Compound, pharmaceutical composition containing same, and use thereof

Abstract

The present application provides a compound represented by Formula 0, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a 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, wherein ring B is a 5- to 10-membered spiro ring or a 5- to 10-membered spiro heterocycle, and the 5- to 10-membered spiro ring and the 5- to 10-membered spiro heterocycle are optionally substituted with 1 to 5 R1F. This can significantly attenuate the cellular integrated stress response (ISR), activate eIF2B activity, and promote normal intracellular protein synthesis. TIFF2025526814000507.tif3489

Description

[Technical Field]

[0001] This application claims priority to Chinese patent application CN202210945768.0, filed August 8, 2022, and Chinese patent application CN202310729419.X, filed June 16, 2023. This application references all of the above Chinese patent applications.

[0002] The present invention relates to a compound, a pharmaceutical composition containing the same, and uses thereof. [Background technology]

[0003] Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), commonly known as gradual frozen man, is an irreversible, fatal motor neuron disease. Its primary symptoms are progressive muscle weakness and atrophy of the limbs and trunk, gradually leading to loss of motor function and a "freezing" appearance, hence the nickname "gradual frozen man." The majority of ALS patients die of respiratory failure, usually within three to five years after the first onset of symptoms. Currently, there is no cure for ALS, and no effective treatments to halt or reverse disease progression. The core pathological finding of ALS is the death of motor neurons in the motor cortex and spinal cord. Degeneration of corticospinal axons leads to thinning and scarring (sclerosis) of the lateral spinal cord.

[0004] Loss of protein folding homeostasis is a hallmark of many of the most common neurodegenerative diseases. As a mechanism to cope with folding pressure within the endoplasmic reticulum (ER), the unfolded protein response (UPR) involves a set of signaling mechanisms that activate gene expression programs to restore protein homeostasis or promote neuronal death when the pressure is chronic or excessive. This function of the UPR has already been proposed to play an important role in ALS.

[0005] The integrated stress response (ISR) is an evolutionarily conservative intracellular signaling network that can help cells, tissues, and organisms adapt to changing environments and maintain health. The ISR responds to various changes and restores balance by reprogramming gene expression. Because long-term memory formation in the brain requires de novo protein synthesis, inhibition of the ISR can enhance long-term memory formation, whereas activation of the ISR blocks this process. Age-related cognitive impairment is commonly associated with ISR activation.

[0006] As a central regulator of protein homeostasis, ISR activation occurs in a wide range of brain diseases. This activation process has been demonstrated by detecting eIF2-P, PKR, PERK, and GCN2 phosphorylation in brain 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 causes cognitive deficits in traumatic brain injury, aging, and mouse models of Alzheimer's disease.

[0007] eIF2B (eukaryotic translation initiation factor 2B, eIF2B) is a key enzyme regulating protein synthesis and a dedicated guanine nucleotide exchange factor (GEF) 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] In addition, the indications of the eIF2B agonists ABBV-CLS-7262 (AbbVie / Calico) and DNL-343 (Denali Therapeutics) are both ALS and both have entered Phase 1 clinical trials. For DNL-343, Phase 1 data in healthy subjects have already been published, demonstrating that it is safe and well tolerated.

[0009] Extensive animal studies have demonstrated that the eIF2B agonist ISRIB can enhance long-term memory in mouse models. Three days after oral administration of the eIF2B agonist ABBV-CLS-7262, brain function in the model animals was restored to youthful levels. This suggests that such drugs may subsequently be able to inhibit several neurodegenerative diseases and have the potential to treat diseases such as Alzheimer's disease and Parkinson's disease. Summary of the Invention

[0010] 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, which can significantly attenuate the cellular integrated stress response (ISR), activate eIF2B activity, and tend to promote normal intracellular protein synthesis. [ka] wherein ring A and ring C are each independently a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl-D-C1-C6 alkyl group, a 5- to 10-membered heteroaryl-D-C1-C6 alkyl group, a C3-C9 cycloalkyl-D-C1-C6 alkyl group, or a 3- to 9-membered heterocyclyl-D-C1-C6 alkyl group, wherein the alkyl group is optionally substituted with halogen or a C1-C6 alkyl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group each optionally contain 1 to 5 R 1 may be substituted with Each of the R 1are each independently hydrogen, deuterium, halogen, hydroxy group, phenyl group, cyano group, C1-C10 alkyl group, C1-C6 alkyl group substituted with a hydroxy group, C1-C6 alkyl group substituted with a halogen, C1-C6 alkoxy group, C1-C6 alkoxy group substituted with a halogen, C1-C6 alkoxy-C1-C6 alkenyl group substituted with a halogen, C1-C6 alkyl group substituted with an amino group, C1-C6 alkyl group substituted with a cyano group, C1-C3 alkoxy-C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C3 alkoxy-C3-C6 cycloalkyl group, C1-C3 alkoxy-3 to 6-membered heterocyclyl group, 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 groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R 1F wherein R is substituted with 1The options of phenyl group, C1-C10 alkyl group, C1-C6 alkoxy group, C1-C3 alkoxy group in C1-C3 alkoxy-C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C3 alkoxy group in C1-C3 alkoxy-C3-C6 cycloalkyl group, and C1-C3 alkoxy group in C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted by halogen; Each of the R 1A , R 1B , R 1C , R 1D , R 1E are each independently selected from the group consisting of hydrogen, deuterium, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C3-C9 cycloalkyl group substituted with halogen, a 3- to 9-membered heterocyclyl group substituted with halogen, and a C1-C6 alkoxy group substituted with halogen; R 1B , R 1C and the atom(s) to which they are jointly linked can form a 3- to 7-membered heterocyclyl group, which can optionally contain 1 to 3 R 1F is replaced by Each of the G 1 are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; 1 each optionally containing 1 to 3 R 1F is replaced by L 1 is empty, -NH-, [ka] where: [ka] The end is linked to the A ring and the * end is linked to the B ring, Preferably, L 1 is empty, -NH-, [ka] and Preferably, L 1 Is, empty, [ka] and Preferably, the L 1 Is, empty, [ka] and Preferably, the L 1 Is, empty, [ka] and preferably, the L 1 Is, empty, [ka] and Ring B is a 5- to 10-membered spiro ring or a 5- to 10-membered spiro hetero ring, and the 5- to 10-membered spiro ring and the 5- to 10-membered spiro hetero ring may optionally contain 1 to 5 R 1F is replaced by Each of the R 1F are each independently hydrogen, deuterium, halogen, hydroxy group, amino group, cyano group, carboxyl group, C1-C6 alkyl group, C3-C9 cycloalkyl group, C1-C6 alkyl group substituted with a hydroxy group, C1-C6 alkyl group substituted with a halogen, C1-C6 alkoxy group substituted with a halogen, C3-C9 cycloalkyl group substituted with a halogen, C1-C6 alkenyl group substituted with a halogen, C1-C6 alkoxy-C1-C6 alkenyl group substituted with a halogen, C1-C6 alkyl group substituted with an amino group, C1-C6 alkyl group substituted with a cyano group, 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 and is selected from the group consisting of: L 2 is empty, -NH-, [ka] where: [ka] The * terminus is linked to the B ring and the * terminus is linked to the C ring, Preferably, L 2 is empty, -NH-, [ka] and Preferably, L 2 Is, empty, [ka] and Preferably, the L 2 Is, empty, [ka] and Preferably, the L 2 Is, empty, [ka] and preferably, the L 2 is empty or [ka] and Each D is independently a linking group containing a heteroatom, and preferably, each D is independently O or NR d or S and R dare each independently selected from hydrogen, deuterium, a C1-C6 alkyl group, and a C1-C6 alkyl group substituted with halogen, and more preferably, each D is independently O or NH. Or, each D is independently a heteroatom, preferably, each D is independently O, N, or S, and more preferably, each D is independently O or N.

[0011] In some embodiments, the A ring is a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl-D-C1-C6 alkyl group, a 5- to 10-membered heteroaryl-D-C1-C6 alkyl group, or a 3- to 9-membered heterocyclyl-D-C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen or a C1-C6 alkyl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group each optionally contain 1 to 5 R 1 may be substituted with Each of the R 1 are each independently hydrogen, halogen, cyano group, C1-C10 alkyl group, C1-C6 alkyl group substituted with a hydroxy group, C1-C6 alkyl group substituted with a halogen, C1-C6 alkoxy group, C1-C6 alkoxy group substituted with a halogen, C1-C6 alkoxy-C1-C6 alkenyl group substituted with a halogen, C1-C6 alkyl group substituted with an amino group, C1-C6 alkyl group substituted with a cyano group, 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 1or two R on adjacent atoms 1 The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R 1F is replaced by Each of the R 1A , R 1B , R 1C , R 1D , R 1E are each independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C3-C9 cycloalkyl group substituted with halogen, a 3- to 9-membered heterocyclyl group substituted with halogen, and a C1-C6 alkoxy group substituted with halogen; R 1B , R 1C and the atom(s) to which they are jointly linked can form a 3- to 7-membered heterocyclyl group, which can optionally contain 1 to 3 R 1F is replaced by Each of the G 1 are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; 1 each optionally containing 1 to 3 R 1F is replaced by Each of the R 1Fare each independently hydrogen, halogen, a hydroxy group, an amino group, a cyano group, a carboxyl group, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a C1-C6 alkenyl group substituted with a halogen, a C1-C6 alkoxy-C1-C6 alkenyl group substituted with a halogen, a C1-C6 alkyl group substituted with an amino group, a C1-C6 alkyl group substituted with a cyano group, 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 and is selected from the group consisting of: The C ring is a 6- to 10-membered aryl-E-C1-C6 alkyl group, a C3-C9 cycloalkyl-E-C1-C6 alkyl group, a 3- to 9-membered heterocyclyl-E-C1-C6 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, phenyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy-C3-C6 cycloalkyl, and C1-C3 alkoxy-3- to 6-membered heterocyclyl, wherein R 2The phenyl group, the C1-C6 alkyl group, the C1-C6 alkoxy group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C1-C6 alkyl group, the C3-C6 cycloalkyl group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C3-C6 cycloalkyl group, and the C1-C3 alkoxy group in the C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted by halogen or two R 2 The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a 5- to 6-membered aryl group (e.g., a phenyl group), or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R 1F is replaced by The D and E are each independently a linking group containing a hetero atom, and preferably, the D and E are each independently O or NR d or S and R d are each independently selected from hydrogen, deuterium, and a C1-C3 alkyl group, and more preferably, D and E are each independently O or NH.

[0012] In some embodiments, the A ring is a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl-D-C1-C6 alkyl group, or a 3- to 9-membered heterocyclyl-D-C1-C6 alkyl group, wherein the heterocyclyl group, aryl group, and heteroaryl group each optionally contain 1 to 5 R 1 may be substituted with Each of the R 1 are each independently hydrogen, halogen, a C1-C6 alkyl group substituted with halogen, a C1-C6 alkoxy group substituted with halogen, -OR 1A , -NR 1B R 1C , -NR 1B C(O)R 1D , -C(O)NR 1B R1C , -C(O)R 1D , -G 1 , -OG 1 , -NR 1B -G 1 or two R on adjacent atoms 1 The groups and the atoms to which they are attached can form a 6- to 10-membered aryl group or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R 1F is replaced by Each of the R 1A , R 1B , R 1C , R 1D are each independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C3-C9 cycloalkyl group substituted with halogen, a 3- to 9-membered heterocyclyl group substituted with halogen, and a C1-C6 alkoxy group substituted with halogen; R 1B , R 1C and the atom(s) to which they are jointly linked can form a 3- to 7-membered heterocyclyl group, which can optionally contain 1 to 3 R 1F is replaced by Each of the G 1 are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, and a 6- to 10-membered aryl group; 1 each optionally containing 1 to 3 R 1F is replaced by G 1 is a phenyl group, optionally, the phenyl group and the 3- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R 1Fare each independently hydrogen, halogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a C1-C6 alkenyl group substituted with a halogen, 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 The group consisting of:

[0013] In some embodiments, the A ring is a 4- to 9-membered heterocyclyl group, a 5- to 7-membered heteroaryl group, a phenyl-D-C1-C6 alkyl group, or a 4- to 9-membered heterocyclyl-D-C1-C6 alkyl group, wherein the heterocyclyl group, heteroaryl group, and phenyl group each optionally contain 1 to 5 R 1 may be substituted with Each of the R 1 are each independently hydrogen, halogen, a C1-C6 alkyl group substituted with halogen, a C1-C6 alkoxy group substituted with halogen, -OR 1A , -NR 1B R 1C , -NR 1B C(O)R 1D , -C(O)NR 1B R 1C , -G 1 , O.G. 1 , -NR 1B -G 1 and is selected from the group consisting of: Each of the R 1A , R 1B , R 1C , R 1Dare each independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C4-C9 cycloalkyl group, a 4- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C4-C9 cycloalkyl group substituted with halogen, a 4- to 9-membered heterocyclyl group substituted with halogen, and a C1-C6 alkoxy group substituted with halogen; R 1B , R 1C and the atom(s) to which they are jointly linked can form a 3- to 7-membered heterocyclyl group, which can optionally contain 1 to 3 R 1F is replaced by Each of the G 1 are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R 1F is replaced by G 1 is a phenyl group, optionally, the phenyl group and the 3- to 9-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R 1F are each independently hydrogen, halogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a C1-C6 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D The group consisting of:

[0014] In some embodiments, the A ring is a 4- to 8-membered heterocyclyl group, a 5- to 6-membered heteroaryl group, a phenyl-D-C1-C3 alkyl group, or a 4- to 8-membered heterocyclyl-D-C1-C3 alkyl group, wherein the heterocyclyl group, heteroaryl group, and phenyl group each optionally contain 1 to 2 R 1may be substituted with Each of the R 1 are each independently hydrogen, halogen, a C1-C3 alkyl group substituted with halogen, a C1-C3 alkoxy group substituted with halogen, -OR 1A , -NR 1B R 1C , -NR B C(O)R 1D , -C(O)NR 1B R 1C , -G 1 , O.G. 1 , -NR 1B -G 1 and is selected from the group consisting of: Each of the R 1A , R 1B , R 1C , R 1D are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; preferably, the C3-C6 cycloalkyl group is a cyclobutanyl group or a cyclopentanyl group; the 3- to 6-membered heterocyclyl group is an oxetanyl group, an azetidinyl group, an oxacyclopentanyl group, or an azacyclopentanyl group; and each of the G 1 each optionally containing 1 to 3 R 1F is replaced by G 1 is a phenyl group, optionally, the phenyl group and the 5- to 6-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R 1Fare each independently hydrogen, halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C3-C6 cycloalkyl group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D The group consisting of:

[0015] In some embodiments, the A ring is a 5- to 6-membered heterocyclyl group, preferably [ka] or preferably, [ka] is.

[0016] Preferably, the R 1 The number n is 1, 2 or 3, Preferably, the R 1 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a C1-C3 alkyl group, and a phenyl group, and R 1 is a phenyl group, the phenyl group and the 3- to 6-membered heterocyclyl group share two carbon atoms to form a fused ring, and preferably, the phenyl group and the 3- to 6-membered heterocyclyl group [ka] means that two carbon atoms are shared to form a fused ring, and the phenyl group is optionally substituted with halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, or a C1-C3 haloalkoxy group; More preferably, the phenyl group and [ka] The condensation method with [ka] wherein the phenyl group is optionally substituted with a halogen.

[0017] In some embodiments, the A ring is a 5- to 6-membered heteroaryl group, preferably (1) [ka] And 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, and preferably the R 1 But hydrogen, -OR 1A , -NR 1B R 1C , -G 1 , -OG 1 , -NR 1B -G 1 and each R 1A , R 1B , R 1C are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R 1F is replaced by Each of the R 1Fare each independently hydrogen, halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D wherein R 1D is selected from the group consisting of hydrogen, C1-C3 alkyl groups, C1-C3 alkyl groups substituted with halogen, and C1-C3 alkoxy groups substituted with halogen; or [ka] wherein the A ring is a 5-membered heteroaryl group, and H 1 , H 2 , H 3 , H 4 are each independently selected from CH, N, O, and S; [ka] is a single bond or a double bond, Preferably, the R 1 However, each independently, -OR 1A , -NR 1B R 1C , -G 1 , -OG 1 , -NR 1B -G 1 and each R 1A , R 1B , R 1Care each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C1-C3 alkoxy-C1-C6 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C4-C6 cycloalkyl group and a 4- to 9-membered heterocyclyl group, and each of the G 1 each optionally containing 1 to 3 R 1F is replaced by Each of the R 1F are each independently hydrogen, halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D wherein R 1D is selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Preferably, the A ring is [ka] and More preferably, the L 1 But it is empty, Preferably, the R 1 But, -OR 1A , -G 1 , -OG 1 , -NR 1B -G 1Selected from R 1A is selected from halogen-substituted C1-C3 alkoxy-C1-C3 alkyl groups; R 1B is selected from H, a C1-C3 alkyl group, and each R 1F are each independently a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -P(O)R 1B R 1C , -S(O)2R 1D and R 1B , R 1C , R 1D are each independently selected from the group consisting of hydrogen and a C1-C3 alkyl group; (2) [ka] And, Preferably, each R 1 is independently selected from any one of hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, and benzene; and R 1 is a phenyl group, [ka] and share two carbon atoms to form a fused ring, and the phenyl group is optionally substituted with halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, or a C1-C3 haloalkoxy group; More preferably, the phenyl group is optionally substituted with halogen, and the R 1 The number m is 1 or 2, (3) [ka] And, Preferably, the R1 is hydrogen, halogen or a phenyl group, said phenyl group being optionally substituted with one or more halogens, and said R 1 The number m is 1 or 2, and R 1 is a phenyl group, optionally [ka] and share two carbon atoms to form a fused ring, More preferably, the R 1 is a phenyl group, m is 1, and [ka] The condensation method with [ka] wherein the phenyl group is optionally substituted with one or more halogens.

[0018] In some embodiments, the A ring is a phenyl-O—C 1 -C 3 alkyl group, wherein the phenyl group optionally contains one or two R 1 and each R is substituted with 1 are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen.

[0019] Preferably, the A ring is a phenyl-O-methyl group, and R 1 is H or a halogen.

[0020] In some embodiments, the A ring is a 4-8 membered heterocyclyl-O—C 1 -C 3 alkyl group, wherein the heterocyclyl group optionally contains 1-3 R 1 and each R is substituted with 1are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen.

[0021] Preferably, the A ring is a 4- to 7-membered heterocyclyl-O-methyl group, and R 1 is a C1-C3 alkyl group substituted with a halogen, or a C1-C3 alkoxy group substituted with a halogen.

[0022] In some embodiments, the A ring is a C3-C7 cycloalkyl-O—C1-C3 alkyl group, and the C3-C7 cycloalkyl group optionally contains 1 to 3 R 1 and each R is substituted with 1 are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen.

[0023] Preferably, the A ring is a C4-C6 cycloalkyl-O-methyl group, and R 1 is a C1-C3 alkyl group substituted with a halogen, or a C1-C3 alkoxy group substituted with a halogen.

[0024] In some embodiments, the A ring is a phenyl group, and the phenyl group is substituted with one selected from a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, and a C1-C6 haloalkoxy group.

[0025] Preferably, the phenyl group is substituted with a group selected from halogen, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, and a C1-C3 haloalkoxy group, and more preferably, the phenyl group is substituted with a C1-C3 haloalkyl group.

[0026] In some embodiments, the A ring is: (1) [ka] And, Preferably, the R 1 But, -G 1 , O.G. 1 , -NR 1B -G 1 and wherein G is selected from the group consisting of 1 each optionally containing one or two R 1F wherein R is substituted with 1B is selected from the group consisting of hydrogen, C1-C3 alkyl groups, and each of the G 1 are each independently selected from a C3-C6 cycloalkyl group and a 4- to 9-membered heterocyclyl group; More preferably, the C3-C6 cycloalkyl group is a cyclobutanyl group or a cyclopentanyl group, and the 4- to 9-membered heterocyclyl group is preferably an oxacycloalkyl group or an N-heterocycloalkyl group, more preferably an oxetanyl group, an azetidinyl group, an oxacyclopentanyl group, an azacyclopentanyl group, [ka] and more preferably an oxetanyl group, an azetidinyl group, an oxacyclopentanyl group, an azacyclopentanyl group, or even more preferably [ka] and Each of the R 1F are each independently selected from the group consisting of oxo, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen, and 1 is preferably empty, (2) A 4- to 8-membered heterocyclyl-O—C1-C3 alkyl group, wherein the heterocyclyl group optionally contains one or two R1 and each R is substituted with 1 are each independently selected from the group consisting of a C1-C3 alkyl group substituted with halogen and a C1-C3 alkoxy group substituted with halogen; (3) a C4-C6 cycloalkyl-O—C1-C3 alkyl group, wherein the C4-C6 cycloalkyl group optionally contains one or two R 1 and each R is substituted with 1 are each independently selected from the group consisting of a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen.

[0027] In some embodiments, the A ring is: [ka] [ka] is selected from any one of the groups:

[0028] Preferably, the A ring is [ka] is selected from any one of the groups:

[0029] Preferably, the A ring is [ka] is selected from any one of the groups:

[0030] Preferably, the A ring is [ka] is selected from any one of the groups:

[0031] In some embodiments, the spiro ring is selected from the group consisting of a spiro[2,5]octanyl ring, a spiro[3,4]octanyl ring, a spiro[3,3]heptanyl ring, a spiro[3,5]nonanyl ring, a spiro[4,5]decanyl ring, a spiro[2,2]pentanyl ring, a spiro[2,3]hexanyl ring, a spiro[2,4]heptanyl ring, a spiro[2,6]nonanyl ring, a spiro[2,7]nonanyl ring, a spiro[3,6]nonanyl ring, and a spiro[4,4]nonanyl ring, wherein the spiro heterocycle is a group formed after one or more carbon atoms in the spiro ring are replaced with heteroatoms, and the number of heteroatoms in the spiro heterocycle is 1, 2, or 3.

[0032] Preferably, the heteroatom in the spiroheterocycle is nitrogen or a combination of nitrogen and oxygen.

[0033] Preferably, the substituent R of the spiro ring or the spiro heterocycle is 1F is hydrogen, halogen, a hydroxy group, an amino group, a cyano group, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, or a C1-C6 alkoxy group substituted with a halogen.

[0034] In some embodiments, preferably, the substituent R of the spiro ring or the spiro heterocycle is 1F The number of is 1 or 2, preferably 1.

[0035] More preferably, the substituent R of the spiro ring or the spiro heterocycle is 1F is a halogen, a hydroxy group, or an amino group.

[0036] Most preferably, the substituent R of said spiro ring or said spiro heterocycle is 1F is a hydroxy group.

[0037] In some embodiments, the B ring is a 7-9 membered spiro ring or a 7-9 membered spiro hetero ring.

[0038] Preferably, the spiro ring is selected from the group consisting of a spiro[2,5]octanyl ring, a spiro[3,4]octanyl ring, a spiro[3,3]heptanyl ring, and a spiro[3,5]nonanyl ring. The 7- to 9-membered spiro heterocycle is a group formed after one or more carbon atoms in the 7- to 9-membered spiro ring are substituted with heteroatoms, and the number of heteroatoms in the spiro heterocycle is 1, 2, or 3.

[0039] Preferably, the heteroatom in the spiroheterocycle is nitrogen or a combination of nitrogen and oxygen.

