Compound, pharmaceutical composition containing compound, and synthetic method and application of compound

Abstract

The invention provides a compound as shown in a formula (0), a pharmaceutical composition containing the compound as well as a synthesis method and application of the compound. The compound provided by the invention can obviously weaken the integrated stress response (ISR) of cells and activate the activity of eIF2B, so that protein in the cells tends to be normally synthesized, and more possible drugs are provided for diseases or diseases related to eIF2B mediated by an integrated stress response (ISR) path, and / or diseases related to regulation of the activity or level of eIF2B and the activity or level of an eIF2 pathway or an ISR pathway. # imgabs0 #

Description

A compound, a pharmaceutical composition containing the same, and a synthesis method and use thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application document claims the priority of Chinese invention patent application 202211455519.X with an application date of November 21, 2022 and Chinese invention patent application 202310731972.7 with an application date of June 19, 2023, and incorporates all their contents into this application as a whole by reference. Technical Field

[0003] The present invention relates to a compound, a pharmaceutical composition containing the compound, a synthesis method and use thereof. Background Art

[0004] Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND), commonly known as Lou Gehrig's disease, is an irreversible and fatal motor neuron disease. The main symptoms are progressive muscle weakness and atrophy of the limbs and trunk muscles, and gradual loss of motor function, as if being "frozen", so it is commonly known as "Lou Gehrig's disease". Most ALS patients die from respiratory failure, usually within three to five years after the first onset of symptoms. Currently, there is no cure for ALS and no effective treatment to stop or reverse the progression of the disease. The core pathological finding of ALS is the death of motor neurons in the motor cortex and spinal cord. The degeneration of cortical spinal axons leads to thinning and scarring (sclerosis) of the lateral aspects of the spinal cord.

[0005] Loss of protein folding homeostasis is a hallmark of many of the most prevalent neurodegenerative diseases. The unfolded protein response (UPR), a response to folding stress within the endoplasmic reticulum (ER), comprises a set of signaling mechanisms that initiate gene expression programs to restore protein homeostasis or, when stress is chronic or excessive, promote neuronal death. This function of the UPR has been proposed to play a key role in ALS.

[0006] The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that helps cells, tissues, and organisms adapt to changing environments and maintain health. The ISR responds to various changes and restores homeostasis by reprogramming gene expression. Long-term memory formation in the brain requires new protein synthesis, so inhibiting the ISR enhances long-term memory formation, while activating the ISR blocks this process. Age-related cognitive impairment is often associated with ISR activation.

[0007] As a central regulator of protein homeostasis, ISR activation occurs in a wide range of brain diseases. This activation has been confirmed by measuring eIF2-P and phosphorylation of PKR, PERK, and GCN2 in the brain, including samples from patients and animal models of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, traumatic brain injury, Down syndrome, and Charcot-Marie-Tooth syndrome. Notably, ISR activation leads to cognitive deficits in traumatic brain injury, aging, and mouse models of Alzheimer's disease.

[0008] eukaryotic translation initiation factor 2B (eIF2B) is a key enzyme regulating protein synthesis. It is a guanine nucleotide exchange factor (GEF) specific for translation initiation factor 2. The eIF2B agonist ISRIB can restore protein translation, restore UPR transcription to basal levels, and reduce the integrated stress response (ISR).

[0009] At the same time, the eIF2B agonists ABBV-CLS-7262 (AbbVie / Calico) and DNL-343 (Denali Therapeutics) are both indicated for ALS and have entered Phase 1 clinical trials. DNL-343 has published Phase 1 data on healthy subjects, showing its safety and tolerability.

[0010] Numerous animal studies have confirmed that the eIF2B activator ISRIB can enhance long-term memory in mouse models. Three days after oral administration of the eIF2B activator ABBV-CLS-7262, the model animals' brain function can be restored to youthful levels. This suggests that this drug may be able to inhibit some neurodegenerative diseases in the later stages of development and has the potential to treat conditions such as Alzheimer's and Parkinson's diseases.

[0011] Summary of the Invention

[0012] The present application provides a compound, a pharmaceutical composition containing the same, and a synthesis method and use thereof, in order to provide a compound that can significantly weaken the integrated stress response (ISR) of cells, activate eIF2B activity, and allow intracellular proteins to tend to be synthesized normally, and provide more possible drugs for diseases or conditions mediated by the integrated stress response (ISR) pathway, eIF2B-related diseases, and / or for diseases related to the regulation of eIF2B activity or level, the activity or level of the eIF2 pathway or the ISR pathway.

[0013] The first aspect of the present application provides a compound represented by formula 0, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

[0014] in,

[0015] Ring A is selected from C3-C10 cycloalkylene, or 3-10 membered heterocycloalkylene, and Ring A is not And the * end is connected to L, The end is connected to the B ring, and n3 is any integer from 0 to 5;

[0016] Ring B is selected from a 5-10 membered heteroarylene group, and n4 is any integer from 0 to 4;

[0017] The C ring is selected from 3-10 membered heterocycloalkylene, C3-C10 membered cycloalkylene, or B -X 21 -C3-C12 cycloalkylene-$ R1 , X 21 -NR 3 or -C(O)NR 3 ,# B - is the connecting bond to the B ring, -$ R1 For R 1 Connecting key; each R 3 are independently H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and when the C ring is a C3-C10 membered cycloalkylene ring, the A ring is not and cyclohexylene, and the * end is connected to L, The end is connected to the B ring, and n5 is any integer from 0 to 5;

[0018] Ring D is selected from C6-C10 arylene, 5-10 membered heteroarylene, C3-C10 cycloalkylene or 3-10 membered heterocycloalkylene;

[0019] L is # D -L 1 -L 2 -L 3 -$ A or 5-6 membered heteroaryl, L 1 is a bond, -O-, -S- or -NR 4 -, L 2 is a bond, a substituted or unsubstituted C1-C10 alkylene group, L 3 -C(X 10 )NR5 -$ A or -C(X 10 )-$ A , X 10 O or S, R 4 and R 5 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, as R 4 and R 5 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 11 Replacement, L 1 Connected to D ring, L 3 Connected to ring A;# D - is the connecting bond to the D ring, -$ A is the connecting bond to the A ring;

[0020] R 1 、R 2 、R 9a 、R 9b 、R 9c Each independently is a substituent R 11 ;

[0021] Each R 11 Each independently selected from 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 R 6 、-S(O) 1-2 NR 6 NR6 S(O) 1- 2R 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 , where R 9a 、R 9b 、R 9c 、R 11 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 12 Replacement; each R 6 、R 7 and R 8 Each is independently selected from H, 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 20 、-C(O)OR 20 、-C(O)NR 20 R 21 、-S(O) 1-2 R 20 、-S(O) 1-2 NR 20 , where R 6 、R 7 and R 8 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 13 Replacement; or R 6 、R 7 and R 8 Two of them form a heterocycloalkyl with the common atom, and the heterocycloalkyl may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 carbonyls, halogens, hydroxyls or aminos; each R 12 and each R 13 Each is independently H, halogen, cyano, nitro, carbonyl, =O, -OR 30 、-SR 30 、SF5、NR 30 R31 , 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)O NR 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 , where R 12 and R 13 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl of the present invention may be substituted by 1 to 6 halogens, or by C1-C10 alkyl groups optionally substituted by 1 to 6 carbonyls, halogens, hydroxyl groups or amino groups;

[0022] Each R 20 and R 21 Each is independently selected from H, or C1-C10 alkyl optionally substituted with 1-6 carbonyls, halogens, hydroxyls or aminos;

[0023] R 20 and R 21 Together with the common atom, they form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 carbonyls, halogens, hydroxyls or amino groups; each R 30 and R 31 Each is independently selected from H, or C1-C10 alkyl optionally substituted with 1-6 carbonyls, halogens, hydroxyls or aminos;

[0024] R30 and R 31 Together with the common atom, they form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 carbonyls, halogens, hydroxyls or aminos;

[0025] n1 and n2 are each independently any integer from 0 to 4.

[0026] It should be noted that although this application is based on (R 2 ) n2 -D ring-LA ring-B ring-C ring-(R 1 ) n1 The A ring, B ring, C ring and D ring in formula 0 are described as divalent groups for the main chain structure. However, those skilled in the art should understand that due to the change of the substituent, the valence of the A ring, B ring, C ring and D ring also changes adaptively according to the chemical valence change rules. Taking the A ring as an example, when n3 is 0, the A ring is a divalent ring. When n3 is not 0, the A ring can be understood as a divalent ring according to R 9a The valence and number of the ring are selected from the trivalent and above multivalent rings, and the same applies to the B ring; taking the D ring as an example, when n2 is 0, the D ring can be understood as a monovalent ring, and when n2 is not 0, the D ring can be understood as a ring based on R 2 The valence and number of the rings are selected from the multivalent rings of divalent and above; taking the C ring as an example, when n1 and n5 are 0, the C ring can be understood as a monovalent ring; when one of n1 and n5 is 0, the C ring can be understood as a ring based on R 9c and R 2 The valence and number of the rings are selected from the divalent and higher valence rings; when n1 and n5 are not 0, the C ring can be understood as the ring according to R 9c and R 2 The valence and number of the rings are selected from trivalent and higher polyvalent rings. The above descriptions of the rings A, B, C and D apply to the entire text.

[0027] In some embodiments, the compound is as shown in Formula 0, wherein:

[0028] Ring A is selected from C3-C10 cycloalkylene, or 3-10 membered heterocycloalkylene, and Ring A is not Among them, the * end is connected to L, The end is connected to the B ring, and n3 is any integer from 0 to 5;

[0029] Ring B is selected from a 5-10 membered heteroarylene group, and n4 is any integer from 0 to 4;

[0030] The C ring is selected from 3-10 membered heterocycloalkylene, C3-C10 cycloalkylene, or B -X 21 -C3-C12 cycloalkylene-$ R1, X 21 -NR 3 or -C(O)NR 3 ,# B - is the connecting bond to the B ring, -$ R1 For R 1 Connecting key; each R 3 Each independently represents H, deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and when the C ring is a C3-C10 cycloalkylene, the A ring is not a cyclohexylene, and n5 is any integer from 0 to 5;

[0031] Ring D is selected from C6-C10 arylene, 5-10 membered heteroarylene, C3-C10 cycloalkylene or 3-10 membered heterocycloalkylene;

[0032] 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 , L 1 is a bond, -O-, -S- or -NR 4 -, L 2 is a bond, a substituted or unsubstituted C1-C10 alkylene group, L 3 -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A , X 10 O or S, R 4 、R 5 and R 14 Each independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, as R 4 、R 5 and R 14 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 11 replace;# D - is the connecting bond to the D ring, -$ A is the connecting bond to the A ring;

[0033] R 1 、R2 、R 9a 、R 9b 、R 9c Each independently is a substituent R 11 ,

[0034] Each R 11 are each independently selected from 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 NR 6 S(O) 1- 2R 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 , where R 9a 、R 9b 、R 9c 、R 11 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 12 replace;

[0035] Each R 6 、R 7 and R 8are each independently selected from H, deuterium, 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 20 、-C(O)OR 20 、-C(O)NR 20 R 21 、-S(O) 1-2 R 20 、-S(O) 1-2 NR 20 , where R 6 、R 7 and R 8 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 13 Replace; or

[0036] R 6 and R 7 Together with the atoms to which they are attached, they form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups; or

[0037] R 7 and R 8 Together with the atoms to which they are attached, they form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;

[0038] 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)NR30 R 31 、-S(O) 1-2 R 30 、-S(O) 1- 2NR 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 , where R 12 and R 13 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl of the present invention may be substituted by 1 to 6 halogens, or by C1-C10 alkyl optionally substituted by 1 to 6 halogens, hydroxyl or amino groups;

[0039] Each R 20 and R 21 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino groups; or

[0040] R 20 and R 21 The atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which is optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;

[0041] Each R 30 and R 31 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino groups; or

[0042] R 30 and R 31 The atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which is optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;

[0043] n1 and n2 are each independently any integer from 0 to 4.

[0044] In some embodiments, the compound is as shown in Formula 0, wherein:

[0045] Ring A is selected from C3-C10 cycloalkylene, or 3-10 membered heterocycloalkylene, and Ring A is not Among them, the * end is connected to L, The end is connected to the B ring, and n3 is any integer from 0 to 5;

[0046] Ring B is selected from a 5-10 membered heteroarylene group, and n4 is any integer from 0 to 4;

[0047] The C ring is selected from 3-10 membered heterocycloalkylene, C3-C10 cycloalkylene, or B -X 21 -C3-C12 cycloalkylene-$ R1 , X 21 -NR 3 or -C(O)NR 3 ,# B - is the connecting bond to the B ring, -$ R1 For R 1 Connecting key; each R 3 are independently H, deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and when the C ring is a C3-C10 cycloalkylene, the A ring is not a cyclohexylene, and the A ring is When the * terminal is connected to L, The end is connected to the B ring, the C ring is a 3-10 membered heterocycloalkylene, and n5 is any integer from 0 to 5;

[0048] Ring D is selected from C6-C10 arylene, 5-10 membered heteroarylene, C3-C10 cycloalkylene or 3-10 membered heterocycloalkylene;

[0049] 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 , L 1 is a bond, -O-, -S- or -NR 4 -, L 2 is a bond, a substituted or unsubstituted C1-C10 alkylene group, L 3 -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A , X 10 O or S, R 4 、R 5 and R14 Each independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, as R 4 、R 5 and R 14 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 11 replace;# D - is the connecting bond to the D ring, -$ A is the connecting bond to the A ring;

[0050] R 1 、R 2 、R 9a 、R 9b 、R 9c Each independently is a substituent R 11 ,

[0051] Each R 11 are each independently selected from 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 NR 6 S(O) 1- 2R 7 、-NR 6 S(O) 1-2 NR 7 R 8 、-NR 6 C(O)R7 、-P(O)R 6 R 7 or -NR 6 C(O)OR 7 , where R 9a 、R 9b 、R 9c 、R 11 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 12 replace;

[0052] Each R 6 、R 7 and R 8 are each independently selected from H, deuterium, 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 20 、-C(O)OR 20 、-C(O)NR 20 R 21 、-S(O) 1-2 R 20 、-S(O) 1-2 NR 20 , where R 6 、R 7 and R 8 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 13 Replace; or

[0053] R 6 and R 7 Together with the atoms to which they are attached, they form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups; or

[0054] R 7 and R 8 Together with the atoms to which they are attached, they form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;

[0055] Each R 12 and each R 13 are each independently H, deuterium, halogen, cyano, nitro, =O, -OR30 、-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- 2NR 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 , where R 12 and R 13 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl of the present invention may be substituted by 1 to 6 halogens, or by C1-C10 alkyl optionally substituted by 1 to 6 halogens, hydroxyl or amino groups;

[0056] Each R 20 and R 21 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino groups; or

[0057] R 20 and R 21 The atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which is optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;

[0058] Each R 30 and R31 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino groups; or

[0059] R 30 and R 31 The atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which is optionally substituted by 1-6 halogens, hydroxyl groups or amino groups;

[0060] n1 and n2 are each independently any integer from 0 to 4.

[0061] Preferably, the compound of formula 0 is not any of the following compounds

[0062] Preferably, the aforementioned scheme does not include any of the following compounds, or their stereoisomers, or their tautomers, or their geometric isomers, or their enantiomers, or their diastereomers, or their racemates, or their polymorphs, or their solvates, or their hydrates, or their N-oxides, or their isotopically labeled compounds, or their metabolites, or their esters, or their prodrugs, or their pharmaceutically acceptable salts;

[0063] The compounds of the present application can significantly weaken the integrated stress response (ISR) of cells, activate eIF2B activity, and allow intracellular proteins to tend to be synthesized normally.

[0064] In some embodiments, n4 is 0, 1, 2 or 3;

[0065] Preferably, each of the R 9b Each of the R 9b Each is independently halogen, cyano, nitro, -OH, C1-C3 alkyl;

[0066] More preferably, the R 9b are each independently halogen, -OH, methyl, ethyl or propyl;

[0067] More preferably, n4 is 0.

[0068] Preferably, the B ring is selected from

[0069] It is further preferred that the B ring is selected from (For example )or (For example ), where X 7O or S, X 8 、X 9 、X 10 Each is independently CH or N, the * end is connected to the C ring, The end is connected to the A ring;

[0070] More preferably, X 8 、X 9 、X 10 At most two of them are N;

[0071] More preferably, X 8 、X 9 、X 10 One of them is N.

[0072] In some embodiments, the B ring is selected from any one of the following groups:

[0073] In some embodiments, the B ring is selected from any one of the following groups:

[0074] (For example ), (For example ), (For example ), (For example ).

[0075] In some embodiments, the B ring is selected from any one of the following groups:

[0076] In some embodiments, the B ring is selected from any one of the following groups:

[0077] (For example ), (For example ).

[0078] In some embodiments, the B ring is

[0079] In some embodiments, the compound has the structure shown in Formula I

[0080] Among them, 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 one of the embodiments above, and X 7O 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 one of the embodiments above, and X 7 O or S.

[0081] Preferably, n1 and n2 are each independently an integer of 1-3;

[0082] More preferably, n1 is 1, and n2 is an integer of 1-3.

[0083] In some embodiments, each of the R 9c are independently halogen, cyano, nitro, carbonyl, =O, -OH, -NR 30 R 31 、C1-C3 alkyl、-C(O)R 30 、-C(O)OR 30 , preferably each of the R 9c are independently halogen, cyano, nitro, =O, -OH, -NR 30 R 31 、C1-C3 alkyl、-C(O)R 30 、-C(O)OR 30 , each R 30 and R 31 Each is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxy or amino;

[0084] Preferably, the C ring may be substituted by 1 or 2 R 9c Substituted, preferably each of the R 9c Each of the R 9c Each is independently halogen, cyano, nitro, -OH, C1-C3 alkyl;

[0085] More preferably, the R 9c are each independently halogen, -OH, methyl, ethyl or propyl;

[0086] More preferably, the R 9c Each independently represents F or methyl.

[0087] Preferably, n5 is 0, 1 or 2;

[0088] More preferably, n5 is 0 or 1.

[0089] Preferably, the 3-10 membered heterocycloalkylene group of the C ring is selected from Among them, X11 、X 23 Each is N or B, X 12 is CH2, NH, O or S, q is an integer from 0 to 3, preferably q is 1 or 2; X 13 is N or B, s is an integer from 1 to 3, preferably s is 1 or 2; X 14 is O, S or NH, t is an integer from 1 to 3, preferably t is 1 or 2; the * end is connected to the B ring, End and R 1 connect;

[0090] Preferably, the 3-10 membered heterocycloalkylene group of the C ring is selected from Among them, X 11 N or B, X 12 is CH2, NH, O or S, q is 0 to 3, preferably q is 1 or 2; X 13 is N or B, s is an integer from 1 to 3, preferably s is 1 or 2; X 14 is O, S or NH, t is an integer from 1 to 3, preferably t is 1 or 2;

[0091] More preferably, the 3-10 membered heterocycloalkylene group of the C ring is selected from

[0092] Preferably, the C ring # B -X 21 -C3-C12 cycloalkylene-$ R1 for Among them, R 3 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, p is an integer from 1 to 3, preferably 1 or 2; B - is the connecting bond to the B ring, -$ R1 For R 1 The connecting key of the connection; the * end is connected to the B ring, End and R 1 connect;

[0093] Further preferably, the # of the C ring B -X 21 -C3-C12 cycloalkylene-$ R1 for

[0094] In some embodiments, the C ring is selected from *End is connected to B ring, End and R 1 connect.

[0095] In some embodiments, the C ring is selected from

[0096] In some embodiments, the C ring is selected from

[0097] In some embodiments, the C ring is selected from Each of q, p, s, and t is independently 1 or 2.

[0098] In some embodiments, the Selected from *End is connected to B ring, End and R 1 connect.

[0099] In some embodiments, the Selected from *End is connected to B ring, End and R 1 connect.

[0100] In some embodiments, the Selected from *End is connected to B ring, End and R 1 connect.

[0101] In some embodiments, the Selected from *End is connected to B ring, End and R 1 connect.

[0102] In some embodiments, the Selected from *End is connected to B ring, End and R 1 connect.

[0103] In some embodiments, each R 1 Each independently is R 11 , each R 1 Each independently is R 11 , each R 11 Each independently selected from 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 selected from 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- 2R 6 、-P(O)R 6 R 7 , where R 11 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl groups are each independently substituted by 1 to 6 R 12 replace,

[0104] Each R 6 、R 7 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, wherein R 6 、R 7 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl groups are each independently substituted by 1 to 3 R 13 replace;

[0105] Each R 12 and each R 13 Each is independently H, halogen, cyano, nitro, carbonyl, =O, -OR 30 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, preferably each R 12 and each R 13are each independently H, halogen, cyano, nitro, =O, -OR 30 , C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, wherein R 12 and R 13 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl groups may be substituted by 1 to 3 halogens, or by C1-C3 alkyl groups which may be optionally substituted by 1 to 3 carbonyls, halogens, hydroxyl groups or amino groups; preferably R 12 and R 13 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl groups of the present invention may each independently be substituted by 1 to 3 halogens, or by C1-C3 alkyl groups which may be optionally substituted by 1 to 3 halogens, hydroxyl groups, or amino groups.

[0106] Each R 30 Each independently selected from H, or C1-C3 alkyl optionally substituted by 1-6 carbonyl, halogen, hydroxyl or amino groups, preferably each R 30 Each is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxy or amino groups.

[0107] In some embodiments, the R 1 Select from -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 Each independently selected from H, C1-C3 alkyl, wherein as R 6 、R 7 The C1-C3 alkyl group may be substituted by 1 to 3 R 13 Substitution; preferably each R 13 Each is independently halogen, cyano, or nitro.

[0108] In some embodiments, the R 1 Select from -OR 6 , C1-C3 alkyl, halogen, -S(O)2R 6 or -P(O)R 6 R 7 , wherein preferably as R 1 The C1-C3 alkyl group may be 1-6 R 12 Replacement, R 12 Selected from halogen, -S(O)2R 30 , R30 Selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl; each R 6 Each independently selected from C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, wherein R 6 The C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl groups are each independently substituted with 1 to 6 R 13 Replacement, R 13 is selected from halogen; R 7 Selected from C1-C3 alkyl.

[0109] In some embodiments, the R 1 -OCH3, -OCF3, -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, -CF3, -F, -OCF=CF2、

[0110] In some embodiments, the R 1 Selected from -OCH3, -OCF3, -CF2CF3, -CF3, -OCHF2, -OCF2CF3, -OCF2Cl, -CH2CF3, -F, -OCF=CF2、

[0111] Preferably, the R 1 Selected from -OCF3, -CF2CF3, -OCH3, -F, -CF3;

[0112] More preferably, the R 1 Selected from -OCF3, -OCF2CF3;

[0113] More preferably, the R 1 is -OCF3.

[0114] In some embodiments, n1 is preferably 0 or 1.

[0115] In some embodiments, the compound has the structure shown in Formula II

[0116] Among them, A ring, D ring, L, R 2 、R 9a , n2 and n3 are as defined in any one of the embodiments above.

[0117] Preferably, the R 1 -OCH3, -OCF3, -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, -OCF=CF2、

[0118] Preferably, the R 1 Selected from -OCH3, -OCF3, -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, F, -OCF=CF2、

[0119] Preferably, the R 1 Selected from -OCH3, -OCF3, -CF2CF3, -CF3, -OCHF2, -OCF2CF3, -OCF2Cl, -CH2CF3, F, -OCF=CF2、

[0120] More preferably, the R 1 Selected from -OCH3, -OCF3, -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, -CF3, -OCF=CF2、

[0121] More preferably, the R 1 Selected from -OCH3, -OCF3, -CF2CF3, -F, -CF3;

[0122] More preferably, the R 1 -OCF3, -OCF2CF3;

[0123] More preferably, the R 1 is -OCF3; preferably, n1 is 1;

[0124] Preferably, n5 is 0, 1 or 2, and each of the R 9c Each of the R 9c Each is independently halogen, cyano, nitro, -OH, C1-C3 alkyl;

[0125] More preferably, the R 9care each independently halogen, -OH, methyl, ethyl or propyl;

[0126] More preferably, the R 9c Each is independently F.

[0127] In some embodiments, the compound has the structure shown in Formula II-1

[0128] Among them, A ring, D ring, L, R 2 、R 9a , n2 and n3 are as defined in any one of the embodiments above.

[0129] Preferably, n5 is 0 or 1, preferably n5 is 1, and the R 9c is selected from halogen, cyano, nitro, carbonyl, -OH, C1-C3 alkyl; preferably, R 9c Selected from halogen, cyano, nitro, -OH, C1-C3 alkyl;

[0130] More preferably, the R 9c is selected from halogen, methyl or ethyl;

[0131] More preferably, the R 9c For F.

