Compounds, pharmaceutical compositions containing same, and methods for their synthesis and use

Abstract

The present application provides a compound represented by Formula 0, a pharmaceutical composition containing the same, and a method for synthesizing and using the same. The compound of the present application significantly suppresses the cellular integrated stress response (ISR), activates eIF2B activity, and normalizes intracellular protein synthesis, providing more potential drugs for integrated stress response (ISR) pathway-mediated diseases or conditions, eIF2B-related diseases, and / or diseases associated with modulation of eIF2B activity or levels, the eIF2 pathway, or the ISR pathway activity or levels. TIFF2025539152000388.tif40108

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to Chinese Invention Patent Application No. 202211455519.X, filed November 21, 2022, and Chinese Invention Patent Application No. 202310731972.7, filed June 19, 2023, the contents of which are incorporated herein by reference in their entireties. The present invention relates to compounds, pharmaceutical compositions containing same, and methods for their synthesis and use. [Background technology]

[0002] Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is an irreversible, fatal motor neuron disease. Its primary symptoms are progressive muscle weakness and atrophy of the limbs and trunk, leading to gradual loss of motor function and the appearance of "frozenness," hence the nickname "gradually frozen man." Most ALS patients die of respiratory failure, usually within three to five years after initial onset. Currently, there is no cure for ALS, nor are there any effective treatments to halt or reverse disease progression. Key pathological findings of ALS include the death of motor neurons in the motor cortex and spinal cord, and degeneration of corticospinal axons, resulting in thinning and scarring (sclerosis) of the lateral spinal cord.

[0003] Many of the most common neurodegenerative diseases are characterized by a loss of protein folding homeostasis. 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 either initiate gene expression programs to restore protein homeostasis or promote neuronal death when stress is chronic or excessive. This function of the UPR has been suggested to play an important role in ALS.

[0004] The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that helps cells, tissues, and organisms adapt to fluctuating 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 the synthesis of new proteins, ISR inhibition can enhance long-term memory formation, whereas ISR activation hinders it. Age-related cognitive impairment is commonly associated with ISR activation.

[0005] 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 the phosphorylation of eIF2-P, PKR, PERK, and GCN2 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. In particular, ISR activation causes cognitive impairment in traumatic brain injury, aging, and mouse models of Alzheimer's disease.

[0006] eukaryotic translation initiation factor 2B (eIF2B) is a key enzyme regulating protein synthesis and a 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 suppress the integrated stress response (ISR).

[0007] In addition, the eIF2B agonists ABBV-CLS-7262 (AbbVie / Calico) and DNL-343 (Denali Therapeutics) are both indicated for ALS and are both in phase I clinical trials. Of these, data from a phase I clinical trial of DNL-343 in healthy subjects has been published, demonstrating its safety and tolerability.

[0008] Numerous animal studies have demonstrated that the eIF2B agonist ISRIB can enhance long-term memory in mouse models. Brain function in model animals can be restored to youthful levels after three days of oral administration of the eIF2B agonist ABBV-CLS-7262. Such drugs may be able to suppress some neurodegenerative diseases in their later stages, potentially offering potential for treating diseases such as Alzheimer's and Parkinson's. Summary of the Invention

[0009] The present application provides compounds, pharmaceutical compositions containing the same, and methods for synthesizing and using the same, thereby providing compounds that can significantly suppress the cellular integrated stress response (ISR), activate eIF2B activity, and normalize intracellular protein synthesis, thereby providing more potential drugs for integrated stress response (ISR) pathway-mediated diseases or conditions, eIF2B-related diseases, and / or diseases associated with modulation of eIF2B activity or levels, the activity or levels of the eIF2 pathway, or the ISR pathway.

[0010] In a first aspect of the present application, a compound of formula 0 [ka] or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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, During the ceremony, Ring A is selected from C3-C10 cycloalkylene or 3- to 10-membered heterocycloalkylene, and ring A is [ka] Instead, the * end is connected to L, [ka] the end is connected to ring B, and n3 is an integer of 0 to 5; Ring B is selected from 5- to 10-membered heteroarylenes, and n4 is any integer from 0 to 4; Ring C is a 3- to 10-membered heterocycloalkylene, a C3-C10 cycloalkylene, or B -X 21 -C3-C12 cycloalkylene-$ R1 Selected from X 21 Ha-NR 3 or -C(O)NR 3 and # B - is a bond connected to ring B, and -$ R1 is R 1 is a connecting bond connected to each R 3 are each independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and when ring C is C3-C10 cycloalkylene, ring A is [ka] and is not cyclohexylene, the * end is connected to L, [ka] The end is connected to the B ring, and n5 is an integer from 0 to 5. Ring D is selected from C6-C10 arylene, 5-10 membered heteroarylene, C3-C10 cycloalkylene, or 3-10 heterocycloalkylene; L is # D -L 1 -L 2 -L 3 -$ A or 5-6 membered heteroaryl, and L 1 is a bond, -O-, -S- or -NR 4 - and L 2 is a bond, substituted or unsubstituted C1-C10 alkylene, and L 3 is -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A and X10 is O or S, and R 4 and R 5 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; R 4 and R 5 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 11 and L 1 is linked to the D ring, and L 3 is connected to the A ring, and # D - is a connecting bond connected to the D ring, -$ A is a connecting bond connected to ring A, R 1 , R 2 , R 9a , R 9b , R 9c are each independently a substituent R 11 and Each R 11 are each independently halogen, cyano, nitro, carbonyl, =O, -OR 6 , -SR 6 , SF5, -NR 6 R 7 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 ,OC(O)R 6 , -C(O)NR 6 R 7 , -C(O)ONR 6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R6 , -S(O) 1-2 NR 6 , N.R. 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , -P(O)R 6 R 7 or -NR 6 C(O)OR 7 Selected from among R 9a , R 9b , R 9c , R 11 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 12 may be substituted with Each R 6 , R 7 and R 8 are each independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , -S(O) 1-2 R 20 , -S(O) 1-2 NR 20 Selected from among R 6 , R 7 and R 8 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 13 or R 6 , R 7 and R8 two of which together with a common atom form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogen atoms, or C1-C10 alkyl optionally substituted with 1 to 6 carbonyl, halogen, hydroxy, or amino atoms; Each R 12 and each R 13 are each independently H, halogen, cyano, nitro, carbonyl, =O, or -OR 30 , -SR 30 , SF5, NR 30 R 31 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 ,OC(O)R 30 , -C(O)NR 30 R 31 , -C(O)ONR 30 R 31 , -NR 30 C(O)NR 30 R 31 , -S(O) 1-2 R 30 , -S(O) 1-2 NR 30 , N.R. 30 S(O) 1-2 R 31 , -NR 30 S(O) 1-2 NR 30 R 31 , -NR 30 C(O)R 31 or -NR 30 C(O)OR 31 Among them, R 12 and R 13each of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as the substituents may independently be substituted with 1 to 6 halogen atoms, or may be substituted with C1-C10 alkyl optionally substituted with 1 to 6 carbonyl, halogen, hydroxy, or amino; Each R 20 and R 21 are each independently selected from H or C1-C10 alkyl optionally substituted with 1 to 6 carbonyl, halogen, hydroxy, or amino; R 20 and R 21 together with a common atom form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogen atoms, or with C1-C10 alkyl optionally substituted with 1 to 6 carbonyl, halogen, hydroxy, or amino atoms; Each R 30 and R 31 are each independently selected from H or C1-C10 alkyl optionally substituted with 1 to 6 carbonyl, halogen, hydroxy, or amino; R 30 and R 31 together with a common atom form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogen atoms, or with C1-C10 alkyl optionally substituted with 1 to 6 carbonyl, halogen, hydroxy, or amino atoms; n1 and n2 each independently represent any integer from 0 to 4. Provided is 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 non-enantiomer 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.

[0011] It should be noted that the present application 2 ) n2 -D ring-LA ring-B ring-C ring-(R 1 ) n1 is the main chain structure, and all of the rings A, B, C, and D in formula 0 are described as divalent groups. However, a person skilled in the art would understand that the valences of the rings A, B, C, and D also change adaptively according to the rules for changing chemical valences as the substituents change. Taking ring A as an example, when n3 is 0, ring A is a divalent ring, and when n3 is not 0, ring A is R 9a The ring D may be understood to be selected from trivalent and higher polyvalent rings depending on the valence and number of atoms, and the same applies to the ring B. For example, when n2 is 0, the ring D may be understood to be a monovalent ring, and when n2 is not 0, the ring D may be understood to be a monovalent ring. 2 It may be understood that the ring is selected from divalent and higher polyvalent rings depending on the valence and number of atoms. For example, when n1 and n5 are 0, the ring C may be understood as a monovalent ring, and when one of n1 and n5 is 0, the ring C may be understood as a monovalent ring. 9c and R 2 may be understood to be selected from divalent and higher polyvalent rings depending on the valence and number of n1 and n5, and when neither n1 nor n5 is 0, the C ring is R 9c and R 2 It may be understood that the rings are selected from trivalent and higher polyvalent rings depending on the valence and number of atoms. The above descriptions of ring A, ring B, ring C and ring D apply throughout the present specification.

[0012] In some embodiments, the compound is as shown in Formula 0, wherein: Ring A is selected from C3-C10 cycloalkylene or 3- to 10-membered heterocycloalkylene, and ring A is [ka] where the * end is connected to L, [ka] the end is connected to ring B, and n3 is an integer of 0 to 5; Ring B is selected from 5- to 10-membered heteroarylenes, and n4 is any integer from 0 to 4; Ring C is a 3- to 10-membered heterocycloalkylene, a C3-C10 cycloalkylene, or B -X 21 -C3-C12 cycloalkylene-$ R1 Selected from X 21 Ha-NR 3 or -C(O)NR 3 and # B - is a bond connected to ring B, and -$ R1 is R 1 is a connecting bond connected to each R 3 are each independently H, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and when ring C is C3-C10 cycloalkylene, ring A is not cyclohexylene, and n5 is any integer from 0 to 5; Ring D is selected from C6-C10 arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocycloalkylene; L is # D -L 1 -L 2 -L 3 -$ A , 5-6 membered heteroaryl or # D -NR 14 C(O)-C1-C6 alkylene-O-$ A and L 1 is a bond, -O-, -S- or -NR 4 - and L 2 is a bond, substituted or unsubstituted C1-C10 alkylene, and L 3 is -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A and X 10 is O or S, and R 4 , R 5 and R 14are each independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; R 4 , R 5 and R 14 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 11 may be replaced by # D - is a connecting bond connected to the D ring, -$ A is a connecting bond connected to ring A, R 1 , R 2 , R 9a , R 9b , R 9c are each independently a substituent R 11 and Each R 11 are each independently deuterium, halogen, cyano, nitro, =O, -OR 6 , -SR 6 , SF5, -NR 6 R 7 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 ,OC(O)R 6 , -C(O)NR 6 R 7 , -C(O)ONR 6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , N.R. 6 S(O) 1-2 R7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , -P(O)R 6 R 7 or -NR 6 C(O)OR 7 Selected from among R 9a , R 9b , R 9c , R 11 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 12 may be substituted with Each R 6 , R 7 and R 8 are each independently H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , -S(O) 1-2 R 20 , -S(O) 1-2 NR 20 Selected from among R 6 , R 7 and R 8 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 13 or R 6 and R 7together with the atom to which they are simultaneously attached form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy, or amino, or R 7 and R 8 together with the atom to which they are simultaneously attached form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy or amino; Each R 12 and each R 13 are each independently H, deuterium, halogen, cyano, nitro, =O, -OR 30 , -SR 30 , SF5, NR 30 R 31 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 ,OC(O)R 30 , -C(O)NR 30 R 31 , -C(O)ONR 30 R 31 , -NR 30 C(O)NR 30 R 31 , -S(O) 1-2 R 30 , -S(O) 1-2 NR 30 , N.R. 30 S(O) 1-2 R 31 , -NR 30 S(O) 1-2 NR 30 R 31 , -NR 30 C(O)R 31 or -NR 30 C(O)OR 31 Among them, R12 and R 13 each of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as the substituents may independently be substituted with 1 to 6 halogen atoms, or may be substituted with C1-C10 alkyl optionally substituted with 1 to 6 halogen atoms, hydroxy, or amino; Each R 20 and R 21 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; or R 20 and R 21 together with the atom to which they are simultaneously attached form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy or amino; Each R 30 and R 31 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; or R 30 and R 31 together with the atom to which they are simultaneously attached form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy or amino; n1 and n2 each independently represent any integer from 0 to 4.

[0013] In some embodiments, the compound is as shown in Formula 0, wherein: Ring A is selected from C3-C10 cycloalkylene or 3- to 10-membered heterocycloalkylene, and ring A is [ka] where the * end is connected to L, [ka] the end is connected to ring B, and n3 is an integer of 0 to 5; Ring B is selected from 5- to 10-membered heteroarylenes, and n4 is any integer from 0 to 4; Ring C is a 3- to 10-membered heterocycloalkylene, a C3-C10 cycloalkylene, or B -X 21 -C3-C12 cycloalkylene-$ R1 Selected from X 21 Ha-NR 3 or -C(O)NR 3 and # B - is a bond connected to ring B, and -$ R1 is R 1 is a connecting bond connected to each R 3 are each independently H, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and when ring C is C3-C10 cycloalkylene, ring A is not cyclohexylene, and ring A is [ka] If * is connected to L, [ka] the end is connected to ring B, ring C is a 3- to 10-membered heterocycloalkylene, and n5 is any integer from 0 to 5; Ring D is selected from C6-C10 arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocycloalkylene; L is # D -L 1 -L 2 -L 3 -$ A , 5-6 membered heteroaryl or # D -NR 14 C(O)-C1-C6 alkylene-O-$ Aand L 1 is a bond, -O-, -S- or -NR 4 - and L 2 is a bond, substituted or unsubstituted C1-C10 alkylene, and L 3 is -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A and X 10 is O or S, and R 4 , R 5 and R 14 are each independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; R 4 , R 5 and R 14 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 11 may be replaced by # D - is a connecting bond connected to the D ring, -$ A is a connecting bond connected to ring A, R 1 , R 2 , R 9a , R 9b , R 9c are each independently a substituent R 11 and Each R 11 are each independently deuterium, halogen, cyano, nitro, =O, -OR 6 , -SR 6 , SF5, -NR 6 R 7 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR6 ,OC(O)R 6 , -C(O)NR 6 R 7 , -C(O)ONR 6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , N.R. 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , -P(O)R 6 R 7 or -NR 6 C(O)OR 7 Selected from among R 9a , R 9b , R 9c , R 11 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 12 may be substituted with Each R 6 , R 7 and R 8 are each independently H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , -S(O) 1-2 R 20 , -S(O) 1-2 NR 20 Selected from among R 6 , R 7 and R 8C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 13 or R 6 and R 7 together with the atom to which they are simultaneously attached form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy, or amino, or R 7 and R 8 together with the atom to which they are simultaneously attached form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy or amino; Each R 12 and each R 13 are each independently H, deuterium, halogen, cyano, nitro, =O, -OR 30 , -SR 30 , -SF5, NR 30 R 31 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 ,OC(O)R 30 , -C(O)NR 30 R 31 , -C(O)ONR 30 R 31 , -NR 30 C(O)NR 30 R 31 , -S(O) 1-2 R 30 , -S(O) 1-2 NR 30 , -NR30 S(O) 1-2 R 31 , -NR 30 S(O) 1-2 NR 30 R 31 , -NR 30 C(O)R 31 or -NR 30 C(O)OR 31 Among them, R 12 and R 13 each of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as the substituents may independently be substituted with 1 to 6 halogen atoms, or may be substituted with C1-C10 alkyl optionally substituted with 1 to 6 halogen atoms, hydroxy, or amino; Each R 20 and R 21 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; or R 20 and R 21 together with the atom to which they are simultaneously attached form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy or amino; Each R 30 and R 31 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; or R 30 and R 31 together with the atom to which they are simultaneously attached form a heterocycloalkyl, and the heterocycloalkyl is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy or amino; n1 and n2 each independently represent any integer from 0 to 4.

[0014] Preferably, the compound of formula 0 is [ka] It is not any of the compounds.

[0015] Preferably, the above solution comprises: [ka] or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

[0016] The compounds of the present application can significantly suppress the cellular integrated stress response (ISR), activate eIF2B activity, and normalize intracellular protein synthesis.

[0017] In some embodiments, n4 is 0, 1, 2, or 3; Preferably, each of said R 9b are each independently halogen, cyano, nitro, carbonyl, —OH, or C1-C3 alkyl, and more preferably each of the R 9b are each independently halogen, cyano, nitro, —OH, or C1-C3 alkyl; More preferably, the R 9b are each independently halogen, —OH, methyl, ethyl, or propyl; More preferably, n4 is 0.

[0018] Preferably, the B ring is [ka] is selected from More preferably, the B ring is [ka] where X is selected from 7 is O or S, and X 8 , X 9 , X 10 are each independently CH or N, and the * end is connected to the C ring; [ka] The end is connected to the A ring, More preferably, X 8 , X 9 , X 10 At most two of them are N, More preferably, X 8 , X 9 , X 10 One of them is N.

[0019] In some embodiments, the B ring is: [ka] is any one selected from the group consisting of:

[0020] In some embodiments, the B ring is: [ka] is any one selected from the group consisting of:

[0021] In some embodiments, the B ring is: [ka] is any one selected from the group consisting of:

[0022] In some embodiments, the B ring is: [ka] is any one selected from the group consisting of:

[0023] In some embodiments, the B ring is [ka] is.

[0024] In some embodiments, the compound has a structure according to general formula I: [ka] In the formula, A ring, C ring, D ring, L, R 1 , R 2 , R 9a , R 9c , n2, n2, n3, and n5 are as defined in any of the above embodiments, and X 7 is O or S. Or, A ring, D ring, L, R 1 , R 2 , R 9a , R 9c , n2, n2, n3, and n5 are as defined in any of the above embodiments, and X 7 is O or S.

[0025] Preferably, n1 and n2 are each independently an integer of 1 to 3, More preferably, n1 is 1 and n2 is an integer of 1-3.

[0026] In some embodiments, each R 9c are each independently halogen, cyano, nitro, carbonyl, ═O, —OH, or —NR 30 R 31 , C1-C3 alkyl, -C(O)R 30 , -C(O)OR 30 and preferably each R 9c are each independently halogen, cyano, nitro, ═O, —OH, or —NR 30 R 31 , C1-C3 alkyl, -C(O)R 30, -C(O)OR 30 and each R 30 and R 31 are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; Preferably, the C ring has one or two R 9c and preferably each of the R 9c are each independently halogen, cyano, nitro, carbonyl, —OH, or C1-C3 alkyl, and more preferably each of said R 9c are each independently halogen, cyano, nitro, —OH, or C1-C3 alkyl; More preferably, the R 9c are each independently halogen, —OH, methyl, ethyl, or propyl; More preferably, the R 9c are each independently F or methyl.

[0027] Preferably, n5 is 0, 1 or 2; More preferably, n5 is 0 or 1.

[0028] Preferably, the 3- to 10-membered heterocycloalkylene of the ring C is [ka] where X is selected from 11 , X 23 are N or B, and X 12 is CH2, NH, O or S, q is an integer of 0 to 3, preferably q is 1 or 2, and X 13 is N or B, s is an integer of 1 to 3, preferably s is 1 or 2, and X 14 is O, S or NH, t is an integer of 1 to 3, preferably t is 1 or 2, and the * end is connected to the B ring; [ka] The edge is R 1 It is connected to Preferably, the 3- to 10-membered heterocycloalkylene of the ring C is [ka] where X is selected from 11 is N or B, and X 12 is CH2, NH, O or S, q is 0 to 3, preferably q is 1 or 2, and X 13 is N or B, s is an integer of 1 to 3, preferably s is 1 or 2, and X 14 is O, S or NH, t is an integer of 1 to 3, preferably t is 1 or 2, More preferably, the 3- to 10-membered heterocycloalkylene of the ring C is [ka] is selected from.

[0029] Preferably, the C ring # B -X 21 -C3-C12 cycloalkylene-$ R1 teeth [ka] where R 3 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, p is an integer of 1 to 3, preferably 1 or 2, B - is a bond connected to ring B, and -$ R1 is R 1 and the * end is connected to ring B, [ka] The edge is R 1 It is connected to More preferably, # of the C ring B -X 21 -C3-C12 cycloalkylene-$ R1 teeth [ka] is.

[0030] In some embodiments, the C ring is: [ka] and the * end is connected to the B ring; [ka] The edge is R 1 is linked to.

[0031] In some embodiments, the C ring is: [ka] is selected from.

[0032] In some embodiments, the C ring is: [ka] is selected from.

[0033] In some embodiments, the C ring is [ka] and each q, p, s, and t is independently 1 or 2.

[0034] In some embodiments, the [ka] teeth, [ka] and the * end is connected to the B ring; [ka] The edge is R 1 is linked to.

[0035] In some embodiments, the [ka] teeth, [ka] and the * end is connected to the B ring; [ka] The edge is R 1 is linked to.

[0036] In some embodiments, the [ka] teeth, [ka] and the * end is connected to the B ring; [ka] The edge is R 1 is linked to.

[0037] In some embodiments, the [ka] teeth, [ka] and the * end is connected to the B ring; [ka] The edge is R 1 is linked to.

[0038] In some embodiments, the [ka] teeth [ka] and the * end is connected to the B ring; [ka] The edge is R 1 is linked to.

[0039] In some embodiments, each R 1 are each independently R 11 and each R 1 are each independently R 11 and each R 11 are each independently halogen, cyano, nitro, carbonyl, =O, -OR 6 , -SR 6 , -NR 6 R 7 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 , -S(O) 1-2 R 6 , -P(O)R 6 R 7 Preferably, each R 11 are each independently halogen, cyano, nitro, =O, -OR 6 , -SR 6 , -NR 6 R 7 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 , -S(O) 1-2 R 6 , -P(O)R 6 R 7 Selected from among R11 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl as each independently represent 1 to 6 R 12 may be substituted with Each R 6 , R 7 are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, among which R 6 , R 7 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl as each independently represent 1 to 3 R 13 may be substituted with Each R 12 and each R 13 are each independently H, halogen, cyano, nitro, carbonyl, =O, or -OR 30 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and preferably each R 12 and each R 13 are each independently H, halogen, cyano, nitro, =O, -OR 30 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, among which R 12 and R 13 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl as R are each independently optionally substituted with 1 to 3 halogens, or optionally substituted with C1-C3 alkyl substituted with 1 to 3 carbonyls, halogens, hydroxyl, or amino, and are preferably R 12 and R 13each of the C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl and 3-10 membered heterocycloalkyl as the substituents may independently be substituted with 1 to 3 halogen atoms, or may be substituted with C1-C3 alkyl optionally substituted with 1 to 3 halogen atoms, hydroxy or amino; Each R 30 are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 carbonyl, halogen, hydroxy, or amino, and preferably each R 30 are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino.

[0040] In some embodiments, the R 1 -OR 6 , C1-C3 alkyl, halogen, C2-C4 alkenyl, -S(O)2R 6 Or-P(O)R 6 R 7 Preferably, each R 6 , R 7 are each independently selected from H, C1-C3 alkyl, among which R 6 , R 7 C1-C3 alkyl as the 13 and preferably each R 13 are each independently halogen, cyano, or nitro.

[0041] In some embodiments, the R 1 -OR 6 , C1-C3 alkyl, halogen, -S(O)2R 6 Or-P(O)R 6 R 7 Among these, R is preferably 1 C1-C3 alkyl as R 12 and R 12 is halogen, -S(O)R 30 Selected from R 30is selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, and halogenated C3-C6 cycloalkyl; and each R 6 are each independently selected from C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl, among which R 6 C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl as R 13 and R 13 is selected from halogens, and R 7 is selected from C1-C3 alkyl.

[0042] In some embodiments, the R 1 -OCH3, -OCF3, [ka] -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, -CF3, -F, [ka] -OCF=CF2, [ka] is.

[0043] In some embodiments, the R 1 are -OCH3, -OCF3, [ka] -CF2CF3, -CF3, -OCHF2, -OCF2CF3, -OCF2Cl, -CH2CF3, -F, [ka] -OCF=CF2, [ka] is selected from.

[0044] Preferably, the R 1 -OCF3, -CF2CF3, -OCH3, -F, [ka] -CF3, More preferably, the R 1 is selected from -OCF3, -OCF2CF3, More preferably, the R 1 is -OCF3.

[0045] In some embodiments, n1 is preferably 0 or 1.

[0046] In some embodiments, the compound has a structure according to general formula II: [ka] In the formula, A ring, D ring, L, R 2 , R 9a , n2 and n3 are as defined in any of the above embodiments.

[0047] Preferably, the R 1 are -OCH3, -OCF3, [ka] -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, [ka] -OCF=CF2, [ka] and Preferably, the R 1 are -OCH3, -OCF3, [ka] , -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, F, [ka] -OCF=CF2, [ka] is selected from Preferably, the R 1 are -OCH3, -OCF3, [ka] -CF2CF3, -CF3, -OCHF2, -OCF2CF3, -OCF2Cl, -CH2CF3, F, [ka] -OCF=CF2, [ka] is selected from More preferably, the R 1 are -OCH3, -OCF3, [ka] -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, -CF3, [ka] -OCF=CF2, [ka] is selected from More preferably, the R 1 are -OCH3, -OCF3, -CF2CF3, -F, [ka] is selected from More preferably, the R 1are -OCF3, -OCF2CF3, More preferably, the R 1 is -OCF3, preferably n1 is 1, Preferably, n5 is 0, 1 or 2, and each R 9c are each independently halogen, cyano, nitro, carbonyl, —OH, C1-C3 alkyl, and preferably each of said R 9c are each independently halogen, cyano, nitro, —OH, or C1-C3 alkyl; More preferably, the R 9c are each independently halogen, —OH, methyl, ethyl, or propyl; More preferably, the R 9c are each independently F.

[0048] In some embodiments, the compound has a structure according to general formula II-1: [ka] In the formula, A ring, D ring, L, R 2 , R 9a , n2 and n3 are as defined in any of the above embodiments.

[0049] Preferably, n5 is 0 or 1, and preferably n5 is 1, and said R 9c is selected from halogen, cyano, nitro, carbonyl, —OH, C1-C3 alkyl, preferably 9c is selected from halogen, cyano, nitro, —OH, C1-C3 alkyl; More preferably, the R 9c is selected from halogen, methyl or ethyl; More preferably, the R 9c is F.

[0050] Preferably, the [ka] teeth, [ka] is selected from More preferably, [ka] teeth, [ka] is selected from Preferably, n1 is 1, and R 1 are -OCH3, -OCF3, [ka] -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, [ka] -OCF=CF2, [ka] is selected from More preferably, the R 1 are -OCH3, -OCF3, [ka] -CF2CF3, -CF3, -OCHF2, -OCF2Cl, -CH2CF3, -OCF2CF3, [ka] -OCF=CF2, [ka] is selected from More preferably, the R 1 -OCH3, -OCF3, [ka] -OCF2CF3, More preferably, the R 1 is selected from -OCF3, -OCF2CF3, More preferably, the R 1 is -OCF3.

[0051] In some embodiments, n3 is 0, 1, or 2; Preferably, the A ring is selected from C5-C8 cycloalkylene or 5- to 8-membered heterocycloalkylene.

[0052] In some embodiments, the A ring is selected from cyclohexylene or 6-membered heterocycloalkylene.

[0053] In some embodiments, the A ring is cyclohexylene or [ka] and the * end is connected to L, [ka] The end is connected to the B ring.

[0054] In some embodiments, the A ring is [ka] C5-C8 bridged cycloalkylene or 6- to 8-membered bridged heterocycloalkylene, wherein X 1 is CH or N, and X 2 , X 3 , X 4 , X 5 , X 6 are each independently CH, CH, NH, N, or O, and the * end is connected to L; [ka] The end is connected to the B ring.

[0055] In some embodiments, the A ring is: [ka] C-C bridged cycloalkylene or 6- to 8-membered bridged heterocycloalkylene, wherein X 1 is CH or N, and X 2 , X 3 , X 4 , X 5 , X 6 are each independently CH, CH, NH, N, or O, and the * end is connected to L; [ka] The end is connected to the B ring.

[0056] In some embodiments, the [ka] In X 5 is CH2 or O, and X 2 , X 3 , X 4 , X 6 are each independently CH or CH; Preferably, the X 2 , X 3 , X 6 is CH2 and X 4 is CH.

