Fused tricyclic compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a fused tricyclic compound, and a preparation method therefor and a use thereof. The compound has a structure shown in a formula (I), has an SARM1 inhibition effect, and can be used for treating neurodegenerative diseases.

Description

A fused tricyclic compound and its preparation method and application

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application No. 202310834844.5 filed on July 7, 2023 and Chinese patent application No. 202311370973.X filed on October 20, 2023, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present invention belongs to the field of medicine, and in particular relates to a fused tricyclic compound and a preparation method and application thereof. Background Art

[0004] Axon degeneration is closely related to the occurrence and development of neurological diseases. Wallerian degeneration is the main pathway of axon degeneration. Wallerian degeneration, also known as secondary degeneration, refers to the process in which the distal nerve fibers begin to degrade after the axons are broken due to trauma. This process involves two key proteins: nicotinamide adenine dinucleotide (NAD + ) synthase NMNAT2 and NAD + Hydrolase SARM1, and SARM1 (Sterile alpha and Toll / interleukin-1 receptor motif-containing 1) is the main execution molecule of this neurodegradation process. The regulation of its activity plays an important role in the treatment of corresponding neurological diseases.

[0005] In healthy neurons, NMNAT2 is transported along axons to maintain high levels of NAD. + When the level of nicotinamide mononucleotide (NMN) is low, SARM1 is maintained at a low activity level. When neurons are damaged, NMNAT2 transport along the axon stops and NMNAT2 is rapidly decomposed, causing NMN levels to begin to rise and NAD + The levels begin to decrease, and this period is called the axonal degeneration latency period. NMN and NAD + Changes in SARM1 lead to the activation of Ca 2+ Influx, calpain activation, and ATP depletion, along with the accumulation of ROS, lead to axonal degeneration. Numerous studies have reported that knocking out or inhibiting SARM1 has protective effects in various neurological disease models, such as peripheral neuropathy, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease, and glaucoma.

[0006] Treatment options for neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic sclerosis, and Huntington's disease are very limited, with no effective treatments available. Currently, treatments are mostly symptomatic, but they cannot halt the progression of the disease, let alone cure it. Furthermore, with the aging population, the incidence of neurodegenerative diseases is also increasing. Therefore, there is an urgent need to develop more effective drugs to help slow disease progression, improve patients' quality of life, and even prevent disease progression in its early stages.

[0007] Summary of the Invention

[0008] The first aspect of the present invention provides a compound represented by formula (I), or a stereoisomer thereof, or a tautomer 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,

[0009] in,

[0010] is selected from a single bond, a double bond, and a triple bond;

[0011] Z is selected from O and S;

[0012] L1 is selected from -C 1-3 Alkylene-, =CH-, -NH- and -O-, or L1 is absent;

[0013] Ring A is selected from phenyl, 5-6 membered heteroaryl, C 4-8 Cycyl and 4-8 membered heterocyclic groups;

[0014] Ring B is selected from phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl;

[0015] Ring C is selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 3-12 Cycyl and 4-10 membered heterocyclic groups;

[0016] Ring E is selected from 5-6 membered heteroaryl and phenyl;

[0017] R1 is selected from H, -OH, halogen, -NH2, -CN, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl, -C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl;

[0018] R2 is selected from H, OH, halogen, -CN, -NH2, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6 alkoxy, C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl;

[0019] R3 is selected from H, C 1-6 Alkyl and -C(=O)C 1-6 Alkyl, the C 1-6 Alkyl or -C(=O)C 1-6 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogens, -OH, -NH2, -CN, -NO2 and -COOH;

[0020] W is selected from -C(R5R6)-, -CR5=, -C(=CH2)- and -NR5-, wherein R5 is selected from H, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; or

[0021] W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 R;

[0022] Alternatively, W and ring B together with the atoms to which they are attached form a 6-10 membered heterocyclic group, which is optionally substituted with 1, 2, 3, 4 or 5 R;

[0023] R4 is selected from halogen, OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0024] R6 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0025] R7 is selected from H, halogen, -OH, -NO2, -CN, -NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6 haloalkyl, C 1-6Alkylene -OH, -OC 1-6 Haloalkyl, -C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl;

[0026] R is selected from halogen, -OH, -CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0027] m is selected from 0 and 1;

[0028] n is selected from 0, 1, 2, 3, 4 and 5;

[0029] r, s, and t are each independently 0, 1, 2, 3, 4, or 5.

