Application of substituted isoxazole-5-ketone derivative
By developing a substituted isoxazole-5-one derivative as a high activity inhibitor of human TyrRs enzyme, the problem of low activity of human TyrRs inhibitors in the prior art is solved, effective inhibition of TyrRs enzyme is achieved, and there are broad therapeutic and preventive application prospects.
Patent Information
- Application Number
- CN202510191363.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-20
- Publication Date
- 2025-05-13
AI Technical Summary
In the prior art, human TyrRs inhibitors have low activity and are difficult to effectively inhibit human TyrRs enzymes, which limits their application in anti-aging, DNA repair and treatment of neurodegenerative diseases.
A substituted isoxazole-5-one derivative was developed as a high activity inhibitor of human TyrRs enzymes. Through specific chemical structure design, the inhibitory effect on human TyrRs enzymes was significantly improved.
As a highly active human TyrRs inhibitor, this compound can effectively inhibit TyrRs enzymes, has potential applications in the treatment and prevention of cancer and neurodegenerative diseases, and provides new options for the development of anti-aging and DNA repair drugs.
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of biomedicine, and specifically relates to the use of a substituted isoxazol-5-one derivative. Background Art
[0002] Aminoacyl-tRNA synthetase (AARS) is of great significance to protein synthesis. It can catalyze the esterification reaction between the carboxyl group of amino acid and the hydroxyl group on the 3'-end adenylate ribose of transfer RNA, thereby promoting the aminoacylation of transfer RNA. The generated aminoacyl transfer RNA is the raw material for ribosome protein synthesis.
[0003] Transfer RNA synthetase belongs to an ancient enzyme family. Nowadays, people no longer only focus on its basic function of assisting the translation of genetic material into protein amino acid components, but also find that its function extends to editing, RNA splicing and transport, transcription and translation regulation, regulation of DNA and amino acid biosynthesis, and association with cytokines.
[0004] Tyrosyl transfer-RNA (tRNA) synthetase (TyrRs) is closely related to neurodegenerative diseases and is a major research hotspot in the field of AARS. TyrRs can recognize the genetic code for designated tyrosine and also protect DNA during cellular stress. Studies have found that "oxidative" stress can send TyrRs into the nucleus, where the activity of genes related to DNA protection and repair is greatly increased, and excluding TyrRs from the nucleus can prevent this. The TyrRs-PARP-1 signaling pathway in human cells can be strongly activated by resveratrol. Experiments have confirmed that resveratrol can simulate tyrosine binding to the TyrRs binding pocket. After binding, TyrRs is separated from its original job of protein translation and enters the cell nucleus to play a role. In the nucleus, it can activate the PARP-1 protein. PARP-1, as an important stress and DNA repair factor, has a significant impact on lifespan. TyrRs activation of PARP-1 can activate a series of protective genes such as the tumor suppressor gene p53, the longevity gene FOXO3A and SIRT6.
[0005] In recent years, many new discoveries of human TyrRs have attracted much attention to this ancient enzyme family. TyrRs inhibitors are divided into two categories: bacterial TyrRs inhibitors and human TyrRs inhibitors. Bacterial TyrRs inhibitors have been comprehensively studied and have typical inhibitors, while reports of human TyrRs inhibitors are rare. At present, only resveratrol (RSV) has been found to mimic its natural ligand tyrosine and bind to the active pocket to inhibit it. It is a known human TyrRs inhibitor. Secondly, a literature reported in 2019 that substituted 6,8-dimercapto-2-phenyl-4H-chromene-4-one derivatives. This series of compounds also has human TyrRs inhibitory activity that is superior to RSV (Huang, Shenzhen et al. "Discovery of human TyrRSinhibitors by structure-based virtual screening, structural optimization, and bioassays." RSC advances 2019.9(16), 9323-9330.). However, the current activity is still not high. Therefore, the development of highly active and highly selective human TyrRs inhibitors is of great research significance for the development of anti-aging and DNA repair drugs. Summary of the invention
[0006] In order to solve the above problems existing in the prior art, the object of the present invention is to provide a use of a substituted isoxazol-5-one derivative.
