Ester compounds and their applications

Abstract

The present invention discloses a compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer or isotope-labeled compound thereof. The compound is represented by Formula I. The present invention further discloses the application of the compound in the manufacture of a medicament for preventing or treating aging-related diseases. 【Chemical 1】 TIFF2025522589000046.tif79127

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to compounds that target and kill senescent cells, and their application in the prevention or treatment of aging-related diseases.

Background Art

[0002] With the increase in age, the biological functions of the living body gradually decline, and the aging process of an individual is often accompanied by the occurrence of various age-related diseases. Therefore, developing effective anti-aging intervention strategies is of great significance for extending the healthy lifespan of the elderly and reducing the incidence of aging-related diseases. The accumulation of senescent cells in the body is an important driving force for individual aging and the occurrence of aging-related diseases. On the other hand, the senescence of some proliferating cells or stem cells leads to a decrease in the regenerative ability of an individual and affects the recovery ability and normal functions of the living body. It is more important that senescent cells secrete a large amount of inflammatory factors, which is called the Senescence-Associated Secretory Phenotype (SASP), causing a chronic inflammatory microenvironment, accelerating the aging process of the living body, and promoting the occurrence of age-related diseases. Studies have shown that specifically removing senescent cells by genetic methods or small chemical molecules can reduce chronic inflammation, improve tissue repair ability, improve the symptoms of age-related diseases such as osteoarthritis and idiopathic pulmonary fibrosis, and alleviate the decline of physiological functions in the aging body. Therefore, selectively removing senescent cells is a promising approach for the treatment of aging-related diseases and the improvement of physiological functions in elderly individuals.

[0003] Senescent cells have many characteristics, and permanent cell cycle arrest is a common feature of all senescent cells, mainly depending on p16 and p21. Another broad spectrum of characteristics is the increase in β-gal activity in senescent cells, that is, enzyme activity can be detected even in a non-optimal enzyme activity environment at pH 6.0, which is called senescence-associated-β-galactosidase (SA-β-gal). Senescent cells cultured in vitro usually show an enlargement of the cell nucleus and cytoplasm and become flat in shape. Markers of senescence also include the activation of the DNA damage response, increased endoplasmic reticulum stress and ROS levels, and enhanced SASP secretion. In addition, anti-apoptotic components in senescent cells are significantly induced to resist cell apoptosis. Typically, for example, the expression of anti-apoptotic proteins such as BCL2 / BCL-XL is increased. Therefore, senescent cells are also called zombie cells, which are old but do not die. The induction of cellular senescence can initially bring beneficial physiological effects by suppressing tumor formation and promoting wound healing. However, subsequent studies have shown that the long-term presence of senescent cells in tissues may promote the occurrence of aging and age-related diseases, and furthermore, inflammatory factors secreted from senescent cells have also been found to promote tumorigenesis.

[0004] The causal relationship between the accumulation of senescent cells and aging and the occurrence of aging-related diseases has already been clearly analyzed through genetic pathways. The research group of Professor Deursen at the Mayo Clinic constructed INK-ATTAC transgenic mice driven by the p16 promoter in 2011. This system selectively expressed the FKBP-CASP8 fusion protein only in p16-positive senescent cells. After treatment with the small molecule AP20187, the FKBP-CASP8 fusion protein dimerized and induced apoptosis of p16-positive senescent cells. In Bub1b mutant progeroid mice, when senescent cells were intermittently removed by this method, it was observed that sarcopenia, cataracts, and lipodystrophy were significantly improved. In a 2016 study, the researchers administered AP20187 to naturally aged INK-ATTAC mice every two weeks to remove senescent cells. As a result, the removal of p16-positive senescent cells alleviated age-related deterioration in some tissues and organs (including the kidney, heart, and fat), and extended the median lifespan. The research group of Professor Kirland demonstrated that simply transplanting a small number of senescent cells into the body of recipient mice could drive persistent physical dysfunction in young mice, leading to functional decline and increased mortality. These research findings, from different perspectives, prove that removing senescent cells in the body can extend lifespan and delay the occurrence of aging-related diseases, providing a theoretical basis for strategies to achieve anti-aging by targeting and killing senescent cells and treating aging-related diseases.

[0005] Currently, multiple small molecule compounds capable of selectively removing senescent cells have been reported, and such small molecules are also called "senolytics". Due to the heterogeneity of senescent cells, these senolytics can achieve a certain degree of selective killing of senescent cells, but there is still room for improvement in reducing toxicity and enhancing the specificity of killing. Many of the early senolytics target important components in the Senescent Cell anti-Apoptotic Pathways (SCAP), that is, they induce the death of senescent cells by blocking the anti-apoptotic signals of senescent cells. Compared with normal cells, the expression of anti-apoptotic proteins BCL2 / BCL-XL in senescent cells is significantly increased, antagonizing the activity of apoptotic proteins such as Bax, and senescent cells can be resistant to apoptosis. As a dual inhibitor of classical anti-apoptotic proteins BCL2 / BCL-XL, ABT263 (navitoclax) has subsequently been proven to be able to specifically induce the apoptosis of senescent cells.

[0006] A-1331852 is a specific small molecule inhibitor of the Bcl-xL protein. In addition to having a very good killing effect on Bcl-xL-dependent cancer cells, A-1331852 also shows high selectivity for the killing of senescent cells. Since Bcl-xl kills senescent cells but still has a strong killing effect on normal cells at a certain concentration, it is necessary to further improve the safety for normal cells.

[0007] Examining the differences existing between senescent cells and non-senescent cells is the basis for achieving target identification and killing of senescent cells. The inventors discovered through research that the carboxylate esterase activity in senescent cells is significantly higher than that in non-senescent cells. Therefore, carboxylate esterase may be a potential marker for senescent cells, providing a theoretical basis for the application of prodrug strategies based on such enzyme activation. Currently, there is no Bcl-xL inhibitor modified based on A-1331852, which can more effectively and specifically induce apoptosis of senescent cells, and the method can be used to prevent senescence and treat senescence-related diseases in mammals. The present invention utilizes the characteristic of high esterase activity in senescent cells to design novel prodrug compounds, meeting these needs and providing related advantages.

Summary of the Invention

[0008] In order to solve at least one technical problem existing in the prior art, the present invention provides a compound that selectively kills senescent cells and tumor cells within a larger safety window, reduces the killing side effects on normal cells, and has higher selectivity and safety.

[0009] The first aspect of the present application provides a compound represented by formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer or isotope-labeled compound thereof.

