A triazone compound and its application

Abstract

The present invention provides a triazine ketone compound and its application. The structure of the compound is shown in Formula I: In Formula I, R1 and R2 are independently selected from any one of substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 arylalkyl, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 cycloalkylalkyl, substituted or unsubstituted C2-C12 heterocyclyl, substituted or unsubstituted C2-C12 heterocyclylalkyl, substituted or unsubstituted C4-C12 heteroaryl, and substituted or unsubstituted C4-C12 heteroarylalkyl. The triazine ketone compound provided by the present invention has high activity and can effectively inhibit the proliferation of prostate cancer cells.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a triazine ketone compound and its application, and especially relates to a highly active triazine ketone compound and its application. Background Art

[0002] Prostate cancer refers to epithelial malignancies that arise in the prostate gland, including adenocarcinoma (acinar adenocarcinoma), ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, and adenosquamous carcinoma. According to statistics, prostate cancer is the second most common malignant tumor among new cancers in men worldwide, and its mortality rate ranks fifth among male cancers. It has seriously affected men's health, and therefore, the development of therapeutic drugs for prostate cancer is urgent.

[0003] CN113354707A discloses a synthesis method and product of a trifunctional integrated prodrug for prostate cancer diagnosis and treatment. This prodrug is capable of labeling three radionuclides: 18F, 68Ga, and 177Lu. This invention achieves a labeling rate of 40% for 18F and over 90% for 68Ga and 177Lu. It can be combined with other targeting molecules beyond PSMA to design more bi- or tri-functional diagnostic and therapeutic drugs. This invention has wide adaptability, eliminating the need to purchase different structures or design different synthesis routes, and reducing costs. This structure will significantly expand the market for PSMA-based drugs, providing more flexible and comprehensive radionuclide labeling options for such drugs. This will significantly enhance the diagnosis and treatment of prostate cancer and is suitable for industrialized use.

[0004] CN114272212A discloses a Rac1 inhibitor nanoparticle targeting prostate cancer. These nanoparticles are engineered based on novel prostate cancer surface markers to create a novel nanodelivery system. By encapsulating anti-tumor drugs within the nanodelivery system, which actively targets prostate cancer, the nanoparticles enhance drug efficacy and minimize side effects. The Rac1 inhibitor NSC23766, specifically encapsulated in the nanoparticles, can better target tumor tissue and more accurately release the drug in an acidic environment, enhancing drug targeting. These nanoparticles are potentially useful in the development of targeted prostate cancer drugs.

[0005] CN104072499A discloses a preparation method and use of a pyrimidine compound, which is a piperazine-substituted pyrimidine compound having the general formula I. The compound of the general formula I in the pyrimidine compound of the invention has a significant inhibitory effect on human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human colon cancer cells, human renal cancer cells, and myeloma, and can be used to prepare a drug for treating human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human colon cancer cells, human renal cancer cells, and myeloma.

[0006] The above methods all provide techniques for diagnosing or treating prostate cancer, but there is still no effective drug for treating prostate cancer. Therefore, how to provide an effective drug for treating prostate cancer has become an urgent problem to be solved. Summary of the Invention

[0007] In response to the shortcomings of the prior art, the present invention aims to provide a triazinone compound and its application, in particular to provide a highly active triazinone compound and its application. The triazinone compound provided by the present invention has high activity and can effectively inhibit the proliferation of prostate cancer cells.

[0008] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides a triazine ketone compound, the structure of which is shown in Formula I:

[0010]

[0011] In Formula I, R1 and R2 are independently selected from any one of substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 arylalkyl, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 cycloalkylalkyl, substituted or unsubstituted C2-C12 heterocyclyl, substituted or unsubstituted C2-C12 heterocyclylalkyl, substituted or unsubstituted C4-C12 heteroaryl, and substituted or unsubstituted C4-C12 heteroarylalkyl.

[0012] The compound with the above-mentioned specific structure can effectively inhibit the proliferation of prostate cancer cells and has the advantage of being more active than the compounds in the prior art.

[0013] Preferably, the substituted substituents include any one of halogen, nitro, carboxyl, cyano, hydroxyl, aldehyde, amino, C1-C12 alkyl ester group, at least one halogen-substituted C1-C12 alkyl ester group, C1-C12 alkyl sulfone group, at least one halogen-substituted C1-C12 alkyl sulfone group, C1-C12 alkyl, at least one halogen-substituted C1-C12 alkyl, C1-C12 alkoxy group, at least one halogen-substituted C1-C12 alkoxy group, C3-C12 cycloalkyl group, and at least one halogen-substituted C3-C12 cycloalkyl group.