[0040] In some embodiments, the B ring is: [ka] and is selected from any one of the groups where: [ka] The end is L 1 The * end is linked to L 2 is linked to.

[0041] In some embodiments, the B ring is: [ka] and is selected from any one of the groups where: [ka] The end is L 1 The * end is linked to L 2 is connected to In some embodiments, the B ring is: [ka] and is selected from any one of the groups where: [ka] The end is L 1 The * end is linked to L 2 is linked to.

[0042] In some embodiments, B is [ka] wherein: [ka] The end is L 1 The * end is linked to L 2 is linked to.

[0043] In some embodiments, the C ring is a 6- to 10-membered aryl-E-C1-C3 alkyl group, a C4-C9 cycloalkyl-E-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl-E-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of hydrogen, halogen, a hydroxyl group, a phenyl group, a C1-C3 alkyl group, and a C1-C3 alkoxy group, 2 The alternatives of phenyl, C1-C3 alkyl, and C1-C3 alkoxy are each optionally substituted with halogen or two R on adjacent atoms. 2 The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R 1Fis replaced by R 2 is a phenyl group, optionally, the phenyl group and the 4- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring; Each E is independently a linking group containing a heteroatom.

[0044] Preferably, each E is independently O or NR d or S and R d are each independently selected from hydrogen, deuterium, and a C1-C3 alkyl group, and more preferably, each E is independently O or NH.

[0045] In some embodiments, the C ring is a phenyl-E-C1-C3 alkyl group, and the phenyl group is selected from 1, 2, or 3 R 2 wherein E is a linking group containing a heteroatom.

[0046] Preferably, E is O or NR d or S and R d is selected from hydrogen, deuterium, and a C1-C3 alkyl group.

[0047] Preferably, E is O or NH.

[0048] Preferably, each of said R 2 are each independently a halogen.

[0049] In some embodiments, Ring C is a C-C cycloalkyl-E-C-C alkyl group or a 4- to 9-membered heterocyclyl-E-C-C alkyl group, and the cycloalkyl or heterocyclyl group is R 2 and E is O or NR d or S and R d is selected from hydrogen, deuterium, and a C1-C3 alkyl group, and said R 2is hydrogen, halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, or a C1-C3 haloalkoxy group, Preferably, E is O or NH, Preferably, the cycloalkyl group is a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group; Preferably, the heterocyclyl group is an oxiranyl group, an oxetanyl group, an oxacyclopentanyl group, an aziridinyl group, an azetidinyl group, or an azacyclopentanyl group.

[0050] In some embodiments, Ring C is a 4- to 9-membered heterocyclyl group, preferably a 5- to 6-membered heterocyclyl group.

[0051] Preferably, the C ring is [ka] and R 2 The number n is 1, 2, or 3, Preferably, each of said R 2 are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a phenyl group, a halophenyl group, and a hydroxy group; 2 is a phenyl group or a halophenyl group, optionally [ka] means that two carbon atoms are shared to form a fused ring, and preferably, the fused ring is [ka] is.

[0052] In some embodiments, the C ring is: [ka] and R 2The number n is 1, 2, or 3.

[0053] Preferably, each of said R 2 are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a phenyl group, and a halophenyl group, 2 is a substituent on the N atom, 2 is any one of the group consisting of hydrogen, halogen, and C1-C3 alkyl groups, 2 is a phenyl group or a halophenyl group, optionally, the phenyl group or the halophenyl group and the morpholine ring group share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] and In some embodiments, the C ring is: [ka] and R 2 The number n is 1, 2, or 3.

[0054] Preferably, each of said R 2 are each independently selected from the group consisting of halogen, phenyl, halophenyl, and hydroxy groups, 2 is a phenyl group or a halophenyl group, optionally with said phenyl group or said halophenyl group [ka] means that two carbon atoms are shared to form a fused ring, and preferably, the fused ring is [ka] is.

[0055] In some embodiments, the C ring is a 5-10 membered heteroaryl group.

[0056] Preferably, the C ring is (1) [ka] And, Preferably, each R 2 are independently selected from any one of hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, and halophenyl groups; 2 The number p of R is 1 or 2, and 2 is a phenyl group or a halophenyl group, [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] and (2) [ka] Preferably, the R 2 is selected from the group consisting of hydrogen, halogen, phenyl, C1-C3 alkyl, and C1-C3 alkoxy-C3-C6 cycloalkyl groups, wherein the phenyl, alkyl, and alkoxy groups are unsubstituted or substituted with halogen, and R 2 is a phenyl group, optionally [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] The heteroaryl group is any one of the 5- to 10-membered heteroaryl groups

[0057] In some embodiments, the C ring is a phenyl group, and the phenyl group is R 2 and preferably, the R 2 is selected from the group consisting of a C1-C3 haloalkyl group and a C1-C3 haloalkoxy group.

[0058] In some embodiments, the C ring is [ka] and is selected from any one of the groups Preferably, the C ring is [ka] and is selected from any one of the groups Preferably, the C ring is [ka] and is selected from any one of the groups Preferably, the C ring is [ka] and is selected from any one of the groups Preferably, the C ring is [ka] is selected from any one of the groups:

[0059] In some embodiments, the compound has the structure shown in Formula I. [ka] Preferably, Ring A is a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl-D-C1-C6 alkyl group, or a 5- to 10-membered heteroaryl-D-C1-C6 alkyl group, wherein the heterocyclyl group, aryl group, and heteroaryl group each optionally contain 1 to 5 R 1 may be substituted with Each of the R 1 each independently represents a halogen, a C1-C10 alkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, -G 1 , -OG 1 or two R on adjacent atoms 1 The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R 1F is replaced by Each of the G 1 are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; 1 each optionally containing 1 to 3 R 1F1 is replaced by Each of the R 1F1 , R 1F2 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, an amino group, a cyano group, a carboxyl group, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, and a C1-C6 alkoxy group substituted with a halogen, and preferably, each of said R 1F2 are each independently selected from hydrogen, halogen, a hydroxy group, and an amino group; L 2 is empty, -NH-, [ka] where: [ka] The terminus is linked to the B ring and the * terminus is linked to the C ring, preferably [ka] The terminus is in Formula I [ka] is linked to the N atom in Preferably, the L 2 is empty, -NH-, [ka] and Preferably, the L 2 Is, empty, [ka] and Preferably, the L 2 Is, empty, [ka] and Preferably, the L 2 teeth, [ka] and Preferably, the L 2 Is, empty, [ka] and Ring C is a 6- to 10-membered aryl-E-C1-C6 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of halogen, hydroxy, phenyl, C1-C6 alkyl, C1-C6 alkoxy, and C1-C3 alkoxy-C1-C6 alkyl groups, 2 The phenyl group, the C1-C6 alkyl group, the C1-C6 alkoxy group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C1-C6 alkyl group, the C3-C6 cycloalkyl group, and the C1-C3 alkoxy group in the C1-C3 alkoxy-C3-C6 cycloalkyl group are each optionally substituted with halogen, and R 2 is a phenyl group, optionally, the phenyl group and the 3- to 9-membered heterocyclyl group or the 6- to 10-membered heteroaryl group share two carbon atoms to form a fused ring; D and E each independently represent a linking group containing a heteroatom, Preferably, D and E are each independently O or NR d or S and R d are each independently selected from hydrogen, deuterium, a C1-C6 alkyl group, and a C1-C6 alkyl group substituted with a halogen; More preferably, D and E are each independently O or NH.

[0060] Preferably, ring A is a 5- to 10-membered heteroaryl group or a 6- to 10-membered aryl-D-C1-C6 alkyl group.

[0061] Preferably, the R 1 each independently represents a C1-C10 alkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, -G 1 , -OG1 is selected from.

[0062] Preferably, Ring C is a 6- to 10-membered aryl group. The aryl group may optionally contain 1 to 3 R 2 and each R 2 are each independently selected from halogen and a C1-C6 alkyl group.

[0063] In some embodiments, the compound has the structure shown in formula I-1. [ka] Here, the R 1 The number of R is 1 to 5, 1 are each independently selected from the group consisting of a halogen, a C1-C10 alkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, and a C1-C6 alkoxy group substituted with a halogen; Preferably, the R 1 The number of R is 1, 2, or 3, and each R 1 are each independently selected from the group consisting of halogen, a C1-C10 alkyl group, a C1-C6 alkyl group substituted with halogen, and a C1-C6 alkoxy group substituted with halogen; More preferably, the R 1 The number of R is 1 or 2, and each R 1 are each independently selected from any one of the halogens; Each of the R 1F2 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, an amino group, a cyano group, a carboxyl group, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, and a C1-C6 alkoxy group substituted with a halogen; Preferably, each of said R 1F2are each independently selected from the group consisting of hydrogen, halogen, and a hydroxy group; Said L 2 teeth, [ka] where: [ka] The terminus is linked to the B ring and the * terminus is linked to the C ring, preferably [ka] The terminus is the group represented by the formula I-1. [ka] is linked to the N atom in The C ring is a 6- to 10-membered aryl-O—C1-C6 alkyl group, a 3- to 9-membered heterocyclyl group, or a 5- to 10-membered heteroaryl group, and the aryl group, heteroaryl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of halogen, hydroxy, phenyl, C1-C6 alkyl, C1-C6 alkoxy, and C1-C3 alkoxy-C1-C6 alkyl groups, 2 The phenyl group, the C1-C6 alkyl group, the C1-C6 alkoxy group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C1-C6 alkyl group, the C3-C6 cycloalkyl group, and the C1-C3 alkoxy group in the C1-C3 alkoxy-C3-C6 cycloalkyl group are each optionally substituted with halogen, and R 2 When is a phenyl group, optionally, the phenyl group and the 3- to 9-membered heterocyclyl group or the 6- to 10-membered heteroaryl group share two carbon atoms to form a fused ring.

[0064] In some embodiments, preferably the C ring is 1) a 4- to 9-membered heterocyclyl group, Preferably, the C ring is [ka] and R 2 The number n is 1, 2, or 3, Preferably, each of said R 2 are each independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, phenyl, halophenyl, and hydroxy; R 2 is a phenyl group or a halophenyl group, optionally, the phenyl group or the halophenyl group and the 4- to 9-membered heterocyclyl group share two carbon atoms to form a fused ring, and optionally, [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] and 2) a 5- to 10-membered heteroaryl group, Preferably, the C ring is (1) [ka] And, Preferably, each R 2 are independently selected from any one of hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, and halophenyl groups; 2 The number p of R is 1 or 2, and 2 is a phenyl group or a halophenyl group, [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] and (2) [ka] And, Preferably, each R 2 are independently selected from any one of hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, and halophenyl groups; 2 The number p of R is 1 or 2, and 2 is a phenyl group or a halophenyl group, [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] and (3) [ka] And, Preferably, the R 2 is selected from the group consisting of hydrogen, halogen, phenyl, C1-C3 alkyl, and C1-C3 alkoxy-C3-C6 cycloalkyl groups, wherein the phenyl, alkyl, and alkoxy groups are unsubstituted or substituted with halogen, and R 2 is a phenyl group, optionally [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] and one of the 5- to 10-membered heteroaryl groups represented by the formula: 3) Phenyl-O—C1-C3 alkyl groups, wherein the phenyl group is selected from the group consisting of 1, 2, or 3 R 2 is replaced by Preferably, each of said R 2 are each independently a halogen; 4) A phenyl group, wherein the phenyl group is R 2 is replaced by Preferably, the R 2 is any one of the groups selected from the group consisting of a C1-C3 haloalkyl group and a C1-C3 haloalkoxy group.

[0065] In some embodiments, the compound has the structure shown in formula I-2. [ka] Here, each of the R 1F2 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, an amino group, a cyano group, a carboxyl group, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, and a C1-C6 alkoxy group substituted with a halogen; Preferably, each of said R 1F2 are each independently selected from the group consisting of hydrogen, halogen, and a hydroxy group; Said L 2 teeth, [ka] where: [ka] The terminus is linked to the B ring and the * terminus is linked to the C ring, preferably [ka] The terminus is the group represented by the formula I-2. [ka] is linked to the N atom in R 1 and the above R 2 The number of each R is independently 1 to 3, and 1 and each of the R 2 each independently represents a halogen, a C1-C10 alkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, -G 1 , -OG 1 and is selected from the group consisting of: Each of the G 1 are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; 1 each optionally containing 1 to 3 R 1F1 and each R is substituted with 1F1 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, an amino group, a cyano group, and a carboxyl group.

[0066] Preferably, the R 1 and the above R 2 is 1 and is selected from the group consisting of a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group, and the 6- to 10-membered aryl group and the 5- to 10-membered heteroaryl group each optionally have 1, 2, or 3 R 1F1 and each R is substituted with 1F1 are each independently selected from the group consisting of hydrogen and halogen.

[0067] More preferably, the R 1 and the above R 2is one and is a phenyl group, each of which is optionally substituted with one, two or three R 1F1 and each R is substituted with 1F1 are each independently selected from the group consisting of hydrogen and halogen.

[0068] In some embodiments, the compound has the structure shown in Formula II or Formula III. [ka] wherein each of the A rings is independently a 5- to 7-membered heteroaryl group, a phenyl-D-C1-C6 alkyl group, or a 3- to 9-membered heterocyclyl group, and wherein the heteroaryl group and the phenyl group each optionally contain one or two R 1 may be substituted with Each of the R 1 are each independently a halogen, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, -OR 1A , -NR 1B R 1C , -G 1 , O.G. 1 , -NR 1B -G 1 and is selected from the group consisting of: Each of the R 1A , R 1B , R 1C , R 1D are each independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C4-C9 cycloalkyl group, a 4- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C4-C9 cycloalkyl group substituted with halogen, a 4- to 9-membered heterocyclyl group substituted with halogen, and a C1-C6 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R1F1 is replaced by G 1 is a phenyl group, optionally, the phenyl group and the 3- to 9-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R 1F1 are each independently a halogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C6 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D and is selected from the group consisting of: L 1 is empty, -NH-, [ka] where: [ka] The terminal is connected to the A ring and the * terminal is connected to the B ring, and preferably the * terminal is [ka] &C atoms in formula III [ka] is connected to the &C atom in Preferably, the L 1 is empty, -NH-, [ka] and Preferably, the L 1 Is, empty, [ka] and Preferably, the L 1 Is, empty, [ka] and More preferably, the L 1 is empty or [ka] and L 2 is empty, -NH-, [ka] where: [ka] The terminus is linked to the B ring and the * terminus is linked to the C ring, preferably [ka] The terminus is in Formula II [ka] the N atom in formula III [ka] @C atom in Preferably, the L 2 is empty, -NH-, [ka] and Preferably, the L 2 Is, empty, [ka] and Preferably, the L in formula II 2 teeth, [ka] and more preferably, [ka] and Preferably, the L in formula III 2 Is, empty, [ka] and more preferably, empty or [ka] and Each of the R 1F2 are independently selected from hydrogen, halogen, a hydroxy group, and an amino group; Preferably, each of said R 1F2 are independently selected from hydrogen and a hydroxy group; The C ring is selected from a 6- to 10-membered aryl-E-C1-C3 alkyl group, a C4-C9 cycloalkyl-E-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl-E-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of hydrogen, halogen, a hydroxyl group, a phenyl group, a C1-C3 alkyl group, and a C1-C3 alkoxy group, 2 The alternatives of phenyl, C1-C3 alkyl, and C1-C3 alkoxy are each optionally substituted with halogen or two R on adjacent atoms. 2The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R 1F is replaced by R 2 is a phenyl group, optionally, the phenyl group and the 4- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring; Each E is independently a linking group containing a heteroatom, Preferably, each E is independently O or NR d or S and R d are each independently selected from hydrogen, deuterium, and a C1-C3 alkyl group; More preferably, each E is independently O or NH.

[0069] In some embodiments, the compound has the structure shown in formula II-1, II-1', III-1, or III-1'. [ka] wherein ring A is a 5-membered heteroaryl group; H 1 , H 2 , H 3 , H 4 are each independently selected from CH, N, O, and S; [ka] is a single or double bond, R 1F2 are each independently hydrogen, halogen, a hydroxy group, or an amino group, preferably hydrogen or a hydroxy group; Preferably, the [ka] teeth, [ka] and Preferably, the R 1 -OR 1A , -NR 1B R 1C , -G 1 , O.G. 1 , -NR 1B -G 1 and each R 1A , R 1B , R 1C are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R 1F1 is replaced by Each of the R 1F1 are each independently a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D wherein R 1D is selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen.

[0070] In some embodiments, the [ka] teeth, [ka] It is one of the groups:

[0071] In some embodiments, the C ring is a 6- to 10-membered aryl-O—C1-C6 alkyl group, a 3- to 9-membered heterocyclyl-O—C1-C3 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy-C3-C6 cycloalkyl group, and a C1-C3 alkoxy-3- to 6-membered heterocyclyl group, wherein R 2 The options of phenyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C3 alkoxy group in C1-C3 alkoxy-C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C3 alkoxy group in C1-C3 alkoxy-C3-C6 cycloalkyl group, and C1-C3 alkoxy group in C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted with halogen.

[0072] In some embodiments, the C ring is a 4-8 membered heterocyclyl-O—C 1 -C 3 alkyl group, and the heterocyclyl group is selected from one R 2 and preferably, the R 2 is a haloalkyl group.

[0073] In some embodiments, the C ring is a phenyl-O—C 1 -C 3 alkyl group, and the phenyl group is selected from 1, 2, or 3 R 2 Preferably, each R 2 are each independently a halogen.

[0074] In some embodiments, the C ring is a 4- to 9-membered heterocyclyl group, and preferably the C ring is [ka] and R 2 The number n is 1, 2 or 3, and preferably, each of the R 2 are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a phenyl group, a halophenyl group, and a hydroxy group; R 2 is a phenyl group or a halophenyl group, optionally [ka] means that two carbon atoms are shared to form a fused ring, and preferably, the fused ring is [ka] is.

[0075] In some embodiments, the C ring is: 1) [ka] And, Preferably, each R 2 are independently selected from any one of hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, and halophenyl groups; 2 The number p of R is 1 or 2, and 2 is a phenyl group or a halophenyl group, [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] and 2) [ka] And, Preferably, the R 2 is selected from the group consisting of hydrogen, halogen, phenyl, C1-C3 alkyl, and C1-C3 alkoxy-C3-C6 cycloalkyl groups, wherein the phenyl, alkyl, and alkoxy groups are unsubstituted or substituted with halogen, and R 2 is a phenyl group, optionally [ka] and form a fused ring by sharing two carbon atoms, and preferably, the fused ring is [ka] The heteroaryl group is any one of the 5- to 10-membered heteroaryl groups

[0076] In some embodiments, the C ring is a phenyl group, and the phenyl group is R 2 and preferably, the R 2 is selected from the group consisting of C1-C3 haloalkyl groups; Preferably, the C ring is [ka] is selected from any one of the groups:

[0077] In some embodiments, the compound has the structure shown in Formula II-2, II-2', III-2', or III-2. [ka] Here, the L 2 teeth, [ka] where: [ka] The terminus is represented by the formula II-2. [ka] the N atom in formula III-2 [ka] each n is independently 1 to 3; 2 The number of R is 1, 2 or 3, 2 are each independently selected from the group consisting of hydrogen, halogen, and hydroxyl groups.

[0078] In some embodiments, the compound has the structure shown in Formula IV. [ka] Preferably, the A ring is a 4- to 8-membered heterocyclyl group, a 5- to 7-membered heteroaryl group, a phenyl-O—C1-C6 alkyl group, or a C4-C8 cycloalkyl-O—C1-C6 alkyl group, wherein the heterocyclyl group, heteroaryl group, phenyl group, and cycloalkyl group each optionally contain 1 to 2 R 1 may be substituted with Each of the R 1 each independently represents a halogen, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, -OR 1A, -NR 1B R 1C , -G 1 , O.G. 1 , -NR 1B -G 1 and is selected from the group consisting of: Each of the R 1A , R 1B , R 1C , R 1D are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R 1F1 is replaced by G 1 is a phenyl group, optionally, the phenyl group and the 5- to 6-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R 1F1 are each independently a halogen, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C3-C6 cycloalkyl group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D and is selected from the group consisting of: Each of the R 1F2 are independently selected from hydrogen, a hydroxy group, an amino group, a carboxyl group, or a halogen; L 1is empty, -NH-, [ka] where: [ka] The * terminus is linked to the A ring and the * terminus is linked to the B ring, preferably the * terminus is [ka] is linked to the N atom of Preferably, the L 1 is empty, -NH-, [ka] and Preferably, the L 1 Is, empty, [ka] and Preferably, the L 1 Is, empty, [ka] and L 2 is empty, -NH-, [ka] where: [ka] The terminus is linked to the B ring and the * terminus is linked to the C ring, preferably [ka] The terminus is in formula IV [ka] @C atom of Preferably, the L 2 is empty, -NH-, [ka] and Preferably, the L 2 Is, empty, [ka] and More preferably, the L 2 teeth, [ka] and The C ring is a 6- to 10-membered aryl-O—C1-C3 alkyl group, a C4-C9 cycloalkyl-O—C1-C3 alkyl group, a 4- to 9-membered heterocyclyl-O—C1-C3 alkyl group, a 4- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of halogen, hydroxy, phenyl, C1-C3 alkyl, and C1-C3 alkoxy groups, 2 The alternatives of phenyl, C1-C3 alkyl, and C1-C3 alkoxy are each optionally substituted with halogen or two R on adjacent atoms. 2 The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R 1F1 is replaced by R 2 When is a phenyl group, optionally, the phenyl group and the 4- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring.

[0079] In some embodiments, the compound has the structure shown in formula IV-1 or formula IV-1′. [ka] Here, the R 1F2 are each independently hydrogen, halogen, a hydroxy group, or an amino group, H 1 , H 2 , H 3 , H 4 are each independently C or a chemically acceptable heteroatom, and at least one is a heteroatom; [ka] is a single or double bond, Preferably, the heteroatom is selected from any one of N, O, and S; Preferably, the [ka] teeth, [ka] and Preferably, the R 1 -OR 1A , -NR 1B R 1C , -G 1 , O.G. 1 , -NR 1B -G 1 and each R 1A , R 1B , R 1Care each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R 1F1 is replaced by Each of the R 1F1 are each independently a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D wherein R 1D is selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen.

[0080] In some embodiments, the [ka] teeth, [ka] It is one of the groups:

[0081] In some embodiments, the C ring is a 6- to 10-membered aryl-O—C1-C6 alkyl group, a 3- to 9-membered heterocyclyl-O—C1-C3 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy-C3-C6 cycloalkyl group, and a C1-C3 alkoxy-3- to 6-membered heterocyclyl group, wherein R 2 The options of phenyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C3 alkoxy group in C1-C3 alkoxy-C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C3 alkoxy group in C1-C3 alkoxy-C3-C6 cycloalkyl group, and C1-C3 alkoxy group in C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted by halogen; In some embodiments, the C ring is a 4-8 membered heterocyclyl-O—C1-C3 alkyl group, and the heterocyclyl group is selected from one R 2 and preferably, the R 2 is a haloalkyl group.

[0082] In some embodiments, the C ring is a phenyl-O—C 1 -C 3 alkyl group, and the phenyl group is selected from 1, 2, or 3 R 2 Preferably, each R 2 are each independently a halogen.

[0083] In some embodiments, the C ring is a 4- to 9-membered heterocyclyl group, and preferably the C ring is [ka] and R 2 The number n is 1, 2 or 3, and preferably, each of the R 2 are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a phenyl group, a halophenyl group, and a hydroxy group; R 2 is a phenyl group or a halophenyl group, optionally [ka] means that two carbon atoms are shared to form a fused ring, and preferably, the fused ring is [ka] is.

