Compound with p53 agonist activity, agonist and application thereof

Abstract

The invention discloses a compound with p53 agonistic activity, an agonist, application of the agonist and pharmaceutically acceptable salt, stereoisomer, tautomer or solvate of the compound, the compound is shown as a formula (I): # imgabs0 #, R1 and R2 are respectively and independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 halogenated alkyl or C1-6 halogenated alkoxy; x and Y are independently C or N optionally substituted heterocyclic rings, and the compound has stable properties and good p53 agonist activity, can be used as a p53 agonist or drug, is used for agonizing expression or activity of p53 protein in cells, and effectively prevents and / or treats related diseases mediated by p53 mutant protein.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a compound with p53 agonist activity, an agonist and use thereof. Background Art

[0002] The protein product of the TP53 gene (p53) is considered to be one of the most important tumor suppressors to date. Unlike RB1, CDKN2A, and PTEN, which are lost in tumors through homozygous deletion, TP53 is often found to have somatic missense mutations. However, targeting p53 mutations has not been validated in clinical therapy to date. TP53 mutant cells accumulate high levels of mutant p53 protein, which has a dominant negative effect on wild-type (WT) p53 and its homologous proteins p63 and p73, causing them to lose their normal regulatory functions for cell cycle and apoptosis. The results of experiments on conditional regulation of p53 expression in mouse tissues have shown that in different mouse models, restoration of p53 expression can inhibit lymphoma and sarcoma growth through apoptosis, providing a theoretical basis for tumor therapy using the restoration of normal p53 function. In addition to enhancing wild-type p53 activity in tumors with an intact Tp53 genotype, restoring its wild-type protein function in tumors expressing mutant p53 is also a promising strategy for cancer treatment.

[0003] The core domain of wild-type p53 is labile, with low thermodynamic and kinetic stability, allowing rapid cycling between folded and unfolded states. Mutations of these core region residues in mutant p53 result in increased thermodynamic and kinetic instability, which in turn renders the core DNA-binding domain inactive for DNA binding. These effects can be exploited to design ligands that selectively bind to the native state of p53 protein to reverse the thermodynamic and kinetic denaturation caused by these mutations. Notably, this particular mutation, Y220C, mediates the formation of a surface pocket distal to the DNA-binding core domain, making it an ideal target for the treatment of tumors harboring this mutation. To date, a number of Y220C pocket binders have been developed to stabilize p53 mutants and reactivate their transcriptional activity, but with limited efficacy.

[0004] Therefore, the development of drugs with p53 mutant agonist activity is of great significance for the prevention / treatment of tumor-related diseases involving p53 protein. Summary of the invention

[0005] The present invention provides a compound having p53 mutant Y220C protein agonist activity and use thereof, so as to improve the stability and agonist activity of the compound.

[0006] In one embodiment, the present invention provides a compound as shown in formula (I), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0007]

[0008] Wherein, R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0009] X and Y are each independently a heterocyclic ring optionally substituted with C or N.

[0010] In one embodiment, the present invention provides a compound as shown in formula (II), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0011]

[0012] Wherein, R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0013] X and Z are each independently a heterocycle optionally substituted by C or N;

[0014] Y is a heterocyclic ring optionally substituted by S or O.

[0015] In one embodiment, the present invention provides a compound as shown in formula (III), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0016]

[0017] Wherein, R is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0018] X is a heterocyclic ring optionally substituted by S or O;

[0019] Y is a heterocycle optionally substituted by C or N;

[0020] n is any integer between 1 and 6.

[0021] In one embodiment, the present invention provides a compound as shown in formula (IV), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0022]

[0023] Wherein, R is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0024] X is a heterocyclic ring optionally substituted by S or O;

[0025] Y and Z are each independently selected from a heterocyclic ring optionally substituted with C or N.

[0026] In one embodiment, the present invention provides a compound as shown in formula (V), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0027]

[0028] Where R represents H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0029] X is a heterocyclic ring optionally substituted by S or O;

[0030] Y and Z are each independently selected from a heterocycle optionally substituted by C or N;

[0031] n is any integer between 1 and 6.

[0032] In one embodiment, the present invention provides a p53 agonist comprising: a compound of formula (I) to formula (V) as described above, and a pharmaceutically acceptable salt.

