Compound, pharmaceutical composition containing same and application thereof

Abstract

The invention provides a compound as shown in a 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, the ring A is a ring A, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, the ring B is a 5-to 10-membered spiro ring or a 5-to 10-membered spiro heterocyclic ring, and the 5-to 10-membered spiro ring and the 5-to 10-membered spiro heterocyclic ring are optionally substituted by 1-5 R1F. The compound can obviously weaken the integrated stress response (ISR) of cells and activate the activity of eIF2B, so that the protein in the cells tends to be normally synthesized. # imgabs0 #

Description

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

[0001] This application claims priority to Chinese patent application CN202210945768.0, filed on August 8, 2022, and Chinese patent application CN202310729419.X, filed on June 16, 2023. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a compound, a pharmaceutical composition containing the compound and use thereof. Background Art

[0003] Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND), commonly known as Lou Gehrig's disease, is an irreversible and fatal motor neuron disease. The main symptoms are progressive muscle weakness and atrophy of the limbs and trunk muscles, and gradual loss of motor function, as if being "frozen", so it is commonly known as "Lou Gehrig's disease". Most ALS patients die from respiratory failure, usually within three to five years after the first onset of symptoms. Currently, there is no cure for ALS and no effective treatment to stop or reverse the progression of the disease. The core pathological finding of ALS is the death of motor neurons in the motor cortex and spinal cord. The degeneration of cortical spinal axons leads to thinning and scarring (sclerosis) of the lateral aspects of the spinal cord.

[0004] 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.

[0005] 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.

[0006] 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.

[0007] eukaryotic translation initiation factor 2B (eIF2B) is a key enzyme regulating protein synthesis. It is a guanine nucleotide exchange factor (GEF) specific for translation initiation factor 2. The eIF2B agonist ISRIB can restore protein translation, restore UPR transcription to basal levels, and reduce the integrated stress response (ISR).

[0008] At the same time, 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 on healthy subjects, showing its safety and tolerability.

[0009] 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.

[0010] Summary of the Invention

[0011] The present invention 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: the compound can significantly weaken the integrated stress response (ISR) of the cell, activate the activity of eIF2B, and allow the intracellular protein to tend to be synthesized normally.

[0012] wherein Ring A and Ring C are each independently C1-C6 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -6-10 membered aryl-D-C1-C6 alkyl, 5-10 membered heteroaryl-D-C1-C6 alkyl, C3-C9 cycloalkyl-D-C1-C6 alkyl or 3-9 membered heterocyclyl-D-C1-C6 alkyl; wherein the alkyl is optionally substituted with halogen or C1-C6 alkyl; the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with 1-5 R 1 replace;

[0013] Each of the R 1 Each is independently selected from the group consisting of any one of the following groups: hydrogen, deuterium, halogen, hydroxy, phenyl, cyano, C1-C10 alkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-COOR 1D 、-SR 1E 、-S(O)R 1D 、-S(O)2R 1D , -G 1 、-OG 1 、-NR 1B -G 1 ; or two R on adjacent atoms 1 The group and the atoms to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a 6-10 membered aryl or a 5-6 membered heteroaryl; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the 6-10 membered aryl or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F Substituted; as the R 1The optional phenyl, C1-C10 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclyl are each optionally substituted with halogen;

[0014] Each of the R 1A 、R 1B 、R 1C 、R 1D 、R 1E Each is independently selected from the group consisting of any one of hydrogen, deuterium, C1-C6 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy; R 1B 、R 1C and the atoms to which they are commonly attached may form a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-3 R 1F replace;

[0015] Each of the G 1 Each is independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; each of the G 1 Each optionally replaced by 1-3 R 1F replace;

[0016] L 1 Empty, -NH-, in, The end is connected to the A ring, and the * end is connected to the B ring;

[0017] Preferably, L 1 Empty,

[0018] Preferably, L 1 Empty,

[0019] Preferably, the L 1 Empty,

[0020] Preferably, the L 1 Empty, Preferably, the L 1 Empty,

[0021] Ring B is a 5-10 membered spiro ring or a 5-10 membered spiro heterocycle, wherein the 5-10 membered spiro ring and the 5-10 membered spiro heterocycle are optionally substituted by 1-5 R 1F replace;

[0022] Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, deuterium, halogen, hydroxy, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-COOR 1D 、-P(O)R 1B R 1C 、-SR 1E 、-S(O)R 1D 、-S(O)2R 1D ;

[0023] L 2 Empty, -NH-, in, The A end is connected to the B ring, and the B end is connected to the C ring;

[0024] Preferably, L 2 Empty, -NH-,

[0025] Preferably, L 2 Empty,

[0026] Preferably, the L 2 Empty,

[0027] Preferably, the L 2 Empty, Preferably, the L 2 Empty or

[0028] The D is independently a linking group containing a heteroatom; preferably, the D is independently O or NR d or S, R d Each D is independently selected from hydrogen, deuterium, C1-C6 alkyl, and halogen-substituted C1-C6 alkyl; more preferably, each D is independently O or NH. Alternatively, each D is independently a heteroatom, preferably each independently O, N, or S, more preferably each independently O or N.

[0029] In some embodiments, the A ring is C1-C6 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 6-10 membered aryl-D-C1-C6 alkyl, 5-10 membered heteroaryl-D-C1-C6 alkyl or 3-9 membered heterocyclyl-D-C1-C6 alkyl; wherein the alkyl is optionally substituted with halogen or C1-C6 alkyl; the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with 1-5 R 1 replace;

[0030] Each of the R 1 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, cyano, C1-C10 alkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-COOR 1D 、-SR 1E 、-S(O)R 1D 、-S(O)2R 1D , -G 1 、-OG 1 、-NR 1B -G 1 ; or two R on adjacent atoms 1 The group and the atoms to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a 6-10 membered aryl or a 5-6 membered heteroaryl; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the 6-10 membered aryl or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F replace;

[0031] Each of the R 1A、R 1B 、R 1C 、R 1D 、R 1E Each is independently selected from any one of the following groups: hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy; R 1B 、R 1C and the atoms to which they are commonly attached may form a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-3 R 1F replace;

[0032] Each of the G 1 Each is independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; each of the G 1 Each optionally replaced by 1-3 R 1F replace;

[0033] Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, hydroxy, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-COOR 1D 、-P(O)R 1B R 1C 、-SR 1E 、-S(O)R 1D 、-S(O)2R 1D ;

[0034] The C ring is a 6-10 membered aryl-E-C1-C6 alkyl, a C3-C9 cycloalkyl-E-C1-C6 alkyl, a 3-9 membered heterocyclyl-E-C1-C6 alkyl, a 3-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2Substitution; each of the R 2 Each independently selected from the group consisting of any one of hydrogen, deuterium, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclic group; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclic group are each optionally substituted with halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a 5-6 membered aryl (such as a phenyl group) or a 5-6 membered heteroaryl; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the 5-6 membered aryl (such as a phenyl group) or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F replace;

[0035] The D and E are each independently a linking group containing a heteroatom; preferably, the D and E are each independently O or NR d or S, R d Each is independently selected from hydrogen, deuterium, and C1-C3 alkyl; more preferably, D and E are each independently O or NH.

[0036] In some embodiments, ring A is a 3-9 membered heterocyclyl, a 6-10 membered aryl, a 5-10 membered heteroaryl, a 6-10 membered aryl-D-C1-C6 alkyl, or a 3-9 membered heterocyclyl-D-C1-C6 alkyl; wherein each of the heterocyclyl, aryl, and heteroaryl groups may be optionally substituted with 1-5 R 1 replace;

[0037] Each of the R 1 Each independently selected from the group consisting of any one of hydrogen, halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D , -G 1 、-OG 1 、-NR 1B -G 1; or two R on adjacent atoms 1 The group and the atom to which it is attached may form a 6-10 membered aryl or a 5-6 membered heteroaryl; the 6-10 membered aryl or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F replace;

[0038] Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy; R 1B 、R 1C and the atoms to which they are commonly attached may form a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-3 R 1F replace;

[0039] Each of the G 1 Each is independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl; each of the G 1 Each optionally replaced by 1-3 R 1F Replace; when G 1 When it is a phenyl group, the phenyl group and the 3-9-membered heterocyclic group or the 5-10-membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0040] Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-P(O)R 1B R 1C 、-S(O)2R 1D .

[0041] In some embodiments, ring A is a 4-9 membered heterocyclyl, a 5-7 membered heteroaryl, a phenyl-D-C1-C6 alkyl group or a 4-9 membered heterocyclyl-D-C1-C6 alkyl group; wherein the heterocyclyl, heteroaryl, and phenyl groups are each optionally substituted by 1-5 R1 replace;

[0042] Each of the R 1 Each independently selected from the group consisting of any one of hydrogen, halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ;

[0043] Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C4-C9 cycloalkyl, halogen-substituted 4-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy; R 1B 、R 1C and the atoms to which they are commonly attached may form a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-3 R 1F replace;

[0044] Each of the G 1 Each independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F Replace; when G 1 When it is a phenyl group, the phenyl group and the 3-9-membered heterocyclic group or the 5-7-membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0045] Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D .

[0046] In some embodiments, ring A is a 4-8 membered heterocyclyl, a 5-6 membered heteroaryl, a phenyl-D-C1-C3 alkyl group or a 4-8 membered heterocyclyl-D-C1-C3 alkyl group; wherein the heterocyclyl, heteroaryl, and phenyl groups are each optionally substituted by 1-2 R 1 replace;

[0047] Each of the R 1 Each independently selected from the group consisting of any one of hydrogen, halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, -OR 1A 、-NR 1B R 1C 、-NR B C(O)R 1D 、-C(O)NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ;

[0048] Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0049] Each of the G 1 Each is independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, preferably, the C3-C6 cycloalkyl is cyclobutane or cyclopentane, the 3-6 membered heterocyclic group is oxetane, azetidinyl, oxolane or azocyclopentane; each of the G 1 Each optionally replaced by 1-3 R 1F Replace; when G 1 When it is a phenyl group, the phenyl group and the 5-6 membered heterocyclic group or the 5-7 membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0050] Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R1C 、-P(O)R 1B R 1C 、-S(O)2R 1D .

[0051] In some embodiments, ring A is a 5-6 membered heterocyclic group; preferably or preferably:

[0052] Preferably, the R 1 The number n is 1, 2 or 3;

[0053] Preferably, the R 1 are each independently selected from any one of the following groups: hydrogen, halogen, hydroxy, C1-C3 alkyl and phenyl, and when R 1 When phenyl is present, the phenyl group and the 3-6 membered heterocyclic group share two carbon atoms to form a condensed ring. Two carbon atoms are shared to form a fused ring, and the phenyl group is optionally substituted by halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 haloalkoxy;

[0054] Further preferably, the phenyl group The fusion method is The phenyl group is optionally substituted with halogen.

[0055] In some embodiments, ring A is a 5-6 membered heteroaryl group; preferably any one of the following groups:

[0056] (1) H 1 、H 2 、H 3 、H 4 are each independently C or a heteroatom, and at least one is a heteroatom, preferably the heteroatom is selected from any one of N, O, and S; preferably, the R 1 Any one selected from the group consisting of hydrogen, -OR 1A 、-NR 1B R 1C , -G 1 、-OG 1 、-NR 1B -G 1 , each of the R 1A 、R 1B 、R 1CEach is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0057] Each of the G 1 Each is independently selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F replace;

[0058] Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D , the R 1D Any one selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy;

[0059] or The A ring is a 5-membered heteroaryl group, H 1 、H 2 、H 3 、H 4 are each independently selected from CH, N, O, S, is a single bond or a double bond;

[0060] Preferably, the R 1 Each independently selected from any one of the following groups: -OR 1A 、-NR 1B R 1C , -G 1 、-OG 1 、-NR 1B -G 1 ; Each of the R 1A 、R 1B 、R 1CEach is independently selected from the group consisting of any one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy-C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0061] Each of the G 1 Each independently selected from C4-C6 cycloalkyl, 4-9 membered heterocyclic group; each of the G 1 Each optionally replaced by 1-3 R 1F replace;

[0062] Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D , the R 1D Any one selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy;

[0063] Preferably, the A ring is

[0064] More preferably, the L 1 is empty;

[0065] Preferably, the R 1 Select from -OR 1A , -G 1 、-OG 1 、-NR 1B -G 1 ; R 1A is selected from halogen-substituted C1-C3 alkoxy-C1-C3 alkyl; R 1B Selected from H, C1-C3 alkyl; each of said R 1F Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -P(O)R1B R 1C 、-S(O)2R 1D ; R 1B 、R 1C 、R 1D Each independently selected from any one of the following groups: hydrogen, C1-C3 alkyl;

[0066] (2)

[0067] Preferably, each R 1 are independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy and benzene, and when R 1 When phenyl, the phenyl Two carbon atoms are shared to form a fused ring, and the phenyl group is optionally substituted by halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 haloalkoxy;

[0068] Further preferably, the phenyl group is optionally substituted by halogen; the R 1 The number m is 1 or 2;

[0069] (3)

[0070] Preferably, the R 1 is hydrogen, halogen or phenyl, the phenyl group is optionally substituted by one or more halogens, the R 1 The number m is 1 or 2; R 1 When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring;

[0071] More preferably, the R 1 is phenyl, m is 1, phenyl and The fusion mode is The phenyl group is optionally substituted with one or more halogens.

[0072] In some embodiments, Ring A is phenyl-O-C1-C3 alkyl, wherein the phenyl group is optionally substituted with 1 or 2 R 1 Substitution; each of the R 1 Each is independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and halogen-substituted C1-C3 alkoxy.

[0073] Preferably, the A ring is phenyl-O-methyl, R 1 is H or halogen.

[0074] In some embodiments, Ring A is a 4-8 membered heterocyclyl-O-C1-C3 alkyl, wherein the heterocyclyl is optionally substituted by 1-3 R 1 Substitution; each of the R 1 Each is independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and halogen-substituted C1-C3 alkoxy.

[0075] Preferably, the A ring is a 4-7 membered heterocyclyl-O-methyl group, R 1 It is a halogen-substituted C1-C3 alkyl group or a halogen-substituted C1-C3 alkoxy group.

[0076] In some embodiments, the A ring is C3-C7 cycloalkyl-O-C1-C3 alkyl, and the C3-C7 cycloalkyl is optionally substituted by 1-3 R 1 Substitution; each of the R 1 Each is independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and halogen-substituted C1-C3 alkoxy.

[0077] Preferably, the A ring is C4-C6 cycloalkyl-O-methyl, R 1 It is a halogen-substituted C1-C3 alkyl group or a halogen-substituted C1-C3 alkoxy group.

[0078] In some embodiments, the A ring is a phenyl group, and the phenyl group is substituted by a group selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0079] Preferably, the phenyl group is substituted by a group selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; further preferably, the phenyl group is substituted by a C1-C3 haloalkyl.

[0080] In some embodiments, Ring A is selected from any one of the following groups:

[0081] (1)

[0082] Preferably, the R 1 Any one selected from the group consisting of: -G 1 , OG 1 、-NR 1B -G 1 , and each of the G 1 Each optionally replaced by 1 or 2 R 1F Substitution; said R 1BAny one selected from the group consisting of: hydrogen, C1-C3 alkyl; each of the G 1 Each is independently selected from C3-C6 cycloalkyl, 4-9 membered heterocyclyl;

[0083] Further preferably, the C3-C6 cycloalkyl group is a cyclobutane group or a cyclopentane group; the 4-9 membered heterocyclic group is preferably an oxetane group, an N-heterocyclic group, and further preferably an oxetane group, an azetidinyl group, an oxolanyl group, an azocyclopentanyl group, More preferably, oxetane, azetidinyl, oxolane, azocyclopentane, or more preferably

[0084] Each of the R 1F Each independently selected from any one of the following groups: oxo, C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy; 1 Preferably empty;

[0085] (2) 4-8 membered heterocyclic-O-C1-C3 alkyl, wherein the heterocyclic group is optionally substituted by 1 or 2 R 1 Substitution; each of the R 1 Each is independently selected from any one of the following groups: a halogen-substituted C1-C3 alkyl group, a halogen-substituted C1-C3 alkoxy group;

[0086] (3) C4-C6 cycloalkyl-O-C1-C3 alkyl, wherein the C4-C6 cycloalkyl is optionally substituted by 1 or 2 R 1 Substitution; each of the R 1 Each is independently selected from halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy.

[0087] In some embodiments, Ring A is selected from any one of the following groups:

[0088] Preferably, ring A is selected from any one of the following groups:

[0089] Preferably, ring A is selected from any one of the following groups:

[0090] Preferably, ring A is selected from any one of the following groups:

[0091] In some embodiments, the spiro ring is selected from any one of the following groups: spiro[2,5]octyl ring, spiro[3,4]octyl ring, spiro[3,3]heptyl ring, spiro[3,5]nonyl ring, spiro[4,5]decyl ring, spiro[2,2]pentyl ring, spiro[2,3]hexyl ring, spiro[2,4]heptyl ring, spiro[2,6]nonyl ring, spiro[2,7]nonyl ring, spiro[3,6]nonyl ring and spiro[4,4]nonyl ring, and the spiroheterocycle is a group formed by replacing any one or more carbon atoms in the spiro ring with heteroatoms, and the number of heteroatoms in the spiroheterocycle is 1, 2 or 3.

[0092] Preferably, the heteroatom in the spiro heterocycle is nitrogen, or a combination of nitrogen and oxygen.

[0093] Preferably, the substituent R of the spiro ring or the spirohetero ring 1F It is hydrogen, halogen, hydroxy, amino, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, C1-C6 alkyl substituted by hydroxy, C1-C6 alkyl substituted by halogen, or C1-C6 alkoxy substituted by halogen.

[0094] In some embodiments, it is preferred that the substituent R of the spiro ring or the spirohetero ring is 1F The number is 1 or 2, preferably 1.

[0095] More preferably, the substituent R of the spiro ring or the spirohetero ring 1F It is halogen, hydroxyl, and amino.

[0096] Most preferably, the substituent R of the spiro ring or the spirohetero ring is 1F It is a hydroxyl group.

[0097] In some embodiments, Ring B is a 7-9 membered spiro ring or a 7-9 membered spirohetero ring.

[0098] Preferably, the spiro ring is selected from any one of the following groups: spiro[2,5]octyl ring, spiro[3,4]octyl ring, spiro[3,3]heptyl ring and spiro[3,5]nonyl ring; the 7-9 membered spiroheterocycle is a group formed by replacing any one or more carbon atoms in the 7-9 membered spiro ring with a heteroatom, and the number of heteroatoms in the spiroheterocycle is 1, 2 or 3.

[0099] Preferably, the heteroatom in the spiro heterocycle is nitrogen, or a combination of nitrogen and oxygen.

[0100] In some embodiments, Ring B is selected from any one of the following groups:

[0101] in, End and L 1 Connect, * end and L2 connect.

[0102] In some embodiments, Ring B is selected from any one of the following groups:

[0103] in, End and L 1 Connect, * end and L 2 connect;

[0104] In some embodiments, the B ring is selected from any one of the following groups:

[0105] in, End and L 1 Connect, * end and L 2 connect.

[0106] In some embodiments, the B ring is selected from any one of the following groups: in, End and L 1 Connect, * end and L 2 connect.

[0107] In some embodiments, the C ring is a 6-10 membered aryl-E-C1-C3 alkyl, a C4-C9 cycloalkyl-E-C1-C3 alkyl, a 4-9 membered heterocyclyl-E-C1-C3 alkyl, a 4-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, phenyl, C1-C3 alkyl, C1-C3 alkoxy; wherein, as the R 2 The optional phenyl, C1-C3 alkyl, C1-C3 alkoxy are each optionally substituted by halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the phenyl group or the 5-6 membered heteroaryl group are each optionally substituted by 1-5 R 1F Replace; when R 2 When it is a phenyl group, the phenyl group and the 4-9 membered heterocyclic group or the 5-10 membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0108] The E's are each independently a linking group containing a heteroatom.

[0109] Preferably, each of the E's is independently O or NRd or S, R d Each E is independently selected from hydrogen, deuterium, and C1-C3 alkyl; more preferably, each E is independently O or NH.

[0110] In some embodiments, the C ring is phenyl-E-C1-C3 alkyl, and the phenyl group is 1, 2 or 3 R 2 Substitution, said E is a linking group containing a heteroatom.

[0111] Preferably, the E is O or NR d or S, R d Selected from hydrogen, deuterium, and C1-C3 alkyl.

[0112] Preferably, E is O or NH.

[0113] Preferably, each of the R 2 are each independently halogen.

[0114] In some embodiments, the C ring is C4-C9 cycloalkyl-E-C1-C3 alkyl or 4-9 membered heterocyclyl-E-C1-C3 alkyl, wherein the cycloalkyl or heterocyclyl is replaced by R 2 Substitution; said E is O or NR d or S, R d is selected from hydrogen, deuterium, C1-C3 alkyl; said R 2 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy;

[0115] Preferably, E is O or NH;

[0116] Preferably, the cycloalkyl group is cyclopropyl, cyclobutyl or cyclopentyl;

[0117] Preferably, the heterocyclic group is an oxirane group, an oxetane group, an oxolanyl group, an azirane group, an azetide group or an azopentanyl group.

[0118] In some embodiments, the C ring is a 4-9 membered heterocyclyl, preferably a 5-6 membered heterocyclyl.

[0119] Preferably, the C ring is The R 2 The number n is 1 or 2 or 3;

[0120] Preferably, each of the R 2 Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, phenyl, halogenated phenyl and hydroxyl; the R 2 When phenyl or halogenated phenyl, optionally phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0121] In some embodiments, the C ring is The R 2 The number n is 1 or 2 or 3.

[0122] Preferably, each of the R 2 Each independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, phenyl and halogenated phenyl; 2 When it is a substituent on the N atom, the R 2 is any one of the following groups: hydrogen, halogen, C1-C3 alkyl; 2 When phenyl or halogenated phenyl, the phenyl or halogenated phenyl and the morpholine ring group may share two carbon atoms to form a fused ring, preferably in the form of

[0123] In some embodiments, the C ring is The R 2 The number n is 1 or 2 or 3.

[0124] Preferably, each of the R 2 Each independently selected from any one of the following groups: halogen, phenyl, halogenated phenyl and hydroxyl; the R 2 When phenyl or halogenated phenyl, optionally the phenyl or the halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0125] In some embodiments, Ring C is a 5-10 membered heteroaryl.

[0126] Preferably, the C ring is any one of the following 5-10 membered heteroaryl groups:

[0127] (1) Preferably, each R 2 Independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, halophenyl, said R 2 The number p is 1 or 2, and when the R 2 When phenyl or halogenated phenyl, the phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0128] (2) Preferably, the R 2Any one selected from the group consisting of: hydrogen, halogen, phenyl, C1-C3 alkyl, C1-C3 alkoxy-C3-C6 cycloalkyl; the phenyl, the alkyl, the alkoxy is unsubstituted or substituted with halogen; the R 2 When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0129] In some embodiments, the C ring is phenyl; the phenyl is R 2 Substituted; preferably, the R 2 Any one selected from the group consisting of C1-C3 haloalkyl, C1-C3 haloalkoxy.

