A nitrile compound, a preparation method and application thereof

Abstract

The present application relates to a kind of nitrile compounds and its preparation method and application.The general formula of the compound described in the present application is wherein, independently selected from substituted or unsubstituted aryl or heteroaryl.And the nitrile compound is used in eEF2K inhibitor and / or degrader, further be used in the preparation of tumor or neuropsychiatric disease drug.The nitrile compound described in the present application shows strong anti-malignant tumor cell activity by targeting eEF2K protein, and the influence on normal cell activity is less, shows strong anti-tumor potential, higher safety, thus extremely with application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a nitrile compound or its isomer, its preparation method, and its use in the prevention and / or treatment of malignant tumors associated with eEF2K. Background Technology

[0002] Currently used antitumor drugs include bioalkylating agents, antimetabolites, antibiotics, natural products and their derivatives, and protein tyrosine kinase inhibitors. However, these antitumor drugs have many drawbacks. For example, bioalkylating agents, while inhibiting tumor cells, also inhibit other rapidly proliferating cells, and these compounds are prone to drug resistance; antimetabolites have a narrow antitumor spectrum; antibiotics have high myelosuppressive toxicity; and natural products are limited in source and difficult to synthesize. Therefore, there is an urgent need to develop antitumor drugs with low toxicity, high activity, and simple sources.

[0003] Eukaryotic elongation factor 2 kinase (eEF2K), a member of the α-kinase family of atypical kinases, is a calcium / calmodulin-dependent kinase with a unique structure and function. In the human body, it participates in calmodulin-mediated signaling pathways, catalyzing phosphorylation at the Thr56 site of eukaryotic elongation factor-2 (eEF2) and leading to its inactivation, thereby inhibiting the process of mRNA translation into protein peptide chain elongation.

[0004] eEF2K is highly expressed in various malignant tumor cells, such as lung cancer, colon cancer, breast cancer, and esophageal cancer. When normal tissues encounter nutrient deficiency, mTORC and Erk are inhibited, the AMP / ATP ratio increases, thereby activating eEF2K to phosphorylate eEF2 and inhibit protein synthesis, promoting autophagy, reducing the need of tumor cells for nutrients from the peripheral environment, and ultimately improving the survival rate of tumor cells. Conversely, when eEF2K is inhibited, the growth of tumor cells will be suppressed (Lung Cancer, 2018, 124, 31-39; Oncotarget, 2017, 8, 11641-11658; Radiother Oncol. 2017, 124, 439-447; Apoptosis. 2014, 19, 241-258; Cell, 2013, 153, 1064-1079).

[0005] In summary, eEF2K is a very promising target for the treatment of malignant tumors, and small molecule compounds targeting the eEF2K protein may alleviate or treat malignant tumors (such as triple-negative breast cancer).

[0006] Currently, various small molecule compounds targeting eEF2K have been discovered, including inhibitors and protein degradation-targeting conjugates (PROTACs) (Int. J. Mol. Sci. 2021, 22, 2408), such as the selective eEF2K inhibitor A-484954 developed by Abbott, which inhibits eEF2K (IC50) by competing with ATP for binding to eEF2K. 50 =0.28μM), but cell viability was weak (IC50 = 0.28μM). 50 >20 μM)(J. Biol. Chem. 2011, 286, 43951-44398; Bioorg. Med. Chem. 2014, 22, 4910-4916). Furthermore, the PROTAC derivative of A-484954 was found to have a maximum eEF2K degradation rate (Dr) of only 56.7%, therefore these compounds are currently used only as pharmacological tool drugs. Summary of the Invention

[0007] Therefore, the technical problem to be solved by the present invention is to overcome the shortcomings of existing eEF2K small molecule inhibitors, such as weak cell inhibitory activity or low degradation rate.

[0008] To address the aforementioned technical problems, this invention provides a nitrile compound, its pharmaceutically acceptable salt or hydrate, and its eEF2K-related anti-tumor applications.

[0009] The first object of the present invention is to provide a 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile compound, the general formula of which is shown in Formula A:

[0010] in, It is independently selected from substituted or unsubstituted aryl or heteroaryl groups.

[0011] In one embodiment of the present invention, the aryl or heteroaryl group is a substituted or unsubstituted benzene ring, naphthyl ring, biphenyl ring, or an aromatic heterocycle composed of one or more N, O, and S groups; further, it includes pyrrole ring, pyrazole ring, thiazole ring, oxazole ring, pyridine ring, etc.; the substituent group in the substituted or unsubstituted aryl or heteroaryl group is selected from one or more of hydrogen, alkyl, aralkyl, heteroaryl, alkoxy, halogen, cyano, acyloxy, carbamoyl, acyl, and sulfonyl groups.

[0012] Furthermore, the aforementioned It is phenyl, 3-methylphenyl, 4-methylphenyl, or 3,4-dimethylphenyl. 3,4-dimethylphenyl is more preferred.

[0013] Furthermore, the aforementioned Preferably, it is 3-fluorophenyl, 3-trifluoromethylphenyl, or 3-methylphenylphenyl.