[0030] The first aspect of the present invention provides a compound represented by formula (I), or a stereoisomer thereof, or a tautomer 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,

[0031] in,

[0032] is selected from a single bond, a double bond, and a triple bond;

[0033] Z is selected from O and S;

[0034] L1 is selected from -C 1-3 Alkylene-, =CH-, -NH- and -O-, or L1 is absent;

[0035] Ring A is selected from phenyl, 5-6 membered heteroaryl, C 4-8 Cycyl and 4-8 membered heterocyclic groups;

[0036] Ring B is selected from phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl;

[0037] Ring C is selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 3-12 Cycyl and 4-10 membered heterocyclic groups;

[0038] Ring E is selected from 5-6 membered heteroaryl and phenyl;

[0039] R1 is selected from H, -OH, halogen, -NH2, -CN, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylene -OH, -OC1-6 Haloalkyl, -C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl;

[0040] R2 is selected from H, OH, halogen, -CN, -NH2, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6 alkoxy, C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl;

[0041] R3 is selected from H, C 1-6 Alkyl and -C(=O)C 1-6 Alkyl, the C 1-6 Alkyl or -C(=O)C 1-6 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogens, -OH, -NH2, -CN, -NO2 and -COOH;

[0042] W is selected from -C(R5R6)-, -CR5=, -C(=CH2)- and -NR5-, wherein R5 is selected from H, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; or

[0043] W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 R;

[0044] R replaces;

[0045] R4 is selected from halogen, OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0046] R6 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0047] R7 is selected from H, halogen, -OH, -NO2, -CN, -NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C1- 6 haloalkyl, C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl, -C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl;

[0048] R is selected from halogen, -OH, -CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy;

[0049] m is selected from 0 and 1;

[0050] n is selected from 0, 1, 2, 3, 4 and 5;

[0051] r, s, and t are each independently 0, 1, 2, 3, 4, or 5.

[0052] In certain embodiments, W is selected from -C(R5R6)-, -CR5=, -C(=CH2)- and -NR5-, or W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Rs.

[0053] In certain embodiments, W is selected from -C(R5R6)-, -C(=CH2)-, or W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Rs.

[0054] In certain embodiments, W is selected from -C(R5R6)-, -C(=CH2)-, or W and R3 together with the atoms to which they are attached form a 5-6 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Rs.

[0055] In certain embodiments, W is selected from -C(R5R6)-, or W and R3 together with the atoms to which they are attached form a 5-6 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Rs.

[0056] In certain embodiments, m is 1.

[0057] In certain embodiments, Ring A is selected from phenyl, dihydropyranyl, pyridinyl, dihydropyridinyl, and oxepanyl.

[0058] In certain embodiments, n is 0, 1, 2, or 3.

[0059] In certain embodiments, r, s, and t are each independently 0, 1, or 2.

[0060] In certain embodiments, r, s, and t are each independently 0 or 1.

[0061] In certain embodiments, the R1 is selected from H, -OH, halogen, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylene -OH, -OC 1-4 Haloalkyl, -C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl.

[0062] In certain embodiments, R1 is selected from H, -OH, F, Cl, Br, I, -NH2, -CN, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, halomethyl, haloethyl, halopropyl, halobutyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0063] In certain embodiments, R1 is selected from H, -OH, F, Cl, Br, -NH2, -CN, -NO2, -COOH, methyl, ethyl, n-propyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl and hydroxyethyl.

[0064] In certain embodiments, R1 is selected from F, Cl, Br and I.

[0065] In certain embodiments, said R1 is selected from -NH2, -CN, -NO2 and -COOH.

[0066] In certain embodiments, the R1 is selected from methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, and hydroxyethyl.

[0067] In certain embodiments, said R1 is selected from H and OH.

[0068] In certain embodiments, R1 is H.

[0069] In certain embodiments, R2 is selected from H, -OH, halogen, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylene -OH, -OC 1-4 Haloalkyl, -C 1-4 Alkylene-C1-4 Alkoxy, -C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl.

[0070] In certain embodiments, R2 is selected from H, -OH, F, Cl, Br, I, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, halomethyl, haloethyl, halopropyl, halobutyl, methoxy, ethoxy, propoxy, butoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, haloethoxy, halopropoxy, halobutoxy, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OCH2CH3, -CH2O(CH2)2CH3, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0071] In certain embodiments, R2 is selected from H, -OH, F, Cl, Br, -NH2, -CN, -NO2, -COOH, methyl, ethyl, n-propyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, -CH2OCH3, -(CH2)2OCH3 and -CH2OCH2CH3.