[0130] In some embodiments, the C ring is selected from any one of the following groups:

[0131] Preferably, the C ring is selected from any one of the following groups:

[0132] Preferably, the C ring is selected from any one of the following groups:

[0133] Preferably, the C ring is selected from any one of the following groups:

[0134] Preferably, the C ring is selected from any one of the following groups:

[0135] In some embodiments, the compound has the structure shown in Formula I:

[0136] Preferably,

[0137] Ring A is a 3-9 membered heterocyclic group, a 5-10 membered heteroaryl group, a 6-10 membered aryl-D-C1-C6 alkyl group or a 5-10 membered heteroaryl-D-C1-C6 alkyl group; wherein the heterocyclic group, aryl group and heteroaryl group are each optionally substituted by 1-5 R 1 replace;

[0138] Each of the R 1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C10 alkyl, hydroxy substituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, -G 1 、-OG 1 ; or two R on adjacent atoms 1The group and the atoms to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a 6-10 membered aryl or a 5-6 membered heteroaryl; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the 6-10 membered aryl or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F replace;

[0139] Each of the G 1 Each is independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; each of the G 1 Each optionally replaced by 1-3 R 1F1 replace;

[0140] Each of the R 1F1 、R 1F2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy; preferably, each of the R 1F2 are independently selected from hydrogen, halogen, hydroxyl, and amino;

[0141] L 2 Empty, -NH-, in, The end is connected to the B ring, and the * end is connected to the C ring; preferably End and in formula I The N atoms in the connection;

[0142] Preferably, the L 2 Empty, -NH-,

[0143] Preferably, the L 2 Empty,

[0144] Preferably, the L 2 Empty,

[0145] Preferably, the L 2 for

[0146] Preferably, the L 2 Empty,

[0147] The C ring is a 6-10 membered aryl-E-C1-C6 alkyl, a 3-9 membered heterocyclic group, a 5-10 membered heteroaryl or a 6-10 membered aryl; each of the aryl, heteroaryl and heterocyclic groups may be optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from any one of the following groups: halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl are each optionally substituted with halogen; when R 2 When it is a phenyl group, the phenyl group and the 3-9-membered heterocyclic group or the 6-10-membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0148] The D and E are each independently a linking group containing a heteroatom;

[0149] Preferably, D and E are each independently O or NR d or S, R d Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, halogen-substituted C1-C6 alkyl;

[0150] More preferably, D and E are each independently O or NH.

[0151] Preferably, ring A is a 5-10 membered heteroaryl group or a 6-10 membered aryl-D-C1-C6 alkyl group.

[0152] Preferably, the R 1 Each is independently selected from C1-C10 alkyl, hydroxy substituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, -G 1 、-OG 1 .

[0153] Preferably, the C ring is a 6-10 membered aryl group. The aryl group may be optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each is independently selected from: halogen, C1-C6 alkyl.

[0154] In some embodiments, the compound has the structure shown in Formula I-1:

[0155] Among them, the R 1 The number is 1-5, each of the R 1Each is independently selected from any one of the following groups: halogen, C1-C10 alkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy;

[0156] Preferably, the R 1 The number is 1, 2, or 3, each of the R 1 Each is independently selected from any one of the following groups: halogen, C1-C10 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy;

[0157] It is further preferred that the R 1 The number is 1 or 2, each of the R 1 Each independently selected from any one of the halogens;

[0158] Each of the R 1F2 Each is independently selected from any one of the following groups: hydrogen, halogen, hydroxy, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy;

[0159] Preferably, each of the R 1F2 Each is independently selected from any one of the following groups: hydrogen, halogen, hydroxyl;

[0160] The L 2 for in, The end is connected to the B ring, and the * end is connected to the C ring; preferably end and in formula I-1 The N atoms in the connection;

[0161] The C ring is a 6-10 membered aryl-O-C1-C6 alkyl, a 3-9 membered heterocyclic group or a 5-10 membered heteroaryl; the aryl, heteroaryl and heterocyclic group are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from any one of the following groups: halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl are each optionally substituted with halogen; when R 2When it is a phenyl group, the phenyl group and the 3-9-membered heterocyclic group or the 6-10-membered heteroaryl group optionally share two carbon atoms to form a condensed ring.

[0162] In some embodiments, preferably, the C ring is any one of the following groups:

[0163] 1) 4-9 membered heterocyclic group;

[0164] Preferably, the C ring is The R 2 The number n is 1 or 2 or 3;

[0165] Preferably, each of the R 2 Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, phenyl, halophenyl and hydroxyl; R 2 When phenyl or halogenated phenyl is present, the phenyl or halogenated phenyl group and the 4-9 membered heterocyclic group may share two carbon atoms to form a condensed ring. Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0166] 2) 5-10 membered heteroaryl;

[0167] Preferably, the C ring is any one of the following 5-10 membered heteroaryl groups:

[0168] (1)

[0169] Preferably, each R 2 Independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, halophenyl, said R 2 The number p is 1 or 2, and when the R 2 When phenyl or halogenated phenyl, the phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0170] (2)

[0171] Preferably, each R 2 Independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, halophenyl, said R 2 The number p is 1 or 2, and when the R 2 When phenyl or halogenated phenyl, the phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0172] (3)

[0173] Preferably, the R 2 Any one selected from the group consisting of: hydrogen, halogen, phenyl, C1-C3 alkyl, C1-C3 alkoxy-C3-C6 cycloalkyl; the phenyl, the alkyl, the alkoxy is unsubstituted or substituted with halogen; the R 2 When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0174] 3) Phenyl-O-C1-C3 alkyl, wherein the phenyl group is substituted by 1, 2 or 3 R 2 replace;

[0175] Preferably, each of the R 2 are each independently halogen;

[0176] 4) phenyl, the phenyl group is R 2 replace;

[0177] Preferably, the R 2 Any one selected from the group consisting of C1-C3 haloalkyl, C1-C3 haloalkoxy.

[0178] In some embodiments, the compound has the structure shown in Formula I-2:

[0179] Among them, each of the R 1F2 Each is independently selected from any one of the following groups: hydrogen, halogen, hydroxy, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy;

[0180] Preferably, each of the R 1F2 Each is independently selected from any one of the following groups: hydrogen, halogen, hydroxyl;

[0181] The L 2 for in, The end is connected to the B ring, and the * end is connected to the C ring; preferably end and in formula I-2 The N atoms in the connection;

[0182] The R 1 and the R 2 The number of each is independently 1-3, and each of the R1 and each of the R 2 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C10 alkyl, hydroxy substituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, -G 1 、-OG 1 ;

[0183] Each of the G 1 Each is independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; each of the G 1 Each optionally replaced by 1-3 R 1F1 Substitution; each of the R 1F1 Each is independently selected from any one of the following groups: hydrogen, halogen, hydroxyl, amino, cyano, and carboxyl.

[0184] Preferably, the R 1 and the R 2 The number of is 1 and is selected from any one of the following groups: 6-10 membered aryl, 5-10 membered heteroaryl; the 6-10 membered aryl, the 5-10 membered heteroaryl are each optionally substituted by 1, 2 or 3 R 1F1 Substituted, each of the R 1F1 Each is independently selected from any one of the following groups: hydrogen, halogen.

[0185] It is further preferred that the R 1 and the R 2 The number of is 1 and is phenyl; each of the phenyl groups is optionally substituted by 1, 2 or 3 R 1F1 Substituted, each of the R 1F1 Each is independently selected from any one of the following groups: hydrogen, halogen.

[0186] In some embodiments, the compound has a structure shown in Formula II or Formula III:

[0187] wherein the A ring is independently a 5-7 membered heteroaryl, a phenyl-D-C1-C6 alkyl, or a 3-9 membered heterocyclic group; wherein the heteroaryl and phenyl groups are each optionally substituted by 1 or 2 R 1 replace;

[0188] Each of the R 1 Each independently selected from the group consisting of any one of the following groups: halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, -OR 1A 、-NR 1B R 1C , -G1 , OG 1 、-NR 1B -G 1 ;

[0189] Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C4-C9 cycloalkyl, halogen-substituted 4-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy;

[0190] Each of the G 1 Each independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 Replace; when G 1 When it is a phenyl group, the phenyl group and the 3-9-membered heterocyclic group or the 5-7-membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0191] Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C6 alkyl, C3-C9 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C6 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D ;

[0192] L 1 Empty, -NH-, in, The end is connected to the A ring, the * end is connected to the B ring; preferably the * end is connected to the & C atoms in formula III &C atoms connected in;

[0193] Preferably, the L 1 Empty, -NH-,

[0194] Preferably, the L 1 Empty,

[0195] Preferably, the L 1 Empty,

[0196] More preferably, the L 1 Empty or

[0197] L 2 Empty, -NH-, in, The end is connected to the B ring, and the * end is connected to the C ring; preferably The end and the The N atom in formula III @C atom connection in;

[0198] Preferably, the L 2 Empty, -NH-,

[0199] Preferably, the L 2 Empty,

[0200] Preferably, L in the formula II 2 for More preferred

[0201] Preferably, L in the formula III 2 Empty, More preferably empty or

[0202] Each of the R 1F2 Independently selected from hydrogen, halogen, hydroxyl, amino;

[0203] Preferably, each of the R 1F2 independently selected from hydrogen, hydroxyl;

[0204] The C ring is selected from 6-10 membered aryl-E-C1-C3 alkyl, C4-C9 cycloalkyl-E-C1-C3 alkyl, 4-9 membered heterocyclyl-E-C1-C3 alkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, phenyl, C1-C3 alkyl, C1-C3 alkoxy; wherein, as the R 2The optional phenyl, C1-C3 alkyl, C1-C3 alkoxy are each optionally substituted by halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the phenyl group or the 5-6 membered heteroaryl group are each optionally substituted by 1-5 R 1F Replace; when R 2 When it is a phenyl group, the phenyl group and the 4-9 membered heterocyclic group or the 5-10 membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0205] The E's are each independently a linking group containing a heteroatom;

[0206] Preferably, each of the E's is independently O or NR d or S, R d Each is independently selected from hydrogen, deuterium, C1-C3 alkyl;

[0207] More preferably, each of the E's is independently O or NH.

[0208] In some embodiments, the compound has a structure shown in Formula II-1, II-1', III-1 or III-1':

[0209] Wherein, ring A is a 5-membered heteroaryl group;

[0210] H 1 、H 2 、H 3 、H 4 are each independently selected from CH, N, O, S;

[0211] is a single bond or a double bond;

[0212] The R 1F2 Each is independently hydrogen, halogen, hydroxyl, amino, preferably hydrogen or hydroxyl;

[0213] Preferably, the for

[0214] Preferably, the R 1 Any one selected from the group consisting of: -OR 1A 、-NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 , each of the R1A 、R 1B 、R 1C Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0215] Each of the G 1 Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 replace;

[0216] Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D , the R 1D Any one selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and halogen-substituted C1-C3 alkoxy.

[0217] In some embodiments, the Any one of the following groups:

[0218] In some embodiments, the C ring is a 6-10 membered aryl-O-C1-C6 alkyl, a 3-9 membered heterocyclyl-O-C1-C3 alkyl, a 3-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; and the aryl, heteroaryl, and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclic group; wherein, as the R 2The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclyl are each optionally substituted by halogen.

[0219] In some embodiments, the C ring is a 4-8 membered heterocyclyl-O-C1-C3 alkyl, the heterocyclyl being replaced by one R 2 Substituted; preferably, the R 2 are each independently a haloalkyl group.

[0220] In some embodiments, the C ring is phenyl-O-C1-C3 alkyl, and the phenyl group is 1, 2 or 3 R 2 Substituted; preferably, each of the R 2 are each independently halogen.

[0221] In some embodiments, the C ring is a 4-9 membered heterocyclic group, preferably the C ring is The R 2 The number n is 1 or 2 or 3; preferably, each of the R 2 Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, phenyl, halophenyl and hydroxyl; R 2 When phenyl or halogenated phenyl, optionally phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0222] In some embodiments, the C ring is any one of the following 5-10 membered heteroaryl groups:

[0223] 1)

[0224] Preferably, each R 2 Independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, halophenyl, said R 2 The number p is 1 or 2, and when the R 2 When phenyl or halogenated phenyl, the phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0225] 2)

[0226] Preferably, the R 2Any one selected from the group consisting of: hydrogen, halogen, phenyl, C1-C3 alkyl, C1-C3 alkoxy-C3-C6 cycloalkyl; the phenyl, the alkyl, the alkoxy is unsubstituted or substituted with halogen; the R 2 When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0227] In some embodiments, the C ring is phenyl; the phenyl is replaced by R 2 Substituted; preferably, the R 2 Any one selected from the group consisting of: C1-C3 haloalkyl;

[0228] Preferably, the C ring is selected from any one of the following groups:

[0229] In some embodiments, the compound has a structure shown in Formula II-2, II-2', Formula III-2' or Formula III-2:

[0230] Among them, the L 2 for in, The end and the The N atom in formula III-2 @C atom connected; n is independently 1-3, the R 2 The number of R is 1, 2 or 3, and each of the R 2 Each is independently selected from any one of the following groups: hydrogen, halogen, and hydroxyl.

[0231] In some embodiments, the compound has a structure shown in Formula IV:

[0232] Preferably, the A ring is a 4-8 membered heterocyclic group, a 5-7 membered heteroaryl group, a phenyl-O-C1-C6 alkyl group, or a C4-C8 cycloalkyl-O-C1-C6 alkyl group; wherein the heterocyclic group, heteroaryl group, phenyl group, and cycloalkyl group are each optionally substituted by 1-2 R 1 replace;

[0233] Each of the R 1 Each independently selected from the group consisting of any one of the following groups: halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, -OR 1A 、-NR 1B R 1C , -G 1, OG 1 、-NR 1B -G 1 ;

[0234] Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0235] Each of the G 1 Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 Replace; when G 1 When it is a phenyl group, the phenyl group and the 5-6 membered heterocyclic group or the 5-7 membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0236] Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D ;

[0237] Each of the R 1F2 are independently selected from hydrogen, hydroxy, amino, carboxyl or halogen;

[0238] L 1 Empty, -NH-, in, The end is connected to the A ring, the * end is connected to the B ring; preferably the * end is connected to the The N atoms are connected;

[0239] Preferably, the L 1 Empty, -NH-,

[0240] Preferably, the L 1 Empty,

[0241] Preferably, the L 1 Empty,

[0242] L 2 Empty, -NH-, in, The end is connected to the B ring, and the * end is connected to the C ring; preferably end and in formula IV @C atom connection;

[0243] Preferably, the L 2 Empty, -NH-,

[0244] Preferably, the L 2 Empty,

[0245] More preferably, the L 2 for

[0246] The C ring is a 6-10 membered aryl-O-C1-C3 alkyl, a C4-C9 cycloalkyl-O-C1-C3 alkyl, a 4-9 membered heterocyclyl-O-C1-C3 alkyl, a 4-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from any one of the following groups: halogen, hydroxyl, phenyl, C1-C3 alkyl, C1-C3 alkoxy; wherein, as the R 2 The optional phenyl, C1-C3 alkyl, C1-C3 alkoxy are each optionally substituted by halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the phenyl group or the 5-6 membered heteroaryl group are each optionally substituted by 1-5 R 1F1 Replace; when R 2 When it is a phenyl group, the phenyl group and the 4-9 membered heterocyclic group or the 5-10 membered heteroaryl group optionally share two carbon atoms to form a condensed ring.

[0247] In some embodiments, the compound has a structure shown in Formula IV-1 or Formula IV-1':

[0248] Among them, the R1F2 Each is independently hydrogen, halogen, hydroxyl, amino;

[0249] H 1 、H 2 、H 3 、H 4 are each independently C or a chemically acceptable heteroatom, and at least one is a heteroatom; is a single bond or a double bond;

[0250] Preferably, the heteroatom is selected from any one of N, O, and S;

[0251] Preferably, the for

[0252] Preferably, the R 1 Any one selected from the group consisting of: -OR 1A 、-NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 , each of the R 1A 、R 1B 、R 1C Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0253] Each of the G 1 Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 replace;

[0254] Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D , the R 1DAny one selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and halogen-substituted C1-C3 alkoxy.

[0255] In some embodiments, the Any one of the following groups:

[0256] In some embodiments, the C ring is a 6-10 membered aryl-O-C1-C6 alkyl, a 3-9 membered heterocyclyl-O-C1-C3 alkyl, a 3-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; and the aryl, heteroaryl, and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclic group; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclyl are each optionally substituted with halogen;

[0257] In some embodiments, the C ring is a 4-8 membered heterocyclyl-O-C1-C3 alkyl, the heterocyclyl being replaced by one R 2 Substituted, preferably, the R 2 are each independently a haloalkyl group.

[0258] In some embodiments, the C ring is phenyl-O-C1-C3 alkyl, and the phenyl group is 1, 2 or 3 R 2 Substituted, preferably, each of the R 2 are each independently halogen.

[0259] In some embodiments, the C ring is a 4-9 membered heterocyclic group, preferably the C ring is The R 2 The number n is 1 or 2 or 3; preferably, each of the R 2 Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, phenyl, halophenyl and hydroxyl; R 2 When phenyl or halogenated phenyl, optionally phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0260] In some embodiments, the C ring is any one of the following 5-10 membered heteroaryl groups:

[0261] 1)

[0262] Preferably, the R 2 is any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, halophenyl, wherein R 2 The number p is 1 or 2, the R 2 When phenyl or halogenated phenyl Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0263] 2)

[0264] Preferably, the R 2 Any one selected from the group consisting of: hydrogen, halogen, phenyl, C1-C3 alkyl, C1-C3 alkoxy-C3-C6 cycloalkyl; the phenyl, the alkyl, the alkoxy is unsubstituted or substituted with halogen; the R 2 When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0265] In some embodiments, the C ring is phenyl; the phenyl is replaced by R 2 Substituted; preferably, the R 2 Any one selected from the group consisting of: C1-C3 haloalkyl.

[0266] In some embodiments, the C ring is selected from any one of the following groups:

[0267] The L 2 for

[0268] In some embodiments, the compound has a structure shown in Formula IV-2 or Formula IV-2':

[0269] The L 2 for in, The end and the @C atom connected; n is 1-3; the R 2 The number of R is 1, 2 or 3, and each of the R 2 Each is independently selected from any one of the following groups: hydrogen, halogen, and hydroxyl.

[0270] In some embodiments, the compound preferably has a structure shown in Formula IV-3:

[0271] Each of the R 1F2 Each is independently hydrogen, halogen, hydroxyl, amino, preferably hydrogen or hydroxyl;

[0272] m is 1, 2, 3, 4 or 5, n is 1 to 3, R 1 The number of R is 1, 2 or 3, and each of the R 1 Each is independently selected from any one of the following groups: hydrogen, halogen, hydroxy, phenyl, cyano, C1-C10 alkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy;

[0273] The C ring is a 6-10 membered aryl-O-C1-C6 alkyl, a 3-9 membered heterocyclyl-O-C1-C3 alkyl, a 3-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; and the aryl, heteroaryl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclic group; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclyl are each optionally substituted by halogen.

[0274] In some embodiments, the C ring is

[0275] Preferably, the R 2 Any one selected from the group consisting of: hydrogen, halogen, phenyl, C1-C3 alkyl, C1-C3 alkoxy-C3-C6 cycloalkyl; the phenyl, the alkyl, the alkoxy is unsubstituted or substituted with halogen; the R 2When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0276] In some embodiments, the C ring is phenyl; the phenyl is replaced by R 2 replace.

[0277] Preferably, the R 2 Any one selected from the group consisting of: C1-C3 haloalkyl.

[0278] In some embodiments, the C ring is

[0279] In some embodiments, the L 2 for in, The end and the The @C atom is connected.

[0280] In some embodiments, the compound has a structure shown in Formula V:

[0281] Preferably, the A ring is a 4-8 membered heterocyclic group, a 5-7 membered heteroaryl group, or a phenyl-O-C1-C6 alkyl group; wherein the heterocyclic group, heteroaryl group, and phenyl group are each optionally substituted by 1-2 R 1 replace;

[0282] Each of the R 1 Each independently selected from the group consisting of any one of the following groups: halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, -OR 1A 、-NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ;

[0283] Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0284] Each of the G 1Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 Replace; when G 1 When it is a phenyl group, the phenyl group and the 5-6 membered heterocyclic group or the 5-7 membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0285] Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D ;

[0286] L 1 Empty, -NH-,

[0287] Preferably, the L 1 Empty, -NH-,

[0288] Preferably, the L 1 Empty,

[0289] Preferably, the L 1 for

[0290] Each R 1F2 Independently selected from hydrogen, halogen, hydroxyl, amino;

[0291] L 2 Empty, -NH-, in, End and V The @C atom is connected to the * end and the C ring;

[0292] Preferably, the L 2 Empty, -NH-,

[0293] Preferably, the L 2 Empty,

[0294] Preferably, the L 2 for

[0295] The C ring is a 6-10 membered aryl-O-C1-C3 alkyl, a 4-9 membered heterocyclyl-O-C1-C3 alkyl, a 4-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from any one of the following groups: halogen, hydroxyl, phenyl, C1-C3 alkyl, C1-C3 alkoxy; wherein, as the R 2 The optional phenyl, C1-C3 alkyl, C1-C3 alkoxy are each optionally substituted by halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the phenyl group or the 5-6 membered heteroaryl group are each optionally substituted by 1-5 R 1F1 Replace; when R 2 When it is a phenyl group, the phenyl group and the 4-9 membered heterocyclic group or the 5-10 membered heteroaryl group optionally share two carbon atoms to form a condensed ring.

[0296] In some embodiments, the compound has a structure shown in Formula V-1 or Formula V-1':

[0297] Among them, each of the R 1F2 Independently selected from hydrogen, hydroxy, amino, halogen, preferably hydrogen or hydroxy;

[0298] H 1 、H 2 、H 3 、H 4 are each independently C or a chemically acceptable heteroatom, and at least one is a heteroatom;

[0299] is a single bond or a double bond;

[0300] Preferably, the heteroatom is selected from any one of N, O, and S;

[0301] Preferably, the for

[0302] Preferably, the R 1 Any one selected from the group consisting of: -OR 1A 、-NR1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 , each of the R 1A 、R 1B 、R 1C Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0303] Each of the G 1 Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 replace;

[0304] Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D , the R 1D Any one selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and halogen-substituted C1-C3 alkoxy.