[0014] In one embodiment of the present invention, the 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile compound is 1-(4-benzyl-2-(3,4-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-cyano, 2-(3,4-dimethylphenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile, 2-(3,4-dimethylphenyl)-4-(3-fluorobenzyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile, 2-(3,4-dimethylphenyl)-4-(4-methylbenzyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxynitrile, or 2-(3,4-dimethylphenyl)-4-(4-methylbenzyl)-3,5-dioxo-2,3,4,5-triazine-6-carboxynitrile. 4,5-Tetrahydro-1,2,4-triazine-6-carboxylonitrile, 2-(3,4-dimethylphenyl)-4-(2-methylbenzyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 2-(3,4-dimethylphenyl)-3,5-dioxo-4-(3-trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 2-(3,4-dimethylphenyl)-3,5-dioxo-4-propyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 4-ethyl-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 4-methyl-3,5-dioxo-2- Phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 4-benzyl-3,5-dioxo-2-pyridine-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 4-benzyl-2-naphthyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 2-(3,4-dimethylphenyl)-3,5-dioxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 2-(1,1'-biphenyl)-4-yl)-4-benzyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 4-benzyl-2-(4-methylsulfonyl)phenyl-3, 5-Dioxo-2,3,4,5-Tetrahydro-1,2,4-triazine-6-carboxylonitrile, 4-benzyl-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 2-(3,4-dimethylphenyl)-4-naphth-2-ylmethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 2-(3,4-dimethylphenyl)-4-(3-methylsulfonyl)benzyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 4-benzyl-3,5-dioxo-2-p-tolyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylonitrile, 4-benzyl-3,5-Dioxo-2-m-Tolyl-2,3,4,5-Tetrahydro-1,2,4-Triazine-6-carboxylonitrile or 4-Benzyl-2-(4-methoxyphenyl)-3,5-dioxo-2,3,4,5-Tetrahydro-1,2,4-Triazine-6-carboxylonitrile.

[0015] In one embodiment of the present invention, the It is phenyl, 3-methylphenyl, 4-methylphenyl or 3,4-dimethylphenyl.

[0016] In one embodiment of the invention, the pharmaceutically acceptable salt is selected from at least one of inorganic acid salts, organic acid salts, alkyl sulfonates, and aryl sulfonates.

[0017] A second objective of this invention is to provide a method for preparing 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile compounds, comprising the following steps:

[0018] (1) The compound shown in formula A1 is reacted with the compound shown in formula A2 by diazotization coupling reaction to obtain the compound shown in formula A3;

[0019] (2) The compound shown in formula A3 undergoes cyclization under acidic conditions to yield the compound shown in formula A4. The compound shown in formula A4 reacts with a haloalkane under alkaline conditions. A substitution reaction yields the compound shown in Formula A, i.e., the nitrile compound, wherein the structural formulas of the compounds shown in Formulas A1-A4 and Formula A are as follows:

[0020]

[0021] It is independently selected from substituted or unsubstituted aryl or heteroaryl groups. Further, it is preferably phenyl, 3,4-dimethylphenyl, pyridyl, biphenyl, or naphthalene ring.

[0022] Furthermore, the halohydrocarbon The halogen X can be F, Cl, Br, or I; Br is preferred.

[0023] Furthermore, in step (1), the molar ratio of the compound shown in formula A1 to the compound shown in formula A2 is 1:1 to 1:2.

[0024] Furthermore, in step (2), the pH value of acidic conditions is 1-4; the pH value of alkaline conditions is 8-10.

[0025] Furthermore, the preparation method of the 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile compound is as follows:

[0026] Step 1: Dissolve the amine compound A1 containing the substituent in a mixture of concentrated hydrochloric acid and water, and add a diazotizing reagent solution under ice bath conditions; after 0.5 to 1 h, add an aqueous solution of N-cyanourea A2 and sodium acetate to the reaction solution, and after the reaction is complete, obtain compound A3.

[0027] Step 2: Dissolve compound A3 and base in acid and reflux at high temperature to induce a ring-closing reaction. After the reaction is complete, compound A4 is obtained.

[0028] Step 3: Compound A4 is dissolved in an organic solvent, and a substitution reaction occurs under alkaline conditions to yield compound A5. See the reaction flowchart below. Figure 2 As shown.

[0029] In one embodiment of the present invention, in step 1, the diazotizing reagent in the diazotizing reagent solution is selected from one or more of sodium nitrite, tert-butyl nitrite, isoamyl nitrite, nitrososulfuric acid, and nitrosotetrafluoroborate.

[0030] Furthermore, the reagent in the diazotizing reagent solution is one or more of water, sulfuric acid, hydrochloric acid, hydrobromic acid, glacial acetic acid, acetone, tetrahydrofuran, and toluene.

[0031] In one embodiment of the present invention, in step 1, the reaction conditions are: reaction temperature -5℃ to 10℃, and reaction time 2h to 6h.

[0032] In one embodiment of the present invention, in step 2, the conditions for the ring-closing reaction are: reaction temperature of 100℃~110℃ and reaction time of 3h~10h.

[0033] In one embodiment of the present invention, in step 2, the alkali is selected from one or more of sodium acetate, potassium carbonate, potassium acetate, sodium carbonate, triethylamine, and DIPEA.

[0034] In one embodiment of the present invention, in step 2, the acid is selected from one or more of glacial acetic acid, formic acid, methanesulfonic acid, and trifluoroacetic acid.

[0035] In one embodiment of the present invention, in step 3, the reaction temperature is 10°C to 40°C and the reaction time is 10h to 16h.

[0036] In one embodiment of the present invention, in step 3, the organic solvent is selected from one or more of acetonitrile, acetone, DMF, tetrahydrofuran, ethanol and DMSO.

[0037] In one embodiment of the present invention, in step 3, the pH value of the alkaline condition is 7-11.

[0038] A third object of the present invention is to provide the use of the aforementioned 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile compounds and their isomers or pharmaceutically acceptable salts or hydrates in the preparation of eEF2K inhibitors and / or degrading agents.

[0039] A fourth object of the present invention is to provide the use of the 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile compounds and their isomers or pharmaceutically acceptable salts or hydrates in the preparation of medicaments for oncological or neuropsychiatric diseases.

[0040] In one embodiment of the present invention, the tumor is triple-negative breast cancer, lung cancer, colon cancer, or breast cancer and esophageal cancer.