[0014] The term "substituted" means that one or more hydrogens on one or more designated atoms are replaced with the selection of the indicated group, provided that the normal valency of the designated atom under the existing circumstances is not exceeded and that the substitution results in a stable compound.

[0015] In the present invention, halogen includes fluorine, chlorine, bromine and iodine.

[0016] In the present invention, C1-C12 alkyl refers to a branched or unbranched chain alkyl group having 1 to 12 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0017] In the present invention, the C1-C12 alkoxy group may be a C1, C2, C3, C4, C5 or C6 alkoxy group, for example, a methoxy group, an ethoxy group, a butoxy group, a hexyloxy group, and the like.

[0018] In the present invention, C3-C12 cycloalkyl refers to a saturated cyclic hydrocarbon having 3-12 carbon atoms, including but not limited to cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0019] In the present invention, C1-C12 alkylsulfone refers to -SO2-C1-C12 alkyl, and C1-C12 alkyl is as defined above.

[0020] In the present invention, C1-C12 alkyl ester group refers to -COO-C1-C12 alkyl, and C1-C12 alkyl is as defined above.

[0021] In the present invention, the heterocyclic group includes but is not limited to piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrothiophenyl, dioxanyl, azetidinyl, acridinyl, oxirane, oxirane or thiirane, etc.

[0022] In the present invention, the heteroaryl group includes but is not limited to imidazolyl, triazolyl, pyrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, piperazinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1,3-dioxolane, isoquinolinyl, indolyl, 1H-indazolyl, 1H-benzo[d]imidazolyl, 1H-indolyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl, H-pyrazol-3(H)-one, etc.

[0023] Preferably, R1 is selected from any one of a substituted or unsubstituted C6-C12 aryl group and a substituted or unsubstituted C6-C12 arylalkyl group.

[0024] Preferably, R1 is selected from any one of substituted or unsubstituted phenyl and substituted or unsubstituted benzyl.

[0025] Preferably, R2 is selected from any one of substituted or unsubstituted phenyl, substituted or unsubstituted phenylalkyl, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 cycloalkylalkyl, substituted or unsubstituted C4-C12 heteroaryl, and substituted or unsubstituted C4-C12 heteroarylalkyl.

[0026] Preferably, the triazine ketone compound is selected from any one of the following structures:

[0027]

[0028]

[0029] In a second aspect, the present invention provides a pharmaceutical composition comprising at least one triazine one compound as described above or a pharmaceutically acceptable salt isomer, racemate, prodrug co-crystallized complex, hydrate or solvate thereof.

[0030] The present invention can synthesize pharmaceutically acceptable salts of the present invention from the compounds of this invention containing basic part or acidic part by conventional chemical methods.Usually, by reacting the salt of basic compound with suitable inorganic or organic acid in a suitable solvent or a combination of multiple solvents.Similarly, by reacting the salt of acidic compound with suitable inorganic or organic base.Therefore, the pharmaceutically acceptable salt of the compounds of this invention comprises the conventional non-toxic salt of the compounds of this invention formed by alkaline compounds of this invention and inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid) or organic acid (such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid) reaction.

[0031] The drugs prepared from the triazinone compounds of the present invention, as well as the pharmaceutical compositions, can be applied to various routes of administration. Typical but non-limiting examples of such routes of administration include oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal, via lumbar puncture, transurethral, ​​transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, and surgical implantation).

[0032] The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres or aerosols, etc.

[0033] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0034] Oral pharmaceutical compositions can be solid, gel, or liquid. Examples of solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, and flavoring agents. Examples of binders include, but are not limited to, microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, and stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, and dicalcium phosphate; examples of glidants include, but are not limited to, silicon dioxide; and examples of disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, and carboxymethylcellulose. Parenteral administration of the pharmaceutical compositions of the present invention is generally by injection, including subcutaneous, intramuscular, or intravenous injection. Injections can be prepared in any conventional form, such as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to injection, or emulsions. Examples of pharmaceutically acceptable carriers that can be used in the injections of the present invention include, but are not limited to, aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifiers, chelating agents, and other pharmaceutically acceptable substances. Examples of aqueous carriers include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection; examples of non-aqueous carriers include plant-derived fixed oils, cottonseed oil, corn oil, sesame oil, and peanut oil; examples of antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.; examples of isotonic agents include sodium chloride and dextrose; and buffers include phosphates and citrates.

