,2H),4.06(t,J＝6.4Hz,2H),3.38(t,J＝6.3Hz,3H),2.35(s,3H),2.17(s,3H),1.81–1.69(m,2H),1.65–1.53(m,2H),1.51–1.38(m,2H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methylbenzamide (ZAC 1) from example 47
Commercially available p-methoxyacetophenone and p-toluenesulfonic acid (TsOH, 0.1 eq) were dissolved in anhydrous dichloromethane and stirred at room temperature, N-bromosuccinimide (NBS, 1.0 eq) was added in portions, heated to reflux, and after 12h TLC detected complete reaction, the reaction solution changed from pale yellow to brownish red. After cooling to room temperature, a proper amount of saturated saline is added for washing, dichloromethane extraction, anhydrous sodium sulfate drying and reduced pressure evaporation of the solvent are carried out, and the residue is separated by column chromatography to obtain a brownish red oily matter. Thiourea (1.2 eq) was dissolved in ethanol, stirred at room temperature, added with an ethanol solution of a reddish brown oil and heated to reflux. After 2h TLC showed complete reaction, the reaction was changed from pale yellow to dark yellow. After cooling, the solvent was evaporated under reduced pressure, washed with a suitable amount of saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue was separated by column chromatography to give 4- (4-methoxyphenyl) thiazol-2-amine as a pale yellow solid in 60% yield.
The preparation method is the same as that of the compound ZA1, and 4- (4-methoxyphenyl) thiazol-2-amine and 8b are used as raw materials to prepare white powdery solid ZA C1, wherein the yield is 68%.
1 H NMR(600MHz,DMSO-d 6 )δ12.51(s,1H),8.07(d,J＝8.4Hz,1H),8.02(s,1H),7.89(d,J＝8.3Hz,2H),7.49(s,1H),7.24(d,J＝8.5Hz,1H),7.01(d,J＝8.3Hz,2H),5.05(s,2H),3.80(s,3H),2.45(s,3H),2.26(s,3H),2.20(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (5-methoxybenzo [ d ] thiazol-2-yl) -3-methylbenzamide (ZEC 1) from example 48
The preparation method is the same as that of the compound ZA1, and 2-amino-5-methoxybenzothiazole and 8b are used as raw materials to prepare white powdery solid ZEC1, and the yield is 51%.
1 H NMR(600MHz,DMSO-d 6 )δ12.67(s,1H),8.11(dd,J＝8.5,2.0Hz,1H),8.05(d,J＝1.3Hz,1H),7.90(d,J＝8.7Hz,1H),7.32(s,1H),7.28(d,J＝8.7Hz,1H),7.00(dd,J＝8.7,2.3Hz,1H),5.08(s,2H),3.87(s,3H),2.48(s,3H),2.29(s,3H),2.23(s,3H).
Synthesis of N- (benzo [ d ] thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-methoxybenzamide from example 49 (ZEC 3)
The preparation method is the same as that of the compound ZA1, and 2-aminobenzothiazole and 8b are used as raw materials to prepare white powdery solid ZEC3, and the yield is 65%.
1 H NMR(600MHz,DMSO-d 6 )δ12.73(s,1H),8.12(dd,J＝8.5,2.0Hz,1H),8.06(s,1H),8.03(d,J＝7.8Hz,1H),7.80(d,J＝8.0Hz,1H),7.49(t,J＝7.6Hz,1H),7.36(t,J＝7.5Hz,1H),7.28(d,J＝8.6Hz,1H),5.09(s,2H),2.48(s,3H),2.29(s,3H),2.23(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-methyl-N- (6- (trifluoromethoxy) benzo [ d ] thiazol-2-yl) benzamide (ZEC 5) example 50
The preparation method is the same as that of the compound ZA1, and riluzole and 8b are used as raw materials to prepare white powdery solid ZEC5, and the yield is 63%.