Chemical Formula

[0010] In some embodiments, the substituents for the substitution are a halogen atom, a hydroxy group, a mercapto 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 linear alkenyl group or a C2-C8 alkynyl group, a C1-C10 alkyl group substituted with halogen and / or a hydroxy group, a C3-C8 cycloalkyl group substituted with halogen and / or a hydroxy group, a C2-C8 linear alkenyl group substituted with halogen and / or a hydroxy group or a C2-C8 alkynyl group substituted with halogen and / or a hydroxy group, a C3-C8 cycloalkyl group substituted with halogen and / or a hydroxy group, and are selected from these.

[0011] In some embodiments, the ring of the C2-C20 heteroalicyclic group optionally further contains one or two heteroatoms selected from N or O.

[0012] In some embodiments, the C2-C20 heteroalicyclic group optionally has a halogen atom, a cyano group, a nitro group, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 chain alkoxy group, a C6-C10 aryloxy group, a C2-C10 heteroalicyclic group, an amino group, a hydroxy group, a mercapto group, a carbonyl group, a carboxyl group, an acyl group,

Chemical formula

[0013] In some embodiments, the compound is represented by formula III, IV, or V,

Chemical formula

[0014] In some embodiments, the C2-C20 heteroalicyclic group is optionally substituted with a substituent selected from a halogen atom, a hydroxy group, a mercapto 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 chain alkenyl group, a C2-C8 alkynyl group,

Chemical Formula

[0015] In some embodiments, the C2-C20 heteroalicyclic group is a C4-C8 heteroalicyclic group, and the heteroalicyclic group is optionally substituted with a substituent selected from a halogen, -NH2, -OH, -NO2, a carbonyl group, -CH2OH, a carboxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group.

[0016] In some embodiments, the C2-C20 heteroalicyclic group is selected from the groups represented by the following group, [Chemical formula] R' each independently represents an unsubstituted group, a single substituent, or a plurality of substituents, and each substituent is independently deuterium, a hydroxy group, a halogen, NH2, a carboxyl group (-COOH), [Chemical formula] a C1-C6 chain alkyl group, a halogen-substituted C1-C6 chain alkyl group, a hydroxy group-substituted C1-C6 chain alkyl group, an amino-substituted C1-C6 chain alkyl group, a morpholine-substituted C1-C6 chain alkyl group, a -COO-C1-C6 chain alkyl group, a cyano group, a C1-C6 chain alkoxy group, a C3-C6 cycloalkyl group, a halogen-substituted C3-C6 cycloalkyl group, a hydroxy group-substituted C3-C6 cycloalkyl group, a phenyl group, or a benzyl group, L2 is absent or is a C1-C6 alkylene group, a halogen, a hydroxy group, or a C1-C6 alkylene group substituted with a C1-C6 alkoxy group, preferably a methylene group, an ethylene group, or a propylene group, R6 is H, deuterium, a halogen, a hydroxy group, NH2, a carboxyl group (-COOH), -CONH2, a sulfonic acid group (-SO3H), a -SO2-C1-C6 chain alkyl group, [Chemical formula] a C1-C6 chain alkyl group, a halogen-substituted C1-C6 chain alkyl group, a morpholine-substituted C1-C6 chain alkyl group, a -COO-C1-C6 chain alkyl group, a cyano group, a C1-C6 chain alkoxy group, a hydroxy group-substituted C1-C6 chain alkyl group, an amino group-substituted C1-C6 chain alkyl group, a C3-C6 cycloalkyl group, a halogen-substituted C3-C6 cycloalkyl group, a hydroxy group-substituted C3-C6 cycloalkyl group, a phenyl group, or a benzyl group.

[0017] In some embodiments, each R ais independently selected from hydrogen, halogen, a substituted or unsubstituted C1-C10 alkoxy group, and a substituted or unsubstituted C1-C10 alkyl group. In some embodiments, each R a is independently selected from hydrogen, halogen, a substituted or unsubstituted C1-C5 alkoxy group, and a substituted or unsubstituted C1-C5 alkyl group.

[0018] In some embodiments, each R a is hydrogen.

[0019] In some embodiments, R b is selected from a substituted or unsubstituted C1-C6 alkyl group, preferably a substituted or unsubstituted C1-C3 alkyl group, more preferably a methyl group.

[0020] In some embodiments, L is selected from a substituted or unsubstituted C1-C6 alkylene group, preferably a substituted or unsubstituted C1-C3 alkylene group. In some embodiments, L is methylene.

[0021] In some embodiments, the compound is represented by Formula II,

Chemical formula

[0022] 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.

[0023] In some embodiments, R3 is selected from a substituted or unsubstituted C1-C8 chain alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C2-C8 chain alkenyl group, a substituted or unsubstituted C2-C8 chain alkynyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C2-C12 heteroaryl group, or a substituted or unsubstituted C1-C12 heterocycloaliphatic group.

[0024] Preferably, R3 is selected from a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C1-C10 heteroaryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted C1-C10 heterocycloaliphatic group.

[0025] In the present application, "substituted or unsubstituted" means that one or more hydrogens in the described group may be substituted with a substituent, and regarding the substituent, it may be substituted with 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 hydroxy group, a mercapto group, a phosphate ester group, -OC(O)R6, -ONR6R7, -NR6R7, and R6 and R7 are independently selected from hydrogen, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C1-C8 chain alkyl group, a C3-C8 cycloalkyl group, a C2-C8 chain alkenyl group and a C2-C8 chain alkynyl group. The aryl group and heteroaryl group may optionally be substituted with a halogen atom, a hydroxy group, a mercapto 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 chain alkenyl group or a C2-C8 chain alkynyl group, among which, optionally, substituents at at least two positions together form an alicyclic ring such as a C3-C20 alicyclic ring, a heteroalicyclic ring such as a C2-C20 alicyclic ring, an aromatic ring such as a C6-C20 aromatic ring or a heteroaromatic ring such as a C1-C20 heteroaromatic ring.

[0026] In some embodiments, R3 is selected from the following groups. [Chemical formula]

[0027] In some embodiments, the compound is selected from the following compounds. [Chemical formula] [Chemical formula] [Chemistry] [Chemistry] [Chemistry]

[0028] The second aspect of the present application provides a method for preventing or treating an aging-related disease, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound described in the first aspect or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer or isotopically labeled compound thereof.

