Ester compound and application thereof

Abstract

The invention discloses a compound or a pharmaceutically acceptable salt, a solvate, a hydrate, a polymorphic substance, a eutectic, a tautomer, a stereoisomer or an isotope labeled compound thereof. The compound is shown as a formula (I). The invention also discloses application of the compound in preparation of medicines for preventing or treating senescence-related diseases. # imgabs0 #

Description

Ester compounds and their applications Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a compound capable of targeting and killing senescent cells and its application in preventing or treating aging-related diseases. Background Art

[0002] With aging, the body's biological functions gradually decline, and the aging process is often accompanied by the onset of various age-related diseases. Therefore, developing effective intervention strategies for aging is crucial for extending the healthy lifespan of the elderly and reducing the incidence of age-related diseases. The accumulation of senescent cells in the body is a key driver of aging and age-related diseases. On the one hand, the senescence of some proliferating cells or stem cells leads to a decline in the body's regenerative capacity, affecting the body's recovery and normal function. More importantly, senescent cells secrete a large number of inflammatory factors, known as the senescence-associated secretory phenotype (SASP), which creates a chronic inflammatory microenvironment, accelerates the aging process, and promotes the development of age-related diseases. Studies have shown that the specific elimination of senescent cells through genetic methods or small chemical molecules can reduce chronic inflammation, enhance tissue repair capacity, improve symptoms of age-related diseases such as osteoarthritis and idiopathic pulmonary fibrosis, and alleviate the decline in physiological function in aging organisms. Therefore, selective elimination of senescent cells is a promising approach for treating age-related diseases and improving physiological function in the elderly.

[0003] Senescent cells possess numerous characteristics, among which permanent cell cycle arrest is a hallmark shared by all senescent cells, primarily dependent on p16 and p21. Another widespread characteristic is increased β-gal activity in senescent cells, which can be detected even at a suboptimal pH of 6.0. This enzyme, termed senescence-associated-β-galactosidase (SA-β-gal), is termed senescence-associated-β-galactosidase (SA-β-gal). Senescent cells cultured in vitro typically exhibit enlarged nuclei and cytoplasm, and a flattened shape. Hallmarks of senescence also include activation of the DNA damage response, increased endoplasmic reticulum stress and ROS levels, and enhanced SASP secretion. Furthermore, anti-apoptotic components in senescent cells are significantly induced to resist apoptosis, exemplified by increased expression of the anti-apoptotic proteins BCL2 / BCL-XL. Consequently, senescent cells are also referred to as zombie cells, aging but not dying. Inducing cellular senescence initially had beneficial physiological effects by inhibiting tumor formation and promoting wound healing. However, subsequent studies have shown that the long-term presence of senescent cells in tissues may contribute to the development of aging-related diseases, and that the inflammatory cytokines secreted by senescent cells can even further promote tumorigenesis.

[0004] The causal relationship between the accumulation of senescent cells and aging and the development of age-related diseases has been clearly elucidated through genetic approaches. In 2011, Professor Deursen's research group at the Mayo Clinic constructed INK-ATTAC transgenic mice driven by the p16 promoter. This system selectively expresses the FKBP-CASP8 fusion protein only in p16-positive senescent cells. Upon treatment with the small molecule AP20187, the FKBP-CASP8 fusion protein dimerizes and induces apoptosis in p16-positive senescent cells. Intermittently depleting senescent cells using this approach in Bub1b mutant progeria mice significantly improved sarcopenia, cataracts, and lipodystrophy. A 2016 study, in which researchers administered AP20187 every two weeks to naturally aged INK-ATTAC mice to deplete senescent cells, demonstrated that depletion of p16-positive senescent cells attenuated age-related degeneration in several tissues and organs, including the kidneys, heart, and fat, and extended median lifespan. Professor Kirland's research team implanted only a small number of senescent cells into recipient mice, which then triggered persistent physical dysfunction in young mice, leading to functional decline and increased mortality. These findings demonstrate from various perspectives that eliminating senescent cells in vivo can extend lifespan and delay the onset of age-related diseases, providing a theoretical basis for strategies to target senescent cells for anti-aging and treatment of age-related diseases.

[0005] Currently, several small molecule compounds that can selectively eliminate senescent cells have been reported, and these small molecules are also called "senolytics." Due to the heterogeneity of senescent cells, although these senolytics can achieve selective killing of senescent cells to a certain extent, there is still room for improvement in reducing toxicity and increasing the specificity of killing. Most early senolytics target important components of the senescent cell anti-apoptotic pathway (SCAP), that is, they induce senescent cells' death by blocking their anti-apoptotic signals. Compared with normal cells, the expression of the anti-apoptotic proteins BCL2 / BCL-XL in senescent cells is significantly increased, antagonizing the activity of pro-apoptotic proteins such as Bax, making senescent cells resistant to apoptosis. As a dual inhibitor of the classic anti-apoptotic proteins BCL2 / BCL-XL, ABT263 (navitoclax) was subsequently shown to specifically induce apoptosis in senescent cells.

[0006] A-1331852 is a small molecule inhibitor specific for the Bcl-xL protein. In addition to its potent cytotoxicity against Bcl-xL-dependent cancer cells, A-1331852 also exhibits high selectivity against senescent cells. While Bcl-xL is cytotoxic against senescent cells, it still has a potent cytotoxic effect on normal cells at certain concentrations. Therefore, its safety profile for normal cells needs to be further improved.

[0007] Discovering the differences between senescent and non-senescent cells is fundamental to achieving targeted recognition and killing of senescent cells. The inventors discovered that carboxylesterase activity in senescent cells is significantly higher than in non-senescent cells. Therefore, carboxylesterases may serve as potential markers for senescent cells, providing a theoretical basis for the application of prodrug strategies based on the activation of this enzyme. Currently, there is a lack of Bcl-xL inhibitors modified from A-1331852 that can more efficiently and specifically induce apoptosis in senescent cells and utilize this approach for anti-aging and treatment of aging-related diseases in mammals. The present invention utilizes the high esterase activity in senescent cells to design novel prodrug compounds that meet these needs and provide related advantages.

[0008] Summary of the Invention

[0009] In order to solve at least one technical problem existing in the prior art, the present invention provides a class of compounds that can selectively kill senescent cells and tumor cells within a larger safety window, while reducing the side effects of killing normal cells, and have higher selectivity and safety.

[0010] The first aspect of the present application provides a compound represented by formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope-labeled compound thereof,

[0011] In Formula I,

[0012] R1 is selected from substituted or unsubstituted C1-C 10 alkylene;

[0013] R2 is selected from -OC(O)- or -OC(O)-O-;

[0014] R3 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, substituted or unsubstituted C2-C20 heteroalicyclic; or, R1 is absent or selected from substituted or unsubstituted C1-C 10Alkylene, R2 is absent, and R3 is selected from substituted or unsubstituted C2-C20 heteroalicyclic groups;

[0015] Each R a independently selected from hydrogen, halogen, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, nitro and cyano;

[0016] R b is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl, and substituted or unsubstituted C1-C20 heteroaryl;

[0017] L is selected from substituted or unsubstituted C1-C 10 alkylene;

[0018] R c is selected from substituted or unsubstituted adamantyl groups.