[0057] In some embodiments, the A ring [ka] The C-C bridged cycloalkylene or 6- to 8-membered bridged heterocycloalkylene each independently represents 1 to 4 R 9a and preferably has one or two R 9a is replaced by .

[0058] In some embodiments, the A ring [ka] Each C5-C8 bridged cycloalkylene or 6- to 8-membered bridged heterocycloalkylene independently has 0 to 4 R 9a may be substituted with Preferably, the A ring contains 0, 1 or 2 R 9a is replaced by More preferably, the A ring contains 0 or 1 R 9a is replaced by .

[0059] In some embodiments, the C6-C8 bridged cycloalkylene is [ka] is.

[0060] In some embodiments, the C5-C8 bridged cycloalkylene is [ka] is.

[0061] In some embodiments, the bridged heterocycloalkylene is [ka] is.

[0062] In some embodiments, the bridged heterocycloalkylene is [ka] is.

[0063] In some embodiments, the R 9a are each independently halogen, cyano, nitro, carbonyl, =O, -OR 6 , -SR 6 , SF5, -NR 6 R 7, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 ,OC(O)R 6 , -C(O)NR 6 R 7 , -C(O)ONR 6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , -NR 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 or -NR 6 C(O)OR 7 and preferably, R 9a are each independently halogen, cyano, nitro, =O, -OR 6 , -SR 6 , -SF5, -NR 6 R 7 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 , -OC(O)R 6 , -C(O)NR 6 R 7 , -C(O)ONR 6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR6 , -NR 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 or -NR 6 C(O)OR 7 Among them, R 9a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R 12 may be substituted with Each R 6 , R 7 and R 8 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , -S(O) 1-2 R 20 , -S(O) 1-2 NR 20 Selected from among R 6 , R 7 and R 8 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 4 R 13 may be substituted with Each R 12 , each R 13 are each independently H, halogen, cyano, nitro, carbonyl, =O, or -OR 30 , -SR 30 , SF5, -NR 30 R 31, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 , -OC(O)R 30 , -C(O)NR 30 R 31 , -C(O)ONR 30 R 31 , -NR 30 C(O)NR 30 R 31 , -S(O) 1-2 R 30 , -S(O) 1-2 NR 30 , N.R. 30 S(O) 1-2 R 31 , -NR 30 S(O) 1-2 NR 30 R 31 , -NR 30 C(O)R 31 or -NR 30 C(O)OR 31 and preferably each R 12 , each R 13 are each independently H, halogen, cyano, nitro, =O, -OR 30 , -SR 30 , SF5, -NR 30 R 31 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 , -OC(O)R 30 , -C(O)NR 30 R 31 , -C(O)ONR 30 R 31 , -NR 30 C(O)NR 30 R 31 , -S(O) 1-2 R 30, -S(O) 1-2 NR 30 , -NR 30 S(O) 1-2 R 31 , -NR 30 S(O) 1-2 NR 30 R 31 , -NR 30 C(O)R 31 or -NR 30 C(O)OR 31 Among them, R 12 and R 13 The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as R are each independently optionally substituted with 1 to 6 halogens, or optionally substituted with C1-C6 alkyl substituted with 1 to 6 carbonyls, halogens, hydroxyl, or amino, and are preferably R 12 and R 13 each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as the substituents may independently be substituted with 1 to 6 halogen atoms, or may be substituted with C1-C6 alkyl optionally substituted with 1 to 6 halogen atoms, hydroxy, or amino; Each R 20 and R 21 are each independently selected from H or C1-C6 alkyl optionally substituted with 1 to 6 carbonyl, halogen, hydroxy, or amino, and preferably each R 20 and R 21 are each independently selected from H or C1-C6 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; Each R 30 and R 31 are each independently selected from H or C1-C6 alkyl optionally substituted with 1 to 6 carbonyl, halogen, hydroxy, or amino, and preferably each R 30 and R31 are each independently selected from H or C1-C6 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino.

[0064] In some embodiments, the R 9a are each independently halogen, cyano, nitro, carbonyl, ═O, —OH, or —NR 30 R 31 , C1-C3 alkyl, C1-C3 haloalkyl, -C(O)R 30 , -C(O)OR 30 and each R 30 and R 31 are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy or amino, and preferably 9a are each independently halogen, cyano, nitro, ═O, —OH, or —NR 30 R 31 , C1-C3 alkyl, C1-C3 haloalkyl, -C(O)R 30 , -C(O)OR 30 and each R 30 and R 31 are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino.

[0065] In some embodiments, the R 9a are each independently halogen, cyano, nitro, carbonyl, ═O, —OH, methyl, ethyl, fluoromethyl or fluoroethyl, and preferably 9a are each independently halogen, cyano, nitro, ═O, —OH, methyl, ethyl, fluoromethyl, or fluoroethyl.

[0066] In some embodiments, the R 9a are each independently -OH or ═O.

[0067] In some embodiments, the R 9a are each independently —OH.

[0068] In some embodiments, the [ka] teeth, [ka] and the * end is connected to L, [ka] The end is connected to the B ring.

[0069] In some embodiments, the [ka] teeth, [ka] and the * end is connected to L, [ka] The end is connected to the B ring.

[0070] In some embodiments, the [ka] teeth, [ka] is selected from.

[0071] In some embodiments, the [ka] teeth, [ka] is selected from.

[0072] In some embodiments, the [ka] teeth, [ka] is selected from.

[0073] In some embodiments, the [ka] teeth, [ka] is selected from.

[0074] In some embodiments, the [ka] teeth, [ka] is selected from.

[0075] In some embodiments, the compound has a structure according to general formula III: [ka] In the formula, X 1 is CH or N, and X 2 , X 3 , X 4 , X 5 , X 6 are each independently CH, CH, NH, N or O, and preferably X 1 and X 4 are each independently CH or N, and X 2 , X 3 , X 5 , X 6are each independently CH, CH, NH, N, or C, v is an integer of 0 to 2, and D ring, L, R 1 , R 2 , R 9a , R 9c , n1, n2, n3 and n5 are as defined in any of the above embodiments.

[0076] Preferably, the R 9a are each independently halogen, ═O, —OH, or C1-C3 alkyl, more preferably —OH.

[0077] D ring, L, R 1 , R 2 , R 9a , R 9c , n1, n2, n3 and n5 are as defined in any embodiment above.

[0078] In some embodiments, the compound has a structure represented by any one of general formulas III-1 to III-6: [ka] In the formula, D ring, L, R 1 , R 2 , R 9a , R 9c , n1, n2, n3 and n5 are as defined in any of the above embodiments.

[0079] Preferably, R 9a is hydroxy or halogen; More preferably, R 9a is hydroxy, Preferably, n3 is an integer of 0 to 3, and more preferably 0, 1 or 2.

[0080] In some embodiments, the compound has any of the compounds having a structure represented by the following general formulas III-1-1 to III-6-1: [ka] [ka] wherein the D ring, L, R 1 , R 2 , n1, n2 are as defined in any of the above embodiments.

[0081] In some embodiments, L is # D -L 1 -L 2 -L 3 -$ A or [ka] and L 1 is a bond, -O-, -S- or -NR 4 -, preferably L 1 is -O-, -S- or -NR 4 - and L 2 is a bond, substituted or unsubstituted C1-C3 alkylene, preferably L 2 is a substituted or unsubstituted C1-C3 alkylene; L 3 is -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A and X 10 is O or S, and R 4 and R 5 are each independently selected from H, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; R 4 and R 5 C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl as each independently represent 1 to 3 R 11 and each R 11 are each independently selected from halogen, cyano, nitro, carbonyl, ═O, —OH, —SH, —NH, and preferably each R 11are each independently selected from halogen, cyano, nitro, ═O, —OH, —SH, —NH, and preferably each R 11 are each independently selected from halogen, cyano, nitro, -OH, -SH, and -NH2; D - is a connecting bond connected to the D ring, -$ A is a connecting bond connected to the A ring, and the * end is connected to the A ring, [ka] The end is connected to a D-ring.

[0082] In some embodiments, L is # D -L 1 -L 2 -L 3 -$ A , [ka] or# D -NR 14 C(O)-C1-C6 alkylene-O-$ A and L 1 is a bond, -O-, -S- or -NR 4 - and L 2 is a bond, substituted or unsubstituted C1-C3 alkylene, and L 3 is -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A and X 10 is O or S, and R 4 , R 5 and R 14 are each independently selected from H, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; R 4 , R 5 and R 14 C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl as each independently represent 1 to 3 R11 and each R 11 are each independently selected from halogen, cyano, nitro, ═O, —OH, —SH, —NH, and preferably each R 11 are each independently selected from halogen, cyano, nitro, -OH, -SH, and -NH2; D - is a connecting bond connected to the D ring, -$ A is a connecting bond connected to the A ring, and the * end is connected to the A ring, [ka] The end is connected to a D-ring.

[0083] In some embodiments, L is [ka] and the * end is connected to the A ring; [ka] The end is connected to a D-ring.

[0084] In some embodiments, L is [ka] and the * end is connected to the A ring; [ka] The end is connected to a D-ring.

[0085] In some embodiments, L is [ka] and the * end is connected to the A ring; [ka] The end is connected to a D-ring.

[0086] In some embodiments, L is [ka] and the * end is connected to the A ring; [ka] The end is connected to a D-ring.

[0087] In some embodiments, L is [ka] and the * end is connected to the A ring; [ka] The end is connected to a D-ring.

[0088] In some embodiments, L is [ka] and the * end is connected to the A ring; [ka] The end is connected to a D-ring.

[0089] In some embodiments, the compound has a structure according to general formula IV-1 or IV-2: [ka] In the formula, D ring, R 1 , R 2 , R 9a , R 9c , n1, n2, n3 and n5 are as defined in any of the above embodiments, preferably A ring, C ring, D ring, R 1 , R 2 , R 9a , R 9c, n1, n2, n3 and n5 are as defined in any of the above embodiments, and X 7 is O or S.

[0090] In some embodiments, the compound has a structure represented by formula V-1 or V-2: [ka] In the formula, v is an integer of 0 to 2, and the D ring, R 1 , R 2 , R 9a , R 9c , n1, n2, n3 and n5 are as defined in any of the above embodiments, and X 7 is O or S.

[0091] In some embodiments, [ka] teeth, [ka] where X is selected from 14 , X 15 , X 16 , X 17 , X 18 are each independently selected from CH and N, and at least one is N, preferably up to 3 N, more preferably up to 2 N, and X 19 , X 20 are each independently selected from CH, N, NH, O, and S, and are not simultaneously S or O; m is 1 or 2; and X 21 , X 22 are each independently selected from CH, N, NH, O, and S, and are not simultaneously S or O; m is 1 or 2; and u is 1, 2, or 3.

[0092] In some embodiments, [ka] teeth, [ka] where X is selected from 14 , X 15 , X 16 , X 17 , X 18 are each independently selected from CH and N, and at least one is N, preferably up to 3 N, more preferably up to 2 N, and X 19 , X 20 are each independently selected from CH, N, NH, O, and S, and are not simultaneously S or O; m is 1 or 2; and X 21 , X 22 are each independently selected from CH, N, NH, O, and S, and are not simultaneously S or O; m is 1 or 2; and u is 1, 2, or 3.

[0093] In some embodiments, the [ka] teeth, [ka] is selected from.

[0094] In some embodiments, the [ka] teeth, [ka] is selected from.

[0095] In some embodiments, the [ka] teeth, [ka] is selected from.

[0096] In some embodiments, the [ka] teeth, [ka] is selected from.

[0097] In some embodiments, the [ka] teeth, [ka] is selected from.

[0098] In some embodiments, the [ka] teeth, [ka] is selected from.

[0099] In some embodiments, the [ka] teeth, [ka] is selected from.

[0100] In some embodiments, the [ka] teeth, [ka] is selected from.

[0101] In some embodiments, R 2 is R 11 and each R 11 are each independently halogen, cyano, nitro, carbonyl, =O, -OR 6 , -SR 6 , -NR 6 R 7 , C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 ,OC(O)R 6 , -C(O)NR 6 R 7 , -C(O)ONR 6 R 7 Preferably, each R 11 are each independently halogen, cyano, nitro, =O, -OR 6 , -SR 6 , -NR 6 R 7 , C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 ,OC(O)R 6 , -C(O)NR 6 R 7 , -C(O)ONR 6 R 7 Selected from among R 11 C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocycloalkyl as each independently represent 1 to 6 R 12 may be substituted with Each R 6 , R 7 and R 8 are each independently H, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR20 R 21 Selected from among R 6 , R 7 and R 8 C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocycloalkyl as each independently represent 1 to 3 R 13 may be substituted with Each R 12 and each R 13 are each independently H, halogen, cyano, nitro, carbonyl, =O, or -OR 30 , N.R. 30 R 31 , C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 ,OC(O)R 30 and preferably each R 12 and each R 13 are each independently H, halogen, cyano, nitro, =O, -OR 30 , N.R. 30 R 31 , C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 ,OC(O)R 30 Among them, R 12 and R 13 The C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocycloalkyl as R may each independently be substituted with 1 to 3 halogens, or may be selectively substituted with C1-C3 alkyl substituted with 1 to 3 carbonyls, halogens, hydroxyl, or amino, and preferably R 12 and R 13 each of the C1-C6 alkyl, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl groups independently may be substituted with 1 to 3 halogen atoms, or may be substituted with C1-C3 alkyl optionally substituted with 1 to 3 halogen atoms, hydroxyl or amino group; Each R20 and R 21 are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; Each R 30 and R 31 are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; n2 is 1, 2, or 3.

[0102] In some embodiments, each R 2 each independently represents halogen, cyano, C1-C3 haloalkyl, C1-C3 alkyl, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NR 6 R 7 , C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl; R 6 , R 7 are each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C3-C6 halocycloalkyl, and preferably, 2 is C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, n is 1, and 2 forms a fused ring with the D ring by sharing two carbon atoms.

[0103] In some embodiments, each R 2 each independently represents halogen, C1-C3 haloalkyl, C1-C3 alkyl, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NH2, [ka] wherein preferably R 2 but [ka] If [ka] forms a fused ring with the D ring by sharing two carbon atoms.

[0104] In some embodiments, each R 2 are each independently selected from F, Cl, Br, —CF3, —CH3, —CFH2, —CF2H, —OCH3, O—CF3, —NH2; and n2 is 1 or 2.

[0105] In some embodiments, each R 2 are each independently selected from F, Cl, Br, —CF3, —CH3, —CF2H, —OCF3, —NH2; and n2 is 1, 2, or 3.

[0106] In some embodiments, the [ka] teeth, [ka] is selected from.

[0107] In some embodiments, the [ka] teeth, [ka] is selected from.

[0108] In some embodiments, the [ka] teeth, [ka] is selected from.

[0109] In some embodiments, the [ka] teeth, [ka] is selected from.

[0110] In some embodiments, the [ka] teeth, [ka] is selected from.

[0111] In some embodiments, the compound preferably has a structure according to general formula VI: [ka] wherein the A ring is selected from cyclohexylene or 6-membered heterocycloalkylene; and the L and R 1 , R 2 , R 9a , R 9c , n1 、 n2, n3 and n5 are as defined in any of the above embodiments.

[0112] In some embodiments, the R 2 are each independently selected from F, Cl, and Br.

[0113] In some embodiments, n2 is 1 or 2.

[0114] In some embodiments, the R 2 and L are in the para and / or meta positions.

[0115] In some embodiments, L is [ka] and the * end is connected to the A ring; [ka] The end is connected to a D-ring.

[0116] Preferably, L is [ka] is selected from.

[0117] In some embodiments, L is [ka] and the * end is connected to the A ring; [ka] The end is connected to a D-ring.

[0118] In some embodiments, L is [ka] is selected from.

[0119] In some embodiments, L is [ka] is selected from.

[0120] In some embodiments, L is [ka] is selected from.

[0121] In some embodiments, n1 and n5 cannot be 0 at the same time.

[0122] In some embodiments, the R 1The N on the C ring where it is located is in a para position.

[0123] In some embodiments, the R 1 -OR 6 , C1-C3 alkyl, halogen, C2-C4 alkenyl, -S(O)2R 6 Or-P(O)R 6 R 7 Preferably, each R 6 , R 7 are each independently selected from H, C1-C3 alkyl, among which R 6 , R 7 C1-C3 alkyl as the group is 1 to 3 R 13 and preferably each R 13 are each independently halogen, cyano, or nitro; Preferably, the R 1 are -OCH3, -OCF3, [ka] -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, -CF3, -F, [ka] -OCF=CF2, [ka] is.

[0124] In some embodiments, the R 1 -OR 6 , C1-C3 alkyl, halogen, -S(O)2R 6 Or-P(O)R 6 R 7 Selected from among R 1 C1-C3 alkyl as the group is 1 to 6 R 12 and R 12 is halogen, -S(O)R 30 Selected from R 30is selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, and halogenated C3-C6 cycloalkyl; and each R 6 are each independently selected from C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl, among which R 6 C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl as R 13 and R 13 is selected from halogens, and R 7 is selected from C1-C3 alkyl.

[0125] In some embodiments, the R 1 are -OCH3, -OCF3, [ka] -CF2CF3, -CF3, -OCHF2, -OCF2CF3, -OCF2Cl, -CH2CF3, -F, [ka] -OCF=CF2, [ka] is.

[0126] In some embodiments, the R 1 are -OCF3, -CF2CF3, -OCH3, -F, [ka] -CF3, In some embodiments, the R 1 are -OCF3, -OCF2CF3, In some embodiments, the R 1 is -OCF3.

[0127] In each embodiment, R 1 , R 2 , R9a , R 9b , R 9c are each independently a substituent R 11 and n1, n2, n3, n4, and n5 are 0, then R 1 , R 2 , R 9a , R 9b , R 9c does not exist, and in this case, the free bonds of C constituting rings D, A, B and C are connected to H.

[0128] In some embodiments, the compound has a structure according to general formula VII: [ka] In the formula, R 9a , X 10 is as defined in any embodiment above, and R 21 is selected from halogens, and R 22 is selected from H and halogen, and t is selected from an integer of 0 to 2; Preferably, R 21 is Cl, Preferably, R 22 is selected from H, F, Cl, and Br; Preferably, R 9a is selected from H, hydroxy; Preferably, t is 0 or 2.

[0129] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0130] In some embodiments, the compound is specifically [ka] [ka] is selected from.

[0131] In some embodiments, the compound is specifically [ka] is selected from.

[0132] In another aspect of the present application, there is provided a method for synthesizing a compound having a structure represented by the above general formula IV-1 or IV-2, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, the method comprising any one of synthetic routes 1 to 6 selected from: Synthetic Route 1 [ka] In the formula, compound 1-1 undergoes an amide condensation reaction with compound 1-2 to obtain compound 1-3, compound 1-3 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 1-4, compound 1-4 is cyclized with N,N-carbonyldiimidazole to obtain compound 1-5, compound 1-5 undergoes a condensation reaction with compound 1-6 to obtain compound IV-1-1, and R 1 , R 2 , R 9a , R 9c, n1 and n2 are as defined in the above embodiments; Synthetic Route 2 [ka] In the formula, compound 2-1 undergoes an amide condensation reaction with compound 2-2 to obtain compound 2-3, compound 2-3 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 2-4, compound 2-4 is cyclized with N,N-carbonyldiimidazole to obtain compound 2-5, compound 2-5 is condensed with compound 2-6 to obtain compound IV-2-1, and R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiments; Synthetic Route 3 [ka] In the formula, compound 3-1 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 3-2, compound 3-2 is cyclized with N,N-carbonyldiimidazole to obtain compound 3-3, compound 3-3 is condensed with compound 3-4 to obtain compound 3-5, compound 3-5 is deprotected under acidic conditions to obtain compound 3-6, compound 3-6 is amide condensed with compound 3-7 to obtain compound IV-1-1, and R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiments; Synthetic Route 4 [ka] In the formula, compound 4-1 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 4-2, compound 4-2 is cyclized with N,N-carbonyldiimidazole to obtain compound 4-3, compound 4-3 is condensed with compound 4-4 to obtain compound 4-5, compound 4-5 is deprotected under acidic conditions to obtain compound 4-6, compound 4-6 is amide condensed with compound 4-7 to obtain compound IV-2-1, and R1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiments; Synthetic Route 5 [ka] In the formula, compound 5-1 undergoes an amide condensation reaction with compound 5-2 to obtain compound 5-3, compound 5-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 5-4, compound 5-4 condenses with compound 5-5 to obtain compound 5-6, compound 5-6 undergoes a ring-closure reaction to obtain compound IV-1-1, and R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiments; Synthetic Route 6 [ka] In the formula, compound 6-1 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 6-2, compound 6-2 undergoes a ring-closure reaction to obtain compound 6-3, compound 6-3 undergoes an oxidation reaction to obtain compound 6-4, compound 6-4 reacts with compound 6-5 to obtain compound 6-6, compound 6-6 is deprotected under acidic conditions to obtain compound 6-7, compound 6-7 is condensed with compound 6-8 to obtain compound IV-1-1, and R 1 , R 2 , R 9a , R 9c , n1 and n2 are as defined in the above embodiments; A synthesis method is provided.

[0133] In yet another aspect of the present application, there is provided a pharmaceutical composition comprising a formulation made from any of the above-mentioned compounds, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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 compound obtained by any of the above-mentioned synthetic methods.

[0134] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or vehicle.

[0135] In some embodiments, the present invention is directed to the prevention and / or treatment of a neurodegenerative disease (e.g., a leukodystrophy, a leukoencephalopathy, a hypomyelination or demyelinating disease, an intellectual disability syndrome, a cognitive dysfunction, a glial cell dysfunction or a brain injury (e.g., a traumatic brain injury or a toxin-induced brain injury), a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobinopathy, a kidney disease, a hearing loss disease, an eye disease, a disease with a mutation that causes induction of the unfolded protein response (UPR), a malaria infection, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease. and (iii) a pharmaceutical composition comprising 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 non-enantiomer 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 of the pharmaceutical compositions described above, in the manufacture of a medicament for treating a disease comprising administering to a patient a therapeutically effective amount of a compound described above.

[0136] In some embodiments, there is provided use of any of the above-mentioned compounds, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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 of the above-mentioned pharmaceutical compositions, in the manufacture of a medicament for preventing and / or treating an integrated stress response (ISR) pathway-mediated disease or condition.

[0137] In some embodiments, provided are methods of treating an integrated stress response (ISR) pathway-mediated disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of any of the compounds described above, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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 therapeutically effective amount of any of the pharmaceutical compositions described above.

[0138] In some embodiments, methods are provided for treating diseases associated with modulation of eIF2B activity or levels, the activity or levels of the eIF2 pathway or the ISR pathway, comprising administering to a subject a therapeutically effective amount of any of the above-mentioned compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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 therapeutically effective amount of any of the above-mentioned pharmaceutical compositions.

[0139] In some embodiments, there is provided a method for preventing and / or treating each of the above diseases, comprising administering to a subject in need thereof an effective amount of any of the above compounds, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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 of the above pharmaceutical compositions.

[0140] In some embodiments, there is provided a method for preventing and / or treating cancer, comprising administering to a subject in need thereof an effective amount of any of the above-mentioned compounds, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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 of the above pharmaceutical compositions.

[0141] In some embodiments, the neurodegenerative disease is a leukodystrophy, a leukoencephalopathy, a myelination or demyelinating disease, an intellectual disability syndrome, cognitive impairment, glial dysfunction or brain injury (e.g., traumatic brain injury or toxin-induced brain injury), Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Voigt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, or any of the following: disease, dystonia, frontotemporal dementia (FTD), Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple system atrophy, multisystem proteinopathy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum's disease, Sandhoff disease, Schilder's disease Subacute combined degeneration of spinal cord secondary to pernicious anemiaThese conditions include, but are not limited to, dyspraxia, encephalopathy, encephalopathy (SCA), encephalopathy (SCA type 1), encephalopathy (SCA type 2), encephalopathy (SCA type 3), encephalopathy (SCA type 4), encephalopathy (SCA type 5), encephalopathy (SCA type 6), encephalopathy (SCA type 7), encephalopathy (SCA type 8), encephalopathy (SCA type 9), encephalopathy (SCA type 10), encephalopathy (SCA type 11), encephalopathy (SCA type 12), encephalopathy (SCA type 13), encephalopathy (SCA type 14), encephalopathy (SCA type 15), encephalopathy (SCA type 16), encephalopathy (SCA type 17), encephalopathy (SCA type 18), encephalopathy (SCA type 19 ...

[0142] The cancers include, but are not limited to, human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid tumors and lymphatic cancers, 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 cancer, esophageal cancer, liver cancer (including hepatocarcinoma), lymphomas (including acute B lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's lymphoma, small cell lymphoma, and large cell lymphoma)), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML) and / or multiple myeloma. In some other cases, "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.

[0143] The above leukemias are acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, nonleukemic leukemia, leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, stem cell leukemia, eosinophilic leukemia, Gross'leukemia, hairy cell leukemia, and hemoblastic leukemia. , erythroblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelocytic granulocytic 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 anaplastic cell leukemia.

[0144] The inflammatory diseases include postoperative cognitive impairment, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, early-onset diabetes mellitus, 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, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, and the like. disease), vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0145] The above-mentioned musculoskeletal disorders 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 muscular dystrophy type 1, or myotonic muscular dystrophy type 2), limb-girdle muscular dystrophy, multisystem proteinopathy, radicular chondrodysplasia punctata, X-linked recessive chondrodysplasia punctata, Conradi-Hunermann syndrome, and the like. syndrome), autosomal dominant chondrodysplasia punctata, stress-induced skeletal disorders (e.g., stress-induced osteoporosis), multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinal-bulbar muscular atrophy, spinal spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, Paget's disease of bone, muscle cramp and fasciculation syndrome, Freidrich's ataxia, muscle wasting disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myositis, motor neuron disease, or paralysis.

[0146] The 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.

[0147] 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, stroke-like syndrome (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged-red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

[0148] 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 resulting from exposure to ototoxins, hearing loss caused by disease, and hearing loss caused by trauma. In some embodiments, the mitochondrial non-syndromic hearing loss and hearing loss is MT-RNR1-associated hearing loss.

[0149] The above-mentioned eye diseases include, but are not limited to, cataract, glaucoma, endoplasmic reticulum (ER) stress, autophagy deficiency, age-related macular degeneration (AMD), or diabetic retinopathy.