[0072] In certain embodiments, said R2 is selected from H, Cl, -CN, -NH2, -CH3 and -CH2OCH3.

[0073] In certain embodiments, said R2 is selected from H, NH2, -CH3 and -CH2OCH3.

[0074] In certain embodiments, said R2 is selected from H, -CH3 and -CH2OCH3.

[0075] In certain embodiments, said R2 is selected from H, NH2.

[0076] In certain embodiments, said R2 is selected from H.

[0077] In certain embodiments, R7 is selected from H, halogen, -OH, -NO2, -CN, -NH2, -COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkylene -OH, -OC 1-4 Haloalkyl, -C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl.

[0078] In certain embodiments, R7 is selected from H, F, Cl, Br, I, -OH, -NO2, -CN, -NH2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0079] In certain embodiments, the R7 is selected from H, F, Cl, Br, I, -OH, -NO2, -CN, -NH2, -COOH, methyl, ethyl, methoxy, and ethoxy.

[0080] In certain embodiments, said R7 is selected from H, F, Cl, Br and CH3.

[0081] In certain embodiments, said R7 is selected from H, F, Cl and Br.

[0082] In certain embodiments, said R7 is selected from H.

[0083] In certain embodiments, the structural unit Selected from in, is selected from a single bond or a double bond; Z1 and Z2 are each independently selected from CH or N; V is selected from C, CH or N, preferably V is selected from C or N; T1, T2 and T3 are each independently selected from CH2, O, S and NH, preferably T1, T2 and T3 are each independently selected from CH2, O and NH; u is selected from 0, 1 and 2, preferably u is selected from 0 or 1. In certain embodiments, the structural unit Selected from

[0084] In certain embodiments, the structural unit Selected from in, is selected from single bonds and double bonds, T1, T2 and T3 are each independently selected from CH2, O and N, and u is selected from 0, 1 and 2.

[0085] In certain embodiments, the structural unit Selected from wherein T1, T2 and T3 are each independently selected from CH2, O and N, and u is selected from 0, 1 and 2.

[0086] In certain embodiments, the structural unit Selected from Selected from single bonds and double bonds.

[0087] In certain embodiments, the structural unit Selected from Wherein, the definitions of E and B are as described in the present invention.

[0088] In certain embodiments, the structural unit Selected from

[0089] In certain embodiments, the ring B is selected from a 5-membered nitrogen-containing heteroaryl and a 5-membered nitrogen-containing heterocycloalkenyl.

[0090] In certain embodiments, the ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, and dihydrotriazolyl.

[0091] In certain embodiments, the ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, and dihydrotriazolyl.

[0092] In certain embodiments, the ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, and oxazolyl.

[0093] In certain embodiments, the ring B is selected from imidazolyl, pyrazolyl, oxazolyl.

[0094] In certain embodiments, the ring E is a 6-membered nitrogen-containing heteroaryl.

[0095] In certain embodiments, the ring E is selected from pyridinyl and pyridazinyl.

[0096] In certain embodiments, the ring E is selected from pyridinyl.

[0097] In certain embodiments, the structural unit Selected from Wherein, Y1 and Y2 are each independently selected from CH and N. Preferably, Y1 is N and Y2 is CH; or Y1 is CH and Y2 is N; or Y1 is N and Y2 is N.

[0098] In certain embodiments, the structural unit Selected from wherein Y1 and Y2 are each independently selected from CH and N, and ring A, ring B, R1, R2, R7, r, s and t are as defined in the present invention.

[0099] In certain embodiments, Y1 is N and Y2 is CH.

[0100] In certain embodiments, Y1 is CH and Y2 is N.

[0101] In certain embodiments, the structural unit Selected from in is selected from a single bond or a double bond; Z1 and Z2 are each independently selected from CH or N; V is selected from C, CH or N, preferably V is selected from C or N; T1, T2 and T3 are each independently selected from CH2, O and NH; u is selected from 0, 1 and 2, preferably u is selected from 0 or 1.

[0102] In certain embodiments, the structural unit Selected from

[0103] In certain embodiments, the structural unit Selected from

[0104] In certain embodiments, the structural unit Selected from

[0105] In certain embodiments, the structural unit is selected from in, is selected from a single bond or a double bond, Y1 and Y2 are each independently selected from CH and N, V ​​is selected from C, CH or N, preferably V is selected from C or N; U1 and U2 are each independently selected from O, N, NH or CH; W1 and W3 are selected from CH or N; W2 is selected from NH or O; Ring A is selected from phenyl, 5-6 membered heteroaryl, C 4-8 Cyclic and 4-8 membered heterocyclic groups; preferably, ring A is selected from phenyl, 6 membered heteroaryl, C 6-7 More preferably, Ring A is selected from phenyl and 6-7 membered heterocyclic group.