[0019] In some embodiments, the substitution involves a substituent selected from a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C10 alkoxy group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group or a C2-C8 alkynyl group, a C1-C10 alkyl group substituted with halogen and / or hydroxyl group, a C3-C8 cycloalkyl group substituted with halogen and / or hydroxyl group, a C2-C8 alkenyl group substituted with halogen and / or hydroxyl group or a C2-C8 alkynyl group substituted with halogen and / or hydroxyl group, a C3-C8 cycloalkyl group substituted with halogen and / or hydroxyl group

[0020] In some embodiments, the C2-C20 heteroalicyclic group optionally contains 1 or 2 heteroatoms selected from N or O in the ring.

[0021] In some embodiments, the C2-C20 heteroalicyclic group is optionally replaced by a halogen atom, a cyano group, a nitro group, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 alkoxy group, a C6-C10 aryloxy group, a C2-C10 heteroalicyclic group, an amino group, a hydroxyl group, a thiol group, a carbonyl group, a carboxyl group, an acyl group, -NR4R5 is substituted by one or more substituents, R4 and R5 are independently selected from hydrogen, C6-C10 aryl, C1-C10 heteroaryl, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl and C2-C8 alkynyl, and the aryl and heteroaryl are optionally substituted by halogen atoms, hydroxyl, thiol, amino, nitro, cyano, carboxyl, acyl, C1-C8 alkoxy, C6-C10 aryl, C1-C10 heteroaryl, C2-C10 heteroalicyclic group, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C8 alkynyl, optionally, the substituents at at least two positions together constitute a C3-C10 alicyclic ring, C2-C10 heteroalicyclic ring, C6-C10 aromatic ring or C1-C10 heteroaromatic ring.

[0022] In some embodiments, the compound is represented by Formula III, IV, or V:

[0023] In formula III and IV, R1 is selected from independently selected from substituted or unsubstituted C1-C 10 Alkylene, preferably, R1 is selected from independently selected from substituted or unsubstituted C1-C6 alkylene, preferably, R1 is selected from independently selected from substituted or unsubstituted C1-C4 alkylene; R a 、R b , R3, R c , L is defined as in formula I;

[0024] In Formula V, R1 is absent or selected from independently selected from substituted or unsubstituted C1-C 10 Alkylene, preferably, R1 is selected from independently selected from substituted or unsubstituted C1-C6 alkylene, preferably, R1 is selected from independently selected from substituted or unsubstituted C1-C4 alkylene, R3 is selected from substituted or unsubstituted C2-C20 heteroalicyclic group, R a 、R b 、R c , L are defined the same as in formula I.

[0025] In some embodiments, the C2-C20 heteroalicyclic group is optionally selected from a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a C1-C10 alkoxy group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, Substituents are substituted, each R5 is independently selected from hydrogen and C1-C6 alkyl.

[0026] In some embodiments, the C2-C20 heteroalicyclic group is a C4-C8 heteroalicyclic group; the heteroalicyclic group is optionally substituted by halogen, -NH2, -OH, -NO2, carbonyl, -CH2OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

[0027] In some embodiments, the C2-C20 heteroalicyclic group is selected from the group shown below:

[0028] R' independently represents no substituent, a single substituent or multiple substituents, each substituent is independently selected from deuterium, hydroxyl, halogen, NH2, carboxyl (-COOH), C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, phenyl, benzyl;

[0029] L2 is absent or C1-C6 alkylene, halogen, hydroxyl, C1-C6 alkoxy substituted C1-C6 alkylene, preferably methylene, ethylene, propylene;

[0030] R6 is H, deuterium, halogen, hydroxyl, NH2, carboxyl (-COOH), -CONH2, sulfonic acid (-SO3H), -SO2-C1-C6 chain alkyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, phenyl or benzyl.

[0031] In some embodiments, each R a In some embodiments, each R a independently selected from hydrogen, halogen, substituted or unsubstituted C1-C5 alkoxy and substituted or unsubstituted C1-C5 alkyl.

[0032] In some embodiments, each R a All are hydrogen.

[0033] In some embodiments, R bIt is selected from substituted or unsubstituted C1-C6 alkyl groups, preferably substituted or unsubstituted C1-C3 alkyl groups, and more preferably methyl groups.

[0034] In some embodiments, L is selected from substituted or unsubstituted C1-C6 alkylene, preferably substituted or unsubstituted C1-C3 alkylene. In some implementations, L is methylene.

[0035] In some embodiments, the compound is represented by Formula II:

[0036] In formula II, the definitions of R1, R2, and R3 are the same as those of formula I, that is:

[0037] R1 is selected from substituted or unsubstituted C1-C 10 alkylene;

[0038] R2 is selected from -OC(O)- or -OC(O)-O-;

[0039] R3 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, substituted or unsubstituted C2-C20 heteroalicyclic.

[0040] In some embodiments, R1 is a substituted or unsubstituted C1-C6 alkylene group, preferably a substituted or unsubstituted C1-C3 alkylene group, and more preferably a methylene group.

[0041] In some embodiments, R3 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C2-C12 heteroaryl, or substituted or unsubstituted C1-C12 heteroalicyclic.

[0042] Preferably, R3 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C1-C10 heteroalicyclic.

[0043] In the present application, "substituted or unsubstituted" means that one or more hydrogen atoms in the group described therein may be replaced by a substituent, and the substituent may be selected from a halogen atom, a cyano group, a nitro group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C1-C10 chain alkyl group, a C1-C10 chain alkoxy group, a C6-C20 aryloxy group, a C1-C20 heteroalicyclic group, preferably a C1-C10 heteroalicyclic group, an amino group, a hydroxyl group, a thiol group, a phosphate group, -OC(O)R6, -ONR6R7, -NR6R7, and R6 and R7 are independently selected from hydrogen, C6-C20 aryl group, C1-C20 heteroaryl group, C1-C8 chain alkyl group, C The aryl and heteroaryl groups are optionally substituted by a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C6 alkoxy group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group or a C2-C8 alkynyl group, wherein the substituents at at least two positions together constitute an aliphatic ring, such as a C3-C20 aliphatic ring, a heteroaliphatic ring, such as a C2-C20 aliphatic ring, an aromatic ring, such as a C6-C20 aromatic ring or a heteroaromatic ring, such as a C1-C20 heteroaromatic ring.

[0044] In some embodiments, R3 is selected from the following groups:

[0045] In some embodiments, the compound is selected from the following compounds:

[0046] The second aspect of the present application provides a method for preventing or treating aging-related diseases, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound described in the first aspect of the present application or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope-labeled compound thereof.