[0035] The pharmaceutical composition of the present invention can also be prepared as a sterile lyophilized powder injection by dissolving the compound in a sodium phosphate buffer solution containing glucose or other suitable excipients, then sterile filtering the solution under standard conditions known to those skilled in the art, followed by freeze-drying to obtain the desired preparation.

[0036] In a second aspect, the present invention further provides a use of the triazine ketone compound or the pharmaceutical composition as described above in the preparation of a medicament for treating cancer, cell proliferative disorders, inflammation, autoimmune diseases, sepsis, viral infections or neurodegenerative diseases.

[0037] In the present invention, the tumor includes all tumors that exceed the normal tissue proliferation rate, including malignant tumors and tumors or cysts, polyps, nodules, etc. with a malignant development trend.

[0038] Preferably, the cancer comprises prostate cancer.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] The present invention provides a triazine ketone compound with a specific structure, which can effectively inhibit the proliferation of prostate cancer cells and has the advantage of higher activity than existing compounds. DETAILED DESCRIPTION

[0041] In order to further illustrate the technical means and effects adopted by the present invention, the technical solutions of the present invention are further described below in conjunction with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0042] Unless otherwise stated, the present invention uses traditional methods such as nuclear magnetic resonance to identify compounds, and each step and condition can refer to the conventional operating steps and conditions in the field. The solvents used in the nuclear magnetic resonance data include CDCl3, DMSO-d6, etc., with tetramethylsilane (0.00ppm) or the residual solvent peak as the benchmark (CDCl3: 7.26ppm, DMSO-d6: 2.50ppm). When annotating peak type diversity, the following abbreviations represent different peak types: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet), td (triplet doublet). The coupling constants given are in Hertz (Hz).

[0043] The present invention provides a representative synthesis route of the compound of formula I. The triazine ketone compound has a structure as shown in formula I, and the preparation method is route 1.

[0044] Route 1 is as follows:

[0045]

[0046] The reagents added in each step and the reaction conditions are as follows: (a) HCl, ethanol, 0°C, 24 hours; (b) (i) sodium bicarbonate, ether, 20°C, 15 minutes; (ii) dichloromethane, glycine ethyl ester hydrochloride, 20°C, overnight; (c) hydrazine hydrate, ethanol, 20°C, overnight; (d) sodium hydride, N,N-dimethylformamide (DMF), R2X (X is a halogen), 20°C, overnight; (e) 2,3-dichloro-5,6-cyanoquinone (DDQ), acetonitrile, 120°C, 45 minutes.

[0047] Example 1 Synthesis of 3-benzyl-1-(3,4-dichlorophenyl)-1,2,4-triazine-6(1H)-one

[0048] Step 1, 2-phenylacetimidic acid ethyl ester hydrochloride

[0049]

[0050] Benzyl cyanide (27.75 g, 0.237 mol) and ethanol (12 mL) were added to a three-necked round-bottom flask and sealed with a rubber septum. The reaction system was stirred under an ice bath and cooled to 0°C. HCl gas was introduced into the solution and bubbled for three hours. The reaction mixture was stored in a refrigerator for 24 hours. Afterwards, the mixture was heated to 20°C and ether (150 mL) was added, and the resulting white precipitate was collected by filtration. The collected precipitate was washed with ether to obtain a white solid (26 g, 0.130 mol, yield: 55%). 1 H NMR (500MHz, CDCl3) 12.71 (brs, 1H), 11.69 (brs, 1H), 7.46-7.42 (m, 2H), 7.38-7.31 (m, 3H), 4.62 (q, J = 7.0Hz, 2H), 4.04 (s, 2H), 1.44 (t, J = 7.0Hz, 3H).

