ALKBH8 small-molecule inhibitor as well as preparation method and application thereof

Abstract

The invention relates to an ALKBH8 small-molecule inhibitor as well as a preparation method and application thereof. Specifically, the invention discloses an ALKBH8 small-molecule inhibitor of a compound as shown in a formula I. The invention also provides a preparation method of the compound, experiments prove that the ALKBH8 is a potential new target of an aging inhibitor, and the invention also discloses application of the compound in the aspect of preventing and / or treating aging-related diseases. # imgabs0 # (I).

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to ALKBH8 small molecule inhibitors and preparation methods and uses thereof. Background Art

[0002] ALKBH8 (alkB homolog 8) is a key RNA-modifying enzyme belonging to the AlkB family of dioxygenases. In humans, it primarily regulates tRNA modification to maintain the accuracy of protein translation and cellular stress responses. Loss of ALKBH8 function can lead to neurodevelopmental disorders, cancer susceptibility, and impaired stress responses, highlighting its importance as a fundamental biological hub and potential therapeutic target.

[0003] Aging contributes to the development and progression of numerous diseases, including cancer, fibrosis, and metabolic disorders. The senescence-associated secretory phenotype, specifically the secretion of inflammatory factors, primarily mediates these biological effects of senescent cells. Inhibiting the secretion of inflammatory factors could effectively inhibit the progression of inflammatory senescence and related diseases, but molecular targets and intervention strategies are currently lacking.

[0004] Although ALKBH8 has been reported to inhibit aging (May Y Lee et al, Redox Biology, 2020, PMID: 31765888), it is unclear whether it affects the expression of aging inflammatory factors in already senescent cells.

[0005] Therefore, there is an urgent need in the art to design a class of ALKBH8 inhibitors with novel structures and to develop new targets for preventing and / or treating aging-related diseases to overcome the shortcomings of existing technologies. Summary of the Invention

[0006] The primary objective of this invention is to provide a novel ALKBH8 inhibitor and, for the first time, to propose ALKBH8 as a therapeutic target for age-related inflammation and aging-related diseases. The invention also provides methods for preparing the compound and its use in preventing and / or treating age-related diseases.

[0007] The first aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, (I) in, R1 is selected from the following groups: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 haloalkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 halocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S; Selected from the following groups: substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S; The substitution refers to substitution by one or more substituents selected from the following groups: halogen, -OH, -CN, azido, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl.

[0008] In another preferred embodiment, R1 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl.

[0009] In another preferred embodiment, R1 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 halocycloalkyl.

[0010] In another preferred embodiment, Selected from the following groups: substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S; In another preferred embodiment, is a substituted or unsubstituted C6-C10 aryl group or a substituted or unsubstituted 5-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; In another preferred embodiment, the heteroaryl group is selected from the following group: pyridine, pyrimidine, pyrazine, thiophene, thiazole, pyrazole, pyrrole, imidazole, furan, oxazole, isoxazole; and the heteroaryl group is optionally substituted by a substituent selected from the following group: halogen, -OH, -CN, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl.

[0011] In another preferred embodiment, the substitution refers to substitution by one or more substituents selected from the following groups: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl.

[0012] In another preferred embodiment, the compound is selected from the following group: .

[0013] The second aspect of the present invention provides a method for preparing the compound described in the first aspect of the present invention, the specific steps are as follows:

[0014] Step 1: Compound I-1 and 4-bromo-2-hydrazinopyridine (II-1) undergo condensation reaction in methanol using hydrochloric acid as a catalyst to obtain a compound of formula III-1; Step 2: The compound of formula III-1 undergoes a Suzuki coupling reaction with the compound of formula IV-1 in the presence of a palladium catalyst in a mixed solvent of water and organic solvent 1 to obtain a compound of formula I; When R1 is H, the method further comprises step three: hydrolyzing the compound represented by formula I in solvent 2 by a base to obtain a compound represented by formula IA.

[0015] The third aspect of the present invention provides a composition comprising: (i) the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable carrier.

[0016] The fourth aspect of the present invention provides a use of the compound according to the first aspect of the present invention, wherein the use comprises: (i) as an ALKBH8 inhibitor; (ii) as a skin anti-aging agent; (iii) for use in the preparation of a medicament for preventing and / or treating aging-related diseases.

[0017] In another preferred embodiment, the aging-related disease is selected from the following group: tumors, liver fibrosis, pulmonary fibrosis, cardiovascular diseases, neurodegenerative diseases, musculoskeletal system diseases, respiratory system diseases, and chronic obstructive pulmonary disease.

[0018] In another preferred embodiment, the cardiovascular disease is atherosclerosis.

