Benzothiazole compounds and their applications

Abstract

The present invention relates to a benzothiazole compound represented by formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer or prodrug thereof. The present invention further relates to the use of the benzothiazole compound in the manufacture of a medicament for preventing or treating aging-related diseases. 【Chemical 1】 TIFF2025522588000080.tif84153

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly relates to a benzothiazole compound that targets and kills senescent cells, and its 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 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 aging of some proliferating cells or stem cells leads to a decline in the regenerative ability of an individual, affecting the recovery ability and normal functions of the living body. More importantly, 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 chemical small molecules can reduce chronic inflammation, improve tissue repair ability, improve symptoms of age-related diseases such as osteoarthritis and idiopathic pulmonary fibrosis, and alleviate the decline in physiological functions of the aging living body. Therefore, selectively removing senescent cells is a promising approach for the treatment of aging-related diseases and the improvement of physiological functions of elderly individuals.

[0003] Researchers have demonstrated that removing senescent cells from the body can extend lifespan and delay the onset of age-related diseases, providing a theoretical basis for strategies to achieve anti-aging and treat age-related diseases by targeting and killing senescent cells. 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 selective killing of senescent cells to a certain extent, but there is still room for improvement in reducing toxicity and enhancing the specificity of killing. Many 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 resist apoptosis. As a classical dual inhibitor of anti-apoptotic proteins BCL2 / BCL-XL, ABT263 (navitoclax) has subsequently been proven to be able to specifically induce apoptosis in senescent cells.

[0004] A-1331852 (CAS1430844-80-6) 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, it also shows high activity against senescent cells. However, on the one hand, due to its extremely strong inhibitory effect on Bcl-xL, A-1331852 kills platelets even at relatively low concentrations and shows significant platelet toxicity under in vivo conditions, restricting the clinical application of this molecule. On the other hand, the physicochemical properties of the A-1331852 molecule have room for improvement. For example, its solubility in water is low, and its oral bioavailability in rats is only about 11%. Based on these defects, A-1331852 only functions as an excellent Bcl-xL specific inhibitor and is only used in research as a tool compound.

[0005] Currently, there is no Bcl-xL inhibitor that not only has a very strong inhibitory effect on Bcl-xL but also has excellent physicochemical properties and better safety.

Summary of the Invention

[0006] In order to solve at least one technical problem existing in the prior art, the present invention provides a novel benzothiazole compound that significantly reduces platelet toxicity, selectively kills aging cells and tumor cells within a larger safety window, reduces the killing side effect on normal cells, and has higher selectivity and safety. In addition, the compound of the present invention can have excellent physicochemical properties, especially significantly improved water solubility.

[0007] In a first aspect, the present application provides a benzothiazole compound having a structure represented by formula I.

Chemical formula

Chemical formula

[0008] Pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopic compounds (preferably deuterides) or prodrugs of the benzothiazole compounds represented by Formula I are all within the scope of protection of this application. Therefore, this application further provides pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopic compounds (preferably deuterides) or prodrugs of the benzothiazole compounds represented by Formula I.

[0009] In some embodiments, the compound is represented by Formula II, [Chemical formula] In Formula II, the definitions of R1 and R2 are the same as those in Formula I.

[0010] In some embodiments, in Formula I and / or Formula II, R1 and R2 together with the N atom to which they are attached form a C2-C20 heteroalicyclic group, for example, a C2-C10 heteroalicyclic group, and the ring of the C2-C20 heteroalicyclic group optionally further contains 1 or 2 heteroatoms selected from N or O.

[0011] In some embodiments, the C2-C20 heteroalicyclic group optionally contains a halogen atom, a cyano group, a nitro group, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 linear 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] - substituted by one or more substituents of NR4R5, wherein R4 and R5 are independently selected from hydrogen, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C8 chain alkyl group, a C3-C8 cycloalkyl group, a C2-C8 chain alkenyl group, and a C2-C8 alkynyl group, and the aryl group and heteroaryl group are optionally substituted by 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-C8 alkoxy group, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C2-C10 heteroalicyclic group, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C2-C6 chain alkenyl group, or a C2-C8 alkynyl group, and optionally, the substituents at at least two positions thereof together form a C3-C10 alicyclic ring, a C2-C10 heteroalicyclic ring, a C6-C10 aromatic ring, or a C1-C10 heteroaromatic ring.

[0012] In some embodiments, the C2-C20 heteroalicyclic group is optionally substituted by 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

[0013] In some embodiments, the C2-C8 heteroalicyclic group is optionally substituted by 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.

[0014] In some embodiments, R1 and R2 are independently selected from a C1-C6 linear alkyl group, a C3-C6 cycloalkyl group, a C2-C6 linear alkenyl group, a C2-C6 alkynyl group, a C6-C10 aryl group, a C1-C10 heteroaryl group, and a C2-C10 heteroalicyclic group, where CH2 in the C1-C6 linear alkyl group, C3-C6 cycloalkyl group, C2-C6 linear alkenyl group, and C2-C6 alkynyl group may be substituted with one or more groups selected from -O-, -S-, -SO2-, -C(O)-, and -NR3-, and the C1-C6 linear alkyl group, C3-C6 cycloalkyl group, C2-C6 linear alkenyl group, C2-C6 alkynyl group, C6-C10 aryl group, C1-C10 heteroaryl group, and C2-C10 heteroalicyclic group are optionally substituted with a halogen atom, a cyano group, a nitro group, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 linear alkoxy group, a C6-C10 aryloxy group, a C2-C10 heteroalicyclic group, an amino group, a hydroxy group, a mercapto group,

Chemical formula

[0015] In some embodiments, the benzothiazole compound is represented by Formula III, [Chemical Formula] In Formula III, R2 is a C1-C10 linear alkyl group, a C3-C8 cycloalkyl group, a C2-C8 linear alkenyl group, a C2-C8 alkynyl group, a C6-C20 aryl group, a C1-C20 heteroaryl group, or a C2-C20 heterocycloaliphatic group, where CH2 in the C1-C10 linear alkyl group, C3-C8 cycloalkyl group, C2-C8 linear alkenyl group, or C2-C8 alkynyl group may be substituted with one or more groups selected from -O-, -S-, -SO2-, -C(O)-, and -NR3-. The C1-C10 linear alkyl group, C3-C8 cycloalkyl group, C2-C8 linear alkenyl group, C2-C8 alkynyl group, C6-C20 aryl group, C1-C20 heteroaryl group, and C2-C20 heterocycloaliphatic group 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 linear alkoxy group, a C6-C20 aryloxy group, a C2-C20 heterocycloaliphatic group, an amino group, a hydroxy group, a mercapto group, [Chemical Formula] - substituted by one or more substituents of NR4R5, and R3, R4 and R5 are independently selected from hydrogen, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 straight-chain alkyl group, a C3-C6 cycloalkyl group, a C2-C6 straight-chain alkenyl group and a C2-C6 alkynyl group, and the aryl group and heteroaryl group are optionally substituted by 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-C10 aryl group, a C1-C10 heteroaryl group, a C2-C10 heteroalicyclic group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C2-C6 straight-chain alkenyl group or a C2-C6 alkynyl group, wherein, optionally, the substituents at at least two positions together form a C3-C10 alicyclic ring, a C2-C10 heteroalicyclic ring, a C6-C10 aromatic ring or a C1-C10 heteroaromatic ring.