[0029] Specifically, an aging-related disease is a disease associated with the accumulation of senescent cells. Preferably, the disease is idiopathic pulmonary fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, viral upper respiratory tract and lung inflammation and tissue fibrosis and atrophy, cystic fibrosis, myelofibrosis, myocardial fibrosis, skin fibrosis, interstitial lung disease, fibrotic 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, dry keratitis, Fuchs corneal dystrophy, presbyopia, cataract, vitreomacular traction syndrome, macular hole, retinal hole, retinal detachment, proliferative vitreoretinopathy including degenerative vitreous disorders, osteoarthritis, intervertebral disc herniation, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease, diabetes, diabetic nephropathy, scar, superficial scar or flat scar, cord-like scar or contracture scar, keloid scar, pitted scar, atrophic scar, bridge-like scar and verrucous scar, hypertrophic scar, scar lump, scar cancer, scleroderma, localized scleroderma, linear scleroderma, guttate scleroderma, acrosclerosis, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, adipose dysfunction, coronary artery disease, cerebrovascular disease, periodontal disease, cancer treatment-related disorders, for example, atrophy and fibrosis in various tissues, brain and heart disorders and myelodysplastic syndrome, promyelocytic syndrome, ataxia telangiectasia, Fanconi anemia, Friedreich ataxia, dyskeratosis congenita, aplastic anemia, aneurysm, inflammatory bowel disease, lipoatrophy, kidney transplant failure, sarcopenia, wound healing, hypotrichosis, cardiomyocyte hypertrophy, glomerulosclerosis, and one or more selected from cancer.

[0030] The second aspect of the present application provides the use of the compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled compound described in the first aspect of the present application in the manufacture of a medicament for preventing or treating an aging-related disease.

[0031] Specifically, an aging-related disease is a disease associated with the accumulation of senescent cells. Preferably, the disease is idiopathic pulmonary fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, viral upper respiratory tract and lung inflammation and tissue fibrosis, and atrophy, cystic fibrosis, myelofibrosis, myocardial fibrosis, dermal fibrosis, interstitial lung disease, fibrotic 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, dry keratitis, Fuchs corneal dystrophy, presbyopia, cataract, vitreomacular traction syndrome, macular hole, retinal tear, retinal detachment, degenerative vitreous diseases including proliferative vitreoretinopathy, osteoarthritis, intervertebral disc herniation, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease, diabetes, diabetic nephropathy, scar, superficial scar or flat scar, cord-like scar or contracture scar, keloid scar, depressed scar, atrophic scar, bridge-like scar and verrucous scar, hypertrophic scar, keloid, scar cancer, scleroderma, localized scleroderma, linear scleroderma, guttate scleroderma, acrosclerosis, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, adipose dysfunction, coronary artery disease, cerebrovascular disease, periodontal disease, cancer treatment-related disorders, for example, atrophy and fibrosis in various tissues, brain and heart disorders, and myelodysplastic syndrome, premyelocytic syndrome, ataxia telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysm, inflammatory bowel disease, lipoatrophy, renal transplant failure, sarcopenia, wound healing, hypotrichosis, cardiomyocyte hypertrophy, glomerulosclerosis, and one or more selected from cancer.

[0032] The compound provided by the present invention can reduce the killing side effects on normal cells, selectively kill senescent cells and tumor cells within a larger safety window, and has higher selectivity and safety.

Brief Description of the Drawings

[0033]

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Mode for Carrying Out the Invention

[0034] Hereinafter, the present invention will be described in detail with reference to examples and drawings. These examples are carried out on the premise of taking the present invention as a technical solution, and detailed embodiments and processes are shown. However, the embodiments provided by the present invention are exemplary and are for interpreting the present invention, and it cannot be understood as limiting the present invention. Conditions, methods, etc. not specified in the following examples are all carried out in the usual way.

[0035] Definition The term "alkyl group" refers to an aliphatic hydrocarbon group, which may be a branched-chain or straight-chain alkyl group. Depending on the structure, the alkyl group may be a monovalent group or a divalent group (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "lower 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, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, etc. The "alkyl group" referred to in this specification includes all possible steric configurations and conformations of the alkyl group. For example, the "propyl group" referred to in this specification includes an n-propyl group and an isopropyl group, the "butyl group" includes an n-butyl group, an isobutyl group, and a tert-butyl group, and the "pentyl group" includes an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, and pentyl-3-yl, etc. It should be understood.

[0036] The term "alkoxy group" refers to an -O-alkyl group, and the alkyl group therein is as defined in this specification. Typical alkoxy groups include, but are not limited to, methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group, etc.

[0037] The term "cycloalkyl group" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. The cycloalkyl group includes groups having 3 - 12 ring atoms. The cycloalkyl group may be a monovalent group or a divalent group (e.g., cycloalkylene group) depending on the structure. In the present invention, as the cycloalkyl group, a cycloalkyl group having 3 - 8 carbon atoms is preferable, and a "lower cycloalkyl group" having 3 - 6 carbon atoms is more preferable. Examples of the cycloalkyl group include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, and adamantyl group.

[0038] The term "aryl group" means that each atom constituting the ring in an aromatic ring is a carbon atom. The aryl group ring may be composed of 5, 6, 7, 8, 9 or more than 9 atoms. The aryl group may be optionally substituted. Examples of the aryl group include, but are not limited to, phenyl group, naphthyl group, phenanthryl group, anthryl group, fluorenyl group, and indenyl group. The aryl group may be a monovalent group or a divalent group (i.e., arylene group) depending on the structure.

[0039] The term "heteroaryl group" means that one or more ring heteroatoms selected from nitrogen, oxygen and sulfur are included in the aryl group. The N-containing "heteroaryl group" moiety means that at least one skeletal atom on the ring in the aromatic group is a nitrogen atom. Depending on the structure, the heteroaryl group may be a monovalent group or a divalent group (i.e., heteroarylene group). Examples of heteroaryl groups include, but are not limited to, pyridyl group, imidazolyl group, pyrimidyl group, pyrazolyl group, triazolyl group, pyrazinyl group, tetrazolyl group, furyl group, thienyl group, isoxazolyl group, thiazolyl group, oxazolyl group, isothiazolyl group, pyrrolyl group, quinolyl group, isoquinolyl group, indolyl group, benzimidazolyl group, benzofuranyl group, indazolyl group, indolizinyl group, phthalazinyl group, pyridazinyl group, isoindolyl group, pteridinyl group, purinyl group, oxadiazolyl group, thiadiazolyl group, furazanyl group, benzofurazanyl group, benzothienyl group, benzothiazolyl group, benzoxazolyl group, quinazolinyl group, naphthyridinyl group and furopyridyl group, etc.

[0040] As used herein, the term "alicyclic group" or "cycloalkyl group" refers to a non-aromatic group ring formed by three or more carbon atoms, and two adjacent carbon atoms in the ring may be 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 group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclohexenyl group, cyclopentenyl group, cyclohexadienyl group, etc.