1 H NMR(600MHz,DMSO-d 6 )δ12.82(s,1H),8.16(d,J＝1.7Hz,1H),8.10(dd,J＝8.5,2.2Hz,1H),8.04(d,J＝1.6Hz,1H),7.86(d,J＝8.7Hz,1H),7.45(dd,J＝8.6,1.9Hz,1H),7.26(d,J＝8.7Hz,1H),5.07(s,2H),2.45(s,3H),2.26(s,3H),2.20(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-methyl-N- (4-methylbenzo [ d ] thiazol-2-yl) benzamide from example 51 (ZEC 6)
The preparation method is the same as that of the compound ZA1, and 2-amino-4-methylbenzothiazole and 8b are used as raw materials to prepare white powdery solid ZEC6, and the yield is 77%.
1 H NMR(600MHz,DMSO-d 6 )δ12.68(s,1H),8.11(dd,J＝8.5,2.2Hz,1H),8.05(d,J＝1.6Hz,1H),7.82(d,J＝7.7Hz,1H),7.25(dt,J＝15.6,7.4Hz,3H),5.06(s,2H),2.63(s,3H),2.45(s,3H),2.26(s,3H),2.20(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-methoxy-N- (6- (trifluoromethoxy) benzene-o [ d ] thiazol-2-yl) benzamide from example 52 (ZEC 7)
The preparation method is the same as that of the compound ZA1, and riluzole and 8a are used as raw materials to prepare white powdery solid ZEC5, and the yield is 78%.
1 H NMR(600MHz,DMSO-d 6 )δ12.92(s,1H),8.17(s,1H),7.91–7.82(m,2H),7.81(d,J＝1.8Hz,1H),7.46(dd,J＝8.7,1.6Hz,1H),7.28(d,J＝8.5Hz,1H),5.03(s,2H),3.88(s,3H),2.42(s,3H),2.23(s,3H).
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-methoxy-N- (6- (trifluoromethoxy) benzene-o [ d ] thiazol-2-yl) benzamide from example 53 (ZAL 1)
3, 5-dimethyl-4-hydroxymethyl isoxazole was dissolved in anhydrous dichloromethane, stirred at room temperature, and phosphorus tribromide (PBr 3.2.0 eq) was added dropwise under nitrogen atmosphere at 0 ℃. After stirring for 4h from 0deg.C to room temperature, TLC was used to detect completion of the reaction, the reaction solution was changed from colorless transparent to pale yellow, saturated sodium bicarbonate solution was added to pH 7-8, extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was separated by column chromatography to give colorless transparent, irritating oil. 4-Hydroxyphenylacetic acid (1.0 eq) and potassium hydroxide (KOH 2.5 eq) were dissolved in ethanol: the water is 9:1, stirring at room temperature, dropwise adding colorless transparent oily matter obtained by upper reaction of a compound into a reaction system, and heating and refluxing. After 12h TLC detection was complete. After cooling to room temperature, 6M HCl is added dropwise to the reaction system until the PH of the solution is 2-3, white solid is generated, the solution is filtered under reduced pressure and dried, and the obtained white solid is the compound 2- (4- ((3, 5-dimethyl isoxazol-4-yl) methoxy) phenyl) acetic acid, and the yield is 58%.
The preparation method is the same as that of the compound ZA1, and 2- (4- ((3, 5-dimethyl isoxazol-4-yl) methoxy) phenyl) acetic acid and 4- (4-methoxyphenyl) thiazole-2-amine are taken as raw materials to prepare white powdery solid ZAL1, and the yield is 68%.
1 H NMR(600MHz,DMSO-d 6 )δ12.41(s,1H),7.83(d,J＝8.2Hz,2H),7.44(s,1H),7.28(d,J＝8.1Hz,2H),6.98(t,J＝8.2Hz,4H),4.89(s,2H),3.79(s,3H),3.71(s,2H),2.39(s,3H),2.20(s,3H).
Synthesis of N- (benzo [ d ] thiazol-2-yl) -2- (4- ((3, 5-dimethylisoxazol-4-yl) methoxy) phenyl) acetamide from example 54 (ZEL 1)
The preparation method is the same as that of the compound ZA1, and 2- (4- ((3, 5-dimethyl isoxazol-4-yl) methoxy) phenyl) acetic acid and 2-aminobenzothiazole are used as raw materials to prepare white powdery solid ZEL1, and the yield is 55%.