[0019] In another preferred embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease and Parkinson's disease.

[0020] In another preferred embodiment, the musculoskeletal system disease is selected from the group consisting of osteoporosis and sarcopenia.

[0021] In another preferred embodiment, the respiratory disease is pneumonia.

[0022] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Figure 2 shows the specific upregulation of ALKBH8 protein during aging, as demonstrated in cell and animal studies. Figures a and b show expression levels of the senescence markers p16 and p21 after 48 hours of cytosine treatment (a) or 4-hydroxytamoxifen-induced RAS expression (b). Figures c and d show expression levels of the senescence marker p21 in liver tissue from young (2-month-old) and aged (18-month-old) mice, or mice irradiated with 4 Gy (d).

[0024] Figure 2 Figures ac and d show that ALKBH8 promotes aging-related secretion. Figures a and c show gene expression changes in young cells, senescent control cells, and senescent cells with ALKBH8 knockdown (a), signaling pathway analysis (b), and expression changes of specific inflammatory cytokine genes (c). d shows cytokine microarray analysis of inflammatory cytokine secretion in normally cultured young cells, senescent control cells, and senescent cells with ALKBH8 knockdown.

[0025] Figure 3 The biological functions of ALKBH8 in regulating the aging-related secretory phenotype are shown. In ab, tumor cells TOV-21G and young cells, aging control cells or aging cells with different sequences of ALKBH8 knockdown were mixed and transplanted subcutaneously into nude mice, and the tumor growth curves at different time points (a) and the tumor weight at the final time point (b) were monitored. ce, using Alkbh8 Flox / FloxConditional knockout mice were irradiated with 4 Gy to induce systemic aging. Seven days later, the mice were randomly divided into two groups, with five mice in each group. AAV-Cre virus was injected into the tail vein to achieve liver-specific knockout of the Alkbh8 gene (gene knockout) or AAV-GFP control virus was injected to retain the Alkbh8 gene (wild type). Seven days later, liver tissue was collected to detect changes in mRNA expression levels of inflammatory factors (d). SA- -gal staining and statistics (e).

[0026] Figure 4 The compounds of the present invention are shown to reduce inflammation in aging tissues. In particular, a, Compound 10, Compound 12, and Compound 13 were analyzed for changes in mcm5U and mchm5U levels through in vitro enzyme activity assays. b, After treating aging IMR90 cells with different concentrations of Compound 1, the mRNA expression of aging inflammatory factors IL1A and IL1B was detected. cg, After intraperitoneal injection of solvent or Compound 1, the mice were monitored for changes in body weight (c), changes in liver weight ratio were compared (d), and changes in alanine aminotransferase (e) and aspartate aminotransferase (f) activity were detected. Seven days after administration, liver tissue was collected to compare changes in the expression of inflammatory factors (g). DETAILED DESCRIPTION

[0027] After extensive and in-depth research, the inventors discovered for the first time that ALKBH8 is significantly overexpressed in senescent cells and tissues, demonstrating its potential as a biomarker for aging. The inventors have developed a series of ALKBH8 inhibitors and, for the first time, applied them in the anti-aging field. These compounds possess novel structures, and in vitro biochemical experiments and in vivo cell and mouse studies have demonstrated that the compounds of the present invention have broad potential applications in reducing aging-related inflammation and inhibiting aging-related diseases. This work has led to the completion of the present invention.

[0028] The inventors discovered for the first time that ALKBH8 promotes the expression and secretion of inflammatory factors in senescent cells, mediating the biological effects of senescent cells, including tumor growth promotion and immune surveillance. The inventors designed and demonstrated that the small molecule compound 10 can inhibit ALKBH8 enzymatic activity in vitro, and compound 1 can inhibit the expression of inflammatory factor genes in senescent cells and the tissue inflammation they mediate in vivo, thereby alleviating aging-related diseases.

[0029] the term In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0030] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0031] In the present invention, "C1-C6 alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. The similar term "C1-C4 alkyl" has a similar definition.

[0032] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and the like. "C1-C4 alkoxy" and similar terms have similar definitions.

[0033] In the present invention, the term "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms and containing at least one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0034] In the present invention, the term "C2-C6 alkynyl" refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms and containing at least one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0035] In the present invention, the term "C3-C8 cycloalkyl" represents a cyclic aliphatic hydrocarbon group consisting of 3 to 8 ring carbon atoms, and so on; it should be understood that the "cycloalkyl" described in the present invention includes not only monocyclic aliphatic hydrocarbon groups, but also cyclic, spirocyclic and bridged ring systems composed of multiple cyclic aliphatic hydrocarbons; the "cycloalkyl" described in the present invention includes not only aliphatic hydrocarbon groups with fully saturated carbon atoms, but also aliphatic hydrocarbon groups with unsaturated bonds in some of the carbon atoms; examples of the "cycloalkyl" described in the present invention include, but are not limited to: 、 、 、 、 、 、 、 When a cycloalkyl group is used as a substituent, the connection site with the main body of the molecule can occur at any chemical bond-permitted position on the cycloalkyl group. Similar terms such as "C3-C6 cycloalkyl" have similar definitions.

