TRADD inhibitors and their applications

Abstract

This application discloses TRADD inhibitors and their applications in the preparation of drugs for the prevention or treatment of inflammation-related diseases and / or cell necrotizing apoptosis, autophagy-related diseases.

Description

[Technical Field]

[0001] <Cross-reference of related applications> This application claims priority to the Chinese patent application No. 2023107525353 filed on 21 June 2023, and all contents of the said Chinese patent application are incorporated into this application by reference.

[0002] <Technical field> This application relates to the biopharmaceutical field, and more specifically to a group of compounds and their applications, particularly in the preparation of drugs for inflammation-related diseases and / or cell necrotizing apoptosis and autophagy-related diseases. [Background technology]

[0003] TRADD is a 34 kDa protein involved in regulating downstream pathways associated with the TNF receptor. Specifically, after TNFR1 is activated, it can recruit molecules such as TRADD, RIPK1, TRAF2 / 5, and cIAP1 / 2 to form complex I, which can further activate MAP3K. MAP3K activates the IKK complex, consisting of IKKα and IKKβ, thereby activating the downstream NF-κB-related inflammatory pathway, and can also induce inflammation by activating inflammatory pathways such as MAPK. On the other hand, complex II, formed by TRADD and RIPK1, FADD, TRAF2, cIAP1 / 2, further activates cell death pathways such as caspase 8, promoting cellular apoptosis. Inhibiting TRADD not only suppresses inflammatory and apoptotic pathways by blocking the formation of complexes between TRADD and other molecules, but more importantly, the complex formed by TRAF2 isolated from the complex and cIAP1 / 2 further activates autophagy by mediated K63 ubiquitination of Beclin 1, thereby promoting the formation of the Vps34 complex. Autophagy is a process of self-degradation that plays a crucial role in normal cellular metabolism and responses to nutritional stress. Autophagy is also important in the removal of misfolded or aggregated proteins, damaged organelles (e.g., mitochondria, endoplasmic reticulum, and peroxisomes), and intracellular pathogens. Autophagy plays a vital role in the prevention and treatment of various diseases, including infections, neurodegenerative diseases, age-related diseases, and heart diseases. Therefore, autophagy is a novel and effective disease progression regulator with scientific and clinical significance.

[0004] As described above, inhibiting TRADD activity can simultaneously modulate and treat diseases from various perspectives, including anti-inflammatory, anti-apoptotic, and autophagy activation, and therefore has significant importance in the treatment and prevention of inflammation-related diseases and / or cell death-related diseases. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] This application aims to provide small molecule drugs that are more effective in treating acute or chronic central or peripheral diseases related to inflammation and / or cell necrotizing apoptosis. [Means for solving the problem]

[0006] Therefore, in the first aspect, this paper provides compounds that are compounds represented by any of formulas I to III, or solvates, tautomers, enantiomers, diastereomers, isotope-labeled compounds (preferably deuterated compounds), or pharmaceutically acceptable salts of compounds represented by any of formulas I to III. [ka] In formula I, R1 represents hydrogen, an alkyl group, or a cycloalkyl group. R2 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R3 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R4 represents hydrogen, alkyl group, or cycloalkyl group. R5 represents a polycyclic alkyl group, a fused ring aryl group, a heteroaryl group, a fused ring alkylaryl group, or a fused ring alkylheteroaryl group. In Equation II, R1 represents hydrogen, alkyl group, cycloalkyl group, or aryl group. R2 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R3 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R4 represents hydrogen, alkyl group, or cycloalkyl group. R5 represents a cycloalkyl group, an aryl group, a heteroaryl group, a fused ring alkylaryl group, or a fused ring alkylheteroaryl group. m is an integer chosen from 1 to 4. In Equation III, R1 represents hydrogen, alkyl group, cycloalkyl group, or aryl group. R2 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R3 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R4 represents hydrogen, alkyl group, or cycloalkyl group. R5 represents a cycloalkyl group, an aryl group, a heteroaryl group, a fused ring alkylaryl group, or a fused ring alkylheteroaryl group. n is an integer chosen from 0 to 4.

[0007] In formulas I to III above, the substituent R on each ring independently represents unsubstituted, monosubstituted, or polysubstituted, and R is independently selected from the group consisting of hydrogen, halogen atom, cyano group, nitro group, amino group, hydroxyl group, thiol group, phosphate ester group, C1-C10 alkyl group, C3-C10 cycloalkyl group, C1-C10 halogenated alkyl group, C1-C10 alkoxy group, C3-C10 cycloalkoxy group, C6-C20 aryl group, C3-C20 heteroaryl group, C6-C20 aryloxy group, and C3-C20 heteroalicyclic group.

[0008] In the above formulas I to III, the alkyl group, cycloalkyl group, polycyclic alkyl group, aryl group, heteroaryl group, fused ring alkylaryl group, or fused ring alkylheteroaryl group represented by R1 to R5 may be unsubstituted or may contain one or more substituents. In some embodiments, the substituent is one or more selected from halogen atoms, cyano groups, nitro groups, C6-C20 aryl groups, C3-C20 heteroaryl groups, C1-C10 alkyl groups, C3-C10 cycloalkyl groups, C1-C10 halogenated alkyl groups, C1-C10 alkoxy groups, C3-C10 cycloalkoxy groups, C6-C20 aryloxy groups, C3-C20 heteroalicyclic groups, amino groups, hydroxyl groups, thiol groups, phosphate ester groups, -OC(O)R6, -ONR6R7, -NR6R7, where R6 and R7 are independently selected from the group consisting of hydrogen, C6-C20 aryl groups, C3-C20 heteroaryl groups, C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C2-C8 alkenyl groups, and C2-C8 alkynyl groups.

[0009] In some preferred embodiments, the compound represented by formula I is [ka] isn't it.

[0010] In some preferred embodiments, the polycyclic alkyl group represented by R5 in formula I does not contain an adamantyl group.

[0011] In some embodiments, R2 and R3 in formula II, together with the nitrogen atom to which they are bonded, form a ring, such as a 5-membered ring, a 6-membered ring, or a 7-membered ring.

[0012] In some embodiments, the compound represented by formula II has the structure represented by formula IIa. [ka] Here, the definitions of R, R1, R4, R5, and m are the same as in Equation II.

[0013] In some embodiments, m is selected from 1, 2, 3, or 4. In some embodiments, m is selected from 2, 3, or 4. In some embodiments, m is selected from 2 or 3.

[0014] In some embodiments, R2 and R3 in formula III, together with the nitrogen atom to which they are bonded, form a ring, for example, a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, or a 7-membered ring.

[0015] In some embodiments, the compound represented by formula III has the structure represented by formula IIIa. [ka] Formula IIIa Here, the definitions of R, R1, R4, R5, and n are the same as in Equation III.

[0016] In some embodiments, n is selected from 0, 1, 2, 3, or 4. In some embodiments, n is selected from 1, 2, 3, or 4. In some embodiments, n is selected from 1 or 2.

[0017] In some embodiments, in formulas I to III above, the substituent R on each ring independently represents unsubstituted, monosubstituted, or polysubstituted, and R is independently selected from the group consisting of hydrogen, halogen atom, cyano group, nitro group, amino group, hydroxyl group, thiol group, phosphate ester group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkoxy group, C6-C12 aryl group, C3-C12 heteroaryl group, C6-C12 aryloxy group, and C3-C10 heteroalicyclic group.

[0018] In some embodiments, in formulas I to III above, the substituent R on each ring is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano group, nitro group, amino group, hydroxyl group, thiol group, phosphate ester group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group. In some specific embodiments, in formulas I to III above, the substituent R on each ring is always hydrogen.

[0019] In some embodiments, in formulas I to III above, each R1 to R5 is independently substituted with one or more of the following: halogen atom, cyano group, nitro group, C6-C15 aryl group, C3-C15 heteroaryl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkoxy group, C6-C12 aryloxy group, C3-C6 heteroalicyclic group, amino group, hydroxy group, thiol group, phosphate ester group, -OC(O)R6, -ONR6R7, -NR6R7, where R6 and R7 are independently selected from the group consisting of hydrogen, C6-C15 aryl group, C3-C15 heteroaryl group, C1-C8 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, and C2-C8 alkynyl group.

[0020] In some embodiments, in formulas I to III above, each R1 to R5 is independently substituted with one or more of the following: fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group.

[0021] In a second aspect, the present application provides a drug composition comprising the above-mentioned compound and one or more pharmaceutically acceptable auxiliary materials, wherein the compound is the compound represented by formula I, formula II, or formula III, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably a deuterated compound) or a pharmaceutically acceptable salt of the compound represented by formula I, formula II, or formula III.

[0022] According to some embodiments of this application, the auxiliary material includes one or more of the following: excipients, diluents, fillers, adhesives, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, absorption enhancers, surfactants, lubricants, buffers, and stabilizers.

[0023] According to some embodiments of this application, the drug composition is a drug formulation selected from tablets, capsules, pills, granules, pellets, emulsions, liquids, suspensions, syrups, tinctures, powders, aerosols, sprays, nasal drops, inhalants, suppositories, enemas, intramuscular injections, intravenous injections, intra-articular injections, ointments, or patches.

[0024] In a third aspect, the present application provides the application of the above compounds or drug compositions in the preparation of drugs for preventing or treating inflammation-related diseases and / or cell necrotizing apoptosis or autophagy-related diseases. The compounds are the compounds represented by formulas I, II, and III, or solvates, tautomers, enantiomers, diastereomers, isotope-labeled compounds (preferably deuterated compounds) or pharmaceutically acceptable salts of the compounds represented by formulas I, II, and III.

[0025] According to some embodiments of this application, the inflammation-related disease is an inflammatory central nervous system condition or disease or an inflammatory peripheral system condition or disease associated with TNF-α.

[0026] According to some embodiments of the present application, the inflammatory central nervous system condition or disease includes diseases or conditions resulting from excessive activation of brain immune cells or involving cytokines, particularly TNF-α, or clinically identified types of inflammatory central nervous system diseases, for example, the types of inflammatory central nervous system diseases include encephalitis, meningitis, encephalomyelitis, viral, bacterial or autoimmune encephalitis, multiple sclerosis, brain injury, brain and spinal cord injury, cerebral contusion, subdural hematoma and spinal cord injury and cerebrovascular vasculitis of various causes.

[0027] According to some embodiments of this application, the inflammatory peripheral system conditions or diseases include pyoderma, vasculitis, dermatitis, herpetiform dermatitis, psoriasis, atopic dermatitis, neurodermatitis, contact dermatitis, eczema, scleroderma, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory myopathy, acute or chronic nephritis, nephrotic syndrome, glomerulonephritis, dry eye syndrome, uveitis, endophthalmitis, blepharitis, glaucoma, age-related macular lesions, conjunctivitis, allergic conjunctivitis, keratitis, autoimmune uveitis, gingivitis, periodontitis, allergic and non-allergic rhinitis, inflammatory bowel disease, lupus nephritis, thyroiditis, alcoholic and This includes non-alcoholic fatty liver disease, viral and non-viral hepatitis, autoimmune hepatitis, chronic relapsing hepatitis, cirrhosis, autoimmune hemolytic anemia, temporal arteritis, Crohn's disease, enteritis, colitis, ulcerative colitis, lupus erythematosus, ankylosing spondylitis, immune complex hematoangitis, myocarditis, ischemic heart disease, hypercholesterolemia, atherosclerosis, pre-eclampsia, diabetes mellitus, diabetic retinopathy, diabetic nephropathy, allograft rejection, pneumonia, acute lung injury, emphysema, chronic obstructive pulmonary disease, tracheitis, bronchitis, asthma, pulmonary fibrosis, various acute or chronic inflammatory diseases due to hepatic fibrosis, and inflammation caused by autoimmune function.

[0028] According to some embodiments of this application, the cell necrotizing apoptosis-related diseases include diseases or conditions resulting from nerve injury, neurobehavioral deficits, neurodegenerative diseases, excitatory toxicity of the nervous system, accumulation of misfolded proteins in cells or impaired autophagy, or clinically identified disease types, e.g., stroke (hemorrhagic stroke, ischemic stroke), chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, Alzheimer's disease, Parkinson's disease, limb weakness due to neurobehavioral deficits, cognitive neurobehavioral deficits due to nerve injury (e.g., visual, gustatory, olfactory, auditory, facial nerve injury, mania, emotional disorders, etc.), psychiatric disorders such as depression, anxiety disorders, schizophrenia, phobias, primary open-angle glaucoma, heart disease, heart failure, myocardial fibrosis, myocardial infarction, myocardial ischemia, chronic renal failure, renal injury, and lung injury.

[0029] In a fourth aspect, the present application provides a method for preventing or treating an acute or chronic central or peripheral disease related to inflammation and / or cell necrosis, the method comprising administering a therapeutically effective amount of the compound or drug composition to a subject in need, wherein the compound is a compound represented by formulas I, II, and III, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably a deuterated compound) or a pharmaceutically acceptable salt of a compound represented by formulas I, II, and III.

[0030] According to some embodiments of this application, the inflammation-related disease is an inflammatory central nervous system condition or disease or an inflammatory peripheral system condition or disease associated with TNF-α.

[0031] According to some embodiments of this application, the inflammatory central nervous system condition or disease includes diseases or conditions resulting from excessive activation of brain immune cells or involving cytokines, particularly TNF-α, or clinically identified types of inflammatory central nervous system diseases, such as encephalitis, meningitis, encephalomyelitis, viral, bacterial or autoimmune encephalitis, multiple sclerosis, brain injury, brain and spinal cord injury, cerebral contusion, subdural hematoma, and spinal cord injury and cerebrovascular vasculitis of various causes.

[0032] According to some embodiments of this application, the inflammatory peripheral system conditions or diseases include pyoderma, vasculitis, dermatitis, herpetiform dermatitis, psoriasis, atopic dermatitis, neurodermatitis, contact dermatitis, eczema, scleroderma, arthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory myopathy, acute or chronic nephritis, nephrotic syndrome, glomerulonephritis, dry eye syndrome, uveitis, endophthalmitis, blepharitis, glaucoma, age-related macular lesions, conjunctivitis, allergic conjunctivitis, keratitis, autoimmune uveitis, gingivitis, periodontitis, allergic and non-allergic rhinitis, inflammatory bowel disease, lupus nephritis, thyroiditis, alcoholic and non-alcoholic rhinitis. This includes fatty liver disease, viral and nonviral hepatitis, autoimmune hepatitis, chronic relapsing hepatitis, cirrhosis, autoimmune hemolytic anemia, temporal arteritis, Crohn's disease, enteritis, colitis, ulcerative colitis, lupus erythematosus, ankylosing spondylitis, immune complex hematoangitis, myocarditis, ischemic heart disease, hypercholesterolemia, atherosclerosis, pre-eclampsia, diabetes mellitus, diabetic retinopathy, diabetic nephropathy, allograft rejection, pneumonia, acute lung injury, emphysema, chronic obstructive pulmonary disease, tracheitis, bronchitis, asthma, pulmonary fibrosis, various acute or chronic inflammatory diseases due to hepatic fibrosis, and inflammation caused by autoimmune function.

[0033] According to some embodiments of this application, the cell necrotizing apoptosis-related disease is selected from a disease or condition resulting from nerve injury, neurobehavioral deficits, neurodegenerative diseases, excitatory toxicity of the nervous system, accumulation of incorrectly folded proteins in cells or impaired autophagy, or clinically identified disease types, such as stroke (hemorrhagic stroke, ischemic stroke), chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, Alzheimer's disease, Parkinson's disease, limb weakness due to neurobehavioral deficits, cognitive neurobehavioral deficits due to nerve injury (e.g., visual, gustatory, olfactory, auditory, facial nerve injury, mania, emotional disorders, etc.), psychiatric disorders such as depression, anxiety disorders, schizophrenia, phobias, primary open-angle glaucoma, heart disease, heart failure, myocardial fibrosis, myocardial infarction, myocardial ischemia, chronic renal failure, renal injury, and lung injury.

[0034] In this application, the subject may be a mammal, and the preferred subject is a human. The method of administration of the compound or drug composition of the present invention is not particularly limited, and typical methods of administration include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracisional, intraperitoneal, intravesical, topical (powder, ointment, or drip), or oral or nasal spray.

[0035] The therapeutic method of the present invention may be administered alone or in combination with other therapeutic methods or therapeutic agents.

[0036] The inflammation-related diseases referred to in this application mean inflammatory central or peripheral system diseases caused primarily by a variety of causes, and in particular related to TNF-α. Here, inflammation-related central system conditions or diseases include a range of diseases or conditions resulting from the overactivation of brain immune cells or involving cytokines, particularly TNF-α, or clinically identified types of inflammatory diseases of the central nervous system, for example, selected from, but not limited to, encephalitis, meningitis, encephalomyelitis, viral, bacterial or autoimmune encephalitis, multiple sclerosis, brain injury, brain and spinal cord injury, cerebral contusion, subdural hematoma and spinal cord injury and cerebrovascular vasculitis of various causes. Inflammation-related peripheral system conditions or diseases include pyoderma, vasculitis, dermatitis, herpetiform dermatitis, psoriasis, atopic dermatitis, neurodermatitis, contact dermatitis, eczema, scleroderma, arthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory myopathy, acute or chronic nephritis, nephrotic syndrome, glomerulonephritis, dry eye syndrome, uveitis, endophthalmitis, blepharitis, glaucoma, age-related macular lesions, conjunctivitis, allergic conjunctivitis, keratitis, autoimmune uveitis, gingivitis, periodontitis, allergic and non-allergic rhinitis, inflammatory bowel disease, lupus nephritis, thyroiditis, alcoholic and non-alcoholic fatty liver, viral and non-alcoholic This includes, but is not limited to, various acute or chronic inflammatory diseases resulting from viral hepatitis, autoimmune hepatitis, chronic relapsing hepatitis, cirrhosis, autoimmune hemolytic anemia, temporal arteritis, Crohn's disease, enteritis, colitis, ulcerative colitis, lupus erythematosus, ankylosing spondylitis, immune complex hematoangitis, myocarditis, ischemic heart disease, hypercholesterolemia, atherosclerosis, pre-eclampsia, diabetes mellitus, diabetic retinopathy, diabetic nephropathy, allograft rejection, pneumonia, acute lung injury, emphysema, chronic obstructive pulmonary disease, tracheitis, bronchitis, asthma, pulmonary fibrosis, hepatic fibrosis, and a range of inflammations resulting from autoimmune function.

[0037] In some embodiments, the cell necrotizing apoptosis-related diseases referred to in this application are selected from diseases or conditions resulting from nerve injury, neurobehavioral deficits, neurodegenerative diseases, excitotoxicity of the nervous system, accumulation of misfolded proteins in cells or impaired autophagy, or clinically identified disease types, e.g., stroke (hemorrhagic stroke, ischemic stroke), chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, Alzheimer's disease, Parkinson's disease, limb weakness due to neurobehavioral deficits, cognitive neurobehavioral deficits due to nerve injury (e.g., visual, gustatory, olfactory, auditory, facial nerve injury, mania, emotional disorders, etc.), psychiatric disorders such as depression, anxiety disorders, schizophrenia, phobias, primary open-angle glaucoma, heart disease, heart failure, myocardial fibrosis, myocardial infarction, myocardial ischemia, chronic renal failure, renal injury, and lung injury.

[0038] In a fifth aspect, the present application provides a method for inhibiting TRADD activity in cells or subjects, comprising the steps of contacting cells with the compound or the drug composition, or administering the compound or the drug composition to a subject. The compound is a compound represented by formulas I, II, and III, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably a deuterated compound) or a pharmaceutically acceptable salt of a compound represented by formulas I, II, and III.

[0039] In some embodiments, the cells are mammalian cells. In some embodiments, the subject is a mammal, preferably a human.

[0040] This application provides novel compounds as TRADD inhibitors that prevent or treat inflammation-related and / or cell necrosis-related acute or chronic central or peripheral system diseases through their pharmacological mechanisms of anti-inflammatory, anti-apoptotic, and autophagy activation. Furthermore, this application demonstrates that such compounds possess excellent anti-inflammatory and anti-apoptotic effects and can treat inflammation-related and / or cell necrosis-related acute or chronic central or peripheral system diseases. [Brief explanation of the drawing]

[0041] [Figure 1] The results of an anti-inflammatory experiment on LPS-stimulated BV2 cells using the compound synthesized in Example 1 of this application are shown. [Figure 2] The results of an anti-inflammatory experiment on MDP-stimulated BV2 cells using the compound synthesized in Example 1 of this application are shown. [Figure 3] The results of an anti-inflammatory experiment on IFN-γ stimulated BV2 using the compound synthesized in Example 1 of this application are shown. [Figure 4] The results of autophagy activation in Jurkat cells using the compound synthesized in Example 1 of this application are shown. [Figure 5] The plasma metabolic dynamics results in rats of the compound synthesized in Example 1 of this application are shown. [Figure 6] The therapeutic results for dry eye syndrome of the compound synthesized in Example 1 of this application are shown. [Figure 7] The results of the inhibitory effect on psoriasis of the compound synthesized in Example 1 of this application are shown. [Figure 8] This is a statistical diagram of the infarct size during treatment for a stroke model using the compound synthesized in Example 1 of this application. [Figure 9] The results of measuring the tau content in the hippocampus body using WB in Example 11 are shown. [Figure 10] This is a statistical chart of the OARSI scores for each group in Example 12. [Figure 11] The Masson staining results for the pulmonary fibrosis model in Example 13 are shown. [Figure 12] The HE staining results for the acute lung injury model in Example 14 are shown. [Figure 13] The results of the EAE model neuronal function score in Example 15 are shown. [Figure 14] The results of the rotorod test in the Parkinson's animal model in Example 16 are shown. [Figure 15] The clinical score results for the mouse autoimmune uveitis model in Example 17 are shown. [Figure 16]The experimental results of the mouse enteritis model in Example 18 are shown. [Figure 17] The experimental results of the mouse rheumatoid arthritis model in Example 19 are shown. [Figure 18] The experimental results for non-alcoholic fatty liver disease in mice in Example 20 are shown. [Figure 19] The experimental results of the mouse sepsis model in Example 21 are shown. [Figure 20] The experimental results of the mouse ALS model in Example 22 are shown. [Modes for carrying out the invention]

[0042] The present application will be described in detail below with reference to the examples and drawings. The following examples are carried out on the premise that this application is a technical proposal and provide detailed methods and processes for implementation. However, the embodiments provided in this application are illustrative and for interpretation purposes only and should not be understood as limiting the present invention. Conditions and methods not explicitly stated in the following examples are all conventional.

[0043] The term "substituted or unsubstituted" means that one or more hydrogen atoms in the described group may or may not be substituted by a substituent.

[0044] The term "alkyl group," either in itself or as part of another substituent, means a linear or branched hydrocarbon group having a given number of carbon atoms, where C1-6 or C1-C6 means a linear or branched hydrocarbon group containing 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyl groups.

[0045] The term "cycloalkyl group," either in itself or as part of another substituent, refers to the cyclic form of an "alkyl group" and is a non-aromatic hydrocarbon. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having two, three, or four fused or crosslinked or spirocyclic rings) alkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornanyl, isocamphanyl, and adamantyl groups. The term "polycyclic alkyl group" refers to a cycloalkyl group having two or more rings, and may include, for example, crosslinked ring alkyl groups (e.g., bicyclic, tricyclic, tetracyclic, and fused ring alkyl groups) and spirocycloalkyl groups. "C3-C6 cycloalkyl group" refers to a cycloalkyl group having 3-6 carbon atoms, such as a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0046] The term "alkenyl group" itself, or as part of another substituent, refers to a hydrocarbon group containing at least one carbon-carbon double bond, while "C2-C8 alkenyl group" refers to a hydrocarbon group containing 2-8 carbon atoms and at least one carbon-carbon double bond.

[0047] The term "alkynyl group" itself or as part of another substituent refers to a hydrocarbon group containing at least one carbon-carbon triple bond, while "C2-C8 alkynyl group" refers to a hydrocarbon group containing 2-8 carbon atoms and at least one carbon-carbon triple bond.

[0048] The term "halogen" includes, but is not limited to, fluorine, chlorine, bromine, and iodine.

[0049] The term "halogenated alkyl group" itself or as part of other substituents refers to any group (RX) consisting of the halogen and alkyl group, i.e., a group in which one or more hydrogens in the alkyl group are substituted with halogens, examples of which include methyl chloride, trifluoromethyl group, isopropyl bromide, tert-butyl chloride, and the like.

[0050] The term "alkoxy group," either in itself or as part of another substituent, refers to any group consisting of the aforementioned alkyl group and oxygen (alkyl-O-group), examples of which include methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy groups.