[0016] In some embodiments, the heteroalicyclic group or heteroalicyclic ring is selected from a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted piperazinyl group, a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted piperazin-2-one group, a substituted or unsubstituted pyrrolidinyl group, and a substituted or unsubstituted imidazolinyl group.

[0017] In some embodiments, R1 and / or R2 are selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a vinyl group, a 6-membered aryl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered carbocyclic group or a 6-membered carbocyclic group, and each heteroaryl group and each heterocyclic group contains 1 or 2 heteroatoms selected from N or O, and each group is independently optionally substituted by -F, -Cl, -Br, -I, -NH2, -OH, -NO2, a carbonyl group, -CH2-OH, 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.

[0018] In some embodiments, R1 and / or R2 is selected from a 6-membered aryl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered carbocyclic group or a 6-membered carbocyclic group, and each heteroaryl and each heterocyclic group contains 1 or 2 heteroatoms selected from N or O, and each group is independently optionally substituted with -F, -Cl, -Br, -I, -NH2, -OH, -NO2, a carbonyl group, =O, -CH2-OH, a carboxy 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.

[0019] In some embodiments, R1 and R2 together with the N atom to which they are attached form a 6-membered aryl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered carbocyclic group or a 6-membered carbocyclic group, and each heteroaryl group and each heterocyclic group contains 1 or 2 heteroatoms selected from N or O, and each group is independently optionally substituted with -F, -Cl, -Br, -I, -NH2, -OH, -NO2, a carbonyl group, =O, -CH2-OH, 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.

[0020] In some embodiments, R1 and R2 together with the N atom to which they are attached form a C2-C20 heteroalicyclic group.

[0021] In some embodiments, the C2-C20 heteroalicyclic group is selected from C4-C20 heteroalicyclic groups.

[0022] In some embodiments, the C4-C20 heteroalicyclic group is selected from a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted piperidinyl group, or a substituted or unsubstituted piperazinyl group.

[0023] In some embodiments, the C4-C20 heteroalicyclic group is selected from the groups represented by the following group [Chemistry] R’ independently represents a non-substituent, a single substituent or a plurality of substituents, and each substituent is independently deuterium, a hydroxy group, a halogen, NH2, a carboxyl group (-COOH), [Chemistry] a C1-C6 chain alkyl group, a halogen-substituted C1-C6 chain alkyl group, a hydroxy-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-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, [Chemistry] 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 C1-C6 chain alkyl group substituted with a hydroxy group, a C1-C6 chain alkyl group substituted with an amino group, a C3-C6 cycloalkyl group, a halogen-substituted C3-C6 cycloalkyl group, a hydroxy-substituted C3-C6 cycloalkyl group, a phenyl group or a benzyl group.

[0024] In some embodiments, the compound has a structure represented by Formula I-1, Formula I-2, Formula I-3, Formula I-4 or Formula I-5,

Chem.

Chem.

Chem.

[0025] In some embodiments, each R’ 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 carboxy group,

Chemical formula

[0026] In some embodiments, each R a 、R b 、R c 、R d is independently selected from hydrogen or a C1-C6 alkyl group. In some embodiments, each R e 、R f 、R g is independently selected from hydrogen or a C1-C6 alkyl group. In some embodiments, each R h 、R i 、R j 、R k 、R l 、R m is independently selected from hydrogen or a C1-C6 alkyl group. In some embodiments, each Rp and R q and R z are each independently selected from hydrogen or a C1-C6 alkyl group. In some embodiments, R a and R b and R c and R d and R e and R f and R g and R h and R i and R j and R k and R l and R m and R p and R q and R z are all hydrogen.

[0027] In some embodiments, L is methylene.

[0028] In some embodiments, R Z is a methyl group.

[0029] In some embodiments, R is

Chemical formula

[0030] In some embodiments, L1 is absent.

[0031] In some embodiments, R6 is H, halogen, hydroxy group, NH2, carboxyl group,

Chemical formula

[0032] In some embodiments, R6 is

Chem.

[0033] In a more specific embodiment, the benzothiazole compound represented by the formula I is selected from the following compounds.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0034] A second aspect of the present application provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable excipient.

[0035] A third aspect of the present application provides a method for preventing or treating an aging-related disease, comprising 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 prodrug thereof, or the pharmaceutical composition described in the second aspect. Specifically, the disease is selected from diseases associated with the accumulation of senescent cells, and the disease is preferably 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 hole, retinal detachment, proliferative vitreoretinopathy including degenerative vitreous diseases, 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, 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, such as atrophy and fibrosis in various tissues, brain and heart disorders and myelodysplastic syndrome, premyelocytic syndrome, ataxia telangiectasia, Fanconi anemia, Friedreich ataxia, dyskeratosis congenita, aplastic anemia, aneurysm, inflammatory bowel disease, lipodystrophy, kidney transplant failure, sarcopenia, wound healing, alopecia, myocardial cell hypertrophy, glomerulosclerosis, and cancer, which is one or more selected from the group consisting of.

[0036] The fourth aspect of the present application provides the use of the compound described in the first aspect or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotope-labeled compound or prodrug thereof, or the pharmaceutical composition described in the second aspect, in the manufacture of a medicament for preventing or treating aging-related diseases. Specifically, the disease is selected from diseases related to the accumulation of senescent cells, and the disease is preferably 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, keratitis sicca, Fuchs endothelial corneal dystrophy, presbyopia, cataract, vitreomacular traction syndrome, macular hole, retinal hole, 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, pitted scar, atrophic scar, bridge 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, such as atrophy and fibrosis in various tissues, brain and heart disorders and myelodysplastic syndrome related to treatment, premyelocytic syndrome, ataxia telangiectasia, Fanconi anemia, Friedreich's ataxia, dyskeratosis congenita, aplastic anemia, aneurysm, inflammatory bowel disease, lipoatrophy, kidney transplant failure, sarcopenia, wound healing, hypotrichosis, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer, and is one or more selected therefrom.