[0041] As used herein, the term "heterocycloalkyl group" or "heteroalicyclic group" means that one or more atoms constituting the ring in a non-aromatic group ring are heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl group may be composed of 3, 4, 5, 6, 7, 8, 9, or more than 9 atoms. The heterocycloalkyl group may optionally be substituted. Examples of heteroalicyclic groups include, but are not limited to, lactam, lactone, cycloimine, cyclothioimine, cyclocarbamate, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiocyclohexane, 1,4-oxathiocyclohexadiene, 1,4-oxathiocyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxapiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxol, 1,3-dioxolane, 1,3-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidone, thiazoline, thiazolidine, and 1,3-oxathiolane. Depending on the structure, the heteroalicyclic group may be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

[0042] The term "halogen" or "halogen element" refers to fluorine, chlorine, bromine, and iodine.

[0043] The term "carbonyl group" is an organic functional group (C=O) in which two kinds of atoms, carbon and oxygen, are linked by a double bond.

[0044] The term "optionally" means that one or more of the elements described below may or may not occur, and includes both the case where they occur and the case where they do not occur.

[0045] The salts that can be formed by the compounds in the present invention also belong to the scope of the present invention. Unless otherwise specified, it is understood that the compounds in the present invention include their salts. As used herein, the term "salt" refers to acidic or basic salts formed from inorganic or organic acids and bases. Also, when the compound in the present invention contains one basic fragment, it includes, but is not limited to, pyridine or imidazole, and when it contains one acidic fragment, it includes, but is not limited to, carboxylic acid. Zwitterions ("inner salts") that can be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are optimal, and other salts are also useful, for example, they can be used in separation or purification steps during the manufacturing process. The compounds of the present invention can form salts. For example, Compound I reacts with a certain amount, for example, an equimolar amount of an acid or a base, salifies in a medium, or is freeze-dried in an aqueous solution to obtain the salt.

[0046] The basic fragment contained in the compound of the present invention includes, but is not limited to, an amine, pyridine or imidazole ring, and may form a salt with an organic or inorganic acid. Typical acids capable of forming salts include acetate (e.g., trihaloacetic acid such as acetic acid or trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, benzenepropionate (e.g., 3-benzenepropionate), phosphate, picrate, neopentanoate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate, e.g., p-toluenesulfonate, dodecanoate, etc.

[0047] The acidic fragments that may be included in some of the compounds of the present invention include, but are not limited to, carboxylic acids, and can form salts with various organic or inorganic bases. Salts formed with typical bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, Hydrabamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-gluconamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. The basic nitrogen-containing groups include quaternary ammonium salts of halides, such as small molecule alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl), aralkyl halides (e.g., benzyl bromide and phenyl bromide), etc.

[0048] Prodrugs and solvates of the compounds in the present invention are also within the scope of coverage. Here, the term "prodrug" means a compound that generates the compounds, salts, or solvates in the present invention through chemical conversion of metabolic or chemical processes when treating related diseases. "Solvate" means a solvate adduct containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to capture a certain molar ratio of solvent molecules in the crystalline solid state to form solvates. If the solvent is water, the formed solvate is a hydrate, and if the solvent is alcohol, the formed solvate is an alcoholate. One or more water molecules bind to one molecule of a substance to form a hydrate, and water maintains its molecular state H2O. Non-limiting examples of solvates include ethanol solvate, acetone solvate, etc.

[0049] The compounds, salts or solvates in the present invention may adopt tautomeric forms (e.g., amide and imino ether). All of these tautomers are part of the present invention.

[0050] All stereoisomers of the compounds (e.g., asymmetric carbon atoms that may exist for various substitutions) include their enantiomeric forms and diastereomeric forms, and all fall within the scope contemplated by the present invention. The independent stereoisomers of the compounds in the present invention may not coexist with other isomers (e.g., have special activity as a single pure or substantially pure optical isomer), or may be a mixture, such as a racemate, or a mixture formed with all other stereoisomers or a part thereof. There are two stereoconfigurations, S or R, at the chiral centers of the present invention, which are defined according to the proposal of the International Union of Pure and Applied Chemistry (IUPAC) in 1974. The racemic form can be resolved by physical methods, such as stepwise crystallization, or crystallization separation by induction into diastereomers, or separation by chiral column chromatography. A single optical isomer can be obtained from the racemate by appropriate methods, including but not limited to conventional methods such as forming a salt with an optically active acid and then recrystallizing.

[0051] The compounds in the present invention are described in the text as having a weight content of the compound obtained in the order of production, separation and purification of 90% or more, for example, 95% or more, 99% or more (a "very pure" compound). Here, such "very pure" compounds of the present invention are also part of the present invention.

[0052] All stereoconfigurational isomers of the compounds of the present invention, whether in a mixture, pure or very pure form, are within the scope of coverage. The definition of the compounds of the present invention includes two olefin isomers, cis (Z) and trans (E), and cis and trans isomers of carbocyclic and heterocyclic rings.

[0053] In the present specification, groups and substituents can be selected to provide stable fragments and compounds.

[0054] The definitions of specific functional groups and chemical terms are described in detail below. In the present invention, chemical elements are consistent with those defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. The definitions of specific functional groups are also described therein. The basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and all of its contents are incorporated into the list of references.

[0055] Some compounds of the present invention may exist in the form of specific geometric or stereoisomers. The present invention encompasses all compounds including cis and trans isomers, R and S enantiomers, diastereomers, (D)-type isomers, (L)-type isomers, racemic mixtures and other mixtures. Also, an asymmetric carbon atom may represent a substituent, for example an alkyl group. All isomers and mixtures thereof are included in the present invention.

[0056] According to the present invention, the ratios of isomers contained in a mixture of isomers are diverse. For example, a mixture of only two isomers may have combinations of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that can be easily understood by those skilled in the art, as well as ratios of more complex mixtures of isomers, are also within the scope of the present invention.

[0057] The present invention further includes compounds labeled with isotopes, which are equivalent to the original compounds disclosed herein. However, in practice, it is generally found that one or more atoms are replaced by atoms with different atomic weights or mass numbers. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine isotopes, respectively, 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 Cl may be mentioned. In the compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, any isotope or other isotope atoms containing the above compounds are within the scope of the present invention. Some isotope-labeled compounds in the present invention, for example, 3 H and 14 radioisotopes of C are also included therein and are useful for tissue distribution experiments of drugs and substrates. Tritium, that is, 3 H, and carbon-14, that is, 14 C are relatively easy to prepare and detect. They are also optimal in isotopes. Also, heavy isotope substitution, for example, deuterium, that is, 2 H, is advantageous in some therapies due to its excellent metabolic stability, and can be preferentially considered in some cases, for example, to increase the half-life or reduce the dose in the body. Compounds labeled with isotopes can be prepared by the methods disclosed in the examples, generally by substituting non-isotope reagents with reagents labeled with readily available isotopes.