[0132] Preferably, the Selected from

[0133] More preferably, the Selected from

[0134] Preferably, n1 is 1, and the R 1 Selected from -OCH3, -OCF3, -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, -OCF=CF2、

[0135] More preferably, the R 1 Selected from -OCH3, -OCF3, -CF2CF3, -CF3, -OCHF2, -OCF2Cl, -CH2CF3, -OCF2CF3, -OCF=CF2、

[0136] More preferably, the R 1 Selected from -OCH3, -OCF3, -OCF2CF3;

[0137] More preferably, the R 1 Selected from -OCF3, -OCF2CF3;

[0138] More preferably, the R 1 is -OCF3.

[0139] In some embodiments, n3 is 0, 1 or 2;

[0140] Preferably, the A ring is selected from C5-C8 cycloalkylene or 5-8 membered heterocycloalkylene.

[0141] In some embodiments, the A ring is selected from cyclohexylene or 6-membered heterocycloalkylene.

[0142] In some embodiments, the A ring is selected from cyclohexane or * terminal is connected to L, The end is connected to the B ring.

[0143] In some embodiments, the A ring is selected from C5-C8 sub-bridged cycloalkyl or 6-8 membered sub-bridged heterocycloalkyl, wherein X 1 CH or N, X 2 、X 3 、X 4 、X 5 、X 6 Each independently represents CH2, CH, NH, N or O, and the * end is connected to L, The end is connected to the B ring.

[0144] In some embodiments, the A ring is selected from C6-C8 sub-bridged cycloalkyl or 6-8 membered sub-bridged heterocycloalkyl, wherein X 1 CH or N, X 2 、X 3 、X 4 、X 5 、X 6 Each independently represents CH2, CH, NH, N or O, and the * end is connected to L, The end is connected to the B ring.

[0145] In some embodiments, the In, X 5 is CH2 or O, X 2 、X 3 、X 4 、X 6 are each independently CH2 or CH;

[0146] Preferably, the X 2 、X 3 、X 6 CH2, X 4 For CH.

[0147] In some embodiments, the A ring C6-C8 sub-bridged cycloalkyl or 6-8 membered sub-bridged heterocycloalkyl are each independently substituted with 1-4 R 9a substituted, preferably by 1 or 2 R 9a replace.

[0148] In some embodiments, the A ring C5-C8 sub-bridged cycloalkyl or 6-8 membered sub-bridged heterocycloalkyl are each independently substituted with 0-4 R 9a replace;

[0149] Preferably, the A ring is surrounded by 0, 1 or 2 R 9a replace;

[0150] More preferably, the A ring is surrounded by 0 or 1 R 9a replace.

[0151] In some embodiments, the C6-C8 cycloalkylene bridge is

[0152] In some embodiments, the C5-C8 bridged cycloalkylene is

[0153] In some embodiments, the bridged heterocycloalkyl group is

[0154] In some embodiments, the bridged heterocycloalkyl group is

[0155] In some embodiments, the R 9a Each is 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 R7 、-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 , preferably the R 9a are 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 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 , where R 9aThe C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 12 replace;

[0156] Each R 6 、R 7 and R 8 Each is independently selected from H, 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 20 、-C(O)OR 20 、-C(O)NR 20 R 21 、-S(O) 1-2 R 20 、-S(O) 1-2 NR 20 , where R 6 、R 7 and R 8 The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted by 1 to 4 R 13 replace;

[0157] Each R 12 , each R 13 Each is independently H, halogen, cyano, nitro, carbonyl, =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- 2NR 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 , 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- 2NR 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 , where R 12 and R 13 The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups may be substituted by 1 to 6 halogens, or by C1-C6 alkyl groups which may be optionally substituted by 1 to 6 carbonyls, halogens, hydroxyl groups or amino groups, preferably as R 12 and R 13The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl of the present invention may be substituted by 1 to 6 halogens, or by C1-C6 alkyl which may be optionally substituted by 1 to 6 halogens, hydroxyl or amino groups,

[0158] Each R 20 and R 21 Each independently selected from H, or C1-C6 alkyl optionally substituted by 1-6 carbonyl, halogen, hydroxyl or amino groups, preferably each R 20 and R 21 Each is independently selected from H, or C1-C6 alkyl optionally substituted by 1-6 halogen, hydroxyl or amino;

[0159] Each R 30 and R 31 Each independently selected from H, or C1-C6 alkyl optionally substituted by 1-6 carbonyl, halogen, hydroxyl or amino groups, preferably each R 30 and R 31 Each is independently selected from H, or C1-C6 alkyl optionally substituted with 1-6 halogen, hydroxy or amino groups.

[0160] In some embodiments, the R 9a are independently halogen, cyano, nitro, carbonyl, =O, -OH, -NR 30 R 31 , C1-C3 alkyl, C1-C3 haloalkyl, -C(O)R 30 、-C(O)OR 30 , each R 30 and R 31 Each independently selected from H, or C1-C3 alkyl optionally substituted by 1-6 halogen, hydroxyl or amino; preferably said R 9a are independently halogen, cyano, nitro, =O, -OH, -NR 30 R 31 , C1-C3 alkyl, C1-C3 haloalkyl, -C(O)R 30 、-C(O)OR 30 , each R 30 and R 31 Each is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxy or amino groups.

[0161] In some embodiments, the R 9a Each is independently halogen, cyano, nitro, carbonyl, =O, -OH, methyl, ethyl, fluoromethyl or fluoroethyl; preferably, R 9aEach is independently halogen, cyano, nitro, =0, -OH, methyl, ethyl, fluoromethyl or fluoroethyl.

[0162] In some embodiments, the R 9a Each is independently -OH or =O.

[0163] In some embodiments, the R 9a Each is independently -OH.

[0164] In some embodiments, the Selected from

[0165] * terminal is connected to L, The end is connected to the B ring.

[0166] In some embodiments, the Selected from

[0167] * terminal is connected to L, The end is connected to the B ring.

[0168] In some embodiments, the Selected from

[0169] In some embodiments, the Selected from

[0170] In some embodiments, the Selected from

[0171] In some embodiments, the Selected from

[0172] In some embodiments, the Selected from

[0173] In some embodiments, the compound has the structure shown in Formula III

[0174] Among them, X 1 CH or N, X 2 、X 3 、X 4 、X 5 、X 6Each independently is CH2, CH, NH, N or O; preferably X 1 and X 4 are independently CH or N, X 2 、X 3 、X 5 、X 6 Each independently represents CH2, CH, NH, N or C, v is an integer from 0 to 2; 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.

[0175] Preferably, the R 9a Each is independently halogen, =O, -OH, C1-C3 alkyl, more preferably -OH.

[0176] 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.

[0177] In some embodiments, the compound has a structure represented by any one of the general formulas III-1 to III-6.

[0178] Among them, 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.

[0179] Preferably, R 9a is hydroxy or halogen;

[0180] More preferably, R 9a is hydroxyl group;

[0181] Preferably, n3 is an integer of 0-3, more preferably 0, 1 or 2.

[0182] In some embodiments, the compound has any one of the compounds represented by the following general formula:

[0183] Wherein, the D ring, L, R 1 、R 2 , n1, n2 are as defined in any of the above embodiments.

[0184] In some embodiments, the L is D -L 1 -L 2 -L 3 -$ A or L 1 is a bond, -O-, -S- or -NR 4 -, preferably L 1 -O-, -S- or -NR 4 -, L 2 is a bond, a substituted or unsubstituted C1-C3 alkylene group, preferably L 2 is a substituted or unsubstituted C1-C3 alkylene group, L 3 -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A , X 10 O or S, R 4 and R 5 Each independently selected from H, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, as R 4 and R 5 The C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl groups are each independently substituted by 1 to 3 R 11 Replacement; each R 11 Each R is independently selected from halogen, cyano, nitro, carbonyl, =O, -OH, -SH, -NH2, preferably each R 11 Each R is independently selected from halogen, cyano, nitro, =O, -OH, -SH, -NH2, preferably each R 11 Each is independently selected from halogen, cyano, nitro, -OH, -SH, -NH2; D - is the connecting bond to the D ring, -$ A is the connecting key connected to the A ring; the * end is connected to the A ring, The end is connected to the D ring.

[0185] In some embodiments, the L is D -L 1 -L 2 -L 3 -$ A 、 or# D -NR 14 C(O)-C1-C6 alkylene-O-$ A , L 1 is a bond, -O-, -S- or -NR4 -, L 2 is a bond, a substituted or unsubstituted C1-C3 alkylene group, L 3 -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A , X 10 O or S, R 4 、R 5 and R 14 Each independently selected from H, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, as R 4 、R 5 and R 14 The C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl groups are each independently substituted by 1 to 3 R 11 Replacement; each R 11 Each R is independently selected from halogen, cyano, nitro, =O, -OH, -SH, -NH2, preferably each R 11 Each is independently selected from halogen, cyano, nitro, -OH, -SH, -NH2; D - is the connecting bond to the D ring, -$ A It is the connecting key connected to the A ring, and the * end is connected to the A ring. The end is connected to the D ring.

[0186] In some embodiments, the L is selected from *end is connected to the A ring, The end is connected to the D ring.

[0187] In some embodiments, the L is selected from *end is connected to the A ring, The end is connected to the D ring.

[0188] In some embodiments, the L is selected from *end is connected to the A ring, The end is connected to the D ring.

[0189] In some embodiments, the L is selected from *end is connected to the A ring, The end is connected to the D ring.

[0190] In some embodiments, the L is selected from *end is connected to the A ring, The end is connected to the D ring.

[0191] In some embodiments, the L is selected from *end is connected to the A ring, The end is connected to the D ring.

[0192] In some embodiments, the compound has a structure shown in Formula IV-1 or IV-2

[0193] Among them, D ring, R 1 、R 2 、R 9a 、R 9c , n1, n2, n3 and n5 are as defined in any one 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 one of the above embodiments, and X 7 O or S.

[0194] In some embodiments, the compound has a structure shown in Formula V-1 or V-2

[0195] Wherein, v is an integer from 0 to 2, D ring, R 1 、R 2 、R 9a 、R 9c , n1, n2, n3 and n5 are as defined in any one of the above embodiments, and X 7 O or S.

[0196] In some embodiments, Selected from Among them, X 14 、X 15 、X 16 、X 17 、X 18 are independently selected from CH, N, and at least one is N, preferably there are at most three N, and more preferably there are at most two N; X 19 、X 20 are each independently selected from CH, N, NH, O, S, and are not S or O at the same time, and m is 1 or 2; X 21 、X 22Each is independently selected from CH, N, NH, O, S, and is not S or O at the same time, m is 1 or 2; u is 1, 2 or 3.

[0197] In some embodiments, Selected from Among them, X 14 、X 15 、X 16 、X 17 、X 18 are independently selected from CH, N, and at least one is N, preferably there are at most three N, and more preferably there are at most two N; X 19 、X 20 are each independently selected from CH, N, NH, O, S, and are not S or O at the same time, and m is 1 or 2; X 21 、X 22 Each is independently selected from CH, N, NH, O, S, and is not S or O at the same time, m is 1 or 2; u is 1, 2 or 3.

[0198] In some embodiments, the Selected from

[0199]

[0200] In some embodiments, the Selected from

[0201] In some embodiments, the Selected from

[0202] In some embodiments, the Selected from

[0203] In some embodiments, the Selected from

[0204] In some embodiments, the Selected from

[0205] In some embodiments, the Selected from

[0206] In some embodiments, the Selected from

[0207] In some embodiments, R 2 R 11 , each R 11 Each independently selected from 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 selected from 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 , where R 11 The C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl groups are each independently substituted by 1 to 6 R 12 replace,

[0208] Each R 6 、R 7 and R 8 Each independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 R 21 , where R 6 、R 7 and R 8 The C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl are each independently substituted by 1 to 3 R 13 replace;

[0209] Each R 12 and each R 13 Each is independently H, halogen, cyano, nitro, carbonyl, =O, -OR 30 NR 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 , preferably each R 12 and each R 13 are each independently H, halogen, cyano, nitro, =O, -OR 30 NR 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 , where R 12 and R 13 The C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl groups may be substituted by 1 to 3 halogens, or by C1-C3 alkyl groups which may be substituted by 1 to 3 carbonyls, halogens, hydroxyl groups or amino groups, preferably as R 12 and R 13 The C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocycloalkyl groups may each independently be substituted by 1 to 3 halogens, or by C1-C3 alkyl groups which may be optionally substituted by 1 to 3 halogens, hydroxyl groups, or amino groups.

[0210] Each R 20 and R 21 Each is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxy or amino;

[0211] Each R 30 and R 31 Each is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxy or amino;

[0212] n2 is 1 or 2 or 3.

[0213] In some embodiments, each R 2 Each independently selected from halogen, cyano, C1-C3 haloalkyl,

[0214] C1-C3 alkyl, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NR 6 R 7 , C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, R 6 、R 7 Each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, preferably, the R 2 When it is a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, n is 1, and the R 2 It shares two carbon atoms with the D ring to form a fused ring.

[0215] In some embodiments, each R 2 Each is independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkyl, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NH2, Among them, it is preferred that R 2 for hour, It shares two carbon atoms with the D ring to form a fused ring.

[0216] In some embodiments, each R 2 Each is independently selected from F, Cl, Br, -CF3, -CH3, -CFH2, -CF2H, -OCH3, O-CF3, -NH2, and n2 is 1 or 2.

[0217] In some embodiments, each R 2 Each is independently selected from F, Cl, Br, -CF3, -CH3, -CF2H, -OCF3, -NH2, and n2 is 1, 2 or 3.

[0218] In some embodiments, the Selected from

[0219] In some embodiments, the Selected from

[0220] In some embodiments, the Selected from

[0221] In some embodiments, the Selected from

[0222] In some embodiments, the Selected from

[0223] In some embodiments, the compound preferably has the structure shown in Formula VI

[0224] Wherein, the A ring is selected from cyclohexane or 6-membered heterocycloalkylene; the L, R 1 、R 2 、R 9a 、R 9c 、n1 、 n2, n3 and n5 are as defined in any of the above embodiments.

[0225] In some embodiments, the R 2 Each is independently selected from F, Cl, and Br.

[0226] In some embodiments, n2 is 1 or 2.

[0227] In some embodiments, the R 2 It is in a para and / or meta position relationship with L.

[0228] In some embodiments, the L is selected from *end is connected to the A ring, The end is connected to the D ring.

[0229] Preferably, said L is selected from

[0230] In some embodiments, the L is selected from *end is connected to the A ring, The end is connected to the D ring.

[0231] In some embodiments, the L is selected from

[0232] In some embodiments, the L is selected from

[0233] In some embodiments, the L is selected from

[0234] In some embodiments, n1 and n5 are not 0 at the same time.

[0235] In some embodiments, the R 1 It is in a para position to the N on the C ring where it is located.

[0236] In some embodiments, the R 1 Select from -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 Each independently selected from H, C1-C3 alkyl, wherein as R 6 、R 7 The C1-C3 alkyl group may be substituted by 1 to 3 R 13 Substitution; preferably each R 13 Each is independently halogen, cyano, or nitro;

[0237] Preferably, the R 1 -OCH3, -OCF3, -CF2CF3, -CF3, -CHF2, -OCF2Cl, -CH2CF3, -CF3, -F, -OCF=CF2、

[0238] In some embodiments, the R 1 Selected from -OR 6 , C1-C3 alkyl, halogen, -S(O)2R 6 or -P(O)R 6 R 7 , where R 1 The C1-C3 alkyl group may be 1-6 R 12 Replacement, R 12 Selected from halogen, -S(O)2R 30 , R 30 Selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl; each R 6 Each independently selected from C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, wherein R 6 The C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl groups are each independently substituted with 1 to 6 R 13 Replacement, R 13 is selected from halogen; R 7 Selected from C1-C3 alkyl.

[0239] In some embodiments, the R 1 -OCH3, -OCF3, -CF2CF3, -CF3, -OCHF2, -OCF2CF3, -OCF2Cl, -CH2CF3, -F, -OCF=CF2、

[0240] In some embodiments, the R 1 -OCF3, -CF2CF3, -OCH3, -F, -CF3;

[0241] In some embodiments, the R 1 -OCF3, -OCF2CF3;

[0242] In some embodiments, the R 1 is -OCF3.

[0243] In each embodiment, R 1 、R 2 、R 9a 、R 9b 、R 9c Each independently is a substituent R 11 , when n1, n2, n3, n4, n5 are 0, it means R 1 、R 2 、R 9a 、R 9b 、R 9c If it does not exist, the free bonds of C constituting the D ring, A ring, B ring and C ring are connected to H.

[0244] In some embodiments, the compound has the structure shown in Formula VII

[0245] Among them, R 9a 、X 10 The definition of R is as defined in any of the above embodiments, 21 Selected from halogen, R 22 is selected from H, halogen, t is selected from an integer of 0-2;

[0246] Preferably, R 21 is Cl;

[0247] Preferably, R 22 Selected from H, F, Cl, Br;

[0248] Preferably, R 9a Selected from H, hydroxyl;

[0249] Preferably, t is 0 or 2.

[0250] In some embodiments, the compound is selected from:

[0251] In some embodiments, the compound is specifically selected from

[0252] In some embodiments, the compound is specifically selected from

[0253] Another aspect of the present application provides a method for synthesizing a compound having a structure represented by the above-mentioned 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 diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the method is selected from any one of Synthesis Routes 1 to 6;

[0254] Synthesis Route 1:

[0255] Among them, compound 1-1 undergoes an amide condensation reaction with compound 1-2 to obtain compound 1-3; the compound 1-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 1-4; the compound 1-4 undergoes a cyclization reaction with N,N-carbonyldiimidazole to obtain compound 1-5; the compound 1-5 undergoes a condensation reaction with compound 1-6 to obtain compound IV-1-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in the above embodiment;

[0256] Synthesis route 2:

[0257] Among them, compound 2-1 undergoes an amide condensation reaction with compound 2-2 to obtain compound 2-3; the compound 2-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 2-4; the compound 2-4 undergoes a cyclization with N,N-carbonyldiimidazole to obtain compound 2-5; the compound 2-5 undergoes a condensation reaction with compound 2-6 to obtain compound IV-2-1; R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in the above embodiment;

[0258] Synthesis route 3:

[0259] Among them, compound 3-1 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 3-2; the compound 3-2 undergoes cyclization with N,N-carbonyldiimidazole to obtain compound 3-3; the compound 3-3 undergoes condensation reaction with compound 3-4 to obtain compound 3-5; the compound 3-5 is deprotected under acidic conditions to obtain compound 3-6; the compound 3-6 undergoes amide condensation reaction with compound 3-7 to obtain compound IV-1-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in the above embodiment;

[0260] Synthesis Route 4:

[0261] Among them, compound 4-1 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 4-2; the compound 4-2 undergoes cyclization with N,N-carbonyldiimidazole to obtain compound 4-3; the compound 4-3 undergoes condensation reaction with compound 4-4 to obtain compound 4-5; the compound 4-5 is deprotected under acidic conditions to obtain compound 4-6; the compound 4-6 undergoes amide condensation reaction with compound 4-7 to obtain compound IV-2-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in the above embodiment;

[0262] Synthesis Route 5:

[0263] Among them, compound 5-1 and compound 5-2 undergo amide condensation reaction to obtain compound 5-3; the compound 5-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 5-4; the compound 5-4 and compound 5-5 undergo condensation to obtain compound 5-6; the compound 5-6 undergoes ring closure reaction to obtain compound IV-1-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in the above embodiment;

[0264] Synthesis Route 6:

[0265] Among them, compound 6-1 reacts with hydrazine hydrate to obtain compound 6-2 through functional group transformation; the compound 6-2 undergoes a ring-closure reaction to obtain compound 6-3; the compound 6-3 undergoes an oxidation reaction to obtain compound 6-4; the compound 6-4 reacts with compound 6-5 to obtain compound 6-6; the compound 6-6 is deprotected under acidic conditions to obtain compound 6-7; the compound 6-7 is condensed with compound 6-8 to obtain compound IV-1-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in the above embodiment.

[0266] Another aspect of the present application provides a pharmaceutical composition comprising any one of the above-mentioned compounds, or a preparation prepared from a stereoisomer, a tautomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a polymorph, a solvate, a hydrate, an N-oxide, an isotope-labeled compound, a metabolite, an ester, a prodrug, or a pharmaceutically acceptable salt thereof, or a compound obtained by any of the above-mentioned synthesis methods.

[0267] In some embodiments, the above-mentioned pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and vehicles.

[0268] In some embodiments, provided is the use of any of the above compounds, or their stereoisomers, or their tautomers, or their geometric isomers, or their enantiomers, or their diastereomers, or their racemates, or their polymorphs, or their solvates, or their hydrates, or their N-oxides, or their isotopically labeled compounds, or their metabolites, or their esters, or their prodrugs, or their pharmaceutically acceptable salts, or their pharmaceutical compositions for the preparation of a medicament for preventing and / or treating neurodegenerative diseases (e.g., leukodystrophy, white matter lesions, myelin dysplasia or demyelinating diseases, intellectual disability syndromes, cognitive dysfunction, glial cell dysfunction or brain injury (e.g., traumatic brain injury or toxin-induced brain injury), cancer, inflammatory diseases, autoimmune diseases, viral infections, skin diseases, fibrotic diseases, hemoglobin diseases, kidney diseases, hearing loss diseases, eye diseases, diseases with mutations that lead to the induction of the unfolded protein response (UPR), malaria infection, musculoskeletal diseases, metabolic diseases, or mitochondrial diseases.

[0269] In some embodiments, provided is the use of any of the above-described compounds, or their stereoisomers, or their tautomers, or their geometric isomers, or their enantiomers, or their diastereomers, or their racemates, or their polymorphs, or their solvates, or their hydrates, or their N-oxides, or their isotopically labeled compounds, or their metabolites, or their esters, or their prodrugs, or their pharmaceutically acceptable salts, or their pharmaceutical compositions for the preparation of a medicament for preventing and / or treating a disease or condition mediated by the integrated stress response (ISR) pathway.

[0270] In some embodiments, provided is a method of treating a disease or condition mediated by the integrated stress response (ISR) pathway in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of any one of the aforementioned compounds, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of any one of the aforementioned pharmaceutical compositions.

[0271] In some embodiments, a method for treating a disease associated with regulation of eIF2B activity or level, eIF2 pathway or ISR pathway activity or level is provided, the method comprising administering to a subject a therapeutically effective amount of any of the above-mentioned compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a therapeutically effective amount of any of the above-mentioned pharmaceutical compositions.

[0272] In some embodiments, a method for preventing and / or treating the above-mentioned diseases is provided, comprising administering to a subject in need thereof an effective amount of any of the above-mentioned compounds, or its stereoisomers, or its tautomers, or its geometric isomers, or its enantiomers, or its diastereomers, or its racemates, or its polymorphs, or its solvates, or its hydrates, or its N-oxides, or its isotope-labeled compounds, or its metabolites, or its esters, or its prodrugs, or its pharmaceutically acceptable salts, or any of the above-mentioned pharmaceutical compositions.

[0273] In some embodiments, a method for preventing and / or treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any of the aforementioned compounds, or its stereoisomers, or its tautomers, or its geometric isomers, or its enantiomers, or its diastereomers, or its racemates, or its polymorphs, or its solvates, or its hydrates, or its N-oxides, or its isotopically labeled compounds, or its metabolites, or its esters, or its prodrugs, or its pharmaceutically acceptable salts, or any of the aforementioned pharmaceutical compositions.

[0274] In some embodiments, the neurodegenerative disease includes, but is not limited to, leukodystrophy, leukoencephalopathy, myelin dysplasia or demyelinating disease, intellectual disability syndrome, cognitive dysfunction, glial cell dysfunction or brain injury (e.g., traumatic brain injury or toxin-induced brain injury), Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease. disease), dystonia, frontotemporal dementia (FTD), Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe disease, kuru, Lewy body dementia, Machado-Joseph disease (spinocerebellar disorder type 3), multiple system atrophy, multisystem proteinopathy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum's disease, Sandhoff disease, Schilder's disease disease), subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar disorders (various types with different characteristics,(e.g., spinocerebellar ataxia type 2 or spinocerebellar ataxia type VIII), spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, corticobasal degeneration, adrenoleukodystrophy, X-linked adrenoleukodystrophy, cerebral adrenoleukodystrophy, Pelizaeus-Merzheimer disease, Krabbe disease, leukodystrophy due to mutations in the DARS2 gene (sometimes called leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL), DARS2-related spectrum disorder, or tabes dorsalis).