[0037] The novel benzothiazole compound provided by the present application has improved physicochemical properties and safety compared with A-1331852, has low platelet toxicity, and has better solubility.

Brief Description of Drawings

[0038]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Mode for Carrying Out the Invention

[0039] Hereinafter, the present invention will be described in detail with reference to examples and drawings. These examples are implemented on the premise that the present invention is a technical solution, and detailed embodiments and processes are shown. However, the embodiments provided by the present invention are exemplary and for the purpose of interpreting the present invention, and should not be understood as limiting the present invention. Conditions, methods, etc. not specified in the following examples are all carried out in the usual manner.

[0040] Definition The term "alkyl group" refers to an aliphatic hydrocarbon group, which may be a branched or straight-chain alkyl group. Depending on the structure, the alkyl group may be a monovalent or 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 still more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, etc. The "alkyl group" referred to in this specification includes alkyl groups in all possible configurations and conformations. For example, the "propyl group" referred to in this specification includes n-propyl group and isopropyl group, the "butyl group" includes n-butyl group, isobutyl group and tert-butyl group, and the "pentyl group" includes n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, and pentyl-3-yl, etc. It should be understood that

[0041] 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.

[0042] The term "cycloalkyl group" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. The cycloalkyl group includes groups having 3 to 12 ring atoms. Depending on the structure, the cycloalkyl group may be a monovalent or divalent group (e.g., a cycloalkylene group). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, more preferably a "lower cycloalkyl group" having 3 to 6 carbon atoms. Examples of cycloalkyl groups 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.

[0043] The term "aryl group" means that each atom constituting the ring in the 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. Depending on the structure, the aryl group may be a monovalent group or a divalent group (i.e., arylene group).

[0044] The term "heteroaryl group" means that the aryl group contains one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. 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 the heteroaryl group 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.

[0045] As used herein, the term "alicyclic group" or "cycloalkyl group" refers to a non-aromatic group ring formed by three or more carbon atoms, where two adjacent carbon atoms in the ring may be a single bond, double bond or 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.

[0046] As used herein, the term "heterocycloalkyl group" or "heteroalicyclic group" or "heteroalicyclic ring" means that one or more atoms constituting the ring in the 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 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-oxathio-cyclohexane, 1,4-oxathio-cyclohexadiene, 1,4-oxathio-cyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxapiperazine, hydantoin, dihydro-uracil, 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, but are not limited thereto. The heteroalicyclic group may be a monovalent group or a divalent group (i.e., a heterocycloalkylene group) depending on the structure.

[0047] The term "halogen" or "halogen element" refers to fluorine, chlorine, bromine and iodine.

[0048] 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.

[0049] The term "optionally" means that one or more of the elements described hereinafter may or may not occur, and includes both the case where they occur and the case where they do not occur.

[0050] 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 the separation or purification steps in the manufacturing process. The compounds of the present invention are capable of forming salts. For example, Compound I reacts with a certain amount, for example, an equimolar amount of an acid or a base, salts out in a medium, or is freeze-dried in an aqueous solution to obtain the salt.

[0051] 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.).

[0052] The acidic fragments that may be contained in some 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 (such as 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. Basic nitrogen-containing groups include quaternary ammonium salts of halides, such as small molecule alkyl halides (such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl), dialkyl sulfates (such as dimethyl, diethyl, dibutyl, and dipentyl sulfates), long-chain halides (such as chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl), aralkyl halides (such as benzyl and phenyl bromides), etc.

[0053] Prodrugs and solvates of the compounds in the present invention are also within the scope. Here, the term "prodrug" means a compound that generates a compound, salt, or solvate in the present invention through a chemical conversion of a metabolic or chemical process when treating related diseases. "Solvate" means a solvate adduct containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to form solvates by capturing solvent molecules in a certain molar ratio in the crystalline solid state. 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 combine with one molecule of a substance to form a hydrate, and water maintains its molecular state H2O. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0054] The compounds, salts or solvates in the present invention may take tautomeric forms (e.g., amide and imino ether). All of these tautomers are part of the present invention.

[0055] Stereoisomers of all 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. Independent stereoisomers of the compounds in the present invention may not coexist with other isomers (e.g., having 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 types of stereoconfigurations, S or R, at the chiral centers of the present invention, which are defined according to the 1974 proposal of the International Union of Pure and Applied Chemistry (IUPAC). 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.

[0056] The compounds in the present invention are described herein 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.

[0057] All stereoisomeric configurations of the compounds of the present invention are within the scope of coverage, regardless of whether they are in a mixture, pure or very pure form. The definition of the compounds of the present invention includes two types of olefin isomers, cis (Z) and trans (E), and cis and trans isomers of carbocyclic and heterocyclic rings.

[0058] In the present specification, groups and substituents can be selected to provide stable fragments and compounds.

[0059] The definitions of specific functional groups and chemical terms are described in detail below. In the present invention, chemical elements conform to 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.

[0060] 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)-isomers, (L)-isomers, racemic mixtures and other mixtures. Also, an asymmetric carbon atom may represent a substituent, for example an alkyl group. All isomers and their mixtures are included in the present invention.

[0061] 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.

[0062] The present invention further includes compounds labeled with isotopes, which are equivalent to the original compounds disclosed herein. However, in practice, it generally appears that one or more atoms are replaced by atoms having a different atomic weight or mass number. 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 contained in 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, i.e., 3 H, and carbon-14, i.e., 14 C are relatively easy to prepare and detect. They are also optimal in terms of isotopes. Also, heavy isotope substitution, for example, deuterium, i.e., 2 H, is advantageous in some therapies due to its excellent metabolic stability. For example, it can be preferentially considered in some cases 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 by substituting non-isotopic reagents with reagents labeled with readily available isotopes in a general manner.

[0063] 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, for example, an amino acid, or an acidic functional group, for example, a carboxyl group, diastereomeric salts 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.

[0064] As described herein, the compounds of the present invention can have their scope of inclusion expanded by substitution with any number of substituents or functional groups. Generally, the term "substituted" may appear before or after the term "selectable", and in the formulations of the present invention, a general formula containing a substituent means using a substituent of a specified structure in place of a hydrogen radical. When multiple positions in a particular structure are substituted with multiple particular substituents, each position of the substituent may be the same or different. As used herein, the term "substituted" 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, a heteroatom nitrogen may have a hydrogen substituent or any of the above acceptable organic compounds to complement its valence state. Further, the present invention does not limit substituted organic compounds in any form. In the present invention, a combination of a substituent and a variable group is considered to be excellent in treating diseases in the form of a stable compound. Here, the term "stable" means having a stable compound and being sufficient to maintain the integrity of the compound's structure within a sufficiently long time, and it is preferably effective within a sufficiently long time, and is used for the above purpose herein.