[0041] In one embodiment of the present invention, the neuropsychiatric disease is epilepsy, depression, anti-Parkinson's disease, Alzheimer's disease, and related dementia.

[0042] The technical solution of the present invention has the following advantages compared with the prior art:

[0043] This invention designs nitrile compounds with the general formula A and discovers that compounds with this structure exhibit excellent selectivity and inhibitory effects on eEF2K. This invention reveals and elucidates the relationship between the structure and activity of nitrile compounds in a broader, more in-depth, and comprehensive manner, and has significant application value. The nitrile compounds of this invention, when acting on eEF2K, can be used to treat malignant tumors (e.g., triple-negative breast cancer). Attached Figure Description

[0044] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings, wherein...

[0045] Figure 1 A diagram showing the SPR binding experiment of the representative compound Z1 with the eEF2K protein.

[0046] Figure 2 Synthesis reaction flowcharts in Examples 1, 11, 12, 14, 15, 16, 17, 18, 22, 23, and 24 of this invention.

[0047] Figure 3 A flowchart illustrating the synthesis reaction of the final product of this invention. Detailed Implementation

[0048] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0049] In the following embodiments of the present invention, the structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was performed using an Agilent 300 MHz or 600 MHz instrument, with deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3) as the solvents and tetramethylsilane (TMS) as the internal standard. MS was performed using a GCT Premier™ (CI) mass spectrometer, with CI source (70 eV) unless otherwise specified.

[0050] Thin-layer chromatography uses Yantai Huanghai HSGZ174 or Qingdao GZ174 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.2mm in size. Column chromatography generally uses Yantai Huanghai 100-200 mesh or 200-300 mesh silica gel as the carrier.

[0051] Nitrogen purging in the reaction conditions refers to connecting a nitrogen balloon with a volume of approximately 1L to the reaction flask. The reaction conditions are room temperature (rt), with a temperature range of 20℃-30℃.

[0052] In the following embodiments of the present invention, all solvents were redistilled before use, and the anhydrous solvents used were obtained by drying according to standard methods.

[0053] Example 1:

[0054] This embodiment provides the synthesis of compound Z1, as detailed below:

[0055] (1) The synthetic route of compound Z1 is as follows: Figure 2 As shown.

[0056] The reaction conditions were as follows: Step a: NaNO2, HCl, AcONa, pyridine, 0℃; Step b: AcONa, AcOH, 110℃; Step c: K2CO3, acetonitrile.

[0057] (2) Specific synthesis steps:

[0058] Step a: Synthesis of compound Z1-C

[0059] 5 g (41.26 mmol) of 3,4-dimethylaniline (Z1-A) was placed in a 250 mL round-bottom flask, and 60 mL of water and 22.5 mL of concentrated hydrochloric acid were added. The solution was cooled and stirred in an ice bath. Then, 3.94 g (57.76 mmol) of sodium nitrite was dissolved in 20 mL of water and slowly added dropwise to the previous solution, and the reaction was detected by TLC. After the 3,4-dimethylaniline reaction was complete, 50 mL of a pyridine:water mixture (1:1 volume ratio) of 6.7 g (41.26 mmol) of N-cyanoacetylurane (Z1-B) and 10 g (123.78 mmol) of sodium acetate was added to the reaction solution. After the reaction was complete, the mixture was filtered, washed three times with water, and dried to obtain 10.04 g of a yellow solid, with a yield of 84.44%. 1 H NMR (300MHz, DMSO-d6) δ11.95 (s, 1H), 10.42 (d, J = 4.5Hz, 1H), 7.50-7.35 (m, 2H), 7.11 ( d,J=7.9Hz,1H),4.15(tt,J=7.7,4.7Hz,2H),2.18(d,J=11.3Hz,6H),1.41-1.16(m,3H).

[0060] Step b: Synthesis of compound Z1-D

[0061] 10.04 g (34.82 mmol) of Z1-C and 14.28 g (174.12 mmol) of sodium acetate were placed in a 250 mL round-bottom flask and dissolved in 120 mL of glacial acetic acid. The mixture was refluxed at 110 °C. After the reaction was complete, a large amount of water was added until no more solid precipitated. The mixture was filtered, washed three times with water, and dried to give 7.8 g of a pale yellow solid, with a yield of 92.46%. 1 H NMR (300MHz, CDCl3) δ9.31 (s, 1H), 7.32 (dd, J = 10.7, 5.0Hz, 3H), 2.40 (s, 6H).

[0062] Step c: Synthesis of compound Z1

[0063] 1.68 g (6.94 mmol) of Z1-D and 1.92 g (13.87 mmol) of potassium carbonate were placed in a 250 mL round-bottom flask. 70 mL of acetonitrile was added and the mixture was stirred in an ice bath. Benzyl bromide was slowly added dropwise. After the reaction was complete, the mixture was extracted, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1 (v / v)) to give 1.99 g of a white solid, with a yield of 86.33%. 1H NMR (300MHz, CDCl3) δ7.62-7.49(m,2H),7.34(q,J=2.8Hz,3H),7.26-7.13(m,3H),5.16(s,2H),2.31(s,6H).

[0064] Example 2:

[0065] This embodiment provides the synthesis of compound Z2, as detailed below:

[0066] (1) The synthetic route of compound Z2 is as follows:

[0067]

[0068] The reaction conditions were as follows: (a) K₂CO₃, iodomethane, acetonitrile, rt; (b) HCl, glacial acetic acid, 110℃; (c) oxalyl chloride, DCM, DMF, N₂, rt; (d) ethyl 3-piperidinecarboxylate, Et₃N, DCM, 0℃.