[0275] The above-mentioned cancers include, but are not limited to, human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid cancers and lymphoid cancers, renal cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, gliomas, esophageal cancer, liver cancer (including hepatocarcinoma), lymphomas (including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (such as Burkitt's lymphoma), In some other instances, "cancer" refers to lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[0276] The leukemias include, but are not limited to, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, stem cell leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, and hemoblastic leukemia. , hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelomorphic granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia leukemia), plasma cell leukemia, multiple myeloma, plasma ball leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0277] The above-mentioned inflammatory diseases include, but are not limited to, postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, disease), ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0278] The musculoskeletal diseases include, but are not limited to, muscular dystrophies (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy type 1, or myotonic dystrophy type 2), limb-girdle muscular dystrophy, multisystem proteinopathy, chondrodysplasia punctata, X-linked recessive chondrodysplasia punctata, Conradi-Hünermann syndrome, and muscular dystrophy. syndrome), autosomal dominant chondrodysplasia punctata, stress-induced bone disorders (e.g., stress-induced osteoporosis), multiple sclerosis, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, spinal cord spasticity, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Machado-Joseph disease, Paget's disease of bone, fasciculations, Friedreich's ataxia, muscle wasting disorders (e.g., muscular dystrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, or paralysis.

[0279] The above-mentioned metabolic diseases include, but are not limited to, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (such as type 1 diabetes, type 2 diabetes or gestational diabetes), phenylketonuria, proliferative retinopathy or Kearns-Sayre disease.

[0280] Such mitochondrial diseases include, but are not limited to, Barth syndrome, chronic progressive external ophthalmoplegia (cPEO), Cohens-Sell syndrome (KSS), Leigh syndrome (e.g., MILS or maternally inherited Leigh syndrome), mitochondrial DNA deletion syndrome (MDDS, e.g., Alpers syndrome), mitochondrial encephalomyopathy (e.g., mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), Leber's hereditary optic neuropathy (LHON), and Pearson syndrome.

[0281] The above-mentioned hearing loss diseases include, but are not limited to, mitochondrial non-syndromic hearing loss and deafness, hair cell death, age-related hearing loss, noise-induced hearing loss, inherited or genetic hearing loss, hearing loss experienced due to ototoxic exposure, disease-induced hearing loss, and trauma-induced hearing loss. In some embodiments, mitochondrial non-syndromic hearing loss and deafness is MT-RNR1-related hearing loss.

[0282] The above-mentioned eye diseases include, but are not limited to, cataracts, glaucoma, endoplasmic reticulum (ER) stress, autophagy defects, age-related macular degeneration (AMD) or diabetic retinopathy.

[0283] Such renal diseases include, but are not limited to, Abderhalden-Kaufmann-Lignac syndrome (Y-type cystic acidosis), abdominal compartment syndrome, acetaminophen-induced nephrotoxicity, acute renal failure / acute kidney injury, acute lobar nephropathy, acute phosphate nephropathy, acute tubular necrosis, adenine phosphoribosyltransferase deficiency, adenoviral nephritis, Alagille syndrome, Alport syndrome, amyloidosis, ANCA vasculitis associated with endocarditis and other infections, angiomyolipoma, analgesic nephropathy, anorexia nervosa nephropathy, vasoconstrictor peptide antibodies and focal segmental glomerulosclerosis, antiphospholipid syndrome, glomerulonephritis associated with anti-TNF-α therapy, APOL1 mutations, apparent mineralocorticoid excess syndrome, aristolochic acid nephropathy, Chinese herbal nephropathy, Balkan endemic nephropathy, and nephropathy. Nephropathy, urinary tract arteriovenous malformations and fistulas, autosomal dominant hypocalcemia, Bardet-Biedl Syndrome, Bartter Syndrome, bath salts-induced acute kidney injury, beer potomania, beeturia, beta-thalassemia nephropathy, bile cast nephropathy, autologous kidney BK polyomavirus nephropathy, bladder rupture, bladder sphincter dyssynergia, bladder tamponade, border-crossers' nephropathy, Bourbon virus Virus-induced acute kidney injury, flaming sugarcane harvesting acute renal dysfunction, Byetta renal failure, Clq nephropathy, C3 glomerulopathy, C3 glomerulopathy with monoclonal gammopathy, C4 glomerulopathy, calcineurin inhibitor nephrotoxicity, atractylodes glycosides (Callilepsis laureola) intoxication, cannabinoid-induced acute renal failure, cardiorenal syndrome, carfilzomib-induced renal injury, CFHR5 nephropathy, Charcot-Marie-Tooth diseaseDisease with glomerulopathy, herbal nephrotoxicity, cherry concentrate acute kidney injury, cholesterol embolism, Churg-Strauss syndrome, chyluria, ciliopathy, cocaine nephropathy, cold diuresis, colistin nephrotoxicity, collagenous fibrillary glomerulopathy, collapsing glomerulopathy, CMV-related collapsing glomerulopathy, combined antiretroviral (cART)-related nephropathy, congenital anomalies of the kidney and urinary tract (CAKUT), congenital nephrotic syndrome, congestive renal failure, cone-shaped Epiphyseal nephrotic syndrome (Mainzer-Saldino syndrome or Saldino-Mainzer disease), contrast-induced nephropathy, copper sulfate poisoning, cortical necrosis, crizotinib-related acute kidney injury, cryoglobulinemia, cryoglobulinemia, crystalloid-induced nephropathy, crystal-induced acute kidney injury, crystal-storing histiocytosis, acquired cystic kidney disease, cystinuria, dasatinib-induced nephrotic-range proteinuria, dense deposit disease (type 2 MPGN), Dent disease Disease (X-linked recessive nephrolithiasis), DHA crystal nephropathy, dialysis imbalance syndrome, diabetes mellitus and diabetic nephropathy, diabetes insipidus, dietary supplement renal failure, diffuse mesangial sclerosis, diuresis, Djenkol bean poisoning (Djenkolism), Down syndrome nephropathy, drug abuse nephropathy, duplicated ureters, East Asian Sterile Syndrome (EAST) syndrome, Ebola nephropathy, ectopic kidney, ectopic ureter, edema, swelling, Erdheim-Chester disease, Fabry's disease, familial hypocalciuric hypercalcemia, Fanconi syndrome, Fraser syndrome, fibronectin glomerulopathy, fibrillary glomerulonephritis and immune tentacle glomerulopathy, Fraley syndrome syndrome), fluid overload, hypervolemia, focal segmental glomerulosclerosis, focal sclerosis, focal glomerulosclerosis, Galloway-Mowat syndrome, giant cell arteritis involving the kidney, pregnancy-induced hypertension, Gitelman syndrome, glomerular disease, glomerular tubular reflux, diabetes mellitus, Goodpasture syndrome, Green Smoothie CleanseNephropathy, HANAC syndrome, Harvoni (ledipasvir and sofosbuvir)-induced kidney injury, hair dye ingestion acute kidney injury, Hantavirus infection podocytopathy, heat stress nephropathy, hematuria (blood in the urine), hemolytic uremic syndrome (HUS), atypical hemolytic uremic syndrome (aHUS), hemophagocytic syndrome, hemorrhagic cystitis, hemorrhagic fever with renal syndrome (HFRS, Hantavirus nephropathy, Korean hemorrhagic fever, epidemic hemorrhagic fever, nephropathis Epidemica), hemosiderosis, hemosiderosis associated with paroxysmal nocturnal hemoglobinuria and hemolytic anemia, hepatic glomerulopathy, hepatic veno-occlusive disease, sinusoidal obstruction syndrome, hepatitis C-associated nephropathy, hepatocyte nuclear factor 1B-associated nephropathy, hepatorenal syndrome, herbal supplement-induced nephropathy, high-altitude renal syndrome, hypertensive nephropathy, HIV-associated immune complex nephropathy (HIVICK), HIV-associated nephropathy (HIVAN), HNF1B-associated autosomal dominant tubulointerstitial nephropathy, horseshoe kidney (renal fusion), Hunner's ulcer Ulcer), hydroxychloroquine-induced nephrolipidosis, hyperaldosteronism, hypercalcemia, hyperclockwise, hypermagnesemia, hypernatremia, hyperoxaluria, hyperphosphatemia, hypocalcemia, hypocomplement urticaria vasculitis syndrome, hypoclockwise, hypoclockwise-induced renal dysfunction, hypoclockwise periodic paralysis, hypomagnesemia, hyponatremia, hypophosphatemia, hypophosphatemia in marijuana users, hypertension, monogenic hypertension, iced tea nephropathy, ifosfamide nephrotoxicity, IgA nephropathy, IgG4 nephropathy, immersion diuresis, immune checkpoint therapy-associated interstitial nephritis, infliximab-associated nephropathy, interstitial cystitis, painful bladder syndrome (questionnaire), interstitial nephritis, megakaryocytic interstitial nephritis, Ivemark's syndrome, JC virus nephropathy, Joubert syndrome Syndrome), ketamine-related bladder dysfunction, kidney stones, nephrolithiasis, kombucha tea toxicity, lead nephropathy and lead-related nephrotoxicity, lecithin cholesterol acyltransferase deficiency (LCAT deficiency), leptospirosis nephropathy, light chain deposition disease, monoclonal immunoglobulin deposition disease, light chain proximal renal tubulopathy, Liddle Syndrome, Lightwood-Albright syndromeSyndrome), lipoprotein glomerulopathy, lithium nephrotoxicity, hereditary FSGS caused by LMX1B mutations, flank pain and hematuria, lupus, systemic lupus erythematosus, lupus nephropathy, lupus nephritis, lupus nephritis with antineutrophil cytoplasmic antibody seropositivity, lupus podocytopathy, Lyme disease-associated glomerulonephritis, lysinuria protein intolerance, lysozyme nephropathy, malarial nephropathy, malignancy-associated nephropathy, malignant hypertension, Malakoplakia, McKit Trick-Wheelock syndrome, MDMA (Molly; Ecstacy; 3,4-methylenedioxymethamphetamine)-induced renal failure, urethral stenosis, medullary cystic kidney disease, uromodulin-related nephropathy, juvenile type 1 hyperuricemic nephropathy, medullary sponge kidney, megaureter, triamcinolone toxic nephropathy, MELAS syndrome, membranous proliferative glomerulonephritis, membranous nephropathy, membranous glomerulopathy with occult IgGk deposits, MesoAmerican nephropathy Nephropathy, metabolic acidosis, metabolic alkalosis, hydrometholone-associated renal failure, microscopic polyangiitis, milk-alkali syndrome, minimal change disease, monoclonal gammopathy of renal significance, dysproteinemia, mouthwash toxicity, MUC1 nephropathy, polycystic dysplastic kidney, multiple myeloma, myeloproliferative neoplastic glomerulopathy, nail-patella syndrome, NARP syndrome, nephrocalcinosis, nephrogenic systemic fibrosis, nephroptosis (floating kidney, renal ptosis), nephrotic syndrome, neurogenic bladder, 9 / 11 and kidney disease, nodular glomerulosclerosis, nongonococcal urethritis, Nutcracker syndrome, nephron oligomegaly, orofacial digital syndrome, orotic aciduria, orthostatic hypotension, orthostatic proteinuria, osmotic diuresis, osmotic nephropathy, ovarian hyperstimulation syndrome, oxalate nephropathy, Paget's kidney Kidney), papillary necrosis, papillorenal syndrome (renal coloboma syndrome, solitary kidney agenesis), PARN mutation nephropathy, parvovirus B19 nephropathy, peritoneal-renal syndrome, posterior urethral valve POEMS syndrome, podocyte infolding glomerulopathy, postinfectious glomerulonephritis, poststreptococcal glomerulonephritis, atypical postinfectious glomerulonephritis, postinfectious glomerulonephritis (IgA dominant), mimicking IgA nephropathy, polyarteritis nodosa, posterior urethral valve polycystic kidney disease, postobstructive diuresis, preeclampsia, propofol infusion syndrome, proliferative glomerulonephritis with monoclonal IgG deposition (Nasr disease),Propolis (bee resin)-related renal failure, proteinuria (protein in the urine), pseudohyperaldosteronism, pseudohypobicarbonateemia, pseudohypoparathyroidism, pulmonary-renal syndrome, pyelonephritis (kidney infection), pyonephrosis, phenazopyridine-induced renal failure, radiation-induced nephropathy, Raynaud's nephropathy, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal agenesis, acute kidney injury associated with renal arcuate vein microthrombosis, renal artery aneurysm, spontaneous renal artery dissection, renal artery stenosis, renal cell carcinoma, renal cyst, renal hypouricemia with exercise-induced acute renal failure, renal infarction, renal osteodystrophy, renal tubular acidosis, renin mutation and autosomal dominant tubulointerstitial nephropathy, renin-secreting tumors (juxtaglomerular cell tumors), osmotic set point reset Osmostat), retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, rhabdomyolysis associated with bariatric surgery, rheumatoid arthritis-related nephropathy, sarcoid nephropathy, salt wasting from the kidneys and brain, schistosomal glomerulopathy, Schimke immunoosseous dysplasia, scleroderma renal crisis, serpentine lung-polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, chronic kidney disease due to silica exposure, Sri Lankan Farmers' Kidney disease Disease), Sjögren's syndrome nephropathy, acute kidney injury due to synthetic cannabinoid use, post-hematopoietic cell transplant nephropathy, nephropathy associated with stem cell transplantation, TAFRO syndrome, tea-and-toast hyponatremia, tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, ranolazine nephropathy associated with monoclonal gammopathy, refeeding syndrome, reflux nephropathy, rapidly progressive glomerulonephritis, renal abscess, perinephric abscess, renal agenesis, acute kidney injury associated with renal arcuate vein microthrombosis, renal artery aneurysm, spontaneous renal artery dissection, renal artery stenosis, renal cell carcinoma, renal cyst, renal hypouricemia with exercise-induced acute renal failure, renal infarction, renal osteodystrophy, renal tubular acidosis, renin mutations and autosomal dominant tubulointerstitial kidney disease, renin-secreting tumors (juxtaglomerular cell tumors), osmotic set point reset Osmostat), retrocaval ureter, retroperitoneal fibrosis, rhabdomyolysis, rhabdomyolysis associated with bariatric surgery, rheumatoid arthritis-related nephropathy, sarcoid nephropathy, renal and cerebral salt wasting, schistosomal glomerulopathy, Schimke immunoosseous dysplasiadysplasia), scleroderma renal crisis, serpentine lung-polycystic kidney syndrome, Exner syndrome, sickle cell nephropathy, silica exposure chronic kidney disease, Sri Lankan Farmers' Kidney Disease, Sjögren's nephropathy, acute kidney injury from synthetic cannabinoid use, post-hematopoietic cell transplant nephropathy, stem cell transplant-associated nephropathy, TAFRO syndrome, tea-and-toast hyponatremia, tenofovir-induced nephrotoxicity, thin basement membrane disease, benign familial hematuria, thrombotic microangiopathy associated with monoclonal gammopathy, war nephritis, trigoneitis, genitourinary tuberculosis, tuberous sclerosis, renal tubular dysgenesis, proximal tubular brush border Immune complex tubulointerstitial nephritis caused by autoantibodies, tumor lysis syndrome, uremia, uremic optic neuropathy, cystic ureteritis, ureterocerebia, urethral caruncle, urethral stricture, urinary incontinence, urinary tract infection, urinary tract obstruction, genitourinary dysfunction, uromodulin-related nephropathy, vancomycin-related cast nephropathy, vasomotor nephropathy, bladder fistula, vesicoureteral reflux, VGEF-inhibited renal thrombotic microangiopathy, volatile anesthetic-induced acute kidney injury, and Von Heber-Lindau disease. Hippel-Lindau Disease, Waldenstrom's Macroglobulinemic Glomerulonephritis, warfarin-related nephropathy, wasp sting acute kidney injury, Wegener's Granulomatosis, Granulomatosis with Polyangiitis, West Nile Virus chronic kidney disease, Wunderlich syndrome, Zellweger syndrome, or cerebrohepatorenal syndrome.

[0284] The above-mentioned skin diseases include, but are not limited to: acne, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic erythropoiesis, contact dermatitis, Darier's disease, disseminated superficial actinic porokeratosis, dystrophic epidermolysis bullosa, eczema (atopic eczema), extramammary Paget's disease, simplex epidermolysis bullosa, erythropoietic protoporphyria, fungal infection of the nails, Hailey-Hailey disease, disease), herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloid, keratosis pilaris, lichen planus, lichen sclerosus, melanoma, dermatosis melanogaster, mucous membrane pemphigoid, pemphigoid, pemphigus vulgaris, pityriasis lichenoides, pityriasis rubra pilaris, plantar warts (warts), polymorphic light eruption, psoriasis, plaque psoriasis, pyoderma gangrenosum, rosacea, scabies, scleroderma, herpes zoster, squamous cell carcinoma, Sweet's syndrome, urticaria, angioedema, and vitiligo.

[0285] Such fibrotic diseases include, but are not limited to, adhesive capsulitis, arteriosclerosis, arthrofibrosis, atrial fibrosis, cardiac fibrosis, cirrhosis, congenital hepatic fibrosis, Crohn's disease, cystic fibrosis, Dupuytren's contracture, endomyocardial fibrosis, glial scars, hepatitis C, hypertrophic cardiomyopathy, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, interstitial lung disease, keloids, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, nonalcoholic fatty liver disease, old myocardial infarction, Peyronie's disease, pneumoconiosis, pneumonia, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma / systemic sclerosis, silicosis, and ventricular remodeling.

[0286] The above-mentioned hemoglobin disorders include, but are not limited to, "dominant" β-thalassemia, acquired (toxic) methemoglobinemia, carboxyhemoglobinemia, congenital Heinz body hemolytic anemia, HbH disease, HbS / β-thalassemia, HbE / β-thalassemia, HbSC disease, homozygous α+-thalassemia (phenotype of α0-thalassemia), hydrops fetalis with Hb Bart's), sickle cell anemia / disease, sickle cell trait, sickle beta-thalassemia disease, alpha+-thalassemia, alpha-thalassemia, alpha-thalassemia associated with myelodysplasia syndrome, alpha-thalassemia with mental retardation (ATR), beta-thalassemia, beta+-thalassemia, delta-thalassemia, gamma-thalassemia, beta-thalassemia major, beta-thalassemia intermedia, delta-thalassemia, and epsilonγdeltaβ-thalassemia.

[0287] The above-mentioned autoimmune diseases include, but are not limited to, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune scrotal inflammation, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baló disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease, and disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Chagas-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), epileptic pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackiemyocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome syndrome), fibromyalgia, fibrosing alveolitis, giant cell arteritis (arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndromesyndrome), leukocytoclastic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease (PR), PANDAS, paraplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry's syndrome Romberg syndrome), pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome syndrome), scleritis, scleroderma, Sjögren's syndrome, semen and testicular autoimmunity, stiff-man syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, head arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

[0288] Such viral infections include, but are not limited to, influenza, human immunodeficiency virus (HIV), and herpes.

[0289] The aforementioned malarial infections include, but are not limited to, infections caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium falciparum.

[0290] The above-mentioned diseases with mutations that lead to the induction of the unfolded protein response (UPR) include, but are not limited to: Marinesco-Sjogren syndrome, neuropathic pain, diabetic neuropathic pain, noise-induced hearing loss, non-syndromic sensorineural hearing loss, age-related hearing loss, Wolfram syndrome, Darier-White disease, Usher syndrome, collagenosis, thin-base nephropathy, Alport syndrome, skeletal chondrodysplasia, metaphyseal chondrodysplasia type Schmid and pseudochondrodysplasia.

[0291] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0292] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, the meanings that can be given to them by those skilled in the art should be given based on the disclosure and context.

[0293] "Substitution" means that the hydrogen atoms in a molecule are replaced by other different atoms or groups; or the lone pair of electrons in an atom in a molecule are replaced by other atoms or groups. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form

[0294] “May be substituted by…” or “optionally substituted by…” means that “substitution” may but does not have to occur, and the description includes situations where it occurs or does not occur.

[0295] The minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix. For example, the prefix C1-C6 alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1-C6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms.

[0296] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. For example, C1-C6 alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.

[0297] The term "C1-C10 alkyl" refers to any straight-chain or branched group containing 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, and the following straight-chain or branched alkyl groups: C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, etc.

[0298] Furthermore, the "C1-C10 alkyl" includes straight-chain or branched groups whose carbon number is between 1 and 10 and whose endpoints are any two integers. For example, the "C1-C10 alkyl" includes C1-C10 alkyl, C1-C8 alkyl, C1-C6 alkyl, C2-C10 alkyl, C2-C8 alkyl, C2-C6 alkyl, C6-C10 alkyl, and the like. The above list is for example only and does not limit the above range.

[0299] The term "alkoxy" and its derivatives refer to any of the above alkyl groups (eg, C1-C10 alkyl, C1-C6 alkyl, etc.) that is attached to the rest of the molecule through an oxygen atom (-O-).

[0300] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having a specified number of member atoms. C-C alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0301] The C1-C4 alkylene group of the present invention may be a C1 alkylene group (eg, -CH2-), a C2 alkylene group (eg, -CH2CH2-, etc.), a C3 alkylene group, or a C4 alkylene group.

[0302] The "cycloalkylene" described in the present invention refers to a divalent saturated cyclic alkane having a single ring or multiple rings (condensed ring, spiro ring, bridged ring) with multiple carbon atoms and no ring heteroatoms. Examples of monocarbocyclic groups include, for example, divalent cyclopropyl, divalent cyclobutyl, divalent cyclohexyl, divalent cyclopentyl, divalent cyclooctyl, divalent cyclopentenyl, and divalent cyclohexenyl. Examples of bridged cycloalkane systems include bicyclo[3,1,0]hexane, bicyclo[3,1,1]hexane, bicyclo[2,2,1]hexane, and bicyclo[2,2,2]hexane.

[0303] The "cycloalkylene" mentioned in the present invention includes but is not limited to wait.

[0304] The term "C3-C10 cycloalkyl" refers to a 3- to 10-membered, all-carbon monocyclic, fused, and bridged ring that may contain zero, one, or more double bonds but does not have a completely conjugated π-electron system. Examples of C3-C10 cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, and the like.

[0305] The "heterocycloalkyl" mentioned in the present invention refers to a monovalent or divalent saturated ring (a divalent saturated ring of a heterocycloalkyl is a heterocycloalkylene) having a single ring or multiple rings (condensed ring, spiro ring, bridged ring) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Examples of 3-10 membered heterocyclic groups can be oxetane, azetidinyl, oxolane, oxahenyl, piperazinyl, piperidinyl, morpholinyl, trioxanyl, etc. The embodiments of the "heterocycloalkyl" mentioned in the present invention include but are not limited to Or piperidinyl, etc.

[0306] The unsaturated group mentioned in the present invention refers to a group or molecule containing a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond, etc.

[0307] As used herein, "aromatic ring" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aromatic groups having multiple carbon atoms. Additionally, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0308] The term "5-10 membered heteroaryl" as used herein refers to an aromatic unsaturated ring containing at least one heteroatom, such as nitrogen, oxygen, or sulfur. It is typically an aromatic monocyclic or bicyclic hydrocarbon ring containing multiple ring atoms, one or more of which is selected from O, N, and S. Preferably, the ring contains one to three heteroatoms. Among them, for example, 5-6 membered heteroaryl represents, for example, pyridyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyranyl, thiopyranyl, piperazinyl, triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, 1,2,3,4-tetrazolyl, 1,2,3,5-tetrazolyl, isoxazolyl, oxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-oxatriazolyl, 1,3,2-dioxazolyl, 1,2,3-Dioxadiazolyl, 1,2,3,4-Dioxadiazolyl, 1,2,3,5-Dioxadiazolyl, 1,3,3,4-Dioxadiazolyl, 1,3,4,5-Dioxadiazolyl, 1,2,3,4-Dioxadiazolyl, isothiazolyl, pyridazinyl, triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, 1,2,4-oxazinyl, 1,2,6-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl, 1,4,2-oxazinyl, 1,2-isoxazinyl, 1,4-isoxazinyl.

[0309] The "halogen" mentioned in the present invention refers to fluorine, chlorine, bromine or iodine.

[0310] The "halogen-substituted alkyl" mentioned in the present invention refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen; for example, a halogen-substituted C 1～4 The alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0311] The "-N(R)2" and the like described in the present invention means that the R group is connected to the nitrogen atom by a single bond.

[0312] The “=O” mentioned in the present invention means that an oxygen atom replaces two hydrogen atoms in a molecule through a double bond.

[0313] In the present invention, it is obvious to those skilled in the art that any group whose name is a composite name, such as "6-10 membered aryl-D-C1-C6 alkyl", should refer to a group conventionally constructed from its derived part such as C1-C6 alkyl from left to right, and it should be understood that the alkyl group here is a divalent alkyl group.

[0314] In the present invention, "stereoisomers" refer to compounds with the same chemical structure but different arrangements of atoms or groups in space, including enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, etc.

[0315] As used herein, "tautomers" generally refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons.

[0316] In the present invention, "geometric isomers" are also called "cis-trans isomers", which are isomers caused by the inability of double bonds (including double bonds of olefins, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms to rotate freely.

[0317] In the present invention, "enantiomers" refer to two isomers of a compound that are non-superimposable but mirror images of each other.

[0318] As used herein, "diastereoisomers" refer to stereoisomers that have two or more chiral neutral atoms and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

[0319] In the present invention, "racemate", "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.

[0320] As used herein, "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) that exhibits a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors may lead to one polymorph dominating.

[0321] In the present invention, "solvate" refers to a mixture formed by dissolving a compound in a solvent.