[0065] Example 1 Synthesis of Compound RX001

Chemical formula

[0066] Example 2 Synthesis of Compound RX002

Chemical Structure

[0067] Example 3 Synthesis of Compound RX003

Chem.

[0068] Example 4 Synthesis of Compound RX004

Chem.

[0069] Example 5 Synthesis of Compound RX005

Chem.

[0070] Example 6 Synthesis of Compound RX006

Chemical Structure

[0071] Example 7 Synthesis of Compound RX007

Chemical Structure

[0072] Example 8 Synthesis of Compound RX008 [Chemical Formula] Compound A-1331852 (100 mg, 0.1519 mmol) was dissolved in 5 ml of DMF. After adding TBTU (59 mg, 0.1823 mmol) and DIPEA (24 mg, 0.1823 mmol), compound B (34 mg, 0.1823 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC (DCM:MeOH = 10:1). H2O (50 ml) was added and stirred for 1 h, followed by suction filtration to collect the filter cake. The crude product was purified by silica gel column chromatography to obtain compound C. Compound C (85 mg, 0.1029 mmol) was dissolved in 1 ml of DCM, and HCl / dioxane (3 ml, 12 mmol) was added, and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated, and the crude product was triturated with ether (10 ml) for 5 h, followed by suction filtration and drying. MS (ESI) m / z = 727.4 [M+H]+; 1 HNMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.36 (s, 2H), 8.08 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.67 - 7.32 (m, 6H), 7.25 (s, 1H), 6.93 (d, J = 8.9 Hz, 1H), 4.95 (s, 2H), 3.86 (t, J = 5.9 Hz, 2H), 3.73 (s, 2H), 3.57 (s, 2H), 3.28 (t, J = 5.1 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.98 (s, 2H), 2.78 (s, 2H), 2.14 (s, 3H), 2.00 - 1.88 (s, 3H), 1.72 - 1.44 (m, 12H).

[0073] Example 9 Synthesis of Compound RX009 [Chemical Formula] Compound A-1331852 (100 mg, 0.1519 mmol) was dissolved in 5 ml of DMF. After adding TBTU (59 mg, 0.1823 mmol) and DIPEA (24 mg, 0.1823 mmol), compound B (15.9 mg, 0.1823 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC (DCM:MeOH = 10:1). H2O (50 ml) was added and stirred for 1 h, followed by suction filtration to collect the filter cake. The crude product was purified by silica gel column chromatography. MS (ESI) m / z = 728.3 [M+H]+; 1 H NMR (400 MHz, CDCl3) δ 10.80 (s, 1H), 7.89 - 7.83 (m, 1H), 7.57 (d, J = 7.7, 1.3 Hz, 1H), 7.49 - 7.30 (m, 6H), 7.25 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.02 (s, 2H), 3.99 (t, J = 6.0 Hz, 2H), 3.75 (s, 2H), 3.64 - 3.53 (dt, 4H), 3.35 (dd, J = 5.7, 3.8 Hz, 2H), 3.12 (t, J = 4.7 Hz, 2H), 3.04 (t, J = 6.0 Hz, 2H), 2.20 (s, 3H), 2.01 (s, 3H), 1.73 (m, 12H).

[0074] Example 10 Synthesis of Compound RX010

Chemical Structure

[0075] Example 11 Synthesis of Compound RX011 [Chemical formula] Compound A - 1331852 (100 mg, 0.1519 mmol) was dissolved in 5 ml of DMF. After adding TBTU (59 mg, 0.1823 mmol) and DIPEA (24 mg, 0.1823 mmol), compound B (21 mg, 0.1823 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC (DCM:MeOH = 10:1). H2O (50 ml) was added and stirred for 1 h, and suction filtration was performed to collect the filter cake. The crude product was purified by silica gel column chromatography. MS (ESI) m / z = 756.5 [M + H]+; 11H NMR (400 MHz, CDCl3) δ 7.87 (m, 1H), 7.62 - 7.49 (m, 2H), 7.47 - 7.30 (m, 5H), 7.25 (m, 1H), 6.82 (d, J = 8.7 Hz, 1H), 5.20 (d, J = 17.3 Hz, 1H), 4.94 (d, J = 17.3 Hz, 1H), 4.58 (d, J = 13.2 Hz, 1H), 4.06 (m, 1H), 3.91 (m, 1H), 3.72 (s, 2H), 3.48 - 3.40 (m, 2H), 3.30 (d, J = 13.4 Hz, 1H), 3.11 - 2.92 (m, 2H), 2.76 - 2.64 (m, 1H), 2.54 - 2.41 (m, 1H), 2.19 (s, 3H), 2.00 (s, 3H), 1.77 - 1.60 (m, 12H), 1.37 (m, J = 15.3 Hz, 2H), 1.32 - 1.27 (m, 2H), 1.18 - 1.05 (m, 1H).

[0076] Example 12 Synthesis of Compound RX012 [Chemical formula] Compound A - 1331852 (100 mg, 0.1519 mmol) was dissolved in 5 ml of DMF. After adding TBTU (59 mg, 0.1823 mmol) and DIPEA (24 mg, 0.1823 mmol), compound B (24 mg, 0.1823 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC (DCM:MeOH = 10:1). H2O (50 ml) was added and stirred for 1 h, and suction filtration was carried out to collect the filter cake. The crude product was purified by silica gel column chromatography. MS (ESI) m / z = 771.4 [M + H]+; 11H NMR (400 MHz, CDCl3) δ 10.55 (s, 2H), 8.06 (d, J = 6.1 Hz, 1H), 7.91 - 7.84 (m, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.43 - 7.30 (m, 4H), 6.93 (d, J = 8.7 Hz, 1H), 5.13 (s, 2H), 4.01 (t, J = 6.0 Hz, 2H), 3.73 (s, 2H), 3.72 (dt, J = 4.7 Hz, 4H), 3.49 (q, J = 5.9, 5.3 Hz, 2H), 3.11 (t, J = 6.0 Hz, 2H), 2.57 (t, J = 6.3 Hz, 2H), 2.50 (m, 4H), 2.11 (s, 3H), 2.00 (s, 3H), 1.80 - 1.63 (m, 12H).