[0058] When attempting to design the synthesis of a specific enantiomer of the compound of the present invention, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting mixture of diastereomers can be separated, and further the chiral auxiliary can be removed to obtain a pure enantiomer. Also, when the molecule contains one basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereomeric salt can be formed with an appropriate optically active acid or base, and further separated by ordinary means such as fractional crystallization or chromatography to obtain a pure enantiomer.

[0059] As described in this specification, the compounds in the present invention can expand their scope of inclusion by substitution with any number of substituents or functional groups. Generally, the term "substituted" may appear before or after the term "selectable", and the general formula containing substituents in the formulation of the present invention means using a substituent of a specified structure in place of a hydrogen radical. When a plurality of positions in a specific structure are substituted with a plurality of specific substituents, each position of the substituent may be the same or different. The term "substituted" as used herein includes substitution of all acceptable organic compounds. In a broad sense, acceptable substituents include acyclic, cyclic, branched-chain, unbranched-chain, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any of the above acceptable organic compounds to supplement its valence state. Further, the present invention does not limit the substitutable organic compounds in any form. In the present invention, the combination of substituents and variable groups is considered to be excellent in treating diseases in the form of stable compounds. Here, the term "stable" means having a stable compound and being sufficient to maintain the integrity of the compound structure within a sufficiently long time, and it is preferably effective within a sufficiently long time. This is used for the above purposes in this specification.

[0060] Example 1 Synthesis of Compound Synthesis of Compound RZ001

Chemical Formula

[0061] Synthesis of Compound RZ003

Chem.

[0062] Synthesis of Compound RZ004

Chem.

[0063] Synthesis of Compound RZ005

Chemical Structure

[0064] Synthesis of Compound RZ012

Chem.

[0065] In the same manner as in the above example, using commercially available compounds or referring to the production method of intermediate compounds, the compounds of the examples in Table 1 below were produced.

Table 1(1)

Table 1(2)

Table 1(3)

[0066] Synthesis of Compound RZ002

Chem.

[0067] Synthesis of Compound RZ006

Chem.

[0068] In the same manner as in the above examples, using commercially available compounds or referring to the production method of intermediate compounds, the compounds of the examples in Table 2 below were produced.

Table 2

[0069] Synthesis of Compound RZ201

Chemical formula

[0070] In the same manner as in the above examples, using commercially available compounds or referring to the production method of intermediate compounds, the compounds of the examples in Table 3 below were produced.

Table 3

[0071] Synthesis of Compound RZ301

Chemical formula

[0072] Example 2 The esterase content in senescent cells is higher than that in normal cells In this example, human non-small cell lung cancer cell line (A549 cells), human retinal pigment epithelial cells (RPE cells), and human lung fibroblast cells (IMR90 cells) were selected. After cell senescence, it was detected whether the intracellular esterase content was higher than that in normal cells. Thereby, the superiority of prodrug release in senescent cells was evaluated. Cells were plated in 100 mm culture dishes and senescence was induced with bleomycin (10 μM) and etoposide (10 μM). Normal and senescent cells were digested and counted. After disrupting the cells by sonication, they were centrifuged for 10 min, the supernatant was placed on ice, and detection was performed according to the requirements of the kit. The calculation formula is as follows. CarE enzyme activity (U / 10 4 cell) = (ΔA measurement tube - ΔA blank tube) × V total reaction volume ÷ 0.5 ÷ (200 ÷ V total cell sample volume × V sample) ÷ T × F V sample: Added sample volume, 0.01 mL; T: Reaction time, 5 min; 200: Total number of cells, 2 million; V total cell sample volume: Volume of extraction liquid added to cells, 0.2 mL; V total reaction volume: Total volume of the reaction system, 0.2 mL; F: Dilution factor. As can be seen from Figure 1A, Figure 1B, and Figure 1C, the esterase content in senescent cells was significantly higher than that in normal cells.

[0073] Example 3 The prodrug compound has a more specific killing effect on senescent cells than A-1331852 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. The above senescent cells were obtained by etoposide induction (10 μM). The effects of the target compounds RZ001-RZ006 and RZ201 on the viability of the above normal and senescent cells were detected, and the specific killing effects of the prodrug compounds RZ001-RZ006 and RZ201 on the above senescent cells were evaluated. Briefly, the above senescent and normal cells were selected and plated (96-well plates) respectively. After adding compounds RZ001-RZ006 and RZ201 (concentration 20 μM) and allowing them to act for 72 h, the CellTiter-GloR Luminescent Cell Viability Assay kit (Promega) was added to detect cell viability, and the results are shown in Figures 2A-2E. As can be seen from FIGS. 2A to 2E, A-1331852 not only killed senescent cells, but also had a sufficiently significant killing effect on normal cells. Compounds RZ001-RZ006 and RZ201 did not significantly kill normal cells except for killing senescent cells. It was shown that RZ001-RZ006 and RZ201 had better specificity and safety. In addition, the senolytic index in normal and senescent A549 cells was also calculated. Referring to Table 4 below, it was shown that the higher the index, the stronger the specificity for removing senescent cells and the better the safety.

[0074]

Table 4(1)

Table 4(2)

Table 4(3)

[0075] Example 4: Efficacy in an animal model of oxygen-induced retinopathy In an oxygen-induced retinopathy (OIR) mouse model, the effects of prodrugs RZ001-RZ006 and RZ201 were studied. The model indicated, to some extent, an in vivo model of retinopathy of prematurity (ROP), diabetic retinopathy, and wet age-related macular degeneration. From postnatal day 7 (P7) to day 12 (P12), C57Bl / 6 mouse pups and their CD1 foster mothers were exposed to a high-oxygen environment (75% O2). At P12, 1 μl of a test composition (compound at 200 μM) prepared with 1% DMSO, 10% Tween 80, and 20% PEG-400 was injected into the vitreous of the animals, and they were returned to room air until day 17 (P17). At P17, the eyeballs were enucleated, and the retinas were dissected for vascular staining. To measure the avascular or neovascular area, the retinas were flattened and stained with isolectin B4 (IB4). Figure 3 shows a statistically significant improvement in avascular areas and angiogenesis by administering RZ001 - RZ006 and RZ201 into the vitreous body (IVT).

[0076] Example 5: Efficacy in an Animal Model of Diabetic Induced Retinopathy The efficacy of the compounds of the present disclosure was studied in a mouse model of diabetic retinopathy by administering streptozotocin (STZ) multiple times. 6 - 7 week old C57BL / 6J mice were weighed and their baseline blood glucose (Sinocare) was measured. The mice were intraperitoneally injected with STZ (Sigma - Alderich) at 55 mg / Kg for 5 consecutive days. The age - matched control group was injected with buffer only. One week after the last STZ injection, the blood glucose was measured again. At 8 and 9 weeks after STZ administration, 1 μl of the compound to be measured (prepared as a suspension at 200 μM, 0.015% polysorbate 80, 0.2% sodium phosphate, 0.75% sodium chloride, pH 7.2) was injected into the vitreous body of the diabetic C57BL / 6J mice treated with STZ. At 10 weeks after STZ treatment, a retinal Evans blue permeability measurement was performed. Figure 4 shows that retinal and choroidal vascular leakage after administering RZ001, RZ002 and RZ201 into the vitreous body (IVT) can improve vascular permeability at this dose level.

