Use of low molecular weight compounds having naphthylamine structure

Abstract

This application discloses the use of a low molecular weight compound having a naphthylamine structure. The present invention is the first to discover that the compound of general formula (I) can be used to treat diseases associated with renal impairment, and is expected to be an effective medicine for the treatment of diseases associated with renal impairment, particularly chronic kidney disease. TIFF2025528014000136.tif40170

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to a Chinese patent application filed on March 20, 2023, bearing application number 2023102998399 and entitled "Use of small molecular weight compounds having naphthylamine structure," the entire text of which is incorporated herein by reference.

[0002] This patent application claims priority to a Chinese patent application filed on November 20, 2023, bearing application number 2023115506763 and entitled "Use of small molecular weight compounds having naphthylamine structure," the entire text of which is incorporated herein by reference. [Technical Field]

[0003] Embodiments of the present invention relate to the field of chemicals, and in particular to the use of small molecule compounds having a naphthylamine structure. [Background technology]

[0004] The kidneys play an essential role in maintaining physiological homeostasis, including excretion, hormone production, blood pressure regulation, ion balance, osmotic balance, and pH balance. Kidney disease generally refers to various kidney disorders. Because kidney functions are diverse, kidney disease often has systemic effects, making diagnosis and treatment very difficult and expensive.

[0005] The kidney ranks second only to the heart in mitochondrial content and oxygen consumption in the human body. Therefore, maintaining mitochondrial homeostasis is crucial for normal kidney function. Mitophagy is crucial for maintaining renal cell homeostasis in vivo, and disruption of mitophagy is associated with several kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD).

[0006] Acute kidney injury (AKI) is a major renal disease characterized by a rapid decline in renal function. Major clinical causes of AKI include renal ischemia-reperfusion (IR), sepsis, and nephrotoxicosis. Recent studies have further suggested that pre-existing kidney diseases, such as chronic kidney disease (CKD) and diabetic nephropathy (DKD), increase susceptibility to AKI. Fatal and sublethal damage to renal tubules is the primary pathological feature of AKI. After AKI, remaining tubular cells undergo dedifferentiation, proliferation, migration, and redifferentiation into mature tubular cells to repair the damaged tubules. While mild kidney damage can be completely repaired, severe or recurrent AKI often results in defective repair, leading to renal fibrosis and ultimately to chronic kidney injury (CKD).

[0007] The main causes of CKD include primary glomerulonephritis, hypertensive arteriosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial diseases (chronic pyelonephritis, chronic urate nephropathy, obstructive nephropathy, drug-induced nephropathy, etc.), ischemic nephropathy, and hereditary nephropathy (polycystic kidney disease, hereditary nephritis). In developed countries, diabetic nephropathy and hypertensive renal arteriosclerosis are the main causes of chronic kidney disease, and these two diseases are also showing a significant increase in China. Major risk factors for CKD include age, family history of CKD, diabetes, hypertension, obesity / metabolic syndrome, high-protein diet, hyperlipidemia, autoimmune disease, urinary tract infection or systemic infection, hepatitis virus infection, urinary tract stones, urethral obstruction, urinary tract or systemic tumors, history of nephrotoxic drug use, cardiovascular disease, anemia, and smoking.

[0008] Currently, three levels of protection have been proposed for the various stages of CKD. Level 1 protection refers to the timely and effective treatment of existing kidney disease or diseases that may cause kidney damage (e.g., diabetes, hypertension) to prevent the onset of chronic kidney disease. Level 2 protection refers to the timely treatment of patients with mild or moderate chronic kidney disease to slow, stop, or reverse the progression of chronic kidney disease and prevent the development of uremia. Level 3 protection refers to the early implementation of therapeutic measures in uremia patients to prevent the development of some serious complications and improve their survival rate and quality of life. The ultimate outcome of chronic kidney disease progression is end-stage renal disease, in which patients must rely on renal replacement therapy to survive. Although significant advances have been made in dialysis treatment, the mortality rate and quality of life of patients with end-stage renal disease remain high. Therefore, treatment for CKD patients includes treatment to slow the progression of chronic kidney disease and treat various complications. Currently, the main measures to slow the onset and progression of chronic kidney disease are blood pressure control, low-protein diet, correction of factors that rapidly worsen chronic kidney disease, prevention and treatment of complications such as maintaining fluid and electrolyte balance, correction of metabolic acidosis, prevention and treatment of cardiovascular disease, correction of renal anemia, prevention and treatment of renal bone disease, etc. At present, there are no effective drugs that can treat chronic kidney disease and the various diseases it causes.

[0009] Mitochondrial dysfunction is thought to be a key factor in the development of many diseases. The accumulation of dysfunctional mitochondria is a hallmark of pathological conditions and is recognized as a key factor promoting disease progression. Increasing evidence indicates that mitochondria are damaged to varying degrees in a variety of acute and chronic diseases, making removal of dysfunctional mitochondria a powerful means of alleviating various diseases. Mitochondria-based therapeutic strategies and personalized drugs targeting mitochondria are key to future drug treatments. However, existing reports lack effective drugs for treating diseases associated with mitochondrial dysfunction. Therefore, it is important to find such therapeutic drugs. Summary of the Invention

[0010] In order to solve the above problems, an object of the present invention is to provide the use of a low molecular weight compound having a naphthylamine structure.

[0011] Another object of the present invention is to provide a method for preventing and / or treating diseases associated with renal damage.

[0012] A first aspect of the present invention relates to the following uses: (i) the preparation of a medicament for the prevention and / or treatment of diseases associated with renal impairment; and / or (ii) prevention and / or treatment of diseases associated with kidney damage; and / or (iii) the prevention and / or treatment of diseases associated with mitochondrial dysfunction; and / or (iv) the preparation of a medicament for the prevention and / or treatment of a disease associated with mitochondrial dysfunction; and / or (v) Use of a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, characterized by being used in the manufacture of cosmetics or medical devices. TIFF2025528014000002.tif54170 where Z is TIFF2025528014000003.tif20170 or sulfur atoms; R 1 is hydrogen, C 1~6 Alkyl, TIFF2025528014000004.tif17170, where R 11 and R 12 are each independently C 1~6 Alkyl or C 1~6 cycloalkyl, and n is 1 to 4; R 2 is hydrogen, C 1~6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom is R 2-1 C replaced with 1~6 Alkyl, at least one hydrogen is R 2-1phenyl substituted with, where R 2-1 is hydroxyl, halogen, amino or C 1~6 is an alkoxy; R 3 teeth TIFF2025528014000005.tif19170 where, R 3-1 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, 3-6 membered epoxyalkyl, amino, C 1~6 Amine group, -CHC(O)R 3-2 , -CH2C(O)OR 3-2 , -CH2C(O)N(R 3-2 R 3-2a ) and R 3-2 and R 3-2a are independently hydrogen, C 1~6 alkyl or 3- to 6-membered cycloalkyl; m is 1 to 6, and Ar is phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom of which is R 3-3 phenyl substituted with at least one hydrogen atom 3-3 naphthyl substituted with at least one hydrogen atom of R 3-3 5- or 6-membered monocyclic heteroaryl substituted with at least one hydrogen atom of R 3-3 and R is an 8- to 10-membered fused bicyclic heteroaryl substituted with 3-3 are hydrogen, halogen, C 1~6 Alkyl, 3-6 membered cycloalkyl, hydroxyl, C 1~6 Alkoxy, 3-6 membered epoxy alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -N(R 3-3a R 3-3b ) or phenyl, R 3-3a and R 3-3b are independently hydrogen, C 1~6 alkyl or 3- to 6-membered cycloalkyl; R 4 teeth TIFF2025528014000006.tif24170 where, R 4-1 is phenyl, naphthyl, and at least one hydrogen atom is R 4-11 phenyl substituted with 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is R 4-11 5- or 6-membered monocyclic heteroaryl substituted with 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom of which is substituted with R 4-11 and R is an 8- to 10-membered fused bicyclic heteroaryl substituted with 4-11 is hydrogen, halogen, nitro, nitrile, hydroxyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -C(O)OR 4-12 , -C(O)R 4-12 , -C(O)N(R 4-1a R 4-1b ), -S(O)R 4-12 , -S(O)R 4-12 , -OC(O)R 4-12 , -OC(O)OR 4-12 or TIFF2025528014000007.tif16170R 4-12 , R 4-1a and R 4-1b are independently hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with at least one hydrogen replaced by halogen 1~6 Alkyl, C with at least one hydrogen replaced by halogen 2~6 Alkenyl, C with at least one hydrogen replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen replaced by halogen 2~6 alkynyl, and R 4-1a and R 4-1bare bonded to each other to form a ring, R 4-2 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C with at least one hydrogen replaced by hydroxyl 1~6 Alkyl, C 3~6 epoxyalkyl, or R 2 C 1~6 Alkyl and R 4-2 C 1~6 If it is alkyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring, R 4-3 is C 1~6 Alkyl or C 1~6 is alkoxy; R 5 The number of is 0 to 5, and R 5 are each independently hydrogen, halogen, nitro, nitrile, -N + (R 5-1 )3, C 1~6 Haloalkyl, -C(O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O)R 5-1 , -S(O)R 5-1 , -S(O)2N(R 5-1 R 5-1a ), -S(O)N(R 5-1 R 5-1a ), -N=C(R 5-1 R 5-1a ), hydroxyl, C 1~6 Alkyl, phenyl, at least one hydrogen is R 5-1 Phenyl substituted with C 1~6 Alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a , -N(R 5-1 )C(O)OR 5-1a , -N(R 5-1 )C(O)N(R 5-1a R 5-1b ), -OC(O)R 5-1 , -OC(O)OR5-1 , -OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 where R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with at least one hydrogen replaced by halogen 1~6 Alkyl, C with at least one hydrogen replaced by halogen 2~6 Alkenyl or C in which at least one hydrogen is replaced by halogen 2~6 It is alkynyl.

[0013] In some preferred embodiments, Z is TIFF2025528014000008.tif20170 or sulfur atoms; R 1 is hydrogen, C 1~4 Alkyl, TIFF2025528014000009.tif17170 where R 11 and R 12 are each independently C 1~4 Alkyl or C 1~4 cycloalkyl, and n is 1 or 2; R 2 is hydrogen, C 1~4 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom is R 2-1 C replaced with 1~4 Alkyl, at least one hydrogen is R 2-1 phenyl substituted with, where R 2-1 is hydroxyl, halogen, amino or C 1~4 is alkoxy; R 3 teeth TIFF2025528014000010.tif19170 where, R 3-1 is hydrogen, hydroxyl, C 1~4 Alkyl, C 1~4 Alkoxy, -N(R 3-2R 3-2a ) and R 3-2 and R 3-2a are each independently hydrogen or C 1~4 alkyl, and R 3-3a and R 3-3b are each independently hydrogen or C 1~4 is alkyl, m is 1 to 4; Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom is R 3-3 and R is a 5- or 6-membered monocyclic heteroaryl substituted with 3-3 are hydrogen, halogen, C 1~4 Alkyl, Hydroxyl, C 1~4 Alkoxy, C 1~4 haloalkyl or -N(R 3-3a R 3-3b ) and; R 4 teeth TIFF2025528014000011.tif24170 where R 4-1 is phenyl, and at least one hydrogen atom is R 4-11 phenyl substituted with 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is R 4-11 and R is a 5- or 6-membered monocyclic heteroaryl substituted with 4-11 are hydrogen, halogen, nitro, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1~4 Haloalkyl, C 1~4 haloalkoxy or TIFF2025528014000012.tif16170R 4-1a and R 4-1b are independently hydrogen, C 1~4 Alkyl or C 3~6 cycloalkyl, and R 4-1a and R 4-1b are bonded to each other to form a ring, R 4-2 is C 1~4Alkyl, C 3~5 Cycloalkyl, C with at least one hydrogen replaced by hydroxyl 1~4 Alkyl, C 3~5 epoxyalkyl, or R 2 C 1~4 Alkyl and R 4-2 C 1~4 If it is alkyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring, R 4-3 is C 1~4 Alkyl or C 1~4 is alkoxy; R 5 are each independently hydrogen, halogen, nitro, nitrile, -N + (R 5-1 )3, C 1~4 Haloalkyl, -C(O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O)R 5-1 , -S(O)R 5-1 , -N=C(R 5-1 R 5-1a ), hydroxyl, C 1~4 Alkyl, phenyl, at least one hydrogen is R 5-1 Phenyl substituted with C 1~4 Alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a or -OC(O)R 5-1 where R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1~4 Alkyl, C with at least one hydrogen replaced by halogen 1~4 It is alkyl.

[0014] In some preferred embodiments, Z is TIFF2025528014000013.tif20170 or sulfur atoms; In some preferred embodiments, R 1 is hydrogen, TIFF2025528014000014.tif17170 where, R 11 and R 12 are each independently methyl, ethyl, n-propyl, or isopropyl, and n is 1.

[0015] In some preferred embodiments, R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, ethyl with one hydrogen replaced by hydroxyl, n-propyl with one hydrogen replaced by hydroxyl, phenyl, The file is TIFF2025528014000015.tif34170.

[0016] In some preferred embodiments, R 3 teeth TIFF2025528014000016.tif19170 where, R 3-1 is hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy or isobutoxy, m is 1, Ar is phenyl, a 5- or 6-membered nitrogen-containing monocyclic heteroaryl.

[0017] In some preferred embodiments, R 4 teeth TIFF2025528014000017.tif24170 where, R 4-1 is phenyl, and at least one hydrogen is R 4-11 phenyl substituted with 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is R 4-11 5- or 6-membered monocyclic heteroaryl substituted with 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom of which is substituted with R 4-11 and R is an 8- to 10-membered fused bicyclic heteroaryl substituted with 4-11 is halogen, nitro, methyl, ethyl, n-propyl, isopropyl, TIFF2025528014000018.tif47170Fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl, iodoisopropyl, fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloro-n-propoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, bromoisopropoxy, iodooxymethyl, iodoethoxy, iodo-n-propoxy, iodoisopropoxy or TIFF2025528014000019.tif14170R 4-2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, ethyl with one hydrogen replaced by hydroxyl, n-propyl with one hydrogen replaced by hydroxyl, n-butyl with one hydrogen replaced by hydroxyl, TIFF2025528014000020.tif14170 or phenyl, or R 2 is methyl, ethyl or n-propyl, and R 4-2 When is methyl or ethyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring, R 4-3 is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.

[0018] In some preferred embodiments, R 5 are each independently hydrogen, halogen, nitro, nitrile, -N + (R 5-1)3, Fluoromethyl, Fluoroethyl, Fluoro-n-propyl, Fluoroisopropyl, Chloromethyl, Chloroethyl, Chloro-n-propyl, Chloroisopropyl, Bromomethyl, Bromoethyl, Bromo-n-propyl, Bromoisopropyl, -C(O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O)R 5-1 , -S(O)R 5-1 , -N=C(R 5-1 R 5-1a ), hydroxyl, methyl, ethyl, n-propyl, isopropyl, phenyl, at least one hydrogen is R 5-1 phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a , -OC(O)R 5-1 where R 5-1 , R 5-1a and R 5-1b are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, or bromoisopropyl.

[0019] In some preferred embodiments, R 1 is hydrogen, TIFF2025528014000021.tif16170

[0020] In some preferred embodiments, R 2 is hydrogen, methyl, TIFF2025528014000022.tif14170 or phenyl.

[0021] In some preferred embodiments, R 3 teeth The file is TIFF2025528014000023.tif16170.

[0022] In some preferred embodiments, R 4 teeth TIFF2025528014000024.tif24170 where, R 4-1 is phenyl, and at least one hydrogen is R 4-11 phenyl substituted with 5-membered monocyclic heteroaryl, at least one hydrogen atom is R 4-11 5-membered monocyclic heteroaryl, 9-membered fused bicyclic heteroaryl, or naphthyl substituted with R 4-11 are bromine, fluorine, chlorine, methyl, nitro, phenyl, trifluoromethyl, TIFF2025528014000025.tif13170Methoxy, cyclopropyl, trifluoromethoxy, nitro or TIFF2025528014000026.tif13170R 4-2 is methyl, ethyl, TIFF2025528014000027.tif14170 or phenyl, or R 2 is methyl, ethyl or n-propyl, and R 4-2 When is methyl or ethyl, R 4-2 and R 2 are bonded to form a 4- to 6-membered ring, R 4-3 is methoxy, ethoxy, n-propoxy or isopropoxy.

[0023] In some preferred embodiments, R 5 is each independently at each occurrence halogen, nitro, nitrile, carboxyl, —NHC(O)CH 3 , methoxy, or hydroxyl.

[0024] In some preferred embodiments, the compound is selected from any one of the following compounds: TIFF2025528014000028.tif221170TIFF2025528014000029.tif221170TIFF2025528014000030.tif214170TIFF2025528014000031.tif214170TIFF202 5528014000032.tif252170TIFF2025528014000033.tif220170TIFF2025528 014000034.tif227170TIFF2025528014000035.tif252170TIFF20255280140 00036.tif251170TIFF2025528014000037.tif220170TIFF2025528014000038.tif252170TIFF2025528014000039.tif252170TIFF2025528014000040.t if226170TIFF2025528014000041.tif221170TIFF2025528014000042.tif239170TIFF2025528014000043.tif214170TIFF2025528014000044.tif177170

[0025] In some preferred embodiments, Z is not a sulfur atom.

[0026] In some preferred embodiments, Z is The file is TIFF2025528014000045.tif38170.

[0027] In some preferred embodiments, Z is Not TIFF2025528014000046.tif35170.

[0028] In some preferred embodiments, the diseases associated with kidney damage include acute kidney injury and chronic kidney injury, preferably chronic kidney injury.

[0029] In some preferred embodiments, the disease associated with renal damage is selected from the group consisting of acute renal ischemia-reperfusion injury, septic nephropathy, nephrotoxic injury, primary glomerulonephritis, hypertensive renal arteriosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial lesions, ischemic nephropathy, lupus nephritis, and hereditary nephropathy.

[0030] In some preferred embodiments, the tubulointerstitial lesion is selected from the group consisting of chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, and drug-induced nephropathy.

[0031] In some preferred embodiments, the hereditary nephropathy is selected from the group consisting of polycystic kidney disease and hereditary nephritis.

[0032] In some preferred embodiments, the disease associated with mitochondrial dysfunction is selected from at least one of inflammatory bowel disease; lung injury; fibrotic disease; sepsis; prostate disease; cardiovascular disease; neurological disease; and aging-related disease.

[0033] In some preferred embodiments, the inflammatory bowel disease is selected from at least one of ulcerative colitis and Crohn's disease.

[0034] In some preferred embodiments, the lung injury is selected from at least one of acute lung injury and chronic lung injury.

[0035] In some preferred embodiments, the chronic lung injury is chronic obstructive pulmonary disease.

[0036] In some preferred embodiments, the fibrotic disease is selected from at least one of tubulointerstitial fibrosis, interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease fibrosis, tissue fibrosis, arthrofibrosis, liver fibrosis, skin fibrosis, fibromatosis, myelofibrosis, cardiac fibrosis, and cystic fibrosis.

[0037] In some preferred embodiments, the cardiovascular disease is selected from at least one of atherosclerosis, heart failure, myocardial ischemia / reperfusion injury and hypertension, cardiomyopathy, and cardiovascular complications of diabetes.

[0038] In some preferred embodiments, the cardiomyopathy is myocarditis.

[0039] In some preferred embodiments, the neurological disorder is selected from at least one of sensorineural hearing loss, abnormal brain development, congenital hydrocephalus, congenital cranial nerve disease, congenital perforating branch malformation, metabolic dysfunction, congenital auditory aphasia, congenital visual aphasia, cerebral palsy, autism, depression, schizophrenia, bipolar disorder, delusional disorder, mania, obsessive-compulsive disorder, psychiatric disorders such as autism, Parkinson's disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, epilepsy, Huntington's disease, spinocerebellar ataxia, cerebral ischemia (CI), stroke (preferably ischemic stroke), multiple sclerosis, and tinnitus.

[0040] In some preferred embodiments, the aging-related disease is progeria.

[0041] In some preferred embodiments, the aging-related disease is early-onset ovarian dysfunction or natural aging ovarian dysfunction.

[0042] In some preferred embodiments, the aging-related disorder is skin aging, and more preferably, the aging-related disorder is radiation-induced skin aging or damage.

[0043] A second aspect of the present invention provides a method for preventing and / or treating a disease associated with nephropathy, which comprises administering to a subject a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0044] A third aspect of the present invention provides a method for preventing and / or treating a disease associated with mitochondrial dysfunction, comprising the step of administering to a subject a therapeutically effective amount of a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0045] In some preferred embodiments, the disease associated with mitochondrial dysfunction is a cardiovascular disease, and the method comprises co-administering to the subject a therapeutically effective amount of a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, and Entresto.

[0046] In some preferred embodiments, the disease associated with mitochondrial dysfunction is benign prostatic hyperplasia, and the method comprises the step of co-administering a therapeutically effective amount of a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof and finasteride to a subject.

[0047] In some combination therapies for treating benign prostatic hyperplasia, the compound represented by general formula (I) is compound I-1.

[0048] In some combination therapies for treating cardiovascular disease, the compound represented by general formula (I) is compound I-1.

[0049] In some preferred embodiments, the single dose of the compound represented by general formula (I) is 0.1-100 mg / kg, for example, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 5 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, or 20 mg / kg, 50 mg / kg.

[0050] In some preferred embodiments, the compound of formula (I) is administered once a day, twice a day, three times a day, every two days, every three days, or once a week.

[0051] In some preferred embodiments, the administration cycle of the compound represented by general formula (I) is 1-365 days, for example, 1 day, 7 days, 10 days, 15 days, 30 days, 60 days, 90 days or 180 days.

[0052] In some preferred embodiments, the method of administration of the compound of general formula (I) is selected from oral, intravenous, intratracheal, intramuscular, subcutaneous, intraperitoneal, spinal or local injection / infusion.

[0053] A fourth aspect of the present invention provides a cosmetic or medical device composition comprising a compound represented by general formula (I) and an adjuvant acceptable for cosmetics or medical devices.

[0054] Compared with the prior art, the present invention has at least the following advantages:

[0055] (1) The present invention is the first to discover that the compound of general formula (I) can be used to treat diseases associated with renal impairment, and is expected to be an effective medicine for the treatment of diseases associated with renal impairment, particularly chronic kidney disease.

[0056] (2) The present invention has found for the first time that the compounds of general formula (I) can be used to manufacture medicines for treating diseases associated with renal impairment.

[0057] (3) The present invention investigates the use of compounds of general formula (I) as mitophagy inducers for treating various mitophagy-related diseases or for preparing medicaments for treating these diseases. Various disease models have been studied at the animal level, and the excellent therapeutic effects of compounds of general formula (I) on these diseases have been confirmed.

[0058] (4) In a preferred embodiment of the present invention, a method of using a compound of general formula (I) (e.g., compound I-1) in combination with other drugs is also contemplated.

[0059] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described one by one here due to space limitations. [Brief explanation of the drawings]