[0051] Step 2, ethyl (Z)-2-((1-ethoxy-2-phenylethylidene)amino)acetate

[0052]

[0053] Saturated sodium bicarbonate solution (100 mL) was added to an ether (150 mL) solution containing ethyl 2-phenylacetimidate hydrochloride (8 g, 0.04 mol), and the reaction mixture was stirred at 20° C. for 15 minutes. The organic layer in the reaction system was dried over magnesium sulfate and concentrated under vacuum. The remaining residue was diluted with dichloromethane (80 mL) and glycine ethyl ester hydrochloride (5.6 g, 0.04 mol) was added. After stirring overnight at 20° C., the white suspension was diluted with ether and water. The organic phase was then dried and the solvent was removed. The residue was purified by silica gel column chromatography to obtain a reddish-brown, transparent, viscous oily compound (6.58 g, yield: 66%). 1 H NMR(400MHz, CDCl3)7.34-7.27(m,2H),7.25-7.19(m,3H),4.17(q,J=7.1Hz,2H),4.16( q,J=7.2Hz,2H),4.09(s,2H),3.59(s,2H),1.27(t,J=7.1Hz,3H),1.25(t,J=7.2Hz,3H).

[0054] Step 3, 3-benzyl-4,5-dihydro-1,2,4-triazine-6(1H)-one

[0055]

[0056] Compound (Z)-2-((1-ethoxy-2-phenylethylidene)amino)acetic acid ethyl ester (6.6 g, 26.50 mmol) was dissolved in ethanol (12 mL) and stirred in an ice bath. Hydrazine hydrate (1.6 g) was added dropwise to the reaction solution through a dropping funnel, and the reaction mixture was stirred at 20°C overnight. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (120 mL) and washed with water (2×30 mL). The organic phase was dried over magnesium sulfate and dried under reduced pressure. The remaining residue was recrystallized from a mixed solution of methanol, dichloromethane and petroleum ether to obtain a white solid (3.6 g, yield: 71%). 1 H NMR (400MHz; DMSO-d6) 10.00 (s, 1H), 7.31-7.19 (m, 5H), 6.89 (s, 1H), 3.64 (d, J = 1.2Hz, 2H), 3.34 (s, 2H).

[0057] Step 4: 3-Benzyl-1-(3,4-dichlorophenyl)-4,5-dihydro-1,2,4-triazine-6(1H)-one

[0058]

[0059] The compound 3-benzyl-4,5-dihydro-1,2,4-triazine-6(1H)-one (500mg, 2.64mmol) was dissolved in DMF (2mL), and a suspension of NaH (112mg, 2.78mmol) dissolved in dry DMF (5mL) was added dropwise in an ice bath. The reaction mixture was then stirred at 20°C for 1 hour. The reaction flask was cooled in an ice bath, and a solution of 4-(bromomethyl)-1,2-dichlorobenzene (635mg, 2.645mmol) dissolved in DMF (2mL) was added dropwise. The reaction mixture was stirred at 20°C overnight. The mixture was partitioned into ethyl acetate and an aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with brine, dried over magnesium sulfate, and dried under reduced pressure. The residue was purified by silica gel column chromatography to obtain a white solid compound 3-benzyl-1-(3,4-dichlorophenyl)-4,5-dihydro-1,2,4-triazine-6(1H)-one (400 mg, yield: 44%). 1 H NMR (400MHz, CDCl3) 7.50 (d, J = 2.0 Hz, 1H), 7.41-7.27 (m, 4H), 7.25-7.20 (m, 3H), 4.81 (s, 2H), 4.37 (brs, 1H), 3.88 (d, J = 1.4Hz, 2H), 3.51 (s, 2H).

[0060] Step 5, 3-benzyl-1-(3,4-dichlorophenyl)-1,2,4-triazine-6(1H)-one

[0061]

[0062] A mixture of compound 7 (250 mg, 0.72 mmol), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ, 276 mg, 1.21 mmol) and acetonitrile (10 mL) was flushed with nitrogen in a microwave reactor tube. The test tube was sealed and the mixture was heated to 120 ° C in a microwave apparatus for 45 minutes. The reaction mixture was then cooled to 20 ° C and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with saturated sodium carbonate solution (2×30 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain a white solid (130 mg, 52% yield). 1 H NMR (400MHz, CDCl3) 8.32 (s, 1H), 7.54 (d, J = 2.0Hz, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.35-7.24 (m, 6H), 4.81 (s, 2H), 5.12 (s, 2H), 4.03 (s, 2H).

[0063] Example 2 1-(2-chlorobenzyl)-3-phenyl-1,2,4-triazine-6(1H)-one

[0064]

[0065] The synthesis method is as follows: Reference Example 1, light yellow solid, yield: 55%. 1 H NMR (500MHz, CDCl3)8.51(s,1H),8.12-8.07(m,2H),7.45-7.41(m,4H),7.35-7.32(m,1H),7.29–7.22(m,2H),5.47(s,2H).

