CN113861186A - 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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CN113861186A
CN113861186A CN202111060327.4A CN202111060327A CN113861186A CN 113861186 A CN113861186 A CN 113861186A CN 202111060327 A CN202111060327 A CN 202111060327A CN 113861186 A CN113861186 A CN 113861186A
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independently selected
androgen
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benzamide
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CN113861186B (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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    • 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
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    • 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
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Abstract

The invention discloses isoxazole substituted benzamide derivatives with structures of a formula (I) and a formula (II) and application of the isoxazole substituted benzamide derivatives to medicaments for resisting prostate cancerThe receptor variable spliceosome is a novel androgen antagonist and can be applied to androgen-dependent anti-prostate cancer drug treatment.
Figure DDA0003256246840000011

Description

Isoxazole-based substituted benzamide derivative and application of anti-prostate cancer drug
Technical Field
The invention relates to the field of medicines, and in particular relates to isoxazole-based substituted benzamide derivatives, 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 the second most fatal tumor in men in developed countries such as europe and america. Androgen Deprivation Therapy (ADT) is currently a widely used clinical treatment regimen for prostate cancer. After a remission period of 18-24 months, the prostate cancer that was originally sensitive to endocrine therapy is transformed to Castration Resistant Prostate Cancer (CRPC), and conventional androgen deprivation therapy is no longer effective, and therefore research on CRPC mechanisms and treatment has become a major and difficult point in the study of prostate cancer.
The Androgen Receptor (AR) is a class of nuclear receptors that comprises four major domains: a Nitrogen Terminal Domain (NTD), a DNA Binding Domain (DBD), a flexible Hinge region (Hinge), and a Ligand Binding Domain (LBD). AR is important for the development and progression of prostate cancer, while its signaling pathway remains active in most CRPC patients, and inhibition of the AR signaling pathway is still of great significance for the treatment of CRPC. At present, the drugs clinically applied to CRPC treatment are mainly second-generation AR antagonists, including Abiraterone, Enzalutamide, Apalutamide and the like. The successful development of these drugs has facilitated the treatment of CRPC patients and further clarified the critical role of inhibiting androgen signaling pathways for the treatment of CRPC.
Clinical treatment and basic studies indicate that CRPC has resistance to both Enzalutamide and Apalutamide. One is as follows: mutation of residue F876L in the AR Hormone Binding Pocket (HBP) can confer resistance to Enzalutamide and apalcuamide to CRPC, which changes from an antagonist to an agonist. The second step is as follows: ARVs lacking the ligand-binding domain have androgen-independent transcriptional activity, and thus Enzalutamide, Apalutamide, etc., acting on HBP sites cannot inhibit ARVs transcriptional activity. In addition, since Abiraterone acts by inhibiting the androgen synthesis pathway, the production of AR alternative spliceosome is also a key factor for Abiraterone to develop resistance. And thirdly: activation of the traditional NF-. kappa.B 2 signaling pathway converts androgen-sensitive prostate cancer cells to androgen-insensitive, thereby conferring resistance to anti-androgen drugs. Fourthly, the method comprises the following steps: GR (Glucocorticoid receptor) high expression acting as a bypass of the AR signaling pathway is a new mechanism for CRPC to develop resistance to Enzalutamide.
In recent years, protein-induced degradation small molecule technologies mainly based on proteolytic targeted chimeric molecules (PROTACs) have made a great breakthrough and become a new strategy for drug development. Compared with the traditional medicine which needs a large excess amount of medicine molecules by occupying binding sites, the protein-induced degradation small molecule can play a good role in inhibiting only by catalytic amount, and the unique advantage which is not possessed by the conventional small molecule inhibitor is shown. This strategy has been applied to the development of AR antagonists with breakthrough and breakthrough, and such molecules can selectively degrade AR, and are called selective androgen receptor degradation molecules (SARDs). However, ProTACs have drawbacks as new technologies, especially in terms of drug development. Firstly, the bifunctional molecules have high molecular weights, so that the drug-like properties cannot be guaranteed, and the water solubility, oral absorption and membrane permeability of the bifunctional molecules are poor, and the pharmacokinetics and pharmacokinetics are poor. Secondly, the large molecular weight of the bifunctional molecules and the complexity of the chemical structure also lead to increased difficulties and costs in chemical synthesis. In addition, the connection molecules of the double-function molecules SARDs are reported to act on the LBD structural domain of AR at present, so that the AR variable spliceosome AR-V7 and the like which lacks the LBD structural domain cannot be degraded, and the problem of drug resistance caused by expression of the AR variable spliceosome cannot be overcome.
Disclosure of Invention
The invention aims to provide an application of isoxazole substituted benzamide derivatives and anti-prostate cancer drugs, and find and optimize the isoxazole substituted benzamide derivatives androgen receptor degradation molecules and the anti-prostate cancer application thereof as a new generation of androgen antagonists.