[0322] In the present invention, "N-oxides" are also called amine oxides, which are organic compounds with the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0323] In the present invention, "isotope-labeled compound" refers to a molecule or group in which one or more atoms are replaced by their isotope atoms, such as hydrogen atoms replaced by deuterium atoms, where the proportion of deuterium atoms is greater than the abundance of deuterium in nature; for example, 12C is replaced by 13C.

[0324] In the present invention, "metabolites" refer to substances generated by chemical structural transformation of drug molecules under the action of the body after the drug molecules are absorbed by the body.

[0325] In the present invention, "prodrug" refers to a compound that is obtained by chemically modifying a drug and is inactive or less active in vitro, but releases an active drug through enzymatic or non-enzymatic conversion in vivo to exert its pharmacological effect.

[0326] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0327] The terms "salts" and "pharmaceutically acceptable salts" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a suitable amount of acid or base (e.g., an equivalent amount). These salts may be precipitated in solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0328] The term "prevention" includes suppressing and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0329] The terms "treat," "treat," "treat," and "treating" mean to reverse, alleviate, or eliminate the progression of the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition.

[0330] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0331] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0332] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0333] The following detailed description of the embodiments of the present application is provided in conjunction with the examples. The detailed description of the following embodiments and the accompanying drawings are used to illustrate the principles of the present application, but are not intended to limit the scope of the present application. That is, the present application is not limited to the described embodiments.

[0334] The known starting materials of the present invention can be synthesized using methods known in the art, or can be purchased from companies such as Bidex Pharmaceuticals, Leyan, Titan, Shaoyuan, Anaiji Chemical, Exploration Platform, Nanjing Yaoshi, Jiangsu Aikang, and Beijing Inokai Technology. Tetrapropylammonium perruthenate was purchased from Exploration Platform, and 1-propylphosphoric cyclic anhydride was purchased from Beijing Inokai Technology Co., Ltd.

[0335] Unless otherwise specified, reactions were conducted under a nitrogen atmosphere. Unless otherwise specified, solutions in the examples are aqueous solutions. Unless otherwise specified, reactions were conducted at room temperature. Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C. Unless otherwise specified, M is moles per liter.

[0336] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6 The units are given in ppm. NMR measurements were performed using a Bruker Avance III 400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4) as the solvents, and tetramethylsilane (TMS) as the internal standard. LC-MS measurements were performed using a Shimadzu LC-MS2020 (ESI) liquid chromatography-mass spectrometer. HPLC measurements were performed using a Shimadzu LC-20A high-pressure liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography (TLC) silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254. The sizes used for TLC separation and purification products were 0.4 mm to 0.5 mm. Column chromatography typically used Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0337] Dimethylformamide is abbreviated as DMF; N,N'-diisopropylethylamine (also known as 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 cyclic anhydride is abbreviated as T3P; N-methylmorpholine-N-oxide is abbreviated as NMO; trifluoroacetic acid is abbreviated as TFA; tetrahydrofuran is abbreviated as THF.

[0338] Example 1: Synthesis of Compound 1

[0339] Step 1: Synthesis of Intermediate 1b

[0340] At 25°C, compound 1a (BiDe Pharmaceuticals, product number: BD57204, 4.0g, 16.44mmol) and dimethylformamide (20.0mL) were added to a 100mL single-necked bottle, and compound N,N'-thiocarbonyldiimidazole (4.1g, 23.02mmol) was added sequentially under stirring. After reacting at 25°C for 1 hour, the reaction temperature was raised to 100 degrees Celsius and stirred for 2 hours. The reaction temperature was then lowered to zero degrees Celsius and iodomethane (2.33g, 16.44mmol) was added. The reaction was completed by stirring at 25°C for 1 hour. 50mL of water was added to the resulting reaction solution, and the mixture was extracted with 50mL of ethyl acetate. The extraction was repeated three times. The resulting organic phases were combined, washed with 100mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 1b. LC-MS: m / z: 243.9 (M+H-56) + .

[0341] Step 2: Synthesis of Intermediate 1c

[0342] At 25°C, intermediate 1b (4.1g, 13.71mmol) and dichloromethane (20.0mL) were added to a 100mL single-necked bottle, and the compound m-chloroperbenzoic acid (4.2g, 20.58mmol) was added under ice bath and stirring. The reaction was completed after 16 hours at 25°C. Saturated sodium bicarbonate aqueous solution was added to the resulting reaction solution to adjust the pH of the solution to about 8, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the filtrate obtained after filtration was concentrated under reduced pressure to obtain a 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) + .

[0343] Step 3: Synthesis of intermediate 1e

[0344] At 25°C, compound 1d (BiDe Pharmaceuticals, product number: BD25596, 197 mg, 2.26 mmol) and tetrahydrofuran (10 mL) were added to a 100 mL single-necked bottle, and compound NaH (181 mg, 4.52 mmol) was added under stirring. After reacting at 25°C for 0.5 hours, intermediate 1c (500 mg, 1.51 mmol) was added, and the reaction was completed by stirring at 25°C for 16 hours. 25 mL of water was added to the resulting reaction solution, extracted with 25 mL of ethyl acetate, and the resulting organic phase was washed with 50 mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate obtained after filtration was concentrated under reduced pressure to obtain a 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) + .

[0345] Step 4: Synthesis of Intermediate 1f

[0346] At 25°C, intermediate 1e (270 mg, 0.80 mmol) and dichloromethane (3.0 mL) were added to a 100 mL single-necked flask. Trifluoroacetic acid (1.0 mL, 4.5 mmol) was added under stirring. The reaction was complete after 2 hours at 25°C. The solution was concentrated under reduced pressure to obtain intermediate 1f. LC-MS: m / z: 239.0 (M+H) + .

[0347] Step 5: Synthesis of Intermediate 1g

[0348] Under ice, to a 100 mL single-necked flask, add intermediate 1f (140 mg, 0.59 mmol), glacial acetic acid (3.5 mL), and water (1.5 mL). Sodium nitrite (121 mg, 1.75 mmol) was added with stirring. After reacting for 1 hour, the temperature was raised to 25°C and the reaction was continued for another hour until the reaction was complete. The resulting reaction solution was concentrated under reduced pressure to obtain intermediate 1g. LC-MS: m / z: 268.0 (M+H) + .

[0349] Step 6: Synthesis of Intermediate 1h

[0350] Under ice-cooling, 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-necked flask. Zinc powder (97 mg, 1.48 mmol) was added under stirring. The reaction was complete after 2 hours at 25°C. The resulting reaction solution was concentrated under reduced pressure to obtain intermediate 1h. LC-MS: m / z: 254.0 (M+H) + .

[0351] Step 7: Synthesis of Compound 1

[0352] Under ice bath, compound 1i (BiDe Pharmaceuticals, product number: BD00901377, 71 mg, 0.35 mmol) and dimethylformamide (3.0 mL) were added to a 50 mL single-necked bottle. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (180 mg, 0.47 mmol) and diisopropylethylamine (123 mg, 0.95 mmol) were added sequentially under stirring. After half an hour of reaction at 25°C, intermediate 1h (55 mg, 0.22 mmol) was added to the resulting reaction solution and the reaction was completed at 25°C overnight. 25 mL of water was added to the resulting reaction solution, and the solution was extracted with 50 mL of ethyl acetate and repeated three times. The organic phases were combined and washed with 100 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration 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 (400MHz, CDCl3) δ7.28–7.26(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) + .

[0353] Example 2: Synthesis of Compound 2

[0354] Step 1: Synthesis of intermediate 2c

[0355] Under ice, compound 1i (467 mg, 2.29 mmol) and dimethylformamide (8.0 mL) were added to a 100 mL single-necked flask. 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 under stirring. After reacting at 25°C for half an hour, compound 2a (Bidec Pharmaceuticals, Cat. No.: BD283560, 300 mg, 1.91 mmol) was added to the resulting reaction solution and allowed to react overnight at 25°C. 100 mL of water was added to the resulting reaction solution, and the solution was 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, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain intermediate 2c. LC-MS: m / z: 344.0 (M+H)+ .

[0356] Step 2: Synthesis of intermediate 2d

[0357] To a 100 mL single-necked bottle at 25°C, intermediate 2c (360 mg, 1.05 mmol) and ethanol (3.0 mL) were added. Hydrazine hydrate (969 mg, 10.50 mmol) was added under stirring, and the temperature was raised to 80°C overnight for completion of the reaction. 25 mL of water was added to the resulting reaction solution, and the mixture was 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 a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 2d. LC-MS: m / z: 344.0 (M+H) + .

[0358] Step 3: Synthesis of intermediate 2f

[0359] Compound 1d (17 mg, 0.2 mmol) and tetrahydrofuran (3.0 mL) were added to a 50 mL single-necked bottle at 25 ° C. Triphosgene (181 mg, 0.61 mmol) was added under stirring. After reacting at 25 ° C for 2 hours, intermediate 2d (70 mg, 0.2 mmol) was added. The temperature was raised to 80 ° C for overnight reaction. A large amount of solid was present in the reaction system. Dimethylformamide (3.0 mL) was then added and the reaction was continued at 80 ° C overnight. After the reaction was completed, 50 mL of water was added to the resulting reaction solution and extracted with 50 mL of ethyl acetate. The resulting organic phase was washed with 100 mL of saturated brine and dried over sodium sulfate. The filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 2f. LC-MS: m / z: 457.0 (M+H) + .

[0360] Step 4: Synthesis of Compound 2

[0361] At 25°C, intermediate 2f (26 mg, 0.06 mmol) and dimethylformamide (3.0 mL) were added to a 50 mL single-necked bottle, and cesium carbonate (55 mg, 0.17 mmol) and p-toluenesulfonyl chloride (22 mg, 0.11 mmol) were added in sequence under stirring. The reaction was completed after 3 hours at 25°C. 35 mL of water was added to the resulting reaction solution, and the mixture was extracted with 35 mL of ethyl acetate. The resulting organic phase was washed with 100 mL of saturated brine and dried over sodium sulfate. The filtrate obtained after filtration was concentrated under reduced pressure to obtain a 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(400MHz, CDCl3)δ7.33(t,J=8.6Hz,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) + .

[0362] Example 3: Synthesis of Compound 21

[0363] Step 1: Preparation of intermediate 21a

[0364] At 25°C, compound 21g (Biode Pharmaceuticals, BD212373, 5.00g, 19.42mmol) and ethanol (50.0mL) were added to a 100mL single-necked flask. Hydrazine hydrate (7.75g, 84.00mmol) was added under stirring, and the temperature was raised to 80°C overnight for completion of the reaction. The reaction solution was cooled and concentrated under reduced pressure to obtain a 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) + .

[0365] Step 2: Preparation of intermediate 21c

[0366] 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-necked bottle, and compound N,N'-carbonyldiimidazole (5.0 g, 26.58 mmol) was added sequentially 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 and dried over anhydrous sodium sulfate. The filtrate obtained after filtration 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) + .

[0367] Step 3: Preparation of intermediate 21d

[0368] At 25°C, intermediate 21c (2.9 g, 9.26 mmol) and dimethylformamide (30 mL) were added to a 100 mL single-necked bottle, and 3-(trifluoromethoxy)-azetidine (1.73 g, 12.28 mmol), diisopropylethylamine (6.65 g, 51.18 mmol) and Carter condensation agent (6.45 g, 15.53 mmol) were added in sequence under stirring. The reaction was completed after sixteen 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 and dried over sodium sulfate. The filtrate obtained after filtration was concentrated under reduced pressure to obtain a 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) + .

[0369] Step 4: Preparation of intermediate 21b

[0370] At 25°C, intermediate 21d (140 mg, 0.34 mmol) and dichloromethane (6.0 mL) were added to a 100 mL single-necked flask. Trifluoroacetic acid (2.0 mL, 4.5 mmol) was added under stirring. The reaction was complete after 2 hours at 25°C. The solution was concentrated under reduced pressure to afford intermediate 21b. LC-MS: m / z: 307.2 (M+H). + .

[0371] Step 5: Synthesis of compound 21.

[0372] At 25°C, compound 21f (Biode Pharmaceuticals, product 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. 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 reaction was stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1H NMR (400MHz, MeOD) δ7.15–6.89(m,4H),5.37–5.20(m,1H),4.60–4.51(m,2H),4.49(s,2H),4.33(dd,J=9.4,4.0Hz,2H),3.84(ddd,J=15.6,7.9,4.0 Hz,1H),2.81(tt,J=12.1,3.5Hz,1H),2.17(d,J=12.1Hz,2H),2.03(d,J= 9.8Hz,2H),1.76–1.60(m,2H),1.59–1.42(m,2H).LC-MS:m / z:459.1(M+H) + .

[0373] Example 4: Synthesis of Compound 22

[0374] At 25°C, compound 22a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration 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(400MHz,DMSO)δ7.90(d,J=7.9Hz,1H),7.45(dd,J=7.9,1.6Hz,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=9.6,6.8Hz,2H),4.19(dd,J=9.6,4.0Hz ,2H),3.63(ddd,J=11.3,7.5,3.8Hz,1H),2.74(ddd,J=11.8,7.7,3.5Hz,1H),2.03(d,J=11.3Hz, 2H),1.88(dd,J=12.8,3.1Hz,2H),1.58–1.45(m,2H),1.43–1.30(m,2H).LC-MS:m / z:475.2(M+H) + .

[0375] Example 5: Synthesis of Compound 23

[0376] Step 1: Synthesis of compound 23

[0377] At 25°C, compound 23a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration 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 (400MHz, DMSO) δ8.04(d,J=8.0Hz,1H),7.32(t,J=8.1Hz,1H),7.03(t,J=5.5Hz,2H),6.93(dd,J=8.3,2.0Hz,1H),5.37– 5.26(m,1H),4.50(s,2H),4.46(dd,J=9.4,6.9Hz,2H),4.19(dd,J=9.5,3.9Hz,2H),3.74(s,1H),2.78–2.67(m,1H),2.03(d, J=11.5Hz,2H),1.85(d,J=9.7Hz,2H),1.51(dd,J=25.0,10.9Hz,2H),1.44–1.31(m,2H).LC-MS:m / z:475.2(M+H) + .

[0378] Example 6: Synthesis of Compound 24

[0379] Step 1: Synthesis of compound 24

[0380] At 25°C, compound 24a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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(400MHz,MeOD)δ7.37–7.26(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=9.6,4.1Hz,2H),3 .84(s,1H),2.81(s,1H),2.17(d,J=11.8Hz,2H),2.09–1.98(m,2H),1.67(dd,J=12.6,2.7Hz,2H),1.58–1.39(m,2H).LC-MS:m / z:459.2(M+H) + .

[0381] Example 7: Synthesis of Compound 25

[0382] Step 1: Synthesis of intermediate 25b

[0383] In a 50 mL reaction flask at 25°C, compound 25a (Biodex Pharmaceuticals, Catalog No. 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). The reaction was complete after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, which was filtered and concentrated under reduced pressure to yield the crude product. The crude product was separated and purified by column chromatography to yield intermediate 25b. 1 H NMR (400MHz, CDCl3) δ7.07(t,J=8.8Hz,1H),6.95(dd,J=5.9,3.1Hz,1H),6.78(dt,J=9.1,3.4Hz,1H),4.49(s,2H),1.51(s,9H).

[0384] Step 2: Synthesis of intermediate 25c

[0385] At 25°C, intermediate 25b (60 mg, 0.23 mmol) and dichloromethane (0.5 mL) were added to a 25 mL single-necked flask. Trifluoroacetic acid (0.5 mL, 6.71 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to afford intermediate 25c. LCMS: m / z: 203.0 (MH) - .

[0386] Step 3: Synthesis of compound 25

[0387] At 25°C, 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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(400MHz,MeOD)δ7.24–7.13(m,2H),6.97(dt,J=9.1,3.4Hz,1H),5.30(ddd,J=10.9, 6.8,4.3Hz,1H),4.60–4.46(m,4H),4.29(dd,J=9.6,4.1Hz,2H),3.84(tt,J=11.5,3.9Hz ,1H),2.80(tt,J=12.1,3.5Hz,1H),2.24–2.08(m,2H),2.03(dd,J=12.7,2.8Hz,2H),1. 67(qd,J=13.2,3.0Hz,2H),1.49(ddd,J=25.5,12.8,3.2Hz,2H).LC-MS:m / z:493.2(M+H) + .

[0388] Example 8: Synthesis of Compound 26

[0389] Step 1: Synthesis of intermediate 26b

[0390] In a 50 mL reaction flask at 25°C, compound 26a (Biodex Pharmaceuticals, Cat. No. 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). The reaction was complete after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, and the filtrate was filtered and 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 (400MHz, CDCl3) δ7.36 (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).

[0391] Step 2: Synthesis of intermediate 26c

[0392] At 25°C, intermediate 26b (200 mg, 0.62 mmol) and dichloromethane (2 mL) were added to a 25 mL single-necked flask. Trifluoroacetic acid (2 mL, 26.84 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to obtain intermediate 26c. LC-MS: m / z: 262.9 (MH) - .

[0393] Step 3: Synthesis of compound 26

[0394] At 25°C, 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1H NMR(400MHz,MeOD)δ7.19–6.98(m,2H),6.69(d,J=8.9Hz,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=54.4Hz,4H),1.25(dd,J=72.6,11.6Hz,4H).LC-MS:m / z:555.2(M+H) + .

[0395] Example 9: Synthesis of Compound 27

[0396] At 25°C, compound 27a (Leyan, 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 bottle. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine and dried over sodium sulfate. The filtrate obtained after filtration was concentrated under reduced pressure to obtain a 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 (400MHz, DMSO) δ7.90 (d, J=7.9Hz, 1H), 7.45 (dd, J=7.9, 1.6Hz, 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=9.6,6.8Hz,2H),4.19(dd,J =9.6,4.0Hz,2H),3.63(ddd,J=11.3,7.5,3.8Hz,1H),2.74(ddd,J=11.8,7.7,3.5Hz,1H),2 .03(d,J=11.3Hz,2H),1.88(dd,J=12.8,3.1Hz,2H),1.58–1.45(m,2H),1.43–1.30(m,2H). LC-MS:m / z:509.2(M+H) + .

[0397] Example 10: Synthesis of Compound 28

[0398] At 25°C, compound 28a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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 (400MHz, MeOD) δ7.46(d,J=8.9Hz,1H),7.22(d,J=2.9Hz,1H),6.97(dd,J=8.9,2.9Hz,1H),5.36–5.22(m,1H),4.61–4.44(m,4H),4.28(dd,J= 9.6,4.2Hz,2H),3.84(t,J=4.0Hz,1H),2.94–2.68(m,1H),2.29–2.09(m, 2H), 2.03(dd,J=13.1,3.2Hz,2H),1.73–1.58(m,2H),1.56–1.41(m,2H). LC-MS:m / z:475.2(M+H) + .

[0399] Example 11: Synthesis of Compound 29

[0400] At 25°C, compound 29a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration 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. 1H NMR (400MHz, MeOD) δ7.22–7.06(m,3H),7.06–6.97(m,1H),5.29(dd,J=9.3,5.3Hz,1H),4.58(s,2H),4.54(dd,J=9.2,7.1Hz,2H),4.29(dd,J=9. 6,4.0Hz,2H),3.90–3.79(m,1H),2.87–2.75(m,1H),2.16(d,J=12.1Hz, 2H), 2.10–1.99 (m, 2H), 1.75–1.59 (m, 2H), 1.51 (dd, J = 17.3, 7.4Hz, 2H). LC-MS:m / z:459.2(M+H) + .

[0401] Example 12: Synthesis of Compound 30

[0402] Step 1: Synthesis of intermediate 30b

[0403] In a 50 mL reaction flask at 25°C, compound 30a (Biodex Pharmaceuticals, Catalog No. 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). The reaction was complete after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, and the filtrate was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 30b. 1 H NMR (400MHz, CDCl3) δ6.88–6.75 (m, 2H), 6.71 (dd, J = 11.4, 5.3Hz, 1H), 4.48 (s, 2H), 1.41 (s, 9H).

[0404] Step 2: Synthesis of intermediate 30c

[0405] At 25°C, intermediate 30b (200 mg, 0.82 mmol) and dichloromethane (2 mL) were added to a 25 mL single-necked flask. Trifluoroacetic acid (2 mL, 26.84 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to obtain intermediate 30c. LC-MS: m / z: 187.0 (MH) - .

[0406] Step 3: Synthesis of compound 30

[0407] At 25°C, 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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(400MHz,MeOD)δ7.05(d,J=84.8Hz,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 = 47.5Hz, 4H), 1.61 (d, J = 65.3Hz, 4H). LC-MS:m / z:477.2(M+H) + .

[0408] Example 13: Synthesis of Compound 31

[0409] Step 1: Synthesis of intermediate 31b

[0410] In a 50 mL reaction flask at 25°C, compound 31a (Biodex Pharmaceuticals, Catalog No. 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). The reaction was complete after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, and the filtrate was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography to obtain intermediate 31b. 1 H NMR (400MHz, CDCl3) δ7.17 (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).

[0411] Step 2: Synthesis of intermediate 31c

[0412] At 25°C, intermediate 31b (200 mg, 0.77 mmol) and dichloromethane (2 mL) were added to a 25 mL single-necked flask. Trifluoroacetic acid (2 mL, 26.84 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to afford intermediate 31c. LC-MS: m / z: 202.9 (MH) - .

[0413] Step 3: Synthesis of compound 31

[0414] At 25°C, 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1 H NMR (400MHz, MeOD) δ7.29 (dd, J=8.2, 2.7Hz, 1H), 7.09 (dt, J=8.3, 3.3Hz, 2H), 5.36–5.24 (m, 1H), 4.60–4.48 (m, 4H), 4.29(dd,J=9.6,4.2Hz,2H),3.89–3.73(m,1H),2.83(tt,J=12.0,3.4Hz,1H),2.25–2.02(m,4H),1.77–1.40(m,4H). LC-MS:m / z:493.2(M+H) + .

[0415] Example 14: Synthesis of Compound 32

[0416] At 25°C, compound 32a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1 H NMR (400MHz, DMSO) δ7.96 (d, J=7.8Hz, 1H), 7.32 (t, J=8.2Hz, 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=9.4,6.9Hz,2 H),4.19(dd,J=9.6,3.9Hz,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, 6.2Hz, 2H). LC-MS: m / z: 509.2 (M+H) + .

[0417] Example 15: Synthesis of Compound 33

[0418] Step 1: Synthesis of intermediate 33b

[0419] Compound 33a (Biode Pharmaceuticals, Product No.: 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) at 25°C in a 10 mL reaction flask. The reaction was complete after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 33b. LC-MS: m / z: 261.1 (M+H) + .

[0420] Step 2: Synthesis of intermediate 33c

[0421] At 25°C, intermediate 33b (160 mg, 0.61 mmol) and dichloromethane (1.5 mL) were added to a 10 mL single-necked flask. Trifluoroacetic acid (0.5 mL, 6.71 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to afford intermediate 33c. LC-MS: m / z: 203.0 (MH) - .

[0422] Step 3: Synthesis of compound 33

[0423] At 25°C, 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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(400MHz,MeOD)δ7.26(dd,J=11.0,2.4Hz,1H),7.18-7.13(m,1H),7.09(t,J =8.7Hz,1H),5.33-5.25(m,1H),4.59(s,2H),4.53(dd,J=9.6,6.8Hz,2H),4.29( dd,J=9.6,4.2Hz,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=13.2,3.1Hz,2H),1.48(qd,J=12.8,3.3Hz,2H). LC-MS: m / z: 493.2 (M+H) + .

[0424] Example 16: Synthesis of Compound 34

[0425] Step 1: Synthesis of intermediate 34b

[0426] Compound 34a (Biodex Pharmaceuticals, Catalog No. 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 vial at 25°C. The reaction was complete after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, and the filtrate was filtered and concentrated under reduced pressure to provide intermediate 34b. LC-MS: m / z: 245.1 (M+H). + .

[0427] Step 2: Synthesis of intermediate 34c

[0428] At 25°C, intermediate 34b (170 mg, 0.69 mmol) and dichloromethane (1.5 mL) were added to a 10 mL single-necked flask. Trifluoroacetic acid (0.5 mL, 6.71 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to afford intermediate 34c. LC-MS: m / z: 189.0 (MH) - .

[0429] Step 3: Synthesis of compound 34

[0430] At 25°C, 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. 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 stirred at 25°C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1H NMR(400MHz,MeOD)δ7.22(dd,J=19.5,9.2Hz,1H),6.98(ddd,J=12.2,6.6,3.0Hz,1H),6 .84–6.77(m,1H),5.34–5.23(m,1H),4.53(dd,J=9.9,7.0Hz,2H),4.51(s,2H),4.29(dd, J=9.7,4.2Hz,2H),3.84(tt,J=11.6,3.9Hz,1H),2.81(tt,J=12.1,3.5Hz,1H),2.25–2.1 1(m,2H),2.07-1.98(m,2H),1.67(qd,J=13.2,3.2Hz,2H),1.49(qd,J=12.8,3.3Hz,2H). LC-MS:m / z:477.1(M+H) + .