[0033] Optionally, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, oxalate, acetate, trifluoroacetate or citrate.

[0034] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) to formula (V) as described above or a p53 agonist as described above; and a pharmaceutically acceptable carrier and / or excipient.

[0035] In one embodiment, the present invention provides a use of a compound of formula (I) to formula (V) as described above in the preparation of a medicament for promoting the expression or activity of p53 protein.

[0036] In one embodiment, the present invention provides a use of a compound of formula (I) to formula (V) as described above for the preparation of a drug for preventing and / or treating a disease or symptom mediated by p53 protein.

[0037] Optionally, the p53 protein-mediated disease is selected from the group consisting of tumors, nervous system diseases, metabolic diseases and respiratory system diseases.

[0038] Optionally, the p53 protein-mediated disease is selected from the group consisting of colorectal cancer, liver cancer, lung cancer, stroke and atherosclerosis.

[0039] In one embodiment, the present invention provides a use of the p53 agonist as described above in the preparation of a medicament for promoting the expression or activity of p53 protein.

[0040] In one embodiment, the present invention provides a use of the p53 agonist as described above in the preparation of a drug for preventing and / or treating a disease or symptom mediated by the p53 protein.

[0041] Optionally, the p53 protein-mediated disease is selected from the group consisting of tumors, nervous system diseases, metabolic diseases and respiratory system diseases.

[0042] Optionally, the p53 protein-mediated disease is selected from the group consisting of colorectal cancer, liver cancer, lung cancer, stroke and atherosclerosis.

[0043] The beneficial effect of the present invention is that the present invention provides a small molecule compound with p53 mutant Y220C agonist activity, the compound has stable properties, has good p53 agonist activity, and can be used as a p53 agonist or drug to stimulate the expression or activity of p53 protein in cells, and effectively prevent and / or treat related diseases mediated by p53 mutant protein. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For those skilled in the art, other drawings can be obtained based on these drawings without creative work.

[0045] Figure 1 is a hydrogen spectrum of the compound represented by formula (VI);

[0046] Figure 2 is a hydrogen spectrum of the compound represented by formula (VII);

[0047] Figure 3is a hydrogen spectrum of the compound represented by formula (VIII);

[0048] Figure 4 is a hydrogen spectrum of the compound represented by formula (IX);

[0049] Figure 5 is a hydrogen spectrum of the compound represented by formula (X);

[0050] Figure 6 The results of the test of compound VI's agonistic activity on the p53 mutant Y220C protein are shown. DETAILED DESCRIPTION

[0051] According to an embodiment of the present invention, a compound as shown in formula (I), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0052]

[0053] Wherein, R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0054] X and Y are each independently a heterocyclic ring optionally substituted with C or N.

[0055] In one embodiment, the compound represented by formula (I) may be represented by the following formula (VI):

[0056]

[0057] In one embodiment, the present invention provides a compound as shown in formula (II), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0058]

[0059] Wherein, R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0060] X and Z are each independently a heterocycle optionally substituted by C or N;

[0061] Y is a heterocyclic ring optionally substituted by S or O.

[0062] In one embodiment, the compound shown in formula (II) may be a structure shown in formula (VII):

[0063]

[0064] In one embodiment, the present invention provides a compound as shown in formula (III), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0065]

[0066] Wherein, R is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0067] X is a heterocyclic ring optionally substituted by S or O;

[0068] Y is a heterocycle optionally substituted by C or N;

[0069] n is any integer between 1 and 6.

[0070] In one embodiment, the compound represented by formula (III) may be represented by the following formula (VIII):

[0071]

[0072] In one embodiment, the present invention provides a compound as shown in formula (IV), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0073]

[0074] Wherein, R is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0075] X is a heterocyclic ring optionally substituted by S or O;

[0076] Y and Z are each independently selected from a heterocyclic ring optionally substituted with C or N.

[0077] In one embodiment, the compound represented by formula (IV) may be represented by the following formula (IX):

[0078]

[0079] In one embodiment, the present invention provides a compound as shown in formula (V), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0080]

[0081] Where R represents H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0082] X is a heterocyclic ring optionally substituted by S or O;

[0083] Y and Z are each independently selected from a heterocycle optionally substituted by C or N;

[0084] n is any integer between 1 and 6.