[0305] In some embodiments, the Any one of the following groups:

[0306] In some embodiments, the C ring is a 6-10 membered aryl-O-C1-C6 alkyl, a 3-9 membered heterocyclyl-O-C1-C3 alkyl, a 3-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; and the aryl, heteroaryl, and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclic group; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclyl are each optionally substituted by halogen.

[0307] In some embodiments, the C ring is a 4-8 membered heterocyclyl-O-C1-C3 alkyl, the heterocyclyl being replaced by one R 2 Substituted, preferably, the R 2 It is a halogenated alkyl group.

[0308] In some embodiments, the C ring is phenyl-O-C1-C3 alkyl, and the phenyl group is 1, 2 or 3 R 2 Substituted, preferably, each of the R 2 are each independently halogen.

[0309] In some embodiments, the C ring is a 4-9 membered heterocyclic group, preferably the C ring is The R 2 The number n is 1 or 2 or 3; preferably, each of the R 2 Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, phenyl, halophenyl and hydroxyl; R 2 When phenyl or halogenated phenyl, optionally phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0310] In some embodiments, the C ring is any one of the following 5-10 membered heteroaryl groups:

[0311] 1)

[0312] Preferably, the R 2 is any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, halophenyl, wherein R 2 The number p is 1 or 2, the R 2 When phenyl or halogenated phenyl Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0313] 2)

[0314] Preferably, the R 2 Any one selected from the group consisting of: hydrogen, halogen, phenyl, C1-C3 alkyl, C1-C3 alkoxy-C3-C6 cycloalkyl; the phenyl, the alkyl, the alkoxy is unsubstituted or substituted with halogen; the R 2 When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0315] In some embodiments, the C ring is phenyl; the phenyl is replaced by R 2 Substituted; preferably, the R 2 Any one selected from the group consisting of: C1-C3 haloalkyl.

[0316] In some embodiments, the C ring is selected from any one of the following groups:

[0317] The L 2 for

[0318] In some embodiments, the compound has a structure shown in Formula V-2 or Formula V-2':

[0319] The L 2 for in, End and formula V-2 The N atom is connected; n is 1-3; the R 2 The number of R is 1, 2 or 3, and each of the R 2 Each is independently selected from any one of the following groups: hydrogen, halogen, and hydroxyl.

[0320] In some embodiments, the compound has a structure shown in Formula VI, Formula VII, Formula VIII, or Formula IX:

[0321] The A ring is a 5-7 membered heteroaryl group; wherein the heteroaryl group may be substituted by 1-2 R 1 replace;

[0322] Each of the R 1Each independently selected from the group consisting of any one of the following groups: halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, -OR 1A 、-NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ;

[0323] Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0324] Each of the G 1 Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 Replace; when G 1 When it is a phenyl group, the phenyl group and the 5-6 membered heterocyclic group or the 5-7 membered heteroaryl group optionally share two carbon atoms to form a condensed ring;

[0325] Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D ;

[0326] L 1 Empty, -NH-, in, The end is connected to the A ring, the * end is connected to the B ring; preferably the * end is connected to the The & C atoms in formula VII The & C atoms in formula VIII The & C atoms in formula IX &C Atom Connection;

[0327] Preferably, the L 1 Empty, -NH-,

[0328] Preferably, the L 1 Empty,

[0329] L 2 Empty, -NH-, in, The end is connected to the B ring, and the * end is connected to the C ring; preferably The terminal and the @C atom, in formula VII @C atom, in formula VIII @C atom, formula IX @C atom connection;

[0330] Preferably, the L 2 Empty, -NH-,

[0331] Preferably, the L 2 Empty,

[0332] Each of the R 1F2 are independently selected from hydrogen, hydroxy, amino, carboxyl or halogen.

[0333] In some embodiments, the compound preferably has a structure shown in Formula VI-1, Formula VII-1, Formula VIII-1, Formula IX-1, Formula VI-1', Formula VII-1', Formula VIII-1', Formula IX-1':

[0334] R in each formula 1F2 Each is independently hydrogen, hydroxy, amino, carboxyl or halogen, preferably hydrogen or hydroxy;

[0335] H 1 、H 2 、H 3 、H 4 are each independently C or a chemically acceptable heteroatom, and at least one is a heteroatom;

[0336] is a single bond or a double bond;

[0337] Preferably, the heteroatom is selected from any one of N, O, and S;

[0338] Preferably, the for

[0339] Preferably, the R 1 Any one selected from the group consisting of: -OR 1A 、-NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 , each of the R 1A 、R 1B 、R 1C Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy;

[0340] Each of the G 1 Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 replace;

[0341] Each of the R 1F1 Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D , the R 1D Any one selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and halogen-substituted C1-C3 alkoxy.

[0342] In some embodiments, the Any one of the following groups:

[0343] In some embodiments, the C ring is a 6-10 membered aryl-O-C1-C6 alkyl, a 3-9 membered heterocyclyl-O-C1-C3 alkyl, a 3-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; and the aryl, heteroaryl, and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclic group; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclyl are each optionally substituted by halogen.

[0344] In some embodiments, the C ring is a 4-8 membered heterocyclyl-O-C1-C3 alkyl, the heterocyclyl being replaced by one R 2 Substituted, preferably, the R 2 are each independently a haloalkyl group.

[0345] In some embodiments, the C ring is phenyl-O-C1-C3 alkyl, and the phenyl group is 1, 2 or 3 R 2 Substituted, preferably, each of the R 2 are each independently halogen.

[0346] In some embodiments, the C ring is a 4-9 membered heterocyclyl.

[0347] Preferably, the C ring is The R 2 The number n is 1 or 2 or 3; preferably, each of the R 2 Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, phenyl, halophenyl and hydroxyl; R 2 When phenyl or halogenated phenyl, optionally phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0348] In some embodiments, the C ring is any one of the following 5-10 membered heteroaryl groups:

[0349] 1)

[0350] Preferably, the R 2 is any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, halophenyl, wherein R 2 The number p is 1 or 2, the R 2 When phenyl or halogenated phenyl Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0351] 2)

[0352] Preferably, the R 2 Any one selected from the group consisting of: hydrogen, halogen, phenyl, C1-C3 alkyl, C1-C3 alkoxy-C3-C6 cycloalkyl; the phenyl, the alkyl, the alkoxy is unsubstituted or substituted with halogen; the R 2 When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner:

[0353] In some embodiments, the C ring is phenyl; the phenyl is replaced by R 2 Substituted; preferably, the R 2 Any one selected from the group consisting of: C1-C3 haloalkyl.

[0354] In some embodiments, the C ring is selected from any one of the following groups:

[0355] The L 2 for in, The end and the @C atom, in formula VII-1 @C atom, in formula VIII-1 @C atom, in formula IX-1 The @C atom.

[0356] In some embodiments, the compound has a structure shown in Formula VI-2, Formula VII-2, Formula VIII-2, Formula IX-2, Formula VI-2', Formula VII-2', Formula VIII-2', Formula IX-2':

[0357] Each of the L 2 for in, The end and the @C atom, in formula VII-2 @C atom, in formula VIII-2 @C atom, in formula IX-2 @C atom; n is 1-3; the R 2 The number of R is 1, 2 or 3, and each of the R 2 Each is independently selected from any one of the following groups: hydrogen, halogen, and hydroxyl.

[0358] In some embodiments, the compound has a structure represented by any of the following formulae:

[0359] The A ring, L 1 , B ring, L 2 , C ring, R 1 、R 1F2 、H 1 、H 2 、H 3 、H 4 、R 2 , n, and m are defined the same as in any of the previous schemes.

[0360] In some embodiments, the compound is specifically:

[0361] In some embodiments, a pharmaceutical composition is provided, comprising a preparation prepared from any one of the above compounds, 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.

[0362] Furthermore, the above-mentioned pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and vehicles.

[0363] In some embodiments, provided is the use of any of the above compounds, or their stereoisomers, or their tautomers, or their geometric isomers, or their enantiomers, or their diastereomers, or their racemates, or their polymorphs, or their solvates, or their hydrates, or their N-oxides, or their isotopically labeled compounds, or their metabolites, or their esters, or their prodrugs, or their pharmaceutically acceptable salts, or their pharmaceutical compositions for the preparation of a medicament for preventing and / or treating neurodegenerative diseases (e.g., leukodystrophy, white matter lesions, myelin dysplasia or demyelinating diseases, intellectual disability syndromes, cognitive dysfunction, glial cell dysfunction or brain injury (e.g., traumatic brain injury or toxin-induced brain injury), 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 the unfolded protein response (UPR), malaria infection, musculoskeletal diseases, metabolic diseases, or mitochondrial diseases.

[0364] In some embodiments, provided is the use of any of the above-described compounds, or their stereoisomers, or their tautomers, or their geometric isomers, or their enantiomers, or their diastereomers, or their racemates, or their polymorphs, or their solvates, or their hydrates, or their N-oxides, or their isotopically labeled compounds, or their metabolites, or their esters, or their prodrugs, or their pharmaceutically acceptable salts, or their pharmaceutical compositions for the preparation of a medicament for preventing and / or treating a disease or condition mediated by the integrated stress response (ISR) pathway.

[0365] 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.

[0366] 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.

[0367] 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.

[0368] 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.

[0369] 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).

[0370] 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.

[0371] 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.

[0372] 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.

[0373] 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.

[0374] 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.

[0375] 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.

[0376] 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.

[0377] 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.

[0378] 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-polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, silica exposure chronic kidney disease, Sri Lankan Farmers' Kidney Disease, Sjögren's nephropathy, acute kidney injury from synthetic cannabinoid use, post-hematopoietic cell transplant nephropathy, stem cell transplant-associated 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, genitourinary tuberculosis, tuberous sclerosis, renal tubular dysgenesis, proximal tubular brush border Immune complex tubulointerstitial nephritis caused by autoantibodies, tumor lysis syndrome, uremia, uremic optic neuropathy, cystic ureteritis, ureterocerebia, urethral caruncle, urethral stricture, urinary incontinence, urinary tract infection, urinary tract obstruction, genitourinary dysfunction, uromodulin-related nephropathy, vancomycin-related cast nephropathy, vasomotor nephropathy, bladder fistula, vesicoureteral reflux, VGEF-inhibited renal thrombotic microangiopathy, volatile anesthetic-induced acute kidney injury, and 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.

[0379] The above-mentioned skin diseases include, but are not limited to: acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic erythropoiesis, contact dermatitis, Darier's disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extramammary Paget's disease, simplex epidermolysis bullosa, erythropoietic protoporphyria, fungal infection of the nails, Hailey-Hailey disease, 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.

[0380] 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.

[0381] 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.

[0382] 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)).

[0383] Such viral infections include, but are not limited to, influenza, human immunodeficiency virus (HIV), and herpes.

[0384] The aforementioned malarial infections include, but are not limited to, infections caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium falciparum.

[0385] 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.

[0386] 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.

[0387] 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.

[0388] "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

[0389] "Optionally substituted by..." means that "substitution" may but need not occur, and the description includes situations where it occurs or does not occur.

[0390] "Optionally" means that it can be selected but not necessarily selected, including the situation of being selected or not selected.

[0391] 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.

[0392] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. An alkyl group can be straight or branched. Representative branched alkyl groups have one, two, or three branches. An alkyl group can optionally be substituted with one or more substituents as defined herein. 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.

[0393] The term "C1-C10 alkyl" refers to any straight-chain or branched group containing 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, and the following straight-chain or branched alkyl groups: C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, etc.

[0394] Furthermore, the "C1-C10 alkyl" includes straight-chain or branched groups whose carbon number is between 1 and 10 and whose endpoints are any two integers. For example, the "C1-C10 alkyl" includes C1-C10 alkyl, C1-C8 alkyl, C1-C6 alkyl, C2-C10 alkyl, C2-C8 alkyl, C2-C6 alkyl, C6-C10 alkyl, and the like. The above list is for example only and does not limit the above range.

[0395] The term "alkoxy" and its derivatives refer to any of the above alkyl groups (eg, C1-C10 alkyl, C1-C6 alkyl, etc.) that is attached to the rest of the molecule through an oxygen atom (-O-).

[0396] "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:

[0397] The C1-C4 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, or a C4 alkylene group.

[0398] The "cycloalkyl" described in the present invention refers to a saturated cyclic alkane having a single ring or multiple rings (condensed ring, spiro ring, bridged ring) with multiple carbon atoms and no ring heteroatoms. Examples of monocarbocyclic groups include, for example, cyclopropane, cyclobutane, cyclohexane, cyclopentane, cyclooctane, cyclopentene and cyclohexene. Examples of condensed cycloalkane systems include dicyclohexane, dicyclopentane, dicyclooctane and the like. The "cycloalkyl" described in the present invention includes, but is not limited to, wait.

[0399] The term "C3-C10 cycloalkyl" refers to a 3- to 10-membered all-carbon monocyclic, fused, bridged, or spirocyclic 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.

[0400] The "heterocyclic group" described in the present invention refers to a saturated ring having a single ring or multiple rings (condensed ring, bridged ring and spiro ring) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Examples of 3-9 membered heterocyclic groups can be oxetane, azetidinyl, oxolane, oxahenyl, piperazinyl, piperidinyl, morpholinyl, s-trioxanyl, etc. The embodiments of the "heterocyclic group" described in the present invention include but are not limited to Or piperidinyl, etc.

[0401] The "5-10 membered spiro ring" as used herein refers to a saturated or non-aromatic partially saturated divalent ring formed by the spiro ring of two or more rings having 5-10 carbon atoms and no ring heteroatoms. Examples of 5-10 membered spiro ring systems may include: spiro[2,5]octyl ring, spiro[3,4]octyl ring, spiro[3,3]heptyl ring, spiro[3,5]nonyl ring, spiro[4,5]decyl ring, spiro[2,2]pentyl ring, spiro[2,3]hexyl ring, spiro[2,4]heptyl ring, spiro[2,6]nonyl ring, spiro[2,7]nonyl ring, spiro[3,6]nonyl ring, and spiro[4,4]nonyl ring.

[0402] The "5-10 membered spiroheterocycle" mentioned in the present invention refers to a saturated ring or a non-aromatic partially saturated divalent ring formed by the spiro-combination of two or more rings formed by replacing at least one carbon atom in the above-mentioned "5-10 membered spiroheterocycle" with a heteroatom; examples of the 5-10 membered spiroheterocycle system include spiroheterocycles formed by replacing at least one carbon atom in the above-mentioned spiro[2,5]octyl ring, spiro[3,4]octyl ring, spiro[3,3]heptyl ring, spiro[3,5]nonyl ring, spiro[4,5]decyl ring, spiro[2,2]pentyl ring, spiro[2,3]hexyl ring, spiro[2,4]heptyl ring, spiro[2,6]nonyl ring, spiro[2,7]nonyl ring, spiro[3,6]nonyl ring and spiro[4,4]nonyl ring with a heteroatom selected from N, O, S, etc., for example, wait.

[0403] 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.

[0404] As used herein, "aromatic ring" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aromatic groups having multiple carbon atoms. Additionally, 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, or tetrahydronaphthyl.

[0405] The term "5-10 membered heteroaryl" as used herein refers to an aromatic unsaturated ring containing at least one heteroatom, such as nitrogen, oxygen, or sulfur. 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, the ring contains 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.

[0406] The "halogen" mentioned in the present invention refers to fluorine, chlorine, bromine or iodine.

[0407] 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 C 1～4 The alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0408] The "-N(R)2" and the like described in the present invention means that the R group is connected to the nitrogen atom by a single bond.

[0409] The "=O" (oxo) described in the present invention means that an oxygen atom replaces two hydrogen atoms in a molecule through a double bond.

[0410] 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.

[0411] The "empty" in the present invention means that the objects it is connected to are directly connected through a key, for example, "L 1Empty" means that 1 The separately connected A ring and B ring are directly linked by a bond.

[0412] In the present invention, the "linking group" refers to a chemical group containing two connectable bonds, such as O, S, -NH-, -N(alkyl)-, alkylene, heteroalkylene, cycloalkylene, heterocyclylene, etc.

[0413] In the present invention, "stereoisomers" refer to compounds with the same chemical structure but different arrangements of atoms or groups in space, including enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, etc.

[0414] 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.

[0415] In the present invention, "geometric isomers" are also called "cis-trans isomers", which are isomers caused by the inability of double bonds (including double bonds of olefins, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms to rotate freely.

[0416] In the present invention, "enantiomers" refer to two isomers of a compound that are non-superimposable but mirror images of each other.

[0417] As used herein, "diastereoisomers" refer to stereoisomers that have two or more chiral neutral atoms and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

[0418] In the present invention, "racemate", "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.

[0419] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention may exist in various forms as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0420] 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.

[0421] In the present invention, "solvate" refers to a mixture formed by dissolving a compound in a solvent.

[0422] 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).

[0423] 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.

[0424] 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.

[0425] 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.

[0426] In the present invention, "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or the salt formed is generally chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form and physiologically compatible with the receptor.

[0427] In the present invention, "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 directly obtained during the final separation and purification of the compound. They can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a certain amount of acid or base, as appropriate (e.g., equivalent amounts). 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.

[0428] "Prevention" in the present invention includes inhibition and delay of 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.

[0429] As used herein, "treat," "treat," or "treating" means reversing, alleviating, or eliminating the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0430] 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.

[0431] 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.

[0432] 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

[0433] The known starting materials of the present invention can be synthesized using methods known in the art, or can be purchased from companies such as Bidex Pharmaceuticals, Anaiji Chemical, Exploration Platform, Nanjing Yaoshi, Jiangsu Aikang, and Beijing Inokai Technology. Tetrapropylammonium perruthenate was purchased from Exploration Platform, and 1-propylphosphoric acid cyclic anhydride was purchased from Beijing Inokai Technology Co., Ltd.

[0434] Unless otherwise specified, reactions were conducted under a nitrogen atmosphere. Unless otherwise specified, solutions in the examples are aqueous solutions. Unless otherwise specified, reactions were conducted at room temperature. Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C. Unless otherwise specified, M is moles per liter.

[0435] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6 The 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.

[0436] N,N'-diisopropylethylamine (also known as diisopropylethylamine) is abbreviated as DIEA or DIPEA; 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is abbreviated as HATU; tetrapropylammonium perruthenate is abbreviated as TPAP; 1-propylphosphoric acid cyclic anhydride is abbreviated as T3P; N-methylmorpholine-N-oxide is abbreviated as NMO; trifluoroacetic acid is abbreviated as TFA; dimethylformamide is abbreviated as DMF; dichloromethane is abbreviated as DCM; petroleum ether is abbreviated as PE.

[0437] Example 1: Synthesis of Compound I-1

[0438] Step 1: Synthesis of intermediate 1b.

[0439] To a mixed solution of tetrahydrofuran (40 mL), methanol (20 mL) and water (10 mL) were added raw material 1a (10 g, 42.98 mmol) and lithium hydroxide (5.97 mL, 214.92 mmol), and the reaction was stirred at 25° C. for 18 hours. The resulting reaction mixture was then adjusted to pH 7 with dilute hydrochloric acid (1 M) and extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 1b.

[0440] 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),7.47(t,J=8.9Hz,1H),7.07(dd,J=11.5,2.9Hz,1H),6.87–6.76(m,1H),4.73(s,2H).

[0441] Step 2: Synthesis of intermediate 1d.

[0442] To N,N-dimethylformamide (5 mL) were added intermediate 1b (100 mg, 0.49 mmol), intermediate 1c (0.11 mL, 0.54 mmol, Bid, BD215605), HATU (278.80 mg, 0.73 mmol) and DIPEA (0.24 mL, 1.47 mmol), and the reaction was stirred at 25 ° C for 1 hour. The resulting reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL x3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by preparative TLC (dichloromethane: methanol = 20: 1) to give intermediate 1d. MS m / z: 357.2 [M + H-56] + .

[0443] 1 H NMR (400MHz, CDCl3) δ7.25(t,J=8.6Hz,1H),6.67(dd,J=10.3,2.9Hz,1H),6.61–6.56(m,1H),6.35(s,1H),4.40(s,2H),3.40–3. 26(m,4H),2.65–2.59(m,1H),1.39(s,9H),1.31(dd,J=7.0,4.3Hz,4H),0.83(dd,J=7.9,5.8Hz,1H),0.41(d,J=5.8,4.3Hz,1H).

[0444] Step 3: Synthesis of intermediate 1e

[0445] Intermediate 1d (150 mg, 0.36 mmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (5 mL) and stirred at 25° C. for 1 hour. The mixture was concentrated to dryness under reduced pressure to obtain Intermediate 1e.

[0446] MS m / z:313.2[M+H] + .

[0447] 1H NMR (400MHz, CDCl3) δ8.40(s,1H),7.28(d,J=8.7Hz,1H),6.76(s,1H),6.69(dd,J=10.1,2.8Hz,1H),6.62–.658(m,1H),4.48(s,2 H),2.67–2.61(m,1H),1.93(d,J=11.7Hz,2H),1.48(s,2H),1.32–1.16(m,4H),0.99(dd,J=8.0,6.3Hz,1H),0.64(t,J=5.5Hz,1H).

[0448] Step 4: Synthesis of compound I-1.

[0449] To N,N-dimethylformamide (2 mL) were added intermediate 1e (30 mg, 0.10 mmol), raw material 1f (0.01 mL, 0.11 mmol), HATU (54.71 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.29 mmol), and the reaction was stirred at 25 ° C for 1 hour. The resulting reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by preparative TLC (eluent: petroleum ether: ethyl acetate = 1:5) to give compound I-1.

[0450] MS m / z:469.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.96(d,J=3.9Hz,2H),8.23(dd,J=21.7,4.1Hz,1H),7.5 5–7.40(m,1H),7.34–6.97(m,2H),6.88–6.77(m,1H),4.58(d,J=19.6Hz,2H),3. 99–3.79(m,1H),3.54–3.39(m,1H),3.30–3.03(m,2H),2.64–2.54(m,1H),1.63– 1.41(m,2H),1.27(d,J=43.9,15.8Hz,2H),0.83–0.74(m,1H),0.68–0.59(m,1H).

[0451] Example 2: Synthesis of Compound I-2

[0452] Step 1: Synthesis of compound I-2.

[0453] To N,N-dimethylformamide (2 mL) were added intermediate 1e (30 mg, 0.10 mmol), raw material 2a (0.01 mL, 0.11 mmol), HATU (54.71 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.29 mmol) and stirred at 25 ° C for 2 hours. The resulting reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (eluent: dichloromethane: methanol = 20: 1) to obtain compound I-2.

[0454] MS m / z:491.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.24 (d, J=4.0Hz, 1H), 7.81 (d, J=2.2Hz, 1H), 7.71 (d, J=8.8Hz, 1 H), 7.47 (dd, J=8.8, 2.3Hz, 2H), 7.31 (s, 1H), 7.04 (dd, J=11.6, 2.9Hz, 1H), 6.84 (dd, J=9. 5, 2.6Hz, 1H), 4.59 (s, 2H), 3.95–3.43 (m, 3H), 3.31 (s, 1H), 2.64–2.57 (m, 1H), 1.53 (d, J =10.3Hz, 2H), 1.30 (d, J=12.0Hz, 2H), 0.79 (dd, J=8.1, 5.4Hz, 1H), 0.65 (t, J=5.0Hz, 1H).