[0084] In some embodiments, the C ring is: 1) [ka] And, Preferably, the R 2 is any one of hydrogen, halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, phenyl group, and halophenyl group, and 2 The number p of R 2 is a phenyl group or a halophenyl group, [ka] and form a fused ring by sharing two carbon atoms, and preferably, the fused ring is [ka] and 2) [ka] And, Preferably, the R 2is selected from the group consisting of hydrogen, halogen, phenyl, C1-C3 alkyl, and C1-C3 alkoxy-C3-C6 cycloalkyl groups, wherein the phenyl, alkyl, and alkoxy groups are unsubstituted or substituted with halogen, and R 2 is a phenyl group, optionally [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] The heteroaryl group is any one of the 5- to 10-membered heteroaryl groups

[0085] In some embodiments, the C ring is a phenyl group, and the phenyl group is R 2 and preferably, the R 2 is selected from the group consisting of C1-C3 haloalkyl groups.

[0086] In some embodiments, the C ring is: [ka] and is selected from any one of the groups Said L 2 teeth, [ka] is.

[0087] In some embodiments, the compound has the structure shown in formula IV-2 or formula IV-2'. [ka] Said L 2 teeth, [ka] where: [ka] The terminus is represented by the formula IV-2. [ka] is linked to a C atom of the formula (I), n is 1 to 3, and the R 2 The number of R is 1, 2 or 3, 2 are each independently selected from the group consisting of hydrogen, halogen, and hydroxyl groups.

[0088] In some embodiments, preferably, the compound has the structure shown in formula IV-3: [ka] Each of the R 1F2 are each independently hydrogen, halogen, a hydroxy group, or an amino group, preferably hydrogen or a hydroxy group; m is 1, 2, 3, 4 or 5, n is 1 to 3, and R 1 The number of R is 1, 2 or 3, and each R 1 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a phenyl group, a cyano group, a C1-C10 alkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group, and a C1-C6 alkoxy group substituted with a halogen; The C ring is a 6- to 10-membered aryl-O—C1-C6 alkyl group, a 3- to 9-membered heterocyclyl-O—C1-C3 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy-C3-C6 cycloalkyl group, and a C1-C3 alkoxy-3- to 6-membered heterocyclyl group, wherein R 2 The options of phenyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C3 alkoxy group in C1-C3 alkoxy-C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C3 alkoxy group in C1-C3 alkoxy-C3-C6 cycloalkyl group, and C1-C3 alkoxy group in C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted with halogen.

[0089] In some embodiments, the C ring is: [ka] is.

[0090] Preferably, the R 2 is selected from the group consisting of hydrogen, halogen, phenyl, C1-C3 alkyl, and C1-C3 alkoxy-C3-C6 cycloalkyl groups, wherein the phenyl, alkyl, and alkoxy groups are unsubstituted or substituted with halogen; 2 is a phenyl group, optionally [ka] means that two carbon atoms are shared to form a fused ring, and preferably, the fused ring is [ka] is.

[0091] In some embodiments, the C ring is a phenyl group, and the phenyl group is R 2 is replaced by

[0092] Preferably, the R 2 is selected from the group consisting of C1-C3 haloalkyl groups.

[0093] In some embodiments, the C ring is: [ka] is.

[0094] In some embodiments, the L 2 teeth, [ka] where: [ka] The terminus is represented by the formula IV-3 [ka] @C atom of the

[0095] In some embodiments, the compound has the structure shown in Formula V. [ka]

[0096] Preferably, the A ring is a 4- to 8-membered heterocyclyl group, a 5- to 7-membered heteroaryl group, or a phenyl-O—C1-C6 alkyl group, wherein the heterocyclyl group, heteroaryl group, and phenyl group each optionally contain 1 to 2 R 1 may be substituted with Each of the R 1 each independently represents a halogen, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, -OR 1A , -NR 1B R 1C , -G 1, O.G. 1 , -NR 1B -G 1 and is selected from the group consisting of: Each of the R 1A , R 1B , R 1C , R 1D are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R 1F1 is replaced by G 1 is a phenyl group, optionally, the phenyl group and the 5- to 6-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R 1F1 are each independently a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C3-C6 cycloalkyl group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D and is selected from the group consisting of: L 1 is empty, -NH-, [ka] and Preferably, the L 1 is empty, -NH-, [ka] and Preferably, the L 1 Is, empty, [ka] and Preferably, the L 1 teeth, [ka] and Each R 1F2 are independently selected from hydrogen, halogen, a hydroxy group, and an amino group; L 2 is empty, -NH-, [ka] where: [ka] The terminus is in formula V [ka] @ is connected to the C atom of the ring, and * is connected to the C ring. Preferably, the L 2 is empty, -NH-, [ka] and Preferably, the L 2 Is, empty, [ka] and Preferably, the L 2 teeth, [ka] and The C ring is a 6- to 10-membered aryl-O—C1-C3 alkyl group, a 4- to 9-membered heterocyclyl-O—C1-C3 alkyl group, a 4- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of halogen, hydroxy, phenyl, C1-C3 alkyl, and C1-C3 alkoxy groups, 2 The alternatives of phenyl, C1-C3 alkyl, and C1-C3 alkoxy are each optionally substituted with halogen or two R on adjacent atoms. 2 The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R 1F1 is replaced by R 2 When is a phenyl group, optionally, the phenyl group and the 4- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring.

[0097] In some embodiments, the compound has the structure shown in Formula V-1 or Formula V-1′. [ka] Here, each of the R 1F2 are independently selected from hydrogen, a hydroxy group, an amino group, and a halogen, and are preferably hydrogen or a hydroxy group; H 1 , H 2 , H 3 , H 4 are each independently C or a chemically acceptable heteroatom, and at least one is a heteroatom; [ka] is a single or double bond, Preferably, the heteroatom is selected from any one of N, O, and S; Preferably, the [ka] teeth, [ka] and Preferably, the R 1 -OR 1A , -NR 1B R 1C , -G 1 , O.G. 1 , -NR 1B -G 1 and each R 1A , R 1B , R 1C are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R 1F1 is replaced by Each of the R 1F1 are each independently a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R1C , -S(O)2R 1D wherein R 1D is selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen.

[0098] In some embodiments, the [ka] teeth, [ka] It is one of the groups:

[0099] In some embodiments, the C ring is a 6- to 10-membered aryl-O—C1-C6 alkyl group, a 3- to 9-membered heterocyclyl-O—C1-C3 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy-C3-C6 cycloalkyl group, and a C1-C3 alkoxy-3- to 6-membered heterocyclyl group, wherein R 2 The options of phenyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C3 alkoxy group in C1-C3 alkoxy-C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C3 alkoxy group in C1-C3 alkoxy-C3-C6 cycloalkyl group, and C1-C3 alkoxy group in C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted with halogen.

[0100] In some embodiments, the C ring is a 4-8 membered heterocyclyl-O—C1-C3 alkyl group, and the heterocyclyl group is selected from one R 2 and preferably, the R 2 is a haloalkyl group.

[0101] In some embodiments, the C ring is a phenyl-O—C 1 -C 3 alkyl group, and the phenyl group is selected from 1, 2, or 3 R 2 Preferably, each R 2 are each independently a halogen.

[0102] In some embodiments, the C ring is a 4- to 9-membered heterocyclyl group, and preferably the C ring is [ka] and R 2 The number n is 1, 2 or 3, and preferably, each of the R 2 are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a phenyl group, a halophenyl group, and a hydroxy group; R 2 is a phenyl group or a halophenyl group, optionally [ka] means that two carbon atoms are shared to form a fused ring, and preferably, the fused ring is [ka] is.

[0103] In some embodiments, the C ring is: 1) [ka] And, Preferably, the R 2is any one of hydrogen, halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, phenyl group, and halophenyl group, and 2 The number p of R 2 is a phenyl group or a halophenyl group, [ka] and form a fused ring by sharing two carbon atoms, and preferably, the fused ring is [ka] and 2) [ka] And, Preferably, the R 2 is selected from the group consisting of hydrogen, halogen, phenyl, C1-C3 alkyl, and C1-C3 alkoxy-C3-C6 cycloalkyl groups, wherein the phenyl, alkyl, and alkoxy groups are unsubstituted or substituted with halogen, and R 2 is a phenyl group, optionally [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] The heteroaryl group is any one of the 5- to 10-membered heteroaryl groups

[0104] In some embodiments, the C ring is a phenyl group, and the phenyl group is R 2 and preferably, the R 2 is selected from the group consisting of C1-C3 haloalkyl groups.

[0105] In some embodiments, the C ring is: [ka] and is selected from any one of the groups Said L 2 teeth, [ka] is.

[0106] In some embodiments, the compound has the structure shown in Formula V-2 or Formula V-2'. [ka] Said L 2 teeth, [ka] where: [ka] The terminal is represented by the formula V-2 [ka] wherein n is 1 to 3, and R 2 The number of R is 1, 2 or 3, 2 are each independently selected from the group consisting of hydrogen, halogen, and hydroxyl groups.

[0107] In some embodiments, the compound has the structure shown in Formula VI, Formula VII, Formula VIII, or Formula IX: [ka] The A ring is a 5- to 7-membered heteroaryl group, and the heteroaryl group is a 5- to 7-membered heteroaryl group. 1 may be substituted with Each of the R 1each independently represents a halogen, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, -OR 1A , -NR 1B R 1C , -G 1 , O.G. 1 , -NR 1B -G 1 and is selected from the group consisting of: Each of the R 1A , R 1B , R 1C , R 1D are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R 1F1 is replaced by G 1 is a phenyl group, optionally, the phenyl group and the 5- to 6-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R 1F1 are each independently a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C3-C6 cycloalkyl group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D and is selected from the group consisting of: L 1 is empty, -NH-, [ka] where: [ka] The * terminus is linked to the A ring and the * terminus is linked to the B ring, preferably the * terminus is [ka] &C atoms in formula VII [ka] & C atoms in formula VIII [ka] & C atoms in formula IX [ka] is connected to the &C atom of Preferably, the L 1 is empty, -NH-, [ka] and Preferably, the L 1 Is, empty, [ka] and L 2 is empty, -NH-, [ka] where: [ka] The terminus is linked to the B ring and the * terminus is linked to the C ring, preferably [ka] The terminus is in formula VI [ka] @C atom in formula VII [ka] @C atom in formula VIII [ka] @C atom, in formula IX [ka] @C atom of Preferably, the L 2 is empty, -NH-, [ka] and Preferably, the L 2 Is, empty, [ka] and Each of the R 1F2 are independently selected from hydrogen, a hydroxy group, an amino group, a carboxyl group, or a halogen.

[0108] In some embodiments, the compound preferably has the 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'. [ka] [ka]

[0109] The R in each formula 1F2are each independently hydrogen, a hydroxy group, an amino group, a carboxyl group, or a halogen, preferably hydrogen or a hydroxy group; H 1 , H 2 , H 3 , H 4 are each independently C or a chemically acceptable heteroatom, and at least one is a heteroatom; [ka] is a single or double bond, Preferably, the heteroatom is selected from any one of N, O, and S; Preferably, the [ka] teeth, [ka] and Preferably, the R 1 -OR 1A , -NR 1B R 1C , -G 1 , O.G. 1 , -NR 1B -G 1 and each R 1A , R 1B , R 1C are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G 1 are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; 1 each optionally containing 1 to 3 R 1F1is replaced by Each of the R 1F1 are each independently hydrogen, halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR 1A , -NR 1B R 1C , -P(O) R 1B R 1C , -S(O)2R 1D wherein R 1D is selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen.

[0110] In some embodiments, the [ka] teeth, [ka] It is one of the groups:

[0111] In some embodiments, the C ring is a 6- to 10-membered aryl-O—C1-C6 alkyl group, a 3- to 9-membered heterocyclyl-O—C1-C3 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, and heterocyclyl group each optionally contain 1 to 3 R 2 and each R 2 are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy-C3-C6 cycloalkyl group, and a C1-C3 alkoxy-3- to 6-membered heterocyclyl group, wherein R2 The options of phenyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C3 alkoxy group in C1-C3 alkoxy-C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C3 alkoxy group in C1-C3 alkoxy-C3-C6 cycloalkyl group, and C1-C3 alkoxy group in C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted with halogen.

[0112] In some embodiments, the C ring is a 4-8 membered heterocyclyl-O—C1-C3 alkyl group, and the heterocyclyl group is selected from one R 2 and preferably, the R 2 is a haloalkyl group.

[0113] In some embodiments, the C ring is a phenyl-O—C 1 -C 3 alkyl group, and the phenyl group is selected from 1, 2, or 3 R 2 Preferably, each R 2 are each independently a halogen.

[0114] In some embodiments, the C ring is a 4- to 9-membered heterocyclyl group.

[0115] Preferably, the C ring is [ka] and R 2 The number n is 1, 2 or 3, and preferably, each of the R 2 are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a phenyl group, a halophenyl group, and a hydroxy group; R 2 is a phenyl group or a halophenyl group, optionally [ka] means that two carbon atoms are shared to form a fused ring, and preferably, the fused ring is [ka] is.

[0116] In some embodiments, the C ring is: 1) [ka] And, Preferably, the R 2 is any one of hydrogen, halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, phenyl group, and halophenyl group, and 2 The number p of R 2 is a phenyl group or a halophenyl group, [ka] and form a fused ring by sharing two carbon atoms, and preferably, the fused ring is [ka] and 2) [ka] And, Preferably, the R 2 is selected from the group consisting of hydrogen, halogen, phenyl, C1-C3 alkyl, and C1-C3 alkoxy-C3-C6 cycloalkyl groups, wherein the phenyl, alkyl, and alkoxy groups are unsubstituted or substituted with halogen, and R 2 is a phenyl group, optionally [ka] and share two carbon atoms to form a fused ring, and preferably, the fused ring is [ka] The heteroaryl group is any one of the 5- to 10-membered heteroaryl groups

[0117] In some embodiments, the C ring is a phenyl group, and the phenyl group is R 2 and preferably, the R 2 is selected from the group consisting of C1-C3 haloalkyl groups.

[0118] In some embodiments, the C ring is: [ka] and is selected from any one of the groups Said L 2 teeth, [ka] where: [ka] The terminus is represented by the formula VI-1. [ka] @C atom in formula VII-1 [ka] @C atom, in formula VIII-1 [ka] @C atom, in formula IX-1 [ka] @C atom of the

[0119] In some embodiments, the compound has the 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'. [ka] [ka] Each said L 2 teeth, [ka] where: [ka] The terminus is represented by the formula VI-2. [ka] @C atom in formula VII-2 [ka] @C atom, in formula VIII-2 [ka] @C atom, in formula IX-2 [ka] is linked to a C atom of the formula (I), n is 1 to 3, and the R 2 The number of R is 1, 2 or 3, 2 are each independently selected from the group consisting of hydrogen, halogen, and hydroxyl groups.

[0120] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] having a structure shown in any one of the following formulas: 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 The definitions of n and m are the same as in any one of the above embodiments.

[0121] In some embodiments, the compound is specifically [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0122] In some embodiments, a pharmaceutical composition is provided, the pharmaceutical composition comprising a formulation made from any one of the compounds above, 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.

[0123] In addition, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or vehicle.

[0124] In some embodiments, any one of the compounds described above, 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 any one of the pharmaceutical compositions described above, is used to treat a neurodegenerative disease (e.g., leukodystrophy). , leukoencephalopathy, hypomyelination or demyelinating disease, intellectual disability syndrome, cognitive dysfunction, glioblastoma dysfunction or brain damage (e.g. traumatic brain injury or toxin-induced brain damage), cancer, inflammatory disease, autoimmune disease, viral infection, skin disease, fibrotic disease, hemoglobin disease, kidney disease, hearing loss disease, eye disease, inducible mutation disease resulting in unfolded protein response (UPR), malarial infection, musculoskeletal disease, metabolic disease or mitochondrial disease.

[0125] In some embodiments, there is provided a use of any one of the compounds described above, 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 any one of the pharmaceutical compositions thereof, in the manufacture of a medicament for preventing and / or treating a disease or condition mediated by the integrated stress response (ISR) pathway.

[0126] In some embodiments, there is provided a method of 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 above 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 above pharmaceutical compositions.

[0127] In some embodiments, 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 is provided, the method comprising administering to a subject a therapeutically effective amount of any one of the above 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 above pharmaceutical compositions.

[0128] In some embodiments, a method for preventing and / or treating each of the above diseases is provided, which comprises administering an effective amount of any one of the above compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition to a subject in need thereof.

[0129] In some embodiments, a method for preventing and / or treating cancer is provided, comprising administering an effective amount of any one of the above compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition to a subject in need thereof.

[0130] In some embodiments, the neurodegenerative disease is a leukodystrophy, a leukoencephalopathy, a dysmyelination or demyelinating disease, an intellectual disability syndrome, cognitive impairment, glioblastoma dysfunction or brain damage (e.g., traumatic brain injury or toxin-induced brain damage), 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, or Creutzfeldt-Jakob disease. , dystonia, frontotemporal dementia (FTD), Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated cognitive impairment, Kennedy's disease, Krabbe disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar degeneration type 3), multiple system atrophy, multisystem protein degeneration, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum's disease, Sandhoff disease Subacute combined degeneration of spinal cord secondary to Pernicious anemia, Schilder's disease, Pernicious anemiaThese conditions include, but are not limited to, encephalopathy (AD), schizophrenia, spinocerebellar degeneration (which has several types with different characteristics, e.g., spinocerebellar degeneration type 2 or spinocerebellar degeneration type 8), spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, corticobasal degeneration, adrenoleukodystrophy, X-linked adrenoleukodystrophy, cerebral adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Krabbe disease, and leukodystrophy due to mutations in the DARS2 gene (leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL), sometimes referred to as DARS2-related spectrum disorder or tabes dorsalis).

[0131] The cancers include, but are not limited to, human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, and the like, as well as solid cancers and cancers of the lymphatic system, kidney 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, glioma, esophageal cancer, liver cancer (including hepatocarcinoma), lymphomas (B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma, e.g., Burkitt's lymphoma), and the like. 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.

[0132] The above leukemias include acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, nonleukemic leukemia, nonleukocytosis leukemia, and basophilic leukemia. Leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, stem cell leukemia, eosinophilic leukemia, gross'leukemia, hairy cell leukemia, erythroblastic leukemia, hematopoiesis Cell leukemia, histocytic leukemia, stem cell leukemia, acute mononuclear leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryoblastic leukemia, micromyeloblastic leukemia, mononuclear leukemia, myeloblastic leukemia, myelocytic leukemia, myelomonocytic leukemia, Naegeli's leukemia leukemia, including, but not limited to, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemia, or undifferentiated leukemia.

[0133] The inflammatory diseases include postoperative cognitive impairment, 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, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, and others. 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.

[0134] The musculoskeletal diseases include 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 protein degeneration, proximal segmental chondrodysplasia punctata, X-linked chondrodysplasia perforans, Conradi-Hunermann syndrome, and the like. syndrome, autosomal dominant chondrodysplasia punctata, stress-induced skeletal diseases (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 spinal-bulbar muscular atrophy, spinal spasm, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Mahad-Joseph disease, Paget's disease of bone, spastic fasciculations syndrome, Friedrich's ataxia, muscle wasting diseases (e.g., muscular atrophy, sarcopenia, cachexia), inclusion body myositis, motor neuron disease or paralysis.

[0135] Such 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 (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes), phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

[0136] The mitochondrial diseases include, but are not limited to, Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Kearns-Sayre syndrome (KSS), Leigh syndrome (e.g., MILS or maternally inherited Leigh syndrome), mitochondrial DNA depletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged-red fibers syndrome (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

[0137] The hearing loss diseases include, but are not limited to, mitochondrial non-syndromic hearing loss and hearing loss, hair cell death, age-related hearing loss, noise-induced hearing loss, genetic or hereditary hearing loss, hearing loss due to ototoxic exposure, disease-induced hearing loss, and trauma-induced hearing loss. In some embodiments, the mitochondrial non-syndromic hearing loss and hearing loss is MT-RNR1-associated hearing loss.