[0077] Example 13 Synthesis of Compound RX013

Chemical Structure

[0078] Example 14 Synthesis of Compound RX014 [Chemical formula] Compound A-1331852 (100 mg, 0.1519 mmol) was dissolved in 5 ml of DMF. After adding TBTU (49 mg, 0.1519 mmol) and DIPEA (24 mg, 0.1823 mmol), compound B (11 mg, 0.1823 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC (DCM:MeOH = 10:1). H2O (50 ml) was added and stirred for 1 h, and suction filtration was performed to collect the filter cake. The crude product was purified by silica gel column chromatography. MS (ESI) m / z = 702.2 [M+H] + ; 1 H NMR (400 MHz, Chloroform-d) δ8.34 - 8.31 (m, 1H), 7.89 - 7.87 (m, 1H), 7.76 - 7.64 (m, 2H), 7.69 (s, 1H), 7.56 (dd, J = 7.5, 2.0 Hz, 1H), 7.36 - 7.27 (m, 1H), 7.28 - 7.13 (m, 3H), 7.05 - 6.93 (m, 2H), 4.58 (s, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.62 - 3.47 (m, 4H), 3.14 (t, J = 3.9 Hz, 2H), 2.90 (td, J = 5.6, 1.0 Hz, 2H), 2.21 (s, 3H), 2.10 - 1.94 (m, 3H), 1.79 - 1.66 (m, 12H), 1.34 (t, J = 5.0 Hz, 1H).

[0079] Example 15 Synthesis of Compound RX015 [Chemical formula] Compound A-1331852 (100 mg, 0.1519 mmol) was dissolved in 5 ml of DMF. After adding TBTU (49 mg, 0.1519 mmol) and DIPEA (24 mg, 0.1823 mmol), compound B (14 mg, 0.1823 mmol) was added, and the reaction was carried out at room temperature for 5 h. The reaction was monitored by TLC (DCM:MeOH = 10:1). H2O (50 ml) was added and stirred for 1 h, and suction filtration was performed to collect the filter cake. The crude product was purified by silica gel column chromatography. MS (ESI) m / z = 716.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 7.5, 1.6 Hz, 1H), 7.73 - 7.64 (m, 1H), 7.68 (s, 1H), 7.54 (dd, J = 7.3, 2.0 Hz, 1H), 7.38 - 7.28 (m, 1H), 7.26 - 7.13 (m, 2H), 7.05 - 6.93 (m, 2H), 4.58 (s, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.60 (d, J = 3.9 Hz, 4H), 2.90 (td, J = 5.6, 1.0 Hz, 2H), 2.22 (s, 3H), 2.10 - 1.95 (m, 3H), 1.87 - 1.66 (m, 12H).

[0080] Example 16 Synthesis of Compound RX016

Chemical Structure

[0081] Examples 17 - 22 Using the same method as the above examples, either using commercially available compounds or referring to the production methods of intermediate compounds, the compounds of the examples in Table 1 below were produced.

Table 1

[0082] Example 23 Synthesis of Compound RX301

Chem.

[0083] Example 24 Synthesis of Compound RX302

Chemical formula

[0084] Example 25 Synthesis of Compound RX303

Chemical formula

[0085] Examples 26 - 30 By the same method as in the above examples, using commercially available compounds or referring to the production methods of the intermediate compounds shown, the compounds of the examples in Table 2 below and their sodium salts were produced.

Table 2(1)

Table 2(2)

[0086] Test Example 1: Solubility Test The following test scheme was adopted for the solubility test of the compounds of the present invention. 1) Each of the compounds to be measured was precisely weighed, and the corresponding volume of pure water was added to prepare the corresponding concentration (1 mg / mL or 10 mg / mL). It was vortexed for 1 minute every 3 minutes and continued for 15 minutes, and the dissolution status was observed. After standing for 1 hour, the dissolution status was observed again. 2) 0.2 mL of 1 mg / mL of the compound or its sodium salt was taken, 1.8 mL of water was added, and each was diluted to 0.1 mg / mL. It was vortexed for 5 minutes, and the dissolution status was observed. After standing for 1 hour, the dissolution status was observed again. 3) 1 mL of 1 mg / mL of the compound or its sodium salt was taken, 1 mL of water was added, and it was diluted to 0.5 mg / mL. It was vortexed for 5 minutes, and the dissolution status was observed. After standing for 1 hour, the dissolution status was observed again. The solubility test results are shown in Table 3 below.

[0087]

Table 3

[0088] Conclusion: The solubility of the sodium salts of compounds RX301, RX302, and RX303 in water is greater than 10 mg / ml, and is significantly superior to the solubility of the sodium salt of A-1331852 (the solubility of the sodium salt of A-1331852 is less than 0.1 mg / ml). From the above results, it can be seen that the water solubility of the compound of the present invention is significantly improved compared to A-1331852 and the sodium salt of A-1331852. Therefore, the compound of the present invention can be a useful drug with excellent pharmaceutical formability.

[0089] Test Example 2 Platelet Toxicity Test In this test example, C57 mice were selected to detect the effect of the target compound on platelets. C56BL / 6J mice aged 7 - 8 weeks were randomly and evenly divided into a Vehicle group and a compound group. The test compound (0.5 mg / kg) or the blank solvent was injected intraperitoneally once. Blood was collected from the retro-orbital venous plexus of the mice at 6 h, placed in a blood collection tube containing the anticoagulant EDTA-K2, gently shaken, and then the blood physiological indices were measured using a blood analyzer. The platelet count was used as the target parameter for this platelet toxicity test. As can be seen from Figure 1, A-1331852 has severe platelet toxicity, and RX001 - RX004, RX007 - 009, RX011, RX013, RX016, RX019, RX301, RX304, RX307 are significantly improved compared to the platelet toxicity of A-1331852.

[0090] Test Example 3 Senescent Cell Activity Data In this test 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 effect of the target compound on the viability of the above normal and senescent cells was detected, and the specific killing effect of the compound on the above senescent cells was evaluated. Briefly speaking, the above senescent and normal cells were selected and plated (96-well plate) respectively. After adding the compound (concentration 1 μM) and allowing it to act for 72 h, the CellTiter-Glo® 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, at a concentration of 1 μM, the compound specifically kills senescent cells and clearly does not kill normal cells. Table 4 summarizes the cytotoxic activity (IC 50 ) of the test compounds against senescent cells.

[0091]

Table 4(1)

Table 4(2)

Table 4(3)

Table 4(4)

Table 4(5)

[0092] Test Example 4: Efficacy in an Animal Model of Oxygen-Induced Retinopathy In an oxygen-induced retinopathy (OIR) mouse model, the effects of prodrugs RX001-RX006 and RX301 were studied, and the model was, to some extent, a pointer for in vivo models 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 hyperoxic 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 intravitreally into the animals, and the air was returned to room air until day 17 (P17). At P17, the eyes 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 RX001 - RX006 and RX301 into the vitreous body (IVT).