[0007] In order to achieve the above object, the present invention adopts the following technical solution:
[0008] The present invention provides a use of a compound or a pharmaceutically acceptable salt, stereoisomer or solvate thereof in the preparation of a TyrRs enzyme inhibitor, wherein the structure of the compound is shown in Formula I:
[0009]
[0010] Where R1 is C 1-6 Alkyl or R3 and R4 are each independently selected from H, halogen, -NO2, -OH, C 1-6 Alkyl or C 1-6 Alkoxy;
[0011] R2 is Ring A is a benzene ring, a six-membered aromatic heterocycle, a five-membered aromatic heterocycle, a naphthalene ring, a benzene ring and a 5-6-membered heterocycle; R5, R6, and R7 are each independently selected from H, halogen, -NO2, -OH, C 1-6 Alkyl, -OCX3, -OCH2COOH, -OCH2C6H5 or X is halogen; p is selected from 0 or 1; n is selected from 0 or 1;
[0012] M is selected from O, N, S or none;
[0013] R8 is selected from H, C 1-6 Alkyl or None;
[0014] R9 is selected from C 1-8 alkyl, Ring B is a benzene ring, a six-membered aromatic heterocycle or a five-membered aromatic heterocycle; R 10 , R 11 Each independently selected from H, halogen, -NO2, -OH, C 1-6 Alkyl or C 1-6 Alkoxy; k is selected from 0, 1, 2, 3, 4, 5 or 6; m is selected from 0, 1, 2, 3, 4, 5 or 6;
[0015] The heteroatom in the six-membered aromatic heterocycle, five-membered aromatic heterocycle, benzene ring and 5-6-membered heterocycle is selected from at least one of S, O and N.
[0016] Furthermore, R1 is C 1-3 Alkyl or R3 and R4 are each independently selected from H, halogen, -NO2, -OH, C 1-3 Alkyl or C 1-3 Alkoxy;
[0017] R2 is Ring A is a benzene ring, a five-membered aromatic heterocycle, a naphthalene ring, a benzene ring and a 5-6-membered heterocycle;
[0018] R5, R6, R7 are each independently selected from H, halogen, -NO2, -OH, C 1-6 Alkyl, -OCX3, -OCH2COOH, -OCH2C6H5 or X is halogen; p is selected from 0 or 1; n is selected from 0 or 1;
[0019] M is selected from O, N, S or none;
[0020] R8 is selected from H, C 1-3 Alkyl or None;
[0021] R9 is selected from C 1-8 alkyl, Ring B is a benzene ring or a five-membered aromatic heterocyclic ring; R 10 , R 11 Each independently selected from H, halogen, -NO2, -OH, C 1-3 Alkyl or C 1-3 Alkoxy; k is selected from 0, 1, 2 or 3; m is selected from 0, 1, 2 or 3;
[0022] The heteroatom in the five-membered aromatic heterocycle, benzene ring and 5-6-membered heterocycle is selected from at least one of S, O and N.
[0023] Furthermore, R1 is R2 is
[0024]
[0025] Or R1 is R2 is
[0026] Or R1 is R2 is
[0027]
[0028] Or R1 is R2 is
[0029] Or R1 is -CH3, R2 is
[0030] Or R1 is R2 is
[0031] Further, the compound is selected from the following structures:
[0032]
[0033] Furthermore, the TyrRs enzyme inhibitor is a human TyrRs enzyme inhibitor, and the human TyrRs enzyme inhibitor is an anti-aging drug, a DNA repair drug, a drug for treating and / or preventing cancer, or a drug for treating and / or preventing neurodegenerative diseases.
[0034] Furthermore, the cancer is cervical cancer, lung cancer, breast cancer, colon cancer, or ovarian cancer.
[0035] Furthermore, the medicine is a spray, a liquid preparation or a solid preparation.
[0036] Furthermore, the spray includes an aerosol; the liquid preparation includes a suspension, an emulsion, a solution or a syrup; the solid preparation includes a tablet, a capsule or an granule.
[0037] Furthermore, the solution includes an injection; and the granules include granules.
[0038] Furthermore, the drug is administered orally, sublingually, by injection or transmucosal dialysis.
[0039] Furthermore, the injection includes intravenous injection, intramuscular injection, intraperitoneal injection or subcutaneous injection.
[0040] Furthermore, the intravenous injection includes intravenous drip.
[0041] In the present invention, the minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by prefixes, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. 1-6 Alkyl refers to straight or branched chain alkyl groups containing 1, 2, 3, 4, 5 or 6 carbon atoms, and so on.
[0042] "Aromatic heterocycle" refers to a heteroaromatic group having a conjugated π electron system and containing at least one heteroatom. The heteroatom referred to herein includes, but is not limited to, oxygen, sulfur, and nitrogen.