[0069] (2) Specific synthesis steps of compound Z2:

[0070] Compound Z1-D 400 mg (1.65 mmol) and potassium carbonate 456.43 mg (3.30 mmol) were placed in a 100 mL round-bottom flask, and 20 mL of acetonitrile was added. The mixture was stirred in an ice bath, and iodomethane was slowly added dropwise. After the reaction was complete, the mixture was extracted, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1 (v / v)) to give 220 mg of a white solid, with a yield of 51.99%.

[0071] Example 3:

[0072] This embodiment provides the synthesis of compound Z3, as detailed below:

[0073] (1) The synthetic route of compound Z3 is as follows:

[0074]

[0075] The reaction conditions are as follows: Step a: K2CO3, acetonitrile, and 3-fluorobenzyl bromide.

[0076] (2) Synthesis of compound Z3

[0077] 1.68 g (6.94 mmol) of compound Z1-D and 1.92 g (13.87 mmol) of potassium carbonate were placed in a 250 mL round-bottom flask. 70 mL of acetonitrile was added and the mixture was stirred in an ice bath. 3-fluorobenzyl bromide was slowly added dropwise. After the reaction was complete, the mixture was extracted, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1 (v / v)) to give 1.90 g of a white solid, yield 78.20%. 1 H NMR (500MHz, CDCl3) δ7.59(dd,J=7.9,2.2Hz,1H),7.41(d,J=2.1Hz,1H),7.34(td,J=8.0,5.0Hz,1H),7.17(dq,J=8.0,1.1Hz,1H),7 .12(dddt,J=8.0,4.2,2.2,0.9Hz,2H),7.03(tdd,J=7.9,2.0,1.3Hz,1H),5.07(t,J=1.0Hz,2H),2.28(d,J=1.1Hz,3H),2.23(s,3H).

[0078] Example 4:

[0079] This embodiment provides the synthesis of compound Z4, as detailed below:

[0080] (1) The synthetic route of compound Z4 is as follows:

[0081]

[0082] The reaction conditions are: (a) ethanol, DMSO, H2O2, NaOH

[0083] (2) Synthesis of compound Z4

[0084] Compound Z1100 mg (300.88 mmol) was dissolved in 2 mL of ethanol and stirred at 0 °C. 6 mg NaOH, 17.47 mg DMSO, and two drops of hydrogen peroxide solution were added, and the reaction was allowed to proceed overnight. After the reaction was complete, the ethanol was evaporated under reduced pressure. The DCM was dissolved and washed 2–3 times with water, once with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The solid was purified by column chromatography to give 50 mg of a white solid, with a yield of 47.43%. 1 H NMR (300MHz, CDCl3) δ8.43 (s, 1H), 7.50-7.44 (m, 2H), 7.30-7.25 (m, 3H), 7.19 (d, J = 2.1Hz, 3H), 5.92 (s, 1H), 5.15 (s, 2H), 2.22 (d, J = 3.2Hz, 6H).

[0085] Example 5:

[0086] This embodiment provides the synthesis of compound Z5, as detailed below:

[0087] (1) The synthetic route of compound Z5 is as follows:

[0088]

[0089] The reaction conditions are: (a) K2CO3, acetonitrile, and 4-methylbenzyl bromide.

[0090] (2) Synthesis of compound Z5

[0091] Compound Z1-D 500 mg (2.06 mmol) and potassium carbonate 458.39 mg (2.48 mmol) were placed in a 100 mL round-bottom flask, and 30 mL of acetonitrile was added. The mixture was stirred in an ice bath, and 4-methylbenzyl bromide was slowly added dropwise. After the reaction was complete, the mixture was extracted, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1 (v / v)) to give 538 mg of a white solid, with a yield of 75.25%.

[0092] Example 6:

[0093] This embodiment provides the synthesis of compound Z6, as detailed below:

[0094] (1) The synthetic route of compound Z6 is as follows:

[0095]

[0096] The reaction conditions were: (a) K2CO3, acetonitrile, and 2-methylbenzyl bromide.

[0097] Synthesis of compound Z6

[0098] (2) Synthesis of compound Z6

[0099] Compound Z1-D 500 mg (2.06 mmol) and potassium carbonate 458.39 mg (2.48 mmol) were placed in a 100 mL round-bottom flask, and 30 mL of acetonitrile was added. The mixture was stirred in an ice bath, and 4-methylbenzyl bromide was slowly added dropwise. After the reaction was complete, the mixture was extracted, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1 (v / v)) to give 538 mg of a white solid, with a yield of 75.25%.

[0100] Example 7:

[0101] This embodiment provides the synthesis of compound Z7, as detailed below:

[0102] (1) The synthetic route of compound Z7 is as follows:

[0103]

[0104] The reaction conditions were: (a) K2CO3, acetonitrile, and 3-trifluoromethylbenzyl bromide.

[0105] (2) Synthesis of compound Z7

[0106] 600 mg (2.48 mmol) of Z1D, 651.27 mg (2.72 mmol) of m-trifluoromethylbenzyl bromide, and 684.64 mg of potassium carbonate were placed in acetonitrile and stirred for 4 h. Extraction was performed using DCM / H2O, and recrystallization yielded 670 mg of a white solid, with a yield of 67.56%. 1 H NMR (400MHz, CDCl3) δ7.79(d,J=2.3Hz,1H),7.74(d,J=7.7Hz,1H),7.61(d,J=7.8Hz, 1H),7.48(t,J=7.8Hz,1H),7.24(s,1H),7.22-7.15(m,2H),5.21(s,2H),2.31(s,6H).

[0107] Example 8:

[0108] This embodiment provides the synthesis of compound Z8, as detailed below:

[0109] (1) The synthetic route of compound Z8 is as follows:

[0110]

[0111] (2) The synthesis of compound Z8 is the same as that of compound Z1, except that benzyl bromide is replaced with iodopropane. 1 H NMR (300MHz, CDCl3) δ7.32-7.10(m,4H),3.98(t,J=7.6Hz,2H),2.32(s,6H),1.74(q,J=7.9Hz,2H),0.99(dd,J=8.5,6.3Hz,3H).