[0138] The above-mentioned ocular diseases include, but are not limited to, cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

[0139] These kidney diseases include Abderhalden-Kaufmann-Lignac syndrome (Y cystinuria), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure / kidney injury, acute lobar nephropathy, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenovirus-induced nephritis, Alagille syndrome, Alport syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, angiomyolipoma, analgesic nephropathy, anorexia nervosa nephropathy, angiotensin-antibody and focal segmental glomerulosclerosis, antiphospholipid syndrome, glomerulonephritis associated with anti-TNF-α therapy, APOL1 mutations, apparent mineralocorticoid excess syndrome, aristolochic acid nephropathy, Chinese herbal medicine nephropathy, and Balkan nephropathy. Endemic Nephropathy, Urinary Arteriovenous Malformations and Fistulas, Autosomal Dominant Hypocalcemia, Bardet-Biedl Syndrome, Bartter Syndrome, Bath Salt Acute Kidney Injury, Beer Potomania, Beetroot Urine, β-Thalassemia Nephropathy, Biliary Cholangionephropathy, Autogenous BK Polyomavirus Nephropathy, Bladder Rupture, Bladder Sphincter Dyssynergia, Bladder Obstruction, Border-Crossers' Nephropathy, Bourbon Virus Virus-induced acute kidney injury, combustion sugarcane harvest acute kidney failure, Byetta renal failure, Clq nephropathy, C3 glomerular disease, C3 glomerular disease with monoclonal gammopathy, C4 glomerular disease, calcineurin inhibitor nephrotoxicity, atractyloside (Callilepsis Laureola) intoxication, cannabinoid hyperemesis acute renal failure, cardiorenal syndrome, carfilzomib-induced renal injury, CFHR5 nephropathy, Charcot-Marie-Tooth disease with glomerular diseaseDisease, Chinese herbal medicine nephrotoxicity, acute kidney injury from cherry concentrate, cholesterol embolism, Churg-Strauss syndrome, chyluria, ciliopathies, cocaine nephropathy, cold diuresis, colistin nephrotoxicity, collagen fibrotic glomerulopathy, collapsing glomerulopathy, CMV-associated collapsing glomerulopathy, combined antiretroviral (cART)-associated nephropathy, congenital anomalies of the kidney and urinary tract (CAKUT), congenital nephrotic syndrome, congestive renal failure, petrous epiphyseal nephropathy Froze syndrome (Mainzer-Saldino syndrome or Saldino-Mainzer disease), contrast nephropathy, copper sulfate poisoning, cortical necrosis, crizotinib-associated acute kidney injury, crystalline cryoglobulinemia, cryoglobulinemia, crystalline cryoglobulin-induced nephropathy, crystalline acute kidney injury, crystal-storing histiocytosis, acquired cystic kidney disease, cystinuria, dasatinib-induced nephropathy with proteinuria, dense deposition disease (type 2 MPGN), Dent disease X-linked recessive nephrolithiasis, DHA crystal nephropathy, dialysis disequilibrium syndrome, diabetes and diabetic nephropathy, diabetic diabetes insipidus, supplement-induced renal failure, diffuse mesangial sclerosis, diuresis, Djenkol bean poisoning (Djenkolism), Down syndrome nephropathy, drug abuse nephropathy, ureteral duplication, EAST syndrome, Ebola nephropathy, ectopic kidney, ectopic ureter, edema, swelling, Erdheim-Chester disease, Fabry's disease, familial hypocalciuric hypercalcemia, Fanconi syndrome, Fraser syndrome, fibronectin nephropathy, fibrillary glomerulonephritis and immunotactoid glomerulopathy, Fraley syndrome syndrome, fluid overload, hypervolemia, focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway-Mowat syndrome, giant cell (temporal) arteritis involving the kidney, pregnancy-induced hypertension, Gitelman syndromeSyndrome, Glomerular Disease, Glomerular Tubular Reflux, Diabetes, Goodpasture Syndrome, Green Smoothie Cleanse Nephropathy, 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, Epidemic Nephropathies Epidemica), hemosiderinuria, paroxysmal nocturnal hemoglobinuria and hemosiderosis associated with hemolytic anemia, hepatic glomerular disease, hepatic veno-occlusive disease, sinusoidal obstruction syndrome, hepatitis C-related nephropathy, hepatocyte nuclear factor 1B-related nephropathy, hepatorenal syndrome, herbal supplement-induced nephropathy, altitude sickness-related renal syndrome, hypertensive nephropathy, HIV-associated immune complex nephropathy (HIVICK), HIV-associated nephropathy (HIVAN), HNF1B-related autosomal dominant tubulointerstitial nephropathy, horseshoe kidney (fused kidney), Hunner's ulcer Ulcer), hydroxychloroquine-induced renal phospholipidosis, hyperaldosteronism, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperoxaluria, hyperphosphatemia, hypocalcemia, hypocomplementemic urticarial vasculitis syndrome, hypokalemia, hypokalemia-induced renal dysfunction, hypokalemic periodic paralysis, hypomagnesemia, Hyponatremia, hypophosphatemia, hypophosphatemia in marijuana users, hypertension, monogenic hypertension, iced tea nephropathy, ifosfamide nephrotoxicity, IgA nephropathy, IgG4 nephropathy, water diuresis, immune checkpoint therapy-associated interstitial nephritis, infliximab-associated nephropathy, interstitial cystitis, bladder pain syndrome (questionnaire), interstitial nephritis, megakaryocytic interstitial nephritis, Ivemark's syndrome, JC virus nephropathy, Joubert syndrome, ketamine-associated 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 tubular disease, Liddle syndrome Syndrome, Lightwood-Albright Syndrome, lipoprotein glomerulopathy, lithium nephrotoxicity, hereditary FSGS due to LMX1B mutations, lumbago and hematuria, lupus, systemic lupus erythematosus, lupus nephropathy, lupus nephritis, lupus nephritis with positive serum antineutrophil cytoplasmic antibodies, lupus podocytopathy, Lyme disease-associated glomerulonephritis, lysinuric protein intolerance, lysozyme nephropathy, malarial nephropathy, malignancy-associated nephropathy, malignant hypertension, malakoplakia , McKittrick-Wheelock syndrome, MDMA (Molly, Ecstasy, 3,4-methylenedioxymethylamphetamine)-induced renal failure, urethral meatal stenosis, medullary cystic kidney disease, uromodulin-associated nephropathy, juvenile type 1 hyperuricemic nephropathy, medullary sponge kidney, megaureter, polyoxyamine toxic nephropathy, MELAS syndrome, membranoproliferative glomerulonephritis, membranous nephropathy, membranous nephropathy-like glomerulopathy with masked IgGk deposition, Mesoamerican nephropathyNephropathy, metabolic acidosis, metabolic alkalosis, methotrexate-associated renal failure, microscopic polyangiitis, milk-alkali syndrome, minimal change nephropathy, monoclonal gammopathy of renal significance, dysproteinemia, oral rinse toxicity, MUC1 nephropathy, polycystic dysplastic kidney, multiple myeloma, myeloproliferative neoplasia glomerular disease, Nail-Patera syndrome, NARP syndrome, nephrocalcinosis, nephrogenic systemic fibrosis, nephroptosis (wandering kidney, nephroptosis), nephrotic syndrome, neurogenic bladder, 9 / 11 and nephropathy, segmental glomerulosclerosis, nongonococcal urethritis, nutcracker syndrome syndrome, oligomegalic glomerulopathy, orofacial-digital syndrome, orotic aciduria, orthostatic hypotension, orthostatic proteinuria, osmotic diuresis, osmotic nephropathy, ovarian hyperstimulation syndrome, oxalate nephropathy, Page kidney, papillary necrosis, papillorenal syndrome Syndrome) (renal coloboma syndrome, isolated renal failure), PARN mutation nephropathy, parvovirus B19 nephropathy, peritoneal-renal syndrome, posterior urethral valve POEMS syndrome, podocyte invagination glomerulopathy, postinfectious glomerulonephritis, poststreptococcal glomerulonephritis, atypical postinfectious glomerulonephritis, postinfectious glomerulonephritis (IgA dominant), mimic IgA nephropathy, polyarteritis nodosa, posterior urethral valve polycystic kidney disease, postobstructive diuresis, preeclampsia, propofol infusion syndrome, proliferative glomerulonephritis with monoclonal IgG deposits (Nasr disease) Disease), propolis (bee resin)-related kidney failure, proteinuria (protein in urine above normal levels), pseudohyperaldosteronism, pseudohypobicarbonate, pseudohypoparathyroidism, pulmonary-renal syndrome, pyelonephritis (kidney infection), pyonephrosis, phenazopyridine-induced kidney failure, radiation nephropathy, ranolazine-induced nephropathy, refeeding syndrome, reflux kidney Renal abscess, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal failure, renal arcuate vein microthrombus-associated acute kidney injury, 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, reninoma (juxtaglomerular cell tumor), reset osmolalityOsmostat, retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, bariatric surgery-associated rhabdomyolysis, rheumatoid arthritis-associated nephropathy, sarcoidosis nephropathy, renal and cerebral salt wasting, schistosomiasis glomerulopathy, Schimke immunoosseous dysplasia, scleroderma renal crisis, serpentine polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, silica exposure-associated chronic nephropathy, Sri Lankan Farmers' Kidney Disease, Sjögren's syndrome nephropathy, acute kidney injury due to synthetic cannabinoid use, post-hematopoietic stem cell transplant nephropathy, stem cell transplant-associated nephropathy, TAFRO syndrome, hyponatremia due to tea and bread consumption, tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, ranolazine nephropathy associated with monoclonal gammopathy, liphidiomyopathy Renal syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal failure, renal arcuate vein microthrombus-associated acute kidney injury, 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, reninoma (juxtaglomerular cell tumor), reset osmolality Osmostat, retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, bariatric surgery-associated rhabdomyolysis, rheumatoid arthritis-associated nephropathy, sarcoidosis nephropathy, renal and cerebral salt wasting, schistosomiasis glomerulopathy, Schimke immunoosseous dysplasia, scleroderma renal crisis, serpentine polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, silica exposure-associated chronic nephropathy, Sri Lankan Farmers' KidneyDisease, Sjögren's syndrome nephropathy, acute kidney injury due to synthetic cannabinoid use, post-hematopoietic stem cell transplant nephropathy, stem cell transplant-associated nephropathy, TAFRO syndrome, hyponatremia due to tea and bread consumption, tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, thrombotic microangiopathy associated with monoclonal gammopathy, war nephritis, bladder trigonitis, genitourinary tuberculosis, tuberous sclerosis, renal tubular dysplasia , immune complex tubulointerstitial nephritis due to autoantibodies against proximal tubule brush border, tumor lysis syndrome, uremia, uremic optic neuropathy, cystic ureteritis, ureterocele, urethral caruncle, urethral stenosis, urinary incontinence, urinary tract infection, urinary tract obstruction, genitourinary fistula, uromodulin-associated nephropathy, vancomycin-associated cast nephropathy, vasomotor nephropathy, vesicoenteric fistula, vesicoureteral reflux, VEGF-inhibitory renal thrombotic microangiopathy, volatile anesthetic-induced acute kidney injury, von Hippel-Lindau disease These conditions include, but are not limited to, Hippel-Lindau Disease, Waldenstrom's Macroglobulinemic Glomerulonephritis, Warfarin-associated nephropathy, acute kidney injury caused by wasp stings, Wegener's Granulomatosis, Granulomatosis with Polyangiitis, West Nile Virus chronic nephropathy, Wunderlich syndrome, Zellweger syndrome, or cerebrohepatorenal syndrome.

[0140] The skin diseases include acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythroporphyria, contact dermatitis, Darier's disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extramammary Paget's disease, epidermolysis bullosa simplex, erythroporphyria, fungal infections of the nails, Hailey-Hailey disease, and others. disease), herpes simplex, hidradenitis suppurativa, hypertrichosis, hyperhidrosis, ichthyosis, pustulosis, keloid, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar verruca (warts), polymorphous light eruption, psoriasis, psoriasis vulgaris, pyoderma gangrenosum, rhinorosacea, scabies, scleroderma, shingles, squamous cell carcinoma, Sweet's syndrome, urticaria and angioedema, and vitiligo vulgaris.

[0141] The fibrotic diseases include, but are not limited to, adhesive capsulitis, arterial stiffness, joint fibrosis, atrial fibrosis, cardiac fibrosis, sclerosis, congenital hepatic fibrosis, Crohn's disease, cystic fibrosis, Dupuytren's contracture, endomyocardial fibrosis, glial scar, hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, nonalcoholic fatty liver disease, previous myocardial infarction, Peyronie's disease, pneumoconiosis, pneumonia, progressive massive fibrosis, pulmonary fibrosis, radiation pneumonitis, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis, and ventricular remodeling.

[0142] The hemoglobinopathies listed above include "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), and vasohemoglobinemia (Hydrops fetalis with Hb). Bart's), sickle cell anemia / disease, sickle cell trait, sickle beta-thalassemia disease, alpha+-thalassemia, alpha0-thalassemia, alpha-thalassemia associated with myelodysplastic syndromes, alpha-thalassemia and mental retardation syndrome (ATR), beta0-thalassemia, beta+-thalassemia, delta-thalassemia, gamma-thalassemia, beta-thalassemia major, beta-thalassemia intermediate, delta beta-thalassemia and epsilon gamma delta beta-thalassemia.

[0143] The autoimmune diseases include achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Balodisease, 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 multiple myelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackievirus myocarditis, 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 (temporal 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 of 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 diseasedisease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A 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 rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, pemphigus, peripheral neuropathy, peripheral venous 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, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon phenomenon), reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, seminal and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndromeThese conditions include, but are not limited to, ulcerative colitis (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

[0144] Such viral infections include, but are not limited to, influenza, human immunodeficiency virus (HIV), and herpes.

[0145] Such malaria infections include, but are not limited to, infections caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium falciparum.

[0146] Inducible mutational diseases that result in 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, collagen diseases, thin basement membrane nephropathy, Alport syndrome, skeletal chondrodysplasia, metaphyseal chondrodysplasia type Schmid, and pseudochondrodysplasia.

[0147] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, Ohio) nomenclature systems.

[0148] Unless otherwise specified, the initial definition of a group or term in this specification applies to that group or term throughout the specification, and terms not specifically defined herein should be given the meaning that a person skilled in the art can give them based on the disclosure and context.

[0149] "Substitution" refers to the replacement of a hydrogen atom in a molecule with another different atom or group, or the replacement of a lone electron pair of an atom in a molecule with another atom or group, for example, the replacement of a lone electron pair on an S atom with an O atom. [ka] can be formed.

[0150] "Optionally replaced by" means that the "replacement" may occur, but does not necessarily occur, and the description includes cases where it occurs or does not occur.

[0151] "Optionally" means that one may choose to, but is not necessarily chosen, and includes the case of choice or not choosing.

[0152] The minimum and maximum carbon atom content in the hydrocarbon group is indicated by a prefix, for example, the prefix Ca-Cb alkyl group refers to any alkyl group containing "a" to "b" carbon atoms, so for example, C1-C6 alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.

[0153] An "alkyl group" refers to a saturated hydrocarbon chain having a specified number of member atoms. An alkyl group may be straight-chained or branched. Representative branched-chain alkyl groups have one, two, or three branches. An alkyl group may be optionally substituted with one or more substituents as defined herein. For example, C1-C6 alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

[0154] The term "C1-C10 alkyl group" refers to any straight or branched chain alkyl 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 straight or branched chain C7 alkyl groups, C8 alkyl groups, C9 alkyl groups, C10 alkyl groups, and the like.

[0155] The "C1-C10 alkyl group" includes straight or branched groups in a range whose endpoints are any two integers having 1 to 10 carbon atoms. For example, a "C1-C10 alkyl group" includes a C1-C10 alkyl group, a C1-C8 alkyl group, a C1-C6 alkyl group, a C2-C10 alkyl group, a C2-C8 alkyl group, a C2-C6 alkyl group, a C6-C10 alkyl group, etc., and the above-listed groups are merely examples and do not limit the range.

[0156] The term "alkoxy group" and derivatives thereof refers to any of the above alkyl groups (e.g., C1-C10 alkyl groups, C1-C6 alkyl groups, etc.), which is linked to the remainder of the molecule via an oxygen atom (-O-).

[0157] An "alkylene group" refers to a divalent saturated aliphatic hydrocarbon group having the specified number of member atoms. A Ca-Cb alkylene group refers to an alkylene group having from a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene group" refers to [ka] Similarly, the term "dimethylbutylene group" may be enumerated by the structure: [ka] may be enumerated by any one of the following structures:

[0158] The C1-C4 alkylene group of the present invention may be a C1 alkylene group (such as -CH2-), a C2 alkylene group (such as -CH2CH2-), a C3 alkylene group, or a C4 alkylene group.

[0159] The "cycloalkyl group" according to the present invention refers to a saturated cyclic alkane having a single ring or multiple rings (fused rings, spiro rings, bridged rings) with multiple carbon atoms and no cycloheteroatoms. Examples of single carbon ring groups include, for example, cyclopropyl, cyclobutanyl, cyclohexanyl, cyclopentanyl, cyclooctanyl, cyclopentenyl, and cyclohexenyl groups. Examples of fused ring alkane systems include bicyclohexanyl, bicyclopentanyl, and bicyclooctanyl groups. Examples of the "cycloalkyl group" according to the present invention include: [ka] Including, but not limited to, the following:

[0160] The term "C3-C10 cycloalkyl group" refers to 3- to 10-membered all-carbon monocyclic, fused, bridged, and spirocyclic rings, which may contain zero, one, or more double bonds but do 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.

[0161] The "heterocyclyl group" according to the present invention refers to a saturated ring having a single ring or multiple rings (fused rings, bridged rings and spiro rings) containing at least one heteroatom, where the heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. Examples of the 3- to 9-membered heterocyclyl group may be an oxetanyl group, an azetidinyl group, an oxacyclopentanyl group, an oxanyl group, a piperazinyl group, a piperidinyl group, a morpholinyl group, a trioxane group, etc. Examples of the "heterocyclyl group" according to the present invention include: [ka] or piperidinyl groups, and the like.

[0162] The term "5- to 10-membered spiro ring" as used herein refers to a saturated or non-aromatic partially saturated bivalent ring formed by the spiro-bonding of two or more rings having 5 to 10 carbon atoms and no cycloheteroatoms. Examples of 5- to 10-membered spiro ring systems include spiro[2,5]octanyl, spiro[3,4]octanyl, spiro[3,3]heptanyl, spiro[3,5]nonanyl, spiro[4,5]decanyl, spiro[2,2]pentanyl, spiro[2,3]hexanyl, spiro[2,4]heptanyl, spiro[2,6]nonanyl, spiro[2,7]nonanyl, spiro[3,6]nonanyl, and spiro[4,4]nonanyl.

[0163] The "5- to 10-membered spiro heterocycle" described in the present invention refers to a saturated ring or a non-aromatic partially saturated divalent ring formed by spiro-bonding two or more rings formed after at least one carbon atom in the above-mentioned "5- to 10-membered spiro ring" is replaced with a heteroatom, and examples of the 5- to 10-membered spiro heterocycle include the above-mentioned spiro[2,5]octanyl ring, spiro[3,4]octanyl ring, spiro[3,3]heptanyl ring, spiro[3, spiroheterocycles formed after at least one carbon atom in a spiro[4,5]decanyl ring, a spiro[2,2]pentanyl ring, a spiro[2,3]hexanyl ring, a spiro[2,4]heptanyl ring, a spiro[2,6]nonanyl ring, a spiro[2,7]nonanyl ring, a spiro[3,6]nonanyl ring, and a spiro[4,4]nonanyl ring is replaced with a heteroatom selected from N, O, S, etc., for example, [ka] Includes:

[0164] Unsaturation according to the present invention refers to the inclusion of 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, or the like in a group or molecule.

[0165] The term "aromatic ring" as used herein refers to an aromatic hydrocarbon group having multiple carbon atoms. An aryl group is generally a monocyclic, bicyclic, or tricyclic aryl group having multiple carbon atoms. As used herein, the term "aryl group" refers to an aromatic substituent of a single aromatic ring or fused aromatic rings. Non-limiting examples include a phenyl group, a naphthyl group, or a tetrahydronaphthyl group.

[0166] The "5- to 10-membered heteroaryl group" described in the present invention refers to an aromatic unsaturated ring containing at least one heteroatom, where the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Generally, it is an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, one or more of which is a heteroatom selected from O, N, and S. Preferably, it has 1 to 3 heteroatoms. Here, examples of the 5- to 6-membered heteroaryl group include a pyridyl group, a pyrrolyl group, a furyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a pyranyl group, a thiopyranyl group, a piperazinyl group, a triazolyl group, a 1,2,4-triazolyl group, a 1,2,5-triazolyl group, a 1,3,4-triazolyl group, a 1,2,3,4-tetrazolyl group, a 1,2,3,5-tetrazolyl group, an isoxazolyl group, an oxazolyl group, a 1,2,3-oxadiazolyl group, a 1,2,4-oxadiazolyl group, a 1,3,4-oxadiazolyl group, a furazan group, a 1,2,3,5-oxatriazolyl group, a 1,2,3,4-oxatriazolyl group, a 1,3,2 -dioxazolyl group, 1,2,3-dioxazolyl group, 1,2,3,4-dioxadiazolyl group, 1,2,3,5-dioxadiazolyl group, 1,3,3,4-dioxadiazolyl group, 1,3,4,5-dioxadiazolyl group, 1,2,3,4-dioxadiazolyl group, isothiazolyl group, pyridazinyl group, triazinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl group, 1,2,4,5-tetrazinyl group, 1,2,4-oxazinyl group, 1,2,6-oxazinyl group, 1,3,2-oxazinyl group, 1,3,6-oxazinyl group, 1,4,2-oxazinyl group, 1,2-isoxazinyl group, 1,4-isoxazinyl group.

[0167] "Halogen" according to the present invention refers to fluorine, chlorine, bromine or iodine.

[0168] The "halogen-substituted alkyl group" according to the present invention refers to an alkyl group in which one or more hydrogen atoms are substituted with halogen, such as a halogen-substituted C 1~4An alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which a hydrogen atom is substituted with one or more halogen atoms, and is, for example, a monofluoromethyl group, a bisfluoromethyl group, or a trifluoromethyl group.

[0169] "-N(R)2" and the like described in the present invention indicate that the R group and the nitrogen atom are connected by a single bond.

[0170] "=O" (oxo) according to the present invention refers to an oxygen atom replacing two hydrogen atoms in a molecule with a double bond.

[0171] In the present invention, as will be apparent to those skilled in the art, any group whose name is a composite name, such as "6-10 membered aryl-D-C1-C6 alkyl group", should generally be understood to be constructed from its derived moieties, such as C1-C6 alkyl groups, from left to right, and it should be understood that the alkyl group here is a divalent alkyl group.

[0172] The "empty" in the present invention means that the object to which it is connected is directly connected via a bond, for example, "L 1 is empty" means that L 1 This means that ring A and ring B, which are respectively connected to ring A and ring B, are directly connected via a bond.

[0173] In the present invention, the "linking group" refers to a chemical group containing two linkable bonds, such as O, S, -NH-, -N(alkyl)-, an alkylene group, a heteroalkylene group, a cycloalkylene group, a heterocyclylene group, and the like.

[0174] In the present invention, "stereoisomers" refer to compounds that have the same chemical structure but differ in the manner in which atoms or groups are arranged, and include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, etc.

[0175] In the present invention, the term "tautomer" generally refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via rearrangement of some bond electrons.

[0176] The "geometric isomers" in the present invention are also called "cis-trans isomers" and are isomers resulting from the inability to freely rotate about double bonds (including olefin double bonds, C=N double bonds, and N=N double bonds) or single bonds of ring carbon atoms.

[0177] As used herein, "enantiomers" refers to two isomers of a compound which are non-superimposable mirror images of one another.

[0178] As used herein, "diastereomer" refers to two or more stereoisomers that are chiral and neutral and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures, such as electrophoresis and chromatography, e.g., HPLC.

[0179] As used herein, the terms "racemate," "racemic product," or "racemic mixture" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

[0180] In this specification, a solid line [ka] Solid wedge [ka] or dotted wedge [ka] The chemical bonds of the compounds of the present invention can be depicted using the following symbols. Drawing bonds connected to asymmetric carbon atoms using a solid line is intended to include all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.). Drawing bonds connected to asymmetric carbon atoms using a solid or dotted wedge is intended to indicate the presence of the depicted stereoisomer. When present in a racemic mixture, the solid or dotted wedge is used to define relative stereochemistry, rather than absolute stereochemistry. Unless otherwise specified, the compounds of the present invention may exist in various forms of stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention can exhibit one or more types of isomerization and can be comprised of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0181] "Polymorphism" in the present invention refers to the crystalline form of a compound (or its salts, hydrates, or solvates) in a specific crystalline stacked arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystalline shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can result in the predominance of one crystalline form.

[0182] A "solvate" in the present invention is a mixture that occurs after a compound is dissolved in a solvent.

[0183] In the present invention, an "N-oxide", also known as an amine oxide, is an organic compound having the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0184] The term "isotopically labeled compound" as used herein refers to a molecule or group in which one or more atoms are substituted with its isotope atom, for example, a hydrogen atom is substituted with a deuterium atom, where the proportion of deuterium atoms is greater than the abundance of deuterium in nature, or, for example, 12C is substituted with 13C.

[0185] The term "metabolite" as used herein refers to a substance that is produced by a chemical structural transformation that occurs under the action of the body after a drug molecule is absorbed into the body.

[0186] The term "prodrug" as used herein refers to a compound obtained by modifying the chemical structure of a drug, which is inactive or has little activity in vitro, but which exerts its medicinal effect by releasing an active drug through enzymatic or non-enzymatic conversion in vivo.

[0187] In the present invention, "pharmaceutically acceptable" generally refers to a carrier, a diluent, an excipient, and / or a salt formed therefrom that is chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form and physiologically compatible with a receptor.

[0188] The terms "salt" and "pharmaceutically acceptable salt" as used herein refer to acidic and / or basic salts formed by the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. They may also be obtained by mixing the above-mentioned compounds or their stereoisomers with a certain number of acids or bases appropriately (e.g., in equal amounts). These salts may be obtained by forming precipitates in a solution and collecting them by filtration, by recovering them after evaporating the solvent, or by reacting them in an aqueous medium and then lyophilizing them.

[0189] "Prevention" in the present invention includes inhibiting or delaying the onset of a disease, and includes not only prevention before the progression of a disease, but also prevention of the recurrence of a disease after treatment.