[0431] Example 17: Synthesis of Compound 35

[0432] Step 1: Synthesis of intermediate 35b

[0433] Compound 35a (Biode Pharmaceuticals, Product No.: 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) at 25°C in a 25 mL reaction flask. The reaction was complete after 2 hours at 25°C. 15 mL of dichloromethane was added to the resulting reaction solution, and the filtrate was filtered and concentrated under reduced pressure to obtain a 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) + .

[0434] Step 2: Synthesis of intermediate 35c

[0435] At 25°C, intermediate 35b (50 mg, 0.20 mmol) and dichloromethane (1.5 mL) were added to a 10 mL single-necked flask. Trifluoroacetic acid (0.5 mL, 6.71 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to afford intermediate 35c. LC-MS: m / z: 189.0 (M+H) + .

[0436] Step 3: Synthesis of compound 35

[0437] At 25°C, 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1 H NMR(400MHz,MeOD)δ8.63(s,1H),5.35–5.24(m,1H),4.85(s,1H),4.52(dd,J=9.7,6.8Hz,1H),4.28(dd,J=9.7,4.2Hz,1H),3.90–3.68(m, 1H), 2.91–2.73 (m, 1H), 2.16 (d, J=12.0Hz, 1H), 2.03 (dd, J=13.4, 3.4Hz, 1H), 1.66 (qd, J=13.3, 3.1Hz, 1H), 1.44 (qd, J=12.9, 3.4Hz, 1H). LC-MS:m / z:477.1(M+H) + .

[0438] Example 18: Synthesis of Compound 36

[0439] At 25°C, compound 36a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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 (400MHz, MeOD) δ7.77(d,J=2.0Hz,1H),7.61(d,J=8.9Hz,1H),7.48(d,J =0.9Hz,1H),7.47–7.44(m,1H),5.40–5.20(m,1H),4.54(dd,J=9.7,6.8Hz,2 H),4.30(dd,J=9.7,4.2Hz,2H),4.05–3.90(m,1H),2.90–2.77(m,1H),2.21 (d,J=12.3Hz,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) + .

[0440] Example 19: Synthesis of Compound 37

[0441] At 25°C, compound 37a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1 H NMR(400MHz,MeOD)δ7.92(dd,J=5.2,3.1Hz,3H),7.45(dd,J=8.7,2.0Hz,1H),5.39–5.21(m,1H),4.54(dd,J=9.7,6.8Hz,2H),4.30 (dd,J=9.7,4.2Hz,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=13.0,9.8Hz,2H). LC-MS:m / z:501.2(M+H) + .

[0442] Example 20: Synthesis of Compound 38

[0443] At 25°C, compound 38a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration 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. 1 H NMR (400MHz, MeOD) δ8.17(d,J=2.0Hz,1H),8.10(d,J=8.7Hz,1H),7.57(dd,J=8.7,2 .0Hz,1H),5.39–5.20(m,1H),4.54(dd,J=9.6,6.8Hz,2H),4.30(dd,J=9.6,4.2Hz,2H ),3.97(t,J=7.5Hz,1H),2.86(ddd,J=11.7,7.7,3.5Hz,1H),2.23(d,J=12.2Hz,2H), 2.15(d,J=11.1Hz,2H), 1.73(dd,J=25.4,11.2Hz,2H), 1.63(dd,J=18.6,8.5Hz,2H). LC-MS:m / z:502.2(M+H) + .

[0444] Example 21: Synthesis of Compound 40

[0445] At 25 ° C, 40a (Bi De Pharmaceuticals, product number: BD28605, 29.49 mg, 0.15 mmol) and intermediate 21b (30 mg, 0.1 mmol) were dissolved in dimethylformamide (1.5 mL) in an 8 mL reaction bottle. 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 stirred at 25 ° C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, extracted with 20 mL of ethyl acetate, and the resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 40.1 H NMR(400MHz,MeOD)δ7.67(dd,J=14.0,5.3Hz,2H),7.35(dd,J=8.7,2.0Hz,1H),5.34–5.28(m,1H),4.55(dd,J=9.6,6.8Hz,2H), 4.31(dd,J=9.7,4.2Hz,2H),4.03–3.89(m,1H),2.88(ddd,J=12.1,7.8,3.4Hz,1H),2.20(t,J=14.9Hz,4H),1.81–1.53(m,4H). LC-MS:m / z:485.1(M+H) + .

[0446] Example 22: Synthesis of Compound 41

[0447] At 25°C, compound 41a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1 H NMR (400MHz, MeOD) δ7.21(s,1H),5.29(td,J=6.8,3.6Hz,1H),4.53(dd,J=9.7,6.8Hz,2H),4.29(dd,J=9.7,4.2Hz,2H),3.95–3.81(m,1 H),2.84(ddd,J=11.8,7.7,3.5Hz,1H),2.20(d,J=11.6Hz,2H),2.11(d,J=9.8Hz,2H),1.77–1.63(m,2H),1.55(dt,J=12.8,6.1Hz,2H). LC-MS:m / z:435.1(M+H) + .

[0448] Example 23: Synthesis of Compound 42

[0449] 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 stirred at 25°C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1 H NMR(400MHz,MeOD)δ7.41(d,J=0.7Hz,1H),5.34–5.25(m,1H),4.58–4.48(m,2H),4.30(dd,J=9.6,4.1Hz,2H),3.91(ddt,J=11.1,7.6,3 .9Hz,1H),2.85(tt,J=11.9,3.4Hz,1H),2.50(d,J=0.6Hz,3H),2.20(d,J=11.9Hz,2H),2.12(dd,J=12.8,2.8Hz,2H),1.76–1.52(m,4H). LC-MS:m / z:432.1(M+H) + .

[0450] Example 24: Synthesis of Compound 43

[0451] Compound 43a (Bidec Pharmaceuticals, Cat. No. 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 with stirring. The reaction was stirred at 25°C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified using high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 43. 1H NMR (400MHz, MeOD) δ6.88(d,J=1.6Hz,1H),6.77(d,J=1.6Hz,1H),5.34–5.25(m,1H),4.53(dd,J=9.6,6.9Hz,2H),4.29(dd,J= 9.6, 4.2Hz, 2H), 3.87 (ddd, J=11.5, 7.7, 4.0Hz, 1H), 2.82 (ddd, J=12.1, 8.7, 3.5Hz, 1H), 2.23–2.04 (m, 4H), 1.80–1.40 (m, 4H). LC-MS:m / z:434.2(M+H) + .

[0452] Example 25: Synthesis of Compound 44

[0453] At 25°C, compound 44a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1 H NMR (400MHz, MeOD) δ8.46(d,J=8.5Hz,1H),8.22(dd,J=21.6,8.8Hz,2H),8.08(d,J=2.3Hz,1H),7.83(dd,J=9.1,2.4Hz,1H),5.31(s,1H) ,4.60–4.48(m,2H),4.30(dd,J=9.8,4.2Hz,2H),4.02(s,1H),2.90(t,J=11.4Hz,1H),2.21(dd,J=20.6,14.6Hz,4H),1.85–1.59(m,4H). LC-MS:m / z:496.1(M+H) + .

[0454] Example 26: Synthesis of Compound 45

[0455] At 25°C, compound 45a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1 H NMR (400MHz, MeOD) δ9.32(s,1H),8.98(s,1H),6.94(t,J=54.3Hz,1H),5.34–5.26(m,1H),4.54(dd,J=9.7,6.8Hz,2H),4.30(dd,J=9.6 ,4.2Hz,2H),4.02(qd,J=11.6,3.6Hz,1H),2.87(tt,J=11.9,3.5Hz,1H),2.22(d,J=12.2Hz,2H),2.18–2.07(m,2H),1.81–1.53(m,4H). LC-MS:m / z:463.1(M+H) + .

[0456] Example 27: Synthesis of Compound 46

[0457] At 25°C, compound 46a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration 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(400MHz,MeOD)δ7.62–7.49(m,2H),6.79(dd,J=8.6,4.0Hz,1H),5.34–5.27(m,1H), 4.53(dd,J=9.7,6.8Hz,2H),4.29(dd,J=9.6,4.2Hz,2H),4.25–4.17(m,2H),3.91(ddd, J=15.4,7.7,3.9Hz,1H),2.83(dt,J=8.7,5.7Hz,3H),2.19(d,J=12.1Hz,2H),2.15–2.0 7(m,2H),2.07–1.99(m,2H),1.70(qd,J=13.2,3.0Hz,2H),1.53(qd,J=12.8,3.2Hz,2H). LC-MS:m / z:467.1(M+H) + .

[0458] Example 28: Synthesis of Compound 47

[0459] Step 1: Synthesis of intermediate 47b

[0460] To a 50 mL three-necked flask at 25°C were added compound 47a (Biode Pharmaceuticals, Cat. 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). Dimethylformamide (4.0 mL) and water (0.15 mL) were then added. The temperature was raised to 85°C under nitrogen protection and the reaction was allowed to proceed for 5 hours. The crude reaction solution (containing intermediate 47b) was used directly in the next step without purification. LC-MS: m / z: 163.0 (MH) - .

[0461] Step 2: Synthesis of intermediate 47c

[0462] At 25°C, tert-butyl bromoacetate (889 mg, 4.56 mmol) was added to the reaction solution 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 reaction solution. The resulting organic phase was washed with saturated brine (40 mL × 3), dried over sodium sulfate, and the filtrate was filtered and 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 (MH).

[0463] Step 3: Synthesis of Intermediate 47d

[0464] At 25°C, intermediate 47c (80 mg, 0.28 mmol) and dichloromethane (1.0 mL) were added to a 10 mL single-necked flask. Trifluoroacetic acid (0.3 mL, 4.03 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to afford intermediate 47d. LC-MS: m / z: 220.9 (MH) - .

[0465] Step 4: Synthesis of compound 47

[0466] At 25°C, 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 47. 1 H NMR(400MHz,MeOD)δ6.94–6.70(m,2H),5.41–5.13(m,1H),4.55(s,2H),4.54–4.37(m,2H),4.28(dd,J=9.6,4.2Hz,2H),4.11– 3.68(m,1H),2.81(ddd,J=12.1,8.6,3.7Hz,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) + .

[0467] Example 29: Synthesis of Compound 48

[0468] Step 1: Synthesis of intermediate 48b

[0469] At 25°C, compound 48a (Biode Pharmaceuticals, product 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-necked flask, followed by dimethylformamide (8.0 mL) and water (0.3 mL). After nitrogen protection, the temperature was raised to 85°C and the reaction was completed for 5 hours. The resulting reaction solution (containing intermediate 48b) was used directly in the next step without purification. LC-MS: m / z: 163.0 (MH) - .

[0470] Step 2: Synthesis of Intermediate 48c

[0471] To the reaction solution obtained in the previous step (containing Intermediate 48b) was added tert-butyl bromoacetate (889 mg, 4.56 mmol) at 25°C. After 2 hours at 25°C, the reaction was complete. To the resulting reaction solution were added 5 mL of water and 15 mL of ethyl acetate. 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 yield the crude product. The crude product was separated and purified by column chromatography to yield Intermediate 48c. 1 H NMR (400MHz, CDCl3): δ7.09 (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).

[0472] Step 3: Synthesis of Intermediate 48d

[0473] At 25°C, intermediate 48c (200 mg, 0.72 mmol) and dichloromethane (2.0 mL) were added to a 25 mL single-necked flask. Trifluoroacetic acid (2.0 mL, 26.84 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to afford intermediate 48d. LC-MS: m / z: 220.9 (MH) - .

[0474] Step 4: Synthesis of Compound 48

[0475] At 25°C, 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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 (400MHz, MeOD) δ7.38 (dd, J=10.6, 7.0Hz,1H),7.11(dd,J=10.3,7.4Hz,1H),5.34–5.24(m,1H),4.62(s,2H),4.53(dd,J=9.7,6.8Hz,2H),4.29(dd,J=9.6,4.2Hz,2H),3.89–3 .75(m,1H),2.87–2.75(m,1H),2.21–2.12(m,2H),2.05(dd,J=13.1,3.4Hz,2H),1.67(qd,J=13.2,3.1Hz,2H),1.48(qd,J=12.8,3.3Hz,2H). LC-MS: m / z: 511.2 (M+H) + .

[0476] Example 30: Synthesis of Compound 49

[0477] Step 1: Synthesis of intermediate 49b

[0478] At 25°C, compound 49a (Biode Pharmaceuticals, product number: 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-necked flask. Dimethylformamide (8.0 mL) and water (0.3 mL) were then added. After nitrogen protection, the temperature was raised to 85°C and the reaction was allowed to proceed for 5 hours to complete. The resulting reaction solution (containing intermediate 49b) was used directly in the next step without purification. LC-MS: m / z: 179.0 (MH) - .

[0479] Step 2: Synthesis of Intermediate 49c

[0480] To the reaction solution obtained in the previous step (containing Intermediate 49b) was added tert-butyl bromoacetate (727.47 mg, 3.73 mmol) at 25°C. After 2 hours at 25°C, the reaction was complete. To the resulting reaction solution were added 5 mL of water and 15 mL of ethyl acetate. 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 yield the crude product. The crude product was separated and purified by column chromatography to yield Intermediate 49c. 1 H NMR (400MHz, CDCl3) δ7.35 (d, J = 7.6Hz, 1H), 6.58 (d, J = 10.2Hz, 1H), 4.50 (s, 2H), 1.42 (d, J = 2.1Hz, 9H).

[0481] Step 3: Synthesis of Intermediate 49d

[0482] At 25°C, intermediate 49c (200 mg, 0.68 mmol) and dichloromethane (2.0 mL) were added to a 25 mL single-necked flask. Trifluoroacetic acid (2.0 mL, 26.84 mmol) was added under stirring. The reaction was complete after 1 hour at 25°C. The solution was concentrated under reduced pressure to afford intermediate 49d. LC-MS: m / z: 236.9 (MH) - .

[0483] Step 4: Synthesis of compound 49

[0484] At 25°C, 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. 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 stirred at 25°C for 10 hours. 20 mL of water was added to the resulting reaction solution, which was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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. 1H NMR (400MHz, DMSO) δ7.96(d,J=7.8Hz,1H),7.80(d,J=7.8Hz,1H),7.22(d,J=11 .2Hz,1H),5.32(dd,J=8.9,5.4Hz,1H),4.66(s,2H),4.51–4.37(m,2H),4.19(dd ,J=9.6,3.8Hz,2H),3.63–3.60(m,1H),2.83–2.69(m,1H),2.03(d,J=11.7Hz,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) + .

[0485] Example 31: Synthesis of Compound 50

[0486] Step 1: Synthesis of intermediate 50b

[0487] At 25°C, compound 50a (Biode Pharmaceuticals, product number: 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-necked flask. Dimethylformamide (4.0 mL) and water (0.15 mL) were then added. After nitrogen protection, the temperature was raised to 85°C and the reaction was completed for 5 hours. The resulting reaction solution (containing intermediate 50b) was used directly in the next step without purification. LC-MS: m / z: 163.0 (MH) - .

[0488] Step 2: Synthesis of Intermediate 50c

[0489] 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). The reaction was completed after 2 hours at 25°C. 5 mL of water and 15 mL of ethyl acetate were added to the reaction solution. The resulting organic phase was washed with 40 mL of saturated brine and dried over sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain intermediate 50c. LC-MS: m / z: 279.2 (M+H) + .

[0490] Step 3: Synthesis of Intermediate 50d

[0491] To a 25 mL single-necked flask at 25°C, intermediate 50c (220 mg, 0.79 mmol) and dichloromethane (2.0 mL) were added, followed by the addition of trifluoroacetic acid (2.0 mL, 26.84 mmol) under stirring. The reaction was complete after 1 hour at 25°C. The mixture was concentrated under reduced pressure to afford intermediate 50d. LC-MS: m / z: 223.0 (M+H) + .

[0492] Step 4: Synthesis of Compound 50

[0493] At 25°C, 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 15 mL of water was added to the resulting reaction solution, and the mixture was extracted with 15 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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(400MHz,MeOD)δ7.32–7.16(m,1H),6.99–6.83(m,1H),5.39–5.23(m,1H), 4.64(s,2H),4.53(dd,J=9.6,6.9Hz,2H),4.28(dd,J=9.6,4.2Hz,2H),3.83(d d,J=13.6,9.6Hz,1H),2.80(tt,J=12.0,3.4Hz,1H),2.18(t,J=12.7Hz,2H),2 .10–1.95(m,2H),1.66(qd,J=13.2,3.1Hz,2H),1.47(qd,J=12.8,3.2Hz,2H). LC-MS: m / z: 511.1 (M+H) + .

[0494] Example 32: Synthesis of Compound 52

[0495] Step 1: Synthesis of Intermediate 52b

[0496] To an 8 mL reaction tube at 25°C, compound 52a (Titan, 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, followed by acetonitrile (2.0 mL). The reaction was allowed to proceed at room temperature for 3 hours. The reaction solution was spin-dried and the crude product was purified by column chromatography to obtain intermediate 52b. LC-MS: m / z: 288.0 (M+H) + .

[0497] Step 2: Synthesis of Intermediate 52c

[0498] To Intermediate 52b (240 mg, 0.83 mmol) was added 1 mL of trifluoroacetic acid and 1 mL of dichloromethane at 25°C. The reaction was complete after 2 hours at 25°C. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Intermediate 52c. LC-MS: m / z: 232.0 (M+H). + .

[0499] Step 3: Synthesis of Intermediate 52d

[0500] To a 25 mL single-necked vial at 25°C, intermediate 52c (177 mg, 0.76 mmol) and N,N-dimethylformamide (2.0 mL) were added, followed by the addition of intermediate 21b (60 mg, 0.196 mmol) under stirring. After 4 hours at 25°C, the reaction was complete. The resulting reaction solution was separated and purified using HPLC (trifluoroacetic acid / acetonitrile / water) to afford intermediate 52d. LC-MS: m / z: 520.1 (M+H).

[0501] Step 4: Synthesis of Compound 52

[0502] At 25°C, 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. Iron powder (11 mg, 0.19 mmol) and ammonium chloride (10.29 mg, 0.19 mmol) were added sequentially under stirring. The reaction was stirred at 70°C for 1 hour to complete. The resulting reaction solution was filtered while hot, and the filtrate was spin-dried 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. 1H NMR (400MHz, DMSO) δ8.00(d,J=8.2Hz,1H),6.76(d,J=8.6Hz,1H),6.66(d,J=2 .5Hz,1H),6.49(d,J=8.5Hz,1H),5.32(td,J=6.5,3.4Hz,1H),4.46(dd,J=9.7, 6.8Hz,3H),4.40(s,2H),4.20(dd,J=9.7,4.1Hz,3H),3.89(s,1H),2.71(d,J=1 1.7Hz, 1H), 2.05 (d, J = 11.7Hz, 2H), 1.85 (d, J = 10.2Hz, 2H), 1.60–1.38 (m, 4H). LC-MS: m / z 490.2 (M+H) + .

[0503] Example 33: Synthesis of Compound 53

[0504] Step 1: Synthesis of intermediate 53b

[0505] In a 25 mL reaction flask at 25°C, compound 53a (Bidec Pharmaceuticals, Catalog No. BD222433, 100 mg, 0.45 mmol), tert-butyl bromoacetate (85.45 mg, 0.65 mmol), cesium carbonate (421.3 mg, 1.3 mmol), and methanesulfonato-(2-(di-tert-butylphosphino)-3-methoxy-6-methyl, 2,4,6-triisopropyl-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). The reaction was allowed to proceed overnight at 95°C until completion. 15 mL of dichloromethane was added to the resulting reaction solution, and the filtrate was filtered and 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 (400MHz, CDCl3) δ7.37(s,1H),4.81(s,2H),1.41(s,9H).

[0506] Step 2: Synthesis of Intermediate 53c

[0507] To a 25 mL single-necked flask at 25°C, intermediate 53b (90 mg, 0.32 mmol) and dichloromethane (1 mL) were added, followed by the addition of trifluoroacetic acid (1 mL, 13.42 mmol) under stirring. The reaction was complete after 1 hour at 25°C. The mixture was concentrated under reduced pressure to afford intermediate 53c. LC-MS: m / z: 225.9 (MH) - .

[0508] Step 3: Synthesis of compound 53

[0509] At 25°C, 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. 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 stirred at 25°C for 10 hours. 15 mL of water was added to the resulting reaction solution, which was extracted with 15 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate was filtered and 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 (400MHz, MeOD) δ8.16(d,J=8.1Hz,1H),7.52(d,J=1.4Hz,1H),5.17(ddd,J=10.9,6. 8,4.3Hz,1H),4.85(s,2H),4.40(dd,J=9.7,6.8Hz,2H),4.16(dd,J=9.6,4.2Hz,2H),3. 68(td,J=11.6,5.9Hz,1H),2.68(ddd,J=12.1,8.6,3.5Hz,1H),2.12–1.99(m,2H),1.97 –1.86(m,2H),1.54(ddd,J=25.6,13.2,3.1Hz,2H),1.33(ddd,J=25.4,13.1,3.5Hz,2H). LC-MS:m / z 516.2(M+H) + .

[0510] Examples 34 and 35: Synthesis of Compound 6 and Compound 12

[0511] Step 1: Synthesis of intermediate 6b

[0512] To a 50 mL single-necked flask at 25°C, compound 6a (Bidec Pharmaceuticals, Cat. No. BD00841787, 1.50 g, 7.75 mmol) and dimethylformamide (30 mL) were added. 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 with stirring. The reaction was complete after 18 hours at 25°C. The resulting reaction solution was poured into 200 mL of water and 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 concentrated under reduced pressure to obtain the crude product. The crude product was 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) + .

[0513] Step 2: Synthesis of intermediate 6c

[0514] Compound 6b (2.2 g, 6.40 mmol) and ethanol (20 mL) were added to a 50 mL single-necked flask at 25°C, and hydrazine hydrate (20 mL) was added dropwise with stirring. The reaction was complete after 16 hours at 85°C. The resulting reaction solution was cooled to room temperature and then concentrated under reduced pressure to obtain the crude product. The crude product was suspended in acetonitrile (50 mL), stirred at 25°C for 2 hours, and filtered and washed to obtain intermediate 6c. 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),7.99(d,J=8.1Hz,1H),7.50(t,J=8.9Hz,1H),7.07(dd,J=11.4,2.8Hz,1H),6.88-6.77(m,1H),4.4 9(s,2H),3.56(tt,J=8.0,4.0Hz,1H),3.18(d,J=6.9Hz,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) + .

[0515] Step 3: Synthesis of intermediate 6d

[0516] At 25°C, intermediate 6c (1 g, 2.91 mmol) and dichloromethane (30 mL) were added to a 50 mL single-necked flask. N,N'-carbonyldiimidazole (0.71 g, 4.37 mmol) was added under stirring. After 16 hours at 25°C, the reaction was complete and 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). + .

[0517] Step 4: Synthesis of compound 6

[0518] To a 50 mL single-necked flask at 25°C, intermediate 6d (100 mg, 0.27 mmol) and dimethylformamide (4 mL) were added. Diisopropylethylamine (0.18 mL, 1.08 mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (179.41 mg, 0.41 mmol), and compound 6f (71.50 mg, 0.40 mmol) were added sequentially under stirring. After 18 hours at 25°C, the reaction was complete. The reaction solution was poured into 20 mL of water and extracted twice with 30 mL of ethyl acetate. The resulting organic phase was washed with 10 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield the crude product. The crude product was separated and purified by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to yield compound 6. 1 H NMR(400MHz,DMSO-d6)δ8.05(d,J=8.0Hz,1H),7.50(t,J=8.9Hz,1H),7.07(dd ,J=11.4,2.9Hz,1H),6.85(dd,J=8.7,2.9Hz,1H),5.37-5.24(m,1H),4.56-4. 37(m,4H),4.19(dd,J=9.7,4.0Hz,2H),3.66(t,J=3.8Hz,1H),2.73(td,J=11. 9,10.1,6.1Hz,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) + .

[0519] Step 5: Synthesis of compound 12

[0520] Compound 6 (40 mg, 0.08 mmol) and toluene (3 mL) were added to a 50 mL single-necked bottle 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 reaction solution was poured into 20 mL of water and then extracted with 30 mL of ethyl acetate each time for a total of two extractions. The obtained organic phase was washed with 10 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration was concentrated under reduced pressure to obtain a 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(400MHz,DMSO-d6)δ8.05(d,J=8.0Hz,1H),7.50(t,J=8.9Hz,1H),7.07(dd ,J=11.4,2.9Hz,1H),6.85(dd,J=8.7,2.9Hz,1H),5.37-5.24(m,1H),4.56-4. 37(m,4H),4.19(dd,J=9.7,4.0Hz,2H),3.66(t,J=3.8Hz,1H),2.73(td,J=11. 9,10.1,6.1Hz,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) + .

