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CN-122003408-A - Triazole compound having novel ring structure, process for producing the same, and use thereof

CN122003408ACN 122003408 ACN122003408 ACN 122003408ACN-122003408-A

Abstract

The present invention relates to a triazole compound having a novel ring structure, a method for producing the same, and use thereof. The triazole compound having a novel ring structure according to the present invention exhibits excellent ASK1 inhibitory ability and inhibits apoptosis of neurons, and thus is useful for preventing or treating ASK 1-related diseases including neurodegenerative diseases, cardiovascular diseases, autoimmune diseases and liver diseases.

Inventors

  • LI GUANGHAO
  • SONG ZHENSHU
  • JIN CHENGHUAN
  • AN XUANZHU
  • Cai Zhongxue
  • K. B. dogilara
  • LI YOUZHEN
  • Chi Xiangxi
  • ZHANG ZHIYUN

Assignees

  • 韩国化学研究院

Dates

Publication Date
20260508
Application Date
20240712
Priority Date
20230712

Claims (17)

  1. 1. A compound represented by chemical formula 1, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof: Chemical formula 1: ; Wherein, the Is a substituted or unsubstituted phenyl or a substituted or unsubstituted C 3-8 cycloalkenyl; wherein the substituted phenyl and the substituted C 3-8 cycloalkenyl are each independently substituted with C 1-6 alkyl, C 1-6 alkoxy or halogen, and R 1 、R 2 and R 3 are each independently H, C 1-6 alkyl, halogen, C 3-6 cycloalkyl or halogenated C 1-6 alkyl.
  2. 2. The compound represented by chemical formula 1, or a stereoisomer, solvate, hydrate or pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein, Is a substituted or unsubstituted phenyl group or a substituted or unsubstituted C 5-8 cycloalkenyl group, Wherein the substituted phenyl and the substituted C 3-8 cycloalkenyl are each independently substituted with C 1-3 alkyl, C 1-3 alkoxy or halogen, and R 1 、R 2 and R 3 are each independently H, C 1-3 alkyl, halogen, C 3-6 cycloalkyl or halogenated C 1-3 alkyl.
  3. 3. The compound represented by chemical formula 1, or a stereoisomer, solvate, hydrate or pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein, Is phenyl or C 5-8 cycloalkenyl containing one double bond; Wherein, the R 1 is C 3-6 cycloalkyl; r 2 is C 1-3 alkyl, and R 3 is halogen.
  4. 4. The compound represented by chemical formula 1, or a stereoisomer, solvate, hydrate or pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein, Is phenyl or C 5-8 cycloalkenyl containing one double bond; wherein R 1 is cyclopropyl; R 2 is methyl, and R 3 is fluorine.
  5. 5. The compound represented by chemical formula 1, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound represented by chemical formula 1 is selected from the group consisting of: <1> N- (6- (1H-benzo [ d ] [1,2,3] triazol-1-yl) pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide; <2> 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5, 6-dihydropyran-o [ d ] [1,2,3] triazol-1 (4H) -yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide; <3> 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (4, 5,6, 7-tetrahydro-1H-benzo [ d ] [1,2,3] triazol-1-yl) pyridin-2-yl) methylbenzamide; <4> 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5, 6,7, 8-tetrahydrocyclohepta [ d ] [1,2,3] triazol-1 (4H) -yl) pyridin-2-yl) benzamide, and <5> 5- (4-Cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (4, 5,6,7,8, 9-hexahydro-1H-cycloocta [ d ] [1,2,3] triazol-1-yl) pyridin-2-yl) -4-methylbenzamide.
  6. 6. The compound represented by chemical formula 1, or a stereoisomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound inhibits ASK1.
  7. 7. A method of preparing the compound represented by chemical formula 1 according to claim 1, comprising: As shown in reaction scheme 1, the compound represented by chemical formula 2 is reacted with the compound represented by chemical formula 3 to prepare the compound represented by chemical formula 1: reaction scheme 1: ; Wherein, the The definitions of R 1 、R 2 and R 3 are the same as those in chemical formula 1 described in claim 1.
  8. 8. A pharmaceutical composition comprising the compound represented by chemical formula 1, or a stereoisomer, solvate, hydrate or pharmaceutically acceptable salt thereof, according to claim 1.
  9. 9. A pharmaceutical composition for preventing or treating ASK 1-related diseases, comprising the compound represented by chemical formula 1, or a stereoisomer, solvate, hydrate or pharmaceutically acceptable salt thereof, as an active ingredient, according to claim 1.
  10. 10. The pharmaceutical composition of claim 9, wherein the ASK 1-related disease is a neurodegenerative disease, a cardiovascular disease, an autoimmune disease, or a liver disease.
  11. 11. The pharmaceutical composition of claim 10, wherein the neurodegenerative disease is one or more selected from the group consisting of Alzheimer's disease, hippocampal sclerosis, frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), huntington's disease, corticobasal degeneration, amyotrophic lateral sclerosis, spinal muscular atrophy, motor neuron disease, inclusion body myositis, parkinson's disease, lewy body dementia, lewy body disease, multiple system atrophy, progressive supranuclear palsy, pick's disease, prion disease, traumatic brain injury, ischemic and hemorrhagic stroke, cerebral ischemia, hypoxia and glutamate neurotoxicity.
  12. 12. The pharmaceutical composition of claim 10, wherein the cardiovascular disease is one or more selected from the group consisting of heart failure, ischemia, recurrent ischemia, myocardial infarction, arrhythmia, acute coronary syndrome, diabetes, atherosclerosis, and intermittent claudication.
  13. 13. The pharmaceutical composition of claim 10, wherein the autoimmune disease is one or more selected from the group consisting of rheumatoid arthritis, fibromyalgia, systemic lupus erythematosus, multiple sclerosis, diabetes, systemic sclerosis, graves ' disease, guillain-Barre syndrome, myasthenia gravis, psoriasis, crohn's disease, ulcerative colitis, optic neuritis, and Sjogren's syndrome.
  14. 14. The pharmaceutical composition of claim 10, wherein the liver disease is one or more selected from the group consisting of non-alcoholic fatty liver (NASH), alcoholic fatty liver, liver fibrosis, liver cancer, liver toxicity, cholestasis, cirrhosis, liver ischemia, liver abscess, hepatic coma and hepatic atrophy.
  15. 15. A method of preventing or treating ASK 1-related diseases, comprising: Administering to a subject a compound of any one of claims 1-6, or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof.
  16. 16. Use of a compound according to any one of claims 1-6, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, for the prevention or treatment of ASK 1-related disorders.
  17. 17. Use of a compound according to any one of claims 1-6, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of an ASK 1-related disorder.