[0036] In the present invention, the term "aryl" refers to a monocyclic ring system and a bicyclic ring system composed of a specific number of carbon atoms and obeying Hückel's rule; it should be understood that when the "aryl" described in the present invention is a bicyclic ring system, it includes not only the case where all rings are aromatic rings, but also the case where only one ring is an aromatic ring and the other ring is a non-aromatic aliphatic ring.

[0037] In the present invention, the term "C6-C10 aryl" refers to a ring system having 6 to 10 carbon atoms, at least one of which is an aromatic ring; examples of the "aryl" of the present invention include but are not limited to 、 、 、 etc.; when "aryl" is used as a substituent, the connection site with the main body of the molecule occurs on the aromatic ring.

[0038] In the present invention, the term "heterocycloalkyl" refers to a cyclic group that indicates a specific number of ring atoms, contains at least one ring heteroatom (N, O or S), is saturated or partially unsaturated, and is non-aromatic; it should be understood that the "heterocyclyl" described in the present invention includes not only monocyclic heterocyclic ring systems, but also polycyclic heterocyclic ring systems, such as cyclic, spirocyclic and bridged rings; when the "heterocyclyl" is a polycyclic system, at least one ring contains a ring heteroatom, and the other rings may contain ring heteroatoms or may be cycloalkyl; for example, the term "4-8 membered heterocycloalkyl" refers to a monocyclic or polycyclic ring system with 4 to 8 ring atoms, at least one of which is a heteroatom, saturated or partially unsaturated; the definitions of other similar terms are similar; preferably, the number of heteroatoms is 1 to 3. Including (but not limited to) the following groups: 、 、 、 、 、 、 、 、 、 、 、 etc.; it should be understood that when a "heterocyclic group" is used as a substituent, the connection site with the main body of the molecule can occur at any chemical bond-allowed position on the "heterocyclic group".

[0039] In the present invention, the term "heteroaryl" refers to a cyclic group with a specific number of ring atoms, containing at least one ring heteroatom (N, O, or S), and having aromatic properties. Unless otherwise specified, the "heteroaryl" herein includes not only monocyclic heteroaromatic systems but also polycyclic heteroaromatic systems, such as bicyclic heteroaromatics, tricyclic heteroaromatics, and tetracyclic heteroaromatics. When the "heteroaryl" is a polycyclic heteroaromatic system, at least one ring is aromatic, and the other rings can be aromatic or non-aromatic, and the heteroatoms can be located in either aromatic or non-aromatic rings. Polycyclic heteroaromatic systems include not only paracyclic systems but also bridged and spirocyclic systems. The term "5-7 membered heteroaryl" refers to a cyclic group with 5 to 7 ring atoms, at least one of which is a heteroatom, and having aromatic properties. The definitions of other similar terms are similar.

[0040] In the present invention, the term "halo" means substituted with halogen.

[0041] In the present invention, the term "optionally" means that when there are a series of candidate groups to choose from, some of them can be selected, or none of them can be selected.

[0042] The term "independently" used in the present invention means that several substituents defined simultaneously do not affect each other when selected from the same series of candidate groups, and they may be the same or different.

[0043] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0044] In the present invention, the term "1-6" refers to 1, 2, 3, 4, 5 or 6, and other similar terms independently have similar meanings.

[0045] It should be understood that when a group is present at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. In other words, the term "selected from the group consisting of:" and the term "each independently selected from the group consisting of:" have the same meaning.

[0046] Compounds of formula I of the present invention The present invention provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, (I) wherein each group is as defined above.

[0047] Preferably, R1 is selected from the following group: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 halocycloalkyl.

[0048] Preferably, is a substituted or unsubstituted C6-C10 aryl group or a substituted or unsubstituted 5-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; In another preferred embodiment, in the compound, R1 and Any one of them is independently the corresponding group in the specific compound described in the present invention.

[0049] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed between a positively charged group on the compound of formula (I) and an anion, or a salt formed between a negatively charged group on the compound of formula (I) and a cation. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronide, lactate, glutarate, or maleate. Suitable cations include, but are not limited to, sodium, potassium, magnesium, calcium, ammonium, and the like.