[0051] The term "cycloalkoxy group," either in itself or as part of another substituent, refers to any group consisting of the aforementioned cycloalkyl group and oxygen (alkyl-O- group), including examples such as the cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, and cyclohexyloxy group.

[0052] The term "aryl group," either in itself or as part of another substituent, refers to an aromatic monocyclic or polycyclic system composed of carbon atoms as ring atoms. An aryl group may be a monocyclic aryl group, a fused aryl group, two or more monocyclic aryl groups conjugated via carbon-carbon bonds, monocyclic aryl groups and fused aryl groups conjugated via carbon-carbon bonds, or two or more fused aryl groups conjugated via carbon-carbon bonds. That is, unless otherwise specified, two or more aromatic groups conjugated via carbon-carbon bonds can also be considered aryl groups in this application. Here, fused aryl groups may include, for example, bicyclic fused aryl groups (e.g., naphthyl group), tricyclic fused aryl groups (e.g., phenanthryl group, fluorenyl group, anthracenyl group), etc. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, anthracenyl, phenanthryl, biphenyl, terphenyl, phenantro[9,10]phenyl, pyrenyl, benzoanthracenyl, and chrysenyl groups.

[0053] The term "condensed ring alkylaryl group" refers, either in itself or as part of another substituent, to a group having one or more aromatic rings that condense with a cycloalkyl ring (i.e., share a bond with the cycloalkyl ring), such as the benzo-condensed derivatives of cyclopentane (i.e., the indanyl group), the benzo-condensed derivatives of cyclopentene, the benzo-condensed derivatives of cyclohexane, and the 5,6,7,8-tetrahydro-2-naphthyl group.

[0054] The term "heteroaryl group," either in itself or as part of another substituent, refers to an aromatic monocyclic or polycyclic system (including fused rings) composed of at least one carbon atom and one or more heteroatoms as ring atoms. The heteroatoms include, but are not limited to, B, N, O, S, P, Si, Se, etc. Examples of heteroaryl groups include, for example, 2-furanyl group, 3-furanyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, pyrazinyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4 -Pyrimidinyl group, 5-pyrimidinyl group, pyridazinyl group (e.g., 3-pyrimadinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group, 5-triazolyl group), 2-thienyl group, 3-thienyl group, pyrazolyl group (e.g., 2-pyrazolyl group), isothiazolyl group, 1,2,3-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,2, 4-Oxadiazolyl group, 1,2,3-Triazolyl group, 1,2,3-Thiasiazolyl group, 1,3,4-Thiasiazolyl group, 1,2,5-Thiasiazolyl group, Pyrazinyl group, 1,3,5-Triadinyl group, Benzimidazolyl group, Benzofuranyl group, Benzothienyl group, Indolyl group (e.g., 2-Indolyl group), Purinyl group, Quinolinyl group (e.g., 2-Quinolinyl group, 3-Quinolinyl group, 4-Quinolinyl group), Isoquinolinyl group (e.g., 1- This includes, but is not limited to, isoquinolinyl groups (3-isoquinolinyl groups or 4-isoquinolinyl groups), imidazo[1,2-a]pyridinyl groups, pyrazolo[1,5-a]pyridinyl groups, pyrazolo[1,5-a]pyrimidinyl groups, imidazo[1,2-b]pyridazinyl groups, [1,2,4]triazolo[4,3-b]pyridazinyl groups, [1,2,4]triazolo[1,5-a]pyrimidinyl groups, and [1,2,4]triazolo[1,5-a]pyridinyl groups.

[0055] The term "aryloxy group," either in itself or as part of another substituent, refers to any group consisting of the aforementioned aryl group and oxygen (aryl-O- group), including examples such as the phenoxy group and the naphthyloxy group.

[0056] The term "heteroalicyclic group" refers to a monocyclic or polycyclic group, either by itself or as part of another substituent, having 3-20, preferably 3-10, ring atoms in the ring, of which one or two are N, O, or S(O). m , P(O) m The ring atoms are selected from a heteroatom of Si or Se (where m is an integer from 0 to 2), and the remaining ring atom is C. These rings may have one or more double bonds, but they do not have a fully conjugated π-electron system. The heteroalicyclic group may be substituted or unsubstituted. Non-restrictive examples of unsubstituted heteroalicyclic groups include pyrrolidinyl, piperidino, morpholino, piperazino, thiomorpholino, and azepanyl groups.

[0057] The term "condensed ring alkyl heteroaryl group," either in itself or as part of another substituent, refers to a group having one or more heteroaromatic rings that condense with a cycloalkyl ring (i.e., share a bond with the cycloalkyl ring), such as the 5-aza-6-indanyl group, pyridocondensed derivatives of cyclopentane, pyridocondensed derivatives of cyclohexane, and so on.

[0058] The term "TNF-α" refers to tumor necrosis factor-α.

[0059] The term "TRADD" refers to the death domain protein (TNF receptor-assisted death domain).

[0060] The term "AIDS" stands for Acquired Immunodeficiency Syndrome.

[0061] The term "IFN-γ" refers to gamma interferon.

[0062] The term "pharmaceutically acceptable" means the whole molecule and other components of a composition that are physiologically acceptable and, when administered to a mammal (e.g., human), do not typically cause an inappropriate reaction, as used in the compositions of this application.

[0063] The term "isomer" refers to a compound that has the same molecular formula but differs in structure ("structural isomer") or the geometric positions of functional groups and / or atoms ("stereoisomer"). "Enantiomer" refers to a pair of stereoisomers that are mirror images of each other and cannot be superimposed. "Diastereomer" refers to a stereoisomer that is not an enantiomer. "Tautomer" is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in a transition of hydrogen atom morphology and involves the transformation of adjacent conjugated double bonds. Chemical equilibrium of tautomers can be achieved in a solution where tautomerism is possible. The specific proportion of tautomers depends on several factors, including temperature, solvent, and pH. The concept that tautomers can be converted into each other through tautomerization is called tautomerism. Common tautomer pairs include keto-enols, amido-nitriles, lactam-lactimes, tautomerism of amido-imide acids in heterocyclic compounds (e.g., in nucleic acid bases such as guanine, thymine, and cytosine), imine-enamines, and enamine-enamines. An example of keto-enol equilibrium is between pyridine-2(1H)-one and the corresponding pyridine-2-ol, and it should be understood that the compounds of this application can be described as different tautomers, as shown in the figure below. Furthermore, it should be understood that if a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this application, and the naming of the compound does not exclude any tautomer form. It should be understood that some tautomers may have a higher level of activity than others.

[0064] Examples of isotopes suitable for incorporation into the compounds of this application include hydrogen (H) isotopes (e.g., 1 H, 2 H, and 3H), isotopes of carbon (C) (e.g., 11 C, 13 C, and 14 C), isotopes of chlorine (Cl) (e.g., 36 Cl), isotopes of fluorine (F) (e.g., 18 F), isotopes of iodine (I) (e.g., 123 I, and 125 I), isotopes of nitrogen (N) (e.g., 13 N, and 15 N), isotopes of oxygen (O) (e.g., 15 O, 17 O, and 18 O), isotopes of phosphorus (P) (e.g., 32 P), and isotopes of sulfur (S) (e.g., 35 S), etc. are included.

[0065] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" means salts that have the biological effectiveness and properties of these parent compounds and are not salts that are undesirable in biological or other respects. The nature of the salt is not strictly required, but it is a prerequisite that it is non-toxic and does not substantially interfere with the desired pharmacological activity. Suitable anions for forming pharmaceutically acceptable salts include chloride ions, bromide ions, iodide ions, sulfate ions, bisulfate ions, amino acid residues, nitrate ions, phosphate ions, citrate ions, methanesulfonate ions, trifluoroacetate ions, glutamate ions, gluconate ions, succinate ions, malate ions, maleate ions, fumarate ions, oxalate ions, tartrate ions, benzenesulfonate ions, salicylate ions, lactate ions, naphthalenesulfonate ions, and acetate ions (e.g., trifluoroacetate ions).

[0066] The term "solvate" refers to a solvation form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to form solvates by capturing solvent molecules in a certain molar ratio within the crystalline solid state. If the solvent is water, the resulting solvate is a hydrate; if the solvent is an alcohol, the resulting solvate is an alcoholate. One or more water molecules combine with one molecule of the substance to form a hydrate, in which the water remains in its molecular state of H2O. Non-exclusive examples of solvates include ethanol solvate and acetone solvate.

[0067] The term “treatment” encompasses both preventive and therapeutic treatments, including those that reverse, reduce, alleviate, or delay the progression of a disease (or symptom or condition) or any tissue damage associated with one or more symptoms of a disease (or symptom or condition).

[0068] TRADD inhibitors This application provides TRADD inhibitors, which are compounds represented by formulas I, II, and III, or solvates, tautomers, enantiomers, diastereomers, isotope-labeled compounds (preferably deuterated compounds), or pharmaceutically acceptable salts of compounds represented by formulas I, II, and III. [ka] In formula I, R1 represents hydrogen, an alkyl group, or a cycloalkyl group. R2 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R3 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R4 represents hydrogen, alkyl group, or cycloalkyl group. R5 represents a polycyclic alkyl group, a fused ring aryl group, a heteroaryl group, a fused ring alkylaryl group, or a fused ring alkylheteroaryl group. In Equation II, R1 represents hydrogen, alkyl group, cycloalkyl group, or aryl group. R2 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R3 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R4 represents hydrogen, alkyl group, or cycloalkyl group. R5 represents a cycloalkyl group, an aryl group, a heteroaryl group, a fused ring alkylaryl group, or a fused ring alkylheteroaryl group. m is an integer chosen from 1 to 4. In Equation III, R1 represents hydrogen, alkyl group, cycloalkyl group, or aryl group. R2 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R3 represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R4 represents hydrogen, alkyl group, or cycloalkyl group. R5 represents a cycloalkyl group, an aryl group, a heteroaryl group, a fused ring alkylaryl group, or a fused ring alkylheteroaryl group. n is an integer chosen from 0 to 4.

[0069] In some embodiments, in formulas I to III above, the substituent R on each ring independently represents unsubstituted, monosubstituted, or polysubstituted, and R is independently selected from the group consisting of hydrogen, halogen atom, cyano group, nitro group, amino group, hydroxyl group, thiol group, phosphate ester group, C1-C10 alkyl group, C3-C10 cycloalkyl group, C1-C10 halogenated alkyl group, C1-C10 alkoxy group, C3-C10 cycloalkoxy group, C6-C20 aryl group, C3-C20 heteroaryl group, C6-C20 aryloxy group, and C3-C20 heteroalicyclic group.

[0070] In some embodiments, in formulas I to III above, the substituent R on each ring independently represents unsubstituted, monosubstituted, or polysubstituted, and R is independently selected from the group consisting of hydrogen, halogen atom, cyano group, nitro group, amino group, hydroxyl group, thiol group, phosphate ester group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkoxy group, C6-C12 aryl group, C3-C12 heteroaryl group, C6-C12 aryloxy group, and C3-C10 heteroalicyclic group.

[0071] In some embodiments, in formulas I to III above, the substituent R on each ring is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano group, nitro group, amino group, hydroxyl group, thiol group, phosphate ester group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group. In some specific embodiments, in formulas I to III above, the substituent R on each ring is always hydrogen.

[0072] In the above formulas I to III, the alkyl group, cycloalkyl group, polycyclic alkyl group, aryl group, heteroaryl group, fused ring alkylaryl group, or fused ring alkylheteroaryl group represented by R1 to R5 may be unsubstituted or may contain one or more substituents. In some embodiments, the substituent is one or more selected from halogen atoms, cyano groups, nitro groups, C6-C20 aryl groups, C3-C20 heteroaryl groups, C1-C10 alkyl groups, C3-C10 cycloalkyl groups, C1-C10 halogenated alkyl groups, C1-C10 alkoxy groups, C3-C10 cycloalkoxy groups, C6-C20 aryloxy groups, C3-C20 heteroalicyclic groups, amino groups, hydroxyl groups, thiol groups, phosphate ester groups, -OC(O)R6, -ONR6R7, -NR6R7, where R6 and R7 are independently selected from the group consisting of hydrogen, C6-C20 aryl groups, C3-C20 heteroaryl groups, C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C2-C8 alkenyl groups, and C2-C8 alkynyl groups.

[0073] In some embodiments, when each R1 to R5 in formulas I to III contains substituents, each substituent is independently selected from the group consisting of halogen atoms, cyano groups, nitro groups, C6-C15 aryl groups, C3-C15 heteroaryl groups, C1-C6 alkyl groups, C3-C6 cycloalkyl groups, C1-C6 halogenated alkyl groups, C1-C6 alkoxy groups, C3-C6 cycloalkoxy groups, C6-C12 aryloxy groups, C3-C6 heteroalicyclic groups, amino groups, hydroxyl groups, thiol groups, phosphate ester groups, -OC(O)R6, -ONR6R7, and -NR6R7, where R6 and R7 are independently selected from the group consisting of hydrogen, C6-C15 aryl groups, C3-C15 heteroaryl groups, C1-C8 alkyl groups, C3-C8 cycloalkyl groups, C2-C8 alkenyl groups, and C2-C8 alkynyl groups.

[0074] In some embodiments, when each R1 to R5 in formulas I to III contains a substituent, each substituent is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group.

[0075] In some embodiments, in formula I, R1 represents H, a substituted or unsubstituted C1-C10 linear alkyl group, a substituted or unsubstituted C3-C10 branched alkyl group, and a substituted or unsubstituted C3-C12 cycloalkyl group. In some embodiments, in formula I, R1 represents H, a substituted or unsubstituted C1-C6 linear alkyl group, a substituted or unsubstituted C3-C6 branched alkyl group, and a substituted or unsubstituted C3-C8 cycloalkyl group. In some embodiments, in formula I, R1 represents H, a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some specific embodiments, in formula I, R1 represents H.

[0076] In some embodiments, in formula I, R2 represents H, a substituted or unsubstituted C1-C10 linear alkyl group, a substituted or unsubstituted C3-C10 branched alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C6-C20 aryl group, or a substituted or unsubstituted C3-C20 heteroaryl group. In some embodiments, in formula I, R2 represents H, a substituted or unsubstituted C1-C6 linear alkyl group, a substituted or unsubstituted C3-C6 branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C15 aryl group, or a substituted or unsubstituted C3-C15 heteroaryl group. In some embodiments, in formula I, R2 represents H, substituted or unsubstituted methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, naphthyl, pyridyl, furanyl, pyrrolyl, or quinolinyl. In some embodiments, in formula I, R2 represents H or a cycloalkyl group. In some specific embodiments, in formula I, R2 represents H, a cyclopropyl group, or a phenyl group.

[0077] In some embodiments, in formula I, R3 represents H, a substituted or unsubstituted C1-C10 linear alkyl group, a substituted or unsubstituted C3-C10 branched alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C6-C20 aryl group, or a substituted or unsubstituted C3-C20 heteroaryl group. In some embodiments, in formula I, R3 represents H, a substituted or unsubstituted C1-C6 linear alkyl group, a substituted or unsubstituted C3-C6 branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C15 aryl group, or a substituted or unsubstituted C3-C15 heteroaryl group. In some embodiments, in formula I, R3 represents H, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, naphthyl, pyridinyl, furanyl, pyrrolyl, or quinolyl. In some embodiments, in formula I, R3 represents H or a cycloalkyl group. In some specific embodiments, in formula I, R3 represents H, a cyclopropyl group, or a phenyl group.

[0078] In some embodiments, in formula I, R4 represents H, a substituted or unsubstituted C1-C10 linear alkyl group, a substituted or unsubstituted C3-C10 branched alkyl group, or a substituted or unsubstituted C3-C12 cycloalkyl group. In some embodiments, in formula I, R4 represents H, a substituted or unsubstituted C1-C6 linear alkyl group, a substituted or unsubstituted C3-C6 branched alkyl group, or a substituted or unsubstituted C3-C8 cycloalkyl group. In some embodiments, in formula I, R4 represents H, a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclopentyl, or cyclohexyl. In some specific embodiments, in formula I, R4 represents H.

[0079] In some embodiments, in formula I, R5 represents a substituted or unsubstituted C4-C20 polycyclic alkyl group, a substituted or unsubstituted C10-C20 fused ring aryl group, a substituted or unsubstituted C3-C20 heteroaryl group, a substituted or unsubstituted C7-C30 fused ring alkylaryl group, or a substituted or unsubstituted C4-C20 fused ring alkyl heteroaryl group. In some embodiments, in formula I, R5 represents a substituted or unsubstituted C4-C12 bicyclic alkyl group, a substituted or unsubstituted C4-C12 tricyclic alkyl group, a substituted or unsubstituted C6-C12 monospirocycloalkyl group, a substituted or unsubstituted C6-C12 bisspirocycloalkyl group, a substituted or unsubstituted C10-C15 fused ring aryl group, a substituted or unsubstituted C3-C15 heteroaryl group, a substituted or unsubstituted C7-C15 fused ring alkylaryl group, or a substituted or unsubstituted C4-C15 fused ring alkyl heteroaryl group.

[0080] In some preferred embodiments, the compound of formula I is [ka] isn't it.

[0081] In some preferred embodiments, the polycyclic alkyl group represented by R5 in formula I does not contain an adamantyl group.

[0082] The bicyclic alkyl groups described in this application may include, but are not limited to, [4.2.1]bicyclic alkyl groups, [3.2.1]bicyclic alkyl groups, [4.1.0]bicyclic alkyl groups, [3.2.2]bicyclic alkyl groups, [3.3.0]bicyclic alkyl groups, [4.3.0]bicyclic alkyl groups, [3.2.0]bicyclic alkyl groups, and [5.3.0]bicyclic alkyl groups.

[0083] The tricyclic alkyl group described in the present invention may include, but is not limited to, the [3.3.1.1] tricyclic alkyl group.

[0084] The spirocycloalkyl groups described in this application may include, but are not limited to, [4,3]spirocycloalkyl groups, [3,3]spirocycloalkyl groups, [3,3]spirocycloalkyl groups, [3,2]spirocycloalkyl groups, [2,2]spirocycloalkyl groups, [5,5]spirocycloalkyl groups, [5,4]spirocycloalkyl groups, [5,3]spirocycloalkyl groups, and [5,2]spirocycloalkyl groups.

[0085] The fused ring aryl group described in this application may include, but is not limited to, a naphthyl group, anthryl group, and a phenanthryl group.

[0086] The heteroaryl groups described in this application may include, but are not limited to, pyridyl, pyrimidyl, thienyl, furanyl, pyridadinyl, pyrazinyl, pyrrolyl, pyranyl, benzopyranyl, benzoxazolyl, benzothiazolyl, carbazolyl, quinolinyl, and isoquinolinyl groups.

[0087] The fused ring alkylaryl group described in this application may include, but is not limited to, a benzocyclopentanyl group, a benzocyclohexanyl group, a benzocycloheptanyl group, and a benzocyclooctanyl group.

[0088] The fused ring alkyl heteroaryl group described in this application may include, but is not limited to, a pyridocyclopentanyl group, a pyridocyclohexanyl group, a pyridocycloheptanyl group, and a pyridocyclooctanyl group.

[0089] In some embodiments, the polycyclic alkyl group represented by R5 in formula I is selected from the following structures: [ka] Here, each x is independently 0, 1, 2, 3, 4, or 5, and each y and z is independently 1, 2, 3, 4, or 5.

[0090] In some embodiments, the condensed ring alkylaryl group represented by R5 in formula I is selected from the following structures: [ka] Here, x is 0, 1, 2, 3, 4, or 5.

[0091] In some embodiments, the condensed ring alkyl heteroaryl group represented by R5 in formula I is selected from the following structures: [ka] , [ka] In this, X1 to X4 are selected from C, N, O, S, P, Si, and Se, and at least one of X1 to X4 is selected from N, O, S, P, Si, and Se, and x is 0, 1, 2, 3, 4, or 5. [ka] In this configuration, X1 to X3 are selected from C, N, O, S, P, Si, and Se, and at least one of X1 to X3 is selected from N, O, S, P, Si, and Se, and x is 0, 1, 2, 3, 4, or 5.

[0092] In some embodiments, in formula I, R5 is selected from the following substituted or unsubstituted groups: [ka] Here, if R5 contains substituents, there may be one substituent or more substituents, and if there are multiple substituents in R5, the substituents may be the same or different, and each substituent is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group. In some examples, the substituent in R5 is a trifluoromethyl group or a phenyl group.

[0093] In some embodiments, formula I has a structure represented by formula Ia. [ka] Here, in equation Ia, the definitions of R1, R2, and R5 are the same as in equation I.

[0094] In some embodiments, the compound has, but is not limited to, the following structure according to the general formula of the compound of formula I. [ka] [ka]

[0095] In some embodiments, in formula II, R2 and R3, together with the nitrogen atom to which they are bonded, form a ring, for example, a five-membered ring, a six-membered ring, or a seven-membered ring.

[0096] In some embodiments, the compound represented by formula II has the structure represented by formula IIa, [ka] Here, the definitions of R, R1, R4, R5, and m are the same as in Equation II.

[0097] In some embodiments, R in formulas II and IIa represents unsubstituted. In some embodiments, R in formulas II and IIa represents monosubstituted. In some embodiments, R in formulas II and IIa represents disubstituted. In some embodiments, R in formulas II and IIa represents trisubstituted. In some specific embodiments, R is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano group, nitro group, amino group, hydroxyl group, thiol group, phosphate ester group, C1-C6 alkyl group, C3-C6 cycloalkyl group, e.g., cyclopropyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C6-C15 aryl group, e.g., phenyl group.

[0098] In some embodiments, in formulas II and IIa, m is selected from 1, 2, 3, or 4. In some embodiments, in formulas II and IIa, m is selected from 2, 3, or 4. In some embodiments, in formulas II and IIa, m is selected from 2 or 3.

[0099] In some embodiments, the alkyl, cycloalkyl, and aryl group represented by R1 in formulas II and IIa may include, but are not limited to, substituted or unsubstituted C1-C10 linear alkyl groups, substituted or unsubstituted C3-C10 branched alkyl groups, substituted or unsubstituted C3-C12 cycloalkyl groups, and substituted or unsubstituted C6-C20 aryl groups. In some embodiments, the alkyl, cycloalkyl, and aryl group represented by R1 in formulas II and IIa may include, but are not limited to, substituted or unsubstituted C1-C6 linear alkyl groups, substituted or unsubstituted C3-C6 branched alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, and substituted or unsubstituted C6-C15 aryl groups. In some embodiments, in formulas II and IIa, R1 independently represents H, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, isohexyl, cyclopentyl, cyclohexyl, phenyl, or naphthyl. In some specific embodiments, in formulas II and IIa, R1 represents H.

[0100] In some embodiments, the alkyl group, aryl group, heteroaryl group, or cycloalkyl group represented by R2 in formulas II and IIa may include, but are not limited to, substituted or unsubstituted C1-C10 linear alkyl groups, substituted or unsubstituted C3-C10 branched alkyl groups, substituted or unsubstituted C3-C12 cycloalkyl groups, substituted or unsubstituted C6-C20 aryl groups, or substituted or unsubstituted C3-C20 heteroaryl groups. In some embodiments, the alkyl group, aryl group, heteroaryl group, or cycloalkyl group represented by R2 in formulas II and IIa may include, but are not limited to, substituted or unsubstituted C1-C6 linear alkyl groups, substituted or unsubstituted C3-C6 branched alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C6-C15 aryl groups, or substituted or unsubstituted C3-C15 heteroaryl groups. In some embodiments, in formulas II and IIa, R2 represents H, a substituted or unsubstituted methyl group, ethyl group, isopropyl group, tert-butyl group, cyclopentyl group, cyclohexyl group, phenyl group, naphthyl group, pyridyl group, furanyl group, pyrrolyl group, or quinolinyl group. In some embodiments, in formulas II and IIa, R2 represents H, a C1-C6 linear alkyl group, or a C3-C6 branched alkyl group. In some specific embodiments, in formulas II and IIa, R2 represents H, a methyl group, or an ethyl group.

[0101] In some embodiments, the alkyl group, aryl group, heteroaryl group, or cycloalkyl group represented by R3 in formulas II and IIa may include, but are not limited to, substituted or unsubstituted C1-C10 linear alkyl groups, substituted or unsubstituted C3-C10 branched alkyl groups, substituted or unsubstituted C3-C12 cycloalkyl groups, substituted or unsubstituted C6-C20 aryl groups, or substituted or unsubstituted C3-C20 heteroaryl groups. In some embodiments, the alkyl group, aryl group, heteroaryl group, or cycloalkyl group represented by R3 in formulas II and IIa may include, but are not limited to, substituted or unsubstituted C1-C6 linear alkyl groups, substituted or unsubstituted C3-C6 branched alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups, substituted or unsubstituted C6-C15 aryl groups, or substituted or unsubstituted C3-C15 heteroaryl groups. In some embodiments, in formulas II and IIa, R3 represents H, a substituted or unsubstituted methyl group, ethyl group, isopropyl group, tert-butyl group, cyclopentyl group, cyclohexyl group, phenyl group, naphthyl group, pyridyl group, furanyl group, pyrrolyl group, or quinolinyl group. In some embodiments, in formulas II and IIa, R3 represents H, a C1-C6 linear alkyl group, or a C3-C6 branched alkyl group. In some specific embodiments, in formulas II and IIa, R3 represents H, a methyl group, or an ethyl group.