[0047] Specifically, the aging-related disease is a disease associated with the accumulation of senescent cells. Preferably, the disease is selected from idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, viral-induced inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrosing pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritic neuropathy, keratitis sicca, Fuch's corneal dystrophy, presbyopia, cataracts, degenerative vitreous disorders including vitreomacular traction syndrome, macular hole, retinal tear, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, herniated disc, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease , diabetes, diabetic nephropathy, scars, superficial or flat scars, cord-like or contracture scars, webbed scars, depressed scars, atrophic scars, bridge-like and hypertrophic scars, hypertrophic scars, keloids, scar cancer, scleroderma, morphea, scleroderma zona, guttate scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, fat dysfunction, coronary artery disease, cerebrovascular disease The invention also includes one or more of: arthritis, periodontal disease, cancer treatment-related disabilities such as atrophy and fibrosis in various tissues, brain and heart damage, and treatment-related myelodysplastic syndrome, promyelocytic syndrome, ataxia-telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysms, inflammatory bowel disease, lipoatrophy, renal transplant failure, sarcopenia, wound healing, alopecia, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

[0048] The second aspect of the present application provides a compound or its pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope-labeled compound for use in the preparation of a medicament for preventing or treating aging-related diseases, wherein the compound is the compound described in the first aspect of the present application.

[0049] Specifically, the aging-related disease is a disease associated with the accumulation of senescent cells. Preferably, the disease is selected from idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, viral-induced inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrosing pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritic neuropathy, keratitis sicca, Fuch's corneal dystrophy, presbyopia, cataracts, degenerative vitreous disorders including vitreomacular traction syndrome, macular hole, retinal tear, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, herniated disc, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease , diabetes, diabetic nephropathy, scars, superficial or flat scars, cord-like or contracture scars, webbed scars, depressed scars, atrophic scars, bridge-like and hypertrophic scars, hypertrophic scars, keloids, scar cancer, scleroderma, morphea, scleroderma zona, guttate scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, fat dysfunction, coronary artery disease, cerebrovascular disease The invention also includes one or more of: arthritis, periodontal disease, cancer treatment-related disabilities such as atrophy and fibrosis in various tissues, brain and heart damage, and treatment-related myelodysplastic syndrome, promyelocytic syndrome, ataxia-telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysms, inflammatory bowel disease, lipoatrophy, renal transplant failure, sarcopenia, wound healing, alopecia, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

[0050] The compounds provided by the present invention can reduce the side effects of killing normal cells, selectively kill senescent cells and tumor cells within a larger safety window, and have higher selectivity and safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] FIG1 shows the results of measuring carboxylesterase activity in normal and senescent cells.

[0052] Figure 2 shows the cell viability assay results of the compounds on normal and senescent cells.

[0053] Figure 3 shows that intravitreal (IVT) administration of RZ001-RZ006 and RZ201 resulted in statistically significant improvements in avascular zone and vascular proliferation.

[0054] Figure 4 shows that intravitreal (IVT) administration of RZ001, RZ002, and RZ201 in the diabetic macular model can improve vascular permeability in both retinal and choroidal vascular leakage at these dose levels.

[0055] FIG5 shows statistically significant improvements in fluorescence intensity metrics of the CNV macular model following intravitreal (IVT) administration of RZ001, RZ002, and RZ201.

[0056] Figure 6 shows that intraperitoneal (IP) administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in WBC, HYP, and pathology scores in an IPF model.

[0057] FIG7 shows that intra-articular administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in plantar mechanical pain threshold and pathological scores of Safranin Fast Green staining in an osteoarthritis (OA) model.

[0058] FIG8 shows that intraperitoneal administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvement in Aβ42 pathogenic protein levels in an Alzheimer's disease (AD) mouse model.

[0059] Figure 9 shows that intraperitoneal (IP) administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and pathology in a liver fibrosis model.

[0060] Figure 10 shows that topical application of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in epidermal thickness scores in a naturally aged mouse model.

[0061] Figure 11 shows that intraperitoneal (IP) administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in serum creatinine (Cr) and urea nitrogen (BUN) levels and pathology in a renal fibrosis model.

[0062] FIG12 shows that administration of RZ001 resulted in a statistically significant improvement in the scar hyperplasia index in the rabbit ear hypertrophic scar model. DETAILED DESCRIPTION

[0063] The present invention is described in detail below with reference to the examples and accompanying drawings. These examples are based on the present invention as a technical solution and provide detailed implementation plans and processes. However, the implementation plans provided herein are exemplary and intended to explain the present invention, and are not to be construed as limiting the present invention. Conditions and methods not specified in the following examples were performed conventionally.

[0064] definition

[0065] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl group. Depending on the structure, the alkyl group can be a monovalent group or a divalent group (i.e., an alkylidene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "low alkyl group" having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, amyl, hexyl, etc. It should be understood that "alkyl" mentioned herein includes all possible configurations and conformations of the alkyl group, for example, "propyl" mentioned herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl and tert-butyl, and "pentyl" includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and penta-3-yl, etc.

[0066] The term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.

[0067] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl includes a group having 3-12 ring atoms. According to structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylidene). In the present invention, cycloalkyl is preferably a cycloalkyl having 3-8 carbon atoms, more preferably a "low cycloalkyl" having 3-6 carbon atoms. The example of cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and adamantyl.

[0068] The term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, an aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0069] The term "heteroaryl" refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The N-containing "heteroaryl" moiety refers to an aromatic group in which at least one skeletal atom on the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monovalent group or a divalent group (i.e., a heteroarylidene group). Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, and furopyridinyl.

[0070] As used herein, the term "alicyclic group" or "cycloalkyl" refers to a non-aromatic ring consisting of three or more carbon atoms, wherein two adjacent carbon atoms within the ring may have a single bond, a double bond, or a triple bond, and the number of rings may be one or more. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclopentenyl, and cyclohexadienyl.

[0071] As used herein, the term "heterocycloalkyl" or "heteroalicyclic" refers to a non-aromatic ring in which one or more of the atoms forming the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. A heterocycloalkyl group may be composed of three, four, five, six, seven, eight, nine, or more than nine atoms. A heterocycloalkyl group may be optionally substituted. Examples of heteroalicyclic groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiinane, 1,4-oxathiinane, 1,4-oxathiinane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbital Acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heteroalicyclic group can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

[0072] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0073] The term "carbonyl" refers to an organic functional group composed of two atoms, carbon and oxygen, connected by a double bond (C=O).

[0074] The term "optionally" means that one or more of the subsequently described events may or may not occur, and includes both events that occur and events that do not occur.

[0075] The salts that may be formed by the compounds of the present invention also fall within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps during the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount, such as an equivalent amount, of an acid or base, salts out in a medium, or is obtained by freeze-drying in an aqueous solution.

[0076] The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,

[0014] Examples of the present invention include, for example, hydroxyethylsulfonates, lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, and the like.