[0455] Example 3: Synthesis of Compound I-3

[0456] Step 1: Synthesis of intermediate 3b.

[0457] To dichloromethane (5 mL) were added starting material 3a (80 mg, 0.27 mmol), tetrapropylammonium perruthenate (18.76 mg, 0.05 mmol) and NMO (187.60 mg, 1.60 mmol). The mixture was stirred at 25°C for 2 hours. The resulting reaction mixture was concentrated to dryness under reduced pressure to obtain intermediate 3b.

[0458] MS m / z:312.1[MH] - .

[0459] Step 2: Synthesis of intermediate 3c.

[0460] To N,N-dimethylformamide (2 mL) were added intermediate 3b (50 mg, 0.16 mmol), intermediate 1e (49.85 mg, 0.16 mmol), HATU (90.90 mg, 0.24 mmol) and DIPEA (0.08 mL, 0.48 mmol) and stirred at 25 ° C for 2 hours. The resulting reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was subjected to preparative TLC (eluent: petroleum ether: ethyl acetate = 1:5) to obtain intermediate 3c.

[0461] MS m / z:508.2[M+H-100] + .

[0462] Step 3: Synthesis of compound I-3.

[0463] To dichloromethane (5 mL) was added intermediate 3c (50 mg, 0.08 mmol) and trifluoroacetic acid (1 mL), and the reaction was stirred at 25 ° C for 1 hour. The resulting reaction mixture was concentrated to dryness under reduced pressure to obtain a crude product. Sodium bicarbonate (100 mg) was added to the crude product and stirred at 25 ° C for 1 hour. The resulting mixture was filtered and the filter cake was washed with dichloromethane (20 mL x 3). The filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was subjected to preparative TLC (eluent: dichloromethane: methanol = 20:1) to obtain compound I-3.

[0464] MS m / z:508.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.21 (s, 1H), 7.49 (t, J=8.9Hz, 1H), 7.03 (d, J=10.4Hz, 1H), 6.83 (d, J=8.7Hz, 1H), 6.67 (d, J=9.5Hz, 1H), 6.58 (d, J=2.5Hz, 1H), 6.45 (dd, J=8.5, 2.5Hz, 1H ), 6.18(s, 1H), 4.87(d, J=11.3Hz, 1H), 4.58(d, J=3.9Hz, 2H), 3.87–3.52(m, 2H), 3.45–3. 35(m, 2H), 2.63–2.55(m, 1H), 1.31(m,, 6H), 0.76(d, J=6.9Hz, 1H), 0.61(t, J=5.2Hz, 1H).

[0465] Example 4: Synthesis of Compound I-4

[0466] Step 1: Synthesis of Compound I-4

[0467] Compound I-3 (30 mg, 0.06 mmol), dimethyl sulfate (0.01 mL, 0.12 mmol) and potassium carbonate (24.47 mg, 0.18 mmol) were added to acetonitrile (3 mL), the mixture was degassed and replaced with nitrogen 3 times, and the reactants were stirred at 70 ° C for 18 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was subjected to preparative TLC (eluent: dichloromethane: methanol = 40: 1) to obtain compound I-4.

[0468] MS m / z:522.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.21 (s, 1H), 7.50 (t, J=8.9Hz, 1H), 7.03 (d, J=9.8H z, 1H), 6.83 (d, J=8.7Hz, 1H), 6.74–6.64 (m, 2H), 6.59–6.53 (m, 1H), 5.08 (d, J=12.3Hz, 1H), 4.58(d, J=3.6Hz, 2H), 3.62(m, 2H), 3.32–3.24(m, 2H), 2.86 (q, J=1.8Hz, 3H), 2.58(s, 1H), 1.47–1.11(m, 6H), 0.76(s, 1H), 0.62(s, 1H).

[0469] Example 5: Synthesis of Compound I-5

[0470] Step 1: Synthesis of intermediate 5a.

[0471] To a mixed solution of water (3 mL) and glacial acetic acid (6 mL) was added intermediate 1e (100 mg, 0.32 mmol) and sodium nitrite (0.07 mL, 1.28 mmol), and the reaction was stirred at 25°C for 18 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate 5a. MS m / z: 341.8 [M+H] + .

[0472] Step 2: Synthesis of intermediate 5b.

[0473] To a mixed solution of tetrahydrofuran (2 mL) and water (2 mL) was added intermediate 5a (100 mg, 0.29 mmol), glacial acetic acid (0.5 mL), and zinc (97 mg, 1.48 mmol), and the reaction was stirred at 25°C for 18 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain intermediate 5b. MS m / z: 312.8 [M+H-16] + .

[0474] Step 3: Synthesis of compound I-5.

[0475] To N,N-dimethylformamide (3 mL) were added intermediate 5b (30 mg, 0.09 mmol), intermediate 1b (20.60 mg, 0.10 mmol), HATU (52.20 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.27 mmol) and stirred at 25 ° C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was subjected to preparative TLC (eluent: dichloromethane: methanol = 20:1) to obtain compound I-5.

[0476] MS m / z:514.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.01(m,,1H),8.08(d,J=4.5Hz,1H),7.53–7.41(m,2H ),7.08–6.96(m,2H),6.86–6.73(m,2H),4.89(s,1H),4.55(d,J=7.1Hz,2H),4. 47(d,J=4.6Hz,1H),3.06–2.72(m,2H),2.71–2.56(m,2H),1.90(s,1H),1.37( d,J=17.5Hz,2H),1.27–0.89(m,2H),0.67(t,J=6.4Hz,1H),0.56–0.46(m,1H).

[0477] Example 6: Synthesis of Compound I-6

[0478] Step 1: Synthesis of compound I-6.

[0479] Intermediate 5b (30 mg, 0.09 mmol), starting material 2a (0.01 mL, 0.10 mmol), HATU (52.20 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.27 mmol) were added to N,N-dimethylformamide (2 mL) and stirred at 25 ° C for 18 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was subjected to preparative TLC (eluent: dichloromethane: methanol = 20:1) to obtain compound I-6.

[0480] MS m / z:506.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 8.09 (d, J = 4.6Hz, 1H), 7.86 (d, J = 2.2Hz, 1H), 7.69 (d, J = 8.7Hz, 1H), 7.55–7.45 (m, 3H), 7.04 (dd, J = 11.4, 2.9H z, 1H), 6.88–6.80 (m, 1H), 4.57 (s, 2H), 2.96–2.71 (m, 4H), 1.45 (s, 4H), 0. 85 (t, J=6.5Hz, 1Hz), 0.70 (d, J=8.0, 5.1Hz, 1Hz), 0.56 (t, J=4.8Hz, 1Hz).

[0481] Example 7: Synthesis of Compound I-7

[0482] Step 1: Synthesis of intermediate 7a.

[0483] To N,N-dimethylformamide (5 mL) were added intermediate 5b (60 mg, 0.18 mmol), intermediate 3b (63.17 mg, 0.20 mmol), HATU (104.40 mg, 0.27 mmol) and DIPEA (0.09 mL, 0.55 mmol) and the reaction was stirred at 25 ° C for 18 hours. The resulting reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was subjected to preparative TLC (eluent: ethyl acetate: petroleum ether = 4:1) to obtain intermediate 7a. MS m / z: 568.8 [M+H-56] + .

[0484] Step 2: Synthesis of compound I-7.

[0485] To a solution of dichloromethane (5 mL) was added intermediate 7a (50 mg, 0.08 mmol) and trifluoroacetic acid (1 mL), and the reaction was stirred at 25°C for 1 hour. The resulting reaction mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was dissolved in dichloromethane (5 mL) and the pH was adjusted to 7 with sodium carbonate. The mixture was filtered and the filter cake was washed with dichloromethane (20 mL x 3). The filtrate was concentrated to dryness under reduced pressure to obtain compound I-7.

[0486] MS m / z:524.4[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03 (s, 1H), 8.09 (d, J = 4.4Hz, 1H), 7.49 (td, J = 8.9, 3.9Hz, 1H), 7.03 (dd, J = 11.3, 2. 9,1.3Hz,1H),6.85–6.80(m,1H),6.75(d,J=8.5Hz,1H),6.61–6.55(m,1H),6.52–6.46(m,1H),6.15(d,J=33. 4Hz,1H),4.59–4.51(m,2H),4.38(dd,J=7.3,2.8Hz,1H),3.44–3.36(m,1H),3.22–3.15(m,1H),2.74(s,2H), 2.69(s,2H),2.58(dt,J=8.3,4.3Hz,1H),1.39(s,2H),1.23(s,2H),0.70–0.65(m,1H),0.53(d,J=4.8Hz,1H).

[0487] Example 8: Synthesis of Compound I-8

[0488] Step 1: Synthesis of intermediate 8a.

[0489] To a solution of dichloromethane (5 mL) was added intermediate 3a (200 mg, 0.67 mmol) and trifluoroacetic acid (1 ml), and the resulting mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated to give intermediate 8a, MS m / z: 200.6 [M+H] + .

[0490] Step 2: Synthesis of intermediate 8b.

[0491] To an acetonitrile (10 mL) solution was added intermediate 8c (133 mg, 0.67 mmol), potassium carbonate (276.22 mg, 2.00 mmol) and dimethyl sulfate (338.03 mg, 2.68 mmol) were added at 25 ° C. Under a nitrogen atmosphere, the resulting mixture was stirred at 70 ° C for 18 hours. The reaction solution was filtered and the filter cake was washed with ethyl acetate (20 mL x 3). The filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was subjected to preparative TLC (eluent: petroleum ether: ethyl acetate = 1:1) to obtain intermediate 8b. MS m / z: 214.6 [M+H] + .

[0492] Step 3: Synthesis of intermediate 8c.

[0493] A solution of intermediate 8b (100 mg, 0.33 mmol), tetrapropylammonium perruthenate (23.45 mg, 0.07 mmol), and NMO (234.50 mg, 2.00 mmol) was added to a dichloromethane (5 mL) solution and stirred at 25°C for 2 hours. The resulting mixture was concentrated to dryness under reduced pressure to obtain intermediate 8c. MS m / z: 228.6 [M+H] + .

[0494] Step 4: Synthesis of compound I-8.

[0495] To a solution of N,N-dimethylformamide (3 mL) were added Intermediate 5b (50 mg, 0.15 mmol), Intermediate 8c (34.72 mg, 0.15 mmol), HATU (87.00 mg, 0.23 mmol), and DIPEA (0.08 mL, 0.46 mmol), and the mixture was stirred at 25°C for 2 hours. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The product was purified by HPLC (Phenomenex Gemini 150 mm*25 mm*10 μm column (eluent: 30% to 60% (v / v) CH3CN and H2O with 0.025% HCOOH)) to obtain compound I-8. MS m / z: 537.4 [M+H] + .

[0496] Example 9: Synthesis of Compound I-9

[0497] Step 1: Synthesis of intermediate 9a

[0498] Starting material 2a (100 mg, 0.51 mmol), starting material 1c (115.12 mg, 0.51 mmol), DIPEA (197.24 mg, 1.53 mmol), and HATU (232.10 mg, 0.61 mmol) were added to DMF (5 mL) and reacted at 25°C for 3 hours. The resulting mixture was washed with water (30 mL) and then extracted with ethyl acetate (10 mL x 3) to obtain an organic phase. The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase: v / v (PE / EtOAc) = 20 / 1 to 1 / 1) to obtain intermediate 9a. MS m / z: 405.0 [M+H] + .

[0499] Step 2: Synthesis of intermediate 9b

[0500] Intermediate 9a (160 mg, 0.40 mmol) and TFA (2 mL) were added to DCM (10 mL) and reacted at 25°C for 2 hours. The resulting reaction mixture was concentrated under reduced pressure to give Intermediate 9b. MS m / z: 305.0 [M+H] + .

[0501] Step 3: Synthesis of Compound I-9

[0502] Intermediate 9b (50 mg, 0.16 mmol), starting material 2a (26.88 mg, 0.14 mmol), DIPEA (53.01 mg, 0.42 mmol), and HATU (62.4 mg, 0.16 mmol) were added to DMF (1 mL) and reacted at 25°C for 2 hours. The resulting reaction mixture was washed with water (10 mL) and then extracted with EtOAc (5 mL x 3) to obtain an organic phase. The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (eluent containing 0.225% formic acid: v / v (acetonitrile / water) = 43% to 100%) to obtain compound I-9.

[0503] MS m / z:483.0[M+H] + . 1H NMR (400MHz, DMSO) δ8.91(d,J=3.5Hz,1H),7.89(d,J=2.0Hz,1H),7.80(s,1H),7.70(d,J=8.8Hz,2H),7.56(s,1H),7.52– 7.43(m,2H),7.34(s,1H),3.82(d,J=39.9Hz,2H),2.79(d,J=3.8Hz,1H),1.68–1.10(m,6H),0.88(dd,J=11.9,4.7Hz,2H).

[0504] Example 10: Synthesis of Compound I-10

[0505] Step 1: Synthesis of intermediate 10a.

[0506] Intermediate 9b (70 mg, 0.23 mmol) and sodium nitrite (135.84 mg, 1.97 mmol) were added to AcOH (4 mL) and water (12 mL) and reacted at 60°C for 18 hours. The resulting mixture was washed with water (20 mL) and then extracted with DCM (5 mL x 3). The organic phase was separated and washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by TLC (PE / EtOAc (v / v) = 1 / 1) to obtain Intermediate 10a.

[0507] MS m / z:334.0[M+H] + . 1 H NMR (400MHz, DMSO) δ8.95 (d, J=3.9Hz, 1H), 7.89 (dd, J=4.2, 2.1Hz, 1H), 7.70 (dd, J=8.8, 5.0Hz, 1H), 7.56 (d, J=8.8Hz, 1H),7.52–7.47(m,1H),4.17(ddd,J=107.1,44.7,36.3Hz,3H),2.82(ddd,J=12.4,7.9,4.3Hz,1H),1.62(m,,5H),0.98 –0.89(m,2H).

[0508] Step 2: Synthesis of Intermediate 10b

[0509] Intermediate 10a (60 mg, 0.18 mmol) and zinc powder (117.53 mg, 1.80 mmol) were added to a mixture of THF (2.5 mL), H₂O (2.5 mL), and AcOH (0.5 mL) and reacted at 25°C for 3 hours. The resulting mixture was adjusted to pH 9 with 20% ammonia solution (3 M), then extracted with EtOAc (8 mL x 3) to obtain an organic phase. The organic phase was washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to yield Intermediate 10b. MS m / z: 320.0 [M+H] + .

[0510] Step 3: Synthesis of Compound I-10

[0511] Intermediate 2a (33.5 mg, 0.17 mmol), intermediate 10b (59.94 mg, 0.19 mmol), DIPEA (66.07 mg, 0.51 mmol), and HATU (77.75 mg, 0.20 mmol) were added to DMF (5 mL) and reacted at 25°C for 2 hours. The resulting mixture was washed with water (10 mL) and then extracted with EtOAc (5 mL x 3) to obtain an organic phase. The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (eluent: 43% to 100% (v / v) CH3CN and H2O with 0.225% HCOOH) to obtain compound I-10.

[0512] MS m / z:498.0[M+H] + .

[0513] 1 H NMR (400MHz, DMSO) δ9.87 (s, 1H), 8.78 (d, J = 4.5Hz, 1H), 7.88 (dd, J = 9.3, 2.2Hz, 2H), 7.70 (dd, J = 8.8, 3.5Hz, 2H),7.54(d,J=6.3Hz,2H),7.50–7.47(m,2H),2.98–2.81(m,5H),1.56(d,J=15.0Hz,4H),0.83–0.78(m,2H).

[0514] Example 11: Synthesis of Compound II-10

[0515] Step 1: Synthesis of intermediate 11b.

[0516] To a solution of intermediate 1b (448.07 mg, 2.19 mmol) in DMF (10 mL) was added intermediate 11a (500 mg, 2.19 mmol), DIPEA (1.09 mL, 6.57 mmol), and HATU (999.36 mg, 2.63 mmol) and stirred at 20°C for 1 hour. The reaction was poured into water (50 mL) and extracted with EtOAc (50 mL x 2) to obtain an organic phase. The organic phase was washed with saturated NaCl solution (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (mobile phase: PE:EtOAc = 1:1) and concentrated in vacuo to obtain intermediate 11b. MS m / z: 359.0 [M+H-56] + .

[0517] Step 2: Synthesis of intermediate 11c

[0518] To a solution of intermediate 11b (100 mg, 0.24 mmol) in DCM (5 mL) was added TFA (1 mL, 13.42 mmol), and the reaction was stirred at 20°C for 3 hours. The mixture was concentrated under reduced pressure to afford intermediate 11c. MS m / z: 315.0 [M+H] + .

[0519] Step 3: Synthesis of Compound II-10

[0520] To a solution of intermediate 11c (76 mg, 0.24 mmol) in DMF (5 mL) were added intermediate 1f (0.03 mL, 0.24 mmol), DIEA (0.12 mL, 0.72 mmol), and HATU (110.18 mg, 0.29 mmol), and the reaction was stirred at 20°C for 1 hour. The resulting mixture was poured into water (20 ml) and extracted with EtOAc (20 ml × 3) to obtain an organic phase. The organic phases were combined, washed with saturated NaCl solution (40 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC, eluted with PE:EtOAc = 1:1, and concentrated in vacuo to obtain compound II-10.

[0521] MS m / z:471.0[M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.22(d,J=1.9Hz,1H),8.98(d,J=2.8Hz,1H),8.34(t,J=5.9Hz,1H),7.50(td,J=8.9,6.7Hz,1H),7.27(dd,J=54.0,2.7Hz,1H), 7.07(dt,J=7.7,2.9Hz,1H),6.88–6.81(m,1H),4.66(dd,J=21.7,11.0,1.6Hz,1H),4.57–4.51(m,3H),4.39–4.2 0(m,2H),4.15–4.06(m,1H),3.95(td,J=8.7,6.2Hz,1H),3.65(td,J=8.2,4.5Hz,1H),2.85(s,1H),2.69(s,1H).

[0522] Example 12: Synthesis of Compound II-11

[0523] Step 1: Synthesis of Compound II-11

[0524] To a solution of intermediate 11c (80 mg, 0.25 mmol), intermediate 1b (52 mg, 0.25 mmol) and DIEPA (0.17 mL, 1.02 mmol) in DMF (3 mL) was added HATU (116 mg, 0.31 mmol) and stirred at 25°C for 2 hours. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (25 mL x 3) to obtain an organic phase. The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (PE:EtOAc = 1:1) to obtain compound II-11.

[0525] MS m / z:501.0[M+H] + . 1H NMR(400MHz,DMSO)δ8.33(d,J=6.4Hz,1H),7.49(td,J=8.9,6.3Hz,2H),7.07(dt ,J=11.4,3.3Hz,2H),6.89–6.76(m,2H),4.76–4.61(m,2H),4.54(s,2H),4.31(dd ,J=16.9,10.0Hz,2H),4.21(t,J=9.0Hz,1H),4.03(dd,J=32.2,10.6Hz,1H),3.95 –3.81(m,2H),3.63(dd,J=8.9,4.4Hz,1H),2.43–2.34(m,1H),2.19–2.10(m,1H).

[0526] Example 13: Synthesis of Compound II-12

[0527] Step 1: Synthesis of Compound II-12

[0528] To a solution of intermediate 11c (113 mg, 0.36 mmol), intermediate 2a (70 mg, 0.36 mmol) and DIEPA (0.24 mL, 1.44 mmol) in DMF (3 mL) was added HATU (164 mg, 0.43 mmol) and stirred at 25°C for 2 hours. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (25 mL x 3) to obtain an organic phase. The combined organic phases were washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (PE:EtOAc = 7:3) to obtain compound II-12.

[0529] MS m / z:493.0[M+H] + . 1H NMR (400MHz, DMSO) δ8.37(d,J=6.4Hz,1H),7.85(s,1H),7.75–7.63(m,1H),7.59–7.43(m,3H ),7.08(dd,J=11.4,2.8Hz,1H),6.85(dd,J=8.9,1.9Hz,1H),4.70(dd,J=26.2,10.0Hz,1H),4 .61–4.50(m,3H),4.36(d,J=7.1Hz,1H),4.22(dd,J=32.4,10.6Hz,1H),4.10–4.03(m,1H),3. 97(dd,J=14.9,5.9Hz,1H),3.67(d,J=4.7Hz,1H),2.44(d,J=12.1Hz,1H),2.25–2.16(m,1H).

[0530] Example 14: Synthesis of Compound II-13

[0531] Step 1: Synthesis of intermediate 14a

[0532] To a solution of intermediate 11c (151.7 mg, 0.48 mmol), intermediate 3b (151 mg, 0.48 mmol), and HATU (219.92 mg, 0.58 mmol) in DMF (3 mL) was added DIPEA (0.32 mL, 1.93 mmol). The mixture was stirred at 25°C for 3 hours. The reaction mixture was poured into water (20 mL), and then extracted with EtOAc (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (eluent EtOAc) to obtain intermediate 14a. MS m / z: 554.0 [M+H-56] + .

[0533] Step 2: Synthesis of Compound II-13

[0534] To a solution of intermediate 14a (140 mg, 0.23 mmol) in DCM (4 mL) was added CF3COOH (1 mL, 13.42 mmol) to form a mixture, which was stirred at 25°C for 20 h. The reaction was concentrated under reduced pressure to obtain a crude product, to which DCM (5 mL) and Na2CO3 (30 mg) were added, and the mixture was stirred at 25°C for 30 min, filtered, and the filtrate was concentrated to obtain compound II-13.

[0535] MS m / z:510.0[M+H] + .1 H NMR (400MHz, DMSO) δ8.42–8.24(m,1H),7.49(tdd,J=9.1,6.2,2.9Hz,1H),7.07(dd,J=1 1.4,2.7Hz,1H),6.84(dd,J=9.0,1.8Hz,1H),6.78–6.68(m,1H),6.59(t,J=2.2Hz,1H), 6.52–6.42(m,1H),6.19(s,1H),4.79–4.66(m,1H),4.54(s,2H),4.52–3.72(m,7H),3.6 2(dd,J=8.9,4.4Hz,1H),3.30(d,J=12.4Hz,1H),2.43–2.28(m,1H),2.20–2.06(m,1H).

[0536] Example 15: Synthesis of Compound II-14

[0537] Step 1: Synthesis of Compound II-14

[0538] To a solution of compound II-13 in ACN (5 mL) were added dimethyl sulfate (0.02 mL, 0.20 mmol) and K2CO3 (40.62 mg, 0.29 mmol). The mixture was stirred at 70°C for 20 hours. The resulting mixture was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (eluent: PE:EtOAc = 2:1) to obtain compound II-14.