[0077] Example 6: Efficacy in an Animal Model of Wet - Age - Related Macular Degeneration with CNV This example adopted a CNV animal model and measured the effect of the compounds of the present disclosure on wet - age - related macular degeneration. Male mice were administered 0.5% pregabalin hydrochloride (Alcon) for local anesthesia and 1% tropicamide to dilate the pupils of the mice. Laser ablation was performed using a laser photocoagulation device (Novus Varia, LUMENIS) with a slit - lamp delivery system. As the contact lens, a glass coverslip artificially torn and attached was used. The bleeding points caused by the laser light are not included in the statistical data. Figure 5 shows a statistically significant improvement in the fluorescence intensity index after administration of RZ001, RZ002, and RZ201 into the vitreous body (IVT).

[0078] Example 7: Efficacy in an animal model of idiopathic pulmonary fibrosis In this example, the effect of the compounds of the present disclosure on idiopathic pulmonary fibrosis was measured using an animal model of idiopathic pulmonary fibrosis. Briefly, anesthetized 6-week-old SD rats were fixed to a foam plate with medical tape. First, the skin on the surface of the trachea was incised with surgical scissors, the trachea was fully exposed, and a 100-microliter micro-needle of a certain volume of bleomycin (BLM 5 mg / kg) solution aspirated according to the rat body weight was inserted into the trachea through the oral cavity and slowly injected. After administering the BLM solution, the foam plate was immediately rotated and rocked to distribute the BLM chemical solution as uniformly as possible to the lung tissue. Then, the skin on the surface of the trachea was sutured with surgical suture needles, and about 0.5 - 1.0 ml of penicillin solution was dropped onto the epidermis to prevent infection of the surgical wound. After the 7th day of modeling, the compound solution of the present disclosure was administered according to the rat body weight, by intraperitoneal injection (IP) (5 mg / kg), and continuously administered for 3 weeks. On the 28th day, the rats were euthanized with carbon dioxide, the lung tissue was collected, the left alveolar lavage fluid was collected to count white blood cells (WBC), hydroxyproline (HYP) detection was performed on the right lung tissue part, and pathological H&E staining and Masson staining were performed on the remaining lung tissue. Figure 6 shows a statistically significant improvement in WBC, HYP, and pathological scores in the IPF model by intraperitoneal injection (IP) administration of RZ001, RZ002, and RZ201.

[0079] Example 8: Efficacy in an animal model of osteoarthritis In this example, the effect of the compounds of the present disclosure on osteoarthritis was measured using an animal model of osteoarthritis. A murine model of osteoarthritis was established through the following steps. Mice were anesthetized with isoflurane, 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 site was incised. Under an optical microscope, the inner side of the right knee joint with the knee bent by a blade was incised longitudinally. Without cutting the patellar ligament, the patellar ligament was pulled to one side and continuously pressed with a sterile cotton swab to stop bleeding. The joint cavity was fully exposed, and physiological saline was dripped in a timely manner to prevent the joint cavity from drying out. Excess muscle tissue was gently separated with blunt forceps to expose the meniscus ligament. The anterior cruciate ligament was searched deep in the joint cavity, and the anterior cruciate ligament was incised with microsurgical scissors. Then, the wound surface was disinfected with penicillin solution, the muscle was sutured with sterile needles and threads, and finally the skin tissue was sutured. The drug efficacy was judged by intra-articular injection. At the end of the experiment, the plantar sustained pain threshold was detected, and the osteoarticular joint was collected for safranin O / fast green staining. Figure 7 shows statistically significant improvements in the mechanical pain threshold of the plantar surface and the pathological score of safranin O / fast green staining in an osteoarthritis (OA) model by intra-articular injection of RZ001, RZ002, and RZ201.

[0080] Example 9: Efficacy against an animal model of Alzheimer's disease This example adopted an animal model of Alzheimer's disease to measure the effect of the compound of the present disclosure against Alzheimer's disease. Briefly, a transgenic mouse model of APP×PS1 (purchased from Cyagen Biosciences) was selected, and the compound of the present disclosure was administered by intraperitoneal injection for 11 consecutive weeks, with injections twice a week. The improvement of amyloid in the mouse cerebral cortex was observed. Figure 8 shows statistically significant improvements in the index of Aβ42 pathogenic protein in an AD mouse model by intraperitoneal injection of RZ001, RZ002, and RZ201.

[0081] Example 10: Efficacy against an animal model of liver fibrosis In this example, the effect of the compound of the present disclosure on liver fibrosis was measured using a liver fibrosis animal model. Briefly, C57BL / 6N mice, male, 7 - 8 weeks old, weighing 24 - 28 g were selected. A CCl4 solution was intraperitoneally injected with a dosage of 1 ml / kg, a dosing frequency of 2 times / week, and a modeling period of 6 weeks to induce a mouse liver fibrosis model. Intraperitoneal injection (5 mg / kg) was started at the 3rd week of modeling and administered twice a week. At the end of the experiment, serum was collected, liver tissue was collected, and Masson staining index detection was performed. Figure 9 shows a statistically significant improvement in the levels of glutamic - oxaloacetic transaminase (AST) and alanine aminotransferase (ALT) in serum and pathological statistics in a liver fibrosis model by administration of RZ001, RZ002, and RZ201 via intraperitoneal injection (IP).

[0082] Example 11: Efficacy on Aging Skin In this example, aged female C57bl / 6J mice (22 months old) were used. They were administered by skin application. Administered twice a week for 6 consecutive weeks. The improvement status of the skin epidermal thickness of the aged mice was observed. Figure 10 shows a statistically significant improvement in the thickness score of the skin epidermis of a natural aging mouse model by application of RZ001, RZ002, and RZ201.