[0106] In certain embodiments, the structural unit Selected from

[0107] In certain embodiments, the structural unit Selected from in Select a single bond or a double bond, connecting two One of them is a single key, the other is a double bond; Y1 and Y2 are each independently selected from CH and N, Z1 and Z2 are each independently selected from CH or N; U1 and U2 are each independently selected from O, N, NH or CH; T1, T2 and T3 are each independently selected from CH2, O and NH; W1 and W3 are selected from CH or N; W2 is selected from NH or O; u is selected from 0 or 1.

[0108] In certain embodiments, the structural unit Selected from

[0109] In certain embodiments, the structural unit wherein, preferably, Y1 is selected from N, and Y2 is selected from CH; or Y1 is selected from N, and Y2 is selected from N; more preferably, Y1 is selected from N, and Y2 is selected from CH; preferably, Z1 is selected from CH, and Z2 is selected from CH; or Z1 is selected from N, and Z2 is selected from CH; or Z1 is selected from CH, and Z2 is selected from N; more preferably, Z1 is selected from CH, and Z2 is selected from CH; preferably, U1 is selected from N and CH, and U2 is selected from NH and O; or U1 is selected from NH and O, and U2 is selected from N and CH; more preferably, U1 is selected from N, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N; or U1 is selected from N, and U2 is selected from O.

[0110] In certain embodiments, the structural unit wherein, preferably, Y1 is selected from N, and Y2 is selected from CH; preferably, T1 is selected from CH2, T2 is selected from O or NH, and T3 is selected from CH2; or T1 is selected from O, and T1 and T3 are selected from CH2; preferably, U1 is selected from N, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N.

[0111] In certain embodiments, the structural unit wherein, preferably, Y1 is selected from N, and Y2 is selected from CH; preferably, T1 is selected from NH, and T3 is selected from CH2; or T1 is selected from CH2, and T3 is selected from NH; or T1 is selected from O, and T3 is selected from CH2; or T1 is selected from CH2, and T3 is selected from O; or T1 is selected from CH2, and T3 is selected from CH2; more preferably, T1 is selected from O, and T3 is selected from CH2; preferably, U1 is selected from N or CH, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N or CH; more preferably, U1 is selected from N, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N.

[0112] In certain embodiments, the structural unit wherein Y1 is preferably selected from N, and Y2 is preferably selected from CH; Z1 is preferably selected from CH, and Z2 is preferably selected from CH; W1 is preferably selected from N, and W2 is preferably selected from NH.

[0113] In certain embodiments, the structural unit wherein Y1 is preferably selected from N, and Y2 is preferably selected from CH; Z1 is preferably selected from CH, and Z2 is preferably selected from CH; W1 is preferably selected from N, and W3 is preferably selected from CH.

[0114] In certain embodiments, the structural unit wherein Y1 is preferably selected from N, Y2 is selected from CH; preferably T1 is selected from O, T2 and T3 are selected from CH2; or T1 is selected from CH2, T2 is selected from O, T3 is selected from CH2; more preferably T1 is selected from O, T2 and T3 are selected from CH2; preferably W1 is selected from N, W2 is selected from NH.

[0115] In certain embodiments, the structural unit In the embodiment, Y1 is preferably selected from N, Y2 is selected from CH; T1 is preferably selected from O, T3 is selected from CH2, or T1 is selected from CH2, T3 is selected from O; or T1 is selected from NH, T3 is selected from CH2; or T1 is selected from CH2, T3 is selected from NH; W1 is preferably selected from N, W2 is selected from NH.

[0116] In certain embodiments, the structural unit wherein Y1 is preferably selected from N, and Y2 is selected from CH; Z1 is preferably selected from CH, and Z2 is selected from CH; U1 is preferably selected from N, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N; more preferably U1 is selected from N, and U2 is selected from NH.

[0117] In certain embodiments, the structural unit wherein Y1 is preferably selected from N, and Y2 is selected from CH; T1 is preferably selected from CH2 or O, and T2 is selected from CH2; U1 is preferably selected from N, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N; more preferably U1 is selected from N, and U2 is selected from NH.

[0118] In certain embodiments, the structural unit wherein Y1 is preferably selected from N, Y2 is selected from CH; T1 is preferably selected from O, T2 and T3 are selected from CH2; and W1 is preferably selected from N.