[0150] The kidney diseases mentioned above include Abderhalden-Kaufmann-Lignac syndrome (nephropathic cystinosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure / acute kidney injury, acute lobar nephronia, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenovirus nephritis, Alagille syndrome, Alport syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, angiomyolipoma, analgesic nephropathy, anorexia nervosa nephropathy, angiotensin-activated antibody and focal segmental glomerulosclerosis, antiphospholipid syndrome, anti-TNF-α therapy-associated glomerulonephritis, APOL1 mutations, apparent mineralocorticoid excess syndrome, aristolochic acid nephropathy, Chinese herbal medicine nephropathy, Balkan endemic nephropathy, and others. Endemic Nephropathy, Arteriovenous Malformations and Fistulas of the Urinary Tract, Autosomal Dominant Hypocalcemia, Bardet-Biedl Syndrome, Bartter Syndrome, Bath Salt Acute Kidney Injury, Beer Potomania, Beet Urinary Tract Disease, Beta-Thalassemia Kidney Disease, Bile Cast Nephropathy, BK Polyomavirus Nephropathy in the Native Kidney, Bladder Rupture, Bladder Sphincter Dyssynergia, Bladder Tamponade, Border-Crossers' Nephropathy, Bourbon Virus Acute Kidney Injury, Sugarcane Burn Harvest Acute Renal Failure, Byetta Renal Failure, C1q Nephropathy, C3 Glomerulopathy, C3 Glomerulopathy with Monoclonal Gammopathy, C4 Glomerulopathy, Calcineurin Inhibitor Nephrotoxicity, Callilepsis laurethra Laureola intoxication, cannabinoid hyperemesis, acute renal failure, cardiorenal syndrome, carfilzomib-induced renal injury, CFHR5 nephropathy, Charcot-Marie-Tooth disease with glomerulopathyDisease, Chinese herbal medicine nephrotoxicity, cherry concentrate acute kidney injury, cholesterol embolism, Churg-Strauss syndrome, chyluria, ciliopathies, cocaine nephropathy, cold diuresis, colistin nephrotoxicity, collagenous glomerulopathy, collapsing glomerulopathy, CMV-associated collapsing glomerulopathy, combined antiretroviral therapy (cART)-associated nephropathy, congenital anomalies of the kidney and urinary tract (CAKUT), congenital nephrotic syndrome, congenital renal failure, renal pyramid Syndrome (Mainzer-Sardino syndrome or Sardino-Mainzer disease), contrast nephropathy, copper sulfate poisoning, renal cortical necrosis, crizotinib-associated acute kidney injury, crystal cryoglobulinemia, cryoglobulinemia, crystalglobulin-induced nephropathy, crystal-induced acute kidney injury, crystal-storing histiocytosis, acquired cystic kidney disease, cystinuria, dasatinib-induced nephrotic-range proteinuria, dense deposit disease (MPGN type 2), Dent disease X-linked Recessive Nephrolithiasis (X-linked Recessive Nephrolithiasis), DHA Crystal Nephropathy, Dialysis Imbalance Syndrome, Diabetes and Diabetic Kidney Disease, Diabetes Insipidus, Renal Failure Due to Dietary Supplements, Diffuse Mesangial Sclerosis, Diuretics, Djenkol Bean Poisoning (Djenkolism), Down Syndrome Kidney Disease, Drug-Dependent Kidney Disease, Duplication of the Ureter, EAST Syndrome, Ebola Kidney Disease, Ectopic Kidney, Ectopic Ureter, Edema, Swelling, Erdheim-Chester Disease, Fabry's Disease, Familial Hypocalciuric Hypercalcemia, Fanconi Syndrome, Fraser Syndrome, Fibronectin Glomerulopathy, Fibrillary and Immunotactoid Glomerulopathy, Fraley Syndrome syndrome, fluid overload, hypervolemia, focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway-Mowat syndrome, giant cell (temporal) arteritis with renal involvement, pregnancy-induced hypertension, Gitelman syndromeSyndrome, Glomerular Disease, Glomerular Tubular Reflux, Renal Glycosuria, Goodpasture Syndrome, Green Smoothie Cleanse Nephropathy, HANAC Syndrome, Harvoni (Ledipasvir and Sofosbuvir)-Induced Kidney Injury, Acute Kidney Injury Due to Hair Dye Ingestion, 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 hemosiderinosis associated with hemolytic anemia, hepatic glomerulopathy, hepatic veno-occlusive disease, sinusoidal obstruction syndrome, hepatitis C-related kidney disease, hepatocyte nuclear factor 1B-related kidney disease, hepatorenal syndrome, herbal supplement kidney disease, high-altitude kidney syndrome, hypertensive kidney disease, HIV-associated immune complex kidney disease (HIVICK), HIV-associated nephropathy (HIVAN), HNF1B-related autosomal dominant tubulointerstitial kidney disease, 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 cannabis users, hypertension, monogenic hypertension, iced tea nephropathy, ifosfamide nephrotoxicity, IgA nephropathy, IgG4 nephropathy, water diuresis, immune checkpoint therapy-associated interstitial nephritis, infliximab-associated kidney disease, interstitial cystitis, bladder pain syndrome (questionnaire), interstitial nephritis, karyomegaly interstitial nephritis, Ivemark's syndrome, JC virus nephropathy, Joubert syndromeSyndrome, ketamine-associated bladder dysfunction, kidney stones, nephrolithiasis, kombucha tea toxicity, lead nephropathy and lead-related nephrotoxicity, lecithin cholesterol acyltransferase deficiency (LCAT deficiency), leptospirosis kidney disease, light chain deposition disease, monoclonal immunoglobulin deposition disease, light chain proximal tubulopathy, Liddle syndrome, Lightwood-Albright syndrome, lipoprotein glomerulopathy, lithium nephrotoxicity, hereditary FSGS due to LMX1B mutations, lower back pain and hematuria, lupus, systemic lupus erythematosus, lupus kidney disease, lupus nephritis, lupus nephritis with antineutrophil cytoplasmic antibody seropositivity, lupus podocytopathy, Lyme disease Disease-associated glomerulonephritis, lysinuric protein intolerance, lysozyme nephropathy, malarial nephropathy, malignancy-associated renal disease, malignant hypertension, malakoplakia, McKittrick-Wheelock syndrome, MDMA (Molly, Ecstasy, 3,4-methylenedioxymethamphetamine) renal failure, external urethral meatal stenosis, medullary cystic renal disease, uromodulin-associated nephropathy, juvenile hyperuricemic nephropathy type 1, sponge kidney, megaureter, melamine toxic nephropathy, MELAS syndrome, membranoproliferative glomerulonephritis, membranous nephropathy, membranous glomerulopathy with masked IgGκ deposition, Mesoamerican nephropathy Nephropathy, metabolic acidosis, metabolic alkalosis, methotrexate-associated renal failure, microscopic polyangiitis, milk-alkali syndrome, minimal change disease, monoclonal gammopathy with nephropathy, dysproteinemia, mouthwash toxicity, MUC1 nephropathy, polycystic dysplastic kidney, multiple myeloma, myeloproliferative neoplasia glomerulopathy, nail-knee-patella syndrome, NARP syndrome, nephrocalcinosis, nephrogenic systemic fibrosis, nephroptosis (wandering kidney, nephroptosis), nephrotic syndrome, neurogenic bladder, 9 / 11 and kidney disease, nodular glomerulosclerosis, nongonococcal urethritis, nutcracker syndromesyndrome, oligomegalic glomerulopathy, orofacial-digital syndrome, orotic aciduria, orthostatic hypotension, orthostatic proteinuria, osmotic diuresis, osmotic nephrosis, ovarian hyperstimulation syndrome, oxalate nephropathy, Page kidney, papillary necrosis, papillary renal syndrome Syndrome (renal coloboma syndrome, isolated renal hypoplasia), PARN mutation renal disease, parvovirus B19 renal disease, peritoneal-renal syndrome, posterior urethral valve POEMS syndrome, podocyte invagination glomerulopathy, postinfectious glomerulonephritis, poststreptococcal glomerulonephritis, atypical postinfectious glomerulonephritis, postinfectious glomerulonephritis (IgA dominant), pseudo-IgA nephropathy, polyarteritis nodosa, posterior urethral valve polycystic kidney disease, post-obstructive diuresis, pre-eclampsia, propofol infusion syndrome, proliferative glomerulonephritis with monoclonal IgG deposition (Nasr syndrome) Disease), propolis (bee resin)-associated renal failure, proteinuria (protein in the urine), pseudohyperaldosteronism, pseudohypobicarbonatemia, pseudohypoparathyroidism, pulmonary-renal syndrome, pyelonephritis (renal infection), pyonephrosis, pyridium renal failure, radiation nephropathy, ranolazine renal disease, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal agenesis, 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, autosomal dominant tubulointerstitial kidney disease, renin-secreting tumor (juxtaglomerular cell tumor), reset osmostat Osmostat, retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, bariatric surgery-associated rhabdomyolysis, rheumatoid arthritis-associated kidney disease, sarcoidosis kidney disease, renal and cerebral salt wasting, schistosomiasis glomerular disease, Schimke immunoosseous dysplasia, scleroderma renal crisis, serpiginous fibula-polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, silica exposure-related chronic kidney disease, Sri Lankan Farmers' KidneyDisease), Sjögren's syndrome kidney disease, acute kidney injury due to synthetic drug use, kidney disease after hematopoietic cell transplantation, kidney disease associated with stem cell transplantation, TAFRO syndrome, tea and toast hyponatremia, tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, monoclonal gammopathy-associated thrombotic microangiopathy, war nephritis, bladder trigonitis, genitourinary tuberculosis, tuberous sclerosis, tubular hypoplasia, proximal tubule brush border disease Autoantibody-induced immune complex tubulointerstitial nephritis, tumor lysis syndrome, uremia, uremic optic neuropathy, cystic ureteritis, ureteral hernia, urethral caruncle, urethral stricture, urinary incontinence, urinary tract infection, urinary tract obstruction, genitourinary fistula, uromodulin-related kidney disease, vancomycin-associated cast nephropathy, vasomotor nephropathy, vesicoenteric fistula, vesicoureteral reflux, VEGF-inhibitory renal thrombotic microangiopathy, volatile anesthetic acute kidney injury, von Hippel-Lindau disease These conditions include, but are not limited to, cerebrohepatic and renal syndrome ...

[0151] The skin diseases mentioned above include acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, disseminated superficial actinic keratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extramammary Paget's disease, epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal nail infections, Hailey-Hailey disease, and others. disease), herpes simplex, hidradenitis suppurativa, hypertrichosis, hyperhidrosis, ichthyosis, impetigo, keloid, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, melasma, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar warts, polymorphous light eruption, psoriasis, psoriasis vulgaris, pyoderma gangrenosum, rosacea, scabies, scleroderma, shingles, squamous cell carcinoma, Sweet's syndrome, urticaria and angioedema, and vitiligo.

[0152] The fibrotic diseases include, but are not limited to, adhesive capsulitis of the shoulder, arthrofibrosis, atrial fibrosis, cardiac fibrosis, cirrhosis, 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-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis, and ventricular remodeling.

[0153] The hemoglobin disorders mentioned 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 hydrops fetalis with Hb Barth disease. Bart's), sickle cell anemia / sickle cell disease, sickle cell trait, sickle beta-thalassemia disease, alpha+-thalassemia, alpha0-thalassemia, alpha-thalassemia with myelodysplastic syndrome, alpha-thalassemia and mental retardation (ATR) syndrome, beta0-thalassemia, beta+-thalassemia, delta-thalassemia, gamma-thalassemia, beta-thalassemia major, beta-thalassemia intermedia, delta beta-thalassemia, and epsilon gamma delta beta-thalassemia.

[0154] The autoimmune diseases mentioned above 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 (CD), celiac disease, and Chagas' disease. disease), chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, 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 contralateralis), 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 disease), multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome (Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular autoimmune syndrome type I, polyglandular autoimmune syndrome type II, polyglandular autoimmune 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, autoimmune disease against semen and testes, 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 include, but are not limited to, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), 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)).

[0155] Such viral infections include, but are not limited to, influenza, human immunodeficiency virus (HIV), and herpes.

[0156] Such malaria infections include, but are not limited to, infections caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium falciparum.

[0157] Diseases with mutations that cause induction of the unfolded protein response (UPR) include, but are not limited to, Marinesco-Sjögren's 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, collagenopathy, thin basement membrane nephropathy, Alport syndrome, skeletal chondrodysplasia, metaphyseal chondrodysplasia type Schmid, and pseudochondrodysplasia.

[0158] The compounds and derivatives provided herein may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming systems.

[0159] Regarding the definitions of terms used in the present invention, unless otherwise specified, the initial definitions provided for groups or terms in this specification apply to the groups or terms throughout the specification. Terms not specifically defined in this specification should be given the meaning that can be given by a person skilled in the art based on the disclosure and context.

[0160] "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 lone electron pair on an S atom is [ka] may be substituted with an O atom to form

[0161] "May be substituted with" or "optionally substituted with" means that the "substitution" may occur but does not necessarily occur, and this description includes cases where it occurs or does not occur.

[0162] The minimum and maximum carbon atom content in the hydrocarbon group is designated by a prefix, for example, alkyl preceded by Ca-Cb refers to any alkyl containing "a" to "b" carbon atoms. Thus, for example, C1-C6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.

[0163] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. An alkyl group may be a straight-chain or branched group. Representative branched alkyl groups have one, two, or three branches. For example, C1-C6 alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

[0164] The term "C1-C10 alkyl" refers to any straight or branched chain 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 C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, and the like.

[0165] Furthermore, the "C1-C10 alkyl" includes straight-chain or branched groups in a range defined by any two integers having a carbon number of 1 to 10. For example, "C1-C10 alkyl" includes C1-C10 alkyl, C1-C8 alkyl, C1-C6 alkyl, C2-C10 alkyl, C2-C8 alkyl, C2-C6 alkyl, C6-C10 alkyl, etc., and the above are merely examples and do not limit the range.

[0166] The term "alkoxy" and derivatives thereof refer to any of the above alkyls (eg, C1-C10 alkyl, C1-C6 alkyl, etc.), linked to the rest of the molecule via an oxygen atom (-O-).

[0167] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group having the specified number of member atoms. Ca-Cb alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight-chain hydrocarbon groups. For example, the term "propylene" [ka] Similarly, for the term "dimethylbutylene", for example, [ka] One of the following structures may be taken as an example.

[0168] The C1-C4 alkylene of the present invention can be a C1 alkylene (such as -CH2-), a C2 alkylene (such as -CH2CH2-), a C3 alkylene, or a C4 alkylene.

[0169] According to the present invention, "cycloalkylene" refers to a divalent saturated cyclic alkane having a single ring or multiple rings (fused, spiro, bridged) with multiple carbon atoms and no ring heteroatoms. Examples of monocyclic carbocyclyl groups include, for example, divalent cyclopropane, divalent cyclobutane, divalent cyclohexane, divalent cyclopentane, divalent cyclooctane, divalent cyclopentene hydrocarbons, and divalent cyclohexene hydrocarbons. Examples of bridged cycloalkane hydrocarbon systems include bicyclo[3,1,0]hexane, bicyclo[3,1,1]hexane, bicyclo[2,2,1]hexane, and bicyclo[2,2,2]hexane.

[0170] The implementation of "cycloalkylene" according to the present invention is [ka] Including, but not limited to, the following:

[0171] The term "C3-C10 cycloalkyl" refers to 3- to 10-membered all-carbon monocyclic, fused, and bridged rings that may contain zero, one, or more double bonds but do not have a completely conjugated π-electron system. Examples of C3-C10 cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, and the like.

[0172] The term "heterocycloalkyl" as used herein refers to a monovalent or divalent saturated ring having a single ring or multiple rings (fused rings, spiro rings, bridged rings) containing at least one heteroatom (the divalent saturated ring of heterocycloalkyl is heterocycloalkylene). Here, the heteroatom is a nitrogen atom, an oxygen atom, a sulfur atom, etc. Examples of 3-10 membered heterocyclyl may be oxetanyl, azetidinyl, oxolanyl, oxanyl, piperazinyl, piperidinyl, morpholinyl, s-trioxanyl, etc. The implementation of "heterocycloalkyl" as used herein may be: [ka] or piperidinyl, and the like.

[0173] The term "unsaturated" as used herein means that a group or molecule contains 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.

[0174] The term "aromatic ring" as used herein refers to an aromatic hydrocarbon group having multiple carbon atoms. The aryl is typically a monocyclic, bicyclic, or tricyclic aryl having multiple carbon atoms. The term "aryl" as used herein may also refer to an aromatic substituent of a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0175] The "5- to 10-membered heteroaryl" described in the present invention refers to an aromatic unsaturated ring containing at least one heteroatom such as a nitrogen atom, an oxygen atom, or a sulfur atom, and is usually an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, one or more of which is a heteroatom selected from O, N, and S, and preferably has 1 to 3 heteroatoms. Representative examples of the 5- to 6-membered heteroaryl include pyridyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyranyl, thiopyranyl, piperazinyl, triazoletriyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, 1,2,3,4-tetrazolyl, 1,2,3,5-tetrazolyl, isoxazolyl, oxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-oxatriazolyl, 1,3,2- Examples include dioxazolyl, 1,2,3-dioxazolyl, 1,2,3,4-dioxadiazolyl, 1,2,3,5-dioxadiazolyl, 1,3,3,4-dioxadiazolyl, 1,3,4,5-dioxadiazolyl, 1,2,3,4-dioxadiazolyl, isothiazolyl, pyridazinyl, triazinetriyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, 1,2,4-oxazinyl, 1,2,6-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl, 1,4,2-oxazinyl, 1,2-isoxazinyl, and 1,4-isoxazinyl.

[0176] "Halogen" according to the present invention refers to fluorine, chlorine, bromine or iodine.

[0177] The term "halogen-substituted alkyl" as used herein refers to alkyl in which one or more hydrogen atoms are substituted with halogen, such as halogen-substituted C 1~4 Alkyl refers to alkyl groups containing 1 to 4 carbon atoms in which a hydrogen atom is replaced by one or more halogen atoms, further examples of which include monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0178] In the present invention, "-N(R)2" and the like refer to a group R and a nitrogen atom connected via a single bond.

[0179] "=O" according to the present invention refers to an oxygen atom replacing two hydrogen atoms in the molecule by a double bond.

[0180] It will be apparent to those skilled in the art that, in the present invention, any group having a compound name such as "6- to 10-membered aryl-D-C1-C6 alkyl" is intended to be a group generally composed from left to right of its derivatives, e.g., C1-C6 alkyl, where alkyl is understood to be a divalent alkyl.

[0181] In the present invention, the term "stereoisomer" refers to compounds that have the same chemical structure but differ in the spatial arrangement of atoms or groups, and includes enantiomers, non-enantiomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, etc.

[0182] In the present invention, the term "tautomer" generally refers to structural isomers with 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 via any rearrangement of bonding electrons.

[0183] In the present invention, "geometric isomers" 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.

[0184] As used herein, "enantiomers" refer to two isomers of a compound that are non-superimposable mirror images of one another.

[0185] As used herein, "non-enantiomer" refers to a stereoisomer having two or more chiral neutral molecules, and the molecules are not mirror images of one another. Non-enantiomers differ in physical properties, such as melting points, boiling points, spectroscopic properties, and reactivity. Non-enantiomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

[0186] As used herein, the terms "racemate," "racemic compound," or "racemic mixture" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

[0187] As used herein, the term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically differ in X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate.

[0188] The "solvate" in the present invention is a mixture formed by dissolving a compound in a solvent.

[0189] In the present invention, "N-oxides", also known as amine oxides, are organic compounds with the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0190] As used herein, the term "isotopically labeled compound" refers to a molecule or group in which one or more atoms have been replaced with an isotope of that atom, such as an oxygen atom being replaced with a deuterium atom, where the proportion of deuterium atoms is greater than the natural abundance of deuterium. A further example is a compound in which 12C has been replaced with 13C.

[0191] In the present invention, the term "metabolite" refers to a substance that is produced when a drug molecule is absorbed into a living body and then undergoes a chemical structural transformation due to the action of the living body.

[0192] In the present invention, the term "prodrug" refers to a compound obtained by modifying the chemical structure of a drug, which is inactive or has low activity in vivo, but which releases an active drug by enzymatic or non-enzymatic conversion in vitro, thereby exerting its efficacy.

[0193] The term "pharmaceutically acceptable" refers to a carrier, vehicle, diluent, excipient, and / or formed salt that is generally chemically or physically compatible with the other ingredients of a pharmaceutical dosage form and physiologically compatible with the receptor.

[0194] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed from the above-mentioned compound or its stereoisomer with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly from the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound or its stereoisomer with a certain amount of acid or base, as appropriate (e.g., equal amounts). These salts can be obtained by precipitation in solution and collection by filtration, or by recovery after evaporation of the solvent, or by reaction in an aqueous medium followed by lyophilization.

[0195] The term "prevention" includes inhibiting or delaying the onset of a disease, and includes not only prevention before the onset of a disease, but also prevention of the recurrence of a disease after treatment.

[0196] The term "treatment" means reversing the progression of, alleviating, or eliminating the disease state or condition to which such term applies, or one or more symptoms of such disease state or condition.

[0197] 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 any other active agent to produce drugs or pharmaceutical compositions for regulating cell function or treating disease.When using a group of compounds, these compounds can be administered to a subject simultaneously, separately, or sequentially.

[0198] From the above content of the present invention, it is apparent that various other modifications, substitutions or alterations can be made using common technical knowledge and conventional means in this field without departing from the above basic technical idea of ​​the present invention.

[0199] The above content of the present invention will be further explained in detail below by specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention is also within the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0200] The embodiments of the present application are described in more detail below in connection with the following examples. The detailed description of the following examples and drawings are intended to exemplify the principles of the present application and are not intended to limit the scope of the present application, i.e., the present application is not limited to the examples described.

[0201] The known starting materials of the present invention can be synthesized by adopting or following methods known in the art, or can be purchased from companies such as BiDe Pharmaceutical, LeJan, TaiTan, ShaoYuan, AnNaiJi Chemical, Discovery Platform, Nanjing Yaoshi, Jiangsu Aikang, Beijing Yinuokai Technology, etc. Among them, tetrapropylammonium perruthenate is purchased from Discovery Platform, and 1-propylphosphonic anhydride is purchased from Beijing Yinuokai Technology Co., Ltd.

[0202] In the examples, unless otherwise specified, the reaction is carried out in a nitrogen gas atmosphere. In the examples, unless otherwise specified, the solution is an aqueous solution. In the examples, unless otherwise specified, the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, and is 20°C to 30°C. In the examples, unless otherwise specified, M is moles / liter.

[0203] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) was 10 -6 The values ​​are expressed in ppm. NMR was measured using a Bruker AvanceIII 400 nuclear magnetic resonance spectrometer. 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 was measured using a Shimadzu liquid chromatograph / mass spectrometer (Shimadzu LC-MS 2020 (ESI)). HPLC was measured using a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium-pressure preparative 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, with 0.4mm to 0.5mm diameters for thin-layer chromatography-separated and purified products. In column chromatography, Yantai Yellow Sea silica gel, 200-300 mesh silica gel, is generally used as the carrier.

[0204] Dimethylformamide is abbreviated as DMF, N,N'-diisopropylethylamine (also called diisopropylethylamine) is abbreviated as DIEA or DIPEA, 2-(7-azobenzotriazole)-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, and tetrahydrofuran is abbreviated as THF.

[0205] Example 1 Synthesis of Compound 1 [ka] Step 1: Synthesis of intermediate 1b Compound 1a (BiDe Pharmaceutical, catalog number BD57204, 4.0 g, 16.44 mmol) and dimethylformamide (20.0 mL) were added to a 100 mL single-neck flask at 25 °C, followed by the addition of compound N,N'-thiocarbonyldiimidazole (4.1 g, 23.02 mmol) under stirring. After 1 hour of reaction at 25 °C, the reaction temperature was raised to 100 °C and stirred for 2 hours. The reaction temperature was then lowered to 0 °C, and iodomethane (2.33 g, 16.44 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour to complete the reaction. 50 mL of water was added to the resulting reaction mixture, which was then extracted with 50 mL of ethyl acetate three times. The resulting organic phases were combined, 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 column chromatography to obtain intermediate 1b. LC-MS: m / z: 243.9 (M+H-56) + .

[0206] Step 2: Synthesis of intermediate 1c At 25°C, intermediate 1b (4.1 g, 13.71 mmol) and dichloromethane (20.0 mL) were placed in a 100 mL single-neck flask, and compound m-chloroperbenzoic acid (4.2 g, 20.58 mmol) was added under stirring in an ice bath. The reaction was completed after 16 hours at 25°C. A saturated aqueous solution of sodium bicarbonate was added to the resulting reaction solution to adjust the solution pH to approximately 8, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, and filtration. The filtrate obtained was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 1c. LC-MS: m / z: 275.9 (M+H-56). + .

[0207] Step 3 Synthesis of intermediate 1e Compound 1d (Bidu Pharmaceutical, catalog number BD25596, 197 mg, 2.26 mmol) and tetrahydrofuran (10 mL) were added to a 100 mL single-neck flask at 25 °C, and compound NaH (181 mg, 4.52 mmol) was added under stirring. After 0.5 hours of reaction at 25 °C, intermediate 1c (500 mg, 1.51 mmol) was added and the mixture was stirred at 25 °C for 16 hours to complete the reaction. 25 mL of water was added to the resulting reaction solution, which was then extracted with 25 mL of ethyl acetate. The resulting organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 1e. LC-MS: m / z: 283.0 (M+H-56). + .

[0208] Step 4 Synthesis of intermediate 1f Intermediate 1e (270 mg, 0.80 mmol) and dichloromethane (3.0 mL) were added to a 100 mL single-neck flask at 25°C, and trifluoroacetic acid (1.0 mL, 4.5 mmol) was added under stirring. The reaction was completed after 2 hours at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 1f. LC-MS: m / z: 239.0 (M+H). + .

[0209] Step 5 Synthesis of intermediate 1g In an ice bath, intermediate 1f (140 mg, 0.59 mmol), glacial acetic acid (3.5 mL), and water (1.5 mL) were added to a 100 mL single-neck flask, and sodium nitrite (121 mg, 1.75 mmol) was added under stirring. The reaction was allowed to proceed for 1 hour, after which the temperature was raised to 25°C and the reaction was continued for 1 hour until completion. The resulting reaction solution was concentrated under reduced pressure to give intermediate 1g. LC-MS: m / z: 268.0 (M+H) + .

[0210] Step 6 Synthesis of intermediate 1h Intermediate 1g (80 mg, 0.30 mmol), glacial acetic acid (1.0 mL), and methanol (3.0 mL) were added to a 100 mL single-neck flask in an ice bath, and zinc powder (97 mg, 1.48 mmol) was added under stirring. The reaction was completed after 2 hours at 25°C. The resulting reaction solution was concentrated under reduced pressure to give Intermediate 1h. LC-MS: m / z: 254.0 (M+H). + .

[0211] Step 7 Synthesis of Compound 1 Compound 1i (Pitt Pharmaceutical, catalog number BD00901377, 71 mg, 0.35 mmol) and dimethylformamide (3.0 mL) were added to a 50 mL single-neck flask in an ice bath. Under stirring, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (180 mg, 0.47 mmol) and diisopropylethylamine (123 mg, 0.95 mmol) were added sequentially. After reacting at 25 °C for half an hour, intermediate 1h (55 mg, 0.22 mmol) was added to the resulting reaction mixture, and the reaction was continued overnight at 25 °C. The resulting reaction mixture was added with 25 mL of water, extracted with 50 mL of ethyl acetate, and the organic phases were combined, 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 separated and purified by high performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 1. 1 H NMR (400 MHz, CDCl3) δ 7.28 - 7.26 (m, 1H), 6.78 - 6.73 (m, 1H), 6.71 - 6.66(m, 1H), 4.81 (s, 1H), 4.50 (s, 2H), 4.38 - 4.28 (m, 3H), 4.08 - 4.12 (m, 2H), 3.33 (s, 3H), 3.14- 3.12 (m, 2H), 2.88 - 2.84 (m, 1H), 2.78 - 2.72 (m, 2H), 2.14 - 2.10 (m, 4H). LC-MS: m / z: 440.0(M+H) + .

[0212] Example 2 Synthesis of Compound 2 [ka] Step 1: Synthesis of intermediate 2c Compound 1i (467 mg, 2.29 mmol) and dimethylformamide (8.0 mL) were added to a 100 mL single-neck flask in an ice bath. Under stirring, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.08 g, 2.86 mmol) and diisopropylethylamine (986 mg, 7.64 mmol) were added sequentially. After reacting at 25 °C for half an hour, compound 2a (BiDe Pharmaceutical, catalog number BD283560, 300 mg, 1.91 mmol) was added to the resulting reaction mixture and reacted overnight at 25 °C. The resulting reaction mixture was added with 100 mL of water and extracted twice with 50 mL of ethyl acetate each time. The combined organic phases were 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 separated and purified by column chromatography to give intermediate 2c. LC-MS: m / z: 344.0 (M+H) + .

[0213] Step 2: Synthesis of intermediate 2d Intermediate 2c (360 mg, 1.05 mmol) and ethanol (3.0 mL) were added to a 100 mL single-neck flask at 25°C, and hydrazine hydrate (969 mg, 10.50 mmol) was added under stirring. The temperature was raised to 80°C and the reaction was completed overnight. 25 mL of water was added to the resulting reaction mixture, which was then extracted with 25 mL of ethyl acetate. The resulting organic phase was washed with 25 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 2d. LC-MS: m / z: 344.0 (M+H) + .

[0214] Step 3 Synthesis of intermediate 2f Compound 1d (17 mg, 0.2 mmol) and tetrahydrofuran (3.0 mL) were added to a 50 mL single-neck flask at 25 °C. Triphosgene (181 mg, 0.61 mmol) was added under stirring, and the mixture was allowed to react at 25 °C for 2 hours. After this, intermediate 2d (70 mg, 0.2 mmol) was added. The temperature was raised to 80 °C and the mixture was allowed to react overnight. A large amount of solid was observed in the reaction system. After this, dimethylformamide (3.0 mL) was added and the mixture was allowed to react overnight at 80 °C to terminate the reaction. 50 mL of water was added to the resulting reaction mixture, which was then extracted with 50 mL of ethyl acetate. The resulting 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 separated and purified by column chromatography to obtain intermediate 2f. LC-MS: m / z: 457.0 (M+H). + .