[0102] In some embodiments, the alkyl and cycloalkyl groups represented by R4 in formulas II and IIa may include, but are not limited to, substituted or unsubstituted C1-C10 linear alkyl groups, substituted or unsubstituted C3-C10 branched alkyl groups, and substituted or unsubstituted C3-C12 cycloalkyl groups. In some embodiments, the alkyl and cycloalkyl groups represented by R4 in formulas II and IIa may include, but are not limited to, substituted or unsubstituted C1-C6 linear alkyl groups, substituted or unsubstituted C3-C6 branched alkyl groups, and substituted or unsubstituted C3-C8 cycloalkyl groups. In some embodiments, R4 in formulas II and IIa independently represents H, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclopentyl, or cyclohexyl. In some specific embodiments, R4 in formulas II and IIa represents H. In some embodiments, the alkyl group represented by R4 in formulas II and IIa is linked to the carbon atom on the adjacent cyclic amide to form a fused ring structure.

[0103] In some embodiments, in formulas II and IIa, R5 represents a substituted or unsubstituted C3-C20 cycloalkyl group, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C3-C20 heteroaryl group, or a substituted or unsubstituted C7-C30 condensed ring alkylaryl group. In some embodiments, R5 represents a substituted or unsubstituted C3-C8 monocyclic alkyl group, a substituted or unsubstituted C4-C12 bicyclic alkyl group, a substituted or unsubstituted C4-C12 tricyclic alkyl group, a substituted or unsubstituted C6-C20 monospirocycloalkyl group, a substituted or unsubstituted C6-C20 bisspirocycloalkyl group, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C3-C20 heteroaryl group, or a substituted or unsubstituted C7-C20 condensed ring alkylaryl group. In some embodiments, the C3-C8 monocyclic alkyl group is selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. In some embodiments, the bicyclic alkyl group is selected from the group consisting of [4.2.1]bicyclic alkyl group, [3.2.1]bicyclic alkyl group, [4.1.0]bicyclic alkyl group, [3.2.2]bicyclic alkyl group, [3.3.0]bicyclic alkyl group, [4.3.0]bicyclic alkyl group, [3.2.0]bicyclic alkyl group, or [5.3.0]bicyclic alkyl group. In some embodiments, the tricyclic alkyl group is selected from [3.3.1.1]tricyclic alkyl groups, and the spirocycloalkyl group is selected from the group consisting of [4,3]spirocycloalkyl groups, [3,3]spirocycloalkyl groups, [3,3]spirocycloalkyl groups, [3,2]spirocycloalkyl groups, [2,2]spirocycloalkyl groups, [5,5]spirocycloalkyl groups, [5,4]spirocycloalkyl groups, [5,3]spirocycloalkyl groups, and [5,2]spirocycloalkyl groups. In some embodiments, the aryl group is selected from the group consisting of phenyl groups, naphthyl groups, biphenyl groups, and terphenyl groups.In some embodiments, the heteroaryl group is selected from the group consisting of pyridyl, pyrimidyl, thienyl, furanyl, pyridazyl, pyrazinyl, pyrrolyl, pyranyl, benzopyranyl, benzoxazolyl, benzothiazolyl, carbazolyl, quinolinyl, and isoquinolinyl groups. In some embodiments, the condensed ring alkylaryl group is selected from the group consisting of benzocyclopentanyl, benzocyclohexanyl, benzocycloheptanyl, and benzocyclooctanyl groups.

[0104] In some embodiments, when R1 to R5 in formulas II and IIa contain substituents, the substituents may be one or more and each is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C6 alkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C6-C12 aryloxy group, C3-C10 heteroalicyclic group, amino group, hydroxyl group, thiol group, phosphate ester group, -OC(O)R6, -ONR6R7, and -NR6R7, where R6 and R7 are independently selected from the group consisting of hydrogen, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C8 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group, and C2-C8 alkynyl group.

[0105] In some embodiments, when R1 to R5 in formulas II and IIa contain substituents, the substituents may be one or more and each is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, C6-C10 aryl group, C3-C10 heteroaryl group, C1-C6 alkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C6-C10 aryloxy group, C3-C8 heteroalicyclic group, amino group, hydroxyl group, thiol group, phosphate ester group, -OC(O)R6, -ONR6R7, and -NR6R7, where R6 and R7 are independently selected from the group consisting of hydrogen, C6-C10 aryl group, C3-C10 heteroaryl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, and C2-C6 alkynyl group.

[0106] In some embodiments, when R1 to R5 in formulas II and IIa contain substituents, the substituents may be one or more and each is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group.

[0107] In some embodiments, in formulas II and IIa, R5 represents the following substituted or unsubstituted groups: [ka] Here, if R5 contains substituents, there may be one substituent or more substituents, and if there are multiple substituents in R5, the multiple substituents may be the same or different, and each substituent is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group.

[0108] In some preferred embodiments, in formulas II and IIa, R5 represents the following substituted or unsubstituted groups: [ka] Here, if R5 contains substituents, there may be one substituent or more substituents, and if there are multiple substituents in R5, the substituents may be the same or different, and each substituent is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, difluoromethyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, trifluoromethoxy group, and phenyl group, and in some examples, the substituent is a trifluoromethyl group or a phenyl group.

[0109] In some embodiments, the compound of formula II has a structure represented by formula II-b, formula II-c, or formula II-d, [ka] Here, in equations II-b, II-c, and II-d, the definitions of R, R1, R4, and R5 are the same as those in equations II and IIa.

[0110] In some embodiments, the compounds include, but are not limited to, the following structures according to the general formulas of the compounds of formula II and formula IIa. [ka] [ka]

[0111] In some embodiments, in formula III, R2 and R3, together with the nitrogen atom to which they are bonded, form a 5-7 membered ring, such as a 5-membered ring, a 6-membered ring, or a 7-membered ring.

[0112] In some embodiments, the compound represented by formula III has the structure represented by formula IIIa, [ka] Here, the definitions of R1, R4, R5, and n are the same as in Equation III.

[0113] In some embodiments, R in formula IIa represents non-substitution.

[0114] In some embodiments, n is selected from 1, 2, 3, or 4. In some embodiments, n is selected from 1 or 2.

[0115] In some embodiments, the alkyl, cycloalkyl, and aryl group represented by R1 in formulas III and IIIa may be, but are not limited to, a substituted or unsubstituted C1-C10 linear alkyl group, a substituted or unsubstituted C3-C10 branched alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, or a substituted or unsubstituted C6-C20 aryl group. In some embodiments, the alkyl, cycloalkyl, and aryl group represented by R1 in formulas III and IIIa may be, but are not limited to, a substituted or unsubstituted C1-C6 linear alkyl group, a substituted or unsubstituted C3-C6 branched alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, or a substituted or unsubstituted C6-C15 aryl group. In some embodiments, in formulas III and IIIa, R1 independently represents H, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclopentyl, cyclohexyl, phenyl, or naphthyl. In some specific embodiments, in formulas III and IIIa, R1 represents H.

[0116] In some embodiments, the alkyl group, aryl group, heteroaryl group, or cycloalkyl group represented by R2 in Formula III may be, but is not limited to, a substituted or unsubstituted C1-C10 linear alkyl group, a substituted or unsubstituted C3-C10 branched alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C6-C20 aryl group, or a substituted or unsubstituted C3-C20 heteroaryl group. In some embodiments, the alkyl group, aryl group, heteroaryl group, or cycloalkyl group represented by R2 in Formula III may be, but is not limited to, a substituted or unsubstituted C1-C6 linear alkyl group, a substituted or unsubstituted C3-C6 branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C15 aryl group, or a substituted or unsubstituted C3-C15 heteroaryl group. In some embodiments, in formula III, R2 represents H, substituted or unsubstituted methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, furanyl, pyrrolyl, or quinolinyl. In some embodiments, in formula III, R2 represents H, a C1-C6 linear alkyl group, or a C3-C6 branched alkyl group. In some specific embodiments, in formula III, R2 represents H, methyl, or ethyl.

[0117] In some embodiments, the alkyl group, aryl group, heteroaryl group, or cycloalkyl group represented by R3 in formula III may be, but is not limited to, a substituted or unsubstituted C1-C10 linear alkyl group, a substituted or unsubstituted C3-C10 branched alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C6-C20 aryl group, or a substituted or unsubstituted C3-C20 heteroaryl group. In some embodiments, the alkyl group, aryl group, heteroaryl group, or cycloalkyl group represented by R3 in formula III may be, but is not limited to, a substituted or unsubstituted C1-C6 linear alkyl group, a substituted or unsubstituted C3-C6 branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C15 aryl group, or a substituted or unsubstituted C3-C15 heteroaryl group. In some embodiments, in formula III, R3 represents H, substituted or unsubstituted methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, furanyl, pyrrolyl, or quinolinyl. In some embodiments, in formula III, R3 represents H, a C1-C6 linear alkyl group, or a C3-C6 branched alkyl group. In some specific embodiments, in formula III, R3 represents H, methyl, or ethyl.

[0118] In some embodiments, the alkyl and cycloalkyl groups represented by R4 in formulas III and IIIa may include, but are not limited to, substituted or unsubstituted C1-C10 linear alkyl groups, substituted or unsubstituted C3-C10 branched alkyl groups, and substituted or unsubstituted C3-C12 cycloalkyl groups. In some embodiments, the alkyl and cycloalkyl groups represented by R4 in formulas III and IIIa may include, but are not limited to, substituted or unsubstituted C1-C6 linear alkyl groups, substituted or unsubstituted C3-C6 branched alkyl groups, and substituted or unsubstituted C3-C8 cycloalkyl groups. In some embodiments, in formulas III and IIIa, R4 independently represents H, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclopentyl, or cyclohexyl. In some specific embodiments, in formulas III and IIIa, R4 represents H.

[0119] In some embodiments, in formulas III and IIIa, R5 represents a substituted or unsubstituted C3-C20 cycloalkyl group, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C3-C20 heteroaryl group, or a substituted or unsubstituted C7-C30 condensed ring alkylaryl group. In some embodiments, R5 represents a substituted or unsubstituted C3-C8 monocyclic alkyl group, a substituted or unsubstituted C4-C12 bicyclic alkyl group, a substituted or unsubstituted C4-C12 tricyclic alkyl group, a substituted or unsubstituted C6-C20 monospirocycloalkyl group, a substituted or unsubstituted C6-C20 bisspirocycloalkyl group, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C3-C20 heteroaryl group, or a substituted or unsubstituted C7-C20 condensed ring alkylaryl group. In some embodiments, the C3-C8 monocyclic alkyl group represented by R5 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the bicyclic alkyl group represented by R5 is selected from the group consisting of [4.2.1]bicyclic alkyl groups, [3.2.1]bicyclic alkyl groups, [4.1.0]bicyclic alkyl groups, [3.2.2]bicyclic alkyl groups, [3.3.0]bicyclic alkyl groups, [4.3.0]bicyclic alkyl groups, [3.2.0]bicyclic alkyl groups, and [5.3.0]bicyclic alkyl groups. In some embodiments, the tricyclic alkyl group represented by R5 is selected from the [3.3.1.1] tricyclic alkyl groups, and the spirocycloalkyl group represented by R5 is selected from the group consisting of [4,3] spirocycloalkyl groups, [3,3] spirocycloalkyl groups, [3,3] spirocycloalkyl groups, [3,2] spirocycloalkyl groups, [2,2] spirocycloalkyl groups, [5,5] spirocycloalkyl groups, [5,4] spirocycloalkyl groups, [5,3] spirocycloalkyl groups, and [5,2] spirocycloalkyl groups. In some embodiments, the aryl group represented by R5 is selected from the group consisting of phenyl groups, naphthyl groups, biphenyl groups, and terphenyl groups.In some embodiments, the heteroaryl group represented by R5 is selected from the group consisting of pyridyl, pyrimidyl, thienyl, furanyl, pyridazyl, pyrazinyl, pyrrolyl, pyranyl, benzopyranyl, benzoxazolyl, benzothiazolyl, carbazolyl, quinolinyl, and isoquinolinyl groups. In some embodiments, the condensed ring alkylaryl group represented by R5 is selected from the group consisting of benzocyclopentanyl, benzocyclohexanyl, benzocycloheptanyl, and benzocyclooctanyl groups.

[0120] In some embodiments, when R1 to R5 in formulas III and IIIa contain substituents, the substituents may be one or more and each is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C6 alkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C6-C12 aryloxy group, C3-C10 heteroalicyclic group, amino group, hydroxyl group, thiol group, phosphate ester group, -OC(O)R6, -ONR6R7, and -NR6R7, where R6 and R7 are independently selected from the group consisting of hydrogen, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C8 alkyl group, C3-C8 cycloalkyl group, C2-C8 linear alkenyl group, and C2-C8 alkynyl group.

[0121] In some embodiments, when R1 to R5 in formulas III and IIIa contain substituents, the substituents may be one or more and each is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, C6-C10 aryl group, C3-C10 heteroaryl group, C1-C6 alkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C6-C10 aryloxy group, C3-C8 heteroalicyclic group, amino group, hydroxyl group, thiol group, phosphate ester group, -OC(O)R6, -ONR6R7, and -NR6R7, where R6 and R7 are independently selected from the group consisting of hydrogen, C6-C10 aryl group, C3-C10 heteroaryl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, and C2-C6 alkynyl group.

[0122] In some embodiments, when R1 to R5 in formulas III and IIIa contain substituents, the substituents may be one or more and each is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group.

[0123] In some embodiments, in formulas III and IIIa, R5 represents the following substituted or unsubstituted groups: [ka] Here, if R5 contains substituents, there may be one substituent or more substituents, and if there are multiple substituents in R5, the substituents may be the same or different, and each substituent is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group and pyrrolyl group, and in some examples, the substituent is a trifluoromethyl group or a phenyl group.

[0124] In some preferred embodiments, in formulas III and IIIa, R5 represents the following substituted or unsubstituted groups: [ka] Here, if R5 contains substituents, there may be one substituent or more substituents, and if there are multiple substituents in R5, the substituents may be the same or different, and each substituent is independently selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, difluoromethyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, trifluoromethoxy group, and phenyl group, and in some examples, the substituent is a trifluoromethyl group or a phenyl group.

[0125] In some embodiments, the compound of formula III has a structure represented by formula III-b, formula III-c, formula III-d, or formula III-e. [ka] Here, in equations III-b, III-c, III-d, and III-e, the definitions of R1, R4, and R5 are the same as in equation III.

[0126] In some embodiments, the compound of formula III includes, but is not limited to, the following structures. [ka]

[0127] In a more specific embodiment, this application discloses that the compound can achieve a therapeutic effect on the disease by controlling disease progression as a TRADD inhibitor from the perspectives of anti-inflammatory, anti-apoptotic, and autophagy activation.

[0128] The specific pharmacological mechanism is as follows: The compounds represented by formulas I to III described in this application, or their solvates, tautomers, enantiomers, diastereomers, isotope-labeled compounds (preferably deuterated compounds), or pharmaceutically acceptable salts can bind to TRADD as TRADD inhibitors, blocking the formation of complex I, which consists of molecules such as TRADD, RIPK1, TRAF2 / 5, and cIAP1 / 2, thereby suppressing the activation of inflammatory pathways such as NF-κB and MAPKs and inhibiting the onset of inflammation. On the other hand, the formation of complex II, which consists of molecules such as TRADD, RIPK1, FADD, TRAF2, and cIAP1 / 2, thereby suppressing the activation of cellular apoptotic pathways such as caspase 8 and reducing cell death. Furthermore, the compounds represented by formulas I to III described in this application, or their solvates, tautomers, enantiomers, diastereomers, isotope-labeled compounds (preferably deuterated compounds), or pharmaceutically acceptable salts, can further activate autophagy by promoting the formation of the Vps34 complex through the complex formed by TRAF2 and cIAP1 / 2 released after binding to TRADD, which mediates the K63 ubiquitination of Beclin 1, thereby removing misfolded proteins and other "waste" in cells and reducing cell death under stress. Accordingly, the compounds represented by formulas I to III described in this application, or their solvates, tautomers, enantiomers, diastereomers, isotope-labeled compounds (preferably deuterated compounds), or pharmaceutically acceptable salts, can be used in the treatment of acute or chronic central or peripheral diseases associated with inflammation and / or cell necrosis.

[0129] Drug composition The drug composition comprises the TRADD inhibitor, which is a compound represented by formula I, formula II, or formula III, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably a deuterated compound), or pharmaceutically acceptable salt of a compound represented by formula I, formula II, or formula III, and one or more pharmaceutically acceptable auxiliary materials.

[0130] The auxiliary materials of this application include, but are not limited to, common excipients, diluents, fillers, adhesives, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, absorption enhancers, surfactants, lubricants, buffers, and stabilizers in the pharmaceutical field.

[0131] In some embodiments, the drug composition may be prepared as needed in any pharmaceutically acceptable formulation, such as tablets, capsules, pills, granules, pellets, aerosols, sprays, nasal drops, inhalants, suppositories, enemas, intramuscular injection formulations, intravenous injection formulations, intra-articular injection formulations, ointments, patches, etc.

[0132] The drug composition described in this application may be administered via parenteral administration, injection, or oral administration. The drug composition may be prepared in a form suitable for administration, such as a solid, semi-solid, or liquid, which may be in the form of an aqueous solution, non-aqueous solution, suspension, powder, tablet, capsule, granule, injection, or infusion. The drug composition may be administered intravascularly, subcutaneously, intraperitoneally, intramuscularly, by inhalation, intranasally, by airway infusion, or intrapleural infusion. The drug composition may be administered in the form of an aerosol or spray, for example, intranasally, intrathecally, or intravenously, or percutaneously, transdermally, topically, intraintestinally, intravaginally, sublingually, or rectally. The drug composition may be prepared in various dosage forms as needed, and a physician may determine and administer a dose beneficial to the patient according to factors such as the patient's type, age, weight, and general disease state, and method of administration.

[0133] According to embodiments of this application, the drug composition is a drug preparation, which is selected from tablets, capsules, pills, granules, pellets, emulsions, liquids, suspensions, syrups, tinctures, powders, aerosols, sprays, nasal drops, inhalants, suppositories, enemas, intramuscular injection preparations, intravenous injection preparations, intra-articular injection preparations, ointments, or patches.

[0134] When the drug formulation described in this application is in solid dosage form, such as capsules, tablets, pills, lozenges, and granules, the compound is mixed with at least one common inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or the following components. (a) Fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) Binders, e.g., hydroxypropylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) Humectants, e.g., glycerin; (d) Disintegrants, e.g., agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) Loosening agents, e.g., paraffin; (f) Absorption accelerators, e.g., quaternary ammonium compounds; (g) Wetting agents, e.g., cetyl alcohol and glycerin monostearate; (h) Adsorbents, e.g., kaolin; and (i) Lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may include a buffer.

[0135] If the drug formulation described in this application is in liquid dosage form, for example, a pharmaceutically acceptable emulsion, solution, suspension, syrup, or elixir, the drug composition may include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, maize germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may include wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. Suspensions may include suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

[0136] If the drug formulation described in this application is a dosage form for parenteral injection, the drug composition may include a physiologically acceptable sterile aqueous or anhydrous solution, dispersion, suspension or emulsion, and a sterile powder for redissolution in a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0137] When the drug formulation described in this application is in a dosage form for topical administration, such as an ointment, powder, patch, propellant, or inhalant, the active ingredient in the drug composition is mixed with a physiologically acceptable carrier and any preservative, buffer, or propellant under sterile conditions.

[0138] Application of TRADD inhibitors and drug compositions This application further provides the use of the above-mentioned TRADD inhibitors and drug compositions in the preparation of drugs for preventing or treating inflammation-related diseases and / or cell necrotizing apoptosis and autophagy-related diseases.

[0139] According to some embodiments of this application, the inflammation-related disease is an inflammatory central nervous system condition or disease or an inflammatory peripheral system condition or disease associated with TNF-α.

[0140] According to some embodiments of this application, the inflammatory central nervous system condition or disease includes diseases or conditions resulting from excessive activation of brain immune cells or involving cytokines, particularly TNF-α, or clinically identified types of inflammatory central nervous system diseases, for example, the types of inflammatory central nervous system diseases are selected from encephalitis, meningitis, encephalomyelitis, viral, bacterial or autoimmune encephalitis, multiple sclerosis, brain injury, brain and spinal cord injury, cerebral contusion, subdural hematoma and spinal cord injury and cerebrovascular vasculitis of various causes.

[0141] According to some embodiments of this application, the inflammatory peripheral system conditions or diseases include pyoderma, vasculitis, dermatitis, herpetiform dermatitis, psoriasis, atopic dermatitis, neurodermatitis, contact dermatitis, eczema, scleroderma, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory myopathy, acute or chronic nephritis, nephrotic syndrome, glomerulonephritis, dry eye syndrome, uveitis, endophthalmitis, blepharitis, glaucoma, age-related macular lesions, conjunctivitis, allergic conjunctivitis, keratitis, autoimmune uveitis, gingivitis, periodontitis, allergic and non-allergic rhinitis, inflammatory bowel disease, lupus nephritis, thyroiditis, alcoholic and This includes non-alcoholic fatty liver disease, viral and non-viral hepatitis, autoimmune hepatitis, chronic relapsing hepatitis, cirrhosis, autoimmune hemolytic anemia, temporal arteritis, Crohn's disease, enteritis, colitis, ulcerative colitis, lupus erythematosus, ankylosing spondylitis, immune complex hematoangitis, myocarditis, ischemic heart disease, hypercholesterolemia, atherosclerosis, pre-eclampsia, diabetes mellitus, diabetic retinopathy, diabetic nephropathy, allograft rejection, pneumonia, acute lung injury, emphysema, chronic obstructive pulmonary disease, tracheitis, bronchitis, asthma, pulmonary fibrosis, various acute or chronic inflammatory diseases due to hepatic fibrosis, and inflammation caused by autoimmune function.

[0142] According to some embodiments of this application, the cell necrotizing apoptosis-related diseases include diseases or conditions resulting from nerve injury, neurobehavioral deficits, neurodegenerative diseases, excitatory toxicity of the nervous system, accumulation of misfolded proteins in cells, or impaired autophagy, or clinically identified disease types, such as stroke (hemorrhagic stroke, ischemic stroke), chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, Alzheimer's disease, Parkinson's disease, limb weakness due to neurobehavioral deficits, cognitive neurobehavioral deficits due to nerve injury (e.g., visual, gustatory, olfactory, auditory, facial nerve injury, mania, emotional disorders, etc.), psychiatric disorders such as depression, anxiety disorders, schizophrenia, phobias, primary open-angle glaucoma, heart disease, heart failure, myocardial fibrosis, myocardial infarction, myocardial ischemia, chronic renal failure, renal injury, and lung injury.

[0143] Prevention or treatment methods This application further provides a method for preventing or treating inflammation-related and / or cell necrosis-related acute or chronic central or peripheral diseases, comprising administering to a subject in need a therapeutically effective amount of a compound represented by formula I, formula II, or formula III, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably a deuterated compound), or a pharmaceutically acceptable salt, or the drug composition thereof, to the subject.

[0144] According to some embodiments of this application, the inflammation-related disease is an inflammatory central nervous system condition or disease or an inflammatory peripheral system condition or disease associated with TNF-α.

[0145] According to some embodiments of this application, the inflammatory central nervous system condition or disease includes diseases or conditions resulting from excessive activation of brain immune cells or involving cytokines, particularly TNF-α, or clinically identified types of inflammatory central nervous system diseases, such as encephalitis, meningitis, encephalomyelitis, viral, bacterial or autoimmune encephalitis, multiple sclerosis, brain injury, brain and spinal cord injury, cerebral contusion, subdural hematoma, and spinal cord injury and cerebrovascular vasculitis of various causes.