[0539] MS m / z:524.0[M+H] + . 1 H NMR (400MHz, DMSO) δ8.32(t,J=5.4Hz,1H),7.49(dd,J=11.3,6.3Hz,1H),7.07(dd,J =11.3,2.6Hz,1H),6.84(d,J=7.6Hz,1H),6.74(ddd,J=16.4,12.9,5.1Hz,2H),6.63 –6.54(m,1H),4.89(s,1H),4.52(d,J=11.8Hz,2H),4.51–3.70(m,7H),3.62(s,1H), 3.30(d,J=9.1Hz,1H),2.85(d,J=15.8Hz,3H),2.43–2.33(m,1H),2.18–2.08(m,1H).

[0540] Example 16: Synthesis of Compound III-10

[0541] Step 1: Synthesis of intermediate 16b

[0542] Intermediate 1b (100 mg, 0.49 mmol), intermediate 16a (121.69 mg, 0.54 mmol), DIPEA (189.53 mg, 1.47 mmol), and HATU (223.04 mg, 0.59 mmol) were added sequentially to DMF (1.5 mL) and reacted at 25°C for 18 hours. The resulting mixture was washed with water (30 mL) and then extracted with EtOAc (10 mL x 3) to obtain an organic phase. The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain intermediate 16b. MS m / z: 413.0 [M+H] + .

[0543] Step 2: Synthesis of intermediate 16c

[0544] Intermediate 16b (100 mg, 0.24 mmol) and TFA (1 mL) were added to DCM (5 mL) and reacted at 25°C for 2 hours. The resulting mixture was concentrated under reduced pressure to afford Intermediate 16c. MS m / z: 313.0 [M+H] + .

[0545] Step 3: Synthesis of Compound III-10

[0546] Intermediate 16c (44 mg, 0.21 mmol), intermediate 1b (47 mg, 0.23 mmol), DIPEA (84 mg, 0.64 mmol) and HATU (102 mg, 0.26 mmol) were added to DMF (5 mL) and reacted at 25°C for 18 hours. The resulting mixture was washed with water (20 mL) and then extracted with EtOAc (5 mL x 3) to obtain an organic phase. The organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by TLC (eluent: petroleum ether:EtOAc = 1:1) to obtain compound III-10.

[0547] MS m / z:499.0[M+H] + . 1H NMR (400MHz, DMSO) δ8.29(d,J=7.8Hz,2H),7.56–7.43(m,2H),7.06(dt,J=9.5,4.7Hz,2H),6.91–6.78(m,2H),4.49 (d,J=14.7Hz,4H),4.17(dt,J=16.1,8.2Hz,2H),2.40–2.31(m,2H),2.16(dd,J=7.8,3.1Hz,2H),2.06–1.94(m,4H).

[0548] Example 17: Synthesis of Compound IV-11

[0549] Step 1: Synthesis of intermediate 17b

[0550] To a solution of Intermediate 1b (85.12 mg, 0.42 mmol) in DMF (5 mL) were added Intermediate 17a (100 mg, 0.42 mmol), DIPEA (0.21 mL, 1.25 mmol), and HATU (189.84 mg, 0.50 mmol), and the mixture was stirred at 20°C for 1 hour. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2) to obtain an organic phase. The resulting organic phase was washed with saturated NaCl solution (100 mL), and the EtOAc layer (100 mL) was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (mobile phase: PE / EtOAc (V / V) = 1 / 1) and concentrated in vacuo to obtain Intermediate 17b. MS m / z: 371.0 [M+H-56] + .

[0551] Step 2: Synthesis of Intermediate 17c

[0552] To a solution of Intermediate 17b (140 mg, 0.33 mmol) in DCM (10 mL) was added TFA (2 mL, 26.84 mmol), and the mixture was stirred at 20°C for 2 hours. After completion, the mixture was concentrated under reduced pressure to afford Intermediate 17c. MS m / z: 327.0 [M+H] + .

[0553] Step 3: Synthesis of Compound IV-11

[0554] To a solution of Intermediate 1b (66.36 mg, 0.32 mmol) in DMF (5 mL) were added Intermediate 17c (106 mg, 0.32 mmol), DIEA (0.16 mL, 0.97 mmol), and HATU (148.00 mg, 0.39 mmol), and the mixture was stirred at 20°C for 1 hour to react. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2) to obtain an organic phase. The resulting organic phase was washed with saturated NaCl solution (100 mL), and the EtOAc layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was separated and purified by silica gel column chromatography (mobile phase: PE / EtOAc (V / V) = 1 / 1) and concentrated in vacuo to obtain Compound IV-11.

[0555] MS m / z:513.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.35 (t, J=7.4Hz, 1H), 7.48 (dt, J=20.2, 8.8Hz, 2H), 7.12–7.02 (m, 2H), 6.89–6.77 (m, 2H), 4.87 (d, J=7.7Hz, 2H), 4.50 (s, 2H), 4.29 (p, J=7.9Hz, 1H), 3.35 (s, 4H), 2.16 (t, J=9.7Hz, 2H), 1.80 (d, J=12.8Hz, 2Hz), 1.55 (dt, J=40.7, 15.8Hz, 4Hz).

[0556] Example 18: Synthesis of Compound V-10

[0557] Step 1: Synthesis of Intermediate 18b

[0558] To a solution of intermediate 1b (85.12 mg, 0.42 mmol) in DMF (5 mL) were added 18a (100 mg, 0.42 mmol), DIPEA (0.21 mL, 1.25 mmol), and HATU (189.84 mg, 0.50 mmol), and the mixture was stirred at 20°C for 1 hour to react. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2) to obtain an organic phase. The resulting organic phase was washed with saturated NaCl solution (100 mL), and the EtOAc layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was separated and purified by silica gel column chromatography (mobile phase: PE / EtOAc (v / v) = 1 / 1) and concentrated under reduced pressure to obtain intermediate 18b. MS m / z: 371.0 [M+H-56] + .

[0559] Step 2: Synthesis of Intermediate 18c

[0560] To a solution of Intermediate 18b (90 mg, 0.21 mmol) in DCM (5 mL) was added TFA (1 mL, 13.42 mmol), and the mixture was stirred at 20°C for 1 hour. After completion of the reaction, the resulting mixture was concentrated under reduced pressure to afford Intermediate 18c. MS m / z: 327.0 [M+H] + .

[0561] Step 3: Synthesis of Compound V-10

[0562] To a solution of Intermediate 1b (42.96 mg, 0.21 mmol) in DMF (5 mL) were added Intermediate 18c (68.63 mg, 0.21 mmol), DIPEA (0.10 mL, 0.63 mmol), and HATU (95.82 mg, 0.25 mmol). The mixture was stirred at 20°C for 1 hour to react. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2) to obtain an organic phase. The resulting organic phase was washed with saturated NaCl solution (100 mL), and the EtOAc layer (100 mL) was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (mobile phase: PE / EtOAc (V / V) = 1 / 1) and concentrated in vacuo to obtain Compound V-10. MS m / z: 513.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.93 (t, J=7.1Hz, 1H), 7.53–7.45 (m, 2H), 7.07 (dd, J=11.4, 3.9, 2.7Hz, 2H), 6.87–6.79 (m, 2H), 4.67 (d, J=7.0Hz, 2H), 4.50 ( d, J=1.9Hz, 2H), 3.88 (d, J=24.1Hz, 2H), 3.61 (s, 2H), 3.54 (s, 1H), 1.85 (d , J=12.9Hz, 2Hz), 1.65 (s, 2H), 1.50 (t, J=13.0Hz, 2H), 1.32–1.22 (m, 2H).

[0563] Example 19: Synthesis of Compound III-11

[0564] Step 1: Synthesis of Compound III-11

[0565] Intermediate 16c (100 mg, 0.32 mmol), intermediate 1f (50.61 mg, 0.29 mmol), DIPEA (112.70 mg, 0.87 mmol), and HATU (132.62 mg, 0.35 mmol) were added to DMF (5 mL) and reacted at 25°C for 2 hours. Water (30 mL) was added to the reaction mixture, and then the mixture was extracted with EtOAc (10 mL x 3) to obtain an organic phase. The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain compound III-11.

[0566] MS m / z:469.0[M+H] + . 1 H NMR (400MHz, DMSO) δ9.42–9.11(m,2H),9.01(s,1H),8.30(d,J=7.8Hz,1H),7.49(d,J=8.9Hz,1H),7.36–7.05(m,2H),6.85(dd,J=8.9, 2.7Hz,1H),4.48(s,2H),4.37(dd,J=16.4,8.2Hz,1H),4.18(dd,J=16.3,8.2Hz,1H),2.40(s,2H),2.22(d,J=8.4Hz,4H),2.04(s,2H).

[0567] Example 20: Synthesis of Compound III-13

[0568] Step 1: Synthesis of intermediate 20a

[0569] To N,N-dimethylformamide (5 mL) were added Intermediate 16c (90 mg, 0.29 mmol), Intermediate 3b (99.30 mg, 0.32 mmol), HATU (164.12 mg, 0.43 mmol), and DIPEA ethyldiisopropylamine (111.58 mg, 0.86 mmol), and the reaction was stirred at 25°C for 2 hours. The resulting mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was analyzed by preparative TLC (eluent: petroleum ether:ethyl acetate = 10:1) to obtain Intermediate 20a. MS m / z: 608.5 [M+H] + .

[0570] Step 2: Synthesis of Compound III-13

[0571] 20a (120 mg, 0.20 mmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (5 mL) and stirred at 25°C for 1 hour. The resulting mixture was concentrated to dryness under reduced pressure to obtain a crude product. Preparative TLC (eluent: petroleum ether:ethyl acetate = 5:1) provided compound III-13.

[0572] MS m / z:508.4[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.28 (d, J=7.8Hz, 1H), 8.18 (d, J=7.8Hz, 1H), 7.50 (t, J=8.9Hz, 1H), 7.07 ( dd, J=11.4, 2.8Hz, 1H), 6.89–6.83 (m, 1H), 6.78 (d, J=8.5Hz, 1H), 6.59 (dd, J=2.5, 1.0Hz, 1H), 6.53 –6.48(m, 1H), 6.18(s, 1H), 4.47(s, 2H), 4.41(dt, J=7.5, 2.8Hz, 1H), 4.14(p, J=8.2Hz, 2H), 3.42( d, J=12.2Hz, 1H), 3.16 (dd, J=11.9, 7.4Hz, 1H), 2.38–2.28 (m, 2H), 2.15 (s, 2H), 2.08–1.95 (m, 4H).

[0573] Example 21: Synthesis of Compound IV-12

[0574] Step 1: Synthesis of Compound IV-12

[0575] To a solution of Intermediate 17c (53 mg, 0.16 mmol) in DMF (5 mL) were added Intermediate 1f (28.24 mg, 0.16 mmol), DIPEA (0.08 mL, 0.48 mmol), and HATU (73.01 mg, 0.19 mmol), and the mixture was stirred at 20°C for 1 hour to react. The resulting mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 2) to obtain an organic phase. The resulting organic phase was washed with saturated NaCl solution (40 mL), and the EtOAc layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was separated and purified by preparative TLC (eluent: DCM / MeOH = 20 / 1) and concentrated under reduced pressure to obtain compound IV-12.

[0576] MS m / z:483.0[M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 8.94 (s, 1H), 8.35 (dd, J = 11.8, 7.7Hz, 1H), 7. 50(td,J=8.9,4.8Hz,1H),7.08(dt,J=11.4,3.0Hz,1H),6.90–6.82(m,1H),4.50(d, J=4.0Hz,2H),4.28(dq,J=16.4,8.2Hz,1H),3.67–3.51(m,2H),3.33–3.19(m,3H), 2.19(q,J=10.0Hz,2H), 1.80(q,J=10.6Hz,2H), 1.58(dt,J=31.9,26.1,6.0Hz,4H).

[0577] Example 22: Synthesis of Compound IV-13

[0578] Step 1: Synthesis of intermediate 22a

[0579] To a solution of Intermediate 17c (53 mg, 0.16 mmol) in DMF (5 mL) were added Intermediate 3b (50.88 mg, 0.16 mmol), DIPEA (0.08 mL, 0.48 mmol), and HATU (73.01 mg, 0.19 mmol), and the mixture was stirred at 20°C for 1 hour. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2) to obtain an organic phase. The organic phase was washed with saturated NaCl solution (100 mL), and the EtOAc layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (mobile phase: PE / EtOAc (v / v) = 1 / 1) and concentrated in vacuo to obtain Intermediate 22a. MS m / z: 522.2 [M+H-100] + .

[0580] Step 2: Synthesis of Compound IV-13

[0581] To a solution of intermediate 22a (90 mg, 0.14 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.71 mmol), and the mixture was stirred at 20°C for 1 hour. The resulting mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative TLC (mobile phase: DCM / MeOH (v / v) = 20 / 1) and concentrated in vacuo to obtain compound IV-13.

[0582] MS m / z:522.0[M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.35 (d, J=7.2Hz, 1H), 7.51 (t, J=8.9Hz, 1H), 7.08 (dd, J=11.4, 2.9Hz, 1H), 6.86 (d d, J=9.0, 2.9, 1.2Hz, 1H), 6.68 (d, J=8.5Hz, 1H), 6.58 (d, J=2.5Hz, 1H), 6.46 (dd, J=8.5, 2.6Hz, 1H), 6.18( t, J=2.6Hz, 1H), 4.90 (d, J=8.5Hz, 1H), 4.50 (s, 2H), 4.28 (q, J=8.2Hz, 1H), 3.58–3.35 (m, 3H), 3.26 (dd, J= 12.5, 7.0, 2.1Hz, 1H), 2.16 (q, J=12.9, 11.3Hz, 2H), 1.79 (t, J=9.9Hz, 2H), 1.54 (dd, J=43.5, 24.0Hz, 4H).

[0583] Example 23: Synthesis of Compound V-11

[0584] Step 1: Synthesis of Compound V-11

[0585] To a solution of Intermediate 18c (23 mg, 0.07 mmol) in DMF (2 mL) were added Intermediate 1f (0.01 mL, 0.07 mmol), DIPEA (0.03 mL, 0.21 mmol), and HATU (32.11 mg, 0.08 mmol), and the mixture was stirred at 20°C for 1 hour to react. The resulting mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 2) to obtain an organic phase. The resulting organic phase was washed with saturated NaCl solution (40 mL), and the EtOAc layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was separated and purified by preparative TLC (mobile phase: PE / EtOAc (V / V) = 1 / 1) and concentrated in vacuo to obtain Compound V-11. MS m / z: 483.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.20 (d, J=5.1Hz, 1H), 8.99 (s, 1H), 7.92 (dd, J=26.8, 8.0Hz, 1H), 7 .50(td, J=8.8, 1.6Hz, 1H), 7.27(dd, J=53.9, 3.3Hz, 1H), 7.10–7.04(m, 1H), 6.85(d, J=9.0 Hz, 1H), 4.50 (d, J=5.2Hz, 2H), 4.25 (d, J=28.7Hz, 2H), 3.80 (d, J=26.3Hz, 2H), 3.63 (s, 1H) , 1.91 (d, J = 12.9Hz, 2H), 1.66 (d, J = 12.7Hz, 2H), 1.54 (t, J = 12.6Hz, 2H), 1.38–1.27 (m, 2H).

[0586] Example 24: Synthesis of Compound V-12

[0587] Step 1: Synthesis of intermediate 24a

[0588] To a solution of Intermediate 18c (38 mg, 0.12 mmol) in DMF (3 mL) were added Intermediate 3b (36.48 mg, 0.12 mmol), DIPEA (0.06 mL, 0.35 mmol), and HATU (53.06 mg, 0.14 mmol), and the mixture was stirred at 20°C for 1 hour. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2) to obtain an organic phase. The organic phase was washed with saturated NaCl solution (100 mL), and the EtOAc layer (100 mL) was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (mobile phase: PE / EtOAc (v / v) = 1 / 1) and concentrated in vacuo to yield Intermediate 24a. MS m / z: 566.2 [M+H-56] + .

[0589] Step 2: Synthesis of Compound V-12

[0590] To a solution of intermediate 24a (48 mg, 0.08 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.71 mmol), and the mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (mobile phase: DCM / MeOH (v / v) = 20 / 1) and concentrated in vacuo to yield the target compound V-12. MS m / z: 522.0 [M+H] + .

[0591] 1 H NMR (400MHz, DMSO-d6) δ7.92 (dd, J=8.1, 3.6Hz, 1H), 7.50 (t, J=8.8Hz, 1H), 7.06 (dd, J=11.4, 2.8Hz, 1H), 6.84 (dd, J=8.9, 2.9, 1.2Hz, 1H), 6.73 (d, J=8.5Hz, 1H), 6.59 (dd, J=3.7, 2.5Hz, 1H), 6.49 (dd, J=8.3, 5.5, 2.5Hz, 1H), 6.18 (d, J=7.1Hz, 1H), 4.70 (dt , J=6.0, 3.0Hz, 1H), 4.49 (d, J=1.1Hz, 2H), 3.97 (dd, J=33.6, 28.2, 8.9Hz, 2H), 3.64–3.55 (m, 2H), 3.55–3.48 (m, 1H), 3.42–3.36 (m, 1H), 3.30 (d, J = 13.0Hz, 1H), 1.81 (d, J = 18.3Hz, 2H), 1.64 (d, J = 12.0Hz, 2H), 1.47 (d, J = 13.2Hz, 2H), 1.27 (d, J = 15.5Hz, 2H).

[0592] Example 25: Synthesis of Compound IV-15

[0593] Step 1: Synthesis of Compound IV-15

[0594] To a solution of compound 22 (40 mg, 0.08 mmol) in CH3CN (5 ml) were added K2CO3 (31.75 mg, 0.23 mmol) and dimethyl sulfate (0.03 ml, 0.31 mmol), and the mixture was stirred at 70°C for 18 hours. The resulting reaction mixture was separated and purified by preparative TLC (mobile phase: DCM / MeOH (v / v) = 20 / 1) to give compound IV-15.

[0595] MS m / z:536.0[M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.35 (d, J=7.8Hz, 1H), 7.51 (t, J=8.9Hz, 1H), 7.08 (dd, J=11.3, 2.9Hz, 1H), 6.86 (dd, J=9.2, 2.9Hz, 1H), 6.73–6.66 (m, 2H), 6.56 (dd, J=8.4, 2.4Hz, 1H), 5.09 (s, 1H), 4.50 (s, 2H), 4.29 (d, J=8.8Hz, 1H), 3.58–3.36 (m, 5H), 3.27 (dd, J=12.3, 6 .8Hz, 1H), 2.85 (s, 3H), 2.15 (d, J=21.8Hz, 2H), 1.86–1.74 (m, 2H), 1.55 (dd, J=47.1, 22.9Hz, 3H), 1.35 (d, J=1.9Hz, 1H).

[0596] Example 26: Synthesis of Compound III-12

[0597] Step 1: Synthesis of Compound III-12

[0598] Compound III-13 (60 mg, 0.12 mmol), dimethyl sulfate (0.01 mL, 0.12 mmol) and potassium carbonate (16.31 mg, 0.12 mmol) were added to acetonitrile (5 mL), the mixture was degassed and replaced with nitrogen 3 times, and the reaction was stirred at 70 ° C for 18 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain an organic phase. The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative TLC (mobile phase: PE / EtOAc (V / V) = 5 / 1) to obtain compound III-12.

[0599] MS m / z:522.0[M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.28(d,J=7.8Hz,1H),8.21(d,J=7.8Hz,1H),7.50(t,J=8.8Hz,1H),7. 07(dd,J=11.4,2.9Hz,1H),6.87–6.79(m,2H),6.69(d,J=2.5Hz,1H),6.62(dd,J=8.4,2.5Hz,1H ),4.60(dt,J=7.3,2.4Hz,1H),4.47(s,2H),4.13(q,J=8.0Hz,2H),3.38(dd,J=12.0,3.0Hz,1H) ,3.17(dd,J=11.9,7.2Hz,1H),2.82(s,3H),2.37–2.32(m,2H),2.15(s,2H),2.08–1.95(m,4H).

[0600] Example 27: Synthesis of Compound IV-14

[0601] Step 1: Synthesis of intermediate 27b

[0602] To a 100 mL single-necked flask at room temperature, compound 27a (1.0 g, 5.86 mmol) and 1,2-dichloroethane (50.0 mL) were added, followed by N,N'-carbonyldiimidazole (1.3 g, 8.21 mmol) under stirring. The mixture was allowed to react at 25°C for 16 hours. 25 mL of water was added to the resulting reaction solution, and the layers were separated. The resulting organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 27b.

[0603] Step 2: Synthesis of Compound IV-14

[0604] At room temperature, intermediate 17c (100 mg, 0.31 mmol) and N'N-dimethylformamide (5.0 mL) were added to a 50 mL single-necked bottle, and intermediate 27b (84 mg, 0.43 mmol), DIEA (159 mg, 1.22 mmol) and Carter condensation agent (BOP) (28 mg, 0.45 mmol) were added in sequence under stirring. The reaction was carried out at 25 ° C for 16 hours. 25 mL of water was added to the resulting reaction solution, the liquid was separated, the organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound IV-14.

[0605] MS m / z:505.0[M+H] + . 1H NMR(400MHz, CDCl3-d)δ7.86–7.83(m,2H),7.46–7.36(m,2H),7.34–7.26(m,1H),6.80–6.77(m,1H),6.71–6.70(m,1H),,6.6 9–6.60(m,1H),4.56–4.49(m,1H),4.44(s,2H),3.65–3.60(m,4H),2.47–2.45(m,2H),1.84–1.82(m,4H),1.79–1.76(m,2H).

[0606] Example 28: Synthesis of Compound IV-18

[0607] Step 1: Synthesis of intermediate 28a

[0608] At room temperature, intermediate 3b (85 mg, 0.27 mmol) and N'N-dimethylformamide (5 mL) were added to a 50 mL single-necked bottle. Intermediate 17a (65 mg, 0.27 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154 mg, 0.41 mmol) and DIEA (130 mg, 1.08 mmol) were added sequentially under stirring. The reaction was carried out at 25°C for 12 hours. 50 mL of water was added to the resulting reaction solution, and the organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 28a. MS m / z: 436.2 [M+H] + .

[0609] Step 2: Synthesis of intermediate 28b

[0610] At 25°C, intermediate 28a (101 mg, 0.19 mmol) and dichloromethane (3 mL) were added to a 50 mL single-necked flask. Trifluoroacetic acid (1 mL) was added under stirring. The reaction was allowed to proceed at 25°C for 30 minutes. The resulting reaction solution was concentrated under reduced pressure to yield intermediate 28b. MS m / z: 336.0 [M+H-100] + .