[0215] Step 4 Synthesis of Compound 2 Intermediate 2f (26 mg, 0.06 mmol) and dimethylformamide (3.0 mL) were placed in a 50 mL single-neck flask at 25 °C, and cesium carbonate (55 mg, 0.17 mmol) and p-toluenesulfonyl chloride (22 mg, 0.11 mmol) were added under stirring. The reaction was completed after 3 hours at 25 °C. 35 mL of water was added to the resulting reaction solution, which was then extracted with 35 mL of ethyl acetate. The resulting 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 separated and purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 2. 1H NMR (400 MHz, CDCl3) δ 7.33 (t, J = 8.6 Hz, 1H), 6.93 - 6.67 (m, 3H), 6.65 - 6.63 (m, 2H), 4.77 - 4.72 (m, 1H), 4.52 - 4.47 (m, 1H), 4.43 (s, 2H), 3.71 - 3.56 (m, 3H), 3.48 - 3.33 (m, 3H), 2.42 - 2.38 (m, 2H), 1.80 - 1.68 (m, 4H), 1.61 - 1.56 (m, 2H). LC-MS: m / z: 439.1 (M+H) + .

[0216] Example 3 Synthesis of Compound 21 [ka] Step 1 Preparation of intermediate 21a Compound 21g (BiDe Pharmaceutical, BD212373, 5.00 g, 19.42 mmol) and ethanol (50.0 mL) were added to a 100 mL single-neck flask at 25°C, and hydrazine hydrate (7.75 g, 84.00 mmol) was added under stirring. The temperature was raised to 80°C and the reaction was completed overnight. After cooling, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 21a. LC-MS: m / z: 202.0 (M+H-56). + .

[0217] Step 2 Preparation of intermediate 21c At 25°C, intermediate 21a (3.8 g, 13.29 mmol) and 1,2-dichloroethane (30.0 mL) were added to a 100 mL single-neck flask, and N,N'-carbonyldiimidazole (5.0 g, 26.58 mmol) was added in sequence under stirring. The reaction was completed after 18 hours at 25°C. 25 mL of water was added to the resulting reaction solution, and the organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 21c. LC-MS: m / z: 228.0 (M+H-56). + .

[0218] Step 3 Preparation of intermediate 21d Intermediate 21c (2.9 g, 9.26 mmol) and dimethylformamide (30 mL) were added to a 100 mL single-neck flask at 25 °C, and 3-(trifluoromethoxy)-azetidine (1.73 g, 12.28 mmol), diisopropylethylamine (6.65 g, 51.18 mmol), and Carter condensation reagent (6.45 g, 15.53 mmol) were added sequentially under stirring. The reaction was completed after 16 hours at 25 °C. 100 mL of water was added to the resulting reaction solution, and the separated organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain intermediate 21d. LC-MS: m / z: 407.2 (M+H). + .

[0219] Step 4 Preparation of intermediate 21b Intermediate 21d (140 mg, 0.34 mmol) and dichloromethane (6.0 mL) were added to a 100 mL single-neck flask at 25°C, and trifluoroacetic acid (2.0 mL, 4.5 mmol) was added under stirring. The reaction was completed after 2 hours at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 21b. LC-MS: m / z: 307.2 (M+H). + .

[0220] Step 5 Synthesis of compound 21 Compound 21f (Bidu Pharmaceutical, catalog number BD11064, 6 mg, 0.03 mmol) and intermediate 21b (5.1 mg, 0.02 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (4.048 mg, 0.04 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (15.21 mg, 0.03 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 21. 1 H NMR (400 MHz, MeOD) δ 7.15 - 6.89 (m, 4H), 5.37 - 5.20 (m, 1H), 4.60 - 4.51 (m, 2H), 4.49 (s, 2H), 4.33 (dd, J = 9.4, 4.0 Hz, 2H), 3.84 (ddd, J = 15.6, 7.9, 4.0 Hz, 1H), 2.81 (tt, J = 12.1, 3.5 Hz, 1H), 2.17 (d, J = 12.1 Hz, 2H), 2.03 (d, J = 9.8 Hz, 2H), 1.76 - 1.60 (m, 2H), 1.59 - 1.42 (m, 2H). LC-MS: m / z: 459.1 (M+H) + .

[0221] Example 4 Synthesis of Compound 22 [ka] Compound 22a (Bidu Pharmaceutical, catalog number BD21790, 28 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 22. 1 H NMR (400 MHz, DMSO) δ 7.90 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 7.9, 1.6 Hz, 1H), 7.36 - 7.22 (m, 1H), 7.09 - 6.91 (m, 2H), 5.39 - 5.23 (m, 1H), 4.59 (s, 2H), 4.46 (dd, J = 9.6, 6.8 Hz, 2H), 4.19 (dd, J = 9.6, 4.0 Hz, 2H), 3.63 (ddd, J = 11.3, 7.5, 3.8 Hz, 1H), 2.74 (ddd, J = 11.8, 7.7, 3.5Hz, 1H), 2.03 (d, J = 11.3 Hz, 2H), 1.88 (dd, J = 12.8, 3.1 Hz, 2H), 1.58 - 1.45 (m, 2H), 1.43 - 1.30 (m, 2H). LC-MS: m / z :475.2(M+H) + .

[0222] Example 5 Synthesis of Compound 23 [ka] Step 1: Synthesis of compound 23 Compound 23a (Bidu Pharmaceutical, catalog number BD21634, 28 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 23. 1 H NMR (400 MHz, DMSO) δ 8.04 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.03 (t, J = 5.5 Hz, 2H), 6.93 (dd, J = 8.3, 2.0 Hz, 1H), 5.37 - 5.26 (m, 1H), 4.50 (s, 2H), 4.46 (dd, J = 9.4, 6.9 Hz, 2H), 4.19 (dd, J = 9.5, 3.9 Hz, 2H), 3.74 (s, 1H), 2.78 - 2.67 (m, 1H), 2.03 (d, J = 11.5 Hz, 2H), 1.85 (d, J = 9.7 Hz, 2H), 1.51 (dd, J = 25.0, 10.9 Hz, 2H), 1.44 - 1.31 (m, 2H). LC-MS: m / z :475.2(M+H) + .

[0223] Example 6 Synthesis of Compound 24 [ka] Step 1: Synthesis of compound 24 Compound 24a (Bidu Pharmaceutical, catalog number BD45137, 25.5 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 24. 1 H NMR (400 MHz, MeOD) δ 7.37 - 7.26 (m, 1H), 6.92 - 6.70 (m, 3H), 5.32 - 5.28 (m, 1H), 4.58 - 4.53 (m, 2H), 4.53 (s, 2H), 4.31 (dd, J = 9.6, 4.1 Hz, 2H), 3.84 (s, 1H), 2.81 (s, 1H), 2.17 (d, J = 11.8 Hz, 2H), 2.09 - 1.98 (m, 2H), 1.67 (dd, J = 12.6, 2.7 Hz, 2H), 1.58 - 1.39 (m, 2H). LC-MS: m / z : 459.2(M+H) + .

[0224] Example 7 Synthesis of Compound 25 [ka] Step 1: Synthesis of intermediate 25b Compound 25a (BiDe Pharmaceutical, catalog number BD9830, 500 mg, 3.41 mmol), tert-butyl bromoacetate (997.68 mg, 5.11 mmol), and cesium carbonate (2.2 g, 6.82 mmol) were dissolved in acetonitrile (7 mL) in a 50 mL reaction flask at 25 °C. The reaction was completed after 2 hours at 25 °C. 15 mL of dichloromethane was added to the resulting reaction solution, which was then filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 25b. 1 H NMR (400 MHz, CDCl3) δ 7.07 (t, J = 8.8 Hz, 1H), 6.95 (dd, J = 5.9, 3.1 Hz, 1H), 6.78 (dt, J = 9.1, 3.4 Hz, 1H), 4.49 (s, 2H), 1.51 (s, 9H).

[0225] Step 2 Synthesis of intermediate 25c Intermediate 25b (60 mg, 0.23 mmol) and dichloromethane (0.5 mL) were added to a 25 mL one-neck flask at 25°C, and trifluoroacetic acid (0.5 mL, 6.71 mmol) was added under stirring. The reaction was completed after 1 hour at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 25c. LCMS: m / z: 203.0 (M−H). - .

[0226] Step 3: Synthesis of compound 25 Intermediate 25c (30.69 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 25. 1 H NMR (400 MHz, MeOD) δ 7.24 - 7.13 (m, 2H), 6.97 (dt, J = 9.1, 3.4 Hz, 1H), 5.30 (ddd, J = 10.9, 6.8, 4.3 Hz, 1H), 4.60 - 4.46 (m, 4H), 4.29 (dd, J = 9.6, 4.1 Hz, 2H), 3.84 (tt, J = 11.5, 3.9 Hz, 1H), 2.80 (tt, J = 12.1, 3.5 Hz, 1H), 2.24 - 2.08 (m, 2H), 2.03 (dd, J = 12.7, 2.8 Hz, 2H), 1.67 (qd, J = 13.2, 3.0 Hz, 2H), 1.49 (ddd, J = 25.5, 12.8, 3.2 Hz, 2H). LC-MS: m / z :493.2(M+H) + .

[0227] Example 8 Synthesis of Compound 26 [ka] Step 1: Synthesis of intermediate 26b At 25°C, compound 26a (BiDe Pharmaceutical, catalog number BD85025, 500 mg, 2.41 mmol), tert-butyl bromoacetate (517.08 mg, 2.65 mmol), and cesium carbonate (1.57 g, 4.82 mmol) were dissolved in acetonitrile (7 mL) in a 50 mL reaction flask. The reaction was completed after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, which was then filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 26b. 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.9 Hz, 1H), 7.17 (d, J = 2.9 Hz, 1H), 6.83 (dd, J = 8.9, 2.9 Hz, 1H), 4.51 (s, 2H), 1.51 (s, 9H).

[0228] Step 2 Synthesis of intermediate 26c Intermediate 26b (200 mg, 0.62 mmol) and dichloromethane (2 mL) were added to a 25 mL one-neck flask at 25°C, and trifluoroacetic acid (2 mL, 26.84 mmol) was added under stirring. The reaction was completed after 1 hour at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 26c. LC-MS: m / z: 262.9 (M−H). - .

[0229] Step 3: Synthesis of compound 26 Intermediate 26c (39.82 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 26. 1 H NMR (400 MHz, MeOD) δ 7.19 - 6.98 (m, 2H), 6.69 (d, J = 8.9 Hz, 1H), 4.97 (s, 1H), 4.28 - 4.11 (m, 4H), 3.95 (s, 2H), 3.51 (s, 1H), 2.48 (s, 1H), 1.76 (d, J = 54.4 Hz, 4H), 1.25 (dd, J = 72.6, 11.6 Hz, 4H). LC-MS: m / z :555.2(M+H) + .

[0230] Example 9 Synthesis of Compound 27 [ka] Compound 27a (Rakuken, 33.16 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 27. 1 H NMR (400 MHz, DMSO) δ 7.90 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 7.9, 1.6 Hz, 1H), 7.36 - 7.22 (m, 1H), 7.09 - 6.91 (m, 2H), 5.39 - 5.23 (m, 1H), 4.59 (s, 2H), 4.46 (dd, J = 9.6, 6.8 Hz, 2H), 4.19 (dd, J = 9.6, 4.0 Hz, 2H), 3.63 (ddd, J = 11.3, 7.5, 3.8 Hz, 1H), 2.74 (ddd, J = 11.8, 7.7, 3.5Hz, 1H), 2.03 (d, J = 11.3 Hz, 2H), 1.88 (dd, J = 12.8, 3.1 Hz, 2H), 1.58 - 1.45 (m, 2H), 1.43 - 1.30 (m, 2H). LC-MS: m / z: 509.2(M+H) + .

[0231] Example 10 Synthesis of Compound 28 [ka] Compound 28a (Bidu Pharmaceutical, catalog number BD81648, 33.16 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 28. 1 H NMR (400 MHz, MeOD) δ 7.46 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 2.9 Hz, 1H), 6.97 (dd, J = 8.9, 2.9 Hz, 1H), 5.36 - 5.22 (m, 1H), 4.61 - 4.44 (m, 4H), 4.28 (dd, J = 9.6, 4.2 Hz, 2H), 3.84 (t, J = 4.0 Hz, 1H), 2.94 - 2.68 (m, 1H), 2.29 - 2.09 (m, 2H), 2.03 (dd, J = 13.1, 3.2 Hz, 2H), 1.73 - 1.58 (m, 2H), 1.56 - 1.41 (m, 2H). LC-MS: m / z :475.2(M+H) + .

[0232] Example 11 Synthesis of Compound 29 [ka] Compound 29a (Bidu Pharmaceutical, catalog number BD75182, 25.5 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 29. 1 H NMR (400 MHz, MeOD) δ 7.22 - 7.06 (m, 3H), 7.06 - 6.97 (m, 1H), 5.29 (dd, J = 9.3, 5.3 Hz, 1H), 4.58 (s, 2H), 4.54 (dd, J = 9.2, 7.1 Hz, 2H), 4.29 (dd, J = 9.6, 4.0 Hz, 2H), 3.90 - 3.79 (m, 1H), 2.87 - 2.75 (m, 1H), 2.16 (d, J = 12.1 Hz, 2H), 2.10 - 1.99 (m, 2H), 1.75 - 1.59 (m, 2H), 1.51 (dd, J = 17.3, 7.4 Hz, 2H). LC-MS: m / z: 459.2(M+H) + .

[0233] Example 12 Synthesis of Compound 30 [ka] Step 1. Synthesis of intermediate 30b Compound 30a (BiDe Pharmaceutical, catalog number BD33414, 500 mg, 3.84 mmol), tert-butyl bromoacetate (1.1 mg, 5.76 mmol), and cesium carbonate (2.5 g, 7.68 mmol) were dissolved in acetonitrile (7 mL) in a 50 mL reaction flask at 25 °C. The reaction was completed after 2 hours at 25 °C. 15 mL of dichloromethane was added to the resulting reaction solution, which was then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 30b. 1 H NMR (400 MHz, CDCl3) δ 6.88 - 6.75 (m, 2H), 6.71 (dd, J = 11.4, 5.3 Hz, 1H), 4.48 (s, 2H), 1.41 (s, 9H).

[0234] Step 2 Synthesis of intermediate 30c Intermediate 30b (200 mg, 0.82 mmol) and dichloromethane (2 mL) were added to a 25 mL single-neck flask at 25°C, and trifluoroacetic acid (2 mL, 26.84 mmol) was added under stirring. The reaction was completed after 1 hour at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 30c. LC-MS: m / z: 187.0 (M−H). - .

[0235] Step 3: Synthesis of compound 30 Intermediate 30c (28.22 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 30. 1 H NMR (400 MHz, MeOD) δ 7.05 (d, J = 84.8 Hz, 3H), 5.33 (s, 2H), 4.58 (s, 4H), 4.32 (s, 2H), 3.87 (s, 1H), 2.84 (s, 1H), 2.13 (d, J = 47.5 Hz, 4H), 1.61 (d, J = 65.3 Hz, 4H). LC-MS: m / z :477.2(M+H) + .

[0236] Example 13 Synthesis of Compound 31 [ka] Step 1: Synthesis of intermediate 31b At 25°C, compound 31a (BiDe Pharmaceutical, catalog number BD19192, 500 mg, 3.41 mmol), tert-butyl bromoacetate (731.63 mg, 3.75 mmol), and cesium carbonate (2.2 g, 6.82 mmol) were dissolved in acetonitrile (7 mL) in a 50 mL reaction flask. The reaction was completed after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, which was then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 31b. 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J = 8.0, 3.0 Hz, 1H), 6.93 (ddd, J = 9.1, 7.8, 3.0 Hz, 1H), 6.83 (dd, J = 9.1, 4.8 Hz, 1H), 4.58 (s, 2H), 1.50 (s, 9H).

[0237] Step 2 Synthesis of intermediate 31c Intermediate 31b (200 mg, 0.77 mmol) and dichloromethane (2 mL) were added to a 25 mL single-neck flask at 25°C, and trifluoroacetic acid (2 mL, 26.84 mmol) was added under stirring. The reaction was completed after 1 hour at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 31c. LC-MS: m / z: 202.9 (M−H). - .

[0238] Step 3: Synthesis of compound 31 Intermediate 31c (30.69 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 31. 1H NMR (400 MHz, MeOD) δ 7.29 (dd, J = 8.2, 2.7 Hz, 1H), 7.09 (dt, J = 8.3, 3.3 Hz, 2H), 5.36 - 5.24 (m, 1H), 4.60 - 4.48 (m, 4H), 4.29 (dd, J = 9.6, 4.2 Hz, 2H), 3.89 - 3.73 (m, 1H), 2.83 (tt, J = 12.0, 3.4 Hz, 1H), 2.25 - 2.02 (m, 4H), 1.77 - 1.40 (m, 4H). LC-MS: m / z :493.2(M+H) + .

[0239] Example 14 Synthesis of Compound 32 [ka] Compound 32a (Bidu Pharmaceutical, catalog number BD65476, 33.16 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 32. 1H NMR (400 MHz, DMSO) δ 7.96 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 8.2 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.08 - 6.92 (m, 1H), 5.36 - 5.28 (m, 1H), 4.64 (s, 2H), 4.46 (dd, J = 9.4, 6.9 Hz, 2H), 4.19 (dd, J = 9.6, 3.9 Hz, 2H), 3.69 - 3.56 (m, 1H), 2.82 - 2.68 (m, 1H), 2.03 (d, J = 11.4Hz, 2H), 1.95 - 1.80 (m, 2H), 1.60 - 1.44 (m, 2H), 1.36 (dt, J = 24.1, 6.2 Hz, 2H). LC-MS: m / z: 509.2(M+H) + .

[0240] Example 15 Synthesis of Compound 33 [ka] Step 1: Synthesis of intermediate 33b At 25°C, compound 33a (BiDe Pharmaceutical, catalog number BD9831, 250 mg, 1.71 mmol), tert-butyl bromoacetate (498.84 mg, 2.55 mmol), and cesium carbonate (1.1 g, 3.41 mmol) were dissolved in acetonitrile (3 mL) in a 10 mL reaction flask. The reaction was completed after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, which was then filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 33b. LC-MS: m / z: 261.1 (M+H). + .

[0241] Step 2: Synthesis of intermediate 33c Intermediate 33b (160 mg, 0.61 mmol) and dichloromethane (1.5 mL) were added to a 10 mL single-neck flask at 25°C, and trifluoroacetic acid (0.5 mL, 6.71 mmol) was added under stirring. The reaction was completed after 1 hour at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 33c. LC-MS: m / z: 203.0 (M−H). - .

[0242] Step 3: Synthesis of compound 33 Intermediate 33c (30.69 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 33. 1 H NMR (400 MHz, MeOD) δ 7.26 (dd, J = 11.0, 2.4 Hz, 1H), 7.18-7.13 (m, 1H), 7.09 (t, J = 8.7 Hz, 1H), 5.33-5.25 (m, 1H), 4.59 (s, 2H), 4.53 (dd, J = 9.6, 6.8 Hz, 2H), 4.29 (dd, J = 9.6, 4.2 Hz, 2H), 3.90-3.75 (m, 1H), 2. 85-2.75 (m, 1H), 2.25-2.10 (m, 2H), 2.09 - 1.95 (m, 2H), 1.67 (qd, J = 13.2, 3.1 Hz, 2H), 1.48 (qd, J = 12.8, 3.3 Hz, 2H). LC-MS: m / z :493.2(M+H) + .

[0243] Example 16 Synthesis of Compound 34 [ka] Step 1: Synthesis of intermediate 34b Compound 34a (BiDe Pharmaceutical, catalog number BD9841, 250 mg, 1.92 mmol), tert-butyl bromoacetate (412.50 mg, 2.11 mmol), and cesium carbonate (1.87 g, 5.76 mmol) were dissolved in acetonitrile (4 mL) in a 10 mL reaction flask at 25 °C. The reaction was completed after 2 hours at 25 °C. 15 mL of dichloromethane was added to the resulting reaction solution, which was then filtered. The filtrate was concentrated under reduced pressure to give intermediate 34b. LC-MS: m / z: 245.1 (M+H). + .

[0244] Step 2 Synthesis of intermediate 34c Intermediate 34b (170 mg, 0.69 mmol) and dichloromethane (1.5 mL) were added to a 10 mL single-neck flask at 25°C, and trifluoroacetic acid (0.5 mL, 6.71 mmol) was added under stirring. The reaction was completed after 1 hour at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 34c. LC-MS: m / z: 189.0 (M−H). - .

[0245] Step 3: Synthesis of compound 34 Intermediate 34c (28.22 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 34. 1 H NMR (400 MHz, MeOD) δ 7.22 (dd, J = 19.5, 9.2 Hz, 1H), 6.98 (ddd, J = 12.2, 6.6, 3.0 Hz, 1H), 6.84 - 6.77 (m, 1H), 5.34 - 5.23 (m, 1H), 4.53 (dd, J = 9.9, 7.0 Hz, 2H), 4.51 (s, 2H), 4.29 (dd, J = 9.7, 4.2 Hz, 2H), 3.84 (tt, J = 11.6, 3.9 Hz, 1H), 2.81 (tt, J = 12.1, 3.5 Hz, 1H), 2.25 - 2.11 (m, 2H), 2.07-1.98 (m, 2H), 1.67 (qd, J = 13.2, 3.2 Hz, 2H), 1.49 (qd, J = 12.8, 3.3 Hz, 2H). LC-MS: m / z :477.1(M+H) + .

[0246] Example 17 Synthesis of Compound 35 [ka] Step 1: Synthesis of intermediate 35b Compound 35a (BiDe Pharmaceutical, catalog number BD9390, 750 mg, 4.54 mmol), tert-butyl bromoacetate (970.01 mg, 5.00 mmol), and cesium carbonate (2.98 g, 9.09 mmol) were dissolved in acetonitrile (10 mL) in a 25 mL reaction flask at 25 °C. The reaction was completed after 2 hours at 25 °C. 15 mL of dichloromethane was added to the resulting reaction solution, which was then filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 35b. LC-MS: m / z: 189.0 (M-56+H). + .

[0247] Step 2 Synthesis of intermediate 35c Intermediate 35b (50 mg, 0.20 mmol) and dichloromethane (1.5 mL) were added to a 10 mL single-neck flask at 25°C, and trifluoroacetic acid (0.5 mL, 6.71 mmol) was added under stirring. The reaction was completed after 1 hour at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 35c. LC-MS: m / z: 189.0 (M+H). + .

[0248] Step 3: Synthesis of compound 35 Intermediate 35c (28.29 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 35. 1H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 5.35 - 5.24 (m, 1H), 4.85 (s, 1H), 4.52 (dd, J = 9.7, 6.8 Hz, 1H), 4.28 (dd, J = 9.7, 4.2 Hz, 1H), 3.90 - 3.68 (m, 1H), 2.91 - 2.73 (m, 1H), 2.16 (d, J = 12.0 Hz, 1H), 2.03 (dd, J = 13.4, 3.4 Hz, 1H), 1.66 (qd, J = 13.3, 3.1 Hz, 1H), 1.44 (qd, J = 12.9, 3.4 Hz, 1H). LC-MS: m / z: 477.1(M+H) + .

[0249] Example 18 Synthesis of Compound 36 [ka] Compound 36a (Bidu Pharmaceutical, catalog number BD11470, 29.5 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 36. 1H NMR (400 MHz, MeOD) δ 7.77 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 0.9 Hz, 1H), 7.47 - 7.44 (m, 1H), 5.40 - 5.20 (m, 1H), 4.54 (dd, J = 9.7, 6.8 Hz, 2H), 4.30 (dd, J = 9.7, 4.2 Hz, 2H), 4.05 - 3.90 (m, 1H), 2.90 - 2.77 (m, 1H), 2.21 (d, J = 12.3 Hz, 2H), 2.17 - 2.06 (m, 2H), 1.78 - 1.66 (m, 2H), 1.66 - 1.53 (m, 2H). LC-MS: m / z: 485.2(M+H) + .

[0250] Example 19 Synthesis of Compound 37 [ka] Compound 37a (Bidu Pharmaceutical, catalog number BD182201, 31.9 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 37. 1H NMR (400 MHz, MeOD) δ 7.92 (dd, J = 5.2, 3.1 Hz, 3H), 7.45 (dd, J = 8.7, 2.0 Hz, 1H), 5.39 - 5.21 (m, 1H), 4.54 (dd, J = 9.7, 6.8 Hz, 2H), 4.30 (dd, J = 9.7, 4.2 Hz, 2H), 4.03 - 3.82 (m, 1H), 2.91 - 2.77 (m, 1H), 2.30 - 2.08 (m, 4H), 1.79 - 1.65 (m, 2H), 1.58 (dt, J = 13.0, 9.8 Hz, 2H). LC-MS: m / z: 501.2(M+H) + .

[0251] Example 20 Synthesis of Compound 38 [ka] Compound 38a (Bidu Pharmaceutical, catalog number BD38284, 32.05 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 38. 1H NMR (400 MHz, MeOD) δ 8.17 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.57 (dd, J = 8.7, 2.0 Hz, 1H), 5.39 - 5.20 (m, 1H), 4.54 (dd, J = 9.6, 6.8 Hz, 2H), 4.30 (dd, J = 9.6, 4.2 Hz, 2H), 3.97 (t, J = 7.5 Hz, 1H), 2.86 (ddd, J = 11.7, 7.7, 3.5 Hz, 1H), 2.23 (d, J = 12.2 Hz, 2H), 2.15 (d, J = 11.1 Hz, 2H), 1.73 (dd, J = 25.4, 11.2 Hz, 2H), 1.63 (dd, J = 18.6, 8.5 Hz, 2H). LC-MS: m / z: 502.2(M+H) + .

[0252] Example 21 Synthesis of Compound 40 [ka] In an 8 mL reaction flask, 40a (BiDe Pharmaceutical, catalog number BD28605, 29.49 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 40. 1H NMR (400 MHz, MeOD) δ 7.67 (dd, J = 14.0, 5.3 Hz, 2H), 7.35 (dd, J = 8.7, 2.0 Hz, 1H), 5.34 - 5.28 (m, 1H), 4.55 (dd, J = 9.6, 6.8 Hz, 2H), 4.31 (dd, J = 9.7, 4.2 Hz, 2H), 4.03 - 3.89 (m, 1H), 2.88 (ddd, J = 12.1, 7.8, 3.4 Hz, 1H), 2.20 (t, J = 14.9 Hz, 4H), 1.81 - 1.53 (m, 4H). LC-MS: m / z: 485.1 (M+H) + .

[0253] Example 22 Synthesis of Compound 41 [ka] Compound 41a (Bidu Pharmaceutical, catalog number BD260228, 21.98 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 41. 1H NMR (400 MHz, MeOD) δ 7.21 (s, 1H), 5.29 (td, J = 6.8, 3.6 Hz, 1H), 4.53 (dd, J = 9.7, 6.8 Hz, 2H), 4.29 (dd, J = 9.7, 4.2 Hz, 2H), 3.95 - 3.81 (m, 1H), 2.84 (ddd, J = 11.8, 7.7, 3.5 Hz, 1H), 2.20 (d, J = 11.6 Hz, 2H), 2.11 (d, J = 9.8 Hz, 2H), 1.77 - 1.63 (m, 2H), 1.55 (dt, J = 12.8, 6.1 Hz, 2H). LC-MS: m / z: 435.1 (M+H) + .

[0254] Example 23 Synthesis of Compound 42 [ka] Compound 42a (21.47 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 42. 1H NMR (400 MHz, MeOD) δ 7.41 (d, J = 0.7 Hz, 1H), 5.34 - 5.25 (m, 1H), 4.58 - 4.48 (m, 2H), 4.30 (dd, J = 9.6, 4.1 Hz, 2H), 3.91 (ddt, J = 11.1, 7.6, 3.9 Hz, 1H), 2.85 (tt, J = 11.9, 3.4 Hz, 1H), 2.50 (d, J = 0.6 Hz, 3H), 2.20 (d, J = 11.9 Hz, 2H), 2.12 (dd, J = 12.8, 2.8 Hz, 2H), 1.76 - 1.52 (m, 4H). LC-MS: m / z: 432.1 (M+H) + .