The isoxazole substituted benzamide derivative disclosed by the invention has the structure shown as a formula (I) and a structural formula (II):
Figure BDA0003256246820000021
ring A is independently selected from: benzene, thiophene, furan, benzothiophene, benzofuran;
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: an S atom, an N atom;
y is independently selected from: an S atom, an O atom;
R1independently selected from: -F, -OCH3、-OCF3、-Br、-Cl、-CF3、-CH3、-CN；
R2Independently selected from: -OCH3、-CH3、-F、-OCF3、-CF3、-Cl、-NO2、-CN、-CHO、-CH2OH；
R3Independently selected from: h;
R4independently selected from: H. -CH3、-OCH3、-OCF3、-F、-Cl；
R5Independently selected from: H. -F, -OCH3、-CH3；
R6Independently selected from: H. -CH3；
n1Independently selected from: 0 to 1;
n2independently selected from: 0 to 1;
n3independently selected from: 2-5;
n4independently selected from: 0 to 1;
n5independently selected from: 1-3.
The structure of the benzamide derivative modified by the A ring of the derivative is shown as the formula (III):
Figure BDA0003256246820000031
the A ring 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 phenylacrylamide 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 B-ring modified benzamide derivative of the derivative is shown as the formula (IV):
Figure BDA0003256246820000032
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 derivative E (AB ring combined) ring modified benzamide derivative disclosed by the invention is shown as a formula (V):
Figure BDA0003256246820000041
R3independently selected from: h;
R4independently selected from: H. -CH3、-OCH3、-OCF3、-F、-Cl；
R5Independently selected from: H. -F, -OCH3、-CH3；
R6Independently selected from: H. -CH3；
Y is independently selected from: s, O are provided.
The synthetic route of the E-ring modified benzamide derivative is shown in figure 4.
The structure of the C-ring modified benzamide derivative disclosed by the invention is shown as a formula (VI) and a formula (VII):
Figure BDA0003256246820000042
r is independently selected from: -OCH3、-CH3、-F、-OCF3、-CF3、-Cl、-NO2、-CN、-CHO、-CH2OH；
E is independently selected from: and N is added.
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 D-ring modified benzamide derivative is shown as a formula (VIII).
Figure BDA0003256246820000043
Figure BDA0003256246820000051
The D ring is independently selected from: pyrazole, indole, indoline, morpholine, cis-2, 6-dimethylmorpholine;
n2independently selected from: 0 to 1;
n3independently selected from: 1-2.
The synthetic route of the D-ring modified benzamide derivative is shown in figure 6.
The structure of the benzamide derivative with the optimized derivative chain is shown as a formula (IX)
Figure BDA0003256246820000052
n2 is independently selected from: 0 to 1;
n3 is independently selected from: 0 to 5;
n4 is independently selected from: 0 to 1;
the synthetic route of the chain-modified benzamide derivative is shown in figure 7.
Application of isoxazole-based substituted benzamide derivatives in preparation of androgen receptor antagonists and androgen receptor downregulators.
The androgen receptor antagonist inhibits the activity of AR-T877A mutant receptors. The androgen receptor antagonist inhibits the activity of AR-F876L mutant receptor. The application of the androgen receptor antagonist in preparing the medicines for treating the androgen imbalance diseases. The androgen imbalance disease is a disease caused by androgen hyperactivity. The androgen imbalance disease is prostatic hyperplasia or prostatic cancer. The androgen imbalance disease is male hypersexuality. The androgen imbalance disease is female acne, female seborrheic dermatitis, female hirsutism and female alopecia.
The androgen receptor down-regulator promotes the degradation of androgen receptor protein.
The application of the androgen receptor antagonist in preparing the medicines for treating the prostatic cancer, and the androgen receptor antagonist is used as the androgen receptor antagonist and a down regulator to treat the prior medicine sensitive prostatic cancer and the drug-resistant prostatic cancer. The application of the androgen receptor antagonist in the preparation of a compound medicine (combined with the existing medicine enzalutamide) for treating prostatic cancer.
Compared with the prior art, the invention has the following advantages:
the AR protein degradation screening model constructed by the subject group and the screening of the AR double-fluorescence report system are synthesized and optimized, and a class of isoxazole substituted benzamide derivatives are found, so that the activity of androgen receptors can be effectively inhibited, and further experiments prove that the compounds can degrade full-length androgen receptors and androgen receptor variable splicers, are novel androgen antagonists and can be applied to androgen-dependent prostate cancer resistant drug treatment.
Drawings
FIG. 1 shows the structure of the A ring of the phenylacrylamide derivative;
FIG. 2 is a synthetic route of ring A modified benzamide derivatives;
FIG. 3 is a scheme for synthesizing B-ring modified benzamide derivatives;
FIG. 4 is a synthetic route for E-ring modified benzamide derivatives;
FIG. 5 is a C-ring modified benzamide derivative synthesis route;
FIG. 6 is a synthetic route for D-ring modified benzamide derivatives;
FIG. 7 is a scheme for the synthesis of chain modified benzamide derivatives;
FIG. 8 shows results of western-blot experiments on a part of benzamide derivatives.
Detailed Description
The following examples are only for the purpose of helping the skilled person to better understand the present invention, but do not limit the present invention in any way.
EXAMPLE 1 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4-phenylthiazol-2-yl) benzamide (ZA1)
Dissolving the compound 1a and p-toluenesulfonic acid (TsOH, 0.1eq) in anhydrous dichloromethane, stirring at room temperature, adding N-bromosuccinimide (NBS, 1.0eq) in batches, heating and refluxing, detecting complete reaction by TLC after 12h, and changing the reaction liquid from light yellow to brown red. After cooling to room temperature, adding a proper amount of saturated saline solution for washing, extracting by dichloromethane, drying by anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and separating the residue by column chromatography to obtain a brownish red oily substance. Thiourea (1.2eq) was dissolved in ethanol, stirred at room temperature, added to an ethanol solution of a reddish-brown oil and heated under reflux. After 2h, the reaction was complete by TLC and the reaction turned from pale yellow to dark yellow. After cooling, the solvent was evaporated under reduced pressure, washed with an appropriate amount of saturated sodium bicarbonate solution, 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 4a in 63% yield.
