Compound, pharmaceutical composition containing same and application thereof

Abstract

The present application provides a compound represented by formula (0), or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereoisomer thereof, or a racemate thereof, or a polymorphic substance thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof;

Description

A compound, a pharmaceutical composition containing the same and its use Technical Field

[0001] The present application relates to the field of biomedicine, and specifically to a compound, a pharmaceutical composition containing the same, and uses thereof. Background Art

[0002] Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is an irreversible and fatal motor neuron disease. Its primary symptoms are progressive weakness and atrophy of the limbs and trunk muscles, leading to a gradual loss of motor function, akin to being "frozen," hence the nickname "Lou Gehrig's disease." The core pathology of ALS is the death of motor neurons in the motor cortex and spinal cord. The degeneration of cortical spinal axons leads to lateral thinning and scarring (sclerosis) of the spinal cord.

[0003] Loss of protein folding homeostasis is a hallmark of many of the most prevalent neurodegenerative diseases. The unfolded protein response (UPR), a response to folding stress within the endoplasmic reticulum (ER), comprises a set of signaling mechanisms that initiate gene expression programs to restore protein homeostasis or, when stress is chronic or excessive, promote neuronal death. This function of the UPR has been proposed to play a key role in ALS.

[0004] The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that helps cells, tissues, and organisms adapt to changing environments and maintain health. The ISR responds to various changes and restores homeostasis by reprogramming gene expression. Long-term memory formation in the brain requires new protein synthesis, so inhibiting the ISR enhances long-term memory formation, while activating the ISR blocks this process. Age-related cognitive impairment is often associated with ISR activation.

[0005] As a central regulator of protein homeostasis, ISR activation occurs in a wide range of brain diseases. This activation has been confirmed by measuring eIF2-P and phosphorylation of PKR, PERK, and GCN2 in the brain, including samples from patients and animal models of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, traumatic brain injury, Down syndrome, and Charcot-Marie-Tooth syndrome. Notably, ISR activation leads to cognitive deficits in traumatic brain injury, aging, and mouse models of Alzheimer's disease.

[0006] eukaryotic translation initiation factor 2B (eIF2B) is a key enzyme regulating protein synthesis and a guanine nucleotide exchange factor (GEF) specific for translation initiation factor 2. The eIF2B agonist ISRIB can restore protein translation, return UPR transcription to basal levels, and reduce the integrated stress response (ISR). Meanwhile, the eIF2B agonists ABBV-CLS-7262 (AbbVie / Calico) and DNL-343 (Denali Therapeutics) are both indicated for ALS and have entered Phase 1 clinical trials. DNL-343 has published Phase 1 data in healthy subjects, demonstrating safety and tolerability.

[0007] Numerous animal studies have confirmed that the eIF2B activator ISRIB can enhance long-term memory in mouse models. Three days after oral administration of the eIF2B activator ABBV-CLS-7262, the model animals' brain function can be restored to youthful levels. This suggests that this drug may be able to inhibit some neurodegenerative diseases in the later stages of development and has the potential to treat conditions such as Alzheimer's and Parkinson's diseases.

[0008] Summary of the Invention

[0009] The present application provides a compound, a pharmaceutical composition containing the same, and a synthesis method and use thereof, to provide a compound that can significantly weaken the integrated stress response (ISR) of cells, activate eIF2B activity, and allow intracellular proteins to tend to be synthesized normally, and the compound has good cellular activity and / or excellent pharmacokinetic properties.

[0010] The first aspect of the present application provides a compound represented by formula 0, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

[0011] In formula 0, R 1 Selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkylhydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy;

[0012] L 1 Selected from C3-C10 cycloalkylene, 3-10 membered heterocycloalkylene, C1-C6 alkylene;

[0013] L 2 Selected from -O-, -NH-, C1-C6 alkylene, carbonyl;

[0014] Ring A is selected from a 5-10 membered heteroaryl group, wherein the heteroaryl group contains at least a heteroatom N, and Ring A is optionally substituted by X R A Replacement, R A is selected from halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and X is any integer from 0 to 4;

[0015] L 2 and -NH- are respectively connected to the adjacent carbon atoms of ring A;

[0016] Ring B is selected from C3-C10 cycloalkylene, 5-10 membered heterocycloalkylene, and is optionally substituted by Y R B Replacement, R B is selected from halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and Y is any integer from 0 to 4;

[0017] L 3 Selected from a single bond, an amide bond, a sulfamide bond, -O-(CH2)n-amide bond, an amide bond-(CH2)nO-, -O-(CH2)m-sulfamide bond, -sulfamide bond-(CH2)mO-, a 5-10 membered heteroarylene group; m and n are each independently 0, 1, 2 or 3;

[0018] The C ring is selected from C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, benzo 3-10 membered heterocycloalkyl; and the C ring is optionally substituted by Z R C Replacement, R C It is selected from halogen, hydroxy, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and Z is any integer from 0 to 4.

[0019] In some embodiments, R 1 is selected from C1-C3 alkoxy, C1-C3 haloalkoxy, preferably the halogen in the C1-C3 haloalkoxy is independently selected from F, Cl or Br; preferably the number of C atoms in the C1-C3 haloalkoxy is p, the number of halogen is any integer from 1 to (2p+1), preferably the halogen in the C1-C3 haloalkoxy is F or Cl; preferably R1 It is a C1-C3 perfluoroalkyl group, more preferably -O-CF3.

[0020] In some embodiments, L 1 Selected from C3-C6 cycloalkylene, 3-6 membered heterocycloalkylene, C1-C3 alkylene; preferably L 1 Selected from cyclobutylene, cyclopentylene, cyclohexylene, azetidinylene, oxacyclobutylene, azetidinylene, oxacyclopentylene, azetidinylene, oxacyclohexylene, oxacyclohexylene, methylene, ethylene, propylene; preferably L1 is selected from Methylene, ethylene; preferably L1 is selected from Methylene, ethylene.

[0021] In some embodiments, the compound of formula 0 is selected from any one of the structures shown in formula I-1 and formula I-2:

[0022] wherein E is CH or N; n1 is 1, 2 or 3, preferably n1 is 1; n2 is 1, 2, 3 or 4, preferably n2 is 2; L 2 , A ring, R A , X, B ring, R B , Y, L 3 , C ring, R C The definitions of , Z are the same as those in the above embodiment.

[0023] In some embodiments, the compound of formula I-1 is selected from any one of the structures shown in the following formula I-1-1 and formula I-1-2:

[0024] Among them, L 2 , A ring, R A , X, B ring, R B , Y, L 3 , C ring, R C The definitions of , Z are the same as those in the above embodiment.

[0025] In some embodiments, L 2 Selected from -O-, -NH-, C1-C3 alkylene, carbonyl, preferably L 2 Selected from -O-, -NH-, methylene, ethylene, carbonyl.

[0026] In some embodiments, the compound of formula 0 is selected from any one of the structures shown in the following formulas II-1 to II-4:

[0027] wherein n3 is 1, 2 or 3, preferably n3 is 1; L1 , A ring, R A , X, B ring, R B , Y, L 3 , C ring, R C The definitions of , Z are the same as those in the above embodiment.

[0028] In some embodiments, the A ring is selected from a 5-6 membered heteroaryl group, and the heteroaryl group contains at least a heteroatom N; preferably, the A ring is selected from a pyridyl group, a pyrimidyl group, a pyrazinyl group, a pyridazinyl group, an imidazole group, a pyrazolyl group, a triazole group, an oxazolyl group, an oxadiazole group, a furazanyl group, a furanyl group, a thiazolyl group, an isoxazolyl group, an isothiazolyl group,

[0029] In some embodiments, Ring A is selected from pyridinyl, pyrazinyl, triazolyl, furazanyl, isoxazolyl,

[0030] In some embodiments, Ring A is selected from

[0031] In some embodiments, Ring A is selected from The end is connected to -NH-, and the * end is connected to L 2 connect.

[0032] In some embodiments, R A is selected from halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, X is any integer from 0 to 4, preferably X is 0 or 1.

[0033] In some embodiments, the compound of formula 0 is selected from any one of the structures shown in formula III-1 and formula III-2 below:

[0034] Among them, T 1 、T 2 、T 3 、T 4 are each independently C or N, and at least one is N; preferably, T 1 N, T 2 and T 3 C, T 4 is C or N; or preferably, T 1 、T 2 and T 3 One is N, T 4 is C;

[0035] T 5 、T 6 、T 7 are each independently C, N, O or S;

[0036] R 1 , L 1 , L 2 , B ring, R B , Y, L 3 , C ring, R C The definitions of Z are the same as those in any of the above embodiments.

[0037] In some embodiments, the compound of formula III-1 is selected from any one of the structures shown in the following formula III-1-1:

[0038] Among them, T 1 C or N, R 1 , L 1 , L 2 , B ring, R B , Y, L 3 , C ring, R C The definitions of Z are the same as those in any of the above embodiments.

[0039] In some embodiments, the compound of formula III-2 is selected from any one of the structures shown in formula III-2-1 or formula III-2-2:

[0040] In the general formula III-21, T 5 、T 6 Each independently is C, N, O or S, preferably, T 5 C or N, T 6 N, O or S;

[0041] In the general formula III-22, T 5 、T 7 Each independently is C, O or S, preferably, T 5 C or O, T 7 is C or O, and T 5 and T 7 different;

[0042] R 1 , L 1 , L 2 , B ring, R B , Y, L 3 , C ring, R C The definitions of Z are the same as those in any of the above embodiments.

[0043] In some embodiments, the B ring is selected from C4-C8 cycloalkylene, 5-6 membered heterocycloalkylene, preferably C4-C8 cycloalkylene is C4-C8 monocycloalkyl or C4-C8 bridged cycloalkyl; preferably, the B ring is selected from cyclobutylene, cyclopentylene, cyclohexylene, bicyclo[2.2.1]heptylene, bicyclo[2.2.2]octylene, bicyclo[1.1.2]pentylene, piperidinylene, oxadiazolylene, preferably, the B ring is selected from It is further preferred that the B ring is selected from

[0044] In some embodiments, R B is selected from halogen, hydroxy, nitro, and cyano, and Y is any integer from 0 to 4, preferably Y is 0.

[0045] In some embodiments, the compound of formula 0 is selected from any one of the structures shown in the following formulas IV-1 to IV-3:

[0046] Among them, R 1 , L 1 , L 2 , A ring, R A , X, L 3 , C ring, R C The definitions of Z are the same as those in any of the above embodiments.

[0047] In some embodiments, the compound of formula IV-1 is selected from any one of the structures shown in the following formula IV-1-1 and formula IV-1-2:

[0048] Preferably, the compound of formula IV-2 is selected from any one of the structures shown in the following formula IV-2-1 and formula IV-2-2:

[0049] R 1 , L 1 , L 2 、R A , X, L 3 , C ring, R C The definitions of Z are the same as those in any of the above embodiments.