[0043] The present invention has achieved the following beneficial effects:
[0044] The present invention discovers for the first time that the substituted isoxazol-5-one derivatives shown in formula I are highly active inhibitors of human TyrRs enzymes, which can be used to treat and / or prevent cancer, treat and / or prevent neurodegenerative diseases, and provide a new option for the development of human TyrRs enzyme inhibitors, anti-aging and DNA repair drugs, and has good application prospects.
[0045] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.
[0046] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
[0047] Figure 1 The Ki value determination curve is fitted with the human TyrRs enzyme activity data of the compounds RSV, 8005-8819, 6281-5629, 6281-5628, 6281-5557, 5408-0004, 8009-2409, 5895-0011, 5895-0014, 8009-1143, 5960-2050, 8008-7140 and AG-690 / 40638979 of the present invention.
[0048] Figure 2 This is a Western blotting diagram showing that the serum starvation group (SS), the positive control compound resveratrol (RSV) and the compounds AG-690 / 40638979, 8005-8819, 8008-7140, and 5895-0014 in the present invention can promote TyrRs to enter the cell nucleus.
[0049] Figure 3 The diagram shows the effect of the positive control compound resveratrol (RSV) and the compound AG-690 / 40638979 in protecting intracellular DNA in the cisplatin-induced DNA damage model experiment. DETAILED DESCRIPTION
[0050] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.
[0051] Unless otherwise specified, the operations in the specific embodiments of the present invention are all carried out at room temperature.
[0052] In the present invention, the room temperature is 25±5°C.
[0053] The beneficial effects of the present invention are demonstrated by experimental examples below.
[0054] Experimental Example 1: In vitro human TyrRs enzyme inhibition activity test of the compounds of the present invention
[0055] The in vitro human TyrRs enzyme inhibition test of the compounds of the present invention was carried out using the ATP pyrophosphate exchange test, and the results were provided by Malvern Reaction Biology, USA.
[0056] The compounds No. 2-81 in Table 1 were purchased from suppliers such as Specs (Netherlands) and Chemdiv (Russia). The positive control compound resveratrol (RSV) was purchased from MCE, USA, and prepared into a storage solution with a concentration of 10 mM using 100% DMSO.
[0057] The structure of resveratrol (RSV) is as follows:
[0058]
[0059] The synthesis of tyrosyl adenylate was measured using a tyrosine-dependent ATP–pyrophosphate (PPi) exchange assay. A 50 μL flask containing 100 mM HEPES-Na (pH 7.5), 20 mM KCl, 2 mM ATP, 1 mM NaPPi, 2 mM DTT, 100 μM L-tyrosine (T3754-50G, Sigma), 0.02% Brij35 (w / v), 10 mM MgCl2, and 0.01 mCi ml -1 A mixture of Na[32P]PPi (NEX 019001MC, PerkinElmer) was added to purified TyrRs at a concentration of 12.5 nM and mixed with each analyte (the structures of the analytes are detailed in Table 1) at 4°C for 30 minutes. The analytes were prepared at 10 mM in DMSO. The ATP-PPi exchange reaction mixture was incubated at room temperature for 2 hours, and aliquots were removed at equal time intervals and quenched in a mixture containing 40 mM NaPPi, 1.4% (w / v) HClO4, 0.4% (w / v) HCl, and 8% (w / v) activated carbon. After thorough mixing, the charcoal was filtered using a Spin-X centrifugal filter (Corning) containing a cellulose acetate filter with a pore size of 0.45 μm and washed with 7% HClO4 (w / v) and 200 mM NaPPi solution. After drying, the charcoal was punched into a scintillation tube, and the radioactivity of ATP bound to the charcoal mixture was measured by scintillation counting. The obtained data were imported into GraphPadPrism software for fitting to obtain the IC of each tested compound. 50 Value. K i The value K is obtained by equation i =IC 50 / (1+[S] / Km), [S] is the substrate concentration and Km is the Michaelis constant.
[0060] The inhibitory effect of the test substance on TryRs at a concentration of 100 μM was tested using the test method described above. The inhibition rate of the compound is shown in Table 1.
[0061] Table 1 Inhibition rate of the tested compounds on TryRs
[0062]
[0063]
[0064]
[0065]
[0066]
[0067]
[0068]
[0069]
[0070]
[0071]
[0072] Note: In Table 1, the R1 of compounds No. 2-40 are The R1 of the compounds corresponding to serial numbers 41-44 are The R1 of the compounds of sequence numbers 45-62 are The R1 of the compounds corresponding to sequence numbers 63-69 are The R1 of the compounds corresponding to serial numbers 70-80 is all -CH3.