[0093] Test Example 5: Efficacy in an animal model of diabetic retinopathy The pharmacological effects of the compounds of the present disclosure were studied in a mouse model of diabetic retinopathy by administering streptozotocin (STZ) multiple times. C57BL / 6J mice at 6 - 7 weeks of age 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 uM, 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 RX001, RX002, RX003 and RX301 into the vitreous body (IVT) can improve vascular permeability at this dose level.

[0094] Test 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 transport system. As the contact lens, a glass coverslip artificially torn and affixed was used. Bleeding points caused by the laser light were not included in the statistical data. In each experimental group, when 6 mice were analyzed, each eye had 4 impacts, overcoming the inherent variability. Figure 5 shows a statistically significant improvement in the fluorescence intensity index after administering RX001, RX002, RX003, and RX301 into the vitreous body (IVT).

[0095] Test Example 7: Efficacy in an Animal Model of Idiopathic Pulmonary Fibrosis In this example, an animal model of idiopathic pulmonary fibrosis was used to measure the effect of the compounds of the present disclosure on 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 sufficiently exposed, and a 100-microliter micro-needle of a certain volume of bleomycin (BLM 5 mg / kg) solution aspirated according to the rat's 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), the right lung tissue part was subjected to hydroxyproline (HYP) detection, and the remaining lung tissue was subjected to pathological H&E staining and Masson staining. Figure 6 shows a statistically significant improvement in WBC, HYP, and pathological scores in an IPF model by intraperitoneal (IP) administration of RX001, RX002, RX003, and RX301.

[0096] Test Example 8: Efficacy in an animal model of osteoarthritis In this example, an animal model of osteoarthritis was used to measure the effect of the compound of the present disclosure on osteoarthritis. An animal model of osteoarthritis was constructed by the following steps. The 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 the blade was incised longitudinally. Without cutting the patellar ligament, the patellar ligament was pulled to one side and constantly pressed with a sterile cotton swab to stop bleeding. The joint cavity was fully exposed, and physiological saline was dropped 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 administration. At the end of the experiment, the plantar persistent pain threshold was detected, and the osteoarticular joints were collected for safranin O / fast green staining. Figure 7 shows a statistically significant improvement in the plantar mechanical pain threshold and the pathological score of safranin O / fast green staining in an osteoarthritis (OA) model by intra-articular injection administration of RX001, RX002, RX003, and RX301.

[0097] Test Example 9: Efficacy against an animal model of Alzheimer's disease In this example, an animal model of Alzheimer's disease was adopted to measure the effect of the compound of the present disclosure on 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 changes in amyloid in the mouse cerebral cortex were observed. Figure 8 shows a statistically significant improvement in the index of Aβ42 pathogenic protein in an AD mouse model by intraperitoneal injection of RX001, RX002, RX003, and RX301.

[0098] Test Example 10: Efficacy against a liver fibrosis animal model 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 was started at the 3rd week of modeling and administered 2 times 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 the pathological score in a liver fibrosis model by administration of RX001 and RX301 by intraperitoneal injection (IP).

[0099] Test Example 11: Efficacy against aged skin In this example, aged female C57bl / 6J mice (22 months old) were used. Administration was by skin application. It was administered 2 times 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 in a natural aging mouse model by application of RX001, RX002, RX003, and RX301.

[0100] Test Example 12: Efficacy against 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 incised longitudinally, the linea alba of the abdominal muscles was found, and the abdominal muscles, fascia and peritoneal layers were cut here. After exposing the surgical field, the stomach and mesentery of the mice were pushed to the right with a 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 RX001 and RX301.

[0101] Test Example 13: Efficacy against 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, 15 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 made 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, an RX001 experimental group and an RX301 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 of scar formation by the drug was evaluated by SEI (scar hypertrophy index). Figure 12 shows a statistically significant improvement in the scar hypertrophy index of the rabbit ear hypertrophic scar model by administration of RX001 and RX301.

Claims

1. A benzothiazole compound having the structure represented by formula I, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, eutectic, tautomer, stereoisomer, or isotope compound thereof, 【Chemistry 1】 however, R 1 and R 2 The C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C20 aryl group, C1-C20 heteroaryl group, and C2-C20 heteroalicyclic group are independently selected from C1-C10 alkyl groups, C3-C8 cycloalkyl groups, C2-C8 alkenyl groups, and C2-C8 alkynyl groups. 2 is -O-, -S-, -SO 2 -, -C(O)- and -NR 3 - may be substituted with one or more groups selected from the following, and the C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C20 aryl group, C1-C20 heteroaryl group and C2-C20 heteroalicyclic group may optionally be a halogen atom, cyano group, nitro group, C6-C20 aryl group, C1-C20 heteroaryl group, C1-C10 alkoxy group, C6-C20 aryloxy group, C2-C20 heteroalicyclic group, amino group, hydroxyl group, mercapto group, 【Chemistry 2】 -NR 4 R 5 Substituted with one or more substituents from among, R 1 and R 2 together with the N atom to which they are attached form a heteroalicyclic group, preferably a C2-C20 heteroalicyclic group, or R 1 is hydrogen, and R 2 The C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C20 aryl group, C1-C20 heteroaryl group, and C2-C20 heteroalicyclic group are selected from C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, and C2-C8 alkynyl group. 2 -O-, -S-, -SO 2 -, -C(O)- and -NR 3 - may be substituted with one or more groups selected from the above, and the C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C20 aryl group, C1-C20 heteroaryl group, C2-C20 heteroalicyclic group is substituted with a halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, carboxyl group, acyl group, C1-C10 alkoxy group, C6-C20 aryl group, C1-C20 heteroaryl group, C2-C20 heteroalicyclic group, C1-C10 alkyl group, C2-C8 alkenyl group, or C2-C8 alkynyl group, and at least two substituents therein together constitute an alicyclic, heteroalicyclic, aromatic ring, or heteroaromatic ring. R 3 , R 4 and R 5 The substituents are independently selected from hydrogen, an aryl group, a heteroaryl group, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, and a C2-C8 alkynyl group, and the aryl group and heteroaryl group are optionally substituted with a halogen atom, a hydroxyl group, a mercapto group, an amino group, a nitro group, a cyano group, a carboxyl group, an acyl group, an alkoxy group, an aryl group, a heteroaryl group, a heteroalicyclic group, a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, or a C2-C8 alkynyl group, and of these, at least two substituents together constitute an alicyclic, heteroalicyclic, aromatic, or heteroaromatic ring. L is a C1-C6 alkylene group, and the alkylene group is optionally substituted with 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-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 chain alkenyl group, or a C2-C8 alkynyl group. R is an adamantyl group, and the adamantyl group is optionally substituted with 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-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 chain alkenyl group, or a C2-C8 alkynyl group. R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R l , R m , R p , R q , R z Each of these is independently selected from hydrogen, halogen-substituted or unsubstituted C1-C8 alkyl groups, halogen-substituted or unsubstituted C3-C8 cycloalkyl groups, halogen-substituted or unsubstituted C2-C8 alkenyl groups, halogen-substituted or unsubstituted C2-C8 alkynyl groups, halogen atoms, hydroxyl groups, amino groups, nitro groups, cyano groups, carboxyl groups, acyl groups, and halogen-substituted or unsubstituted C2-C8 alkoxy groups.