[0050] In some embodiments, the compound of formula IV-3 is selected from any one of the structures shown in the following formula IV-3-1 and formula IV-3-2:

[0051] R1 , L 1 , L 2 、R A , X, L 3 , C ring, R C The definitions of Z are the same as those in any of the above embodiments.

[0052] In some embodiments, L 3 Selected from 5-6 membered heteroarylene; preferably The end is connected to the C ring, The end is connected to the B ring; preferably the 5-6 membered heteroaryl group is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, Preferred L 3 Selected from The end is connected to the C ring, The end is connected to the B ring; further preferably L 3 Selected from The end is connected to the C ring, The end is connected to the B ring.

[0053] In some embodiments, the compound of formula 0 is selected from any one of the structures shown in the following formulas V-1 to V-3:

[0054] Among them, R 1 , L 1 , L 2 , A ring, R A , X, B ring, R B , Y, C ring, R C The definitions of Z are the same as those in any of the above embodiments.

[0055] In some embodiments, the compound of formula V-1 is selected from any one of the structures shown in the following formulas V-1-1 to V-1-11:

[0056] Among them, R 1 , L 1 , L 2 、R A , X, B ring, R B , Y, C ring, R C , Z is defined as in any of the above embodiments;

[0057] Among them, R 1 , L1 , L 2 , A ring, R A , X, R B , Y, C ring, R C , Z is defined as in any of the above embodiments;

[0058] Among them, R 1 , L 1 , L 2 、R A , X, R B , Y, C ring, R C The definitions of Z are the same as those in any of the above embodiments.

[0059] In some embodiments, the compound of formula V-2 is selected from any one of the structures shown in the following formulas V-2-1 to V-2-11:

[0060] Among them, R 1 , L 1 , L 2 、R A , X, B ring, R B , Y, C ring, R C , Z is defined as in any of the above embodiments;

[0061] Among them, R 1 , L 1 , L 2 , A ring, R A , X, R B , Y, C ring, R C , Z is defined as in any of the above embodiments;

[0062] Among them, R 1 , L 1 , L 2 、R A , X, R B , Y, C ring, R C The definitions of Z are the same as those in any of the above embodiments.

[0063] In some embodiments, the C ring is selected from C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-C10 aryl, 5-6 membered heteroaryl, benzo 3-6 membered heterocycloalkyl; preferably, the C ring is selected from cyclobutyl, cyclohexyl, azetidinyl, piperidinyl, phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzomorpholinyl, benzoxocyclohexyl; preferably, the C ring is selected from cyclobutyl, phenyl, pyrazinyl, quinolyl, benzomorpholinyl, benzoxocyclohexyl; preferably, the C ring is selected from

[0064] In some embodiments, the C ring is selected from

[0065] In some embodiments, R C is selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -C1-C3 haloalkoxy, Z is any integer from 0 to 4, preferably halogen, halogen in C1-C3 haloalkyl, halogen in C1-C3 haloalkoxy are each independently F, Cl or Br, more preferably F or Cl, preferably R C Selected from F, Cl, hydroxy, -CH2F, -CHF2, -CF3, -O-CF3; preferably Z is 1 or 2.

[0066] In some embodiments, the compound of formula 0 is selected from any one of the structures shown in the following formula VI-1 and formula VI-2:

[0067] Among them, R in the general formula VI-1 C Selected from F, Cl, hydroxy, -CN, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCF3; preferably Z is 1 or 2;

[0068] In the general formulas VI-1 and VI-2, ring A, R A , X, B ring, R B , Y, L 3 The definition of is the same as that in any of the above embodiments.

[0069] In some embodiments, the compound of formula 0 is selected from any one of the structures shown in formula VII below:

[0070] Ring A is selected from a 5-membered nitrogen-containing heteroaryl group or a 6-membered nitrogen-containing heteroaryl group; L 1 is selected from C3-C6 membered cycloalkylene or 4-6 membered heterocyclylene; L 2Selected from -O-; and R 1 Selected from C1-C3 alkoxy or C1-C3 haloalkoxy.

[0071] In some embodiments, Ring A is selected from a 6-membered nitrogen-containing heteroarylene group.

[0072] In some embodiments, L 1 Selected from C3-C5 membered cycloalkylene or 4-5 membered heterocyclylene.

[0073] In some embodiments, L 1 It is selected from cyclobutylene or azetidinyl, preferably cyclobutylene.

[0074] In some embodiments, R 1 Selected from C1-C3 haloalkoxy, preferably -OCF3.

[0075] In some embodiments, the compound of formula 0 is selected from any one of the structures shown in the following formula VIII:

[0076] Ring A is selected from a 5-membered nitrogen-containing heteroaryl group or a 6-membered nitrogen-containing heteroaryl group; Ring B is selected from a 4-8-membered cycloalkyl group; Ring C is selected from a phenyl group or a cyclobutyl group, and each of them is optionally substituted by 1 or 2 R C Substituted, the R C is selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy.

[0077] In some embodiments, Ring A is selected from a 6-membered nitrogen-containing heteroarylene group.

[0078] In some embodiments, the compound of formula VIII is selected from any one of the structures shown in the following formula VIII-A:

[0079] In some embodiments, the compound of formula VIII-A is selected from any one of the structures shown in formula VIII-A-1 or formula VIII-A-2:

[0080] In some embodiments, the C ring is selected from cyclobutyl optionally substituted with C1-C3 haloalkoxy.

[0081] In some embodiments, the compound is selected from any one of the following compounds:

[0082] The second aspect of the present application further provides a method for synthesizing the compounds of the structures represented by the above-mentioned general formula V-1 to general formula V-3, which comprises:

[0083] Synthetic intermediate 3 Make raw material 1 With raw material 2 Substitution reaction occurs to obtain intermediate 3, or raw material 4 With raw materials Substitution reaction occurs to obtain intermediate 3;

[0084] According to route 1, the compound represented by the structure of formula V-1 is synthesized.

[0085] Route 1:

[0086] Among them, the raw material 6 undergoes a substitution reaction with methyl bromoacetate and is then hydrolyzed to obtain intermediate 7; intermediate 7 undergoes an amidation reaction with raw material 8 to obtain intermediate 9; intermediate 9 is deprotected to obtain intermediate 10; intermediate 10 undergoes a coupling reaction with intermediate 3 to obtain a compound with the structure shown in general formula V-1;

[0087] According to route 2, the compound of the structure shown in general formula V-2 is synthesized.

[0088] Route 2:

[0089] Among them, raw material 11 reacts with raw material 8 to produce intermediate 12; intermediate 12 is deprotected to produce intermediate 13; intermediate 13 and intermediate 3 undergo coupling reaction to produce a compound represented by general formula V-2;

[0090] According to route 3, the compound of the structure shown in general formula V-3 is synthesized.

[0091] Route 3:

[0092] Among them, raw material 14 reacts with hydrazine hydrate and obtains intermediate 15 through functional group transformation; intermediate 15 undergoes cyclization with N,N-carbonyldiimidazole to obtain intermediate 16; compound 16 undergoes condensation reaction with raw material 6 to obtain intermediate 17; intermediate 17 is deprotected to obtain intermediate 18; intermediate 18 is coupled with intermediate 3 to obtain a compound with the structure shown in general formula V-2.

[0093] The third aspect of the present application provides a pharmaceutical composition comprising a preparation prepared from any one of the compounds of the first aspect above, or its stereoisomers, or its tautomers, or its geometric isomers, or its enantiomers, or its diastereomers, or its racemates, or its polymorphs, or its solvates, or its hydrates, or its N-oxides, or its isotope-labeled compounds, or its metabolites, or its esters, or its prodrugs, or its pharmaceutically acceptable salts.

[0094] In some embodiments, the above-mentioned pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and vehicles.

[0095] The fourth aspect of the present application provides the use of the compound of the first aspect above, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, or the pharmaceutical composition provided in the second aspect in the preparation of a drug for preventing and / or treating neurodegenerative diseases, cancer, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobin diseases, kidney diseases, hearing loss diseases, eye diseases, diseases with mutations that lead to the induction of unfolded protein response (UPR), malaria infection, musculoskeletal diseases, metabolic diseases or mitochondrial diseases.

[0096] The fifth aspect of the present application provides the use of the compound of the first aspect above, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, or the pharmaceutical composition provided in the third aspect in the preparation of a medicament for preventing and / or treating a disease or condition mediated by the integrated stress response (ISR) pathway.

[0097] In some embodiments, provided is a method for treating a disease or condition mediated by the integrated stress response (ISR) pathway in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of any one of the aforementioned compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a therapeutically effective amount of any one of the aforementioned pharmaceutical compositions.

[0098] In some embodiments, a method for treating a disease associated with regulation of eIF2B activity or level, eIF2 pathway or ISR pathway activity or level is provided, the method comprising administering to a subject a therapeutically effective amount of any of the above-mentioned compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a therapeutically effective amount of any of the above-mentioned pharmaceutical compositions.

[0099] In some embodiments, a method for preventing and / or treating the above-mentioned diseases is provided, comprising administering an effective amount of any of the above-mentioned compounds, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions to a subject in need thereof.

[0100] In some embodiments, a method for preventing and / or treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any one of the aforementioned compounds, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions.

[0101] In some embodiments, the neurodegenerative disease includes, but is not limited to, leukodystrophy, leukoencephalopathy, myelin dysplasia or demyelinating disease, intellectual disability syndrome, cognitive dysfunction, glial cell dysfunction or brain injury (e.g., traumatic brain injury or toxin-induced brain injury), Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease. disease), dystonia, frontotemporal dementia (FTD), Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe disease, kuru, Lewy body dementia, Machado-Joseph disease (spinocerebellar disorder type 3), multiple system atrophy, multisystem proteinopathy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum's disease, Sandhoff disease, Schilder's disease disease), subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar disorders (various types with different characteristics,(e.g., spinocerebellar ataxia type 2 or spinocerebellar ataxia type VIII), spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, corticobasal degeneration, adrenoleukodystrophy, X-linked adrenoleukodystrophy, cerebral adrenoleukodystrophy, Pelizaeus-Merzheimer disease, Krabbe disease, leukodystrophy due to mutations in the DARS2 gene (sometimes called leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL), DARS2-related spectrum disorder, or tabes dorsalis).

[0102] The above-mentioned cancers include, but are not limited to, human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid cancers and lymphoid cancers, renal cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, gliomas, esophageal cancer, liver cancer (including hepatocarcinoma), lymphomas (including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (such as Burkitt's lymphoma), In some other instances, "cancer" refers to lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[0103] The leukemias include, but are not limited to, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, stem cell leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, and hemoblastic leukemia. , hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelomorphic granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia leukemia), plasma cell leukemia, multiple myeloma, plasma ball leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0104] The above-mentioned inflammatory diseases include, but are not limited to, postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, disease), ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0105] The musculoskeletal diseases include, but are not limited to, muscular dystrophies (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1, or myotonic dystrophy type 2), limb-girdle muscular dystrophy, multisystem proteinopathy, chondrodysplasia punctata, X-linked recessive chondrodysplasia punctata, Conradi-Hünermann syndrome, and muscular dystrophy. syndrome), autosomal dominant chondrodysplasia punctata, stress-induced bone disorders (e.g., stress-induced osteoporosis), multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, Paget's disease of bone, fasciculations, Friedreich's ataxia, muscle wasting disorders (e.g., muscular dystrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, or paralysis.

