阅读说明：本技术 新型雄激素受体降解剂、制备方法和医药用途 (Novel androgen receptor degradation agent, preparation method and medical application ) 是由 向华 蔚翰林 候强强 池幸龙 付子璇 傅晓颖 敬怡辰 吉辰轩 欧诗榕 哈斯 陈明 于 2021-08-19 设计创作，主要内容包括：本发明公开了具有通式I或通式II结构的新型雄激素受体降解剂、制备方法和医药用途。经药理实验证明该类化合物具有良好的抗前列腺癌活性,特别适用于制备治疗雄激素受体相关疾病如前列腺癌等的药物。(The invention discloses a novel androgen receptor degrading agent with a structure shown in a general formula I or a general formula II, a preparation method and medical application. Medicine for treating menopathyExperiments prove that the compounds have good activity of resisting prostate cancer, and are particularly suitable for preparing medicaments for treating androgen receptor related diseases such as prostate cancer and the like.)

1. A novel androgen receptor degrading agent with a structure shown in a general formula I or a general formula II, a pharmaceutically acceptable salt thereof or a prodrug thereof,

wherein the content of the first and second substances,

R₁represents H, CN, NO₂、CF₃Or halogen;

R₂represents H, a mono-substituted or multi-substituted benzene ring, a heterocycle, a condensed ring or a fused heterocycle;

R₃represents H, a mono-substituted or multi-substituted benzene ring, a heterocyclic ring, a condensed ring or a fused heterocyclic ring.

2. The novel androgen receptor degrading agent having the structure of formula I or formula II, its pharmaceutically acceptable salt or prodrug thereof according to claim 1, characterized in that:

R₁represents CN or NO₂；

R₂Represents a mono-substituted or poly-substituted benzene ring, nitrogen-containing heterocycle, condensed ring or nitrogen-containing condensed heterocycle;

R₃represents H, a mono-or poly-substituted benzene ring, a nitrogen-containing heterocycle, a condensed ring or a nitrogen-containing condensed ringA heterocyclic ring.

3. The novel androgen receptor degrading agent having the structure of formula I or formula II, its pharmaceutically acceptable salt or prodrug thereof according to claim 2, characterized in that:

R₁represents CN;

R₂represents mono-or poly-substituted nitrogen-containing heterocycle or nitrogen-containing fused heterocycle;

R₃represents mono-or poly-substituted nitrogen-containing heterocycle or nitrogen-containing fused heterocycle.

4. The novel androgen receptor degrading agent having the structure of general formula I or general formula II, its pharmaceutically acceptable salt or prodrug thereof according to claim 2, being any one of the following:

5. a pharmaceutical composition comprising a novel androgen receptor degrading agent having the structure of formula I or formula II of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier.

6. Use of a novel androgen receptor degrading agent having a structure of general formula I or general formula II, a pharmaceutically acceptable salt thereof, or a prodrug thereof according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of an androgen receptor-related disorder.

7. The use according to claim 6, characterized in that: androgen receptor-related diseases are androgen-dependent abnormal cell proliferation, prostate cancer, hirsutism or androgen alopecia.

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a series of novel androgen receptor degradation agents, a preparation method and medical application thereof.

Background

Prostate cancer is a malignant tumor that occurs in the epithelial cells of the prostate in men and is one of the most common cancers in men. The Androgen Receptor (AR) is one of the members of the nuclear receptor family, and the AR contains four main regions: an N-terminal active transcription control region (NTD), a DNA binding region (DBD), a hinge region, and a C-terminal Ligand binding region (LBD). Since Huggins and Hodges discovered that androgens promote the growth of prostate cancer in the early 40's of the 20 th century, AR has been an important target for prostate cancer therapy.

Currently, Androgen Deprivation Therapy (ADT) is the first choice for clinical prostate cancer treatment. Most advanced prostate cancer patients are initially effective for ADT, but after 1-2 years, almost all prostate cancer patients will gradually develop Castration-resistant prostate cancer (CRPC). Studies have shown that the occurrence of CRPC is closely related to increased AR expression, which is mainly due to AR gene sequence amplification. AR mutations are another important cause for the development of castration resistance. Most mutations occur in the LBD region of the AR, which also provides a mechanistic explanation for the development of resistance to antiandrogens. Mutations in the AR-LBD region can induce a shift of AR antagonists to AR agonists, leading to further tumor progression. AR splice variants (ARVs) are also one of the mechanisms that lead to the development of castration resistance. Alternative splicing is a regulatory process in normal cells that allows a single gene to encode multiple proteins using different exon and intron combinations during expression. Splice variants are active products obtained by alternative splicing of mRNA. Currently, more than 20 different ARVs have been discovered, several of which are clinically significant are splice variants lacking the LBD region, such as AR-V7 and ARv567 es. These ARVs lack the LBD region compared to full-length AR, and therefore AR antagonists cannot bind to them, and cannot prevent ARVs from transcriptional activation. Therefore, the development of new AR-targeted therapies may bring benefit to prostate cancer patients who are resistant to current therapies. Unlike AR antagonists, AR degradants, which are compounds capable of reducing the level of AR protein, do not directly occupy the lumen of the AR, but rather reduce the AR protein through some mechanism of action, such as ubiquitination, and thus are promising in overcoming the resistance mechanisms common in current AR-targeted therapies.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide a novel androgen receptor degradation agent with a structure shown in a general formula I or a general formula II, a pharmaceutically acceptable salt thereof or a prodrug thereof.

The technical scheme is as follows: the compounds of the general formula of the present invention have the following structure:

wherein R is₁Represents CN or NO₂；

Wherein R is₂Represents a mono-substituted or poly-substituted benzene ring, nitrogen-containing heterocycle, condensed ring or nitrogen-containing condensed heterocycle;

wherein R is₃Represents H, a mono-substituted or multi-substituted benzene ring, a nitrogen-containing heterocyclic ring, a condensed ring or a nitrogen-containing condensed heterocyclic ring.

Some preferred compounds of the invention are as follows:

the code of the compound in the pharmacological experiment and experimental examples is equal to the structure of the compound corresponding to the code.

34a-34h

Reactants and reaction conditions: a) k₂CO₃，DMF，45℃，7h；b)NaH，BrCH₂COOEt，r.t.，2h；c)CH₃OH，K₂CO₃，r.t.10h，；d)HATu，DIPEA，DMF，r.t.，overnight.

35a-35h，38a-38w

Reactants and reaction conditions: a) NaH, BrCH₂COOEt，r.t.，2h；b)CH₃OH，K₂CO₃，r.t.10h，；c)EDC.HCl，DMAP，CH₂Cl₂，r.t.，overnight；d)NaH，BrCH₂CH₂NHBoc，r.t.，5h；e)CF₃COOH，CH₂Cl₂，ice bath，0.5h；f)Pd₂(dba)₃，t-BuONa，BINAP，toluene，110℃，12h；g)Pd₂(dba)₃，t-BuONa，X-phos，toluene，110℃，12h；h)Pd₂(dba)₃，Cs₂CO₃，Xphos，toluene，50℃，12h；i)Pd₂(dba)₃，Cs₂CO₃，X-phos，toluene，110℃，12h.

In the above synthetic route R₂、R₃、R₄The different heterocycles and the substituent groups on the heterocycles are changed to obtain the compound with the structure of the general formula I or the general formula II.

A pharmaceutical composition comprising a novel androgen receptor degrading agent having the structure of formula I or formula II of any one of claims 1 to 4, a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier.

Use of a novel androgen receptor degrading agent having a structure of general formula I or general formula II, a pharmaceutically acceptable salt thereof or a prodrug thereof in the preparation of a medicament for treating androgen receptor-related diseases.

Further, the androgen receptor-associated disease is androgen-dependent abnormal cell proliferation, prostate cancer, hirsutism, or androgen alopecia.

Has the advantages that: pharmacological experiments prove that the degradation agent has good activity of resisting prostatic cancer, and is particularly suitable for preparing medicaments for treating androgen receptor related diseases such as prostatic cancer and the like.

Drawings

FIG. 1 is a graph of the ability of compounds 38d, 38e and Enzalutamide to degrade AR at the same concentration;

FIG. 2 is a graph of the ability of compounds 38d, 38e and Enzalutamide to degrade AR at different concentrations;

FIG. 3 is a graph of the ability of compounds 38d, 38m, 38t, 38k, 38j, 38i and Enzalutamide to degrade AR at the same concentration;

FIG. 4 is a graph of the ability of compound 38k and Enzalutamide to degrade AR at different concentrations.

Detailed Description

The sources of reagents and instruments used in compound synthesis and structure confirmation;

mass spectrometry was performed with an Agilent1946A-MSD type mass spectrometer (ESI-MS);¹h NMR was measured using a Bruker AV300 MHz or 400MHz NMR spectrometer (deuterated DMSO or deuterated CDCl was used as the solvent)₃TMS is internal standard and chemical shift δ is in ppm). Column chromatography in the experiment adopts column chromatography silica gel (Qingdao ocean chemical plant) of 100-.

Example 1

Synthesis of 5, 5-dimethyl-3- (4-nitro-3 (trifluoromethyl) phenyl) imidazolidine-2, 4-dione (28)

Under the protection of nitrogen, compound 26(5g, 0.024mol) and 5, 5-dimethylhydantoin (6.15g, 0.048mol) are dissolved in 20ml DMF, then anhydrous potassium carbonate (6.6g, 0.048mol) is added, the temperature is raised to 40 ℃ for reaction for 7h, TLC point plates show that the raw materials are completely reacted, heating is stopped, after the reaction is cooled to room temperature, the reaction solution is poured into ice water, and is filtered, dried to obtain 8g of light yellow solid, and the light yellow solid is directly fed without purification.

Example 2

Synthesis of 5, 5-dimethyl-3- (4-cyano-3 (trifluoromethyl) phenyl) imidazolidine-2, 4-dione (29)

Under the protection of nitrogen, dissolving compound 27(5g, 0.026mol) and 5, 5-dimethylhydantoin (6.66g, 0.052mol) in 20mL of DMF, then adding anhydrous potassium carbonate (7.15g, 0.052mol), heating to 40 ℃ for reaction for 7h, stopping heating when TLC point plates show that raw materials are completely reacted, cooling the reaction to room temperature, pouring the reaction liquid into ice water, carrying out suction filtration, drying to obtain a white solid, and directly feeding the white solid without purification.