[0073] The compounds of the present invention have an inhibitory effect on TryRs. According to the results in Table 1, some preferred compounds were selected to calculate their corresponding K i The results are shown in Table 2.
[0074] Table 2 K of some compounds against TryRs enzyme in vitro i value
[0075]
[0076]
[0077] As shown in Table 2, the inhibition constants Ki of compounds 8005-8819, 6281-5629, 6281-5628, 6281-5557, 5408-0004, 8009-2409, 5895-0011, 5895-0014, 8009-1143, 5960-2050, 8008-7140 and AG-690 / 40638979 of the present invention are much smaller than that of resveratrol (RSV) in the positive control group.
[0078] In summary, the compounds of the present invention can effectively inhibit TryRs enzyme and can be used as TryRs enzyme inhibitors. Among them, the inhibitory effect and affinity of compounds 8005-8819, 6281-5629, 6281-5628, 6281-5557, 5408-0004, 8009-2409, 5895-0011, 5895-0014, 8009-1143, 5960-2050, 8008-7140 and AG-690 / 40638979 on TryRs enzyme are significantly better than the positive control resveratrol (RSV).
[0079] Experimental Example 2: In vitro binding stability test of the compound of the present invention with human TyrRs enzyme
[0080] The purpose of this experiment is to determine the stability of some of the compounds of the present invention, 8005-8819, 8008-7140, AG-690 / 40638979, and the positive control molecule resveratrol after binding to the human TyrRs enzyme in vitro. The experiment is divided into two steps. The first step is to purify the human TyrRs protein. The second step is to co-incubate the compounds of the present invention with the TyrRs protein to test the binding degree.
[0081] Purification of human TyrRs protein. The TyrRs (amino acids 1-341) plasmid was transformed into Escherichia coli ArcticExpress (DE3) cells. The cells were cultured at 37°C in fresh LB liquid medium (containing 5 g NaCl, 10 g bacterial peptone and 10 g yeast extract per liter). When the OD600 nm dilution was 1, isopropyl-β-d-1-thiogalactoside (IPTG, 0.5 mM) was used to induce expression, and the culture was grown at 16°C for 20 hours. The cells were collected by centrifugation at 4000 rpm / min for 15 minutes at 4°C and then resuspended in lysis buffer (50 mM Hepes-Na, pH 7.5, 5 mM imidazole pH 7.5, 400 mM NaCl, 1× PMSF (phenylmethylsulfonyl fluoride) and 2 mM BME (β-mercaptoethanol)). The cells were lysed using a cell disruptor. After centrifugation at 14000rpm / min for 25 minutes at 4°C, the supernatant was loaded onto a nickel affinity chromatography column (GE-Healthcare) pre-equilibrated with lysis buffer. The protein was eluted with a linear gradient of imidazole (0-300mM). The desired fractions were combined, concentrated and subjected to gel filtration (Superdex 200GE-Healthcare) chromatography, and the protein peak corresponding to homogeneous protein in buffer (20mM Hepes-Na, pH 7.5, 50mM NaCl and 2mM BME) was collected for subsequent testing.
[0082] Differential scanning fluorimetry (DSF): DSF experiments were performed on a RT-PCR detection system (BIO-RAD CFX96). SYPRO orange (5000×, Invitrogen) was monitored using a FRET filter at 492 nm for excitation and a ROX filter at 610 nm for emission. Buffer (20 mM Hepes-Na, pH 7.4 and 100 mM NaCl), 5×SYPRO orange, and 10 μL of a solution containing 50 μM compound (8005-8819, 8008-7140, AG-690 / 40638979, or RSV) and 2 μM TyrRs protein were mixed and heated from 25°C to 95°C at 1°C / min. Fluorescence intensity was recorded at 1°C / min intervals and plotted as a function of temperature. The transition curve (T) was calculated by fitting the Boltzmann equation to a sigmoid curve in GraphPad Prism 5.0. m )’s turning point.
[0083] The results are shown in Table 3. When the ratio of compounds 8005-8819, 8008-7140, AG-690 / 40638979 and RSV to TyrRs protein was 25:1, the shift difference of melting temperature (T m The shifts of the melting temperatures of compounds 8005-8819, 8008-7140, AG-690 / 40638979 and TyrRs protein are greater than those of RSV and TyrRs protein.