[0190] "Treatment" in the present invention means reversing, alleviating or eliminating the progression of the disease or condition to which such term applies, or one or more symptoms of such disease or condition.

[0191] In some embodiments, one or more compounds of the present invention can be used in combination with each other. The compounds of the present invention can also be used in combination with other active agents to produce drugs or pharmaceutical compositions for regulating cellular function or treating disease. When a set of compounds is used, these compounds can be administered to a subject simultaneously, separately, or in an orderly manner.

[0192] Obviously, according to the above content of the present invention, many other forms of modifications, substitutions or alterations can be made according to the common technical knowledge and common means of those skilled in the art without departing from the above basic technical idea of the present invention.

[0193] The above content of the present invention will be described in more detail below with reference to specific embodiments in the form of examples. However, it should not be understood that the scope of the above theme of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0194] The known starting materials of the present invention can be synthesized by methods known in the art or purchased from companies such as BiDe Pharmaceutical, Anaiji Chemical, Discovery Platform, Nanjing Yaoshi, Jiangsu Aikang, Beijing Yinuokai Technology, etc., where tetrapropylammonium perruthenate is purchased from Discovery Platform, and 1-propylphosphonic anhydride is purchased from Beijing Yinuokai Technology Co., Ltd.

[0195] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen gas atmosphere. Unless otherwise specified in the examples, the solution is an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, and is 20°C to 30°C. Unless otherwise specified in the examples, M is mol / L.

[0196] The structure of the compound is confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR displacements (δ) are 10 -6 The values are given in ppm. NMR measurements were performed using a Bruker AvanceIII 400 nuclear magnetometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (methanol-d4), and the internal standard was tetramethylsilane (TMS). LC-MS measurements were performed using a Shimadzu liquid chromatograph mass spectrometer (Shimadzu LC-MS 2020 (ESI)). HPLC measurements were performed using a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium-pressure liquid chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a 0.4mm to 0.5mm thickness. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as a carrier.

[0197] N,N'-Diisopropylethylamine (also called 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-propylphosphonic 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, and petroleum ether is abbreviated as PE.

[0198] Example 1: Synthesis of Compound I-1 [ka]

[0199] Step 1: Synthesis of intermediate 1b.

[0200] To a mixture of tetrahydrofuran (40 mL), methanol (20 mL), and water (10 mL), starting material 1a (10 g, 42.98 mmol) and lithium hydroxide (5.97 mL, 214.92 mmol) were added and the mixture was stirred at 25 °C for 18 hours. The resulting reaction mixture was adjusted to pH 7 with dilute hydrochloric acid (1 M) and extracted three times with ethyl acetate (100 mL). The combined organic phase was 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. 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).

[0201] Step 2: Synthesis of intermediate 1d.

[0202] Intermediate 1b (100 mg, 0.49 mmol), Intermediate 1c (0.11 mL, 0.54 mmol, BD215605), HATU (278.80 mg, 0.73 mmol), and DIPEA (0.24 mL, 1.47 mmol) were added to N,N-dimethylformamide (5 mL) 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 obtain the crude product. The crude product was purified by preparative TLC (dichloromethane:methanol = 20:1) to obtain Intermediate 1d. MS m / z: 357.2 [M+H-56] + . 1H 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).

[0203] Step 3: Synthesis of intermediate 1e Intermediate 1d (150 mg, 0.36 mmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (5 mL) and the reaction was stirred for 1 hour at 25° C. The mixture was concentrated to dryness under reduced pressure to give Intermediate 1e. MS m / z: 313.2[M+H] + . 1 H 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,2H),2.67-2.6 1(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).

[0204] Step 4: Synthesis of compound I-1.

[0205] Intermediate 1e (30 mg, 0.10 mmol), starting material 1f (0.01 mL, 0.11 mmol), HATU (54.71 mg, 0.14 mmol), and DIPEA (0.05 mL, 0.29 mmol) were added to N,N-dimethylformamide (2 mL) and stirred at 25 °C for 1 h. 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 the crude product. The crude product was purified by preparative TLC (eluent: petroleum ether: ethyl acetate = 1:5) to give compound I-1.

[0206] MS m / z: 469.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.96 (d,J=3.9Hz,2H),8.23(dd,J=21.7,4.1Hz,1H),7.55-7.40(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).

[0207] Example 2: Synthesis of Compound I-2 [ka]

[0208] Step 1: Synthesis of compound I-2.

[0209] Intermediate 1e (30 mg, 0.10 mmol), starting material 2a (0.01 mL, 0.11 mmol), HATU (54.71 mg, 0.14 mmol), and DIPEA (0.05 mL, 0.29 mmol) were added to N,N-dimethylformamide (2 mL) 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 phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (eluent: dichloromethane:methanol = 20:1) to obtain compound I-2. 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,1H),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,1 H),4.59(s,2H),3.95-3.43(m,3H),3.31(s,1H),2.64-2.57(m,1H),1.53(d,J=10.3 Hz,2H),1.30(d,J=12.0Hz,2H),0.79(dd,J=8.1,5.4Hz,1H),0.65(t,J=5.0Hz,1H).

[0210] Example 3: Synthesis of Compound I-3 [ka]

[0211] Step 1: Synthesis of intermediate 3b.

[0212] 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), and the mixture was stirred at 25°C for 2 hours to react. The resulting reaction mixture was concentrated under reduced pressure to dryness to obtain intermediate 3b. MS m / z: 312.1[MH] - .

[0213] Step 2: Synthesis of intermediate 3c.

[0214] 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) were added to N,N-dimethylformamide (2 mL) 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 phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (eluent: petroleum ether:ethyl acetate = 1:5) to obtain Intermediate 3c. MS m / z: 508.2 [M+H-100] + .

[0215] Step 3: Synthesis of compound I-3.

[0216] Intermediate 3c (50 mg, 0.08 mmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (5 mL) and stirred at 25 °C for 1 hour. The resulting reaction mixture was concentrated to dryness under reduced pressure to give 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, the filter cake was washed with dichloromethane (20 mL x 3), and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by preparative TLC (rinse: dichloromethane:methanol = 20:1) to give compound I-3. 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,1 H),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).

[0217] Example 4: Synthesis of Compound I-4 [ka]

[0218] Step 1: Synthesis of compound I-4 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 purged with nitrogen gas three times, and the reaction was stirred at 70 °C for 18 h. 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 the crude product. The crude product was purified by preparative TLC (eluent: dichloromethane:methanol = 40:1) to obtain compound I-4. MS m / z: 522.3[M+H] + . 1H NMR(400MHz,DMSO-d6) δ8.21(s,1H),7.50(t,J=8.9Hz,1H),7.03(d,J=9.8Hz,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).

[0219] Example 5: Synthesis of Compound I-5 [ka]

[0220] Step 1: Synthesis of intermediate 5a.

[0221] Intermediate 1e (100 mg, 0.32 mmol) and sodium nitrite (0.07 mL, 1.28 mmol) were added to a mixture of water (3 mL) and glacial acetic acid (6 mL), and the mixture 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 phase was 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] + .

[0222] Step 2: Synthesis of intermediate 5b.

[0223] Intermediate 5a (100 mg, 0.29 mmol), glacial acetic acid (0.5 mL), and zinc (97 mg, 1.48 mmol) were added to a mixture of tetrahydrofuran (2 mL) and water (2 mL) and 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 the 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 Intermediate 5b. MS m / z: 312.8 [M+H-16] + .

[0224] Step 3: Synthesis of compound I-5.

[0225] 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) were added to N,N-dimethylformamide (3 mL) 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 phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (rinse: dichloromethane:methanol = 20:1) to obtain compound I-5. 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).

[0226] Example 6: Synthesis of Compound I-6 [ka]

[0227] Step 1: Synthesis of compound I-6.

[0228] 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 the crude product. The crude product was purified by TLC (rinse: dichloromethane:methanol = 20:1) to obtain compound I-6. 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=11.4,2.9Hz,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).

[0229] Example 7: Synthesis of Compound I-7 [ka]

[0230] Step 1: Synthesis of intermediate 7a.

[0231] 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) were added to N,N-dimethylformamide (5 mL) and 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 phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (eluent: ethyl acetate:petroleum ether = 4:1) to obtain Intermediate 7a. MS m / z: 568.8 [M+H-56] + .

[0232] Step 2: Synthesis of compound I-7.

[0233] To a solution of dichloromethane (5 mL), intermediate 7a (50 mg, 0.08 mmol) and trifluoroacetic acid (1 mL) were added, and the mixture was stirred at 25 ° C. for 1 hour. The resulting reaction mixture was concentrated under reduced pressure to dryness 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 × 3). The filtrate was concentrated under reduced pressure to dryness to obtain compound I-7. MS m / z: 524.4[M+H] + . 1H 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).

[0234] Example 8: Synthesis of Compound I-8 [ka]

[0235] Step 1: Synthesis of intermediate 8a.

[0236] To a solution of dichloromethane (5 mL) were 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 mixture was concentrated to give intermediate 8a. MS m / z: 200.6 [M+H] + is.

[0237] Step 2: Synthesis of intermediate 8b.

[0238] To a solution of intermediate 8c (133 mg, 0.67 mmol) in acetonitrile (10 mL), potassium carbonate (276.22 mg, 2.00 mmol) and dimethyl sulfate (338.03 mg, 2.68 mmol) were added at 25 °C, and the resulting mixture was stirred at 70 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (20 mL x 3), and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (rinse: petroleum ether: ethyl acetate = 1:1) to obtain intermediate 8b. MS m / z: 214.6 [M+H] + .

[0239] Step 3: Synthesis of intermediate 8c.

[0240] 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 to react. The resulting mixture was concentrated under reduced pressure to dryness to give intermediate 8c. MS m / z: 228.6 [M+H] + .

[0241] Step 4: Synthesis of compound I-8.

[0242] To a solution of 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) in N,N-dimethylformamide (3 mL) was added and the mixture was stirred at 25 °C for 2 h. The resulting reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3) to obtain the 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 the crude product. Purification by HPLC (Phenomenex Gemini 150 mm x 25 mm x 10 μm column (eluent: 30%-60% (v / v) CHCN and HO with 0.025% HCOOH)) gave compound I-8. MS m / z: 537.4[M+H] + .

[0243] Example 9: Synthesis of Compound I-9 [ka]

[0244] Step 1: Synthesis of intermediate 9a 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 extracted with ethyl acetate (10 mL x 3). The organic phase was separated and washed with saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the 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] + .

[0245] Step 2: Synthesis of intermediate 9b 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] + .

[0246] Step 3: Synthesis of compound I-9 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 extracted with EtOAc (5 mL x 3). The organic phase was separated and washed with saturated brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was separated by HPLC (eluent containing 0.225% formic acid: v / v (acetonitrile / water) = 43% to 100%) to give compound I-9. MS m / z: 483.0[M+H] + . 1 H NMR (400MHz,DMSO) δ 8.91 (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).

[0247] Example 10: Synthesis of Compound I-10 [ka]

[0248] Step 1: Synthesis of intermediate 10a.

[0249] 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 extracted with DCM (5 mL×3). The organic phase was separated and washed with saturated brine (20 mL), dried over anhydrous NaSO, 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. MS m / z: 334.0[M+H] + . 1 H NMR (400MHz,DMSO) δ 8.95 (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).

[0250] Step 2: Synthesis of intermediate 10b 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), HO (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 aqueous ammonia (20%, 3 M), extracted with EtOAc (8 mL x 3), and separated to obtain the organic phase. The organic phase was washed with saturated brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to obtain Intermediate 10b. MS m / z: 320.0 [M+H] + .

[0251] Step 3: Synthesis of compound I-10 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 extracted with EtOAc (5 mL x 3). The organic phase was separated and washed with saturated brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was separated by HPLC (eluent: 43% to 100% (v / v) CHCN and HO with 0.225% HCOOH) to give compound I-10. MS m / z: 498.0[M+H] + . 1 H NMR (400MHz,DMSO) δ 9.87 (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).

[0252] Example 11: Synthesis of Compound II-10 [ka]

[0253] Step 1: Synthesis of intermediate 11b.

[0254] A solution of intermediate 11a (500 mg, 2.19 mmol), DIPEA (1.09 mL, 6.57 mmol), and HATU (999.36 mg, 2.63 mmol) was added to intermediate 1b (448.07 mg, 2.19 mmol) in DMF (10 mL) and stirred at 20 °C for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 2) to obtain an organic phase. The organic phase was washed with saturated NaCl solution (100 mL), and the organic layer was 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] + .

[0255] Step 2: Synthesis of intermediate 11c 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. Concentration under reduced pressure gave Intermediate 11c. MS m / z: 315.0 [M+H] + .

[0256] Step 3: Synthesis of Compound II-10 To a solution of intermediate 11c (76 mg, 0.24 mmol) in DMF (5 mL), intermediate 1f (0.03 mL, 0.24 mmol), DIEA (0.12 mL, 0.72 mmol), and HATU (110.18 mg, 0.29 mmol) were added and the mixture 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 combined organic phases were washed with saturated NaCl solution (40 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC eluting with PE: EtOAc = 1:1 and concentrated in vacuo to give compound II-10. 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),4.6 6(dd,J=21.7,11.0,1.6Hz,1H),4.57-4.51(m,3H),4.39-4.20(m,2H),4.15-4.06(m,1 H),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).

[0257] Example 12: Synthesis of Compound II-11 [ka]

[0258] Step 1: Synthesis of Compound II-11 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 h. The resulting mixture was poured into HO (50 mL) and extracted with EtOAc (25 mL x 3) to obtain an organic phase. The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (PE: EtOAc = 1:1) to obtain compound II-11. MS m / z: 501.0[M+H] + . 1H NMR (400MHz,DMSO) δ 8.33 (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).

[0259] Example 13: Synthesis of Compound II-12 [ka]

[0260] Step 1: Synthesis of compound II-12 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 h. The resulting mixture was poured into HO (50 mL) and extracted with EtOAc (25 mL x 3) to obtain an organic phase. The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (PE: EtOAc = 7:3) to obtain compound II-12. 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).

[0261] Example 14: Synthesis of Compound II-13 [ka]

[0262] Step 1: Synthesis of intermediate 14a 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 extracted with EtOAc (30 mL x 3) to obtain an organic phase. The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (eluent EtOAc) to obtain intermediate 14a. MS m / z: 554.0 [M+H-56] + .

[0263] Step 2: Synthesis of compound II-13 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 mixture was concentrated under reduced pressure to give the crude product, which was then added with DCM (5 mL) and Na2CO3 (30 mg), stirred at 25 °C for 30 min, filtered, and the filtrate was concentrated to give compound II-13. 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=11.4,2.7Hz,1H ),6.84(dd,J=9.0,1.8Hz,1H),6.78-6.68(m,1H),6.59(t,J=2.2Hz,1H),6.52-6.4 2(m,1H),6.19(s,1H),4.79-4.66(m,1H),4.54(s,2H),4.52-3.72(m,7H),3.62(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).

[0264] Example 15: Synthesis of Compound II-14 [ka]

[0265] Step 1: Synthesis of compound II-14 To a solution of compound II-13 in ACN (5 mL) was 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 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. MS m / z: 524.0[M+H] + . 1H NMR (400 MHz, 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).

[0266] Example 16: Synthesis of Compound III-10 [ka]

[0267] Step 1: Synthesis of intermediate 16b 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 to DMF (1.5 mL) sequentially and reacted at 25 °C for 18 hours. The resulting mixture was washed with water (30 mL) and extracted with EtOAc (10 mL x 3). The organic phase was separated and washed with saturated brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the 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] + .

[0268] Step 2: Synthesis of intermediate 16c 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 mixture obtained in the reaction was concentrated under reduced pressure to give Intermediate 16c. MS m / z: 313.0 [M+H] + .

[0269] Step 3: Synthesis of compound III-10 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 extracted with EtOAc (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 give the crude product. The crude product was separated by TLC preparative separation (eluent: petroleum ether: EtOAc = 1:1) to give compound III-10. MS m / z: 499.0[M+H] + . 1 H 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).

[0270] Example 17: Synthesis of Compound IV-11 [ka]

[0271] Step 1: Synthesis of intermediate 17b 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 × 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] + .

[0272] Step 2: Synthesis of intermediate 17c 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 to allow the reaction to proceed. After completion, the mixture was concentrated under reduced pressure to give intermediate 17c. MS m / z: 327.0 [M+H] + .

[0273] Step 3: Synthesis of compound IV-11 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. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 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 purified by silica gel column chromatography (mobile phase: PE / EtOAc (V / V) = 1 / 1) and concentrated in vacuo to give compound IV-11. MS m / z: 513.0[M+H] + . 1H 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).

[0274] Example 18: Synthesis of Compound V-10 [ka]

[0275] Step 1: Synthesis of intermediate 18b 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. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 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 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] + .

[0276] Step 2: Synthesis of intermediate 18c 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 give intermediate 18c. MS m / z: 327.0 [M+H] + .

[0277] Step 3: Synthesis of compound V-10 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), 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 × 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).

[0278] Example 19: Synthesis of Compound III-11 [ka]

[0279] Step 1: Synthesis of compound III-11 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 resulting mixture, which was then extracted with EtOAc (10 mL x 3). The organic phase was separated and washed with saturated brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (PE / EtOAc (v / v) = 1 / 1) to give compound III-11. 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).

[0280] Example 20: Synthesis of Compound III-13 [ka]

[0281] Step 1: Synthesis of intermediate 20a 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) were added to N,N-dimethylformamide (5 mL) and 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 phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (eluent: petroleum ether: ethyl acetate = 10:1) to obtain Intermediate 20a. MS m / z: 608.5 [M+H] + .

[0282] Step 2: Synthesis of compound III-13 20a (120 mg, 0.20 mmol) and trifluoroacetic acid (1 mL) were added to dichloromethane (5 mL) and stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to dryness to give the crude product, which was purified by preparative TLC (eluent: petroleum ether: ethyl acetate = 5:1) to give compound III-13. 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=11.4,2.8H z,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,1 H),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=1 2.2Hz, 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).

[0283] Example 21: Synthesis of Compound IV-12 [ka]

[0284] Step 1: Synthesis of compound IV-12 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. The resulting mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 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 NaSO, filtered, and concentrated. The resulting residue was purified by preparative TLC (eluent: DCM / MeOH = 20 / 1) and concentrated under reduced pressure to obtain compound IV-12. MS m / z: 483.0[M+H] + . 1 H 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).

[0285] Example 22: Synthesis of Compound IV-13 [ka]

[0286] Step 1: Synthesis of intermediate 22a 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 × 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 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] + .

[0287] Step 2: Synthesis of compound IV-13 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 to react. The mixture obtained in the reaction 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 under vacuum to give compound IV-13. MS m / z: 522.0[M+H] + . 1 H 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(dd,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).

[0288] Example 23: Synthesis of Compound V-11 [ka]

[0289] Step 1: Synthesis of compound V-11 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. The resulting mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 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 NaSO, 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] + . 1 H 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=9.0Hz,1H),4.5 0(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).

[0290] Example 24: Synthesis of Compound V-12 [ka]

[0291] Step 1: Synthesis of intermediate 24a 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 × 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 intermediate 24a. MS m / z: 566.2 [M+H-56] + .

[0292] Step 2: Synthesis of compound V-12 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 to allow the reaction to proceed. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (mobile phase: DCM / MeOH (V / V) = 20 / 1) and concentrated under vacuum to obtain the target compound V-12. MS m / z: 522.0 [M+H] + . 1H 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=6.0,3.0 Hz,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).

[0293] Example 25: Synthesis of Compound IV-15 [ka]

[0294] Step 1: Synthesis of compound IV-15 To a solution of compound 22 (40 mg, 0.08 mmol) in CHCN (5 mL), KCO (31.75 mg, 0.23 mmol) and dimethyl sulfate (0.03 mL, 0.31 mmol) were added, and the mixture was stirred at 70 °C for 18 hours to react. The resulting reaction mixture was separated and purified by preparative TLC (mobile phase: DCM / MeOH (V / V) = 20 / 1) to give compound IV-15. 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=9.2,2.9 Hz,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=8.8 Hz,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).

[0295] Example 26: Synthesis of Compound III-12 [ka]

[0296] Step 1: Synthesis of compound III-12 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 purged with nitrogen gas three times and stirred at 70 °C for 18 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 phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the 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. 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).

[0297] Example 27: Synthesis of Compound IV-14 [ka]

[0298] Step 1: Synthesis of intermediate 27b Compound 27a (1.0 g, 5.86 mmol) and 1,2-dichloroethane (50.0 mL) were added to a 100 mL single-neck flask at room temperature, and N,N'-carbonyldiimidazole (1.3 g, 8.21 mmol) was added under stirring. The mixture was allowed to react at 25°C for 16 hours. 25 mL of water was added to the resulting reaction mixture, 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 a crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 27b.

[0299] Step 2: Synthesis of compound IV-14 Intermediate 17c (100 mg, 0.31 mmol) and N'N-dimethylformamide (5.0 mL) were added to a 50 mL single-neck flask at room temperature. Under stirring, intermediate 27b (84 mg, 0.43 mmol), DIEA (159 mg, 1.22 mmol), and Castro condensation agent (BOP) (28 mg, 0.45 mmol) were sequentially added. The reaction was allowed to proceed at 25 °C for 16 hours. 25 mL of water was added to the resulting reaction mixture, and the layers were 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 the crude product. The crude product was separated and purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound IV-14. MS m / z: 505.0[M+H] + . 1 H NMR (400MHz,CDCl3-d) δ 7.86 - 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),,6.69- 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).

[0300] Example 28: Synthesis of Compound IV-18 [ka]

[0301] Step 1: Synthesis of intermediate 28a Intermediate 3b (85 mg, 0.27 mmol) and N'N-dimethylformamide (5 mL) were placed in a 50 mL single-neck flask at room temperature. Under stirring, intermediate 17a (65 mg, 0.27 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154 mg, 0.41 mmol), and DIEA (130 mg, 1.08 mmol) were sequentially added. The reaction was allowed to proceed at 25 °C for 12 hours. 50 mL of water was added to the resulting reaction mixture, 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 purified by silica gel column chromatography to obtain intermediate 28a. MS m / z: 436.2 [M+H] + .

[0302] Step 2: Synthesis of intermediate 28b Intermediate 28a (101 mg, 0.19 mmol) and dichloromethane (3 mL) were placed in a 50 mL one-neck flask at 25°C, and 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 give Intermediate 28b. MS m / z: 336.0 [M+H-100] + .

[0303] Step 3: Synthesis of intermediate 28c Intermediate 28b (76 mg, 0.23 mmol) and N'N-dimethylformamide (5 mL) were placed in a 50 mL single-neck flask at room temperature. Under stirring, intermediate 3b (92 mg, 0.29 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (128 mg, 0.34 mmol), and DIEA (108 mg, 0.90 mmol) were sequentially added. The reaction was allowed to proceed at 25 °C for 12 hours. 50 mL of water was added to the resulting reaction mixture, 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 the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 28c. MS m / z: 629.2 [MH-100] + .

[0304] Step 4: Synthesis of compound IV-18 Intermediate 28c (106 mg, 0.17 mmol) and dichloromethane (3 mL) were placed in a 50 mL single-neck flask at 25°C, and trifluoroacetic acid (1 mL) was added 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 separated and purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound IV-18. MS m / z: 531.0[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.20 - 8.18 (m,1H),6.74 - 6.72 (m,1H),6.62 - 6.60(m,1H),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).