[0146] According to some embodiments of this application, the inflammatory peripheral system conditions or diseases include pyoderma, vasculitis, dermatitis, herpetiform dermatitis, psoriasis, atopic dermatitis, neurodermatitis, contact dermatitis, eczema, scleroderma, arthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory myopathy, acute or chronic nephritis, nephrotic syndrome, glomerulonephritis, dry eye syndrome, uveitis, endophthalmitis, blepharitis, glaucoma, age-related macular lesions, conjunctivitis, allergic conjunctivitis, keratitis, autoimmune uveitis, gingivitis, periodontitis, allergic and non-allergic rhinitis, inflammatory bowel disease, lupus nephritis, thyroiditis, alcoholic and non-alcoholic rhinitis. This includes fatty liver disease, viral and nonviral hepatitis, autoimmune hepatitis, chronic relapsing hepatitis, cirrhosis, autoimmune hemolytic anemia, temporal arteritis, Crohn's disease, enteritis, colitis, ulcerative colitis, lupus erythematosus, ankylosing spondylitis, immune complex hematoangitis, myocarditis, ischemic heart disease, hypercholesterolemia, atherosclerosis, pre-eclampsia, diabetes mellitus, diabetic retinopathy, diabetic nephropathy, allograft rejection, pneumonia, acute lung injury, emphysema, chronic obstructive pulmonary disease, tracheitis, bronchitis, asthma, pulmonary fibrosis, various acute or chronic inflammatory diseases due to hepatic fibrosis, and inflammation caused by autoimmune function.

[0147] According to some embodiments of this application, the cell necrotizing apoptosis-related disease is selected from a disease or condition resulting from nerve injury, neurobehavioral deficits, neurodegenerative diseases, excitatory toxicity of the nervous system, accumulation of misfolded proteins in cells, or impaired autophagy, or clinically identified disease types, such as stroke (hemorrhagic stroke, ischemic stroke), chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, Alzheimer's disease, Parkinson's disease, limb weakness due to neurobehavioral deficits, cognitive neurobehavioral deficits due to nerve injury (e.g., visual, gustatory, olfactory, auditory, facial nerve injury, mania, emotional disorders, etc.), psychiatric disorders such as depression, anxiety disorders, schizophrenia, phobias, primary open-angle glaucoma, heart disease, heart failure, myocardial fibrosis, myocardial infarction, myocardial ischemia, chronic renal failure, renal injury, and lung injury.

[0148] In this application, the subject may be a mammal, and the preferred subject is a human.

[0149] The inflammation-related diseases referred to in this invention mean inflammatory central or peripheral system diseases caused primarily by a variety of causes, and particularly those related to TNF-α. Here, inflammation-related central system conditions or diseases include a range of diseases or conditions resulting from the overactivation of brain immune cells or involving cytokines, particularly TNF-α, or clinically identified types of inflammatory diseases of the central nervous system, for example, selected from, but not limited to, encephalitis, meningitis, encephalomyelitis, viral, bacterial or autoimmune encephalitis, multiple sclerosis, brain injury, brain and spinal cord injury, cerebral contusion, subdural hematoma and spinal cord injury and cerebrovascular vasculitis of various causes. Inflammation-related peripheral system conditions or diseases include pyoderma, vasculitis, dermatitis, herpetiform dermatitis, psoriasis, atopic dermatitis, neurodermatitis, contact dermatitis, eczema, scleroderma, arthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory myopathy, acute or chronic nephritis, nephrotic syndrome, glomerulonephritis, dry eye syndrome, uveitis, endophthalmitis, blepharitis, glaucoma, age-related macular lesions, conjunctivitis, allergic conjunctivitis, keratitis, autoimmune uveitis, gingivitis, periodontitis, allergic and non-allergic rhinitis, inflammatory bowel disease, lupus nephritis, thyroiditis, alcoholic and non-alcoholic fatty liver, viral and non-alcoholic This includes, but is not limited to, various acute or chronic inflammatory diseases resulting from viral hepatitis, autoimmune hepatitis, chronic relapsing hepatitis, cirrhosis, autoimmune hemolytic anemia, temporal arteritis, Crohn's disease, enteritis, colitis, ulcerative colitis, lupus erythematosus, ankylosing spondylitis, immune complex hematoangitis, myocarditis, ischemic heart disease, hypercholesterolemia, atherosclerosis, pre-eclampsia, diabetes mellitus, diabetic retinopathy, diabetic nephropathy, allograft rejection, pneumonia, acute lung injury, emphysema, chronic obstructive pulmonary disease, tracheitis, bronchitis, asthma, pulmonary fibrosis, hepatic fibrosis, and a range of inflammations resulting from autoimmune function.

[0150] In some embodiments, the cell necrotizing apoptosis-related diseases referred to in this application are selected from diseases or conditions resulting from nerve injury, neurobehavioral deficits, neurodegenerative diseases, excitotoxicity of the nervous system, accumulation of misfolded proteins in cells, or impaired autophagy, or clinically identified disease types, e.g., stroke (hemorrhagic stroke, ischemic stroke), chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, Alzheimer's disease, Parkinson's disease, limb weakness due to neurobehavioral deficits, cognitive neurobehavioral deficits due to nerve injury (e.g., visual, gustatory, olfactory, auditory, facial nerve injury, mania, emotional disorders, etc.), psychiatric disorders such as depression, anxiety disorders, schizophrenia, phobias, primary open-angle glaucoma, heart disease, heart failure, myocardial fibrosis, myocardial infarction, myocardial ischemia, chronic renal failure, renal injury, and lung injury.

[0151] Methods to inhibit TRADD activity This application further provides a method for inhibiting TRADD activity in cells or subjects, comprising the steps of contacting cells with the compound or the drug composition, or administering the compound or the drug composition to a subject. The compound is a compound represented by formulas I, II, or III, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably a deuterated compound), or a pharmaceutically acceptable salt of a compound represented by formulas I, II, or III.

[0152] In some embodiments, the cells are mammalian cells. In some embodiments, the subject is a mammal, preferably a human.

[0153] Example 1 Compound Synthesis Synthesis method 1 Synthesis of TRL-1 [ka] Step 1: Synthesis of TRL-1-A2 TRL-1-A1 (11.10 g, 81.02 mmol) was dissolved in acetonitrile (50 mL), and 1,4-diiodobutane (5.00 g, 16.18 mmol) and N,N-diethylcyclohexylamine (7.50 g, 48.39 mmol) were added. The mixture was reacted overnight at 80°C with reflux stirring under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was diluted with water (80 mL) and ethyl acetate (80 mL). Extraction was performed with ethyl acetate (80 mL x 2), the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether) to obtain a yellow oily substance, TRL-1-A2 (1.20 g, 53.8%). MS(ESI)m / z=139.1[M+H] + . 1 H NMR(Cd3Od,400 MHz): δ 2.26-2.21 (m,2H), 1.91-1.87(m,4H), 1.81-1.68(m,6H), 1.51-1.47(m,2H). Step 2: Synthesis of TRL-1-A3 TRL-1-A2 (1.00 g, 7.24 mmol) was dissolved in ethanol (20 mL) and water (10 mL), and hydroxylamine hydrochloride (750 mg, 10.87 mmol) and sodium acetate (750 mg, 9.14 mmol) were added. The mixture was reacted overnight under reflux and stirring. After cooling the reaction mixture, the solvent was removed under reduced pressure, and the mixture was concentrated under reduced pressure. The resulting crude product was diluted with water (80 mL) and ethyl acetate (80 mL), extracted with ethyl acetate (80 mL x 2), washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and after vacuum concentration, it was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether) to obtain a yellow oily substance, TRL-1-A3 (235 mg, 21.4%). MS(ESI)m / z=154.1[M+H] + Step 3: Synthesis of TRL-1-A4 TRL-1-A3 (235 mg, 1.54 mmol) was dissolved in acetic acid (15 mL), and platinum dioxide (35 mg, 0.15 mmol) was added. The reaction was carried out with a double-layered hydrogen balloon and stirred at room temperature for 36 hours. After filtering the reaction mixture, the filtrate was vacuum-dried to obtain a colorless oily substance, TRL-1-A4 acetate (178 mg, 83.1%). MS(ESI)m / z=140.1[M+H] + Step 4: Synthesis of TRL-1-A5 TRL-1-A4 (178 mg, 0.89 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (250 mg, 1.94 mmol) was added. Then, chloroacetyl chloride (213 mg, 1.90 mmol) was added with imida at 0°C. The reaction was stirred at room temperature for 16 hours under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain TRL-1-A5 (289 mg, crude product), which was then used directly in the next step. MS(ESI)m / z=216.1[M+H] + Step 5: Synthesis of TRL-1 TRL-1-A5 (289 mg, crude product) was dissolved in acetonitrile (10 mL), imidazole-2-thione (205 mg, 2.01 mmol) was added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and dried to obtain a brown solid, which was then prepared and purified by high-performance liquid chromatography. Acetonitrile was removed under reduced pressure, and the mixture was freeze-dried to obtain a pale yellow oily substance, TRL-1 formate (24.31 mg, yield 8.4%). MS(ESI)m / z=282.1[M+H] + ; 1 H NMR(CdCl3, 400 MHz): δ 9.04 (d, J = 12.8 Hz, 1H), 8.62 (s, 1H), 4.06-4.04 (m, 1H), 4.04-3.98 (m, 2H), 3.96(s, 4H), 2.25-2.02 (m, 2H), 1.78-1.64 (m, 4H), 1.58-1.30 (m, 8H).

[0154] Synthesis method 2 Synthesis of TRL-2 [ka] Step 1: Synthesis of TRL-2-A2 TRL-2-A1 (50.0 mg, 0.31 mmol) was dissolved in dichloromethane (10 mL), triethylamine (81.0 mg, 0.8 mmol) was added, and then chloroacetyl chloride (67.0 mg, 0.6 mmol) was slowly added at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain TRL-2-A2 (87.0 mg, crude product), which was then used directly in the next step. MS(ESI)m / z=202.1[M+H] + Step 2: Synthesis of TRL-2 TRL-2-A2 (87.0 mg, crude product) was dissolved in ethanol (10 mL), imidazole-2-thione (66.0 mg, 0.64 mmol) was added, and the mixture was stirred and reacted at 80°C for 4 hours. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography, and after lyophilization, a brown solid TRL-2 formate (8.03 mg, yield 8.3%) was obtained. MS(ESI)m / z=268.1[M+H] + ; 1 H NMR (DMSO-d6,400 MHz):δ 8.30(d, J = 6.4 Hz, 1H), 6.04(s, 1H), 3.81-3.67(m, 4H), 3.54-3.48(m, 3H), 2.14(s, 2H), 1.82-1.52(m, 8H), 1.42-1.31(m, 2H).

[0155] Synthesis of TRL-3 [ka] Step 1: Synthesis of TRL-3-A2 TRL-3-A1 (25.0 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL). After adding triethylamine (51.0 mg, 0.51 mmol), chloroacetyl chloride (23.0 mg, 0.20 mmol) was slowly added at 0 °C. The reaction was carried out overnight with stirring at room temperature under the protection of nitrogen gas. The reaction solution was concentrated under reduced pressure to obtain TRL-3-A2 (32.0 mg, crude product), which was used directly in the next step. MS(ESI) m / z = 188.2 [M+H] + Step 2: Synthesis of TRL-3 TRL-3-A2 (32.0 mg, 0.17 mmol) was dissolved in ethanol (5 mL). Imidazole-2-thione (26.0 mg, 0.25 mmol) was added, and the mixture was stirred and reacted at 90 °C for 5 hours. After cooling the reaction solution, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was purified by preparative high performance liquid chromatography and freeze-dried to obtain yellow oily TRL-3 formate (7.95 mg, yield 15.6%). MS(ESI) m / z = 254.1[M+H] + ; 1 1H NMR (CdCl3, 400 MHz): δ 9.50 (s, 1H), 8.51 (s, 1H), 3.94 (s, 4H), 3.88 (s, 2H), 3.46 - 3.17 (m, 1H), 2.49 - 2.43 (m, 1H), 1.96 - 1.77 (m, 3H), 1.75 - 1.65 (m, 2H), 1.35 - 1.14 (m, 4H).

[0156] Synthesis of TRL-5

Chemical Structure

[0157] Synthesis of TRL-6

Chemical Structure

[0158] Synthesis of TRL-7 [ka] Step 1: Synthesis of TRL-7-A1 Spiro[2,3]hexane-5-amine hydrochloride (20.0 mg, 0.15 mmol) and N,N-diisopropylethylamine (58.0 mg, 0.45 mmol) were dissolved in anhydrous dichloromethane (2 mL), and chloroacetyl chloride (20.0 g, 0.18 mmol) was slowly added at 0°C. After the addition was complete, the mixture was allowed to react overnight at room temperature with stirring. The reaction was monitored by liquid chromatography, and the reaction mixture was concentrated under reduced pressure. The resulting light brown oily substance, TRL-7-A1, was used directly in the next reaction without further purification (25.0 mg, 100% yield). LCMS(ESI)m / z=174.1[M+H] + Step 2: Synthesis of TRL-7 The crude oily product TRL-7-A1 (25.0 mg, 0.15 mmol) and imidazole-2-thione (23.0 mg, 0.225 mmol) were dissolved in anhydrous ethanol (3 mL) and reacted with stirring at 90°C for 5 hours. After cooling the reaction mixture, it was concentrated under reduced pressure, and the oily residue obtained after concentration was subjected to high-performance liquid chromatography to prepare a white solid TRL-7 formate (16.45 mg, yield 41.2%). MS(ESI)m / z=240.1[M+H] + ; 1 H NMR(CdCl3,400 MHz):δ 9.70-9.68(br s,1H),8.56(s,1H),4.50-4.43(m,1H),3.93(s,4H),3.90(s,2H),2.30(d,J = 8.0 Hz,4H), 0.49-0.39(m,4H).

[0159] TRL-8 synthesis [ka] Step 1: Synthesis of TRL-8-A2 TRL-8-A1 (25.0 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL), triethylamine (37.0 mg, 0.37 mmol) was added, and then chloroacetyl chloride (16.0 mg, 0.14 mmol) was slowly added at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain TRL-8-A2 (30.0 mg, crude product), which was then used in the next step. MS(ESI)m / z=244.3 [M+H] + Step 2: Synthesis of TRL-8 TRL-8-A2 (30.0 mg, 0.12 mmol) was dissolved in ethanol (5 mL), imidazole-2-thione (19.0 mg, 0.18 mmol) was added, and the mixture was stirred and reacted at 90°C for 6 hours. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography, and after lyophilization, a yellow oily substance, TRL-8 formate (6.21 mg, yield 14.2%), was obtained. MS(ESI)m / z=310.1[M+H] + ; 1 H NMR(CdCl3,400 MHz):δ 9.17(d,J = 7.6 Hz,1H), 8.53(s,1H),3.92(s,4H),3.89(s,2H),3.64-3.57(m,1H),1.71-1.67(m,4H),1.48-1.38(m,10H),1.25-1.10(m,4H).

[0160] TRL-9 synthesis [ka] Step 1: Synthesis of TRL-9-A2 TRL-9-A1 (30.0 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), triethylamine (52.0 mg, 0.51 mmol) was added, and then chloroacetyl chloride (29.0 mg, 0.26 mmol) was slowly added at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain TRL-9-A2 (37.0 mg, crude product), which was then used directly in the next step. MS(ESI)m / z=216.2 [M+H] + Step 2: Synthesis of TRL-9 TRL-9-A2 (37.0 mg, 0.17 mmol) was dissolved in acetonitrile (5 mL), imidazole-2-thione (26.0 mg, 0.26 mmol) was added, and the mixture was stirred and reacted at 25°C for 3 days. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by silica gel chromatography column (dichloromethane:methanol = 10:1) and high-performance liquid chromatography, and after lyophilization, a yellow oily substance, TRL-9 formate (20.16 mg, yield 35.9%), was obtained. MS(ESI)m / z=282.1[M+H] + ; 1 H NMR(CdCl3,400 MHz):δ 8.94(d,J = 6.8 Hz,1H),8.41(s,1H),3.90(s,4H),3.88(s,2H),3.59-3.56(m,1H),1.86-1.74(m,2H),1.72-1.67(m,8H),1.37-1.31(m,4H).

[0161] Synthesis of TRL-10 [ka] Step 1: Synthesis of TRL-10-A2 [5.1.0] Octane-8-amine hydrochloride (20.0 g, 0.12 mmol) and N,N-diisopropylethylamine (48.0 mg, 0.37 mmol) were dissolved in anhydrous dichloromethane (2 mL), and chloroacetyl chloride (21.0 g, 0.19 mmol) was slowly added at 0 °C. After the addition was completed, the reaction was carried out overnight with stirring at room temperature. The reaction was monitored by liquid chromatography, and the reaction solution was concentrated under reduced pressure. The light brown oily substance TRL-10-A2 obtained after concentration was used in the next reaction without further purification (30.0 mg, yield 100%). MS(ESI) m / z = 202.1 [M+H] + Step 2: Synthesis of TRL-10 The crude oily product TRL-10-A2 (30.0 mg, 0.12 mmol) and imidazole-2-thione (19.0 mg, 0.19 mmol) were dissolved in anhydrous ethanol (3 mL), and the reaction was carried out with stirring at 70 °C for 5 hours. The reaction was monitored by liquid chromatography until completion. After the reaction solution was cooled, it was concentrated under reduced pressure. The oily residue obtained after concentration was subjected to high performance liquid chromatography to prepare colorless oily TRL-10 formate (6.0 mg, yield 16%). MS(ESI) m / z = 268.1 [M+H] + ; 1 1H NMR (CdCl3, 400 MHz): δ 9.56 (s, 1H), 8.54 (s, 1H), 3.94 (s, 4H), 3.88 (s, 2H), 2.50 (s, 1H), 2.22 - 2.20 (m, 2H), 1.81 - 1.69 (m, 4H), 1.38 - 1.25 (m, 3H), 1.12 - 1.06 (m, 1H), 1.03 - 1.01 (m, 2H).

[0162] Synthesis of TRL-11

Chemical Structure

[0163] TRL-14 synthesis [ka] Step 1: Synthesis of TRL-14-A1 Octahydropentadiene-2-amine hydrochloride (20.0 mg, 0.12 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolved in dichloromethane (2 mL), and chloroacetyl chloride (17.0 mg, 0.15 mmol) was slowly added at 0°C. After the addition was complete, the mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. The reaction mixture was concentrated under reduced pressure to obtain a yellow solid TRL-14-A1 (25 mg, crude product). MS(ESI)m / z=202.1[M+H] + Step 2: Synthesis of TRL-14 TRL-14-A1 (25.0 mg, 0.1 mmol) and imidazole-2-thione (15.0 mg, 0.1 mmol) were dissolved in ethanol (2 mL) and stirred at 70°C for 5 hours. The reaction was cooled to room temperature, and TRL-14 formate (4.1 mg, yield: 10.6%) was obtained by high-performance liquid chromatography. MS(ESI)m / z=268.1[M+H] + ; 1 H NMR (DMSO-d6,400 MHz):δ 8.27-8.26 (m,1H),6.04 (br s,1H),4.02-3.93 (m,1H),3.80-3.70 (m,1H), 3.59-3.27 (m,5H),2.46-2.44 (m,1H),2.33-2.29 (m,2H),2.08-1.98 (m,2H),1.73-1.69 (m,2H)) ,1.68-1.654(m,3H),1.50-1.28 (m,1H),0.91-0.73 (m,1H).

[0164] Synthesis of TRL-15 [ka] Step 1: Synthesis of TRL-15-A1 Decahydroazulene-2-amine hydrochloride (30.0 mg, 0.16 mmol) and N,N-diisopropylethylamine (62.0 mg, 0.5 mmol) were dissolved in dichloromethane (2 mL), and chloroacetyl chloride (20.0 mg, 0.2 mmol) was slowly added at 0°C. After the addition was complete, the mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. The reaction mixture was concentrated under reduced pressure to obtain a yellow oily substance, TRL-15-A1 (32.0 mg, crude product). MS(ESI)m / z=230.1[M+H] + Step 2: Synthesis of TRL-15 TRL-15-A1 (32.0 mg, 0.1 mmol) and imidazolidine-2-thione (17.0 mg, 0.2 mmol) were dissolved in ethanol (2 mL) and stirred at 70°C for 5 hours. The reaction was cooled to room temperature and subjected to high-performance liquid chromatography to prepare TRL-15 formate (16 mg, yield: 34%). MS(ESI)m / z=296.1[M+H] + ; 1 H NMR (CdCl3,400 MHz):δ 9.21-9.19 (m, 1H), 8.59 (s, 1H), 4.16-4.12 (m, 1H), 3.92-3.87 (m, 4H), 3.86-3.70 (m, 2 H), 2.26-2.11 (m, 3H), 1.81-1.79 (m, 4H), 1.67-1.62 (m, 2H), 1.54-1.46 (m, 1H), 1.37-1.31 (m, 2H), 1.28-1.13 (m, 4H).

[0165] Synthesis of TRL-16 [ka] Step 1: Synthesis of TRL-16-A1 Spiro[3,4]octane-2-amine hydrochloride (30.0 mg, 0.19 mmol) and N,N-diisopropylethylamine (74.0 mg, 0.57 mmol) were dissolved in dichloromethane (2 mL), and chloroacetyl chloride (23.0 mg, 0.21 mmol) was slowly added at 0°C. After the addition was complete, the mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. The reaction mixture was concentrated under reduced pressure to obtain a yellow solid TRL-16-A1 (38.1 mg, crude product). MS(ESI)m / z=202.1[M+H] + Step 2: Synthesis of TRL-16 TRL-16-A1 (38.1 mg, 0.2 mmol) and imidazolidine-2-thione (24.0 mg, 0.24 mmol) were dissolved in ethanol (2 mL) and stirred at 70°C for 5 hours. The reaction was cooled to room temperature and subjected to high-performance liquid chromatography to prepare TRL-16 (20.0 mg, yield: 40%). MS(ESI)m / z=268.1[M+H] + ; 1 H NMR(CdCl3,400 MHz):δ 9.61-9.59 (m, 1H), 8.60 (s, 1H), 4.23-4.16 (m, 1H), 3.93 (s, 4H), 3.91 (s, 2H), 2.25-2.20 (m, 2H), 1.94-1.89 (m, 2H), 1.61-1.49 (m, 8H).

[0166] Synthesis of TRL-22 [ka] Step 1: Synthesis of TRL-22-A1 6,7,8,9-tetrahydro-5H-benzo[7]cycloalkene-7-amine (50.0 mg, 0.3 mmol) and N,N-diisopropylethylamine (80.0 mg, 0.6 mmol) were dissolved in dichloromethane (2 mL), and chloroacetyl chloride (42.0 mg, 0.4 mmol) was slowly added at 0°C. After the addition was complete, the mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. After cooling the reaction mixture, it was concentrated under vacuum to obtain a white solid TRL-22-A1 (70 mg, crude product). Step 2: Synthesis of TRL-22 TRL-22-A1 (70.0 mg, 0.3 mmol) and imidazoline-2-thione (36.2 mg, 0.4 mmol) were dissolved in ethanol (2 mL) and stirred at 70°C for 5 hours. The reaction was cooled to room temperature, and a white solid TRL-22 formate (34.6 mg, yield: 33.6%) was obtained by high-performance liquid chromatography. MS(ESI)m / z=304.1[M+H] + ; 1 H NMR(DMSO-d6,400 MHz):δ 8.57-8.56(m,1H),8.21(s,1H),7.16-7.10(m,4H),3.94-3.91(m,1H),3.81( s,2H),3.63(s,4H),2.84-2.69(m,4H),1.93-1.92(m,2H),1.34-1.30(m,2H).

[0167] Combination of TRL-31 and TRL-71 [ka] Step 1: Synthesis of TRL-31A2 TRL-31A1 (50 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (81 mg, 0.63 mmol) was added. Then, chloroacetyl chloride (53 mg, 0.47 mmol) was slowly added at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain TRL-31A2 (61 mg, crude product), which was then used in the next step. MS(ESI)m / z=273.1 [M+H]+ Step 2: Synthesis of TRL-31 TRL-31A2 (61 mg, crude product) was dissolved in tetrahydrofuran (5 mL), imidazole-2-thione (32 mg, 0.31 mmol) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography, and lyophilized to obtain a brown oily substance, TRL-31 formate (20.32 mg, two-step reaction yield 18.9%). MS(ESI)m / z=302.0[M+H] + ; 1 H NMR(CdCl3,400 MHz):δ 10.03(s, 1H), 8.56(s, 1H), 7.32-7.28(m, 2H), 7.26-7.20(m, 3H), 3.94(s, 4H), 3.89(s, 2H), 2.37(s, 6H).

[0168] Compound TRL-71, shown in Table 1 below, was prepared using a method similar to that used for the synthesis of TRL-31, and by using commercially available compounds or the preparation methods for intermediate compounds shown for reference.