[0060] One or more embodiments are illustrated by way of example in the figures of the accompanying drawings, and these illustrative illustrations do not constitute limitations on the embodiments. [Figure 1] FIG. 1 shows statistical graphs of serum creatinine and urea nitrogen after administration of I-1 to mice undergoing renal ischemia-reperfusion. [Figure 2] Figure 2 shows HE stained images of kidney tissue after administration of I-1 to mice undergoing renal ischemia-reperfusion. [Figure 3] Figure 3 shows immunofluorescence images of the kidney after administration of I-1 to mice undergoing renal ischemia-reperfusion. [Figure 4] FIG. 4 is a statistical graph of the body weight of 5 / 6 nephrectomized rats after 27 days of I-1 administration. [Figure 5] FIG. 5 is a statistical graph of serum creatinine in 5 / 6 nephrectomized rats after 27 days of I-1 administration. [Figure 6] FIG. 6 is a statistical graph of urinary albumin at the end point after 27 days of I-1 administration in 5 / 6 nephrectomized rats. [Figure 7] FIG. 7 is a statistical graph of creatinine clearance rate in 5 / 6 nephrectomized rats after 27 days of I-1 administration. [Figure 8] FIG. 8 shows HE staining of kidney tissue from 5 / 6 nephrectomized rats after 27 days of I-1 administration. [Figure 9] FIG. 9 is a statistical graph showing the body weight of adenine-induced nephropathy model rats after 21 days of I-1 administration. [Figure 10] FIG. 10 is a statistical graph of serum creatinine levels in adenine-induced nephropathy model rats after 21 days of I-1 administration. [Figure 11]FIG. 11 is a statistical graph showing the effect of 21-day administration of I-1 on serum uric acid levels in adenine-induced nephropathy model rats. [Figure 12] FIG. 12 is a statistical graph showing the effect of 21-day administration of I-1 on inflammatory factors in kidney tissue in adenine-induced nephropathy model rats. [Figure 13] FIG. 13 shows HE stained images of kidney tissues in adenine-induced nephropathy model rats after 21 days of I-1 administration. [Figure 14] FIG. 14 is a statistical graph showing the weight gain before and after 27 days of I-1 administration in type I diabetic nephropathy model rats. [Figure 15] FIG. 15 is a statistical graph of serum creatinine in type I diabetic nephropathy model rats after 27 days of I-1 administration. [Figure 16] FIG. 16 is a statistical graph of blood glucose levels in type I diabetic nephropathy model rats after 27 days of I-1 administration. [Figure 17] FIG. 17 is a statistical diagram of urinary protein levels in type I diabetic nephropathy model rats after 27 days of I-1 administration. [Figure 18] FIG. 18 shows HE staining images of kidney tissues in a type I diabetic nephropathy model rat after 27 days of I-1 administration. [Figure 19] FIG. 19 shows the results of in vitro liver microsome stability experiments of compounds I-1 and UMI-77. [Figure 20] FIG. 20 is a schematic diagram showing changes in body weight of mice in the group intraperitoneally injected with the small molecule compound TJ01-013 during DSS induction according to an embodiment of the present invention. [Figure 21] FIG. 21 is a graph showing disease activity indexes for a group intraperitoneally injected with the small molecule compound TJ01-013 during DSS induction according to an embodiment of the present invention. [Figure 22] FIG. 22 is a graph showing changes in the length of the colon and rectum of mice according to an embodiment of the present invention. [Figure 23] FIG. 23 is a schematic diagram of stained sections and histopathological scoring of tissue sections according to an embodiment of the present invention. [Figure 24]FIG. 24 shows changes in inflammatory factors in mouse colorectal tissues according to an embodiment of the present invention. [Figure 25] FIG. 25 is a diagram showing changes in the total number of each cell according to an embodiment of the present invention. [Figure 26] FIG. 26 shows changes in inflammatory factors in bronchoalveolar lavage fluid according to an embodiment of the present invention. [Figure 27] FIG. 27 shows changes in transcription levels of tissue inflammatory factors according to an embodiment of the present invention. [Figure 28] FIG. 28 is an acute lung injury survival curve according to an embodiment of the present invention. [Figure 29] FIG. 29 is a Masson's Trichrome staining image showing the degree of fibrosis in kidney tissue samples according to an embodiment of the present invention. [Figure 30] FIG. 30 shows changes in mRNA levels of α-smooth muscle actin, fibronectin, and type I collagen in kidney tissue homogenates detected by fluorescent quantitative PCR according to an embodiment of the present invention. [Figure 31] FIG. 31 is a grayscale quantitative analysis of α-smooth muscle actin, fibronectin, and type I collagen levels according to an embodiment of the present invention. [Figure 32] FIG. 32 is a diagram of mitochondrial morphology in renal tubular epithelial cells according to an embodiment of the present invention. [Figure 33] FIG. 33 is a schematic diagram of sepsis survival rate according to an embodiment of the present invention. [Figure 34] FIG. 34 is a graph of rat prostate and urethra weights according to an embodiment of the present invention. [Figure 35] FIG. 35 is a diagram of rat prostate organ index according to an embodiment of the present invention. [Figure 36] FIG. 36 is a graph showing the effects of TJ01-013, finasteride and combined administration on rat prostate and urethra weights according to an embodiment of the present invention. [Figure 37] FIG. 37 is a graph showing the effects of TJ01-013, Entresto, and their combined administration on myocardial infarction area in rats according to an embodiment of the present invention. [Figure 38] FIG. 38 is a graph showing the effects of TJ01-013, Entresto, and combined administration on left ventricular end-diastolic diameter in rats according to an embodiment of the present invention. [Figure 39] FIG. 39 is a graph showing the effects of TJ01-013, Entresto, and combined administration on end-systolic diameter in rats according to an example of the present invention. [Figure 40] FIG. 40 is a graph showing the effects of TJ01-013, Entresto, and combined administration on left ventricular ejection fraction (EF) in rats according to an embodiment of the present invention. [Figure 41] FIG. 41 is a graph showing the effects of TJ01-013, Entresto, and their combined administration on the short-axis shortening fraction of the left ventricle in rats according to an embodiment of the present invention. [Figure 42] FIG. 42 is a diagram of the time taken to find the platform in a water maze experiment according to an embodiment of the present invention. [Figure 43] FIG. 43 is a diagram showing a trajectory passing through a platform in a water maze experiment according to an embodiment of the present invention. [Figure 44] FIG. 44 shows the number of activated astrocytes in the hippocampus region of mice according to an embodiment of the present invention. [Figure 45] FIG. 45 is a diagram of Aβ content in mouse brain tissue according to an embodiment of the present invention. [Figure 46] FIG. 46 is a diagram showing the amplitude of fluctuation in mouse hearing threshold at each frequency according to an embodiment of the present invention. [Figure 47] FIG. 47 shows fluorescent images of Myo7a-labeled mouse hair cells in the parietal, middle, and basal gyri according to an embodiment of the present invention. [Figure 48] FIG. 48 is a schematic diagram showing the percentage of SA-β-gal positive cells in Con-O compared with Con-Y in mouse bone marrow mesenchymal stem cells according to an embodiment of the present invention. [Figure 49] FIG. 49 shows changes in the level of the DNA damage marker γ-H2AX in old cells (Con-O) in mouse bone marrow mesenchymal stem cells according to an embodiment of the present invention. [Figure 50]FIG. 50 is a diagram showing the expression level of heterochromatin modification H3K9me3 in Con-O cells among mouse bone marrow mesenchymal stem cells according to an embodiment of the present invention. [Figure 51] FIG. 51 is a schematic diagram showing the percentage of SA-β-gal positive cells in CMC cells according to an embodiment of the present invention. [Figure 52] FIG. 52 is a schematic diagram of γ-H2AX levels in CMC cells according to an embodiment of the present invention. [Figure 53] FIG. 53 is a schematic diagram of H3K9me3 expression levels in CMC cells according to an embodiment of the present invention. [Figure 54] FIG. 54 is a schematic diagram showing the percentage of SA-β-gal positive cells in HGPS-CMC cells according to an embodiment of the present invention. [Figure 55] FIG. 55 is a schematic diagram of γ-H2AX levels in HGPS-CMC cells according to an embodiment of the present invention. [Figure 56] FIG. 56 is a schematic diagram of H3K9me3 expression levels in HGPS-CMC cells according to an embodiment of the present invention. [Figure 57] FIG. 57 shows the results of an experiment on sugar water preference in mice according to an embodiment of the present invention. [Figure 58] FIG. 58 shows the results of a mouse tail suspension experiment according to an embodiment of the present invention. [Figure 59] FIG. 59 is a diagram showing the distance of activity in an open field experiment of a mouse according to an embodiment of the present invention. [Figure 60] FIG. 60 is a time chart of a mouse in the edge region of an open field in an open field experiment according to an embodiment of the present invention. [Figure 61] FIG. 61 is a graph showing the average movement speed of mice in an open field experiment according to an embodiment of the present invention. [Figure 62] FIG. 62 is a quantitative analysis diagram of serum TNFα and CXCL1 after administering compound TJ0113 to a subject with chronic obstructive pulmonary disease in an example of the present invention. [Figure 63]FIG. 63 is a quantitative analysis of seizure levels following administration of compound TJ01-013 in an epilepsy model according to an embodiment of the present invention. [Figure 64] FIG. 64 is a quantitative analysis of post-stimulus latency in the jumping platform test after administration of compound TJ01-013 in an epilepsy model according to an embodiment of the present invention. [Figure 65] FIG. 65 is a graph showing quantitative analysis of post-stimulus latency in a dark avoidance experiment after administration of compound TJ01-013 in an epilepsy model according to an embodiment of the present invention. [Figure 66] FIG. 66 is a quantitative analysis diagram of serum inflammatory factors after administration of compound TJ01-013 in an epilepsy model according to an embodiment of the present invention. [Figure 67] FIG. 67 is a quantitative analysis diagram of body weight, ovary weight and ovarian organ index after administration of compound TJ0113 to mice in a chemotherapy-induced premature ovarian failure model according to an embodiment of the present invention. [Figure 68] FIG. 68 is a quantitative analysis graph of serum FSH after administration of compound TJ0113 to mice in a chemotherapy-induced premature ovarian failure model according to an embodiment of the present invention. [Figure 69] FIG. 69 is a quantitative analysis diagram of serum E2 after administration of compound TJ0113 to mice in a chemotherapy-induced premature ovarian disorder model according to an embodiment of the present invention. [Figure 70] FIG. 70 is a quantitative analysis diagram of BDNF in ovarian tissue after administration of compound TJ0113 to mice in a chemotherapy-induced premature ovarian disorder model according to an embodiment of the present invention. [Figure 71] FIG. 71 is a quantitative analysis diagram of body weight, ovary weight and ovarian organ index after administration of compound TJ0113 to mice in a natural aging ovarian dysfunction model according to an embodiment of the present invention. [Figure 72] FIG. 72 is a quantitative analysis graph of FSH after administering compound TJ0113 to mice in a natural aging ovarian dysfunction model according to an embodiment of the present invention. [Figure 73] FIG. 73 is a quantitative analysis diagram of E2 after administering compound TJ0113 to mice in a natural aging ovarian dysfunction model according to an embodiment of the present invention. [Figure 74] FIG. 74 is a quantitative analysis diagram of random urinary uPCR after administration of compound TJ0113 to mice in a lupus nephritis model according to an embodiment of the present invention. [Figure 75] FIG. 75 is a quantitative analysis diagram of serum creatinine and urea nitrogen after administration of compound TJ0113 to mice in a lupus nephritis model according to an embodiment of the present invention. [Figure 76] FIG. 76 is a quantitative analysis diagram of serum ANA after administration of compound TJ0113 to mice in a lupus nephritis model according to an embodiment of the present invention. [Figure 77] FIG. 77 is a quantitative analysis diagram of serum dsDNA after administration of compound TJ0113 to mice in a lupus nephritis model according to an embodiment of the present invention. [Figure 78] FIG. 78 is a quantitative analysis diagram of TNFα and IL-6 in kidney tissue after administration of compound TJ0113 to mice in a lupus nephritis model according to an embodiment of the present invention. [Figure 79] FIG. 79 is a quantitative analysis diagram of LVIDd and LVIDs after administration of compound TJ01-013 to mice in a myocarditis model according to an embodiment of the present invention. [Figure 80] FIG. 80 is a quantitative analysis diagram of EF and FS after administration of compound TJ01-013 to mice in a myocarditis model according to an embodiment of the present invention. [Figure 81] FIG. 81 is a quantitative analysis diagram of serum CK-MB levels after administration of compound TJ01-013 to mice in a myocarditis model according to an embodiment of the present invention. [Figure 82] FIG. 82 is a graph showing quantitative analysis of escape latency after administration of compound TJ01-013 in a stroke model according to an embodiment of the present invention. [Figure 83] FIG. 83 is a graph showing a quantitative analysis of the number of times the platform is crossed after administration of compound TJ01-013 in a stroke model according to an embodiment of the present invention. [Figure 84] FIG. 84 is a quantitative analysis diagram of the apoptosis rate of nerve cells after administration of compound TJ01-013 in a stroke model according to an embodiment of the present invention. [Figure 85] FIG. 85 is a quantitative analysis diagram of tinnitus index after administration of compound TJ0113 for tinnitus in an example of the present invention. [Figure 86] FIG. 86 is a quantitative analysis graph of the number of times mice entered the elevated plus maze after administration of compound TJ01-013 in a multiple sclerosis model according to an embodiment of the present invention. [Figure 87] FIG. 87 is a quantitative analysis graph of the distance walked by mice on an elevated platform after administration of compound TJ01-013 in a multiple sclerosis model according to an embodiment of the present invention. [Figure 88] FIG. 88 is a quantitative analysis graph of the time it takes for mice to enter the elevated plus maze after administering compound TJ01-013 to the mice in a multiple sclerosis model according to an embodiment of the present invention. [Figure 89] FIG. 89 is a quantitative analysis graph of the number of times mice cross the platform after administering compound TJ01-013 to the mice in a multiple sclerosis model according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0061] Acute kidney injury (AKI) is a major kidney disease characterized by a rapid decline in renal function. While kidney damage is fully repaired after mild acute kidney injury, severe or repeated acute kidney injury often results in impaired repair, leading to renal fibrosis and ultimately chronic kidney disease. With existing technologies, the common treatments for chronic kidney disease are causal therapy and renal replacement therapy (RRT). Because the causative factors of this disease are highly complex and often involve multiple factors, the effectiveness of causal therapy remains unclear. Renal replacement therapy includes 1) hemodialysis, 2) peritoneal dialysis, and 3) kidney transplantation. However, these three treatments require patients to undergo traumatic surgical procedures, which are time-consuming and labor-intensive. Mitochondrial accumulation is a hallmark of the disease and is thought to be a key factor promoting disease progression. Therefore, induction of mitophagy is expected to be an effective treatment for various acute and chronic diseases. The present inventors have developed a compound represented by general formula (I) through extensive and thorough research and conducted numerous experiments, and have proven that the compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof can be used for the prevention and / or treatment of diseases associated with kidney damage, and for the preparation of a medicament for the prevention and / or treatment of diseases associated with kidney damage, and / or for the prevention and / or treatment of diseases associated with mitophagy, and / or for the preparation of a medicament for the prevention and / or treatment of diseases associated with mitophagy.

[0062] compound In some embodiments of the present invention, the compound represented by general formula (I) is as follows: TIFF2025528014000047.tif54170 where Z is TIFF2025528014000048.tif20170 or sulfur atom.

[0063] R 1 is hydrogen, C 1~6 Alkyl, TIFF2025528014000049.tif17170 where, R 11 and R 12 are each independently C 1~6 Alkyl or C1~6 cycloalkyl, and n is 1 to 4; R 2 is hydrogen, C 1~6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom is R 2-1 C replaced with 1~6 Alkyl, at least one hydrogen is R 2-1 phenyl substituted with, where R 2-1 is hydroxyl, halogen, amino or C 1~6 is an alkoxy; R 3 teeth TIFF2025528014000050.tif19170 where, R 3-1 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, 3-6 membered epoxyalkyl, amino, C 1~6 Amine group, -CHC(O)R 3-2 , -CH2C(O)OR 3-2 , -CH2C(O)N(R 3-2 R 3-2a ) and R 3-2 and R 3-2a are independently hydrogen, C 1~6 alkyl or 3- to 6-membered cycloalkyl; m is 1 to 6, and Ar is phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom of which is R 3-3 phenyl substituted with at least one hydrogen atom 3-3 naphthyl substituted with at least one hydrogen atom of R 3-3 5- or 6-membered monocyclic heteroaryl substituted with at least one hydrogen atom of R 3-3 and R is an 8- to 10-membered fused bicyclic heteroaryl substituted with 3-3 are hydrogen, halogen, C 1~6 Alkyl, 3-6 membered cycloalkyl, hydroxyl, C 1~6 Alkoxy, 3-6 membered epoxy alkyl, C 1~6Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -N(R 3-3a R 3-3b ) or phenyl, R 3-3a and R 3-3b are independently hydrogen, C 1~6 alkyl or 3- to 6-membered cycloalkyl; R 4 teeth TIFF2025528014000051.tif24170 where R 4-1 is phenyl, naphthyl, and at least one hydrogen atom is R 4-11 phenyl substituted with 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is R 4-11 5- or 6-membered monocyclic heteroaryl substituted with 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom of which is substituted with R 4-11 and R is an 8- to 10-membered fused bicyclic heteroaryl substituted with 4-11 is hydrogen, halogen, nitro, nitrile, hydroxyl, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 1~6 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -C(O)OR 4-12 , -C(O)R 4-12 , -C(O)N(R 4-1a R 4-1b ), -S(O)R 4-12 , -S(O)R 4-12 , -OC(O)R 4-12 , -OC(O)OR 4-12 or TIFF2025528014000052.tif16170R 4-12 , R 4-1a and R 4-1b are independently hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C with at least one hydrogen replaced by halogen 1~6 Alkyl, C with at least one hydrogen replaced by halogen 2~6 Alkenyl, C with at least one hydrogen replaced by halogen 3~6 Cycloalkyl, C with at least one hydrogen replaced by halogen 2~6 alkynyl, and R 4-1a and R 4-1b are bonded to each other to form a ring, R 4-2 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C with at least one hydrogen replaced by hydroxyl 1~6 Alkyl, C 3~6 epoxyalkyl, or R 2 C 1~6 Alkyl and R 4-2 C 1~6 If it is alkyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring, R 4-3 is C 1~6 Alkyl or C 1~6 is alkoxy; R 5 The number of is 0 to 5, and R 5 are each independently hydrogen, halogen, nitro, nitrile, -N + (R 5-1 )3, C 1~6 Haloalkyl, -C(O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O)R 5-1 , -S(O)R 5-1 , -S(O)2N(R 5-1 R 5-1a ), -S(O)N(R 5-1 R 5-1a ), -N=C(R 5-1 R 5-1a ), hydroxyl, C 1~6 Alkyl, phenyl, at least one hydrogen is R 5-1 Phenyl substituted with C 1~6Alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a , -N(R 5-1 )C(O)OR 5-1a , -N(R 5-1 )C(O)N(R 5-1a R 5-1b ), -OC(O)R 5-1 , -OC(O)OR 5-1 , -OC(O)N(R 5-1 R 5-1a ) or -SR 5-1 where R 5-1 , R 5-1a and R 5-1b are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C with at least one hydrogen replaced by halogen 1~6 Alkyl, C with at least one hydrogen replaced by halogen 2~6 Alkenyl or C in which at least one hydrogen is replaced by halogen 2~6 It is alkynyl.

[0064] In some preferred embodiments, Z is TIFF2025528014000053.tif20170 or sulfur atoms; R 1 is hydrogen, C 1~4 Alkyl, TIFF2025528014000054.tif17170 where, R 11 and R 12 are each independently C 1~4 Alkyl or C 1~4 cycloalkyl, and n is 1 or 2; R 2 is hydrogen, C 1~4 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom is R 2-1 C replaced with 1~4 Alkyl, at least one hydrogen is R 2-1 phenyl substituted with, where R 2-1is hydroxyl, halogen, amino or C 1~4 is alkoxy; R 3 teeth TIFF2025528014000055.tif19170 where, R 3-1 is hydrogen, hydroxyl, C 1~4 Alkyl, C 1~4 Alkoxy, -N(R 3-2 R 3-2a ) and R 3-2 and R 3-2a are each independently hydrogen or C 1~4 alkyl, and R 3-3a and R 3-3b are each independently hydrogen or C 1~4 is alkyl, m is 1 to 4; Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom is R 3-3 and R is a 5- or 6-membered monocyclic heteroaryl substituted with 3-3 are hydrogen, halogen, C 1~4 Alkyl, Hydroxyl, C 1~4 Alkoxy, C 1~4 haloalkyl or -N(R 3-3a R 3-3b ) and; R 4 teeth TIFF2025528014000056.tif24170 where, R 4-1 is phenyl, and at least one hydrogen atom is R 4-11 phenyl substituted with 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is R 4-11 and R is a 5- or 6-membered monocyclic heteroaryl substituted with 4-11 are hydrogen, halogen, nitro, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, -N(R 4-1a R 4-1b ), phenyl, C 1~4 Haloalkyl, C 1~4 haloalkoxy or TIFF2025528014000057.tif16170R 4-1a and R 4-1b are independently hydrogen, C 1~4 Alkyl or C 3~6 cycloalkyl, and R 4-1a and R 4-1b are bonded to each other to form a ring, R 4-2 is C 1~4 Alkyl, C 3~5 Cycloalkyl, C with at least one hydrogen replaced by hydroxyl 1~4 Alkyl, C 3~5 epoxyalkyl, or R 2 C 1~4 Alkyl and R 4-2 C 1~4 If it is alkyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring, R 4-3 is C 1~4 Alkyl or C 1~4 is alkoxy; R 5 are each independently hydrogen, halogen, nitro, nitrile, -N + (R 5-1 )3, C 1~4 Haloalkyl, -C(O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O)R 5-1 , -S(O)R 5-1 , -N=C(R 5-1 R 5-1a ), hydroxyl, C 1~4 Alkyl, phenyl, at least one hydrogen is R 5-1 Phenyl substituted with C 1~4 Alkoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a or -OC(O)R 5-1 where R 5-1 , R 5-1a and R 5-1bare independently hydrogen, C 1~4 Alkyl, C with at least one hydrogen replaced by halogen 1~4 It is alkyl.

[0065] In some preferred embodiments, Z is TIFF2025528014000058.tif20170 or sulfur atoms; In some preferred embodiments, R 1 is hydrogen, TIFF2025528014000059.tif17170 where, R 11 and R 12 are each independently methyl, ethyl, n-propyl, or isopropyl, and n is 1.

[0066] In some preferred embodiments, R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, ethyl with one hydrogen replaced by hydroxyl, n-propyl with one hydrogen replaced by hydroxyl, phenyl, The file is TIFF2025528014000060.tif34170.

[0067] In some preferred embodiments, R 3 teeth TIFF2025528014000061.tif19170 where, R 3-1 is hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy or isobutoxy, m is 1, Ar is phenyl, a 5- or 6-membered nitrogen-containing monocyclic heteroaryl.

[0068] In some preferred embodiments, R 4 teeth TIFF2025528014000062.tif24170 where, R 4-1 is phenyl, and at least one hydrogen is R 4-11phenyl substituted with 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is R 4-11 5- or 6-membered monocyclic heteroaryl substituted with 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom of which is substituted with R 4-11 and R is an 8- to 10-membered fused bicyclic heteroaryl substituted with 4-11 is halogen, nitro, methyl, ethyl, n-propyl, isopropyl, TIFF2025528014000063.tif47170Fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl, iodoisopropyl, fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloro-n-propoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, bromoisopropoxy, iodooxymethyl, iodoethoxy, iodo-n-propoxy, iodoisopropoxy or TIFF2025528014000064.tif14170R 4-2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, ethyl with one hydrogen replaced by hydroxyl, n-propyl with one hydrogen replaced by hydroxyl, n-butyl with one hydrogen replaced by hydroxyl, TIFF2025528014000065.tif14170 or phenyl, or R 2 is methyl, ethyl or n-propyl, and R 4-2 When is methyl or ethyl, R 4-2 and R 2 are bonded to form a 4- to 8-membered ring, R 4-3 is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.

[0069] In some preferred embodiments, R 5 are each independently hydrogen, halogen, nitro, nitrile, -N + (R 5-1 )3, Fluoromethyl, Fluoroethyl, Fluoro-n-propyl, Fluoroisopropyl, Chloromethyl, Chloroethyl, Chloro-n-propyl, Chloroisopropyl, Bromomethyl, Bromoethyl, Bromo-n-propyl, Bromoisopropyl, -C(O)OR 5-1 , -C(O)R 5-1 , -C(O)N(R 5-1 R 5-1a ), -S(O)R 5-1 , -S(O)R 5-1 , -N=C(R 5-1 R 5-1a ), hydroxyl, methyl, ethyl, n-propyl, isopropyl, phenyl, at least one hydrogen is R 5-1 phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, -N(R 5-1 R 5-1a ), -N(R 5-1 )C(O)R 5-1a , -OC(O)R 5-1 where R 5-1 , R 5-1a and R 5-1b are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, or bromoisopropyl.

[0070] In some preferred embodiments, R 1 is hydrogen, The file is TIFF2025528014000066.tif16170.

[0071] In some preferred embodiments, R 2 is hydrogen, methyl, TIFF2025528014000067.tif16170 or phenyl.

[0072] In some preferred embodiments, R 3 teeth The file is TIFF2025528014000068.tif16170.

[0073] In some preferred embodiments, R 4 teeth TIFF2025528014000069.tif24170 where, R 4-1 is phenyl, and at least one hydrogen is R 4-11 phenyl substituted with 5-membered monocyclic heteroaryl, at least one hydrogen atom is R 4-11 5-membered monocyclic heteroaryl, 9-membered fused bicyclic heteroaryl, or naphthyl substituted with R 4-11 are bromine, fluorine, chlorine, methyl, nitro, phenyl, trifluoromethyl, TIFF2025528014000070.tif13170Methoxy, cyclopropyl, trifluoromethoxy, nitro or TIFF2025528014000071.tif13170R 4-2 is methyl, ethyl, TIFF2025528014000072.tif16170 or phenyl, or R 2 is methyl, ethyl or n-propyl, and R 4-2 When is methyl or ethyl, R 4-2 and R 2 are bonded to form a 4- to 6-membered ring, R 4-3 is methoxy, ethoxy, n-propoxy or isopropoxy.

[0074] In some preferred embodiments, R 5 is each independently at each occurrence halogen, nitro, nitrile, carboxyl, —NHC(O)H, methoxy, or hydroxyl.

[0075] In some preferred embodiments, the C 1~6 Alkyl is C 1~4alkyl, 1~4 Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl or ethyl.

[0076] In some preferred embodiments, the 3- to 6-membered cycloalkyl is preferably C 3~5 cycloalkyl, wherein C 3~5 Cycloalkyl is preferably The file is TIFF2025528014000073.tif14170.

[0077] In some preferred embodiments, the 3- to 6-membered epoxy alkyl is preferably The file is TIFF2025528014000074.tif34170.

[0078] In some preferred embodiments, the C 1~6 The alkyl-substituted phenyl is preferably C 1~4 It is phenyl substituted with alkyl, more preferably phenyl substituted with any of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0079] In some preferred embodiments, the C 1~6 The alkoxy is preferably C 1~4 Alkoxy is more preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy or isobutoxy.

[0080] In some preferred embodiments, the —N(R 3-2 R 3-2a ), -N(R 3-3a R 3-3b ), -N(R 4-1a R 4-1b ), -N(R 5-1 R 5-1a ) is preferably The file is TIFF2025528014000075.tif45170.

[0081] In some preferred embodiments, the 5- or 6-membered monocyclic heteroaryl is preferably TIFF2025528014000076.tif21170 wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9 are each independently selected from C, N, O, or S, and Y1, Y2, Y3, and Y4 are not all C, and Y5, Y6, Y7, Y8, and Y9 are not all C; the 5- or 6-membered monocyclic heteroaryl is more preferably pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazolyl, or tetrazolyl; the 5- or 6-membered monocyclic heteroaryl is more preferably TIFF2025528014000077.tif142170 More preferably, the 5- or 6-membered monocyclic heteroaryl is a 5- or 6-membered nitrogen-containing monocyclic heteroaryl, such as: TIFF2025528014000078.tif36170 Most preferably, the 5- or 6-membered monocyclic heteroaryl is a 5-membered nitrogen-containing monocyclic heteroaryl, such as: The file is TIFF2025528014000079.tif18170.

[0082] In some preferred embodiments, the 8- to 10-membered fused bicyclic heteroaryl is TIFF2025528014000080.tif60170; where Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 and Y 19 are each independently selected from C, N, O, or S, and Y 11 , Y 12 , Y 13 , Y 14 , Y15 , Y 16 , Y 17 , Y 18 and Y 19 All are Y instead of C. 21 , Y 22 , Y 23 , Y 24 , Y 25 and Y 26 are each independently selected from C, N, O, or S, and Y 21 , Y 22 , Y 23 , Y 24 , Y 25 and Y 26 All are Y instead of C. 31 , Y 32 , Y 33 , Y 34 , Y 35 , Y 36 and Y 37 are each independently selected from C, N, O, or S, and Y 31 , Y 32 , Y 33 , Y 34 , Y 35 , Y 36 and Y 37 are not all C; the 8- to 10-membered fused bicyclic heteroaryl is more preferably indolyl, benzindolyl, benzothienyl, carbazolyl, quinolyl, pteridinyl, or purinyl; the 8- to 10-membered fused bicyclic heteroaryl is most preferably The file is TIFF2025528014000081.tif22170.

[0083] In some preferred embodiments, the halogen is preferably fluorine, chlorine, bromine, or iodine.

[0084] In some preferred embodiments, the C 1~6 Haloalkyl is preferably C 1~3It is haloalkyl; more preferably fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl, iodoisopropyl; and most preferably trifluoromethyl.

[0085] In some preferred embodiments, the C 1~6 Haloalkoxy is preferably C 1~3 It is haloalkoxy; more preferably fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloro-n-propoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, bromoisopropoxy, iodooxymethyl, iodoethoxy, iodo-n-propoxy, iodoisopropoxy; and most preferably trifluoromethoxy.

[0086] In some preferred embodiments, the C 2~6 Alkenyl is preferably C 2~4 Alkenyl, more preferably -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2.

[0087] In some preferred embodiments, the C 2~6 Alkynyl is preferably C 2~6 Alkynyl, more preferably -C≡CH, -CH2-C≡CH, -CH2-CH2-C≡CH, -CH2-C≡C-CH3.

[0088] In some preferred embodiments, Z is not a sulfur atom, based on the beneficial effects of improving the metabolic stability of the compound and reducing toxicity.

[0089] Furthermore, based on the beneficial effect of improving the efficacy of the compound in treating kidney-related diseases, particularly chronic kidney disease, in some preferred embodiments, Z is TIFF2025528014000082.tif38170. In some preferred embodiments, Z is Not TIFF2025528014000083.tif35170.

[0090] In a preferred embodiment of the present invention, the compound of general formula I is compound I-1 (also known as TJ01-013 or TJ0113), the structure of which is shown in the following formula: TIFF2025528014000084.tif41170

[0091] In the present invention, the compound of general formula I can be prepared by the method described in Chinese Patent Application No. 202111108417.6, the contents of which are incorporated herein in their entirety.