[0112] Example 9:

[0113] This embodiment provides the synthesis of compound Z9.

[0114]

[0115] The synthesis of compound Z9 is the same as that of compound Z1, except that 3,4-dimethylaniline is replaced with aniline and benzyl bromide is replaced with iodoethane. 1H NMR (300MHz, CDCl3) δ7.59 (s, 5H), 4.19 (q, J = 7.2Hz, 2H), 1.42 (t, J = 7.1Hz, 3H).

[0116] Example 10:

[0117] This embodiment provides the synthesis of compound Z10.

[0118]

[0119] The synthesis of compound Z10 is the same as that of compound Z1, except that 3,4-dimethylaniline is replaced with aniline and benzyl bromide is replaced with iodomethane. 1 H NMR (300MHz, CDCl3) δ7.59 (s, 5H), 4.19 (q, J = 7.2Hz, 3H).

[0120] Example 11:

[0121] This embodiment provides the synthesis of compound Z11.

[0122] (1) The synthetic route of compound Z11 is as follows Figure 2 As shown.

[0123] The reaction conditions were: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile.

[0124] (2) Synthesis steps of compound Z11

[0125] a) Synthesis of compound Z11-B

[0126] The synthesis of compound Z11-B is the same as that of compound Z1-C, except that compound Z1-A is replaced by compound Z11-A. 1 H NMR (500MHz, CDCl3) δ9.24(s,1H),8.28(dd,J=4.3,1.6Hz,1H),7.67(td,J=7.0,1.7Hz,1H),7.30(dd ,J=7.0,1.5Hz,1H),6.93(ddd,J=7.0,4.2,1.5Hz,1H),4.21(q,J=6.4Hz,2H),1.27(t,J=6.2Hz,3H).

[0127] b) Synthesis of compound Z11-C

[0128] The synthesis of compound Z11-C is the same as that of compound Z1-D, except that compound Z1-C is replaced by compound Z11-B.

[0129] c) Synthesis of compound Z11

[0130] The synthesis of compound Z11 is the same as that of compound Z1, except that compound Z1-D is replaced with compound Z11-C. 1 H NMR (500MHz, CDCl3) δ8.41 (dd, J = 4.5, 1.7Hz, 1H), 7.72 (dd, J = 6.5, 1.5Hz, 1H), 7.64-7.58 (m, 1H), 7.33-7.21 (m, 6H), 5.08 (d, J = 1.0Hz, 2H).

[0131] Example 12:

[0132] This embodiment provides the synthesis of compound Z12.

[0133] (1) The synthetic route of compound Z12 is as follows Figure 2 As shown.

[0134] The reaction conditions were as follows: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile.

[0135] (2) Synthesis steps of compound Z12

[0136] a) Synthesis of compound Z12-B

[0137] The synthesis of compound Z12-B is the same as that of compound Z1-C, except that compound Z1-A is replaced by compound Z12-A. 1 H NMR(500MHz, CDCl3)δ9.23(s,1H),7.92(d,J=7.6Hz,1H),7.85-7.80(m,2H),7.74(dt,J=7.4,1.9Hz ,1H),7.50-7.44(m,2H),7.37(dd,J=7.7,2.2Hz,1H),4.21(q,J=6.3Hz,2H),1.27(t,J=6.2Hz,3H).

[0138] b) Synthesis of compound Z12-C

[0139] The synthesis of compound Z12-C is the same as that of compound Z1-D, except that compound Z1-C is replaced by compound Z12-B.

[0140] c) Synthesis of compound Z12

[0141] The synthesis of compound Z12-D was the same as that of compound Z1, except that compound Z1-D was replaced with compound Z12-C. ¹H NMR (500 MHz, CDCl₃) δ 8.12 (t, J = 2.0 Hz, ¹H), 7.99 (d, J = 7.2 Hz, ¹H), 7.93–7.80 (m, 2H), 7.72 (dd, J = 7.2, 2.3 Hz, ¹H), 7.55–7.41 (m, 2H), 7.36–7.23 (m, 5H), 5.08 (d, J = 1.1 Hz, 2H).

[0142] Example 13:

[0143] This embodiment provides the synthesis of compound Z13.

[0144] (1) Synthetic route of compound Z13

[0145]

[0146] The reaction conditions are: (a) K2CO3, acetonitrile, 2-bromomethylpyridine

[0147] (2) Synthesis of compound Z13

[0148] Compound Z1-D 500 mg (2.06 mmol) and potassium carbonate 458.39 mg (2.48 mmol) were placed in a 100 mL round-bottom flask, and 30 mL of acetonitrile was added. The mixture was stirred in an ice bath, and 2-bromomethylpyridine was slowly added dropwise. After the reaction was complete, the mixture was extracted, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1). 1 H NMR (500MHz, CDCl3) δ8.49(dd,J=4.1,1.7Hz,1H),7.74(td,J=7.6,1.7Hz,1H),7.59(dd,J=7.9,2.2Hz,1H),7.52(ddd,J=7.5,4.2 ,1.5Hz,1H),7.41(d,J=2.2Hz,1H),7.35(dd,J=7.8,1.3Hz,1H),7.17(dq,J=8.0,1.1Hz,1H),4.92(s,2H),2.28(d,J=1.1Hz,3H).

[0149] Example 14:

[0150] This embodiment provides the synthesis of compound Z14.

[0151] (1) The synthetic route of compound Z14 is as follows Figure 2 As shown.

[0152] The reaction conditions were as follows: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile.

[0153] (1) Synthesis of compound Z14

[0154] a) Synthesis of compound Z14-B

[0155] The synthesis of compound Z14-B is the same as that of compound Z1-C, except that compound Z1-A is replaced by compound Z14-A.