[0106] The above-mentioned metabolic diseases include, but are not limited to, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (such as type 1 diabetes, type 2 diabetes or gestational diabetes), phenylketonuria, proliferative retinopathy or Kearns-Sayre disease.

[0107] Such mitochondrial diseases include, but are not limited to, Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Cohens-Sell syndrome (KSS), Leigh syndrome (e.g., MILS or maternally inherited Leigh syndrome), mitochondrial DNA deletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

[0108] The above-mentioned hearing loss diseases include, but are not limited to, mitochondrial non-syndromic hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, inherited or genetic hearing loss, hearing loss experienced due to ototoxic exposure, disease-induced hearing loss, and trauma-induced hearing loss. In some embodiments, mitochondrial non-syndromic hearing loss and deafness is MT-RNR1-related hearing loss.

[0109] The above-mentioned eye diseases include, but are not limited to, cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy defects, age-related macular degeneration (AMD) or diabetic retinopathy.

[0110] Such renal diseases include, but are not limited to, Abderhalden-Kaufmann-Lignac syndrome (Y-type cystic acidosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure / acute kidney injury, acute lobar nephropathy, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenoviral nephritis, Alagille syndrome, Alport syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, angiomyolipoma, analgesic nephropathy, anorexia nervosa nephropathy, vasoconstrictor peptide antibodies and focal segmental glomerulosclerosis, antiphospholipid syndrome, glomerulonephritis associated with anti-TNF-α therapy, APOL1 mutations, apparent mineralocorticoid excess syndrome, aristolochic acid nephropathy, Chinese herbal nephropathy, Balkan endemic nephropathy, and nephropathy. Nephropathy, urinary tract arteriovenous malformations and fistulas, autosomal dominant hypocalcemia, Bardet-Biedl Syndrome, Bartter Syndrome, bath salts-induced acute kidney injury, beer potomania, beeturia, beta-thalassemia nephropathy, bile cast nephropathy, autologous kidney BK polyomavirus nephropathy, bladder rupture, bladder sphincter dyssynergia, bladder tamponade, border-crossers' nephropathy, Bourbon virus Virus-induced acute kidney injury, flaming sugarcane harvesting acute renal dysfunction, Byetta renal failure, Clq nephropathy, C3 glomerulopathy, C3 glomerulopathy with monoclonal gammopathy, C4 glomerulopathy, calcineurin inhibitor nephrotoxicity, atractylodes glycosides (Callilepsis laureola) intoxication, cannabinoid-induced acute renal failure, cardiorenal syndrome, carfilzomib-induced renal injury, CFHR5 nephropathy, Charcot-Marie-Tooth diseaseDisease with glomerulopathy, herbal nephrotoxicity, cherry concentrate acute kidney injury, cholesterol embolism, Churg-Strauss syndrome, chyluria, ciliopathy, cocaine nephropathy, cold diuresis, colistin nephrotoxicity, collagenous fibrillary glomerulopathy, collapsing glomerulopathy, CMV-related collapsing glomerulopathy, combined antiretroviral (cART)-related nephropathy, congenital anomalies of the kidney and urinary tract (CAKUT), congenital nephrotic syndrome, congestive renal failure, cone-shaped Epiphyseal nephrotic syndrome (Mainzer-Saldino syndrome or Saldino-Mainzer disease), contrast-induced nephropathy, copper sulfate poisoning, cortical necrosis, crizotinib-related acute kidney injury, cryoglobulinemia, cryoglobulinemia, crystalloid-induced nephropathy, crystal-induced acute kidney injury, crystal-storing histiocytosis, acquired cystic kidney disease, cystinuria, dasatinib-induced nephrotic-range proteinuria, dense deposit disease (type 2 MPGN), Dent disease Disease (X-linked recessive nephrolithiasis), DHA crystal nephropathy, dialysis imbalance syndrome, diabetes mellitus and diabetic nephropathy, diabetes insipidus, dietary supplement renal failure, diffuse mesangial sclerosis, diuresis, Djenkol bean poisoning (Djenkolism), Down syndrome nephropathy, drug abuse nephropathy, duplicated ureters, East Asian Sterile Syndrome (EAST) syndrome, Ebola nephropathy, ectopic kidney, ectopic ureter, edema, swelling, Erdheim-Chester disease, Fabry's disease, familial hypocalciuric hypercalcemia, Fanconi syndrome, Fraser syndrome, fibronectin glomerulopathy, fibrillary glomerulonephritis and immune tentacle glomerulopathy, Fraley syndrome syndrome), fluid overload, hypervolemia, focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway-Mowat syndrome, giant cell arteritis involving the kidney, pregnancy-induced hypertension, Gitelman syndrome, glomerular disease, glomerular tubular reflux, diabetes mellitus, Goodpasture syndrome, Green Smoothie CleanseNephropathy, HANAC syndrome, Harvoni (ledipasvir and sofosbuvir)-induced kidney injury, hair dye ingestion acute kidney injury, Hantavirus infection podocytopathy, heat stress nephropathy, hematuria (blood in the urine), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), hemophagocytic syndrome, hemorrhagic cystitis, hemorrhagic fever with renal syndrome (HFRS, Hantavirus nephropathy, Korean hemorrhagic fever, epidemic hemorrhagic fever, nephropathis Epidemica), hemosiderosis, hemosiderosis associated with paroxysmal nocturnal hemoglobinuria and hemolytic anemia, hepatic glomerulopathy, hepatic veno-occlusive disease, sinusoidal obstruction syndrome, hepatitis C-associated nephropathy, hepatocyte nuclear factor 1B-associated nephropathy, hepatorenal syndrome, herbal supplement-induced nephropathy, high-altitude renal syndrome, hypertensive nephropathy, HIV-associated immune complex nephropathy (HIVICK), HIV-associated nephropathy (HIVAN), HNF1B-associated autosomal dominant tubulointerstitial nephropathy, horseshoe kidney (renal fusion), Hunner's ulcer Ulcer), hydroxychloroquine-induced nephrolipidosis, hyperaldosteronism, hypercalcemia, hyperclockwise, hypermagnesemia, hypernatremia, hyperoxaluria, hyperphosphatemia, hypocalcemia, hypocomplement urticaria vasculitis syndrome, hypoclockwise, hypoclockwise-induced renal dysfunction, hypoclockwise periodic paralysis, hypomagnesemia, hyponatremia, hypophosphatemia, hypophosphatemia in marijuana users, hypertension, monogenic hypertension, iced tea nephropathy, ifosfamide nephrotoxicity, IgA nephropathy, IgG4 nephropathy, immersion diuresis, immune checkpoint therapy-associated interstitial nephritis, infliximab-associated nephropathy, interstitial cystitis, painful bladder syndrome (questionnaire), interstitial nephritis, megakaryocytic interstitial nephritis, Ivemark's syndrome, JC virus nephropathy, Joubert syndrome Syndrome), ketamine-related bladder dysfunction, kidney stones, nephrolithiasis, kombucha tea toxicity, lead nephropathy and lead-related nephrotoxicity, lecithin cholesterol acyltransferase deficiency (LCAT deficiency), leptospirosis nephropathy, light chain deposition disease, monoclonal immunoglobulin deposition disease, light chain proximal renal tubulopathy, Liddle Syndrome, Lightwood-Albright syndromeSyndrome), lipoprotein glomerulopathy, lithium nephrotoxicity, hereditary FSGS caused by LMX1B mutations, flank pain and hematuria, lupus, systemic lupus erythematosus, lupus nephropathy, lupus nephritis, lupus nephritis with antineutrophil cytoplasmic antibody seropositivity, lupus podocytopathy, Lyme disease-associated glomerulonephritis, lysinuria protein intolerance, lysozyme nephropathy, malarial nephropathy, malignancy-associated nephropathy, malignant hypertension, Malakoplakia, McKit Trick-Wheelock syndrome, MDMA (Molly; Ecstacy; 3,4-methylenedioxymethamphetamine)-induced renal failure, urethral stenosis, medullary cystic kidney disease, uromodulin-related nephropathy, juvenile type 1 hyperuricemic nephropathy, medullary sponge kidney, megaureter, triamcinolone toxic nephropathy, MELAS syndrome, membranous proliferative glomerulonephritis, membranous nephropathy, membranous glomerulopathy with occult IgGk deposits, MesoAmerican nephropathy Nephropathy, metabolic acidosis, metabolic alkalosis, hydrometholone-associated renal failure, microscopic polyangiitis, milk-alkali syndrome, minimal change disease, monoclonal gammopathy of renal significance, dysproteinemia, mouthwash toxicity, MUC1 nephropathy, polycystic dysplastic kidney, multiple myeloma, myeloproliferative neoplastic glomerulopathy, nail-patella syndrome, NARP syndrome, nephrocalcinosis, nephrogenic systemic fibrosis, nephroptosis (floating kidney, renal ptosis), nephrotic syndrome, neurogenic bladder, 9 / 11 and kidney disease, nodular glomerulosclerosis, nongonococcal urethritis, Nutcracker syndrome, nephron oligomegaly, orofacial digital syndrome, orotic aciduria, orthostatic hypotension, orthostatic proteinuria, osmotic diuresis, osmotic nephropathy, ovarian hyperstimulation syndrome, oxalate nephropathy, Paget's kidney Kidney), papillary necrosis, papillorenal syndrome (renal coloboma syndrome, solitary kidney agenesis), PARN mutation nephropathy, parvovirus B19 nephropathy, peritoneal-renal syndrome, posterior urethral valve POEMS syndrome, podocyte infolding glomerulopathy, postinfectious glomerulonephritis, poststreptococcal glomerulonephritis, atypical postinfectious glomerulonephritis, postinfectious glomerulonephritis (IgA dominant), mimicking IgA nephropathy, polyarteritis nodosa, posterior urethral valve polycystic kidney disease, postobstructive diuresis, preeclampsia, propofol infusion syndrome, proliferative glomerulonephritis with monoclonal IgG deposition (Nasr disease)Disease), propolis (bee resin)-related renal failure, proteinuria (protein in the urine), pseudohyperaldosteronism, pseudohypobicarbonateemia, pseudohypoparathyroidism, pulmonary-renal syndrome, pyelonephritis (kidney infection), pyonephrosis, phenazopyridine-induced renal failure, radiation nephropathy, Raynaud's nephropathy, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal agenesis, acute kidney injury associated with renal arcuate vein microthrombosis, renal artery aneurysm, spontaneous renal artery dissection, renal artery stenosis, renal cell carcinoma, renal cyst, renal hypouricemia with exercise-induced acute renal failure, renal infarction, renal osteodystrophy, renal tubular acidosis, renin mutation and autosomal dominant tubulointerstitial nephropathy, renin-secreting tumors (juxtaglomerular cell tumors), osmotic set point reset Osmostat), retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, rhabdomyolysis associated with bariatric surgery, rheumatoid arthritis-related nephropathy, sarcoid nephropathy, salt wasting from the kidneys and brain, schistosomal glomerulopathy, Schimke immunoosseous dysplasia, scleroderma renal crisis, serpentine lung-polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, chronic kidney disease due to silica exposure, Sri Lankan Farmers' Kidney disease Disease), Sjögren's syndrome nephropathy, acute kidney injury due to synthetic cannabinoid use, post-hematopoietic cell transplant nephropathy, nephropathy associated with stem cell transplantation, TAFRO syndrome, tea-and-toast hyponatremia, tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, ranolazine nephropathy associated with monoclonal gammopathy, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal agenesis, acute kidney injury associated with renal arcuate vein microthrombosis, renal artery aneurysm, spontaneous renal artery dissection, renal artery stenosis, renal cell carcinoma, renal cyst, renal hypouricemia with exercise-induced acute renal failure, renal infarction, renal osteodystrophy, renal tubular acidosis, renin mutations and autosomal dominant tubulointerstitial kidney disease, renin-secreting tumors (juxtaglomerular cell tumors), osmotic set point reset Osmostat), retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, rhabdomyolysis associated with bariatric surgery, rheumatoid arthritis-related nephropathy, sarcoid nephropathy, renal and cerebral salt wasting, schistosomal glomerulopathy, Schimke immunoosseous dysplasiadysplasia), scleroderma renal crisis, serpentine lung bone-polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, silica exposure chronic kidney disease, Sri Lankan farmers' kidney disease, Sjögren's syndrome nephropathy, acute kidney injury caused by synthetic cannabinoid use, post-hematopoietic cell transplant nephropathy, stem cell transplant-related nephropathy, TAFRO syndrome, tea-and-toast hyponatremia, tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, thrombotic microangiopathy associated with monoclonal gammopathy, war nephritis, trigoneitis, urogenital tuberculosis, tuberous sclerosis, renal tubular dysgenesis, immune complex tubulointerstitial nephritis due to autoantibodies to the brush border of the proximal tubules, tumor lysis syndrome, uremia, ureteritis cystica, ureterocereum, urethral caruncle, urethral stricture, urinary incontinence, urinary tract infection, urinary tract obstruction, urogenital incontinence, uromodulin-associated nephropathy, vancomycin-associated cast nephropathy, vasomotor nephropathy, bladder fistula, vesicoureteral reflux, renal thrombotic microangiopathy associated with VGEF inhibition, volatile anesthetic acute kidney injury, Von Heber-Lindau disease Hippel-Lindau Disease, Waldenstrom's Macroglobulinemic Glomerulonephritis, warfarin-related nephropathy, wasp sting acute kidney injury, Wegener's Granulomatosis, Granulomatosis with Polyangiitis, West Nile Virus chronic kidney disease, Wunderlich syndrome, Zellweger syndrome, or cerebrohepatorenal syndrome.