3, 5-dimethyl-4-hydroxymethyl isoxazole is dissolved in anhydrous dichloromethane, stirred at room temperature, and phosphorus tribromide (PBr32.0eq) is added dropwise at 0 ℃ under nitrogen atmosphere. Heating to room temperature from 0 ℃, stirring for 4h, detecting by TLC that the reaction is complete, changing the reaction solution from colorless transparency to light yellow, adding saturated sodium bicarbonate solution until the pH is 7-8, extracting by dichloromethane, drying by anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and separating the residue by column chromatography to obtain colorless transparent irritant oily matter. 4-hydroxybenzoic acid (1.0eq) and potassium hydroxide (KOH 2.5eq) were dissolved in ethanol: the water content is 9: 1, stirring at room temperature, adding a colorless transparent oily substance obtained by the reaction of the upper part of the compound dropwise into the reaction system, and heating and refluxing. The reaction was complete after 12h by TLC. After cooling to room temperature, 6M HCl is dripped into the reaction system until the pH of the solution is 2-3 and white solid is generated, and the white solid is obtained by decompression, suction filtration and drying, namely the compound 8 with the yield of 56%.
Dissolving the compound 8 in 1, 2-dichloroethane, stirring at room temperature, and adding 1.2eq HOBT, 1.5eq EDCI, 0.12eq DMAP and 3.0eq Et to the stirred mixture in turn3And N, stirring for one hour at room temperature, adding a compound 4, heating and refluxing, detecting complete reaction by TLC after 24 hours, changing the reaction liquid from light yellow to brownish red, cooling to room temperature, washing by adding distilled water, extracting by dichloromethane for three times, drying by saturated saline, drying by anhydrous sodium sulfate, evaporating the solvent under reduced pressure, separating and purifying the obtained residue by column chromatography, and then purifying by petroleum ether: the volume ratio of ethyl acetate is 3: 1 to yield Z15 as a white solid in 66% yield.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 2 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (3-fluorophenyl) thiazol-2-yl) benzamide (ZA2)
The preparation method uses compound ZA1 and takes 4b and 8 as raw materials to prepare white powder solid ZA2 with the yield of 71 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 3 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (3-methoxyphenyl) thiazol-2-yl) benzamide (ZA3)
Preparation method using compound ZA1, 4c and 8 as raw materials, white powder solid ZA3 was obtained with yield of 65%.
1H NMR(400MHz,CDCl3)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).
EXAMPLE 4 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (4-fluorophenyl) thiazol-2-yl) benzamide (ZA4)
The preparation method uses compound ZA1 and takes 4d and 8 as raw materials to prepare white powder solid ZA4 with the yield of 62 percent.
1H NMR(400MHz,CDCl3)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).
EXAMPLE 5 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (2-fluorophenyl) thiazol-2-yl) benzamide (ZA5)
Preparation method using compound ZA1, 4e and 8 as raw materials, white powder solid ZA5 was obtained with a yield of 64%.
1H NMR(400MHz,CDCl3)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).
EXAMPLE 6 Synthesis of N- ([4,4' -bithiazol ] -2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide (ZA6)
Preparation method using compound ZA1, 4f and 8 as raw materials, white powder solid ZA6 was obtained with yield of 58%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 7 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (4- (trifluoromethoxy) phenyl) thiazol-2-yl) benzamide (ZA7)
Preparation method Using compound ZA1, 4g and 8 as raw materials, white powdery solid ZA7 was obtained with a yield of 64%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 8 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (5-methylthiophen-2-yl) thiazol-2-yl) benzamide (ZA8)
The preparation method uses compound ZA1 as raw material for 4h and 8 to prepare white powder solid ZA8 with yield of 45%.
1H 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).
EXAMPLE 9 Synthesis of N- (4- (5-bromothien-2-yl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide (ZA9)
Preparation method using compound ZA1, 4i and 8 as raw materials, white powder solid ZA9 was obtained with yield of 58%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 10 Synthesis of N- (4- (5-chlorothien-2-yl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide (ZA10)
Preparation method using compound ZA1, 4j and 8 as raw materials, white powder solid ZA10 was obtained with yield of 53%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 11 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (furan-2-yl) thiazol-2-yl) benzamide (ZA11)
Preparation method using compound ZA1, 4k and 8 as raw materials, white powder solid ZA11 was obtained with a yield of 68%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 12 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (4- (trifluoromethyl) phenyl) thiazol-2-yl) benzamide (ZA12)
Preparation method using compound ZA1, 4l and 8 as raw materials, white powder solid ZA12 was obtained with yield 49%.
1H NMR(400MHz,DMSO-d6)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).
EXAMPLE 13 Synthesis of N- (4- (3-cyanophenyl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide (ZA13)
Preparation method using compound ZA1, 4m and 8 as raw materials, white powder solid ZA13 was obtained with yield of 62%.