Example 3

Synthesis of ethyl 2- (5, 5-dimethyl-3- (4-nitro-3- (trifluoromethyl) phenyl) -2, 4-dioxaimidazolin-1-yl) acetate (30)

The starting material 28(8g, 24mmol) was dissolved in 30mL of anhydrous DMF under nitrogen blanket, NaH (1.44g, 63mol) was added slowly in ice bath, the ice bath was removed, the reaction was allowed to react at room temperature for 2h, ethyl bromoacetate (5.3mL, 3mmol) was added to the reaction system, and the reaction was warmed to 55 ℃ for 7 h. TLC shows that the raw materials react completely, heating is stopped, reaction liquid is poured into ice water after the reaction is cooled to room temperature, crude products are obtained by suction filtration and drying, light yellow solid 6.5g is obtained by column chromatography purification, and the yield is 67.2%.¹H NMR(400MHz，CDCl₃)δ8.09(d，J＝7.5Hz，1H)，8.02(s，1H)，7.61(dd，J＝7.4，1.6Hz，1H)，4.19(q，J＝8.0Hz，2H)，3.92(s，2H)，1.47(s，6H)，1.25(t，J＝8.0Hz，3H)。

Example 4

Synthesis of ethyl 2- (5, 5-dimethyl-3- (4-cyano-3- (trifluoromethyl) phenyl) -2, 4-dioxaimidazolin-1-yl) acetate (31)

Compound 29(8g, 25mmol) was dissolved in 30mL of anhydrous DMF under nitrogen blanket, NaH (1.53g, 67mol) was added slowly in an ice bath, the ice bath was removed, the reaction was allowed to react at room temperature for 2h, ethyl bromoacetate (5.3mL, 3mmol) was added to the reaction, and the reaction was warmed to 55 ℃ for 7 h. TLC shows that the raw materials react completely, heating is stopped, reaction liquid is poured into ice water after the reaction is cooled to room temperature, crude products are obtained through suction filtration and drying, and 3.7g of off-white solid is obtained through column chromatography purification. ESI-MS m/z: 378[ M + Na ]]⁺。

Example 5

Synthesis of 2- (5, 5-dimethyl-3- (4-nitro-3- (trifluoromethyl) phenyl) -2, 4-dioxaimidazolin-1-yl) acetic acid (32)

Dissolving a compound 30(6.5g, 0.021mol) in 50mL of methanol, adding 13mL of 40% NaOH aqueous solution, stirring overnight at room temperature, performing TLC (thin layer chromatography) plate to show that raw materials completely react, concentrating a reaction solution, adding 4N HCl to adjust the pH to 3-4, extracting with ethyl acetate for three times, combining organic layers, washing the organic layers with saturated salt water for3 times, adding anhydrous magnesium sulfate, drying for 10 minutes, filtering to obtain a filtrate, spin-drying the filtrate to obtain a crude product, and performing column chromatography to obtain 6g of a light yellow solid with the yield of 76.1%. ESI-MS m/z: 398[ M + Na ]]⁺。

Example 6

Synthesis of 2- (5, 5-dimethyl-3- (4-cyano-3- (trifluoromethyl) phenyl) -2, 4-dioxaimidazolin-1-yl) acetic acid (33)

Dissolving a compound 31(6.5g, 0.022mol) in 50mL of methanol, adding 14mL of 40% NaOH aqueous solution, stirring overnight at room temperature, performing TLC (thin layer chromatography) plate to show that raw materials completely react, concentrating a reaction solution, adding 4N HCl to adjust the pH to 3-4, extracting with ethyl acetate for three times, combining organic layers, washing the organic layers with saturated salt water for3 times, adding anhydrous magnesium sulfate, drying for 10 minutes, filtering to obtain a filtrate, spin-drying the filtrate to obtain a crude product, and performing column chromatography to obtain a white solid 3.7 g. ESI-MS m/z: 378[ M + Na ]]⁺。

Example 7

Synthesis of 2- (5, 5-dimethyl-3- (4-nitro-3- (trifluoromethyl) phenyl) -2, 4-dioxoimidazolin-1-yl) -N- (pyridin-3-yl) acetamide (34a)

Compound 32(100mg, 0.26mmol) was dissolved in 3mL of anhydrous DMF under nitrogen protection, and 429. mu.L DipPEA, 197mg of HATu were added and reacted at room temperature for half an hour, followed by addition of 3-aminopyridine (30mg, 0.312mmol) and stirring at room temperature overnight. TLC point plate shows that the raw material reacts completely, water is added to quench the reaction, ethyl acetate is used for extraction three times, organic phases are combined, saturated ammonium chloride is used for washing twice, saturated saline solution is used for washing three times, anhydrous magnesium sulfate is used for drying for 10 minutes, filtrate is obtained through filtration, crude product is obtained through spin drying of the filtrate, light yellow powder 75mg is obtained through column chromatography, and the yield is 64.1%. Data for34 a: m.p.: 220 ℃ and 222 ℃;¹H NMR(400MHz，CDCl₃)δ9.61-9.42(m，1H)，8.69-8.53(m，1H)，8.30(dt，J＝4.8，2.7Hz，1H)，8.17-8.11(m，1H)，8.09-8.03(m，1H)，8.02-7.93(m，2H)，7.26(ddd，J＝13.0，7.8，4.0Hz，1H)，4.18(d，J＝3.8Hz，2H)，1.68-1.38(m，6H).¹³C NMR(101MHz，CDCl₃)δ174.25，166.13，153.79，145.87，145.04，140.84，135.89，134.97，128.85，127.66，126.05，124.57，124.12，122.87，62.34，51.83，43.48，22.97.HRMS(ESI)m/z calcd for C₁₉H₁₆F₃N₅O₅[M+H]⁺452.1176，found 452.1172。

example 8

Synthesis of 2- (5, 5-dimethyl-3- (4-nitro-3- (trifluoromethyl) phenyl) -2, 4-dioxoimidazolin-1-yl) -N- (pyridin-2-yl) acetamide (34b)

Compound 32(100mg, 0.26mmol) was dissolved in 3mL of anhydrous DMF under nitrogen protection, and 429. mu.L of DIPEA and 197mg of HATu were added and reacted at room temperature for half an hour, followed by addition of 2-aminopyridine (30mg, 0.312mmol) and stirring at room temperature overnight. TLC point plate shows that the raw material reacts completely, water is added to quench the reaction, ethyl acetate is used for extraction three times, organic phases are combined, saturated ammonium chloride is used for washing twice, saturated saline solution is used for washing three times, anhydrous magnesium sulfate is used for drying for 10 minutes, filtrate is obtained through filtration, crude product is obtained through spin drying of the filtrate, white powder 59mg is obtained through column chromatography, and the yield is 50.4%. Data for34 b: m.p.:92-94℃；¹H NMR(400MHz，DMSO-d₆)δ10.84-10.63(m，1H)，8.53-8.00(m，5H)，7.84(ddt，J＝39.9，15.7，7.9Hz，1H)，7.30-7.05(m，1H)，4.52-4.08(m，2H)，1.66-1.44(m，6H).¹³C NMR(101MHz，DMSO)δ175.14，167.47，153.45，152.07，148.50，145.72，138.79，136.66，131.47，131.35，127.04，125.47，120.11，113.96，62.26，43.12，22.67.HRMS(ESI)m/z calcd for C₁₉H₁₆F₃N₅O₅[M+H]⁺452.1176，found 452.1174。

example 9

Synthesis of 2- (5, 5-dimethyl-3- (4-nitro-3- (trifluoromethyl) phenyl) -2, 4-dioxoimidazolin-1-yl) -N- (pyridin-3-ylmethyl) acetamide (34c)

Compound 32(100mg, 0.26mmol) was dissolved in 3mL of anhydrous DMF under nitrogen protection, and 429. mu.L DipPEA, 197mg of HATu were added and reacted at room temperature for half an hour, followed by addition of 3-aminomethylpyridine (34mg, 0.312mmol) and stirring at room temperature overnight. TLC point plate shows that the raw material reacts completely, water is added to quench the reaction, ethyl acetate is used for extraction three times, organic phases are combined, saturated ammonium chloride is used for washing twice, saturated saline solution is used for washing three times, anhydrous magnesium sulfate is used for drying for 10 minutes, filtrate is obtained through filtration, crude product is obtained through spin drying of the filtrate, light yellow powder 77mg is obtained through column chromatography, and the yield is 63.6%. Data for34 c: m.p.: 76-78 ℃;¹H NMR(400MHz，CDCl₃)δ8.38(d，J＝4.7Hz，1H)，8.33(s，1H)，8.05(s，1H)，7.92(p，J＝1.7Hz，2H)，7.64-7.58(m，2H)，7.57-7.53(m，1H)，7.21(ddd，J＝7.7，4.9，2.1Hz，1H)，4.52-4.27(m，2H)，4.04(d，J＝2.2Hz，2H)，1.51(d，J＝2.3Hz，6H).¹³C NMR(101MHz，CDCl₃)δ174.28，167.59，153.55，148.74，148.59，145.76，135.95，133.87，128.72，125.96，124.07，123.83，62.20，43.01，41.05，22.93.HRMS(ESI)m/z calcd for C₂₀H₁₈F₃N₅O₅[M+H]⁺466.1332，found 466.1328。

example 10

Synthesis of 2- (5, 5-dimethyl-3- (4-nitro-3- (trifluoromethyl) phenyl) -2, 4-dioxoimidazolin-1-yl) -N- (pyridin-2-ylmethyl) acetamide (34d)