[0066] Example 3 1-(Cyclopentyl)-3-phenyl-1,2,4-triazine-6(1H)-one

[0067]

[0068] The synthesis method is as follows: Reference Example 1, light yellow solid, yield: 50%. 1 H NMR(500MHz, CDCl3)8.41(s,1H),8.17-8.10(m,2H),7.51-7.41(m,3H),5. 39-5.32(m,1H),2.17-2.07(m,2H),2.05-1.92(m,4H),1.79-1.69(m,2H).

[0069] Example 4 1-(4-chlorobenzyl)-3-phenyl-1,2,4-triazine-6(1H)-one

[0070]

[0071] Synthesis method: refer to Example 1, white solid, yield: 43%. White solid. 1 H NMR (400MHz, CDCl3)8.48(s,1H),8.16-8.11(m,2H),7.49-7.44(m,5H),7.35-7.31(m,2H),5.27(s,2H).

[0072] Example 5 3-phenyl-1-(3-trifluoromethylbenzyl)-1,2,4-triazine-6(1H)-one

[0073]

[0074] The synthesis method is as follows: Reference Example 1, brown solid, yield: 36%. 1H NMR(400MHz, CDCl3)8.50(s,1H),8.17-8.11(m,2H),7.79(s,1H),7.70(d,J=7.7Hz ,1H),7.60(d,J=7.7Hz,1H),7.50(d,J=7.7Hz,1H),7.49-7.45(m,3H),5.35(s,2H).

[0075] Example 6 1-(3-chlorobenzyl)-3-(3-chlorophenyl)-1,2,4-triazine-6(1H)-one

[0076]

[0077] The synthesis method is as follows: Reference Example 1, white solid, yield: 51%. 1 H NMR (400MHz, CDCl3)8.48(s,1H),8.14(t,J=1.9Hz,1H),8.03(dt,J=7.3,1.6H z,1H),7.50-7.48(m,1H),7.45-7.37(m,3H),7.33–7.29(m,2H),5.27(s,2H).

[0078] Example 7 3-(3-bromophenyl)-1-(3-chlorobenzyl)-1,2,4-triazine-6(1H)-one

[0079]

[0080] The synthesis method is as follows: Reference Example 1, white solid, yield: 56%. 1 H NMR(400MHz, CDCl3)8.48(s,1H),8.29(t,J=1.8Hz,1H),8.07(dt,J=7.9,1.2H z,1H),7.61-7.57(m,1H),7.50-7.47(m,1H),7.40–7.29(m,4H),5.27(s,2H).

[0081] Example 8 1-(2,4-dichlorophenyl)-3-(3-methoxyphenyl)-1,2,4-triazine-6(1H)-one

[0082]

[0083] The synthesis method is as follows: Reference Example 1, yellow solid, yield: 11%. 1H NMR (400MHz, CDCl3)8.50(s,1H),7.69(ddd,J=7.7,1.6,1.0Hz,1H),7.62(dd,J=2.5,1.6Hz,1H),7.45(d,J=2.1Hz,1H),7.36(d ,J=8.0Hz,1H),7.32(d,J=7.9Hz,1H),7.24(dd,J=8.3,2.1Hz,1H),6.99(ddd,J=8.3,2.6,1.0Hz,1H),5.42(s,2H),3.85(s,3H).

[0084] Example 9 1-(4-methoxybenzyl)-3-(3-methoxyphenyl)-1,2,4-triazine-6(1H)-one

[0085]

[0086] The synthesis method is as follows: Reference Example 1, yellow solid, yield: 11%. 1 H NMR(500MHz, CDCl3)8.44(s,1H),7.76-7.72(m,1H),7.68(dd,J=2.4,1.6Hz,1H),7.48-7.44(m,2H),7.37(t ,J=8.0Hz,1H),7.00(ddd,J=8.2,2.6,0.7Hz,1H),6.89-6.86(m,2H),5.24(s,2H),3.88(s,3H),3.78(s,3H).