[0077] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromide), etc.

[0078] Prodrugs and solvates of the compounds of the present invention are also within the scope of this invention. The term "prodrug" herein refers to a compound that undergoes chemical transformation by metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when treating a related disease. "Solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. The combination of one or more water molecules with a molecule of a substance forms a hydrate, in which the water remains in its molecular state H2O. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

[0079] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0080] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0081] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0082] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0083] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0084] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The definitions of specific functional groups are consistent with those in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, which is incorporated by reference in its entirety.

[0085] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0086] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0087] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0088] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0089] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms of nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0090] Example 1 Synthesis of Compounds

[0091] Synthesis of compound RZ001

[0092] Procedure: To a solution of A-1331852 (398 mg, 0.6041 mmol, 1.00 eq) in DMF (8.0 ml) were added potassium carbonate (160 mg, 1.92 eq) and potassium iodide (99 mg, 0.98 eq) in sequence. After stirring for 10 minutes, chloromethyl isobutyrate (100 mg, 1.21 eq) was added. Heat and stir in an oil bath at 50°C for 4 hours, then cool and add water. Extract with ethyl acetate, wash with saturated brine, and dry. Concentrate and column chromatography was performed.

[0093] 1 HNMR(400MHz,Chloroform-d)δ7.85(m,1H),7.59(d,1H),7.42-7.45(m,2H),7.31-7.34(m,4H),7.22-7.24(m,1H),6.93(d,1H),5.78(s,2H),5.0 1(s,2H), 4.03(t,2H), 3.72(s,2H), 3.04(t,2H), 2.51-2.55(m,1H), 2.12 (s,3H), 1.95-2.05(m,3H), 1.59-1.72(m,12H), 1.14(s,3H), 1.12(s,3H)

[0094] Synthesis of compound RZ003

[0095] Procedure: To a solution of A-1331852 (40 mg, 0.06071 mmol, 1.00 eq) in DMF (1.0 mL) was added potassium carbonate (15 mg, 1.79 eq). Stir at room temperature for 30 min, followed by the addition of a solution of chloromethyl pivalate (SM7, 11 mg, 1.20 eq) in DMF (1.0 mL). Heat in an oil bath at 50°C and stir for 5 h. Dilute with ethyl acetate, wash with water, and dry. Filter and concentrate. Purify by column chromatography.

[0096] 1 HNMR(400MHz,Chloroform-d)δ11.00(s,1H),7.85(m,1H),7.54(d,1H),7.43(m,1H),7.33(m,1H),7.28-7.30(m,4H),7.21-7.23(m,1H),6.9 3(d,1H), 5.78(s,2H), 5.00(s,2H), 4.01(t,2H), 3.71(s,2H), 3.03(t ,2H), 2.11(s,3H), 1.99-2.05(m,3H), 1.58-1.72(m,12H), 1.16(s,9H)

[0097] Synthesis of compound RZ004

[0098] Procedure: To a solution of A-1331852 (50 mg, 0.07589 mmol, 1.00 eq) in DMF (1.0 mL) was added potassium carbonate (17 mg, 1.62 eq). The mixture was stirred at room temperature for 20 min, followed by the addition of a solution of chloromethyl butyrate (SM8, 12 mg, 1.20 eq) in 0.8 mL of DMF. Stirred in an oil bath at 50°C for 4 h. The product was diluted with ethyl acetate, washed with water, and dried. Filtered, concentrated, and purified by column chromatography.

[0099] 1 HNMR (400MHz, Chloroform-d) δ11.20(s,1H), 7.85(m,1H), 7.55(d,1H), 7.43(d,1H), 7.22-7.33(m,5H), 7.17-7.21(m,1H), 6.93(d,1H), 5.77(s,2H), 5.01(s,2H), 4.01(t,2H), 3.71(s,2H), 3.03(t,2H), 2.28(t,2H), 2.10(s,3 H), 1.94-1.99(m,3H), 1.57-1.72(m,12H), 1.24-1.33(m,2H), 0.92(t,3H).

[0100] Synthesis of compound RZ005

[0101] Procedure: To a solution of A-1331852 (50 mg, 0.07589 mmol, 1.00 eq) in DMF (1.0 ml) was added potassium carbonate (16 mg, 1.53 eq). The mixture was stirred at room temperature for 30 minutes, followed by the addition of a solution of chloromethyl acetate (SM9, 10 mg, 1.21 eq) in 0.8 ml of DMF. Stirring was performed in an oil bath at 50°C for 8 hours, followed by the addition of a solution of chloromethyl acetate (SM9, 8 mg, 0.97 eq) in 0.5 ml of DMF. Stirring was continued in an oil bath at 50°C for 3 hours. The product was diluted with ethyl acetate, washed with water, and dried. Filtered, concentrated, and purified by column chromatography.

[0102] 1 HNMR (400MHz, Chloroform-d) δ7.85(m,1H), 7.55(m,2H), 7.44(m,1H), 7.28-7.38(m,5H), 6.93(d,1H), 5.74(s ,2H), 5.01(s,2H), 4.03(t,2H), 3.72(s,2H), 3.05(t,2H), 2.12(s,3H), 1.95-2.10(m,6H), 1.55-1.70(m,12H).

[0103] Synthesis of compound RZ012

[0104] Procedure: To a solution of A-1331852 (50 mg, 0.07589 mmol, 1.00 eq) in DMF (1.0 ml) was added potassium carbonate (16 mg, 1.53 eq). The mixture was stirred at room temperature for 30 minutes, followed by a solution of chloromethyl benzoate (10 mg, 1.21 eq) in DMF (0.8 ml). Heating and stirring were continued in an oil bath at 50°C for 3 hours. The product was diluted with ethyl acetate, washed with water, and dried. Filtered, concentrated, and purified by column chromatography.

[0105] MS (ESI) m / z = 793.5 [M+H] +;

[0106] The example compounds in the following Table 1 were prepared by the same methods as in the above examples using commercially available compounds or referring to the preparation methods of the intermediate compounds shown.

[0107] Table 1

[0108] Synthesis of compound RZ002

[0109] Procedure: To a solution of A-1331852 (30 mg, 0.04554 mmol, 1.00 eq) in DMF (0.8 mL) was added KHCO₃ (17 mg, 3.73 eq). The mixture was stirred at room temperature for 30 minutes, followed by the addition of a solution of isopropyl chloromethyl carbonate (8 mg, 1.20 eq) in DMF (0.7 mL). Heat in an oil bath at 60°C with stirring for 4.5 hours. The product was diluted with ethyl acetate, washed with water, and dried. Purification by column chromatography was then performed.

[0110] 1 HNMR(400MHz,Chloroform-d)δ10.80(s,1H),7.85(m,1H),7.55(d,1H),7.4 2-7.45(m,2H), 7.30-7.35(m,4H), 7.21-7.24(m,1H), 6.94(d,1H), 5.77(s,2 H), 5.00(s,2H), 4.86-4.89(m,1H), 4.03-4.06(m,2H), 3.71(s,2H), 3.04(t, 2H), 2.09(s,3H), 1.95-2.05(m,3H), 1.59-1.71(m,12H), 1.24-1.33(m,6H).