Compound 32(100mg, 0.26mmol) was dissolved in 3mL of anhydrous DMF under nitrogen, and 429. mu.L of DIPEA and 197mg of HATu were added to the solution and reacted at room temperature for half an hour, followed by addition of 2-aminomethylpyridine (34mg, 0.312mmol) and stirring at room temperature overnight. TLC point plate shows that the raw material reacts completely, water is added to quench the reaction, ethyl acetate is used for extraction three times, organic phases are combined, saturated ammonium chloride is used for washing twice, saturated saline solution is used for washing three times, anhydrous magnesium sulfate is used for drying for 10 minutes, filtrate is obtained through filtration, crude product is obtained through spin drying of the filtrate, light yellow powder 53mg is obtained through column chromatography, and the yield is 43.8%. Data for34 d: m.p.: 174-175 ℃;¹H NMR(400MHz，CDCl₃)δ8.50(dt，J＝4.7，2.3Hz，1H)，8.20(t，J＝2.4Hz，1H)，8.07(dd，J＝8.8，2.3Hz，1H)，8.02(d，J＝8.8Hz，1H)，7.70(tt，J＝7.7，2.2Hz，1H)，7.45(d，J＝6.3Hz，1H)，7.29(t，J＝3.9Hz，1H)，7.24(dd，J＝7.4，4.8Hz，1H)，4.61(dd，J＝4.9，2.7Hz，2H)，4.13(d，J＝2.6Hz，2H)，1.56(d，J＝2.6Hz，6H).HRMS(ESI)m/z calcd for C₂₀H₁₈F₃N₅O₅[M+Na]⁺488.1152，found 488.1150。

example 11

Synthesis of 2- (5, 5-dimethyl-3- (4-cyano-3- (trifluoromethyl) phenyl) -2, 4-dioxoimidazolin-1-yl) -N- (pyridin-3-yl) acetamide (34e)

Compound 33(100mg, 0.27mmol) was dissolved in 3mL of anhydrous DMF under nitrogen, 450. mu.L of DIPEA and 207mg of HATu were added, and the mixture was reacted at room temperature for half an hour, followed by addition of 3-aminopyridine (32mg, 0.33mmol) and stirring at room temperature overnight. TLC point plate shows that the raw material reacts completely, water is added to quench the reaction, ethyl acetate is used for extraction three times, organic phases are combined, saturated ammonium chloride is used for washing twice, saturated saline solution is used for washing three times, anhydrous magnesium sulfate is used for drying for 10 minutes, filtrate is obtained through filtration, crude product is obtained through spin drying of the filtrate, white powder 34mg is obtained through column chromatography, and the yield is 30.3%. Data for34 e: m.p.: 95-96 ℃;¹H NMR(400MHz，CDCl₃)δ9.12(s，1H)，8.60(d，J＝2.5Hz，1H)，8.34(d，J＝4.7Hz，1H)，8.17-8.07(m，2H)，8.01(dd，J＝8.5，2.2Hz，1H)，7.92(d，J＝8.5Hz，1H)，7.29(d，J＝5.6Hz，1H)，4.19(s，2H)，1.59(s，6H).¹³C NMR(101 MHz，CDCl₃)δ174.15，166.03，153.89，145.37，140.99，136.14，135.42，134.68，128.03，127.53，124.00，123.00，120.53，115.01，108.42，62.38，43.86，23.06.¹³C NMR(101MHz，CDCl₃)δ174.43，167.20，155.42，153.52，148.88，137.09，135.99，128.85，125.97，124.35，122.70，122.17，77.37，62.27，44.31，43.16，23.02.HRMS(ESI)m/z calcd for C₂₀H₁₆F₃N₅O₃[M+H]⁺432.1278，found 432.1276。

example 12

Synthesis of 2- (5, 5-dimethyl-3- (4-cyano-3- (trifluoromethyl) phenyl) -2, 4-dioxoimidazolin-1-yl) -N- (pyridin-2-yl) acetamide (34f)

Compound 33(100mg, 0.27mmol) was dissolved in 3mL of anhydrous DMF under nitrogen, 450. mu.L of DIPEA and 207mg of HATu were added, and the mixture was reacted at room temperature for half an hour, followed by addition of 2-aminopyridine (32mg, 0.33mmol) and stirring at room temperature overnight. TLC point plate shows that the raw material reacts completely, water is added to quench the reaction, ethyl acetate is used for extraction three times, organic phases are combined, saturated ammonium chloride is used for washing twice, saturated saline solution is used for washing three times, anhydrous magnesium sulfate is used for drying for 10 minutes, filtrate is obtained through filtration, crude product is obtained through spin drying of the filtrate, white powder 48mg is obtained through column chromatography, and the yield is 42.8%. Data for34 f: m.p.: 228 ℃ and 230 ℃;¹H NMR(400MHz，CDCl₃)δ8.85(s，1H)，8.30(dd，J＝4.8，2.2Hz，1H)，8.21-8.13(m，2H)，8.05(dd，J＝8.3，2.2Hz，1H)，7.94(d，J＝8.4Hz，1H)，7.75(td，J＝8.4，8.0，2.0Hz，1H)，7.15-7.04(m，1H)，4.24(s，2H)，1.60(d，J＝1.6Hz，6H).¹³C NMR(101MHz，DMSO)δ175.15，167.48，153.32，152.10，148.51，137.13，136.64，131.46，130.23，124.24，120.13，115.66，113.97，107.25，62.23，43.00，22.69.HRMS(ESI)m/z calcd for C₂₀H₁₆F₃N₅O₃[M+H]⁺432.1278，found 432.1274。

example 13

Synthesis of 2- (5, 5-dimethyl-3- (4-cyano-3- (trifluoromethyl) phenyl) -2, 4-dioxoimidazolin-1-yl) -N- (pyridin-3-ylmethyl) acetamide (34g)

Compound 33(100mg, 0.26mmol) was dissolved in 3mL of anhydrous DMF under nitrogen protection, and 429. mu.L of DIPEA and 197mg of HATu were added and reacted at room temperature for half an hour, followed by addition of 3-aminomethylpyridine (36mg, 0.33mmol) and stirring at room temperature overnight. TLC point plate shows that the raw material reacts completely, water is added to quench the reaction, ethyl acetate is used for extraction three times, organic phases are combined, saturated ammonium chloride is used for washing twice, saturated saline solution is used for washing three times, anhydrous magnesium sulfate is used for drying for 10 minutes, filtrate is obtained through filtration, crude product is obtained through spin drying of the filtrate, white powder 57mg is obtained through column chromatography, and the yield is 49.2%. Data for34 g: m.p.: 84-85 ℃;¹H NMR(400MHz，CDCl₃)δ8.47(d，J＝4.9Hz，1H)，8.42(s，1H)，8.09(d，J＝2.0Hz，1H)，7.96(dd，J＝8.4，2.1Hz，1H)，7.87(d，J＝8.4Hz，1H)，7.64(dt，J＝7.8，1.9Hz，1H)，7.26(dd，J＝8.2，5.2Hz，1H)，7.17(t，J＝6.0Hz，1H)，4.45(d，J＝6.0Hz，2H)，4.05(s，1H)，1.54(s，5H).¹³C NMR(101MHz，CDCl₃)δ174.20，167.49，153.60，148.86，136.20，135.86，135.35，133.70，133.37，127.92，123.80，122.88，115.00，108.26，62.23，43.26，41.16，23.02.HRMS(ESI)m/z calcd for C₂₁H₁₈F₃N₅O₃[M+H]⁺446.1434，found 446.1429。

example 14

Synthesis of 2- (5, 5-dimethyl-3- (4-cyano-3- (trifluoromethyl) phenyl) -2, 4-dioxoimidazolin-1-yl) -N- (pyridin-2-ylmethyl) acetamide (34h)

Compound 33(100mg, 0.26mmol) was dissolved in 3mL of anhydrous DMF under nitrogen protection, and 429. mu.L of DIPEA and 197mg of HATu were added and reacted at room temperature for half an hour, followed by addition of 2-aminomethylpyridine (36mg, 0.33mmol) and stirring at room temperature overnight. TLC spot plate shows that the raw material is reacted completely, water is added to quench the reaction, ethyl acetate is extracted for three times, organic phases are combined, saturated ammonium chloride is washed twice, saturated saline solution is washed for three timesDrying over anhydrous magnesium sulfate for 10min, filtering to obtain filtrate, spin drying the filtrate to obtain crude product, and column chromatography to obtain white powder 63mg with yield 54.4%. Data for34 h: m.p.: 158 ℃ and 160 ℃;¹H NMR(400MHz，CDCl₃)δ8.61-8.33(m，1H)，8.17(d，J＝2.1Hz，1H)，8.03(dd，J＝8.5，2.0Hz，1H)，7.93(d，J＝8.4Hz，1H)，7.69(td，J＝7.7，1.8Hz，1H)，7.47(t，J＝5.0Hz，1H)，7.28(s，1H)，7.22(dd，J＝7.5，5.0Hz，1H)，4.60(d，J＝5.0Hz，2H)，4.12(s，2H)，1.55(s，6H).¹³C NMR(101MHz，CDCl₃)δ174.25，166.13，153.79，145.87，145.04，140.84，135.89，134.97，128.85，127.66，126.05，124.57，124.12，122.87，120.15，62.34，53.50，43.48，22.97.HRMS(ESI)m/z calcd for C₂₁H₁₈F₃N₅O₃[M+H]⁺446.1434，found446.1431.

example 15

Synthesis of N- ([ [1, 1' -biphenyl ] -3-yl) -2- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-2, 4-dioxoimidazolin-1-ylacetamide (35a)

Under the protection of nitrogen, compound 33(150mg, 0.43mmol) is dissolved in anhydrous dichloromethane, DMAP (10mg, 0.087mmol) and EDC.HCl (91mg, 0.47mmol) are added to react at room temperature for 5 minutes, then 3-benzidine (80mg, 0.47mmol) is added to react at room temperature overnight, TLC detects that the raw materials are completely reacted, water is added to quench the reaction, ethyl acetate is extracted for three times, the organic phase is washed twice with saturated ammonium chloride, washed three times with saturated saline, and dried by spinning to pass through a column to obtain 37mg of white solid, and the yield is 17.9%. Data for 35 a: m.p.: 173-174 ℃;¹H NMR(300MHz，CDCl₃)δ8.68(s，1H)，8.21(s，1H)，8.08-8.00(m，2H)，7.95(d，J＝8.5Hz，3H)，7.77(s，1H)，7.63-7.48(m，3H)，4.33(s，2H)，1.67(s，6H).¹³C NMR(75MHz，CDCl₃)δ174.13，166.36，154.18，136.00，135.39，134.09，131.78，128.90，127.97，126.65，126.27，125.68，123.04，120.29，114.97，108.60，62.57，44.78，23.04.HRMS(ESI)m/z calcd for C₂₅H₁₉F₃N₄O₃[M+Na]⁺503.1301，found 503.1301。

example 16

Synthesis of N- ([ [1, 1' -biphenyl ] -3-yl) -2- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-2, 4-dioxoimidazolin-1-ylacetamide (35b)