[0111] The above-mentioned skin diseases include, but are not limited to: acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic ... disease), herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloid, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, dermatosis melanogaster, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar warts (warts), polymorphic light eruption, psoriasis, plaque psoriasis, pyoderma gangrenosum, rosacea, scabies, scleroderma, herpes zoster, squamous cell carcinoma, Sweet's syndrome, urticaria, angioedema, and vitiligo.

[0112] Such fibrotic diseases include, but are not limited to, adhesive capsulitis, arteriosclerosis, arthrofibrosis, atrial fibrosis, cardiac fibrosis, cirrhosis, congenital hepatic fibrosis, Crohn's disease, cystic fibrosis, Dupuytren's contracture, endomyocardial fibrosis, glial scars, hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloids, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, nonalcoholic fatty liver disease, old myocardial infarction, Peyronie's disease, pneumoconiosis, pneumonia, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis, and ventricular remodeling.

[0113] The above-mentioned hemoglobin disorders include, but are not limited to, "dominant" β-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS / β-thalassemia, HbE / β-thalassemia, HbSC disease, homozygous α+-thalassemia (phenotype of α0-thalassemia), hydrops fetalis with Hb Bart's), sickle cell anemia / disease, sickle cell trait, sickle beta-thalassemia disease, alpha+-thalassemia, alpha-thalassemia, alpha-thalassemia associated with myelodysplasia syndrome, alpha-thalassemia with mental retardation (ATR), beta-thalassemia, beta+-thalassemia, delta-thalassemia, gamma-thalassemia, beta-thalassemia major, beta-thalassemia intermedia, delta-thalassemia, and epsilonγdeltaβ-thalassemia.

[0114] The above-mentioned autoimmune diseases include, but are not limited to, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune scrotal inflammation, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baló disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease, and disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Chagas-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), epileptic pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackiemyocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome syndrome), fibromyalgia, fibrosing alveolitis, giant cell arteritis (arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndromesyndrome), leukocytoclastic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease (PR), PANDAS, paraplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry's syndrome Romberg syndrome), pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome syndrome), scleritis, scleroderma, Sjögren's syndrome, semen and testicular autoimmunity, stiff-man syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, head arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

[0115] Such viral infections include, but are not limited to, influenza, human immunodeficiency virus (HIV), and herpes.

[0116] The aforementioned malarial infections include, but are not limited to, infections caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium falciparum.

[0117] The above-mentioned diseases with mutations that lead to the induction of the unfolded protein response (UPR) include, but are not limited to: Marinesco-Sjogren syndrome, neuropathic pain, diabetic neuropathic pain, noise-induced hearing loss, non-syndromic sensorineural hearing loss, age-related hearing loss, Wolfram syndrome, Darier-White disease, Usher syndrome, collagenosis, thin-base nephropathy, Alport syndrome, skeletal chondrodysplasia, metaphyseal chondrodysplasia type Schmid and pseudochondrodysplasia.

[0118] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0119] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, the meanings that can be given to them by those skilled in the art should be given based on the disclosure and context.

[0120] "Substitution" means that the hydrogen atoms in a molecule are replaced by other different atoms or groups; or the lone pair of electrons in the atoms in the molecule are replaced by other atoms or groups. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form

[0121] “May be”, “optionally substituted by…” means that “substitution” may but does not have to occur, and the description includes situations where it occurs or does not occur.

[0122] The minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix. For example, the prefix C1-C6 alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1-C6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.

[0123] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. For example, C1-C6 alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

[0124] The term "C1-C6 alkyl" refers to any straight chain or branched chain group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, etc.

[0125] Furthermore, the "C1-C6 alkyl" includes straight-chain or branched groups whose carbon number is between 1 and 6 and whose endpoints are any two integers. For example, "C1-C6 alkyl" includes C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C2-C6 alkyl, C2-C5 alkyl, C2-C4 alkyl, C1-C3 alkyl, and the like. The above list is for example only and does not limit the above range.

[0126] The term "alkoxy" and its derivatives refer to any of the above alkyl groups (eg, C1-C6 alkyl, C1-C3 alkyl, etc.) that is attached to the rest of the molecule through an oxygen atom (-O-).

[0127] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having a specified number of member atoms. C-C alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0128] The C1-C6 alkylene group of the present invention may be a C1 alkylene group (eg, -CH2-), a C2 alkylene group (eg, -CH2CH2-, etc.), a C3 alkylene group, a C4 alkylene group, a C5 alkylene group, or a C6 alkylene group.

[0129] The "cycloalkylene" described in the present invention refers to a divalent saturated cyclic alkane having a single ring or multiple rings (fused ring, spiro ring, bridged ring) with multiple carbon atoms and no ring heteroatoms. Examples of monocarbocyclic groups include, for example, divalent cyclopropyl, divalent cyclobutyl, divalent cyclohexyl, divalent cyclopentyl, divalent cyclooctyl, divalent cyclopentenyl, and divalent cyclohexenyl. Examples of bridged cycloalkane systems include bicyclo[3,1,0]hexane, bicyclo[3,1,1]hexane, bicyclo[2,2,1]hexane, bicyclo[2,2,2]hexane, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[1.1.2]pentanyl.

[0130] The "cycloalkylene" mentioned in the present invention includes but is not limited to wait.

[0131] The term "C3-C10 cycloalkyl" refers to a 3- to 10-membered, all-carbon monocyclic, fused, and bridged ring that may contain zero, one, or more double bonds but does not have a completely conjugated π-electron system. Examples of C3-C10 cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, and the like.

[0132] The "heterocycloalkyl" mentioned in the present invention refers to a monovalent or divalent saturated ring (a divalent saturated ring of a heterocycloalkyl is a heterocycloalkylene) having a single ring or multiple rings (condensed ring, spiro ring, bridged ring) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Examples of 3-10 membered heterocyclic groups can be oxetane, azetidinyl, oxolane, oxahenyl, piperazinyl, piperidinyl, morpholinyl, trioxanyl, etc. The embodiments of the "heterocycloalkyl" mentioned in the present invention include but are not limited to Or piperidinyl, etc.

[0133] The unsaturated group mentioned in the present invention refers to a group or molecule containing a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond, etc.

[0134] The term "aryl" as used herein refers to an aromatic hydrocarbon group having multiple carbon atoms, and arylene refers to a divalent aromatic group. Aryl groups are typically monocyclic, bicyclic, or tricyclic aromatic groups having multiple carbon atoms. In addition, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, tetrahydronaphthyl,

[0135] The term "5-10 membered heteroaryl" as used herein refers to an aromatic unsaturated ring containing at least one heteroatom. A heteroarylene group refers to a divalent heteroaryl group; wherein the heteroatom is a nitrogen atom, an oxygen atom, a sulfur atom, or the like. It is typically an aromatic monocyclic or bicyclic hydrocarbon ring containing multiple ring atoms, one or more of which is selected from O, N, and S. Preferably, there are one to three heteroatoms. Among them, for example, 5-6 membered heteroaryl represents, for example, pyridyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyranyl, thiopyranyl, piperazinyl, triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, 1,2,3,4-tetrazolyl, 1,2,3,5-tetrazolyl, isoxazolyl, oxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-oxatriazolyl, 1,3,2-dioxazolyl, 1,2,3-Dioxadiazolyl, 1,2,3,4-Dioxadiazolyl, 1,2,3,5-Dioxadiazolyl, 1,3,3,4-Dioxadiazolyl, 1,3,4,5-Dioxadiazolyl, 1,2,3,4-Dioxadiazolyl, isothiazolyl, pyridazinyl, triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, 1,2,4-oxazinyl, 1,2,6-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl, 1,4,2-oxazinyl, 1,2-isoxazinyl, 1,4-isoxazinyl.

[0136] The "halogen" mentioned in the present invention refers to fluorine, chlorine, bromine or iodine.

[0137] The "halogen-substituted alkyl" mentioned in the present invention refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen; for example, a halogen-substituted C1-C6 alkyl group refers to an alkyl group containing 1 to 6 carbon atoms in which hydrogen atoms are replaced by one or more halogen atoms; examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0138] The “=O” mentioned in the present invention means that an oxygen atom replaces two hydrogen atoms in a molecule through a double bond.