[0050] In another preferred embodiment, the pharmaceutically acceptable salts of the present invention refer to salts formed by the compound represented by general formula (I) with the following acid groups, such as but not limited to: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, malonic acid, fumaric acid , propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or a salt formed by the compound represented by general formula (I) and an inorganic base, such as but not limited to sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt; or a salt formed by the compound represented by general formula (I) and an organic base, such as but not limited to methylamine salt, ethylamine salt, ethanolamine salt, hydroxymethylaminomethane (TRIS) ammonium salt, etc.

[0051] Preparation method of the compound of formula I of the present invention The examples of the present invention specifically describe the preparation methods of the compounds of formula (I) of the present invention, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily made by those skilled in the art.

[0052] Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0053] Specifically, the present invention provides a chemical synthesis method for preparing the compound, the specific steps are as follows:

[0054] Step 1: Compound I-1 and 4-bromo-2-hydrazinopyridine (II-1) undergo condensation reaction in methanol using hydrochloric acid as a catalyst to obtain a compound of formula III-1; Step 2: The compound of formula III-1 undergoes a Suzuki coupling reaction with the compound of formula IV-1 in the presence of a palladium catalyst in a mixed solvent of water and organic solvent 1 to obtain a compound of formula I; When R1 is H, the method further comprises step three: hydrolyzing the compound represented by formula I in solvent 2 by a base to obtain a compound represented by formula IA.

[0055] The palladium-containing catalyst in step 2 is selected from the group consisting of tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, or a combination thereof.

[0056] Preferably, the organic solvent 1 is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, acetonitrile, N , N -dimethylformamide, N , N -dimethylacetamide, or a combination thereof.

[0057] Preferably, the base in step 3 is selected from the group consisting of lithium hydroxide (including its monohydrate), sodium hydroxide, potassium hydroxide, or a combination thereof.

[0058] Preferably, the solvent 2 is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, water, or a combination thereof.

[0059] Pharmaceutical compositions and methods of administration The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-1000 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0060] A "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein refers to the ability of the components of the composition to blend with the compound of the invention, and with each other, without significantly reducing the compound's efficacy. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0061] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0062] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0063] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0064] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0065] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0066] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0067] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0068] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0069] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0070] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-aging drugs).

[0071] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0072] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0073] Compared with the prior art, the advantages of the present invention are mainly: 1. This invention is the first to discover ALKBH8 as a new target for the treatment of inflammatory aging.

[0074] 2. This invention designs a series of compounds for the first time, which achieve the effect of inflammatory aging treatment by targeting ALKBH8 receptor.

[0075] 3. The compounds described in the present invention can effectively inhibit the secretion of inflammatory factors and the ability of senescent cells to promote tumor growth.

[0076] 4. The compounds described in the present invention specifically inhibit the catalytic activity of ALKBH8 and block downstream aging-related inflammatory pathways.

[0077] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally performed according to conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0078] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0079] Unless otherwise specified, in the following examples, NMR measurements were performed using a Varian Mercury Plus 400 (400 MHz room temperature probe) and the solvent used was deuterated dimethyl sulfoxide (DMSO- d 6 ), deuterated chloroform (CDCl3), internal standard is tetramethylsilane (TMS), chemical shift is expressed in δ, in ppm, peak type is expressed as: s (singlet), d (doublet), t (triplet), dd (double of doublets), q (quartet), dt (double of triplets), m (multiplet). Coupling constant ( J ) in Hz. Results were analyzed using a MestReNova 14. MS measurements were performed using an Agilent 6120 liquid chromatograph-mass spectrometer (ESI); column chromatography was performed using a SANTAI SepaBean machine T rapid preparative instrument.

[0080] Compound Preparation Examples Example 1: 1-(4-phenylpyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 1)

[0081] Step 1: 1-(4-bromopyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate Ethyl 2-formyl-3-oxopropanoate (317.1 mg, 2.2 mmol, 1.1 equiv.) and 4-bromo-2-hydrazinopyridine (376.5 mg, 2.0 mmol, 1.0 equiv.) were dissolved in 5 mL of methanol, 0.7 mL of 6 mol / L hydrochloric acid was added, and the mixture was stirred at 25 °C for 8 h. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was filtered under reduced pressure. The filter cake was washed with 5 mL of water and dried under reduced pressure to obtain 1-(4-bromopyridin-2-yl)- ... H -Ethyl pyrazole-4-carboxylate was obtained as a light yellow solid, 510 mg, with a yield of 85%. 1 H NMR (400MHz, CDCl3) δ 8.93 (s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H), 8.04 (s,1H), 7.35 (dd, J = 5.2, 1.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz,3H). Step 2: 1-(4-phenylpyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 1) 1-(4-bromopyridin-2-yl)-1 H 1-(4-phenylpyridin-2-yl)-1-(4-phenylpyridin-2-yl)-2-nitropropane-1-yl)-1-nitropropane-1-ylpyridin-2 ... H -Ethyl pyrazole-4-carboxylate was obtained as a white solid, 89 mg, with a yield of 90%. 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.48 (d, J= 5.2 Hz, 1H), 8.26 (d, J = 1.0 Hz, 1H), 8.14 (s, 1H), 7.77 – 7.70 (m, 2H), 7.54 – 7.47 (m, 4H), 4.35(q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). Example 2: 1-(4-(4-methoxyphenyl)pyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 2)