Under the protection of nitrogen, compound 33(150mg, 0.43mmol) is dissolved in anhydrous dichloromethane, DMAP (10mg, 0.087mmol) and EDC.HCl (91mg, 0.47mmol) are added to react at room temperature for 5 minutes, then 3-aminobiphenyl (79mg, 0.47mmol) is added to react at room temperature overnight, TLC detects that the raw materials are completely reacted, water is added to quench the reaction, ethyl acetate is extracted for three times, the organic phase is washed twice by saturated ammonium chloride, washed three times by saturated saline, and is dried by spinning to pass through a column to obtain 21mg of pink solid, and the yield is 9.6%. Data for 35 b: m.p.: 170 ℃ and 172 ℃;¹H NMR(300MHz，CDCl₃)δ8.24(s，1H)，8.21(d，J＝1.8Hz，1H)，8.05(dd，J＝8.4，2.0Hz，1H)，7.96(d，J＝8.4Hz，1H)，7.78(s，1H)，7.61(d，J＝6.8Hz，2H)，7.55-7.36(m，6H)，4.20(d，J＝11.1Hz，2H)，1.65(s，6H).¹³C NMR(75MHz，CDCl₃)δ174.16，165.45，153.96，142.36，140.38，137.60，136.09，135.40，129.54，128.84，127.99，127.71，127.17，123.78，122.99，118.70，115.02，62.45，44.53，23.07.HRMS(ESI)m/z calcd for C₂₇H₂₁F₃N₄O₃[M-H]^-505.1493，found 505.1492。

example 17

Synthesis of 2- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-2, 4-dioxaimidazolin-1-yl) -N- (naphthalen-1-yl) acetamide (35c)

Dissolving compound 33(150mg, 0.43mmol) in anhydrous dichloromethane under nitrogen protection, adding EDC.HCl (91mg, 0.47mmol) and HOBt (64mg, 0.47mmol) to react at room temperature for 5min, then adding 1-naphthylamine (80mg, 0.47mmol) and DIPEA (86 uL, 0.52mmol), reacting at room temperature overnight, detecting by TLC for complete reaction, adding water to quench the reaction, extracting with ethyl acetate three times, washing the organic phase twice with saturated ammonium chloride, washing with saturated saline three times, spin-drying to obtain 66mg of white solid,the yield thereof was found to be 30.3%. Data for 35 c: m.p.: 182 ℃ and 184 ℃;¹H NMR(300MHz，CDCl₃)δ8.24-8.16(m，2H)，8.06(dd，J＝8.4，2.1Hz，1H)，7.98(d，J＝8.5Hz，6H)，7.59(d，J＝7.8Hz，2H)，7.47(t，J＝7.5Hz，1H)，7.38(dd，J＝8.4，6.0Hz，1H)，4.21(s，2H)，1.66(s，6H).¹³C NMR(75MHz，CDCl₃)δ174.15，165.40，154.01，140.20，137.89，136.37，136.08，135.42，128.87，128.00，127.74，127.36，126.86，123.07，120.29，115.00，108.55，106.57，62.49，44.61，23.09.HRMS(ESI)m/z calcd for C₂₇H₂₁F₃N₄O₃[M-H]^-505.1492，found 505.1485。

example 18

Synthesis of 2- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-2, 4-dioxaimidazolin-1-yl) -N- (quinolin-3-yl) acetamide (35d)

Under the protection of nitrogen, compound 33(150mg, 0.43mmol) is dissolved in anhydrous dichloromethane, DMAP (10mg, 0.087mmol) and EDC.HCl (91mg, 0.47mmol) are added to react at room temperature for 5 minutes, then 3-aminoquinoline (68mg, 0.47mmol) is added to react at room temperature overnight, TLC detects that the raw materials are completely reacted, water is added to quench the reaction, ethyl acetate is extracted for three times, the organic phase is washed twice by saturated ammonium chloride, washed by saturated saline water for three times, and is dried by spinning to pass through a column to obtain 28mg of light yellow solid, and the yield is 13.5%. Data for 35 d: m.p.: 106 ℃ and 107 ℃;¹H NMR(300MHz，CDCl₃)δ9.43-9.12(m，1H)，8.77(d，J＝2.4Hz，1H)，8.67(d，J＝2.5Hz，1H)，8.16(d，J＝2.0Hz，1H)，8.06-7.96(m，2H)，7.90(d，J＝8.5Hz，1H)，7.71(dd，J＝8.2，1.5Hz，1H)，7.63(ddd，J＝8.4，6.9，1.5Hz，1H)，7.51(ddd，J＝8.1，6.9，1.2Hz，1H)，4.25(s，2H)，1.61(s，6H).¹³C NMR(75MHz，CDCl₃)δ174.14，166.14，153.98，145.02，143.60，136.08，135.42，133.86，131.19，128.80，128.57，128.03，127.81，127.57，124.40，123.00，114.98，108.45，62.42，43.95，23.10.HRMS(ESI)m/z calcd for C₂₄H₁₈F₃N₅O₃[M+H]⁺482.1434，found 482.1430。

example 19

Synthesis of 2- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-2, 4-dioxaimidazolin-1-yl) -N- (quinolin-4-yl) acetamide (35e)

Under the protection of nitrogen, compound 33(150mg, 0.43mmol) is dissolved in anhydrous dichloromethane, DMAP (10mg, 0.087mmol) and EDC.HCl (91mg, 0.47mmol) are added to react at room temperature for 5 minutes, 4-aminoquinoline (68mg, 0.47mmol) is added to react at room temperature overnight, TLC detects that the raw materials are completely reacted, water is added to quench the reaction, ethyl acetate is extracted for three times, the organic phase is washed twice with saturated ammonium chloride, washed three times with saturated saline, and dried by spinning to pass through a column to obtain 45mg of light yellow solid, and the yield is 21.7%. Data for 35 e: m.p.: 108-109 ℃;¹H NMR(300MHz，CDCl₃)δ9.47(s，1H)，8.89(d，J＝5.1Hz，1H)，8.33(d，J＝5.1Hz，1H)，8.22-8.14(m，2H)，8.09-7.95(m，3H)，7.79(t，J＝7.6Hz，1H)，7.64(t，J＝7.7Hz，1H)，4.36(s，2H)，1.68(s，6H).¹³C NMR(101MHz，CDCl₃)δ173.81，166.54，154.58，151.08，148.81，140.22，135.82，135.45，129.69，127.99，126.90，123.00，119.35，114.86，110.65，62.77，45.54，23.02.HRMS(ESI)m/z calcd for C₂₄H₁₈F₃N₅O₃[M+H]⁺482.1434，found 482.1435。

example 20

Synthesis of 2- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-2, 4-dioxaimidazolin-1-yl) -N- (quinolin-5-yl) acetamide (35f)

Under the protection of nitrogen, compound 33(150mg, 0.43mmol) is dissolved in anhydrous dichloromethane, DMAP (10mg, 0.087mmol) and EDC.HCl (91mg, 0.47mmol) are added for reaction at room temperature for 5 minutes, then 5-aminoquinoline (68mg, 0.47mmol) is added for reaction at room temperature overnight, TLC is used for detecting that the raw materials are completely reacted, water is added for quenching reaction, ethyl acetate is extracted for three times, the organic phase is washed twice by saturated ammonium chloride, washed by saturated saline water for three times, and is dried by spinning to pass through a column to obtain 31mg of light yellow solid, and the yield is 14.9%. Data for 35 f: m.p.: 174-175 ℃;¹H NMR(300MHz，CDCl₃)δ8.97(dd，J＝4.3，1.5Hz，1H)，8.85(s，1H)，8.32(d，J＝8.6Hz，1H)，8.19(d，J＝2.1Hz，1H)，8.08-7.98(m，3H)，7.94(d，J＝8.4Hz，1H)，7.73(t，J＝8.1Hz，1H)，7.48(dd，J＝8.6，4.2Hz，1H)，4.32(s，2H)，1.67(s，6H).¹³C NMR(101MHz，CDCl₃)δ174.07，166.56，154.18，150.43，148.33，136.05，135.38，133.78，133.46，132.01，130.00，129.28，127.97，127.53，123.01，122.97，121.26，121.19，114.95，108.48，62.54，44.48，23.07.HRMS(ESI)m/z calcd for C₂₄H₁₈F₃N₅O₃[M+H]⁺482.1434，found 482.1429。

example 21

Synthesis of 2- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-2, 4-dioxaimidazolin-1-yl) -N- (quinolin-6-yl) acetamide (35g)

Under the protection of nitrogen, compound 33(150mg, 0.43mmol) is dissolved in anhydrous dichloromethane, DMAP (10mg, 0.087mmol) and EDC.HCl (91mg, 0.47mmol) are added to react at room temperature for 5 minutes, then 5-aminoquinoline (68mg, 0.47mmol) is added to react at room temperature overnight, TLC detects that the raw materials are completely reacted, water is added to quench the reaction, ethyl acetate is extracted for three times, the organic phase is washed twice with saturated ammonium chloride, washed three times with saturated saline, and dried to pass through a column to obtain 54mg of white solid, and the yield is 26.1%. Data for 35 g: m.p.: 112 ℃ and 114 ℃;¹H NMR(400MHz，CDCl₃)δ9.28(d，J＝68.3Hz，1H)，8.81(t，J＝5.5Hz，1H)，8.31(d，J＝2.8Hz，1H)，8.16(d，J＝5.3Hz，1H)，8.01(dq，J＝19.1，9.8，8.9Hz，3H)，7.88(t，J＝9.6Hz，1H)，7.56(dd，J＝9.0，2.5Hz，1H)，7.37(dd，J＝8.3，4.5Hz，1H)，4.24(s，2H)，1.59(d，J＝7.9Hz，6H).¹³C NMR(101 MHz，CDCl₃)δ174.23，165.86，153.87，149.42，145.24，136.17，135.37，129.79，128.74，127.98，123.28，121.83，120.55，116.49，115.05，108.27，62.35，43.98，23.07.HRMS(ESI)m/z calcd for C₂₄H₁₈F₃N₅O₃[M+H]⁺482.1434，found 482.1436。

example 22

Synthesis of 2- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-2, 4-dioxaimidazolin-1-yl) -N- (quinolin-8-yl) acetamide (35h)