[0111] Synthesis of compound RZ006

[0112] Procedure: To a solution of A-1331852 (50 mg, 0.07589 mmol, 1.00 eq) in DMF (1.0 mL) was added KHCO₃ (31 mg, 4.08 eq). The mixture was stirred at room temperature for 20 minutes, followed by the addition of a solution of chloromethyl ethyl carbonate (SM10, 13 mg, 1.24 eq) in 0.8 mL of DMF. Stirred in an oil bath at 60°C for 5.0 h. The product was diluted with ethyl acetate, washed with water, and dried. Filtered, concentrated, and purified by column chromatography.

[0113] 1 HNMR(400MHz,Chloroform-d)δ10.80(s,1H),7.85(m,1H),7.55(d,1H),7.4 1-7.45(m,2H), 7.29-7.35(m,4H), 7.22-7.24(m,1H), 6.94(d,1H), 5.77(s,2 H), 5.00(s,2H), 4.17-4.23(q,2H), 4.02-4.05(m,2H), 3.71(s,2H), 3.04(t, 2H), 2.09(s,3H), 1.95-2.05(m,3H), 1.58-1.71(m,12H), 1.24-1.35(m,3H).

[0114] The example compounds in Table 2 below were prepared by the same methods as in the above examples using commercially available compounds or referring to the preparation methods of the intermediate compounds shown.

[0115] Table 2

[0116] Synthesis of compound RZ201

[0117] Procedure: To a solution of A-1331852 (50 mg, 0.07589 mmol, 1.00 eq) in DCM (5.0 ml) was added thionyl chloride (0.1 ml). Stirred at room temperature for 30 min, followed by the addition of 4-(hydroxymethyl)-5-methyl-1,3-dioxolan-2-one (SM1, 10 mg, 1.0 eq). Stirred at room temperature for 3 h. Diluted with dichloromethane, washed with water, dried, and concentrated. Purified by column chromatography.

[0118] MS (ESI) m / z = 771.3 [M+H] + ;

[0119] 1H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.81–7.70(m,2H),7.61(td,J=8.0,1.2Hz,2H),7.44(dq,J=8.1,1.1Hz,1H ),7.32(dd,J=7.7,1.7Hz,1H),7.19(td,J=7.4,1.6Hz,1H),7.06(d,J=7.9Hz,1H),6.99(td,J=7.5,1.2Hz,1H), 5.05(q,J=1.1Hz,2H),4.31(d,J=17.0Hz,1H),4.07(d,J=17.2Hz,1H),3.96–3.88(m,2H),3.59(s,2H),2.90(dd d,J=6.8,4.3,1.0Hz,2H),2.71(s,2H),2.08(t,J=1.0Hz,3H),1.97(pt,J=5.9,4.2Hz,3H),1.61–1.47(m,13H).

[0120] The example compounds in the following Table 3 were prepared by the same methods as in the above examples using commercially available compounds or referring to the preparation methods of the intermediate compounds shown.

[0121] Table 3

[0122] Synthesis of compound RZ301

[0123] Step 1: To a solution of A-1331852 (50 mg, 0.076 mmol, 1.00 eq) in DMF (1.0 ml) was added potassium carbonate (16 mg). The mixture was stirred at room temperature for 30 min, followed by the addition of N-{[(2-methylpropan-2-yl)oxy]carbonyl}-L-valine chloromethyl ester (24 mg, 1.2 eq). The mixture was heated and stirred at 50°C in an oil bath for 4 h, then cooled and water was added. The mixture was extracted with ethyl acetate, washed with saturated brine, dried, concentrated, and purified by column chromatography to afford Compound A (50 mg, yield: 74.1%).

[0124] Step 2: To a solution of Compound A (50 mg, 0.056 mmol) in 2 ml of dioxane was added 4 M hydrochloric acid / dioxane solution (0.1 ml) and stirred at room temperature for 1 h. The mixture was diluted with dichloromethane and the pH was adjusted to 7 with saturated aqueous sodium bicarbonate solution. The product was extracted, dried, concentrated, and purified by column chromatography.

[0125] MS (ESI) m / z = 788.5 [M+H] + ;

[0126] 1H NMR (400MHz, DMSO-d6) δ8.90(d,J=7.4Hz,2H),7.90(s,1H),7.77(t,J=8.2Hz,1H),7.73(d,J=7.9Hz,1H),7.61(td,J=8.0,1.3Hz,2H),7.44 (dq,J=8.1,1.1Hz,1H),7.32(dd,J=7.7,1.7Hz,1H),7.19(td,J=7.4,1.6Hz,1H),7.09–7.03(m,2H),7.03(d,J=3.3Hz,1H),6.99(td,J=7.5, 1.2Hz,1H),4.31(d,J=17.0Hz,1H),4.07(d,J=17.2Hz,1H),3.96–3.88(m,2H),3.55(td,J=7.2,6.4Hz,1H),2.90(ddd,J=6.8,4.3,1.0Hz,2H ),2.71(s,2H),2.27(dt,J=13.0,6.5Hz,1H),1.97(pt,J=5.9,4.2Hz,3H),1.61–1.47(m,15H),1.08(d,J=6.5Hz,3H),1.02(d,J=6.5Hz,3H).

[0127] Example 2. Esterase levels in senescent cells are higher than those in normal cells

[0128] In this example, human non-small cell lung cancer cell lines (A549 cells), human retinal pigment epithelial cells (RPE cells), and human pulmonary fibrosis cells (IMR90 cells) were selected to test whether the intracellular esterase content of senescent cells was higher than that of normal cells. This was to evaluate the advantages of prodrug release in senescent cells.

[0129] Cells were plated in 100 mm culture dishes and senescence was induced with bleomycin (10 μM) and etoposide (10 μM). Normal cells and senescent cells were digested and counted. After ultrasonic disruption of cells, centrifugation was performed for 10 min, and the supernatant was collected and placed on ice. The supernatant was tested according to the kit instructions. Calculation formula: CarE enzyme activity (U / 10 4 cell) = (ΔA measurement tube - ΔA blank tube) × V 反总 ÷0.5÷(200÷V total cell sample × V sample)÷T×F

[0130] Vsample: added sample volume, 0.01 mL; T: reaction time, 5 min; 200: total number of cells, 2 million; Vcell sample total: volume of extract added to cells, 0.2 mL; Vreaction total: total volume of reaction system, 0.2 mL; F: dilution factor.

[0131] As can be seen from Figures 1A, 1B, and 1C, the esterase content in senescent cells is significantly higher than that in normal cells.