[0156] b) Synthesis of compound Z14-C

[0157] The synthesis of compound Z14-C is the same as that of compound Z1-D, except that compound Z1-C is replaced by compound Z14-B.

[0158] c) Synthesis of compound Z14

[0159] The synthesis of compound Z14 is the same as that of compound Z1, except that compound Z1-D is replaced with compound Z14-C. 1 H NMR (500MHz, CDCl3) δ7.76-7.70(m,2H),7.70-7.65(m,2H),7.59(dd,J=8.1,1.5Hz,2H),7.48-7.35(m,3H),7.34-7.23(m,5H),5.08(d,J=1.0Hz,2H).

[0160] Example 15:

[0161] This embodiment provides the synthesis of compound Z15.

[0162] (1) The synthetic route of compound Z15 is as follows: Figure 2 .

[0163] The reaction conditions were as follows: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile.

[0164] (2) Synthesis of compound Z15

[0165] a) Synthesis of compound Z15-B

[0166] The synthesis of compound Z15-B is the same as that of compound Z15-B, except that compound Z15-A is replaced by compound Z15-A.

[0167] b) Synthesis of compound Z15-C

[0168] The synthesis of compound Z15-C is the same as that of compound Z15-C, except that compound Z15-B is replaced by compound Z15-B.

[0169] c) Synthesis of compound Z15

[0170] The synthesis of compound Z15 is the same as that of compound Z1, except that compound Z1-D is replaced with compound Z15-C. 1 H NMR (500MHz, CDCl3) δ7.72-7.67(m,2H),7.67-7.62(m,2H),7.34-7.23(m,5H),5.08(d,J=1.0Hz,2H),3.18(s,3H).

[0171] Example 16:

[0172] This embodiment provides the synthesis of compound Z16.

[0173] (1) The synthetic route of compound Z16 is as follows Figure 2 As shown.

[0174] The reaction conditions were: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile.

[0175] (2) Synthesis of compound Z16

[0176] a) Synthesis of compound Z16-B

[0177] The synthesis of compound Z16-B is the same as that of compound Z1-C, except that compound Z1-A is replaced by compound Z16-A.

[0178] b) Synthesis of compound Z16-C

[0179] The synthesis of compound Z16-C is the same as that of compound Z1-D, except that compound Z1-C is replaced by compound Z16-B.

[0180] c) Synthesis of compound Z16

[0181] The synthesis of compound Z16 is the same as that of compound Z1, except that compound Z1-D is replaced with compound Z16-C. 1 H NMR (500MHz, CDCl3) δ7.69-7.63(m,2H),7.34-7.23(m,6H),7.16-7.10(m,2H),5.08(d,J=1.1Hz,2H).

[0182] Example 17:

[0183] This embodiment provides the synthesis of compound Z17.

[0184] (1) The synthetic route of compound Z17 is as follows: Figure 2 As shown.

[0185] The reaction conditions were as follows: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile.

[0186] (2) Synthesis of compound Z17

[0187] a) Synthesis of compound Z17-B

[0188] The synthesis of compound Z17-B is the same as that of compound Z1-C, except that compound Z1-A is replaced with compound Z17-A.

[0189] b) Synthesis of compound Z17-C

[0190] The synthesis of compound Z17-C is the same as that of compound Z1-D, except that compound Z1-C is replaced by compound Z17-B.

[0191] c) Synthesis of compound Z17

[0192] The synthesis of compound Z17 is the same as that of compound Z1, except that compound Z1-D is replaced with compound Z17-C. 1 H NMR (500MHz, CDCl3) δ9.30 (s, 1H), 7.68-7.62 (m, 2H), 7.57-7.52 (m, 2H), 7.34-7.23 (m, 6H), 5.08 (d, J = 1.0Hz, 2H), 2.16 (s, 3H).

[0193] Example 18:

[0194] This embodiment provides the synthesis of compound Z18.

[0195] (1) The synthetic route of compound Z18 is as follows: Figure 2 As shown.

[0196] The reaction conditions were as follows: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile.

[0197] (2) Synthesis of compound Z18

[0198] a) Synthesis of compound Z18-B

[0199] The synthesis of compound Z18-B is the same as that of compound Z1-C, except that compound Z1-A is replaced with compound Z18-A.

[0200] b) Synthesis of compound Z18-C

[0201] The synthesis of compound Z18-C is the same as that of compound Z1-D, except that compound Z1-D is replaced by compound Z18-B.

[0202] c) Synthesis of compound Z18

[0203] The synthesis of compound Z18 is the same as that of compound Z1, except that compound Z1-D is replaced with compound Z18-C. 1 H NMR (500MHz, CDCl3) δ7.68-7.62(m,2H),7.34-7.26(m,4H),7.30-7.22(m,2H),7.25-7.20(m,2H),5.08(d,J=1.0Hz,2H),2.28(s,3H).

[0204] Example 19:

[0205] This embodiment provides the synthesis of compound Z19.

[0206] (1) Synthetic route of compound Z19

[0207]

[0208] The reaction conditions were: (a) K2CO3, acetonitrile, β-bromomethylnaphthalene.

[0209] (2) Synthesis of compound Z19

[0210] Compound Z1-D 500 mg (2.06 mmol) and potassium carbonate 458.39 mg (2.48 mmol) were placed in a 100 mL round-bottom flask, and 30 mL of acetonitrile was added. The mixture was stirred in an ice bath with β-bromomethylnaphthalene. After the reaction was complete, the mixture was extracted, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the concentrated solution was purified by column chromatography (PE:EA = 10:1). 1H NMR (500MHz, CDCl3) δ8.13-8.07(m,1H),7.86-7.78(m,2H),7.77-7.71(m,1H),7.59(dd,J=7.9,2.2Hz,1H),7.55-7.43(m,2 H),7.41(d,J=2.1Hz,1H),7.27-7.22(m,1H),7.17(dq,J=8.0,1.1Hz,1H),5.14(s,2H),2.28(d,J=1.1Hz,3H),2.23(s,3H).