[0082] The preparation method refers to Example 1, except that the phenylboric acid in step 2 is replaced by 4-methoxyphenylboric acid. 1 H NMR (400MHz, CDCl3) δ 9.11 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 1.0 Hz, 1H),8.14 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.47 (dd, J = 5.1, 1.3 Hz, 1H), 7.36 (d, J = 8.5 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 2.54 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). Example 3: 1-(4-(4-fluorophenyl)pyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 3)

[0083] The preparation method refers to Example 1, except that the phenylboric acid in step 2 is replaced by 4-fluorophenylboric acid. 1 H NMR (400MHz, CDCl3) δ 9.08 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.20 (s, 1H), 8.13 (s,1H), 7.71 (dd, J= 8.7, 5.2 Hz, 2H), 7.49 – 7.42 (m, 1H), 7.25 – 7.06 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). Example 4: 1-(4-(3-fluorophenyl)pyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 4)

[0084] The preparation method is as described in Example 1, except that the phenylboric acid in step 2 is replaced by 3-fluorophenylboric acid. 1 H NMR (400MHz, CDCl3) δ 9.01 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 0.8 Hz, 1H),8.07 (s, 1H), 7.48 – 7.32 (m, 4H), 7.12 (d, J = 7.4 Hz, 1H), 4.28 (q, J = 7.1 Hz,2H), 1.32 (t, J = 7.1 Hz, 3H). Example 5: 1-(4-(4-trifluoromethylphenyl)pyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 5)

[0085] The preparation method is as described in Example 1, except that the phenylboric acid in step 2 is replaced with 4-trifluoromethylphenylboric acid. 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.26 (s, 1H), 8.14(s, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.48 (dd, J = 5.1, 1.4Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). Example 6: 1-(4-(4-trifluoromethoxyphenyl)pyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 6)

[0086] The preparation method is as described in Example 1, except that the phenylboric acid in step 2 is replaced by 4-trifluoromethoxyphenylboric acid. 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 8.14(s, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.45 (dd, J = 5.1, 1.4 Hz, 1H), 7.36 (d, J = 8.5Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). Example 7: 1-(4-(3,5-dimethoxyphenyl)pyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 7)

[0087] The preparation method is as described in Example 1, except that the phenylboric acid in step 2 is replaced with 3,5-dimethoxyphenylboric acid. 1 H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.25 – 8.19 (m, 1H), 8.14 (s, 1H), 7.45 (dd, J = 5.2, 1.6 Hz, 1H), 6.83 (d, J = 2.2 Hz, 2H), 6.57 (t, J = 2.2 Hz, 1H), 3.87 (s, 6H). Example 8: 1-([4,4'-bipyridyl]-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 8)

[0088] The preparation method is as described in Example 1, except that the phenylboronic acid in step 2 is replaced by pyridin-4-ylboronic acid. 1 H NMR (400MHz, CDCl3) δ 9.09 (s, 1H), 8.80 (d, J = 6.0 Hz, 2H), 8.58 (d, J = 5.1 Hz, 1H),8.30 (s, 1H), 8.15 (s, 1H), 7.69 (d, J = 5.6 Hz, 2H), 7.51 (dd, J = 5.2, 1.5 Hz,1H), 4.36 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). Example 9: 1-(4-(4-methylthiazol-5-yl)pyridin-2-yl)-1 H -Ethyl pyrazole-4-carboxylate (Compound 9)

[0089] The preparation method refers to Example 1, except that the phenylboric acid in step 2 is replaced with (4-methylthiazol-5-yl)boronic acid pinacol ester. 1 H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.82 (s, 1H), 8.48 (d, J = 5.1 Hz,1H), 8.12 (d, J = 5.9 Hz, 2H), 7.33 (dd, J = 5.1, 1.1 Hz, 1H), 4.35 (q, J = 7.1 Hz,2H), 2.68 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). Example 10: 1-(4-phenylpyridin-2-yl)-1 H -Pyrazole-4-carboxylic acid (Compound 10)