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

3. R 1 and R 2 These, together with the N atoms to which they are bonded, constitute a C2-C20 heteroalicyclic group, for example, a C2-C10 heteroalicyclic group, and the ring of the C2-C20 heteroalicyclic group further comprises one or two heteroatoms optionally selected from N or O. The C2-C20 heteroalicyclic group can optionally be 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 mercapto group, a carbonyl group, a carboxyl group, an acyl group, 【Chemistry 4】 -NR 4 R 5 Substituted with one or more substituents from R 4 and R 5 The substituents are independently selected from hydrogen, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, and a C2-C8 alkynyl group, and the aryl group and heteroaryl group are optionally substituted with 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-C8 alkoxy group, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C2-C10 heteroalicyclic group, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C2-C6 alkenyl group, or a C2-C8 alkynyl group, and optionally at least two substituents therein constitute a C3-C10 alicyclic ring, a C2-C10 heteroalicyclic ring, a C6-C10 aromatic ring, or a C1-C10 heteroaromatic ring. For example, the C2-C20 heteroalicyclic group may 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 5】 Substituted with a substituent selected from R 4 and R 5 These are independently selected from hydrogen and C1-C6 alkyl groups. For example, the C2-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.

4. R 1 and R 2 The C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C6-C10 aryl group, C1-C10 heteroaryl group, and C2-C10 heteroalicyclic group are independently selected from the C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, and C2-C6 alkynyl group. 2 is -O-, -S-, -SO 2 -, -C(O)- and -NR 3 - may be substituted with one or more groups selected from the following, and the C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C6-C10 aryl group, C1-C10 heteroaryl group and C2-C10 heteroalicyclic group may optionally be a halogen atom, cyano group, nitro group, C6-C10 aryl group, C1-C10 heteroaryl group, C1-C6 alkoxy group, C6-C10 aryloxy group, C2-C10 heteroalicyclic group, amino group, hydroxyl group, mercapto group, 【Transformation 6】 -NR 4 R 5 Substituted with one or more substituents from R 3 , R 4 and R 5 The group is independently selected from hydrogen, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, and a C2-C6 alkynyl group, and 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-C10 group. The compound according to claim 1, characterized in that it is substituted with an aryl group, a C1-C10 heteroaryl group, a C2-C10 heteroalicyclic group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C2-C6 chain alkenyl group, or a C2-C6 alkynyl group, and of which, optionally, at least two substituents together constitute a C3-C10 alicyclic ring, a C2-C10 heteroalicyclic ring, a C6-C10 aromatic ring, or a C1-C10 heteroaromatic ring.

5. The aforementioned compound is represented by formula III, 【Transformation 7】 R 2 These are C1-C10 chain alkyl groups, C3-C8 cycloalkyl groups, C2-C8 chain alkenyl groups, C2-C8 alkynyl groups, C6-C20 aryl groups, C1-C20 heteroaryl groups, and C2-C20 heteroalicyclic groups, where CH in the C1-C10 chain alkyl groups, C3-C8 cycloalkyl groups, C2-C8 chain alkenyl groups, and C2-C8 alkynyl groups is... 2 is -O-, -S-, -SO 2 -, -C(O)- and -NR 3 - may be substituted with one or more groups selected from the following, and the C1-C10 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, C2-C8 alkynyl group, C6-C20 aryl group, C1-C20 heteroaryl group and C2-C20 heteroalicyclic group may be a halogen atom, cyano group, nitro group, C6-C20 aryl group, C1-C20 heteroaryl group, C1-C10 alkoxy group, C6-C20 aryloxy group, C2-C20 heteroalicyclic group, amino group, hydroxyl group, mercapto group, 【Transformation 8】 -NR 4 R 5 Substituted with one or more substituents from R 3 , R 4 and R 5 The group is independently selected from hydrogen, a C6-C10 aryl group, a C1-C10 heteroaryl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, and a C2-C6 alkynyl group, and 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-C10 group. The compound according to claim 1, characterized in that it is substituted with an aryl group, a C1-C10 heteroaryl group, a C2-C10 heteroalicyclic group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C2-C6 chain alkenyl group, or a C2-C6 alkynyl group, and of which, optionally, at least two substituents together constitute a C3-C10 alicyclic ring, a C2-C10 heteroalicyclic ring, a C6-C10 aromatic ring, or a C1-C10 heteroaromatic ring.

6. The compound according to claim 1, characterized in that the heteroalicyclic group or heteroalicyclic group is selected from a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted piperazinyl group, a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted piperazine-2-one group, a substituted or unsubstituted pyrrolidinyl group, and a substituted or unsubstituted imidazoline group.

7. R 1 and / or R 2 The group is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, vinyl, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic, or 6-membered carbocyclic, and each heteroaryl group and each heterocyclic group contains one or two heteroatoms selected from N or O, and each group is independently and optionally -F, -Cl, -Br, -I, -NH 2 -OH, -NO 2 , carbonyl group, -CH 2 The compound according to claim 1, characterized in that it is substituted with an -OH group, 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.

8. R 1 and / or R 2 The group is selected from a 6-membered aryl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered carbon ring group, or a 6-membered carbon ring group, and each heteroaryl and each heterocyclic group contains one or two heteroatoms selected from N or O, and each group is independently and optionally -F, -Cl, -Br, -I, -NH 2 -OH, -NO 2 , carbonyl group, =O, -CH 2 Substituted with -OH, carboxyl group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group or isopropoxy group, Or, R 1 and R 2 These groups, together with the N atoms to which they are bonded, constitute a 6-membered aryl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered carbon ring, or a 6-membered carbon ring, and each heteroaryl group and each heterocyclic group contains one or two heteroatoms selected from N or O, and each group can independently and optionally contain -F, -Cl, -Br, -I, or -NH 2 -OH, -NO 2 , carbonyl group, =O, -CH 2 The compound according to claim 1, characterized in that it is substituted with an -OH group, 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.