[0255] Example 24 Synthesis of Compound 43 [ka] Compound 43a (Bidu Pharmaceutical, catalog number BD95552, 21.83 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 43. 1H NMR (400 MHz, MeOD) δ 6.88 (d, J = 1.6 Hz, 1H), 6.77 (d, J = 1.6 Hz, 1H), 5.34 - 5.25 (m, 1H), 4.53 (dd, J = 9.6, 6.9 Hz, 2H), 4.29 (dd, J = 9.6, 4.2 Hz, 2H), 3.87 (ddd, J = 11.5, 7.7, 4.0 Hz, 1H), 2.82 (ddd, J = 12.1, 8.7, 3.5 Hz, 1H), 2.23 - 2.04 (m, 4H), 1.80 - 1.40 (m, 4H). LC-MS: m / z: 434.2 (M+H) + .

[0256] Example 25 Synthesis of Compound 44 [ka] Compound 44a (Bidu Pharmaceutical, catalog number BD334736, 31.14 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 44. 1H NMR (400 MHz, MeOD) δ 8.46 (d, J = 8.5 Hz, 1H), 8.22 (dd, J = 21.6, 8.8 Hz, 2H), 8.08 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 9.1, 2.4 Hz, 1H), 5.31 (s, 1H), 4.60 - 4.48 (m, 2H), 4.30 (dd, J = 9.8, 4.2 Hz, 2H), 4.02 (s, 1H), 2.90 (t, J = 11.4 Hz, 1H), 2.21 (dd, J = 20.6, 14.6 Hz, 4H), 1.85 - 1.59 (m, 4H). LC-MS: m / z: 496.1 (M+H) + .

[0257] Example 26 Synthesis of Compound 45 [ka] Compound 45a (Bidu Pharmaceutical, catalog number BD232348, 26.12 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 45. 1H NMR (400 MHz, MeOD) δ 9.32 (s, 1H), 8.98 (s, 1H), 6.94 (t, J = 54.3 Hz, 1H), 5.34 - 5.26 (m, 1H), 4.54 (dd, J = 9.7, 6.8 Hz, 2H), 4.30 (dd, J = 9.6, 4.2 Hz, 2H), 4.02 (qd, J = 11.6, 3.6 Hz, 1H), 2.87 (tt, J = 11.9, 3.5 Hz, 1H), 2.22 (d, J = 12.2 Hz, 2H), 2.18 - 2.07 (m, 2H), 1.81 - 1.53 (m, 4H). LC-MS: m / z: 463.1 (M+H) + .

[0258] Example 27 Synthesis of Compound 46 [ka] Compound 46a (Bidu Pharmaceutical, catalog number BD160922, 26.73 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 46. 1H NMR (400 MHz, MeOD) δ 7.62 - 7.49 (m, 2H), 6.79 (dd, J = 8.6, 4.0 Hz, 1H), 5.34 - 5.27 (m, 1H), 4.53 (dd, J = 9.7, 6.8 Hz, 2H), 4.29 (dd, J = 9.6, 4.2 Hz, 2H), 4.25 - 4.17 (m, 2H), 3.91 (ddd, J = 15.4, 7.7, 3.9 Hz, 1H), 2.83 (dt, J = 8.7, 5.7 Hz, 3H), 2.19 (d, J = 12.1 Hz, 2H), 2.15 - 2.07 (m, 2H), 2.07 - 1.99 (m, 2H), 1.70 (qd, J = 13.2, 3.0 Hz, 2H), 1.53 (qd, J = 12.8, 3.2 Hz, 2H). LC-MS: m / z :467.1(M+H) + .

[0259] Example 28 Synthesis of Compound 47 [ka] Step 1: Synthesis of intermediate 47b Compound 47a (Bidu Pharmaceutical, Catalog No. BD9715, 0.4 g, 1.76 mmol), Rockphos-pd-G3 (22.15 mg, 0.02 mmol), and cesium carbonate (1.7 g, 5.27 mmol) were added to a 50 mL three-neck flask at 25 °C, followed by dimethylformamide (4.0 mL) and water (0.15 mL). After protecting with nitrogen gas, the temperature was raised to 85 °C and the reaction was carried out for 5 hours. The crude reaction mixture (containing intermediate 47b) was used in the next step without further purification. LC-MS: m / z: 163.0 (M−H). - .

[0260] Step 2 Synthesis of intermediate 47c At 25°C, tert-butyl bromoacetate (889 mg, 4.56 mmol) was added to the reaction mixture obtained in the previous step (containing intermediate 47b). The reaction was completed after 2 hours at 25°C. 5 mL of water and 15 mL of ethyl acetate were added to the resulting reaction mixture, and the resulting organic phase was washed with saturated brine (40 mL x 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 47c (80 mg, 0.28 mmol). LC-MS: m / z: 277.0 (M−H).

[0261] Step 3 Synthesis of intermediate 47d Intermediate 47c (80 mg, 0.28 mmol) and dichloromethane (1.0 mL) were added to a 10 mL single-neck flask at 25°C, and trifluoroacetic acid (0.3 mL, 4.03 mmol) was added under stirring. The reaction was completed after 1 hour at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 47d. LC-MS: m / z: 220.9 (M−H). - .

[0262] Step 4: Synthesis of compound 47 Intermediate 47d (33 mg, 0.1 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 47. 1H NMR (400 MHz, MeOD) δ 6.94 - 6.70 (m, 2H), 5.41 - 5.13 (m, 1H), 4.55 (s, 2H), 4.54 - 4.37 (m, 2H), 4.28 (dd, J = 9.6, 4.2 Hz, 2H), 4.11 - 3.68 (m, 1H), 2.81 (ddd, J = 12.1, 8.6, 3.7 Hz, 1H), 2.22 - 2.10 (m, 2H), 2.10 - 1.91 (m, 2H), 1.74 - 1.58 (m, 2H), 1.54 - 1.38 (m, 2H). LC-MS: m / z: 511.1 (M+H) + .

[0263] Example 29 Synthesis of Compound 48 [ka] Step 1: Synthesis of intermediate 48b Compound 48a (Bidu Pharmaceutical, catalog number BD297147, 0.8 g, 3.52 mmol), Rockphos-pd-G3 (44.29 mg, 0.05 mmol), and cesium carbonate (3.4 g, 10.55 mmol) were added to a 50 mL three-neck flask at 25 °C, followed by dimethylformamide (8.0 mL) and water (0.3 mL). After protecting with nitrogen gas, the temperature was raised to 85 °C and the reaction was continued for 5 hours to complete the reaction. The resulting reaction solution (containing intermediate 48b) was used directly in the next step without further purification. LC-MS: m / z: 163.0 (M−H). - .

[0264] Step 2 Synthesis of intermediate 48c At 25°C, tert-butyl bromoacetate (889 mg, 4.56 mmol) was added to the reaction mixture obtained in the previous step (containing intermediate 48b). After 2 hours at 25°C, the reaction was completed. 5 mL of water and 15 mL of ethyl acetate were added to the resulting reaction mixture, and the resulting organic phase was washed with 40 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 and purified by column chromatography to obtain intermediate 48c. 1 H NMR (400 MHz, CDCl3): δ 7.09 (dd, J = 10.4, 6.9 Hz, 1H), 6.67 (dd, J = 9.8, 7.3 Hz, 1H), 4.49 (s, 1H), 1.42 (s, 9H).

[0265] Step 3 Synthesis of intermediate 48d Intermediate 48c (200 mg, 0.72 mmol) and dichloromethane (2.0 mL) were added to a 25 mL one-neck flask at 25 °C, and trifluoroacetic acid (2.0 mL, 26.84 mmol) was added under stirring. The reaction was completed after 1 hour at 25 °C. The mixture was concentrated under reduced pressure to give Intermediate 48d. LC-MS: m / z: 220.9 (M−H). - .

[0266] Step 4 Synthesis of compound 48 Intermediate 48d (22.26 mg, 0.1 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 48. 1 H NMR (400 MHz, MeOD) δ 7.38 (dd, J = 10.6, 7.0 Hz, 1H), 7.11 (dd, J = 10.3, 7.4 Hz, 1H), 5.34 - 5.24 (m, 1H), 4.62 (s, 2H), 4.53 (dd, J = 2.05 (dd, J = 13.1, 3.4 Hz, 2H), 1.67 (qd, J = 13.2, 3.1 Hz, 2H), 1.48 (qd, J = 12.8, 3.3 Hz, 2H). LC-MS: m / z :511.2(M+H) + .

[0267] Example 30 Synthesis of Compound 49 [ka] Step 1: Synthesis of intermediate 49b Compound 49a (Bidu Pharmaceutical, Catalog No. BD66669, 0.8 g, 3.28 mmol), Rockphos-pd-G3 (41.3 mg, 0.05 mmol), and cesium carbonate (3.2 g, 9.84 mmol) were added to a 50 mL three-neck flask at 25 °C, followed by dimethylformamide (8.0 mL) and water (0.3 mL). After protecting with nitrogen gas, the temperature was raised to 85 °C and the reaction was continued for 5 hours to complete the reaction. The resulting reaction mixture (containing intermediate 49b) was used directly in the next step without further purification. LC-MS: m / z: 179.0 (M−H). - .

[0268] Step 2 Synthesis of intermediate 49c At 25°C, tert-butyl bromoacetate (727.47 mg, 3.73 mmol) was added to the reaction mixture obtained in the previous step (containing intermediate 49b). After 2 hours at 25°C, the reaction was completed. 5 mL of water and 15 mL of ethyl acetate were added to the resulting reaction mixture, and the resulting organic phase was washed with 40 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 and purified by column chromatography to obtain intermediate 49c. 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 10.2 Hz, 1H), 4.50 (s, 2H), 1.42 (d, J = 2.1 Hz, 9H).

[0269] Step 3 Synthesis of intermediate 49d Intermediate 49c (200 mg, 0.68 mmol) and dichloromethane (2.0 mL) were added to a 25 mL one-neck flask at 25 °C, and trifluoroacetic acid (2.0 mL, 26.84 mmol) was added under stirring. The reaction was completed after 1 hour at 25 °C. The mixture was concentrated under reduced pressure to give Intermediate 49d. LC-MS: m / z: 236.9 (M−H). - .

[0270] Step 4: Synthesis of compound 49 Intermediate 49d (23.9 mg, 0.1 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 20 mL of water was added to the resulting reaction mixture, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 49. 1 H NMR (400 MHz, DMSO) δ 7.96 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 11.2 Hz, 1H), 5.32 (dd, J = 8.9, 5.4 Hz, 1H), 4.66 (s, 2H), 4.51 - 4.37 (m, 2H), 4.19 (dd, J = 9.6, 3.8 Hz, 2H), 3.63 - 3.60 (m, 1H), 2.83 - 2.69 (m, 1H), 2.03 (d, J = 11.7 Hz, 2H), 1.89 (d, J = 10.0 Hz, 2H), 1.51 (q, J = 10.6 Hz, 2H), 1.35 (dd, J = 24.1, 9.9 Hz, 2H). LC-MS: m / z: 527.2(M+H) + .

[0271] Example 31 Synthesis of Compound 50 [ka] Step 1. Synthesis of intermediate 50b Compound 50a (Bidu Pharmaceutical, Catalog No. BD322259, 0.4 g, 1.76 mmol), Rockphos-pd-G3 (22.15 mg, 0.02 mmol), and cesium carbonate (1.7 g, 5.27 mmol) were added to a 50 mL three-neck flask at 25 °C, followed by dimethylformamide (4.0 mL) and water (0.15 mL). After protecting with nitrogen gas, the temperature was raised to 85 °C and the reaction was continued for 5 hours to complete the reaction. The resulting reaction mixture (containing intermediate 50b) was used directly in the next step without further purification. LC-MS: m / z: 163.0 (M−H). - .

[0272] Step 2 Synthesis of intermediate 50c At 25°C, tert-butyl bromoacetate (889 mg, 4.56 mmol) was added to the reaction solution obtained in the previous step (containing intermediate 50b). After reacting at 25°C for 2 hours, the reaction was completed. 5 mL of water and 15 mL of ethyl acetate were added to the resulting reaction solution, and the resulting organic phase was washed with 40 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 and purified by column chromatography to obtain intermediate 50c. LC-MS: m / z: 279.2 (M+H). + .

[0273] Step 3 Synthesis of intermediate 50d Intermediate 50c (220 mg, 0.79 mmol) and dichloromethane (2.0 mL) were added to a 25 mL one-neck flask at 25°C, and trifluoroacetic acid (2.0 mL, 26.84 mmol) was added under stirring. The reaction was completed after 1 hour at 25°C. The mixture was concentrated under reduced pressure to give Intermediate 50d. LC-MS: m / z: 223.0 (M+H). + .

[0274] Step 4: Synthesis of compound 50 Intermediate 50d (33.15 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 15 mL of water was added to the resulting reaction mixture, which was then extracted with 15 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 50. 1 H NMR (400 MHz, MeOD) δ 7.32 - 7.16 (m, 1H), 6.99 - 6.83 (m, 1H), 5.39 - 5.23 (m, 1H), 4.64(s, 2H), 4.53 (dd, J = 9.6, 6.9 Hz, 2H), 4.28 (dd, J = 9.6, 4.2 Hz, 2H), 3.83 (dd, J = 13.6, 9.6 Hz, 1H), 2.80 (tt, J = 12.0, 3.4 Hz, 1H), 2.18 (t, J = 12.7 Hz, 2H), 2.10 - 1.95 (m, 2H), 1.66 (qd, J= 13.2, 3.1 Hz, 2H), 1.47 (qd, J = 12.8, 3.2 Hz, 2H). LC-MS: m / z :511.1(M+H) + .

[0275] Example 32 Synthesis of Compound 52 [ka] Step 1. Synthesis of intermediate 52b Compound 52a (0.2 g, 1.15 mmol), tert-butyl bromoacetate (0.25 g, 1.27 mmol), and potassium carbonate (0.317 g, 9.84 mmol) were added to an 8 mL reaction tube at 25 °C, followed by acetonitrile (2.0 mL). The mixture was allowed to react at room temperature for 3 hours. The reaction solution was centrifuged and dried, and the crude product was purified by column chromatography to obtain intermediate 52b. LC-MS: m / z: 288.0 (M+H). + .

[0276] Step 2 Synthesis of intermediate 52c At 25°C, 1 mL of trifluoroacetic acid and 1 mL of dichloromethane were added to intermediate 52b (240 mg, 0.83 mmol). The reaction was completed after 2 hours at 25°C. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 52c. LC-MS: m / z: 232.0 (M+H). + .

[0277] Step 3 Synthesis of intermediate 52d Intermediate 52c (177 mg, 0.76 mmol) and N,N-dimethylformamide (2.0 mL) were placed in a 25 mL single-neck flask at 25 °C, and intermediate 21b (60 mg, 0.196 mmol) was added under stirring. The reaction was completed after 4 hours at 25 °C. The resulting reaction mixture was separated and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to give intermediate 52d. LC-MS: m / z: 520.1 (M+H).

[0278] Step 4 Synthesis of compound 52 Intermediate 52d (20 mg, 0.038 mmol) was dissolved in methanol (1.5 mL) and water (0.5 mL) in a 25 mL reaction flask at 25 °C, and iron powder (11 mg, 0.19 mmol) and ammonium chloride (10.29 mg, 0.19 mmol) were added sequentially under stirring. The mixture was stirred at 70 °C for 1 hour to complete the reaction. The resulting reaction solution was filtered while hot, and the filtrate was centrifuged to dryness to obtain the crude product. The crude product was separated and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 52. 1 H NMR (400 MHz, DMSO) δ 8.00 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 5.32 (td, J = 6.5, 3.4 Hz, 1H), 4.46 (dd, J = 9.7, 6.8 Hz, 3H), 4.40 (s, 2H), 4.20 (dd, J = 9.7, 4.1 Hz, 3H), 3.89 (s, 1H), 2.71 (d, J = 11.7 Hz, 1H), 2.05 (d, J = 11.7 Hz, 2H), 1.85 (d, J = 10.2 Hz, 2H), 1.60 - 1.38 (m, 4H). LC-MS: m / z 490.2(M+H) + .

[0279] Example 33 Synthesis of Compound 53 [ka] Step 1: Synthesis of intermediate 53b Compound 53a (Bidu Pharmaceutical, catalog number BD222433, 100 mg, 0.45 mmol), tert-butyl bromoacetate (85.45 mg, 0.65 mmol), cesium carbonate (421.3 mg, 1.3 mmol), and methanesulfonyl (2-(di-tert-butylphosphino)-3-methoxy-6-methyl,2,4,6-methoxytriisopropyl-1,1-biphenyl) (2-amino-1,1-biphenyl-2-yl) palladium(II) (7 mg, 0.009 mmol) were dissolved in 1,4-dioxane (5 mL) at 25 °C in a 25 mL reaction flask. The reaction was carried out overnight at 95 °C to complete the reaction. 15 mL of dichloromethane was added to the resulting reaction mixture, which was then filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 53b. 1 H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 4.81 (s, 2H), 1.41 (s, 9H).

[0280] Step 2 Synthesis of intermediate 53c Intermediate 53b (90 mg, 0.32 mmol) and dichloromethane (1 mL) were added to a 25 mL one-neck flask at 25 °C, and trifluoroacetic acid (1 mL, 13.42 mmol) was added under stirring. The reaction was completed after 1 hour at 25 °C. The mixture was concentrated under reduced pressure to give Intermediate 53c. LC-MS: m / z: 225.9 (M−H). - .

[0281] Step 3: Synthesis of compound 53 Intermediate 53c (34.07 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The mixture was stirred at 25 °C for 10 hours to complete the reaction. 15 mL of water was added to the resulting reaction mixture, which was then extracted with 15 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 53. 1 H NMR (400 MHz, MeOD) δ 8.16 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 1.4 Hz, 1H), 5.17 (ddd, J = 10.9, 6.8, 4.3 Hz, 1H), 4.85 (s, 2H), 4.40 (dd, J = 9.7, 6.8 Hz, 2H), 4.16 (dd, J = 9.6, 4.2 Hz, 2H), 3.68 (td, J = 11.6, 5.9 Hz, 1H), 2.68 (ddd, J = 12.1, 8.6, 3.5 Hz, 1H), 2.12 - 1.99 (m, 2H), 1.97 - 1.86 (m, 2H), 1.54 (ddd, J = 25.6, 13.2, 3.1 Hz, 2H), 1.33 (ddd, J = 25.4, 13.1, 3.5 Hz, 2H). LC-MS: m / z 516.2(M+H) + .

[0282] Examples 34 and 35 Synthesis of Compound 6 and Compound 12 [ka] Step 1: Synthesis of intermediate 6b Compound 6a (Bidu Pharmaceutical, catalog number BD00841787, 1.50 g, 7.75 mmol) and dimethylformamide (30 mL) were added to a 50 mL single-neck flask at 25 °C. Under stirring, compound 1i (1.58 g, 7.75 mmol), diisopropylethylamine (5.13 mL, 30.98 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.42 g, 11.62 mmol) were added sequentially. The reaction was completed after 18 hours at 25 °C. The resulting reaction solution was poured into 200 mL of water and then extracted twice with 300 mL of ethyl acetate. The resulting organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate overnight, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=10:1 to 1:2) to obtain intermediate 6b. LC-MS: m / z: 344.0 (M+H) + .

[0283] Step 2 Synthesis of intermediate 6c Compound 6b (2.2 g, 6.40 mmol) and ethanol (20 mL) were added to a 50 mL single-neck flask at 25°C, and hydrazine hydrate (20 mL) was added dropwise under stirring. The reaction was completed after 16 hours at 85°C. The resulting reaction solution was cooled to room temperature and then concentrated under reduced pressure to obtain a crude product. The crude product was suspended in acetonitrile (50 mL), and the suspension was stirred at 25°C for 2 hours, filtered, and washed to obtain intermediate 6c. 1H NMR (400 MHz, DMSO-d6)δ8.93 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.88-6.77 (m, 1H), 4.49 (s, 2H), 3.56 (tt, J = 8.0, 4.0 Hz, 1H), 3.18 (d, J = 6.9 Hz, 1H), 2.00 (s, 1H), 1.79-1.62 (m, 4H), 1.46-1.22 (m, 4H). LC-MS: m / z :344.0(M+H) + .

[0284] Step 3 Synthesis of intermediate 6d Intermediate 6c (1 g, 2.91 mmol) and dichloromethane (30 mL) were placed in a 50 mL single-neck flask at 25 °C, and N,N'-carbonyldiimidazole (0.71 g, 4.37 mmol) was added under stirring. After 16 hours of reaction at 25 °C, the reaction was completed and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:methanol = 10:1 to 5:1) to obtain intermediate 6d. LC-MS: m / z: 370.0 (M+H). + .

[0285] Step 4 Synthesis of compound 6 Intermediate 6d (100 mg, 0.27 mmol) and dimethylformamide (4 mL) were added to a 50 mL single-neck flask at 25 °C. Under stirring, diisopropylethylamine (0.18 mL, 1.08 mmol), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (179.41 mg, 0.41 mmol), and compound 6f (71.50 mg, 0.40 mmol) were added sequentially. The reaction was completed after 18 hours at 25 °C. The reaction solution was poured into 20 mL of water and then extracted with 30 mL of ethyl acetate, for a total of two extractions. The resulting organic phase was washed with 10 mL of saturated brine, dried over sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 6. 1 H NMR (400 MHz, DMSO-d6)δ8.05 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (dd, J = 8.7, 2.9 Hz, 1H), 5.37-5.24 (m, 1H), 4.56-4.37 (m, 4H), 4.19 (dd, J = 9.7, 4.0 Hz, 2H), 3.66 (t, J = 3.8 Hz, 1H), 2.73 (td, J = 11.9, 10.1, 6.1 Hz, 1H), 2.09-1.97 (m, 2H), 1.90-1.79 (m, 2H), 1.55-1.35 (m, 4H). LC-MS: m / z :493.1(M+H) + .

[0286] Step 5 Synthesis of compound 12 Compound 6 (40 mg, 0.08 mmol) and toluene (3 mL) were placed in a 50 mL single-neck flask at 25 °C, and Lawesson's reagent (32.82 mg, 0.08 mmol) was added under stirring. The reaction was completed after 1 hour at 120 °C. After cooling to 25 °C, the resulting reaction solution was poured into 20 mL of water and then extracted twice with 30 mL of ethyl acetate each time. The resulting 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 12. 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (dd, J = 8.7, 2.9 Hz, 1H), 5.37-5.24 (m, 1H), 4.56-4.37 (m, 4H), 4.19 (dd, J = 9.7, 4.0 Hz, 2H), 3.66 (t, J = 3.8 Hz, 1H), 2.73 (td, J = 11.9, 10.1, 6.1 Hz, 1H), 2.09-1.97 (m, 2H), 1.90-1.79 (m, 2H), 1.55-1.35 (m, 4H). LC-MS: m / z :509.0(M+H) + .

[0287] Example 36 Synthesis of Compound 13 [ka] Compound 12 (80 mg, 0.16 mmol) and toluene (5 mL) were added to a 50 mL single-neck flask at 25 °C, and Lawesson's reagent (64.71 mg, 0.16 mmol) was added under stirring. The reaction was completed after 18 hours at 120 °C. After cooling to 25 °C, the resulting reaction solution was poured into 20 mL of water and then extracted twice with 30 mL of ethyl acetate each time. The resulting 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 liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 13. 1 H NMR (400 MHz, DMSO-d6)δ8.05 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 (dd, J = 8.7, 2.9 Hz, 1H), 5.37-5.24 (m, 1H), 4.56-4.37 (m, 4H), 4.19 (dd, J = 9.7, 4.0 Hz, 2H), 3.66 (t, J = 3.8 Hz, 1H), 2.73 (td, J = 11.9, 10.1, 6.1 Hz, 1H), 2.09-1.97 (m, 2H), 1.90-1.79 (m, 2H), 1.55-1.35 (m, 4H). LC-MS: m / z :525.0(M+H) + .

[0288] Example 37 Synthesis of Compound 11 [ka] Step 1: Synthesis of intermediate 11b Compound 11a (Bidu Pharmaceutical, catalog number BD254006, 150 mg, 0.89 mmol), tert-butanol (0.5 mL), and toluene (3 mL) were added to a 50 mL single-neck flask at 25°C. Diphenylphosphoryl azide (0.25 mL, 1.16 mmol) and triethylamine (0.27 mL, 1.96 mmol) were added sequentially under stirring. The reaction was completed after 8 hours at 85°C. The resulting reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 11b. LC-MS: m / z: 240.1 (M+H). + .

[0289] Step 2 Synthesis of intermediate 11c Intermediate 11b (200 mg, 0.42 mmol) and dioxane hydrochloride (5 mL) were added to a 50 mL one-neck flask at 25° C. The reaction was completed after 3 hours at 25° C. The resulting reaction solution was concentrated under reduced pressure to give Intermediate 11c. LC-MS: m / z: 140.0 (M+H) + .

[0290] Step 3: Synthesis of compound 11 Intermediate 6d (50 mg, 0.14 mmol) and dimethylformamide (2 mL) were added to a 50 mL single-neck flask at 25 °C. Under stirring, diisopropylethylamine (0.09 mL, 0.54 mmol), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (89.71 mg, 0.20 mmol), and intermediate 11c (28.22 mg, 0.20 mmol) were sequentially added. The reaction was completed after 18 h at 25 °C. The resulting reaction solution was poured into 20 mL of water and then extracted twice with 30 mL of ethyl acetate each time. The resulting 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 liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 11. 1H NMR (400 MHz, DMSO-d6)δ7.97 (d, J = 67.1 Hz, 1H), 7.50 (s, 1H), 7.08 (s, 1H), 6.85 (d, J = 9.0 Hz, 1H), 4.50 (s, 2H), 3.97 (s, 2H), 3.72-3.59 (m, 1H), 3.11 (s, 1H), 2.92 (s, 1H), 2.68 (s, 1H), 2.36 (s, 1H), 1.91 (d, J = 64.6 Hz, 6H), 1.43 (d, J = 30.2 Hz, 4H). LC-MS: m / z :491.0(M+H) + .

[0291] Example 38 Synthesis of Compound 14 [ka] Intermediate 6d (50 mg, 0.14 mmol) and dimethylformamide (2 mL) were added to a 50 mL single-neck flask at 25 °C. Under stirring, diisopropylethylamine (0.09 mL, 0.54 mmol), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (89.71 mg, 0.20 mmol), and compound 14a (BiDe Pharmaceutical, catalog number BD00841787, 71.61 mg, 0.41 mmol) were added sequentially. The reaction was completed after 18 hours at 25 °C. The resulting reaction solution was poured into 20 mL of water and then extracted twice with 30 mL of ethyl acetate each time. The resulting 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 liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 14. 1H NMR (400 MHz, DMSO-d6)δ7.88 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 6.94 (dd, J = 11.1, 2.9 Hz, 1H), 6.83-6.74 (m, 1H), 4.46 (s, 2H), 4.02 (d, J = 7.1 Hz, 1H), 3.78-3.62 (m, 1H), 2.95 (d, J = 14.9 Hz, 3H), 2.81 (q, J = 8.7 Hz, 1H), 2.13-2.03 (m, 2H), 1.90 (dd, J = 13.2, 3.8 Hz, 2H), 1.61-1.13 (m, 9H). LC-MS: m / z: 505.2 (M+H) + .

[0292] Example 39 Synthesis of Compound 4 [ka] Step 1: Synthesis of intermediate 4b Compound 4a (BiDe Pharmaceutical, catalog number BD163186, 15.5 g, 68.5 mmol) and glacial acetic acid (125 mL) were added to a 500 mL single-neck flask at 25 °C, and chromium trioxide (13.70 g, 137 mmol) was added under stirring. The reaction was completed after stirring at 90 °C for 16 hours. Ethyl acetate (100 mL) was added to the reaction mixture, which was then poured into HO (200 mL). The pH was adjusted to 9 with solid NaHCO3, followed by extraction. The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 4b. LC-MS: m / z: 241.0 (M+H). + .

[0293] Step 2 Synthesis of intermediate 4c Intermediate 4b (5.023 g, 20.91 mmol), tetrahydrofuran (60 mL), and methanol (15 mL) were added to a 250 mL single-neck flask at 25°C, followed by an aqueous solution (15 mL) of LiOH (400 mg, 16.73 mmol). The reaction was completed after stirring at 25°C for 16 hours. The tetrahydrofuran was removed by concentration under reduced pressure, and the pH was adjusted to 2-3 by adding 2 mol / L HCl. A solid precipitated, which was filtered to obtain the filter cake, intermediate 4c. LC-MS: m / z: 225.0 (MH). - .