1H NMR(400MHz,DMSO-d6)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).
EXAMPLE 14 Synthesis of N- (4- (3-cyanophenyl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide (ZA14)
Preparation method using compound ZA1, 4n and 8 as raw materials, white powder solid ZA14 was obtained with yield of 57%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 15 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (3- (trifluoromethyl) phenyl) thiazol-2-yl) benzamide (ZA15)
Preparation method using compound ZA1, 4o and 8 as raw materials, white powder solid ZA15 was obtained with yield of 60%.
1H 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).
EXAMPLE 16 Synthesis of N- (4- (benzofuran-2-yl) thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide (ZA16)
Preparation method using compound ZA1, 4p and 8 as raw materials, white powder solid ZA16 was obtained with yield of 66%.
1H 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).
EXAMPLE 17 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (thien-2-yl) -1H-imidazol-2-yl) benzamide (ZB1)
Dissolving 2-acetylthiophene and TsOH (0.1eq) in dichloromethane, stirring at room temperature, adding NBS (1.0eq) in batches, heating and refluxing, detecting complete reaction by TLC after 12h, and changing the reaction liquid from light yellow to brownish red. After cooling to room temperature, a proper amount of saturated saline solution is added for washing, dichloromethane is used for extraction, anhydrous sodium sulfate is used for drying, the solvent is evaporated under reduced pressure, and the residue is separated by column chromatography to obtain a brownish red oily substance 2. The oil 2 was dissolved in DMF and 3a (1-acetylguanidine, 3.0eq) was added to the stirred solution, which was then warmed to 60 ℃ and stirred. After 12h, the reaction was completed by TLC detection, and the reaction solution changed from light yellow to brownish red. After cooling, DMF was washed off 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 separated pale yellow solid was dissolved in methanol, and 8M HCl was added to the stirred mixture, followed by heating and refluxing. After 4h, TLC detection shows that the reaction is complete, the reaction is cooled to room temperature, the pH value of a 6M NaOH solution is adjusted to 10, ethyl acetate is used for extraction, anhydrous sodium sulfate is used for drying, the solvent is evaporated under reduced pressure, and the residue is subjected to column chromatography to obtain a light yellow solid 4' a with the yield of 37%.
Preparation method with compound ZA1, using 4' a and 8 as raw materials, white powdery solid ZB1 was obtained with a yield of 47%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 18 Synthesis of N- (benzo [ d ] oxazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide (ZE1)
The preparation method uses compound ZA1 and takes 9a and 8 as raw materials to prepare white powder solid ZE1 with the yield of 37 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 19 Synthesis of 4- ((3, 5-Dimethylisoxazol-4-yl) methoxy) -N- (5-fluorobenzo [ d ] thiazol-2-yl) benzamide (ZE2)
The preparation method uses compound ZA1 and takes 9b and 8 as raw materials to prepare white powder solid ZE2 with the yield of 55 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 20 Synthesis of 4- ((3, 5-Dimethylisoxazol-4-yl) methoxy) -N- (5-methoxybenzo [ d ] thiazol-2-yl) benzamide (ZE3)
The preparation method uses compound ZA1 and takes 9c and 8 as raw materials to prepare white powder solid ZE3 with the yield of 58 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 21 Synthesis of 4- ((3, 5-Dimethylisoxazol-4-yl) methoxy) -N- (6- (trifluoromethoxy) benzo [ d ] thiazol-2-yl) benzamide (ZE4)
The preparation method uses compound ZA1 as raw material, and uses 9d and 8 as raw materials to prepare white powder solid ZE4 with the yield of 43%.
1H NMR(600MHz,DMSO-d6) δ 12.88(s,1H), 8.24-8.13 (m,3H),7.87(d, J ═ 8.7Hz,1H),7.46(d, J ═ 8.8Hz,1H),7.20(d, J ═ 8.8Hz,2H),5.06(s,2H),2.44(s,3H),2.24(s, 3H): example 22 [ 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (6-fluorobenzo [ d, 3H ]]Synthesis of thiazol-2-yl) benzamide (ZE5)
The preparation method uses compound ZA1 and takes 9e and 8 as raw materials to prepare white powder solid ZE5 with the yield of 38 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 23 Synthesis of N- (6-chlorobenzo [ d ] thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide (ZE6)
The preparation method uses compound ZA1 as raw material, and uses 9f and 8 as raw materials to prepare white powder solid ZE6 with the yield of 63%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 24 Synthesis of N- (5, 6-dimethylbenzo [ d ] thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzamide (ZE7)
The preparation method uses compound ZA1 as raw materials to prepare white powder solid ZE7 with the yield of 54 percent by taking 9g and 8 as raw materials.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 25 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -3-methoxy-N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZC1)
The preparation method uses compound ZA1 and takes 8a and 4 as raw materials to prepare white powdery solid ZC1 with the yield of 36 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 26 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -3-methyl-N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZC2)
The preparation method uses compound ZC2 and 8b and 4 as raw materials to prepare white powdery solid ZC2 with the yield of 62 percent.
1H NMR(400MHz,DMSO-d6)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).