[0169] [Table 1]

[0170] Synthesis method 3 Synthesis of TRL-4 [ka] Step 1: Synthesis of TRL-4-A2 TRL-4-A1 (100.0 mg, 0.59 mmol) was dissolved in methanol (10 mL), and platinum dioxide (30.0 mg) was added. The reaction was carried out with stirring at 50°C for 16 hours under hydrogen and a 50 psi environment. After cooling the reaction mixture, it was filtered and concentrated under reduced pressure to obtain a light brown solid TRL-4-A2 hydrochloride (89 mg, yield 86.2%). MS(ESI)m / z=140.4[M+H] + Step 2: Synthesis of TRL-4-A3 TRL-4-A2 (70.0 mg, 0.4 mmol) was dissolved in dichloromethane (10 mL), triethylamine (102.0 mg, 1.0 mmol) was added, and then chloroacetyl chloride (85.0 mg, 0.76 mmol) was slowly added at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain TRL-4-A3 (87 mg, crude product), which was then used in the next step. MS(ESI)m / z=216.1[M+H] + Step 3: Synthesis of TRL-4 TRL-4-A3 (87.0 mg, crude product) was dissolved in acetonitrile (10 mL), imidazole-2-thione (62.0 mg, 0.61 mmol) was added, and the mixture was stirred at room temperature for 36 hours. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography, and after lyophilization, a yellow oily substance, TRL-4 formate (8.64 mg, yield 6.6%), was obtained. MS(ESI)m / z=282.1[M+H] + ; 1 H NMR (CdCl3,400 MHz): δ 9.38 (br s,1H),8.58 (s,1H),4.31-4.06(m,1H),3.97 (s,6H),2.11-1.94(m,4H),1.59-1.48(m,6H),1.32-1.30(m,4H).

[0171] Synthesis method 4 Synthesis of TRL-12 [ka] Step 1: Synthesis of TRL-12-A1 2-trifluoromethyl-6-aminopyridine (160.0 mg, 1.0 mmol) and N,N-diisopropylethylamine (390.0 g, 3.0 mmol) were dissolved in anhydrous dichloromethane (6 mL), and chloroacetyl chloride (135.0 g, 1.2 mmol) was slowly added at 0°C. After the addition was complete, the mixture was reacted overnight at room temperature with stirring. The reaction mixture was concentrated under reduced pressure, and the resulting light brown oily substance TRL-12-A1 was used in the next reaction without further purification (240.0 mg, 100% yield). MS(ESI)m / z=239.1[M+H] + Step 2: Synthesis of TRL-12 The crude oily product TRL-12-A1 (240 mg, crude product) and imidazole-2-thione (153.0 mg, 1.5 mmol) were dissolved in anhydrous ethanol (5 mL) and reacted with stirring at 70°C for 5 hours. After cooling the reaction mixture, it was concentrated under reduced pressure, and the oily residue obtained after concentration was subjected to high-performance liquid chromatography to prepare a white solid TRL-12 formate (20.1 mg, yield 5.8%). MS(ESI)m / z=305.0[M+H] + 1 H NMR(DMSO-d6,400 MHz):δ 11.61-11.55(br s, 1H), 8.31-8.21(d, J = 8.4 Hz, 1H), 8.24-8.21(m, 1H), 8.08(t, J = 8.4 Hz, 1H), 7.60(d, J = 8.4 Hz, 1H), 3.96(s, 2H), 3.54(s, 4H).

[0172] Synthesis of TRL-13 [ka] Step 1: Synthesis of TRL-13-A1 2-aminonaphthalene (216.0 mg, 1.51 mmol) and N,N-diisopropylethylamine (260.0 mg, 2.00 mmol) were dissolved in anhydrous dichloromethane (5.0 mL). Chloroacetyl chloride (226.0 mg, 2.00 mmol) was slowly added at 0°C, and after the addition was complete, the mixture was reacted overnight at room temperature with stirring. The reaction mixture was concentrated under reduced pressure, and the resulting light brown oily residue was purified using a flash column (ethyl acetate:petroleum ether = 1:1) to obtain the yellow oily substance TRL-13-A1 (210.0 mg, yield 64.0%). MS(ESI)m / z=220.1[M+H] + Step 2: Synthesis of TRL-13 The crude oily product TRL-13-A1 (210.0 mg, 0.96 mmol) and imidazole-2-thione (98.0 mg, 0.96 mmol) were dissolved in anhydrous ethanol (5 mL) and reacted by stirring at 70°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the oily residue obtained after concentration was subjected to high-performance liquid chromatography to prepare the white solid TRL-13 trifluoroacetate (51.0 mg, yield 13.4%). MS(ESI)m / z=286.0[M+H] + ; 1 H NMR (CdCl3, 400MHz): δ 11.32 (s, 1H), 10.98-10.95 (brs, 2H), 8.22 (s, 1H), 7.76-7.72 (m, 3H),7.58 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.44-7.39 (m, 2H), 4.24 (s, 2H), 3.94 (s, 4H).

[0173] Synthesis of TRL-18 [ka] Step 1: Synthesis of TRL-18-A1 6-aminoquinoline (212 mg, 1.47 mmol) and N,N-diisopropylethylamine (379 mg, 2.94 mmol) were dissolved in anhydrous dichloromethane (5 mL), and chloroacetyl chloride (332 mg, 2.94 mmol) was slowly added at 0°C. After the addition was complete, the mixture was reacted overnight at room temperature with stirring. The reaction mixture was concentrated under reduced pressure, and the resulting light brown oily residue was purified using a flash column (methanol:dichloromethane = 1:20) to obtain the yellow oily substance TRL-18-A1 (201 mg, yield 62%). MS(ESI)m / z=221.0[M+H] + Step 2: Synthesis of TRL-18 The crude oily product TRL-18-A1 (201.0 mg, 0.91 mmol) and imidazole-2-thione (93.0 mg, 0.91 mmol) were dissolved in anhydrous ethanol (4 mL) and reacted with stirring at 70°C for 5 hours. After cooling the reaction mixture, it was concentrated under reduced pressure, and the oily residue obtained after concentration was subjected to high-performance liquid chromatography to prepare the white solid TRL-18 (57.08 mg, yield 18.9%). MS(ESI)m / z=287.0[M+H] + ; 1 H NMR(DMSO-d6,400 MHz):δ11.06 (s, 1H), 8.78 (dd, J 1= 4.0 Hz, J 2= 1.6 Hz, 1H),8.33 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H),7.97 (d, J = 9.2 Hz, 1H), 7.74 (dd, J 1= 9.2 Hz, J 2= 2.4 Hz, 1H), 7.48 (q, J = 4.0 Hz, 1H), 3.96 (s, 2H), 3.58 (s, 4H).

[0174] Synthesis of TRL-19 [ka] Step 1: Synthesis of TRL-19-A1 5-(trifluoromethyl)thiophene-2-amine hydrochloride (80.0 mg, 0.39 mmol) and N,N-diisopropylethylamine (150.9 mg, 1.17 mmol) were dissolved in dichloromethane (3 mL), and chloroacetyl chloride (65.5 mg, 0.59 mmol) was slowly added at 0°C. After the addition was complete, the mixture was stirred at room temperature and reacted for 16 hours. After cooling the reaction mixture, it was concentrated under reduced pressure to obtain a yellow solid TRL-19-A1 (115 mg, crude product). MS(ESI)m / z=244.0[M+H] + Step 2: Synthesis of TRL-19 TRL-19-A1 (115.0 mg, 0.47 mmol) and imidazole-2-thione (58.0 mg, 0.57 mmol) were dissolved in ethanol (2 mL) and stirred at 70°C for 5 hours. The reaction was cooled to room temperature and subjected to high-performance liquid chromatography to prepare TRL-19 (58.8 mg, yield: 35.0%). MS(ESI)m / z=309.9[M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 8.18-8.17 (m, 1H),7.46 (d, J=3.2Hz, 1H), 6.73 (d, J=4.0Hz, 1H), 4.03 (s, 2H), 3.58 (s, 4H).

[0175] Synthesis of TRL-20 [ka] Step 1: Synthesis of TRL-20-A1 6-aminoisoquinoline (300.0 mg, 2.1 mmol) was dissolved in tetrahydrofuran (20 mL), NaH (166.4 mg, 4.2 mmol) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Chloroacetyl chloride (350.0 mg, 3.1 mmol) was then added, and the mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. Water was added to the reaction mixture to quench it, ethyl acetate was added for extraction, the mixture was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid TRL-20-A1 (350 mg, crude product). MS(ESI)m / z=221.0[M+H] + Step 2: Synthesis of TRL-20 TRL-20-A1 (300.0 mg, 1.4 mmol) and imidazole-2-thione (167.3 mg, 1.6 mmol) were dissolved in ethanol (10 mL) and stirred at 70°C for 5 hours. The reaction was cooled to room temperature and subjected to high-performance liquid chromatography to prepare a white solid TRL-20 formate (5.8 mg, yield: 1.3%). MS(ESI)m / z=287.0[M+H] + ; 1 H NMR (DMSO-d6,400 MHz):δ 11.20(s,1H),9.18(s,1H),8.42-8.41(m,1H),8.31-8.28(m,2 H),8.07(d,J =9.2 Hz,1H),7.74(d,J =5.2 Hz,1H)7.63(d,J =8.8 Hz,1H),3.97(s,2H),3.72(s,4H).

[0176] TRL-21 synthesis [ka] Step 1: Synthesis of TRL-21-A2 TRL-21-A1 (200.0 mg, 1.39 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (269.0 mg, 2.08 mmol) was added. Then, chloroacetyl chloride (231.0 mg, 2.06 mmol) was slowly added at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain TRL-21-A2 (178.0 mg, crude product), which was then used in the next step. MS(ESI)m / z=221.0[M+H] + Step 2: Synthesis of TRL-21 TRL-21-A2 (178.0 mg, crude product) was dissolved in acetonitrile (10 mL), imidazole-2-thione (123.0 mg, 1.20 mmol) was added, and the reaction was carried out with stirring at room temperature for 24 hours. After cooling the reaction solution, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was purified by preparative high performance liquid chromatography and freeze-dried to obtain yellow solid TRL-21 formate (31 mg, yield 7.8%). MS (ESI) m / z = 287.1 [M+H] + ; 1 H NMR (CdCl3, 400 MHz): δ 11.84 (s, 1H) 8.74(d, J = 3.2 Hz, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 8.00 - 7.91(m, 2H), 7.89 - 7.63(m, 2H), 7.25 - 7.20(m, 1H), 4.19 (s, 2H), 3.85(s, 4H).

[0177] Synthesis of TRL-28

Chemical Structure

[0178] Synthesis of TRL-29 [ka] Step 1: Synthesis of TRL-29A2 TRL-29A1 (50 mg, 0.24 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol) were dissolved in dichloromethane (2 mL), and chloroacetyl chloride (41 mg, 0.36 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the product TRL-29A2 (intermediate 2, crude product of 68 mg, based on the starting material TRL-29A1 0.24 mmol), a yellow oily substance. MS(ESI)m / z=289.1[M+H] + Step 2: Synthesis of TRL-29 TRL-29A2 (68 mg, 0.24 mmol) and imidazole-2-thione (29 mg, 0.28 mmol) were dissolved in ethanol (2 mL), and the mixture was stirred at 70 °C for 5 h. The reaction was cooled to room temperature and concentrated under reduced pressure to obtain a brown solid. The solid was purified by preparative high performance liquid chromatography and freeze-dried to obtain a pale gray solid, TRL-29 formate (26.11 mg, two-step reaction yield 27.2%). MS (ESI) m / z = 354.9 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ = 11.32 (br s, 1H), 9.11 (d, J = 2.0 Hz, 1H), 8.84 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.15 (m, 2H), 7.76 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 4.00 (s, 2H), 3.58 (s, 4H).

[0179] Synthesis of TRL-30

Chemical Structure

[0180] Synthesis of TRL-32 [ka] Step 1: Synthesis of TRL-32A2 TRL-32A1 (50 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (59 mg, 0.46 mmol) was added. Then, chloroacetyl chloride (38 mg, 0.34 mmol) was slowly added at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain TRL-32A2 (58 mg, crude product), which was then used in the next step. MS(ESI)m / z=294.9[M+H] + Step 2: Synthesis of TRL-32 TRL-32A2 (58 mg, crude product) was dissolved in tetrahydrofuran (5 mL), imidazole-2-thione (35 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography and freeze-dried to obtain a brown solid TRL-32 (11.03 mg, two-step reaction yield 11.8%). MS(ESI)m / z=360.9 [M+H] + ; 1H NMR (DMSO-d6, 400 MHz): δ 11.23(s, 1H), 8.71(d, J =2.0Hz, 1H), 8.19(d, J =8.2Hz, 1H), 8.16(s, 1H), 7.70-7.67(m, 1H), 3.98(s, 2H), 3.59(s, 4H).

[0181] The compounds listed in Table 2 below were prepared using a method similar to that used for the synthesis of compound TRL-32, and by using commercially available compounds or the intermediate compounds shown for reference.

[0182] [Table 2-1] [Table 2-2]

[0183] Synthesis method 5 Synthesis of TRL-46 [ka] Step 1: Synthesis of TRL-46A2 TRL-46A1 (300 mg, 1.12 mmol) was dissolved in ethanol (10 mL), and thiourea (112 mg, 1.47 mmol) was added. The mixture was reacted overnight at 80°C with stirring. After vacuum concentration of the reaction mixture, it was purified by silica gel column chromatography (eluent: methanol / dichloromethane) to obtain a white solid TRL-46A2 (212 mg, yield 77.5%). MS (ESI) m / z = 245.2[M+H] + . Step 2: Synthesis of TRL-46A3 TRL-46A2 (212 mg, 0.87 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (224 mg, 1.73 mmol) was added. Then, chloroacetyl chloride (145 mg, 1.29 mmol) was slowly added at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was diluted with water (40 mL) and ethyl acetate (80 mL). Extraction was performed with ethyl acetate (40 mL x 2), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: 20%~40% ethyl acetate / petroleum ether) to obtain a yellow oily substance, TRL-46A3 (210 mg, yield 75.4%). MS (ESI) m / z = 321.0[M+H] + . Step 3: Synthesis of TRL-46 TRL-46A3 (210 mg, 0.66 mmol) was dissolved in tetrahydrofuran (10 mL), imidazole-2-thione (74 mg, 0.73 mmol) was added, and the mixture was stirred at room temperature for 2 days. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography, and lyophilized to obtain a white solid TRL-46 formate (34.12 mg, yield 11.95%). MS (ESI) m / z = 386.9[M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 8.17(s, 1H), 8.13(s, 1H), 8.11(s, 1H), 7.88(s, 1H), 7.81(s, 1H), 7.79(s, 1H), 4.03(s, 2H), 3.56(s, 4H).

[0184] Synthesis method 5* Synthesis of TRL-51 [ka] Step 1: Synthesis of TRL-51A2 Quinoline-7-amine (100 mg, 0.69 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (179 mg, 1.39 mmol) was added. Then, chloroacetyl chloride (115 mg, 1.04 mmol) was slowly added at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under the protection of nitrogen gas. After vacuum concentration of the reaction mixture, it was purified by silica gel column chromatography (eluent: methanol / dichloromethane) to obtain a yellow oily substance TRL-51A2 (70 mg, yield 46.0%). MS (ESI) m / z = 221.2[M+H] + . Step 2: Synthesis of TRL-51 TRL-51A2 (70 mg, 0.32 mmol) was dissolved in tetrahydrofuran (10 mL) and ethanol (10 mL), and 1-methylimidazolidined-2-thione (55 mg, 0.47 mmol) was added. The mixture was stirred at 70°C for 20 hours. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown oily substance. The solid was prepared and purified by high-performance liquid chromatography, and freeze-dried to obtain the brown oily substance TRL-51 (3.97 mg, yield 3.9%). MS(ESI) m / z=301.0 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ10.97 (s, 1H), 8.86 (d, J=2.4Hz, 1H), 8.41 (s, 1H), 8.30 (d, J=7.6Hz, 1H), 7.96 (d, J=8.8Hz, 1H), 7.73 (d, J=8.8Hz, 1H), 7.46-7.43 (m, 1H), 4.41 (s, 2H), 3.91-3.80 (m, 4H), 3.09 (s, 3H).

[0185] Synthesis method 6 Synthesis of TRL-17 [ka] Step 1: Synthesis of TRL-17-A2 TRL-17-A1 (500 mg, 2.60 mmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), and lithium hydroxide (125 mg, 5.21 mmol) was added. The reaction was stirred overnight at room temperature. The solvent was removed from the reaction mixture under reduced pressure, and the mixture was dissolved in dichloromethane. After filtration, the filtrate was dried under reduced pressure to obtain a colorless oil, TRL-17-A2 (417.0 mg, 87.2%). MS(ESI)m / z=178.9[M+H] + Step 2: Synthesis of TRL-17-A3 TRL-17-A2 (417.0 mg, 2.34 mmol) was dissolved in thionyl chloride (10 mL), and 1-2 drops of N,N-dimethylformamide were added. The mixture was then stirred and allowed to react at 70°C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove excess thionyl chloride, and TRL-17-A3 (476.0 mg, crude product) was obtained and used directly in the next step. MS(ESI)m / z=196.9[M+H] + Step 3: Synthesis of TRL-17-A4 2-aminoindan (318.0 mg, 2.39 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (455.0 mg, 3.50 mmol) was added. Further, TRL-17-A3 (476.0 mg, crude product) was dissolved in dichloromethane (5 mL) and slowly added to the reaction mixture at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was diluted with water (20 mL) and dichloromethane (20 mL). The organic phase was extracted with dichloromethane (20 mL x 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: dichloromethane / methanol) to obtain a light brown solid TRL-17-A4 (270 mg, 39.4%). MS(ESI)m / z=294.0 [M+H] + Step 4: Synthesis of TRL-17 TRL-17-A4 (170 mg, 0.58 mmol) was dissolved in ethanol (10 mL), imidazole-2-thione (88 mg, 0.87 mmol) was added, and the mixture was stirred at 70°C for 48 hours to allow the reaction to proceed. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography, and then freeze-dried to obtain a white solid TRL-17 formate (5.14 mg, yield 2.5%). LCMS(ESI)m / z=316.1[M+H] + ; 1 H NMR(Cd3Od,400 MHz):δ 8.52(s,1H),7.22-7.13(m,4H),4.58-4.54(m,1H),3.92(s,4H),3.26-3.19(m,4H),2.86-2.80 (m,2H),1.67-1.63(m,2H),1.24-1.19(m,1H),0.92-0.88(m,1H).

[0186] Synthesis of TRL-33 [ka] Step 1: Synthesis of TRL-33A2 TRL-33A1 (150 mg, 0.70 mmol) was dissolved in thionyl chloride (10 mL), and 1-2 drops of N,N-dimethylformamide were added. The reaction was then carried out under reflux at 70°C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove excess thionyl chloride, and TRL-33A2 (150 mg, crude product) was obtained and used directly in the next step. Step 2: Synthesis of TRL-33A3 7-aminoquinoline (100 mg, 0.69 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (180 mg, 1.39 mmol) was added. Further, TRL-33A2 (150 mg, crude product) was dissolved in dichloromethane (5 mL) and slowly added to the reaction mixture at 0°C. The reaction was allowed to proceed overnight at room temperature with stirring under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was diluted with water (20 mL) and dichloromethane (20 mL). The organic phase was extracted with dichloromethane (20 mL x 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol) to obtain brown solid TRL-33A3 (150 mg, two-step reaction yield 72.2%). MS(ESI)m / z=297.2[M+H] + Step 3: Synthesis of TRL-33 TRL-33A3 (150 mg, 0.51 mmol) was dissolved in a mixed solution of tetrahydrofuran and ethanol (5 mL + 5 mL), and imidazole-2-thione (67 mg, 0.66 mmol) was added. The mixture was reacted overnight under reflux at 100°C. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a yellow oily substance. The oily substance was prepared and purified by high-performance liquid chromatography and freeze-dried to obtain a yellow solid TRL-33 formate (12.11 mg, yield 5.8%). MS(ESI)m / z=363.0 [M+H] + ; 1 H NMR(DMSO-d6, 400 MHz): δ 11.01(s, 1H), 8.84-8.83(m, 1H), 8.39(d, J =2Hz, 1H), 8.26(d, J =7.2Hz, 1H), 8.18(s, 1H), 7.91(d, J =8.8Hz, 1H), 7.68(dd, J1=8.8Hz, J2=2.0Hz, 1H), 7.57-7.55(m, 2H), 7.43-7.32(m, 4H), 5.79(s, 1H), 3.51(s, 4H).

[0187] Synthesis method 7 Synthesis of TRL-49 [ka] Step 3: Synthesis of TRL-49 150 mg, 0.51 mmol of 2-chloro-2-phenyl-N-(quinoline-7-yl)acetamide was dissolved in a mixed solution of tetrahydrofuran and ethanol (5 mL + 5 mL), and 77 mg, 0.66 mmol of 1-methylimidazolidine-2-thione was added. The mixture was reacted overnight at 70°C under reflux and stirring. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a yellow oily substance. The oily substance was prepared and purified by high-performance liquid chromatography and freeze-dried to obtain a yellow solid 2-((1-methyl-4,5-dihydro-1H-imidazole-2-yl)thio)-2-phenyl-N-(quinoline-7-yl)acetamidoformate (35.28 mg, yield 16.4%). MS (ESI) m / z = 377.0[M+H] + ; 1 H NMR(DMSO-d6, 400 MHz): δ 11.01(s, 1H), 8.84-8.83(m, 1H), 8.40(s, 1H), 8.26(d, J =7.6Hz, 1H), 8.17(d, J =2.4Hz, 1H), 7.91(d, J =9.2Hz, 1H), 7.68(dd, J1=2.0Hz, J2=9.2Hz, 1H), 7.59(s, 1H), 7.57(s, 1H), 7.43-7.33(m, 4H), 5.78(d, J =2.4Hz, 1H), 3.65-3.60(m, 2H), 3.33-3.29(m, 2H), 2.72 (s, 3H).

[0188] Synthesis method 8 Synthesis of TRL-23 [ka] Step 1: Synthesis of TRL-23-A1 2-hydroxybutyrate ketone (1.0 g, 9.8 mmol) monohydrate, p-toluenesulfonic acid (0.4 g, 1.96 mmol), and 3-(trifluoromethyl)aniline (1.9 g, 11.76 mmol) were mixed and microwaved at 220°C for 10 minutes. After the reaction mixture cooled, water was added, and the mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid TRL-23-A1 (1.8 g, yield: 75%). MS(ESI)m / z=246.1[M+H] + Step 2: Synthesis of TRL-23-A2 Triphenylphosphine (1.7 g, 6.4 mmol) and bromine (0.9 g, 5.6 mmol) were dissolved in dichloromethane (20 mL), stirred at 0°C for 10 minutes, and imidazole (0.4 g, 6.4 mmol) and TRL-23-A1 (1.2 g, 4.9 mmol) were added. After the addition was complete, the mixture was stirred at room temperature for 4 hours to allow the reaction to proceed. The reaction mixture was concentrated under reduced pressure and passed through a silica gel column (ethyl acetate / petroleum ether) to obtain a yellow solid TRL-23-A2 (600 mg, yield: 40%). MS(ESI)m / z=308.0[M+H]+ Step 3: Synthesis of TRL-23 TRL-23-A2 (200.0 mg, 0.65 mmol) and imidazole-2-thione (80.0 mg, 0.8 mmol) were dissolved in ethanol (5 mL) and stirred at 70°C for 5 hours. The reaction was cooled to room temperature, and TRL-23 formate (11.3 mg, yield: 4.6%) was obtained by high-performance liquid chromatography. MS(ESI)m / z=330.0[M+H] + ; 1 H NMR(CdCl3, 400MHz): δ 10.42 (s, 2H), 7.93 (s, 1H),7.70 (d, J = 7.6 Hz,1H), 7.55-7.47 (m, 2H), 5.21-2.18 (m, 1H), 4.06-4.05 (m, 6H), 3.07-3.06 (m, 1H), 2.29-2.28 (m,1H).