[0085] In one embodiment, the compound represented by formula (V) may be a structure represented by formula (X):

[0086]

[0087] In one embodiment, the present invention provides a p53 agonist comprising: a compound of formula (I) to formula (V) as shown above, and a pharmaceutically acceptable salt, including but not limited to hydrochloride, sulfate, oxalate, acetate, trifluoroacetate or citrate.

[0088] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) to formula (V) as shown above or a p53 agonist as described above; and a pharmaceutically acceptable carrier.

[0089] In one embodiment, the present invention provides a use of a compound of formula (I) to formula (V) as described above in the preparation of a medicament for promoting the expression or activity of p53 protein.

[0090] In one embodiment, the present invention provides a use of a compound of formula (I) to formula (V) as described above for the preparation of a drug for preventing and / or treating a disease or symptom mediated by p53 protein.

[0091] Optionally, the p53 protein-mediated disease is selected from the group consisting of tumors, nervous system diseases, metabolic diseases and respiratory system diseases, including but not limited to colorectal cancer, liver cancer, lung cancer, stroke, atherosclerosis, etc.

[0092] In one embodiment, the present invention provides a use of the p53 agonist as described above in the preparation of a medicament for promoting the expression or activity of p53 protein.

[0093] In one embodiment, the present invention provides a use of the p53 agonist as described above in the preparation of a drug for preventing and / or treating a disease or symptom mediated by the p53 protein.

[0094] Optionally, the p53 protein-mediated disease is selected from the group consisting of tumors, nervous system diseases, metabolic diseases and respiratory system diseases, including but not limited to colorectal cancer, liver cancer, lung cancer, stroke, atherosclerosis, etc.

[0095] As used herein, the term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or subject, including water, oil, minerals, cream base, lotion base, ointment base, etc. The above-mentioned base includes suspending agents, viscosity increasing agents, transdermal enhancers, etc. In addition, their preparations are well known to those skilled in the field of cosmetics or topical medicines.

[0096] The pharmaceutical composition of the present invention can be prepared into various conventional dosage forms known in the art, including, but not limited to, tablets suitable for oral administration (including various coated tablets, sustained-release or controlled-release tablets), capsules (including soft capsules and hard capsules), granules, dispersible powders, aqueous or oily suspensions, emulsions, elixirs or syrups, etc.; creams, ointments, gels, aqueous or oily solutions or suspensions, etc. suitable for topical use; powders or liquid aerosols suitable for inhalation, sterile aqueous or oily intravenous, subcutaneous or intramuscular injections, suppositories, etc. suitable for parenteral administration. Typical routes of use of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal routes, etc. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intradermal injection or infusion techniques.

[0097] As used herein, the term "treatment" refers to a method for obtaining beneficial or desired results (including clinical results). For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation or improvement of one or more symptoms, alleviation of the extent of the disease, stabilization of the disease state (i.e., no worsening), prevention of disease spread, delay or slowing of disease progression, improvement of the disease state, alleviation, and relief (partial or complete relief). The term "treatment" can also mean that the survival period is prolonged if compared to the expected survival period without treatment.

[0098] As used herein, the term "therapeutically effective amount" refers to an amount that effectively achieves the desired therapeutic result at the required dosage and within the required time period. "Therapeutically effective amount" can vary according to a variety of factors, such as disease state, age, sex and weight of individual patients, and the ability of the compounds of the present invention to cause the desired response in individuals. "Therapeutically effective amount" is also the amount in which the beneficial effects of treatment exceed any toxic or harmful effects of treatment. The therapeutically effective amount of tumor therapy can also be measured by the ability to stabilize disease progression, or reduce the size of the tumor, or completely eliminate it. The ability of the treatment to inhibit cancer can be evaluated in an animal model system predicted to be effective in human tumors. Alternatively, this property of the composition can be evaluated by using an in vitro analysis known to a person skilled in the art to examine the ability of the compound to inhibit cell growth or induce apoptosis. Skilled practitioners will be able to determine these amounts based on the patient's physique, the severity of the patient's symptoms, and a specific route of administration.