[0139] In the present invention, it is obvious to those skilled in the art that any group whose name is a composite name, such as "6-10 membered aryl-D-C1-C6 alkyl", should refer to a group conventionally constructed from its derived part such as C1-C6 alkyl from left to right, and it should be understood that the alkyl group here is a divalent alkyl group.

[0140] In the present invention, "stereoisomers" refer to compounds with the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formula described in the present invention fall within the scope of the present invention. The term "enantiomer" used in the present invention refers to stereoisomers that are real objects and mirror images of each other and cannot be superimposed. "Diastereomers" refer to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules, wherein For example, it represents the chiral center of the compound.

[0141] The term "geometric isomers" used in the present invention includes: cis-trans isomers, isomeric polymers and syndiotactic polymers, rotational isomers caused by steric barriers, etc. For example, it represents a cis configuration, that is, the two substituents on the cyclobutyl ring are located on the same side.

[0142] Stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0143] As used herein, "tautomers" generally refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons.

[0144] As used herein, "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) that exhibits a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors may lead to one polymorph dominating.

[0145] In the present invention, "solvate" refers to a mixture formed by dissolving a compound in a solvent.

[0146] In the present invention, "N-oxides" are also called amine oxides, which are organic compounds with the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0147] In the present invention, "isotope-labeled compound" refers to a molecule or group in which one or more atoms are replaced by their isotope atoms, such as hydrogen atoms replaced by deuterium atoms, where the proportion of deuterium atoms is greater than the abundance of deuterium in nature; for example, 12C is replaced by 13C.

[0148] In the present invention, "metabolites" refer to substances generated by chemical structural transformation of drug molecules under the action of the body after the drug molecules are absorbed by the body.

[0149] In the present invention, "prodrug" refers to a compound that is obtained by chemically modifying a drug and is inactive or less active in vitro, but releases an active drug through enzymatic or non-enzymatic conversion in vivo to exert its pharmacological effect.

[0150] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0151] The terms "salts" and "pharmaceutically acceptable salts" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a suitable amount of acid or base (e.g., an equivalent amount). These salts may be precipitated in solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0152] The term "prevention" includes suppressing and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0153] The terms "treat," "treat," "treat," and "treating" mean to reverse, alleviate, or eliminate the progression of the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition.

[0154] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0155] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0156] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0157] The following embodiments of the present invention are further described in detail with reference to the following examples. The detailed description of the following examples is used to illustrate the principles of the present invention, but is not intended to limit the scope of the present invention, that is, the present invention is not limited to the described examples.

[0158] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Bidex Pharmaceuticals, Anage Chemical, Exploration Platform, Nanjing Yaoshi, Jiangsu Aikon, and Beijing Inokai Technology.

[0159] Unless otherwise specified in the Examples, reactions were carried out under a nitrogen atmosphere. Unless otherwise specified in the Examples, the reaction temperature was room temperature. Room temperature is a conventional indoor temperature in the art, typically 20°C to 30°C. Unless otherwise specified in the Examples, M is moles per liter.

[0160] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6The units of concentration are given in ppm. NMR measurements were performed using a Bruker AvanceIII 400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4) as the solvents, and tetramethylsilane (TMS) as the internal standard. LC-MS measurements were performed using a Shimadzu LC-MS 2020 (ESI) liquid chromatography-mass spectrometer. HPLC measurements were performed using a Shimadzu LC-20A high-pressure liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography (TLC) silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a size of 0.4 mm to 0.5 mm for TLC separation and purification. Column chromatography typically used Yantai Huanghai 200-300 mesh silica gel as the support.

[0161] N,N'-dimethylformamide (also known as dimethylformamide) is abbreviated as DMF; N,N'-diisopropylethylamine is abbreviated as DIEA or DIPEA; 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is abbreviated as HATU; trifluoroacetic acid is abbreviated as TFA.

[0162] The following examples and comparative examples will further illustrate the beneficial effects of the present application, but the scope of the present invention is not limited to these examples.

[0163] Example 1: Synthesis of Compound 1

[0164] Step 1: Preparation of intermediate 1c

[0165] At room temperature, 1a (500 mg, 2.44 mmol) and dichloromethane (10 mL) were added to a single-necked flask. 1b (576 mg, 2.68 mmol), N,N'-diisopropylethylamine (632 mg, 4.89 mmol), and 1-propylphosphonic anhydride (3.11 g, 4.88 mmol) were added with stirring, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 1c (795 mg). LC-MS: m / z: 401.1 (M+H). + .

[0166] Step 2: Preparation of intermediate 1d

[0167] At room temperature, 1c (795 mg, 1.98 mmol) and dichloromethane (10 mL) were added to a single-necked flask. Trifluoroacetic acid (3 mL) was added with stirring and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate 1d (732 mg), which was used directly in the next step without purification. LC-MS: m / z: 300.1 (M+H) + .

[0168] Step 3: Preparation of Intermediate 1g

[0169] At room temperature, 1f (50 mg, 0.32 mmol) and tetrahydrofuran (3 mL) were added to a single-necked flask. Sodium hydroxide (19 mg, 0.48 mmol) (60% in oil) was added under ice-bath conditions. After stirring under ice-bath conditions for half an hour, 1e (76 mg, 0.32 mmol) was added to the reaction solution and stirred at room temperature for one hour. 10 mL of aqueous ammonium chloride was added to the reaction solution to quench the reaction, and the mixture was extracted three times with 15 mL of dichloromethane. The combined organic layers were washed with 30 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 1g (33 mg). LC-MS: m / z: 312.9 (M+H) + .

[0170] Step 4: Preparation of compound 1

[0171] At room temperature, 1g (33 mg, 0.11 mmol), 1d (59 mg, 0.13 mmol) and 1,4-dioxane (2 mL) were added to a single-necked bottle. Under stirring, sodium tert-butoxide (30.5 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (19.4 mg, 0.02 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (24.5 mg, 0.04 mmol) were added in sequence. After nitrogen replacement three times, the reaction was carried out at 100 degrees Celsius for 18 hours. After filtration, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 1 (3 mg). LC-MS: m / z: 533.2 (M+H) + . 1H NMR(DMSO-d6)δ:8.00(d,J=8.0Hz,1H),7.44-7.58(m,2H),7.16(d,J=3.1Hz,1H),7.07(d d,J=11.4,2.8Hz,1H),6.85(dd,J=9.0,1.9Hz,1H),6.29(d,J=8.0Hz,1H),4.85(t,J=6.9H z,1H),4.66(t,J=7.0Hz,1H),4.51(s,2H),3.72-3.87(m,1H),3.56-3.70(m,1H),2.98(m, 2H), 2.34-2.48 (m, 2H), 1.93 (d, J = 9.9Hz, 2H), 1.81 (d, J = 10.4Hz, 2H), 1.29-1.51 (m, 4H).

[0172] Example 2: Synthesis of Compound 2

[0173] Step 1: Preparation of intermediate 2b

[0174] At 0 degrees Celsius, 2a (33 mg, 0.19 mmol), 1f (30 mg, 0.19 mmol) and tetrahydrofuran (5 mL) were added to a single-necked flask. Triphenylphosphine (60 mg, 0.23 mmol) and diisopropyl azodicarboxylate (0.04 mL, 0.21 mmol) were added under stirring and stirred at room temperature for 5 hours. The reaction solution was diluted with 10 ml of water and then extracted three times with 15 ml of ethyl acetate each time. The combined organic layer was washed with 20 ml of saturated brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 2:1) to obtain intermediate 2b (33 mg). LC-MS: m / z: 311.9 (M+H) + .

[0175] Step 2: Preparation of compound 2

[0176] At room temperature, 2b (33 mg, 0.11 mmol), 1d (60 mg, 0.13 mmol) and 1,4-dioxane (2 mL) were added to a single-necked flask. Sodium tert-butoxide (31 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (26 mg, 0.04 mmol) were added sequentially under stirring. After nitrogen substitution three times, the reaction was continued at 100 degrees Celsius for 18 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 2 (9 mg). LC-MS: m / z: 532.2 (M+H)+ . 1 H NMR(DMSO-d6)δ:8.00(d,J=7.9Hz,1H),7.57(d,J=4.5Hz,1H),7.50(t,J=8.9Hz,1H),7.07(dd,J =11.4,2.7Hz,1H),6.85(dd,J=8.8,1.9Hz,1H),6.76(d,J=7.8Hz,1H),6.41(dd,J=7.6,5.2Hz,1 H),5.58(d,J=8.0Hz,1H),5.09(s,1H),4.85-4.93(m,1H),4.51(s,2H),3.81(s,1H),3.57-3.72 (m,1H),2.66-2.75(m,2H),2.55-2.66(m,2H),1.96(s,2H),1.79(s,2H),1.37(t,J=9.6Hz,4H).

[0177] Example 3: Synthesis of Compound 3

[0178] Step 1: Preparation of intermediate 3b

[0179] To a single-necked flask at room temperature, 1f (135 mg, 0.86 mmol), toluene (2 mL), and water (0.6 mL) were added. 3a (219 mg, 1.30 mmol), tetrabutylammonium hydrogensulfate (15 mg, 0.04 mmol), and sodium hydroxide (520 mg, 12.98 mmol) were added sequentially with stirring. The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (10 mL) and extracted three times with 5 mL of ethyl acetate each time. The combined organic phases were washed with 5 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 4:1) to afford 3b (219 mg). 1 H NMR (DMSO-d6) δ: 4.47 (t, J = 7.1 Hz, 1H), 3.92 (s, 2H), 3.73 (t, J = 6.9 Hz, 1H), 2.69-2.80 (m, 2H), 2.09 (m, 2H), 1.42 (s, 9H).

[0180] Step 2: Preparation of intermediate 3c

[0181] To a single-necked flask at 0°C, 3b (219 mg, 0.81 mmol) and dichloromethane (2 mL) were added, followed by trifluoroacetic acid (2 mL) with stirring. The mixture was allowed to react at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to afford crude product 3c (145 mg), which was used directly in the next step without purification.

[0182] Step 3: Preparation of intermediate 3e

[0183] At room temperature, 3c (145 mg, 0.67 mmol) and dichloromethane (3 mL) were added to a single-necked flask. 3d (175.92 mg, 0.89 mmol), N,N'-diisopropylethylamine (0.59 mL, 3.55 mmol), and 1-propylphosphonic anhydride (1.13 g, 1.77 mmol) were added with stirring. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain 3e (290 mg). LC-MS: m / z: 339.1 (M+H-56). + .

[0184] Step 4: Preparation of intermediate 3f

[0185] At 0°C, 3e (290 mg, 0.74 mmol) and dichloromethane (3 mL) were added to a single-necked flask. 4 M dioxane hydrochloride (3 mL) was added with stirring, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 3f (217 mg). The crude product was used directly in the next step without purification. LC-MS: m / z: 295.1 (M+H) + .