[0189] Synthesis method 9 TRL-52 synthesis [ka] Step 1: Synthesis of TRL-52A2 2-(trifluoromethyl)-7-bromoquinoline (250 mg, 0.91 mmol) was dissolved in 1,4-dioxane (10 mL), and 3-hydroxypyrrolidine-2-one (130 mg, 1.29 mmol), trisdibenzylideneacetone dipalladium (39 mg, 0.04 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (74 mg, 0.13 mmol), and cesium carbonate (838 mg, 2.58 mmol) were added. The mixture was stirred under reflux at 100°C overnight. After vacuum concentration of the reaction mixture, it was purified by silica gel column chromatography (eluent: methanol / dichloromethane) to obtain the gray solid TRL-52A2 (140 mg, yield 52.0%). MS (ESI) m / z = 297.0[M+H] + . Step 2: Synthesis of TRL-52A3 Triphenylphosphine (58 mg, 0.22 mmol) was dissolved in dichloromethane (10 mL), and liquid bromine (33 mg, 0.21 mmol) was added under the protection of nitrogen gas and in an ice bath, and the mixture was stirred for 10 minutes. Imidazole (15 mg, 0.22 mmol) and TRL-52A2 (50 mg, 0.17 mmol) were then dissolved in dichloromethane and added to the reaction mixture. The mixture was allowed to react overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was diluted with water (40 mL) and ethyl acetate (80 mL). The product was extracted with ethyl acetate (40 mL x 2), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: methanol / dichloromethane) to obtain yellow solid TRL-52A3 (40 mg, yield 65.6%). MS (ESI) m / z = 358.9[M+H] + . Step 3: Synthesis of TRL-52 3-Bromo-1-(2-(trifluoromethyl)quinoline-7-yl)pyrrolidine-2-one (30 mg, 0.08 mmol) was dissolved in tetrahydrofuran (10 mL), imidazole-2-thione (30 mg, 0.26 mmol) was added, and the mixture was stirred overnight at room temperature. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography, and lyophilized to obtain a light gray solid TRL-52 (7.77 mg, yield 22.1%). MS (ESI) m / z = 395.0[M+H] + ; 1 H NMR (CdCl3, 400 MHz): δ 8.62(dd, J1=8.8Hz, J2=2.0Hz, 1H), 8.43(s, 1H), 8.33(d, J=8.4Hz, 1H), 7.93(s, 1H), 7.91(d, J=8.8Hz, 1H), 7.70(d,J=8.4Hz, 1H),5.10(t, J=8.8Hz, 1H), 4.10-4.04(m, 2H), 3.90(d,J=9.6Hz, 2H). 3.65-3.59(m, 2H), 3.05-3.00(m, 1H), 2.97(s, 3H),2.35-2.30(m, 1H).

[0190] TRL-64 synthesis [ka] Step 1: Synthesis of TRL-64A2 1-Bromo-3-(trifluoromethyl)benzene (1498 mg, 6.66 mmol) was dissolved in 1,4-dioxane (50 mL), and 5-methylpyrrolidine-2-one (600 mg, 6.05 mmol), tris(dibenzylideneacetone)dipalladium (277 mg, 0.30 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (175 mg, 0.30 mmol), and cesium carbonate (3944 mg, 12.11 mmol) were added. The reaction was carried out under reflux stirring at 80°C under nitrogen gas protection for 16 hours. After vacuum concentration of the reaction mixture, it was purified by silica gel column chromatography (eluent: methanol / dichloromethane) to obtain a brown oily substance TRL-64A2 (831 mg, yield 51.14%). MS (ESI) m / z = 243.8[M+H] + . Step 2: Synthesis of TRL-64A3 TRL-64A2 (380 mg, 1.56 mmol) was dissolved in dichloromethane (20 mL), triethylamine (632 mg, 6.25 mmol) was added, and then trimethylsilyl trifluoromethanesulfonate (521 mg, 2.34 mmol) was added dropwise under ice bath. The reaction was allowed to proceed overnight at room temperature. After confirming the completion of the reaction by monitoring, liquid bromine (300 mg, 1.87 mmol) was added to the reaction mixture and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, diluted with saturated sodium thiosulfate aqueous solution (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL x 2), washed the organic phase with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered, vacuum concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether) to obtain TRL-64A3P1 yellow oil (110.0 mg, yield 21.9%) and P2 yellow oil (80.0 mg, yield 15.9%). MS (ESI) m / z = 323.7[M+H] + . Step 2: Synthesis of TRL-64 TRL-64A3P1 (110 mg, 0.34 mmol) was dissolved in ethanol (15 mL), imidazole-2-thione (42 mg, 0.41 mmol) was added, and the mixture was stirred at 80°C for 16 hours. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a light gray oily substance. The solid was prepared and purified by high-performance liquid chromatography, and lyophilized to obtain TRL-64 (59.89 mg, yield 45.2%). MS (ESI) m / z = 344.0[M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 8.15 -8.10(m, 1H), 7.83-7.78(m, 1H), 7.70-7.58(m, 3H), 4.97-4.73(m, 1H), 4.65-4.48(m, 1H), 3.78-3.75(m, 4H), 3.00-2.48(m, 1H), 2.45-1.82(m, 1H), 1.23-1.04(m, 3H).

[0191] The compounds listed in Table 3 below were prepared using a method similar to that used for the synthesis of compound TRL-64, and by using commercially available compounds or the intermediate compounds shown for reference.

[0192] [Table 3-1] [Table 3-2]

[0193] Synthesis method 10 Synthesis of TRL-24 [ka] Step 1: Synthesis of TRL-24A1 3-Trifluoromethyliodobenzene (1.9 g, 7.0 mmol), piperidine-2-one (1.0 g, 10.0 mmol), cuprous oxide (200.0 mg, 1.4 mmol), tripotassium phosphate (2.97 g, 14.0 mmol), and tetrabutylammonium bromide (450.0 mg, 1.4 mmol) were suspended in water (10 mL) and reacted overnight with stirring at 130 °C. The reaction conversion rate was monitored by liquid chromatography to approximately 80%, and after cooling the reaction mixture, it was extracted with dichloromethane (100 mL x 3). After concentrating the combined organic phase, the resulting brown residue was separated by flash column (ethyl acetate / petroleum ether) to obtain a light brown solid TRL-24-A1 (701.0 mg, yield 41%). MS(ESI)m / z=244.1[M+H] + ; 1 H NMR(CdCl3,300 MHz):δ 7.58-7.55(m,4H),3.73(t,J = 4.5 Hz,2H),2.63(t,J = 5.7 Hz, 2H), 2.02(t, J (= 3.3 Hz, 4H). Step 2: Synthesis of TRL-24A2 To a 5 mL solution of TRL-24-A1 (122.0 mg, 0.5 mmol) in tetrahydrofuran, sec-butyllithium (1.3 M in hexane, 1.0 mmol, 0.75 mL) was slowly added at -78°C. The mixture was then stirred for 30 minutes while maintaining the temperature. Bromosuccinimide (90.0 mg, 0.5 mmol) / tetrahydrofuran (2 mL) solution was then slowly added, and the mixture was stirred for 2 hours while maintaining the temperature at -78°C. The disappearance of the starting material was monitored by liquid chromatography. The reaction was quenched with saturated ammonium chloride solution, then extracted with dichloromethane (50 mL x 3), washed with water (50 mL x 3), and the organic phase was concentrated. The resulting brown residue was separated by flash column (ethyl acetate / petroleum ether) to obtain a colorless oily substance, TRL-24-A2 (30.0 mg, yield 18.6%). MS(ESI)m / z=322.0[M+H] + ; 1H NMR (CdCl3, 300 MHz): δ 7.58-7.50(m,4H),4.76-4.75(m,1H),3.93-3.84(m,1H),3.79-3.74(m,1H),2.56-2.44(m,3H),2.08-1.99(m,1H). Step 3: Synthesis of TRL-24 TRL-24-A2 (30.0 mg, 0.09 mmol) and imidazole-2-thione (10.0 mg, 0.10 mmol) were dissolved in anhydrous ethanol (2 mL) and reacted by stirring at 70°C for 5 hours. The reaction was monitored for completion by liquid chromatography, and after cooling the reaction mixture, it was concentrated under reduced pressure. The oily residue obtained after concentration was subjected to high-performance liquid chromatography to prepare white crystalline TRL-24 formate (20.0 mg, yield 57.1%). MS(ESI)m / z=344.0 [M+H] + ; 1 H NMR(CdCl3, 400 MHz): δ 8.51 (s, 1H), 7.61-7.55 (m, 2H), 7.53 (s, 1H),7.46 (d, J = 7.6 Hz, 1H), 4.40 (t, J = 6.0 Hz, 2H), 3.86 (s, 4H), 3.75 (t, J = 6.0 Hz, 1H), 2.56-2.50 (m, 1H), 2.25-2.19 (m, 1H), 2.12-2.07 (m, 2H).

[0194] The compounds listed in Table 4 below were prepared using a method similar to that used for the synthesis of compound TRL-24, and by using commercially available compounds or the intermediate compounds shown for reference.

[0195] [Table 4]

[0196] Synthesis method 11* Synthesis of TRL-38 [ka] Step 1: Synthesis of TRL-38A2 TRL-38A1 (228 mg, 0.83 mmol) was dissolved in 1,4-dioxane (15 mL), and 3-hydroxypiperidine-2-one (144 mg, 1.25 mmol), trisdibenzylideneacetone dipalladium (37 mg, 0.04 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (69 mg, 0.12 mmol), and cesium carbonate (809 mg, 2.49 mmol) were added. The mixture was stirred at 100°C and reacted for 4 hours. After vacuum concentration of the reaction mixture, it was purified by silica gel column chromatography (eluent: methanol / dichloromethane) to obtain a pale yellow gel-like solid TRL-38A2 (210 mg, yield 40.9%). MS (ESI) m / z = 311.1[M+H] + . Step 2: Synthesis of TRL-38A3 Triphenylphosphine (163 mg, 0.62 mmol) was dissolved in dichloromethane (5 mL), and liquid bromine (93 mg, 0.58 mmol) was added under the protection of nitrogen gas and in an ice bath, and the mixture was stirred for 10 minutes. Then, imidazole (42 mg, 0.62 mmol) and TRL-38A2 (210 mg, 50% purity, 0.34 mmol) were dissolved in dichloromethane and added to the reaction mixture. The mixture was allowed to react overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was diluted with water (50 mL) and ethyl acetate (100 mL). Extraction was performed with ethyl acetate (50 mL x 2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether) to obtain yellow solid TRL-38A3 (45 mg, yield 35.4%). MS (ESI) m / z = 373.1[M+H] + . Step 3: Synthesis of TRL-38 TRL-38A3 (45 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL), imidazole-2-thione (20 mg, 0.20 mmol) was added, and the mixture was stirred overnight at room temperature. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography and freeze-dried to obtain a pale yellow solid TRL-38 (12.83 mg, yield 25.8%). MS (ESI) m / z = 368.9[M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ 8.97-8.95(brs, 1H), 8.76(s, 1H), 8.31(d, J=8.0Hz, 1H), 7.76(d, J=8.8Hz, 1H), 7.47(d, J=8.4Hz, 1H), 7.20-7.17(m, 1H), 7.75(d, J =2.0Hz, 1H), 6.72(t, J=9.2Hz, 1H), 4.35-4.32(m, 1H), 3.22-3.18(m, 2H), 2.18-2.12(m, 1H), 1.81-1.74 (m, 2H), 1.61-1.56(m, 1H).

[0197] The compounds listed in Table 5 below were prepared using a method similar to that used for the synthesis of compound TRL-38, and by using commercially available compounds or the intermediate compounds shown for reference.

[0198] [Table 5]

[0199] Synthesis method 11 Synthesis of TRL-25 [ka] Step 1: Synthesis of TRL-25-A2 TRL-25-A1 (300.0 mg, 1.69 mmol) was dissolved in thionyl chloride (10 mL), and 1-2 drops of N,N-dimethylformamide were added. The mixture was then stirred and allowed to react at 70°C for 4 hours. After cooling the reaction mixture, it was concentrated under reduced pressure to remove excess thionyl chloride, yielding TRL-25-A2 (371.0 mg, crude product), which was then used directly in the next step. MS(ESI)m / z=196.9[M+H] + Step 2: Synthesis of TRL-25-A3 m-aminotrifluorotoluene (371.0 mg, 2.30 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (368.0 mg, 2.85 mmol) was added. Furthermore, TRL-25-A2 (371.0 mg, crude product) was dissolved in dichloromethane (5 mL) and slowly added to the reaction mixture at 0°C. The reaction was carried out overnight at room temperature with stirring under the protection of nitrogen gas. The solvent was removed from the reaction mixture under reduced pressure, diluted with dichloromethane, washed, dried, concentrated, and flash purified (dichloromethane / methanol) to obtain a pale brown solid TRL-25-A3 (450 mg, 83.2%). MS(ESI)m / z=323.0 [M+H] + ; 1 H NMR(CdCl3,300 MHz):δ 8.19-8.11(br s,1H),7.93(s,1H),7.77(d,J = 7.8 Hz,1H), 7.52(t,J = 8.1 Hz,1H),7.44(d,J = 8.1 Hz, 1H), 3.21-3.12 (m, 2H), 2.78-2.68 (m, 2H), 2.43-2.38 (m, 1H), 2.16-2.09 (m, 1H). Step 3: Synthesis of TRL-25 TRL-25-A3 (110.0 mg, 0.34 mmol) was dissolved in NMP (2 mL), and imidazole-2-thione (52.0 mg, 0.51 mmol) and potassium iodide (56.4 mg, 0.34 mmol) were added. The reaction was carried out at 120°C for 4 hours. After cooling the reaction, the solution was prepared and purified by direct high-performance liquid chromatography, and lyophilized to obtain a white solid TRL-25 formate (2.5 mg, yield 2.1%). MS(ESI)m / z=344.0[M+H] + ; 1 H NMR(CdCl3,400 MHz):δ 10.89-10.81(br s,1H),8.39(s,1H),7.91-7.89(m,2H), 7.41(t,J = 8.0 Hz,1H),7.32(d,J = 7.6 Hz,1H),3.79(s,4H),3.69-3.68(m,2H), 1.52-1.49(m,2H),0.88-0.85(m,2H).

[0200] Synthesis of TRL-26 [ka] Step 1: Synthesis of TRL-26-A1 Cyclopentanecarboxylic acid (1.0 g, 8.77 mmol) was dissolved in thionyl chloride (10 mL) and stirred at 60°C for 2 hours. Boron tribromide (0.2 g, 0.88 mmol) and bromine (1.7 g, 10.62 mmol) were added, and the reaction mixture was stirred at 70°C for 3 hours. After cooling the reaction mixture, it was concentrated under vacuum to obtain pale yellow oil TRL-26-A1 (1.8 g, crude product). MS(ESI)m / z=212.9[M+H] + Step 2: Synthesis of TRL-26-A2 m-aminotrifluorotoluene (1.7 g, 10.56 mmol) and N,N-diisopropylethylamine (2.21 g, 17.2 mmol) were dissolved in dichloromethane (5 mL), and TRL-26-A1 (1.8 g, 8.57 mmol) was slowly added at 0 °C. The mixture was stirred and reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a white solid TRL-26-A2 (900.0 mg, yield: 31.4%). MS(ESI)m / z=336.0[M+H] + ; 1H NMR (DMSO-d6,400 MHz): δ 10.13 (s,1H),8.13 (s,1H),7.97 (d,J = 8.00,1H ),7.58 (t,J = 8.0 Hz,1H ),7.45 (d,J = 7.6 Hz,1H), 2.43-2.31 (m,4H),1.94-1.78(m,4H). Step 3: Synthesis of TRL-26 TRL-26-A2 (700.0 mg, 2.09 mmol) and imidazole-2-thione (255.8 mg, 2.51 mmol) were dissolved in ethanol (20 mL) and stirred at 70°C for 48 hours. The reaction was cooled to room temperature, and a colorless gel-like substance, TRL-26 formate (61.0 mg, yield: 7.2%), was obtained by high-performance liquid chromatography. MS(ESI)m / z=358.0[M+H] +

[0201] The compounds listed in Table 6 below were prepared using a method similar to that used for the synthesis of compound TRL-26, and by using commercially available compounds or the intermediate compounds shown for reference.

[0202] [Table 6-1] [Table 6-2]

[0203] Synthesis method 12 Synthesis of TRL-27 [ka] Step 1: Synthesis of TRL-27A2 TRL-27A1 (200 mg, 0.71 mmol) was dissolved in 1,4-dioxane (10 mL), and 3-hydroxypyrrolidine-2-one (86 mg, 0.85 mmol), trisdibenzylideneacetone dipalladium (32 mg, 0.03 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (20 mg, 0.03 mmol), and cesium carbonate (460 mg, 1.42 mmol) were added. The mixture was stirred at 80°C and reacted for 4 hours. After vacuum concentration of the reaction mixture, it was purified by silica gel column chromatography (eluent: methanol / dichloromethane) to obtain a white solid TRL-27A2 (112 mg, yield 52.2%). MS (ESI) m / z = 303.0[M+H] + . Step 2: Synthesis of TRL-27A3 Triphenylphosphine (126 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL), and liquid bromine (72 mg, 0.45 mmol) was added under the protection of nitrogen gas and in an ice bath, and the mixture was stirred for 10 minutes. Then, imidazole (33 mg, 0.49 mmol) and TRL-27A2 (112 mg, 0.37 mmol) were dissolved in dichloromethane, respectively, and added to the reaction mixture. The mixture was allowed to react overnight at room temperature with stirring under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was diluted with water (40 mL) and ethyl acetate (80 mL). Extraction was performed with ethyl acetate (40 mL x 2), the organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (eluent: methanol / dichloromethane) to obtain yellow solid TRL-27A3 (78 mg, yield 57.7%). MS (ESI) m / z = 364.9[M+H] + . Step 3: Synthesis of TRL-27 TRL-27A3 (78 mg, 0.21 mmol) was dissolved in tetrahydrofuran (10 mL), imidazole-2-thione (33 mg, 0.32 mmol) was added, and the mixture was stirred overnight at room temperature. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a brown solid. The solid was prepared and purified by high-performance liquid chromatography, and lyophilized to obtain a white solid TRL-27 formate (40.96 mg, yield 45.1%). MS (ESI) m / z = 386.9[M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ 8.47(d, J=2.0Hz, 1H), 8.35(d, J=9.2Hz, 1H), 8.17(s, 1H), 8.12(dd, J1=2.4Hz, J2=9.2Hz, 1H), 4.66(t, J=9.2Hz, 1H), 4.00-3.95(m, 2H), 3.50(s, 4H), 2.74-2.70 (m, 1H), 2.33-2.25(m, 1H).

[0204] The compounds listed in Table 7 below were prepared using a method similar to that used for the synthesis of compound TRL-27, and by using commercially available compounds or the intermediate compounds shown for reference.

[0205] [Table 7-1] [Table 7-2]

[0206] Synthesis method 13 TRL-54 synthesis [ka] Step 1: Synthesis of TRL-54A2 TRL-54A1 (3.50 g, 17.49 mmol), n-butyl nitrite (3.89 g, 43.75 mmol), and concentrated hydrochloric acid (1.5 mL) were dissolved in methanol (35 mL) and stirred at 40°C for 26 hours. The reaction mixture was cooled to room temperature, concentrated under vacuum to obtain the crude product, and purified by silica gel column chromatography to obtain the yellow solid TRL-54A2 (2.0 g, yield 49.8%). MS (ESI) m / z = 294.1 [M+H] + Step 2: Synthesis of TRL-54A3 TRL-54A2 (2.00 g, 8.73 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium borohydride (3.32 g, 87.30 mmol) and boron trifluoride diethyl ether (12.40 g, 87.30 mmol) were added at 0°C. The mixture was stirred at 70°C for 3 hours. The reaction mixture was cooled to room temperature, quenched in ice water, and the reaction mixture was prepared with aqueous sodium hydroxide solution. After vacuum concentration, the mixture was purified by silica gel column chromatography (eluent: 1%~10% methanol / dichloromethane) to obtain white solid TRL-54A3 (70 mg, yield 4.0%). Step 3: Synthesis of TRL-54A4 TRL-54A3 (65 mg, 0.32 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (83 mg, 0.64 mmol) was added. Then, chloroacetyl chloride (55 mg, 0.48 mmol) was slowly added at 0°C. The reaction was stirred at room temperature for 8 hours under the protection of nitrogen gas. The reaction mixture was concentrated under reduced pressure to obtain a white solid TRL-54A4 (80 mg, yield 90.0%). Step 4: Synthesis of TRL-54 TRL-54A4 (60 mg, 0.22 mmol) was dissolved in ethanol (2 mL), imidazole-2-thione (34 mg, 0.33 mmol) was added, and the mixture was stirred and reacted at 70°C for 5 hours. After cooling the reaction mixture, it was concentrated under reduced pressure and dried to obtain a yellow oily substance. The oily substance was prepared and purified by high-performance liquid chromatography and freeze-dried to obtain a white solid TRL-54 formate (30.90 mg, yield 36.1%). MS (ESI) m / z = 344.0[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ 8.23 ​​(s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.55-7.51 (m, 1H), 7.43-7.41 (m, 1H),4.83(s, 1H), 4.70 (s, 1H), 4.21 (s, 2H), 3.79-3.70 (m, 2H), 3.51 (d, 4H), 3.04-2.90(m, 2H).

[0207] The example compounds shown in Table 8 below were prepared using a method similar to that used for the synthesis of compound TRL-54, and by using commercially available compounds or the preparation methods for intermediate compounds shown for reference.

[0208] [Table 8]

[0209] Synthesis of TRL-59 [ka] Step 1: Synthesis of TRL-59A2 TRL-59A1 (499 g, 3.10 mmol) was dissolved in dioxane (20 mL), 4-aminobutyric acid (750 mg, 6.20 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, sodium borohydride acetate (1.32 g, 6.20 mmol) was added. The mixture was stirred at 40°C and reacted for 24 hours. After quenching the reaction mixture, it was concentrated under vacuum and purified by silica gel column chromatography (eluent: methanol / dichloromethane) to obtain a white solid TRL-59A2 (321 mg, yield 45.0%). MS (ESI) m / z = 230.1[M+H] + . Step 2: Synthesis of TRL-59A3 TRL-59A2 (100 mg, 0.44 mmol) was dissolved in tetrahydrofuran (15 mL), and sec-butyllithium (0.25 mL) was slowly added at -78°C. The mixture was stirred and reacted at -78°C for 30 minutes, after which 2-bromocyclopentane-1,3-dione (172 mg, 0.96 mmol) was added, and the reaction was continued at -78°C for 2 hours. After quenching the reaction mixture, it was concentrated under vacuum to obtain a yellow solid mixture, which was used as is. MS (ESI) m / z = 310.0 [M+H] + . Step 2: Synthesis of TRL-59 Crude TRL-59A3 product (calculated at 0.44 mmol) was dissolved in tetrahydrofuran (15 mL), imidazole-2-thione (54 mg, 0.53 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and dried to obtain a brown oily substance. The oily substance was prepared and purified by high-performance liquid chromatography, and freeze-dried to obtain a white solid TRL-59 (7.12 mg, yield 2.04%). MS (ESI) m / z = 330.1[M+H] + . 1 H NMR (CdCl3, 400 MHz): δ 8.44 (s, 1H), 7.10-7.05 (m, 4H), 4.19-4.13 (m, 2H), 3.81 (s, 4H), 3.33-3.24 (m, 2H), 2.85-2.71 (m, 4H), 2.54-2.52 (m, 1H), 1.94-1.88 (m, 3H), 1.52-1.43 (m, 2H).

[0210] Example 2: Anti-apoptotic experiment of compounds against Jurkat cells This example primarily aims to investigate the inhibitory effect of compounds from the TRL series of compounds in Example 1 on cell apoptosis after TRADD inhibition. Methods: Jurkat cells were selected and seeded on plates. After the cells stabilized for one day, 50 nM Velcade was added to each group to induce apoptosis. Compounds were also added to each group at concentrations of 0.04 μM, 0.2 μM, 1 μM, 5 μM, 10 μM, 20 μM, and 40 μM, respectively, and allowed to react for 24 hours. Then, Cell Titer-Glo Luminescent (manufacturer: Promega) cell activity detection reagent was added, homogeneously mixed, and allowed to react for 10 minutes. Detection was then performed by scanning the entire wavelength range with a microplate reader. Results: As can be seen from Table 9, each compound possesses excellent anti-cell apoptotic efficacy.

[0211] [Table 9] Note: Anti-apoptotic Emax represents the degree of maximum apoptosis inhibition in percent, where Emax = (optimal cell activity value at each test dose - cell activity value of the velcade group).