[0132] Example 3. Prodrug compounds have a more specific killing effect on senescent cells than A-1331852

[0133] In this example, human non-small cell lung cancer cell line (A549 cells), human embryonic lung fibroblast cell line (IMR90 cells), human retinal pigment epithelial cells (RPE cells), mouse chondrocytes, and mouse skin fibroblasts were selected. Senescent cells were obtained by etoposide induction (10 μM). The effects of the target compounds RZ001-RZ006 and RZ201 on the viability of normal and senescent cells were tested, thereby evaluating the specific killing effect of the compound prodrugs RZ001-RZ006 and RZ201 on the senescent cells.

[0134] Briefly, the senescent and normal cells were plated (96-well plate) respectively. Compounds RZ001-RZ006 and RZ201 (at a concentration of 20 μM) were added for 72 hours, and then Cell viability was detected using the Luminescent Cell Viability Assay Kit (Promega), and the results are shown in Figures 2A to 2E.

[0135] As shown in Figures 2A to 2E, A-1331852 not only kills senescent cells but also has a significant killing effect on normal cells. In contrast, compounds RZ001-RZ006 and RZ201, in addition to killing senescent cells, have no significant killing effect on normal cells. This suggests that RZ001-RZ006 and RZ201 have superior specificity and safety.

[0136] In addition, the senescent cell clearance index (Senolytic index) on normal and senescent A549 cells was also calculated, see Table 4 below. A higher index indicates a stronger specificity for clearing senescent cells and better safety.

[0137] Table 4 Senescent cell clearance index Note: A represents greater than 200; B represents greater than 100-200; C represents 50-100; D represents 30-50; E represents 10-30; F represents less than 10.

[0138] Example 4: Efficacy in an animal model of hyperoxia-induced retinopathy

[0139] The effects of prodrugs RZ001-RZ006 and RZ201 were studied in the oxygen-induced retinopathy (OIR) mouse model, which is somewhat indicative of an in vivo model of retinopathy of prematurity (ROP), diabetic retinopathy, and wet age-related macular degeneration.

[0140] From postnatal day 7 (P7) to day 12 (P12), C57Bl / 6 mouse pups and their CD1 foster mothers were exposed to a hyperoxic environment (75% O2). At P12, the animals were intravitreally injected with 1 μl of a test composition (compound at 200 μM) prepared in 1% DMSO, 10% Tween 80, 20% PEG-400 and returned to room air until day 17 (P17). At P17, the eyes were enucleated and the retinas dissected for vascular staining. To determine the area of ​​avascularity or neovascularization, the retinas were flattened and stained with isolectin B4 (IB4).

[0141] Figure 3 shows that intravitreal (IVT) administration of RZ001-RZ006 and RZ201 resulted in statistically significant improvements in avascular zone and vascular proliferation.

[0142] Example 5: Efficacy in an animal model of diabetic-induced retinopathy

[0143] The efficacy of the compounds disclosed herein was studied in a mouse model of diabetic retinopathy by multiple administration of streptozotocin (STZ). C57BL / 6J mice aged 6 to 7 weeks were weighed and their baseline blood glucose (Sino) was measured. STZ (Sigma-Alderich) was injected intraperitoneally with 55 mg / Kg of mice for 5 consecutive days. Only buffer was injected into the age-matched control group. One week after the last STZ injection, blood glucose was measured again. 8 and 9 weeks after STZ administration, 1 μl of the test compound (200 uM, formulated as a suspension in 0.015% polysorbate 80, 0.2% sodium phosphate, 0.75% sodium chloride, pH 7.2) was injected into the vitreous of STZ-treated diabetic C57BL / 6J mice. Retinal Evans blue penetration assay was performed 10 weeks after STZ treatment.

[0144] Figure 4 shows that intravitreal (IVT) administration of RZ001, RZ002, and RZ201 can improve vascular permeability in the retina and choroid.

[0145] Example 6: Efficacy in an Animal Model of Wet-Age-Related Macular Degeneration with CNV

[0146] This example uses a CNV animal model to test the effects of the disclosed compounds on wet age-related macular degeneration.

[0147] Male mice were given 0.5% propacaine hydrochloride (Alcon) for local anesthesia, and 1% tropicamide was administered to dilate the pupils. Laser ablation was performed using a laser photocoagulator (Novus Varia, LUMENIS) with a slit lamp delivery system. A manually ruptured glass coverslip was used as a contact lens. Laser-induced hemorrhages were not included in the statistical analysis.

[0148] FIG5 shows statistically significant improvements in fluorescence intensity indices following intravitreal (IVT) administration of RZ001, RZ002, and RZ201.

[0149] Example 7: Efficacy in an animal model of idiopathic pulmonary fibrosis

[0150] This example uses an idiopathic pulmonary fibrosis animal model to test the effects of the disclosed compounds on idiopathic pulmonary fibrosis.

[0151] In simple terms, anesthetized 6-week-old SD rats were fixed on a foam board with medical tape. First, the skin on the tracheal surface was cut open with surgical scissors to fully expose the trachea. A 100-microliter microinjection needle of a certain volume of bleomycin (BLM 5mg / kg) solution drawn according to the rat's weight was inserted into the trachea through the mouth for slow push administration. After the BLM solution was given, the foam board was immediately rotated and shaken to distribute the BLM solution evenly in the lung tissue as much as possible. The skin on the tracheal surface was then sutured with surgical sutures, and about 0.5-1.0ml of penicillin solution was dripped on the epidermis to prevent infection of the surgical wound. After the 7th day of modeling, the compound solution of the present invention was given according to the rat's weight and intraperitoneal injection (IP) was performed (5mg / kg) for 3 consecutive weeks.

[0152] On the 28th day, the rats were euthanized by carbon dioxide, and lung tissues were collected. The left alveolar lavage fluid was collected for white blood cell (WBC) count, the right lung tissue was partially tested for hydroxyproline (HYP), and the remaining lung tissue was subjected to pathological H&E staining and Masson staining.

[0153] Figure 6 shows that intraperitoneal (IP) administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in WBC, HYP, and pathology scores in the IPF model.

[0154] Example 8: Efficacy in an animal model of osteoarthritis

[0155] This example uses an osteoarthritis animal model to test the effects of the compounds of the present disclosure on osteoarthritis.

[0156] An osteoarthritis animal model was constructed by the following steps. The mice were anesthetized with isoflurane and fixed. The hair on the right hind limb of the mice was shaved, the skin was wiped and disinfected with alcohol, and the skin at the joint was cut. Under an optical microscope, the inner side of the right knee joint with the knee flexed was cut longitudinally with a blade. The patellar ligament was not cut. The patellar ligament was pulled to one side and compression was continuously applied with a sterile cotton swab to stop bleeding. The joint cavity was fully exposed and physiological saline was added in time to prevent the joint cavity from drying out. The excess muscle tissue was gently separated with blunt forceps to expose the meniscus ligament and the anterior cruciate ligament was searched deep in the joint cavity. The anterior cruciate ligament was cut open with micro-scissors, and the wound was disinfected with penicillin solution. The muscles were sutured with sterilized needles and thread, and finally the skin tissue was sutured. The efficacy of the drug was determined by intra-articular injection. At the end of the experiment, the plantar pain threshold was tested and the bone joints were stained with safranin and fast green.