[0305] Example 29: Synthesis of Compound IV-19 [ka]

[0306] Step 1: Synthesis of compound IV-19 To a solution of intermediate 17c (170 mg, 0.39 mmol) and intermediate 2a (85 mg, 0.43 mmol) in dichloromethane (6 mL), DIEA (102 mg, 0.79 mmol) and 1-propylphosphonic anhydride (493 mg, 0.77 mmol) were added to obtain a mixture. The mixture was stirred at 25 °C for 12 h. The resulting mixture was poured into HO (15 mL) and extracted with EtOAc (10 mL x 3) to obtain an organic phase. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The obtained crude product was separated and purified by preparative TLC (eluent: PE / EtOAc (V / V) = 3 / 1) to obtain compound IV-19. 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).

[0307] Example 30: Synthesis of Compound IV-20 [ka]

[0308] Step 1: Synthesis of intermediate 30a Intermediate 2a (150 mg, 0.76 mmol) and DMF (5.0 mL) were added to a 100 mL single-neck flask at 25 °C, and then, with stirring, Intermediate 17a (220 mg, 0.92 mmol), 1-propylphosphonic anhydride (970 mg, 1.53 mmol), and DIEA (395 mg, 3.04 mmol) were added sequentially. The reaction was allowed to proceed at 25 °C for 16 h. The resulting reaction solution was poured into 50 mL of water and 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 purified by silica gel column chromatography to obtain Intermediate 30a. MS m / z: 363.0 [M+H-56] + .

[0309] Step 2: Synthesis of intermediate 30b Intermediate 30a (120 mg, 0.29 mmol) and dichloromethane (3 mL) were placed in a 50 mL one-neck flask at 25°C, and 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 give Intermediate 30b. MS m / z: 319.0 [M+H] + .

[0310] Step 3: Synthesis of compound IV-20 Intermediate 30b (89 mg, 0.28 mmol) and DMF (5 mL) were added to a 50 mL single-neck flask at 25 °C. Under stirring, intermediate 2a (65 mg, 0.33 mmol), 1-propylphosphonic anhydride (355 mg, 0.56 mmol, 50% dimethylformamide solution), and DIEA (134 mg, 1.12 mmol) were sequentially added. The reaction was allowed to proceed at 25 °C for 16 h. The resulting reaction solution was poured into 50 mL of water and extracted three times with 50 mL of EtOAc. 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 give the crude product. The crude product was purified by HPLC (formic acid / acetonitrile / water system) to finally give compound IV-20. MS m / z: 497.0[M+H] +. 1 H NMR (400MHz,DMSO-d6) δ 9.05 (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).

[0311] Example 31: Synthesis of Compound IV-16 [ka]

[0312] Step 1: Synthesis of intermediate 31b Intermediate 31a (300 mg, 1.61 mmol) and ethyl acetate (20 mL) were placed in a 100 mL three-neck flask in an ice bath. Silver trifluoromethanesulfonate (1.41 g, 4.83 mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(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 and in the dark. The reaction was carried out at 25 °C for 16 h. The resulting reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain Intermediate 31b. 1 H NMR (400MHz,DMSO-d6) δ 4.62 - 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).

[0313] Step 2: Synthesis of intermediate 31c Intermediate 31b (246 mg, 0.97 mmol) and dichloromethane (3 mL) were placed in a 50 mL one-neck flask at 25°C, and 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 give Intermediate 31c.

[0314] Step 3: Synthesis of intermediate 31d Intermediate 31c (230 mg, 1.07 mmol) and DMF (5 mL) were added to a 50 mL single-neck flask at 25 °C. Under stirring, intermediate 17a (283 mg, 1.18 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (610 mg, 1.60 mmol), and DIEA (556 mg, 4.28 mmol) were sequentially added. The reaction was allowed to proceed at 25 °C for 12 h. 50 mL of water was added to the resulting reaction mixture, which was then 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 a crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 31d. MS m / z: 381.0 [M+H-56] + .

[0315] Step 4: Synthesis of intermediate 31e Intermediate 31d (140 mg, 0.32 mmol) and dichloromethane (3 mL) were placed in a 50 mL one-neck flask at 25°C, and trifluoroacetic acid (1 mL) was added under stirring. The reaction was allowed to proceed at 25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to give Intermediate 31e. MS m / z: 337.0 [M+H] + .

[0316] Step 5: Synthesis of compound IV-16 Intermediate 31e (66 mg, 0.21 mmol) and DMF (5 mL) were added to a 50 mL single-neck flask at 25 °C. Under stirring, intermediate 2a (50 mg, 0.25 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol), and DIEA (109 mg, 0.84 mmol) were sequentially added. The reaction was allowed to proceed at 25 °C for 12 h. 50 mL of water was added to the resulting reaction mixture, 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 purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound IV-16. MS m / z: 515.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.04 (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).

[0317] Example 32: Synthesis of Compound IV-17 [ka]

[0318] Step 1: Synthesis of compound IV-17 Intermediate 31e (106 mg, 0.31 mmol) and DMF (5 mL) were added to a 50 mL single-neck flask at 25 °C. Under stirring, intermediate 1b (74 mg, 0.35 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (78 mg, 0.21 mmol), and DIEA (161 mg, 1.24 mmol) were sequentially added. The reaction was allowed to proceed at 25 °C for 12 h. 50 mL of water was added to the resulting reaction mixture, 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 purified by HPLC (formic acid / acetonitrile / water system) to obtain compound IV-17. MS m / z: 523.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.00 (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),4.35 - 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).

[0319] Example 33: Synthesis of Compound VIII-1 [ka]

[0320] Step 1: Synthesis of compound 33c 33a (11 g, 63.15 mmol) and dichloromethane (36 mL) were added to a single-neck flask at room temperature, and 33b (20 g, 57.41 mmol), acetic acid (1.93 g, 32.15 mmol), and tetraethylene glycol dimethyl ether (40 mL) were added under stirring. The reaction was carried out at 100°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by high-performance column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 33c. 1 H NMR (400MHz,DMSO) δ 6.22 (t,J=1.9Hz,1H),4.13 (m,2H),1.41 (m,2H),1.30 - 1.26 (m,2H),1.22 (t,J=7.1Hz,3H).

[0321] Step 2: Synthesis of compound 33e 33c (2.3 g, 17.57 mmol) and toluene (10 mL) were added to a single-neck flask at room temperature, and 33d (1.0 g, 1.03 mmol) was added under stirring. The reaction was carried out at 130°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by high-performance column chromatography (petroleum ether:ethyl acetate = 100:1 to 7:1) to obtain intermediate 33e. LC-MS: m / z: 269.0 (M+H). + .

[0322] Step 3: Synthesis of compound 33f 33e (2.4 g, 5.36 mmol), potassium fluoride (0.36 g, 8.05 mmol), and methanol (10 mL) were added to a single-neck flask at room temperature, stirred, and reacted for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by high-performance column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 33f. LC-MS: m / z: 197.0 (M+H). + .

[0323] Step 4: Synthesis of compound 33g At room temperature, 33f (877 mg, 1.45 mmol) and methanol (30 mL) were added to a single-neck flask. Acetic acid (80.0 mg, 0.44 mmol) and 2,4-dimethoxybenzylamine (1.76 g, 10.26 mmol) were added under stirring. The mixture was allowed to react at room temperature for two hours. After that, sodium cyanoborohydride (258.03 mg, 6.6 mmol) was added and the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 33g. LC-MS: m / z: 348.0 (M+H). + .

[0324] Step 5: Synthesis of compound 33h In an ice bath, 1b (1 g, 0.4 mmol) and dichloromethane (30 mL) were added to a single-neck flask, and oxalyl chloride (600 mg, 0.4 mmol) 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 (20 mL), and triethylamine (4 mL) and 33g (1.45 g, 4.17 mmol) were added to the reaction solution in an ice bath. The reaction was allowed to react for 2 hours in an ice bath. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance column chromatography (petroleum ether:ethyl acetate = 100:1 to 2:1) to obtain intermediate 33h. LC-MS: m / z: 534.1 (M+H) + .

[0325] Step 6: Synthesis of compound 33i 33h (1.2 g, 2.24 mmol) and dichloromethane (30 mL) were added to a single-neck flask at room temperature, and TFA (15 mL) was added under stirring. The mixture 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 high-performance 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) + .

[0326] Step 7: Synthesis of compound 33j 33i (800 mg, 2.09 mmol), ethanol (20 mL), and water (7 mL) were added to a single-neck flask at room temperature, and lithium hydroxide (160 mg, 4.10 mmol) was added under stirring. The mixture was allowed to react for 3 hours at room temperature. The reaction mixture was adjusted to pH 6 with 1N hydrochloric acid and extracted three times with 20 mL of ethyl acetate. The combined organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give intermediate 33j. LC-MS: m / z: 356.1 (M+H). + .

[0327] Step 8: Synthesis of compound 33k At room temperature, 33j (532 mg, 1.50 mmol) and tetrahydrofuran (20 mL) were added to a single-neck flask, and N,N'-carbonyldiimidazole (2.43 g, 15 mmol) and 80% hydrazine hydrate (1.0 mL) were added under stirring. The reaction was carried out at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance column chromatography (petroleum ether:ethyl acetate = 100:1 to 0:1) to finally obtain intermediate 33k. LC-MS: m / z: 370.1 (M+H). + .

[0328] Step 9: Synthesis of compound 33l At room temperature, 33k (407 mg, 1.1 mmol) and 1,2-dichloroethane (10 mL) were added to a single-neck flask, and N,N'-carbonyldiimidazole (891 mg, 5.5 mmol) was added under stirring. The reaction was carried out 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 high-performance column chromatography (petroleum ether: ethyl acetate = 100:1 to 0:1) to finally obtain compound 33l. LC-MS: m / z: 396.0 (M+H) + .

[0329] Step 10: Synthesis of Compound VIII-1 33K (356 mg, 0.9 mmol) and N,N-dimethylformamide (3.0 mL) were added to a single-neck flask at room temperature. Under stirring, D (132 mg, 0.94 mmol), N,N-diisopropylethylamine (0.19 mL, 1.12 mmol), and Castro condensation agent (166 mg, 0.37 mmol) were added and reacted at room temperature for 18 hours. The reaction mixture 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 finally obtain compound VIII-1. 1 H NMR (400MHz,MeOD) δ 7.38 (t,J=8.7Hz,1H),6.94 (dd,J=11.0,2.7Hz,1H),6.85 - 6.79 (m,1H),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) + .

[0330] Example 34: Synthesis of Compound III-1 [ka]

[0331] Step 1: Synthesis of compound 34b 34a (2.5 g, 9.28 mmol) and ethanol (20 mL) were added to a 100 mL single-neck flask at room temperature. 50% hydrazine hydrate (9.83 g, 139.2 mmol) was added under stirring. The temperature was raised to 80°C and the reaction was allowed to proceed overnight until completion. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by recrystallization from acetonitrile to obtain intermediate 34b (2.1 g, 7.02 mmol). LC-MS: m / z: 214.0 (M+H-56).+ .

[0332] Step 2: Synthesis of compound 34c 34b (2.1 g, 7.80 mmol) and 1,2-dichloroethane (25 mL) were added to a 100 mL single-neck flask at room temperature, and 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, which was then extracted with ethyl acetate. The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified using a column purifier to obtain intermediate 34c (850 mg, 2.59 mmol). LC-MS: m / z: 240 (M+H-56). + .

[0333] Step 3: Synthesis of compound 34e In an ice bath, 34d (611 mg, 3.46 mmol) and dimethylformamide (10.0 mL) were added to a 50 mL single-neck flask. Under stirring, 2-(7-azabenzotriazole)-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. The reaction was allowed to proceed overnight at room temperature. 25 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified using a column purifier to obtain colorless oily intermediate 34e. LC-MS: m / z: 419 (M+H). + .

[0334] Step 4: Synthesis of compound 34f At room temperature, 34e (220 mg, 0.53 mmol) and dichloromethane (8 mL) were added to a 100 mL one-neck flask, and trifluoroacetic acid (3.0 mL) was added under stirring. The reaction was completed after 1 hour at room temperature. The mixture was concentrated under reduced pressure to give crude product 34f. LC-MS: m / z: 319 (M+H)+ is.

[0335] Step 4: Synthesis of compound III-1 In an ice bath, 1b (115 mg, 0.56 mmol) and dimethylformamide (5.0 mL) were added to a 50 mL single-neck flask. Under stirring, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (268 mg, 0.71 mmol) and diisopropylethylamine (245 mg, 1.88 mmol) were sequentially added. After 30 minutes of reaction at room temperature, compound 34f (150 mg, 0.47 mmol) was added to the reaction mixture, and the mixture was allowed to react overnight at room temperature. The reaction mixture was then added with 25 mL of water, extracted with ethyl acetate, washed with 100 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to finally obtain compound III-1. 1 H NMR (400MHz,DMSO-d6) δ 8.30 - 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 - 4.44 (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) + .

[0336] Example 35: Synthesis of Compound VI-1 [ka]

[0337] Step 1: Synthesis of compound 35c In an ice bath, 35a (3 g, 17.83 mmol), zinc-copper reagent (4.6 g, 35.66 mmol), and tetrahydrofuran (50 mL) were added to a single-neck flask, and 35b (6.04 mL, 53.50 mmol) was slowly added dropwise under stirring for 20 minutes. The mixture was then reacted at 35°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 35c.

[0338] Step 2: Synthesis of compound 35d 35c (4.7 g, 16.84 mmol) and acetic acid (10 mL) were added to a single-neck flask at room temperature. Zinc powder (4.4 g, 67.34 mmol) was added under stirring, and the mixture was allowed to react at 100°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance column chromatography (petroleum ether:ethyl acetate = 100:1 to 4:1) to obtain intermediate 35d. LC-MS: m / z: 211.0 (M+H). + .

[0339] Step 3: Synthesis of compound 35e 35d (1 g, 4.76 mmol) and methanol (35 mL) were added to a single-neck flask at room temperature. 2,4-Dimethoxybenzylamine (0.86 mL, 5.71 mmol) was added under stirring. The mixture was allowed to react at room temperature for 16 hours. Sodium cyanoborohydride (597 mg, 9.51 mmol) was then added to the reaction mixture and the mixture was allowed to react at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 35e. LC-MS: m / z: 362.2 (M+H). + .

[0340] Step 4: Synthesis of compound 35f 35e (400 mg, 1.11 mmol) and ethanol (5 mL) were added to a single-neck flask at room temperature, and 80% hydrazine hydrate (5 mL) was added under stirring. The mixture was refluxed for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (aqueous ammonia / acetonitrile / water system) to obtain intermediate 35f (360 mg). LC-MS: m / z: 348.2 (M+H). + .

[0341] Step 5: Synthesis of compound 35g 35f (360 mg, 1.04 mmol) and 1,2-dichloroethane (10 mL) were added to a single-neck flask at room temperature. N,N'-carbonyldiimidazole (252 mg, 1.55 mmol) was added under stirring, and the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was poured into 20 mL of water and extracted three times with 10 mL of dichloromethane. The organic phase was washed with 10 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by high-performance column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 35g. LC-MS: m / z: 374.1 (M+H). + .

[0342] Step 6: Synthesis of compound 35h 35g (70 mg, 0.19 mmol) and N,N-dimethylformamide (3.0 mL) were added to a single-neck flask at room temperature. 34d (132 mg, 0.94 mmol), N,N-diisopropylethylamine (0.19 mL, 1.12 mmol), and Castro 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 mixture was poured into 20 mL of water and extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 30 mL of saturated brine, dried over sodium sulfate, and filtered. 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). + .

[0343] Step 7: Synthesis of compound 35i In an ice bath, 1b (10 mg, 0.04 mmol) and dichloromethane (3.0 mL) were added to a single-neck flask, and oxalyl chloride (6 mg, 0.04 mmol) and one drop of N,N-dimethylformamide were added under stirring. After reacting at room temperature for 30 minutes, triethylamine (12 mg, 0.12 mmol) and 35h (20 mg, 0.04 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for one hour. The reaction mixture was diluted with 20 mL of saturated aqueous ammonium chloride solution and extracted three times with 20 mL of dichloromethane. The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate 35i. The crude product was used directly in the next step without further purification. LC-MS: m / z: 683.2 (M+H). + .

[0344] Step 8: Synthesis of compound VI-1 In an ice bath, 35i (30 mg, 0.04 mmol) and dichloromethane (3.0 mL) were added to a single-neck flask. Trifluoroacetic acid (1.5 mL) was added under stirring, and the mixture was allowed to react at room temperature for 10 minutes. 25 mL of water was added to the reaction mixture, which was then extracted once with 20 mL of dichloromethane. The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to finally obtain compound VI-1. 1H NMR (400MHz,DMSO) δ 8.31 (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) + .

[0345] Example 36: Synthesis of Compound IV-1 [ka]

[0346] Step 1: Synthesis of compound 36a 17c (1.3 g, 3.98 mmol) and tetrahydrofuran (15.0 mL) were added to a single-neck flask at room temperature, and N,N'-carbonyldiimidazole (1.29 g, 7.96 mmol) was added under stirring. After reacting at room temperature for 2 hours, diisopropylethylamine (2.59 g, 19.89 mmol) and 80% hydrazine hydrate (1.59 g, 15.91 mmol) were added sequentially. The temperature was raised to 45°C and the reaction was allowed to proceed overnight. 50 mL of water was added to the reaction mixture, which was then extracted twice with 50 mL of ethyl acetate. 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 product. The crude product was triturated with acetonitrile to obtain intermediate 36a. LC-MS: m / z: 385.2 (M+H). + .

[0347] Step 2: Synthesis of compound 36b In an ice bath, 36a (200 mg, 0.52 mmol), 1,4-dioxane (5.0 mL), and water (0.5 mL) were added to a single-neck flask. Sodium bicarbonate (65 mg, 1.49 mmol) and bromoacetonitrile (60 mg, 0.57 mmol) were added sequentially under stirring. The mixture was allowed to warm to room temperature and react overnight. 25 mL of water was added to the reaction mixture, which was then extracted twice with 20 mL of ethyl acetate. The organic phase was washed with 30 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude compound 36b, which was used directly in the next step without further purification. LC-MS: m / z: 410.2 (M+H). + .

[0348] Step 3: Synthesis of compound 36c 36b (180 mg, 0.44 mmol) and anhydrous acetonitrile (5 mL) were added to a single-neck flask at room temperature. Cuprous bromide (126.0 mg, 0.88 mmol) was added under 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 concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 36c. LC-MS: m / z: 473.1 (M+H). + .

[0349] Step 4: Synthesis of compound VI-1 In an ice bath, 36c (50 mg, 0.11 mmol) and tetrahydrofuran (5.0 mL) were added to a single-neck flask. Under stirring, potassium carbonate (15 mg, 0.11 mmol) and compound B (22 mg, 0.16 mmol) were added sequentially. The temperature was raised to 80°C and the mixture was allowed to react overnight. 25 mL of water was added to the reaction mixture, which was then extracted once with 25 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound IV-1. 1HNMR (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) + .

[0350] It should be noted that other compounds in this application can be prepared by methods analogous to those of the above examples (with appropriate adjustments, e.g., substitution of reaction raw materials, as needed).

[0351] Biological Testing The ATF4 luciferase reporter plasmid consists of two parts: the 5' untranslated region sequence of the ATF4 gene and the luciferase coding sequence. Specifically, the ATF4 5' untranslated region sequence (NCBI database no. BC022088.2) containing two upstream open reading frames (uORFs) and the firefly luciferase coding gene were cloned into the pLVX-Puro vector (Yuba Bio, VT1465). The lentiviral packaging plasmids were psPAX2 (Yuba Bio, VT1444) and pMD2.G (Yuba Bio, VT1443). 650,000 HEK293T cells were seeded 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, the supernatant discarded, and replaced with DMEM complete medium containing 0.8 μg / ml puromycin. The cells were then resuspended and cultured. After one week of screening with puromycin, surviving cells were identified as polyclonal HEK293T-ATF4 uORF-Luc-Puro. 200 polyclonal cells were taken and subjected to gradient dilution in a 96-well plate to obtain monoclonal cells.

[0352] The specific method for monoclonal cell screening is as follows: 200 polyclonal cells were placed in well A1 of a 96-well plate. In step 1, gradient dilution was performed from columns A1 to H1 at a ratio of 1:2. In step 2, gradient dilution was performed from rows A to H at a ratio of 1:2 from wells 1 to 12 in each row. Wells with a theoretical cell count of less than 0.5 were labeled and observed one by one under a microscope. Wells with only one cell were labeled. After two weeks of culture, monoclonal cells were obtained.

[0353] The cell line could be used to detect translational regulation of ATF4 by low-temperature fluorescence readout and to test activation of eIF2B activity by compounds.

[0354] The specific experimental procedure was as follows: 6,000 HEK293T / 17-ATF4 uORF-Luc-Puro monoclonal cells were plated in a 384-well plate and allowed to adhere overnight. Test compounds were 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. The effect of thapsigargin was to induce cell pressure and upregulate ATF4 protein translation. Six hours after administration, the cells were lysed using the One-Glo Luciferase Detection Kit (Promega #E6120), and then the low-temperature fluorescence values were read using the LUM program on the EnVision 2104 reader.

[0355] EC values were calculated based on the fluorescence values at nine 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 was calculated and recorded in Table 1.

[0356] The relative expression level of the ATF4 reporter gene (ATF4 reporter expression) was calculated using the following method. ATF4 reporter expression=(ave_sample-ave_vc) / (ave_pc-ave_vc) where 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. Fitting the dose-effect curve and EC 50 values were calculated.

[0357] The correspondence between the relative expression level of the ATF4 reporter gene and the compound concentration was fitted using the nonlinear regression log(inhibitor) vs. response -- variable slope (four parameters) method in GraphPad 9 software.

[0358] The X-axis represents the log value of the compound concentration, and the Y-axis represents the relative expression level of the ATF4 reporter gene. Formula: Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0359] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0360] "+" indicates ATF4-luc EC 50 indicates that the EC 50 is between 10 nM and 100 nM, and "+++" indicates that the ATF4-luc EC 50 was less than 10 nM.

[0361] Experimental results (some of which are not shown) showed that the compounds of the present application can weaken the fluorescence intensity by increasing eIF2B activity and reducing the expression level of ATF4, and it was revealed that the compounds of the present application can significantly alleviate the cellular pressure caused by thapsigargin, weaken the integrated stress response of cells, and promote the normal synthesis of intracellular proteins.

[0362] 2. Dynamic solubility evaluation Test compounds were dissolved in DMSO to prepare a 10 mM stock solution. 8.71 g of K2HPO4 was added to 500 mL of deionized water to prepare a 100 mM K2HPO4 solution. 2.05 g of potassium dihydrogen phosphate was added to 150 mL of deionized water to prepare a 100 mM potassium dihydrogen phosphate solution. 405 mL of 100 mM K2HPO4 was mixed with 95 mL of 100 mM KH2PO4, and the pH of the mixture was adjusted to 7.4 with the 100 mM K2HPO4 / KH2PO4 solution. 10.41 g of FaSSIF buffer concentrate was added to 240.3 g of deionized water to prepare a buffer solution (simulated intestinal fluid under fasting conditions, pH = 6.5). 4.071 g of FeSSIF buffer concentrate was added to 45.97 g of deionized water to produce a buffer solution (simulated intestinal fluid in the fed state, pH = 5.0).