[0092] Pharmaceutical Composition The compound of general formula I of the present invention can be used to prepare a pharmaceutical composition for preventing and / or treating renal damage, which comprises (i) an effective amount of the compound of general formula I or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable salt or excipient.

[0093] A "pharmaceutical composition" refers to a mixture of a compound described herein with an "excipient," such as a carrier, stabilizer, diluent, dispersant, suspending agent, and / or thickener. The pharmaceutical composition facilitates administration of the compound to an organism. Various techniques exist in the art for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0094] "Subject" refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., with reference to a mammalian subject (e.g., a human).

[0095] In some embodiments, the effective amount refers to a therapeutically effective amount.

[0096] An "effective amount" or "therapeutically effective amount" refers to the amount of a chemical entity (e.g., compound I-1, or a pharmaceutically acceptable salt and / or hydrate, and / or cocrystal thereof) sufficient, when administered, to relieve to some extent one or more of the symptoms of the disease or condition being treated. Results include reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration in a biological system. An appropriate "effective" amount in any individual's situation is determined using appropriate techniques, such as a dose escalation study.

[0097] In some embodiments, the present invention provides a composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the amount of the compound of general formula I in the pharmaceutical composition is 0.005 to 5 grams.

[0098] In some embodiments, the present invention provides a composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the amount of the compound of general formula I in the pharmaceutical composition is 0.005 to 3 grams.

[0099] In some embodiments, the present invention provides a composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the amount of the compound of general formula I in the pharmaceutical composition is 0.005 to 2 grams.

[0100] In some embodiments, the present invention provides a composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the amount of the compound of general formula I in the pharmaceutical composition is 0.005 to 1 gram.

[0101] In some embodiments, the present invention provides a composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the amount of the compound of general formula I in the pharmaceutical composition is 0.005 to 0.5 grams.

[0102] In some embodiments, the present invention provides a composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the amount of the compound of general formula I in the pharmaceutical composition is 0.005 to 0.2 grams.

[0103] In some embodiments, the present invention provides a composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the amount of the compound of general formula I in the pharmaceutical composition is 0.005 to 0.15 grams.

[0104] In some embodiments, when an effective amount of the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof is administered to a subject, the effective amount is 0.001 to 500 nmol / L, preferably 0.01 to 200 nmol / L.

[0105] The compound of general formula I of the present invention has excellent effects in treating diseases associated with renal impairment, and therefore, the pharmaceutical composition containing the compound of general formula I as the main active ingredient can be used to treat diseases associated with renal impairment.

[0106] The pharmaceutical composition of the present invention contains a safe and effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve symptoms without causing serious side effects. Typically, the pharmaceutical composition contains 0.05 to 2 g of the compound of formula I of the present invention per dose, and more preferably 5 to 200 mg of the compound of formula I of the present invention per dose.

[0107] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable addition salt prepared from a pharmaceutically acceptable non-toxic acid (including inorganic and organic acids). In some cases, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid. The term "pharmaceutically acceptable salt" may also refer to a pharmaceutically acceptable addition salt prepared by reacting a compound having an acidic group with a base to form a salt, or by other methods previously specified. Pharmacologically acceptable salts are not particularly limited as long as they can be used in pharmaceuticals. Examples of salts of the compounds described herein with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; or salts formed by reaction with dicyclohexylamine, N-methyl-D-glucosamine, or tris(hydroxymethyl)methylamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, specific examples of which include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and addition salts with acidic amino acids such as aspartic acid and glutamic acid.

[0108] "Excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, suitable for contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit-risk ratio.

[0109] Unless otherwise specified, the pharmaceutical compositions according to the present invention are prepared by methods known per se, for example, by conventional mixing, granulating, coating, dissolving or lyophilizing processes. When preparing compositions for oral dosage forms, commonly used pharmaceutical vehicles such as water, glycols, oils, ethanol, etc.; carriers such as starch, sugar or microcrystalline cellulose; diluents; granulating agents; lubricants; binders; disintegrants, etc. are used. Tablets and capsules are the most advantageous oral dosage unit forms due to their ease of administration, and it is obvious that solid pharmaceutical carriers are used.

[0110] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the composition is a tablet or a capsule.

[0111] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the composition is a tablet.

[0112] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of general formula I and at least one pharmaceutically acceptable carrier, wherein the composition is a capsule.

[0113] The terms "treat," "treating," and "treatment" in the context of treating a disease or disorder are intended to include alleviating or eliminating the disorder, disease, or condition; or slowing the progression, spread, or worsening of the disorder or condition or one or more symptoms thereof, where the term "disorder" as used herein shall always be understood to mean "disorder, disease, or condition," or one or more symptoms associated with the disorder.

[0114] Cosmetic or medical device compositions In the present invention, the compound of general formula I (preferably compound TJ01-013) or pharmaceutical composition may also be combined with cosmetically acceptable adjuvants to form a cosmetic composition.

[0115] In the present invention, the term "cosmetic composition" refers to industrial chemical products or fine chemical products that are applied by rubbing, spraying, or other similar methods to any part of the human body surface, such as the skin, hair, nails, lips, and teeth, for the purpose of cleaning, maintaining, beautifying, modifying and changing the appearance, correcting body odor, and maintaining good condition. The above-mentioned cosmetic categories include toners, lotions, creams, essences, facial masks, gels, sprays, soaps, face washes, shower gels, shampoos, conditioners, foundations, powder creams, body lotions, and massage creams.

[0116] For purposes of the present invention, the term medical device may be a Class III, Class II, or Class I device, an instrument, equipment, instrument, in vitro diagnostic reagent and calibrator, material, and other similar or related item for direct or indirect use on the human body, including, but not limited to, facial masks, coatings, etc.

[0117] The term "cosmetically or medically acceptable adjuvant" is selected from solvents, solubilizers, preservatives, antioxidants, pH adjusters, penetration enhancers, liposomes, humectants, thickeners, chelating agents, skin feel conditioners, surfactants, emulsifiers, propellants / propellants, fragrances, pigments, and other functional additives.

[0118] Indications and uses In the present invention, a compound of general formula I (preferably compound TJ01-013) or a pharmaceutical composition can be used for (i) preparing a medicament for treating inflammatory bowel disease, or (ii) preventing and / or treating inflammatory bowel disease. The term "inflammatory bowel disease (IBD)" refers to an idiopathic intestinal inflammatory disease involving the ileum, rectum, and colon. Typical symptoms include diarrhea, weight loss, and abdominal pain. Preferably, inflammatory bowel disease can include Crohn's disease (CD) and ulcerative colitis (UC). In the present invention, it has been discovered that inflammatory bowel disease is associated with mitochondrial dysfunction, and that compound TJ01-013, a therapeutic agent for mitochondrial dysfunction, contributes to improving the symptoms of inflammatory bowel disease. In some embodiments, administering compound TJ01-013 to a subject can reduce the expression level of inflammatory factors in diseased tissue, including at least one of Cxcl1, G-CSF, IL6, IL-1β, S100A8, and TNF-α. In some embodiments, administering compound TJ01-013 to a subject can reduce the accumulation of inflammatory cells (e.g., neutrophils, lymphocytes, monocytes, eosinophils, etc.) at sites of inflammation in diseased tissue. In some embodiments, administering compound TJ01-013 to a subject prevents or slows weight loss in the subject.

[0119] In the present invention, a compound of general formula I (preferably compound TJ01-013) or a pharmaceutical composition can be used for (i) preparing a medicament for treating lung injury, or (ii) preventing and / or treating lung injury. The term "lung injury" refers to the destruction of lung parenchymal structure caused by various factors inside and outside the lung. Preferably, the lung injury herein is acute lung injury (ALI), which is an acute hypoxic respiratory disorder caused by damage to alveolar epithelial cells and capillary endothelial cells caused by direct and indirect damaging factors, resulting in diffuse interstitial edema and alveolar edema, characterized by transepithelial neutrophil migration, uncontrolled inflammatory responses, damage to lung epithelial cells and endothelial cells, and the resulting destruction of cell barriers. Preferably, the lung injury is a chronic lung injury, such as chronic obstructive pulmonary disease (COPD), which is a chronic bronchitis and / or emphysema characterized by airflow obstruction and may further develop into cardiopulmonary and respiratory disorders. The present invention has demonstrated that mitochondrial dysfunction is associated with the progression of lung injury, and that mitochondrial dysfunction can lead to lung cell death and even lung tissue damage. Compound TJ01-013, a therapeutic agent for mitochondrial dysfunction, has significant effects on improving symptoms associated with lung injury. In some embodiments, administration of compound TJ01-013 to a subject can reduce inflammatory factor levels (including IL-6, CXCL1, and CXCL2) and inflammatory factor transcription levels in diseased tissue (bronchoalveolar tissue). In some embodiments, administration of compound TJ01-013 to a subject can reduce the number of neutrophils in affected tissue. In some embodiments, administration of compound TJ01-013 to a subject can slow the increase in inflammatory factor levels (including IL-6, CXCL1, and CXCL2) and inflammatory factor transcription levels in diseased tissue (bronchoalveolar tissue). In some embodiments, administration of compound TJ01-013 to a subject can slow the increase in inflammatory factor levels (including IL-6, CXCL1, and CXCL2) and inflammatory factor transcription levels in diseased tissue (bronchoalveolar tissue). In some embodiments, administration of compound TJ01-013 to a patient with acute or chronic lung injury improves their survival rate.

[0120] In the present invention, a compound of general formula I (preferably compound TJ01-013) or a pharmaceutical composition can be used for (i) preparing a medicament for treating fibrotic diseases or (ii) preventing and / or treating fibrotic diseases. The term "fibrotic disease" refers to an increase in fibrous connective tissue and a decrease in parenchymal cells in organ tissues such as the heart, liver, kidneys, and lungs. Continued progression can lead to structural damage, functional decline, and even organ failure. The process of fibrosis in damaged tissues is characterized by oxidative stress, hypoxia, and inflammation. Fibrotic diseases include tubulointerstitial fibrosis, interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary fibrosis, tissue fibrosis, arthrofibrosis, liver fibrosis, skin fibrosis, fibromatosis, myelofibrosis, cardiac fibrosis, and cystic fibrosis. The present invention has found that mitochondrial dysfunction contributes to the development of fibrosis in diseased tissues, and that compound TJ01-013 can significantly alleviate the symptoms of fibrosis. In some embodiments, administration of compound TJ01-013 to a subject can reduce the expression levels of fibrosis-associated genes and / or proteins or slow the progression of the expression levels of fibrosis-associated genes and / or proteins in diseased tissues. Preferably, the fibrosis-associated genes include at least one of Acta2, Fn1, and Col1a1, and the fibrosis-associated proteins include at least one of FN, collagen I, and α-SMA.

[0121] In the present invention, a compound of general formula I (preferably compound TJ01-013) or a pharmaceutical composition can be used for (i) preparing a medicament for treating sepsis or (ii) preventing and / or treating sepsis. The term "sepsis" refers to a systemic inflammatory response syndrome caused by the invasion of pathogenic microorganisms such as bacteria into the body. It is characterized by increased inflammation and immunosuppression, an inappropriate response to infection, leading to cellular dysfunction and ultimately to organ damage. In the present invention, mitochondrial dysfunction has been found to have a significant impact on the pathogenesis of sepsis-induced organ damage. During sepsis, various mitochondrial functions are altered, including decreased oxidative phosphorylation, resulting in ATP production, increased ROS production, increased cell apoptosis, and altered mitochondrial biogenesis. Mitochondrial damage further enhances the immune response, resulting in decreased ATP content, baseline oxygen consumption rate, proton leak oxygen consumption rate, maximal respiratory capacity oxygen consumption rate, and ATP turnover oxygen consumption rate. Administration of compound TJ01-013 significantly alleviates these adverse effects. In some embodiments, administering the compound TJ01-013 to a patient with sepsis increases their survival rate. In some embodiments, administering the compound TJ01-013 to a patient with sepsis prevents or slows the rate of weight loss.

[0122] In the present invention, a compound of general formula I (preferably compound TJ01-013) or a pharmaceutical composition can be used for (i) preparing a medicament for treating prostate diseases, or (ii) preventing and / or treating prostate diseases. Prostate diseases in the present invention include prostatitis, prostate cancer, benign prostatic hyperplasia (BPH), etc. In a preferred embodiment of the present invention, compound TJ01-013 can be used for (i) preparing a medicament for treating benign prostatic hyperplasia (BPH), or (ii) preventing and / or treating benign prostatic hyperplasia (BPH). Benign prostatic hyperplasia (BPH) is a common benign disease manifested as cell proliferation and causing urological disorders in elderly men. In the present invention, it has been found that mitochondrial dysfunction may be one of the factors causing benign prostatic hyperplasia, and compound TJ01-013 can reduce the level of benign prostatic hyperplasia. In some embodiments, administration of compound TJ01-013 to a subject prevents growth in prostate weight and / or volume or slows the rate of growth in prostate weight and / or volume.

[0123] In the present invention, a compound of general formula I (preferably compound TJ01-013) or a pharmaceutical composition can be used for (i) preparing a medicament for treating cardiovascular disease, or (ii) preventing and / or treating cardiovascular disease. The term "cardiovascular disease" refers to various cardiovascular diseases involving mitophagy, including atherosclerosis, heart failure, myocardial ischemia / reperfusion injury, hypertension, myocarditis, and cardiovascular complications of diabetes. In the present invention, it has been found that compound TJ01-013 can selectively remove dysfunctional mitochondria, maintain the balance of mitochondrial numbers in cells, ensure the integrity of mitochondrial structure and function, maintain balance in the body, and promote the survival of cells, including cells of cardiovascular origin (e.g., cardiomyocytes, endothelial cells, vascular smooth muscle cells). In some embodiments, administration of compound TJ01-013 to a subject can reduce myocardial infarction size or prevent an increase in myocardial infarction size. In some embodiments, administration of compound TJ01-013 to a subject can reduce left ventricular end-diastolic diameter. In some embodiments, administering the compound TJ01-013 to a subject decreases the left ventricular end-systolic diameter. In some embodiments, administering the compound TJ01-013 to a subject increases the left ventricular ejection fraction. In some embodiments, administering the compound TJ01-013 to a subject increases the left ventricular fractional short-axis shortening.

[0124] In the present invention, the compound of general formula I (preferably compound TJ01-013) or pharmaceutical composition can be used for (i) preparing a medicament for treating a neurological disease, (ii) preventing and / or treating a neurological disease. "Neuropsychiatric disorders" include neurodevelopmental disorders such as autism, sensorineural hearing loss, brain developmental abnormalities, congenital hydrocephalus, congenital cranial nerve diseases, congenital perforating artery malformations, metabolic dysfunction, congenital auditory aphasia, congenital visual aphasia, and cerebral palsy; psychiatric disorders such as depression, schizophrenia, bipolar disorder, delusional disorder, mania, and obsessive-compulsive disorder; and neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), brain injury (BI), amyotrophic lateral sclerosis (ALS), epilepsy, Huntington's disease, spinocerebellar ataxia (SCA), cerebral ischemia (CI), stroke (preferably ischemic stroke), multiple sclerosis, and tinnitus. The present invention has discovered that mitochondrial dysfunction is an established marker of neurodegeneration, and that compound TJ01-013 has therapeutic potential for neurological disorders. In some embodiments, administering compound TJ01-013 to a subject significantly improves cognitive impairment in the subject. In some embodiments, administering compound TJ01-013 to a subject improves cisplatin-induced hearing loss. In some embodiments, administering compound TJ01-013 to a subject reduces cochlear basilar membrane cell loss in the patient.

[0125] In the present invention, a compound of general formula I (preferably compound TJ01-013) or a pharmaceutical composition can be used for (i) preparing a medicament for treating progeria, (ii) preventing and / or treating progeria, (iii) preventing and treating skin aging or damage, and (iv) preparing a medicament for treating skin aging or damage. The term "progeria" stands for Hutchinson-Gilford Progeria syndrome, also known as childhood progeria, which is characterized by a child's physical aging 5 to 10 times faster than normal, resulting in an elderly appearance, rapid organ deterioration, and a decline in physiological function. Symptoms include short stature, hair loss, and delayed tooth eruption. In the present invention, compound TJ01-013 has been found to have a certain effect in delaying both natural physiological aging and pathological aging. In some embodiments, administering the compound TJ01-013 to a subject increases the expression level of the heterochromatin modification H3K9me3 in Con-O cells. In some embodiments, administering the compound TJ01-013 to a subject can prevent or slow the decrease in the expression level of the heterochromatin modification H3K9me3 in Con-O cells. In some embodiments, the compound TJ01-013 non-therapeutically reduces the proportion of SA-β-gal positive cells in a mesenchymal stem cell population in vitro.

[0126] In the present invention, the compound of general formula I (preferably compound TJ01-013) or pharmaceutical composition can be used for (i) preparing a medicament for treating premature ovarian dysfunction, (ii) preventing and / or treating premature ovarian dysfunction, (iii) preventing and treating natural ovarian dysfunction; (iv) preparing a medicament for treating natural ovarian dysfunction. In some embodiments, administering compound TJ01-013 to a subject can improve the decline in ovarian function caused by chemotherapy or aging.

[0127] In the present invention, the compound of general formula I or pharmaceutical composition is used for the prevention and / or treatment of diseases associated with renal impairment, and for the preparation of a medicament for the prevention and / or treatment of diseases associated with renal impairment. Preferably, the diseases associated with renal impairment are chronic kidney disease or acute kidney injury, more preferably chronic kidney disease. Preferably, the diseases associated with renal impairment include acute kidney injury and chronic kidney disease, preferably chronic kidney injury. Preferably, the diseases associated with renal impairment are selected from the group consisting of acute renal ischemia-reperfusion injury, septic nephropathy, nephrotoxic injury, primary glomerulonephritis, hypertensive renal arteriosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial lesions, ischemic nephropathy, lupus nephritis, and hereditary nephropathy. Preferably, the tubulointerstitial lesions are selected from the group consisting of chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, and drug-induced nephropathy. Preferably, the hereditary nephropathy is selected from the group consisting of polycystic kidney disease and hereditary nephritis.

[0128] In the present invention, the compounds of general formula I can also be added to cosmetics or medical devices for preventing skin aging and / or reducing hair loss.

[0129] Treatment method Some embodiments of the present invention also provide a method for treating a disease associated with renal impairment, comprising administering to a subject a compound of general formula I or a pharmaceutical composition comprising the same.

[0130] In the present invention, the term "administration" refers to the physical introduction of each active ingredient of the medicament of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration of each active ingredient in the medicament of the present invention include oral, intravenous (e.g., infusion (also called drip infusion) or injection), airway, intramuscular, subcutaneous, intraperitoneal, spinal, topical, or other parenteral administration routes. Accordingly, each active ingredient in the medicament of the present invention can be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes, suppositories, or the like.

[0131] The administration route of the compound of general formula I or pharmaceutical composition of the present invention is not particularly limited, and is preferably suitable for enteral administration such as oral or rectal administration, or parenteral administration such as intramuscular, intravenous, nasal or transdermal administration, and for warm-blooded animals (humans and animals), the typical administration route is enteral administration.

[0132] In some embodiments, the disease associated with mitochondrial dysfunction is inflammatory bowel disease and the mode of administration is intraperitoneal injection. In some embodiments, the disease associated with mitochondrial dysfunction is lung injury and the mode of administration is by instillation into the airways. In some embodiments, the disease associated with mitochondrial dysfunction is a fibrotic disease and the mode of administration is oral gavage. In some embodiments, the disease associated with mitochondrial dysfunction is sepsis and the mode of administration is intraperitoneal injection. In some embodiments, the disease associated with mitochondrial dysfunction is prostate disease and the mode of administration is oral gavage. In some embodiments, the disease associated with mitochondrial dysfunction is cardiovascular disease and the mode of administration is oral gavage. In some embodiments, the disease associated with mitochondrial dysfunction is a neurological disease and the mode of administration is oral gavage.

[0133] The compounds of general formula I of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0134] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) in need of treatment at a pharmaceutically effective dose, and the daily dose for a person weighing 60 mg is typically 1 to 2,000 mg, or 5 to 1,000 mg, or 10 to 500 mg, preferably 20 to 500 mg, and more preferably 30 to 300 mg. Of course, the specific dose should take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0135] Compositions for enteral or parenteral administration are, for example, in unit dosage form, such as tablets, capsules, suppositories or ampoules.

[0136] The unit content of the active ingredient in a single dose does not necessarily have to be a therapeutically effective amount per se, and such an amount can be achieved by administering multiple dose units. The composition according to the present invention can contain, for example, about 10 to 100% of the therapeutically effective amount of the active ingredient.

[0137] In the present invention, the compound of general formula I of the present invention or the pharmaceutical composition of the present invention may be administered to a subject once a day, twice a day, three times a day, once every two days, once every three days, or once a week. The period during which the compound TJ01-013 of the present invention or the pharmaceutical composition of the present invention is administered to a subject is 1 to 90 days, for example, 90 days, 30 days, 28 days, 7 days, 8 days, or 9 days.

[0138] In some preferred embodiments, the compound TJ01-013 of the present invention or the pharmaceutical composition of the present invention can be administered in combination with other drugs. For example, in some embodiments, the present invention provides a method for treating cardiovascular disease, comprising co-administering therapeutically effective amounts of the compound TJ01-013 and Entresto to a subject. The compounds TJ01-013 and Entresto can be administered simultaneously, or one can be administered first and then the other. The combination of the compound TJ01-013 and Entresto can improve the therapeutic effect of cardiovascular disease. In other embodiments, the present invention provides a method for treating benign prostatic hyperplasia, comprising co-administering therapeutically effective amounts of the compound TJ01-013 and finasteride to a subject. The combination of the compound TJ01-013 and finasteride can further reduce the weight and volume of the prostate and improve prostatic hyperplasia.

[0139] term The term "diseases associated with kidney damage" as used herein refers to acute kidney injury and chronic kidney disease. Acute kidney injury and chronic kidney disease mainly include acute renal ischemia-reperfusion injury, septic nephropathy, nephrotoxic injury, primary glomerulonephritis, hypertensive renal arteriosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial lesions (such as chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, and drug-induced nephropathy), ischemic nephropathy, and hereditary nephropathy (polycystic kidney disease, hereditary nephritis). The term "acute kidney injury" as used herein refers to abnormalities in kidney structure or function that occur within 48 hours and do not persist for more than 3 months, including abnormalities in markers of kidney damage in blood, urine, histology, or imaging. Acute kidney injury has various causes and can be broadly divided into three categories: prerenal, renal, and postrenal. The diagnostic criteria for acute kidney injury are a sudden decline in renal function within 48 hours and an absolute increase in serum creatinine of more than 26.4 μmol / L (0.3 mg / dL); or an increase in serum creatinine of more than 50% compared to previous levels; or a decrease in urine output of less than 0.5 ml / kg / h for more than 6 hours (urinary tract obstruction or other factors that may lead to a decrease in urine output must be excluded). In an embodiment of the present invention, acute kidney injury includes kidney injury induced by diabetic nephropathy and acute kidney injury caused by renal ischemia-reperfusion.

[0140] As used herein, the term "chronic kidney disease (CKD)" refers to: 1) renal damage (structural or functional abnormalities) of any cause that has persisted for 3 months or more, with or without a reduction in glomerular filtration rate (GFR); 2) a GFR < 60 ml / (min·1.73 m), with or without evidence of renal damage. 2) for more than three months. Chronic kidney injury refers to a syndrome caused by a decrease in glomerular filtration rate (GFR) due to chronic kidney disease and the associated metabolic disorders and clinical symptoms. During the compensated and early decompensated stages of chronic kidney injury, patients may experience no symptoms or only mild discomfort such as fatigue, lower back pain, and nocturia. Some patients may also experience loss of appetite, metabolic acidosis, and mild anemia. After the renal injury stage, the above symptoms become more pronounced. During the uremia stage, serious complications such as acute cardiac injury, severe hyperkalemia, gastrointestinal bleeding, and central nervous system disorders may occur, which may be life-threatening. In an embodiment of the present invention, chronic kidney injury includes adenine-induced nephropathy and nephrectomy-induced nephropathy.

[0141] As used herein, the terms "inflammatory bowel disease (IBD)" and "inflammatory bowel disease" are used interchangeably and refer to a group of chronic, recurrent, non-specific inflammatory diseases of the intestine of unknown cause. Examples of inflammatory bowel diseases include ulcerative colitis and Crohn's disease.

[0142] As used herein, the terms "pyemia" and "sepsis" are used interchangeably and refer to a systemic inflammatory response syndrome caused by a variety of infectious agents (bacteria, fungi, viruses, parasites, etc.).

[0143] As used herein, "lung injury" refers to the destruction of the lung parenchyma structure caused by various factors inside and outside the lung in a living body. The meaning of lung injury in this invention includes acute and chronic lung injury. The term "acute lung injury (ALI)" refers to damage to the alveolar-capillary membrane that occurs after a shock, such as severe infection, trauma, or shock, resulting in pathological changes such as pulmonary edema and atelectasis. The term "chronic lung injury" refers to long-term lung diseases characterized by fibrosis, including diffuse lung injury and chronic obstructive pulmonary disease (COPD). The term "chronic obstructive pulmonary disease" refers to chronic bronchitis and / or emphysema characterized by airflow obstruction, a common chronic disease that can progress to pulmonary heart disease and respiratory disorders.

[0144] The term "cerebral ischemia (CI)" as used herein refers to a condition caused by a transient lack of blood supply to the brain, also known as a transient ischemic attack. Cerebral ischemia is a type of cerebrovascular disease. Severe cerebral ischemia often causes ischemic necrosis or softening of localized brain tissue, resulting in ischemic stroke.

[0145] The term "stroke" as used herein refers to a disease in which cerebral blood circulation is impaired and the function or structure of brain tissue is damaged due to the blockage or rupture of cerebral blood vessels. The term "ischemic stroke" is a general term for necrosis of brain tissue caused by insufficient blood supply to the brain due to stenosis or blockage of arteries that supply blood to the brain (carotid arteries and vertebral arteries).

[0146] The term "cardiomyopathies" as used herein refers to cardiomyopathy in a broad sense, including diseases caused by myocardial lesions, such as diseases caused by myocardial inflammation (e.g., myocarditis); diseases caused by myocardial ischemia or myocardial necrosis (e.g., myocardial infarction); and diseases characterized by abnormalities in myocardial morphology, structure, and function (e.g., primary cardiomyopathies and secondary cardiomyopathies). Examples of primary cardiomyopathies include dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and atypical cardiomyopathy. Examples of secondary cardiomyopathies include ischemic cardiomyopathy, alcoholic cardiomyopathy, peripartum cardiomyopathy, Keshan disease, and neuromuscular cardiomyopathy.