[0157] FIG7 shows that intra-articular administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in plantar mechanical pain threshold and pathological scores of Safranin Fast Green staining in an osteoarthritis (OA) model.

[0158] Example 9: Efficacy in Alzheimer's disease animal models

[0159] This example uses an Alzheimer's disease animal model to test the effects of the disclosed compounds on Alzheimer's disease.

[0160] Briefly, an APP×PS1 transgenic mouse model (purchased from Saiye Bio) was selected and the disclosed compound was administered via intraperitoneal injection for 11 consecutive weeks, twice a week, to observe the improvement of amyloid protein in the cerebral cortex of the mice.

[0161] FIG8 shows that intraperitoneal administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvement in Aβ42 pathogenic protein levels in the AD mouse model.

[0162] Example 10: Efficacy in an animal model of liver fibrosis

[0163] This embodiment uses an animal model of liver fibrosis to test the effect of the disclosed compounds on liver fibrosis. Briefly, C57BL / 6N mice, male, 7-8 weeks old, weighing 24-28g, were selected. CCl4 solution was injected intraperitoneally with a dose of 1 ml / kg, twice a week, and the modeling period was 6 weeks to induce a mouse liver fibrosis model. Intraperitoneal injection (5 mg / kg) was started in the third week of modeling and administered twice a week. Serum was collected at the end of the experiment, and liver tissue was taken for Masson staining index detection.

[0164] Figure 9 shows that intraperitoneal (IP) administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and pathology in a liver fibrosis model.

[0165] Example 11: Effect on aging skin

[0166] This example used elderly female C57bl / 6J mice (22 months old). The drug was administered via skin application twice weekly for 6 consecutive weeks. The improvement in epidermal thickness of the elderly mice was observed.

[0167] Figure 10 shows that topical application of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in epidermal thickness scores in a naturally aged mouse model.

[0168] Example 12: Efficacy in an animal model of renal fibrosis

[0169] This embodiment uses a renal fibrosis animal model to test the effect of the compounds disclosed herein on renal fibrosis. Briefly, C57BL / 6J male mice, 7-8 weeks old, were selected. After being anesthetized, the mice were placed supine on a foam board, disinfected with iodine, and a longitudinal incision was made in the middle of the lower abdomen to find the white line of the abdominal muscles. The abdominal muscles, fascia, and peritoneum were cut open here. After exposing the surgical field, the stomach and mesentery of the mice were pushed to the right side with gauze soaked in normal saline to expose the kidney. From the renal pelvis, the transparent ureter was found along the renal artery, the left ureter was separated, and the upper 1 / 3 of the left ureter was ligated. The incision was sutured layer by layer, and finally disinfected with iodine to construct a renal fibrosis model. Intraperitoneal injection was performed starting from the second week of modeling. Mouse serum was collected at the end of the experiment, and kidney tissue was taken for Masson staining index detection.

[0170] Figure 11 shows that intraperitoneal (IP) administration of RZ001, RZ002, and RZ201 resulted in statistically significant improvements in serum creatinine (Cr) and urea nitrogen (BUN) levels and pathology in a renal fibrosis model.

[0171] Example 13: Efficacy in rabbit ear hypertrophic scar model

[0172] This embodiment uses a rabbit ear hypertrophic scar animal model to test the effect of the disclosed compounds on hypertrophic scars. Briefly, 10 male New Zealand white rabbits, 3 months old, were selected. After the New Zealand rabbits were anesthetized with sodium pentobarbital, 6 circular full-thickness wounds with a diameter of 10 mm were made on the ventral surface of each ear by removing the epidermis, dermis and perichondrium to the exposed cartilage. The rabbits were randomly divided into a control group and an RZ001 experimental group. On the 14th day after surgery, after the wound was completely re-epithelialized, the compound (150uM, 100ul, dissolved in DMSO solution) or negative control DMSO 100ul was taken and the solution was injected from the edge of the wound to the center of each lesion, once a week, for a total of 4 injections. The SEI (scar hyperplasia index) was used to evaluate the improvement effect of the compound on scar formation.

[0173] FIG12 shows that administration of RZ001 resulted in a statistically significant improvement in the scar hyperplasia index in the rabbit ear hypertrophic scar model.

Claims

1. A compound having the structure shown in Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope-labeled compound thereof, in, R1 is selected from substituted or unsubstituted C1-C 10 Alkylene; R2 is selected from -OC(O)- or -OC(O)-O-; R3 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C1-C20 heteroaryl, substituted or unsubstituted C2-C20 heteroalicyclic; Alternatively, R1 is absent or selected from substituted or unsubstituted C1-C 10 Alkylene, R2 is absent, and R3 is selected from substituted or unsubstituted C2-C20 heteroalicyclic groups; R c is selected from substituted or unsubstituted adamantyl groups; Alternatively, the substituents in the substitution are selected from halogen atoms, cyano groups, nitro groups, C6-C20 aryl groups, C1-C20 heteroaryl groups, C1-C10 chain alkyl groups, C1-C10 chain alkoxy groups, C6-C20 aryloxy groups, C1-C20 heteroalicyclic groups, preferably C1-C10 heteroalicyclic groups, amino groups, hydroxyl groups, sulfhydryl groups, phosphate groups, -OC(O)R6, -ONR6R7, -NR6R7, and R6 and R7 are independently selected from hydrogen, C6-C20 aryl groups, C1-C20 heteroaryl groups, C1-C8 chain alkyl groups, C3-C8 cycloalkyl groups, C2-C8 alkenyl groups. and C2-C8 alkynyl, the aryl and heteroaryl groups are optionally substituted by a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C6 alkoxy group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group or a C2-C8 alkynyl group, wherein the substituents at at least two positions together constitute an aliphatic ring, such as a C3-C20 aliphatic ring, a heteroaliphatic ring, such as a C2-C20 aliphatic ring, an aromatic ring, such as a C6-C20 aromatic ring or a heteroaromatic ring, such as a C1-C20 heteroaromatic ring.

2. The compound according to claim 1, characterized in that The compound is shown in formula III, IV or V: In formula III and IV, R1 is selected from independently selected from substituted or unsubstituted C1-C 10 Alkylene, preferably, R1 is selected from independently selected from substituted or unsubstituted C1-C6 alkylene, preferably, R1 is selected from independently selected from substituted or unsubstituted C1-C4 alkylene; R a 、R b , R3, R c , L is defined as in formula I; In Formula V, R1 is absent or selected from independently selected from substituted or unsubstituted C1-C 10 Alkylene, preferably, R1 is selected from independently selected from substituted or unsubstituted C1-C6 alkylene, preferably, R1 is selected from independently selected from substituted or unsubstituted C1-C4 alkylene, R3 is selected from substituted or unsubstituted C2-C20 heteroalicyclic group, R a 、R b 、R c , L are defined the same as in formula I.