[0611] Step 3: Synthesis of intermediate 28c

[0612] At room temperature, intermediate 28b (76 mg, 0.23 mmol) and N'N-dimethylformamide (5 mL) were added to a 50 mL single-necked flask. Intermediate 3b (92 mg, 0.29 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (128 mg, 0.34 mmol), and DIEA (108 mg, 0.90 mmol) were added sequentially under stirring. The mixture was reacted at 25°C for 12 hours. 50 mL of water was added to the resulting reaction solution, and the organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column analysis to obtain intermediate 28c. MS m / z: 629.2 [MH-100] + .

[0613] Step 4: Synthesis of Compound IV-18

[0614] To a 50 mL single-necked flask at 25°C, intermediate 28c (106 mg, 0.17 mmol) and dichloromethane (3 mL) were added, followed by trifluoroacetic acid (1 mL) under stirring. The mixture was allowed to react at 25°C for 30 minutes. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound IV-18.

[0615] MS m / z:531.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.20–8.18(m,1H),6.74–6.72(m,1H),6.62–6.60(m,1 H),6.53–6.50(m,2H),6.43–6.41(m,1H),6.40–6.38(m,1H),6.13–6.11(m,2H ),4.83–4.80(m,1H),4.35–4.32(m,1H),4.20–4.18(m,1H),3.52–3.35(m,4H) ,3.20–3.18(m,4H),2.20–1.99(m,2H),1.85–1.65(m,2H),1.65–1.28(m,4H).

[0616] Example 29: Synthesis of Compound IV-19

[0617] Step 1: Synthesis of Compound IV-19

[0618] To a solution of intermediate 17c (170 mg, 0.39 mmol) and intermediate 2a (85 mg, 0.43 mmol) in dichloromethane (6 mL) were added DIEA (102 mg, 0.79 mmol) and 1-propylphosphonic anhydride (493 mg, 0.77 mmol) to obtain a mixture. The reaction was stirred at 25°C for 12 h. The resulting mixture was poured into H2O (15 mL) and extracted with EtOAc (10 mL x 3) to obtain an organic phase. The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was separated and purified by preparative TLC (eluent: PE / EtOAc (V / V) = 3 / 1) to obtain compound IV-19.

[0619] MS m / z:505.1[M+H] + . 1 H NMR(DMSO-d6)δ:8.35(d,J=7.6Hz,1H),7.81(d,J=2.1Hz,1H),7.71(d,J=8 .8Hz,1H),7.44-7.53(m,2H),7.31(s,1H),7.05-7.11(m,1H),6.86(dd,J=8 .9,1.8Hz,1H),4.50(s,2H),4.24-4.35(m,1H),3.62(s,2H),3.54(s,2H),2 .16-2.24(m,2H),1.76-1.87(m,2H),1.61-1.69(m,2H),1.55-1.61(m,2H).

[0620] Example 30: Synthesis of Compound IV-20

[0621] Step 1: Synthesis of intermediate 30a

[0622] At 25°C, intermediate 2a (150 mg, 0.76 mmol) and DMF (5.0 mL) were added to a 100 mL single-necked flask. Intermediate 17a (220 mg, 0.92 mmol), 1-propylphosphoric acid cyclic anhydride (970 mg, 1.53 mmol), and DIEA (395 mg, 3.04 mmol) were added sequentially under stirring. The reaction was allowed to proceed at 25°C for 16 h. The resulting reaction solution was poured into 50 mL of water and then extracted three times with 50 mL of EtOAc to obtain an organic phase. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 30a. MS m / z: 363.0 [M+H-56] + .

[0623] Step 2: Synthesis of intermediate 30b

[0624] At 25°C, intermediate 30a (120 mg, 0.29 mmol) and dichloromethane (3 mL) were added to a 50 mL single-necked flask. Trifluoroacetic acid (1 mL) was added under stirring. The reaction was allowed to proceed at 25°C for 30 minutes. The resulting reaction solution was concentrated under reduced pressure to yield intermediate 30b. MS m / z: 319.0 [M+H] + .

[0625] Step 3: Synthesis of Compound IV-20

[0626] At 25°C, intermediate 30b (89 mg, 0.28 mmol) and DMF (5 mL) were added to a 50 mL single-necked flask. Intermediate 2a (65 mg, 0.33 mmol), 1-propylphosphoric acid cyclic anhydride (355 mg, 0.56 mmol, 50% dimethylformamide solution), and di-DIEA (134 mg, 1.12 mmol) were added sequentially under stirring. The reaction was allowed to proceed at 25°C for 16 h. The resulting reaction solution was poured into 50 mL of water and then extracted three times with 50 mL of EtOAc each time to obtain the organic phase. The organic phase was washed with 100 mL of saturated brine, 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 HPLC (formic acid / acetonitrile / water system) to obtain compound IV-20.

[0627] MS m / z:497.0[M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.05(d,J=7.7Hz,1H),7.88(d,J=2.3Hz,1H),7.83(d,J=2.2Hz,1H),7.74–7.70(m,2H),7.53(s,1H)7.51 –7.46(m,2H),7.33(s,1H),4.50–4.44(m,1H),3.61(d,J=31.6Hz,4H),2.30–2.24(m,2H),2.00–1.94(m,2H),1.70–1.62(m,4H).

[0628] Example 31: Synthesis of Compound IV-16

[0629] Step 1: Synthesis of intermediate 31b

[0630] To a 100 mL three-necked flask, under ice-cooling, was added intermediate 31a (300 mg, 1.61 mmol) and ethyl acetate (20 mL). Silver trifluoromethanesulfonate (1.41 g, 4.83 mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (855 mg, 2.42 mmol), potassium fluoride (374 mg, 6.44 mmol), 2-fluoropyridine (469 mg, 4.83 mmol), and (trifluoromethyl)trimethylsilane (686 mg, 4.83 mmol) were added under stirring in the dark. The mixture was allowed to react at 25°C for 16 h. The resulting reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 31b. 1 H NMR (400MHz, DMSO-d6) δ4.62–4.35(m,1H),3.92(s,2H),3.73(t,J=6.9Hz,1H),2.87–2.68(m,2H),2.12–2.10(m,2H),1.42(s,9H).

[0631] Step 2: Synthesis of intermediate 31c

[0632] At 25°C, intermediate 31b (246 mg, 0.97 mmol) and dichloromethane (3 mL) were added to a 50 mL single-necked flask. Trifluoroacetic acid (1 mL) was added under stirring. The mixture was reacted at 25°C for 30 minutes. The resulting reaction solution was concentrated under reduced pressure to obtain intermediate 31c.

[0633] Step 3: Synthesis of Intermediate 31d

[0634] At 25°C, intermediate 31c (230 mg, 1.07 mmol) and DMF (5 mL) were added to a 50 mL single-necked flask. Intermediate 17a (283 mg, 1.18 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (610 mg, 1.60 mmol), and DIEA (556 mg, 4.28 mmol) were added sequentially under stirring. The reaction was allowed to proceed at 25°C for 12 h. 50 mL of water was added to the resulting reaction solution, and the separated organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 31d. MS m / z: 381.0 [M+H-56] + .

[0635] Step 4: Synthesis of Intermediate 31e

[0636] At 25°C, intermediate 31d (140 mg, 0.32 mmol) and dichloromethane (3 mL) were added to a 50 mL single-necked flask. Trifluoroacetic acid (1 mL) was added under stirring. The reaction was incubated at 25°C for 30 minutes. The reaction solution was concentrated under reduced pressure to yield intermediate 31e. MS m / z: 337.0 [M+H] + .

[0637] Step 5: Synthesis of Compound IV-16

[0638] At 25°C, intermediate 31e (66 mg, 0.21 mmol) and DMF (5 mL) were added to a 50 mL single-necked flask. Intermediate 2a (50 mg, 0.25 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol), and DIEA (109 mg, 0.84 mmol) were added sequentially with stirring. The reaction was allowed to proceed at 25°C for 12 h. 50 mL of water was added to the resulting reaction solution, and the separated organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound IV-16.

[0639] MS m / z:515.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.04(d,J=8.0Hz,1H),7.82(d,J=2.2Hz,1H),7.73–7 .71(m,1H),7.48–7.44(m,1H),7.32(s,1H),4.54–4.46(m,1H),4.32–4.26(m ,1H),3.76(s,2H),3.75–3.68(m,1H),3.64–3.62(m,2H),3.60–3.54(m,2H), 2.78–2.74(m,2H),2.20–2.14(m,4H),1.86–1.80(m,2H),1.66–1.58(m,4H).

[0640] Example 32: Synthesis of Compound IV-17

[0641] Step 1: Synthesis of Compound IV-17

[0642] At 25°C, intermediate 31e (106 mg, 0.31 mmol) and DMF (5 mL) were added to a 50 mL single-necked flask. Intermediate 1b (74 mg, 0.35 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (78 mg, 0.21 mmol), and DIEA (161 mg, 1.24 mmol) were added sequentially under stirring. The reaction was allowed to proceed at 25°C for 12 h. 50 mL of water was added to the resulting reaction solution, and the separated organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by HPLC (formic acid / acetonitrile / water system) to obtain compound IV-17.

[0643] MS m / z:523.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.00(t,J=8.8Hz,1H),7.46(t,J=8.9Hz,1H),7.05(ddd,J=11. 4,2.8,1.4Hz,1H),6.88–6.73(m,1H),4.86(d,J=7.9Hz,2H),4.49(p,J=7.1Hz,1H),4.3 5–4.20(m,1H),3.73(d,J=18.1Hz,3H),3.46–3.39(m,3H),3.25(d,J=6.0Hz,1H),2.75 (dtd,J=9.7,6.7,3.3Hz,2H),2.23–2.06(m,4H),1.87–1.74(m,2H),1.65–1.41(m,4H).

[0644] Example 33: Synthesis of Compound VIII-1

[0645] Step 1: Synthesis of compound 33c

[0646] To a single-necked flask at room temperature, 33a (11 g, 63.15 mmol) and dichloromethane (36 mL) were added. 33b (20 g, 57.41 mmol), acetic acid (1.93 g, 32.15 mmol), and tetraethylene glycol dimethyl ether (40 mL) were added with stirring. The reaction was allowed to proceed at 100°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford intermediate 33c. 1H NMR (400MHz, DMSO) δ6.22 (t, J = 1.9 Hz, 1H), 4.13 (m, 2H), 1.41 (m, 2H), 1.30–1.26 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0647] Step 2: Synthesis of compound 33e

[0648] At room temperature, 33c (2.3 g, 17.57 mmol) and toluene (10 mL) were added to a single-necked flask, followed by the addition of 33d (1.0 g, 1.03 mmol) under stirring. The reaction was allowed to proceed at 130°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 7:1) to afford intermediate 33e. LC-MS: m / z: 269.0 (M+H). + .

[0649] Step 3: Synthesis of compound 33f

[0650] At room temperature, 33e (2.4 g, 5.36 mmol), potassium fluoride (0.36 g, 8.05 mmol), and methanol (10 mL) were added to a single-necked flask and stirred under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 33f. LC-MS: m / z: 197.0 (M+H) + .

[0651] Step 4: Synthesis of compound 33g

[0652] At room temperature, 33f (877 mg, 1.45 mmol) and methanol (30 mL) were added to a single-necked flask. Acetic acid (80.0 mg, 0.44 mmol) and 2,4-dimethoxybenzylamine (1.76 g, 10.26 mmol) were added under stirring. After reacting at room temperature for two hours, sodium cyanoborohydride (258.03 mg, 6.6 mmol) was added and the reaction was continued 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 flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 33g. LC-MS: m / z: 348.0 (M+H) + .

[0653] Step 5: Synthesis of compound 33h

[0654] Under ice bath, 1b (1g, 0.4mmol) and dichloromethane (30mL) were added to a single-necked flask, and oxalyl chloride (600mg, 0.4mmol) and three drops of N,N-dimethylformamide were added under stirring. After reacting at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in dichloromethane (20mL) and triethylamine (4mL) and 33g (1.45g, 4.17mmol) were added to the reaction solution under ice bath, and the reaction was carried out under ice bath for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (petroleum ether: ethyl acetate = 100:1 to 2:1) to obtain intermediate 33h. LC-MS: m / z: 534.1 (M+H) + .

[0655] Step 6: Synthesis of compound 33i

[0656] At room temperature, 33h (1.2 g, 2.24 mmol) and dichloromethane (30 mL) were added to a single-necked flask, and TFA (15 mL) was added under stirring. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 33i (800 mg). LC-MS: m / z: 384.1 (M+H) + .

[0657] Step 7: Synthesis of compound 33j

[0658] At room temperature, 33i (800 mg, 2.09 mmol), ethanol (20 mL), and water (7 mL) were added to a single-necked flask, and lithium hydroxide (160 mg, 4.10 mmol) was added under stirring. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was adjusted to pH 6 with hydrochloric acid (1N) and extracted three times with 20 mL of ethyl acetate each time. The combined organic phases were washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 33j. LC-MS: m / z: 356.1 (M+H) + .

[0659] Step 8: Synthesis of compound 33k

[0660] At room temperature, 33j (532 mg, 1.50 mmol) and tetrahydrofuran (20 mL) were added to a single-necked flask. N,N'-carbonyldiimidazole (2.43 g, 15 mmol) and 80% hydrazine hydrate (1.0 mL) were added with stirring. The reaction was allowed to proceed at 60°C for 16 hours. The reaction solution 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 0:1) to obtain intermediate 33k. LC-MS: m / z: 370.1 (M+H). + .

[0661] Step 9: Synthesis of compound 331

[0662] At room temperature, 33k (407 mg, 1.1 mmol) and 1,2-dichloroethane (10 mL) were added to a single-necked flask, followed by N,N'-carbonyldiimidazole (891 mg, 5.5 mmol) under stirring. The mixture was allowed to react at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 0:1) to afford compound 33l. LC-MS: m / z: 396.0 (M+H) + .

[0663] Step 10: Synthesis of Compound VIII-1

[0664] To a single-necked flask at room temperature, 33K (356 mg, 0.9 mmol) and N,N-dimethylformamide (3.0 mL) were added. D (132 mg, 0.94 mmol), N,N-diisopropylethylamine (0.19 mL, 1.12 mmol), and Carter condensation agent (166 mg, 0.37 mmol) were added under stirring. 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 high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound VIII-1. 1 H NMR(400MHz,MeOD)δ7.38(t,J=8.7Hz,1H),6.94(dd,J=11.0,2.7Hz,1H),6.85–6.79(m,1 H),5.32–5.18(m,1H),4.51(s,2H),4.50–4.46(m,2H),4.25(dd,J=9.5,4.1Hz,2H),4.04 (t,J=10.2Hz,1H),3.06(d,J=7.7Hz,1H),2.14–1.90(m,3H),1.85–1.73(m,1H),1.56(dd ,J=19.2,10.5Hz,1H),1.39(d,J=12.8Hz,1H),0.50–0.27(m,4H), LC-MS:m / z:519.1(M+H) + .

[0665] Example 34: Synthesis of Compound III-1

[0666] Step 1: Synthesis of compound 34b

[0667] At room temperature, 34a (2.5 g, 9.28 mmol) and ethanol (20 mL) were added to a 100 mL single-necked flask. 50% hydrazine hydrate (9.83 g, 139.2 mmol) was added under stirring, and the temperature was raised to 80°C overnight for completion of the reaction. The crude product was concentrated under reduced pressure to obtain the crude product. The crude product was purified by recrystallization using acetonitrile solvent to obtain intermediate 34b (2.1 g, 7.02 mmol). LC-MS: m / z: 214.0 (M+H-56) + .

[0668] Step 2: Synthesis of compound 34c

[0669] At room temperature, 34b (2.1 g, 7.80 mmol) and 1,2-dichloroethane (25 mL) were added to a 100 mL single-necked bottle, and compound N,N'-carbonyldiimidazole (1.9 g, 11.69 mmol) was added sequentially under stirring. The reaction was completed after 18 hours at room temperature. 50 mL of water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was washed with 100 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 column chromatography to obtain intermediate 34c (850 mg, 2.59 mmol). LC-MS: m / z: 240 (M+H-56) + .

[0670] Step 3: Synthesis of compound 34e

[0671] Under ice bath, 34d (611 mg, 3.46 mmol) and dimethylformamide (10.0 mL) were added to a 50 mL single-necked bottle. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.93 g, 4.61 mmol), diisopropylethylamine (1.87 mg, 14.38 mmol), and compound 34c (850 mg, 2.88 mmol) were added sequentially under stirring. The reaction was completed overnight at room temperature. 25 mL of water was added to the reaction solution, extracted with ethyl acetate, and 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 a crude product. The crude product was purified by column chromatography to obtain a colorless oily intermediate 34e. LC-MS: m / z: 419 (M+H) + .

[0672] Step 4: Synthesis of compound 34f

[0673] At room temperature, 34e (220 mg, 0.53 mmol) and dichloromethane (8 mL) were added to a 100 mL single-necked flask, and trifluoroacetic acid (3.0 mL) was added under stirring. The reaction was complete after 1 hour at room temperature. The product was concentrated under reduced pressure to give the crude product 34f. LC-MS: m / z: 319 (M+H) +.

[0674] Step 4: Synthesis of Compound III-1

[0675] Under ice bath, 1b (115 mg, 0.56 mmol) and dimethylformamide (5.0 mL) were added to a 50 mL single-necked bottle, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (268 mg, 0.71 mmol) and diisopropylethylamine (245 mg, 1.88 mmol) were added sequentially under stirring. After half an hour of reaction at room temperature, compound 34f (150 mg, 0.47 mmol) was added to the reaction solution, and the reaction was completed overnight at room temperature. 25 mL of water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was washed with 100 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 compound III-1.

[0676] 1 H NMR (400MHz, DMSO-d6) δ8.30–8.28(m,1H),7.52–7.47(m,1H),7.09–7.05(m,1H),6.86–6.83(m,1H),5.33–5.30(m,1H),4.48–4.4 4(m,4H),4.21–4.13(m,3H), 3.48–3.44(m,1H), 2.51–2.43(m,2H), 2.33–2.23(m,4H), 2.07–2.01(m,2H), LC-MS: m / z:505.0(M+H) + .

[0677] Example 35: Synthesis of Compound VI-1

[0678] Step 1: Synthesis of compound 35c

[0679] Under ice, 35a (3 g, 17.83 mmol), zinc copper reagent (4.6 g, 35.66 mmol), and tetrahydrofuran (50 mL) were added to a single-necked flask. 35b (6.04 mL, 53.50 mmol) was slowly added dropwise with stirring over 20 minutes. The mixture was allowed to react at 35°C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 35c.

[0680] Step 2: Synthesis of compound 35d

[0681] At room temperature, 35c (4.7 g, 16.84 mmol) and acetic acid (10 mL) were added to a single-necked flask. Zinc powder (4.4 g, 67.34 mmol) was added with stirring, and the mixture was allowed to react at 100°C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then separated by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 4:1) to obtain intermediate 35d. LC-MS: m / z: 211.0 (M+H) + .

[0682] Step 3: Synthesis of compound 35e

[0683] At room temperature, 35d (1 g, 4.76 mmol) and methanol (35 mL) were added to a single-necked flask. 2,4-dimethoxybenzylamine (0.86 mL, 5.71 mmol) was added with stirring. After 16 hours of reaction at room temperature, sodium cyanoborohydride (597 mg, 9.51 mmol) was added to the reaction solution and allowed to react at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by flash column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 35e. LC-MS: m / z: 362.2 (M+H) + .

[0684] Step 4: Synthesis of compound 35f

[0685] At room temperature, 35e (400 mg, 1.11 mmol) and ethanol (5 mL) were added to a single-necked flask. 80% hydrazine hydrate (5 mL) was added with stirring, and the mixture was refluxed for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by HPLC (ammonia / acetonitrile / water system) to obtain intermediate 35f (360 mg). LC-MS: m / z: 348.2 (M+H) + .

[0686] Step 5: Synthesis of compound 35g

[0687] At room temperature, 35f (360 mg, 1.04 mmol) and 1,2-dichloroethane (10 mL) were added to a single-necked flask. N,N'-carbonyldiimidazole (252 mg, 1.55 mmol) was added with stirring and allowed to react at room temperature for 16 hours. The reaction solution was poured into 20 mL of water and extracted three times with 10 mL of dichloromethane 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 flash column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 35g. LC-MS: m / z: 374.1 (M+H) + .

[0688] Step 6: Synthesis of compound 35h

[0689] At room temperature, 35g (70mg, 0.19mmol) and N,N-dimethylformamide (3.0mL) were added to a single-necked flask. 34d (132mg, 0.94mmol), N,N-diisopropylethylamine (0.19mL, 1.12mmol), and Carter condensation agent (166mg, 0.37mmol) were added under stirring and reacted at room temperature for 18 hours. The reaction solution was poured into 20mL of water and extracted three times with 20mL of ethyl acetate each time. The organic phase was washed with 30mL 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 (ammonium bicarbonate / acetonitrile / water system) to obtain intermediate 35h. LC-MS: m / z: 497.2 (M+H) + .

[0690] Step 7: Synthesis of compound 35i

[0691] Under ice bath, 1b (10 mg, 0.04 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask, and oxalyl chloride (6 mg, 0.04 mmol) and a drop of N,N-dimethylformamide were added under stirring. After 30 minutes of reaction at room temperature, triethylamine (12 mg, 0.12 mmol) and 35h (20 mg, 0.04 mmol) were added to the reaction solution and reacted at room temperature for one hour. The reaction solution was diluted with 20 mL of saturated aqueous ammonium chloride solution and extracted 3 times with 20 mL of dichloromethane each time. The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude intermediate 35i. The crude product was used directly in the next step without purification. LC-MS: m / z: 683.2 (M+H) + .

[0692] Step 8: Synthesis of Compound VI-1

[0693] Under ice bath, 35i (30 mg, 0.04 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask, and trifluoroacetic acid (1.5 mL) was added under stirring. The reaction mixture was reacted at room temperature for 10 minutes. 25 mL of water was added to the reaction solution, and the mixture was extracted once with 20 mL of dichloromethane. The organic phase was washed with 100 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 (trifluoroacetic acid / acetonitrile / water system) to obtain compound VI-1. 1H NMR (400MHz, DMSO) δ8.31(d,J=7.7Hz,1H),7.50(t,J=8.9Hz,1H),7.08(dd,J=11.4,2. 8Hz,1H),6.85(ddd,J=9.0,2.8,1.0Hz,1H),5.36–5.27(m,1H),4.49(s,2H),4.45(m,2H ),4.23(m,1H),4.18(m,2H),2.76–2.66(m,1H),2.20–2.11(m,1H),2.07–1.96(m,1H),1 .84(m,1H),1.76(m,3H),1.71–1.60(m,2H),1.57–1.36(m,4H), LC-MS:m / z:533.0(M+H) + .