[0099] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids or with organic acids, such as nitric acid, phosphoric acid, carbonic acid; the organic acids are such as propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid; or salts formed when the acidic protons present on the parent compound are replaced by metal ions, for example, alkali metal ions or alkaline earth metal ions; or coordination compounds formed with organic bases, such as ethanolamine and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. In addition to the form of salts,

[0100] As used herein, the term "solvate" refers to a substance formed by combining a compound of the present invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid. Solvates include stoichiometric solvates and non-stoichiometric solvates. Certain compounds of the present invention may exist in unsolvated or solvated forms. Generally speaking, solvated forms are comparable to unsolvated forms and are included within the scope of the present invention.

[0101] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers, and the compounds of the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as meso, racemate, equal mixture of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. The compounds of the present invention have optical isomers derived from asymmetric carbons, etc., and if necessary, a single isomer can be obtained by methods known in the art, such as crystallization or chiral chromatography.

[0102] As used herein, the term "C1-C6 alkyl" refers to straight and branched aliphatic groups consisting of 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0103] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and monofluoromethyl.

[0104] As used herein, the term "C1-C6 alkoxy" refers to an -O-C1-C6 alkyl group.

[0105] As used herein, the term "C1-C6 haloalkoxy" refers to -O-C1-C6 haloalkyl.

[0106] As used herein, the term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, for example, a monocyclic heterocyclic group, a spiro heterocyclic group, a fused heterocyclic group, and a bridged heterocyclic group.

[0107] Those skilled in the art know that in the pharmaceutical composition of the present invention, the appropriate amount of the p53 agonist as the active ingredient and the pharmaceutically acceptable carrier, and the selection of the preferred effective amount can be determined by those of ordinary skill in the art based on various factors. The factors include, but are not limited to: pharmacokinetic parameters of the active ingredient such as metabolism, half-life, bioavailability, etc.; severity of the patient's condition, the patient's weight, immune status, route of administration, etc. Those skilled in the art also know how to prepare a pharmaceutical composition containing the present invention.

[0108] The present invention will be further described below in conjunction with specific examples. The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial sources. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0109] Example 1: Acquisition of Compounds

[0110] Compounds VI, VII, VIII, IX, and X were synthesized by Shanghai Taoshu Biotechnology Co., Ltd. The hydrogen spectra of compounds VI, VII, VIII, IX, and X are shown in Figure 1 , 2 , 3, 4, and 5.

[0111] Example 2: Testing of the agonistic activity of single concentration compounds VI to X on the p53 mutant Y220C protein in vitro.

[0112] An in vitro screening system for p53 mutant Y220C protein agonists was established, and the ability of compounds to activate p53 mutant Y220C protein was evaluated using time-resolved fluorescence resonance energy transfer assay (TR-FRET assay).

[0113] (1) Expression and purification of p53 mutant Y220C protein. Construct a prokaryotic expression vector APC-Y220C and express a large amount of p53 mutant Y220C protein in strain BL-21. Then, use affinity ion exchange, gel filtration and other chromatography methods to obtain the purified protein p53-Y220C expressed by the recombinant plasmid;

[0114] (2) Preparation of compound stock solution: 1 mg of each compound molecule was accurately weighed and dissolved in DMSO to an initial concentration of 20 mM.

[0115] (3) Prepare 1× reaction buffer.

[0116] (4) Add 4 μL of 4× diluted compound working solution to the reaction plate.

[0117] (5) Prepare 4× P53 Y220C solution and make up with 1× reaction buffer.

[0118] (6) Add 4 μL of 4×P53 Y220C solution to the reaction plate.

[0119] (7) Seal the reaction plate with a sealing film, centrifuge at 1000 rpm for 1 minute, and incubate in a 25°C incubator for 60 minutes. Prepare 4× Bio-DNA solution and make up to 1× reaction buffer.

[0120] (8) Prepare 4×Detection (HIS-Eu and Streptavidin-d2) solution and make up with 1× reaction buffer.

[0121] (9) Add 4 μL of 4×Bio-DNA solution and 4 μL of 4×Detection solution to the reaction plate.