[0521] Example 36: Synthesis of Compound 13

[0522] At 25°C, compound 12 (80 mg, 0.16 mmol) and toluene (5 mL) were added to a 50 mL single-necked bottle, 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 reaction solution was poured into 20 mL of water and then extracted with 30 mL of ethyl acetate each time for a total of two extractions. The obtained organic phase was washed with 10 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 13. 1H NMR(400MHz,DMSO-d6)δ8.05(d,J=8.0Hz,1H),7.50(t,J=8.9Hz,1H),7.07(dd ,J=11.4,2.9Hz,1H),6.85(dd,J=8.7,2.9Hz,1H),5.37-5.24(m,1H),4.56-4. 37(m,4H),4.19(dd,J=9.7,4.0Hz,2H),3.66(t,J=3.8Hz,1H),2.73(td,J=11. 9,10.1,6.1Hz,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) + .

[0523] Example 37: Synthesis of Compound 11

[0524] Step 1: Synthesis of intermediate 11b

[0525] At 25°C, compound 11a (Biode Pharmaceuticals, product number: BD254006, 150 mg, 0.89 mmol), tert-butyl alcohol (0.5 mL), and toluene (3 mL) were added to a 50 mL single-necked flask. Diphenylphosphoryl azide (0.25 mL, 1.16 mmol) and triethylamine (0.27 mL, 1.96 mmol) were added sequentially under stirring. The reaction was complete after 8 hours at 85°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 (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 11b. LC-MS: m / z: 240.1 (M+H) + .

[0526] Step 2: Synthesis of intermediate 11c

[0527] To a 50 mL single-necked flask at 25°C, add intermediate 11b (200 mg, 0.42 mmol) and dioxane hydrochloride (5 mL). After 3 hours at 25°C, the reaction is complete. The resulting reaction solution is concentrated under reduced pressure to yield intermediate 11c. LC-MS: m / z: 140.0 (M+H). + .

[0528] Step 3: Synthesis of compound 11

[0529] At 25°C, intermediate 6d (50 mg, 0.14 mmol) and dimethylformamide (2 mL) were added to a 50 mL single-necked flask. Diisopropylethylamine (0.09 mL, 0.54 mmol), 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (89.71 mg, 0.20 mmol), and intermediate 11c (28.22 mg, 0.20 mmol) were added sequentially under stirring. After 18 hours at 25°C, the reaction was complete. The resulting reaction solution was poured into 20 mL of water and 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 the filtrate was filtered and 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. 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=67.1Hz,1H),7.50(s,1H),7.08(s,1H),6.85(d,J=9.0Hz,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=64.6Hz,6H),1.43(d,J=30.2Hz,4H). LC-MS:m / z:491.0(M+H) + .

[0530] Example 38: Synthesis of Compound 14

[0531] To a 50 mL single-necked flask at 25°C, intermediate 6d (50 mg, 0.14 mmol) and dimethylformamide (2 mL) were added. Diisopropylethylamine (0.09 mL, 0.54 mmol), 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (89.71 mg, 0.20 mmol), and compound 14a (Bidec Pharmaceuticals, Catalog No. BD00841787, 71.61 mg, 0.41 mmol) were added sequentially with stirring. The reaction was complete after 18 hours at 25°C. The resulting reaction solution was poured into 20 mL of water and 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 the filtrate was filtered and concentrated under reduced pressure to yield the crude product. The crude product was separated by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to yield compound 14. 1H NMR (400MHz, DMSO-d6) δ7.88(d,J=8.1Hz,1H),7.36(s,1H),6.94(dd,J=11.1,2.9Hz,1H),6.83-6.74(m,1H),4.46(s,2H),4.02(d,J=7.1Hz ,1H),3.78-3.62(m,1H),2.95(d,J=14.9Hz,3H),2.81(q,J=8.7Hz,1H),2.13-2.03(m,2H),1.90(dd,J=13.2,3.8Hz,2H),1.61-1.13(m,9H). LC-MS:m / z:505.2(M+H) + .

[0532] Example 39: Synthesis of Compound 4

[0533] Step 1: Synthesis of intermediate 4b

[0534] At 25°C, compound 4a (Biode Pharmaceuticals, product number: BD163186, 15.5 g, 68.5 mmol) and glacial acetic acid (125 mL) were added to a 500 mL single-necked flask. Chromium trioxide (13.70 g, 137 mmol) was then added with stirring. The reaction was complete after stirring at 90°C for 16 hours. Ethyl acetate (100 mL) was added to the reaction mixture, which was then poured into H2O (200 mL). Solid NaHCO3 was added to adjust the pH to 9 before extraction. The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 4b. LC-MS: m / z: 241.0 (M+H) + .

[0535] Step 2: Synthesis of intermediate 4c

[0536] To a 250 mL single-necked flask at 25°C was added intermediate 4b (5.023 g, 20.91 mmol), tetrahydrofuran (60 mL), and methanol (15 mL), followed by a 15 mL solution of LiOH (400 mg, 16.73 mmol). After stirring at 25°C for 16 hours, the reaction was complete. 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, and the filter cake was filtered to obtain intermediate 4c. LC-MS: m / z: 225.0 (MH) - .

[0537] Step 3: Synthesis of intermediate 4d

[0538] At 25°C, intermediate 4c (2.15 g, 9.5 mmol) and tert-butanol (30 mL) were added to a 100 mL single-necked flask. Pyridine (5.37 mL, 66.53 mmol), DMAP (1.16 g, 9.5 mmol), and (Boc)2O (4.07 mL, 19.01 mmol) were also added. The reaction was complete after stirring at 35°C for 16 hours. After concentration under reduced pressure, the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 4d. LC-MS: m / z: 283.10 (M+H) + .

[0539] Step 4: Synthesis of intermediate 4e

[0540] At 25°C, intermediate 4d (1.204 g, 4.26 mmol), tetrahydrofuran (20 mL), and methanol (5 mL) were added to a 100 mL single-necked flask. A solution of lithium hydroxide (100 mg, 4.26 mmol) in water (4 mL) was then added. After stirring at 25°C for 16 hours, the reaction was complete. The tetrahydrofuran was removed by concentration under reduced pressure, and the pH was adjusted to 2-3 by adding 2M HCl. A solid precipitated, and the filter cake was filtered to obtain intermediate 4e. LC-MS: m / z: 269.10 (M+H). + .

[0541] Step 5: Synthesis of intermediate 4f

[0542] To a 100 mL single-necked flask at 25°C, intermediate 4e (800 mg, 2.98 mmol) and toluene (50 mL) were added. Triethylamine (1.24 mL, 8.94 mmol) and diphenylphosphoryl azide (1641.09 mg, 5.96 mmol) were added with stirring, and the mixture was stirred at 120°C for 2 hours. Benzyl alcohol (0.93 mL, 8.94 mmol) was then added, and the reaction was complete after stirring at 120°C for 12 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford intermediate 4f. LC-MS: m / z: 374.2 (M+H). +

[0543] Step 6: Synthesis of Intermediate 4g

[0544] At 25°C, intermediate 4f (890 mg, 2.38 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL single-necked flask. Palladium hydroxide (297.79 mg, 2.12 mmol) was added under stirring. The atmosphere was replaced with hydrogen three times. The reaction was complete after stirring at 25°C for 16 hours. The filtrate was filtered and concentrated under reduced pressure to obtain intermediate 4g. LC-MS: m / z: 240.1 (M+H) + .

[0545] Step 7: Synthesis of intermediate 4i

[0546] At 25°C, intermediate 4g obtained in the previous step and dichloromethane (6 mL) were added to a 25 mL single-necked flask. Intermediate 1i (300.39 mg, 1.26 mmol), diisopropylethylamine (0.83 mL, 5.02 mmol), and 1-propylphosphoric anhydride (1597.59 mg, 2.51 mmol) were added under stirring. The reaction was completed after stirring at 25°C for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 ml × 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain intermediate 4i. LC-MS: m / z: 426.2 (M+H) + .

[0547] Step 8: Synthesis of intermediate 4j

[0548] To a 25 mL single-necked flask at 0°C, intermediate 4i (260 mg, 0.61 mmol) and dichloromethane (5 mL) were added. Trifluoroacetic acid (5 mL) was added under stirring, and the reaction was complete 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) + .

[0549] Step 9: Synthesis of intermediate 4k

[0550] To a 25 mL single-necked flask at 25°C, intermediate 4j (225.7 mg, 0.61 mmol) and dimethylformamide (5 mL) were added. 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 with stirring. The reaction mixture was stirred at 25°C for 16 hours until completion. Water (10 mL) was added to the reaction mixture, and the mixture was 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 column chromatography (petroleum ether:ethyl acetate = 1:1) to afford intermediate 4k. LC-MS: m / z: 484.2 (M+H) + .

[0551] Step 10: Synthesis of Intermediate 41

[0552] To a 25 mL single-necked flask at 0°C, intermediate 4k (296 mg, 0.61 mmol) and dichloromethane (3 mL) were added. 4 M hydrochloric acid in dioxane (3 mL) was added with stirring. After stirring at 25°C for 1 hour, the reaction was complete. The solvent was removed by concentration under reduced pressure to yield intermediate 4l. LC-MS: m / z: 385.8 (M+H).

[0553] Step 11: Synthesis of Intermediate 4m

[0554] To a 10 mL single-necked flask at 25°C, intermediate 41 obtained in the previous step and tetrahydrofuran (2 mL) were added. N,N-diisopropylethylamine (0.09 mL, 0.57 mmol) and thiocarbonyldiimidazole (61.29 mg, 0.34 mmol) were added with stirring. The mixture was stirred at 25°C for 16 hours and then at 70°C for 3 hours, after which the reaction was complete. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with brine (3 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (pure ethyl acetate) to afford intermediate 4m. LC-MS: m / z: 426.1 (M+H).

[0555] Step 12: Synthesis of Intermediate 4n

[0556] At 25°C, intermediate 4m (122 mg, 0.29 mmol) and dimethylformamide (1.5 mL) were added to a 10 mL single-necked flask. Potassium carbonate (79.18 mg, 0.57 mmol) and iodomethane (35.68 μL, 0.57 mmol) were added under stirring. The reaction was complete after stirring at 25°C for 3 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (6 mL × 3). The organic layers were combined, washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 4n. LC-MS: m / z: 440.1 (M+H) + .

[0557] Step 13: Synthesis of Intermediate 4o

[0558] At 0°C, intermediate 4n (65 mg, 0.15 mmol) and dichloromethane (1 mL) were added to a 10 mL single-necked flask. m-Chloroperoxybenzoic acid (105.00 mg, 0.52 mmol) was added under stirring. The reaction was complete after stirring at 25°C for 16 hours. Saturated sodium thiosulfate solution was added to the reaction mixture, followed by water (3 mL). Extraction was performed with ethyl acetate (5 mL x 3). The organic layers were combined, washed with brine (3 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 4o. LC-MS: m / z: 472.1 (M+H) + .

[0559] Step 14: Synthesis of Intermediate 4q

[0560] At 25°C, intermediate 4o (44 mg, 0.09 mmol) and dimethylformamide (1 mL) were added to a 10 mL single-necked flask. Compound 4p (65.78 mg, 0.47 mmol) and potassium carbonate (90.20 mg, 0.65 mmol) were added under stirring. The reaction was complete after stirring at 25°C for 4 hours. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic layers were combined, washed with brine (3 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 4q. LC-MS: m / z: 533.2 (M+H) + .

[0561] Step 15: Synthesis of Compound 4

[0562] At 0°C, intermediate 4q (35 mg, 0.07 mmol) and methanol (1 mL) were added to a 10 mL single-necked flask. Sodium borohydride (4.97 mg, 0.13 mmol) was added under stirring, and the reaction was complete after stirring at 25°C for 1 hour. 2M hydrochloric acid solution was added to the reaction mixture until pH = 7, followed by addition of water (2 mL) and extraction with ethyl acetate (3 mL × 3). The organic layers were combined, 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=8.9Hz,1H),7.42(s,1H),7.13(dd,J=11.4,2.8Hz,1H),6.90(dd,J=8.9,2.7Hz,1H),5. 33-5.41(m,1H),5.12-5.32(m,1H),4.55(s,2H),4.51(dd,J=9.4,6.9Hz,2H),4.25(dd,J=9.6,3.9Hz,2H),4.17(br d,J=7.1Hz,1H),2.23-2.37(m,1H),2.13(br d, J=5.0Hz, 1H), 1.80-2.05 (m, 7H), 1.74 (dd, J=13.6, 2.5Hz, 1H).

[0563] Example 40: Synthesis of Compound 3

[0564] Step 1: Synthesis of intermediate 3b

[0565] To a solution of 3a (Biodex Pharmaceuticals, Catalog No. BD234253, 1 g, 5.46 mmol) and 1i (1 g, 4.96 mmol) in DCM (20 mL) were 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 hours. The reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL x 3). The resulting organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford intermediate 3b. m / z ES+[M+H]+ = 370.1.

[0566] Step 2: Synthesis of intermediate 3c

[0567] 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 x 3). The resulting organic layers were combined, washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford Intermediate 3c. m / z ES + [M+H] + =370.1.

[0568] Step 3: Synthesis of intermediate 3d

[0569] 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 x 3). The organic layers were combined, washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (pure ethyl acetate) to obtain intermediate 3d. m / z ES + [M+H] + =396.1.

[0570] Step 4: Synthesis of compound 3

[0571] 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 agent (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 × 3). The organic layers were combined, washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 3, m / z ES + [M+H] + =519.1. 1H NMR(DMSO-d6)δ:7.58(s,1H),7.48(t,J=8.8Hz,1H),7.03(dd,J=11.4,2.6Hz,1H), 6.82(d,J=9.1Hz,1H),5.26-5.35(m,1H),4.46(s,2H),4.40-4.45(m,2H),4.18(br dd,J=9.5,3.6Hz,2H),1.90(br d,J=5.1Hz,12H).

[0572] Example 41: Synthesis of Compound 10

[0573] Step 1: Preparation of intermediate 10b

[0574] To a 100 mL single-necked flask at 25°C, compound 10a (Biode Pharmaceuticals, Catalog No. BD234295, 2 g, 7.06 mmol) and dichloromethane (15 mL) were added. Trifluoroacetic acid (5.0 mL) was added with stirring. The reaction was complete after 3 hours at 25°C. The mixture was concentrated under reduced pressure to yield intermediate 10b.

[0575] Step 2: Preparation of intermediate 10c

[0576] Under ice, compound 1i (1.74 g, 8.51 mmol) and dimethylformamide (15 mL) were added to a 100 mL single-necked flask. 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 under stirring. After reacting at 25 degrees Celsius for half an hour, intermediate 10b (1.3 g, 7.09 mmol) was added to the resulting reaction solution. The reaction was allowed to complete overnight at 25 degrees Celsius. 150 mL of water was added to the resulting reaction solution, and the mixture was extracted with 150 mL of ethyl acetate. The organic phase was 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 purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain intermediate 10c. LC-MS: m / z: 393.0 (M+Na) + .

[0577] Step 3: Preparation of Intermediate 10d

[0578] At 25°C, intermediate 10c (1.6 g, 4.33 mmol) and ethanol (15 mL) were added to a 100 mL single-necked flask. 50% hydrazine hydrate (3.61 g, 43.3 mmol) was added under stirring and the temperature was raised to 80°C overnight for completion. The crude product was concentrated under reduced pressure to obtain the crude product. The crude product was purified by recrystallization from acetonitrile to obtain intermediate 10d. LC-MS: m / z: 370.2 (M+H) + .

[0579] Step 4: Preparation of intermediate 10e

[0580] At 25 degrees Celsius, intermediate 10d (616 mg, 1.67 mmol) and 1,2-dichloroethane (5 mL) were added to a 100 mL single-necked bottle, and compound N,N'-carbonyldiimidazole (350 mg, 2.16 mmol) was added sequentially under stirring. The reaction was completed after 18 hours at 25 degrees Celsius. 50 mL of water was added to the reaction solution, and it was extracted with 50 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 a crude product. The crude product was purified by column chromatography to obtain intermediate 10e. LC-MS: m / z: 396.0 (M+H) + .

[0581] Step 5: Preparation of intermediate 10g

[0582] Under ice, compound 10f (1.0 g, 4.83 mmol) and ethyl acetate (20 mL) were added to a 100 mL three-necked flask. The flask was covered with tinfoil to shield it 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 then added with stirring. After reacting at 25°C for 16 hours, the reaction was complete by TLC. The resulting reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain intermediate 10 g. 1 H NMR (400MHz, DMSO-d6) δ7.32–7.18(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).

[0583] Step 6: Preparation of Intermediate 10h

[0584] To a 50 mL single-necked flask at 25°C was added intermediate 10 g (110 mg, 0.34 mmol) and anhydrous methanol (5.0 mL). Palladium on carbon (22 mg) and a few drops of concentrated hydrochloric acid were added sequentially with stirring. The atmosphere was replaced with hydrogen three times, and the reaction was completed after 16 hours at 25°C under a hydrogen balloon. After filtration, the filtrate was concentrated under reduced pressure to yield intermediate 10h.

[0585] Step 7: Preparation of compound 10

[0586] Under ice bath, intermediate 10h (51 mg, 0.13 mmol) and dimethylformamide (5.0 mL) were added to a 50 mL single-necked bottle, and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (86 mg, 0.19 mmol), diisopropylethylamine (68 mg, 0.78 mmol), and intermediate 10e (22 mg, 0.12 mmol) were added sequentially under stirring. The reaction was completed overnight at 25 degrees Celsius. 25 mL of water was added to the reaction solution, extracted with 25 mL of ethyl acetate, and 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 a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 10. 1 H NMR(400MHz,DMSO-d6)δ7.60(s,1H),7.53–7.48(m,1H),7.06–7.02(m,1H),6.87–6.84(m,1H),5.4 8–5.45(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) + .

[0587] Example 42: Synthesis of Compound 8

[0588] Step 1: Synthesis of intermediate 8b

[0589] Under ice, compound 8a (Biode Pharmaceuticals, catalog number: BD159912, 1000 mg, 4.73 mmol) and dichloromethane (50 mL) were added to a 250 mL single-necked flask. Diethylaminosulfur trifluoride (2.5 mL, 18.93 mmol) was slowly added dropwise under stirring. The reaction was complete after 16 hours at 25°C. The resulting reaction solution was slowly added dropwise to 20 mL of ice water to quench the reaction. The mixture was extracted with 20 mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain intermediate 8b. 1H NMR (400MHz, MeOD) δ = 3.99 (s, 4H), 2.75 (t, J = 12.1Hz, 4H), 1.43 (s, 9H).

[0590] Step 2: Synthesis of Intermediate 8c

[0591] To a 50 mL single-necked flask at 25°C, intermediate 8b (100 mg, 0.43 mmol) and dichloromethane (1 mL) were added, followed by the addition of trifluoroacetic acid (0.3 mL, 4.03 mmol) under stirring. The reaction was complete after 16 hours. The solvent was then dried to yield intermediate 8c. 1 H NMR (400MHz, CDCl3) δ = 4.57-3.89 (m, 4H), 3.13-2.57 (m, 4H).

[0592] Step 3: Synthesis of Compound 8

[0593] At 25 degrees Celsius, intermediate 10e (30 mg, 0.08 mmol) and dimethylformamide (1 mL) were added to a 50 mL single-necked bottle. Intermediate 8c (20.18 mg, 0.15 mmol), Carter condensation agent (67.0 mg, 0.15 mmol) and diisopropylethylamine (0.08 mL, 0.45 mmol) were added sequentially under stirring. The reaction was completed after 16 hours at 25 degrees Celsius. The reaction solution was filtered and sent to the preparation. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 8. LC-MS: m / z: 511.0 (M+H) + . 1 H NMR (400MHz, MeOD) δ = 7.37 (t, J = 8.7Hz, 1H), 6.91 (dd, J = 2.8, 11.0Hz, 1H), 6.80 (ddd, J=1.3,2.9,8.9Hz,1H),4.43(s,2H),4.21(s,4H),2.84(t,J=12.1Hz,4H),2.09-1.98 (m,12H).

[0594] Example 43: Synthesis of Compound 9

[0595] Step 1: Preparation of intermediate 9b

[0596] At 25°C, dimethylphosphine oxide (0.55 g, 7.06 mmol) and tetrahydrofuran (30 mL) were added to a 50 mL single-necked bottle, and sodium bis(trimethylsilyl)amide (3.53 mL, 7.06 mmol) was added under stirring in an ice bath. After reacting at 25°C for 1 hour, compound 9a (Bidec Pharmaceuticals, product number: BD32891, 1 g, 3.53 mmol) was added. The reaction was completed after 16 hours of reaction at 25°C. The resulting reaction solution was poured into 100 mL of water, and then extracted twice with 200 mL of ethyl acetate each time. 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) + .

[0597] Step 2: Preparation of compound 9c

[0598] At 25 degrees Celsius, 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-necked flask. Benzyl chloroformate (0.32 mL, 2.25 mmol) was added dropwise with stirring. The reaction was complete after 16 hours at 25 degrees Celsius. The resulting reaction solution was poured into 100 mL of water and extracted twice with 200 mL of ethyl acetate each time. 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 intermediate 9c. LC-MS: m / z: 268.0 (M+H) + .

[0599] Step 3: Preparation of intermediate 9d

[0600] 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-necked flask. After addition, the atmosphere was replaced with hydrogen three times. The reaction was then allowed to proceed under hydrogen at 25°C for 16 hours. After completion, the reaction was filtered and concentrated under reduced pressure to yield intermediate 9d. LC-MS: m / z: 134.0 (M+H). + .

[0601] Step 4: Preparation of compound 9

[0602] At 25 degrees Celsius, 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-necked bottle. Diisopropylethylamine (0.05 mL, 0.30 mmol) and Carter condensation agent (50.28 mg, 0.11 mmol) were added sequentially under stirring. The reaction was completed after 18 hours at 25 degrees Celsius. 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, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain compound 9. 1 H NMR (400MHz, DMSO-d6) δ8.36(s,1H),7.60(s,1H),7.49(t,J=8.9Hz,1H),7.04(dd,J=11.4,2.9Hz,1H),6.85–6.8 0(m,1H),4.46(s,2H),4.30–4.03(m,4H),3.12(d,J=9.3Hz,1H),1.90(d,J=5.9Hz,11H),1.41(d,J=13.1Hz,6H). LC-MS:m / z:511.2(M+H) + .

[0603] Example 44: Synthesis of Compound 15

[0604] At 25°C, compound 15a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration 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 (400MHz, DMSO-d6) δ = 8.00 (d, J = 8.0Hz, 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=3.9,9.5Hz,2H),3.70-3.59(m,1H),2.71(tt,J=3.4,11.7Hz,1H),2.02(br d,J=11.9Hz,2H),1.84(br dd,J=2.9,12.5Hz,2H),1.56-1.32(m,4H).LC-MS:m / z:475.2(M+H) + .

[0605] Example 45: Synthesis of Compound 16

[0606] Step 1: Preparation of intermediate 16b

[0607] At 25°C, 16a (Biode Pharmaceuticals, product number: BD263092, 800 mg, 3.26 mmol) and anhydrous tetrahydrofuran (8 mL) were added to a 100 mL single-necked flask. N,N'-thiocarbonyldiimidazole (821 mg, 4.89 mmol) was added under stirring. The reaction was stirred at 25°C for 16 hours, followed by the addition of hydrazine hydrate (1.92 g, 32.6 mmol) 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) + .

[0608] Step 2: Preparation of intermediate 16c

[0609] At 25°C, intermediate 16b (710 mg, 2.46 mmol) and 1,2-dichloroethane (10.0 mL) were added to a 100 mL single-necked bottle, and compound N,N'-carbonyldiimidazole (887 mg, 5.46 mmol) was added sequentially 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, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 16c. LC-MS: m / z: 230.0 (M+H-56) + .

[0610] Step 3: Preparation of intermediate 16d

[0611] At 25°C, intermediate 16c (680 mg, 2.03 mmol) and dimethylformamide (10 mL) were added to a 100 mL single-necked bottle, and compound 3-(trifluoromethoxy)-azetidine (336 mg, 2.38 mmol), diisopropylethylamine (1.2 g, 9.53 mmol) and Carter condensation agent (1.6 g, 3.6 mmol) were added in sequence under stirring. The reaction was completed after 16 hours of reaction. 100 mL of water was added to the resulting reaction solution, and the mixture was 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 a 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) + .

[0612] Step 4: Preparation of intermediate 16e

[0613] At 25°C, intermediate 16d (70 mg, 0.17 mmol) and dichloromethane (5.0 mL) were added to a 100 mL single-necked flask. Trifluoroacetic acid (2.0 mL, 4.5 mmol) was added under stirring. The reaction was complete after 2 hours. The mixture was concentrated under reduced pressure to give intermediate 16e. LC-MS: m / z: 309.1 (M+H) + .