1 H NMR(600MHz,DMSO-d 6 )δ12.56(s,1H),7.96(d,J＝7.9Hz,1H),7.75(d,J＝8.0Hz,1H),7.43(t,J＝7.6Hz,1H),7.30(t,J＝7.9Hz,3H),6.99(d,J＝8.1Hz,2H),4.89(s,2H),3.77(s,2H),2.39(s,3H),2.20(s,3H).
EXAMPLE 55 Synthesis of 2- (4- ((3, 5-dimethylisoxazol-4-yl) methoxy) phenyl) -N- (5-methoxybenzo [ d ] thiazol-2-yl) acetamide (ZEL 2)
The preparation method is the same as that of the compound ZA1, and 2- (4- ((3, 5-dimethyl isoxazol-4-yl) methoxy) phenyl) acetic acid and 2-amino-5-methoxybenzothiazole are used as raw materials to prepare white powdery solid ZEL2 with the yield of 77%.
1 H NMR(600MHz,DMSO-d 6 )δ12.52(s,1H),7.82(d,J＝8.6Hz,1H),7.29(d,J＝8.3Hz,3H),6.98(d,J＝7.9Hz,2H),6.93(d,J＝8.7Hz,1H),4.89(s,2H),3.82(s,3H),3.76(s,2H),2.39(s,3H),2.20(s,3H).
Data on the transcriptional inhibition activity of benzamide derivatives on AR in LNCaP cells, example 55.
The method comprises the following specific steps: LNCap cells well grown were digested with pancreatin and diluted to about 1.2X10 5 The individual/mL cell suspensions were inoculated into 24-well plates at a volume of 500. Mu.L per well, and after incubation for 24h, 100ng of PSA-luc and 2ng of pCMV-Renilla plasmid per well were transfected; after 24h, the compound solution with the prepared concentration is diluted with RPMI 1640 complete culture medium, old culture medium in a 24-well plate is sucked and removed, fresh culture medium after administration is added, and a positive medicine control group and a blank group are set. After 24h, the original medium was aspirated, 100. Mu.L of 1 XPLB lysate was added to each well, the well plates were then kept from shaking in a high speed shaker for 20min to mix well, 1.5mL of cell lysate was aspirated in EP tube, centrifuged at 12000rpm for 1min, 20. Mu.L of supernatant was taken into a white opaque 96 well plate, and fluorescence values were determined using a 960 microplate reader according to the instructions of the double luciferase reporter system assay kit.
This example provides primarily data (Table 1) representing the transcriptional repression activity of compounds of structural formulas (I) and (II) on AR in LNCaP cells.
TABLE 1 transcriptional inhibition Activity of example Compounds against AR
Cytotoxicity of benzamide derivatives from example 56 against prostate cancer cells LNCaP and PC-3.
LNCaP and PC-3 cells well grown were digested with trypsin and diluted to about 2X 10 4 And inoculating 200 mu L of cell suspension into each well of a 96-well plate, culturing for 24 hours, adding medicine solutions with different concentration gradients into the 96-well plate, adding 1 mu L of medicine into each well, and respectively making three groups of medicines with different concentration points into parallel, wherein a blank group and a positive medicine control group are arranged at the same time. After further culturing for 72h, 20 mu L of 5g/L MTT PBS solution is added into each well respectively, the wells are continuously placed in a carbon dioxide incubator for culturing for 2-4h, then the 96-well plates are taken out from the incubator, the culture medium in the 96-well plates is carefully sucked away, 100 mu L of isopropanol is added into each well to dissolve the precipitate, the 96-well plates are placed on a high-speed shaking table for shaking and uniformly mixing for 20min, and the absorbance value of each well is measured at 570nm by using a multifunctional enzyme-labeled instrument. Normalization was performed with DMSO group as 100%. As can be seen from table 2, compounds ZA1, ZA3 and ZA5 have higher activity against the proliferation of AR positive LNCaP cells and less effect on the proliferation of AR negative PC-3 cells, indicating better selectivity of the compounds.