[0122] (10) Seal the reaction plate with a sealing film and centrifuge at 1000 rpm for 1 minute.

[0123] (11) Incubate the cells in a 25°C incubator in the dark overnight.

[0124] (12) Read the 665nm / 615nm data using a multifunctional microplate reader.

[0125] (13) Data processing: The activity percentage (%Activity) is calculated as follows:

[0126] C=(Ave_Ac-Ave_Ba) / (Ave_Dc-Ave_Bd)

[0127] R data=(A-Ave_Ba-CD) / (D-Ave_Bd)*(Ave_Dc-Ave_Bd)

[0128] %Activity=R data / Ave_VC*100

[0129] Table 1

[0130] A Data of compounds at 665nm D Data of compounds at 615nm Ba Blank hole data at 665nm B Blank hole data at 615nm Dc HIS-Eu data at 615nm Ac Streptavidin-d2 data at 665nm

[0131] The results are shown in Table 2:

[0132] Table 2: Ability of Compounds VI-X (100 μM) to Activate p53 Y220C Protein

[0133]

[0134]

[0135] Example 3: Compound VI was tested for its agonistic activity against p53 mutant Y220C protein. The test results are shown in Figure 6 shown.

[0136] Referring to the steps in Example 1, the data was processed using a nonlinear fitting formula to obtain the EC of the compound. 50 (half agonist concentration): GraphPad 8.0 software was used for data analysis and the corresponding dose-effect curve was drawn. The results are shown in Figure 6As shown, it can be known that the agonist activity of compound VI on the p53 mutant Y220C protein in vitro is 104.8 μM.

[0137] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and modifications without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, in, R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; X and Y are each independently a heterocyclic ring optionally substituted with C or N.

2. A compound represented by formula (II), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, in, R1 and R2 are each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; X and Z are each independently a heterocycle optionally substituted by C or N; Y is a heterocyclic ring optionally substituted by S or O.

3. A compound represented by formula (III), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, in, R is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; X is a heterocyclic ring optionally substituted by S or O; Y is a heterocyclic ring optionally substituted by C or N; n is any integer between 1 and 6.

4. A compound represented by formula (IV), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, in, R is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; X is a heterocyclic ring optionally substituted by S or O; Y and Z are each independently selected from a heterocyclic ring optionally substituted with C or N.

5. A compound represented by formula (V), a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, in, R stands for H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; X is a heterocyclic ring optionally substituted by S or O; Y and Z are each independently selected from a heterocycle optionally substituted by C or N; n is any integer between 1 and 6.

6. A p53 agonist, characterized in that Comprising: the compound according to any one of claims 1 to 5; and a pharmaceutically acceptable salt.

7. The p53 agonist according to claim 6, characterized in that: The pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, oxalate, acetate, trifluoroacetate and citrate.

8. A pharmaceutical composition, characterized in that The invention comprises: the compound according to any one of claims 1 to 5 or the p53 agonist according to claim 6; and a pharmaceutically acceptable carrier and / or excipient.

9. Use of the composition according to any one of claims 1 to 5 for preparing a medicament for promoting the expression or activity of p53 protein.

10. Use of the composition according to any one of claims 1 to 5 for the preparation of a drug for preventing and / or treating a disease or symptom mediated by p53 protein.

11. The use according to claim 10, characterized in that: The p53 protein-mediated disease is selected from the group consisting of tumors, nervous system diseases, metabolic diseases and respiratory system diseases.

12. The use according to claim 11, characterized in that: The p53 protein-mediated disease is selected from the group consisting of colorectal cancer, liver cancer, lung cancer, stroke and atherosclerosis.

13. Use of the p53 agonist as claimed in claim 6 in the preparation of a drug for promoting the expression or activity of p53 protein.

14. Use of the p53 agonist according to claim 6 in the preparation of a drug for preventing and / or treating a disease or symptom mediated by p53 protein.

15. The use according to claim 14, characterized in that: The p53 protein-mediated disease is selected from the group consisting of tumors, nervous system diseases, metabolic diseases and respiratory system diseases.

16. The use according to claim 15, characterized in that: The p53 protein-mediated disease is selected from the group consisting of colorectal cancer, liver cancer, lung cancer, stroke and atherosclerosis.

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