[0212] Example 3: Anti-inflammatory experiment on LPS-stimulated BV2 cells using a compound This example primarily aims to investigate the anti-inflammatory effects of the compounds in Example 1 on BV2 cells stimulated by LPS. Methods: BV2 cells were selected and seeded into plates. After the plates were nearly full, compounds TRL-13, TRL-24, and TRL-26 were added at a concentration of 10 μM. After 1 hour of pre-culture, LPS at a concentration of 100 ng / ml was added and allowed to react for 6 hours. The cell supernatant was then collected and TNF-α expression was detected by ELISA. The kit used was purchased from Dako Life Sciences, and the ELISA detection method was performed according to the instructions. The specific groupings are as follows: Control group: Cells were seeded onto plates, and after the plates were nearly full, the culture medium was replaced and allowed to react for 6 hours, after which the supernatant was collected. LPS group: Cells were seeded into plates, and after the plates were nearly full, the medium was replaced with one containing 100 ng / mL of LPS and allowed to react for 6 hours, after which the supernatant was collected. TRL-13 group: Cells were seeded into plates, and after the plates were nearly full, the medium was changed to one containing 10 μM TRL-13 and allowed to react for 1 hour. Then, the medium was changed again to one containing 100 ng / mL LPS and 10 μM TRL-13 and allowed to react for 6 hours, after which the supernatant was collected. TRL-24 group: Cells were seeded into plates, and after the plates were nearly full, the medium was changed to one containing 10 μM TRL-24 and allowed to react for 1 hour. Then, the medium was changed again to one containing 100 ng / mL LPS and 10 μM TRL-24 and allowed to react for 6 hours, after which the supernatant was collected. TRL-26 group: Cells were seeded into plates, and after the plates were nearly full, the medium was changed to one containing 10 μM TRL-26 and allowed to react for 1 hour. Then, the medium was changed again to one containing 100 ng / mL LPS and 10 μM TRL-26 and allowed to react for 6 hours, after which the supernatant was collected. Results: As can be seen from the results in Figure 1 and Table 10, compounds TRL-13, TRL-24, and TRL-26 were able to significantly reduce the expression of TNF-α produced under LPS stimulation.

[0213] [Table 10]

[0214] Example 4: Anti-inflammatory experiment on MDP-stimulated BV2 cells using a compound This example primarily aims to investigate the anti-inflammatory effects of the compounds in Example 1 on BV2 cells under MDP stimulation. Methods: BV2 cells were selected and seeded into plates. After the plates were nearly full, compounds TRL-13, TRL-24, and TRL-26 were added at a concentration of 10 μM. After 1 hour of pre-culture, MDP at a concentration of 10 μg / ml was added and allowed to react for 7 hours. The cell supernatant was then collected and TNF-α expression was detected by ELISA. The kit used was purchased from Dako Life Sciences, and the ELISA detection method was performed according to the instructions. The specific groupings are as follows: Control group: Cells were seeded onto plates, and after the plates were nearly full, the culture medium was replaced and allowed to react for 7 hours, after which the supernatant was collected. MDP group: Cells were seeded into plates, and after the plates were nearly full, the medium was replaced with one containing 10 μg / mL MDP. After 7 hours of incubation, the supernatant was collected. TRL-13 group: Cells were seeded into plates, and after the plates were nearly full, the medium was replaced with one containing 10 μM TRL-13 and allowed to react for 1 hour. Then, the medium was replaced again with one containing 10 μg / mL MDP and 10 μM TRL-13 and allowed to react for 7 hours, after which the supernatant was collected. TRL-24 group: Cells were seeded into plates, and after the plates were nearly full, the medium was changed to one containing 10 μM TRL-24 and allowed to react for 1 hour. Then, the medium was changed again to one containing 10 μg / mL MDP and 10 μM TRL-24 and allowed to react for 7 hours, after which the supernatant was collected. TRL-26 group: Cells were seeded into plates, and after the plates were nearly full, the medium was changed to one containing 10 μM TRL-26 and allowed to react for 1 hour. Then, the medium was changed again to one containing 10 μg / mL MDP and 10 μM TRL-26 and allowed to react for 7 hours, after which the supernatant was collected. Results: As can be seen from the results in Figure 2 and Table 11, compounds TRL-13, TRL-24, and TRL-26 were able to significantly reduce the expression of TNF-α produced under MDP stimulation.

[0215] [Table 11]

[0216] Example 5: Anti-inflammatory experiment on IFN-γ stimulated BV2 cells with a compound This example primarily aims to investigate the anti-inflammatory effects of the compounds in Example 1 on BV2 cells under IFN-γ stimulation. Methods: BV2 cells were selected and seeded into plates. After the plates were nearly full, compounds TRL-13, TRL-24, and TRL-26 were added at a concentration of 10 μM. After 1 hour of pre-culture, IFN-γ at a concentration of 200 ng / ml was added and allowed to react for 24 hours. The cell supernatant was then collected and TNF-α expression levels were detected by ELISA. The kits used were purchased from Dako Life Sciences, and the ELISA detection method was performed according to the instructions. The specific groupings are as follows: Control group: Cells were seeded onto plates, and after the plates were nearly full, the culture medium was replaced and allowed to react for 24 hours, after which the supernatant was collected. IFN-γ group: Cells were seeded into plates, and after the plates were nearly full, the medium was replaced with one containing 200 ng / mL of IFN-γ. After 24 hours of incubation, the supernatant was collected. TRL-13 group: Cells were seeded into plates, and once the plates were nearly full, the medium was replaced with one containing 200 ng / ml IFN-γ and 10 μM TRL-13. After 24 hours of incubation, the supernatant was collected. TRL-24 group: Cells were seeded into plates, and after the plates were nearly full, the medium was replaced with one containing 200 ng / mL of IFN-γ and 10 μM of TRL-24. After 24 hours of incubation, the supernatant was collected. TRL-26 group: Cells were seeded into plates, and once the plates were nearly full, the medium was replaced with one containing 200 ng / mL of IFN-γ and 10 μM of TRL-26. After 24 hours of incubation, the supernatant was collected. Results: As can be seen from the results in Figure 3 and Table 12, the compound was able to significantly reduce the expression of TNF-α produced under IFN-γ stimulation.

[0217] [Table 12]

[0218] Example 6: Activation of autophagy in Jurkat cells by a compound This example primarily aims to investigate the activating effect of the compounds in Example 1 on cellular autophagy after TRADD inhibition. Method: Jurkat cells were selected and seeded on plates. After the cells stabilized for one day, 25 μM chloroquine (CQ), 10 μM TRL-26, and 10 μM TRL-26 + 25 μM CQ were added to each group, respectively. After 16 hours of reaction, the cells were stained with CYTO-ID® Green Detection Reagent (manufacturer: enzo) to detect the degree of autophagy activation. Specifically, fluorescence intensity was detected using a microplate reader according to the instructions in the manual, with detection conditions being a FITC filter (Excitation ~480 nm, Emission ~530 nm). Results: As can be seen from Figure 4, TRL-26 has a good effect in activating autophagy.

[0219] Example 7: Study of compound plasma dynamics in rats This example primarily aims to investigate the plasma stability and half-life of the compounds described in Example 1 by conducting plasma dynamics studies in rats. Method: Male SD rats, 200-300g, were injected with 1 mg / kg of the compound into their tail vein. Approximately 0.2 mL of blood samples were collected at 3 min, 10 min, 0.5 h, 1 h, 2 h, and 4 h after administration and placed in centrifuge tubes containing K2EDTA anticoagulant. After blood collection, the samples were centrifuged at 8000 rpm for 5 minutes at 2-8°C. After centrifugation, the plasma was transferred to a centrifuge tube, and the drug concentration in the K2EDTA anticoagulant rat plasma was measured by LC-MS / MS. A drug-time curve was created based on the results. Results: As can be seen from Figure 5, compound TRL-00 (structure: [ka] In comparison to the above, the TRL series compound synthesized in Example 1 of this application showed significantly improved plasma stability and a significantly extended half-life.

[0220] Example 8: Effect of the compound in a dry eye syndrome model This example primarily aims to examine the efficacy evaluation of the compounds in Example 1 against a dry eye syndrome model. Methods: Dry eye syndrome was induced by eye drops of 0.2% BAC (benzalkonium chloride). A BAC model was created using male, 6-8 week old C57BL / 6 mice, and 5 μL of BAC solution was instilled into each eye three times a day for 15 days. The tear volume of the mice administered the evaluation drug was measured to evaluate its efficacy. The specific groupings are as follows: Blank group: 6 C57BL / 6 mice, administration: physiological saline, 5 μL / eye, 3 times a day. Model group: 6 C57BL / 6 mice; Administration: 0.2% BAC, 5 μL / eye, 3 times daily. TRL-19 group: 6 C57BL / 6 mice, administration: 0.2% BAC, 5 μL / eye instilled 3 times daily; 0.05 mg / ml TRL-19, 5 μL / eye instilled 3 times daily. TRL-22 group: 6 C57BL / 6 mice, administration: 0.2% BAC, 5 μL / eye instilled 3 times daily; 0.05 mg / ml TRL-22, 5 μL / eye instilled 3 times daily. TRL-26 group: 6 C57BL / 6 mice, administration: 0.2% BAC, 5 μL / eye instilled 3 times daily; 0.05 mg / ml TRL-26, 5 μL / eye instilled 3 times daily. TRL-29 group: 6 C57BL / 6 mice, administration: 0.2% BAC, 5 μL / eye instilled 3 times daily; 0.05 mg / ml TRL-29, 5 μL / eye instilled 3 times daily. TRL-30 group: 6 C57BL / 6 mice, administration: 0.2% BAC, 5 μL / eye instilled 3 times daily; 0.05 mg / ml TRL-30, 5 μL / eye instilled 3 times daily. Results: As can be seen in Figure 6, the TRL series compounds synthesized in this application were able to significantly alleviate the symptoms of mouth dry eye syndrome.

[0221] Example 9: Effects of the compound in a psoriasis model This example primarily aims to examine the efficacy evaluation of the compounds in Example 1 against a psoriasis model. Methods: A psoriasis model was induced with imiquimod. Male, 6-8 week old BALB / c mice were used to create the model. Most of the hair was shaved from the backs of the BALB / c mice, and after removing fine hairs with depilatory cream, the mice were washed with clean water and wiped dry. Approximately 62.5 mg of imiquimod cream was then applied evenly to the backs of the mice. The dosage was weighed and photographed before administration once daily, and administered 30 minutes before the start of model creation. This continued for 7 days, and the mice were killed after 7 days based on their disease status. The specific groupings are as follows: Blank group: 5 BALB / c mice, 6-8 weeks old, administration: petrolatum, topical application, once daily. Model group: 5 BALB / c mice, 6-8 weeks old. Model creation drug: Imiquimod. Administration: Ethanol, topical application, once daily. TRL-26 group: 5 BALB / c mice, 6-8 weeks old, model drug: imiquimod, administration: 1 mg / kg of TRL-26 dissolved in ethanol, applied topically once daily. Results: As can be seen in Figure 7, 1 mg / kg of TRL-26 has a significant inhibitory effect on psoriasis-like inflammation.

[0222] Example 10: Effects of the compound in a stroke model This example primarily aims to examine the efficacy evaluation of the compounds in Example 1 against a stroke model. Methods: A rat model of middle cerebral artery occlusion was induced by suture occlusion. Male SD rats, 6-8 weeks old, were selected to create the model. After anesthetizing the rats, the common carotid artery (CCA), external carotid artery (ECA), and internal carotid artery (ICA) were separated. The distal and proximal ends of the CCA and ECA were sutured together in preparation for later use. The ICA was temporarily closed with a carotid clamp, and then the proximal ends of the CCA and ECA were ligated. Subsequently, a suture line was inserted into the ICA, and after occlusion for 1 hour, the suture line was removed, TRL-26 was administered, and brain tissue was extracted and stained with TTC. The cerebral infarction area was measured to assess the disease state, and the efficacy of the drug was evaluated by comparing the treatment group with the model group and the sham surgery group. The specific group divisions are as follows: Sham surgery group: 15 male SD rats, 6-8 weeks old, administered: saline solution via tail vein injection. Model group: 15 male SD rats, 6-8 weeks old. Administration: saline solution, administered via tail vein injection. TRL-26 group: 15 SD rats, male, 6-8 weeks old, administered 3 mg / kg of TRL-26 via tail vein injection. Positive drug group: 15 male SD rats, 6-8 weeks old, administered 6 mg / kg of edaravone via tail vein injection. Results: As can be seen from Figure 8 and Table 13, TRL-26 administered at a dose of 3 mg / kg has a significant therapeutic effect on the incidence of stroke.

[0223] [Table 13]

[0224] Example 11: Effects of the compound in an Alzheimer's disease model This example primarily aims to examine the efficacy of the compounds in Example 1 against an Alzheimer's disease model. Methods: Male, 8-week-old PS19 mice were selected and injected with tau fibrin into the lateral ventricles to accelerate pathological tau deposition and entanglement in the brain. Simultaneously, a certain amount of TRL-26 was administered and continued for 4 weeks. After that, the mouse hippocampus was taken and the tau content in the hippocampus was measured by the Western Blood Blot method. Blank group: PS19 mice, male, 8 weeks old, 6 mice. Administration: Physiological saline, administered by continuous injection into the lateral ventricle for 4 weeks. Model group: Six male PS19 mice, 8 weeks old, were used to create the model. Administration: Physiological saline was continuously injected into the lateral ventricle for 4 weeks. TRL-26 group: Six male, 8-week-old PS19 mice were used to create a model. Administration: 20 mM TRL-26 was administered by continuous injection into the lateral ventricle for 4 weeks. Results: As can be seen in Figure 9, tau levels in the hippocampus of mice treated with TRL-26 were significantly reduced compared to the model group.

[0225] Example 12: Action of the compound in an osteoarthritis model This example primarily aims to evaluate the efficacy of the compound from Example 1 on an osteoarthritis model. Methods: Wistar rats, male, 6-8 weeks old, were injected into the right knee joint cavity of the rats with 50 μL of a 40 mg / mL solution of MIA (sodium iodoacetate) dissolved in 0.9% physiological saline. Administration of TRL-26 was started the day after injection and continued for 5 weeks. The disease state was evaluated using the OARSI score, and the efficacy of the drug was evaluated by comparing the treatment group with a model group and a blank group. The specific group divisions are as follows. Blank group: Wistar rats, male, 6-8 weeks old, 6 rats, administration: physiological saline, intraarticular injection, once daily. Model group: Wistar rats, male, 6-8 weeks old, 6 rats; Model creation drug: MIA; Administration: Physiological saline, intra-articular injection, once daily. TRL-26 group: Wistar rats, male, 6-8 weeks old, 6 rats, model drug: MIA, administration: 0.1 mg / kg of TRL-26, intra-articular injection, once daily. Results: As can be seen in Figure 10, the TRL-26 group can significantly alleviate the symptoms of rat arthritis.

[0226] Example 13: Effects of the compound in a pulmonary fibrosis model This example primarily aims to examine the efficacy of the compounds in Example 1 on a pulmonary fibrosis model. Methods: C57BL / 6 male mice, 6-8 weeks old, were anesthetized and administered a single dose of bleomycin 5 mg / kg intratracheally to induce a pulmonary fibrosis model. Five days after model creation, TRL-26 was administered once daily for 14 consecutive days. Lung tissue was then collected and Masson staining was performed to evaluate the disease state. The efficacy of the drug was also evaluated by comparing the treatment group with the model group and the blank group. The specific group divisions are as follows. Blank group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, administration: physiological saline, intraperitoneal injection, once daily. Model group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice; Model creation drug: Bleomycin; Administration: Physiological saline, intraperitoneal injection, once daily. TRL-26 group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, model drug: bleomycin, administration: 1 mg / kg of TRL-26, intraperitoneal injection, once daily. Results: As can be seen in Figure 11, 1 mg / kg of TRL-26 can significantly alleviate the severity of pulmonary fibrosis in mice.

[0227] Example 14: Action of the compound in an acute lung injury model This example primarily aims to examine the efficacy evaluation of the compounds in Example 1 against an acute lung injury model. Methods: C57BL / 6 male mice, 6-8 weeks old, were anesthetized and intratracheally injected with LPS (5 mg / kg). The mice were then placed vertically and rotated for 1 minute to distribute droplets to the lungs to create a model. The treatment group received intraperitoneal administration of TRL-26 (1 mg / kg) before LPS stimulation. Lung tissue was taken from the mice 24 hours after LPS administration and stained with HE to evaluate the degree of inflammatory infiltration in the lung tissue. Blank group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, administration: physiological saline, intraperitoneal injection. Model group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, model creation drug: LPS, administration: physiological saline, intraperitoneal injection. TRL-26 group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, model drug: LPS, administration: 1 mg / kg of TRL-26, intraperitoneal injection. Results: As can be seen in Figure 12, 1 mg / kg of TRL-26 can significantly reduce the degree of inflammatory infiltration in a mouse model of acute lung injury.

[0228] Example 15: Action of the compound in a mouse EAE model This example primarily aims to examine the efficacy evaluation of the compounds in Example 1 against the EAE model. Methods: Female, 8-week-old C57BL / 6 mice were selected. MOG33-55 was diluted to 10 mg / kg with physiological saline and added to a complete Freund's adjuvant containing Mycobacterium tuberculosis H37Ra at a final concentration of 4 mg / mL in a 1:1 equivolute ratio. After mixing, the mixture was emulsified and 0.1 mL was subcutaneously injected into four points on both sides of the mouse spine. 0.5 mL of pertussis toxin (500 ng / mouse) was intraperitoneally injected on the day of immunization and again 48 hours later. After creating the model, the drug TRL-26 was administered for 18 consecutive days. The disease state of the mice was evaluated using the mouse EAE neurological function score, and the efficacy of the drug was evaluated by comparing the treatment group with the model group and the blank group. Blank group: C57BL / 6 mice, female, 8 weeks old, 6 mice, administration: physiological saline, intraperitoneal injection. Model group: C57BL / 6 mice, female, 8 weeks old, 6 mice, EAE model induction, administration: physiological saline, intraperitoneal injection. TRL-26 group: C57BL / 6 mice, female, 8 weeks old, 6 mice, EAE model induction, administration: 1 mg / kg of TRL-26, intraperitoneal injection. Results: As can be seen in Figure 13, 1 mg / kg of TRL-26 can significantly alleviate symptoms in the mouse EAE model.

[0229] Example 16: Mechanism of action of the compound in the Parkinson's model This example primarily aims to examine the efficacy evaluation of the compounds in Example 1 against a Parkinson's model. Methods: A mouse Parkinson's disease animal model was induced using MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). C57BL / 6 male mice, 3-4 months old, were administered 30 mg / kg of MPTP intraperitoneally daily for 5 consecutive days. After the model was established, TRL-26 was administered at 1 mg / kg for 3 consecutive weeks. The motor function of the mice was then tested using a rotarod test, and the disease state was observed. The efficacy of the drug was evaluated by comparing the treatment group with the model group and the blank group. The specific group divisions are as follows. Blank group: C57BL / 6 mice, male, 3-4 months old, 6 mice, administration: physiological saline, intraperitoneal injection. Model group: C57BL / 6 mice, male, 3-4 months old, 6 mice, administration: 30 mg / kg MPTP, physiological saline, intraperitoneal injection, once daily. TRL-26 group: C57BL / 6 mice, male, 3-4 months old, 6 mice, administration: 30 mg / kg MPTP, 1 mg / kg TRL-26, intraperitoneal injection, once daily. Results: As can be seen in Figure 14, 1 mg / kg of TRL-26 can significantly alleviate symptoms in a mouse Parkinson's model.

[0230] Example 17: Action of the compound in an autoimmune uveitis model This example primarily aims to evaluate the efficacy of the compounds in Example 1 against an autoimmune uveitis model. Methods: Male B10RIII mice aged 6-8 weeks were selected. Human IRBP161-180 polypeptide solution dissolved in PBS and complete Freund's adjuvant containing 1 mg / mL tuberculin (H37Ra) were mixed in a 1:1 ratio. After thorough emulsification, 200 μL of the mixture was taken and dispersed into three points for subcutaneous injection: 100 μL at the base of the tail and 50 μL at the base of both legs. TRL-26 was administered simultaneously with the creation of the model, and the clinical inflammation score of the mouse eye was performed 28 days later to assess the disease state. The efficacy of the drug was evaluated by comparing the treatment group with the model group and the blank group. The specific group divisions are as follows. Blank group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, administration: physiological saline, intraperitoneal injection. Model group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, uveitis induced, administration: physiological saline, intraperitoneal injection, once daily. TRL-26 group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, uveitis induced, administration: 3 mg / kg of TRL-26, intraperitoneal injection, once daily. Results: As can be seen in Figure 15, 3 mg / kg of TRL-26 can significantly alleviate the symptoms of a mouse uveitis model.

[0231] Example 18: Action of the compound in a colitis model This example primarily aims to examine the efficacy evaluation of the compounds in Example 1 against a model of enteritis. Methods: A mouse inflammation model induction method using DSS was employed. Male C57BL / 6 mice, 6-8 weeks old, were administered a 2.5% DSS solution as drinking water for 7 days. The mice were weighed daily, and simultaneously administered a fixed dose of TRL-26 daily. After 8 days, they were killed, and colon tissue was removed and its length measured to assess the disease state. The drug efficacy was evaluated by comparing the treatment group with the model group and the blank group. The specific group divisions are as follows: Blank group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, administration: physiological saline, intraperitoneal injection. Model group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, drinking water with DSS, administration: physiological saline, intraperitoneal injection, once daily. TRL-26 group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, drinking water with DSS, administration: 5 mg / kg of TRL-26, intraperitoneal injection, once daily. Results: As can be seen in Figure 16, 5 mg / kg of TRL-26 can significantly alleviate the symptoms of enteritis in a mouse model.

[0232] Example 19: Effects of the compound in a rheumatoid arthritis model This example primarily aims to examine the efficacy evaluation of the compounds in Example 1 against a rheumatoid arthritis model. Methods: A mouse model of chronic inflammation with type II collagen arthritis was used. DBA / 1 mice, male, 6-8 weeks old, were selected and immunized for the first time with chicken type II collagen (CII). Chicken type II collagen (CII) was dissolved in 0.1 mmol / L acetic acid, stirred at 4°C to a concentration of 4 mg / mL, and left overnight in a refrigerator at 4°C. On the day of the test, the CII acetic acid solution was uniformly mixed in equal volumes with complete Freund's adjuvant containing 4 mg / mL of Mycobacterium tuberculosis H37RA, and thoroughly emulsified to prepare a CII emulsion. 50 μL of the emulsifier (containing 100 μg / mouse) was intradermally injected into the tail root of the mice to sensitize them. 21 days later, the same dose of emulsifier was used to immunize again in the tail root, using incomplete Freund's adjuvant (IFA) as the adjuvant this time. Approximately 29 days into the experiment, arthritis symptoms such as redness or swelling appeared in the toe joints of the model mice. After creating the model, TRL-26 was administered once daily for 14 consecutive days. Then, the ankle joints were taken and pathologically evaluated to assess the disease state, and the efficacy of the drug was evaluated by comparing the treatment group with the model group and the blank group. The specific group divisions are as follows. Blank group: DBA / l mice, male, 6-8 weeks old, 6 mice, administration: physiological saline, intraperitoneal injection. Model group: DBA / l mice, male, 6-8 weeks old, 6 mice, rheumatoid arthritis induced, administration: physiological saline, intraperitoneal injection, once daily. TRL-26 group: DBA / l mice, male, 6-8 weeks old, 6 mice, rheumatoid arthritis induced, administration: 3 mg / kg of TRL-26, intraperitoneal injection, once daily. Results: As can be seen in Figure 17, 3 mg / kg of TRL-26 can significantly alleviate the symptoms of rheumatoid arthritis in mice.

[0233] Example 20: Effects of the compound in a non-alcoholic fatty liver model This example primarily aims to examine the efficacy of the compounds in Example 1 on a non-alcoholic fatty liver model. Methods: C57BL / 6 male mice, 6-8 weeks old, were fed a high-fat diet (the control group received a normal diet). After 8 weeks, they were divided into groups. Each group continued to receive the treatment once a day, and after 4 weeks of continuous feeding of the high-fat diet (except for the control group), mouse liver tissue was taken and stained with HE to observe the degree of liver lesions. The specific group divisions are as follows. Blank group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, administration: physiological saline, intraperitoneal injection. Model group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, high-fat diet, administration: physiological saline, intraperitoneal injection, once daily. TRL-26 group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, high-fat diet, administration: 3 mg / kg of TRL-26, intraperitoneal injection, once daily. Results: As can be seen in Figure 18, 3 mg / kg of TRL-26 can significantly alleviate the symptoms of non-alcoholic fatty liver disease in mice.

[0234] Example 21: Action of the compound in a sepsis model This example primarily aims to examine the efficacy of the compounds in Example 1 against a sepsis model. Methods: A sepsis model was induced using LPS. C57BL / 6 mice, male, 6-8 weeks old, were administered LPS at a dose of 10 mg / kg intraperitoneally, and TRL-26 was administered simultaneously. After 4 hours of action, the mice were killed, serum was collected, and the disease state of the mice was evaluated by measuring TNF-α secretion using ELISA. The efficacy of the drug was evaluated by comparing the treatment group with the model group and the blank group. The specific group divisions are as follows. Blank group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, administration: physiological saline, intraperitoneal injection. Model group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, model creation drug: LPS, administration: physiological saline, intraperitoneal injection, once daily. TRL-26 group: C57BL / 6 mice, male, 6-8 weeks old, 6 mice, model drug: LPS, administration: 10 mg / kg of TRL-26, intraperitoneal injection, once daily. Results: As can be seen in Figure 19, 10 mg / kg of TRL-26 can significantly alleviate the symptoms of sepsis in mice.