Under the protection of nitrogen, compound 33(150mg, 0.43mmol) is dissolved in anhydrous dichloromethane, DMAP (10mg, 0.087mmol) and EDC.HCl (91mg, 0.47mmol) are added to react at room temperature for 5 minutes, then 6-aminoquinoline (68mg, 0.47mmol) is added to react at room temperature overnight, TLC detects that the raw materials are completely reacted, water is added to quench the reaction, ethyl acetate is extracted for three times, the organic phase is washed twice with saturated ammonium chloride, washed three times with saturated saline, and dried by spin-drying to pass through a column to obtain 60mg of white solid, and the yield is 29.0%. Data for 35 h: m.p.: 179-180 ℃;¹H NMR(300MHz，CDCl₃)δ10.28(s，1H)，8.81(dd，J＝4.3，1.6Hz，1H)，8.75(dd，J＝6.0，3.1Hz，1H)，8.32-8.20(m，2H)，8.12(dd，J＝8.5，2.1Hz，1H)，7.99(d，J＝8.4Hz，1H)，7.63-7.58(m，2H)，7.53(dd，J＝8.3，4.3Hz，1H)，4.41(s，2H)，1.67(s，6H).¹³C NMR(75MHz，CDCl₃)δ174.44，165.23，153.45，148.49，138.28，136.62，136.34，135.39，133.53，128.10，128.01，127.31，123.10，122.45，121.92，116.86，115.05，108.46，108.44，62.26，44.01，23.15.HRMS(ESI)m/z calcd for C₂₄H₁₈F₃N₅O₃[M+Na]⁺504.1254，found 504.1252。

example 23

Synthesis of tert-butyl (2- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5, 5-dimethyl-2, 4-dioxaimidazolin-1-yl) ethyl) carbamate (36)

Under nitrogen, starting material 29(5g, 16.8mmol) was dissolved in dry DMF and NaH (604.8mg, 25.2mmol) was added slowly under ice-bath conditions allowing the temperature to rise to room temperature for 2 h. N-tert-Butoxycarbonylbromithylamine (4.1g, 18.5mmol) was then added and the temperature was raised to 55 ℃ for 7 h. TLC point plate shows that the raw material is reacted completely, heating is stopped, reaction liquid is poured into ice water after the reaction is cooled to room temperature, suction filtration and drying are carried out to obtain crude product, and the crude product is purified by column chromatography3.3g of a white solid was obtained. The yield thereof was found to be 44.6%.¹H NMR(400MHz，CDCl₃)δ8.14-7.80(m，1H)，7.47(dd，J＝7.5，1.5Hz，1H)，6.18-5.68(m，1H)，3.65(t，J＝7.0Hz，2H)，3.43(td，J＝7.1，6.0Hz，2H)，1.43(d，J＝7.7Hz，15H)。

Example 24

Synthesis of 4- (3- (2-aminoethyl) -4, 4-dimethyl-2, 5-dioxaimidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (37)

Dissolving a compound 36(3.3g, 7.5mmol) in dichloromethane, slowly adding 10mL of trifluoroacetic acid under an ice bath condition, maintaining the ice bath for half an hour for reaction, detecting by TLC to find that the raw material completely reacts, concentrating the reaction solution to dryness, adjusting the reaction solution to alkalinity by using a 4M NaOH solution, extracting the dichloromethane for three times, combining organic phases, washing the organic phases for three times by using saturated saline solution, drying the anhydrous magnesium sulfate for 10 minutes, spin-drying the organic layer to obtain a foamy solid, and drying the foamy solid under an infrared lamp to obtain a crude product of 2.7 g. ESI-MS m/z: 363[ M + Na]⁺。

Example 25

Synthesis of 4- (4, 4-dimethyl-3- (3- (quinolin-2-ylamino) ethyl) -2, 5-dioxoimidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38a)

Starting material 37(120mg, 0.35mmol), 2-bromonaphthalene (150mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen blanket, followed by addition of sodium tert-butoxide (115mg, 0.52mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction product for three times by using ethyl acetate, collecting an organic phase, washing the organic phase for three times by using saturated saline solution, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, performing spin drying, and performing column chromatography to obtain light yellow powder 43mg with the yield of 26.3%. Data for 38 a: m.p.: 172-173 ℃;¹H NMR(300MHz，CDCl₃)δ8.21(s，1H)，8.00(q，J＝8.4Hz，2H)，7.70(q，J＝8.3，7.3Hz，3H)，7.43(t，J＝7.5Hz，1H)，7.29(d，J＝11.9Hz，2H)，7.01-6.84(m，2H)，3.85-3.52(m，4H)，1.59(s，6H).¹³C NMR(75MHz，CDCl₃)δ174.45，153.85，145.01，145.01，136.29，135.39，135.12，129.34，128.09，127.76，127.66，126.59，125.93，123.16，122.34，117.82，115.09，108.44，103.97，62.17，43.28，39.57，23.49.HRMS(ESI)n/z calcd for C₂₄H₂₁F₃N₄O₂[M+Na]⁺489.1508，found 489.1507。

example 26

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (quinolin-3-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38b)

Starting material 37(240mg, 0.7mmol), 3-bromoquinoline (300mg, 1.4mmol) were dissolved in 5mL of toluene under nitrogen, followed by the addition of sodium tert-butoxide (330mg, 1.05mmol), Pd2(dba)3(32mg, 0.035mmol) and BINAP (30mg, 0.035 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction by ethyl acetate for three times, collecting an organic phase, washing the organic phase by saturated saline solution for three times, drying by anhydrous magnesium sulfate for 10 minutes, spinning, and passing through a column to obtain 56mg of white powder with the yield of 17.1%. Data for 38 b: m.p.: 146-147 ℃;¹H NMR(400MHz，DMSO-d₆)δ10.24(s，1H)，9.35(d，J＝2.6Hz，1H)，8.41-8.27(m，1H)，8.21(d，J＝2.6Hz，1H)，8.17(d，J＝8.7Hz，1H)，8.06(d，J＝8.7Hz，1H)，7.94(d，J＝8.3Hz，1H)，7.89(d，J＝8.0Hz，1H)，7.57(dt，J＝22.9，7.2Hz，2H)，4.06(t，J＝7.7Hz，2H)，3.70(t，J＝7.6Hz，2H)，1.49(s，6H).¹³C NMR(101MHz，DMSO)δ174.35，157.36，144.53，143.86，143.02，136.79，134.66，131.80，128.97，128.24，127.92，127.81，127.49，122.82，119.78，117.50，116.34，101.71，60.08，42.57，40.37，22.41.HRMS(ESI)m/z calcd for C₂₄H₂₀F₃N₅O₂[M+H]⁺468.1641，found 468.1638。

example 27

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (quinolin-4-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38c)

Nitrogen protection stripNext, starting material 37(120mg, 0.35mmol), 4-bromoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene, followed by addition of sodium tert-butoxide (115mg, 0.52mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction by ethyl acetate for three times, collecting an organic phase, washing the organic phase by saturated saline solution for three times, drying by anhydrous magnesium sulfate for 10 minutes, spinning, and passing through a column to obtain 41 mg of light yellow powder with the yield of 25.1%. Data for 38 c: m.p.: 156 ℃ and 158 ℃;¹H NMR(300MHz，DMSO-d₆)δ10.39(s，1H)，8.90(d，J＝4.7Hz，1H)，8.37(s，1H)，8.20(d，J＝8.7Hz，1H)，8.13(d，J＝8.6Hz，1H)，8.04(d，J＝8.4Hz，1H)，7.97(d，J＝8.4Hz，1H)，7.76(t，J＝7.7Hz，1H)，7.52-7.42(m，2H)，4.07(t，J＝7.4Hz，2H)，3.78(t，J＝7.5Hz，2H)，1.54(s，6H).¹³C NMR(75MHz，DMSO)δ174.41，158.01，153.84，153.01，151.12，149.53，145.30，144.63，136.87，130.04，129.62，126.00，125.37，124.42，122.78，117.42，116.36，116.05，60.07，45.86，22.53.HRMS(ESI)m/z calcd for C₂₄H₂₀F₃N₅O₂[M+H]⁺468.1641，found 468.1635。

example 28

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (quinolin-5-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38d)

Starting material 37(120mg, 0.35mmol), 5-bromoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction by ethyl acetate for three times, collecting an organic phase, washing the organic phase by saturated saline solution for three times, drying by anhydrous magnesium sulfate for 10 minutes, spinning, and passing through a column to obtain 39mg of light yellow powder with the yield of 23.8%. Data for 38d：m.p.：201-202℃；¹H NMR(300MHz，DMSO-d₆)δ8.83(dd，J＝4.1，1.5Hz，1H)，8.56(d，J＝8.6Hz，1H)，8.37(d，J＝8.4Hz，1H)，8.25(d，J＝2.0Hz，1H)，8.10(dd，J＝8.4，2.0Hz，1H)，7.57(t，J＝8.0Hz，1H)，7.44(dd，J＝8.6，4.2Hz，1H)，7.27(d，J＝8.4Hz，1H)，6.75(d，J＝7.7Hz，1H)，6.63(d，J＝5.7Hz，1H)，3.76-3.54(m，4H)，1.49(s，6H).¹³C NMR(101 MHz，CDCl₃)δ174.19，154.73，150.22，149.25，143.23，136.14，135.38，130.27，128.95，128.05，123.12，119.64，118.75，118.33，114.93，108.58，103.55，62.34，44.97，39.35，23.47.HRMS(ESI)m/z calcd for C24H20F3N5O2[M+H]+468.1641，found 468.1635。