[0694] Example 36: Synthesis of Compound IV-1

[0695] Step 1: Synthesis of compound 36a

[0696] At room temperature, 17c (1.3 g, 3.98 mmol) and tetrahydrofuran (15.0 mL) were added to a single-necked flask, and compound N,N'-carbonyldiimidazole (1.29 g, 7.96 mmol) was added under stirring. After 2 hours of reaction at room temperature, diisopropylethylamine (2.59 g, 19.89 mmol) and 80% hydrazine hydrate (1.59 g, 15.91 mmol) were added in sequence, and the temperature was raised to 45 degrees Celsius to react overnight. 50 mL of water was added to the reaction solution, and the mixture was extracted twice with 50 mL of ethyl acetate each time. The organic phase was washed with 100 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 slurried with acetonitrile solvent to obtain intermediate 36a. LC-MS: m / z: 385.2 (M+H) + .

[0697] Step 2: Synthesis of compound 36b

[0698] Under ice bath, 36a (200 mg, 0.52 mmol), 1,4-dioxane (5.0 mL) and water (0.5 mL) were added to a single-necked flask. Sodium bicarbonate (65 mg, 1.49 mmol) and bromoacetonitrile (60 mg, 0.57 mmol) were added sequentially with stirring. The temperature was raised to room temperature and the reaction was allowed to react overnight. 25 mL of water was added to the reaction solution, and the mixture was extracted twice with 20 mL of ethyl acetate each time. The organic phase was washed with 30 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 36b, which was used directly in the next step without purification. LC-MS: m / z: 410.2 (M+H)+ .

[0699] Step 3: Synthesis of compound 36c

[0700] At room temperature, 36b (180 mg, 0.44 mmol) and anhydrous acetonitrile (5 mL) were added to a single-necked flask. Cuprous bromide (126.0 mg, 0.88 mmol) was added with stirring. After 5 minutes, tert-butyl nitrite (25 mg, 0.24 mmol) was added and the mixture was allowed to react overnight at room temperature. The reaction mixture was decompressed and concentrated to obtain the crude product, which was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 36c. LC-MS: m / z: 473.1 (M+H). + .

[0701] Step 4: Synthesis of Compound VI-1

[0702] Under ice bath, 36c (50 mg, 0.11 mmol) and tetrahydrofuran (5.0 mL) were added to a single-necked flask. Potassium carbonate (15 mg, 0.11 mmol) and compound B (22 mg, 0.16 mmol) were added sequentially under stirring. The temperature was raised to 80 degrees Celsius and the reaction was allowed to react overnight. 25 mL of water was added to the reaction solution, and the mixture was extracted once with 25 mL of ethyl acetate. The organic phase was washed with 25 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 compound IV-1. 1 HNMR (400MHz, MeOD) δ = 7.38 (t, J = 8.7Hz, 1H), 7.00-6.92 (m, 1H), 6.87-6.79 (m, 1H), 4.67-4.56 (m, 2H), 4. 50(s,2H),4.46-4.39(m,2H),4.18(dd,J=4.4,9.5Hz,2H),3.39-3.34(m,2H),3.30-3.25(m,2H),2.31(br t,J=10.5Hz,2H),1.87(br t,J=10.2Hz,2H),1.78-1.53(m,4H), LC-MS:m / z:534.2(M+H) + .

[0703] It should be noted that other compounds in the present application can be prepared by methods similar to those in the above embodiments (if necessary, appropriate adjustments are made, such as replacing the reaction raw materials).

[0704] Biological testing

[0705] The ATF4 luciferase reporter plasmid consists of two parts, the 5' untranslated region sequence of the ATF4 gene and the coding sequence of luciferase. Specifically, the ATF4 5' untranslated region sequence 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). 650,000 HEK293T cells were inoculated into each well of a 6-well plate and cultured overnight in a 5% CO2 incubator. After 48 hours of transfection with the packaged lentivirus, the cells were centrifuged and the supernatant discarded. The cells were replaced with DMEM complete medium containing 0.8μg / ml puromycin and resuspended and cultured. After one week of puromycin selection, the surviving cells were polyclonal HEK293T-ATF4 uORF-Luc-Puro. 200 polyclonal cells were selected and subjected to limiting gradient dilution in a 96-well plate to obtain monoclonal cells.

[0706] The specific method for monoclonal cell screening is as follows: 200 polyclonal cells are placed in well A1 of a 96-well plate. In the first step, a gradient dilution is performed from columns A1 to H1 at a ratio of 1:2. In the second step, a gradient dilution is performed from wells 1 to 12 in each row from rows A to H at a ratio of 1:2. Wells with a theoretical cell count of less than 0.5 are marked and observed one by one under a microscope. Wells with only one cell are marked. After two weeks of culture, monoclonal cells are obtained.

[0707] This cell line allows for the examination of translational regulation of ATF4 using a cold fluorescence readout and for testing compounds that activate eIF2B activity.

[0708] The specific experimental process is as follows: 6,000 HEK293T / 17-ATF4 uORF-Luc-Puro monoclonal cells were plated in a 384-well plate and allowed to adhere overnight. The test compound was dissolved in DMSO and diluted to 10 different concentrations. Each was added to the cell culture medium along with 50 nM thapsigargin and incubated for 6 hours. Thapsigargin acts by causing cellular stress and upregulating ATF4 protein translation. Six hours after drug addition, the cells were lysed using the One-Glo Luciferase Assay Kit (Promega #E6120), and the cold fluorescence value was then read using the LUM program on an EnVision 2104 plate reader.

[0709] EC was calculated based on the fluorescence values ​​at 9 concentrations of each compound (0.1 nM, 0.3 nM, 1.0 nM, 3.0 nM, 10.0 nM, 30.0 nM, 100.0 nM, 300.0 nM, 1000.0 nM). 50, and recorded in Table 1.

[0710] The relative expression of ATF4 reporter gene was calculated as follows:

[0711] ATF4 reporter expression=(ave_sample-ave_vc) / (ave_pc-ave_vc)

[0712] Wherein, ave_vc represents the average signal value of the negative control, ave_pc represents the average signal value of the positive control, and ave_sample represents the average signal value of the sample;

[0713] Fit dose-effect curves and calculate EC 50 value:

[0714] The nonlinear regression log (inhibitor) vs. response--variable slope (four parameters) method of GraphPad 9 software was used to fit the corresponding relationship between the relative expression level of the ATF4 reporter gene and the compound concentration.

[0715] The X-axis represents the log value of the compound concentration; the Y-axis represents the relative expression level of the ATF4 reporter gene.

[0716] Formula: Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0717] Table 1 EC values ​​of exemplary compounds of the invention in the ATF4-Luc assay 50 value

[0718] “+” indicates ATF4-luc EC 50 Greater than 100nM; “++” indicates ATF4-luc EC 50 Between 10nM and 100nM; "+++" indicates ATF4-luc EC 50 Less than 10nM.

[0719] The experimental results (partially not shown) show that the compounds of the present application can enhance the activity of eIF2B and reduce the expression of ATF4, thereby weakening the fluorescence intensity, indicating that the compounds of the present application can significantly alleviate the cell stress caused by thapsigargin, weaken the integrated stress response of the cells, and allow the synthesis of intracellular proteins to tend to be normal.

[0720] 2. Kinetic solubility evaluation

[0721] Dissolve the test compound in DMSO to prepare a 10mM stock solution. Add 8.71g K2HPO4 to 500mL deionized water to prepare a 100mM K2HPO4 solution. Add 2.05g potassium dihydrogen phosphate to 150mL deionized water to prepare a 100mM potassium dihydrogen phosphate solution. Mix 405mL 100mM K2HPO4 and 95mL 100mM KH2PO4, and adjust the pH of the mixed solution to 7.4 with 100mM K2HPO4 / KH2PO4 solution. Add 10.41g FaSSIF buffer concentrate to 240.3g deionized water to prepare a buffer solution (simulated intestinal fluid in the fasted state, pH=6.5). Add 4.071g FeSSIF buffer concentrate to 45.97g deionized water to prepare a buffer solution (simulated intestinal fluid in the fed state, pH=5.0).

[0722] Using a 96-well plate, add 16 μL of a 10 mM compound stock solution to 784 μL of various buffers (n=3). Seal the plate and shake at 1000 rpm for 1.5 hours at 25°C (PBS) or 37°C (other). After incubation, transfer the solution to a filter plate. Filter all samples. Take 5 μL of the filtrate and add 5 μL of DMSO and 490 μL of an acetonitrile-water solution containing an internal standard (1:1 ratio) and mix thoroughly. Dilute the solution with an acetonitrile-water solution containing an internal standard (1:1 ratio) based on the compound's properties and its mass spectrometric response. Adjust the dilution factor based on solubility and UPLC-MS / MS signal response.

[0723] Experiments show that at least some of the compounds of the present application have good solubility under the above-mentioned different simulated environments.

[0724] 3. Evaluation of cell membrane permeability

[0725] Test compounds were diluted from a 10 mM stock solution to a 10 μM concentration in transport buffer (HBSS + BSA) and applied to the apical or basolateral sides of the cell monolayer. Permeability of the test compounds was determined duplexly in the A-to-B and B-to-A directions over a 120-minute incubation period at 37°C, 5% CO₂, and 95% relative humidity. The efflux ratio (Papp B to A / Papp A to B) of each compound was also determined. Quantification of the analyte and reference compounds was performed using LC-MS / MS based on the analyte / IS peak area ratio.

[0726] Table 2 Cell membrane permeability of exemplary compounds

[0727] The experimental results show that at least some of the compounds of the present application (such as III-1) have good cell membrane permeability and are not P-glycoprotein substrates.

[0728] 4. Pharmacokinetic evaluation in mice

[0729] Test compound was dissolved in vehicle to prepare a clear solution or homogenous suspension. Three mice per group were administered 1 mg / kg intravenously (IV) 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 IV administration, and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after PO administration. Plasma samples were centrifuged, and the supernatant was collected for quantitative analysis by LC / MS / MS.

[0730] Table 3 Mouse PK properties of exemplary compounds

[0731] The experimental results show that at least some of the compounds of the present application (such as III-1) have excellent pharmacokinetic properties in mice (including but not limited to C0 (initial drug concentration), CL (clearance rate), AUC, t1 / 2 (half-life), C max (peak concentration), T max (time to peak), AUC (area under the concentration-time curve), F (bioavailability), Vss (apparent volume of distribution at steady state), etc.).

[0732] The technical solution of the present invention is not limited to the above-mentioned specific embodiments. Any technical variations made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. A compound represented by Formula 0, or a stereoisomer, or a tautomer, or a geometric isomer, or an enantiomer, or a diastereomer, or a racemate, or a polymorph, or a solvate, or a hydrate, or an N-oxide, or an isotope-labeled compound, or a metabolite, or an ester, or a prodrug, or a pharmaceutically acceptable salt thereof: in, Ring A and Ring C are each independently C1-C6 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 6-10 membered aryl-D-C1-C6 alkyl, 5-10 membered heteroaryl-D-C1-C6 alkyl, C3-C9 cycloalkyl-D-C1-C6 alkyl or 3-9 membered heterocyclyl-D-C1-C6 alkyl; wherein the alkyl is optionally substituted with deuterium, halogen or C1-C6 alkyl; the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with 1-5 R 1 replace; Each of the R 1 Each is independently selected from the group consisting of any one of the following groups: hydrogen, deuterium, halogen, hydroxy, phenyl, cyano, C1-C10 alkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-COOR 1D 、-SR 1E 、-S(O)R 1D 、-S(O)2R 1D , -G 1 、-OG 1 、-NR 1B -G 1 ; or two R on adjacent atoms 1 The group and the atoms to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a 6-10 membered aryl or a 5-6 membered heteroaryl; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the 6-10 membered aryl or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F Substituted; as the R 1 The optional phenyl, C1-C10 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclyl are each optionally substituted with halogen; Each of the R 1A 、R 1B 、R 1C 、R 1D 、R 1E Each is independently selected from the group consisting of any one of hydrogen, deuterium, C1-C6 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy; R 1B 、R 1C and the atoms to which they are commonly attached may form a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-3 R 1F replace; Each of the G 1 Each is independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; each of the G 1 Each optionally replaced by 1-3 R 1F replace; L 1 Empty, -NH-, in, The end is connected to the A ring, and the * end is connected to the B ring; Preferably, the L 1 Empty, -NH-, Preferably, the L 1 Empty, Preferably, the L 1 Empty, Preferably, the L 1 Empty, Preferably, the L 1 Empty, Ring B is a 5-10 membered spiro ring or a 5-10 membered spiro heterocycle, wherein the 5-10 membered spiro ring and the 5-10 membered spiro heterocycle are optionally substituted by 1-5 R 1F replace; Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, deuterium, halogen, hydroxy, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-COOR 1D 、-P(O)R 1B R 1C 、-SR 1E 、-S(O)R 1D 、-S(O)2R 1D ; L 2 Empty, -NH-, in, The A end is connected to the B ring, and the B end is connected to the C ring; Preferably, the L 2 Empty, -NH-, Preferably, the L 2 Empty, Preferably, the L 2 Empty, Preferably, the L 2 Empty, Preferably, the L 2 Empty or The D is independently a linking group containing a heteroatom; preferably, the D is independently O or NR d or S, R d Each D is independently selected from hydrogen, deuterium, C1-C6 alkyl, and halogen-substituted C1-C6 alkyl; more preferably, each D is independently O or NH.

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: The A ring is a C1-C6 alkyl, a C3-C9 cycloalkyl, a 3-9 membered heterocyclyl, a 6-10 membered aryl, a 5-10 membered heteroaryl, a 6-10 membered aryl-D-C1-C6 alkyl, a 5-10 membered heteroaryl-D-C1-C6 alkyl or a 3-9 membered heterocyclyl-D-C1-C6 alkyl; wherein the alkyl is optionally substituted with halogen or C1-C6 alkyl; the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with 1-5 R 1 replace; Each of the R 1 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, cyano, C1-C10 alkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-COOR 1D 、-SR 1E 、-S(O)R 1D 、-S(O)2R 1D , -G 1 、-OG 1 、-NR 1B -G 1 ; or two R on adjacent atoms 1 The group and the atoms to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a 6-10 membered aryl or a 5-6 membered heteroaryl; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the 6-10 membered aryl or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F replace; Each of the R 1A 、R 1B 、R 1C 、R 1D 、R 1E Each is independently selected from any one of the following groups: hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy; R 1B 、R 1C and the atoms to which they are commonly attached may form a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-3 R 1F replace; Each of the G 1 Each is independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; each of the G 1 Each optionally replaced by 1-3 R 1F replace; Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, hydroxy, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, halogen-substituted C1-C6 alkoxy-C1-C6 alkenyl, amino-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-COOR 1D 、-P(O)R 1B R 1C 、-SR 1E 、-S(O)R 1D 、-S(O)2R 1D ; The C ring is a 6-10 membered aryl-E-C1-C6 alkyl, a C3-C9 cycloalkyl-E-C1-C6 alkyl, a 3-9 membered heterocyclyl-E-C1-C6 alkyl, a 3-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of hydrogen, deuterium, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclic group; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclic group are each optionally substituted with halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a 5-6 membered aryl (such as a phenyl group) or a 5-6 membered heteroaryl; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the 5-6 membered aryl (such as a phenyl group) or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F replace; The D and E are each independently a linking group containing a heteroatom; preferably, the D and E are each independently O or NR d or S, R d Each is independently selected from hydrogen, deuterium, and C1-C3 alkyl; more preferably, D and E are each independently O or NH.

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: The A ring is a 3-9 membered heterocyclic group, a 6-10 membered aryl group, a 5-10 membered heteroaryl group, a 6-10 membered aryl group-D-C1-C6 alkyl group or a 3-9 membered heterocyclic group-D-C1-C6 alkyl group; wherein the heterocyclic group, aryl group and heteroaryl group are each optionally substituted by 1-5 R 1 replace; Each of the R 1 Each independently selected from the group consisting of any one of hydrogen, halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D , -G 1 、-OG 1 、-NR 1B -G 1 ; or two R on adjacent atoms 1 The group and the atom to which it is attached may form a 6-10 membered aryl or a 5-6 membered heteroaryl; the 6-10 membered aryl or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F replace; Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C6 alkyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted 3-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy; R 1B 、R 1C and the atoms to which they are commonly attached may form a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-3 R 1F replace; Each of the G 1 Each is independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl; each of the G 1 Each optionally replaced by 1-3 R 1F Replace; when G 1 When it is a phenyl group, the phenyl group and the 3-9-membered heterocyclic group or the 5-10-membered heteroaryl group optionally share two carbon atoms to form a condensed ring; Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C 、-C(O)R 1D 、-P(O)R 1B R 1C 、-S(O)2R 1D .

4. The compound according to any one of claims 1 to 3, 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 a 4-9 membered heterocyclic group, a 5-7 membered heteroaryl group, a phenyl-D-C1-C6 alkyl group or a 4-9 membered heterocyclic group-D-C1-C6 alkyl group; wherein the heterocyclic group, heteroaryl group and phenyl group are each optionally substituted by 1-5 R 1 replace; Each of the R 1 Each independently selected from the group consisting of any one of hydrogen, halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, -OR 1A 、-NR 1B R 1C 、-NR 1B C(O)R 1D 、-C(O)NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ; Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C4-C9 cycloalkyl, halogen-substituted 4-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy; R 1B 、R 1C and the atoms to which they are commonly attached may form a 3-7 membered heterocyclic group, wherein the 3-7 membered heterocyclic group is optionally substituted by 1-3 R 1F replace; Each of the G 1 Each independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F Replace; when G 1 When it is a phenyl group, the phenyl group and the 3-9-membered heterocyclic group or the 5-7-membered heteroaryl group optionally share two carbon atoms to form a condensed ring; Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C6 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、- S(O)2R 1D 。 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: The A ring is a 4-8 membered heterocyclic group, a 5-6 membered heteroaryl group, a phenyl-D-C1-C3 alkyl group or a 4-8 membered heterocyclic group-D-C1-C3 alkyl group; wherein the heterocyclic group, heteroaryl group and phenyl group are each optionally substituted by 1-2 R 1 replace; Each of the R 1 Each independently selected from the group consisting of any one of hydrogen, halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, -OR 1A 、-NR 1B R 1C 、-NR B C(O)R 1D 、-C(O)NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ; Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy; Each of the G 1 Each is independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, preferably, the C3-C6 cycloalkyl is cyclobutane or cyclopentane, the 3-6 membered heterocyclic group is oxetane, azetidinyl, oxolane or azocyclopentane; each of the G 1 Each optionally replaced by 1-3 R 1F Replace; when G 1 When it is a phenyl group, the phenyl group and the 5-6 membered heterocyclic group or the 5-7 membered heteroaryl group optionally share two carbon atoms to form a condensed ring; Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D .

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 A ring is a 5-6 membered heterocyclic group; preferably or preferably Preferably, the R 1 The number n is 1, 2 or 3; Preferably, the R 1 are each independently selected from any one of the following groups: hydrogen, halogen, hydroxy, C1-C3 alkyl and phenyl, and when R 1 When phenyl is present, the phenyl group and the 3-6 membered heterocyclic group share two carbon atoms to form a condensed ring. Two carbon atoms are shared to form a fused ring, and the phenyl group is optionally substituted by halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 haloalkoxy; Further preferably, the phenyl group The fusion method is The phenyl group is optionally substituted with halogen; Alternatively, the A ring is a 5-6 membered heteroaryl group, preferably any one of the following groups: (1) H 1 、H 2 、H 3 、H 4 are each independently C or a heteroatom, and at least one is a heteroatom, preferably the heteroatom is selected from any one of N, O, and S; preferably, the R 1 Any one selected from the group consisting of hydrogen, -OR 1A 、-NR 1B R 1C , -G 1 、-OG 1 、-NR 1B -G 1 , each of the R 1A 、R 1B 、R 1C Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy; Each of the G 1 Each is independently selected from 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F replace; Each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D , the R 1D Any one selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy; or The A ring is a 5-membered heteroaryl group, H 1 、H 2 、H 3 、H 4 are each independently selected from CH, N, O, S, is a single bond or a double bond; the R 1 Each independently selected from any one of the following groups: -OR 1A 、-NR 1B R 1C , -G 1 、-OG 1 、-NR 1B -G 1 ; Each of the R 1A 、R 1B 、R 1C Each of the Gs is independently selected from the group consisting of any one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy-C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy; each of the Gs 1 Each independently selected from C4-C6 cycloalkyl, 4-9 membered heterocyclic group; each of the G 1 Each optionally replaced by 1-3 R 1F Substitution; each of the R 1F Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D , the R 1D Any one selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy; Preferably, the A ring is More preferably, the L 1 is empty; Preferably, the R 1 Select from -OR 1A , -G 1 、-OG 1 、-NR 1B -G 1 ; R 1A is selected from halogen-substituted C1-C3 alkoxy-C1-C3 alkyl; R 1B Selected from H, C1-C3 alkyl; each of said R 1F Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkenyl, oxo, -P(O)R 1B R 1C 、-S(O)2R 1D ; R 1B 、R 1C 、R 1D Each independently selected from any one of the following groups: hydrogen, C1-C3 alkyl; (2) Preferably, each R 1 are independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy and benzene, and when R 1 When phenyl, the phenyl Two carbon atoms are shared to form a fused ring, and the phenyl group is optionally substituted by halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 haloalkoxy; Further preferably, the phenyl group is optionally substituted by halogen; the R 1 The number m is 1 or 2; (3) Preferably, the R 1 is hydrogen, halogen or phenyl, the phenyl group is optionally substituted by one or more halogens, the R 1 The number m is 1 or 2; R 1 When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring; More preferably, the R 1 is phenyl, m is 1, phenyl and The fusion mode is The phenyl group is optionally substituted with one or more halogens; Alternatively, the A ring is phenyl-O-C1-C3 alkyl, wherein the phenyl group is optionally substituted by 1 or 2 R 1 Substitution; each of the R 1 Each is independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy; Preferably, the A ring is phenyl-O-methyl, R 1 is H or halogen; Alternatively, the A ring is a 4-8 membered heterocyclic group-O-C1-C3 alkyl group, wherein the heterocyclic group is optionally substituted by 1-3 R 1 Substitution; each of the R 1 Each is independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy; Preferably, the A ring is a 4-7 membered heterocyclyl-O-methyl group, R 1 is a halogen-substituted C1-C3 alkyl group or a halogen-substituted C1-C3 alkoxy group; Alternatively, the A ring is C3-C7 cycloalkyl-O-C1-C3 alkyl, and the C3-C7 cycloalkyl is optionally substituted by 1-3 R 1 Substitution; each of the R 1 Each is independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy; Preferably, the A ring is C4-C6 cycloalkyl-O-methyl, R 1 is a halogen-substituted C1-C3 alkyl group or a halogen-substituted C1-C3 alkoxy group; Alternatively, the A ring is a phenyl group, and the phenyl group is substituted by a group selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; Preferably, the phenyl group is selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy substitution; Further preferably, the phenyl group is substituted by a C1-C3 haloalkyl group; Preferably, the A ring is selected from any one of the following groups: (1) Preferably, the R 1 Any one selected from the group consisting of: -G 1 , OG 1 、-NR 1B -G 1 , preferably each of the G 1 Each optionally replaced by 1 or 2 R 1F Substitution; said R 1B Any one selected from the group consisting of: hydrogen, C1-C3 alkyl; each of the G 1 Each is independently selected from C3-C6 cycloalkyl, 4-9 membered heterocyclyl; Further preferably, the C3-C6 cycloalkyl group is a cyclobutane group or a cyclopentane group; the 4-9 membered heterocyclic group is preferably an oxetane group, an N-heterocyclic group, and further preferably an oxetane group, an azetidinyl group, an oxolanyl group, an azocyclopentanyl group, More preferably, oxetane, azetidinyl, oxolane, azocyclopentane, or more preferably Each of the R 1F Each independently selected from any one of the following groups: oxo, C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy; 1 Preferably empty; (2) 4-8 membered heterocyclic-O-C1-C3 alkyl, wherein the heterocyclic group is optionally substituted by 1 or 2 R 1 Substitution; each of the R 1 Each is independently selected from any one of the following groups: a halogen-substituted C1-C3 alkyl group, a halogen-substituted C1-C3 alkoxy group; (3) C4-C6 cycloalkyl-O-C1-C3 alkyl, wherein the C4-C6 cycloalkyl is optionally substituted by 1 or 2 R 1 Substitution; each of the R 1 Each is independently selected from halogen-substituted C1-C3 alkyl and halogen-substituted C1-C3 alkoxy.