EXAMPLE 27 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -3-fluoro-N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZC3)
The preparation method uses compound Za1 and takes 8c and 4 as raw materials to prepare white powdery solid ZC3 with the yield of 63 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 28 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (thien-2-yl) thiazol-2-yl) -3- (trifluoromethyl) benzamide (ZC4)
The preparation method uses compound ZA1 and takes 8d and 4 as raw materials to prepare white powdery solid ZC4 with the yield of 65 percent.
1H NMR(400MHz,DMSO-d6)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).
EXAMPLE 29 Synthesis of 6- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (thien-2-yl) thiazol-2-yl) nicotinamide (ZC5)
The preparation method uses compound ZC5 and 8e and 4 as raw materials to prepare white powdery solid ZC5 with the yield of 57 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 30 Synthesis of 3-chloro-4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZC6)
The preparation method uses compound ZA1 and 8f and 4 as raw materials to prepare white powdery solid ZC6 with the yield of 59 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 31 Synthesis of 4'- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (thien-2-yl) thiazol-2-yl) - [1,1' -biphenyl ] -4-carboxamide (ZC7)
The preparation method uses compound ZA1 as raw materials to prepare white powdery solid ZC7 with the yield of 68 percent, wherein the solid ZC7 is prepared by the method.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 32 Synthesis of 6- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (thien-2-yl) thiazol-2-yl) -2-naphthamide (ZC8)
The preparation method uses the compound Z15 as raw materials for 8h and 4 to prepare white powdery solid ZC8 with the yield of 56 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 33 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -3-formyl-N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZC9)
The preparation method uses compound ZA1 as raw material to prepare white powdery solid ZC9 with the yield of 66 percent by taking 8i and 4 as raw materials.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 34 Synthesis of 3-cyano-4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZC10)
The preparation method uses the compound Z15 and takes 8j and 4 as raw materials to prepare white powdery solid ZC10 with the yield of 53 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 35 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -3-nitro-N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZC11)
The preparation method uses compound ZA1 as raw materials to prepare white powdery solid ZC11 with the yield of 57 percent.
1H NMR(400MHz,DMSO-d6)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).
EXAMPLE 36 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -3- (hydroxymethyl) -N- (4- (thien-2-yl) t-thiazol-2-yl) benzamide (ZC12)
ZC12 is obtained by reducing ZC9 with sodium borohydride.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 37 Synthesis of 4- ((1H-pyrazol-1-yl) methoxy) -N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZD1)
Commercially available compound 1-pyrazolemethanol (5a) was dissolved in thionyl chloride and heated under reflux. After 4h the reaction was complete by TLC and the solvent was evaporated under reduced pressure to give residue 6 a. Mixing Compound 14 with cesium carbonate (Cs)2CO32.5eq) was dissolved in DMF and stirred at room temperature, and Compound 6a was added to the reaction system and stirred with heating at 70 ℃. The reaction was complete after 12h by TLC. 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 (4eq) were dissolved in methanol: water 9: 1, heating and refluxing, and detecting the reaction completion by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise to adjust the pH of the solution to 4-6, and a white solid precipitated. Vacuum filtering and drying to obtain white solid compound 15 a.
The preparation method uses compound Z15 and takes 15a and 4 as raw materials to prepare white powdery solid ZD1 with the yield of 46 percent.
1H NMR(600MHz,DMSO-d6)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)
EXAMPLE 38 Synthesis of 4- ((1H-indol-1-yl) methyl) -N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZD2)
Mixing indole and cesium carbonate (Cs)2CO32.5eq) in DMF, stirring at room temperature, and adding Compound 14 to the reaction systema, heating and stirring at 70 ℃. The reaction was complete after 12h by TLC. 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 (4eq) were dissolved in methanol: water 9: 1, heating and refluxing, and detecting the reaction completion by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise to adjust the pH of the solution to 4-6, and a white solid precipitated. Vacuum filtering and drying to obtain white solid compound 15 c.
Preparation method using compound ZA1, 15c and 4 as raw materials, to obtain ZD2 as white powder with yield of 76%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 39 Synthesis of 4- (indol-1-ylmethyl) -N- (4- (thiophen-2-yl) thiazol-2-yl) benzamide (ZD3)
The preparation method is the same as the compound ZD2, and the yield is 64%.
1H NMR(600MHz,DMSO-d6)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- (thien-2-yl) thiazol-2-yl) benzamide (ZD4)
Mixing indole and cesium carbonate (Cs)2CO32.5eq) in DMF, stirring at room temperature, adding the compound 2-bromoethanol to the reaction system, and heating and stirring at 70 ℃. The reaction was complete after 12h by TLC. 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 (4eq) were dissolved inMethanol: water 9: 1, heating and refluxing, and detecting the reaction completion by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise to adjust the pH of the solution to 4-6, and a white solid precipitated. Vacuum filtering and drying to obtain white solid compound 16 with yield of 85%.
The compound 16 was dissolved in toluene, stirred at room temperature, and to the stirred mixture were added N-methylimidazole (nmi1.5eq), p-toluenesulfonyl chloride (TsCl 1.5eq), and triethylamine (1.5eq) in this order, stirred at room temperature, and after 1 hour, the reaction was complete by TLC detection. Methanol was added, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to give white solid 17. Mixing Compound 16 with cesium carbonate (Cs)2CO32.5eq) in DMF, stirring at room temperature, adding methylparaben (compound 14) to the reaction system, and heating and stirring at 70 ℃. The reaction was complete after 12h by TLC. After cooling to room temperature, DMF was washed off with a large amount of saturated brine, extracted with ethyl acetate, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give a white solid. The solid obtained by separation and sodium hydroxide (4eq) were dissolved in methanol: water 9: 1, heating and refluxing, and detecting the reaction completion by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise to adjust the pH of the solution to 4-6, and a white solid precipitated. Vacuum filtering and drying to obtain white solid compound 15e with yield of 81%.