[0084] Table 3 Shift temperature of the compounds of the present invention binding to TyrRs protein
[0085] serial number Compound ID number <![CDATA[T m shift(℃)]]> 1 RSV 1.95 2 8005-8819 2.83 12 8008-7140 2.58 13 AG-690 / 40638979 3.65
[0086] The above results prove that the compounds 8005-8819, 8008-7140, AG-690 / 40638979 of the present invention bind to human TyrRs enzyme T m The displacement temperatures are 2.83, 2.58, and 3.65, respectively, which are greater than the T of RSV. m The shift temperature is 1.95, indicating that the compounds 8005-8819, 8008-7140, and AG-690 / 40638979 of the present invention have better binding stability to human TyrRs enzyme than RSV.
[0087] Example 3: In vitro experiment on the promotion of TyrRs nuclear entry by the compounds of the present invention
[0088] The purpose of this experiment is to detect the localization and distribution of TyrRs in the cell nucleus after the cells are treated with the compounds of the present invention, and the method used is protein immunoblotting (Western Blot, WB).
[0089] Cellular localization of TyrRs: HeLa cells were treated with 1 μM of compounds AG-690 / 40638979, 8005-8819, 8008-7140, 5895-0014, RSV or an equal volume of DMSO for 8 h. The cells treated with the above compounds were then cultured in serum-free medium for 8 h, and the cells were serum-starved. The cytoplasmic and nuclear fractions were separated using NE-PER nuclear and cytoplasmic extraction reagents (Thermo Scientific, 78835) according to the manufacturer's instructions. Both fractions were then subjected to immunoblot analysis. Anti-tyrosyl tRNA synthetase antibody (Abcam, ab150429, 1:1000 dilution) was used to detect TyrRs in the nucleus and cytoplasm. Anti-Beta-actin antibody (Proteintech, 1:1000 dilution) and anti-lamin B1 (Proteintech, 1298.7-1-AP, 1:1000 dilution) antibodies were used to detect Beta-actin and lamin B1 as controls for the cytoplasmic and nuclear fractions, respectively.
[0090] The results are as follows Figure 2 As shown, the serum starvation group (SS) and the positive control compound resveratrol can promote the entry of TyrRs into the cell nucleus. Compounds AG-690 / 40638979, 8005-8819, 8008-7140, and 5895-0014 can also regulate the distribution of TyrRs in cells, and their proportions are significantly higher than the positive control compound resveratrol, indicating that the effect of the compounds of the present invention in promoting the entry of TyrRs into the nucleus is significantly better than that of the positive compound resveratrol.
[0091] Example 4: In vitro experiment on the protection of intracellular DNA damage by the compounds of the present invention
[0092] HeLa cells (cervical cancer cells) were maintained in Dulbecco's modified Eagle's medium supplemented with 10% (v / v) fetal bovine serum. In order to simulate oxidative stress in cells, serum starvation was used, and the above Hela cells were cultured in serum-free Dulbecco's modified Eagle's medium. The cells were grown in a humidified incubator at 37°C and 5% CO2. In order to determine the protective effect of human TyrRs enzyme inhibitors on DNA damage, HeLa cells pre-seeded in 6-well plates were pretreated with compound AG-690 / 40638979 and positive control compound RSV for 24 hours. In order to induce DNA damage, cells were treated with cisplatin (30 μM) or DMSO in the presence of 1 μM compound AG-690 / 40638979 of the present invention and positive control compound RSV (10 mM mother solution concentration diluted, with DMSO as solvent) or DMSO for 24 hours. Then whole cell anti-histone H2A.XS139ph (phospho-Ser139) antibody (GeneTex, GTX127340, 1:1000 dilution) was used to detect the level of DNA damage in cells. Anti-Beta-actin antibody (Proteintech, 60008-1-Ig, 1:1000 dilution) was used to detect β-actin as a control.
[0093] like Figure 3 As shown, the addition of 30 μM cisplatin to the model group caused DNA damage to the cells. After the addition of compound AG-690 / 40638979 and positive control compound RSV, the DNA damage in the cells could be significantly protected.
[0094] The compound of the present invention has a significant effect on protecting DNA damage in cells and is expected to be used in the development of anti-aging and DNA repair drugs.