[0090] Compound 1 (60 mg, 0.20 mmol) was dissolved in 2 mL of a methanol / tetrahydrofuran (v / v / v=4:1) mixed solvent, and 2 mol / L NaOH solution (1 mL, 2 mmol, 10.0 equiv.) was added. The reaction was carried out at 50 °C for 8 h. After cooling to room temperature, 5 mL of water was added, and the pH was adjusted to 4 with 6 mol / L hydrochloric acid solution. Most of the organic solvent was removed under reduced pressure, and the product was filtered under reduced pressure. The filter cake was washed with 2 mL of water and dried under reduced pressure to obtain compound 10 as a white solid, 40.7 mg, in a yield of 75%. 1 H NMR (400 MHz, DMSO) δ12.82 (s, 1H), 9.00 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.25 – 8.19 (m, 2H), 7.91 (dd, J = 8.0, 1.4 Hz, 2H), 7.80 (dd, J = 5.2, 1.6 Hz, 1H), 7.63 – 7.53 (m,3H). Example 11: 1-(4-(4-methoxyphenyl)pyridin-2-yl)-1 H -Pyrazole-4-carboxylic acid (Compound 11)

[0091] The preparation method refers to Example 10, except that compound 1 is replaced by compound 2. 1 H NMR (400 MHz, DMSO) δ12.82 (s, 1H), 8.99 (s, 1H), 8.58 (d, J = 5.3 Hz, 1H), 8.21 (d, J = 2.6 Hz, 2H),7.87 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 5.3, 1.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H),2.56 (s, 3H). Example 12: 1-(4-(4-fluorophenyl)pyridin-2-yl)-1 H -Pyrazole-4-carboxylic acid (Compound 12)

[0092] The preparation method refers to Example 10, except that compound 1 is replaced by compound 3. 1H NMR (400 MHz, DMSO) δ12.83 (s, 1H), 8.97 (s, 1H), 8.58 (s, 1H), 8.19 (s, 2H), 7.96 (s, 2H), 7.77 (s, 1H), 7.40 (s, 2H). Example 13: 1-(4-(4-trifluoromethylphenyl)pyridin-2-yl)-1 H -Pyrazole-4-carboxylic acid (Compound 13)

[0093] The preparation method refers to Example 10, except that compound 1 is replaced by compound 5. 1 H NMR (400 MHz, DMSO) δ12.83 (s, 1H), 9.02 (s, 1H), 8.67 (s, 1H), 8.26 (d, J = 21.7 Hz, 2H), 8.13 (s,2H), 7.94 (d, J = 6.9 Hz, 2H), 7.87 (s, 1H). Example 14: 1-([4,4'-bipyridyl]-2-yl)-1 H -Pyrazole-4-carboxylic acid (Compound 14)

[0094] The preparation method was similar to that of Example 10, except that compound 1 was replaced with compound 8. ESI-MS: m / z 267.2 [M+H] + C 14 H 10 N4O2. Example 15: 1-(4-(4-methylthiazol-5-yl)pyridin-2-yl)-1 H -Pyrazole-4-carboxylic acid (Compound 15)

[0095] The preparation method refers to Example 10, except that compound 1 is replaced by compound 9. 1 H NMR (400 MHz, DMSO) δ12.81 (s, 1H), 9.21 (s, 1H), 8.98 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.22 (s,1H), 8.04 (s, 1H), 7.62 (dd, J= 5.2, 1.4 Hz, 1H), 2.63 (s, 3H). Biological experiment test case Test Example 1 Verifies that specific upregulation of ALKBH8 protein is a biomarker of senescence or aging Experimental principle: Using various aging models, including those induced by the chemotherapy drug etoposide or 4-hydroxytamoxifen (4-OHT) to induce expression of the proto-oncogene RAS, the researchers used immunoblotting to analyze the relationship between ALKBH8 protein levels and the classic aging markers p16 and p21. ALKBH8 protein levels were compared between young and aged tissues in mice irradiated with 4 Gy of X-rays to induce systemic aging, as well as in naturally aged (18-month-old) mice.

[0096] Experimental materials and instruments:

[0097] Experimental methods: Western blotting: Cells or tissue samples are lysed using RIPA, and protein concentration is determined using a BCA assay kit. Equal amounts of protein are loaded onto the sample and then subjected to protein gel electrophoresis.

[0098] 1. Gel running conditions: constant voltage 110 V, electrophoresis 80 min.

[0099] 2. Transfer (wet transfer) conditions: constant voltage 110 V, transfer time 80 min.

[0100] 3. Block the plate with 5% skim milk powder and shake at room temperature for 1 hour.