Preparation method Using Compound ZA1, starting from 15e and 4, ZD4 was obtained as a white powder with a yield of 73%.
1H NMR(400MHz,DMSO-d6)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 (ZD5)
The preparation method uses a compound ZD4 with the yield of 63 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 42 Synthesis of 4- (((5-methylisoxazol-4-yl) methoxy) methyl) -N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZLN1)
Compound 5 was dissolved in anhydrous THF, stirred at room temperature, and after adding sodium hydride (NaH 1.5eq) under nitrogen atmosphere and stirring for 1h, tetrabutylammonium iodide (TBAI 0.12eq) and compound 6 were added to the stirred mixture in succession. The reaction was complete after 12h by TLC. Quenching the residual sodium hydride by saturated ammonium chloride aqueous solution, extracting by ethyl acetate, drying by anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and separating the residue by column chromatography to obtain a light yellow solid. The solid obtained by separation and sodium hydroxide (4eq) were dissolved in methanol: water 9: 1, heating and refluxing, and detecting the reaction completion by TLC after 2 h. The reaction solution was cooled to room temperature, 6M hydrochloric acid was added dropwise to adjust the pH of the solution to 4-6, and a white solid precipitated. Vacuum filtration and drying were carried out to obtain a white solid compound 8' e with a yield of 37%.
Preparation method using compound ZA1, 8' e and 4 as raw materials, white powder solid ZLN1 was obtained with yield 66%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 43 Synthesis of 4- (2- ((3, 5-Dimethylisoxazol-4-yl) methoxy) ethoxy) -N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZLN2)
Compound 14 and potassium carbonate (K)2CO32.5eq) was dissolved in DMF and stirred at room temperature, and compound 17a was added to the reaction system and stirred with heating at 70 ℃. The reaction was complete after 12h by TLC. 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 18a as a white solid with a yield of 85%.
The preparation was carried out in the same manner as for 8'e, starting from 18a and 6, to give 8' a as a white powdery solid in 49% yield.
The preparation method uses compound Z15 and takes 8' a and 4 as raw materials to prepare ZLN3 as white powder solid with the yield of 54 percent.
1H NMR(600MHz,DMSO-d6)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-Dimethylisooxazol-4-yl) methoxy) propoxy) -N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZLN3)
The preparation method used compound ZLN2, and 8' b and 4 were used as raw materials to obtain ZLN3 as white powder solid with yield of 67%.
1H NMR(600MHz,DMSO-d6)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-Dimethylisooxazol-4-yl) methoxy) butoxy) -N- (4- (thien-2-yl) thiazol-2-yl) benzamide (ZLN4)
The preparation method used compound ZLN2, and 8' c and 4 were used as raw materials to prepare ZLN4 as white powder solid with yield 46%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 46 Synthesis of 4- (((5- ((3, 5-Dimethylisoxazol-4-yl) methoxy) pentyl) oxy) -N- (4- (thien-2-yl) thiazol-ol-2-yl) benzamide (ZLN5)
The preparation method uses compound ZLN2 and takes 8'd and 4 as raw materials to prepare ZLN5 as white powder solid with the yield of 42 percent.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 47 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methylbenzamide (ZAC1)
Commercially available p-methoxyacetophenone and p-toluenesulfonic acid (TsOH, 0.1eq) were dissolved in anhydrous dichloromethane, stirred at room temperature, N-bromosuccinimide (NBS, 1.0eq) was added in portions, heated under reflux, and after 12h the reaction was complete by TLC, and the reaction liquid changed from pale yellow to brownish red. After cooling to room temperature, adding a proper amount of saturated saline solution for washing, extracting by dichloromethane, drying by anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and separating the residue by column chromatography to obtain a brownish red oily substance. Thiourea (1.2eq) was dissolved in ethanol, stirred at room temperature, added to an ethanol solution of a reddish-brown oil and heated under reflux. After 2h, the reaction was complete by TLC and the reaction turned from pale yellow to dark yellow. After cooling, the solvent is evaporated under reduced pressure, a proper amount of saturated sodium bicarbonate solution is added for washing, ethyl acetate is used for extraction, anhydrous sodium sulfate is used for drying, the solvent is evaporated under reduced pressure, and the residue is separated by column chromatography to obtain light yellow solid 4- (4-methoxyphenyl) thiazole-2-amine with the yield of 60%.