[0211] Example 20:

[0212] This embodiment provides the synthesis of compound Z20.

[0213] (1) Synthetic route of compound Z20

[0214]

[0215] The reaction conditions were: (a) K2CO3, acetonitrile, 1-bromomethyl-3-methylsulfonebenzene

[0216] (2) Synthesis of compound Z20

[0217] Compound Z1-D 500 mg (2.06 mmol) and potassium carbonate 458.39 mg (2.48 mmol) were placed in a 100 mL round-bottom flask, and 30 mL of acetonitrile was added. The mixture was stirred in an ice bath with 1-bromomethyl-3-methylsulfonylbenzene. After the reaction was complete, the mixture was extracted, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1). 1 H NMR (500MHz, CDCl3) δ7.78-7.72(m,2H),7.59(dd,J=7.9,2.2Hz,1H),7.46-7.37(m,3H),7.17( dq,J=8.0,1.1Hz,1H),5.06(t,J=0.9Hz,2H),3.18(s,3H),2.28(d,J=1.1Hz,3H),2.23(s,3H).

[0218] Example 21:

[0219] This embodiment provides the synthesis of compound Z21.

[0220] (1) Synthetic route of compound Z21

[0221]

[0222] Among them, the reaction conditions are (a) K2CO3, acetonitrile, ethyl 3-(bromomethyl)benzoate, and (2) the synthesis of compound Z21.

[0223] Compound Z1-D 500 mg (2.06 mmol) and potassium carbonate 458.39 mg (2.48 mmol) were placed in a 100 mL round-bottom flask, and 30 mL of acetonitrile was added. The mixture was stirred in an ice bath, along with ethyl 3-(bromomethyl)benzoate. After the reaction was complete, the mixture was extracted, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the concentrated solution was purified by column chromatography (PE:EA = 10:1). 1 H NMR (500MHz, CDCl3) δ7.87 (dt, J=7.8, 1.7Hz, 1H), 7.83 (dp, J=2.0, 0.9Hz, 1H), 7.59 (dd, J=7.9, 2.2Hz, 1H), 7.44-7.37 (m, 2H), 7.36 (dtt, J=8. 2,1.7,0.9Hz,1H),7.20-7.14(m,1H),5.09(t,J=1.0Hz,2H),4.35(q,J=6.4Hz,2H),2.28(d,J=1.1Hz,3H),2.23(s,3H),1.38(d,J=12.8Hz,3H).

[0224] Example 22:

[0225] This embodiment provides the synthesis of compound Z22.

[0226] (1) The synthetic route of compound Z22 is as follows Figure 2 As shown.

[0227] The reaction conditions were as follows: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile.

[0228] (1) Synthesis of compound Z22

[0229] a) Synthesis of compound Z22-B:

[0230] The synthesis of compound Z22-B is the same as that of Z1-C, except that 3,4-dimethylaniline (Z1-A) is replaced with p-methylaniline.

[0231] b) Synthesis of compound Z22-C:

[0232] The synthesis of compound Z22-C is the same as that of compound Z1-D, except that Z1-C is replaced by compound Z22-B.

[0233] c) Synthesis of compound Z22:

[0234] The synthesis of compound Z22 is the same as that of compound Z1, except that Z1-D is replaced with compound Z22-C. 1 HNMR (300MHz, CDCl3) δ7.63-7.21(m,9H),5.15(s,2H),2.41(s,3H).

[0235] Example 23:

[0236] This embodiment provides the synthesis of compound Z23.

[0237] (1) The synthetic route of compound Z23 is as follows: Figure 2 As shown.

[0238] The reaction conditions were as follows: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile; (d) HCl, AcOH, 110℃; (e) oxalyl chloride, DMF, DCM, N2; (f) Et3N, DCM, 0℃.

[0239] a) Synthesis of compound Z23-B:

[0240] The synthesis of compound Z23-B is the same as that of Z1-C, except that 3,4-dimethylaniline (Z1-A) is replaced with m-methylaniline.

[0241] b) Synthesis of compound Z23-C:

[0242] The synthesis of compound Z23-C is the same as that of compound Z1-D, except that Z1-C is replaced by compound Z23-B.

[0243] c) Synthesis of compound Z23:

[0244] The synthesis of compound Z23 is the same as that of compound Z1, except that Z1-D is replaced with compound Z23-C. 1 HNMR (300MHz, CDCl3) δ7.50(qd,J=5.5,3.5,2.9Hz,2H),7.40-7.28(m,4H),7.28-7.17(m,3H),5.13(q,J=3.9,2.9Hz,2H),2.39(t,J=3.8Hz,3H).

[0245] Example 24:

[0246] This invention provides the synthesis of compound Z24.

[0247] (1) The synthetic route of compound Z24 is as follows: Figure 2 As shown.

[0248] The reaction conditions were as follows: (a) NaNO2, HCl, AcONa, pyridine, 0℃; (b) AcONa, AcOH, 110℃; (c) K2CO3, acetonitrile.

[0249] (2) Synthesis of Z24

[0250] a) Synthesis of compound Z24-B:

[0251] The synthesis of compound Z24-B is the same as that of Z1-C, except that 3,4-dimethylaniline (Z1-A) is replaced with p-methoxyaniline;

[0252] b) Synthesis of compound Z24-C:

[0253] The synthesis of compound Z24-C is the same as that of compound Z1-D, except that Z1-C is replaced by compound Z24-B.