[0147] The term "myocardial infarction (MI)" used herein refers to myocardial ischemic necrosis caused by a sudden reduction or interruption of coronary artery blood supply, resulting in severe and persistent ischemia of the corresponding myocardium. The term "myocarditis" used herein refers to focal or diffuse acute, subacute, or chronic inflammatory lesions in the myocardium, primarily affecting children and young adults. Prolonged and unhealed myocarditis may lead to dilated cardiomyopathy and chronic heart damage. Myocarditis can generally be classified into three categories: idiopathic myocarditis, autoimmune myocarditis, and infectious myocarditis. Clinical treatment for myocarditis mainly involves intervention in the early stages of acute inflammation. Once myocarditis progresses to the chronic phase, no specific treatment is available, and conservative treatment and reduction of cardiac load are the main treatments.

[0148] The term "aging-related disease" as used in the present invention includes all diseases caused by changes in physiological functions, organs, etc., which are caused by various physiological and pathological factors. In an embodiment of the present invention, aging-related diseases include skin aging, progeria, ovarian dysfunction (preferably premature ovarian dysfunction, natural aging ovarian dysfunction), etc.

[0149] The term "senilism" as used herein refers to a phenomenon in which an individual's number of cell division generations decreases, the rate of aging of certain organs and tissues doubles, and disease and death progress rapidly. Minors develop characteristics of the elderly, such as arteriosclerosis, wrinkled skin, gray hair, and aged appearance and behavior.

[0150] As used herein, the terms "premature ovarian insufficiency (POI)" and "premature ovarian disorder" are used interchangeably and refer to the development of ovarian dysfunction in women under the age of 40, characterized primarily by abnormal menstruation (amenorrhea, oligomenorrhea, or frequent menstruation), elevated gonadotropins (at least two serum basal follicle-stimulating hormone (FSH) >25 U / L), and fluctuatingly low estrogen levels.

[0151] The term "natural aging ovarian dysfunction" as used in the present invention refers to the decline in female ovarian function due to natural aging, which may lead to diseases such as endocrine disorders, premature ovarian failure, and infertility.

[0152] As used herein, the terms "lupus nephritis" and "lupus nephritis" are used interchangeably and refer to a type of immune complex nephritis caused by systemic lupus erythematosus, which affects the kidneys. In addition to the systemic symptoms of systemic lupus erythematosus, the main clinical symptoms include hematuria, proteinuria, and renal damage.

[0153] The term "multiple sclerosis (MS)" as used herein refers to an autoimmune demyelinating disease of the central nervous system with a complex etiology, which involves multiple lesions, a relapsing disease course, a high disability rate, and a severe impact on patients' normal lives. The etiology of this disease is still unknown and may be caused by multiple factors, including immune, environmental, and genetic factors.

[0154] The term "tinnitus" as used herein refers to a condition in which a subjective sound is heard continuously in the absence of external sound stimulation. This is caused by pathological stimulation of the auditory receptors and their conduction pathways or by a lesion in the auditory center. In some embodiments, the tinnitus is preferably neurogenic tinnitus, and examples of neurogenic tinnitus include sensorineural tinnitus (originating from the cochlea), peripheral tinnitus (originating from the auditory nerve), and central tinnitus.

[0155] As used herein, the terms "sensorineural hearing loss" and "sensorineural hearing impairment" are used interchangeably and refer to hearing impairment caused by disease of the inner ear, auditory nerve, and hearing pathways.

[0156] As used herein, the terms "brain developmental abnormality" and "brain malformation" are used interchangeably and refer to a condition characterized by mental retardation and impaired growth and development caused by a loss of brain tissue and developmental disorders or damage to brain nerve cells due to any cause.

[0157] As used herein, the term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. 1-6 "Alkyl" refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof. 1-4 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms, 1-4When the alkyl is at the end of the molecule, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; or when two parts of the molecule are connected via an alkyl, non-limiting examples include -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-; 1-4 Each hydrogen at an alkyl carbon may be optionally substituted with a substituent as further listed herein.

[0158] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen at an alkenyl carbon may be replaced with a substituent as further listed herein. 2~6 "Alkenyl" refers to a straight or branched hydrocarbon chain of 1 to 6 carbon atoms containing at least one carbon-carbon double bond. When it appears at the end of a molecule, non-limiting examples include -CH=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH=CH-CH=CH2, or when two parts of a molecule are connected through the alkenyl, non-limiting examples include -CH=CH-. 2~6 Each hydrogen at an alkenyl carbon may be optionally replaced with a substituent as further mentioned herein.

[0159] The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen at an alkynyl carbon may be replaced with a substituent as further listed herein. 2~6"Alkynyl" refers to a straight or branched hydrocarbon chain of 1 to 6 carbon atoms containing at least one carbon-carbon triple bond. When it appears at the end of a molecule, non-limiting examples include -C≡CH, -CH2-C≡CH, -CH2-CH2-C≡CH, -CH2-C≡C-CH3, or when two parts of a molecule are connected through the alkynyl, non-limiting examples include -C≡C-. 2~6 Each hydrogen at an alkynyl carbon may be optionally replaced with a substituent as further mentioned herein.

[0160] The term "alkoxy" as used herein refers to a group having the structure "-O-alkyl," where alkyl is as defined above. The term "C alkoxy" refers to an alkoxy having from 1 to 6 carbon atoms, non-limiting examples of which include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentyloxy, and the like.

[0161] As used herein, the term "amine group" refers to a group formed by replacing at least one hydrogen atom of an amino group with alkyl, e.g., TIFF2025528014000085.tif15170R 3-11 and R 3-12 is alkyl and the other is hydrogen; or 3-11 and R 3-12 are all alkyl groups; 3-11 and R 3-12 If all of R 3-11 and R 3-12 may be bonded to form a ring.

[0162] As used herein, the term "haloalkyl" refers to an alkyl in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced with halogen, where alkyl is defined above.

[0163] As used herein, "(O)" means TIFF2025528014000086.tif12170. In one embodiment, -CHC(O)R 3-2 teeth, Points to TIFF2025528014000087.tif13170.

[0164] The term "haloalkoxy," as used herein, refers to an alkoxy in which one or more hydrogen atoms have been replaced with a halogen, where alkoxy is defined above.

[0165] As used herein, the terms "aryl," "aryl ring," and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic ring, an all-carbon non-fused polycyclic ring (the rings are connected by covalent bonds and are not fused), or an all-carbon fused polycyclic ring (i.e., rings that share adjacent pairs of carbon atoms) group in which at least one ring is aromatic, i.e., has a ring-forming conjugated π-electron system.

[0166] The term "heteroaryl," as used herein, refers to an aryl in which at least one of the ring carbon atoms that make up the aryl is replaced by a non-carbon heteroatom such as S, N, or O.

[0167] The term "monocyclic heteroaryl" as used herein refers to a heteroaryl having only one aromatic ring, where heteroaryl is defined above. The term "5- or 6-membered monocyclic heteroaryl" refers to a monocyclic heteroaryl having 5 or 6 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms selected from nitrogen, oxygen, or S(=O)m', where m' is an integer from 0 to 2, non-limiting examples of which include thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, 20-triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

[0168] As used herein, the term "fused-ring heteroaryl" refers to at least two aromatic rings in which two ring atoms are adjacent to one another, where heteroaryl is as defined above. The term "fused bicyclic heteroaryl" refers to a fused-ring heteroaryl having two aromatic rings, where fused-ring heteroaryl is as defined above. The term "8-10-membered fused bicyclic heteroaryl" refers to a fused bicyclic heteroaryl having 8 to 10 ring atoms, of which 1, 2, 3, 4, or 5 ring atoms are heteroatoms selected from nitrogen, oxygen, or S(=O)m', where m' is an integer from 0 to 2, including, but not limited to, benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]ox ... These include benzo[d]thiazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, and imidazo[1,2-b]pyridazine.

[0169] In order to clarify the objectives, technical solutions, and advantages of the embodiments of the present invention, the present invention will be further described below based on specific examples. It should be understood that these examples are used only to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods that do not specify specific experimental conditions generally follow conventional conditions or conditions recommended by manufacturers. Unless otherwise specified, percentages and parts are percentages and parts by weight. Experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

[0170] Unless otherwise specified, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It should be noted that the terminology used herein is intended to describe specific embodiments only and is not intended to limit the exemplary embodiments of the present application.

[0171] Experimental Example 1: Reduction of acute kidney injury caused by renal ischemia-reperfusion, suppression of apoptosis of renal tissue cells caused by renal ischemia-reperfusion 1) Unilateral renal ischemia-reperfusion Eight-week-old C57BL / 6 mice (approximately 20-25 g body weight) were anesthetized by intraperitoneal injection of 50 mg / kg pentobarbital sodium. After the mice were anesthetized, their skin was prepared and they were placed on a thermostatic stand. The skin and muscle on the right side were incised from the back to expose the right kidney. Tweezers were used to peel away the tissue around the renal pedicle, exposing the blood vessels and ureter. Sutures were used to ligate the arterial and venous blood vessels and ureter, respectively. After the kidney was removed, the muscles and skin were sutured and the mice were placed at 37°C for recovery. After recovery, I-1 was injected intraperitoneally. Mice were divided into three groups: a sham-operated group (the right kidney was exposed but not removed), a control group (vehicle-treated, administered by oral gavage), a 10 mg / kg group (administered by oral gavage of 10 mg / kg I-1), and a 30 mg / kg group (administered by oral gavage of 30 mg / kg I-1). They were administered once daily, and left renal ischemia-reperfusion was performed on day 6. The specific design was as follows: mice were anesthetized with an intraperitoneal injection of 50 mg / kg sodium pentobarbital, then the skin was prepared and placed on a thermostatic table. The left skin and muscle were incised from the back to expose the left kidney. The tissue around the renal pedicle was peeled off using tweezers to expose the blood vessels, which were then clamped with an arterial clamp. After 45 minutes of ischemia, the arterial clamp was released, and the kidney tissue was returned to its original position using a cotton swab. Finally, the muscle and skin were sutured and placed at 37°C for recovery, after which another drug administration was performed. After 24 hours of reperfusion, blood was collected from the eyeballs and left at room temperature for 45 minutes, then centrifuged at 12,000 g and 4°C for 10 minutes. The supernatant (serum) was collected, and the serum creatinine and urea nitrogen levels were measured using a biochemical analyzer.

[0172] As shown in Figure 1, after oral gavage of 10 mg / kg and 30 mg / kg of I-1, the serum creatinine and serum urea nitrogen levels in mice after 24 hours of renal ischemia-reperfusion were significantly reduced, indicating that I-1 can significantly reduce serum creatinine levels after renal ischemia-reperfusion and has a certain protective effect against acute kidney injury.

[0173] 2) HE staining analysis of kidney tissue After collecting blood from the mouse's eyeball, cardiac perfusion was performed using PBS. After anesthetizing the mouse, it was secured to a foam board with a needle. The skin and ribs of the chest and abdomen were cut to expose the heart. A syringe needle was inserted into the mouse's left ventricle, and the pericardium was simultaneously cut. PBS was perfused at a perfusion rate of 7 rpm until the liver turned white. After stopping the perfusion, the kidney was removed, the kidney capsule was peeled off, and the kidney was fixed in 4% paraformaldehyde for 72 hours. The tissue was then embedded, sectioned, and stained with HE. The specific procedures were as follows: tissue embedding The tissue embedding steps were as follows: Ethanol dehydration: The tissue was dehydrated in a series of ethanol solutions with varying concentrations (75%, 85%, 95%, 100%, and 100%) for 40 minutes each time. Clearance: The tissue was immersed in three xylene baths in sequence, for 30 minutes in each bath. Paraffin immersion: The tissue was immersed in three paraffin baths in sequence, for 1 hour in the first bath, 1.5 hours in the second bath, and 2 hours in the third bath. Embedding: Liquid paraffin was poured into a mold box, and the paraffin-soaked tissue block was placed flat on the bottom with the cut surface facing down. After the paraffin solidified, the embedding frame was removed. After complete cooling and hardening, the paraffin block was trimmed, and the paraffin surrounding the tissue was properly preserved for sectioning.

[0174] Section preparation The pre-cooled paraffin block was fixed in the paraffin microtome so that the cut surface of the paraffin block was parallel to the knife blade. The knife was typically tilted at 15°, and the rotary pusher was rotated to adjust the section thickness to 3 μm, resulting in uniformly thick sections. Holding a brush in the left hand, the microtome handle was rotated with the right hand. As the section emerged, it was gently lifted with the brush and gently tweezed with tweezers. The paraffin section was then placed in a section extension box with the front facing forward, in a water bath at approximately 40°C. After flattening, the section was removed. The section was then mounted by holding one edge of the slide with the left hand, vertically filling it with water, and pressing it with tweezers with the right hand until it was two-thirds of the way up the slide. After mounting, the section was left to dry slightly in the air, then baked in a baking machine at 60°C for 1 hour, and then baked in an oven for 2 hours.

[0175] Deparaffinization and rehydration of paraffin sections Paraffin sections were deparaffinized in the following gradient: xylene I for 15 minutes, xylene II for 15 minutes, absolute ethanol I for 10 minutes, absolute ethanol II for 10 minutes, 95% alcohol for 10 minutes, and 85% alcohol for 10 minutes.

[0176] HE staining Paraffin sections were stained with hematoxylin for 5–10 min, rinsed with tap water, fractionated in 1% hydrochloric acid alcohol for a few seconds, rinsed with tap water, then reverted to blue with saturated lithium carbonate solution for 1 min, rinsed with running water for a few seconds, immersed in eosin staining solution for a few seconds, and rinsed with running water.

[0177] Dehydration, mounting and image acquisition Paraffin sections were cleared by sequentially immersing them in 75% ethanol for 2 minutes, 85% ethanol for 2 minutes, absolute ethanol for 2 minutes, and xylene for 2 minutes. The sections were then removed from the xylene and mounted in neutral gum. Microscopic examination was performed, and images were collected and analyzed.

[0178] As shown in Figure 2, renal ischemia-reperfusion damages normal renal tissue, but I-1 treatment reduced renal tissue damage caused by renal ischemia-reperfusion.

[0179] 3) Immunostaining of kidney tissue After tissue embedding and sectioning, the sections were deparaffinized and antigen retrieval was performed. A 5% goat serum blocking solution was applied for 40 minutes at 37°C. 50 μL of KIM-1 and caspase 3 primary antibodies (1:500) were applied and incubated overnight at 4°C. After 30 minutes of rewarming at 37°C, the sections were washed four times with PBS for 5 minutes each. Fluorescent secondary antibodies were then applied for 1 hour, followed by four 5-minute washes with PBS. Finally, DAPI was added for 10 minutes. The sections were mounted with nail polish and images were acquired using Cytation 3. As shown in Figure 3, both KIM-1 and cleaved-caspase 3 were significantly expressed after renal ischemia-reperfusion. I-1 treatment suppressed the levels of KIM-1 and cleaved-caspase 3 after renal ischemia-reperfusion.

[0180] Furthermore, the results showed that the therapeutic effect of UMI-77 group on renal ischemia-reperfusion injury was not as good as the ameliorative effect of I-1 on renal ischemia-reperfusion injury.

[0181] Mice used in the experiment were purchased from GemPharmatech Co., Ltd.

[0182] Experimental Example 2 Treatment of 5 / 6 nephrectomy-induced kidney damage A 5 / 6 nephrectomy directly leads to a significant reduction in nephrons, a high burden on the remaining nephrons, and concomitant hypertension (or non-hypertension). These characteristics are similar to the clinical symptoms of patients with nephrectomy, CKD hypertension, and solitary kidney disease. Similarly, the pathological changes are primarily glomerular sclerosis and tubular fibrosis, making this a good model for studying CKD. The model was prepared as follows: Male SD rats weighing 230–250 g were anesthetized with isoflurane gas. A 3 cm incision was made 1 cm below the left costal angle to fully expose the left kidney. In the sham-operated group, the kidney was exposed, and the muscles and skin were sutured without ligation or resection. In the model group, approximately one-third of the upper and lower cortex of the left kidney was resected using ophthalmic surgical scissors. Hemostasis was achieved by compressing the bleeding area with absorbable gelatin sponge for 3 minutes, after which the hemostatic clamp was released and the remaining kidney was repositioned. The muscles and skin were sutured. One week later, a second surgery was performed to fully expose the right kidney. The renal pedicle and ureter were ligated and the right kidney was removed. Similarly, in the sham-operated group, the kidney was exposed and the muscles and skin were sutured without ligation or resection. Penicillin (80 kU / rat) was injected periodically for three days after surgery. One week after right nephrectomy, serum samples were collected weekly, and serum creatinine levels were measured in each model group. If serum creatinine levels were significantly higher than those in the sham-operated group, the modeling was considered successful. In the experiment, the serum creatinine levels of rats increased 10 days after right nephrectomy, and this was statistically significant compared to the sham-operated group, so intergroup administration of medication was initiated.

[0183] The rats were divided into three groups: a sham-operated group (bilateral kidneys exposed but not removed), a control group (model group, vehicle-treated and administered orally by gavage), and a 15 mg / kg I-1 group (administered orally by gavage at 15 mg / kg). They were administered once daily for a total of 27 days. On day 28, 24-hour urine samples were collected from each group in metabolic cages for urine volume, urinary creatinine, and urinary protein levels. Blood samples were collected from the heart and allowed to stand at room temperature for 45 minutes. Then, the blood was centrifuged at 12,000 g for 10 minutes at 4°C. The supernatant (serum) was analyzed for serum creatinine levels, and the creatinine clearance rate was calculated. At the end of the experiment, the rats were euthanized and dissected. Four kidneys were then extracted, fixed in 4% paraformaldehyde for 48 hours, embedded in paraffin, sectioned, and stained with HE. The specific procedures were as described above.

[0184] As shown in Figure 4, compared with the sham-operated group, the body weight of the rats in the model control group was significantly decreased (P<0.001), while the body weight of the model group administered 15 mg / kg of I-1 for 27 days was significantly increased (P<0.05), indicating that I-1 has a certain protective effect on weight recovery in rats.

[0185] As shown in Figure 5, compared with the sham-operated group, the blood creatinine levels of rats in the model control group were significantly elevated (P<0.001), and administration of I-1 could significantly reduce the blood creatinine levels of rats in the model group (P<0.001), indicating that I-1 has a certain ameliorative effect on the creatinine levels of 5 / 6 nephrectomy-induced renal injury.

[0186] After 27 days of oral gavage, 24-hour urine analysis results were collected. As shown in Figure 6, the 24-hour urinary protein content of rats in the model control group was significantly increased compared to the sham-operated group. After I-1 treatment, the urinary protein content of the model group was significantly reduced, indicating that I-1 has a certain protective effect against protein leakage due to chronic kidney injury. As shown in Figure 7, the creatinine clearance rate also showed a tendency to improve after 27 days of I-1 treatment compared to the model control group.

[0187] The results of HE staining are shown in Figure 8. Statistical analysis was performed on pathological sections of kidney tissue from four cases, and the results are shown in Table 1. Sham-operated group: Four kidneys had intact glomeruli and renal tubule structures, clear cell morphology, and no obvious abnormalities in the interstitium (4 / 4, no abnormalities). Model control group: Four kidneys showed significant thickening of the renal cortex under a low-magnification microscope, indicating compensatory hypertrophy. Under a high-magnification microscope, the cytoplasm of the renal tubules was loose and granular, with some vacuoles and a small amount of pink-stained material in the tubule lumen. Individual kidneys showed inflammatory cell infiltration and thickening of the renal capsule (3 / 4, mild; 1 / 4, moderate). Even in the treated groups, the renal cortex thickened significantly to varying degrees, indicating compensatory hypertrophy; under a high-magnification microscope, the cytoplasm of the renal tubules was loose and granular, with some vacuoles present, a small amount of pink-stained material in the tubule lumen, and inflammatory cell infiltration and thickening of the renal capsule were observed in the interstitium of individual kidneys (1 / 4, mild; 3 / 4, moderate). Compared with the sham-operated group, the renal tissue of the model control group rats was significantly damaged, and I-1 treatment improved the degree of renal tissue damage in the model group rats. Furthermore, the protective effect of UMI-77 against 5 / 6 nephrectomy-induced renal injury was inferior to that of the I-1 group, at least in the above indicators. Rats used in the experiment were purchased from SPF (Beijing) Biotechnology Co. Ltd.

[0188] TIFF2025528014000088.tif166170

[0189] Experimental Example 3 Treatment of adenine-induced nephropathy Adenine-induced nephropathy is an animal model of chronic kidney injury. The model was prepared as follows: 1500 mg / kg potassium oxalate and 50 mg / kg adenine were crushed and suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) solution and administered orally at a volume of 10 mL / kg once daily to 180-200 g male SD rats. A sham-operated group received an equivalent volume of 0.5% CMC-Na solution by oral gavage. After one week of modeling, serum creatinine (Cr) was measured weekly to determine whether the model was successful. In this experiment, the increase in serum creatinine on day 21 of modeling was statistically different from that in the sham-operated group. At this time, group administration was initiated, and the model was created by continuing daily administration of 1500 mg / kg potassium oxalate and 50 mg / kg adenine along with medication. The rats were divided into three groups according to their serum creatinine levels: a sham group (a sham-operated group, no adenine modeling, and administered vehicle by oral gavage), a control group (a model control group, administered vehicle by oral gavage), and a 15 mg / kg group (administered 15 mg / kg of compound I-1 by oral gavage). The animals were administered 10 ml / kg of compound I-1 once daily for 21 consecutive days. After administration, blood was collected from the heart and allowed to stand at room temperature for 45 minutes. The blood was then centrifuged at 12,000 g and 4°C for 10 minutes to collect the supernatant (serum). Serum creatinine and uric acid levels were then determined. At the end of the study, the rats were euthanized and the kidneys were dissected. Four rat kidneys were then removed, fixed in 4% paraformaldehyde for 48 hours, embedded in paraffin, sectioned, and stained with HE. The specific procedures were as described above. Left kidney tissue was collected and crushed, and the inflammatory factors IL-1β and TNFα were detected by ELISA.

[0190] As shown in FIG. 9, compared with the sham-operated group, the body weight of the rats in the model control group tended to decrease, and there was no significant change in body weight after treatment with compound I-1.

[0191] As shown in Figure 10, the serum creatinine levels of rats in the model control group were significantly increased compared with those in the sham-operated group (P<0.001). After 21 days of I-1 treatment, serum creatinine was reduced by 20.7% (P<0.05), indicating that I-1 can significantly alleviate the increase in creatinine levels caused by adenine-induced renal injury.

[0192] As shown in Figure 11 , compared with the sham-operated group, the serum urea nitrogen level of rats in the model control group was significantly increased 21 days after treatment ( P < 0.001), and the serum urea nitrogen level was significantly decreased 21 days after 15 mg / kg I-1 treatment ( P < 0.05).

[0193] As shown in Figure 12, compared with the sham-operated group, the levels of inflammatory factors TNF-α and IL-1β in the kidney tissue of rats in the model group were significantly increased (P<0.05~0.01). After 21 days of treatment with 15 mg / kg I-1, the levels of inflammatory factors TNF-α in the kidney tissue were significantly decreased (P<0.05~0.01), and the levels of IL-1β showed a tendency to decrease. This indicates that compound I-1 can inhibit the increased inflammation caused by adenine-induced kidney injury.

[0194] The results of HE staining are shown in Figure 13. The pathological statistics of the kidney tissues of four rats are shown in Table 2. The kidneys of four rats in the sham-operated group had intact glomeruli and renal tubule structures, clear cell morphology, and no obvious abnormalities in the mesenchyme (4 / 4, no abnormalities). Four rats in the model control group showed renal tubule dilation, edema, basophilic degeneration, and thickening of the basement membrane, a few small blood vessels, grass-green crystals in the tubule lumen, thickening of some glomerular capsules, atrophy of a few glomeruli, and inflammatory cell infiltration and fibrous tissue proliferation in the interstitium (3 / 4, moderate; 1 / 4, severe). Even in the treated group (15 mg / kg of compound I-1), varying degrees of renal tubular dilation, edema, basophilic degeneration, and thickening of the basement membrane were observed. Grass-green crystals were observed in a few small blood vessels and the tubular lumen. Some glomerular capsules were thickened, a few glomeruli were atrophied, and inflammatory cell infiltration and fibrous tissue proliferation were observed in the interstitium (1 / 4, mild; 3 / 4, moderate). The results indicated that I-1 ameliorated the histopathology of adenine-induced renal injury to some extent. Specific results are shown in Table 2. Furthermore, the efficacy of UMI-77 in treating adenine-induced renal injury was not as good as that of I-1, at least in the above-mentioned indicators. Experimental rats were purchased from SPF (Beijing) Biotechnology Co. Ltd., and adenine and potassium oxonate were purchased from Yuanye Bio-Technology.

[0195] TIFF2025528014000089.tif168170

[0196] Experimental Example 4 Treatment of type 1 diabetic nephropathy-induced kidney damage Male SD rats weighing 150-170 g were fasted for 12 hours with only water before surgery. A longitudinal incision approximately 1 cm long was made at the intersection of the lower end of the right costal arch. Next, the three layers of skin, mucosa, and muscle were separated layer by layer to expose the perirenal fat. The perirenal fat was then clamped with hemostat forceps, and the right kidney was lifted and exposed. The right renal pedicle was ligated, and the right kidney was resected. After confirming the absence of bleeding, each tissue was sutured layer by layer. One week after surgery, 1% streptozotocin (STZ) was intraperitoneally injected at 50 mg / kg in a volume of 2 mL / kg. In the sham-operated group, the abdominal cavity was opened without right nephrectomy, and only the fat capsule of the right kidney was removed. After surgery, the abdominal cavity was closed and the incision was sutured. One week later, an equal volume of citrate solution was injected into the tail vein.

[0197] Random blood glucose measurements were performed 72 hours after STZ injection. Diabetes modeling was successful if blood glucose levels were 16.65 mmol / L or higher. Rats with successful modeling were selected and continued to receive regular chow and drinking water ad libitum. 14 days after STZ modeling, if random blood glucose levels were 16.65 mmol / L or higher, serum creatinine levels increased, and serum creatinine levels were significantly different from those of the sham-operated group, the model was considered successful. Rats were randomly assigned to groups according to creatinine levels. The study consisted of a sham-operated group (no STZ modeling, administered vehicle by oral gavage), a control group (STZ modeling, administered vehicle by oral gavage), and a 15 mg / kg I-1 group (STZ modeling, administered 15 mg / kg I-1 by oral gavage). The group received 10 ml / kg of I-1 once daily for 27 consecutive days. At the end of the experiment, 24-hour urine was collected from each group of rats in metabolic cages to test for urine volume, urinary protein, and creatinine. Blood was drawn from the heart and left at room temperature for 45 minutes before being centrifuged at 12,000 g and 4°C for 10 minutes to collect the supernatant (serum). Serum creatinine and urea nitrogen levels were measured, and the creatinine clearance rate was calculated. At the end of the experiment, the rats were euthanized and dissected, and the kidneys were removed. Four rat kidneys were then fixed in 4% paraformaldehyde for 48 hours, paraffin-embedded, sectioned, and HE stained. The specific staining procedures were as described above.

[0198] As shown in Figure 14, compared with the sham-operated group, the body weight of rats in the model control group was significantly decreased (P<0.001), and I-1 treatment tended to increase the body weight of rats.

[0199] As shown in Figure 15, compared with the sham-operated group, the serum creatinine levels of rats in the model control group were significantly increased (P<0.01-0.001), and in the model group, after 27 days of I-1 treatment, the serum creatinine levels were significantly decreased (P<0.5), indicating that I-1 treatment can alleviate the increase in creatinine caused by type 1 diabetic nephropathy.