Preparation method using compound ZA1, 4- (4-methoxyphenyl) thiazole-2-amine and 8b as raw materials, white powdery solid ZAC1 was obtained with a yield of 68%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 48 Synthesis of 4- ((3, 5-Dimethylisoxazol-4-yl) methoxy) -N- (5-methoxybenzo [ d ] thiazol-2-yl) -3-methylbenzamide (ZEC1)
The preparation method uses compound ZA1 and 2-amino-5-methoxybenzothiazole and 8b as raw materials to prepare white powdery solid ZEC1 with the yield of 51%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 49 Synthesis of N- (benzo [ d ] thiazol-2-yl) -4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -3-methoxybenzamide (ZEC3)
The preparation method uses compound ZA1 and 2-aminobenzothiazole and 8b as raw materials to prepare white powdery solid ZEC3 with the yield of 65%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 50 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -3-methyl-N- (6- (trifluoromethoxy) benzo [ d ] thiazol-2-yl) benzamide (ZEC5)
The preparation method uses compound ZA1 and riluzole and 8b as raw materials to prepare white powder solid ZEC5 with the yield of 63%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 51 Synthesis of 4- ((3, 5-Dimethylisoxazol-4-yl) methoxy) -3-methyl-N- (4-methylbenzo [ d ] thiazol-2-yl) benzamide (ZEC6)
The preparation method uses compound ZA1 and 2-amino-4-methylbenzothiazole and 8b as raw materials to prepare white powdery solid ZEC6 with the yield of 77%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 52 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -3-methoxy-N- (6- (trifluoromethoxy) benzene-o [ d ] thiazol-2-yl) benzamide (ZEC7)
The preparation method uses compound ZA1 and riluzole and 8a as raw materials to prepare white powder solid ZEC5 with the yield of 78%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 53 Synthesis of 4- ((3, 5-Dimethylisooxazol-4-yl) methoxy) -3-methoxy-N- (6- (trifluoromethoxy) benzene-o [ d ] thiazol-2-yl) benzamide (ZAL1)
3, 5-dimethyl-4-hydroxymethyl isoxazole is dissolved in anhydrous dichloromethane, stirred at room temperature, and phosphorus tribromide (PBr32.0eq) is added dropwise at 0 ℃ under nitrogen atmosphere. Heating to room temperature from 0 ℃, stirring for 4h, detecting by TLC that the reaction is complete, changing the reaction solution from colorless transparency to light yellow, adding saturated sodium bicarbonate solution until the pH is 7-8, extracting by dichloromethane, drying by anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and separating the residue by column chromatography to obtain colorless transparent irritant oily matter. 4-Hydroxyphenylacetic acid (1.0eq) and potassium hydroxide (KOH 2.5eq) were dissolved in ethanol: the water content is 9: 1, stirring at room temperature, adding a colorless transparent oily substance obtained by the reaction of the upper part of the compound dropwise into the reaction system, and heating and refluxing. The reaction was complete after 12h by TLC. After cooling to room temperature, 6M HCl is dripped into the reaction system until the pH of the solution is 2-3 and white solid is generated, and the solution is filtered under reduced pressure and dried to obtain the white solid, namely the compound 2- (4- ((3, 5-dimethylisoxazol-4-yl) methoxy) phenyl) acetic acid with the yield of 58%.
Preparation method Using compound ZA1, 2- (4- ((3, 5-dimethylisoxazol-4-yl) methoxy) phenyl) acetic acid and 4- (4-methoxyphenyl) thiazol-2-amine were used as raw materials to prepare ZAL1 as a white powdery solid with a yield of 68%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 54 Synthesis of N- (benzo [ d ] thiazol-2-yl) -2- (4- ((3, 5-dimethylisoxazol-4-yl) methoxy) phenyl) acetamide (ZEL1)
The preparation method uses a compound ZA1, and 2- (4- ((3, 5-dimethylisoxazol-4-yl) methoxyl) phenyl) acetic acid and 2-aminobenzothiazole as raw materials to prepare white powdery solid ZEL1 with the yield of 55%.
1H NMR(600MHz,DMSO-d6)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 (ZEL2)
Preparation method of compound ZA1, using 2- (4- ((3, 5-dimethylisoxazol-4-yl) methoxy) phenyl) acetic acid and 2-amino-5-methoxybenzothiazole as raw materials, to obtain ZEL2 as white powder solid with yield of 77%.
1H NMR(600MHz,DMSO-d6)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).
EXAMPLE 55 benzamide derivatives data on the transcriptional repression activity of AR in LNCaP cells.
The method comprises the following specific steps: LNCap cells in good growth state were digested with trypsin and diluted to about 1.2X 105one/mL cell suspension was inoculated into 24-well plates at a volume of 500. mu.L per well, and after 24h of culture, 100ng of PSA-luc and 2ng of pCMV-Renilla plasmid were transfected per well; after 24h, the compound solution with the adjusted concentration was diluted with RPMI 1640 complete medium, the old medium in the 24-well plate was discarded, and the fresh culture after administration was addedMeanwhile, a positive drug control group and a blank group are set. After 24h, the original culture medium is removed, then 100 mu L of 1 XPLB lysate is added into each well, the well plate is prevented from shaking for 20min and is mixed evenly on a high-speed shaking table, 1.5mL of cell lysate is absorbed into an EP tube and is centrifuged for 1min at 12000rpm, 20 mu L of supernatant is taken to be placed into a white opaque 96 well plate, and the fluorescence value is measured by using a 960 microplate reader according to the use instruction of the dual-luciferase reporter system detection kit.
This example provides data representing the transcriptional repression activity of compounds of structural formulae (I) and (II) on AR in LNCaP cells (table 1).
TABLE 1 transcriptional repression Activity of the Compounds of the examples against AR
Figure BDA0003256246820000221
EXAMPLE 56 cytotoxicity of benzamide derivatives on prostate cancer cells LNCaP and PC-3.