[0235] Example 22: Effect of the compound on amyotrophic lateral sclerosis (ALS) This example primarily aims to examine the efficacy evaluation of the compounds in Example 1 against the ALS model. Methods: Male, 10-week-old SOD1-G93A mice were administered the drug, and behavioral tests were performed 12 weeks after administration to evaluate the disease status of the mice. The specific groupings are as follows: Blank group: C57BL / 6 mice (normal genotype), 6 mice, administration: physiological saline, intraperitoneal injection. Model group: SOD1-G93A mice, 10 weeks old, 6 mice, administration: physiological saline, intraperitoneal injection, once daily. TRL-26 group: SOD1-G93A mice, 10 weeks old, 6 mice, administration: 1 mg / kg of TRL-26, intraperitoneal injection, once daily. Results: As can be seen in Figure 20, 1 mg / kg of TRL-26 significantly alleviated the symptoms of ALS mice.

[0236] The technical proposal of this application is not limited to the specific embodiments described above, and any technical modifications made based on the technical proposal of this application are all included within the scope of protection of this application.

Claims

1. A compound represented by formula I, formula II, formula III, or a solvate, tautomer, enantiomer, diastereomer, isotope-labeled compound (preferably a deuterated compound) or pharmaceutically acceptable salt of a compound represented by formula I, formula II, formula III, 【Chemistry 1】 In equation I, R １ This represents hydrogen, alkyl group, or cycloalkyl group. R ２ This represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R ３ This represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R ４ This represents hydrogen, alkyl group, or cycloalkyl group. R ５ This represents a polycyclic alkyl group, a fused ring aryl group, a heteroaryl group, a fused ring alkylaryl group, or a fused ring alkylheteroaryl group. In Equation II, R １ This represents hydrogen, alkyl group, cycloalkyl group, or aryl group. R ２ This represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R ３ This represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R ４ represents hydrogen, an alkyl group or a cycloalkyl group, R ５ This represents a cycloalkyl group, an aryl group, a heteroaryl group, a fused ring alkylaryl group, or a fused ring alkylheteroaryl group. m is selected from integers between 1 and 4. Optionally, R ２ and R ３ They form a ring together with the nitrogen atom to which they bond, In equation III, R １ This represents hydrogen, alkyl group, cycloalkyl group, or aryl group. R ２ This represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R ３ This represents hydrogen, alkyl group, cycloalkyl group, aryl group, or heteroaryl group. R ４ This represents hydrogen, alkyl group, or cycloalkyl group. R ５ This represents a cycloalkyl group, an aryl group, a heteroaryl group, a fused ring alkylaryl group, or a fused ring alkylheteroaryl group. n is an integer chosen from 0 to 4. Optionally, R ２ and R ３ They form a ring together with the nitrogen atom to which they bond, Optionally, in formulas I to III, the substituent R on each ring independently represents unsubstituted, monosubstituted, or polysubstituted, and R is independently selected from the group consisting of hydrogen, halogen atom, cyano group, nitro group, amino group, hydroxyl group, thiol group, phosphate ester group, C1-C10 alkyl group, C3-C10 cycloalkyl group, C1-C10 halogenated alkyl group, C1-C10 alkoxy group, C3-C10 cycloalkoxy group, C6-C20 aryl group, C3-C20 heteroaryl group, C6-C20 aryloxy group, and C3-C20 heteroalicyclic group. Optionally, in equations I to III, each R １ ~Each R ５ These are, independently, halogen atoms, cyano groups, nitro groups, C6-C20 aryl groups, C3-C20 heteroaryl groups, C1-C10 alkyl groups, C3-C10 cycloalkyl groups, C1-C10 halogenated alkyl groups, C1-C10 alkoxy groups, C3-C10 cycloalkoxy groups, C6-C20 aryloxy groups, C3-C20 heteroalicyclic groups, amino groups, hydroxyl groups, thiol groups, phosphate ester groups, and -OC(O)R groups. ６ , -ONR ６ R ７ , -NR ６ R ７ Replaced by one or more selected from, where R ６ and R ７ A compound independently selected from the group consisting of hydrogen, a C6-C20 aryl group, a C3-C20 heteroaryl group, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C2-C8 alkenyl group, and a C2-C8 alkynyl group.

2. In equation I, R １ The group is selected from the group consisting of H, C1-C6 linear alkyl groups, C3-C6 branched alkyl groups, and C3-C8 cycloalkyl groups, and preferably from the group consisting of H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, cyclopentyl group, or cyclohexyl group. R ２ and R ３ Each of these is independently selected from the group consisting of H, C1-C6 linear alkyl groups, C3-C6 branched alkyl groups, C3-C6 cycloalkyl groups, C6-C20 aryl groups, and C3-C20 heteroaryl groups, preferably selected from the group consisting of H, methyl groups, ethyl groups, propyl groups, isopropyl groups, butyl groups, isobutyl groups, tert-butyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, phenyl groups, naphthyl groups, pyridyl groups, furanyl groups, pyrrolyl groups, or quinolinyl groups. R ４ The group is selected from the group consisting of H, C1-C6 linear alkyl groups, C3-C6 branched alkyl groups, and C3-C8 cycloalkyl groups, and preferably from the group consisting of H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, cyclopentyl group, or cyclohexyl group. R ５ This is selected from the group consisting of C4-C12 bicyclic alkyl groups, C4-C12 tricyclic alkyl groups, C6-C20 spirocycloalkyl groups, C10-C20 fused ring aryl groups, C3-C20 heteroaryl groups, C7-C20 fused ring alkylaryl groups, and C4-C20 fused ring alkylheteroaryl groups. Preferably, R ５ The bicyclic alkyl group relating to is selected from the group consisting of [4.2.1] bicyclic alkyl group, [3.2.1] bicyclic alkyl group, [4.1.0] bicyclic alkyl group, [3.2.2] bicyclic alkyl group, [3.3.0] bicyclic alkyl group, [4.3.0] bicyclic alkyl group, [3.2.0] bicyclic alkyl group, and [5.3.0] bicyclic alkyl group, R ５ The tricyclic alkyl group related to is selected from [3.3.1.1] tricyclic alkyl groups, R ５ The spirocycloalkyl group relating to R is selected from the group consisting of [4,3]spirocycloalkyl group, [3,3]spirocycloalkyl group, [3,3]spirocycloalkyl group, [3,2]spirocycloalkyl group, [2,2]spirocycloalkyl group, [5,5]spirocycloalkyl group, [5,4]spirocycloalkyl group, [5,3]spirocycloalkyl group, and [5,2]spirocycloalkyl group, ５ The fused ring aryl group involved is selected from naphthyl, anthryl, and phenanthryl groups, R ５ The heteroaryl group relating to R is selected from the group consisting of pyridyl group, pyrimidyl group, thienyl group, furanyl group, pyridazyl group, pyrazinyl group, pyrrolyl group, pyranyl group, benzopyranyl group, benzoxazolyl group, benzothiazolyl group, carbazolyl group, quinolinyl group, and isoquinolinyl group. ５ The fused ring alkylaryl group is selected from the group consisting of benzocyclopentanyl group, benzocyclohexanyl group, benzocycloheptanyl group and benzocyclooctanyl group. Preferably, the compound of formula I is 【Chemistry 2】 Rather, preferably, R ５ It is not an adamantyl group, Optionally, in equation I, R １ ~R ５ These are, independently, fluorine, chlorine, bromine, iodine, cyano group, nitro group, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkoxy group, C6-C12 aryloxy group, C3-C10 heteroalicyclic group, amino group, hydroxyl group, thiol group, phosphate ester group, and -OC(O)R. ６ , -ONR ６ R ７ , -NR ６ R ７ Replaced by one or more selected from, where R ６ and R ７ These are independently selected from the group consisting of hydrogen, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C8 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group and C2-C8 alkynyl group, Optionally, in equation I, each R １ ~Each R ５ The compound according to claim 1, characterized in that each is independently substituted with one or more selected from fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group.

3. In equation I, R ５ The polycyclic alkyl group related to this is selected from the following structures: 【Transformation 3】 Or, In equation I, R ５ The fused ring alkylaryl group or fused ring alkylheteroaryl group relating to this is selected from the following structures: 【Chemistry 4】 、 【Transformation 5】 In X １ ~X ４ Each is independently selected from C, N, O, S, P, Si, and Se, and X １ ~X ４ At least one of these is selected from N, O, S, P, Si, and Se, and x is 0, 1, 2, 3, 4, or 5. 【Transformation 6】 In X １ ~X ３ is selected from C, N, O, S, P, Si and Se, and X １ ~X ３ At least one of these is selected from N, O, S, P, Si, and Se, and x is 0, 1, 2, 3, 4, or 5. The compound according to claim 1, characterized in that, in the above structure, each x is independently 0, 1, 2, 3, 4, or 5, and each y and z are independently 1, 2, 3, 4, or 5.

4. In equation I, R ５ The following groups are selected from substituted or unsubstituted groups: 【Transformation 7】 Here, R ５ The compound according to claim 1 or 3, characterized in that, if it contains one or more substituents, each of the one or more substituents is independently selected from fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group.

5. In equation II, R １ The group is selected from the group consisting of H, C1-C6 linear alkyl, C3-C6 branched alkyl, C3-C8 cycloalkyl, and C6-C20 aryl group, and preferably from the group consisting of H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, cyclopentyl group, cyclohexyl group, phenyl group, or naphthyl group. R ２ and R ３ Each of these is independently selected from the group consisting of H, C1-C6 linear alkyl groups, C3-C6 branched alkyl groups, C3-C8 cycloalkyl groups, C6-C20 aryl groups, and C3-C20 heteroaryl groups, preferably selected from the group consisting of H, methyl groups, ethyl groups, isopropyl groups, tert-butyl groups, cyclopentyl groups, cyclohexyl groups, phenyl groups, naphthyl groups, pyridyl groups, furanyl groups, pyrrolyl groups, or quinolinyl groups. R ４ The group is selected from the group consisting of H, C1-C6 linear alkyl groups, C3-C6 branched alkyl groups, and C3-C8 cycloalkyl groups, and preferably from the group consisting of H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, cyclopentyl group, or cyclohexyl group. R ５ This is selected from the group consisting of C3-C20 cycloalkyl groups, C6-C20 aryl groups, C3-C20 heteroaryl groups, or C7-C20 fused ring alkylaryl groups, and is preferably selected from the group consisting of C3-C8 monocyclic alkyl groups, C4-C12 bicyclic alkyl groups, C4-C12 tricyclic alkyl groups, C6-C20 spirocycloalkyl groups, C6-C20 bispyrocycloalkyl groups, C6-C20 aryl groups, C3-C20 heteroaryl groups, or C7-C20 fused ring alkylaryl groups. Preferably, R ５ The monocyclic alkyl group relating to R is selected from the group consisting of cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctyl group, ５ The bicyclic alkyl group relating to is selected from the group consisting of [4.2.1] bicyclic alkyl group, [3.2.1] bicyclic alkyl group, [4.1.0] bicyclic alkyl group, [3.2.2] bicyclic alkyl group, [3.3.0] bicyclic alkyl group, [4.3.0] bicyclic alkyl group, [3.2.0] bicyclic alkyl group, and [5.3.0] bicyclic alkyl group, R ５ The tricyclic alkyl group related to is selected from [3.3.1.1] tricyclic alkyl groups, R ５ The spirocycloalkyl group relating to R is selected from the group consisting of [4,3]spirocycloalkyl group, [3,3]spirocycloalkyl group, [3,3]spirocycloalkyl group, [3,2]spirocycloalkyl group, [2,2]spirocycloalkyl group, [5,5]spirocycloalkyl group, [5,4]spirocycloalkyl group, [5,3]spirocycloalkyl group, and [5,2]spirocycloalkyl group, ５ The aryl group relating to this is selected from the group consisting of phenyl group, naphthyl group, biphenyl group, and terphenyl group, R ５ The heteroaryl group relating to R is selected from the group consisting of pyridyl group, pyrimidyl group, thienyl group, furanyl group, pyridazyl group, pyrazinyl group, pyrrolyl group, pyranyl group, benzopyranyl group, benzoxazolyl group, benzothiazolyl group, carbazolyl group, quinolinyl group, and isoquinolinyl group. ５ The fused ring alkylaryl group is selected from the group consisting of benzocyclopentanyl group, benzocyclohexanyl group, benzocycloheptanyl group and benzocyclooctanyl group. Optionally, in equation II, R １ ~R ５ These are, independently, fluorine, chlorine, bromine, iodine, cyano group, nitro group, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C6 alkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C6-C12 aryloxy group, C3-C10 heteroalicyclic group, amino group, hydroxyl group, thiol group, phosphate ester group, and -OC(O)R. ６ , -ONR ６ R ７ , -NR ６ R ７ Replaced by one or more selected from, where R ６ and R ７ These are independently selected from the group consisting of hydrogen, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C8 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group and C2-C8 alkynyl group, Optionally, in Formula II, R １ ~R ５ are each independently fluorine, chlorine, bromine, iodine, cyano group, nitro group, C6-C10 aryl group, C3-C10 heteroaryl group, C1-C6 alkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C6-C10 aryloxy group, C3-C8 heterocycloaliphatic group, amino group, hydroxy group, thiol group, phosphate ester group, -OC(O)R ６ , -ONR ６ R ７ , -NR ６ R ７ is selected from one or more of the following and substituted thereby, where R ６ and R ７ are independently selected from the group consisting of hydrogen, C6-C10 aryl group, C3-C10 heteroaryl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group and C2-C6 alkynyl group, Optionally, in equation II, R １ ~R ５ The compound according to claim 1, characterized in that each is independently substituted with one or more selected from fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group.

6. In formula II, R ２ and R ３ together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, Preferably, the compound represented by formula II has the structure represented by formula IIa, 【Transformation 8】 Here, R, R １ , R ４ , R ５ The definitions of and m are the same as in Equation II, Preferably, in formulas II and IIa, R ５ This represents the following substituted or unsubstituted groups: 【Chemistry 9】 R ５ The compound according to claim 1 or 5, characterized in that, if it contains one or more substituents, each of the one or more substituents is independently selected from fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, difluoromethyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, trifluoromethoxy group, and phenyl group.

7. In equation III, R １ The group is selected from the group consisting of H, C1-C6 linear alkyl, C3-C6 branched alkyl, C3-C8 cycloalkyl, and C6-C20 aryl group, and preferably from the group consisting of H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, cyclopentyl group, cyclohexyl group, phenyl group, or naphthyl group. R ２ and R ３ Each of these is independently selected from the group consisting of H, C1-C6 linear alkyl groups, C3-C6 branched alkyl groups, C3-C8 cycloalkyl groups, C6-C20 aryl groups, and C3-C20 heteroaryl groups, preferably selected from the group consisting of H, methyl groups, ethyl groups, isopropyl groups, tert-butyl groups, cyclopentyl groups, cyclohexyl groups, phenyl groups, naphthyl groups, pyridyl groups, furanyl groups, pyrrolyl groups, or quinolinyl groups. R ４ The group is selected from the group consisting of H, C1-C6 linear alkyl groups, C3-C6 branched alkyl groups, and C3-C8 cycloalkyl groups, and preferably from the group consisting of H, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, cyclopentyl group, or cyclohexyl group. R ５ This is selected from the group consisting of C3-C20 cycloalkyl groups, C6-C20 aryl groups, C3-C20 heteroaryl groups, or C7-C20 fused ring alkylaryl groups, and is preferably selected from the group consisting of C3-C8 monocyclic alkyl groups, C4-C12 bicyclic alkyl groups, C4-C12 tricyclic alkyl groups, C6-C20 spirocycloalkyl groups, C6-C20 bisspirocycloalkyl groups, C6-C20 aryl groups, C3-C20 heteroaryl groups, or C7-C20 fused ring alkylaryl groups. Preferably, R ５ The C3-C8 monocyclic alkyl group is selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group, R ５ The bicyclic alkyl group relating to is selected from the group consisting of [4.2.1] bicyclic alkyl group, [3.2.1] bicyclic alkyl group, [4.1.0] bicyclic alkyl group, [3.2.2] bicyclic alkyl group, [3.3.0] bicyclic alkyl group, [4.3.0] bicyclic alkyl group, [3.2.0] bicyclic alkyl group, and [5.3.0] bicyclic alkyl group, R ５ The tricyclic alkyl group related to is selected from [3.3.1.1] tricyclic alkyl groups, R ５ The spirocycloalkyl group relating to R is selected from the group consisting of [4,3]spirocycloalkyl group, [3,3]spirocycloalkyl group, [3,3]spirocycloalkyl group, [3,2]spirocycloalkyl group, [2,2]spirocycloalkyl group, [5,5]spirocycloalkyl group, [5,4]spirocycloalkyl group, [5,3]spirocycloalkyl group, and [5,2]spirocycloalkyl group, ５ The aryl group relating to this is selected from the group consisting of phenyl group, naphthyl group, biphenyl group, and terphenyl group, R ５ The heteroaryl group relating to this is selected from the group consisting of pyridyl group, pyrimidyl group, thienyl group, furanyl group, pyridazyl group, pyrazinyl group, pyrrolyl group, pyranyl group, benzopyranyl group, benzoxazolyl group, benzothiazolyl group, carbazolyl group, quinolinyl group, and isoquinolinyl group, and the condensed ring alkylaryl group is selected from the group consisting of benzocyclopentanyl group, benzocyclohexanyl group, benzocycloheptanyl group, and benzocyclooctanyl group. Optionally, in equation III, R １ ~R ５ These are, independently, fluorine, chlorine, bromine, iodine, cyano group, nitro group, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C6 alkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C6-C12 aryloxy group, C3-C10 heteroalicyclic group, amino group, hydroxyl group, thiol group, phosphate ester group, and -OC(O)R. ６ , -ONR ６ R ７ , -NR ６ R ７ Replaced by one or more selected from, where R ６ and R ７ These are independently selected from the group consisting of hydrogen, C6-C12 aryl group, C3-C12 heteroaryl group, C1-C8 alkyl group, C3-C8 cycloalkyl group, C2-C8 alkenyl group and C2-C8 alkynyl group, Optionally, in equation III, R １ ~R ５ These are, independently, fluorine, chlorine, bromine, iodine, cyano group, nitro group, C6-C10 aryl group, C3-C10 heteroaryl group, C1-C6 alkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C6-C10 aryloxy group, C3-C8 heteroalicyclic group, amino group, hydroxyl group, thiol group, phosphate ester group, and -OC(O)R. ６ , -ONR ６ R ７ , -NR ６ R ７ Replaced by one or more selected from, where R ６ and R ７ These are independently selected from the group consisting of hydrogen, C6-C10 aryl group, C3-C10 heteroaryl group, C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group and C2-C6 alkynyl group, Optionally, in equation III, R １ ~R ５ The compound according to claim 1, characterized in that each is independently substituted with one or more selected from fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, phenoxy group, phenyl group, naphthyl group, biphenyl group, pyridyl group, pyrimidyl group, furanyl group, thienyl group, and pyrrolyl group.

8. In equation III, R ２ and R ３ These, together with the nitrogen atoms to which they are bonded, form a 5- to 7-membered ring. Preferably, the compound represented by formula III has the structure represented by formula IIIa, 【Chemistry 10】 Here, R, R １ , R ４ , R ５ The definitions of n and n are the same as in Equation III, Preferably, in formulas III and IIIa, R ５ This represents the following substituted or unsubstituted groups: 【Chemistry 11】 Here, R ５ The compound according to claim 1 or 7, characterized in that, if the compound contains one or more substituents, each of the one or more substituents is independently selected from fluorine, chlorine, bromine, iodine, cyano group, nitro group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, difluoromethyl group, trifluoromethyl group, methoxy group, ethoxy group, propoxy group, trifluoromethoxy group, and phenyl group.

9. The compound according to claim 1, characterized in that the aforementioned compound is selected from the group consisting of the following compounds. 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】

10. A drug composition comprising the compound described in any one of claims 1 to 9 and one or more pharmaceutically acceptable auxiliary materials.

11. The drug composition according to claim 10, characterized in that the auxiliary material includes one or more of the following: diluents, fillers, adhesives, wetting agents, absorption enhancers, surfactants, lubricants, and stabilizers.

12. The drug composition according to claim 10 or 11, characterized in that the drug composition is a drug preparation selected from tablets, capsules, pills, granules, pellets, aerosols, sprays, nasal drops, inhalants, suppositories, enemas, intramuscular injection preparations, intravenous injection preparations, intra-articular injection preparations, ointments, or patches.

13. Application of a compound according to any one of claims 1 to 9 or a drug composition according to any one of claims 10 to 12 in the preparation of a drug for preventing or treating inflammation-related diseases and / or cell necrotizing apoptosis and autophagy-related diseases.

14. The application according to claim 13, characterized in that the inflammation-related disease is an inflammatory central nervous system condition or disease or an inflammatory peripheral system condition or disease related to TNF-α.

15. The inflammatory central nervous system condition or disease includes diseases or conditions resulting from excessive activation of brain immune cells or involving cytokines, particularly TNF-α, or clinically identified types of inflammatory central nervous system diseases, for example, the type of inflammatory central nervous system disease being selected from encephalitis, meningitis, encephalomyelitis, viral, bacterial or autoimmune encephalitis, multiple sclerosis, brain injury, brain and spinal cord injury, cerebral contusion, subdural hematoma, and spinal cord injury and cerebrovascular vasculitis of various causes, as described in claim 14.

16. The aforementioned inflammatory peripheral system conditions or diseases include pyoderma, vasculitis, dermatitis, herpetiform dermatitis, psoriasis, atopic dermatitis, neurodermatitis, contact dermatitis, eczema, scleroderma, arthritis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory myopathy, acute or chronic nephritis, nephrotic syndrome, glomerulonephritis, dry eye syndrome, uveitis, endophthalmitis, blepharitis, glaucoma, age-related macular lesions, conjunctivitis, allergic conjunctivitis, keratitis, autoimmune uveitis, gingivitis, periodontitis, allergic and non-allergic rhinitis, inflammatory bowel disease, lupus nephritis, thyroiditis, alcoholic and non-alcoholic fatty liver, viral and non-alcoholic The application of the claim in 14 is characterized by including various acute or chronic inflammatory diseases due to viral hepatitis, autoimmune hepatitis, chronic relapsing hepatitis, cirrhosis, autoimmune hemolytic anemia, temporal arteritis, Crohn's disease, enteritis, colitis, ulcerative colitis, lupus erythematosus, ankylosing spondylitis, immune complex hematoangitis, myocarditis, ischemic heart disease, hypercholesterolemia, atherosclerosis, pre-eclampsia, diabetes mellitus, diabetic retinopathy, diabetic nephropathy, allograft rejection, pneumonia, acute lung injury, emphysema, chronic obstructive pulmonary disease, tracheitis, bronchitis, asthma, pulmonary fibrosis, hepatic fibrosis, and inflammation caused by autoimmune function.

17. The aforementioned cell necrotizing apoptosis-related disease is characterized by including diseases or conditions resulting from nerve injury, neurobehavioral deficits, neurodegenerative diseases, excitotoxicity of the nervous system, accumulation of incorrectly folded proteins in cells, or impaired autophagy, or clinically identified disease types, preferably including stroke such as hemorrhagic stroke and ischemic stroke, chronic demyelinating diseases of the nervous system, amyotrophic lateral sclerosis, Huntington's disease, chronic traumatic encephalopathy and frontotemporal dementia, AIDS-related neurodegeneration, Alzheimer's disease, Parkinson's disease, limb weakness due to neurobehavioral deficits, cognitive neurobehavioral deficits due to nerve injury (e.g., visual, gustatory, olfactory, auditory, facial nerve injury, mania, emotional disorders, etc.), depression, anxiety disorders, schizophrenia, phobias and other psychiatric disorders, primary open-angle glaucoma, heart disease, heart failure, myocardial fibrosis, myocardial infarction, myocardial ischemia, chronic renal failure, renal injury, and lung injury.

18. A method for preventing or treating an acute or chronic central or peripheral disease related to inflammation and / or cell necrosis, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a drug composition according to any one of claims 10 to 12 to a subject in need.

19. A method for inhibiting TRADD activity in cells or a subject, comprising the steps of contacting cells with a compound according to any one of claims 1 to 9 or a drug composition according to any one of claims 10 to 12, or administering a subject with a compound according to any one of claims 1 to 9 or a drug composition according to any one of claims 10 to 12.

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