[0087] Example 10 1-(6-chloropyridin-3-ylmethyl)-3-phenyl-1,2,4-triazine-6(1H)-one

[0088]

[0089] The synthesis method is as follows: Reference Example 1, brown solid, yield: 30%. 1 H NMR(400MHz, CDCl3)8.59(d,J=2.5Hz,1H),8.49(s,1H),8.14-8.09(m,2H),7.8 4(dd,J=8.2,2.5Hz,1H),7.50-7.44(m,3H),7.33(d,J=8.2Hz,1H),5.29(s,2H).

[0090] Example 11 1-(2-Methylthiazol-4-ylmethyl)-3-phenyl-1,2,4-triazine-6(1H)-one

[0091]

[0092] The synthesis method is as follows: Reference Example 1, white solid, yield: 36%. 1 H NMR (400MHz, CDCl3)8.50(s,1H),8.17-8.11(m,2H),7.47-7.42(m,3H),7.16(s,1H),5.41(s,2H),2.68(s,3H).

[0093] Example 12 1-(Isopropyl)-3-phenyl-1,2,4-triazine-6(1H)-one

[0094]

[0095] The synthesis method is as follows: Reference Example 1, white solid, yield: 46%. 1 H NMR (400MHz, CDCl3) 8.45 (s, 1H), 8.20-8.14 (m, 2H), 7.51-7.44 (m, 3H), 5.23 (septet, J = 6.7Hz, 1H), 1.46 (d, J = 6.7Hz, 6H).

[0096] Example 13 1-(Isopentyl)-3-phenyl-1,2,4-triazine-6(1H)-one

[0097]

[0098] The synthesis method is as follows: Reference Example 1, white solid, yield: 41%. 1 H NMR(400MHz, CDCl3)8.45(s,1H),8.17-8.12(m,2H),7.50-7.44(m,3H),4.22-4. 17(m,2H),1.80-1.74(m,2H),1.68(septet,J=6.6Hz,1H),1.00(d,J=6.5Hz,6H).

[0099] Example 14 1-(3-cyanopropan-1-yl)-3-phenyl-1,2,4-triazine-6(1H)-one

[0100]

[0101] The synthesis method is as follows: Reference Example 1, yellow solid, yield: 41%. 1 H NMR (400MHz, CDCl3) 8.50 (s, 1H), 8.18-8.13 (m, 2H), 7.51-7.46 (m, 3H), 4.32 (t, J = 6.7Hz, 2H), 2.51 (t, J = 7.2Hz, 2H), 2.28 (quintet, J = 7.0Hz, 6H).

[0102] Example 15 1,3-Dibenzyl-1,2,4-triazine-6(1H)-one

[0103]

[0104] The synthesis method is as follows: Example 1, yellow solid, yield: 30%. 1 H NMR (400MHz, CDCl3)8.33(s,1H),7.49-7.45(m,2H),7.41-7.26(m,8H),5.22(s,2H),4.06(s,2H).

[0105] Example 16 3-Benzyl-1-(3-trifluoromethylbenzyl)-1,2,4-triazine-6(1H)-one

[0106]

[0107] The synthesis method is as follows: Reference Example 1, white solid, yield: 19%. 1 H NMR(400MHz, CDCl3)8.32(s,1H),7.71(s,1H),7.63(d,J=7.7Hz,1H),7.59(d,J= 7.9Hz,1H),7.47(t,J=7.8Hz,1H),7.33-7.24(m,5H),5.23(s,2H),4.00(s,2H).

[0108] Example 17 3-Benzyl-1-(2,4-dichlorobenzyl)-1,2,4-triazine-6(1H)-one

[0109]

[0110] The synthesis method is as follows: Example 1, with a yield of 39%. 1 H NMR (400MHz, CDCl3) 8.35 (s, 1H), 7.43 (d, J = 2.0Hz, 1H), 7.33-7.16 (m, 7H), 5.30 (s, 2H), 4.00 (s, 2H).

[0111] Example 18 1,3-Diphenyl-1,2,4-triazine-6(1H)-one

[0112]

[0113] The synthesis method is the same as Example 1, yellow solid, yield: 42%. 1H NMR (400MHz, CDCl3)8.61(s,1H),8.24-8.20(m,2H),7.88-7.84(m,2H),7.56-7.51(m,2H),7.50-7.43(m,2H).

[0114] Example 19 1-(4-chlorophenyl)-3-phenyl-1,2,4-triazine-6(1H)-one

[0115]

[0116] The synthesis method is the same as Example 1, yellow solid, yield: 42%. 1 H NMR (400MHz, CDCl3)8.61(s,1H),8.23-8.18(m,2H),7.89-7.84(m,2H),7.52-7.47(m,5H).