[0083] Example 12: Efficacy on a Renal Fibrosis Animal Model This example adopted a renal fibrosis animal model and measured the effect of the compound of the present disclosure on renal fibrosis. Briefly, C57BL / 6J mice, male, 7 - 8 weeks old were selected. After anesthetizing the mice, the mice were placed supine on a foam plate, disinfected with iodophor, the skin in the middle of the lower abdomen was cut longitudinally, the linea alba of the abdominal muscles was found, and the abdominal muscles, fascia and peritoneal layer were cut here. After the surgical field was exposed, the stomach and mesentery of the mice were pushed to the right with gauze soaked in physiological saline to expose the kidneys. A transparent ureter was found downward along the renal artery from the renal pelvis, the left ureter was separated, ligated at 1 / 3 of the left ureter, the incisions were sutured layer by layer, and finally disinfected with iodophor to construct a renal fibrosis model. Intraperitoneal injection was started at the second week of modeling. At the end of the experiment, mouse serum was collected, and kidney tissues were collected for Masson staining index detection. Figure 11 shows the levels of serum creatinine (Cr) and blood urea nitrogen (BUN) and a statistically significant improvement in a renal fibrosis model by intraperitoneal (IP) administration of RZ001, RZ002 and RZ201.

[0084] Example 13: Efficacy against a rabbit ear hypertrophic scar model This example adopted a rabbit ear hypertrophic scar animal model and measured the effect of the compound of the present disclosure on hypertrophic scars. Briefly, 10 New Zealand white rabbits, male, 3 months old were selected. After anesthetizing the New Zealand rabbits with sodium pentobarbital, six circular full - thickness wounds with a diameter of 10 mm were created on the ventral surface of each ear by removing the epidermis, dermis and perichondrium down to the bare cartilage. The rabbits were randomly divided into a control group and an RZ001 experimental group. On the 14th day after surgery, after the wound surface was completely re - epithelialized, the compound (150 uM, 100 ul, dissolved in DMSO solution) or 100 ul of negative control DMSO 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 improvement effect of the compound on scar formation was evaluated by SEI (scar hypertrophy index). Figure 12 shows a statistically significant improvement in the scar hypertrophy index of a rabbit ear hypertrophic scar model by administration of RZ001.

Claims

1. A compound having the structure represented by formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, eutectic, tautomer, stereoisomer, or isotope-labeled compound thereof, 【Chemistry 1】 however, R 1 C is either substituted or non-substituted. 1 -C 10 Selected alkylene group, R 2 is selected from -O-C(O)- or -O-C(O)-O-, R 3 This is selected from substituted or unsubstituted C1-C10 chain alkyl groups, substituted or unsubstituted C3-C20 cycloalkyl groups, substituted or unsubstituted C2-C20 chain alkenyl groups, substituted or unsubstituted C2-C20 chain alkynyl groups, substituted or unsubstituted C6-C20 aryl groups, substituted or unsubstituted C1-C20 heteroaryl groups, and substituted or unsubstituted C2-C20 heteroalicyclic groups. Or, R 1 R is either non-existent or selected from substituted or unsubstituted C1-C10 alkylene groups. 2 It does not exist, and R 3 This is selected from substituted or unsubstituted C2-C20 heteroalicyclic groups. R c is selected from a substituted or unsubstituted adamantyl group, Selectively, the substituents in the substitution include halogen atoms, cyano groups, nitro groups, C6-C20 aryl groups, C1-C20 heteroaryl groups, C1-C10 alkyl groups, C1-C10 alkoxy groups, C6-C20 aryloxy groups, C1-C20 heteroalicyclic groups, preferably C1-C10 heteroalicyclic groups, amino groups, hydroxyl groups, mercapto groups, phosphate ester groups, and -OC(O)R. 6 , -ONR 6 R 7 , -NR 6 R 7 Substituted with a substituent selected from R 6 and R 7 The group is independently selected from hydrogen, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, and a C2-C8 alkynyl group. The aryl group and heteroaryl group are optionally selected from a halogen atom, a hydroxyl group, a mercapto group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, a C1-C6 alkoxy group, and a C6-C20 aryl group. The group is substituted with a C1-C20 heteroaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 chain alkenyl group, or a C2-C8 chain alkynyl group, and optionally, at least two substituents together constitute an alicyclic ring, such as a C3-C20 alicyclic ring, a heteroalicyclic ring, such as a C2-C20 alicyclic ring, an aromatic ring, such as a C6-C20 aromatic ring, or a heteroaromatic ring, such as a C1-C20 heteroaromatic ring.

2. The aforementioned compound is represented by formula III, IV, or V, 【Chemistry 2】 In formulas III and IV, R 1 C is independently substituted or unsubstituted. 1 -C 10 Selected from alkylene groups, preferably R 1 C is independently substituted or unsubstituted. 1 -C 6 Selected from alkylene groups, preferably R 1 C is independently substituted or unsubstituted. 1 -C 4 Selected alkylene group, R a , R b , R 3 , R c The definition of L is the same as in equation I, In equation V, R 1 C does not exist or is independently substituted or unsubstituted. 1 -C 10 Selected from alkylene groups, preferably R 1 C is independently substituted or unsubstituted. 1 -C 6 Selected from alkylene groups, preferably R 1 C is independently substituted or unsubstituted. 1 -C 4 Selected alkylene group, R 3 R is selected from substituted or unsubstituted C2-C20 heteroalicyclic groups, a , R b , R c The compound according to claim 1, characterized in that the definition of L is the same as that of formula I.

3. The C2-C20 heteroalicyclic group can optionally be a halogen atom, a hydroxyl group, a mercapto 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 chain alkenyl group, or a C2-C8 alkynyl group. 【Transformation 3】 Substituting with a substituent selected from, each R 5 The compound according to claim 1, characterized in that it is independently selected from hydrogen and a C1-C6 alkyl group.

4. The aforementioned C2-C20 heteroalicyclic group is a C4-C8 heteroalicyclic group, The C4-C8 heteroalicyclic group can optionally be a halogen, -NH 2 -OH, -NO 2 , carbonyl group, -CH 2 The compound according to claim 1, characterized in that it is substituted with a group selected from OH, carboxyl group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, or isopropoxy group.

5. The C2-C20 heteroalicyclic group is selected from the groups represented by the following group: 【Chemistry 4】 Each R' independently represents no substituent, a single substituent, or multiple substituents, and each substituent independently represents deuterium, a hydroxyl group, a halogen, or NH 2 carboxyl group (-COOH), 【Transformation 5】 Selected from C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, hydroxyl-substituted C1-C6 alkyl groups, amino-substituted C1-C6 alkyl groups, morpholine-substituted C1-C6 alkyl groups, -COO-C1-C6 alkyl groups, cyano groups, C1-C6 alkoxy groups, C3-C6 cycloalkyl groups, halogen-substituted C3-C6 cycloalkyl groups, hydroxyl-substituted C3-C6 cycloalkyl groups, phenyl groups, and benzyl groups. L 2 This is a C1-C6 alkylene group that is either absent or substituted with a C1-C6 alkylene group, halogen, hydroxyl group, or C1-C6 alkoxy group, preferably a methylene group, ethylene group, or propylene group. R 6 H, deuterium, halogen, hydroxyl group, NH 2 carboxyl group (-COOH), -CONH 2 , sulfonic acid group (-SO 3 H), sulfonyl-SO 2 -C1-C6 chain alkyl group, 【Transformation 6】 The compound according to claim 1, characterized in that it is a C1-C6 chain alkyl group, a halogen-substituted C1-C6 chain alkyl group, a hydroxyl-substituted C1-C6 chain alkyl group, an amino-substituted C1-C6 chain alkyl group, a C3-C6 cycloalkyl group, a halogen-substituted C3-C6 cycloalkyl group, a hydroxyl-substituted C3-C6 cycloalkyl group, a phenyl group, or a benzyl group.