[0186] Step 5: Preparation of compound 3

[0187] At room temperature, 3f (217 mg, 0.74 mmol), 1g (133 mg, 0.42 mmol) and 1,4-dioxane (3 mL) were added to a single-necked bottle. Sodium tert-butoxide (123 mg, 1.47 mmol), tris(dibenzylideneacetone)dipalladium (78 mg, 0.08 mmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (106 mg, 0.17 mmol) were added sequentially under stirring. After nitrogen replacement three times, the reaction was carried out at 100 degrees Celsius for 18 hours. After filtration, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 3 (19.02 mg). LC-MS: m / z: 527.2 (M+H) + . 1H NMR(DMSO-d6)δ:8.43(s,1H),7.64(d,J=3.1Hz,1H),7.30(d,J=3.1Hz,1H),4.92(t,J=6.9Hz,1H),4.73(s,1H),4.55(t,J=7.1Hz,1H) ,3.80(s,2H),3.73-3.79(m,1H),3.04(m,2H),2.77-2.85(m,2H),2.41-2.48(m,2H),2.37-2.41(m,6H),2.22(dd,J=9.6,2.5Hz,2H).

[0188] Example 4: Synthesis of Compound 4

[0189] Step 1: Preparation of intermediate 4b

[0190] At room temperature, 4a (4.0 g, 15.54 mmol) and anhydrous ethanol (50.0 mL) were added to a single-necked flask, and hydrazine hydrate (9.1 g, 155.54 mmol) was added sequentially under stirring. The reaction temperature was raised to 80 degrees Celsius and stirred for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by acetonitrile beating to obtain intermediate 4b (3.8 g). LC-MS: m / z: 202.1 (M+H-56) + .

[0191] Step 2: Preparation of intermediate 4c

[0192] At room temperature, 4b (3.8 g, 13.29 mmol) and 1,2-dichloroethane (30.0 mL) were added to a single-necked flask. N,N'-carbonyldiimidazole (5.0 g, 26.58 mmol) was added under stirring, and the mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 4c (2.9 g). LC-MS: m / z: 228.0 (M+H-56). + .

[0193] Step 3: Preparation of intermediate 4e

[0194] At room temperature, 4c (2.9 g, 9.26 mmol) and dimethylformamide (30 mL) were added to a single-necked flask. Compound 4d (1.73 g, 12.28 mmol), N,N'-diisopropylethylamine (6.65 g, 51.18 mmol) and Carter condensation agent (6.45 g, 15.53 mmol) were added in sequence under stirring, and the mixture was reacted at room temperature for 16 hours. 300 mL of water was added to the reaction solution, and the mixture was extracted once with 300 mL of ethyl acetate. The organic phase was washed with 300 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid intermediate 4e (1.82 g). LC-MS: m / z: 407.2 (M+H) + .

[0195] Step 4: Preparation of intermediate 4f

[0196] At room temperature, 4e (140 mg, 0.34 mmol) and dichloromethane (6.0 mL) were added to a single-necked flask. Trifluoroacetic acid (2.0 mL, 4.5 mmol) was added under stirring and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate 4f (98 mg). The crude product was used directly in the next step without purification. LC-MS: m / z: 307.2 (M+H) + .

[0197] Step 5: Preparation of compound 4

[0198] To a single-necked flask at room temperature were added compound 1g (30.66 mg, 0.10 mmol), 4f (25 mg, 0.08 mmol), tris(dibenzylideneindeneacetone)dipalladium (7.47 mg, 0.01 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (10.17 mg, 0.02 mmol), sodium tert-butoxide (23.53 mg, 0.24 mmol), and anhydrous toluene (2 mL). The reaction mixture was sparged with nitrogen for 5 minutes while stirring, then incubated at 100°C under a nitrogen balloon for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water) to afford compound 4 (2.11 mg). 1H NMR(400MHz,MeOD)δ7.46(d,J=3.2Hz,1H),7.18(d,J=3.2Hz,1H),5.28(s,1H),4. 93–4.88(m,1H),4.64–4.55(m,1H),4.55–4.47(m,2H),4.27(dd,J=9.4,4.0Hz,2H) ,3.87(s,1H),3.10–2.97(m,2H),2.83(s,1H),2.44(d,J=6.7Hz,2H),2.16(d,J=11 .1Hz,4H),1.70(d,J=11.1Hz,2H),1.49(d,J=11.0Hz,2H), LC-MS:m / z:539.2(M+H) + .

[0199] Example 5: Synthesis of Compound 5

[0200] Step 1: Preparation of intermediate 5a

[0201] At room temperature, 3c (100 mg, 0.42 mmol), 1b (100.08 mg, 0.47 mmol), and dimethylformamide (2 mL) were added to a single-necked flask. 2-(7-Azophenyltriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (266.35 mg, 0.70 mmol) and N,N'-diisopropylethylamine (0.23 mL, 1.40 mmol) were added with stirring and allowed to react at room temperature for 16 hours. The reaction solution was poured into 30 mL of water and extracted twice with 30 mL of ethyl acetate each time. The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1 to 10:1) to obtain intermediate 5a (100 mg). LC-MS: m / z: 355.0 (M+H-56). + .

[0202] Step 2: Preparation of intermediate 5b

[0203] Compound 5a (50 mg, 0.12 mmol) and dichloromethane (10 mL) were added to a single-necked flask at room temperature. Trifluoroacetic acid (0.05 mL, 0.73 mmol) was added under stirring in an ice bath. The reaction was allowed to react for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure to obtain crude intermediate 5b (17 mg). The crude product was used directly in the next step without purification. LC-MS: m / z: 311.0 (M+H) + .

[0204] Step 3: Preparation of compound 5

[0205] At room temperature, 5b (17 mg, 0.05 mmol), 1g (17.15 mg, 0.05 mmol), and 1,4-dioxane (5 mL) were added to a single-necked flask. Tris(dibenzylideneacetone)dipalladium (5.02 mg, 0.01 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (6.82 mg, 0.01 mmol), and sodium tert-butoxide (7.90 mg, 0.08 mmol) were added sequentially with stirring. The reaction was allowed to proceed at 100°C under nitrogen for 18 hours. The reaction solution was poured into 20 mL of water and extracted twice with 30 mL of ethyl acetate each time. The organic phase was washed with 10 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to obtain compound 5 (2.34 mg). 1 H NMR (400MHz, CDCl3) δ7.56(d,J=3.6Hz,1H),7.32(s,1H),6.36(s,1H),4.98–4.88(m,1H),4.47(t,J=7.0Hz,1H),4.35–4.23(m,1H),3.83 (s,3H),3.71(t,J=6.9Hz,1H),3.08(d,J=7.1Hz,2H),2.82(m,2H),2.50(s,2H),2.26(m,4H),2.08(d,J=12.6Hz,2H),1.51–1.17(m,6H). LC-MS:m / z:543.2(M+H) + Example 6: Synthesis of Compound 6

[0206] Step 1: Preparation of intermediate 6b

[0207] To a single-necked flask at room temperature, 6a (4.0 g, 30.74 mmol) and ethyl acetate (120.0 mL) were added. Silver trifluoromethanesulfonate (23.69 g, 92.21 mmol), potassium fluoride (7.14 g, 122.94 mmol), N-fluoro-N'-(fluoromethyl)triethylenediamine bistetrafluoroborate (16.33 g, 46.10 mmol), 2-fluoropyridine (7.99 mL, 92.21 mmol), and (trifluoromethyl)trimethylsilane (13.80 mL, 92.21 mmol) were added with stirring. The reaction was allowed to proceed under nitrogen protection at room temperature for 48 hours in the dark. The reaction mixture was filtered, and the filter cake was washed with 100 mL of ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 6b (760 mg).

[0208] Step 2: Preparation of intermediate 6c

[0209] At room temperature, 6b (760 mg, 3.84 mmol), tetrahydrofuran (10.0 mL), methanol (5 mL), and water (5.0 mL) were added to a single-necked flask. Lithium hydroxide (276 mg, 11.51 mmol) was added with stirring and allowed to react at room temperature for 3 hours. The reaction solution was adjusted to pH 3 with 1N hydrochloric acid and extracted with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 6c (700 mg). LC-MS: m / z: 183.0 (MH) - .

[0210] Step 3: Preparation of intermediate 6d

[0211] To a single-necked flask at room temperature, 6c (650 mg, 3.53 mmol) and N,N-dimethylformamide (10.0 mL) were added. N,N'-diisopropylethylamine (3.51 mL, 21.18 mmol), N,O-dimethylhydroxylamine hydrochloride (431 mg, 7.06 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.01 g, 5.30 mmol) were added with stirring. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was poured into 50 mL of water and extracted once with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 6d (640 mg). LC-MS: m / z: 228.2 (M+H). + , 1 H NMR (400MHz, DMSO-d6) δ4.85-4.75(m,1H),3.64(s,3H),3.20-3.00(m,4H),2.59-2.51(m,2H),2.35-2.23(m,2H).

[0212] Step 4: Preparation of intermediate 6e

[0213] To a 50 mL single-necked flask at room temperature, 1e (848 mg, 3.56 mmol) and tetrahydrofuran (6.0 mL) were added dropwise at -60°C. Butyl lithium (1.43 mL, 3.57 mmol) was added dropwise at -60°C and stirred for 0.5 h. 6d (540 mg, 2.38 mmol) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the reaction mixture. The mixture was allowed to react at -60°C for 1.5 h. The reaction mixture was poured into ice water (50 mL) and extracted once with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 6e (480 mg). LC-MS: m / z: 325.1 / 327.1 (M+H). + , 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=2.4Hz,1H),8.69(d,J=2.4Hz,1H),5.00-4.87(m,1H),3.90-3.78(m,1H),2.72-2.61(m,2H),2.46-2.34(m,2H).

[0214] Step 5: Preparation of intermediate 6f

[0215] 6e (300 mg, 0.92 mmol) and methanol (3.0 mL) were added to a single-necked flask under ice-cooling. Sodium borohydride (52 mg, 1.38 mmol) was added with stirring and the mixture was allowed to react in an ice-cooling bath for 2 hours. The reaction solution was poured into 30 mL of water and extracted once with 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 6f (240 mg). LC-MS: m / z: 327.1 / 329.1 (M+H) + .

[0216] Step 6: Preparation of Intermediate 6g

[0217] At room temperature, 6f (130 mg, 0.40 mmol) and tetrahydrofuran (2.0 mL) were added to a single-necked flask. Imidazole (81 mg, 1.19 mmol), triphenylphosphine (156 mg, 0.60 mmol), and iodine (151 mg, 0.60 mmol) were added sequentially under stirring. The reaction was allowed to proceed at 65°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 6g (60 mg). LC-MS: m / z: 311.0 / 313.0 (M+H) + .