LNCaP and PC-3 cells in good growth were digested with trypsin and diluted to about 2X 104Inoculating 200 mu L of cell suspension into each well of a 96-well plate, culturing for 24h, adding drug solutions with different concentration gradients into the 96-well plate, adding 1 mu L of drug into each well, paralleling three groups of drugs with different concentration points, and simultaneously setting a blank group and a positive drug control group. After further culturing for 72h, respectively adding 20 μ L of 5g/L MTT PBS solution into each well, continuing to put the wells in a carbon dioxide incubator for culturing for 2-4h, then taking the 96-well plate out of the incubator, carefully absorbing and removing the culture medium in the 96-well plate, adding 100 μ L isopropanol into each well to dissolve the precipitate, placing the 96-well plate on a high-speed shaker, shaking and uniformly mixing for 20min, and measuring the absorbance value of each well by using a multifunctional microplate reader at the wavelength of 570 nm. Normalization treatment was performed with DMSO group as 100%. As can be seen from table 2, compounds ZA1, ZA3 and ZA5 had higher activity against proliferation of AR positive LNCaP cells and less effect on proliferation of AR negative PC-3 cells, indicating that the compounds had better selectivity.
Table 2: EXAMPLE cytotoxicity Studies of prostate cancer
Figure BDA0003256246820000231
EXAMPLE 57 effects of benzamide derivatives on the Down-Regulation of AR proteins
LNCaP, VCaP and 22Rv1 cells in good growth state were digested with trypsin and diluted to about 2X 105And inoculating the cell suspension per mL into a 6-well plate according to the volume of 2mL per well, culturing for 48h, adding the medicine solution prepared according to the corresponding concentration into the 6-well plate, adding 8 mu L per well, and simultaneously setting a blank group, an activation group and a positive medicine control group. After further incubation for 24h, protein samples were collected.
And (3) collecting a cell protein sample: the medium in the 6-well plate was aspirated away, 80. mu.L of pre-chilled RIPA (strong) lysate was added to each well, and the cells in the 6-well plate were scraped off and collected in 1.5mL EP tubes. Cracking in ice bath for 30min, shaking and mixing once every 5 min. Cells were then lysed by adding 20 μ L of 5 × protein loading buffer. Boiling in metal bath at 100 deg.C for 30 min. Protein samples were stored at-20 ℃ or-80 ℃. Western Blot procedure: protein samples were separated at 80V 40min, 120V 100min using a prepared 10% SDS-PAGE. The membrane is transferred by a 70V constant pressure wet method for 80min (using PVDF membrane), and is sealed by 5% skimmed milk powder at room temperature and low speed shaking for 1 h. The primary antibody is incubated overnight, the membrane is washed, the secondary antibody is incubated for 1h, the membrane is washed, and then ECL color development is carried out. 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 figure 8, compounds ZA5, ZA11, ZC1 all concentration-dependently down-regulated AR levels in LNCaP cells.

Claims (10)

1. The isoxazole-based substituted benzamide derivative is characterized by having a structure shown in a formula (I) and a structural formula (II):
Figure FDA0003256246810000011
ring A is independently selected from: benzene, thiophene, furan, benzothiophene, benzofuran;
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: an S atom, an N atom;
y is independently selected from: an S atom, an O atom;
R1independently selected from: -F, -OCH3、-OCF3、-Br、-Cl、-CF3、-CH3、-CN；
R2Independently selected from: -OCH3、-CH3、-F、-OCF3、-CF3、-Cl、-NO2、-CN、-CHO、-CH2OH；
R3Independently selected from: h;
R4independently selected from: H. -CH3、-OCH3、-OCF3、-F、-Cl；
R5Independently selected from: H. -F, -OCH3、-CH3；
R6Independently selected from: H. -CH3；
n1Independently selected from: 0 to 1;
n2independently selected from: 0 to 1;
n3independently selected from: 2-5;
n4independently selected from: 0 to 1;
n5independently selected from: 1-3.
2. The use of isoxazole-based substituted benzamide derivatives according to claim 1 for the preparation of androgen receptor antagonists.
3. The use of claim 2 wherein the androgen receptor antagonist inhibits the activity of wild-type androgen receptor.
4. The use of claim 2, wherein said androgen receptor antagonist inhibits the activity of an AR-T877A mutant receptor and said androgen receptor antagonist inhibits the activity of an AR-F876L mutant receptor.
5. The use according to claim 2, wherein said androgen receptor antagonist is for the manufacture of a medicament for the treatment of an androgen-mediated disorder.
6. The use of claim 5, wherein the androgen mediated disorder is a disorder caused by androgen hyperactivity.
7. The use according to claim 6, wherein the androgen mediated disorder is prostatic hyperplasia or prostate cancer;
alternatively, the androgen imbalance disease is male hypersexuality;
alternatively, the androgen imbalance disease is female acne, female seborrheic dermatitis, female hirsutism, female alopecia.
8. The use of isoxazole-based substituted benzamide derivatives according to claim 1 for the preparation of androgen receptor down-regulators.
9. The use of claim 8, wherein said androgen receptor down-modulator promotes degradation of androgen receptor protein.
10. The use of isoxazole-based substituted benzamide derivatives according to claim 1 in combination with enzalutamide for the preparation of a compound for the treatment of prostate cancer.
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