[0200] As shown in Figure 16, compared with the sham-operated group, the blood glucose levels of rats in the model control group were significantly elevated, and I-1 treatment had no significant effect on the blood glucose levels of rats in the model group.

[0201] As shown in Figure 17, compared with the sham-operated group, the 24-hour urinary protein levels of rats in the model control group were significantly increased (P<0.001), and I-1 treatment reduced the 24-hour urinary protein levels of rats, but the difference was not significant.

[0202] The results of HE staining are shown in Figure 18. The pathological and histological statistical analysis of the four cases is shown in Table 3. In the sham-operated group, focal glomerular telangiectasia, renal tubular edema, and dilation were observed in one kidney (1 / 4, mild); three kidneys had intact glomerular and renal tubular structures with clear cell morphology and no obvious interstitial abnormalities (3 / 4, no abnormalities). In the model control group, four kidneys showed partial glomerular and renal tubular necrosis, partial glomerular capillary dilation, increased mesangial matrix, pink-stained exudates in the renal capsule, a small amount of glomerular structural damage, renal tubular edema, vacuolar degeneration, basophilic degeneration, and dilation (1 / 4, mild; 1 / 4, moderate; 2 / 4, severe). In the I-1 treatment group, some glomeruli and renal tubules were necrotic, some glomerular capillaries were dilated, the mesangial matrix was increased, pink-stained exudates were observed in the renal capsule, and small amounts of glomerular structural damage were observed. The renal tubules showed edema, vacuolar degeneration, basophilic degeneration, and dilation (3 / 4, mild; 1 / 4, severe). This indicates that I-1 can significantly reduce the severity of renal pathology caused by diabetic nephropathy compared with the model group. Furthermore, the protective effect of UMI-77 against renal damage in type 1 diabetes was inferior to that of the I-1 group, at least in the above indicators.

[0203] The rats used in the experiment were purchased from SPF (Beijing) biotechnology Co. Ltd., and STZ was purchased from Shanghai Taoshu Biotechnology Co., Ltd.

[0204] TIFF2025528014000090.tif168170

[0205] Experimental Example 5 In vitro liver microsome stability test Ketanserin was selected as the reference compound. The specific method is as follows.

[0206] 0.1 M K3PO4 (pH 7.4) buffer and 3x NADPH stock solution (6 mM, 5 mg / mL) were prepared and preheated in a 37°C water bath. Preparation of spiking solutions for test and control compounds: 5 μL of compound stock solution (10 nM) was added to 95 μL of acetonitrile. Preparation of 1.5 μM spiking solution in microsomes (0.75 mg / mL): 1.5 μL of spiking solution and 18.75 μL of liver microsome solution (20 mg / mL) were added to 479.75 μL of K3PO4 buffer. 30 μL of spiking solution in microsomes was added to a multiwell plate and incubated at 37°C for 5 minutes. 15 μL of NADPH stock solution was added to each well to initiate the reaction, and the time was measured. The reaction was terminated by adding 150 μL of acetonitrile solution containing IS at 0, 5, 15, 30, and 45 minutes. After shaking for 10 minutes, the mixture was centrifuged at 6000 rpm for 15 minutes. 80 μL of the supernatant was collected from each well for LC / MS detection, and the T1 / 2 was calculated. The test results are shown in Figure 19.

[0207] Figure 19 shows the elimination of compounds in vitro in mouse or human liver microsomes, as measured by elimination half-life T. In vitro liver microsome stability experiments with UMI-77 showed that UMI-77 was unstable in the liver microsome environment and was rapidly eliminated; compounds I-1 and I-2 showed excellent liver microsome stability.

[0208] NOTE: Mouse and human liver microsomes used in the experiments were purchased from Xenotech.

[0209] Example 6: Alleviation of Inflammatory Bowel Disease DSS-induced colitis is the most commonly used IBD model in mice. DSS is a polyanionic derivative of dextran formed by the esterification of dextran with chlorosulfonic acid, and has the molecular formula (C6H7Na3O 14S3)n, with a molecular weight ranging from 36,000 to 50,000 and a sulfur content typically between 17% and 20%. Current research primarily suggests that DSS increases intestinal permeability, disrupts the intestinal mucosal barrier, upregulates cytokines (tumor necrosis factor, interleukin, interferon, IL-10, and IL-12), and activates pathways (NF-κB and TRPV1 pathways), which are associated with gut microbiota dysbiosis. At the same time, some studies have shown that DSS induction can upregulate intracellular reactive oxygen species. The acute colitis model is one of the commonly used colitis models. Because it is easy to establish, has a high success rate, and resembles human UC lesions, it is an ideal model for studying the pathogenesis of UC and evaluating the efficacy of pharmaceuticals.

[0210] (1) Model preparation Eight-week-old C57BL / 6J male mice were randomly divided into six groups: G1 blank control group (8 mice), G2 positive control group (8 mice, intraperitoneal injection of infliximab 10 mg / kg), G3 group (12 mice, intraperitoneal injection of small molecule drug TJ01-013 5 mg / kg), G4 group (12 mice, intraperitoneal injection of small molecule drug TJ01-013 10 mg / kg), and G5 group (12 mice, intraperitoneal injection of small molecule drug TJ01-013 20 mg / kg). The drug preparation for intraperitoneal injection was 5% DMSO + 30% PEG 400 + 65% ddH2O. Small molecule compounds were first dissolved in 5% DMSO, then 30% PEG 400 and 65% DDH2O were added sequentially. After 2 weeks of adaptation, the mice were given 2% DSS solution as drinking water, and then switched to regular drinking water 6 days later. During the experiment, the mice were intraperitoneally injected with the corresponding concentrations of small molecule compounds every day, and their weights, fecal appearance, and bloody stool changes were recorded daily.During the experiment, changes in stool appearance and bloody stool were scored, and disease activity indices were calculated on days 3, 6, and 8.

[0211] As shown in Figures 20 and 21, during the DSS induction period, the mice in the group receiving intraperitoneal administration of the small molecule compound TJ01-013 showed some improvement in the symptoms of enteritis, which was mainly reflected in a slower weight loss and a decrease in the disease activity index.

[0212] (2) Observation of colorectal morphology and measurement of colorectal length At the end of the experiment, the mice were sacrificed with CO2, and all intestinal segments from the cecum to the anus were excised, photographed, and measured. As shown in Figure 22, the colon and rectum lengths of the mice in the small molecule compound TJ01-013 group were significantly longer than those of the model control group.

[0213] (3) HE staining analysis of colorectal tissue A central 1 cm section of the intestine was taken, placed in an embedding box, immersed in 4% paraformaldehyde, fixed, and immersed for 72 hours to prepare a pathological specimen for HE staining, and the histopathological results were scored. The specific procedures for tissue embedding, sectioning, and HE staining were as follows:

[0214] (a) Tissue embedding Ethanol dehydration: Tissues were dehydrated in a series of ethanol solutions (75%, 85%, 95%, 100%, and 100%) for 40 minutes each time. Clearance: Tissues were immersed in three xylene baths in sequence, for 30 minutes each. Paraffin immersion: Tissues were immersed in three paraffin baths in sequence, for 1 hour in the first bath, 1.5 hours in the second bath, and 2 hours in the third bath. Embedding: Liquid paraffin was poured into a mold box, and the paraffin-soaked tissue block was placed flat on the bottom with the cut surface facing down. After the paraffin solidified, the embedding frame was removed. After complete cooling and hardening, the paraffin block was trimmed, preserving the paraffin surrounding the tissue in an appropriate location for sectioning.

[0215] (b) Section preparation The pre-cooled paraffin block was fixed in the paraffin microtome so that the cut surface of the paraffin block was parallel to the knife blade. The knife was typically tilted at 15°, and the rotary pusher was rotated to adjust the section thickness to 3 μm, resulting in uniformly thick sections. Holding a brush in the left hand, the microtome handle was rotated with the right hand. As the section emerged, it was gently lifted with the brush and gently tweezed with tweezers. The paraffin section was then placed in a section extension box with the front facing forward, in a water bath at approximately 40°C. After flattening, the section was removed. The section was then mounted by holding one edge of the slide with the left hand, vertically filling it with water, and pressing it with tweezers with the right hand until it was two-thirds of the way up the slide. After mounting, the section was left to dry slightly in the air, then baked in a baking machine at 60°C for 1 hour, and then baked in an oven for 2 hours.

[0216] (c) Deparaffinization of paraffin sections Paraffin sections were deparaffinized in the following gradient: xylene I for 15 minutes, xylene II for 15 minutes, absolute ethanol I for 10 minutes, absolute ethanol II for 10 minutes, 95% alcohol for 10 minutes, and 85% alcohol for 10 minutes.

[0217] (d) HE staining Paraffin sections were stained with hematoxylin for 5–10 min, rinsed with tap water, fractionated in 1% hydrochloric acid alcohol for a few seconds, rinsed with tap water, then reverted to blue with saturated lithium carbonate solution for 1 min, rinsed with running water for a few seconds, immersed in eosin staining solution for a few seconds, and rinsed with running water.

[0218] (e) Dehydration, mounting, and image acquisition Paraffin sections were cleared by sequentially immersing them in 75% ethanol for 2 minutes, 85% ethanol for 2 minutes, absolute ethanol for 2 minutes, and xylene for 2 minutes. The sections were then removed from the xylene and mounted in neutral gum. Microscopic examination was performed, and images were collected and analyzed.

[0219] The results, as shown in Figure 23, showed that staining of tissue sections showed that the colorectal tissue morphology of mice treated with the small molecule compound TJ01-013 was more complete and had reduced inflammatory infiltration than the model control group. Histopathological scoring also showed that treatment with the small molecule compound TJ01-013 significantly reduced the pathological changes of inflammatory bowel disease and resulted in more complete tissue morphology.

[0220] (4) Detection of inflammatory factor transcription levels by q-PCR in colorectal tissues The remaining intestinal segments were rinsed with pre-cooled saline using a 50 mL syringe to flush out any remaining fluid in the intestinal lumen. They were then cut into small pieces with small scissors, mixed evenly, wrapped in aluminum foil, and frozen in liquid nitrogen. All procedures were completed within 10 minutes of the mouse's death. The tissue was lysed using Trizol, and RNA was extracted according to the Trizol manufacturer's instructions. The resulting RNA was reverse-transcribed using an ABI reverse transcription kit. The SYBR Green method was used to detect inflammatory factors such as Cxcl1, G-CSF, IL6, IL-1β, S100A8, and TNF-α in the reverse transcription product. The housekeeping gene Actin was used as an internal standard. 2 -ΔΔCt The calculations and analysis were carried out using the method.

[0221] As shown in Figure 24, the results of real-time PCR showed that the expression levels of inflammatory factors Cxcl1, G-CSF, IL6, IL-1β, S100A8, and TNF-α in the colorectal tissues of mice treated with the small molecule compound TJ01-013 were all significantly reduced compared to the model control group.

[0222] Example 7 Reduction of Acute Lung Injury Lipopolysaccharide (LPS), a major bioactive component of the cell wall of Gram-negative bacteria, has been widely used to induce acute lung injury models. This model has pathological characteristics similar to those of human acute lung injury. The model was prepared as follows.

[0223] (1)Acute lung injury Male C57BL / 6J mice aged 6-8 weeks and weighing 18-22 g were selected as study subjects. After immobilization, 50 μl of PBS was injected into the airways of the mice under direct vision with a laryngoscope to form the control group, and 5 mg / kg of LPS (E. coli) was dissolved in 50 μl of PBS and injected to form the model group. The experiment was conducted in five groups, each containing six mice: NS group (control group, 50 μl of PBS instilled into the airways), LPS group (model control group, 50 μl of LPS instilled into the airways), LPS + 10 mg / kg group (50 μl of LPS instilled into the airways and treated with 10 mg / kg of TJ01-013), LPS + 20 mg / kg group (50 μl of LPS instilled into the airways and treated with 20 mg / kg of TJ01-013), LPS + 30 mg / kg group (50 μl of LPS instilled into the airways and treated with 30 mg / kg of TJ01-013), and LPS + Sivelestat group (positive control group, 50 μl of LPS instilled into the airways and treated with 5 mg / kg of Sivelestat). All groups were intraperitoneally injected once with a dose volume of 200 μl at 1 and 7 hours after airway instillation. After 24 hours, the mice were euthanized and bronchoalveolar lavage fluid (BALF) was collected to detect changes in the levels of inflammatory factors in the bronchoalveolar lavage fluid and the transcription levels of tissue-associated inflammatory factors.

[0224] (2) Collection and observation of bronchoalveolar lavage fluid (BALF) Mice were rapidly anesthetized by intraperitoneal injection of chloral hydrate and placed supine on a dissection table with their limbs immobilized. The neck skin was disinfected with 75% ethanol and an incision was made along the midline of the neck. Using hemostats, the subcutaneous connective tissue and muscle were bluntly separated to expose the trachea. The connective tissue on both sides of the trachea and between the trachea and esophagus was separated to free the trachea. Two approximately 20 cm long surgical sutures were then passed between the trachea and esophagus. A 24-gauge intravenous trocar needle was inserted at a 30-degree angle through the connective tissue membrane between the thyroid cricoid and cricoid cartilages and advanced toward the tracheal carina. The surgical sutures placed between the trachea and esophagus were ligated at the point where the cannula entered the trachea and at the distal end of the cannula, and tied as tightly as possible to secure the cannula and trachea. 0.8 ml of PBS was aspirated into a 1 ml syringe and connected to the liquid inlet end of the intravenous cannula. The PBS was slowly injected into the trachea, and after waiting 30 seconds, it was withdrawn. A milky white foamy liquid was observed to be withdrawn. After three washes and centrifugation at 1500 rpm / min for 10 minutes, the supernatant was used for cytokine detection, and the cell pellet was resuspended in PBS and then smeared for Giemsa staining and differentiation.

[0225] As shown in Figure 25, the total cell count increased rapidly after LPS treatment, but decreased after TJ01-013 treatment. Furthermore, the degree of decrease in the total cell count after 20 mg / kg TJ01-013 treatment was greater than that of the positive control, sivelestat sodium. Fractionation of alveolar lavage fluid showed that TJ01-013 treatment had no significant effect on the number of macrophages, but significantly reduced the number of neutrophils, indicating that TJ01-013 can alleviate the increased inflammation caused by acute lung injury.

[0226] (3) Measurement of inflammatory factors The levels of inflammatory factors in the BALF supernatant were detected according to the instructions of the ELISA detection kit (inflammatory factors include IL-6, CXCL1, CXCL2, etc.).

[0227] As shown in Figure 26, the levels of inflammatory factors IL-6, CXCL1, and CXCL2 in bronchoalveolar lavage fluid after LPS treatment were significantly increased compared to controls. After TJ01-013 treatment, the levels of these related inflammatory factors were significantly reduced, with a certain concentration-dependent effect. The positive control, sivelestat sodium, only significantly reduced CXCL1 levels, but had no significant effect on IL-6 or CXCL2 levels. This indicates that TJ01-013 can attenuate the increased inflammation caused by acute lung injury.

[0228] (4) Small pieces of lung tissue were collected and pulverized in liquid nitrogen. Cells were lysed in a lysis solution containing β-mercaptoethanol. RNA from the relevant lung tissue was extracted according to the instructions in the RNA extraction kit. RNA concentration and mass were determined. 1 μg of RNA was taken and the corresponding reaction system was prepared. The reaction was incubated at 37°C for 15 minutes, then at 85°C for 5 seconds, and then placed on ice for reverse transcription to cDNA. The resulting cDNA was amplified in a 96-well PCR plate using the LightCycle 480 system, and gene levels were measured using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard.

[0229] As shown in Figure 27, after LPS treatment, the transcription levels of the tissue inflammatory factors IL-6, CXCL1, and CXCL2 were significantly increased compared to the control. After TJ01-013 treatment, the transcription levels of the related inflammatory factors were significantly decreased in a concentration-dependent manner. The positive control, sivelestat sodium, only significantly reduced the level of CXCL1, but had no significant effect on the levels of IL-6 and CXCL2. This indicates that TJ01-013 can attenuate the increase in inflammatory transcription levels caused by acute lung injury.

[0230] Example 8: Increased survival from acute lung injury The model was constructed as follows. Male C57 mice, 6-8 weeks old and weighing 18-22 g, were anesthetized and immobilized. 20 mg / kg LPS (E. coli) dissolved in 50 μl of PBS was injected under direct vision using a laryngoscope to form the model groups. Experiments were conducted in three groups, each containing six mice: the LPS group (model control group, 50 μl LPS instilled into the airways), the LPS + 20 mg / kg group (50 μl LPS instilled into the airways and treated with 20 mg / kg TJ01-013), and the LPS + Sivelesta group (positive control group, 50 μl LPS instilled into the airways and treated with 5 mg / kg Sivelesta). Administration was by intraperitoneal injection at a volume of 5 ml / kg daily. Biological mortality and body weight changes were observed and recorded. Mice that lost more than 20% of their pre-injection body weight were considered physiologically dead. A survival curve was plotted based on the mortality observed up to 9 days after administration.

[0231] As shown in Figure 28, the survival rate of the LPS group was reduced by approximately 70%, and after treatment with 20 mg / kg of TJ01-13, the survival rate was significantly increased, indicating that TJ01-13 can significantly increase the survival rate of acute lung injury.

[0232] Example 9 Alleviation of fibrosis by UUO The UUO model is currently the most widely used experimental animal model for studying tubulointerstitial fibrosis. Unilateral ureteral ligation causes obstruction of the renal drainage system, resulting in acute changes in renal function and chronic renal structural damage, simulating the renal interstitial damage caused by ureteral obstruction commonly seen in clinical settings. The model was constructed as follows:

[0233] (1) On the first day of the experiment, mice were anesthetized with 50 mg / kg pentobarbital sodium. After confirming that the mice were under anesthesia, the skin was prepared and disinfected. A 1 cm incision was made on the left side, 1 cm below the costal angle, to fully expose the left kidney. The ureter was located inferiorly along the renal hilum and ligated with 6-0 nylon suture. After ligation, the muscle and skin layers were sutured one layer at a time. In the sham-operated group, only the kidney of the mice was exposed and directly sutured without ligation. The experiment consisted of a sham-operated group (vehicle gavage), a model control group (vehicle gavage), a 10 mg / kg TJ01-013 treatment group (10 mg / kg TJ01-013 gavage), and a 20 mg / kg TJ01-013 treatment group (20 mg / kg TJ01-013 gavage). The vehicle was 0.5% CMC-Na, the dose was 10 ml / kg, and the frequency was once daily. After UUO surgery, mice were sacrificed at the end of the experiment. Immediately afterward, saline was perfused transcardially until the kidneys were completely drained of blood, causing the kidneys to change color from dark red to earth-yellow. The kidney on the operated side was harvested, dissected along the short axis, and the kidney tissue was divided into samples for assay and preserved.

[0234] (2) Renal histopathology Kidney tissues were fixed in 4% paraformaldehyde for 48 hours, embedded in paraffin, cut into 4 μm-thick sections, and stained with Masson's stain. The specific experimental procedures were as described above. After the sections were prepared and scanned, the results were semi-quantitatively analyzed using Image J software.

[0235] As shown in Figure 29, the degree of fibrosis in kidney tissue samples was determined by Masson's trichrome staining, with collagen fibers appearing blue. Images of the renal cortex and medulla were randomly collected from each mouse sample and analyzed using ImageJ software to quantify the percentage of blue areas, i.e., collagen volume fraction (%). As shown in the figure, compared with the sham-operated group, UUO modeling resulted in significant tubular dilatation and tubular cell compression, accompanied by significant renal interstitial fibrosis. UUO modeling significantly increased the degree of interstitial fibrosis in the renal cortex (sham-operated group: 0.28% vs. model control group: 4.67%, p<0.05). Compared to the model control group (UUO+Vehicle), 10 mg / kg TJ01-013 treatment had no significant effect (5.58% vs. model control group: 4.67%, p<0.05). While 30 mg / kg TJ01-013 significantly reduced the degree of interstitial fibrosis in the renal cortex (0.61% vs. model control group: 4.67%, p<0.05). Similar to the trend in the renal cortex, UUO modeling also induced some fibrosis in the renal medulla, and TJ01-013 was also effective in reducing fibrosis. In summary, TJ01-013 treatment significantly reduced renal fibrosis caused by UUO.

[0236] (3) Expression of fibrosis-related genes and proteins Total RNA was extracted from kidney tissue samples using a tissue RNA rapid extraction kit. After measuring the RNA concentration and purity using a micro-volume UV spectrophotometer, the procedure was carried out according to the HiScript™ II 1st Strand cDNA Synthesis Kit instructions. A total of 1 μg of cDNA was reverse transcribed using a 15 μL amplification system, 5 μL of cDNA, 7.5 μL of 2×SYBR Premix Ex Taq™, 0.3 μL of forward and 0.3 μL of reverse primers, and the remainder supplemented with double-distilled water. The Bio-Rad reaction conditions were 95°C for 5 minutes, 40 cycles of denaturation at 95°C for 10 seconds, annealing / extension at 60°C for 30 seconds, and 65°C for 15 minutes. -△△CtThe expression of the target gene was calculated using the relative quantification method. The Ct value of the target gene was first corrected with an internal reference gene (β-actin), and then the relative expression level was calculated compared with the control group.

[0237] As shown in Figure 30, changes in the mRNA levels of three key indicators of renal fibrosis, alpha-smooth muscle actin (α-SMA, corresponding gene: Acta2), fibronectin (Fn1), and type I collagen (Col1a1), were detected in renal tissue homogenates by fluorescent quantitative PCR. The results showed that, compared with the sham-operated group, UUO modeling was able to induce the expression of fibrosis-related genes, with significant increases in the mRNA levels of the key fibrosis genes Acta2, Fn1, and Col1a1. Compared with UUO + Vehicle, TJ01-013 intervention significantly reduced the expression of the Fn1 gene and showed a tendency to suppress the Col1a1 gene as well.

[0238] (4) Expression of fibrosis-related proteins After adding RIPA lysis solution (containing protease inhibitors) to the kidney tissue, the tissue was crushed to form a homogenate, incubated on ice for 30 minutes, and centrifuged at 12,000 g for 10 minutes. The supernatant was removed and added to an equal volume of 2x loading buffer. The mixture was heated at 100°C for 10 minutes and centrifuged. After that, the tissue was transferred to a PVDF membrane using a BioRad Semi-Dry Transfer System 0.2A on a 10%-12% SDS-PAGE gel. The membrane was then blocked in PBST buffer containing 5% (w / v) nonfat milk for 1 hour and incubated overnight at 4°C with corresponding antibodies, including fibronectin (FN), collagen I, and α-smooth muscle acinar (α-SMA), in PBST containing 5% (w / v) BSA. After washing with PBST, the expression of fibrosis-associated proteins was detected using HRP-conjugated secondary antibodies and a chemiluminescent reagent. Grayscale quantitative analysis was performed using ImageJ 1.53a.

[0239] As shown in Figure 31, compared with the sham-operated group, UUO modeling resulted in a significant increase in the levels of three major fibrosis proteins (FN, collagen I, and α-SMA); compared with the UUO + Vehicle group, TJ01-013 treatment significantly reduced the protein levels of fibronectin FN and type I collagen (collagen I).

[0240] (5) Mitochondrial morphological analysis of kidney tissue Renal tubules are the primary site of injury in UUO models and an important contributor to the pathogenesis of renal interstitial fibrosis. To further characterize the therapeutic effects of TJ01-013, we used transmission electron microscopy to observe the intracellular structure of renal tubular epithelial cells and evaluate mitochondrial morphology. Four groups of mouse kidney samples, each containing three mice, were collected and subjected to electron microscopy. Renal cortices were excised into approximately 1 cubic millimeter pieces and fixed overnight in 2.5% glutaraldehyde at 4°C. The following day, the sections were washed three times for 10 minutes in PBS, fixed for 1 hour in 1% osmium chloride, washed three times for 10 minutes in double-distilled water, and stained with 2% uranyl acetate for 30 minutes. Subsequently, the sections were dehydrated in 50%, 70%, 90%, 100% ethanol, and 100% acetone. The sections were embedded overnight in complete embedding medium, and ultrathin sections (Leica UC7) were prepared and stained with uranyl acetate and lead nitrate for 30 minutes each. The mitochondrial morphology of the ductal epithelial cells was observed under a transmission electron microscope at 4000x and 10000x magnification.

[0241] As shown in Figure 32, normal renal tubular epithelial cells have a clear brush border structure and numerous, dense, elongated mitochondria within the cells. In the UUO model, the renal tubules were dilated, the renal tubular epithelial cells were compressed and shortened, and the brush border was lost; the mitochondria were swollen, irregular, or nearly round, and less dense; after TJ01-013 intervention, the morphology of the renal tubular epithelial cells and mitochondria was intermediate between the previous two models, and more autophagic vesicles with bilayer or multilayer membrane structures were observed within the vesicles.

[0242] The above experimental results demonstrated that TJ01-013 could improve mitochondrial swelling and homeostatic imbalance in renal tubular epithelial cells and ameliorate renal interstitial fibrosis in a UUO model.

[0243] Example 10: Improving survival rate from sepsis The preclinical sepsis model we developed was LPS-induced sepsis in mice. Purified LPS was injected intraperitoneally or intravenously into mice to activate the innate immune system and simulate a severe Gram-negative bacterial infection. The specific modeling method was as follows: C57 mice weighing 20–25 g were selected and intraperitoneally injected with 20 mg / kg LPS (dissolved in PBS) according to their body weight. The mice were divided into three groups: a model control group (LPS), a positive control treatment group (prednisone, 10 mg / kg), and a TJ01-013 treatment group. The mice were administered intraperitoneally in a volume of 5 ml / kg once daily. Biological mortality and body weight changes were recorded daily, and mice with a weight loss of 20% or more compared to baseline were considered physiologically dead. Survival curves were plotted based on the mortality observed up to 8 days after administration.

[0244] As shown in Figure 33, the survival rate of sepsis caused by LPS treatment decreased to about 20% on day 8, but the survival rate of hormone prednisone treatment could maintain 100%, and the survival rate of TJ01-013 treatment maintained 80%, indicating that TJ01-013 treatment significantly increased the survival rate of sepsis.

[0245] Example 11: Reduction of the level of prostatic hyperplasia Androgen-induced benign prostatic hyperplasia in rats has been used in many research fields. The specific model construction method is as follows: Male SD rats weighing 180-200 g were intramuscularly injected with 30 mg / kg androgen every other day for 15 consecutive androgen injections to create the model. The experiment was divided into four groups: a negative control group (Sham), a model control group (Control), a TJ01-013 treatment group (TJ01-013, 30 mg / kg), a finasteride treatment group (finasteride, 10 mg / kg), and a TJ01-013 + finasteride treatment group (13 + F). Androgen was administered to model the disease, and drugs were administered to treat the disease. The administration method was oral gavage, the administration volume was 10 ml / kg, the administration frequency was daily, and the administration ended on the 30th day, at which point the rats were weighed and euthanized, and the prostate and urethra of the rats were collected and weighed, and finally the organ index (prostate weight / rat weight) was calculated.