[0254] c) Synthesis of compound Z24:

[0255] The synthesis of compound Z24 is the same as that of compound Z1, except that Z1-D is replaced with compound Z24-C. 1 HNMR (400MHz, CDCl3) δ7.55-7.52(m,2H),7.37(d,J=2.2Hz,1H),7.35-7.33(m,4H),6.99-6.96(m,2H),5.15(s,2H),3.85(s,3H).

[0256] Test Example 1: Determination of the inhibitory activity of the compound on breast cancer MDA-MB-231 cells

[0257] The MDA-MB-231 cell line of this invention was obtained from the Kunming Institute of Zoology, Chinese Academy of Sciences. This invention uses the MDA-MB-231 breast cancer cell line to detect antitumor activity. The drug concentration gradient was set at 0, 0.1 μM, 0.2 μM, 0.4 μM, 0.8 μM, and 1 μM, at a concentration of 3 × 10⁻⁶ cells / cell. 3 After seeding each well with the drug for 72 hours, cell viability was detected using the CCK-8 assay, and the half-maximal inhibitory concentration (IC50) was determined. Specifically, after treatment, 10 μM CCK-8 reagent was added to each well, and the cells were incubated for 2 hours. The absorbance was then read at a wavelength of 450 nm. The results are shown in Table 1.

[0258] Test Example 2: Determination of the binding activity of the compound to eEF2K

[0259] This invention employs the SPR (surface plasmon resonance) method to detect the binding affinity of Z1 eEF2K. The SPR experiment was performed using Amersham Life Sciences 110397-04. A 1 mM / L concentration of the compound was prepared in DMSO and immobilized on the photocrosslinking agent SensorCHIP™. eEF2K protein was diluted with PBST at concentrations of 200 nM, 400 nM, 1600 nM, and 3200 nM, with PBST used as the running buffer. eEF2K protein was injected at a flow rate of 0.5 μL / s for 600 s. The experiment was conducted from low to high concentrations; regeneration was performed using a regeneration solution of glycine hydrochloride (pH = 2.0) at a flow rate of 2 μL / s. The detection time for the dissociation process was 360 s. The laboratory temperature was 4 °C. The raw data collected on the SPR biosensor were further processed to eliminate any artifacts, such as nonspecific binding and differences in buffer composition. Results are shown below. Figure 1 .

[0260] As shown in Table 1, 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile compounds all exhibited good inhibitory activity against triple-negative breast cancer MDA-MB-231 cells. However, compound Z4, obtained by cyano-derived formamide, completely lost its activity. Furthermore, compounds Z2, Z8, and Z10, obtained by deriving the benzene rings from both sides to methyl or ethyl groups, also lost their activity. This suggests the importance of the 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile structure for inhibiting the activity of triple-negative breast cancer MDA-MB-231 cells.

[0261] Table 1: Inhibition rate of the compound on MDA-MB-231 breast cancer cells at a concentration of 20 μM

[0262]

[0263]

[0264] *** represents a strong inhibition rate, i.e., an inhibition rate of over 80%; ** represents a moderate inhibition rate, i.e., an inhibition rate of 60-80%; ** represents a low inhibition rate, i.e., an inhibition rate of 30-60%; NA represents no activity, i.e., an inhibition rate of less than 30%.

[0265] As shown in Table 2, the IC50 values ​​of representative compounds against triple-negative breast cancer cells MDA-MB-231 and normal breast cancer cells MCF-10A were tested. 50 Activity. Literature indicates that paclitaxel has an IC50 value for MDA-MB-231. 50 =1μM (Cong HJ et al. JNat Prod. 2013), IC50 for MCF-10A 50=5.64 nM (Journal of Cellular Physiology (2019), 234, (4), 4277-4290), while the compounds protected in this invention have comparable inhibitory activity against MDA-MB-231 cells to paclitaxel, but weaker activity against MCF-10A cells (IC50). 50 Compounds with a concentration of >10 μM, namely 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitriles, exhibit strong antitumor activity and low toxicity.

[0266] Table 2: Inhibitory activity of representative compounds against breast cancer MDA-MB-231 cells and normal breast cancer MCF-10A cells

[0267]

[0268] like Figure 1 As shown, the representative compound Z1 exhibits a strong binding affinity to eEF2K, meaning that the compound selectively targets the eEF2K protein.

[0269] In summary, 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitriles exhibit strong anti-malignant tumor cell activity by targeting the eEF2K protein, while having little impact on normal cell activity. They demonstrate strong anti-tumor potential and high safety, thus showing great application prospects.

[0270] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A nitrile compound or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the nitrile compound is shown in Formula A: The structure of the nitrile compound is as follows:

2. The use of a nitrile compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a tumor-treating drug, characterized in that, The tumors mentioned are triple-negative breast cancer, lung cancer, colon cancer, breast cancer, and esophageal cancer.

3. A method for preparing the nitrile compound as described in claim 1, characterized in that, Includes the following steps: (1) The compound shown in formula A1 is reacted with the compound shown in formula A2 by diazotization coupling reaction to obtain the compound shown in formula A3; (2) The compound shown in formula A3 undergoes cyclization under acidic conditions to yield the compound shown in formula A4. The compound shown in formula A4 reacts with a haloalkane under alkaline conditions. A substitution reaction yields the compound shown in Formula A, i.e., the nitrile compound, wherein the structural formulas of the compounds shown in Formulas A1-A4 and Formula A are as follows:

4. The preparation method according to claim 3, characterized in that, In step (1), the molar ratio of the compound shown in formula A1 to the compound shown in formula A2 is 1:1 to 1:

2.

5. The preparation method according to claim 3, characterized in that, In step (2), the pH value of acidic conditions is 1-4; the pH value of alkaline conditions is 8-10.

Images