[0117] Example 20 3-Benzyl-1-(cyclohexylmethyl)-1,2,4-triazine-6(1H)-one

[0118]

[0119] The synthesis method is as follows: Reference Example 1, white solid, yield: 55%. 1 H NMR(400MHz, CDCl3)8.30(s,1H),7.35-7.23(m,5H),4.03(s,2H),3.90(d,J=7.4Hz ,2H),2.02-1.90(m,1H),1.78-1.60(m,5H),1.30-1.14(m,3H),1.12-0.98(m,2H).

[0120] Example 21 3-Benzyl-1-(cyclopropylmethyl)-1,2,4-triazine-6(1H)-one

[0121]

[0122] The synthesis method is as follows: Reference Example 1, white solid, yield: 64%. 1 H NMR (400MHz, CDCl3) 8.31 (s, 1H), 7.36-7.23 (m, 5H), 4.04 (s, 2H), 3.91 (d, J = 7.3Hz, 2H), 1.40-1.29 (m, 1H), 0.59-0.52 (m, 2H), 0.46-0.41 (m, 2H).

[0123] Effect test:

[0124] The compounds obtained in Examples 1-21 were tested for their inhibitory effects on 22Rv1 cells (ARv7-positive CRPC cell line) and PC3 cells (AR-independent prostate cancer cell line). The purpose was to distinguish the differences in the activities of these compounds on AR-dependent prostate cancer cells and AR-independent prostate cancer cells.

[0125] Materials: EnSpire Alpha 2390 Multi-Purpose Microplate Reader (Perkin Elmer); 384-well clear-bottom microplate; Cell-Titer GLO Luminescent Reagent; prostate cancer cell lines 22Rv1 and PC3; culture medium and fetal bovine serum. Positive drug: Enzalutamide.

[0126] Experimental method: 500-1000 cells / well of the test cells in 20 μL of medium were plated in a 384-well transparent microplate (the actual number of cells selected is related to the cell cycle and the volume of the cells themselves). After 12 hours, 10 μL of culture medium containing the compound (compound concentration ranges from 5nM to 100nM) was added to each well. After incubation with the compound for 72 hours, Cell-TiterGLO reagent was added to each well and the plate was shaken for 20 minutes to lyse the cells. After incubation for 10 minutes, centrifugation was performed for 1 minute, and the luminescence 384 signal value was measured. GraphPad Prism software was used to fit the inhibition curve and calculate the IC 50 .

[0127] Experimental results: The anti-proliferative activities of the compounds prepared in Examples 1-21 of the present application on 22Rv1 cells and PC3 cells are shown in Table 1.

[0128] Table 1 Antiproliferative activity of the compounds prepared in Examples 1-21 on 22Rv1 cells and PC3 cells

[0129]

[0130] Note: “A” refers to IC 50 <1μM, "B" refers to 1μM ≤ IC 50 <5μM, "C" refers to 5μM ≤ IC 50 .

[0131] It can be found that the compounds provided by the present invention can effectively inhibit the proliferation of 22Rv1 cells and PC3 cells, and compared with the positive drug Enzalutamide, IC 50 Significantly decreased, with more effective inhibitory effect.

[0132] The applicant declares that while the above-described embodiments illustrate the triazinone compounds and their applications, the present invention is not limited to these embodiments, nor does it necessarily rely on these embodiments for implementation. Those skilled in the art will appreciate that any improvements to the present invention, equivalent substitutions for raw materials in the products of the present invention, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

[0133] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0134] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A triazine ketone compound, characterized in that The triazine ketone compound is selected from any one of the following structures:

2. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises at least one triazineone compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of the triazine ketone compound according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a drug for treating prostate cancer.

4. Use of a triazine ketone compound in the preparation of a drug for treating prostate cancer, characterized in that: The triazine ketone compound has a structure shown in the following formula I: In formula I, R1 is selected from substituted or unsubstituted phenyl or benzyl, and the substituent is halogen or C1-C12 alkoxy; R2 is selected from any one of substituted or unsubstituted phenyl, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C4-C12 heteroaryl, and the substituent is any one of halogen, cyano, C1-C12 alkyl substituted with at least one halogen, or C1-C12 alkoxy.

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