[0246] As shown in Figure 34, the prostate weight of the model group (Control) was significantly increased compared to the negative control group (Sham). Treatment with the active agent finasteride reduced the prostate weight, and combined administration of TJ01-013 and finasteride further reduced the prostate weight. Regarding the prostate organ index, as shown in Figure 35, the prostate organ index of the model group (Control) was significantly increased compared to the negative control group (Sham). Treatment with the active agent finasteride reduced the prostate organ index, but there was no significant difference between the two. Combined administration of TJ01-013 and finasteride significantly reduced the prostate organ index. At the same time, the weights of the urethra and bladder were measured separately. The results, as shown in Figure 36, showed that the model group (Control) had significantly increased urethral and bladder weights compared to the negative control group (Sham), and finasteride treatment tended to reduce the weights. Combined administration of TJ01-013 and finasteride significantly reduced the urethral and bladder weights. In summary, TJ01-013 can further reduce prostate weight and volume when used in combination with drugs treating benign prostatic hyperplasia.

[0247] Example 12 Reduction of myocardial infarction As the largest energy-consuming organ in the human body, the heart relies primarily on mitochondria for its energy. Cardiomyocytes are among the cells with the highest number of mitochondria, accounting for 40-60% of their total volume. Under human physiological conditions, mitochondria in cardiomyocytes provide energy for normal contraction and metabolism of cardiomyocytes, thereby maintaining cardiomyocyte homeostasis.

[0248] (1) Model preparation and administration method SD rats weighing 180–200 g were fasted for 12 hours and anesthetized with chloral hydrate. The hair from the lower jaw to the upper abdominal cavity and ventral surface of the limbs was removed. The rat was then secured to the operating table. A small 1.5 cm incision was made in the neck with a scalpel, and the subcutaneous muscle layer was bluntly separated with surgical scissors to expose the trachea. A tracheal tube was then inserted and connected to an animal ventilator. After disinfection with iodophor, the skin between the third and fourth ribs on the left side of the chest was incised, and the muscle was bluntly separated to expose the ribs. The third rib was then cut with surgical scissors, and the cut rib was clamped and fractured with hemostat forceps. A retractor was inserted and the pericardium was peeled away. After cutting the pericardium, the heart was gently rotated using a saline-moistened cotton swab to identify the location of the left atrial appendage and coronary artery. Using a microneedle holder, a suture needle with a thread was fixed, and the coronary artery was ligated 2-3 mm below the left auricle, crossing the myocardium from right to left. After ligation, the intrathoracic organs were returned to their original position using a saline-soaked cotton swab, and the third and fourth ribs were sutured with a figure-of-eight suture. After completing the rib layer suture, the subcutaneous muscle layer was sutured, and finally the skin was sutured. After removing the tracheal tube, the rat was carefully observed for spontaneous breathing. If not, chest compressions were immediately performed and cardiopulmonary resuscitation was initiated. An electrocardiogram was connected and a postoperative electrocardiogram was recorded. A successful myocardial infarction model was observed as ST-segment elevation. Based on the electrocardiogram data, the rats were divided into five groups: a sham-operated group (Sham), a model control group (MI), a TJ01-013 group (30 mg / kg), an Entresto group (Entresto, 10 mg / kg), and a TJ01-013 + Entresto combination group. The administration was by oral gavage, with a volume of 10 ml / kg and a frequency of once daily. After 4 weeks of continuous administration, the rats were anesthetized and subjected to cardiac ultrasound examination.

[0249] (2) Echocardiography Rats were anesthetized with an intraperitoneal injection of 40 mg / kg pentobarbital sodium and placed in a supine position with their limbs fixed to a wooden board tilted 30 degrees to the left. Chest hair was shaved, and a lead II electrocardiogram was connected. An ultrasound diagnostic system, ULTRAMARK9 (ATL, USA), was used with a 10-5 MHz wideband line array probe. The Doppler detection frequency was 6.0 MHz, the probe length was 38 mm, the gain was fixed at 50 dB during the experiment, and the imaging depth was adjusted to 2.5 cm. To obtain a parasternal left ventricular long-axis view, the probe was positioned to the left of the sternum, 10-30 degrees from the sternal midline, and rotated 90 degrees clockwise to obtain the left ventricular image. Doppler blood flow detection was performed at the mitral and aortic valves on the parasternal left ventricular long-axis view and the pulmonary artery long-axis view. Ultrasound measurement indices included left ventricular end-diastolic diameter (LVDd), end-systolic diameter (LVDs), left ventricular ejection fraction (EF), left ventricular short-axis shortening (FS), and infarct size.

[0250] As shown in Figure 37, the myocardial infarction area in the model control group was significantly increased compared to the sham-operated group. Both TJ01-013 and Entresto positive drug treatment were able to reduce the myocardial infarction area, and combined treatment with TJ01-013 and Entresto further reduced the myocardial infarction area. LVDd, which represents the left ventricular end-diastolic internal diameter, is an important indicator of cardiac color ultrasound and can reflect abnormalities in left ventricular size. As shown in Figure 38, the left ventricular end-diastolic internal diameter (LVDd) in the model control group was significantly increased compared to the sham-operated group. Treatment with TJ01-013 and Entresto positive drug treatment had no significant effect on LVDd, but combined treatment with TJ01-013 and Entresto significantly reduced LVDd. LVDd represents the left ventricular end-systolic internal diameter and is primarily used to reflect left ventricular systolic function. As shown in Figure 39, the left ventricular end-systolic internal diameter (LVDs) in the model control group was significantly increased compared to the sham-operated group. Treatment with TJ01-013 and the active drug Entresto had no significant effect on LVDs, but combined treatment with TJ01-013 and Entresto significantly reduced LVDs. EF, which represents the quality of cardiac function, is an important indicator for assessing cardiac function decline. As shown in Figure 40, the left ventricular ejection fraction (EF) in the model control group was significantly decreased compared to the sham-operated group. TJ01-013 treatment significantly increased LVDs in the model group. Treatment with the active drug Entresto had no significant effect on LVDs, but combined treatment with TJ01-013 and Entresto further increased LVDs. Left ventricular short-axis shortening (FS) is one of the parameters used to measure left ventricular systolic function. As shown in Figure 41, the left ventricular short axis shortening (FS) in the model control group was significantly reduced compared with the sham operation group, and TJ01-013 treatment significantly increased FS in the model group. Treatment with the positive drug Entresto had no obvious effect on FS, but combined treatment with TJ01-013 and Entresto could further increase left ventricular short axis shortening.

[0251] Example 13 Alleviation of cognitive dysfunction in APP / PS1 mice Clinical symptoms of Alzheimer's disease (AD) primarily include comprehensive dementia symptoms, such as memory impairment, aphasia, apraxia, agnosia, visuospatial impairment, and executive dysfunction. The main pathological manifestations are brain tissue atrophy, neurofibrillary tangles, senile plaques, and massive amyloid deposition. In addition to the Aβ toxicity hypothesis, abnormal tau protein metabolism and mitochondrial dysfunction may also be involved in the pathogenesis of AD. APP / PS1 double transgenic mice can express mutant human presenilin 1 (PS1-dE9) and amyloid precursor protein (APPswe). Expression of these two genes is driven by the mouse prion protein promoter. These mutations can cause early-onset dementia, a classic model for Alzheimer's disease research. Specific modeling and administration methods are as follows:

[0252] (1) Model construction Male transgenic APP / PS1 mice were purchased from the Animal Model Research Center of Nanjing University and raised to 12 weeks of age. They were then divided into three groups: a normal C57 group (WT), a model control group (APP / PS1 + Vehicle), and a TJ01-013-treated group (APP / PS1 + TJ01-013). Both the normal and model control groups received oral gavage of the vehicle. TJ01-013 was administered at a concentration of 30 mg / kg, in a volume of 5 ml / kg, once daily, over a 3-month treatment cycle.

[0253] (2) Water maze experiment The water maze apparatus consisted of a circular pool (140 cm in diameter) filled with titanium dioxide water, maintained at 22°C. A 12 cm diameter platform was placed in a fixed position 1 cm below the water surface, and mice were trained in four quadrants daily for five consecutive days. Each quadrant lasted 60 seconds or until the mouse found the platform. If the mouse failed to find the platform within the specified time, the experimenter had to allow the mouse to stand on the platform for 20 seconds. All parameters were recorded by a video tracking system.

[0254] As shown in Figure 42, compared with wild-type control mice (WT), the time it took for APP / PS1 mice to find the platform was significantly longer, indicating obvious cognitive impairment. Treatment with 30 mg / kg of TJ01-013 significantly reduced the time it took for the mice to find the platform and improved the learning and spatial memory abilities of APP / PS1 mice. As shown in Figure 43, the number of times the APP / PS1 mice in the vehicle group crossed the platform was significantly less than that in the wild-type control mice (WT), while the number of times the mice in the TJ01-013-treated group crossed the platform was significantly more than that in the APP / PS1 mice in the vehicle group, further verifying that TJ01-013 improves cognitive impairment in APP / PS1 mice.

[0255] (3) Immunohistochemistry Mouse cardiac perfusion for brain extraction: APP / PS1 and control C57BL / 6J mice were anesthetized and rendered unconscious. After the limbs were secured to a dissection table in a fume cupboard, the abdominal skin was cut with scissors to expose the liver. The diaphragm was quickly cut, and the xiphoid process was clamped with hemostat forceps. The mouse was then rotated upward to expose the heart. The prepared PBS was carefully injected into the left ventricle, directed toward the aorta. After cutting the right atrial appendage, the peristaltic pump was turned on and the blood was initially expelled at a slow speed. Once the heart stopped beating or the fluid pumped from the right atrial appendage became colorless and transparent, the mouse liver was observed to turn grayish-white. The fur was cut along the midline of the mouse hindbrain with scissors to expose the skull. Forceps were then inserted through the cross section of the brain box and the skull was removed with the help of scissors to extract the intact whole brain. Fresh whole mouse brains were cut in half and placed in a 5 mL centrifuge tube. 4 mL of 4% paraformaldehyde fixative was added for 24 hours. Sections were then prepared, antigen retrieval was performed, and the sections were incubated with 3-5% BSA for 30 minutes. They were then stained overnight with polyclonal rabbit anti-GFAP antibody (1:100) and mouse anti-β-amyloid 1-16 antibody (1:100). After washing the sections three times with PBS, the corresponding fluorescent secondary antibodies were added and incubated in the dark for 1 hour. The slides were then washed, stained with DAPI staining solution for 10 minutes, mounted with resin mounting medium, and finally imaged using Cytation 3.

[0256] GFAP is a marker of astrocyte activation, and astrocyte proliferation is a pathological sign of structural damage in the central nervous system. As shown in Figure 44, astrocytes were activated in the hippocampus of the model control mice, and numerous Aβ plaques simultaneously appeared. Astrocyte activation in the hippocampus of the TJ01-013-treated mice was significantly reduced, as were the number and size of Aβ plaques. This indicates that TJ01-013 treatment can reduce astrocyte activation and the number and size of Aβ plaques in APP / PS1 mice.

[0257] (4) Elisa assay of Aβ levels in brain tissue homogenates Mouse brain tissue homogenates were prepared according to the brain tissue homogenization method described in the Life Technologies ELISA Technical Guide. Approximately 100 mg of brain tissue was weighed and placed in a centrifuge tube. Approximately 8 volumes of grinding buffer (5 M guanidine hydrochloride, 50 mM Tris) was added, and the tissue was homogenized in a homogenizer. The homogenized tissue was placed on an oscillator at room temperature and mixed for 3–4 hours. The tissue was then diluted 10-fold with PBS containing protease inhibitors and centrifuged at 16,000 x g for 20 minutes at 4°C. The supernatant was removed and placed on ice for later use. ELISA detection was performed according to the instructions for the Aβ detection kit. As shown in Figure 45, the Aβ content in the brain tissue of model control APP / PS1 mice was significantly increased, while the Aβ content in the brain tissue of mice treated with TJ01-013 was significantly decreased. This indicates that TJ01-013 treatment can reduce Aβ content and thereby alleviate cognitive impairment in APP / PS1 mice.

[0258] Example 14 Protective effect against cisplatin-induced hearing loss Cisplatin-related ototoxicity is a serious side effect of chemotherapy and can cause irreversible hearing loss. The murine cisplatin-induced hearing loss model is an important model for simulating hearing loss caused by ototoxic drugs. The construction method of this model is as follows.

[0259] (1) Model construction Eight-week-old C57 male mice weighing 22-25 g were selected. Following previous studies and laboratory studies, hearing loss was induced by administering 4 mg / kg of cisplatin to the mice. A fixed amount of cisplatin was weighed and dissolved in 0.9% saline for the model and control groups. The mice were intraperitoneally injected at 5 ml / kg for four consecutive days, followed by four consecutive intraperitoneal injections of 0.9% saline for recovery. The mice were injected at the same time each day. On the ninth day, the mice were left untreated. For subsequent experiments, hearing tests or autopsies were performed. TJ01-013 was administered orally by gavage every day. The vehicle used for the gavage was 0.5% CMC-Na, at a dose of 30 mg / kg, in a volume of 5 ml / kg, for a total of eight days.

[0260] (2) Mouse hearing function test: Auditory Brainstem Response (ABR) test Sodium pentobarbital was prepared in 0.9% saline and injected intraperitoneally at a dose of 50 mg / kg into the test mice. The mice were deeply anesthetized and placed on a 37°C heating pad to maintain body temperature. They were then transferred to a soundproof room. Three hearing electrodes were inserted into the mice at corresponding positions. The active electrode was inserted under the skin on the skull of both ears, the ground electrode was inserted under the skin on the back, and the reference electrode was inserted at the base of the ear. After checking the electrode indicator and the frequency of the resistance, one ear was positioned approximately 10 cm from the speaker. Stimulation was performed using a mix of clicks at different frequencies (4 kHz, 8 kHz, 12 kHz, 16 kHz, 24 kHz, and 32 kHz). The test started at 90 dB and gradually decreased by 10 dB or 5 dB each time. Signal acquisition and recording of responses were performed using a TDT system. Final hearing thresholds were recorded using SigGen32 software. Multiple mice were sequentially tested for hearing. Because ABR is a test of the auditory nerve, multiple measurements could be made on a single mouse, but the mouse had to be kept anesthetized during the measurements, and data were then statistically analyzed at the end.

[0261] As shown in Figure 46, the ABR hearing test showed that the model control group (Cis) had significantly higher hearing thresholds at all frequencies measured (4 kHz, 8 kHz, 16 kHz, 24 kHz, 32 kHz) compared to the negative control group (wild-type rats), and TJ01-013 treatment significantly reduced the hearing thresholds at all frequencies measured (4 kHz, 8 kHz, 16 kHz, 24 kHz, 32 kHz). This indicates that TJ01-013 has a protective effect against hearing impairment in mice.

[0262] (3) Immunofluorescent staining of the cochlear basilar membrane Mice were killed by cervical crush, and the cochleae were removed and processed under a dissecting microscope. The round and oval windows were exposed, and the cochlear apex was perforated. The round and oval windows and the cochlear apex were perfused with 4% PFA solution. The whole cochlea was then fixed in 4% PFA solution and shaken overnight at 4°C on a shaking table. After washing with PBS, the cochleae were decalcified in 10% EDTA solution for 2–4 hours. After softening, the basement membrane was removed and the tissue was sectioned under a dissecting microscope. The superior, middle, and inferior gyri were excised and placed in a U-shaped 96-well plate and labeled. The tissue was permeabilized with 0.2% Triton-X100 solution for 15 minutes and blocked with 10% goat serum for 1 hour. After overnight incubation with primary antibodies, the tissue was washed with PBS and then incubated with fluorescent secondary antibodies for 1 hour at room temperature in the dark. The basilar membrane was gently removed using tweezers, and the specimen was placed on a glass slide containing a drop of mounting medium (containing DAPI staining solution) with the front hair cells facing up. A coverslip was then placed on the slide, and the periphery of the coverslip was sealed with nail polish. Finally, the specimen was photographed using a fluorescence microscope.

[0263] As shown in Figure 47, using Myo7a as a hair cell marker, the fluorescence spread of hair cells in the parietal, middle, and basal gyri of the cisplatin-treated mice showed loss, and TJ01-013 treatment significantly reduced hair cell loss. These results indicate that TJ01-013 treatment has a certain protective effect against hearing impairment caused by cisplatin.

[0264] Example 15: Alleviation of aging-related diseases and cell damage In addition to natural physiological aging, the body can also undergo pathological aging, which is accelerated by physiological changes caused by various factors, leading to the onset of illness and chronic diseases. A representative example of pathological aging is progeria, a rare autosomal dominant childhood disorder. Bone mesenchymal stromal cells (BMSCs) are pluripotent stem cells with self-renewal and multidirectional differentiation capabilities, and can undergo senescence when passaged in vitro. The specific experimental method is as follows:

[0265] (1) Experiments with mouse bone marrow mesenchymal stem cells Extraction of bone marrow mesenchymal stem cells: Select a C57 mouse weighing approximately 25g and anesthetize it with 30mg / kg chloral hydrate. Remove the femur and tibia and place them in a culture dish. Cut off one end of the femur and tibia to completely expose the marrow cavity. Extract the DMEM / F12 medium with a 1ml syringe, insert the needle tip into the marrow cavity, and then connect a 15ml centrifuge tube underneath. The washing solution was poured into the centrifuge tube and repeated several times until the marrow cavity was completely flushed. The washed suspension was then pipetted repeatedly to separate the cells as much as possible. After leaving it for several minutes, the supernatant was transferred to another tube and the cell suspension was sprayed to completely disperse the cells. The resulting cell suspension was centrifuged at 1000 rpm for 5 minutes, the remaining supernatant removed, 1 ml of DMEM / F12 medium added, and pipetting was repeated. High-purity CD45-Sca-1+PDGFRα+ primary mouse bMSC cell lines were selected using flow cytometry. The selected cells were then placed in a culture flask and observed under a microscope. After 72 hours in an incubator at 37°C and 5% CO2, the medium was changed. Treatments included 10 μM TJ01-013 at passage 1, followed by 10 μM TJ01-013 at each subsequent passage. Con-Y was added at passage 2, and Con-O was added at passage 9. All treatments were performed up to passage 9. Cell morphology was monitored under a microscope, and the percentage of SA-β-gal-positive cells was counted. Immunofluorescence techniques (specific operating procedures are as described above) were used to detect the levels of DNA damage marker γ-H2AX and heterochromatin modification H3K9me3 after TJ01-013 treatment.

[0266] Senescence-associated β-galactosidase (SA-β-gal) is one of the most widely used senescence markers, and its intracellular concentration can reflect the degree of cellular senescence. As shown in Figure 48, the percentage of SA-β-gal-positive cells in mouse bone marrow mesenchymal stem cells (Con-O) was significantly increased compared to Con-Y. At passage 9 after treatment with TJ01-013, the percentage of SA-β-gal-positive cells was significantly decreased compared to Con-O, indicating that TJ01-013 inhibited the senescence process of mouse mesenchymal stem cells. As shown in Figure 49, the level of the DNA damage marker γ-H2AX increased in old cells (Con-O), and its level significantly decreased after TJ01-013 treatment. Furthermore, as shown in Figure 50, the expression level of the heterochromatin modification H3K9me3 was low in Con-O cells, and its expression level was partially restored by TJ01-013 treatment. As shown in Figure 49, the level of the DNA damage marker γ-H2AX was increased in senescent cells (Con-O), and the level was significantly reduced by TJ01-013 treatment. Also, as shown in Figure 50, the expression level of the heterochromatin modification H3K9me3 was low in Con-O cells, and the expression level was partially restored by TJ01-013 treatment.

[0267] (2) Experiments with normal human-derived mesenchymal stem cells Mesenchymal stem cells (MSCs) differentiated from normal human pluripotent stem cells (iPSCs) were cultured. The experiment consisted of three groups: young cells (Con-Y) cultured for six generations, senescent cells (Con-O) cultured for 16 generations, and a treatment group (Con-O+TJ01-013) cultured for 16 generations with 10 μM TJ01-013 added during the culture process. After treatment, all cells were placed under a microscope to observe cell morphology and count the percentage of SA-β-gal-positive cells. The levels of the DNA damage marker γ-H2AX and the heterochromatin modification H3K9me3 were detected after TJ01-013 treatment using immunofluorescence techniques (see above for specific procedures).

[0268] As shown in Figure 51, the percentage of SA-β-gal-positive cells in CMC cells was significantly increased in Con-O compared to Con-Y. After treatment with TJ01-013, the percentage of SA-β-gal-positive cells was significantly decreased compared to Con-O, indicating that TJ01-013 can inhibit the senescence process in human-derived CMC cells. As shown in Figure 52, the level of the DNA damage marker γ-H2AX was increased in senescent cells (Con-O), and its level was significantly decreased by TJ01-013 treatment. Furthermore, as shown in Figure 53, the expression level of the heterochromatin modification H3K9me3 was low in Con-O cells, and its expression level was partially restored by TJ01-013 treatment.

[0269] (3) Experiments with mesenchymal stem cells derived from patients with progeria syndrome (HGPS) Mesenchymal stem cells (HGPS-MSCs) differentiated from pluripotent stem cells (iPSCs) from patients with HGPS were collected and cultured. The experiment was divided into three groups: young cells cultured for seven generations (Con-Y); senescent cells cultured for 12 generations (Con-O); a treatment group cultured for 12 generations with 10 μM TJ01-013 (Con-O+TJ01-013); and a treatment group cultured for 12 generations with 10 μM ionafarnib (ionafarnib). After treatment, all cells were placed under a microscope for morphological observation and the percentage of SA-β-gal-positive cells was counted. Immunofluorescence techniques (specific procedures are as described above) were used to detect the levels of the DNA damage marker γ-H2AX and heterochromatin modification H3K9me3 after treatment with TJ01-013 and Ionafarnib.

[0270] As shown in Figure 54, the percentage of SA-β-gal-positive cells in HGPS-CMC cells was significantly increased in Con-O compared to Con-Y. Treatment with TJ01-013 and Ionafarnib significantly decreased the percentage of SA-β-gal-positive cells compared to Con-O, indicating that both TJ01-013 and Ionafarnib could inhibit the aging process in HGPS-CMC cells. As shown in Figure 55, the level of the DNA damage marker γ-H2AX was increased in senescent cells (Con-O), and treatment with TJ01-013 and Ionafarnib significantly reduced DNA damage levels. Furthermore, as shown in Figure 56, the expression level of the heterochromatin modification H3K9me3 was low in Con-O cells, and treatment with TJ01-013 and Ionafarnib partially restored this expression level. In summary, TJ01-013 was able to delay the aging process to some extent in normal and progeria patients.

[0271] (4) Experiments with human epidermal melanocytes HEMn-LP and NHEM-Neo Skin is a high-turnover organ, and its constant renewal depends on the rapid proliferation of progenitor cells. The energy needs of these cells are met through mitochondrial respiration, an ATP-generating process driven by a series of protein complexes. However, reactive oxygen species are inevitably generated during the respiration process and, if not scavenged by the antioxidant system, can damage macromolecules and cellular structures. Oxidative damage caused by mitochondrial ROS generation has been identified as the molecular basis of various pathophysiological conditions. Mitochondria are the primary organelles affected during aging and UV-induced skin aging, which manifests as a direct result of mitochondrial dysfunction. Recent studies have shown that mitochondria have an innate role in maintaining skin homeostasis and pigmentation, and that these roles are affected when basic mitochondrial function is impaired. Mitochondria are involved in several common and rare skin disorders, including cutaneous manifestations of primary mitochondrial diseases and congenital skin disorders caused by damaged mitochondria. Increasing evidence supports a strong link between mitochondrial and skin health. Skin aging is caused by a combination of intrinsic and extrinsic factors that ultimately impair the structural integrity and physiological function of the skin. Recent studies have shown that melanocytes expressing aging markers accumulate in human skin and are significantly associated with increased facial wrinkles, increased perceived age, and age-related elastin formation in the dermis.

[0272] The specific experimental scheme is as follows.

[0273] Human epidermal melanocytes, HEMn-LP and NHEM-Neo, were harvested and cultured. Experiments were divided into four groups: normal cultured human epidermal melanocytes (Control); a treatment group in which 10 μM TJ0113 was added during normal culture (Control + TJ0113); a group in which normal cultured human epidermal melanocytes were irradiated with 10 Gy of X-rays to induce melanocyte senescence (Senescence); and a group in which normal cultured human epidermal melanocytes were irradiated with 10 Gy of X-rays to induce melanocyte senescence and simultaneously added with 10 μM TJ0113 (Senescence + TJ0113). All experimental treatments and treatments lasted for 12 days. After treatment, all cells were placed under a microscope to observe cell morphology and count the percentage of SA-β-gal-positive cells. Immunofluorescence techniques (specific operating procedures are as described above) were used to detect the levels of DNA damage marker γ-H2AX and heterochromatin modification H3K9me3 after TJ01-013 treatment.

[0274] Example 16 Treatment of depression-like disorders Depressive disorder, also known as major depressive disorder, is characterized by a pronounced and persistent low mood as its primary clinical feature. The CUMS depression animal model is a chronic unpredictable animal stress model that simulates external environmental stressors. Various stressful stimuli induce functional impairment in the animal body, resulting in the development of the psychiatric disorder depression. After chronic unpredictable stress, the animals exhibited reduced motor performance, a lack of anhedonia, and elevated plasma corticosterone levels, which are similar to the symptoms of human depression. This model more realistically simulates the etiology and symptoms of depression, making it an ideal and reliable animal model of depression. The model construction method was as follows: Eight-week-old male C57BL / 6J mice were selected and constructed according to the following method.

[0275] (1) Food and water deprivation: Mice were deprived of food and drinking water for 24 hours.

[0276] (2) Electrical plantar stimulation: Mice were placed in a fear memory device and stimulated with a 0.3 mA electric current for 2 seconds at 30-second intervals for 500 seconds.

[0277] (3) Wet bedding: Water was poured onto the dry bedding until the bedding was completely wet, and then the mice were placed in the wet bedding for 24 hours.

[0278] (4) Cage tilt: The mouse cage was placed against the wall at a 45° incline and kept for 24 hours.

[0279] (5) Behavioral restraint: Mice were placed in a behavior restraint device, confined to a small space, and prevented from normal behavior for 1 hour. During this time, the condition of each mouse was observed.

[0280] (6) Cage shaking: A mouse was placed in an empty cage, and the cage was vigorously shaken until the mouse could not stay still in the cage and was shaking due to the cage shaking. This was maintained for one hour.

[0281] (7) Olfactory stimulation: Spices such as anise were placed in the mice's cages to stimulate their sense of smell.

[0282] The seven experiments described above were conducted randomly over a one-week period, with stimulation administered for four consecutive weeks, to achieve unpredictability. TIFF2025528014000091.tif80170

[0283] After modeling, an open-field test was performed to screen for modeling animals, and animals that successfully modeled were grouped. The entire experiment was divided into five groups: a normal group (control), a model control group (model), a positive drug treatment group (fluoxetine), a TJ0113 10 mg / kg treatment group (10 mg / kg), and a TJ0113 30 mg / kg treatment group (30 mg / kg). Each group contained 10 mice. Treatment was by oral gavage. The normal group and the model control group received vehicle administration (0.5% CMC-Na). The positive drug was fluoxetine hydrochloride dissolved in saline at a dose of 30 mg / kg. The vehicle for TJ0113 was 0.5% CMC-Na at doses of 10 mg / kg and 30 mg / kg, respectively. Behavioral testing was performed 4 weeks after the end of treatment.