7. The compound according to any one of claims 1 to 6, 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 A ring is selected from any one of the following groups: Preferably, ring A is selected from any one of the following groups: Preferably, ring A is selected from any one of the following groups: Preferably, ring A is selected from any one of the following groups:

8. The compound according to any one of claims 1 to 7, 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 spiro ring is selected from any one of the following groups: spiro[2,5]octyl ring, spiro[3,4]octyl ring, spiro[3,3]heptyl ring, spiro[3,5]nonyl ring, spiro[4,5]decyl ring, spiro[2,2]pentyl ring, spiro[2,3]hexyl ring, spiro[2,4]heptyl ring, spiro[2,6]nonyl ring, spiro[2,7]nonyl ring, spiro[3,6]nonyl ring and spiro[4,4]nonyl ring, the spiroheterocycle is a group formed by replacing any one or more carbon atoms in the spiro ring with heteroatoms, and the number of heteroatoms in the spiroheterocycle is 1, 2 or 3; Preferably, the heteroatom in the spiro heterocycle is nitrogen, or a combination of nitrogen and oxygen; Preferably, the substituent R of the spiro ring or the spirohetero ring 1F is hydrogen, halogen, hydroxy, amino, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy; More preferably, the substituent R of the spiro ring or the spirohetero ring 1F is halogen, hydroxyl, amino; Most preferably, the substituent R of the spiro ring or the spirohetero ring is 1F It is a hydroxyl group.

9. The compound according to claim 8, 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 a 7-9 membered spiro ring or a 7-9 membered spiro heterocycle; Preferably, the spiro ring is selected from any one of the following groups: spiro[2,5]octyl ring, spiro[3,4]octyl ring, spiro[3,3]heptyl ring and spiro[3,5]nonyl ring; the 7-9 membered spiroheterocycle is a group formed by replacing any one or more carbon atoms in the 7-9 membered spiro ring with a heteroatom, and the number of heteroatoms in the spiroheterocycle is 1, 2 or 3; Preferably, the heteroatom in the spiro heterocycle is nitrogen, or a combination of nitrogen and oxygen; Preferably, the B ring is selected from any one of the following groups: in, End and L 1 Connect, * end and L 2 connect; Preferably, the B ring is selected from any one of the following groups: Further preferably, the B ring is selected from any one of the following groups: Further preferably, the B ring is selected from any one of the following groups:

10. The compound according to any one of claims 1 to 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: The C ring is a 6-10 membered aryl-E-C1-C3 alkyl, a C4-C9 cycloalkyl-E-C1-C3 alkyl, a 4-9 membered heterocyclyl-E-C1-C3 alkyl, a 4-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, phenyl, C1-C3 alkyl, C1-C3 alkoxy; wherein, as the R 2 The optional phenyl, C1-C3 alkyl, C1-C3 alkoxy are each optionally substituted by halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the phenyl group or the 5-6 membered heteroaryl group are each optionally substituted by 1-5 R 1F Replace; when R 2 When it is a phenyl group, the phenyl group and the 4-9 membered heterocyclic group or the 5-10 membered heteroaryl group optionally share two carbon atoms to form a condensed ring; The E's are each independently a linking group containing a heteroatom; Preferably, each of the E's is independently O or NR d or S, R d Each is independently selected from hydrogen, deuterium, C1-C3 alkyl; More preferably, each of the E's is independently O or NH.

11. The compound according to any one of claims 1 to 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: The C ring is phenyl-E-C1-C3 alkyl, and the phenyl group is 1, 2 or 3 R 2 Substitution, wherein E is a linking group containing a heteroatom; Preferably, the E is O or NR d or S, R d is selected from hydrogen, deuterium, and C1-C3 alkyl; Preferably, E is O or NH; Preferably, each of the R 2 are each independently halogen; Preferably, the C ring is phenyl-O-C1-C3 alkyl; Alternatively, the C ring is a C4-C9 cycloalkyl-E-C1-C3 alkyl or a 4-9 membered heterocyclyl-E-C1-C3 alkyl, wherein the cycloalkyl or heterocyclyl is replaced by R 2 Substitution; said E is O or NR d or S, R d is selected from hydrogen, deuterium, C1-C3 alkyl; said R 2 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C1-C3 haloalkoxy; Preferably, the cycloalkyl group is cyclopropyl, cyclobutyl or cyclopentyl; Preferably, the heterocyclic group is oxirane, oxetane, oxolane, aziridine, azetidine or azopentane; Preferably, E is O or NH; Alternatively, the C ring is a 4-9 membered heterocyclic group, preferably a 5-6 membered heterocyclic group; preferably, the C ring is The R 2 The number n is 1 or 2 or 3; Preferably, each of the R 2 Each independently selected from the group consisting of any one of hydrogen, halogen, C1-C3 alkyl, phenyl, halogenated phenyl and hydroxyl; the R 2 When phenyl or halogenated phenyl, optionally phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner: Preferably, the C ring is The R 2 The number n is 1 or 2 or 3; Preferably, each of the R 2 Each independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, phenyl and halogenated phenyl; 2 When it is a substituent on the N atom, the R 2 is any one of the following groups: hydrogen, halogen, C1-C3 alkyl; 2 When phenyl or halogenated phenyl, the phenyl or halogenated phenyl and the morpholine ring group may share two carbon atoms to form a fused ring, preferably in the form of Preferably, the C ring is The R 2 The number n is 1 or 2 or 3; Preferably, each of the R 2 Each independently selected from any one of the following groups: halogen, phenyl, halogenated phenyl and hydroxyl; the R 2 When phenyl or halogenated phenyl, optionally the phenyl or the halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner: Alternatively, the C ring is a 5-10 membered heteroaryl group, preferably, the C ring is any one of the following 5-10 membered heteroaryl groups: (1) Preferably, each R 2 Independently selected from any one of the following groups: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, halophenyl, said R 2 The number p is 1 or 2, and when the R 2 When phenyl or halogenated phenyl, the phenyl or halogenated phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following ways: (2) Preferably, the R 2 Any one selected from the group consisting of: hydrogen, halogen, phenyl, C1-C3 alkyl, C1-C3 alkoxy-C3-C6 cycloalkyl; the phenyl, the alkyl, the alkoxy is unsubstituted or substituted with halogen; the R 2 When phenyl, optionally the phenyl and Share two carbon atoms to form a fused ring, preferably fused in the following manner: Alternatively, the C ring is a phenyl group; the phenyl group is R 2 Substituted; preferably, the R 2 Any one selected from the group consisting of C1-C3 haloalkyl, C1-C3 haloalkoxy.

12. The compound according to any one of claims 1 to 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: The C ring is selected from any one of the following groups: Preferably, the C ring is selected from any one of the following groups: Preferably, the C ring is selected from any one of the following groups: Preferably, the C ring is selected from any one of the following groups: Preferably, the C ring is selected from any one of the following groups:

13. The compound according to any one of claims 1 to 12, 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 has the structure shown in Formula I: Preferably, Ring A is a 3-9 membered heterocyclic group, a 5-10 membered heteroaryl group, a 6-10 membered aryl-D-C1-C6 alkyl group or a 5-10 membered heteroaryl-D-C1-C6 alkyl group; wherein the heterocyclic group, aryl group and heteroaryl group are each optionally substituted by 1-5 R 1 replace; Each of the R 1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C10 alkyl, hydroxy substituted C1-C6 alkyl, halogen substituted C1-C6 alkyl, halogen substituted C1-C6 alkoxy, -G 1 、-OG 1 ; or two R on adjacent atoms 1 The group and the atoms to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a 6-10 membered aryl or a 5-6 membered heteroaryl; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the 6-10 membered aryl or the 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F1 replace; Each of the G 1 Each is independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; each of the G 1 Each optionally replaced by 1-3 R 1F1 replace; Each of the R 1F1 、R 1F2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, C1-C6 alkyl, C3-C9 cycloalkyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy; preferably, each of the R 1F2 are independently selected from hydrogen, halogen, hydroxyl, and amino; L 2 Empty, -NH-, in, The end is connected to the B ring, the * end is connected to the C ring, preferably End and in formula I The N atoms in the connection; Preferably, the L 2 Empty, -NH-, Preferably, the L 2 Empty, Preferably, the L 2 Empty, Preferably, the L 2 for Preferably, the L 2 Empty, The C ring is a 6-10 membered aryl-E-C1-C6 alkyl, a 3-9 membered heterocyclic group, a 5-10 membered heteroaryl or a 6-10 membered aryl; each of the aryl, heteroaryl and heterocyclic groups may be optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from any one of the following groups: halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl are each optionally substituted with halogen; when R 2 When it is a phenyl group, the phenyl group and the 3-9-membered heterocyclic group or the 6-10-membered heteroaryl group optionally share two carbon atoms to form a condensed ring; The D and E are each independently a linking group containing a heteroatom; preferably, the D and E are each independently O or NR d or S, R d Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, and halogen-substituted C1-C6 alkyl; more preferably, D and E are each independently O or NH.

14. The compound according to any one of claims 1 to 12, 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 has a structure shown in Formula II or Formula III: Preferably, The A rings are each independently a 5-7 membered heteroaryl, a phenyl-D-C1-C6 alkyl, or a 3-9 membered heterocyclic group; wherein the heteroaryl and phenyl groups are each optionally substituted by 1 or 2 R 1 replace; Each of the R 1 Each independently selected from the group consisting of any one of the following groups: halogen, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, -OR 1A 、-NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ; Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C6 alkyl, C4-C9 cycloalkyl, 4-9 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C4-C9 cycloalkyl, halogen-substituted 4-9 membered heterocyclyl, halogen-substituted C1-C6 alkoxy; Each of the G 1 Each independently selected from C3-C9 cycloalkyl, 3-9 membered heterocyclic group, phenyl; each of the G 1 Each one can choose Ground cover 1-3 R 1F1 Replace; when G 1 When it is a phenyl group, the phenyl group and the 3-9-membered heterocyclic group or the 5-7-membered heteroaryl group optionally share two carbon atoms to form a condensed ring; Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C6 alkyl, C3-C9 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C9 cycloalkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C6 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D ; L 1 Empty, -NH-, in, The end is connected to the A ring, the * end is connected to the B ring; preferably the * end is connected to the & C atoms in formula III &C atoms connected in; Preferably, the L 1 Empty, -NH-, Preferably, the L 1 Empty, Preferably, the L 1 Empty, More preferably, the L 1 Empty or L 2 Empty, -NH-, in, The end is connected to the B ring, and the * end is connected to the C ring; preferably The end and the The N atom in formula III @C atom connection in; Preferably, the L 2 Empty, -NH-, Preferably, the L 2 Empty, Preferably, L in the formula II 2 for More preferred Preferably, L in the formula III 2 Empty, More preferably empty or Each of the R 1F2 are independently selected from hydrogen, halogen, hydroxyl, amino; preferably, each of the R 1F2 independently selected from hydrogen, hydroxyl; The C ring is selected from 6-10 membered aryl-E-C1-C3 alkyl, C4-C9 cycloalkyl-E-C1-C3 alkyl, 4-9 membered heterocyclyl-E-C1-C3 alkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of the following groups: hydrogen, halogen, hydroxyl, phenyl, C1-C3 alkyl, C1-C3 alkoxy; wherein, as the R 2 The optional phenyl, C1-C3 alkyl, C1-C3 alkoxy are each optionally substituted by halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the phenyl group or the 5-6 membered heteroaryl group are each optionally substituted by 1-5 R 1F Replace; when R 2 When it is a phenyl group, the phenyl group and the 4-9 membered heterocyclic group or the 5-10 membered heteroaryl group optionally share two carbon atoms to form a condensed ring; The E's are each independently a linking group containing a heteroatom; preferably, the E's are each independently O or NR d or S, R d Each E is independently selected from hydrogen, deuterium, and C1-C3 alkyl; more preferably, each E is independently O or NH.

15. The compound according to any one of claims 1 to 12, 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 has a structure shown in Formula IV: Preferably, The A ring is a 4-8 membered heterocyclic group, a 5-7 membered heteroaryl group, a phenyl-O-C1-C6 alkyl group, or a C4-C8 cycloalkyl-O-C1-C6 alkyl group; wherein the heterocyclic group, heteroaryl group, phenyl group, and cycloalkyl group are each optionally substituted by 1-2 R 1 replace; Each of the R 1 Each independently selected from the group consisting of any one of the following groups: halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, -OR 1A 、-NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ; Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy; Each of the G 1 Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 Replace; when G 1 When it is a phenyl group, the phenyl group and the 5-6 membered heterocyclic group or the 5-7 membered heteroaryl group optionally share two carbon atoms to form a condensed ring; Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D ; Each of the R 1F2 are independently selected from hydrogen, halogen, hydroxyl, amino; preferably, each of the R 1F2 independently selected from hydrogen, hydroxyl; L 1 Empty, -NH-, in, The end is connected to the A ring, the * end is connected to the B ring; preferably the * end is connected to the The N atoms are connected; Preferably, the L 1 Empty, -NH-, Preferably, the L 1 Empty, Preferably, the L 1 Empty, L 2 Empty, -NH-, in, The end is connected to the B ring, and the * end is connected to the C ring; preferably end and in formula IV @C atom connection; Preferably, the L 2 Empty, -NH-, Preferably, the L 2 Empty, More preferably, the L 2 for The C ring is a 6-10 membered aryl-O-C1-C3 alkyl, a C4-C9 cycloalkyl-O-C1-C3 alkyl, a 4-9 membered heterocyclyl-O-C1-C3 alkyl, a 4-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from any one of the following groups: halogen, hydroxyl, phenyl, C1-C3 alkyl, C1-C3 alkoxy; wherein, as the R 2 The phenyl, C1-C3 alkyl, C1-C3 alkoxy groups are each optionally substituted with halogen; or two R groups on adjacent atoms 2 The group and the atoms to which it is connected can form a C3-C7 cycloalkyl, a 3-7 membered heterocyclic group, a phenyl group or a 5-6 membered heteroaryl group. The C3-C7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are each optionally substituted by 1-5 R 1F1 Replace; when R 2 When it is a phenyl group, the phenyl group and the 4-9 membered heterocyclic group or the 5-10 membered heteroaryl group optionally share two carbon atoms to form a condensed ring.

16. The compound according to any one of claims 1 to 12, 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 has the structure shown in Formula V: Preferably, The A ring is a 4-8 membered heterocyclic group, a 5-7 membered heteroaryl group, or a phenyl-O-C1-C6 alkyl group; wherein the heterocyclic group, heteroaryl group, and phenyl group are each optionally substituted by 1-2 R 1 replace; Each of the R 1 Each independently selected from the group consisting of any one of the following groups: halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, -OR 1A 、-NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ; Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy; Each of the G 1 Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 Replace; when G 1 When it is a phenyl group, the phenyl group and the 5-6 membered heterocyclic group or the 5-7 membered heteroaryl group optionally share two carbon atoms to form a condensed ring; Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D ; L 1 Empty, -NH-, in, The end is connected to the A ring, the * end is connected to the B ring; preferably the * end is connected to the The N atoms are connected; Preferably, the L 1 Empty, -NH-, Preferably, the L 1 Empty, Preferably, the L 1 for Each R 1F2 Independently selected from hydrogen, halogen, hydroxyl, amino; Preferably, each of the R 1F2 independently selected from hydrogen, hydroxyl; L 2 Empty, -NH-, in, The end is connected to the B ring, and the * end is connected to the C ring; preferably End and V @C atom connection; Preferably, the L 2 Empty, -NH-, Preferably, the L 2 Empty, Preferably, the L 2 for The C ring is a 6-10 membered aryl-O-C1-C3 alkyl, a 4-9 membered heterocyclyl-O-C1-C3 alkyl, a 4-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from any one of the following groups: halogen, hydroxyl, phenyl, C1-C3 alkyl, C1-C3 alkoxy; wherein, as the R 2 The optional phenyl, C1-C3 alkyl, C1-C3 alkoxy are each optionally substituted by halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the phenyl group or the 5-6 membered heteroaryl group are each optionally substituted by 1-5 R 1F1 Replace; when R 2 When it is a phenyl group, the phenyl group and the 4-9 membered heterocyclic group or the 5-10 membered heteroaryl group optionally share two carbon atoms to form a condensed ring.

17. The compound according to any one of claims 1 to 12, 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 has the structure shown in Formula VI, Formula VII, Formula VIII, and Formula IX: Preferably, The A ring is a 3-9 membered heterocyclic group, a 5-10 membered heteroaryl group, a 6-10 membered aryl-D-C1-C6 alkyl group, a 5-10 membered heteroaryl-D-C1-C6 alkyl group, or a 3-9 membered heterocyclic group-D-C1-C6 alkyl group; wherein the heterocyclic group, heteroaryl group, and aryl group may be optionally substituted by 1-5 R 1 replace; Each of the R 1 Each independently selected from the group consisting of any one of the following groups: halogen, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, -OR 1A 、-NR 1B R 1C , -G 1 , OG 1 、-NR 1B -G 1 ; Each of the R 1A 、R 1B 、R 1C 、R 1D Each is independently selected from any one of the following groups: hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C6 cycloalkyl, halogen-substituted 4-6 membered heterocyclyl, halogen-substituted C1-C3 alkoxy; Each of the G 1 Each independently selected from C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl; each of the G 1 Each optionally replaced by 1-3 R 1F1 Replace; when G 1 When it is a phenyl group, the phenyl group and the 5-6 membered heterocyclic group or the 5-7 membered heteroaryl group optionally share two carbon atoms to form a condensed ring; Each of the R 1F1 Each independently selected from the group consisting of any one of the following groups: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, halogen-substituted C3-C6 cycloalkyl, halogen-substituted C1-C3 alkenyl, oxo, -OR 1A 、-NR 1B R 1C 、-P(O)R 1B R 1C 、-S(O)2R 1D ; More preferably, the A ring is a 5-7 membered heteroaryl group, which may be substituted by 1-2 R 1 replace; L 1 Empty, -NH-, in, The end is connected to the A ring, the * end is connected to the B ring; preferably the * end is connected to the The & C atoms in formula VII The & C atoms in formula VIII The & C atoms in formula IX &C Atom Connection; Preferably, the L 1 Empty, -NH-, Preferably, the L 1 Empty, L 2 Empty, -NH-, in, The end is connected to the B ring, and the * end is connected to the C ring; preferably The terminal and the @C atom, in formula VII @C atom, in formula VIII @C atom, formula IX @C atom connection; Preferably, the L 2 Empty, -NH-, Preferably, the L 2 Empty, Each of the R 1F2 independently selected from hydrogen, halogen, hydroxy, amino, carboxyl; Preferably, each of the R 1F2 independently selected from hydrogen, hydroxyl; The C ring is a 6-10 membered aryl-E-C1-C6 alkyl, a C3-C9 cycloalkyl-E-C1-C6 alkyl, a 3-9 membered heterocyclyl-E-C1-C6 alkyl, a 3-9 membered heterocyclyl, a 5-10 membered heteroaryl or a 6-10 membered aryl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are each optionally substituted by 1-3 R 2 Substitution; each of the R 2 Each independently selected from the group consisting of any one of hydrogen, deuterium, halogen, hydroxyl, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 alkoxy-3-6 membered heterocyclic group; wherein, as the R 2 The optional phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy in C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy in C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy in C1-C3 alkoxy-3-6 membered heterocyclic group are each optionally substituted with halogen; or two R on adjacent atoms 2 The group and the atom to which it is attached may form a C3-C7 cycloalkyl, a 3-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; the C3-C7 cycloalkyl, the 3-7 membered heterocyclyl, the phenyl group or the 5-6 membered heteroaryl group are each optionally substituted by 1-5 R 1F replace; The D and E are each independently a linking group containing a heteroatom; preferably, the D and E are each independently O or NR d or S, R d Each is independently selected from hydrogen, deuterium, and C1-C3 alkyl; more preferably, D and E are each independently O or NH.

18. The compound according to any one of claims 1 to 17, 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 specifically:

19. A pharmaceutical composition comprising a preparation prepared from the compound of any one of claims 1 to 18, 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.

20. The pharmaceutical composition according to claim 19, characterized in that: It further includes pharmaceutically acceptable carriers, excipients, and vehicles.

21. A compound according to any one of claims 1 to 18, 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 19 or 20 for the preparation of a medicament for preventing and / or treating a neurodegenerative disease, a 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) induction, a malarial infection, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease.

22. Use of a compound according to any one of claims 1 to 18, 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 isotopically 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 19 or 20 in the preparation of a medicament for preventing and / or treating a disease or condition mediated by the integrated stress response (ISR) pathway.

23. A method of treating a disease or condition mediated by the integrated stress response (ISR) pathway in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 18, 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 isotopically 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 19 or 20.

24. A method for treating a disease associated with modulation of eIF2B activity or levels, the activity or levels of the eIF2 pathway or the ISR pathway, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 18, 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 isotopically 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 19 or 20.

25. A method for preventing and / or treating a disease or condition mediated by an integrated stress response (ISR) pathway, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18, 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 isotopically 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 19 or 20.

26. A method for preventing and / or treating cancer, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 18, 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 19 or 20.

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