[0363] Using a 96-well plate, 16 μL of 10 mM compound stock solution was added to 784 μL of different buffer solutions (n=3). The plate was sealed and shaken at 1000 rpm for 1.5 h at 25°C (PBS) or 37°C (other buffers). After incubation, the solution was transferred to a filter board. All samples were filtered. 5 μL of the filtrate was added to 5 μL of DMSO and 490 μL of an aqueous acetonitrile solution containing an internal standard (1:1) and mixed uniformly. Further dilutions were made with an aqueous acetonitrile solution containing an internal standard (1:1) based on the compound's properties and mass spectral response. The dilution factor was varied based on the solubility value and UPLC-MS / MS signal response.

[0364] Experiments have shown that at least some of the compounds of the present application have good solubility in all of the above different simulated environments.

[0365] 3. Cell Membrane Permeability Assessment Test compounds were diluted to a concentration of 10 μM from a 10 mM stock solution in transport buffer (HBSS + BSA) and applied to the apical or basal outer surface of the cell monolayer. After 120 minutes of incubation at 37°C, 5% CO2, and 95% relative humidity, the permeability of the test compounds in the A to B or B to A directions was measured in duplicate. The efflux ratio (Papp B to A / Papp A to B) of each compound was also measured. Quantitative analysis of the analyte and reference compounds was performed using an LC-MS / MS method based on the analyte / IS peak area ratio.

[0366] [Table 2]

[0367] 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.

[0368] 4. Pharmacokinetic evaluation in mice Test compounds were dissolved in vehicle to prepare clear solutions or homogeneous suspensions. Each group consisted of three mice, and the compound was administered intravenously at 1 mg / kg (IV) or orally at 30 mg / kg (PO). Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration. Plasma samples were centrifuged, and the supernatant was collected and quantitatively analyzed by LC / MS / MS.

[0369] [Table 3]

[0370] Experimental results show that at least some of the compounds of the present application (e.g., III-1) have excellent pharmacokinetic properties in mice (C0 (initial drug concentration), CL (clearance), AUC, t1 / 2 (half-life), C max (peak concentration), T max(time to peak), AUC (area under the drug concentration-time curve), F (bioavailability), Vss (apparent volume of distribution at steady state), etc.

[0371] The technical solution of the present invention is not limited to the specific embodiments described above, and all technical modifications made based on the technical solution of the present invention are within the protection scope of the present invention.

Claims

1. A compound of 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 isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, 【Chemical 1】 Ring A and ring C are each independently a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl-D-C1-C6 alkyl group, a 5- to 10-membered heteroaryl-D-C1-C6 alkyl group, a C3-C9 cycloalkyl-D-C1-C6 alkyl group, or a 3- to 9-membered heterocyclyl-D-C1-C6 alkyl group, wherein the alkyl group is optionally substituted with deuterium, halogen, or a C1-C6 alkyl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group each optionally contain 1 to 5 R １ may be substituted with Each of the R １ are each independently hydrogen, deuterium, halogen, a hydroxy group, a phenyl group, a cyano group, a C1-C10 alkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group, a C1-C6 alkoxy group substituted with a halogen, a C1-C6 alkoxy-C1-C6 alkenyl group substituted with a halogen, a C1-C6 alkyl group substituted with an amino group, a C1-C6 alkyl group substituted with a cyano group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy-C3-C6 cycloalkyl group, a C1-C3 alkoxy-3 to 6-membered heterocyclyl group, 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) ２ R １Ｄ , -G １ , -O-G １ , -NR １Ｂ -G １ and is selected from the group consisting of: or two R on adjacent atoms １ The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ and R １ the phenyl group, the C1-C10 alkyl group, the C1-C6 alkoxy group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C1-C6 alkyl group, the C3-C6 cycloalkyl group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C3-C6 cycloalkyl group, and the C1-C3 alkoxy group in the C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted by halogen; Each of the R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ , R １Ｅ are each independently selected from the group consisting of hydrogen, deuterium, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a 3- to 9-membered heterocyclyl group substituted with a halogen, and a C1-C6 alkoxy group substituted with a halogen; R １Ｂ , R １Ｃ and the atoms to which they are jointly linked can form a 3- to 7-membered heterocyclyl group, which can optionally contain 1 to 3 R １Ｆ is replaced by Each of the G １ are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; １ each optionally containing 1 to 3 R １Ｆ is replaced by L １ is empty, -NH-, 【Chemistry 2】 where: 【Chemistry 3】 The end is linked to the A ring, the * end is linked to the B ring, Preferably, the L １ is empty, -NH-, 【Chemistry 4】 and Preferably, the L １ Is, empty, 【Chemistry 5】 and Preferably, the L １ Is, empty, 【Chemistry 6】 and Preferably, the L １ Is, empty, 【Chemistry 7】 and Preferably, the L １ Is, empty, 【Chemistry 8】 and Ring B is a 5- to 10-membered spiro ring or a 5- to 10-membered spiro hetero ring, and the 5- to 10-membered spiro ring and the 5- to 10-membered spiro hetero ring optionally contain 1 to 5 R １Ｆ is replaced by Each of the R １Ｆ are each independently hydrogen, deuterium, halogen, a hydroxy group, an amino group, a cyano group, a carboxyl group, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a C1-C6 alkenyl group substituted with a halogen, a C1-C6 alkoxy-C1-C6 alkenyl group substituted with a halogen, a C1-C6 alkyl group substituted with an amino group, a C1-C6 alkyl group substituted with a cyano group, 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) ２ R １Ｄ and is selected from the group consisting of: L ２ is empty, -NH-, 【Chemistry 9】 where: 【Chemistry 10】 The * terminus is linked to the B ring and the * terminus is linked to the C ring; Preferably, the L ２ is empty, -NH-, 【Chemistry 11】 and Preferably, the L ２ Is, empty, 【Chemistry 12】 and Preferably, the L ２ Is, empty, 【Chemistry 13】 and Preferably, the L ２ Is, empty, 【Chemistry 14】 and Preferably, the L ２ is empty or 【Chemistry 15】 and Each D is independently a linking group containing a hetero atom, and preferably, each D is independently O or NR ｄ or S and R ｄ are each independently selected from hydrogen, deuterium, a C1-C6 alkyl group, and a C1-C6 alkyl group substituted with halogen, and more preferably, each D is independently O or NH.

2. The A ring is a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl-D-C1-C6 alkyl group, a 5- to 10-membered heteroaryl-D-C1-C6 alkyl group, or a 3- to 9-membered heterocyclyl-D-C1-C6 alkyl group, wherein the alkyl group is optionally substituted with a halogen or a C1-C6 alkyl group, and the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group each optionally contain 1 to 5 R １ may be substituted with Each of the R １ are each independently hydrogen, halogen, cyano group, C1-C10 alkyl group, C1-C6 alkyl group substituted with a hydroxy group, C1-C6 alkyl group substituted with a halogen, C1-C6 alkoxy group, C1-C6 alkoxy group substituted with a halogen, C1-C6 alkoxy-C1-C6 alkenyl group substituted with a halogen, C1-C6 alkyl group substituted with an amino group, C1-C6 alkyl group substituted with a cyano group, 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) ２ R １Ｄ , -G １ , -O-G １ , -NR １Ｂ -G １ or two R on adjacent atoms １ The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ is replaced by Each of the R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ , R １Ｅ are each independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a 3- to 9-membered heterocyclyl group substituted with a halogen, and a C1-C6 alkoxy group substituted with a halogen; １Ｂ , R １Ｃ and the atoms to which they are jointly linked can form a 3- to 7-membered heterocyclyl group, which can optionally contain 1 to 3 R １Ｆ is replaced by Each of the G １ are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; １ each optionally containing 1 to 3 R １Ｆ is replaced by Each of the R １Ｆ are each independently hydrogen, halogen, a hydroxy group, an amino group, a cyano group, a carboxyl group, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a C1-C6 alkenyl group substituted with a halogen, a C1-C6 alkoxy-C1-C6 alkenyl group substituted with a halogen, a C1-C6 alkyl group substituted with an amino group, a C1-C6 alkyl group substituted with a cyano group, 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) ２ R １Ｄ and is selected from the group consisting of: The C ring is a 6- to 10-membered aryl-E-C1-C6 alkyl group, a C3-C9 cycloalkyl-E-C1-C6 alkyl group, a 3- to 9-membered heterocyclyl-E-C1-C6 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R ２ and each R ２ are each independently selected from the group consisting of hydrogen, deuterium, halogen, a hydroxy group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy-C3-C6 cycloalkyl group, and a C1-C3 alkoxy-3- to 6-membered heterocyclyl group, wherein R ２ The phenyl group, the C1-C6 alkyl group, the C1-C6 alkoxy group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C1-C6 alkyl group, the C3-C6 cycloalkyl group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C3-C6 cycloalkyl group, and the C1-C3 alkoxy group in the C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted with halogen or two R ２ The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a 5- to 6-membered aryl group (e.g., a phenyl group), or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ is replaced by The D and E are each independently a linking group containing a hetero atom, and preferably, the D and E are each independently O or NR ｄ or S and R ｄ are each independently selected from hydrogen, deuterium, and a C1-C3 alkyl group, and more preferably, D and E are each independently O or NH. The compound according to claim 1, 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.

3. The A ring is a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl-D-C1-C6 alkyl group, or a 3- to 9-membered heterocyclyl-D-C1-C6 alkyl group, wherein the heterocyclyl group, aryl group, and heteroaryl group each optionally contain 1 to 5 R １ may be substituted with Each of the R １ are each independently hydrogen, halogen, a C1-C6 alkyl group substituted with halogen, a C1-C6 alkoxy group substituted with halogen, -OR １Ａ , -NR １Ｂ R １Ｃ , -NR １Ｂ C(O)R １Ｄ , —C(O)NR １Ｂ R １Ｃ , -C(O)R １Ｄ , -G １ , -O-G １ , -NR １Ｂ -G １ or two R on adjacent atoms １ The groups and the atoms to which they are attached can form a 6- to 10-membered aryl group or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ is replaced by Each of the R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ are each independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a 3- to 9-membered heterocyclyl group substituted with a halogen, and a C1-C6 alkoxy group substituted with a halogen; １Ｂ , R １Ｃ and the atoms to which they are jointly linked can form a 3- to 7-membered heterocyclyl group, which can optionally contain 1 to 3 R １Ｆ is replaced by Each of the G １ are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, and a 6- to 10-membered aryl group; １ each optionally containing 1 to 3 R １Ｆ is substituted with G １ is a phenyl group, optionally, said phenyl group and the 3- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R １Ｆ are each independently hydrogen, halogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a C1-C6 alkenyl group substituted with a halogen, 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) ２ R １Ｄ 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, of the compound according to claim 1 or 2, which is selected from any one of the group consisting of:

4. Ring A is a 4- to 9-membered heterocyclyl group, a 5- to 7-membered heteroaryl group, a phenyl-D-C1-C6 alkyl group, or a 4- to 9-membered heterocyclyl-D-C1-C6 alkyl group, wherein the heterocyclyl group, heteroaryl group, and phenyl group each optionally contain 1 to 5 R １ may be substituted with Each of the R １ are each independently hydrogen, halogen, a C1-C6 alkyl group substituted with halogen, a C1-C6 alkoxy group substituted with halogen, -OR １Ａ , -NR １Ｂ R １Ｃ , -NR １Ｂ C(O)R １Ｄ , —C(O)NR １Ｂ R １Ｃ , -G １ , O-G １ , -NR １Ｂ -G １ and is selected from the group consisting of: Each of the R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ are each independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C4-C9 cycloalkyl group, a 4- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with a halogen, a C4-C9 cycloalkyl group substituted with a halogen, a 4- to 9-membered heterocyclyl group substituted with a halogen, and a C1-C6 alkoxy group substituted with a halogen; R １Ｂ , R １Ｃ and the atoms to which they are jointly linked can form a 3- to 7-membered heterocyclyl group, which can optionally contain 1 to 3 R １Ｆ is replaced by Each of the G １ are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, and a phenyl group; １ each optionally containing 1 to 3 R １Ｆ is substituted with G １ is a phenyl group, optionally, said phenyl group and the 3- to 9-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R １Ｆ are each independently hydrogen, halogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a C1-C6 alkenyl group substituted with a halogen, oxo, -OR １Ａ , -NR １Ｂ R １Ｃ , -P(O)R １Ｂ R １Ｃ , -S(O) ２ R １Ｄ 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, of the compound according to any one of claims 1 to 3, which is selected from any one of the group consisting of

5. The A ring is a 4- to 8-membered heterocyclyl group, a 5- to 6-membered heteroaryl group, a phenyl-D-C1-C3 alkyl group, or a 4- to 8-membered heterocyclyl-D-C1-C3 alkyl group, wherein the heterocyclyl group, heteroaryl group, and phenyl group each optionally contain 1 to 2 R １ may be substituted with Each of the R １ are each independently hydrogen, halogen, a C1-C3 alkyl group substituted with halogen, a C1-C3 alkoxy group substituted with halogen, -OR １Ａ , -NR １Ｂ R １Ｃ , -NR Ｂ C(O)R １Ｄ , —C(O)NR １Ｂ R １Ｃ , -G １ , O-G １ , -NR １Ｂ -G １ and is selected from the group consisting of: Each of the R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G １ are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; preferably, the C3-C6 cycloalkyl group is a cyclobutanyl group or a cyclopentanyl group; the 3- to 6-membered heterocyclyl group is an oxetanyl group, an azetidinyl group, an oxacyclopentanyl group, or an azacyclopentanyl group; and each of the G １ each optionally containing 1 to 3 R １Ｆ is substituted with G １ is a phenyl group, optionally, said phenyl group and the 5- to 6-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R １Ｆ are each independently hydrogen, halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C3-C6 cycloalkyl group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR １Ａ , -NR １Ｂ R １Ｃ , -P(O)R １Ｂ R １Ｃ , -S(O) ２ R １Ｄ 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, of the compound according to any one of claims 1 to 4, which is selected from any one of the group consisting of

6. The ring A is a 5- to 6-membered heterocyclyl group, preferably 【Chemistry 16】 or preferably, 【Chemistry 17】 and Preferably, the R １ The number n is 1, 2 or 3, Preferably, the R １ are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a C1-C3 alkyl group, and a phenyl group, and R １ is a phenyl group, the phenyl group and the 3- to 6-membered heterocyclyl group share two carbon atoms to form a fused ring, and preferably 【Chemistry 18】 means that two carbon atoms are shared to form a fused ring, and the phenyl group is optionally substituted with halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, or a C1-C3 haloalkoxy group; More preferably, the phenyl group and 【Chemistry 19】 The condensation method with 【Chemistry 20】 wherein the phenyl group is optionally substituted with a halogen; Alternatively, the A ring is a 5- to 6-membered heteroaryl group, preferably （１） 【Chemical 21】 And 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, and preferably the R １ is hydrogen, -OR １Ａ , -NR １Ｂ R １Ｃ , -G １ , -O-G １ , -NR １Ｂ -G １ and each R １Ａ , R １Ｂ , R １Ｃ are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G １ are each independently selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; １ each optionally containing 1 to 3 R １Ｆ is replaced by Each of the R １Ｆ are each independently hydrogen, halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group substituted with halogen, a C1-C3 alkoxy group substituted with halogen, a C1-C3 alkenyl group substituted with halogen, oxo, -OR １Ａ , -NR １Ｂ R １Ｃ , -P(O)R １Ｂ R １Ｃ , -S(O) ２ R １Ｄ wherein R １Ｄ is selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; or 【Chemical 22】 wherein the A ring is a 5-membered heteroaryl group, and H １ , H ２ , H ３ , H ４ are each independently selected from CH, N, O, and S; 【Chemical 23】 is a single bond or a double bond, and the R １ are each independently -OR １Ａ , -NR １Ｂ R １Ｃ , -G １ , -O-G １ , -NR １Ｂ -G １ and each R １Ａ , R １Ｂ , R １Ｃ are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C3 alkyl group substituted with halogen, a C1-C3 alkoxy-C1-C6 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; １ are each independently selected from a C4-C6 cycloalkyl group and a 4- to 9-membered heterocyclyl group, and each of said G １ each optionally containing 1 to 3 R １Ｆ and each R １Ｆ are each independently hydrogen, halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group substituted with halogen, a C1-C3 alkoxy group substituted with halogen, a C1-C3 alkenyl group substituted with halogen, oxo, -OR １Ａ , -NR １Ｂ R １Ｃ , -P(O)R １Ｂ R １Ｃ , -S(O) ２ R １Ｄ wherein R １Ｄ is selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Preferably, the A ring is 【Chemistry 24】 and More preferably, the L １ But it is empty, Preferably, the R １ But, -OR １Ａ , -G １ , -O-G １ , -NR １Ｂ -G １ and R １Ａ is selected from halogen-substituted C1-C3 alkoxy-C1-C3 alkyl groups; R １Ｂ is selected from H, a C1-C3 alkyl group, and each R １Ｆ each independently represents a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -P(O)R １Ｂ R １Ｃ , -S(O) ２ R １Ｄ and R １Ｂ , R １Ｃ , R １Ｄ are each independently selected from the group consisting of hydrogen and a C1-C3 alkyl group; （２） 【Chemistry 25】 And, Preferably, each R １ is independently selected from any one of hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, and benzene; and R １ is a phenyl group, 【Chemical 26】 and share two carbon atoms to form a fused ring, and the phenyl group is optionally substituted with halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, or a C1-C3 haloalkoxy group; More preferably, the phenyl group is optionally substituted with halogen, and the R １ The number m is 1 or 2; （３） 【Chemical 27】 And, Preferably, the R １ is hydrogen, halogen or a phenyl group, said phenyl group being optionally substituted with one or more halogens, and said R １ The number m is 1 or 2, and R １ is a phenyl group, optionally 【Chemical Formula 28】 and share two carbon atoms to form a fused ring, More preferably, the R １ is a phenyl group, m is 1, and 【Chemical Formula 29】 The condensation method with 【Chemistry 30】 wherein the phenyl group is optionally substituted with one or more halogens; Or, the A ring is a phenyl-O—C1-C3 alkyl group, and the phenyl group optionally contains one or two R １ and each R １ are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Preferably, the A ring is a phenyl-O-methyl group, and R １ is H or a halogen, Or, the A ring is a 4-8 membered heterocyclyl-O-C1-C3 alkyl group, the heterocyclyl group optionally containing 1-3 R １ and each R １ are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Preferably, the A ring is a 4- to 7-membered heterocyclyl-O-methyl group, and R １ is a C1-C3 alkyl group substituted with halogen, or a C1-C3 alkoxy group substituted with halogen, Or, the A ring is a C3-C7 cycloalkyl-O—C1-C3 alkyl group, and the C3-C7 cycloalkyl group optionally contains 1 to 3 R １ and each R １ are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Preferably, the A ring is a C4-C6 cycloalkyl-O-methyl group, and R １ is a C1-C3 alkyl group substituted with halogen, or a C1-C3 alkoxy group substituted with halogen, Or, the A ring is a phenyl group, and the phenyl group is substituted with one selected from a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, and a C1-C6 haloalkoxy group; Preferably, the phenyl group is substituted with one selected from halogen, C1-C3 alkyl group, C1-C3 alkoxy group, C1-C3 haloalkyl group, C1-C3 haloalkoxy group; More preferably, the phenyl group is substituted with a C1-C3 haloalkyl group; Preferably, the A ring is （１） 【Chemical 31】 And, Preferably, the R １ But, -G １ , O-G １ , -NR １Ｂ -G １ Preferably, each G １ each optionally containing one or two R １Ｆ and R １Ｂ is selected from the group consisting of hydrogen, C1-C3 alkyl groups, and each of the G １ are each independently selected from a C3-C6 cycloalkyl group and a 4- to 9-membered heterocyclyl group; More preferably, the C3-C6 cycloalkyl group is a cyclobutanyl group or a cyclopentanyl group, and the 4- to 9-membered heterocyclyl group is preferably an oxacycloalkyl group or an N-heterocycloalkyl group, more preferably an oxetanyl group, an azetidinyl group, an oxacyclopentanyl group, or an azacyclopentanyl group. 【Chemical 32】 and more preferably an oxetanyl group, an azetidinyl group, an oxacyclopentanyl group, an azacyclopentanyl group, or even more preferably 【Chemical 33】 and Each of the R １Ｆ are each independently selected from the group consisting of oxo, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen, and １ is preferably empty, (2) A 4- to 8-membered heterocyclyl-O—C1-C3 alkyl group, wherein the heterocyclyl group optionally contains one or two R １ and each R １ are each independently selected from the group consisting of a C1-C3 alkyl group substituted with halogen and a C1-C3 alkoxy group substituted with halogen; (3) A C4-C6 cycloalkyl-O—C1-C3 alkyl group, wherein the C4-C6 cycloalkyl group optionally contains one or two R １ and each R １ are each independently selected from the group consisting of a C1-C3 alkyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a polymorph thereof, a solvate thereof, a hydrate thereof, an N-oxide thereof, an isotope-labeled compound thereof, a metabolite thereof, an ester thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

7. The A ring is 【Chemical 34】 【Chemistry 35】 and is selected from any one of the groups Preferably, the A ring is 【Chemical 36】 and is selected from any one of the groups Preferably, the A ring is 【Chemical 37】 and is selected from any one of the groups Preferably, the A ring is 【Chemical Formula 38】 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,

8. the spiro ring is selected from the group consisting of a spiro[2,5]octanyl ring, a spiro[3,4]octanyl ring, a spiro[3,3]heptanyl ring, a spiro[3,5]nonanyl ring, a spiro[4,5]decanyl ring, a spiro[2,2]pentanyl ring, a spiro[2,3]hexanyl ring, a spiro[2,4]heptanyl ring, a spiro[2,6]nonanyl ring, a spiro[2,7]nonanyl ring, a spiro[3,6]nonanyl ring, and a spiro[4,4]nonanyl ring; the spiro heterocycle is a group formed after one or more carbon atoms in the spiro ring are replaced with heteroatoms, and the number of heteroatoms in the spiro heterocycle is 1, 2, or 3; Preferably, the heteroatom in the spiroheterocycle is nitrogen or a combination of nitrogen and oxygen; Preferably, the substituent R of the spiro ring or the spiro heterocycle is １Ｆ is hydrogen, halogen, a hydroxy group, an amino group, a cyano group, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, or a C1-C6 alkoxy group substituted with a halogen, More preferably, the substituent R of the spiro ring or the spiro heterocycle is １Ｆ is a halogen, a hydroxy group, or an amino group, Most preferably, the substituent R of said spiro ring or said spiro heterocycle is １Ｆ is a hydroxy group, 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.

9. the ring B is a 7- to 9-membered spiro ring or a 7- to 9-membered spiro hetero ring, Preferably, the spiro ring is selected from any one of a spiro[2,5]octanyl ring, a spiro[3,4]octanyl ring, a spiro[3,3]heptanyl ring, and a spiro[3,5]nonanyl ring; the 7- to 9-membered spiro heterocycle is a group formed after one or more carbon atoms in the 7- to 9-membered spiro ring are substituted with heteroatoms, and the number of heteroatoms in the spiro heterocycle is 1, 2, or 3; Preferably, the heteroatom in the spiroheterocycle is nitrogen or a combination of nitrogen and oxygen; Preferably, the B ring is 【Chemical 39】 and is selected from any one of the groups where: 【Chemistry 40】 The end is L １ and the * end is L ２ is connected to Preferably, the B ring is 【Chemistry 41】 and is selected from any one of the groups More preferably, the B ring is 【Chemistry 42】 and is selected from any one of the groups More preferably, the B ring is 【Chemistry 43】 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,

10. The C ring is a 6- to 10-membered aryl-E-C1-C3 alkyl group, a C4-C9 cycloalkyl-E-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl-E-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R ２ and each R ２ are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a phenyl group, a C1-C3 alkyl group, and a C1-C3 alkoxy group, ２ The phenyl group, C1-C3 alkyl group, and C1-C3 alkoxy group as options are each optionally substituted with halogen or two R ２ The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ and R ２ is a phenyl group, optionally, said phenyl group and the 4- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring; Each E is independently a linking group containing a heteroatom, Preferably, each E is independently O or NR ｄ or S and R ｄ are each independently selected from hydrogen, deuterium, and a C1-C3 alkyl group; More preferably, each E is independently O or NH. The compound according to any one of claims 1 to 9, 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.