3. The compound according to claim 1 or 2, characterized in that The C2-C20 heteroalicyclic group is optionally selected from halogen atoms, hydroxyl groups, mercapto groups, amino groups, nitro groups, cyano groups, C1-C10 alkoxy groups, C1-C10 alkyl groups, C3-C8 cycloalkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, Substituents are substituted, each R5 is independently selected from hydrogen and C1-C6 alkyl.

4. The compound according to claim 1 or 2, characterized in that The C2-C20 heteroalicyclic group is a C4-C8 heteroalicyclic group; The C4-C8 heteroalicyclic group is optionally substituted by halogen, -NH2, -OH, -NO2, carbonyl, -CH2OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

5. The compound according to any one of claims 1 to 4, characterized in that The C2-C20 heteroalicyclic group is selected from the following groups: R' independently represents no substituent, a single substituent or multiple substituents, each substituent is independently selected from deuterium, hydroxyl, halogen, NH2, carboxyl (-COOH), C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, morpholine-substituted C1-C6 alkyl, -COO-C1-C6 alkyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, phenyl, benzyl; L2 is a C1-C6 alkylene group not substituted by a C1-C6 alkylene group, a halogen group, a hydroxyl group, or a C1-C6 alkoxy group, preferably a methylene group, an ethylene group, or a propylene group; R6 is H, deuterium, halogen, hydroxyl, NH2, carboxyl (-COOH), -CONH2, sulfonic acid (-SO3H), sulfonyl-(SO2)-C1-C6 chain alkyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, hydroxy-substituted C3-C6 cycloalkyl, phenyl or benzyl.

6. The compound according to any one of claims 1 to 5, characterized in that Each R a are all hydrogen; and / or R b is selected from substituted or unsubstituted C1-C6 alkyl, preferably substituted or unsubstituted C1-C3 alkyl, more preferably methyl; and / or L is selected from substituted or unsubstituted C1-C6 alkylene groups, preferably substituted or unsubstituted C1-C3 alkylene groups, and more preferably methylene groups.

7. The compound according to any one of claims 1 to 6, characterized in that The compound is shown in Formula II: In formula II, the definitions of R1, R2, and R3 are the same as those in formula I.

8. The compound according to any one of claims 1 to 7, characterized in that R1 is a substituted or unsubstituted C1-C6 alkylene group, preferably a substituted or unsubstituted C1-C3 alkylene group, more preferably a methylene group, and / or R3 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C2-C12 heteroaryl or substituted or unsubstituted C1-C12 heteroalicyclic; Preferably, R3 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C1-C10 heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C1-C10 heteroalicyclic.

9. The compound according to any one of claims 1 to 8, characterized in that Said substitution is substituted by a substituent selected from halogen atoms, cyano groups, nitro groups, C6-C20 aryl groups, C1-C20 heteroaryl groups, C1-C10 chain alkyl groups, C1-C10 chain alkoxy groups, C6-C20 aryloxy groups, C1-C20 heteroalicyclic groups, preferably C1-C10 heteroalicyclic groups, amino groups, hydroxyl groups, mercapto groups, phosphate groups, -OC(O)R6, -ONR6R7, -NR6R7, R6 and R7 are independently selected from hydrogen, C6-C20 aryl groups, C1-C20 heteroaryl groups, C1-C8 chain alkyl groups, C3-C8 cycloalkyl groups, C2-C8 alkenyl groups and C2- C8 chain alkynyl, the aryl and heteroaryl are optionally substituted by a halogen atom, a hydroxyl group, a thiol group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C6 alkoxy group, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group or a C2-C8 chain alkynyl group, wherein the substituents at at least two positions together constitute an aliphatic ring such as a C3-C20 aliphatic ring, a heteroaliphatic ring such as a C2-C20 aliphatic ring, an aromatic ring such as a C6-C20 aromatic ring or a heteroaromatic ring such as a C1-C20 heteroaromatic ring.

10. The compound according to any one of claims 1 to 9, characterized in that R3 is selected from the following groups:

11. The compound according to claim 1, characterized in that The compound is selected from the following compounds:

12. A method for preventing or treating a disease associated with aging, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope-labeled compound thereof.

13. The method according to claim 12, characterized in that The aging-related disease is a disease associated with the accumulation of senescent cells. Preferably, the disease is selected from idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, viral-induced inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrosing pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritic neuropathy, keratitis sicca, Fuch's corneal dystrophy, presbyopia, cataracts, degenerative vitreous disorders including vitreomacular traction syndrome, macular hole, retinal tear, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, herniated disc, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease, diabetes, Diabetes, diabetic nephropathy, scars, superficial or flat scars, cord-like or contracture scars, webbed scars, depressed scars, atrophic scars, bridge-like and hypertrophic scars, hypertrophic scars, keloids, scar cancer, scleroderma, morphea, scleroderma zona flexica, guttate scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, adipose tissue dysfunction, coronary artery disease, cerebrovascular disease , periodontal disease, cancer treatment-related disabilities such as atrophy and fibrosis in various tissues, brain and heart damage and treatment-related myelodysplastic syndrome, promyelocytic syndrome, ataxia telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysm, inflammatory bowel disease, lipoatrophy, renal transplant failure, sarcopenia, wound healing, alopecia, cardiomyocyte hypertrophy, glomerulosclerosis, and one or more of cancer.

14. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer or isotope-labeled compound thereof in the preparation of a medicament for preventing or treating aging-related diseases.

15. The use according to claim 14, characterized in that The aging-related disease is a disease associated with the accumulation of senescent cells. Preferably, the disease is selected from diseases associated with the accumulation of senescent cells. The disease is preferably selected from idiopathic pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, Renal fibrosis, viral-induced inflammation and tissue fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, cutaneous fibrosis, interstitial lung disease, fibrosing pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritic neuropathy, keratitis sicca, Fuch's corneal dystrophy, presbyopia, cataracts, degenerative vitreous conditions including vitreomacular traction syndrome, macular hole, retinal tear, retinal detachment, proliferative vitreoretinopathy, osteoarthritis, herniated disc, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease, diabetes, diabetic nephropathy, scars, superficial or flat scars, cord One or more of linear or contracture scars, webbed scars, depressed scars, atrophic scars, bridge-like and hypertrophic scars, hypertrophic scars, keloids, scar cancer, scleroderma, morphea, scleroderma bands, guttate scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, adipose dysfunction, coronary artery disease, cerebrovascular disease, periodontal disease, cancer treatment-related disabilities such as atrophy and fibrosis in various tissues, brain and heart damage and treatment-related myelodysplastic syndrome, promyeloid syndrome, ataxia-telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysm, inflammatory bowel disease, lipoatrophy, renal transplant failure, sarcopenia, wound healing, alopecia, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

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