CN113024513A - Novel androgen receptor degradation agent, preparation method and medical application - Google Patents

Novel androgen receptor degradation agent, preparation method and medical application Download PDF

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CN113024513A
CN113024513A CN202110304654.3A CN202110304654A CN113024513A CN 113024513 A CN113024513 A CN 113024513A CN 202110304654 A CN202110304654 A CN 202110304654A CN 113024513 A CN113024513 A CN 113024513A
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androgen receptor
reaction
nitrogen
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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
陈明琪
陈德英
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

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.
Figure DDA0002986129940000011

Description

Novel androgen receptor degradation agent, preparation method and medical application
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:
Figure BDA0002986129920000021
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:
Figure BDA0002986129920000022
Figure BDA0002986129920000023
Figure BDA0002986129920000031
Figure BDA0002986129920000032
Figure BDA0002986129920000033
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
Figure BDA0002986129920000041
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-38h
Figure BDA0002986129920000042
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.
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 AV300MHz 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, a TLC point plate shows 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)
Compound 30(6.5g, 0.021mol) was dissolved in 50mL of methanol, 13mL of 40% aqueous NaOH solution was added, the mixture was stirred at room temperature overnight, and the mixture was subjected to TLCAnd (3) completely reacting the raw materials, concentrating the reaction solution, adding 4N HCl to adjust the pH value 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 light yellow solid with the yield of 76.1 percent, wherein the light yellow solid is 6 g. 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 of DIPEA and 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, 429. mu.L of DIPEA and 197mg of HATu were added, and the mixture was reacted at room temperature for half an hour, followed by addition of 3-aminomethylpyridine (34mg, 0.312mmol) and stirring at room temperatureOvernight. 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-mono (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(101MHz，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 under nitrogen protectionmu.L of DIPEA and 207mg of HATu were added to 3mL of anhydrous DMF, 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/zcalcd 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 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 63mg is obtained through column chromatography, and the yield is 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 forC21H18F3N5O3[M+H]+446.1434，found 446.1431.
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)
Under the protection of nitrogen, compound 33(150mg, 0.43mmol) is dissolved in anhydrous dichloromethane, EDC.HCl (91mg, 0.47mmol) and HOBt (64mg, 0.47mmol) are added to react at room temperature for 5 minutes, then 1-naphthylamine (80mg, 0.47mmol) and DIPEA (86 uL, 0.52mmol) are added to react at room temperature overnight, TLC detects that the raw materials are completely reacted, water quenching is added to quench the reaction, ethyl acetate is extracted for three times, the organic phase is washed twice with saturated ammonium chloride, saturated saline water is washed for three times, and the mixture is dried by spinning to obtain 66mg of white solid, and the yield is 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)
Compound 33(150mg, 0.43mmol) was dissolved under nitrogen protectionDMAP (10mg, 0.087mmol) and EDC.HCl (91mg, 0.47mmol) were added to anhydrous dichloromethane and reacted for 5 minutes at room temperature, followed by the addition of 3-aminoquinoline (68mg, 0.47mmol) and overnight reaction at room temperature, TLC detection of the completion of the reaction of the starting materials was performed, water quenching was added to quench the reaction, ethyl acetate was extracted three times, the organic phase was washed twice with saturated ammonium chloride and three times with saturated saline and spin dried on the column to give 28mg of a pale yellow solid with a yield of 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 nitrogen protection, compound 33(150mg, 0.43mmol)Dissolving in anhydrous dichloromethane, adding DMAP (10mg, 0.087mmol), EDC.HCl (91mg, 0.47mmol) to react at room temperature for 5 minutes, then adding 5-aminoquinoline (68mg, 0.47mmol), reacting at room temperature overnight, detecting the completion of the raw material reaction by TLC, 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, and spin-drying to obtain a white solid 54mg, with the yield of 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(101MHz，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/zcalcd for C24H18F3N5O3[M+Na]+504.1254，found504.1252。
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, crude product is obtained after suction filtration and drying, and 3.3g of white solid is obtained after column chromatography purification. 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-l-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 materials completely react, concentrating the reaction solution to dryness, adjusting the reaction solution to be alkaline 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 foamed solid, and drying the organic layer 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 for38 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)m/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 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, washing with saturated salt solution for three times, and removing anhydrous sulfurMagnesium was dried for 10 minutes, spin dried, and column passed to give 56mg of white powder, 17.1% yield. Data for38 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)
Starting material 37(120mg, 0.35mmol), 4-bromoquinoline (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 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 41mg of light yellow powder with the yield of 25.1%. Data for38 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 for38 d: m.p.: 201-202 ℃;1HNMR(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(101MHz，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)
Under the protection of nitrogen, the raw material 37 (240) is addedmg, 0.7mmol), 6-bromoquinoline (150mg, 0.7mmol) was dissolved in 3mL of toluene, 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 for38 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 for38 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). 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 25mg of light yellow powder with the yield of 12.0%. Data for38 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/zcalcd 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 for38 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，found595.2600。
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 (22RVl)
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.
Figure BDA0002986129920000201
(-for not measured test results)
(3) Western Blot assay based on the MTT assay results, the most active compound 38d was selected for Western Blot assay to determine whether the target compound synthesized had AR 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 the BCA protein quantitative assay kit, according to the kit instructions, and then following the protein solution: protein loading buffer 5 × protein loading buffer was added at a ratio of 4: 1 and boiled in a boiling water bath for 15min in preparation for the next 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.

Claims (7)

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,
Figure FDA0002986129910000011
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-substituted or multi-substituted benzene ring, a nitrogen-containing heterocyclic ring, a condensed ring or a nitrogen-containing condensed 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:
Figure FDA0002986129910000012
Figure FDA0002986129910000021
Figure FDA0002986129910000022
Figure FDA0002986129910000023
Figure FDA0002986129910000031
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.
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