[0284] Sugar water preference test (1) Adaptation feeding: Before the start of the test, the animals were fed 1% sucrose water and plain water for 2 days. To avoid differences in the animals' positions, the sugar water and plain water were replaced on the 1st day. After the acclimatization, the animals were fasted for 1 day. (2) Formal test: After fasting and deprivation of water, the rats were given pre-prepared 1% sucrose water and white water (the initial masses of the sugar water and white water were known). After 24 hours, the remaining masses of the sugar water and white water were measured, and the consumption rates of sugar water A and white water B were calculated. (3) Data analysis: Sugar water preference rate = (A / A+B) × 100%.

[0285] Tail suspension test (1) Environmental adaptation: Before testing, animals were placed in the testing environment for 60 min; (2) Formal test: The posterior third of the mouse's tail was fixed with tape, and the mouse was suspended from the stand of the experimental apparatus with its head 15 cm below; (3) The timing recording was started, stopped after 6 minutes, and the immobility time of the mouse was recorded for the next 4 minutes; (4) After the test was completed, the bottom and inner walls of the test box were wiped with 75% alcohol.

[0286] Open field test (1) Environmental adaptation: Before testing, animals were placed in the testing environment for 60 min; (2) Formal test: The test animals were placed in the central position of the open field, and data were collected using ANY-Maze software. The test time was 10 minutes, and feces and urine had to be removed at the end of each round and dried with 75% alcohol disinfectant; (3) Analysis of results: total distance traveled and average speed during the activity, time spent in the central area and time spent in the corners.

[0287] The data were compiled and statistically analyzed using SPSS data statistical software, and images were plotted using Graph Pad software based on the analysis results of SPSS.

[0288] As shown in Figure 57, in the sugar water preference experiment, both TJ0113 30 mg / kg treatment and treatment with the positive drug fluoxetine significantly increased the sugar water preference of mice. As shown in Figure 58, in the tail suspension experiment, the model control group mice spent significantly longer periods of immobility and despair, while both TJ0113 30 mg / kg treatment and treatment with the positive drug fluoxetine significantly reduced this period of despair. As shown in Figure 59, in the open field experiment, the distance traveled by the model control group mice was significantly reduced compared to the control group mice, while both TJ0113 30 mg / kg treatment and treatment with the positive drug fluoxetine significantly increased the distance traveled by the model mice. As shown in Figure 60, in the open field experiment, the model control group mice spent significantly more time in the edge zone of the open field compared to the control group mice, while both TJ0113 30 mg / kg treatment and treatment with the positive drug fluoxetine significantly reduced the time spent in the edge zone of the field by the model mice. As shown in Figure 61, in the open field experiment, the average movement speed of the model control group mice was significantly lower than that of the normal group mice, while treatment with TJ0113 at 10 mg / kg, 30 mg / kg, and the positive drug fluoxetine all significantly increased the average movement speed of the model mice. The above behavioral experiment results indicate that TJ0113 can significantly alleviate depression-like phenotypes in mice.

[0289] Example 17 Treatment of chronic obstructive pulmonary disease After 1 week of dietary adaptation, 5-week-old male SD rats were randomly assigned to five groups according to their body weight: normal control group (n = 10), model control group (n = 10), TJ01-013 7.5 mg / kg treatment group (n = 10), TJ01-013 15 mg / kg treatment group (n = 10), and TJ01-013 30 mg / kg treatment group (n = 10). This model was reproduced by injecting lipopolysaccharide into the airways in combination with passive smoking, which is recognized as a model of chronic obstructive pulmonary disease (COPD). Except for the normal control group, the remaining groups were anesthetized with an intraperitoneal injection of pentobarbital sodium on the first day of modeling. The rats were secured to a rat table, their neck hair removed, and disinfected. A 0.5 cm incision was made in the center of the neck, and the subcutaneous tissue and fascia were separated to expose the rat's trachea. The rat's head was elevated at a 45-degree angle, and a 1 ml syringe filled with 0.2 ml of LPS at a concentration of 1 mg / ml was slowly injected into the rat's airway. After the injection was complete, the rat was lifted by its tail, gently rotated, and shaken to ensure uniform distribution of the drug throughout the rat's airway and lungs. Finally, the surgical wound was sutured. On the second postoperative day, the rats were exposed to passive smoking. A cigarette was inserted into the fumigation chamber, and approximately 10 cigarettes were consumed once per day for 1 hour. The chamber was tapped once every 5 minutes to prevent uneven distribution of smoke in the airway and lung tissue. The normal control group underwent sham surgery without smoking. From the second day of modeling, the normal control group and model control group were forced to orally administer the vehicle (0.5% CMC-Na). The TJ01-013 treatment group received the corresponding concentration of TJ01-013 at a volume of 10ml / kg for a total of 3 weeks. After administration, blood was collected from the rats' retrobulbar vein. The blood was allowed to stand at room temperature for 30 minutes, then centrifuged at 6000 rpm for 10 minutes, and the upper layer of serum was collected. The levels of TNFα and CXCL1 in the serum were detected by enzyme-linked immunosorbent assay (ELISA).

[0290] The results are shown in Figure 62. The serum TNFα and CXCL1 levels of rats in the model group were significantly higher than those in the normal control group. Treatment with 15 mg / kg and 30 mg / kg TJ01-013 both reduced serum CXCL1 levels; treatment with 30 mg / kg TJ01-013 also significantly reduced serum TNFα levels. These results indicate that TJ01-013 treatment can suppress the increase in inflammatory indicators caused by chronic obstructive pulmonary disease and alleviate its symptoms.

[0291] Example 18 Treatment of epilepsy, reduction of epilepsy-induced behavioral and cognitive impairment, and reduction of inflammatory factor levels We selected clean-grade, 8- to 10-week-old male ICR mice to prepare a chronic epileptic mouse model. They were randomly divided into four groups: normal control group (control, 0.5% CMC-Na gavage, n = 8), model group (model, 0.5% CMC-Na gavage, n = 8), TJ01-013-treated group (TJ01-013, 30 mg / kg TJ01-013 gavage, n = 8), and I-14-1-treated group (I-14-1, 30 mg / kg I-14-1 gavage, n = 8). Starting on day 1 of the experiment, mice in each group, except the normal control group, were intraperitoneally injected with 40 mg / kg PTZ at 10:00–11:00 AM every day. The normal control group was injected with the corresponding volume of saline for a total of 21 days. The injections were administered immediately after the start of modeling, once daily for a total of 21 days, and the corresponding tests were performed at the end of the administration period.

[0292] (1) Animal behavior observation Epileptic seizures were graded according to the Racine classification: grade 0, no convulsive response, normal behavior; grade I, facial muscle spasms, rhythmic chewing, eye blinking, and whisker movements; grade II, cervical muscle spasms, head drooping with or without tail upright; grade III, clonic or rhythmic convulsions with forelimb lifting; grade IV, hind limbs straightened or standing upright; grade V, generalized clonic convulsions, standing upright and collapsing, loss of balance. After the experiment, the animals' behavior was observed. The results are shown in Figure 63. The normal control group had no epileptic seizures, while the model group had grade V epileptic seizures. The TJ0113 and I-14-1 treatment groups were able to reduce the epileptic seizure grades through administration, and TJ0113 had a significant difference in alleviating epileptic seizures, indicating that the therapeutic effect of TJ01-013 was significantly better than that of I-14-1.

[0293] (2) Step-down test The platform jumping experiment is an experimental method designed to take advantage of the tendency of experimental mice to quickly jump off a high platform and explore their surroundings. Experimental mice are placed on a high platform and an electric stimulus is administered at the moment of jumping. In this case, animals stop jumping off the high platform to avoid the electric stimulus, but experimental mice with poor learning and memory abilities still maintain the habit of jumping off the high platform. After each experimental round, the surface was sprayed with 75% alcohol and wiped down to prevent odor interference between mice. This experiment was conducted after drug administration. The experimental apparatus was a 30 cm high cubic box with a 10 cm x 10 cm electric fence at the bottom, inside which was placed a 3.2 cm high, 4.2 cm diameter platform. The experimental procedure and process for this experiment were as follows: (1) The mouse was placed in the bottom of the non-electrical experimental apparatus and allowed to freely explore and adapt to the environment for 10 seconds. (2) Mice were placed on a raised platform in the experimental apparatus. The time it took for the mice to jump off the platform was recorded as the initial latency, and electrical stimulation (50 Hz, 20 V, 5 seconds) was administered. (3) After 24 hours, the mice were placed back on the platform, and the time it took for the mice to jump off the platform was recorded as the step-down latency. The time the mice spent on the platform was limited to 60 seconds or less; any time longer than 60 seconds was also recorded as 60 seconds. As shown in Figure 64, the model group had a significantly reduced step-down latency compared to the normal control group, indicating cognitive impairment in the model mice. Both the TJ0113 and I-14-1 groups were able to increase the latency to some extent after administration, and the TJ0113 group showed a significant difference, indicating that the therapeutic effect of TJ01-013 was significantly superior to that of I-14-1.

[0294] (3) Darkness avoidance experiment The dark avoidance experiment was designed to take advantage of the fact that mice tend to be more active in dark environments than in light ones. Mice were placed in the light environment of a device that connected the light and dark environments, and an electrical stimulus was administered when they entered the dark environment. While the animals tended to move in the light environment to avoid the electrical stimulus, experimental mice with poor learning and memory abilities still maintained the habit of entering the dark environment. After each experimental round, the mice were sprayed and wiped with 75% alcohol to prevent odor interference between mice. This experiment was conducted after drug administration. The experimental procedure and process were as follows: (1) The mouse was placed in the light compartment with its back facing the dark compartment. The time it took to enter the dark compartment was recorded as the initial latency. The small door was then closed, and an electrical stimulus (50 Hz, 20 V, 5 seconds) was administered. (2) After 24 hours, the mouse was placed in the light compartment again, and the time it took to enter the dark compartment was recorded as the step-through latency. As shown in Figure 65, the results showed that the post-stimulation latency in the model group was significantly reduced compared to the normal control group, indicating that the mice in the model group had cognitive dysfunction. Both the TJ0113-administered group and the I-14-1-administered group were able to increase the latency to a certain extent after administration, and there was a significant difference with TJ0113, indicating that the therapeutic effect of TJ01-013 was significantly better than that of I-14-1.

[0295] (4) After the mouse experiment, blood was collected and the levels of TNF-α and IL-1β in the serum were measured. Twenty-four hours after the water maze experiment, the mice's whiskers were cut, and their eyes were removed for blood collection. Approximately 0.5 mL of blood was collected in a centrifuge tube, left for 2 hours, and then centrifuged (3000 rpm / min, 10 minutes). The supernatant was collected and frozen for later use. The levels of TNF-α and IL-1β in the serum were detected using ELISA.

[0296] Enzyme-linked immunosorbent assay (ELISA) principle: The sample, standard antibody, and HRP-labeled detection antibody were sequentially added to microwells precoated with mouse TNF-α and IL-1β capture antibodies, incubated, and then thoroughly washed. The substrate TMB was used for color development, converting it to blue through the catalytic action of peroxidase and finally to yellow through the action of acid. The absorbance (OD value) at 450 nm was measured using a microplate reader, and the sample concentration was calculated. As shown in Figure 66, the model group had significantly increased serum TNF-α and IL-1β levels compared with the normal control group, indicating that the model increased serum inflammation levels. Both the TJ0113 and I-14-1 groups were able to reduce serum TNF-α and IL-1β levels to some extent after administration, and the therapeutic effect of TJ01-013 was significantly superior to that of I-14-1.

[0297] Example 19: Alleviation of premature ovarian dysfunction and delay of progression of ovarian dysfunction 1) Chemotherapy-induced POF mouse model Infertility after premature ovarian failure is one of the most serious side effects of chemotherapy in young women with cancer, yet there are no effective treatments for gonadotoxic ovarian damage. Cyclophosphamide (Cy), a commonly used chemotherapy drug that can induce severe ovarian damage, is recognized as a risk factor for POF. Cyclophosphamide can induce primordial follicle damage. Eight-week-old C57BL / 6J mice (approximately 20-25 g body weight) were selected and adaptively fed for 7 days, and then randomly divided into three groups according to body weight: control group (n=8), model group (Cy, vehicle 0.5% CMC-Na administration, n=8), TJ01-013 treatment group (Cy + TJ01-013, 30 mg / kg TJ01-013 gavage administration, n=8), and I-14-1 treatment group (Cy + I-14-1, 30 mg / kg Cy + I-14-1 gavage administration, n=8). The model group and TJ01-013-treated group received a single intraperitoneal injection of cyclophosphamide (75 mg / kg, 200-300 μl), while the control group received a single intraperitoneal injection of the same volume of saline. After 12 days of administration, samples were collected and the body weight, ovarian weight, and serum concentrations of hormones E2 and FSH were measured.

[0298] 2) Measurement of ovarian organ index The body weight and wet weight of both ovaries of each group of mice were measured using an electronic balance and an analytical balance, respectively, and the testis organ index of each group of mice was calculated based on the body weight (g) and wet weight of both ovaries (mg). See the calculation formula below: Testis organ index = wet weight of both testes (mg) / mouse body weight (g).

[0299] As shown in Figure 67, after chemotherapy and 14 days of treatment, there was no significant change in the body weight of the mice, but chemotherapy significantly decreased the ovarian weight, and after treatment with TJ01-013 and I-14-1, the ovarian weight significantly increased. The same chemotherapy significantly decreased the ovarian index (the ratio of ovarian weight to body weight), and after treatment with TJ01-013 and I-14-1, the ovarian index also significantly increased, with TJ01-013 being more effective than I-14-1.

[0300] 3) Elisa detection of serum hormone levels After the experiment reached its end point, orbital blood was collected, and the blood was left at room temperature for 45 minutes, then centrifuged at 12,000 g for 10 minutes. The supernatant (serum) was collected, and the levels of E2, FSH, and BDNF in the serum were detected by ELISA.

[0301] The results, as shown in Figure 68, showed that serum FSH concentrations were significantly higher after chemotherapy modeling compared to the normal modeling group, and serum FSH concentrations were significantly reduced after treatment with TJ01-013 and I-14-1. As shown in Figure 69, serum E2 concentrations were significantly reduced after chemotherapy modeling, and significantly increased after treatment with I-14-1 and TJ01-013. These results indicated that both TJ01-013 and I-14-1 treatment significantly improved mouse ovarian function.

[0302] 4) ELISA detection of BDNF in ovarian tissue.

[0303] Brain-derived neurotrophic factor (BDNF) is a widely studied neurotrophic factor, now known as ovarian endocrine factor, and a growing body of evidence suggests that BDNF plays a role in ovarian follicle development. After the experimental endpoint was reached, mice were euthanized, and the ovaries were removed and crushed to detect BDNF levels in the ovarian tissue by ELISA.

[0304] The results, as shown in Figure 70, showed that after chemotherapy modeling, BDNF levels in ovarian tissue were significantly reduced, while after treatment with TJ01-013 and I-14-1, BDNF levels in ovarian tissue were significantly increased, indicating that TJ01-013 and I-14-1 treatment improved ovarian function in mice. TJ01-013 improved FSH levels, serum E2 levels, and BDNF levels more significantly than I-14-1, with a more significant effect on serum FSH levels.

[0305] Example 20: Treatment of ovarian dysfunction due to natural aging 1) Construction of a naturally aged POF (NA-POF) model The natural aging POF model (NA-POF) simulates the condition of progressive ovarian degeneration. Female C57BL / 6J mice were purchased at 9-10 months of age and raised to 12 months of age. They were then randomly divided into three groups: control group (control, 0.5% CMC-Na gavage, n = 8), TJ01-013-treated group (TJ01-013, 30 mg / kg gavage, n = 8), and I-14-1-treated group (I-14-1, 30 mg / kg gavage, n = 8). The mice were treated daily for a total of 30 days. At the end of the experiment, body weight, ovarian weight, ovarian organ index, and serum hormone E2 and FSH levels were measured.

[0306] 2) Measurement of ovarian organ index The body weight and wet weight of both ovaries of each group of mice were measured using an electronic balance and an analytical balance, respectively, and the ovarian organ index of each group of mice was calculated based on the body weight (g) and wet weight of both ovaries (mg). See the following calculation formula: Ovarian organ index = wet weight of both ovaries (mg) / mouse body weight (g).

[0307] As shown in Figure 71, the results showed that there was no significant change in the body weight of mice after natural aging and treatment with TJ01-013 and I-14-1, but ovarian weight significantly decreased due to aging, and ovarian weight significantly increased after treatment with TJ01-013 and I-14-1. Similarly, ovarian index significantly decreased due to aging, and ovarian index significantly increased after treatment with TJ01-013. I-14-1 treatment did not show a significant increase, but showed a tendency to increase.

[0308] 3) Elisa detection of serum hormone levels After the experiment reached its end point, orbital blood was collected, and the blood was left to stand at room temperature for 45 minutes, then centrifuged at 12,000 g for 10 minutes. The supernatant (serum) was collected, and the levels of E2 and FSH in the serum were detected by ELISA.

[0309] As shown in Figure 72, after treatment with TJ01-013 after aging, serum FSH levels were significantly decreased. As shown in Figure 73, after treatment with TJ01-013 and I-14-1 after aging, serum E2 levels were significantly increased. These results indicate that treatment with both TJ01-013 and I-14-1 can improve the decline in ovarian function in aging mice to some extent, with TJ01-013 being more effective.

[0310] Example 21 Treatment of lupus nephritis 1) Model creation and treatment administration The MRL / lpr mouse is the most classic animal model of lupus and immune-related diseases. This model ultimately develops a systemic lupus erythematosus-like disease characterized by generalized lymphadenopathy, skin lesions, alopecia, infiltrative arthritis, and immune complex deposition-mediated glomerulonephritis. Disease onset typically occurs between 14 and 16 weeks of age. Given that the etiology of SLE is gender-related, with a male-to-female incidence ratio of approximately 1:9, female MRL / lpr mice were selected for this study.

[0311] Ten-week-old female MRL / lpr mice were selected and housed in a specific-pathway (SPF) environment with a 12-hour light-dark cycle and a temperature maintained at 24-26°C. Mice were randomly divided into three groups based on their body weight: the model group (control, n = 8, administered by oral gavage with 0.5% CMC-Na), the TJ01-013 10 mg / kg treatment group (10 mg / kg, n = 8, administered by oral gavage with 10 mg / kg TJ01-013), and the TJ01-013 30 mg / kg treatment group (30 mg / kg, n = 8, administered by oral gavage with 30 mg / kg TJ01-013). The animals were housed for one week for adaptation and then treated daily from week 11. Random urinary protein and urinary creatinine concentrations were monitored every two weeks from week 11 onward in each group, and the urinary protein / creatinine concentration ratio (uPCR) was calculated. The treatment was continued for a total of 10 weeks, and at the end of the treatment, blood was collected from the orbit and serum was measured for serum creatinine, urea nitrogen, serum ANA, and anti-dsDNA concentrations.

[0312] 2) Detection of urinary protein and urinary creatinine concentrations Coomassie brilliant blue staining was used to detect the levels of urinary protein and urinary creatinine. The results are shown in Figure 74. After 10 weeks of administration, the normal group and the TJ01-013-treated group showed essentially the same uPCR trends, both of which were significantly lower than the MRL / lpr model group. This indicates that TJ01-013 treatment can reduce the occurrence of proteinuria.

[0313] 3) Detection of serum creatinine and urea nitrogen Serum creatinine and urea nitrogen were detected by biochemical analyzer. The results are shown in Figure 75. The serum creatinine and urea nitrogen levels of MRL / lpr model mice were significantly increased compared with normal mice. After TJ01-013 treatment, the serum creatinine and urea nitrogen levels of the mice were significantly reduced compared with the model group, indicating that TJ01-013 treatment can significantly alleviate renal function.

[0314] 4) Detection of serum ANA and anti-dsDNA concentrations Serum ANA and anti-dsDNA levels were detected by ELISA. The results are shown in Figures 76-77. The serum ANA and dsDNA levels of MRL / lpr model mice were significantly increased compared to those of normal mice. After treatment with TJ01-013, the serum ANA and dsDNA levels were significantly reduced compared to the model group, indicating that TJ01-013 treatment can significantly reduce systemic lupus erythematosus-specific antibody levels.

[0315] 5) Detection of inflammatory factor levels in kidney tissue The kidney tissue was placed in a homogenizer and thoroughly minced with clean scissors. 400 μl of the lysis solution was added to the homogenizer, homogenized, and placed on ice. This was repeated several times on ice until the kidney tissue was pulverized as much as possible. After 30 minutes of lysis, the lysis solution was transferred to a 1.5 ml centrifuge tube using a pipette and centrifuged at 12,000 rpm for 10 minutes at 4°C. The supernatant was stored at -20°C. ELISA was used to detect the inflammatory factors TNFα and IL-6 in kidney tissue proteins.

[0316] The results are shown in Figure 78. The levels of TNFα and IL-6 in the kidney tissue of MRL / lpr model mice were significantly increased compared with those of normal mice. After TJ01-013 treatment, the levels of TNFα and IL-6 were significantly reduced compared with those of the model group, indicating that TJ01-013 treatment can significantly reduce the inflammation level in kidney tissue.

[0317] Experimental Example 22 Treatment of myocarditis (1) Model construction Eight-week-old male SPF Lewis rats were adaptively housed for one week to establish an autoimmune myocarditis model. They were divided into two groups: a normal control group (normally housed normal rats) and a model group. In the model group, the porcine cardiac myosin used for autoimmune induction was thoroughly mixed with Freund's adjuvant in a 1:1 ratio (purified porcine cardiac myosin was dissolved in PBS to a concentration of 10 g / L, and then mixed with complete Freund's adjuvant (CFA) in a 1:1 ratio under aseptic conditions and thoroughly emulsified to achieve uniformity). A total of 0.2 ml of the immunization mixture was injected subcutaneously into multiple sites, including the groin and axilla, on both sides of the rat. Rats in the normal control group were immunized with PBS and CFA emulsion without myosin. The model groups were divided into three groups starting on day 14 after immunization: the model group (model, 0.5% CMC-Na gavage, n = 8), the TJ01-013-treated group (TJ01-013, 30 mg / kg TJ01-013 gavage, n = 8), and the I-14-1-treated group (I-14-1, 30 mg / kg I-14-1 gavage, n = 8). A normal control group (control, 0.5% CMC-Na gavage, n = 8) was also included. The rats were administered the drugs immediately after grouping for a total of 4 weeks. After the end of the treatment, the rats were weighed, anesthetized, and blood was collected. Serum was extracted to detect corresponding physiological indices. After euthanasia, the rats' hearts were removed and weighed, and cardiac organ indices were calculated.

[0318] (2) Evaluation of cardiac function by echocardiography At the end of drug administration, rats were weighed and anesthetized with an intraperitoneal injection of 10% chloral hydrate. After removing the chest hair, echocardiography was performed in the supine and slightly left lateral positions. Measurement parameters included left ventricular end-diastolic diameter (LVIDd), left ventricular end-systolic diameter (LVIDs), fractional shortening (FS), and ejection fraction (EF). As shown in Figure 79, after immune modeling, both LVIDd and LVIDs were significantly increased in the model group compared to the normal control group. Both TJ01-013 and IL-14-1 treatments were able to reduce LVIDd and LVIDs levels, with TJ01-013 treatment demonstrating a significant improvement over IL-14-1. As shown in Figure 80, after immune modeling, EF and FS were significantly decreased in the model group compared with the normal control group, and both TJ01-013 and I-14-1 treatments could increase EF and FS levels, with TJ01-013 treatment being significantly superior to I-14-1. As shown in Figure 81, after immune modeling, CK-MB levels were significantly increased in the model compared with the normal control group, and both TJ01-013 and I-14-1 treatments could reduce CK-MB levels, with TJ01-013 treatment being significantly superior to I-14-1.

[0319] Experimental Example 23: Treatment of stroke Stroke is a disease that seriously threatens human health. The incidence of stroke is increasing year by year worldwide. In Japan, it is the disease with the highest disability rate, placing a serious burden on society and the economy. Late-stage stroke rehabilitation is an important and difficult problem that needs to be solved urgently in clinical practice.

[0320] Stroke is a serious cerebrovascular disease and one of the leading causes of long-term disability and premature death. Most strokes (approximately 80%) are ischemic strokes (i.e., cerebral ischemia) caused by vascular occlusion, primarily due to arterial thrombosis. Currently, stroke poses a serious threat to human health. The incidence of stroke is increasing year by year worldwide. It is the disease with the highest disability rate in Japan, placing a significant burden on society and the economy. Late-stage stroke rehabilitation is an important and challenging issue that urgently needs to be resolved in clinical practice. Rapid restoration of blood supply is the most effective way to treat ischemic stroke. However, ischemia-reperfusion injury caused by revascularization can further exacerbate brain damage and neuromotor dysfunction, making neurological recovery a critical issue that urgently needs to be resolved.

[0321] (1) Model construction The middle cerebral artery occlusion (MACO) model is a focal cerebral ischemia model and is the most widely used. The pathogenesis of this model is similar to that of ischemic stroke, and it is easy to operate and allows precise control of reperfusion characteristics. The middle cerebral artery (MCA) is responsible for the largest blood supply to the brain, and occlusion primarily causes cortical and striatal lesions. The extent of infarction depends on the location and duration of occlusion and the amount of collateral circulation in the MCA.

[0322] Male SD rats aged 7-8 weeks were selected and reared for one week to establish a rat medium artery occlusion model. The rats were anesthetized using a small animal anesthesia machine, followed immediately by maintenance anesthesia. The rats were placed in a supine position on the operating table. The central and right sides of the neck were shaved and disinfected with alcohol and povidone-iodine. After a central neck incision was made, the carotid artery was separated from the tissue under a microscope to prevent bleeding and avoid damaging blood vessels or nerves. The small arteries on the side branches were cut with an electrocoagulator, and the external carotid artery was ligated with another loose knot for later use. The proximal ends of the internal carotid artery and common carotid artery were clipped with an artery clip. The external carotid artery was cut at a 45° angle with surgical scissors, and a suture plug was carefully inserted. The marked point reached the bifurcation point of the internal and external carotid arteries, indicating that the tip of the suture plug had reached the middle cerebral artery. The skin was sutured, and the animals were observed for symptoms and neurological function after awakening. Two hours after surgery, the sutures were cut, the suture plug was removed, and the external carotid artery stump was tightly ligated. The skin was re-suturized, and careful postoperative care was given to the rats. After modeling, rats were divided into three groups: the model group (model, 0.5% CMC-Na gavage, n = 8), the TJ01-013-treated group (TJ01-013, 30 mg / kg TJ01-013 gavage, n = 8), and the I-14-1-treated group (I-14-1, 30 mg / kg I-14-1 gavage, n = 8). A normal control group (control, 0.5% CMC-Na gavage, n = 8) underwent the corresponding surgical procedure, but without carotid artery ligation or suture plug insertion. The rats were treated for a total of 8 weeks. After the treatment period, the rats' cognitive functions were tested using a water maze.