[0294] Step 3 Synthesis of intermediate 4d Intermediate 4c (2.15 g, 9.5 mmol) and tert-butanol (30 mL) were added to a 100 mL single-neck flask at 25 °C, and pyridine (5.37 mL, 66.53 mmol), DMAP (1.16 g, 9.5 mmol), and (Boc)2O (4.07 mL, 19.01 mmol) were added. The reaction was completed after stirring at 35 °C for 16 h. The mixture was concentrated under reduced pressure, poured into water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give intermediate 4d. LC-MS: m / z: 283.10 (M+H). + .

[0295] Step 4 Synthesis of intermediate 4e Intermediate 4d (1.204 g, 4.26 mmol), tetrahydrofuran (20 mL), and methanol (5 mL) were added to a 100 mL single-neck flask at 25°C, followed by an aqueous solution (4 mL) of lithium hydroxide (100 mg, 4.26 mmol). The reaction was completed after stirring at 25°C for 16 hours. The tetrahydrofuran was removed by concentration under reduced pressure, and the pH was adjusted to 2-3 with 2 M HCl. A solid precipitated, which was filtered to obtain the filter cake, intermediate 4e. LC-MS: m / z: 269.10 (M+H). + .

[0296] Step 5 Synthesis of intermediate 4f Intermediate 4e (800 mg, 2.98 mmol) and toluene (50 mL) were added to a 100 mL single-neck flask at 25 °C. Triethylamine (1.24 mL, 8.94 mmol) and diphenylphosphoryl azide (1641.09 mg, 5.96 mmol) were added under stirring, and the mixture was stirred at 120 °C for 2 h. Benzyl alcohol (0.93 mL, 8.94 mmol) was then added, and the reaction was completed after stirring at 120 °C for 12 h. Water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give intermediate 4f. LC-MS: m / z: 374.2 (M+H). +

[0297] Step 6 Synthesis of intermediate 4g Intermediate 4f (890 mg, 2.38 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL single-neck flask at 25°C. Palladium hydroxide (297.79 mg, 2.12 mmol) was added under stirring, and the mixture was purged with hydrogen three times. The reaction was completed after stirring at 25°C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 4g. LC-MS: m / z: 240.1 (M+H) + .

[0298] Step 7 Synthesis of intermediate 4i Intermediate 4g obtained in the previous step and dichloromethane (6 mL) were added to a 25 mL single-neck flask at 25 °C. Under stirring conditions, intermediate 1i (300.39 mg, 1.26 mmol), diisopropylethylamine (0.83 mL, 5.02 mmol), and 1-propylphosphoric acid anhydride (1597.59 mg, 2.51 mmol) were added. The reaction was completed after stirring at 25 °C for 16 h. Water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 4:1) to give intermediate 4i. LC-MS: m / z: 426.2 (M+H). + .

[0299] Step 8 Synthesis of intermediate 4j Intermediate 4i (260 mg, 0.61 mmol) and dichloromethane (5 mL) were added to a 25 mL one-neck flask at 0° C., and trifluoroacetic acid (5 mL) was added under stirring. The reaction was completed after stirring at 50° C. for 1 hour. The solvent was removed by concentration under reduced pressure to obtain intermediate 4j. LC-MS: m / z: 370.1 (M+H). + .

[0300] Step 9 Synthesis of intermediate 4k Intermediate 4j (225.7 mg, 0.61 mmol) and dimethylformamide (5 mL) were added to a 25 mL single-neck flask at 25 °C. Under stirring conditions, tert-butyl carbazate (0.09 mL, 0.73 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234.02 mg, 1.22 mmol), 1-hydroxybenzotriazole (315.54 mg, 2.44 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.22 mmol) were added. The reaction was completed after stirring at 25 °C for 16 h. Water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give intermediate 4k. LC-MS: m / z: 484.2 (M+H) + .

[0301] Step 10 Synthesis of intermediate 4l Intermediate 4k (296 mg, 0.61 mmol) and dichloromethane (3 mL) were added to a 25 mL single-neck flask at 0 °C, and 4 M hydrochloric acid in dioxane (3 mL) was added under stirring. The reaction was completed after stirring at 25 °C for 1 hour. The solvent was removed by concentration under reduced pressure to obtain intermediate 4l. LC-MS: m / z: 385.8 (M+H).

[0302] Step 11 Synthesis of intermediate 4m Intermediate 4l obtained in the previous step and tetrahydrofuran (2 mL) were added to a 10 mL single-neck flask at 25 °C. N,N-diisopropylethylamine (0.09 mL, 0.57 mmol) and thiocarbonyldiimidazole (61.29 mg, 0.34 mmol) were added under stirring. The mixture was stirred at 25 °C for 16 hours, and then at 70 °C for 3 hours to complete the reaction. Water (3 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (3 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (pure ethyl acetate) to give intermediate 4m. LC-MS: m / z: 426.1 (M+H).

[0303] Step 12 Synthesis of intermediate 4n Intermediate 4m (122 mg, 0.29 mmol) and dimethylformamide (1.5 mL) were added to a 10 mL single-neck flask at 25 °C. Potassium carbonate (79.18 mg, 0.57 mmol) and iodomethane (35.68 μL, 0.57 mmol) were added under stirring. The reaction was completed after 3 hours of stirring at 25 °C. Water (5 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (6 mL × 3). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give intermediate 4n. LC-MS: m / z: 440.1 (M+H). + .

[0304] Step 13 Synthesis of intermediate 4o Intermediate 4n (65 mg, 0.15 mmol) and dichloromethane (1 mL) were added to a 10 mL single-neck flask at 0 °C, and m-chloroperbenzoic acid (105.00 mg, 0.52 mmol) was added under stirring. The reaction was completed after 16 hours of stirring at 25 °C. Saturated sodium thiosulfate solution was added to the reaction mixture, followed by water (3 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (3 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 4o. LC-MS: m / z: 472.1 (M+H). + .

[0305] Step 14 Synthesis of intermediate 4q Intermediate 4o (44 mg, 0.09 mmol) and dimethylformamide (1 mL) were added to a 10 mL single-neck flask at 25 °C. Compound 4p (65.78 mg, 0.47 mmol) and potassium carbonate (90.20 mg, 0.65 mmol) were added under stirring. The reaction was completed after 4 hours of stirring at 25 °C. Water (2 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (3 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 4q. LC-MS: m / z: 533.2 (M+H) + .

[0306] Step 15 Synthesis of Compound 4 Intermediate 4q (35 mg, 0.07 mmol) and methanol (1 mL) were added to a 10 mL single-neck flask at 0 °C. Sodium borohydride (4.97 mg, 0.13 mmol) was added under stirring, and the reaction was completed after stirring at 25 °C for 1 hour. 2 M hydrochloric acid solution was added to the reaction mixture until pH = 7, followed by water (2 mL) and extraction with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine (3 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was subjected to preparative thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 4. LC-MS: m / z: 535.2 (M+H). + . 1 H NMR (DMSO-d6) δ: 7.55 (t, J=8.9 Hz, 1H), 7.42 (s, 1H), 7.13 (dd, J=11.4, 2.8 Hz, 1H), 6.90 (dd, J=8.9, 2.7 Hz, 1H), 5.33-5.41 (m, 1H), 5.12-5.32 (m, 1H), 4.55 (s, 2H), 4.51 (dd, J=9.4, 6.9 Hz, 2H), 4.25 (dd, J=9.6, 3.9 Hz, 2H), 4.17 (br d, J=7.1 Hz, 1H), 2.23-2.37 (m, 1H), 2.13 (br d, J=5.0 Hz, 1H), 1.80-2.05 (m, 7H), 1.74 (dd, J=13.6, 2.5 Hz, 1H).

[0307] Example 40 Synthesis of Compound 3 [ka] Step 1: Synthesis of intermediate 3b To a solution of 3a (BiDe Pharmaceutical, catalog number BD234253, 1 g, 5.46 mmol) and 1i (1 g, 4.96 mmol) in DCM (20 mL) was added DIEA (3.28 mL, 19.84 mmol) and T3P (3.16 g, 9.92 mmol), and the mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give intermediate 3b. m / z ES+ [M+H]+ = 370.1.

[0308] Step 2 Synthesis of intermediate 3c To a solution of intermediate 3b (1.13 g, 3.06 mmol) in EtOH (8 mL) was added N2H4·H2O (9 mL), and the mixture was stirred at 100 °C overnight. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give intermediate 3c. m / z ES + [M+H] + =370.1.

[0309] Step 3 Synthesis of intermediate 3d To a solution of intermediate 3c (100 mg, 0.27 mmol) and DIEA (90 μL, 0.54 mmol) in THF (1.5 mL) was added CDI (48 mg, 0.30 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was poured into water (5 mL) and extracted with dichloromethane (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (pure ethyl acetate) to give intermediate 3d. m / z ES + [M+H] + =396.1.

[0310] Step 4 Synthesis of compound 3 To a solution of intermediate 3d (75 mg, 0.19 mmol) and 3-(trifluoromethoxy)azetidine (67 mg, 0.38 mmol) in dimethylformamide (1.5 mL) was added DIEA (94 μL, 0.57 mmol). The resulting mixture was stirred at room temperature for 10 minutes, followed by the addition of Carter condensation reagent (92 mg, 0.21 mmol), and the mixture was stirred at room temperature overnight. The resulting reaction mixture was poured into water (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 3. m / z ES + [M+H] + =519.1. 1 H NMR (DMSO-d6) δ: 7.58 (s, 1H), 7.48 (t, J=8.8 Hz, 1H), 7.03 (dd, J=11.4, 2.6 Hz, 1H), 6.82 (d, J=9.1 Hz, 1H), 5.26-5.35(m, 1H), 4.46 (s, 2H), 4.40-4.45 (m, 2H), 4.18 (br dd, J=9.5, 3.6 Hz, 2H), 1.90 (br d, J=5.1 Hz, 12H).

[0311] Example 41 Synthesis of Compound 10 [ka] Step 1 Preparation of intermediate 10b Compound 10a (BiDe Pharmaceutical, catalog number BD234295, 2 g, 7.06 mmol) and dichloromethane (15 mL) were added to a 100 mL single-neck flask at 25°C, and trifluoroacetic acid (5.0 mL) was added under stirring. The reaction was completed after 3 hours at 25°C. The mixture was concentrated under reduced pressure to obtain intermediate 10b.

[0312] Step 2 Preparation of intermediate 10c Compound 1i (1.74 g, 8.51 mmol) and dimethylformamide (15 mL) were added to a 100 mL single-neck flask in an ice bath. Under stirring, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.04 g, 10.64 mmol) and diisopropylethylamine (3.69 g, 28.83 mmol) were added sequentially. After reacting at 25°C for half an hour, intermediate 10b (1.3 g, 7.09 mmol) was added to the resulting reaction mixture, and the mixture was allowed to react overnight at 25°C. The resulting reaction mixture was added with 150 mL of water, extracted with 150 mL of ethyl acetate, washed with 150 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 then subjected to high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain intermediate 10c. LC-MS: m / z: 393.0 (M+Na) + .

[0313] Step 3 Preparation of intermediate 10d Intermediate 10c (1.6 g, 4.33 mmol) and ethanol (15 mL) were added to a 100 mL single-neck flask at 25°C, and 50% hydrazine hydrate (3.61 g, 43.3 mmol) was added under stirring. The mixture was heated to 80°C and allowed to react overnight to completion. The crude product was obtained by concentration under reduced pressure. The crude product was purified by recrystallization from acetonitrile solvent to obtain intermediate 10d. LC-MS: m / z: 370.2 (M+H) + .

[0314] Step 4 Preparation of intermediate 10e At 25°C, intermediate 10d (616 mg, 1.67 mmol) and 1,2-dichloroethane (5 mL) were added to a 100 mL single-neck flask, and N,N'-carbonyldiimidazole (350 mg, 2.16 mmol) was added in sequence under stirring. The reaction was completed after 18 hours at 25°C. 50 mL of water was added to the reaction mixture, which was then extracted with 50 mL of ethyl acetate. The resulting 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 by column chromatography to obtain intermediate 10e. LC-MS: m / z: 396.0 (M+H). + .

[0315] Step 5 Preparation of intermediate 10g Compound 10f (1.0 g, 4.83 mmol) and ethyl acetate (20 mL) were added to a 100 mL three-neck flask in an ice bath. The flask was then wrapped in tin foil to protect from light. Silver trifluoromethanesulfonate (3.72 g, 14.48 mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (2.56 g, 7.24 mmol), potassium fluoride (1.12 g, 19.32 mmol), 2-fluoropyridine (1.34 g, 14.48 mmol), and (pentafluoroethyl)trimethylsilane (2.78 mg, 11.48 mmol) were added under stirring. The reaction was allowed to proceed at 25°C for 16 hours, after which completion of the reaction was confirmed by TLC. 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 column chromatography to give 10 g of intermediate. 1 H NMR (400 MHz, DMSO-d6) δ 7.32 - 7.18 (m, 5H), 5.13 - 5.10 (s, 2H), 4.97 - 4.98 (m,1H), 4.28 - 4.26(m, 2H), 4.04 -4.02 (m, 2H).

[0316] Step 6 Preparation of intermediate 10h At 25°C, intermediate 10g (110mg, 0.34mmol) and anhydrous methanol (5.0mL) were added to a 50mL single-neck flask, and while stirring, palladium on carbon (22mg) and a few drops of concentrated hydrochloric acid were added in that order. After purging with hydrogen three times, the reaction was carried out under a hydrogen gas atmosphere at 25°C for 16 hours, at which point the reaction was completed. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 10h.

[0317] Step 7 Preparation of compound 10 Intermediate 10h (51 mg, 0.13 mmol) and dimethylformamide (5.0 mL) were added to a 50 mL single-neck flask in an ice bath. Under stirring, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (86 mg, 0.19 mmol), diisopropylethylamine (68 mg, 0.78 mmol), and intermediate 10e (22 mg, 0.12 mmol) were added sequentially. The reaction was allowed to proceed overnight at 25°C. 25 mL of water was added to the reaction mixture, which was then extracted with 25 mL of ethyl acetate. The resulting organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 10. 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.53 - 7.48 (m, 1H), 7.06 - 7.02(m, 1H), 6.87 - 6.84 (m, 1H), 5.48 - 5.45 (m, 1H), 4.49 - 4.45 (m, 4H), 4.20 - 4.16 (m, 2H), 1.93 - 1.86 (m, 12H), LC-MS: m / z: 569.0(M+H) + .

[0318] Example 42 Synthesis of Compound 8 [ka] Step 1: Synthesis of intermediate 8b In an ice bath, compound 8a (BiDe Pharmaceutical, catalog number BD159912, 1000 mg, 4.73 mmol) and dichloromethane (50 mL) were added to a 250 mL single-neck flask, and diethylaminosulfur trifluoride (2.5 mL, 18.93 mmol) was slowly added dropwise under stirring. The reaction was completed after 16 hours at 25°C. The resulting reaction solution was quenched by slowly adding dropwise to 20 mL of ice water, extracted with 20 mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain intermediate 8b. 1 H NMR (400 MHz, MeOD) δ = 3.99 (s, 4H), 2.75 (t, J = 12.1 Hz, 4H), 1.43 (s, 9H).

[0319] Step 2 Synthesis of intermediate 8c Intermediate 8b (100 mg, 0.43 mmol) and dichloromethane (1 mL) were placed in a 50 mL single-neck flask at 25°C, and trifluoroacetic acid (0.3 mL, 4.03 mmol) was added under stirring. The reaction was completed after 16 hours. The solvent was evaporated to dryness to obtain Intermediate 8c. 1 H NMR (400 MHz, CDCl3) δ = 4.57 - 3.89 (m, 4H), 3.13 - 2.57 (m, 4H).

[0320] Step 3 Synthesis of compound 8 At 25°C, intermediate 10e (30 mg, 0.08 mmol) and dimethylformamide (1 mL) were added to a 50 mL single-neck flask, and under stirring, intermediate 8c (20.18 mg, 0.15 mmol), Carter condensation reagent (67.0 mg, 0.15 mmol), and diisopropylethylamine (0.08 mL, 0.45 mmol) were added in that order. The reaction was completed after 16 hours at 25°C. The reaction mixture was filtered and subjected to further purification. The crude product was subjected to high-performance liquid chromatography (formic acid / acetonitrile / water system) to finally obtain compound 8. LC-MS: m / z: 511.0 (M+H). + . 1H NMR (400 MHz, MeOD) δ = 7.37 (t, J = 8.7 Hz, 1H), 6.91 (dd, J = 2.8, 11.0 Hz, 1H), 6.80 (ddd, J = 1.3, 2.9, 8.9 Hz, 1H), 4.43 (s, 2H), 4.21 (s, 4H), 2.84 (t, J = 12.1 Hz, 4H), 2.09 - 1.98 (m, 12H).

[0321] Example 43 Synthesis of Compound 9 [ka] Step 1 Preparation of intermediate 9b Dimethylphosphine oxide (0.55 g, 7.06 mmol) and tetrahydrofuran (30 mL) were added to a 50 mL single-neck flask at 25 °C, and sodium bis(trimethylsilyl)amide (3.53 mL, 7.06 mmol) was added under ice-bath stirring. After 1 hour of reaction at 25 °C, compound 9a (Bidu Pharmaceutical, catalog number BD32891, 1 g, 3.53 mmol) was added. After 16 hours of reaction at 25 °C, the reaction was completed. The resulting reaction solution was poured into 100 mL of water, extracted twice with 200 mL of ethyl acetate each time, and 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 intermediate 9b. LC-MS: m / z: 134.0 (M+H) + .

[0322] Step 2 Preparation of compound 9c At 25°C, intermediate 9b (200 mg, 1.50 mmol), sodium bicarbonate (378.62 mg, 4.51 mmol), tetrahydrofuran (20 mL), and water (10 mL) were added to a 50 mL single-neck flask, and benzyl chloroformate (0.32 mL, 2.25 mmol) was added dropwise under stirring. The reaction was completed after 16 hours at 25°C. The resulting reaction solution was poured into 100 mL of water and then extracted twice with 200 mL of ethyl acetate. The resulting 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 intermediate 9c. LC-MS: m / z: 268.0 (M+H). + .

[0323] Step 3 Preparation of intermediate 9d At 25°C, intermediate 9c (100 mg, 0.37 mmol), 1 mol / L hydrochloric acid (2 mL), methanol (10 mL), and 10% palladium on carbon (39.82 mg, 0.37 mmol) were added to a 50 mL single-neck flask. After the addition, the mixture was purged with hydrogen three times, and then the mixture was reacted under hydrogen gas at 25°C for 16 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to give intermediate 9d. LC-MS: m / z: 134.0 (M+H). + .

[0324] Step 4 Preparation of compound 9 Intermediate 9d (15.98 mg, 0.12 mmol), intermediate 10e (30 mg, 0.08 mmol), and dimethylformamide (4 mL) were added to a 50 mL single-neck flask at 25°C. Diisopropylethylamine (0.05 mL, 0.30 mmol) and Carter condensation reagent (50.28 mg, 0.11 mmol) were added sequentially under stirring. The reaction was completed after 18 hours at 25°C. The resulting reaction solution was poured into 20 mL of water and then extracted twice with 30 mL of ethyl acetate. The resulting 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 liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 9. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.60 (s, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.9 Hz, 1H), 6.85 - 6.80 (m, 1H), 4.46 (s, 2H), 4.30 - 4.03 (m, 4H), 3.12 (d, J = 9.3 Hz, 1H), 1.90 (d, J = 5.9 Hz, 11H), 1.41 (d, J = 13.1 Hz, 6H). LC-MS: m / z :511.2(M+H) + .

[0325] Example 44 Synthesis of Compound 15 [ka] Compound 15a (Bidu Pharmaceutical, catalog number BD17826, 28 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 15. 1H NMR (400 MHz, DMSO-d6 ) δ = 8.00 (d, J = 8.0 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.04 - 6.90 (m, 2H), 5.35 - 5.24 (m, 1H), 4.48 - 4.41 (m, 4H), 4.19 (dd, J = 3.9, 9.5 Hz, 2H), 3.70 - 3.59 (m, 1H), 2.71 (tt, J = 3.4, 11.7 Hz, 1H), 2.02 (br d, J = 11.9 Hz, 2H), 1.84 (br dd, J = 2.9, 12.5 Hz, 2H), 1.56 - 1.32 (m, 4H). LC-MS: m / z :475.2(M+H) + .

[0326] Example 45 Synthesis of Compound 16 [ka] Step 1 Preparation of intermediate 16b At 25°C, 16a (Bidu Pharmaceutical, catalog number BD263092, 800 mg, 3.26 mmol) and anhydrous tetrahydrofuran (8 mL) were added to a 100 mL single-neck flask, and N,N'-thiocarbonyldiimidazole (821 mg, 4.89 mmol) was added under stirring. The reaction was stirred at 25°C for 16 hours, after which hydrazine hydrate (1.92 g, 32.6 mmol) was added and the reaction was continued for half an hour. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from acetonitrile to obtain intermediate 16b. LC-MS: m / z: 260.0 (M+H) + .

[0327] Step 2 Preparation of intermediate 16c Intermediate 16b (710 mg, 2.46 mmol) and 1,2-dichloroethane (10.0 mL) were added to a 100 mL single-neck flask at 25 °C, and N,N'-carbonyldiimidazole (887 mg, 5.46 mmol) was added in sequence under stirring. The reaction was completed after 18 hours at 25 °C. 25 mL of water was added to the resulting reaction solution, and 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 by column chromatography to obtain intermediate 16c. LC-MS: m / z: 230.0 (M+H-56). + .

[0328] Step 3 Preparation of intermediate 16d Intermediate 16c (680 mg, 2.03 mmol) and dimethylformamide (10 mL) were placed in a 100 mL single-neck flask at 25 °C, and under stirring, 3-(trifluoromethoxy)azetidine (336 mg, 2.38 mmol), diisopropylethylamine (1.2 g, 9.53 mmol), and Carter condensation reagent (1.6 g, 3.6 mmol) were sequentially added. The reaction was completed after 16 hours. 100 mL of water was added to the resulting reaction mixture, which was then extracted with 100 mL of ethyl acetate. The resulting 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 purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain intermediate 16d. LC-MS: m / z: 409.0 (M+H). + .

[0329] Step 4 Preparation of intermediate 16e Intermediate 16d (70 mg, 0.17 mmol) and dichloromethane (5.0 mL) were added to a 100 mL one-neck flask at 25 °C, and trifluoroacetic acid (2.0 mL, 4.5 mmol) was added under stirring. The reaction was completed after 2 hours. The mixture was concentrated under reduced pressure to give Intermediate 16e. LC-MS: m / z: 309.1 (M+H). + .

[0330] Step 5 Preparation of compound 16 Compound 1i (47 mg, 0.23 mmol) and dimethylformamide (5.0 mL) were added to a 50 mL single-neck flask in an ice bath. Under stirring, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol), diisopropylethylamine (101 mg, 0.78 mmol), and 16e (65 mg, 0.21 mmol) were added sequentially. The reaction mixture was allowed to react overnight at room temperature. 25 mL of water was added to the resulting reaction mixture, which was then extracted with 25 mL of ethyl acetate. The resulting organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 16. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 - 8.01 (m, 1H), 7.53 - 7.48 (m, 1H), 7.10 - 7.06(m, 1H),6.87 - 6.84 (m, 1H), 5.35 - 5.31 (m, 1H), 4.55 - 4.49 (m, 5H), 4.26 - 4.21 (m, 2H), 3.88 - 3.80 (m, 2H), 3.29- 3.26 (m, 1H), 2.04 - 2.0 (m, 2H), 1.90 - 1.86 (m, 1H), 1.69 - 1.65 (m, 1H), LC-MS: m / z: 495.0(M+H) + .

[0331] Example 46 Synthesis of Compound 17 [ka] Compound 17a (Bidu Pharmaceutical, catalog number BD01523901, 76 mg, 0.35 mmol) and intermediate 21b (90 mg, 0.22 mmol) were dissolved in dimethylformamide (5.0 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (101.0 mg, 0.95 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (167 mg, 0.47 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 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 and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 17. 1 H NMR (400 MHz, DMSO-d6) δ 7.65 - 7.63 (m, 1H), 5.33 - 5.30 (m, 1H), 4.50 - 4.43(m, 3H), 4.20 - 4.17 (m, 2H), 3.76 (s, 2 H), 3.73- 3.69 (m, 1H), 3.64 - 3.62 (m, 1H), 2.78 - 2.72 (m, 3H), 2.17 - 2.14 (m, 2H), 1.84 - 1.80 (m, 2H), 1.52 - 1.48 (m, 2H), 1.46 - 1.38 (m, 4H).LC-MS: m / z :503.02(M+H) + .

[0332] Example 47 Synthesis of Compound 18 [ka] Compound 18a (Bidu Pharmaceutical, catalog number BD00971063, 28 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction flask at 25 °C. Triethylamine (40.48 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57.03 mg, 0.15 mmol) were added sequentially under stirring. The reaction was completed by stirring at 25 °C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was then extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 18. 1 H NMR (400 MHz, Methanol-d4) δ 8.09 (d, J = 2.7 Hz, 1H), 7.72 (dd, J = 8.8, 2.7 Hz, 1H), 6.94 (d, J = 8.9 Hz, 1H), 5.44 - 5.21 (m, 2H), 4.75 (s, 2H), 4.50 (dd, J = 9.7, 6.7 Hz, 2H), 4.25 (dd, J = 9.6, 4.2 Hz, 2H), 3.77 (t, J = 4.0 Hz, 1H), 2.92 - 2.64 (m, 1H), 2.20 - 2.09 (m, 2H), 2.00 (ddd, J = 13.6, LC-MS: m / z :476.1(M+H) + .

[0333] Example 48 Synthesis of Compound 7 [ka] Step 1 Preparation of intermediate 7a Intermediate 1c (1000 mg, 3.02 mmol), 3-(trifluoromethoxy)azetidine (1277.25 mg, 9.06 mmol), potassium carbonate (2085.15 mg, 15.1 mmol), and N,N-dimethylformamide (20 mL) were added to a single-neck flask at room temperature and stirred for 12 hours. 50 mL of water was added to the reaction mixture, which was then extracted three times with 50 mL of ethyl acetate. The combined organic layers were washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to give intermediate 7a. LC-MS: m / z: 393.2 (M+H)+.

[0334] Step 2 Preparation of intermediate 7b Intermediate 7a (1100 mg, 2.80 mmol) and dichloromethane (3 mL) were placed in a single-neck flask at room temperature, and a 4 M solution of hydrochloric acid in dioxane (3 mL) was added in an ice bath. The mixture was stirred at room temperature for 2 hours. The reaction mixture was directly concentrated to give Intermediate 7b. LC-MS: m / z: 293.2 (M+H)+.

[0335] Step 3 Preparation of intermediate 7c 7b (230 mg, 0.79 mmol) and water (1 mL) were added to a single-neck flask at room temperature, and acetic acid (3 mL) and sodium nitrite (162.88 mg, 2.36 mmol) were added in an ice bath. The reaction was completed after stirring for 1 hour in an ice bath. The reaction mixture was directly concentrated under reduced pressure to give intermediate 7c. LC-MS: m / z: 322.1 (M+H)+.

[0336] Step 4 Preparation of intermediate 7d 7c (890 mg, 2.77 mmol), acetic acid (2 mL), and methanol (6 mL) were added to a single-neck flask at room temperature. Zinc powder (905.62 mg, 13.85 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was directly filtered, and the filtrate was concentrated under reduced pressure to give intermediate 7d. LC-MS: m / z: 308.1 (M+H)+.

[0337] Step 5 Preparation of compound 7 Intermediate 7d (100 mg, 0.33 mmol), 1i (66.58 mg, 0.33 mmol), and N,N-dimethylformamide (1 mL) were added to a single-neck flask at room temperature. Under stirring, 1-propylphosphoric acid anhydride (414.19 mg, 0.65 mmol) and N,N-diisopropylethylamine (126.19 mg, 0.98 mmol) were added sequentially, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was directly 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 7 (6 mg). LC-MS: m / z: 494.5 (M+H)+. 1 H NMR (DMSO-d6) δ: 8.77-9.19 (m, 1H), 7.32-7.48 (m, 1H), 6.90-7.03 (m, 1H), 6.68-6.80 (m, 1H), 5.22-5.29 (m, 1H), 4.84(s, 1H), 4.35-4.44 (m, 3H), 4.13 (m, 2H), 2.87 (d, J=11.1 Hz, 1H), 2.56-2.81 (m, 3H), 1.83-2.00 (m, 3H),1.60-1.78 (m, 2H).