Example 29

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (quinolin-6-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38e)

Starting material 37(240mg, 0.7mmol), 6-bromoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen, followed by addition of cesium carbonate (456mg, 1.4mmol), Pd₂(dba)₃(32mg, 0.035mmol) and X-phos (24mg, 0.035 mmol). Heating to 50 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are completely reacted, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction product for three times by using ethyl acetate, collecting an organic phase, washing the organic phase for three times by using saturated saline solution, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, performing spin drying, and performing column chromatography to obtain light green powder 36mg with the yield of 11.0%. Data for 38 e: m.p.: 159 ℃ and 160 ℃;¹H NMR(300MHz，DMSO-d₆)δ8.53(d，J＝4.2Hz，1H)，8.38(d，J＝8.4Hz，1H)，8.25(s，1H)，8.11(d，J＝8.4Hz，1H)，8.01(d，J＝8.3Hz，1H)，7.77(d，J＝9.0Hz，1H)，7.34(dd，J＝8.3，4.2Hz，1H)，7.28-7.20(m，1H)，6.91-6.84(m，1H)，3.57(dt，J＝22.0，6.5Hz，4H)，1.50(s，6H).¹³C NMR(75MHz，DMSO)δ175.18，153.40，146.74，145.76，142.84，137.25，136.66，133.69，131.82，130.48，124.57，122.01，115.72，107.28，101.90，62.24，41.66，22.98.HRMS(ESI)m/z calcd for C₂₄H₂₀F₃N₅O₂[M+H]+468.1641，found 468.1636。

example 30

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (quinolin-7-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38f)

Starting material 11(240mg, 0.7mmol), 7-bromoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen, followed by addition of cesium carbonate (456mg, 1.4mmol), Pd₂(dba)₃(32mg, 0.035mmol) and X-phos (24mg, 0.035 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction by ethyl acetate for three times, collecting an organic phase, washing the organic phase by saturated saline solution for three times, drying by anhydrous magnesium sulfate for 10 minutes, spinning, and passing through a column to obtain 81mg of light yellow powder with the yield of 22.1%. Data for 38 f: m.p.: 198 ℃ and 199 ℃;¹H NMR(300MHz，CDCl3)δ8.76(dd，J＝4.4，1.8Hz，1H)，8.16(d，J＝2.0Hz，1H)，8.07-7.90(m，3H)，7.60(d，J＝8.8Hz，1H)，7.15(dd，J＝8.1，4.3Hz，1H)，7.06(d，J＝2.3Hz，1H)，6.94(dd，J＝8.8，2.4Hz，1H)，4.85(t，J＝5.0Hz，1H).3.84-3.56(m，4H)，1.54(s，6H).¹³C NMR(75MHz，CDCl₃)δ174.34，154.00，150.68，148.27，136.25，135.68，135.33，128.96，128.03，123.07，122.06，118.58，117.65，108.46，104.48，62.20，43.26，39.39，23.46.HRMS(ESI)m/z calcd for C₂₄H₂₀F₃N₅O₂[M+H]⁺468.1641，found 468.1666。

example 31

Synthesis of 4- (3- (2- (bis (quinolin-6-yl) amino) ethyl) -4, 4-dimethyl-2, 5-dioxaimidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38g)

Starting material 37(120mg, 0.35mmol), 6-bromoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). The temperature is increased to 110 ℃,the reaction is carried out overnight, TLC point plate shows that the raw materials are completely reacted, heating is stopped, after the reaction is cooled to room temperature, water is added for quenching reaction, ethyl acetate is used for extraction for three times, organic phase is collected, the organic phase is washed with saturated saline solution for three times, anhydrous magnesium sulfate is used for drying for 10 minutes, the organic phase is dried in a spinning mode, and the light yellow powder 25mg is obtained after column chromatography, and the yield is 12.0%. Data for 38 g: m.p.: 180 ℃ and 181 ℃;¹H NMR(300MHz，CDCl₃)δ8.82(dd，J＝4.4，1.6Hz，2H)，8.17(d，J＝2.0Hz，1H)，8.09-7.96(m，5H)，7.94(d，J＝8.4Hz，1H)，7.54(dq，J＝4.8，2.7Hz，4H)，7.38(dd，J＝8.3，4.2Hz，2H)，4.35(dd，J＝9.3，6.1Hz，2H)，3.74(dd，J＝9.2，5.9Hz，2H)，1.50(s，6H).¹³C NMR(75MHz，CDCl₃)δ174.22，153.32，149.00，144.83，136.22，135.39，135.00，130.96，129.47，127.99，125.37，123.00，121.80，114.95，108.51，61.99，50.80，37.79，23.42.HRMS(ESI)m/z calcd for C₃₃H₂₅F₃N₆O₂[M+H]⁺595.2063，found 595.2500。

example 32

Synthesis of 4- (3- (2- (bis (quinolin-7-yl) amino) ethyl) -4, 4-dimethyl-2, 5-dioxaimidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38h)

Starting material 37(120mg, 0.35mmol), 7-bromoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction by ethyl acetate for three times, collecting an organic phase, washing the organic phase by saturated saline solution for three times, drying by anhydrous magnesium sulfate for 10 minutes, spinning, and passing through a column to obtain 66mg of light yellow powder with the yield of 31.7%. Data for 38 h: m.p.: 244 ℃ and 245 ℃;¹H NMR(300MHz，DMSO-d₆)δ8.85(dd，J＝4.3，1.7Hz，1H)，8.40(d，J＝8.4Hz，1H)，8.31(dd，J＝8.3，1.8Hz，1H)，8.24(d，J＝2.0Hz，1H)，8.10(dd，J＝8.4，2.0Hz，1H)，7.95(d，J＝8.9Hz，1H)，7.78(d，J＝2.3Hz，1H)，7.50(dd，J＝8.9，2.4Hz，1H)，7.43(dd，J＝8.2，4.3Hz，1H)，4.37(t，J＝7.1Hz，1H)，3.79(t，J＝7.4Hz，1H)，1.47(s，3H).HRMS(ESI)m/z calcd for C₃₃H₂₅F₃N₆O₂[M+H]⁺595.2063，found 595.2600。

example 33

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (8-nitroquinolin-5-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38i)

Starting material 37(120mg, 0.35mmol), 5-bromo 8-nitroquinoline (177mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction product for three times by using ethyl acetate, collecting an organic phase, washing the organic phase for three times by using saturated saline solution, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, performing spin drying, and performing column chromatography to obtain 22mg of yellow powder with the yield of 13.4%. Data for 38 i:¹H NMR(300MHz，DMSO-d₆)δ9.14-9.06(m，1H)，8.83(d，J＝8.6Hz，1H)，8.42(dd，J＝20.4，8.5Hz，2H)，8.30(s，1H)，8.21-8.12(m，1H)，7.88(s，1H)，7.71(dd，J＝8.5，4.0Hz，1H)，6.85(d，J＝9.0Hz，1H)，3.82-3.70(m，4H)，1.55(s，J＝3.1Hz，6H).ESI-MS m/z：535[M+Na]⁺。

example 34

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (8-cyanoquinolin-5-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38j)

Starting material 37(120mg, 0.35mmol), 5-bromo 8-cyanoquinoline (163mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 deg.C, reacting overnight, stopping heating when TLC point plate shows that the raw material reaction is finished, cooling to room temperature, adding water to quench reaction, and reactingThe organic phase was washed three times with saturated brine, dried over anhydrous magnesium sulfate for 10 minutes, and spin-dried, and the resulting product was purified by column chromatography to give 31mg of a pale yellow powder with a yield of 18.9%. Data for 38 j:¹H NMR(300MHz，DMSO-d₆)δ9.00(dd，J＝4.2，1.4Hz，1H)，8.72(dd，J＝8.7，1.6Hz，1H)，8.38(d，J＝8.4Hz，1H)，8.23(d，J＝1.9Hz，1H)，8.15-8.04(m，2H)，7.70-7.55(m，2H)，6.82(d，J＝8.4Hz，1H)，3.66(p，J＝6.0Hz，4H)，1.47(s，6H).ESI-MS m/z：515[M+Na]⁺。

example 35

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (8-fluoroquinolin-5-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38k)

Starting material 37(120mg, 0.35mmol), 5-bromo 8-fluoroquinoline (158mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are completely reacted, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction product for three times by using ethyl acetate, collecting an organic phase, washing the organic phase for three times by using saturated saline solution, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, performing spin drying, and performing column chromatography to obtain 37mg of dark yellow powder with the yield of 22.6%. Data for 38 k:¹H NMR(300MHz，DMSO-d₆)δ8.91(dd，J＝4.2，1.5Hz，1H)，8.61(dt，J＝8.8，1.7Hz，1H)，8.37(d，J＝8.4Hz，1H)，8.24(d，J＝2.0Hz，1H)，8.10(dd，J＝8.4，2.0Hz，1H)，7.56(dd，J＝8.6，4.2Hz，1H)，7.43(dd，J＝11.0，8.5Hz，1H)，6.64(dd，J＝8.6，3.7Hz，1H)，6.49(t，J＝5.5Hz，1H)，3.61(dt，J＝25.8，6.6Hz，4H)，1.49(s，6H).ESI-MS m/z：493[M+Na]⁺。

example 36

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (8-methylquinolin-5-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38l)

Under the protection of nitrogen, 37(120mg, 0.35mmol) of raw material, 5-bromo-8-methylQuinoline (155mg, 0.7mmol) was dissolved in 3mL of toluene, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are completely reacted, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction product for three times by using ethyl acetate, collecting an organic phase, washing the organic phase for three times by using saturated saline solution, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, performing spin drying, and performing column chromatography to obtain 55mg of yellow powder with the yield of 33.5%. Data for 38 l:¹H NMR(300MHz，DMSO-d₆)δ8.88(dd，J＝4.1，1.5Hz，1H)，8.59-8.50(m，1H)，8.38(d，J＝8.3Hz，1H)，8.25(d，J＝1.9Hz，1H)，8.10(d，J＝8.6Hz，1H)，7.51-7.39(m，2H)，6.66(d，J＝7.8Hz，1H)，6.42(d，J＝5.5Hz，1H)，3.64(d，J＝6.4Hz，2H)，3.55(d，J＝6.5Hz，2H)，1.49(s，9H)。

example 37

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (isoquinolin-1-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38m)