[0095] In summary, the present invention discovered for the first time that substituted isoxazol-5-one derivatives are highly active inhibitors of human TyrRs enzymes, which can be used to treat and / or prevent cancer, treat and / or prevent neurodegenerative diseases, and provide a new option for the development of human TyrRs enzyme inhibitors, anti-aging and DNA repair drugs, and have good application prospects.
Claims
1. Use of a compound or a pharmaceutically acceptable salt, stereoisomer or solvate thereof in the preparation of a TyrRs enzyme inhibitor, characterized in that: The structure of the compound is shown in Formula I: Where R1 is C 1-6 Alkyl or R3 and R4 are each independently selected from H, halogen, -NO2, -OH, C 1-6 Alkyl or C 1-6 Alkoxy; R2 is Ring A is a benzene ring, a six-membered aromatic heterocycle, a five-membered aromatic heterocycle, a naphthalene ring, a benzene ring and a 5-6-membered heterocycle; R5, R6, and R7 are each independently selected from H, halogen, -NO2, -OH, C 1-6 Alkyl, -OCX3, -OCH2COOH, -OCH2C6H5 or X is halogen; p is selected from 0 or 1; n is selected from 0 or 1; M is selected from O, N, S or none; R8 is selected from H, C 1-6 Alkyl or None; R9 is selected from C 1-8 alkyl, Ring B is a benzene ring, a six-membered aromatic heterocycle or a five-membered aromatic heterocycle; R 10 , R 11 Each independently selected from H, halogen, -NO2, -OH, C 1-6 Alkyl or C 1-6 Alkoxy; k is selected from 0, 1, 2, 3, 4, 5 or 6; m is selected from 0, 1, 2, 3, 4, 5 or 6; The heteroatom in the six-membered aromatic heterocycle, five-membered aromatic heterocycle, benzene ring and 5-6-membered heterocycle is selected from at least one of S, O and N.
2. The use according to claim 1, characterized in that R1 is C 1-3 Alkyl or R3 and R4 are each independently selected from H, halogen, -NO2, -OH, C 1-3 Alkyl or C 1-3 Alkoxy; R2 is Ring A is a benzene ring, a five-membered aromatic heterocycle, a naphthalene ring, a benzene ring and a 5-6-membered heterocycle; R5, R6, R7 are each independently selected from H, halogen, -NO2, -OH, C 1-6 Alkyl, -OCX3, -OCH2COOH, -OCH2C6H5 or X is halogen; p is selected from 0 or 1; n is selected from 0 or 1; M is selected from O, N, S or none; R8 is selected from H, C 1-3 Alkyl or None; R9 is selected from C 1-8 alkyl, Ring B is a benzene ring or a five-membered aromatic heterocyclic ring; R 10 , R 11 Each independently selected from H, halogen, -NO2, -OH, C 1-3 Alkyl or C 1-3 Alkoxy; k is selected from 0, 1, 2 or 3; m is selected from 0, 1, 2 or 3; The heteroatom in the five-membered aromatic heterocycle, benzene ring and 5-6-membered heterocycle is selected from at least one of S, O and N.
3. The use according to claim 2, characterized in that: R1 is R2 is Or R1 is R2 is Or R1 is R2 is Or R1 is R2 is Or R1 is -CH3, R2 is Or R1 is R2 is 4. The use according to any one of claims 1 to 3, characterized in that: The compound is selected from the following structures:
5. The use according to any one of claims 1 to 4, characterized in that: The TyrRs enzyme inhibitor is a human TyrRs enzyme inhibitor, and the human TyrRs enzyme inhibitor is an anti-aging drug, a DNA repair drug, a drug for treating and / or preventing cancer, or a drug for treating and / or preventing neurodegenerative diseases; preferably, the cancer is cervical cancer, lung cancer, breast cancer, colon cancer, or ovarian cancer.
6. The use according to claim 5, characterized in that The medicine is a spray, a liquid preparation or a solid preparation.
7. The use according to claim 6, characterized in that The spray includes aerosol; the liquid preparation includes suspension, emulsion, solution or syrup; the solid preparation includes tablet, capsule or granule.
8. The use according to claim 7, characterized in that The solution includes injection; the granules include granules.
9. The use according to claim 5, characterized in that The administration route of the drug is oral administration, sublingual administration, injection or mucosal dialysis.
10. The use according to claim 9, characterized in that The injection includes intravenous injection, intramuscular injection, intraperitoneal injection or subcutaneous injection; preferably, the intravenous injection includes intravenous drip.