Table 2: example prostate cancer cytotoxicity study
Effect of benzamide derivatives on AR protein Down-regulation from example 57
LNCaP, VCaP and 22Rv1 cells well grown were digested with pancreatin and diluted to about 2X 10 5 The cell suspension of each mL is inoculated into a 6-hole plate according to the volume of 2mL of each hole, after culturing for 48h, the drug solution prepared according to the corresponding concentration is added into the 6-hole plate, 8 mu L of each hole is added, and a blank group, an activated group and a positive drug control group are simultaneously arranged. Continuous cultivationAfter 24h of incubation, protein samples were harvested.
Cell protein sample collection: the medium in the 6-well plate was pipetted off, 80. Mu.L of pre-chilled RIPA (strong) lysate was added to each well, the cells in the 6-well plate were scraped off and collected in a 1.5mL EP tube. Cracking in ice bath for 30min, and shaking and mixing once every 5 min. Cells were then lysed by adding 20 μl of 5 x protein loading buffer. Metal bath at 100 ℃ for 30min. Protein samples were stored at-20℃or-80 ℃. Western Blot procedure: protein samples were separated using 10% SDS-PAGE at 80V 40min,120V 100min. The membrane was wet-transferred at a constant pressure of 70V for 80min (using PVDF membrane), and closed with 5% nonfat milk powder by shaking at low speed at room temperature for 1h. The primary antibody was incubated overnight, washed, the secondary antibody was incubated for 1h, washed, and then ECL developed. The antibody was used at a concentration of AR (1:500), PSA (1:100), beta-actin (1:5000), goat anti-rabbit (1:5000), goat anti-mouse (1:5000), rabbit anti-goat (1:5000). As can be seen from fig. 8, compounds ZA5, ZA11, ZC1 all can down-regulate AR levels in LNCaP cells in concentration-dependent.

Claims (9)

1. The isoxazole-based substituted benzamide derivative is characterized by having the following structure:
；
；
；
；
ZE1, R 3 =H, R 4 =H, R 5 =H, R 6 =H；
In ZE2, R 3 =H, R 4 =H, R 5 =F, R 6 =H；
ZE3, R 3 =H, R 4 =H, R 5 =OCH 3 , R 6 =H；
ZE4, R 3 =H, R 4 = OCF 3 , R 5 = H, R 6 =H；
ZE5, R 3 =H, R 4 =F, R 5 = H, R 6 =H；
ZE6, R 3 =H, R 4 =Cl, R 5 = H, R 6 =H；
ZE7, R 3 =H, R 4 = CH 3 , R 5 = CH 3 , R 6 =H。
2. Use of isoxazole-based substituted benzamide derivatives according to claim 1 for the preparation of androgen receptor antagonists.
3. The use according to claim 2, wherein the androgen receptor antagonist inhibits the activity of a wild-type androgen receptor.
4. The use according to claim 2, wherein the androgen receptor antagonist is used in the manufacture of a medicament for the treatment of androgen imbalance diseases.
5. The use according to claim 4, wherein the androgen dysregulation is a disorder caused by androgen stimulation.
6. The use according to claim 5, wherein the androgen disorder is prostatic hyperplasia, prostate cancer, male hypersexy, female acne, female seborrheic dermatitis, female hirsutism or female alopecia.
7. Use of isoxazole-based substituted benzamide derivatives according to claim 1 for the preparation of androgen receptor down-regulators.
8. The use of claim 7, wherein the androgen receptor down-regulator promotes degradation of androgen receptor proteins.
9. The use of an isoxazole-substituted benzamide derivative and enzalutamide-based combination according to claim 1 in the preparation of a compound medicament for treating prostate cancer.
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新型雄激素受体拮抗剂治疗去势抵抗性前列腺癌的研究进展;王玉;邢嵘;万山荣;王阳;;大连医科大学学报(05);第502-506页 *

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