Under the protection of nitrogen, raw material 37(120mg, 0.35mmol), 1-bromoisoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction by ethyl acetate for three times, collecting an organic phase, washing the organic phase by saturated saline solution for three times, drying by anhydrous magnesium sulfate for 10 minutes, spinning, and passing through a column to obtain 18mg of light yellow powder with the yield of 11.0%. Data for 38 m:¹H NMR(300MHz，DMSO-d₆)δ8.36(d，J＝8.4Hz，1H)，8.26-8.16(m，2H)，8.09(dd，J＝8.4，2.0Hz，1H)，7.93(d，J＝5.8Hz，1H)，7.74(d，J＝8.1Hz，1H)，7.64(q，J＝6.6，5.9Hz，2H)，7.52(ddd，J＝8.4，6.8，1.4Hz，1H)，6.95(d，J＝5.8Hz，1H)，3.83(q，J＝6.3Hz，2H)，3.63(t，J＝6.6Hz，2H)，1.49(s，6H)。

example 38

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (isoquinolin-3-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38n)

Under the protection of nitrogen, raw material 37(120mg, 0.35mmol), 3-bromoisoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction by ethyl acetate for three times, collecting an organic phase, washing the organic phase by saturated saline solution for three times, drying by anhydrous magnesium sulfate for 10 minutes, spinning, and passing through a column to obtain 35mg of light yellow powder with the yield of 21.4%. Data for 38 n:¹H NMR(300MHz，DMSO-d₆)δ10.35(s，1H)，9.18(s，1H)，8.40(d，J＝12.7Hz，2H)，8.28-8.19(m，1H)，8.07(dd，J＝18.0，8.4Hz，2H)，7.84(d，J＝8.4Hz，1H)，7.67(t，J＝7.5Hz，1H)，7.49(t，J＝7.5Hz，1H)，4.20(t，J＝8.0Hz，2H)，3.68(t，J＝7.9Hz，2H)，1.51(s，6H)。

example 39

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (isoquinolin-4-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38o)

Under the protection of nitrogen, raw material 37(120mg, 0.35mmol), 4-bromoisoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction by ethyl acetate for three times, collecting an organic phase, washing the organic phase by saturated saline solution for three times, drying by anhydrous magnesium sulfate for 10 minutes, spinning, and passing through a column to obtain 16mg of light yellow powder with the yield of 9.7%. Data for 38 o:¹H NMR(300MHz，DMSO-d₆)δ8.61(s，1H)，8.37(d，J＝8.4Hz，1H)，8.25(s，1H)，8.20-8.06(m，2H)，8.04-7.90(m，2H)，7.77-7.59(m，2H)，6.46(s，1H)，3.71-3.61(m，4H)，1.49(s，6H)。

example 40

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (isoquinolin-5-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38p)

Under the protection of nitrogen, raw material 37(120mg, 0.35mmol), 5-bromoisoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are completely reacted, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction product for three times by using ethyl acetate, collecting an organic phase, washing the organic phase for three times by using saturated saline solution, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, performing spin drying, and performing column chromatography to obtain 22mg of dark yellow powder with the yield of 13.3%. Data for 38 p:¹H NMR(300MHz，DMSO-d₆)δ9.17(s，1H)，8.44(d，J＝6.0Hz，1H)，8.37(d，J＝8.4Hz，1H)，8.25(d，J＝2.0Hz，1H)，8.11(dd，J＝8.3，2.0Hz，1H)，7.99(d，J＝6.1Hz，1H)，7.52(t，J＝7.9Hz，1H)，7.32(d，J＝8.1Hz，1H)，6.91(d，J＝7.7Hz，1H)，6.61(t，J＝5.4Hz，1H)，3.69-3.57(m，4H)，1.50(s，6H)。

EXAMPLE 41

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (isoquinolin-6-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38q)

Under the protection of nitrogen, raw material 37(120mg, 0.35mmol), 6-bromoisoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are completely reacted, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction product for three times by using ethyl acetate, collecting an organic phase, washing the organic phase for three times by using saturated saline solution, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, performing spin drying, and performing column chromatography to obtain 22mg of dark yellow powder with the yield of 13.3%. Data for 38 q:¹H NMR(300MHz，DMSO-d₆)δ8.92(s，1H)，8.38(d，J＝8.4Hz，1H)，8.28-8.19(m，2H)，8.11(dd，J＝8.4，2.0Hz，1H)，7.83(d，J＝8.9Hz，1H)，7.46(d，J＝5.8Hz，1H)，7.11(dd，J＝8.9，2.2Hz，1H)，6.82(d，J＝2.2Hz，1H)，6.73(s，1H)，3.58(t，J＝5.6Hz，4H)，1.50(s，6H)。

example 42

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (isoquinolin-7-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38r)

Under the protection of nitrogen, raw material 37(120mg, 0.35mmol), 7-bromoisoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction product for three times by using ethyl acetate, collecting an organic phase, washing the organic phase for three times by using saturated saline solution, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, performing spin drying, and performing column chromatography to obtain 25mg of yellow powder with the yield of 15.1%. Data for 38 r:¹H NMR(300MHz，DMSO-d₆)δ8.99(s，1H)，8.38(d，J＝8.4Hz，1H)，8.25(d，J＝1.9Hz，1H)，8.17(s，1H)，8.11(dd，J＝8.4，2.0Hz，1H)，7.72(d，J＝8.9Hz，1H)，7.59(d，J＝5.1Hz，1H)，7.26(dd，J＝8.9，2.2Hz，1H)，7.01(d，J＝2.3Hz，1H)，6.47(t，J＝5.5Hz，1H)，3.63-3.51(m，4H)，1.49(s，6H)。

example 43

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (isoquinolin-8-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38s)

Under the protection of nitrogen, raw material 37(120mg, 0.35mmol), 8-bromoisoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 deg.C, reacting overnight, stopping heating when TLC spot plate shows that the raw materials have reacted completely, cooling to room temperature, quenching with water, extracting with ethyl acetate for three times, collecting organic phase, and collecting organic phaseWashed three times with saturated brine, dried over anhydrous magnesium sulfate for 10 minutes, spin-dried, and passed through a column to give 27mg of a dark yellow powder with a yield of 16.3%. Data for 38 s:¹H NMR(300MHz，DMSO-d₆)δ9.51(s，1H)，8.40(dd，J＝15.3，7.0Hz，2H)，8.25(d，J＝2.0Hz，1H)，8.11(dd，J＝8.4，2.0Hz，1H)，7.65(d，J＝5.6Hz，1H)，7.57(t，J＝7.9Hz，1H)，7.12(d，J＝8.1Hz，1H)，7.01-6.91(m，1H)，6.81(d，J＝7.7Hz，1H)，3.65(m，4H)，1.50(s，6H)。

example 44

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (pyridin-2-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38t)

Starting material 37(120mg, 0.35mmol), 2-bromopyridine (110mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are completely reacted, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction product for three times by using ethyl acetate, collecting an organic phase, washing the organic phase for three times by using saturated saline solution, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, performing spin drying, and performing column chromatography to obtain light yellow powder 33mg with the yield of 19.2%. Data for 38 t:¹H NMR(300MHz，Chloroform-d)δ8.19-8.09(m，2H)，8.09-7.91(m，2H)，7.45(ddd，J＝8.8，7.1，1.9Hz，1H)，6.69-6.58(m，1H)，6.49(d，J＝8.4Hz，1H)，4.97(t，J＝5.7Hz，1H)，3.75(q，J＝6.2，5.7Hz，2H)，3.66(dd，J＝6.8，4.9Hz，2H)，1.57(s，6H)。

example 45

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (pyrimidin-5-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38u)

Starting material 37(120mg, 0.35mmol), 5-bromopyrimidine (110mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen blanket followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). The temperature is raised to 110 ℃, the reaction is carried out overnight, and the raw materials are found to be reversed by TLC point plateAfter the reaction is finished, stopping heating, cooling the reaction to room temperature, adding water to quench the reaction, extracting the reaction by using ethyl acetate for three times, collecting an organic phase, washing the organic phase by using saturated saline water for three times, drying the organic phase for 10 minutes by using anhydrous magnesium sulfate, carrying out spin drying, and carrying out column chromatography to obtain 27mg of white powder with the yield of 15.7%. Data for 38 u:¹H NMR(300MHz，DMSO-d₆)δ8.44(s，1H)，8.36(d，J＝8.4Hz，1H)，8.23(d，J＝2.3Hz，3H)，8.09(dd，J＝8.4，2.0Hz，1H)，6.38(t，J＝5.9Hz，1H)，3.49(m，4H)，1.48(s，6H)。

example 46

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2- (pyrimidin-2-ylamino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38v)

Starting material 37(120mg, 0.35mmol), 2-bromopyrimidine (110mg, 0.7mmol) was dissolved in 3mL of toluene under nitrogen blanket followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, stopping heating when TLC (thin layer chromatography) plates find that the raw materials are reacted completely, adding water to quench the reaction after the reaction is cooled to room temperature, extracting the reaction by ethyl acetate for three times, collecting an organic phase, washing the organic phase by saturated saline solution for three times, drying by anhydrous magnesium sulfate for 10 minutes, spinning, and passing through a column to obtain 33mg of light yellow powder with the yield of 19.2%. Data for 38 v:¹H NMR(300MHz，DMSO-d₆)δ8.40-8.28(m，3H)，8.21(d，J＝1.9Hz，1H)，8.07(dd，J＝8.4，2.0Hz，1H)，7.29(t，J＝6.0Hz，1H)，6.61(t，J＝4.8Hz，1H)，3.60(q，J＝6.4Hz，2H)，3.49(t，J＝6.5Hz，2H)，1.45(s，6H)。

example 47

Synthesis of 4- (4, 4-dimethyl-2, 5-dioxo-3- (2-di (quinoxalin-6-yl) amino) ethyl) imidazolin-1-yl) -2- (trifluoromethyl) benzonitrile (38w)