11. The C ring is a phenyl-E-C1-C3 alkyl group, and the phenyl group is selected from 1, 2, or 3 R ２ wherein E is a linking group containing a heteroatom; Preferably, E is O or NR ｄ or S and R ｄ is selected from hydrogen, deuterium, and a C1-C3 alkyl group; Preferably, E is O or NH, Preferably, each of the R ２ are each independently a halogen; Preferably, the C ring is a phenyl-O—C1-C3 alkyl group; Alternatively, the C ring is a C4-C9 cycloalkyl-E-C1-C3 alkyl group or a 4- to 9-membered heterocyclyl-E-C1-C3 alkyl group, and the cycloalkyl group or heterocyclyl group is R ２ and E is O or NR ｄ or S and R ｄ is selected from hydrogen, deuterium, and a C1-C3 alkyl group, and said R ２ is hydrogen, halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, or a C1-C3 haloalkoxy group, Preferably, the cycloalkyl is a cyclopropyl, cyclobutyl or cyclopentyl group; Preferably, the heterocyclyl group is an oxiranyl group, an oxetanyl group, an oxacyclopentanyl group, an aziridinyl group, an azetidinyl group, or an azacyclopentanyl group; Preferably, E is O or NH, Alternatively, the C ring is a 4- to 9-membered heterocyclyl group, preferably a 5- to 6-membered heterocyclyl group, and preferably the C ring is 【Chemical 44】 and R ２ The number n is 1, 2, or 3, Preferably, each of the R ２ are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a phenyl group, a halophenyl group, and a hydroxy group, ２ is a phenyl group or a halophenyl group, optionally 【Chemistry 45】 means that two carbon atoms are shared to form a fused ring, and preferably, the fused ring is 【Chemistry 46】 and Preferably, the C ring is 【Chemistry 47】 and R ２ The number n is 1, 2, or 3, Preferably, each of the R ２ are each independently selected from the group consisting of hydrogen, halogen, a C1-C3 alkyl group, a phenyl group, and a halophenyl group, ２ is a substituent on the N atom, ２ is any one of the group consisting of hydrogen, halogen, and C1-C3 alkyl groups, ２ is a phenyl group or a halophenyl group, optionally, the phenyl group or the halophenyl group and the morpholine ring group share two carbon atoms to form a fused ring, and preferably, the fused ring is 【Chemistry 48】 and Preferably, the C ring is 【Chemistry 49】 and R ２ The number n is 1, 2, or 3, Preferably, each of the R ２ are each independently selected from the group consisting of halogen, phenyl, halophenyl, and hydroxy groups, ２ is a phenyl group or a halophenyl group, optionally with said phenyl group or said halophenyl group 【Chemistry 50】 means that two carbon atoms are shared to form a fused ring, and preferably, the fused ring is 【Chemistry 51】 and Alternatively, the C ring is a 5- to 10-membered heteroaryl group, and preferably, the C ring is （１） 【Chemistry 52】 And, Preferably, each R ２ are independently selected from any one of hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, phenyl, and halophenyl groups; ２ The number p of R is 1 or 2, and ２ is a phenyl group or a halophenyl group, 【Chemistry 53】 and form a fused ring by sharing two carbon atoms, and preferably, the fused ring is 【Chemical 54】 and （２） 【Chemistry 55】 And, Preferably, the R ２ is selected from the group consisting of hydrogen, halogen, phenyl group, C1-C3 alkyl group, and C1-C3 alkoxy-C3-C6 cycloalkyl group, wherein the phenyl group, the alkyl group, and the alkoxy group are unsubstituted or substituted with halogen, and R ２ is a phenyl group, optionally 【Chemical Formula 56】 and share two carbon atoms to form a fused ring, and preferably, the fused ring is 【Chemical 57】 or the C ring is a phenyl group, and the phenyl group is any one of R ２ and preferably, the R ２ is selected from the group consisting of a C1-C3 haloalkyl group and a C1-C3 haloalkoxy group, or a stereoisomer thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a polymorph thereof, a solvate thereof, a hydrate thereof, an N-oxide thereof, an isotope-labeled compound thereof, a metabolite thereof, an ester thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

12. The C ring is 【Chemistry 58】 【Chemical Formula 59】 and is selected from any one of the groups Preferably, the C ring is 【Chemistry 60】 and is selected from any one of the groups Preferably, the C ring is 【Hua 61】 and is selected from any one of the groups Preferably, the C ring is 【Hua 62】 and is selected from any one of the groups Preferably, the C ring is 【Chemistry 63】 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,

13. The compound has the structure shown in Formula I: 【Hua 64】 Preferably, Ring A is a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl-D-C1-C6 alkyl group, or a 5- to 10-membered heteroaryl-D-C1-C6 alkyl group, wherein the heterocyclyl group, aryl group, and heteroaryl group each optionally contain 1 to 5 R １ may be substituted with Each of the R １ are each independently a halogen, a C1-C10 alkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, -G １ , -O-G １ or two R on adjacent atoms １ The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ１ is replaced by Each of the G １ are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; １ each optionally containing 1 to 3 R １Ｆ１ is replaced by Each of the R １Ｆ１ , R １Ｆ２ are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, an amino group, a cyano group, a carboxyl group, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a hydroxy group, a C1-C6 alkyl group substituted with a halogen, and a C1-C6 alkoxy group substituted with a halogen, and preferably, each of the R １Ｆ２ are each independently selected from hydrogen, halogen, a hydroxy group, and an amino group; L ２ is empty, -NH-, 【Chemistry 65】 where: 【Hua 66】 The terminal is linked to the B ring and the * terminal is linked to the C ring, preferably 【Chemical 67】 The termini are as in Formula I 【Chemistry 68】 is linked to an N atom in Preferably, the L ２ is empty, -NH-, 【Chemical Formula 69】 and Preferably, the L ２ Is, empty, 【Chemistry 70】 and Preferably, the L ２ Is, empty, 【Chemical Formula 71】 and Preferably, the L ２ teeth, 【Chemical 72】 and Preferably, the L ２ Is, empty, 【Chemical 73】 and Ring C is a 6- to 10-membered aryl-E-C1-C6 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, and heterocyclyl group each optionally contain 1 to 3 R ２ and each R ２ are each independently selected from the group consisting of halogen, hydroxy, phenyl, C1-C6 alkyl, C1-C6 alkoxy, and C1-C3 alkoxy-C1-C6 alkyl groups, ２ The phenyl group, the C1-C6 alkyl group, the C1-C6 alkoxy group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C1-C6 alkyl group, the C3-C6 cycloalkyl group, and the C1-C3 alkoxy group in the C1-C3 alkoxy-C3-C6 cycloalkyl group are each optionally substituted with halogen, and R ２ is a phenyl group, optionally, said phenyl group and the 3- to 9-membered heterocyclyl group or the 6- to 10-membered heteroaryl group share two carbon atoms to form a fused ring; The D and E are each independently a linking group containing a hetero atom, and preferably, the D and E are each independently O or NR ｄ or S and R ｄ are each independently selected from hydrogen, deuterium, a C1-C6 alkyl group, and a C1-C6 alkyl group substituted with halogen, and more preferably, D and E are each independently O or NH. The compound according to any one of claims 1 to 12, or a stereoisomer thereof, a tautomer thereof, a geometric isomer thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a polymorph thereof, a solvate thereof, a hydrate thereof, an N-oxide thereof, an isotopically labeled compound thereof, a metabolite thereof, an ester thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

14. The compound has the structure shown in Formula II or Formula III: 【Chemical 74】 Preferably, Each of the A rings is independently a 5- to 7-membered heteroaryl group, a phenyl-D-C1-C6 alkyl group, or a 3- to 9-membered heterocyclyl group, wherein the heteroaryl group and the phenyl group each optionally contain one or two R １ may be substituted with Each of the R １ are each independently a halogen, a C1-C6 alkyl group substituted with a halogen, a C1-C6 alkoxy group substituted with a halogen, -OR １Ａ , -NR １Ｂ R １Ｃ , -G １ , O-G １ , -NR １Ｂ -G １ and is selected from the group consisting of: Each of the R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ are each independently selected from the group consisting of hydrogen, a C1-C6 alkyl group, a C4-C9 cycloalkyl group, a 4- to 9-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C4-C9 cycloalkyl group substituted with halogen, a 4- to 9-membered heterocyclyl group substituted with halogen, and a C1-C6 alkoxy group substituted with halogen; Each of the G １ are each independently selected from a C3-C9 cycloalkyl group, a 3- to 9-membered heterocyclyl group, and a phenyl group; １ each optionally containing 1 to 3 R １Ｆ１ is substituted with G １ is a phenyl group, optionally, said phenyl group and the 3- to 9-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R １Ｆ１ are each independently a halogen, a C1-C6 alkyl group, a C3-C9 cycloalkyl group, a C1-C6 alkyl group substituted with a halogen, a C3-C9 cycloalkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C1-C6 alkenyl group substituted with a halogen, oxo, -OR １Ａ , -NR １Ｂ R １Ｃ , -P(O)R １Ｂ R １Ｃ , -S(O) ２ R １Ｄ and is selected from the group consisting of: L １ is empty, -NH-, 【Chemistry 75】 where: 【Chemical 76】 The terminal is connected to the A ring and the * terminal is connected to the B ring, and preferably the * terminal is 【Chemical 77】 & C atoms in formula III 【Chemical 78】 is connected to the &C atom in Preferably, the L １ is empty, -NH-, 【Chemical Formula 79】 and Preferably, the L １ Is, empty, 【Chemistry 80】 and Preferably, the L １ Is, empty, 【Chemistry 81】 and More preferably, the L １ is empty or 【Chemistry 82】 and L ２ is empty, -NH-, 【Chemistry 83】 where: 【Chemistry 84】 The terminal is linked to the B ring and the * terminal is linked to the C ring, preferably 【Chemistry 85】 The terminus is in Formula II 【Chemistry 86】 the N atom in formula III 【Hua 87】 is connected to the @C atom in Preferably, the L ２ is empty, -NH-, 【Hua 88】 and Preferably, the L ２ Is, empty, 【Chemistry 89】 and Preferably, the L in formula II ２ teeth, 【Chemistry 90】 and more preferably, 【Chemistry 91】 and Preferably, the L in formula III ２ Is, empty, 【Chemistry 92】 and more preferably, empty or 【Chemistry 93】 and Each of the R １Ｆ２ are independently selected from hydrogen, halogen, a hydroxy group, and an amino group, and preferably, each R １Ｆ２ are independently selected from hydrogen and a hydroxy group; The C ring is selected from a 6- to 10-membered aryl-E-C1-C3 alkyl group, a C4-C9 cycloalkyl-E-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl-E-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R ２ and each R ２ are each independently selected from the group consisting of hydrogen, halogen, a hydroxy group, a phenyl group, a C1-C3 alkyl group, and a C1-C3 alkoxy group, ２ The phenyl group, C1-C3 alkyl group, and C1-C3 alkoxy group as options are each optionally substituted with halogen or two R ２ The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ is substituted with R ２ is a phenyl group, optionally, said phenyl group and the 4- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring; Each E is independently a linking group containing a heteroatom, and preferably each E is independently O or NR ｄ or S and R ｄ are each independently selected from hydrogen, deuterium, and a C1-C3 alkyl group, and more preferably, each E is independently O or NH. The compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

15. The compound has the structure shown in Formula IV: 【Chemistry 94】 Preferably, The A ring is a 4- to 8-membered heterocyclyl group, a 5- to 7-membered heteroaryl group, a phenyl-O—C1-C6 alkyl group, or a C4-C8 cycloalkyl-O—C1-C6 alkyl group, wherein the heterocyclyl group, heteroaryl group, phenyl group, and cycloalkyl group each optionally contain 1 to 2 R １ may be substituted with Each of the R １ are each independently a halogen, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, -OR １Ａ , -NR １Ｂ R １Ｃ , -G １ , O-G １ , -NR １Ｂ -G １ and is selected from the group consisting of: Each of the R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G １ are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; １ each optionally containing 1 to 3 R １Ｆ１ is substituted with G １ is a phenyl group, optionally, said phenyl group and the 5- to 6-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R １Ｆ１ are each independently a halogen, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C3-C6 cycloalkyl group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR １Ａ , -NR １Ｂ R １Ｃ , -P(O)R １Ｂ R １Ｃ , -S(O) ２ R １Ｄ and is selected from the group consisting of: Each of the R １Ｆ２ are independently selected from hydrogen, halogen, a hydroxy group, and an amino group, and preferably, each R １Ｆ２ are independently selected from hydrogen and a hydroxy group; L １ is empty, -NH-, 【Chemistry 95】 where: 【Chemistry 96】 The * terminus is linked to the A ring and the * terminus is linked to the B ring, preferably the * terminus is 【Chemistry 97】 is linked to the N atom of Preferably, the L １ is empty, -NH-, 【Chemistry 98】 and Preferably, the L １ Is, empty, 【Hua99】 and Preferably, the L １ Is, empty, 【Chemistry 100】 and L ２ is empty, -NH-, 【Chemistry 101】 where: 【Chemistry 102】 The terminal is linked to the B ring and the * terminal is linked to the C ring, preferably 【Chemistry 103】 The terminus is represented by Formula IV 【Chemistry 104】 is connected to the @C atom of Preferably, the L ２ is empty, -NH-, 【Chemistry 105】 and Preferably, the L ２ Is, empty, 【Chemistry 106】 and More preferably, the L ２ teeth, 【Chemistry 107】 and The C ring is a 6- to 10-membered aryl-O-C1-C3 alkyl group, a C4-C9 cycloalkyl-O-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl-O-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R ２ and each R ２ are each independently selected from the group consisting of halogen, hydroxy, phenyl, C1-C3 alkyl, and C1-C3 alkoxy groups, ２ Each of the options of phenyl group, C1-C3 alkyl group, and C1-C3 alkoxy group is optionally substituted with halogen or two R ２ The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ１ is substituted with R ２ is a phenyl group, optionally, the phenyl group and the 4- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring, 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.

16. The compound has the structure shown in Formula V: 【Chemistry 108】 Preferably, The A ring is a 4- to 8-membered heterocyclyl group, a 5- to 7-membered heteroaryl group, or a phenyl-O-C1-C6 alkyl group, wherein the heterocyclyl group, heteroaryl group, and phenyl group each optionally contain 1 to 2 R １ may be substituted with Each of the R １ are each independently a halogen, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, -OR １Ａ , -NR １Ｂ R １Ｃ , -G １ , O-G １ , -NR １Ｂ -G １ and is selected from the group consisting of: Each of the R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G １ are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; １ each optionally containing 1 to 3 R １Ｆ１ is substituted with G １ is a phenyl group, optionally, said phenyl group and the 5- to 6-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R １Ｆ１ are each independently a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C3-C6 cycloalkyl group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR １Ａ , -NR １Ｂ R １Ｃ , -P(O)R １Ｂ R １Ｃ , -S(O) ２ R １Ｄ and is selected from the group consisting of: L １ is empty, -NH-, 【Chemistry 109】 where: 【Chemistry 110】 The terminal is connected to the A ring and the * terminal is connected to the B ring, and preferably the * terminal is 【Chemistry 111】 is linked to the N atom of Preferably, the L １ is empty, -NH-, 【Chemistry 112】 and Preferably, the L １ Is, empty, 【Chemistry 113】 and Preferably, the L １ teeth, 【Chemistry 114】 and Each R １Ｆ２ are independently selected from hydrogen, halogen, a hydroxy group, and an amino group; Preferably, each of the R １Ｆ２ are independently selected from hydrogen and a hydroxy group; L ２ is empty, -NH-, 【Chemistry 115】 where: 【Chemistry 116】 The terminal is linked to the B ring and the * terminal is linked to the C ring, preferably 【Chemistry 117】 The terminus is in formula V 【Chemistry 118】 is connected to the @C atom of Preferably, the L ２ is empty, -NH-, 【Chemistry 119】 and Preferably, the L ２ Is, empty, 【Chemistry 120】 and Preferably, the L ２ teeth, 【Chemistry 121】 and The C ring is a 6- to 10-membered aryl-O-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl-O-C1-C3 alkyl group, a 4- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R ２ and each R ２ are each independently selected from the group consisting of halogen, hydroxy, phenyl, C1-C3 alkyl, and C1-C3 alkoxy groups, ２ The phenyl group, C1-C3 alkyl group, and C1-C3 alkoxy group as options are each optionally substituted with halogen or two R ２ The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ１ is substituted with R ２ is a phenyl group, optionally, the phenyl group and the 4- to 9-membered heterocyclyl group or the 5- to 10-membered heteroaryl group share two carbon atoms to form a fused ring, 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.

17. The compounds have the structure shown in Formula VI, Formula VII, Formula VIII, Formula IX, 【Chemical 122】 Preferably, The A ring is a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, a 6- to 10-membered aryl-D-C1-C6 alkyl group, a 5- to 10-membered heteroaryl-D-C1-C6 alkyl group, or a 3- to 9-membered heterocyclyl-D-C1-C6 alkyl group, wherein the heterocyclyl group, heteroaryl group, and aryl group optionally contain 1 to 5 R １ may be substituted with Each of the R １ are each independently a halogen, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, -OR １Ａ , -NR １Ｂ R １Ｃ , -G １ , O-G １ , -NR １Ｂ -G １ and is selected from the group consisting of: Each of the R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ are each independently selected from the group consisting of hydrogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclyl group, a C1-C6 alkyl group substituted with halogen, a C3-C6 cycloalkyl group substituted with halogen, a 4- to 6-membered heterocyclyl group substituted with halogen, and a C1-C3 alkoxy group substituted with halogen; Each of the G １ are each independently selected from a C3-C6 cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a phenyl group; １ each optionally containing 1 to 3 R １Ｆ１ is substituted with G １ is a phenyl group, optionally, said phenyl group and the 5- to 6-membered heterocyclyl group or the 5- to 7-membered heteroaryl group share two carbon atoms to form a fused ring; Each of the R １Ｆ１ are each independently a halogen, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkyl group substituted with a halogen, a C1-C3 alkoxy group substituted with a halogen, a C3-C6 cycloalkyl group substituted with a halogen, a C1-C3 alkenyl group substituted with a halogen, oxo, -OR １Ａ , -NR １Ｂ R １Ｃ , -P(O)R １Ｂ R １Ｃ , -S(O) ２ R １Ｄ and is selected from the group consisting of: More preferably, the A ring is a 5- to 7-membered heteroaryl group, and the heteroaryl group is a 5- to 7-membered heteroaryl group having 1 to 2 R １ may be substituted with L １ is empty, -NH-, 【Chemical 123】 where: 【Chemical 124】 The terminal is connected to the A ring and the * terminal is connected to the B ring, and preferably the * terminal is 【Chemistry 125】 & C atoms in formula VII 【126】 & C atoms in formula VIII 【Chemistry 127】 & C atoms in formula IX 【128】 is connected to the &C atom of Preferably, the L １ is empty, -NH-, 【129】 and Preferably, the L １ Is, empty, 【Chemistry 130】 and L ２ is empty, -NH-, 【Chemistry 131】 where: 【Chemistry 132】 The terminal is linked to the B ring and the * terminal is linked to the C ring, preferably 【Chemistry 133】 The terminus is in Formula VI 【Chemistry 134】 @C atom of formula VII 【Chemistry 135】 @C atom of formula VIII 【Chemistry 136】 @C atom of formula IX 【Chemistry 137】 is connected to the @C atom of Preferably, the L ２ is empty, -NH-, 【Chemistry 138】 and Preferably, the L ２ Is, empty, 【Chemistry 139】 and Each of the R １Ｆ２ are independently selected from hydrogen, halogen, a hydroxy group, an amino group, and a carboxyl group; Preferably, each of the R １Ｆ２ are independently selected from hydrogen and a hydroxy group; The C ring is a 6- to 10-membered aryl-E-C1-C6 alkyl group, a C3-C9 cycloalkyl-E-C1-C6 alkyl group, a 3- to 9-membered heterocyclyl-E-C1-C6 alkyl group, a 3- to 9-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, and heterocyclyl group each optionally contain 1 to 3 R ２ and each R ２ are each independently selected from the group consisting of hydrogen, deuterium, halogen, a hydroxy group, a phenyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C3 alkoxy-C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy-C3-C6 cycloalkyl group, and a C1-C3 alkoxy-3- to 6-membered heterocyclyl group, wherein R ２ The phenyl group, the C1-C6 alkyl group, the C1-C6 alkoxy group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C1-C6 alkyl group, the C3-C6 cycloalkyl group, the C1-C3 alkoxy group in the C1-C3 alkoxy-C3-C6 cycloalkyl group, and the C1-C3 alkoxy group in the C1-C3 alkoxy-3-6 membered heterocyclyl group are each optionally substituted with halogen or two R ２ The groups and the atoms to which they are attached can form a C3-C7 cycloalkyl group, a 3- to 7-membered heterocyclyl group, a phenyl group, or a 5- to 6-membered heteroaryl group, each of which optionally contains 1 to 5 R １Ｆ is replaced by The D and E are each independently a linking group containing a hetero atom, and preferably, the D and E are each independently O or NR ｄ or S and R ｄ are each independently selected from hydrogen, deuterium, and a C1-C3 alkyl group, and more preferably, D and E are each independently O or NH. The compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

18. The compound is specifically 【Chemistry 140】 【Chemistry 141】 【Chemistry 142】 【143】 【Chemical 144】 【Chemistry 145】 【Chemistry 146】 【147】 【148】 【149】 【Chemistry 150】 【Chemistry 151】 【Chemistry 152】 【Chemistry 153】 【Chemistry 154】 【Chemistry 155】 【Chemistry 156】 【Chemistry 157】 【158】 【Chemistry 159】 【Chemistry 160】 【Chemistry 161】 【Chemistry 162】 18. The compound according to any one of claims 1 to 17, wherein:

19. A pharmaceutical composition comprising a formulation made 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 isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

20. 20. The pharmaceutical composition of claim 19, further comprising a pharmaceutically acceptable carrier, excipient, or vehicle.

21. 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 manufacture of a medicament for the prevention and / or treatment of 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 an inducible mutation that leads to an unfolded protein response (UPR), 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 manufacture of a medicament for preventing and / or treating a disease or condition mediated by the integrated stress response (ISR) pathway.

23. 21. A method of treating a disease or condition mediated by the integrated stress response (ISR) pathway in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a 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 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 of claim 19 or 20.

24. A method for treating a disease associated with modulation of eIF2B activity or levels, eIF2 pathway or ISR pathway activity or levels, comprising administering to a subject a therapeutically effective amount of a 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 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 of claim 19 or 20.

25. 21. A method for preventing and / or treating a disease or condition mediated by the 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. 21. 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 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.

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