[0338] Example 49 Synthesis of Compounds 51-1 and 51-2 [ka] Step 1 Preparation of intermediate 51b 51a (Shaoyuan, 800 mg, 4.32 mmol) and 1,4-dioxane (2.0 mL) were added to a single-neck flask at room temperature, and a hydrochloric acid / dioxane solution (4 M, 6.0 mL) was added under stirring. The reaction mixture was then reacted at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give intermediate 51b.

[0339] Step 2 Preparation of intermediate 51c Intermediate 51b (350 mg, 4.11 mmol) and dimethylformamide (8.0 mL) were added to a single-neck flask at room temperature. Under stirring, benzyl chloroformate (1.08 g, 6.34 mmol) and potassium carbonate (2.34 g, 16.92 mmol) were added and stirred at room temperature for 18 hours. 50 mL of water was added to the reaction mixture, which was then extracted once with 50 mL of 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 the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain Intermediate 51c.

[0340] Step 3 Preparation of intermediate 51d 51c (620 mg, 2.83 mmol) and anhydrous methanol (10.0 mL) were placed in a single-neck flask at room temperature, and sodium borohydride (214 mg, 5.63 mmol) was added under stirring. The temperature was raised to 50°C and the reaction was carried out for 3 hours. The reaction mixture was quenched with 50 mL of aqueous ammonium chloride solution and extracted with 30 mL of ethyl acetate each time. The combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 51d.

[0341] Step 4 Preparation of intermediates 51ea and 51eb Intermediate 51d (300 mg, 1.36 mmol) and ethyl acetate (20 mL) were added to a three-necked flask in an ice bath. The flask was then wrapped in tin foil to protect it from light. Silver trifluoromethanesulfonate (1.05 g, 4.07 mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (0.72 g, 2.03 mmol), potassium fluoride (0.32 g, 5.42 mmol), 2-fluoropyridine (0.38 g, 4.07 mmol), and (trifluoromethyl)trimethylsilane (0.58 mg, 4.07 mmol) were added under stirring, and the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=100:1 to 8:1) to give intermediate 51ea (60 mg) and intermediate 51eb (110 mg). 1 H- 1 Confirmed by H NOESY (two-dimensional nuclear magnetic resonance). 51ea: 1 H NMR (400 MHz, DMSO) δ 7.40 - 7.30 (m, 5H), 5.06 (s, 2H), 4.79 - 4.75 (m, 1H), 4.38 - 4.35 (m, 1H), 4.21 - 4.17 (m, 1H), 3.92 - 3.90 (m, 1H), 1.37 (d, J = 6.6 Hz, 3H). 51eb: 1 H NMR (400 MHz, DMSO) δ 7.46 - 7.21 (m, 5H), 5.19 - 5.15 (m, 1H), 5.05 (s, 2H), 4.65 - 4.62(m, 1H), 4.28 - 4.25 (m, 1H), 3.92 - 3.90 (m, 1H), 1.30 (d, J = 6.6 Hz, 3H).

[0342] Step 5 Preparation of intermediate 51-1a Intermediate 51ea (60 mg, 0.21 mmol) and anhydrous methanol (5.0 mL) were placed in a single-neck flask at room temperature, and palladium on carbon (12 mg) and two drops of concentrated hydrochloric acid were added sequentially under stirring. After hydrogen substitution three times, the mixture was reacted at room temperature for 16 hours under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 51-1a.

[0343] Step 6 Preparation of compound 51-1 Intermediate 51-1a (30 mg, 0.18 mmol) and dimethylformamide (5.0 mL) were added to a single-neck flask in an ice bath. Under stirring, Carter condensation reagent (125 mg, 0.27 mmol), diisopropylethylamine (70 mg, 0.54 mmol), and intermediate 6d (70 mg, 0.18 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 30 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 51-1 (7.34 mg). 1 H NMR (400 MHz, DMSO) δ 8.02 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.9 Hz, 1H), 6.87 - 6.85 (m, 1H), 4.98 - 4.94 (m, 1H), 4.51 (s, 2H), 4.48 - 4.45 (m, 1H), 4.30 - 4.26 (m, 1H), 4.03 - 4.00 (m, 1H), 3.67 - 3.63 (m, 1H), 2.86 - 2.61 (m, 1H), 2.06 - 2.01 (m, 2H), 1.87 - 1.83 (m, 2H), 1.56- 1.47 (m, 2H), 1.44 (t, J = 5.8 Hz, 3H), 1.41 - 1.29 (m, 2H), LC-MS: m / z :507.0(M+H)+.

[0344] Step 7 Preparation of intermediate 51-2a Intermediate 51eb (70 mg, 0.24 mmol) and anhydrous methanol (5.0 mL) were placed in a single-neck flask at room temperature, and palladium on carbon (12 mg) and two drops of concentrated hydrochloric acid were added sequentially under stirring. After purging with hydrogen three times, the mixture was reacted at room temperature for 16 hours under a hydrogen gas atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 51-2a.

[0345] Step 8 Preparation of compound 51-2 Intermediate 51-2a (32 mg, 0.20 mmol) and dimethylformamide (5.0 mL) were added to a 50 mL single-neck flask in an ice bath. Carter condensation reagent (149 mg, 0.34 mmol), diisopropylethylamine (88 mg, 0.68 mmol), and intermediate 6d (83 mg, 0.22 mmol) were added sequentially under stirring. The reaction mixture was allowed to react overnight at room temperature. 25 mL of water was added to the reaction mixture, which was then extracted three times with 30 mL of ethyl acetate. The combined organic phases were washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to give compound 51-2 (4.54 mg). 1 H NMR (400 MHz, DMSO) δ 8.02 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.08- 7.06(m, 1H), 7.05 - 6.86 (m, 1H), 5.26 - 5.22 (m, 1H), 4.75 - 4.73 (m, 1H), 4.40 (s, 2H), 4.39 - 4.36 (m, 1H), 4.03 - 4.02 (m, 1H), 3.65 - 3.63 (m, 1H), 2.74 - 2.70 (m, 1H), 2.04- 2.01 (m, 2H), 1.86 - 1.83 (m, 2H), 1.55- 1.49 (m, 2H), 1.48 - 1.42 (m, 2H), 1.37 (t, J = 5.8 Hz, 3H), LC-MS: m / z :507.1(M+H)+.

[0346] Example 50 Synthesis of Compound 90 [ka] Step 1 Preparation of intermediate 90b 90a (BiDe Pharmaceutical, catalog number BD253909, 5.0 g, 31.61 mmol) and N,N-dimethylformamide (40.0 mL) were added to a single-neck flask at room temperature. Imidazole (4.30 g, 63.22 mmol) and tert-butyldimethylsilyl chloride (5.24 g, 34.77 mmol) were added under stirring, and the mixture was allowed to react for 3 hours at room temperature. 200 mL of water was added to the reaction mixture, which was then extracted three times with 100 mL of ethyl acetate. The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to give intermediate 90b. 1 H NMR (400 MHz, CDCl3) δ 3.65 (s, 3H), 3.59 - 3.51 (m, 1H), 2.30 - 2.15 (m, 1H), 2.00 - 1.84 (m, 4H), 1.54 - 1.40 (m, 2H), 1.36 - 1.23 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H).

[0347] Step 2 Preparation of intermediate 90c Intermediate 90b (4.50 g, 16.52 mmol) and ethanol (40.0 mL) were added to a single-neck flask at room temperature, and hydrazine hydrate (9.73 g, 165.16 mmol) was added at room temperature. The mixture was then reacted at 85°C for 18 hours. The reaction mixture was concentrated under reduced pressure to give Intermediate 90c. LC-MS: m / z: 273.3 (M+H)+.

[0348] Step 3 Preparation of intermediate 90d Intermediate 90c (1.80 g, 6.61 mmol) and 1,2-dichloroethane (20.0 mL) were added to a single-neck flask at room temperature. Triethylamine (2.75 mL, 19.82 mmol) and N,N'-carbonyldiimidazole (1.50 g, 9.25 mmol) were added under stirring, and the mixture was allowed to react for 18 hours at room temperature. The reaction mixture was poured into 80 mL of water and extracted three times with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain Intermediate 90d. LC-MS: m / z: 299.3 (M+H)+ 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 3.69 - 3.57 (m, 1H), 2.63 - 2.52 (m, 1H), 2.00 -1.88 (m, 2H), 1.87 - 1.78 (m, 2H), 1.51 - 1.38 (m, 2H), 1.37 - 1.25 (m, 2H), 0.86 (s, 9H), 0.04 (d, J = 3.0 Hz, 6H).

[0349] Step 4 Preparation of intermediate 90e 90d (900 mg, 3.02 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-neck flask at room temperature. N,N-diisopropylethylamine (2.00 mL, 12.06 mmol), 3-(trifluoromethoxy)-azetidine (425 mg, 3.02 mmol), and Carter condensation reagent (1.60 g, 3.62 mmol) were added under stirring, and the mixture was allowed to react for 18 hours at room temperature. The reaction mixture was poured into 60 mL of water, extracted three times with 50 mL of ethyl acetate each time, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 2:1) to obtain intermediate 90e. LC-MS: m / z: 422.4 (M+H)+ 1H NMR (400 MHz, DMSO-d6) δ 5.38 - 5.26 (m, 1H), 4.50 - 4.40 (m, 2H), 4.24 - 4.14 (m, 2H), 3.73 - 3.58 (m, 1H), 2.83 - 2.64 (m, 1H), 2.01 - 1.93 (m, 2H), 1.90 - 1.80 (m, 2H), 1.57 - 1.28 (m, 4H), 0.87 (s, 9H), 0.06 (s, 6H).

[0350] Step 5 Preparation of intermediate 90f Intermediate 90e (850 mg, 2.02 mmol) and tetrahydrofuran (10.0 mL) were placed in a 50 mL single-neck flask at room temperature. Tetrabutylammonium fluoride (6.05 mL, 6.05 mmol, 1 M) was added under stirring and the mixture was allowed to react for 5 hours at room temperature. The reaction mixture was poured into 60 mL of water and extracted three times with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 90f. LC-MS: m / z: 308.2 (M+H)+.

[0351] Step 6 Preparation of intermediate 90g Intermediate 90f (480 mg, 1.56 mmol) and N,N-dimethylformamide (6.0 mL) were added to a single-neck flask at room temperature. Sodium hydride (125 mg, 3.12 mmol) and tert-butyl bromoacetate (456 mg, 2.34 mmol) were added under stirring, and the mixture was allowed to react at 60°C for 18 hours. The reaction mixture was poured into 40 mL of ice water and extracted three times with 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain Intermediate 90g. LC-MS: m / z: 422.3 (M+H) +.

[0352] Step 7 Preparation of intermediate 90h Intermediate 90g (70 mg, 0.17 mmol) and dichloromethane (2.0 mL) were placed in a single-neck flask at room temperature, and trifluoroacetic acid (0.5 mL) was added under stirring. The mixture was allowed to react at room temperature for 2 hours. The reaction filtrate was concentrated under reduced pressure to give Intermediate 90h. LC-MS: m / z: 366.2 (M+H)+.

[0353] Step 8 Preparation of Compound 90 Intermediate 90h (50 mg, 0.14 mmol) and N,N-dimethylformamide (1.0 mL) were added to a single-neck flask at room temperature, and N,N-diisopropylethylamine (53 mg, 0.41 mmol), compound 90i (20 mg, 0.14 mmol), and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (86 mg, 0.16 mmol) were added under stirring. The reaction was allowed to proceed at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 90. LC-MS: m / z: 493.3 (M+H)+ 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.84 (dd, J = 12.0, 2.0 Hz, 1H), 7.59 - 7.40 (m, 2H), 5.37 - 5.23 (m, 1H), 4.52 - 4.40 (m, 2H), 4.23 - 4.15 (m, 2H), 4.11 (s, 2H), 3.47 - 3.37 (m, 1H), 2.82 - 2.70 (m, 1H), 2.17 - 1.94 (m, 4H), 1.60 - 1.30 (m, 4H).

[0354] Example 51 Synthesis of Compound 19 [ka] 19a (BiDe Pharmaceutical, catalog number BD00755909, 16 mg, 0.13 mmol) and dimethylformamide (3 mL) were added to a single-neck flask at room temperature. Diisopropylethylamine (52 mg, 0.40 mmol), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (90 mg, 0.20 mmol), and compound 6d (50 mg, 0.14 mmol) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was poured into 30 mL of water and extracted twice with 30 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 (formic acid / acetonitrile / water system) to obtain compound 19. LC-MS: m / z: 475.0 (M+H). + , 1H NMR (400 MHz, DMSO) δ 8.02 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.9 Hz, 1H), 6.97 - 6.57 (m, 2H), 5.15 - 5.04 (m, 1H), 4.51 (s, 2H), 4.40 -4.36 (m, 2H), 4.07- 4.04 (m, 2H), 3.73 - 3.57 (m, 1H), 2.83 - 2.63 (m, 1H), 2.05- 2.01 (m, 2H), 1.87- 1.85 (m, 2H), 1.61 - 1.43 (m, 2H), 1.43 - 1.28 (m, 2H).

[0355] Example 52 Synthesis of Compound 86 [ka] Step 1 Preparation of intermediate 86b Compound 86a (Nanjing medicinal stone, 470 mg, 1.72 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-neck flask at room temperature. Imidazole (334 mg, 4.91 mmol) and tert-butyldimethylsilyl chloride (370 mg, 2.45 mmol) were added under stirring, and the mixture was allowed to react for 18 hours at room temperature. 50 mL of water was added to the reaction mixture, which was then extracted twice with 50 mL of ethyl acetate. The combined organic phase was washed with 50 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 flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 86b. LC-MS: m / z: 424.2 (M+Na). + .

[0356] Step 2 Preparation of intermediate 86c Intermediate 86b (570 mg, 1.47 mmol) and ethanol (10.0 mL) were placed in a single-neck flask at room temperature, and hydrazine hydrate (836 mg, 14.19 mmol) was added at room temperature. The mixture was then reacted at 80°C for 18 hours. The reaction mixture was concentrated under reduced pressure to give Intermediate 86c as a white solid. LC-MS: m / z: 410.2 (M+Na)+.

[0357] Step 3 Preparation of intermediate 86d Intermediate 86c (520 mg, 1.34 mmol) and 1,2-dichloroethane (10.0 mL) were added to a single-neck flask at room temperature, and triethylamine (0.56 mL, 4.02 mmol) and N,N'-carbonyldiimidazole (326 mg, 2.01 mmol) were added under stirring. The mixture was allowed to react for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to give Intermediate 86d. LC-MS: m / z: 436.2 (M+Na). + .

[0358] Step 4 Preparation of intermediate 86e Intermediate 86d (470 mg, 1.14 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-neck flask at room temperature. N,N-diisopropylethylamine (589 mg, 4.56 mmol), 3-(trifluoromethoxy)-azetidine (176 mg, 1.25 mmol), and Carter condensation reagent (603 mg, 1.36 mmol) were added under stirring, and the mixture was allowed to react for 18 hours at room temperature. The reaction mixture was poured into 50 mL of water and extracted three times with 50 mL of ethyl acetate. The combined organic phases were 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 flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 2:1) to give Intermediate 86e. LC-MS: m / z: 537.4 (M+H)+.

[0359] Step 5 Preparation of intermediate 86f Intermediate 86e (100 mg, 0.19 mmol) and dichloromethane (2.0 mL) were added to a single-neck flask at room temperature, followed by trifluoroacetic acid (0.5 mL), and the mixture was allowed to react at room temperature for 2 hours. The reaction filtrate was concentrated under reduced pressure to give Intermediate 86f. LC-MS: m / z: 437.4 (M+H)+.

[0360] Step 6 Preparation of intermediate 86g Intermediate 86f (82 mg, 0.19 mmol) and N,N-dimethylformamide (2.0 mL) were added to a single-neck flask at room temperature. N,N-diisopropylethylamine (98 mg, 0.76 mmol), compound 1i (42 mg, 0.14 mmol), and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (119 mg, 0.23 mmol) were added under stirring. The mixture was allowed to react for 18 hours at room temperature. The reaction mixture was poured into 30 mL of water and extracted three times with 30 mL of ethyl acetate. The combined organic phases were 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 flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to give intermediate 86g. LC-MS: m / z: 623.4 (M+H) +.

[0361] Step 7 Preparation of compound 86 Intermediate 86g (117 mg, 0.19 mmol) and tetrahydrofuran (2.0 mL) were added to a single-neck flask at room temperature, and tetrabutylammonium fluoride (0.38 mL, 0.38 mmol, 1 M) was added under stirring. The mixture was allowed to react at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 86. LC-MS: m / z: 509.2 (M+H). + , 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 (dd, J = 8.9, 1.9 Hz, 1H), 5.36 - 5.27 (m, 1H), 4.83 (d, J = 5.0 Hz, 1H), 4.52 (s, 2H), 4.49 - 4.42 (m, 2H), 4.23 - 4.16 (m, 2H), 3.58 - 3.41 (m, 2H), 2.91 - 2.80 (m, 1H), 2.24 - 2.16 (m, 1H), 1.99 - 1.90 (m, 1H), 1.88 - 1.80 (m, 1H), 1.50 - 1.30 (m, 3H).

[0362] Other compounds of the invention can be prepared by methods similar to those described in the examples above, with appropriate modifications as necessary.

[0363] Biological Testing 1. Cellular activity test The ATF4 luciferase reporter plasmid consists of two parts: the 5' untranslated region sequence of the ATF4 gene and the luciferase coding sequence. Specifically, the 5' untranslated region sequence of ATF4 (NCBI database number BC022088.2), which contains two 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). HEK293T / 17 cells were co-transfected with the above three plasmids using X-tremeGENE 9 DNA transfection reagent, and the lentivirus-containing culture medium was collected 48 hours later. The transfected HEK293T / 17 cells were screened with 1 μg / mL puromycin, and then monoclonal cells were obtained by limiting dilution.

[0364] This cell line can be used to detect ATF4 translation regulation and test the activity of eIF2B activators by low-temperature fluorescence reading. The specific experimental procedure is as follows: 6,000 HEK293T / 17-ATF4 uORF-Luc-Puro monoclonal cells were plated in a 384-well plate and allowed to adhere overnight. Test compounds were dissolved in DMSO and added to the cell culture medium together with 50 nM thapsigargin, followed by incubation for 6 hours. Thapsigargin induces cell stress and upregulates ATF4 protein translation. Six hours after drug addition, cells were lysed using the One-Glo Luciferase Assay Kit (Promega #E6120), and then low-temperature fluorescence readings were performed using the LUM program on an EnVision 2104 plate reader.

[0365] The relative expression level of the ATF4 reporter gene (ATF4 reporter expression %) was calculated according to the following method.

[0366] ATF4 reporter expression % = (ave_sample-ave_vc) / (ave_pc-ave_vc)*100%. ave_vc: average signal value of negative control ave_pc: average signal value of the positive control ave_sample: average signal value of the sample Fitting the dose-effect curve and EC 50 values ​​were calculated.

[0367] The relationship 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 GraphPad9 software.

[0368] X-axis: logarithm of compound concentration. Y-axis: relative expression level of the ATF4 reporter gene. Top: estimated asymptote above the curve. Bottom: estimated asymptote below the curve. Hillslope: slope of the fitting curve.

[0369] Formula: Y=Bottom + (Top-Bottom) / (1+10^((LogEC 50 -X) × HillSlope)), i.e. LogEC 50 =X+(1 / HillSlope)×log((Top-Y) / (Y-Bottom)).

[0370] In Table 1, "+" indicates an EC > 100 nM 50 "++" indicates an EC of 10nM to 100nM 50 "+++" indicates an EC of 1 nM to 10 nM. 50 "++++" indicates an EC<1 nM 50 Represents. [Table 1]

[0371] Experimental results (some not shown) showed that the compounds of the present application can enhance / activate eIF2B activity and reduce the expression level of ATF4, thereby reducing the fluorescence intensity, which indicates that the compounds of the present application can significantly alleviate thapsigargin-induced cell stress, suppress the cellular integrated stress response, and normalize the synthesis of intracellular proteins, and are eIF2B agonists. Most of the compounds of the present application have an EC 50 The EC values ​​for HEK293T / 17 cells were <100 nM, and many compounds 50 The EC values ​​ranged from 10 nM to 100 nM, and most compounds showed EC 50 The EC value of some preferred compounds is 10 nM or less, and some preferred compounds have an EC 50 The most preferred compounds have an EC 50 The value is less than 10 pM.

[0372] 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 fasting intestinal fluid, pH = 6.5). 4.071 g of FeSSIF buffer concentrate was added to 45.97 g of deionized water to prepare a buffer solution (simulated fed intestinal fluid, pH=5.0).

[0373] 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 plate. 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) depending on the compound's properties and its mass spectrometry response. The dilution factor was varied depending on the solubility value and UPLC-MS / MS signal response.

[0374] Experiments have shown that at least some of the compounds of the present application have high solubility in all of the different simulated environments, for example, compound 6 has a solubility of >10 μg / mL in simulated fasting intestinal fluid (pH=6.5) and >80 μg / mL in simulated fed intestinal fluid (pH=5.0).

[0375] 3. In vitro liver microsome stability assessment 100 mM K-Mg buffer containing 5 mM MgCl2 was preheated. 5 μL of 10 mM compound and reference stock solutions were added to 95 μL of acetonitrile (ACN) to prepare spike solutions. 1.5 μL of 500 μM spike solution and 18.75 μL of 20 mg / mL liver microsomes were added to 479.8 μL of K-Mg buffer. NADPH stock solution (3 mM) was prepared by dissolving NADPH in K-Mg buffer. 30 μL of the 1.5 μM spike solution containing microsomes was evenly dispensed onto the assay plate at different time points (0, 5, 15, 30, and 45 min). The plate was preincubated at 37°C for 5 min. At 0 min, 200 μL of IS (internal standard, tolbutamide / terfenadine)-containing CAN was added to each well, followed by 15 μL of 6 mM NADPH stock solution. At other time points, 15 μL of 6 mM NADPH stock solution was added to each well to initiate the reaction and time it was measured. At 5, 15, 30, and 45 min, 200 μL of IS-containing ACN was added to the corresponding wells to terminate the reaction. After quenching, the plate was shaken at 600 rpm for 10 min and then centrifuged at 4000 rpm for 50 min. 80 μL of supernatant per well was aspirated and transferred to a 96-well sample plate containing 160 μL of purified water for UPLC / MS / MS analysis. [Table 2]

[0376] Experiments have shown that at least some compounds of the present application have high in vitro liver microsomal stability.

[0377] 4. 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 basolateral side of the cell monolayer. The A → B or B → A permeability of the test compounds was measured in duplicate by incubation for 120 min at 37 °C, 5% CO2, and 95% relative humidity. The efflux ratio of each compound was also measured. Quantitative analysis of the analyte and reference compounds was performed using LC-MS / MS based on the analyte / IS peak area ratio. [Table 3]

[0378] Experimental results have shown that at least some of the compounds of the present application have high cell membrane permeability and are not P-glycoprotein substrates.

[0379] 5. P450 enzyme inhibition evaluation A phosphate buffer solution of liver microsomes was prepared. 169 μL of the phosphate buffer solution of liver microsomes and 1 μL of a working solution of multiple concentrations of test compound or positive control compound were added to a 96-well plate. The culture plate was preheated in a water bath at 37°C for 15 minutes. After the incubation, 10 μL of substrate was added to the culture plate (for CYP3A4-T, 1 μL of substrate and 9 μL of K-Mg buffer were added to the culture plate). The incubation mixture was mixed for 10 seconds on a rotary mixer, and then 20 μL of 10 mM NADPH solution was added to initiate the reaction at a final concentration of 1 mM. The experiment was repeated twice. At the designated time points shown in Table 4, the reaction was quenched by adding 400 μL of quench solution (cold ACN containing 500 nM tolbutamine and 10 nM terfenadine). The mixture was centrifuged at 3220 g for 50 minutes at 4°C. 100 μL of the supernatant was transferred to a new plate. The supernatant was diluted with 100 μL of pure water, mixed uniformly, and analyzed by UPLC-MS / MS. [Table 4]

[0380] Experimental results show that at least some of the compounds in the present application have low inhibition of the five major P450 enzymes (CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4) and have a low risk of drug-drug interactions. For example, Compound 6 has an IC 50 The IC values ​​are generally >10 μM, especially for CYP2D6 and CYP3A4. 50 are all >30 μM.

[0381] 6. Pharmacokinetic evaluation in mice The test compound was dissolved in a solvent to form a clear solution or a homogeneous suspension. Mice in each group (3 mice per group) were injected via the tail vein at 1 mg / kg and orally administered PO at 10 mg / kg. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after intravenous injection, and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration. Plasma samples were centrifuged to remove the supernatant, which was then quantitatively analyzed by LC / MS / MS. [Table 5]

[0382] Experimental results have shown that at least some of the compounds of the present application (e.g., Compound 6) have excellent pharmacokinetic properties (Cl (clearance), T 1 / 2 (half-life), C max (peak concentration), AUC (area under the concentration-time curve), F (bioavailability), etc.

[0383] Although the present application has been described with reference to preferred embodiments, various modifications may be made and equivalents may be substituted for the components thereof without departing from the scope of the present application. In particular, unless structurally inconsistent, all technical features recited in each embodiment may be combined in any manner. The present application is not limited to the specific embodiments disclosed herein, but is intended to encompass all technical solutions encompassed by the claims.

Claims

1. Compound represented by formula 0 【Chemistry 1】 or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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, During the ceremony, Ring A is selected from C3-C10 cycloalkylene or 3- to 10-membered heterocycloalkylene, and ring A is 【Chemistry 2】 Instead, the * end is connected to L, 【Transformation 3】 The end is connected to ring B, and n3 is an integer of 0 to 5. Ring B is selected from 5- to 10-membered heteroarylene, and n4 is any integer from 0 to 4; Ring C is a 3- to 10-membered heterocycloalkylene, a C3-C10 cycloalkylene, or Ｂ -X ２１ -C3-C12 cycloalkylene-$ Ｒ１ is selected from X ２１ Ha-NR ３ or -C(O)NR ３ and # Ｂ - is a bond connected to ring B, -$ Ｒ１ is R １ and each R ３ are each independently H, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and when ring C is C3-C10 cycloalkylene, ring A is not cyclohexylene, and ring A is 【Chemistry 4】 If * is connected to L, 【Transformation 5】 the end is connected to ring B, ring C is a 3- to 10-membered heterocycloalkylene, and n5 is any integer from 0 to 5; Ring D is selected from C6-C10 arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocycloalkylene; L is # Ｄ -L １ -L ２ -L ３ -$ Ａ , 5-6 membered heteroaryl or # Ｄ -NR １４ C(O)-C1-C6 alkylene-O-$ Ａ and L １ is a bond, —O—, —S— or —NR ４ - and L ２ is a bond, substituted or unsubstituted C1-C10 alkylene, and L ３ is -C(X １０ ) NR ５ -$ Ａ or -C(X １０ )-$ Ａ and X １０ is O or S, and R ４ , R ５ and R １４ are each independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; R ４ , R ５ and R １４ C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R １１ may be replaced by # Ｄ - is a bond connected to the D ring, -$ Ａ is a connecting bond connected to ring A, R １ , R ２ , R ９ａ , R ９ｂ , R ９ｃ are each independently a substituent R １１ and Each R １１ are each independently deuterium, halogen, cyano, nitro, ═O, or —OR ６ , -SR ６ , SF ５ , -NR ６ R ７ , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, —C(O)R ６ , -C(O)OR ６ , -OC(O)OR ６ , O.C.(O.)R ６ , —C(O)NR ６ R ７ , —C(O)ONR ６ R ７ , -NR ６ C(O)NR ７ R ８ , -S(O) １－２ R ６ , -S(O) １－２ NR ６ , N.R. ６ S (O) １－２ R ７ , -NR ６ S (O) １－２ NR ７ R ８ , -NR ６ C(O)R ７ , -P(O)R ６ R ７ or -NR ６ C(O)OR ７ Among these, R ９ａ , R ９ｂ , R ９ｃ , R １１ C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R １２ may be substituted with Each R ６ , R ７ and R ８ are each independently H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, —C(O)R ２０ , -C(O)OR ２０ , —C(O)NR ２０ R ２１ , -S(O) １－２ R ２０ , -S(O) １－２ NR ２０ Among these, R ６ , R ７ and R ８ C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R １３ or R ６ and R ７ together with the atom to which they are simultaneously attached form a heterocycloalkyl, which is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy, or amino, or R ７ and R ８ together with the atom to which they are simultaneously attached form a heterocycloalkyl, which is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy or amino; Each R １２ and each R １３ are each independently H, deuterium, halogen, cyano, nitro, ═O, or —OR ３０ , -SR ３０ , -SF ５ , N.R. ３０ R ３１ , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, —C(O)R ３０ , -C(O)OR ３０ , -OC(O)OR ３０ , O.C.(O.)R ３０ , —C(O)NR ３０ R ３１ , —C(O)ONR ３０ R ３１ , -NR ３０ C(O)NR ３０ R ３１ , -S(O) １－２ R ３０ , -S(O) １－２ NR ３０ , -NR ３０ S (O) １－２ R ３１ , -NR ３０ S (O) １－２ NR ３０ R ３１ , -NR ３０ C(O)R ３１ or -NR ３０ C(O)OR ３１ Among them, R １２ and R １３ and the C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as the above are each independently optionally substituted with 1 to 6 halogens, or optionally substituted with C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy, or amino; Each R ２０ and R ２１ are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; R ２０ and R ２１ together with the atom to which they are simultaneously attached form a heterocycloalkyl, which is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy or amino; Each R ３０ and R ３１ are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; R ３０ and R ３１ together with the atom to which they are simultaneously attached form a heterocycloalkyl, which is optionally substituted with 1 to 6 halogens or C1-C10 alkyl optionally substituted with 1 to 6 halogens, hydroxy or amino; n1 and n2 each independently represent any integer from 0 to 4. 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 non-enantiomer 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.