Starting material 37(120mg, 0.35mmol), 6-bromoquinoxaline (150mg, 0.7mmol) was dissolved in 3mL of toluene under a nitrogen blanket, followed by addition of cesium carbonate (228mg, 0.7mmol), Pd₂(dba)₃(16mg, 0.0175mmol) and X-phos (12mg, 0.0175 mmol). Heating to 110 ℃, reacting overnight, and performing TLC plate chromatographyAfter the reaction of the raw materials is finished, stopping heating, cooling the reaction to room temperature, adding water to quench the reaction, extracting the reaction by using ethyl acetate for three times, collecting an organic phase, washing the organic phase by using saturated saline water for three times, drying the organic phase by using anhydrous magnesium sulfate for 10 minutes, carrying out spin drying, and passing the organic phase through a column to obtain 21mg of yellow powder with the yield of 11.7 percent. Data for 38 w:¹H NMR(300MHz，DMSO-d₆)δ8.89(d，J＝1.9Hz，2H)，8.83(d，J＝1.9Hz，2H)，8.38(d，J＝8.4Hz，1H)，8.22(d，J＝2.0Hz，1H)，8.07(t，J＝8.9Hz，3H)，7.88(d，J＝2.6Hz，2H)，7.76(dd，J＝9.1，2.6Hz，2H)，4.41(t，J＝7.3Hz，2H)，3.81(t，J＝7.3Hz，2H)，1.48(s，6H)。

the following are some of the pharmacological experiments and results of the compounds of the invention:

MTT method for testing inhibition of proliferation capability of compound on prostate cancer cell line (22RV1)

Experiment on anti-proliferative Activity of prostate cancer cell line 22RV1

1 materials and methods

1) Experimental Material

(1) Cell lines

Human prostate cancer cell 22RV1 (south kyakyl biotechnology).

(2) Instruments and reagents

BioTek microplate reader (Boteng instruments, Inc. USA). (ii) a Inverted microscope (japan nikon Ts 100); CO2 incubator (ESCO).

RPMI1640 medium, double antibody (Gibco), high grade fetal bovine serum (Gibco); 3- (4, 5) -2-thiazole- (2, 5) -dimethyltetrazolium bromide blue (MTT) (south kyakyl bio-inc); dmso (amresco); other reagents are all domestic analytical purifiers.

2) Solvent preparation method

PBS: 8.0g of NaCl, 0.13g of Na2HPO4 & 12H2O, 0.06g of KH2PO4, 0.4g of KCl, and 0.35g of NaHCO3 were weighed, dissolved by adding 1mL of ultrapure water, adjusted to pH 7.4 by adding NaOH, and then autoclaved and stored at 4 ℃.

0.25% pancreatin digest: 0.25g of trypsin was weighed, dissolved sufficiently in 100mL of ultrapure water, filtered through a 0.22 μm microporous filter, and stored at-20 ℃.

RPMI1640 culture solution: 13.3g of RPMI1640 medium powder and 2.0g of NaHCO3 were weighed out, respectively, and 100mL of ultrapure water was added thereto to sufficiently dissolve the mixture, followed by addition of 10% diabody, filtration through a 0.22 μm microporous membrane, addition of 10% fetal bovine serum when used, and storage at 4 ℃.

3) Experimental methods

(1) Cell culture

Cell recovery: taking the freezing tube with the cells out of the liquid nitrogen tank, immediately placing the tube in a constant-temperature water bath kettle at 37 ℃, repeatedly shaking the tube by hands to melt the cells, pouring the cells into a culture bottle, adding 5.5mL of culture medium (containing 10% fetal calf serum) for dilution, transferring the cells into a centrifuge tube, centrifuging the cells at 2000r/min for3 minutes, removing supernatant, adding fresh culture medium, repeatedly blowing and beating the cells for several times, and transferring the cells into the culture bottle for culture.

Cell passage: human prostate cancer 22Rv1 cells are anchorage-dependent growth cells, RPMI1640 culture solution containing the cells is placed in an incubator at 37 ℃ and 5% CO2, and subculture is carried out when the bottom of the flask is 80% -90% full of the cells. When subculturing, firstly pouring out the culture medium in a culture flask, washing twice with PBS, then adding 2-3 mL of 0.25% trypsin solution, digesting for3 minutes at 37 ℃, observing cell rounding under a microscope, and adding 2mL of fresh RPMI1640 culture medium (containing 10% fetal calf serum) to terminate digestion. Pouring off the liquid in the culture bottle, washing twice with PBS, adding 6mL of fresh culture medium, repeatedly blowing and beating uniformly, equally dividing into two culture bottles, and continuing to culture.

Freezing and storing cells: collecting cells in logarithmic phase, adding trypsin solution for digestion, centrifuging, discarding supernatant, adding serum-free frozen stock solution, repeatedly beating for several times, and transferring into a frozen stock tube. Placing the freezing tube into a freezing box, placing the freezing box in a refrigerator at minus 80 ℃ overnight, taking out the freezing tube the next day, and placing the freezing tube into a liquid nitrogen tank. Record cell name, cryopreservation date and storage location.

Cell counting: the blood counting chamber was wiped clean with 75% ethanol solution, a small amount of cell resuspension (about 10uL) was taken, dropped onto the counting chamber, covered with a cover slip, and left to stand for a while. The counting plate is placed under an inverted microscope for observation, and the total number of the four cells in the counting plate is recorded, if the cells are pressed into the line, only the upper side and the left side are recorded. (cell count/mL-total number of cells obtained/4X 104)

(2) MTT assay

Taking cells in logarithmic growth phase, pouring out old culture medium, adding 0.25% trypsin solution for digestion for3 minutes, observing cell rounding under a microscope, adding 3mL of fresh RPMI1640 culture medium containing 10% fetal calf serum to stop digestion, transferring the solution to a centrifuge tube, centrifuging at 2000r/min for3 minutes, and discarding supernatant. Cells were resuspended by adding 2mL of medium and counted. After counting, the cells are planted in a 96-well plate according to the concentration of 4000-6000 cells per well, and each well is 100 mu L. The 96-well plate with the cells laid out was placed at 37 ℃ in a 5% CO2 incubator for further 24 h. Drug gradients were diluted with medium to 100. mu. mol/L, 20. mu. mol/L, 2. mu. mol/L, 0.2. mu. mol/L and then added to 96-well plates at 100. mu.L per well, with three duplicate wells per concentration set. The control group was added with medium containing corresponding concentration, the same volume of blank medium was added to the zero-adjusted wells, and incubated in 5% CO2, 37C incubator for 4 days with medium change every two days. mu.L of MTT (5mg/mL) was added to each well, mixed well, and cultured in a 5% CO2, 37C incubator for 4 hours in the absence of light. The liquid in the 96-well plate was removed, 150. mu.L DMSO was added to each well, and the plate was placed on a micro-shaker and shaken to completely dissolve the crystals at the bottom. The 96-well plate is then placed into a microplate reader for detection, the absorbance is measured at 490nm, a curve is drawn, and the inhibition rate of the drug on the cells and the IC50 are calculated. The inhibition ratio was [ (control average OD value-experimental average OD value)/(control average OD value-blank control average OD value) ] × 100%.

Results and analysis of growth inhibitory Activity of Compound on 22RV1 cell line

The prostate cancer cell line 22RV1 is a human prostate cancer epithelial cell line from xenografts (serial passages in mice that have been castrated to cause prostate cancer regression and recurred after androgen-dependent CWR22 engraftment in its father line). The growth of 22RV1 cells was androgen sensitive and highly expressed the AR splice variant, thus the cell line was resistant to enzalutamide. The antiproliferative effect of the compounds on the 22RV1 cell line was tested under the administration of 0.1 μ M testosterone, and it was examined whether the target compound could produce a cell proliferation inhibitory effect through an antiandrogenic effect.

(-for not measured test results)

(3) Western Blot experiment

According to the MTT experiment result, the compounds 38d and 38k with the best activity are selected to be subjected to Western Blot experiment, so as to detect whether the synthesized target compound has AR and AR-V7 degradation.

The experimental method comprises the following steps: after the human prostate cancer 22RV1 cells are treated by the compound, the culture medium is discarded, PBS is washed for 2-3 times, protease inhibitor and RIPA lysate are sequentially added, the culture plate is repeatedly shaken to enable the cells to be in full contact with the culture plate, and then the cells are scraped by a scraper. Transferring the obtained cell suspension into a centrifuge tube, cracking on ice for 30min, repeatedly blowing with a pipette to promote cell lysis, and centrifuging (4 deg.C, 12,000g, 10min) to obtain supernatant as total protein solution. Protein concentration was determined using BCA protein quantitative assay kit according to the kit instructions, then 5 × protein loading buffer was added at a ratio of 4: 1 protein solution to protein loading buffer and boiled in boiling water bath for 15min in preparation for the next step of protein isolation. An equal amount of the above protein solution was added to the gel loading well and prepared for electrophoresis, wherein the voltage of the concentrated gel was 75V and the voltage of the separation gel was 120V. And (5) electrophoretic until bromophenol blue just runs out, and then carrying out mold conversion. Stripping off the band of the target protein, sticking a PVDF membrane, transferring the band to the PVDF membrane through electrophoresis, and then sealing the band for 1h on a decoloring shaking table by using 5% skimmed milk. Primary antibody was added and incubated overnight at 4 ℃ followed by three washes with TBST for 5min each. Secondary antibody was added and incubated at room temperature for 30min, followed by three washes with TBST for 5min each. Preparing ECL mixed solution in a dark room according to the proportion of ECLA to ECLB being 1: 1, then placing the processed PVDF film face upwards in an exposure box, adding the prepared ECL mixed solution to react for 1-2min, discarding the reaction solution, adjusting the exposure condition according to the luminous intensity of the developing reagent, and starting exposure. The resulting films were scanned, destained using Photoshop, and analyzed for optical density values using Alpha software.

The experimental results are shown in the figure, compound 38d can significantly degrade AR at 0.1 μ M with the addition of 0.1 μ M testosterone, and the degradation capability of AR is increased in a gradient manner. Compound 38k was able to significantly degrade AR and AR-V7 with the addition of 0.1 μ M testosterone with a gradient of increasing degradation of AR and AR-V7.