[0614] Step 5: Preparation of compound 16

[0615] Under ice, compound 1i (47 mg, 0.23 mmol) and dimethylformamide (5.0 mL) were added to a 50 mL single-necked flask. 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 with stirring. The reaction mixture was allowed to react overnight at room temperature. 25 mL of water was added to the resulting reaction solution, and the mixture was 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 purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 16. 1H NMR(400MHz, DMSO-d6)δ8.08–8.01(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) + .

[0616] Example 46: Synthesis of Compound 17

[0617] At 25°C, compound 17a (Bidec Pharmaceuticals, product 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 bottle. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was extracted with 20 mL of ethyl acetate. The resulting organic phase was washed with 20 mL of saturated brine, dried over sodium sulfate, and the filtrate obtained after filtration was concentrated under reduced pressure to obtain a 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 (400MHz, DMSO-d6) δ7.65–7.63(m,1H),5.33–5.30(m,1H),4.50–4.43(m,3H),4.20–4.17(m,2H),3.76(s,2H),3.73–3.69(m,1H),3.6 4–3.62(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) + .

[0618] Example 47: Synthesis of Compound 18

[0619] At 25°C, compound 18a (Biode Pharmaceuticals, product 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. 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 stirred at 25°C for 10 hours and the reaction was completed. 20 mL of water was added to the resulting reaction solution, and the mixture was 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 the filtrate obtained after filtration 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 (400MHz, Methanol-d4) δ8.09(d,J=2.7Hz,1H),7.72(dd,J=8.8,2.7Hz,1H),6.94(d,J=8.9 Hz,1H),5.44–5.21(m,2H),4.75(s,2H),4.50(dd,J=9.7,6.7Hz,2H),4.25(dd,J=9.6,4.2Hz,2 H),3.77(t,J=4.0Hz,1H),2.92–2.64(m,1H),2.20–2.09(m,2H),2.00(ddd,J=13.6,8.9,4.7Hz ,2H),1.63(qd,J=13.1,3.3Hz,2H),1.43(td,J=12.4,12.0,3.5Hz,2H).LC-MS:m / z:476.1(M+H) + .

[0620] Example 48: Synthesis of Compound 7

[0621] Step 1: Preparation of intermediate 7a

[0622] To a single-necked flask at room temperature, 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 and stirred at room temperature for 12 hours. The reaction mixture was added with 50 mL of water and 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 column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to afford intermediate 7a. LC-MS: m / z: 393.2 (M+H)+.

[0623] Step 2: Preparation of intermediate 7b

[0624] To a single-necked flask at room temperature, intermediate 7a (1100 mg, 2.80 mmol) and dichloromethane (3 mL) were added. A 4M solution of dioxane hydrochloride (3 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was directly concentrated to afford intermediate 7b. LC-MS: m / z: 293.2 (M+H)+.

[0625] Step 3: Preparation of intermediate 7c

[0626] At room temperature, 7b (230 mg, 0.79 mmol) and water (1 mL) were added to a single-necked flask. Acetic acid (3 mL) and sodium nitrite (162.88 mg, 2.36 mmol) were added under ice-cooling. After stirring under ice-cooling for 1 hour, the reaction was complete. The reaction solution was directly concentrated under reduced pressure to obtain intermediate 7c. LC-MS: m / z: 322.1 (M+H)+.

[0627] Step 4: Preparation of intermediate 7d

[0628] To a single-necked flask at room temperature, 7c (890 mg, 2.77 mmol), acetic acid (2 mL), and methanol (6 mL) were added. Zinc powder (905.62 mg, 13.85 mmol) was added under ice-cooling and stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield intermediate 7d. LC-MS: m / z: 308.1 (M+H)+.

[0629] Step 5: Preparation of compound 7

[0630] To a single-necked flask at room temperature were added intermediate 7d (100 mg, 0.33 mmol), 1i (66.58 mg, 0.33 mmol), and N,N-dimethylformamide (1 mL). 1-Propylphosphonic anhydride (414.19 mg, 0.65 mmol) and N,N-diisopropylethylamine (126.19 mg, 0.98 mmol) were added sequentially with stirring. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water) to afford compound 7 (6 mg). LC-MS: m / z: 494.5 (M+H)+. 1H 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=11.1Hz,1H),2.56-2.81(m,3H),1.83-2.00(m,3H),1.60-1.78(m,2H).

[0631] Example 49: Synthesis of Compounds 51-1 and 51-2

[0632] Step 1: Preparation of intermediate 51b

[0633] At room temperature, 51a (Shaoyuan, 800 mg, 4.32 mmol) and 1,4-dioxane (2.0 mL) were added to a single-necked flask. A hydrochloric acid / dioxane solution (4 M, 6.0 mL) was added with stirring and allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate 51b.

[0634] Step 2: Preparation of Intermediate 51c

[0635] At room temperature, intermediate 51b (350 mg, 4.11 mmol) and dimethylformamide (8.0 mL) were added to a single-necked flask. Benzyl chloroformate (1.08 g, 6.34 mmol) and potassium carbonate (2.34 g, 16.92 mmol) were added sequentially with stirring. The mixture was stirred at room temperature for 18 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted once with 50 mL of ethyl acetate. The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 51c.

[0636] Step 3: Preparation of Intermediate 51d

[0637] To a single-necked flask at room temperature, 51c (620 mg, 2.83 mmol) and anhydrous methanol (10.0 mL) were added, followed by sodium borohydride (214 mg, 5.63 mmol) with stirring. The temperature was raised to 50°C and the reaction was allowed to proceed for 3 hours. The reaction solution was quenched with 50 mL of aqueous ammonium chloride and extracted with 30 mL of ethyl acetate each time. The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to provide intermediate 51d.

[0638] Step 4: Preparation of intermediates 51ea and 51eb

[0639] Under ice-cooling, intermediate 51d (300 mg, 1.36 mmol) and ethyl acetate (20 mL) were added to a three-necked flask. The flask was covered with tinfoil to shield 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 then added with stirring. 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) (by 1 H- 1 H NOESY (2D NMR) confirmation).

[0640] 51ea: 1 H NMR(400MHz,DMSO)δ7.40–7.30(m,5H),5.06(s,2H),4.79–4.75(m,1H),4.3 8–4.35(m,1H),4.21–4.17(m,1H),3.92–3.90(m,1H),1.37(d,J=6.6Hz,3H).

[0641] 51eb: 1 H NMR(400MHz,DMSO)δ7.46–7.21(m,5H),5.19–5.15(m,1H),5.05(s,2H),4.6 5–4.62(m,1H),4.28–4.25(m,1H),3.92–3.90(m,1H),1.30(d,J=6.6Hz,3H).

[0642] Step 5: Preparation of Intermediate 51-1a

[0643] To a single-necked flask at room temperature, intermediate 51ea (60 mg, 0.21 mmol) and anhydrous methanol (5.0 mL) were added. Palladium on carbon (12 mg) and 2 drops of concentrated hydrochloric acid were added sequentially with stirring. The mixture was replaced with a hydrogen balloon three times and allowed to react at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to provide intermediate 51-1a.

[0644] Step 6: Preparation of compound 51-1

[0645] Under ice, intermediate 51-1a (30 mg, 0.18 mmol) and dimethylformamide (5.0 mL) were added to a single-necked flask. Carter condensation agent (125 mg, 0.27 mmol), diisopropylethylamine (70 mg, 0.54 mmol), and intermediate 6d (70 mg, 0.18 mmol) were added sequentially under stirring. The reaction was allowed to proceed overnight at room temperature. 25 mL of water was added to the reaction solution, and each extraction was performed with 30 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 51-1 (7.34 mg). 1 H NMR (400MHz, DMSO) δ8.02(d,J=8.0Hz,1H),7.50(t,J=8.9Hz,1H),7.07(dd,J=11.4,2.9Hz,1 H),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=5.8Hz, 3H), 1.41–1.29 (m, 2H), LC-MS: m / z: 507.0 (M+H)+.

[0646] Step 7: Preparation of Intermediate 51-2a

[0647] To a single-necked flask at room temperature, intermediate 51eb (70 mg, 0.24 mmol) and anhydrous methanol (5.0 mL) were added. Palladium on carbon (12 mg) and 2 drops of concentrated hydrochloric acid were added sequentially under stirring. The mixture was replaced with a hydrogen balloon three times and allowed to react at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 51-2a.

[0648] Step 8: Preparation of compound 51-2

[0649] Under ice bath, intermediate 51-2a (32 mg, 0.20 mmol) and dimethylformamide (5.0 mL) were added to a 50 mL single-necked flask. Carter condensation agent (149 mg, 0.34 mmol), diisopropylethylamine (88 mg, 0.68 mmol) and intermediate 6d (83 mg, 0.22 mmol) were added sequentially with stirring. The reaction was allowed to proceed overnight at room temperature. 25 mL of water was added to the reaction solution, and the mixture was extracted three times with 30 mL of ethyl acetate each time. The combined organic phases were washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 51-2 (4.54 mg). 1 H NMR(400MHz,DMSO)δ8.02(d,J=8.0Hz,1H),7.50(t,J=8.9Hz,1H),7.08–7.06(m,1H),7.0 5–6.86(m,1H),5.26–5.22(m,1H),4.75–4.73(m,1H),4.40(s,2H),4.39–4.36(m,1H),4.0 3–4.02(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 = 5.8Hz, 3H), LC-MS: m / z: 507.1 (M+H)+.

[0650] Example 50: Synthesis of Compound 90

[0651] Step 1: Preparation of intermediate 90b

[0652] At room temperature, 90a (Biode Pharmaceuticals, Catalog No. BD253909, 5.0 g, 31.61 mmol) and N,N-dimethylformamide (40.0 mL) were added to a single-necked flask. Imidazole (4.30 g, 63.22 mmol) and tert-butyldimethylsilyl chloride (5.24 g, 34.77 mmol) were added with stirring and allowed to react at room temperature for 3 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 90b. 1H NMR(400MHz, CDCl3)δ3.65(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).

[0653] Step 2: Preparation of intermediate 90c

[0654] To a single-necked flask at room temperature, intermediate 90b (4.50 g, 16.52 mmol) and ethanol (40.0 mL) were added. Hydrazine hydrate (9.73 g, 165.16 mmol) was then added at room temperature and allowed to react at 85°C for 18 hours. The reaction mixture was concentrated under reduced pressure to yield intermediate 90c. LC-MS: m / z: 273.3 (M+H)+.

[0655] Step 3: Preparation of intermediate 90d

[0656] At room temperature, intermediate 90c (1.80 g, 6.61 mmol) and 1,2-dichloroethane (20.0 mL) were added to a single-necked flask, and triethylamine (2.75 mL, 19.82 mmol) and N,N'-carbonyldiimidazole (1.50 g, 9.25 mmol) were added under stirring. The reaction was allowed to react at room temperature for 18 hours. The reaction solution was poured into 80 ml of water and extracted three times with 50 ml of ethyl acetate each time. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by 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(400MHz,DMSO-d6)δ12.05(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=3.0Hz,6H).

[0657] Step 4: Preparation of intermediate 90e

[0658] At room temperature, 90d (900 mg, 3.02 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-necked flask. N,N-diisopropylethylamine (2.00 mL, 12.06 mmol), 3-(trifluoromethoxy)-azetidine (425 mg, 3.02 mmol) and Carter condensation agent (1.60 g, 3.62 mmol) were added under stirring and reacted at room temperature for 18 hours. The reaction solution was poured into 60 mL of water and extracted three times with 50 mL of ethyl acetate each time. The product was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 100:1 to 2:1) to obtain intermediate 90e. LC-MS: m / z: 422.4 (M+H)+, 1 H NMR(400MHz,DMSO-d6)δ5.38-5.26(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).

[0659] Step 5: Preparation of Intermediate 90f

[0660] To a 50 mL single-necked flask at room temperature, intermediate 90e (850 mg, 2.02 mmol) and tetrahydrofuran (10.0 mL) were added. Tetrabutylammonium fluoride (6.05 mL, 6.05 mmol, 1 M) was added with stirring and allowed to react at room temperature for 5 hours. The reaction solution was poured into 60 mL of water and extracted three times with 50 mL of ethyl acetate each time. 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)+.

[0661] Step 6: Preparation of Intermediate 90g

[0662] To a single-necked flask at room temperature, intermediate 90f (480 mg, 1.56 mmol) and N,N-dimethylformamide (6.0 mL) were added. Sodium hydride (125 mg, 3.12 mmol) and tert-butyl bromoacetate (456 mg, 2.34 mmol) were stirred and reacted 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 each time. 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)+.

[0663] Step 7: Preparation of Intermediate 90h

[0664] At room temperature, intermediate 90 g (70 mg, 0.17 mmol) and dichloromethane (2.0 mL) were added to a single-necked flask. Trifluoroacetic acid (0.5 mL) was added with stirring and the mixture was allowed to react at room temperature for 2 hours. The filtrate was concentrated under reduced pressure to yield intermediate 90h. LC-MS: m / z: 366.2 (M+H).

[0665] Step 8: Preparation of compound 90

[0666] At room temperature, intermediate 90h (50 mg, 0.14 mmol) and N,N-dimethylformamide (1.0 mL) were added to a single-necked flask, and N,N-diisopropylethylamine (53 mg, 0.41 mmol), compound 90i (20 mg, 0.14 mmol) and (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (86 mg, 0.16 mmol) were added under stirring. The reaction was allowed to proceed at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was prepared 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(400MHz, DMSO-d6)δ9.96(s,1H),7.84(dd,J=12.0,2.0Hz,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).

[0667] Example 51: Synthesis of Compound 19

[0668] At room temperature, 19a (Bi De Pharmaceuticals, product number: BD00755909, 16 mg, 0.13 mmol) and dimethylformamide (3 mL) were added to a single-necked bottle, and diisopropylethylamine (52 mg, 0.40 mmol), 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (90 mg, 0.20 mmol) and compound 6d (50 mg, 0.14 mmol) were added sequentially under stirring, and the reaction was carried out at room temperature for 18 hours. The reaction solution was poured into 30 mL of water and extracted twice with 30 mL of ethyl acetate each time. The organic phase was washed with 30 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was 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 (400MHz, DMSO) δ8.02(d,J=8.0Hz,1H),7.50(t,J=8.9Hz,1H),7.07(dd,J=11.4,2.9Hz,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).

[0669] Example 52: Synthesis of Compound 86

[0670] Step 1: Preparation of intermediate 86b

[0671] At room temperature, compound 86a (Nanjing Yaoshi, 470 mg, 1.72 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-necked flask. Imidazole (334 mg, 4.91 mmol) and tert-butyldimethylsilyl chloride (370 mg, 2.45 mmol) were added under stirring and reacted at room temperature for 18 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted twice with 50 mL of ethyl acetate. The combined organic phases were 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) + .

[0672] Step 2: Preparation of Intermediate 86c

[0673] To a single-necked flask at room temperature, intermediate 86b (570 mg, 1.47 mmol) and ethanol (10.0 mL) were added, followed by hydrazine hydrate (836 mg, 14.19 mmol). The mixture was reacted at 80°C for 18 hours. The reaction solution was concentrated under reduced pressure to afford intermediate 86c as a white solid. LC-MS: m / z: 410.2 (M+Na)+.

[0674] Step 3: Preparation of Intermediate 86d

[0675] At room temperature, intermediate 86c (520 mg, 1.34 mmol) and 1,2-dichloroethane (10.0 mL) were added to a single-necked flask. Triethylamine (0.56 mL, 4.02 mmol) and N,N'-carbonyldiimidazole (326 mg, 2.01 mmol) were added with stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 86d. LC-MS: m / z: 436.2 (M+Na) + .

[0676] Step 4: Preparation of Intermediate 86e

[0677] Intermediate 86d (470 mg, 1.14 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-necked flask at room temperature. N,N-diisopropylethylamine (589 mg, 4.56 mmol), 3-(trifluoromethoxy)-azetidine (176 mg, 1.25 mmol), and Carter's condensation agent (603 mg, 1.36 mmol) were added with stirring and allowed to react at room temperature for 18 hours. The reaction solution 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 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 86e. LC-MS: m / z: 537.4 (M+H)+.

[0678] Step 5: Preparation of Intermediate 86f

[0679] To a single-necked flask at room temperature, intermediate 86e (100 mg, 0.19 mmol) and dichloromethane (2.0 mL) were added, followed by trifluoroacetic acid (0.5 mL). The mixture was allowed to react at room temperature for 2 hours. The filtrate was concentrated under reduced pressure to afford intermediate 86f. LC-MS: m / z: 437.4 (M+H).

[0680] Step 6: Preparation of Intermediate 86g

[0681] At room temperature, intermediate 86f (82 mg, 0.19 mmol) and N,N-dimethylformamide (2.0 mL) were added to a single-necked flask. 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 with stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution 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 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 86g. LC-MS: m / z: 623.4 (M+H)+.

[0682] Step 7: Preparation of Compound 86

[0683] At room temperature, intermediate 86g (117 mg, 0.19 mmol) and tetrahydrofuran (2.0 mL) were added to a single-necked flask. Tetrabutylammonium fluoride (0.38 mL, 0.38 mmol, 1 M) was added under stirring, and the mixture was allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then 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(400MHz,DMSO-d6)δ7.90(d,J=7.7Hz,1H),7.49(t,J=8.9Hz,1H),7.08(dd,J=11 .4,2.8Hz,1H),6.87(dd,J=8.9,1.9Hz,1H),5.36-5.27(m,1H),4.83(d,J=5.0Hz,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).

[0684] Other compounds of the present invention can be prepared by methods similar to those described in the above examples (with appropriate modifications, if necessary).

[0685] Biological testing

[0686] 1. Cell activity test

[0687] The ATF4 luciferase reporter plasmid consists of two parts: the 5' untranslated region sequence of the ATF4 gene and the luciferase coding sequence. Specifically, the 5' untranslated region sequence of ATF4 containing two upstream open reading frames (uORFs) (NCBI database number BC022088.2) and the firefly luciferase coding gene were cloned into the pLVX-Puro vector (Ubao Bio, VT1465). The packaging plasmids of the lentivirus are psPAX2 (Ubao Bio, VT1444) and pMD2.G (Ubao Bio, VT1443). The above three plasmids were transfected simultaneously in HEK293T / 17 cells using X-tremeGENE 9 DNA transfection reagent, and the culture medium containing the lentivirus was collected after 48 hours. The virus-transduced HEK293T / 17 cells were screened with 1μg / mL of puromycin, and then monoclonal cells were obtained by limiting dilution.

[0688] Using this cell line, the translational regulation of ATF4 can be detected and the activity of eIF2B activators can be tested by cold fluorescence readings. The specific experimental process is as follows: 6000 HEK293T / 17-ATF4uORF-Luc-Puro monoclonal cells are plated in a 384-well plate and allowed to adhere overnight. The test compound is dissolved in DMSO and added to the cell culture medium together with 50nM thapsigargin and incubated for 6 hours. Among them, the role of thapsigargin is to cause cell stress and upregulate the protein translation of ATF4. After 6 hours of drug addition, the cells are lysed using the One-Glo Luciferase Assay Kit (Promega #E6120), and the cold fluorescence value is then read using the LUM program of the EnVision 2104 plate reader.

[0689] The relative expression of the ATF4 reporter gene (ATF4 reporter expression %) was calculated as follows:

[0690] ATF4 reporter expression%=(ave_sample-ave_vc) / (ave_pc-ave_vc)*100%.

[0691] ave_vc: average signal value of negative control

[0692] ave_pc: average signal value of positive control

[0693] ave_sample: average signal value of the sample

[0694] Fitting dose-effect curves and calculating EC 50 value:

[0695] The nonlinear regression log (inhibitor) vs. response--variable slope (four parameters) method of GraphPad 9 software was used to fit the corresponding relationship between the relative expression level of the ATF4 reporter gene and the compound concentration.

[0696] X-axis: log value of compound concentration; Y-axis: relative expression level of ATF4 reporter gene; Top: estimated asymptote on the curve; Bottom: estimated asymptote below the curve; Hillslope: slope of the fitting curve.

[0697] Formula: Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)×HillSlope)), that is, LogEC 50 =X+(1 / HillSlope)×log((Top-Y) / (Y-Bottom)).

[0698] In Table 1, “+” indicates an EC > 100 nM 50 , “++” indicates EC values ​​between 10 nM and 100 nM 50 "+++" indicates an EC range of 1 nM to 10 nM. 50 “++++” indicates an EC less than 1 nM 50 .

[0699] Table 1 Structures of exemplary compounds and their HEK293T / 17-ATF4uORF-Luc-Puro monoclonal cell activities

[0700] The experimental results (partially not shown) show that the compounds of the present application can enhance / activate eIF2B activity and reduce the expression of ATF4, thereby reducing the fluorescence intensity, indicating that the compounds of the present application can significantly alleviate the cell stress caused by thapsigargin, weaken the integrated stress response of the cell, and allow the normal synthesis of intracellular proteins, and are eIF2B agonists. Most of the compounds of the present application have an effect on the EC of HEK293T / 17 cells. 50 The EC values ​​of many compounds for HEK293T / 17 cells were less than 100 nM. 50 The values ​​range from 10nM to 100nM, and many compounds have EC values ​​of HEK293T / 17 cells. 50 The values ​​were below 10 nM, and the EC values ​​of some preferred compounds on HEK293T / 17 cells were 50 The EC values ​​of the most preferred compounds for HEK293T / 17 cells were less than 1 nM.50 The value is less than 10pM.

[0701] 2. Kinetic solubility evaluation

[0702] Dissolve the test compound in DMSO to prepare a 10mM stock solution. Add 8.71g K2HPO4 to 500mL deionized water to prepare a 100mM K2HPO4 solution. Add 2.05g potassium dihydrogen phosphate to 150mL deionized water to prepare a 100mM potassium dihydrogen phosphate solution. Mix 405mL 100mM K2HPO4 and 95mL 100mM KH2PO4, and adjust the pH of the mixed solution to 7.4 with 100mM K2HPO4 / KH2PO4 solution. Add 10.41g FaSSIF buffer concentrate to 240.3g deionized water to prepare a buffer solution (simulated intestinal fluid in the fasted state, pH=6.5). Add 4.071g FeSSIF buffer concentrate to 45.97g deionized water to prepare a buffer solution (simulated intestinal fluid in the fed state, pH=5.0).

[0703] Using a 96-well plate, add 16 μL of a 10 mM compound stock solution to 784 μL of various buffers (n=3). Seal the plate and shake at 1000 rpm for 1.5 hours at 25°C (PBS) or 37°C (other). After incubation, transfer the solution to a filter plate. Filter all samples. Take 5 μL of the filtrate and add 5 μL of DMSO and 490 μL of an acetonitrile-water solution containing an internal standard (1:1 ratio) and mix thoroughly. Dilute the solution with an acetonitrile-water solution containing an internal standard (1:1 ratio) based on the compound's properties and its mass spectrometric response. Adjust the dilution factor based on solubility and UPLC-MS / MS signal response.

[0704] Experiments show that at least some of the compounds of the present application have good solubility under the above-mentioned different simulated environments. For example, the solubility of compound 6 in the simulated intestinal fluid environment (pH = 6.5) in the fasting state is greater than 10 μg / mL, and the solubility in the simulated intestinal fluid environment (pH = 5.0) in the fed state is greater than 80 μg / mL.

[0705] 3. In vitro liver microsome stability evaluation

[0706] Preheat 100 mM K-Mg buffer containing 5 mM MgCl2. Prepare the spiking solution by adding 5 μL of 10 mM compound and reference stock solutions to 95 μL of acetonitrile (ACN). Add 1.5 μL of the 500 μM spiking solution and 18.75 μL of 20 mg / mL liver microsomes to 479.8 μL of K-Mg buffer. Prepare a 3 mM NADPH stock solution by dissolving NADPH in K-Mg buffer. At various time points (0, 5, 15, 30, and 45 minutes), evenly dispense 30 μL of the 1.5 μM spiking solution containing microsomes into the assay plate. Preincubate at 37°C for 5 minutes. At 0 minutes, add 200 μL of IS (internal standard, tolbutamid / terfenadine) in ACN to the wells, followed by 15 μL of the 6 mM NADPH stock solution. At other time points, 15 μL of NADPH stock solution (6 mM) was added to the wells to initiate the reaction and time the reaction. At 5, 15, 30, and 45 minutes, 200 μL of ACN containing IS was added to the corresponding wells to stop the reaction. After quenching, the plate was shaken at 600 rpm for 10 minutes and then centrifuged at 4000 rpm for 50 minutes. 80 μL of supernatant from each well was transferred to a 96-well sample plate containing 160 μL of purified water for UPLC / MS / MS analysis.

[0707] Table 2 In vitro liver microsomal stability of exemplary compounds

[0708] Experiments show that at least some of the compounds of the present application have good in vitro liver microsome stability.

[0709] 4. Evaluation of cell membrane permeability

[0710] Test compounds were diluted from a 10 mM stock solution to a 10 μM concentration in transport buffer (HBSS + BSA) and applied to the apical or basolateral sides of the cell monolayer. Permeability of the test compounds was determined duplexly in the A-to-B and B-to-A directions over a 120-minute incubation period at 37°C, 5% CO₂, and 95% relative humidity. The efflux ratio of each compound was also determined. Quantification of the analyte and reference compounds was performed using LC-MS / MS based on the analyte / IS peak area ratio.