[0101] 4. Primary Antibody Incubation: Add the corresponding primary antibody and incubate overnight at 4°C on a shaker.

[0102] 5. Secondary Antibody Incubation. After recovering the primary antibody, wash the membrane three times with 1x TBST on a shaker at room temperature. Add the corresponding rabbit or mouse antibody and incubate on a shaker at room temperature for 1 hour. After incubation, wash the membrane three times with 1x TBST on a shaker at room temperature.

[0103] 6. Visualize protein bands using ECL. Collect data using a protein imaging device.

[0104] The structure of etoposide is as follows:

[0105] The structure of 4-OHT is as follows:

[0106] Experimental conclusion: like Figure 1 A and Figure 1 As shown in Figure b, in senescent cells, ALKBH8 protein levels were specifically upregulated, consistent with the classic senescence markers p16 and p21. Figure 1 Middle C and Figure 1 As shown in middle d, ALKBH8 is also specifically upregulated in aged tissues, which together indicate that ALKBH8 is a biomarker of senescence or aging.

[0107] Test Example 2 Verifies that ALKBH8 promotes mRNA expression and protein secretion of aging inflammatory factors Experimental Materials:

[0108] Experimental methods: Three experimental groups were used: young cells, control senescent cells with knockdown of ALKBH8, and senescent cells with knockdown of ALKBH8. Transcriptome sequencing was used to compare transcriptome changes among the three groups. Cytokine arrays were used to detect changes in inflammatory cytokine secretion levels among the three groups.

[0109] Experimental results: from Figure 2 As shown in Figure a, the loss of ALKBH8 caused a large number of gene expression changes. Figure 2 As shown in middle b, multiple signaling pathways related to inflammatory factors changed significantly in the ALKBH8 knockdown senescent cell group, such as Figure 2 As shown in Figure c, the expression levels of some important aging inflammatory factors are significantly reduced. Cytokine chip is a high-throughput secretory protein detection technology that uses this technology to analyze the expression levels of multiple cytokines (such as interleukins, chemokines, growth factors, etc.). Figure 2 As shown in middle d, ALKBH8 deficiency significantly reduces the secretion of aging-related inflammatory factors. Therefore, the transcriptome data combined with the cytokine array data indicate that ALKBH8 promotes the expression and secretion of aging-related inflammatory factors.

[0110] Test Example 3: ALKBH8 mediates the biological effects of aging inflammatory factors in promoting tumor growth and immune surveillance Experimental Materials:

[0111] Experimental methods: The ability of ALKBH8 to regulate senescent cells and promote tumor cell proliferation was tested in immunodeficient mice. TOV-21G tumor cells and cells were mixed in PBS / Matrigel at a 1:2 ratio (5x105 tumor cells, 1x106 senescent cells) and inoculated subcutaneously on the dorsal flanks of nude mice. The cells were divided into young cells, senescent control cells, and senescent cells with different ALKBH8 knockdown sequences. After one week, the body weight and tumor volume of the nude mice were monitored every three days, and tumor growth curves were plotted and compared.

[0112] Using 4Gy sublethal dose of radiation, Alkbh8 flox / flox After 7 days, AAV-TBG-Cre or AAV-TBG-GFP control virus was injected into the tail vein to reach the liver, achieving liver-specific knockout of the Alkbh8 gene. After another 7 days, liver tissue was collected for analysis of inflammatory factor mRNA expression and SA- -gal staining and statistical analysis.

[0113] SA- -Gal staining: The staining solution is formulated with a pH of 5.5.

[0114]

[0115] (1) Obtain liver tissue, embed it in OCT, and cut it on ice.

[0116] (2) Fix with 0.5% glutaraldehyde at room temperature for 15 minutes.

[0117] (3) Add SA-β-gal staining solution and place in a 37°C CO2-free constant temperature incubator. After 6-8 hours, observe the tissue staining under bright field. After appropriate color development, wash with PBS to terminate the reaction, stain with eosin and seal the slides. Take photos under a microscope and calculate the positive ratio.

[0118] RNA extraction and quantitative PCR: RNA was extracted using the Bio-Tech RNA Extraction Kit. The same amount of RNA was reverse transcribed using the Novozymes Reverse Transcription Kit to obtain cDNA, which was diluted at a ratio of 1:25 to prepare a template. The quantitative PCR system was prepared according to the following ingredients:

[0119] Quantitative PCR procedure:

[0120] Repeat steps 2-3 for 40 cycles. Analyze the expression of target gene mRNA based on the Ct value using the 2-ΔΔCt method.