2. n4 is 0, 1, 2 or 3, and each R ９ｂ are each independently halogen, cyano, nitro, —OH, or C1-C3 alkyl, and preferably, ９ｂ are each independently halogen, —OH, methyl, ethyl, or propyl; Preferably, n4 is 0, Preferably, the B ring is 【Transformation 6】 is selected from X ７ is O or S, and X ８ , X ９ , X １０ are each independently CH or N, and the * end is connected to the C ring; 【Transformation 7】 The end is connected to the A ring, More preferably, X ８ , X ９ , X １０ At most two of them are N, More preferably, X ８ , X ９ , X １０ One of them is N, Preferably, the B ring is 【Transformation 8】 is any one selected from the group More preferably, the B ring is 【Chemistry 9】 is any one selected from the group More preferably, the B ring is 【Chemistry 10】 That is, A compound according to claim 1, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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 compound has a structure according to general formula I: 【Chemistry 11】 In the formula, A ring, C ring, D ring, L, R １ , R ２ , R ９ａ , R ９ｃ , n1, n2, n3 and n5 are as defined in claim 1 or 2, and X ７ is O or S, Preferably, n1 and n2 are each independently an integer from 1 to 3; More preferably, n1 is 1 and n2 is an integer from 1 to 3. A compound according to claim 1 or 2, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

4. Each of the R ９ｃ are each independently a halogen, cyano, nitro, ═O, —OH, or —NR ３０ R ３１ , C1-C3 alkyl, —C(O)R ３０ , -C(O)OR ３０ and each R ３０ and R ３１ are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; Preferably, the C ring has one or two R ９ｃ and each R ９ｃ are each independently halogen, cyano, nitro, —OH, or C1-C3 alkyl; More preferably, the R ９ｃ are each independently halogen, —OH, methyl, ethyl, or propyl; More preferably, the R ９ｃ are each independently F or methyl; Preferably, n5 is 0, 1 or 2; More preferably, n5 is 0 or 1; Preferably, the 3- to 10-membered heterocycloalkylene of ring C is 【Chemistry 12】 is selected from X １１ , X ２３ are each N or B, and X １２ is CH ２ , NH, O or S, q is an integer of 0 to 3, preferably q is 1 or 2, and X １３ is N or B, s is an integer of 1 to 3, preferably s is 1 or 2, and X １４ is O, S or NH, t is an integer of 1 to 3, preferably t is 1 or 2, and the * end is connected to the B ring; 【Chemistry 13】 The edge is R １ It is connected to More preferably, the 3- to 10-membered heterocycloalkylene of the ring C is 【Chemistry 14】 is selected from Preferably, the C ring # Ｂ -X ２１ -C3-C12 cycloalkylene-$ Ｒ１ teeth 【Chemistry 15】 and R ３ is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, p is an integer from 1 to 3, preferably 1 or 2, and the * end is connected to ring B; 【Chemistry 16】 The edge is R １ It is connected to More preferably, the # of the C ring Ｂ -X ２１ -C3-C12 cycloalkylene-$ Ｒ１ teeth 【Chemistry 17】 and Preferably, the C ring is [Chemistry 18] and the * end is connected to the B ring; 【Chemistry 19】 The edge is R １ It is connected to More preferably, the C ring is 【Chemistry 20】 is selected from More preferably, the C ring is 【Chemistry 21】 wherein each q, p, s, and t is independently 1 or 2; Preferably, the 【Chemistry 22】 teeth, 【Chemistry 23】 and the * end is connected to the B ring; 【Chemistry 24】 The edge is R １ It is connected to More preferably, 【Chemistry 25】 teeth, 【Chemistry 26】 is selected from More preferably, 【Chemistry 27】 teeth 【Chemistry 28】 Selected from: A compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

5. Each of the R １ are each independently R １１ and Each R １１ are each independently a halogen, cyano, nitro, ═O, or —OR ６ , -SR ６ , -NR ６ R ７ , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, —C(O)R ６ , -C(O)OR ６ , -OC(O)OR ６ , -S(O) １－２ R ６ , -P(O)R ６ R ７ Among these, R １１ C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl as each independently represent 1 to 6 R １２ may be substituted with Each R ６ , R ７ are each independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, among which R ６ , R ７ C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl as each independently represent 1 to 3 R １３ may be substituted with Each R １２ and each R １３ are each independently H, halogen, cyano, nitro, ═O, or —OR ３０ , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, among which R １２ and R １３ and each of the C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl as the above is optionally substituted with 1 to 3 halogens, or optionally substituted with C1-C3 alkyl optionally substituted with 1 to 3 halogens, hydroxy, or amino, Each R ３０ are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; Preferably, the R １ is -OR ６ , C1-C3 alkyl, halogen, —S(O) ２ R ６ or -P(O)R ６ R ７ Among these, R １ C1-C3 alkyl as R １２ and R １２ is halogen, -S(O) ２ R ３０ and R ３０ is selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, and each R ６ are each independently selected from C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl, among which R ６ C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl as each independently represent 1 to 6 R １３ and R １３ is selected from halogen, and R ７ is selected from C1-C3 alkyl; More preferably, the R １ is -OCH ３ , -OCF ３ , 【Chemistry 29】 -CF ２ CF ３ 、-CF ３ 、-OCHF ２ 、-OCF ２ CF ３ 、-OCF ２ Cl、-CH ２ CF ３ 、-F、 【Transformation 30】 -OCF=CF ２ 、 【Chemistry 31】 is selected from More preferably, the R １ is -OCF ３ , -CF ２ CF ３ , -OCH ３ , -F, 【Chemistry 32】 -CF ３ is selected from More preferably, the R １ Ha-OCF ３ , -OCF ２ CF ３ is selected from More preferably, the R １ Ha-OCF ３ and Preferably, n1 is 0 or 1. A compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

6. The compound has a structure shown in general formula II: 【Transformation 33】 In the formula, A ring, D ring, L, R １ , R ２ , R ９ａ , R ９ｃ , n1, n2, n3 and n5 are as defined in any one of claims 1 to 5, Preferably, the R １ is -OCH ３ , -OCF ３ , 【Transformation 34】 -CF ２ CF ３ 、-CF ３ 、-OCHF ２ 、-OCF ２ CF ３ 、-OCF ２ Cl、-CH ２ CF ３ 、F、 【Chemistry 35】 -OCF=CF ２ 、 【Transformation 36】 is selected from More preferably, the R １ is -OCH ３ , -OCF ３ , -CF ２ CF ３ , -F, 【Chemistry 37】 is selected from More preferably, the R １ Ha-OCF ３ , -OCF ２ CF ３ and More preferably, the R １ Ha-OCF ３ and Preferably, n1 is 1, Preferably, n5 is 0, 1 or 2, and each R ９ｃ are each independently halogen, cyano, nitro, —OH, or C1-C3 alkyl; More preferably, the R ９ｃ are each independently halogen, —OH, methyl, ethyl, or propyl; More preferably, the R ９ｃ are each independently F, A compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

7. The compound has a structure represented by general formula II-1: 【Transformation 38】 In the formula, A ring, D ring, L, R １ , R ２ , R ９ａ , R ９ｃ , n1, n2, n3 and n5 are as defined in any one of claims 1 to 6, Preferably, n5 is 0 or 1; Preferably, the R ９ｃ is selected from halogen, cyano, nitro, —OH, C1-C3 alkyl; More preferably, the R ９ｃ is selected from halogen, methyl or ethyl; More preferably, the R ９ｃ is F, Preferably, the 【Chemistry 39】 teeth 【Chemistry 40】 is selected from Preferably, n1 is 1, and the R １ is -OCH ３ , -OCF ３ , 【Chemistry 41】 -CF ２ CF ３ 、-CF ３ 、-OCHF ２ 、-OCF ２ Cl、-CH ２ CF ３ 、-OCF ２ CF ３ 、 【Chemistry 42】 -OCF=CF ２ 、 【Chemistry 43】 is selected from More preferably, the R １ Ha-OCH ３ , -OCF ３ , 【Chemistry 44】 -OCF ２ CF ３ is selected from More preferably, the R １ Ha-OCF ３ , -OCF ２ CF ３ is selected from More preferably, the R １ Ha-OCF ３ That is, A compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

8. n3 is 0, 1 or 2; Preferably, the A ring is selected from C5-C8 cycloalkylene or 5- to 8-membered heterocycloalkylene; More preferably, the A ring is selected from cyclohexylene or 6-membered heterocycloalkylene; More preferably, the A ring is cyclohexylene or 【Chemistry 45】 and the * end is connected to L; 【Chemistry 46】 The end is connected to the B ring, Preferably, the A ring is 【Chemistry 47】 C5-C8 bridged cycloalkylene or 6- to 8-membered bridged heterocycloalkylene; X １ is CH or N, and X ２ , X ３ , X ４ , X ５ , X ６ are each independently CH ２ , CH, NH, N or O, and the * end is connected to L; 【Chemistry 48】 The end is connected to the B ring, More preferably, 【Chemistry 49】 In this case, X ５ is CH ２ or O, X ２ , X ３ , X ４ , X ６ are each independently CH ２ or CH, More preferably, [Transformation 50] In this case, X ２ , X ３ , X ６ is CH ２ and X ４ is CH, Preferably, the A ring 【Chemistry 51】 Each C5-C8 bridged cycloalkylene or 6- to 8-membered bridged heterocycloalkylene independently has 0 to 4 R ９ａ may be substituted with More preferably, the A ring is 0, 1 or 2 R ９ａ is replaced by More preferably, the A ring contains 0 or 1 R ９ａ is replaced by More preferably, the C5-C8 bridged cycloalkylene is 【Chemistry 52】 and More preferably, the 6- to 8-membered bridged heterocycloalkylene is 【Chemistry 53】 and Preferably, the R ９ａ are each independently a halogen, cyano, nitro, ═O, or —OR ６ , -SR ６ , S.F. ５ , -NR ６ R ７ , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, —C(O)R ６ , -C(O)OR ６ , -OC(O)OR ６ , O.C.(O.)R ６ , —C(O)NR ６ R ７ , —C(O)ONR ６ R ７ , -NR ６ C(O)NR ７ R ８ , -S(O) １－２ R ６ , -S(O) １－２ NR ６ , N.R. ６ S (O) １－２ R ７ , -NR ６ S (O) １－２ NR ７ R ８ , -NR ６ C(O)R ７ or -NR ６ C(O)OR ７ Among them, R ９ａ C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 6 R １２ may be substituted with Each R ６ , R ７ and R ８ are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, —C(O)R ２０ , -C(O)OR ２０ , —C(O)NR ２０ R ２１ , -S(O) １－２ R ２０ , -S(O) １－２ NR ２０ Among these, R ６ , R ７ and R ８ C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as each independently represent 1 to 4 R １３ may be substituted with Each R １２ , each R １３ are each independently H, halogen, cyano, nitro, ═O, or —OR ３０ , -SR ３０ , S.F. ５ , -NR ３０ R ３１ , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, —C(O)R ３０ , -C(O)OR ３０ , -OC(O)OR ３０ , O.C.(O.)R ３０ , —C(O)NR ３０ R ３１ , —C(O)ONR ３０ R ３１ , -NR ３０ C(O)NR ３０ R ３１ , -S(O) １－２ R ３０ , -S(O) １－２ NR ３０ , N.R. ３０ S (O) １－２ R ３１ , -NR ３０ S (O) １－２ NR ３０ R ３１ , -NR ３０ C(O)R ３１ or -NR ３０ C(O)OR ３１ Among them, R １２ and R １３ and each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl as the above is optionally substituted with 1 to 6 halogen atoms, or optionally substituted with C1-C6 alkyl optionally substituted with 1 to 6 halogen atoms, hydroxy, or amino, Each R ２０ and R ２１ are each independently selected from H or C1-C6 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; Each R ３０ and R ３１ are each independently selected from H or C1-C6 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; More preferably, the R ９ａ are each independently a halogen, cyano, nitro, ═O, —OH, or —NR ３０ R ３１ , C1-C3 alkyl, C1-C3 haloalkyl, —C(O)R ３０ , -C(O)OR ３０ and each R ３０ and R ３１ are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; More preferably, the R ９ａ are each independently halogen, cyano, nitro, ═O, —OH, methyl, ethyl, fluoromethyl, or fluoroethyl; More preferably, the R ９ａ are each independently —OH or ═O, More preferably, the R ９ａ are each independently —OH, Preferably, the 【Chemistry 54】 teeth, 【Transformation 55】 and the * end is connected to L; 【Transformation 56】 The end is connected to the B ring, More preferably, 【Chemistry 57】 teeth, 【Chemistry 58】 is selected from More preferably, 【Chemistry 59】 teeth, 【Transformation 60】 is selected from More preferably, 【Chemistry 61】 teeth, 【Transformation 62】 is selected from More preferably, 【Transformation 63】 teeth, 【Chemistry 64】 is selected from More preferably, 【Transformation 65】 teeth, 【Chemical Formula 66】 Selected from: A compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

9. The compound has a structure shown in general formula III: 【Transformation 67】 In the formula, D ring, L, R １ , R ２ , R ９ａ , R ９ｃ , n1, n2, n3 and n5 are as defined in any one of claims 1 to 8, and X １ and X ４ are each independently CH or N, and X ２ , X ３ , X ５ , X ６ are each independently CH ２ , CH, NH, N, or C, and v is an integer from 0 to 2; Preferably, the R ９ａ are each independently halogen, ═O, —OH, or C1-C3 alkyl, more preferably —OH; A compound according to any one of claims 1 to 8, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

10. The compound has a structure represented by any one of general formulas III-1 to III-6, 【Transformation 68】 In the formula, D ring, L, R １ , R ２ , R ９ａ , R ９ｃ , n1, n2, n3 and n5 are as defined in any one of claims 1 to 9, Preferably, R ９ａ is hydroxy or halogen; More preferably, R ９ａ is hydroxy, Preferably, n3 is an integer from 0 to 3, More preferably, n3 is 0, 1 or 2. A 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 non-enantiomer 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.

11. The L is # Ｄ -L １ -L ２ -L ３ -$ Ａ , 【Transformation 69】 or # Ｄ -NR １４ C(O)-C1-C6 alkylene-O-$ Ａ and L １ is a bond, —O—, —S— or —NR ４ - and L ２ is a bond, substituted or unsubstituted C1-C3 alkylene, and L ３ is -C(X １０ ) NR ５ -$ Ａ or -C(X １０ )-$ Ａ and X １０ is O or S, and R ４ , R ５ and R １４ are each independently selected from H, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; R ４ , R ５ and R １４ C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl as each independently represent 1 to 3 R １１ and each R １１ are each independently a halogen, cyano, nitro, ═O, —OH, —SH, or —NH ２ Preferably, each R １１ are each independently a halogen, cyano, nitro, —OH, —SH, or —NH ２ Selected from # Ｄ - is a bond connected to the D ring, -$ Ａ is a connecting bond connected to the A ring, and the * end is connected to the A ring, 【Transformation 70】 The end is connected to a D-ring, Preferably, L is 【Chemistry 71】 and the * end is connected to the A ring; 【Chemistry 72】 The end is connected to a D-ring, More preferably, L is 【Transformation 73】 is selected from More preferably, L is 【Chemistry 74】 is selected from More preferably, L is 【Chemistry 75】 Selected from: A compound according to any one of claims 1 to 10, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

12. The compound has a structure represented by general formula IV-1 or IV-2: 【Transformation 76】 In the formula, A ring, C ring, D ring, R １ , R ２ , R ９ａ , R ９ｃ , n1, n2, n3 and n5 are as defined in any one of claims 1 to 9, and X ７ is O or S, Preferably, the compound has a structure represented by general formula V-1 or V-2: 【Chemical 77】 In the formula, v is an integer of 0 to 2, and the D ring, R １ , R ２ , R ９ａ , R ９ｃ , n1, n2, n3 and n5 are as defined in any one of claims 1 to 9, and X ７ is O or S, and X １ and X ４ are each independently CH or N, and X ２ , X ３ , X ５ , X ６ are each independently CH ２ , CH, NH, N or C; A compound according to any one of claims 1 to 9 and 11, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

13. The aforementioned 【Transformation 78】 teeth, 【Chemistry 79】 is selected from X １４ , X １５ , X １６ , X １７ , X １８ are each independently selected from CH and N, and at least one is N, preferably up to 3 N, more preferably up to 2 N, and X １９ , X ２０ are each independently selected from CH, N, NH, O, and S, and are not simultaneously S or O; m is 1 or 2; X ２１ , X ２２ are each independently selected from CH, N, NH, O, and S, and are not simultaneously S or O; m is 1 or 2; and u is 1, 2, or 3; Preferably, the 【Chemistry 80】 teeth, 【Chemistry 81】 is selected from More preferably, 【Chemistry 82】 teeth, 【Chemistry 83】 is selected from More preferably, 【Chemical 84】 teeth, 【Chemical 85】 is selected from More preferably, 【Chemical 86】 teeth, 【Chemistry 87】 is selected from More preferably, 【Chemical 88】 teeth, 【Chemical 89】 Selected from: A 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 non-enantiomer 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.

14. R ２ is R １１ and Each R １１ are each independently a halogen, cyano, nitro, ═O, or —OR ６ , -SR ６ , -NR ６ R ７ , C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 8-membered heterocycloalkyl, —C(O)R ６ , -C(O)OR ６ , -OC(O)OR ６ , O.C.(O.)R ６ , —C(O)NR ６ R ７ , —C(O)ONR ６ R ７ Among these, R １１ C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocycloalkyl as each independently represent 1 to 6 R １２ may be substituted with Each R ６ , R ７ and R ８ are each independently H, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, —C(O)R ２０ , -C(O)OR ２０ , —C(O)NR ２０ R ２１ Among these, R ６ , R ７ and R ８ C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocycloalkyl as each independently represent 1 to 3 R １３ may be substituted with Each R １２ and each R １３ are each independently H, halogen, cyano, nitro, ═O, or —OR ３０ , N.R. ３０ R ３１ , C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, —C(O)R ３０ , -C(O)OR ３０ , -OC(O)OR ３０ , O.C.(O.)R ３０ Among them, R １２ and R １３ each of the C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocycloalkyl groups may independently be substituted with 1 to 3 halogen atoms, or may be substituted with C1-C3 alkyl optionally substituted with 1 to 3 halogen atoms, hydroxyl, or amino; Each R ２０ and R ２１ are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; Each R ３０ and R ３１ are each independently selected from H or C1-C3 alkyl optionally substituted with 1 to 6 halogen, hydroxy, or amino; n2 is 1, 2, or 3; Preferably, each R ２ are each independently halogen, cyano, C1-C3 haloalkyl, C1-C3 alkyl, —OC1-C3 alkyl, —OC1-C3 haloalkyl, —NR ６ R ７ , C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl; R ６ , R ７ are each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C3-C6 halocycloalkyl, and preferably, ２ is C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, n is 1, and ２ forms a fused ring with the ring D by sharing two carbon atoms, More preferably, each R ２ are each independently halogen, C1-C3 haloalkyl, C1-C3 alkyl, —O—C1-C3 alkyl, —O—C1-C3 haloalkyl, —NH ２ , [Chemical 90] and R ２ but 【Chemistry 91】 If 【Chemistry 92】 forms a fused ring with the ring D by sharing two carbon atoms, More preferably, each R ２ are each independently F, Cl, Br, or —CF ３ , -CH ３ , -CF ２ H, -OCF ３ , -NH ２ and n2 is 1, 2 or 3; Preferably, the 【Chemistry 93】 teeth, 【Chemical 94】 is selected from More preferably, 【Chemical 95】 teeth, 【Chemistry 96】 is selected from More preferably, 【Chemistry 97】 teeth, 【Chem.98】 is selected from More preferably, 【Chem.99】 teeth, 【Chemistry 100】 is selected from More preferably, 【Chemistry 101】 teeth, 【Chemical Engineering 102】 Selected from: A compound according to any one of claims 1 to 13, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

15. The compound has a structure represented by general formula VI: 【Chemistry 103】 wherein the A ring is selected from cyclohexylene or 6-membered heterocycloalkylene; １ , R ２ , R ９ａ , R ９ｃ , n1 、 n2, n3 and n5 are as defined in any one of claims 1 to 14, Preferably, the R ２ are each independently selected from F, Cl, and Br; Preferably, n2 is 1 or 2, Preferably, the R ２ and L are in the para and / or meta positions, Preferably, L is 【Chemical 104】 and the * end is connected to the A ring; 【Chemistry 105】 The end is connected to a D-ring, More preferably, L is 【Chemistry 106】 is selected from More preferably, L is 【Chemistry 107】 is selected from More preferably, L is 【Chemistry 108】 is selected from Preferably, n1 and n5 are not 0 at the same time, Preferably, the R １ and the N atom on the C ring is in the para position. Preferably, the R １ is -OR ６ , C1-C3 alkyl, halogen, —S(O) ２ R ６ or -P(O)R ６ R ７ Among these, R １ C1-C3 alkyl as the １２ and R １２ is halogen, -S(O) ２ R ３０ and R ３０ is selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, and each R ６ are each independently selected from C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl, among which R ６ C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl as each independently represent 1 to 6 R １３ and R １３ is selected from halogen, and R ７ is selected from C1-C3 alkyl; More preferably, the R １ is -OCH ３ , -OCF ３ , 【Chemistry 109】 -CF ２ CF ３ 、-CF ３ 、-OCHF ２ 、-OCF ２ CF ３ 、-OCF ２ Cl、-CH ２ CF ３ 、-F、 【Chemical 110】 -OCF=CF ２ 、 【Chemistry 111】 and More preferably, the R １ Ha-OCF ３ , -CF ２ CF ３ , -OCH ３ , -F, 【Chemistry 112】 -CF ３ and More preferably, the R １ Ha-OCF ３ , -OCF ２ CF ３ and More preferably, the R １ Ha-OCF ３ That is, A compound according to any one of claims 1 to 14, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

16. The compound has a structure shown in general formula VII: 【Chemistry 113】 In the formula, R ９ａ , X １０ is defined as in claim 1, and R ２１ is selected from halogen, and R ２２ is selected from H and halogen, and t is selected from an integer from 0 to 2; Preferably, R ２１ is Cl, Preferably, R ２２ is selected from H, F, Cl, Br, Preferably, R ９ａ is selected from H, hydroxy; Preferably, t is 0 or 2. A compound according to any one of claims 1 to 15, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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.

17. The compound is 【Chemistry 114】 【Chemical 115】 【Chemistry 116】 【Chemistry 117】 【Chemistry 118】 【Chemical 119】 【Chemical 120】 is selected from Preferably, the compound is 【Chemistry 121】 Selected from: A compound according to any one of claims 1 to 16, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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. A method for synthesizing a compound having a structure represented by general formula IV-1 or IV-2 according to claim 12, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, the method being selected from synthetic routes 1 to 6, Synthetic Route 1 【Chemistry 122】 In the formula, Compound 1-1 and Compound 1-2 undergo an amide condensation reaction to obtain Compound 1-3, Compound 1-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain Compound 1-4, Compound 1-4 is cyclized with N,N-carbonyldiimidazole to obtain Compound 1-5, Compound 1-5 undergoes a condensation reaction with Compound 1-6 to obtain Compound IV-1-1, and R １ , R ２ , R ９ａ , R ９ｃ , n1 and n2 are as defined in claim 12; Synthetic Route 2 【Chemical 123】 In the formula, compound 2-1 undergoes an amide condensation reaction with compound 2-2 to obtain compound 2-3, compound 2-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 2-4, compound 2-4 is cyclized with N,N-carbonyldiimidazole to obtain compound 2-5, compound 2-5 undergoes a condensation reaction with compound 2-6 to obtain compound IV-2-1, and R １ , R ２ , R ９ａ , R ９ｃ , n1 and n2 are as defined in claim 12; Synthetic Route 3 【Chemistry 124】 In the formula, compound 3-1 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 3-2, compound 3-2 is cyclized with N,N-carbonyldiimidazole to obtain compound 3-3, compound 3-3 undergoes a condensation reaction with compound 3-4 to obtain compound 3-5, compound 3-5 is deprotected under acidic conditions to obtain compound 3-6, compound 3-6 undergoes an amide condensation reaction with compound 3-7 to obtain compound IV-1-1, and R １ , R ２ , R ９ａ , R ９ｃ , n1 and n2 are as defined in claim 12; Synthetic Route 4 【Chemistry 125】 In the formula, compound 4-1 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 4-2, compound 4-2 is cyclized with N,N-carbonyldiimidazole to obtain compound 4-3, compound 4-3 is condensed with compound 4-4 to obtain compound 4-5, compound 4-5 is deprotected under acidic conditions to obtain compound 4-6, compound 4-6 is amide condensed with compound 4-7 to obtain compound IV-2-1, and R １ , R ２ , R ９ａ , R ９ｃ , n1 and n2 are as defined in claim 12; Synthetic Route 5 【Chemistry 126】 In the formula, compound 5-1 undergoes an amide condensation reaction with compound 5-2 to obtain compound 5-3, compound 5-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 5-4, compound 5-4 condenses with compound 5-5 to obtain compound 5-6, compound 5-6 undergoes a ring-closure reaction to obtain compound IV-1-1, and R １ , R ２ , R ９ａ , R ９ｃ , n1 and n2 are as defined in claim 12; Synthetic Route 6 【Chemistry 127】 In the formula, compound 6-1 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 6-2, compound 6-2 undergoes a ring-closing reaction to obtain compound 6-3, compound 6-3 undergoes an oxidation reaction to obtain compound 6-4, compound 6-4 reacts with compound 6-5 to obtain compound 6-6, compound 6-6 is deprotected under acidic conditions to obtain compound 6-7, compound 6-7 is condensed with compound 6-8 to obtain compound IV-1-1, and R １ , R ２ , R ９ａ , R ９ｃ , n1 and n2 are as defined in claim 12; Synthesis method.

19. A pharmaceutical composition comprising a preparation produced from the compound according to any one of claims 1 to 17, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a compound obtained by the synthesis method according to claim 18.

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

21. Use of the compound according to any one of claims 1 to 17, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 or 20, in the manufacture of a medicament for preventing and / or treating a neurodegenerative disease, cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobinopathy, a kidney disease, a hearing loss disease, an eye disease, a disease having a mutation that causes induction of unfolded protein response (UPR), a malaria infection, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease.

22. Use of a compound according to any one of claims 1 to 17, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a non-enantiomer 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 an integrated stress response (ISR) pathway-mediated disease or condition.

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