9. R 1 and R 2 These, together with the N atoms to which they are bonded, constitute a C2-C20 heteroalicyclic group, and / or, The aforementioned heteroalicyclic group is selected from C4-C20 heteroalicyclic groups. Preferably, the C4-C20 heteroalicyclic group is selected from a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted piperidinyl group, or a substituted or unsubstituted piperazinyl group. Preferably, the C4-C20 heteroalicyclic group is selected from the groups shown below, 【Chemistry 9】 Each R' independently represents a non-substituted, single-substituted, or multiple-substituted element, and each substituent independently represents deuterium, a hydroxyl group, a halogen, or NH 2 carboxyl group (-COOH), 【Chemistry 10】 Selected from C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, hydroxy-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, hydroxy-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), -SO 2 -C1-C6 chain alkyl group, 【Chemistry 11】 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 morpholine-substituted C1-C6 chain alkyl group, a -COO-C1-C6 chain alkyl group, a cyano group, a C1-C6 chain alkoxy 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.

10. The compound has a structure represented by formula I-1, formula I-2, formula I-3, formula I-4, or formula I-5, 【Chemistry 12】 L 1 is absent or -NHL 3 - and L 3 is absent or is a C1-C6 alkylene group, a halogen, a hydroxy group, a C1-C6 alkylene group substituted with a C1-C6 alkoxy group, preferably a methylene group, an ethylene group, a propylene group L 2 It is either absent or a C1-C6 alkylene group 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 is H, deuterium, halogen, hydroxy group, NH 2 , carboxyl group (-COOH), -CONH 2 , sulfonic acid group (-SO 3 H), -SO 2 -C1-C6 chain alkyl group, 【Chemistry 13】 C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, morpholine-substituted C1-C6 alkyl groups, -COO-C1-C6 alkyl groups, cyano groups, C1-C6 alkoxy groups, hydroxyl-substituted C1-C6 alkyl groups, amino-substituted C1-C6 alkyl groups, C3-C6 cycloalkyl groups, halogen-substituted C3-C6 cycloalkyl groups, hydroxyl-substituted C3-C6 cycloalkyl groups, phenyl groups, or benzyl groups. Each R' independently represents a non-substituted, single-substituted, or multiple-substituted, and each substituent independently represents R 6 H, deuterium, halogen, hydroxyl group, NH 2 carboxyl group (-COOH), -CONH 2 , sulfonic acid group (-SO 3 H), -SO 2 -C1-C6 chain alkyl group, 【Chemistry 14】 Selected from C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, morpholine-substituted C1-C6 alkyl groups, -COO-C1-C6 alkyl groups, cyano groups, C1-C6 alkoxy groups, hydroxy-substituted C1-C6 alkyl groups, amino-substituted C1-C6 alkyl groups, C3-C6 cycloalkyl groups, halogen-substituted C3-C6 cycloalkyl groups, hydroxy-substituted C3-C6 cycloalkyl groups, phenyl groups, or benzyl groups. The compound according to claim 1, characterized in that the definitions of other symbols are the same as those of formula I.

11. R a , R b , R c , R d Each is independently selected from hydrogen or a C1-C6 alkyl group, and / or R e , R f , R g Each is independently selected from hydrogen or a C1-C6 alkyl group, and / or R h , R i , R j , R k , R l , R m Each is independently selected from hydrogen or a C1-C6 alkyl group, and / or R p , R q , R z Each is independently selected from hydrogen or a C1-C6 alkyl group, and / or L is methylene, and / or R Z is a methyl group, and / or, R is 【Chemistry 15】 The compound according to claim 1, characterized in that it is the compound described above.

12. L 1 It does not exist, and / or, R 6 H, halogen, hydroxyl group, NH 2 carboxyl group, 【Chemistry 16】 These are C1-C3 chain alkyl groups, halogen-substituted C1-C3 chain alkyl groups, or hydroxy-substituted C1-C3 chain alkyl groups. Preferably, R 6 teeth, 【Chemistry 17】 The compound according to claim 10, characterized in that it is the compound described above.

13. The compound according to claim 1, characterized in that the benzothiazole compound is selected from the following compounds. 【Chemistry 18(1)】 【Chemistry 18(2)】 【Chemistry 18(3)】 【Chemistry 18(4)】 【Chemistry 18(5)】

14. The compound according to claim 1, characterized in that the salt of the aforementioned compound is an alkali metal salt, preferably a sodium salt, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, eutectic, tautomer, stereoisomer, or isotope compound thereof.

15. A pharmaceutical composition comprising the compound described in Claim 14 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, eutectic, tautomer, stereoisomer or isotope compound thereof, and a pharmaceutically acceptable excipient.

16. A method for preventing or treating age-related diseases, comprising administering to a subject in need a therapeutically effective amount of the compound according to claim 14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, eutectic, tautomer, stereoisomer, or isotope compound thereof, or the pharmaceutical composition according to claim 15.

17. The aforementioned diseases are selected from diseases related to the accumulation of senescent cells, and the aforementioned diseases are preferably 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. Macular degeneration, glaucoma, sickle cell retinopathy, ischemic arteritis neuropathy, keratitis dryness, Fuchs corneal endothelial 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 mellitus, diabetic nephropathy, scarring, superficial scarring or flat scars, cord-like or contracture scars, webbed scars, depressed scars, atrophic scars, pontine and splenic scars, hypertrophic scars, keloids, scar carcinoma, scleroderma, focal scleroderma, shingles scleroderma, drip scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary artery syndrome, myocardial infarction, stroke, hypertension, obesity, fatty dysplasia, coronary artery disease, cerebrovascular disease, periodontal disease, cancer treatment-related disorders, for example, atrophy in various tissues The method according to 16, 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.

18. Application of the compound described in Claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, eutectic, tautomer, stereoisomer or isotope compound thereof, or the pharmaceutical composition described in Claim 15, in the manufacture of a pharmaceutical for the prevention or treatment of aging-related diseases.

19. The aforementioned diseases are selected from diseases related to the accumulation of senescent cells, and the aforementioned diseases are preferably 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 dryness, Fuchs corneal endothelial 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, and other conditions. Scars, flat scars, cord-like or contracture-like scars, webbed scars, depressed scars, atrophic scars, pontine and striated scars, hypertrophic scars, keloids, scar carcinoma, scleroderma, focal scleroderma, shingles scleroderma, drip-like scleroderma, acroscleroderma, diffuse scleroderma, CREST syndrome, acute coronary artery syndrome, myocardial infarction, stroke, hypertension, obesity, fatty dysplasia, coronary artery disease, cerebrovascular disease, periodontal disease, cancer treatment-related disorders, for example, various combinations The application according to claim 15, which is one or more selected from atrophy or fibrosis in tissues, myelodysplastic syndromes, 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, baldness, cardiomyocyte hypertrophy, glomerulosclerosis, and cancer.

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