[0121] Experimental results: like Figure 3 A and Figure 3 As shown in middle b, the experimental results show that the growth of tumor cells in the mixed senescent cell group with ALKBH8 knockdown is slowed down. Figure 3 Middle C and Figure 3 As shown in Figure d, compared with the wild-type control, after knocking out Alkbh8 using the Cre enzyme expressed in the liver, the expression of liver inflammatory factors was analyzed and it was found that the Alkbh8 knockout mouse group expressed lower levels of inflammatory factors, suggesting that the degree of tissue inflammation was at a lower level than that of the wild-type control group. Figure 3 As shown in middle e, further SA-β-gal staining analysis of the liver revealed that the staining signal was significantly reduced after gene knockout, which also indicated a lower degree of tissue aging.

[0122] Test Example 4 The compounds of the present invention specifically inhibit the enzyme activity of ALKBH8 and its biological function of promoting the expression of aging inflammatory factors Experimental methods: The effects of the compounds of the present invention on the levels of 5-carboxymethoxyuridine (mchm5U) were detected by performing in vitro enzyme activity experiments using recombinant protein ALKBH8 and combining with LC-MS characterization.

[0123] The enzyme activity reaction system was configured at pH 7.5.

[0124]

[0125] Senescent cells were treated with different doses of Compound 1 for 96 hours, and the mRNA expression levels of aging-related inflammatory factors were analyzed. To test the toxicity of the small molecule, mice were intraperitoneally administered 25 mg / kg daily for one month. The biosafety of the compound was verified by measuring the liver weight ratio and the enzyme activity levels of alanine aminotransferase and aspartate aminotransferase in the serum of the mice. One week after irradiation, the mice were treated with the same concentration of Compound 1 or the solvent (10% Solutol HS15) for one week, and the mRNA expression levels of aging-related inflammatory factors were observed.

[0126] Experimental results: like Figure 4 As shown in Figure a, using in vitro enzyme activity reaction experiments, it was found that compound 10, compound 12 and compound 13 specifically reduced the production of ALKBH8 product mchm5U. Figure 4 As shown in Figure b, compound 1 can significantly reduce the mRNA expression of aging-related inflammatory factors. Figure 4 Middle C to Figure 4The results of the experiment showed that the body weight of normal mice did not change significantly, and the liver-to-weight ratio and the activity levels of alanine aminotransferase and aspartate aminotransferase in serum did not change either, proving the biosafety of the small molecule compound. Figure 4 As shown in Figure 2, compound 1 significantly reduced the expression of aging-related inflammatory factors (Cxcl1, Oas1 and Mmp3).

[0127] This study identifies ALKBH8 as a novel target for the treatment of inflammatory aging and successfully develops a series of small-molecule inhibitor compounds. These compounds effectively inhibit the secretion of inflammatory factors and the tumor-promoting ability of senescent cells, as well as inflammation in aging tissues. Experiments at the enzyme, cell, and animal levels demonstrate that these compounds specifically inhibit the catalytic activity of ALKBH8, blocking downstream aging-related inflammatory pathways. This study develops novel targets for the prevention and / or treatment of aging-related diseases and has potential applications as anti-aging agents for the skin, promising broad applications.

[0128] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, (I) in, R1 is selected from the following groups: H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 haloalkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 halocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S; Selected from the following groups: substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S; The substitution refers to substitution by one or more substituents selected from the following groups: halogen, -OH, -CN, azido, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl.

2. The compound according to claim 1, wherein R1 is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, and substituted or unsubstituted C3-C8 cycloalkyl.

3. The compound according to claim 1, wherein R1 is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C8 halocycloalkyl.

4. The compound according to claim 1, wherein Selected from the following groups: substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S.

5. The compound according to claim 1, wherein is a substituted or unsubstituted C6-C10 aryl group or a substituted or unsubstituted 5-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S.

6. The compound according to claim 1, wherein The heteroaryl group is selected from the following group: pyridine, pyrimidine, pyrazine, thiophene, thiazole, pyrazole, pyrrole, imidazole, furan, oxazole, isoxazole; and the heteroaryl group is optionally substituted by a substituent selected from the following group: halogen, -OH, -CN, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl.

7. The compound according to claim 1, wherein The compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 8. A composition, characterized in that Include: (i) the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable carrier.

9. A use of the compound according to claim 1, characterized in that, The uses include: (i) as an ALKBH8 inhibitor; (ii) as a skin anti-aging agent; (iii) for use in the preparation of a medicament for preventing and / or treating aging-related diseases.

10. The use according to claim 9, characterized in that The aging-related diseases are selected from the group consisting of tumors, liver fibrosis, pulmonary fibrosis, cardiovascular diseases, neurodegenerative diseases, musculoskeletal system diseases, respiratory system diseases, and chronic obstructive pulmonary disease.

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