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

7. The aforementioned compound is represented by formula II, 【Transformation 7】 In equation II, R 1 , R 2 , R 3 The compound according to claim 1, characterized in that the definition of is the same as that of formula I.

8. R 1 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 R 3 This is selected from substituted or unsubstituted C1-C8 chain alkyl groups, substituted or unsubstituted C3-C10 cycloalkyl groups, substituted or unsubstituted C2-C8 chain alkenyl groups, substituted or unsubstituted C2-C8 chain alkynyl groups, substituted or unsubstituted C6-C12 aryl groups, substituted or unsubstituted C2-C12 heteroaryl groups, or substituted or unsubstituted C1-C12 heteroalicyclic groups. Preferably, R 3 The compound according to claim 1, characterized in that it is selected from a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C1-C10 heteroaryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted C1-C10 heteroalicyclic group.

9. The substitutions include halogen atoms, cyano groups, nitro groups, C6-C20 aryl groups, C1-C20 heteroaryl groups, C1-C10 alkyl groups, C1-C10 alkoxy groups, C6-C20 aryloxy groups, C1-C20 heteroalicyclic groups, preferably C1-C10 heteroalicyclic groups, amino groups, hydroxyl groups, mercapto groups, phosphate ester groups, and -OC(O)R. 6 , -ONR 6 R 7 , -NR 6 R 7 Substituted with a substituent selected from R 6 and R 7 The group is independently selected from hydrogen, a C6-C20 aryl group, a C1-C20 heteroaryl group, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, and a C2-C8 alkynyl group. The aryl group and heteroaryl group are optionally selected from a halogen atom, a hydroxyl group, a mercapto 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, and a C1-C20 heteroaryl group. The compound according to claim 1, characterized in that it is substituted with a teloaryl group, a C2-C20 heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 chain alkenyl group, or a C2-C8 chain alkynyl group, and of which, optionally, at least two substituents together constitute an alicyclic ring, such as a C3-C20 alicyclic ring, a heteroalicyclic ring, such as a C2-C20 alicyclic ring, an aromatic ring, such as a C6-C20 aromatic ring, or a heteroaromatic ring, such as a C1-C20 heteroaromatic ring.

10. R 3 The compound according to claim 1, characterized in that it is selected from the following groups. 【Transformation 8】

11. The compound according to claim 1, characterized in that the compound is selected from the following compounds. 【Chemistry 9(1)】 【Chemistry 9(2)】 【Chemistry 9(3)】 【Chemistry 9(4)】 【Chemistry 9(5)】

12. A method for preventing or treating age-related diseases, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, eutectic, tautomer, stereoisomer, or isotope-labeled compound thereof to a subject in need.

13. Age-related diseases are diseases associated with the accumulation of senescent cells, and preferably include idiopathic pulmonary fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, viral inflammation and histological fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, cutaneous fibrosis, interstitial lung disease, fibrotic pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, and dry age-related macular degeneration. Age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritis neuropathy, keratitis sicca, Fuchs corneal dystrophy, presbyopia, cataracts, vitreomacular traction syndrome, macular tear, retinal tear, retinal detachment, degenerative vitreoretinal diseases including proliferative vitreoretinopathy, osteoarthritis, herniated disc, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease, diabetes, diabetic nephropathy, scarring, superficial scarring or This includes flat scars, cord-like or contracture scars, webbed scars, atrophic scars, briny scars, pontine and striated scars, hypertrophic scars, keloids, scar carcinoma, scleroderma, focal scleroderma, shingles scleroderma, drip scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, fatty dysplasia, coronary artery disease, cerebrovascular disease, periodontal disease, cancer treatment-related disorders, and, for example, atrophy in various tissues. The method according to 12, characterized in that it is one or more selected from atrophy and fibrosis, myelodysplastic syndromes associated with brain and heart disorders and treatment, promyelocytic syndromes, ataxic telangiectasia, Fanconi anemia, Friedreich's ataxia, congenital dyskeratosis, aplastic anemia, aneurysm, inflammatory bowel disease, lipoatrophy, kidney transplant failure, muscle loss, wound healing, hair loss, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

14. Application of the compound described in any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, eutectic, tautomer, stereoisomer, or isotope-labeled compound thereof, in the manufacture of a pharmaceutical product for the prevention or treatment of age-related diseases.

15. Age-related diseases are diseases associated with the accumulation of senescent cells, and preferably include idiopathic pulmonary fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, viral inflammation and histological fibrosis and atrophy of the upper respiratory tract and lungs, cystic fibrosis, myelofibrosis, myocardial fibrosis, cutaneous fibrosis, interstitial lung disease, fibrotic pancreatitis, retinopathy of prematurity, macular degeneration, diabetic macular edema, diabetic retinopathy, age-related macular degeneration, wet age-related macular degeneration, and dry age-related macular degeneration. Age-related macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritis neuropathy, keratitis sicca, Fuchs corneal dystrophy, presbyopia, cataracts, vitreomacular traction syndrome, macular tear, retinal tear, retinal detachment, degenerative vitreoretinal diseases including proliferative vitreoretinopathy, osteoarthritis, herniated disc, osteoporosis, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic obstructive pulmonary disease, diabetes, diabetic nephropathy, scarring, superficial scarring or This includes flat scars, cord-like or contracture scars, webbed scars, atrophic scars, briny scars, pontine and striated scars, hypertrophic scars, keloids, scar carcinoma, scleroderma, focal scleroderma, shingles scleroderma, drip scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary syndrome, myocardial infarction, stroke, hypertension, obesity, fatty dysplasia, coronary artery disease, cerebrovascular disease, periodontal disease, cancer treatment-related disorders, and, for example, atrophy in various tissues. The application according to claim 14, characterized in that it is one or more selected from atrophy and fibrosis, myelodysplastic syndromes associated with brain and heart disorders and treatment, promyelocytic syndromes, ataxic telangiectasia, Fanconi anemia, Friedreich's ataxia, congenital dyskeratosis, aplastic anemia, aneurysm, inflammatory bowel disease, lipoatrophy, kidney transplant failure, muscle loss, wound healing, hair loss, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

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