[0323] Ischemic stroke causes insufficient perfusion of brain tissue, making it prone to ischemia and hypoxia during surgery, and the accumulation of large amounts of calcium ions in brain tissue can damage brain tissue and lead to a decline in cognitive function after surgery.

[0324] (2) Water maze experiment The night before the experiment, the experimental room and water maze were cleaned, the water maze water source was emptied, and animal waste was removed. The experimental room was ventilated and odor-free. The water maze was filled with clean water, and the water level should be approximately 2 cm higher than the platform. All four groups of rats underwent five days of water maze adaptation training. This training was divided into four days of stereotactic navigation and one day of spatial exploration. The water maze apparatus consisted of a circular pool, equally divided into quadrants I, II, III, and IV at four equidistant points on the pool wall. A circular hidden platform was located in the center of quadrant IV. Fixed reference objects were placed around the pool, and the pool and platform were black. Black ink was poured into the water and mixed thoroughly to prevent the rats from seeing the circular platform. The water temperature was maintained at 22–24°C, and the room lighting was stable. After administration to each group of rats, a water maze test was conducted to test the cognitive status of the experimental animals. Each time, rats were placed in the pool facing the wall from one of the three quadrants, excluding the quadrant containing the platform. If the rats failed to find the platform hidden under the water in the target quadrant within 2 minutes, they were guided to the platform in the target quadrant and allowed to remain there for 15 seconds. All four groups of rats underwent this training four times a day, twice in the morning and twice in the afternoon, for four days. At the end of each training session, the experimenter thoroughly cleaned the water maze apparatus to prevent the rats' odor from affecting the results on the second day of the experiment. The time from when the rats were placed in the water facing the wall of the pool until they climbed onto the hidden platform in the target quadrant was recorded. This was defined as the escape latency, and the average of the four results was taken. Each stereotactic navigation experiment had a time limit of 60 seconds. If the rats failed to find the hidden platform in the target quadrant within the time limit, the experimenter guided the rats to the hidden platform and allowed them to remain there for 15 seconds to memorize the platform, after which the rats' escape latency was measured. The escape latency for the rats in this experiment was recorded as 60 seconds. Towels and hairdryers were prepared for the experiment, and after each swimming session, the rats were wiped with towels and dried with a hairdryers to prevent them from catching a cold. The experiment was carried out as quietly as possible to avoid interference.As shown in Figure 82, the model group had a significantly increased escape latency compared with the normal control group, and the escape latency of both the TJ0113 and I-14-1 administration groups could be shortened by drug administration, indicating that TJ0113 and I-14-1 have therapeutic functions and that the therapeutic effect of TJ01-013 is significantly better than that of I-14-1.

[0325] After the above experiment was completed, the platform was removed for the spatial exploration experiment. A central location in the quadrant facing the circular hidden platform was selected, and the rat was placed in the pool and allowed to swim for 60 seconds. The number of times the rat crossed the circular hidden platform in the center of the target quadrant during the 60 seconds was recorded as the number of times the rat crossed the platform. As shown in Figure 83, the number of times the rats crossed the platform was significantly reduced in the model group compared to the normal control group. Both the TJ0113 and I-14-1 treatment groups increased the number of times the rats crossed the platform, and TJ01-013 significantly shortened the escape latency, indicating that TJ0113 and I-14-1 have therapeutic functions and that the therapeutic effect of TJ01-013 is significantly better than that of I-14-1.

[0326] Flow cytometric determination of apoptosis in rat hippocampal neurons At the end of drug administration and behavioral testing, all rats were sacrificed by intraperitoneal injection of chloral hydrate. Their heads were rapidly decapitated, their brains removed, and hippocampal tissue was rapidly isolated on ice. The hippocampal tissue was weighed, and approximately 1 g of the required amount was placed on a 100-mesh copper mesh. The connective tissue membrane on the surface was cut off, and buffer solution was added. The tissue was finely cut and gently rubbed with tweezers. The single-cell suspension was then filtered through a 300-mesh nylon mesh to remove large aggregates. The collected cell suspension was then centrifuged at 3000 rpm, a radius of 10 cm, and a centrifugal force of 13000 g for 5 minutes. The supernatant was discarded, and 500 μl of 1× buffer solution was added. 1×10 5 ~5×10 5A single-cell suspension was prepared at a concentration of 1 / L. 5 μL of phospholipid-binding protein V (Annexin V) was added first, followed by 10 μL of propidium iodide (PI), mixed thoroughly, and incubated for 5 minutes in the dark. The procedure was performed based on the instructions and instructions provided, combined with practical experience. The fluorescence intensity of apoptotic hippocampal neurons was detected by flow cytometry, and the apoptosis rate of hippocampal neurons was calculated. As shown in Figure 84, the apoptosis rate of rat hippocampal neurons was significantly increased in the model group compared to the normal control group. Both TJ0113 and I-14-1 treatment groups significantly reduced the apoptosis rate of hippocampal neurons. This indicates that TJ0113 and I-14-1 have therapeutic functions, and that the therapeutic effect of TJ01-013 is significantly superior to that of I-14-1.

[0327] Example 24 Treatment of tinnitus Seven-week-old C57BL / 6 male mice were screened for tinnitus-free mice using the acoustic startle (AS) response and gap prepulse inhibition of the acoustic startle (GPIAS) response. Seven-week-old C57BL / 6 male mice with normal hearing were screened for tinnitus-free mice using the acoustic startle (AS) response and gap prepulse inhibition of the acoustic startle (GPIAS). Mice were randomly divided into five groups: normal control group (n = 10), model control group (n = 10), TJ01-013 7.5 mg / kg treatment group (7.5 mg / kg, n = 10), TJ01-013 15 mg / kg treatment group (15 mg / kg, n = 10), and TJ01-013 30 mg / kg treatment group (30 mg / kg, n = 10). Except for the normal control group, all other groups were modeled using an intraperitoneal injection of 450 mg / kg sodium salicylate. The normal control group received an intraperitoneal injection of a corresponding volume of saline, and drug administration began on the day of modeling. Of these, the normal control and model control groups were administered vehicle (0.5% CMC-Na) by oral gavage. The TJ01-013-treated group received an equivalent concentration of TJ01-013 at a volume of 10 ml / kg. After four consecutive days of administration, acoustic startle activity was measured again 3 hours after the final administration. The behavioral test, a pair of AS and GPLAS responses, was used to detect the presence of tinnitus. Before the test, all mice were placed in a transparent box for one minute and allowed to adapt for three consecutive days. The background noise used in the experiment was narrowband noise at 8 kHz and 16 kHz with a bandwidth of 1 kHz to understand the frequency range in which tinnitus occurs. During the GPIAS experiments, each mouse was placed in a transparent box in a darkened room, which was placed over a sensitive piezoelectric transducer that generated a voltage proportional to the magnitude of the response evoked by the sound generated by a digital signal processor. The output of the platform was amplified, sampled, and stored on a computer for offline analysis.The GPIAS consisted of 100 tests with a front gap (gap tests) and 100 tests without a front gap (no gap tests), and the front gap and no gap tests were randomly paired. The severity of tinnitus was calculated as the ratio of the amplitude of the response evoked by the front gap stimulus to the amplitude of the response evoked by the no gap stimulus (Ratio = gap / no gap × 100%).

[0328] As shown in Figure 85, the AS response amplitude ratio of the tinnitus model group injected with sodium salicylate was significantly higher than that of the vehicle group under noise exposure at 8 kHz and 16 kHz, indicating successful modeling; the AS response amplitude ratio of the TJ0113-treated group was significantly reduced compared to that of the model group and showed dose-dependence, indicating that TJ0113 significantly improved tinnitus disease in mice.

[0329] Experimental Example 25 Treatment of Multiple Sclerosis The currently recognized pathogenesis of multiple sclerosis (MS) is that an abnormal immune attack damages the blood-brain barrier, allowing various inflammatory factors and immune cells to invade the central nervous system and act on microglia and immune cells in the central nervous system, resulting in an inflammatory response that leads to myelin loss, neuronal death, and axonal damage. Current treatments for MS primarily consist of anti-inflammatory drugs, but these are only effective during the relapsing and remission phases of the disease. Therefore, the development of a treatment for MS is an urgent issue. The CUP model induces demyelination in mice through the dietary addition of CUP, which can be used to simulate multiple sclerosis. CUP is a copper chelator that is added to animal feed and ultimately induces oligodendrocyte apoptosis, leading to demyelination.

[0330] 1. Building the Model After 1 week of dietary adaptation, 7-8 week-old C57BL / 6 female mice were randomly divided into four groups according to body weight: normal control group (control, 0.5% CMC-Na gavage, n = 8), model group (model, 0.5% CMC-Na gavage, n = 8), TJ01-013-treated group (TJ01-013, 30 mg / kg TJ01-013 gavage, n = 8), and I-14-1-treated group (I-14-1, 30 mg / kg I-14-1 gavage, n = 8). The normal control group was fed a basal diet for 12 weeks, while the model group, TJ01-013-treated group, and I-14-1-treated group were fed a 0.2% CUP diet throughout the entire period. Treatment for all groups began 6 weeks after modeling and continued for a total of 12 weeks. The administration volume was 5 ml / kg.

[0331] 2. Behavioral Testing (1) Elevated plus maze test The elevated plus maze consisted of two open arms (35cm x 6cm), two closed arms (35cm x 6cm x 14cm), and a middle area (6cm x 6cm), elevated 70cm above the ground. Mice were placed in the middle area facing the open arms and allowed to move around within the 50cm x 50cm open field for 5 minutes before the start of the test. The activity time, activity distance, and number of times mice entered the open arms during the test were recorded. After each mouse was tested, the maze was wiped with 75% alcohol. The experimental results are shown in Figure 86. Compared to the control group, the number of times mice entered the open arms in the model group was significantly increased. After treatment with TJ01-013 and I-14-1, the number of times mice entered the open arms was significantly decreased. Both treatments were statistically significant, and TJ01-013 treatment was significantly superior to I-14-1. As shown in Figure 87, compared with the control group, the distance walked by the mice in the model group in the open arms was significantly increased, and after treatment with TJ01-013 and I-14-1, the distance walked by the mice in the open arms was decreased, with TJ01-013 treatment being significantly superior to I-14-1 and statistically significant difference. As shown in Figure 88, compared with the control group, the time spent by the mice in the model group in the open arms was significantly increased, and after treatment with TJ01-013 and I-14-1, the time spent by the mice in the open arms was significantly decreased, with both statistically significant difference, with TJ01-013 treatment being significantly superior to I-14-1.

[0332] (2) Water maze test Mice were placed in a 70 cm diameter, 30 cm high tank with water temperature at approximately 22-24°C. The tank was divided into four quadrants, and a 5 cm diameter platform, placed 1 cm below the water surface, was placed in the target quadrant. Before the formal test, mice were allowed to acclimate for one day and then train for four days. During training, mice were guided to enter the tank against the wall and then find the platform for 60 seconds. Otherwise, they were guided to train on the platform for 30 seconds. The time it took to find the platform during the training period was recorded. On the day of testing, the platform was removed, and the number of times the mice crossed the platform after entering from the quadrant opposite the target quadrant was recorded to measure the mice's spatial learning and memory abilities. As shown in Figure 89, compared with the normal group, in the model group, the number of times the mice crossed the platform was significantly reduced, and after treatment with TJ01-013 and I-14-1, the number of times the mice crossed the platform was increased, and TJ01-013 treatment was significantly superior to I-14-1, with a statistically significant difference.

[0333] It will be understood by those skilled in the art that the above-described embodiments are specific examples for implementing the present invention, and that in actual applications, various changes in form and details may be made without departing from the spirit and scope of the present invention.

Claims

1. (i) the preparation of a medicament for the prevention and / or treatment of diseases associated with renal impairment; and / or (ii) prevention and / or treatment of diseases associated with renal impairment; and / or (iii) prevention and / or treatment of diseases associated with mitochondrial dysfunction; and / or (iv) the preparation of a medicament for the prevention and / or treatment of a disease associated with mitochondrial dysfunction; and / or (v) for the manufacture of cosmetics or medical devices; 1. Use of a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which is used in: (where Z is or a sulfur atom; R １ is hydrogen, C １～６ Alkyl, Here, R １１ and R １２ are each independently C １～６ Alkyl or C １～６ cycloalkyl, and n is 1 to 4; R ２ is hydrogen, C １～６ alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom is R ２－１ C substituted with １～６ alkyl, at least one hydrogen is R ２－１ phenyl substituted with, where R ２－１ is hydroxyl, halogen, amino or C １～６ is an alkoxy; R ３ teeth Here, R ３－１ is hydrogen, hydroxyl, C １～６ Alkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, 3- to 6-membered epoxyalkyl, amino, C １～６ Amine group, —CH ２ C(O)R ３－２ , -CH ２ C(O)OR ３－２ , -CH ２ C(O)N(R ３－２ R ３－２ａ ) and R ３－２ and R ３－２ａ are each independently hydrogen, C １～６ alkyl or 3- to 6-membered cycloalkyl; m is 1 to 6, and Ar is phenyl, naphthyl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, at least one hydrogen atom is R ３－３ phenyl substituted with at least one hydrogen atom of R ３－３ naphthyl substituted with at least one hydrogen atom of R ３－３ 5- or 6-membered monocyclic heteroaryl substituted with at least one hydrogen atom of R ３－３ and R is an 8- to 10-membered fused bicyclic heteroaryl substituted with ３－３ is hydrogen, halogen, C １～６ Alkyl, 3- to 6-membered cycloalkyl, hydroxyl, C １～６ Alkoxy, 3-6 membered epoxy alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, —N(R ３－３ａ R ３－３ｂ ) or phenyl, R ３－３ａ and R ３－３ｂ are each independently hydrogen, C １～６ alkyl or 3- to 6-membered cycloalkyl; Here, R ４－１ is phenyl, naphthyl, at least one hydrogen atom is R ４－１１ phenyl substituted with 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is R ４－１１ a 5- or 6-membered monocyclic heteroaryl substituted with 8- to 10-membered fused bicyclic heteroaryl; ４－１１ and R is an 8- to 10-membered fused bicyclic heteroaryl substituted with ４－１１ is hydrogen, halogen, nitro, nitrile, hydroxyl, C １～６ Alkyl, C ３～６ Cycloalkyl, C １～６ Alkoxy, —N(R ４－１ａ R ４－１ｂ ), phenyl, C １～６ Haloalkyl, C １～６ Haloalkoxy, —C(O)OR ４－１２ , -C(O)R ４－１２ , -C(O)N(R ４－１ａ R ４－１ｂ ), -S(O) ２ R ４－１２ , -S(O)R ４－１２ , -OC(O)R ４－１２ , -OC(O)OR ４－１２ or R ４－１２ , R ４－１ａ and R ４－１ｂ are each independently hydrogen, C １～６ Alkyl, C ３～６ Cycloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C in which at least one hydrogen is replaced by halogen １～６ Alkyl, C in which at least one hydrogen is replaced by halogen ２～６ Alkenyl, C in which at least one hydrogen is replaced by halogen ３～６ Cycloalkyl, C in which at least one hydrogen is replaced by halogen ２～６ alkynyl, and R ４－１ａ and R ４－１ｂ are bonded to each other to form a ring, R ４－２ is C １～６ Alkyl, C ３～６ Cycloalkyl, C in which at least one hydrogen is replaced by hydroxyl １～６ Alkyl, C ３～６ epoxyalkyl; or R ２ is C １～６ Alkyl and R ４－２ is C １～６ When R is alkyl, ４－２ and R ２ are bonded to form a 4- to 8-membered ring, R ４－３ is C １～６ Alkyl or C １～６ is alkoxy; R ５ The number of is 0 to 5, and R ５ is independently in each occurrence hydrogen, halogen, nitro, nitrile, -N ＋ (R ５－１ ) ３ , C １～６ Haloalkyl, —C(O)OR ５－１ , -C(O)R ５－１ , -C(O)N(R ５－１ R ５－１ａ ), -S(O) ２ R ５－１ , -S(O)R ５－１ , -S(O) ２ N (R ５－１ R ５－１ａ ), -S(O)N(R ５－１ R ５－１ａ ), -N=C(R ５－１ R ５－１ａ ), hydroxyl, C １～６ alkyl, phenyl, at least one hydrogen is R ５－１ phenyl substituted with C １～６ Alkoxy, —N(R ５－１ R ５－１ａ ), -N(R ５－１ ) C(O)R ５－１ａ , -N(R ５－１ )C(O)OR ５－１ａ , -N(R ５－１ )C(O)N(R ５－１ａ R ５－１ｂ ), -OC(O)R ５－１ , -OC(O)OR ５－１ , -OC(O)N(R ５－１ R ５－１ａ ) or -SR ５－１ where R ５－１ , R ５－１ａ and R ５－１ｂ are each independently hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C in which at least one hydrogen is replaced by halogen １～６ Alkyl, C in which at least one hydrogen is replaced by halogen ２～６ Alkenyl or C in which at least one hydrogen is replaced by halogen ２～６ It is alkynyl.

2. The Z is or a sulfur atom; R １ is hydrogen, C １～４ Alkyl, Here, R １１ and R １２ are each independently C １～４ Alkyl or C １～４ cycloalkyl, and n is 1 or 2; R ２ is hydrogen, C １～４ alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered epoxyalkyl, phenyl, at least one hydrogen atom is R ２－１ C substituted with １～４ alkyl, at least one hydrogen is R ２－１ phenyl substituted with, where R ２－１ is hydroxyl, halogen, amino or C １～４ is alkoxy; R ３ teeth Here, R ３－１ is hydrogen, hydroxyl, C １～４ Alkyl, C １～４ Alkoxy, —N(R ３－２ R ３－２ａ ) and R ３－２ and R ３－２ａ are each independently hydrogen or C １～４ is alkyl, m is 1 to 4, Ar is phenyl, 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom is R ３－３ 5- or 6-membered monocyclic heteroaryl substituted with R ３－３ is hydrogen, halogen, C １～４ Alkyl, hydroxyl, C １～４ Alkoxy, C １～４ haloalkyl or —N(R ３－３ａ R ３－３ｂ ) and R ３－３ａ and R ３－３ｂ are each independently hydrogen or C １～４ is alkyl; R ４ teeth Here, R ４－１ is phenyl, and at least one hydrogen atom is R ４－１１ phenyl substituted with 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is R ４－１１ and R is a 5- or 6-membered monocyclic heteroaryl substituted with ４－１１ is hydrogen, halogen, nitro, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Alkoxy, —N(R ４－１ａ R ４－１ｂ ), phenyl, C １～４ Haloalkyl, C １～４ haloalkoxy or R ４－１ａ and R ４－１ｂ are each independently hydrogen, C １～４ Alkyl or C ３～６ is cycloalkyl, and R ４－１ａ and R ４－１ｂ can be linked together to form a ring, R ４－２ is C １～４ Alkyl, C ３～５ Cycloalkyl, C in which at least one hydrogen is replaced by hydroxyl １～４ Alkyl, C ３～５ epoxyalkyl; or R ２ is C １～４ Alkyl and R ４－２ is C １～４ When R is alkyl, ４－２ and R ２ are bonded to form a 4- to 8-membered ring, R ４－３ is C １～４ Alkyl or C １～４ is alkoxy; R ５ are each independently hydrogen, halogen, nitro, nitrile, -N ＋ (R ５－１ ) ３ , C １～４ Haloalkyl, —C(O)OR ５－１ , -C(O)R ５－１ , -C(O)N(R ５－１ R ５－１ａ ), -S(O) ２ R ５－１ , -S(O)R ５－１ , -N=C(R ５－１ R ５－１ａ ), hydroxyl, C １～４ alkyl, phenyl, at least one hydrogen is R ５－１ phenyl substituted with C １～４ Alkoxy, —N(R ５－１ R ５－１ａ ), -N(R ５－１ ) C(O)R ５－１ａ or -OC(O)R ５－１ where R ５－１ , R ５－１ａ and R ５－１ｂ are each independently hydrogen, C １～４ Alkyl, C in which at least one hydrogen is replaced by halogen １～４ 2. The use according to claim 1, characterized in that it is alkyl.

3. The Z is or a sulfur atom; and / or R １ is hydrogen, Here, R １１ and R １２ are each independently methyl, ethyl, n-propyl, or isopropyl, and n is 1; and / or R ２ is hydrogen, methyl, ethyl, n-propyl, isopropyl, ethyl in which one hydrogen is replaced by hydroxyl, n-propyl in which one hydrogen is replaced by hydroxyl, phenyl, and / or R ３ teeth Here, R ３－１ is hydrogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy or isobutoxy; m is 1, Ar is phenyl, a 5- or 6-membered nitrogen-containing monocyclic heteroaryl; and / or R ４ teeth Here, R ４－１ is phenyl, and at least one hydrogen is R ４－１１ phenyl substituted with 5- or 6-membered monocyclic heteroaryl, at least one hydrogen atom of which is R ４－１１ a 5- or 6-membered monocyclic heteroaryl substituted with 8- to 10-membered fused bicyclic heteroaryl; ４－１１ and R is an 8- to 10-membered fused bicyclic heteroaryl substituted with ４－１１ is halogen, nitro, methyl, ethyl, n-propyl, isopropyl, Fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo-n-propyl, iodoisopropyl, fluoromethoxy, fluoroethoxy, fluoro-n-propoxy, fluoroisopropoxy, chloromethoxy, chloroethoxy, chloro-npropoxy, chloroisopropoxy, bromomethoxy, bromoethoxy, bromo-n-propoxy, bromoisopropoxy, iodomethoxy, iodoethoxy, iodo-n-propoxy, iodoisopropoxy or R ４－２ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, ethyl in which one hydrogen is replaced by hydroxyl, n-propyl in which one hydrogen is replaced by hydroxyl, n-butyl in which one hydrogen is replaced by hydroxyl, or phenyl, or R ２ is methyl, ethyl or n-propyl, and R ４－２ is methyl or ethyl, R ４－２ and R ２ are bonded to form a 4- to 8-membered ring, R ４－３ is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy; and / or R ５ are each independently hydrogen, halogen, nitro, nitrile, -N ＋ (R ５－１ ) ３ , fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, bromoisopropyl, —C(O)OR ５－１ , -C(O)R ５－１ , -C(O)N(R ５－１ R ５－１ａ ), -S(O) ２ R ５－１ , -S(O)R ５－１ , -N=C(R ５－１ R ５－１ａ ), hydroxyl, methyl, ethyl, n-propyl, isopropyl, phenyl, at least one hydrogen atom is R ５－１ phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, -N(R ５－１ R ５－１ａ ), -N(R ５－１ ) C(O)R ５－１ａ , -OC(O)R ５－１ where R ５－１ , R ５－１ａ and R ５－１ｂ are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, fluoro-n-propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro-n-propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo-n-propyl, or bromoisopropyl.

4. Z is or a sulfur atom; and / or R １ is hydrogen, and / or R ２ is hydrogen, methyl, or phenyl; and / or R ３ teeth and / or R ４ teeth Here, R ４－１ is phenyl, and at least one hydrogen is R ４－１１ phenyl substituted with 5-membered monocyclic heteroaryl, at least one hydrogen atom is R ４－１１ a 5-membered monocyclic heteroaryl, a 9-membered fused bicyclic heteroaryl, or naphthyl substituted with R ４－１１ are bromine, fluorine, chlorine, methyl, nitro, phenyl, trifluoromethyl, methoxy, cyclopropyl, trifluoromethoxy, nitro or R ４－２ is methyl, ethyl, or phenyl, or R ２ is methyl, ethyl or n-propyl, and R ４－２ is methyl or ethyl, R ４－２ and R ２ are bonded to form a 4- to 6-membered ring, R ４－３ is methoxy, ethoxy, n-propoxy or isopropoxy; and / or R ５ each occurrence independently represents halogen, nitro, nitrile, carboxyl, —NHC(O)CH ３ , methoxy or hydroxyl.

5. 2. The use according to claim 1, characterized in that the compound is selected from any one of the following compounds:

6. The diseases associated with kidney damage include acute kidney injury and chronic kidney injury, preferably chronic kidney injury; and / or the disease associated with mitochondrial dysfunction is selected from at least one of inflammatory bowel disease; lung injury; fibrotic disease; sepsis; prostate disease; cardiovascular disease; neurological disease; and ageing-related disease.

7. The disease associated with kidney damage is selected from the group consisting of acute renal ischemia-reperfusion injury, septic nephropathy, nephrotoxic injury, primary glomerulonephritis, hypertensive renal arteriosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial lesions, ischemic nephropathy, lupus nephritis, and hereditary nephropathy; and / or the inflammatory bowel disease is selected from at least one of ulcerative colitis and Crohn's disease; and / or the lung injury is selected from at least one of acute lung injury and chronic lung injury; and / or the fibrotic disease is selected from at least one of tubulointerstitial fibrosis, interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease fibrosis, tissue fibrosis, arthrofibrosis, liver fibrosis, skin fibrosis, fibromatosis, myelofibrosis, cardiac fibrosis, and cystic fibrosis; and / or the cardiovascular disease is selected from at least one of atherosclerosis, heart damage, myocardial ischemia / reperfusion injury and hypertension, cardiomyopathy, and diabetic cardiovascular complications; and / or said neurological disorder is selected from at least one of sensorineural hearing loss, abnormalities of brain development, congenital hydrocephalus, congenital cranial nerve diseases, congenital perforating vein malformations, metabolic dysfunction, congenital auditory aphasia, congenital visual aphasia, cerebral palsy, autism, depression, schizophrenia, bipolar disorder, delusional disorder, mania, obsessive-compulsive disorder, psychiatric disorders such as autism, Parkinson's disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, epilepsy, Huntington's disease, spinocerebellar ataxia, cerebral ischemia, stroke (preferably ischemic stroke), multiple sclerosis, and tinnitus; and / or the use according to claim 6, characterized in that the ageing-related disease is progeria, early-onset ovarian failure, natural ageing ovarian failure or skin ageing.

8. The tubulointerstitial lesion is selected from the group consisting of chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, and drug-induced nephropathy; and / or the chronic lung injury is chronic obstructive pulmonary disease.

9. 8. The use according to claim 7, wherein the hereditary nephropathy is selected from the group consisting of polycystic kidney disease and hereditary nephritis.

10. A method for preventing and / or treating a disease associated with renal impairment, comprising administering to a subject a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

11. A method for preventing and / or treating a disease associated with mitochondrial dysfunction, comprising the step of administering to a subject a therapeutically effective amount of a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

12. The method according to claim 11, characterized in that the disease associated with mitochondrial dysfunction is a cardiovascular disease, and the method comprises a step of co-administering a therapeutically effective amount of a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof and Entresto to a subject.

13. The method according to claim 11, wherein the disease associated with mitochondrial dysfunction is benign prostatic hyperplasia, and the method comprises administering to a subject a therapeutically effective amount of a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof in combination with finasteride.

14. A composition characterized in that it is a cosmetic or medical device composition comprising a compound represented by general formula (I) and an adjuvant acceptable for cosmetics or medical devices.

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