[0711] Table 3 Cell membrane permeability of exemplary compounds

[0712] The experimental results show that at least some of the compounds of the present application have good cell membrane permeability and are not P-glycoprotein substrates.

[0713] 5. P450 enzyme inhibition evaluation

[0714] Prepare phosphate-buffered saline (PBS) from liver microsomes. Add 169 μL of phosphate-buffered saline from liver microsomes and 1 μL of various concentrations of test compound or positive control compound to a 96-well plate. Preheat the plate in a water bath at 37°C for 15 minutes. After incubation, add 10 μL of substrate (for CYP3A4-T, add 1 μL of substrate and 9 μL of K-Mg buffer) to the plate. Mix the mixture on a rotary mixer for 10 seconds, then add 20 μL of 10 mM NADPH solution to initiate the reaction at a final concentration of 1 mM. Repeat the experiment twice. At the predetermined time points listed in Table 4, quench the reaction by adding 400 μL of quenching solution (cold ACN containing 500 nM tolbutamine and 10 nM terfenadine). Centrifuge at 3220 g for 50 minutes at 4°C. Transfer 100 μL of supernatant to a new plate. Dilute the supernatant with 100 μL of purified water. Mix well and analyze the samples by UPLC-MS / MS.

[0715] Table 4 Configuration of substrate stock solution

[0716] The experimental results show that at least some of the compounds of the present application have weak inhibition on five major P450 enzymes (CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4), and the risk of drug-drug interactions is low. For example, the IC of compound 6 on these five major P450 enzymes is 50 The values ​​are generally >10 μM, especially the IC values ​​of CYP2D6 and CYP3A4. 50 All were greater than 30μM.

[0717] 6. Pharmacokinetic evaluation in mice

[0718] Dissolve the test compound in the vehicle to prepare a clear solution or homogenous suspension. Three mice per group were administered 1 mg / kg via the tail vein or 10 mg / kg orally (PO). Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. Plasma samples were centrifuged, and the supernatant was collected for quantitative analysis by LC / MS / MS.

[0719] Table 5 PK properties of compound 6 in mice

[0720] The experimental results show that at least some of the compounds of the present invention (such as compound 6) have excellent pharmacokinetic properties in mice (including but not limited to Cl (clearance rate), T 1 / 2 (half-life), Cmax (peak concentration), AUC (area under the drug-time curve), F (bioavailability), etc.).

[0721] Although the present application has been described with reference to preferred embodiments, various modifications may be made thereto and components may be substituted with equivalents without departing from the scope of the present application. In particular, the various technical features described in the various embodiments may be combined in any manner as long as there are no structural conflicts. The present application is not limited to the specific embodiments disclosed herein, but encompasses all technical solutions within the scope of the claims.

Claims

1. A compound represented by Formula 0, or a stereoisomer, or a tautomer, or a geometric isomer, or an enantiomer, or a diastereomer, or a racemate, or a polymorph, or a solvate, or a hydrate, or an N-oxide, or an isotope-labeled compound, or a metabolite, or an ester, or a prodrug, or a pharmaceutically acceptable salt thereof: in, Ring A is selected from C3-C10 cycloalkylene, or 3-10 membered heterocycloalkylene, and Ring A is not Among them, the * end is connected to L, The end is connected to the B ring, and n3 is any integer from 0 to 5; Ring B is selected from a 5-10 membered heteroarylene group, and n4 is any integer from 0 to 4; The C ring is selected from 3-10 membered heterocycloalkylene, C3-C10 cycloalkylene, or B -X 21 -C3-C12 cycloalkylene-$ R1 , X 21 -NR 3 or -C(O)NR 3 ,# B - is the connecting bond to the B ring, -$ R1 For R 1 Connecting key; each R 3 are independently H, deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and when the C ring is a C3-C10 cycloalkylene, the A ring is not a cyclohexylene, and the A ring is When the * terminal is connected to L, The end is connected to the B ring, the C ring is a 3-10 membered heterocycloalkylene, and n5 is any integer from 0 to 5; Ring D is selected from C6-C10 arylene, 5-10 membered heteroarylene, C3-C10 cycloalkylene or 3-10 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 , L 1 is a bond, -O-, -S- or -NR 4 -, L 2 is a bond, a substituted or unsubstituted C1-C10 alkylene group, L 3 -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A , X 10 O or S, R 4 、R 5 and R 14 Each independently selected from H, deuterium, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, as R 4 、R 5 and R 14 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 11 replace;# D - is the connecting bond to the D ring, -$ A is the connecting bond to the A ring; R 1 、R 2 、R 9a 、R 9b 、R 9c Each independently is a substituent R 11 , Each R 11 are each independently selected from 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 NR 6 S(O) 1- 2R 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 , where R 9a 、R 9b 、R 9c 、R 11 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 12 replace; Each R 6 、R 7 and R 8 are each independently selected from H, deuterium, 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 20 、-C(O)OR 20 、-C(O)NR 20 R 21 、-S(O) 1-2 R 20 、-S(O) 1-2 NR 20 , where R 6 、R 7 and R 8 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 13 Replace; or R 6 and R 7 Together with the atoms to which they are attached, they form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups; or R 7 and R 8 Together with the atoms to which they are attached, they form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which may be optionally substituted by 1-6 halogens, hydroxyl groups or amino groups; 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- 2NR 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 , where R 12 and R 13 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl of the present invention may be substituted by 1 to 6 halogens, or by C1-C10 alkyl optionally substituted by 1 to 6 halogens, hydroxyl or amino groups; Each R 20 and R 21 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino groups; or R 20 and R 21 The atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which is optionally substituted by 1-6 halogens, hydroxyl groups or amino groups; Each R 30 and R 31 are each independently selected from H, deuterium, or C1-C10 alkyl optionally substituted with 1-6 halogens, hydroxyl or amino groups; or R 30 and R 31 The atoms to which they are simultaneously attached form a heterocycloalkyl group, and the heterocycloalkyl group may be substituted by 1-6 halogens, or by a C1-C10 alkyl group which is optionally substituted by 1-6 halogens, hydroxyl groups or amino groups; n1 and n2 are each independently any integer from 0 to 4.

2. The compound according to claim 1, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein: n4 is 0, 1, 2 or 3; each of the R 9b Each independently represents halogen, cyano, nitro, -OH, C1-C3 alkyl; preferably, the R 9b are each independently halogen, -OH, methyl, ethyl or propyl; Preferably, n4 is 0; Preferably, the B ring is selected from Among them, X 7 O or S, X 8 、X 9 、X 10 Each is independently CH or N, the * end is connected to the C ring, 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 selected from any one of the following groups: Further preferably, the B ring is selected from any one of the following groups: More preferably, the B ring is 3. The compound according to claim 1 or 2, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein: The compound has the structure shown in formula I Among them, A ring, C ring, D ring, L, R 1 、R 2 、R 9a 、R 9c , n1, n2, n2, n3 and n5 are as defined in claim 1 or 2, X 7 O or S; Preferably, n1 and n2 are each independently an integer of 1-3; More preferably, n1 is 1, and n2 is an integer of 1-3.

4. The compound according to any one of claims 1 to 3, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein: Each of the R 9c are independently halogen, cyano, nitro, =O, -OH, -NR 30 R 31 、C1-C3 alkyl、-C(O)R 30 、-C(O)OR 30 , each R 30 and R 31 Each is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxy or amino; Preferably, the C ring may be substituted by 1 or 2 R 9c Substituted, each of the R 9c Each is independently halogen, cyano, nitro, -OH, 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, methyl; Preferably, n5 is 0, 1 or 2; Further preferably, n5 is 0 or 1; Preferably, the 3-10 membered heterocycloalkylene group of the C ring is selected from Among them, X 11 、X 23 Each is N or B, X 12 is CH2, NH, O or S, q is an integer from 0 to 3, preferably q is 1 or 2; X 13 is N or B, s is an integer from 1 to 3, preferably s is 1 or 2; X 14 is O, S or NH, t is an integer from 1 to 3, preferably t is 1 or 2; the * end is connected to the B ring, End and R 1 connect; More preferably, the 3-10 membered heterocycloalkylene group of the C ring is selected from Preferably, the C ring # B -X 21 -C3-C12 cycloalkylene-$ R1 for Among them, R 3 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, p is an integer from 1 to 3, preferably 1 or 2; the * end is connected to the B ring, End and R 1 connect; Further preferably, the # of the C ring B -X 21 -C3-C12 cycloalkylene-$ R1 for Preferably, the C ring is selected from *End is connected to B ring, End and R 1 connect; Further preferably, the C ring is selected from More preferably, the C ring is selected from Each q, p, s, and t are independently 1 or 2; Preferably, the Selected from *End is connected to B ring, End and R 1 connect; More preferably, the Selected from More preferably, the Selected from 5. The compound according to any one of claims 1 to 4, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein: Each of the R 1 Each independently is R 11 , Each R 11 are each independently selected from 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 , where R 11 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl groups are each independently substituted by 1 to 6 R 12 replace; Each R 6 、R 7 Each is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, wherein R 6 、R 7 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl groups are each independently substituted by 1 to 3 R 13 replace; 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, 3-10 membered heterocycloalkyl, wherein R 12 and R 13 The C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl groups of the present invention may each independently be substituted by 1 to 3 halogens, or by C1-C3 alkyl groups which may be optionally substituted by 1 to 3 halogens, hydroxyl groups, or amino groups. Each R 30 Each is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxy or amino; Preferably, the R 1 Select from -OR 6 , C1-C3 alkyl, halogen, -S(O)2R 6 or -P(O)R 6 R 7 , where R 1 The C1-C3 alkyl group may be 1-6 R 12 Replacement, R 12 Selected from halogen, -S(O)2R 30 , R 30 Selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl; each R 6 Each independently selected from C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, wherein R 6 The C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl groups are each independently substituted with 1 to 6 R 13 Replacement, R 13 is selected from halogen; R 7 Selected from C1-C3 alkyl; More preferably, the R 1 Selected from -OCH3, -OCF3, -CF2CF3、-CF3、-OCHF2、-OCF2CF3、-OCF2Cl、-CH2CF3、-F、 -OCF=CF2、 More preferably, the R 1 Selected from -OCF3, -CF2CF3, -OCH3, -F, -CF3; More preferably, the R 1 Selected from -OCF3, -OCF2CF3; More preferably, the R 1 for -OCF3; Preferably, n1 is 0 or 1.

6. The compound according to any one of claims 1 to 5, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein: The compound has the structure shown in formula II Among them, 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 Selected from -OCH3, -OCF3, -CF2CF3、-CF3、-OCHF2、-OCF2CF3、-OCF2Cl、-CH2CF3、F、 -OCF=CF2、 More preferably, the R 1 Selected from -OCH3, -OCF3, -CF2CF3, -F, -CF3; More preferably, the R 1 -OCF3, -OCF2CF3; More preferably, the R 1 for -OCF3; Preferably, n1 is 1; Preferably, n5 is 0, 1 or 2, and each of the R 9c Each is independently halogen, cyano, nitro, -OH, C1-C3 alkyl; More preferably, the R 9c are each independently halogen, -OH, methyl, ethyl or propyl; More preferably, the R 9c Each is independently F.

7. A compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure shown in formula II-1 Among them, 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 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 Selected from Preferably, n1 is 1, and the R 1 Selected from -OCH3, -OCF3, -CF2CF3、-CF3、-OCHF2、-OCF2Cl、-CH2CF3、-OCF2CF3、 -OCF=CF2、 More preferably, the R 1 Selected from -OCH3, -OCF3, -OCF2CF3; More preferably, the R 1 Selected from -OCF3, -OCF2CF3; More preferably, the R 1 is -OCF3.

8. A compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: n3 is 0, 1, or 2; Preferably, the A ring is selected from C5-C8 cycloalkylene or 5-8 membered heterocycloalkylene; Further preferably, the A ring is selected from cyclohexane or 6-membered heterocycloalkylene; Further preferably, the A ring is selected from cyclohexane or * terminal is connected to L, The end is connected to the B ring; Preferably, the A ring is selected from C5-C8 sub-bridged cycloalkyl or 6-8 membered sub-bridged heterocycloalkyl, wherein X 1 CH or N, X 2 、X 3 、X 4 、X 5 、X 6 Each independently represents CH2, CH, NH, N or O, and the * end is connected to L, The end is connected to the B ring; More preferably, the In, X 5 is CH2 or O, X 2 、X 3 、X 4 、X 6 are each independently CH2 or CH; More preferably, the Medium X 2 、X 3 、X 6 CH2, X 4 for CH; Preferably, the A ring C5-C8 sub-bridged cycloalkyl or 6-8 membered sub-bridged heterocycloalkyl are each independently substituted with 0-4 R 9a replace; Further preferably, the A ring is surrounded by 0, 1 or 2 R 9a replace; More preferably, the A ring is surrounded by 0 or 1 R 9a replace; Further preferably, the C5-C8 cycloalkylene bridge is More preferably, the 6-8 membered heterocycloalkyl group is Preferably, the R 9a are 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 NR 6 NR 6 S(O) 1- 2R 7 、-NR 6 S(O) 1-2 NR 7 R 8 、-NR 6 C(O)R 7 or -NR 6 C(O)OR 7 , where R 9a The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted with 1 to 6 R 12 replace; Each R 6 、R 7 and R 8 Each is independently selected from H, 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 20 、-C(O)OR 20 、-C(O)NR 20 R 21 、-S(O) 1-2 R 20 、-S(O) 1-2 NR 20 , where R 6 、R 7 and R 8 The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl groups are each independently substituted by 1 to 4 R 13 replace; 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- 2NR 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 , where R 12 and R 13 The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl of the present invention may be substituted by 1 to 6 halogens, or by C1-C6 alkyl which may be optionally substituted by 1 to 6 halogens, hydroxyl or amino groups, Each R 20 and R 21 Each is independently selected from H, or C1-C6 alkyl optionally substituted by 1-6 halogen, hydroxyl or amino; Each R 30 and R 31 Each is independently selected from H, or C1-C6 alkyl optionally substituted by 1-6 halogen, hydroxyl or amino; More preferably, the R 9a are independently halogen, cyano, nitro, =O, -OH, -NR 30 R 31 , C1-C3 alkyl, C1-C3 haloalkyl, -C(O)R 30 、-C(O)OR 30 , each R 30 and R 31 Each is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxy or amino; More preferably, the R 9a Each is independently halogen, cyano, nitro, =O, -OH, methyl, ethyl, fluoromethyl or fluoroethyl; More preferably, the R 9a Each independently represents -OH, =O; More preferably, the R 9a each independently -OH; Preferably, the Selected from * terminal is connected to L, The end is connected to the B ring; More preferably, the Selected from More preferably, the Selected from More preferably, the Selected from More preferably, the Selected from More preferably, the Selected from 9. The compound according to any one of claims 1 to 8, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein: The compound has the structure shown in formula III Among them, 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; X 1 and X 4 are independently CH or N, X 2 、X 3 、X 5 、X 6 are each independently CH2, CH, NH, N or C, and v is an integer from 0 to 2; Preferably, the R 9a Each is independently halogen, =O, -OH, C1-C3 alkyl, more preferably -OH.

10. The compound according to any one of claims 1 to 9, or its stereoisomer, or its tautomer, or its geometric isomer, or its enantiomer, or its diastereomer, or its racemate, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein: The compound has a structure represented by any one of the general formulas III-1 to III-6. Among them, 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 hydroxyl group; Preferably, n3 is an integer from 0 to 3; More preferably, n3 is 0, 1 or 2.

11. 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 diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: The L is # D -L 1 -L 2 -L 3 -$ A 、 or# D -NR 14 C(O)-C1-C6 alkylene-O-$ A , L 1 is a bond, -O-, -S- or -NR 4 -, L 2 is a bond, a substituted or unsubstituted C1-C3 alkylene group, L 3 -C(X 10 )NR 5 -$ A or -C(X 10 )-$ A , X 10 O or S, R 4 、R 5 and R 14 Each independently selected from H, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, as R 4 、R 5 and R 14 The C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl groups are each independently substituted by 1 to 3 R 11 Replacement; each R 11 Each R is independently selected from halogen, cyano, nitro, =O, -OH, -SH, -NH2, preferably each R 11 Each is independently selected from halogen, cyano, nitro, -OH, -SH, -NH2; D - is the connecting bond to the D ring, -$ A It is the connecting key connected to the A ring, and the * end is connected to the A ring. The end is connected to the D ring; Preferably, said L is selected from *end is connected to the A ring, The end is connected to the D ring; More preferably, the L is selected from More preferably, the L is selected from More preferably, said L is selected from 12. 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 diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown in general formula IV-1 or IV-2 Among them, 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, X 7 O or S; Preferably, the compound has the structure shown in formula V-1 or V-2 Wherein, v is an integer from 0 to 2, D ring, R 1 、R 2 、R 9a 、R 9c , n1, n2, n3 and n5 as As defined in any one of claims 1 to 9, X 7 O or S, X 1 and X 4 are independently CH or N, X 2 、X 3 、X 5 、X 6 Each is independently CH2, CH, NH, N or C.

13. 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 diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: described Selected from Among them, X 14 、X 15 、X 16 、X 17 、X 18 are independently selected from CH, N, and at least one is N, preferably there are at most three N, and more preferably there are at most two N; X 19 、X 20 are each independently selected from CH, N, NH, O, S, and are not S or O at the same time, and m is 1 or 2; X 21 、X 22 Each is independently selected from CH, N, NH, O, S, and is not S or O at the same time, m is 1 or 2; u is 1 or 2 or 3; Preferably, the Selected from More preferably, the Selected from More preferably, the Selected from More preferably, the Selected from More preferably, the Selected from 14. 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 diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 R 11 , Each R 11 are each independently selected from 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 , where R 11 The C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl groups are each independently substituted by 1 to 6 R 12 replace; Each R 6 、R 7 and R 8 Each independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 R 21 , where R 6 、R 7 and R 8 The C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl are each independently substituted by 1 to 3 R 13 replace; Each R 12 and each R 13 are each independently H, halogen, cyano, nitro, =O, -OR 30 NR 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 , where R 12 and R 13 The C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocycloalkyl groups may each independently be substituted by 1 to 3 halogens, or by C1-C3 alkyl groups which may be optionally substituted by 1 to 3 halogens, hydroxyl groups, or amino groups. Each R 20 and R 21 Each is independently selected from H, or C1-C3 alkyl optionally substituted with 1-6 halogen, hydroxy or amino; Each R 30 and R 31 Each independently selected from H, or optionally substituted by 1-6 halogen, hydroxyl or amino C1-C3 alkyl; n2 is 1, 2 or 3; Preferably, each R 2 Each is independently selected from halogen, cyano, C1-C3 haloalkyl, C1-C3 alkyl, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NR 6 R 7 , C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, R 6 、R 7 Each independently selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, preferably, the R 2 When it is a C3-C6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, n is 1, and the R 2 Shares two carbon atoms with the D ring to form a fused ring; More preferably, each R 2 Each is independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkyl, -O-C1-C3 alkyl, -O-C1-C3 haloalkyl, -NH2, Among them, when R 2 for hour, Shares two carbon atoms with the D ring to form a fused ring; More preferably, each R 2 Each is independently selected from F, Cl, Br, -CF3, -CH3, -CF2H, -OCF3, -NH2, n2 is 1, 2 or 3; Preferably, the Selected from More preferably, the Selected from More preferably, the Selected from More preferably, the Selected from More preferably, the Selected from 15. 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 diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure shown in general formula VI Wherein, the A ring is selected from cyclohexane or 6-membered heterocycloalkylene; the L, R 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 Each independently selected from F, Cl, Br; Preferably, n2 is 1 or 2; Preferably, the R 2 It is in a para and / or meta position relationship with L; Preferably, said L is selected from *end is connected to the A ring, The end is connected to the D ring; More preferably, the L is selected from More preferably, the L is selected from More preferably, said L is selected from Preferably, n1 and n5 are not 0 at the same time; Preferably, the R 1 It is in a para position relationship with the N on the C ring where it is located; Preferably, the R 1 Select from -OR 6 , C1-C3 alkyl, halogen, -S(O)2R 6 or -P(O)R 6 R 7 , where R 1 The C1-C3 alkyl group may be 1-6 R 12 Replacement, R 12 Selected from halogen, -S(O)2R 30 , R 30 Selected from C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl; each R 6 Each independently selected from C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, wherein R 6 The C1-C3 alkyl, C2-C4 alkenyl, and C3-C6 cycloalkyl groups are each independently substituted with 1 to 6 R 13 Replacement, R 13 is selected from halogen; R 7 Selected from C1-C3 alkyl; More preferably, the R 1 -OCH3, -OCF3, -CF2CF3、-CF3、-OCHF2、-OCF2CF3、-OCF2Cl、-CH2CF3、-F、 -OCF=CF2、 More preferably, the R 1 -OCF3, -CF2CF3, -OCH3, -F, -CF3; More preferably, the R 1 -OCF3, -OCF2CF3; More preferably, the R 1 is -OCF3.

16. 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 diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure shown in formula VII Among them, R 9a 、X 10 As defined in claim 1, R 21 Selected from halogen, R 22 is selected from H, halogen, t is selected from an integer of 0-2; Preferably, R 21 is Cl; Preferably, R 22 Selected from H, F, Cl, Br; Preferably, R 9a Selected from H, hydroxyl; Preferably, t is 0 or 2.

17. 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 diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from: Preferably, the compound is selected from:

18. A method for synthesizing a compound having the structure represented by the general formula IV-1 or IV-2 according to claim 12, or a stereoisomer, a tautomer, a geometric isomer, an enantiomer, a diastereomer, a racemate, a polymorph, a solvate, a hydrate, an N-oxide, an isotope-labeled compound, a metabolite, an ester, a prodrug, or a pharmaceutically acceptable salt thereof, wherein the method is selected from any one of Synthesis Routes 1 to 6; Synthesis Route 1: in, Compound 1-1 and compound 1-2 undergo amide condensation reaction to obtain compound 1-3; the compound 1-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 1-4; the compound 1-4 undergoes cyclization with N,N-carbonyldiimidazole to obtain compound 1-5; the compound 1-5 undergoes condensation reaction with compound 1-6 to obtain compound IV-1-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in claim 12; Synthesis route 2: Among them, compound 2-1 undergoes an amide condensation reaction with compound 2-2 to obtain compound 2-3; the compound 2-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 2-4; the compound 2-4 undergoes a cyclization with N,N-carbonyldiimidazole to obtain compound 2-5; the compound 2-5 undergoes a condensation reaction with compound 2-6 to obtain compound IV-2-1; R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in claim 12; Synthesis route 3: Among them, compound 3-1 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 3-2; the compound 3-2 undergoes cyclization with N,N-carbonyldiimidazole to obtain compound 3-3; the compound 3-3 undergoes condensation reaction with compound 3-4 to obtain compound 3-5; the compound 3-5 is deprotected under acidic conditions to obtain compound 3-6; the compound 3-6 undergoes amide condensation reaction with compound 3-7 to obtain compound IV-1-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in claim 12; Synthesis Route 4: Among them, compound 4-1 reacts with hydrazine hydrate and undergoes functional group transformation to obtain compound 4-2; the compound 4-2 undergoes cyclization with N,N-carbonyldiimidazole to obtain compound 4-3; the compound 4-3 undergoes condensation reaction with compound 4-4 to obtain compound 4-5; the compound 4-5 is deprotected under acidic conditions to obtain compound 4-6; the compound 4-6 undergoes amide condensation reaction with compound 4-7 to obtain compound IV-2-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in claim 12; Synthesis Route 5: Among them, compound 5-1 and compound 5-2 undergo amide condensation reaction to obtain compound 5-3; the compound 5-3 reacts with hydrazine hydrate and undergoes functional group conversion to obtain compound 5-4; the compound 5-4 and compound 5-5 undergo condensation to obtain compound 5-6; the compound 5-6 undergoes ring closure reaction to obtain compound IV-1-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in claim 12; Synthesis Route 6: Among them, compound 6-1 reacts with hydrazine hydrate to obtain compound 6-2 through functional group transformation; the compound 6-2 undergoes a ring-closure reaction to obtain compound 6-3; the compound 6-3 undergoes an oxidation reaction to obtain compound 6-4; the compound 6-4 reacts with compound 6-5 to obtain compound 6-6; the compound 6-6 is deprotected under acidic conditions to obtain compound 6-7; the compound 6-7 is condensed with compound 6-8 to obtain compound IV-1-1, R 1 、R 2 、R 9a 、R 9c , n1 and n2 are as defined in claim 12.

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

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

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

22. Use of a compound according to any one of claims 1 to 17, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19 or 20 in the preparation of a medicament for preventing and / or treating a disease or condition mediated by the integrated stress response (ISR) pathway.

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