[0218] Step 7: Preparation of compound 6

[0219] At room temperature, 6g (50mg, 0.16mmol) and dioxane (2.0mL) were added to a single-necked flask, and cesium carbonate (157mg, 0.48mmol), 3f (47mg, 0.16mmol), tris(dibenzylideneacetone)dipalladium (15mg, 0.02mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20mg, 0.03mmol) were added in sequence under stirring. The reaction was carried out at 100 degrees Celsius for 18 hours. The reaction solution was filtered, the filter cake was washed with 10mL of ethyl acetate, the filtrate was concentrated under reduced pressure, and the crude product was prepared by high performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 6 (12mg). LC-MS: m / z: 525.2 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ8.35(s,1H),7.87(d,J=2.7Hz,1H),7.66(d,J=2.8Hz,1H),7.06(s,1H),4.74-4.64(m,1H),4.54-4.44(m,1 H),3.74(s,2H),3.73-3.66(m,1H),2.80-2.69(m,4H),2.47-2.43(m,1H),2.40-2.23(m,8H),2.20-2.10(m,2H),1.95-1.83(m,2H).

[0220] Example 7: Synthesis of Compound 7

[0221] Step 1: Preparation of intermediate 7b

[0222] At room temperature, 7a (300.0 mg, 1.48 mmol) and N,N-dimethylformamide (3.0 mL) were added to a single-necked flask. N,N'-diisopropylethylamine (380.02 mg, 2.96 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (842.9 mg, 2.22 mmol), and 3d (313.0 mg, 2.22 mmol) were added sequentially with stirring. The mixture was allowed to react at room temperature for 18 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted once with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 7b (130 mg). LC-MS: m / z: 326.0 (M+H). + .

[0223] Step 2: Preparation of compound 7

[0224] At room temperature, intermediate 7b (100 mg, 0.31 mmol) and 1,4-dioxane (0.50 mL) were added to a single-necked flask. 3f (90.25 mg, 0.31 mmol), cesium carbonate (299.77 mg, 0.92 mmol), tris(dibenzylideneacetone)dipalladium (34 mg, 0.04 mmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (46 mg, 0.07 mmol) were added sequentially under stirring. After nitrogen substitution three times, the reaction was continued at 100 degrees Celsius for 18 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 7 (26 mg). 1 HNMR(400MHz,DMSO-d6)δ8.91(s,1H),8.45(s,1H),8.27(d,J=2.3Hz,1H),7.88( d,J=2.3Hz,1H),5.21(dd,J=6.5,3.1Hz,1H),4.92(dd,J=11.3,6.6Hz,1H),4.65– 4.57(m,1H),4.54–4.40(m,2H),4.11(d,J=9.4Hz,1H),3.75(s,2H),3.73–3.66(m ,1H),2.81–2.68(m,2H),2.35(s,6H),2.19–2.12(m,2H), LC-MS:m / z:540.2(M+H) + .

[0225] Example 8: Synthesis of Compound 8

[0226] At room temperature, 6e (120 mg, 0.37 mmol) and dioxane (2.0 mL) were added to a single-necked flask, and cesium carbonate (361 mg, 1.11 mmol), 3f (109 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (34 mg, 0.04 mmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (46 mg, 0.07 mmol) were added sequentially under stirring. After nitrogen replacement three times, the reaction was carried out at 100 degrees Celsius for 18 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was prepared by high performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 6 (12 mg). LC-MS: m / z: 539.3 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.44(s,1H),8.42(d,J=2.1Hz,1H),7.99(d,J=2.2Hz,1H),4.98-4.86(m,1H),4.55-4.43(m,1H),4.1 1-3.99(m,1H),3.75(s,2H),3.73-3.67(m,1H),2.79-2.70(m,2H),2.64-2.56(m,2H),2.39(s,6H),2.37-2.32(m,2H),2.21-2.10(m,2H).

[0227] Biological testing

[0228] 1. Cell activity test

[0229] The ATF4 luciferase reporter plasmid consists of two parts, the 5' untranslated region sequence of the ATF4 gene and the luciferase coding sequence. Specifically, the 5' untranslated region sequence of ATF4 containing two upstream open reading frames (uORFs) (NCBI database number BC022088.2) and the firefly luciferase coding gene were cloned into the pLVX-Puro vector (Ubao Bio, VT1465). The packaging plasmids of the lentivirus are psPAX2 (Ubao Bio, VT1444) and pMD2.G (Ubao Bio, VT1443). The above three plasmids were transfected simultaneously in HEK293T / 17 cells using X-tremeGENE 9 DNA transfection reagent, and the culture medium containing the lentivirus was collected after 48 hours. The virus-transduced HEK293T / 17 cells were screened with 1μg / mL of puromycin, and then monoclonal cells were obtained by limiting dilution.

[0230] Using this cell line, the translational regulation of ATF4 can be detected and the activity of eIF2B activators can be tested by cold fluorescence readings. The specific experimental process is as follows: 6000 HEK293T / 17-ATF4uORF-Luc-Puro monoclonal cells are plated in a 384-well plate and allowed to adhere overnight. The test compound is dissolved in DMSO and added to the cell culture medium together with 50nM thapsigargin and incubated for 6 hours. Among them, the role of thapsigargin is to cause cell stress and upregulate the protein translation of ATF4. After 6 hours of drug addition, the cells are lysed using the One-Glo Luciferase Assay Kit (Promega #E6120), and the cold fluorescence value is then read using the LUM program of the EnVision 2104 plate reader.

[0231] The relative expression of the ATF4 reporter gene (ATF4 reporter expression %) was calculated as follows:

[0232] ·ATF4 reporter expression%=(ave_sample-ave_vc) / (ave_pc-ave_vc)*100%.

[0233] ave_vc: average signal value of negative control

[0234] ave_pc: average signal value of positive control

[0235] ave_sample: average signal value of the sample

[0236] Fitting dose-effect curves and calculating EC 50 value:

[0237] The nonlinear regression log (inhibitor) vs. response--variable slope (four parameters) method of GraphPad 9 software was used to fit the correspondence between the relative expression level of the ATF4 reporter gene and the compound concentration.

[0238] X-axis: log value of compound concentration; Y-axis: relative expression level of ATF4 reporter gene.

[0239] ·Formula: Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0240] In Table 1, “+” indicates an EC > 100 nM 50 , “++” indicates EC values ​​between 10 nM and 100 nM 50 "+++" indicates an EC range of 1 nM to 10 nM. 50 “++++” indicates an EC less than 1 nM 50 .

[0241] Table 1 Structures of the compounds and their activities in HEK293T / 17-ATF4 uORF-Luc-Puro monoclonal cells.

[0242] 2. Pharmacokinetic evaluation in mice

[0243] Dissolve the test compound in the vehicle to create a clear solution or homogenous suspension. Three mice per group were administered 1 mg / kg via the tail vein or 30 mg / kg orally (PO). Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. Plasma samples were centrifuged, and the supernatant was collected for quantitative analysis by LC / MS / MS.

[0244] Table 2 PK properties of compound 3 in mice

[0245] The experimental results show that some of the compounds of the present invention have excellent pharmacokinetic properties in mice (including but not limited to CL (clearance rate), AUC, t1 / 2 (half-life), C max (peak concentration), AUC (area under the drug-time curve), F (bioavailability), etc.).

[0246] It should be noted that the present application is not limited to the above-mentioned embodiments. The above-mentioned embodiments are merely examples, and any embodiments having substantially the same structure and effect as the technical concept within the scope of the present application are all included in the technical scope of the present application. In addition, without departing from the scope of the present application, any other embodiments that can be conceived by those skilled in the art and that combine some of the constituent elements in the embodiments are also included in the scope of the present application.

Claims

1. A compound represented by formula (0), or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof: In formula 0, R 1 Selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkylhydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy; L 1 Selected from C3-C10 cycloalkylene, 3-10 membered heterocycloalkylene, C1-C6 alkylene; L 2 Selected from -O-, -NH-, C1-C6 alkylene, carbonyl; Ring A is selected from a 5-10 membered heteroaryl group, wherein the heteroaryl group contains at least a heteroatom N, and Ring A is optionally substituted by X R A Replacement, R A is selected from halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and X is any integer from 0 to 4; L 2 and -NH- are respectively connected to the ortho carbon atoms of ring A; Ring B is selected from C3-C10 cycloalkylene, 5-10 membered heterocycloalkylene, and ring B is optionally substituted by Y R B Replacement, R B is selected from halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, and Y is any integer from 0 to 4; L 3 Selected from a single bond, an amide bond, a sulfamide bond, -O-(CH2)n-amide bond, an amide bond-(CH2)nO-, -O-(CH2)m-sulfamide bond, -sulfamide bond-(CH2)mO-, and a 5-10 membered heteroarylene group; m and n are each independently 0, 1, 2 or 3; The C ring is selected from C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, benzo 3-10 membered heterocycloalkyl; and the C ring is optionally substituted by Z R C Replacement, R C It is selected from halogen, hydroxy, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and Z is any integer from 0 to 4.

2. The compound according to claim 1, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: R 1 is selected from C1-C3 alkoxy, C1-C3 haloalkoxy, preferably the halogen in the C1-C3 haloalkoxy is independently selected from F, Cl or Br; preferably the number of C atoms in the C1-C3 haloalkoxy is p, the number of halogen is any integer from 1 to (2p+1), preferably the halogen in the C1-C3 haloalkoxy is F or Cl; preferably R 1 It is a C1-C3 perfluoroalkyl group, more preferably -O-CF3.

3. The compound according to claim 1 or 2, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: L 1 is selected from C3-C6 cycloalkylene, 3-6 membered heterocycloalkylene, C1-C3 alkylene; preferably L 1 is selected from cyclobutylene, cyclopentylene, cyclohexylene, azetidinylene, oxacyclobutylene, azacyclopentylene, oxacyclopentylene, azacyclohexylene, oxacyclohexylene, methylene, ethylene, propylene; preferably L1 is selected from Methylene, ethylene; preferably L1 is selected from Methylene, ethylene Preferably, the compound of the general formula 0 is selected from any one of the structures shown in the following general formula I-1 and general formula I-2: wherein E is CH or N; n1 is 1, 2 or 3, preferably n1 is 1; n2 is 1, 2, 3 or 4, preferably n2 is 2; L 2 , A ring, R A , X, B ring, R B , Y, L 3 , C ring, R C , Z is as defined in claim 1 or 2; Preferably, the compound of the general formula I-1 is selected from any one of the structures shown in the following general formula I-1-1 and general formula I-1-2: Among them, L 2 , A ring, R A , X, B ring, R B , Y, L 3 , C ring, R C , Z is defined as in claim 1 or 2.