Description

Triazole compound having novel ring structure, process for producing the same, and use thereof Technical Field The present invention relates to a triazole compound having a novel ring structure, a method for producing the same, and use thereof. Background ASK1 (apoptosis-signaling kinase 1; ASK 1) is a c-Jun N-terminal protein kinase (JNK), also a member of the stress-responsive mitogen-activated protein kinase (mitogen-ACTIVATED PROTEIN KINASE; MAP 3K) family, also known as MAP3K5.ASK1 is a core regulator of apoptosis and is known to be involved in a variety of stress-induced and receptor-mediated apoptotic pathways triggered by various forms of stress, including oxidative stress, reactive Oxygen Species (ROS), endoplasmic Reticulum (ER) stress, and Unfolded Protein Response (UPRs), as well as mitochondrial stress. Furthermore, ASK1 plays a key role not only in the apoptotic pathway, but also in inflammatory and innate immune responses including cytokine responses and cell differentiation. Depending on the cell type, phosphorylation of ASK1 protein can lead to apoptosis or other cellular responses. In particular, ASK1 activation and signaling have been reported to play an important role in a wide range of diseases including neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, autoimmune diseases and metabolic diseases. Furthermore, ASK1 is known to be involved in mediating organ damage caused by ischemia and reperfusion of the heart, brain and kidneys (Zhang et al J Clin invest 2003; 111 (12): 1933-1943.). On the other hand, parkinson's disease is a neurodegenerative disease mainly occurring in the elderly. Parkinson's disease causes death of dopaminergic neurons in the substantia nigra, leading to behavioral disorders. In addition, lewis bodies formed by alpha-synuclein deposition at various brain sites and peripheral nerves are the main neuropathological features of parkinson's disease patients. Typical symptoms of parkinson's disease include bradykinesia (i.e., abnormal slowing of body movement), tremor of the hands and feet, rigidity leading to stiffness in muscles and joints, and non-motor symptoms including mental disorders and autonomic nervous system dysfunction. It has been reported that excessive ASK1 is closely related to heart disease, inflammatory disease, liver disease, infectious disease and degenerative brain disease, and the possibility of treating parkinson's disease based on ASK1 inhibition has been proposed from various angles. When parkinsonism is induced by alpha-synuclein pre-fibers (PFFs), accumulation of phosphorylated alpha-synuclein (p-alpha-synuclein) in striatum and cerebral cortex of ASK 1-deficient mice is reduced. In addition, neuroinflammation is relieved, resulting in improved behavior. In addition, in neurons in the substantia nigra region of parkinsonism patients, the degree of activation of p-ASK1 was observed to be four times or more than normal. Thus, in the course of studying ASK1 derivatives, the present inventors completed the present invention by confirming that the novel triazole compound has excellent ASK1 inhibitory activity, protects nerve cells, easily penetrates cell membranes, and is not an efflux transporter. Detailed description of the invention Technical problem The object of the present invention is to provide a triazole compound having a novel ring structure. The object of the present invention is to provide a method for producing triazole compounds having a novel ring structure. The object of the present invention is to provide a pharmaceutical composition comprising a triazole compound having a novel ring structure as an active ingredient. The object of the present invention is to provide a pharmaceutical composition for preventing or treating ASK 1-related diseases, which comprises a triazole compound of a novel ring structure as an active ingredient. It is an object of the present invention to provide a method for preventing or treating ASK 1-related diseases, comprising the step of administering a triazole compound of a novel ring structure to a subject in need thereof. The purpose of the invention is to provide a novel triazole compound with a ring structure and application thereof in preventing or treating ASK1 related diseases. The invention aims to provide an application of a triazole compound with a novel ring structure in preparing a medicament for preventing or treating ASK1 related diseases. Solution to the problem In one aspect of the present invention, there is provided a compound represented by the following chemical formula 1, or a stereoisomer, solvate, hydrate or pharmaceutically acceptable salt thereof: [ chemical formula 1] In the above-mentioned chemical formula 1, Is a substituted or unsubstituted phenyl group or a substituted or unsubstituted C 3-8 cycloalkenyl group, Wherein the substituted phenyl and substituted C 3-8 cycloalkenyl are each independently substituted with C 1-6 alkyl, C 1-6 alkoxy or halog