4. A compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: L 2 is selected from -O-, -NH-, C1-C3 alkylene, carbonyl, preferably L 2 Selected from -O-, -NH-, methylene, ethylene, carbonyl; Preferably, the compound of the general formula 0 is selected from any one of the structures shown in the following general formulas II-1 to II-4: Wherein, n3 is 1, 2 or 3, preferably n3 is 1; L 1 , A ring, R A , X, B ring, R B , Y, L 3 , C ring, R C , Z is defined as in claim 1 or 2.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: Ring A is selected from a 5-6 membered heteroaryl group, and the heteroaryl group contains at least a heteroatom N; preferably, Ring A is selected from pyridylene, pyrimidylene, pyrazinylene, pyridazinylene, imidazoleene, pyrazolylene, triazolylene, oxazolylene, oxadiazolylene, furazanylene, furanylene, thiazolylene, isoxazolylene, isothiazolylene, Preferably, ring A is selected from pyridylene, pyrazinylene, triazolylene, furazanylene, isoxazolylene, Preferably, the A ring is selected from It is further preferred that the A ring is selected from The end is connected to -NH-, and the * end is connected to L 2 connect; R A is selected from halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, X is any integer from 0 to 4, preferably X is 0 or 1; Preferably, the compound of the general formula 0 is selected from any one of the structures shown in the following general formula III-1 and general formula III-2: Among them, T 1 、T 2 、T 3 、T 4 are each independently C or N, and at least one is N; preferably, T 1 N, T 2 and T 3 C, T 4 is C or N; or preferably, T 1 、T 2 and T 3 One is N, T 4 is C; T 5 , T 6 , T 7 Each independently is C, N, O or S; R 1 , L 1 , L 2 , B ring, R B , Y, L 3 , C ring, R C , Z is as defined in any one of claims 1 to 4; Preferably, the compound of the general formula III-1 is selected from any one of the structures shown in the following general formula III-1-1: Among them, T 1 C or N, R 1 , L 1 , L 2 , B ring, R B , Y, L 3 , C ring, R C , Z is as defined in any one of claims 1 to 4; Preferably, the compound of the general formula III-2 is selected from any one of the structures shown in the following general formula III-2-1 or general formula III-2-2: In the general formula III-21, T 5 , T 6 Each independently is C, N, O or S. Preferably, T 5 C or N, T 6 N, O or S; In the general formula III-22, T 5 、T 7 Each independently is C, O or S, preferably, T 5 C or O, T 7 is C or O, and T 5 and T 7 different; R 1 , L 1 , L 2 , B ring, R B , Y, L 3 , C ring, R C , Z is defined as in any one of claims 1 to 4.

6. The compound according to any one of claims 1 to 5, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The B ring is selected from C4-C8 cycloalkylene, 5-6 membered heterocycloalkylene, preferably C4-C8 cycloalkylene is C4-C8 monocycloalkylene or C4-C8 bridged cycloalkylene; preferably B ring is selected from cyclobutylene, cyclopentylene, cyclohexylene, bicyclo[2.2.1]heptylene, bicyclo[2.2.2]octylene, bicyclo[1.1.2]pentylene, piperidinylene, oxacyclohexylene, preferably B ring is selected from It is further preferred that the B ring is selected from R B is selected from halogen, hydroxyl, nitro, cyano, Y is any integer from 0 to 4, preferably Y is 0; Preferably, the compound of the general formula 0 is selected from any one of the structures shown in the following general formulas IV-1 to IV-3: Among them, R 1 , L 1 , L 2 , A ring, R A ,X,L 3 , C ring, R C , Z is as defined in any one of claims 1 to 5; Preferably, the compound of the general formula IV-1 is selected from any one of the structures shown in the following general formula IV-1-1 and general formula IV-1-2: Preferably, the compound of the general formula IV-2 is selected from any one of the structures shown in the following general formula IV-2-1 and general formula IV-2-2: Preferably, the compound of the general formula IV-3 is selected from any one of the structures shown in the following general formula IV-3-1 and general formula IV-3-2: R 1 , L 1 , L 2 , R A ,X,L 3 , C ring, R C , Z is defined as in any one of claims 1 to 5.

7. A compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: L 3 Selected from 5-6 membered heteroarylene; preferably The -* end is connected to the C ring, and the -* end is connected to the B ring; preferably, the 5-6 membered heteroaryl group is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, Preferred L 3 Selected from The - end is connected to the C ring, and the -* end is connected to the B ring; further preferably L 3 Selected from The - end is connected to the C ring, and the -* end is connected to the B ring; Preferably, the compound of the general formula 0 is selected from any one of the structures shown in the following general formulas V-1 to V-3: Among them, R 1 , L 1 , L 2 , A ring, R A , X, B ring, R B , Y, C ring, R C Definition of Z As defined in any one of claims 1 to 6; Preferably, the compound of the general formula V-1 is selected from any one of the structures shown in the following general formulas V-1-1 to V-1-11: Among them, R 1 , L 1 , L 2 , R A , X, B ring, R B ,Y,C ring,R C , Z is as defined in any one of claims 1 to 6; Among them, R 1 , L 1 , L 2 , A ring, R A ,X,R B , Y, C ring, R C , Z is as defined in any one of claims 1 to 6; Among them, R 1 , L 1 , L 2 , R A ,X,R B ,Y,C ring,R C , Z is as defined in any one of claims 1 to 6; Preferably, the compound of the general formula V-2 is selected from any one of the structures shown in the following general formulas V-2-1 to V-2-11: Among them, R 1 , L 1 , L 2 , R A , X, B ring, R B ,Y,C ring,R C , Z is as defined in any one of claims 1 to 6; Among them, R 1 , L 1 , L 2 , A ring, R A ,X,R B ,Y,C ring,R C , Z is as defined in any one of claims 1 to 6; Among them, R 1 , L 1 , L 2 , R A ,X,R B ,Y,C ring,R C 、Z is defined as in claim 1 As defined in any one of items 6 to 6.

8. A compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The C ring is selected from C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-C10 aryl, 5-6 membered heteroaryl, benzo 3-6 membered heterocycloalkyl; preferably, the C ring is selected from cyclobutyl, cyclohexyl, azetidinyl, piperidinyl, phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzomorpholinyl, benzoxocyclohexyl; preferably, the C ring is selected from cyclobutyl, phenyl, pyrazinyl, quinolyl, benzomorpholinyl, benzoxocyclohexyl; preferably, the C ring is selected from It is further preferred that the C ring is selected from R C is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, -C1-C3 haloalkoxy, Z is any integer from 0 to 4, preferably the halogen, the halogen in the C1-C3 haloalkyl, the halogen in the C1-C3 haloalkoxy are each independently F, Cl or Br, more preferably F or Cl, preferably R C Selected from F, Cl, hydroxyl, -CH2F, -CHF2, -CF3, -O-CF3; preferably Z is 1 or 2; Preferably, the compound of the general formula 0 is selected from any one of the structures shown in the following general formula VI-1 and general formula VI-2: Among them, R in the general formula VI-1 C Selected from F, Cl, hydroxyl, -CN, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCF3; preferably Z is 1 or 2; In the general formulas VI-1 to VI-2, ring A, R A , X, B ring, R B , Y, L 3 The definition is the same as that in any one of claims 1 to 7.

9. The compound according to claim 1, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula 0 is selected from any one of the structures shown in the following general formula VII: Ring A is selected from a 5-membered nitrogen-containing heteroarylene group or a 6-membered nitrogen-containing heteroarylene group; L 1 is selected from C3-C6 membered cycloalkylene or 4-6 membered heterocyclylene; L 2 Selected from -O-; and R 1 Selected from C1-C3 alkoxy or C1-C3 haloalkoxy.

10. The compound according to claim 9, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: Ring A is selected from 6-membered nitrogen-containing heteroarylene groups.

11. The compound according to claim 9 or 10, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that L 1 Selected from C3-C5 membered cycloalkylene or 4-5 membered heterocyclylene.

12. The compound according to claim 11, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: L 1 It is selected from cyclobutylene or azetidinyl, preferably cyclobutylene.

13. A compound according to any one of claims 8 to 12, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from C1-C3 haloalkoxy, preferably -OCF3.

14. The compound according to claim 1, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula 0 is selected from any one of the structures shown in the following general formula VIII: Ring A is selected from a 5-membered nitrogen-containing heteroarylene group or a 6-membered nitrogen-containing heteroarylene group; Ring B is selected from 4-8 membered cycloalkylene; The C ring is selected from phenyl or cyclobutyl, and each is optionally substituted by 1 or 2 R C Substitution, the R C Selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy.

15. The compound according to claim 14, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: Ring A is selected from 6-membered nitrogen-containing heteroarylene groups.

16. The compound according to claim 13, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound of the general formula VIII is selected from any one of the structures shown in the following general formula VIII-A:

17. A compound according to any one of claims 13 to 16, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound of the general formula VIII-A is selected from any one of the structures shown in the following general formula VIII-A-1 or general formula VIII-A-2:

18. A compound according to any one of claims 13 to 16, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The C ring is selected from cyclobutyl optionally substituted by C1-C3 haloalkoxy.

19. The compound according to claim 1, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, characterized in that: The compound is selected from any one of the following compounds:

20. A method for synthesizing the compounds of the structures represented by the general formula V-1 to V-3 according to claim 7, the method comprising: Synthetic intermediate 3 Make raw material 1 With raw materials 2 Substitution reaction occurs to obtain intermediate 3, or raw material 4 With raw material 5 Substitution reaction occurred to obtain intermediate 3; According to route 1, the compound represented by the structure of general formula V-1 is synthesized. Route 1: The raw material 6 undergoes a substitution reaction with methyl bromoacetate and then is hydrolyzed to obtain an intermediate 7; the intermediate 7 undergoes an amidation reaction with the raw material 8 to obtain an intermediate 9; the intermediate 9 is deprotected to obtain an intermediate 10; the intermediate 10 undergoes a coupling reaction with the intermediate 3 to obtain a compound with the structure shown in the general formula V-1; According to route 2, the compound of the structure shown in the general formula V-2 is synthesized. Route 2: Among them, the raw material 11 reacts with the raw material 8 to produce the intermediate 12; the intermediate 12 is deprotected to produce the intermediate 13; the intermediate 13 and the intermediate 3 undergo a coupling reaction to produce the compound of the structure shown in the general formula V-2; According to route 3, the compound of the structure shown in the general formula V-3 is synthesized. Route 3: Among them, the raw material 14 reacts with hydrazine hydrate and obtains the intermediate 15 through functional group transformation; the intermediate 15 undergoes cyclization with N,N-carbonyldiimidazole to obtain the intermediate 16; the compound 16 undergoes condensation reaction with the raw material 6 to obtain the intermediate 17; the intermediate 17 is deprotected to obtain the intermediate 18; the intermediate 18 is coupled with the intermediate 3 to obtain the compound with the structure shown in the general formula V-2.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a preparation prepared from its stereoisomer, tautomer, geometric isomer, enantiomer, diastereomer, racemate, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt.

22. The pharmaceutical composition according to claim 21, characterized in that: It further includes pharmaceutically acceptable carriers, excipients, and vehicles.

23. Use of a compound according to any one of claims 1 to 19, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20 or 21 in the preparation of a medicament for preventing and / or treating a neurodegenerative disease, cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss disease, an eye disease, a disease with a mutation that causes an unfolded protein response (UPR) to be induced, a malarial infection, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease.

24. Use of a compound according to any one of claims 1 to 19, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20 or 21 in the preparation of a medicament for preventing and / or treating a disease or condition mediated by an integrated stress response (ISR) pathway.

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