[0119] In certain embodiments, the structural unit Selected from

[0120] In certain embodiments, the structural unit Selected from

[0121] In certain embodiments, the structural unit Selected from

[0122] In certain embodiments, the structural unit Selected from

[0123] In certain embodiments, the structural unit Selected from

[0124] In certain embodiments, the structural unit Selected from

[0125] In certain embodiments, the structural unit Selected from

[0126] In certain embodiments, the structural unit Selected from

[0127] In certain embodiments, the structural unit Selected from

[0128] In certain embodiments, the structural unit Selected from

[0129] In certain embodiments, the structural unit Selected from

[0130] In certain embodiments, the structural unit Selected from

[0131] In certain embodiments, the structural unit Selected from

[0132] In certain embodiments, the structural unit for

[0133] In certain embodiments, the structural unit for

[0134] In certain embodiments, the structural unit for

[0135] In certain embodiments, W is selected from -C(R5R6)-, -C(=CH2)-, and -NR5-, wherein R5 and R6 are as defined herein.

[0136] In certain embodiments, the R5 is selected from H, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Halogenated alkoxy.

[0137] In certain embodiments, said R6 is selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Halogenated alkoxy.

[0138] In certain embodiments, R5 is selected from H, -OH, methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, butoxy, halomethyl, haloethyl, halopropyl, halobutyl, halomethoxy, haloethoxy, halopropoxy, and halobutoxy.

[0139] In certain embodiments, R6 is selected from H, methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, butoxy, halomethyl, haloethyl, halopropyl, halobutyl, halomethoxy, haloethoxy, halopropoxy, and halobutoxy.

[0140] In certain embodiments, the R5 is selected from H, -OH, methyl, methoxy, monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0141] In certain embodiments, the R6 is selected from H, methyl, ethyl, methoxy, monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0142] In certain embodiments, said R5 is selected from H, -OH.

[0143] In certain embodiments, said R6 is selected from H.

[0144] In certain embodiments, said R5 is selected from H.

[0145] In certain embodiments, W is selected from -CH2-, -CH(OH)-, -C(=CH2)-, and -NH-.

[0146] In certain embodiments, said W is selected from -CH2- and -NH-.

[0147] In certain embodiments, said W is selected from -CH2- and -C(=CH2)-.

[0148] In certain embodiments, said W is selected from -CH2-.

[0149] In certain embodiments, said R3 is selected from H, C 1-4 Alkyl and -C(=O)C 1-4 Alkyl, the C 1-4 Alkyl or -C(=O)C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogens -OH, -NH2, -CN, -NO2 and -COOH.

[0150] In certain embodiments, R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)(CH2)2CH3 and -C(=O)(CH2)3CH3.

[0151] In certain embodiments, said R3 is selected from H, -CH3 and -C(=O)CH3.

[0152] In certain embodiments, said R3 is H.

[0153] In certain embodiments, the structural unit Selected from Among them, * The bond indicated by " is connected to ring B.

[0154] In certain embodiments, the structural unit Selected from

[0155] In certain embodiments, the structural unit Selected from

[0156] In certain embodiments, the structural unit Selected from

[0157] In certain embodiments, the structural unit Selected from -C(=O)-CH2-, -NH-C(=O)-CH2-, -N(CH3)-C(=O)-CH2-, -N(C(=O)CH3)-C(=O)-CH2-, -N(CH3)-C(=O)-CH(OH)-, -NH-C(=O)-C(=CH2)- and -NH-C(=S)-CH2-.

[0158] In certain embodiments, the structural unit It is -NH-C(=O)-CH2-.

[0159] In certain embodiments, the structural unit for Wherein "*" is connected to ring B.

[0160] In certain embodiments, the structural unit Selected from *-C(=O)-CH2-, *-NH-C(=O)-CH2-, *-N(CH3)-C(=O)-CH2-, *-N(C(=O)CH3)-C(=O)-CH2-, *-N(CH3)-C(=O)-CH(OH)-, *-NH-C(=O)-C(=CH2)- and *-NH-C(=S)-CH2-, wherein "*" is connected to ring B.

[0161] In certain embodiments, the structural unit It is *-NH-C(=O)-CH2-, wherein "*" is connected to ring B.

[0162] In certain embodiments, R is selected from halogen, OH, CN, ═O, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 haloalkyl and C 1-4 Halogenated alkoxy.

[0163] In certain embodiments, R is selected from F, Cl, Br, I, OH, CN, =O, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, halomethyl, haloethyl, halopropyl, halobutyl, halomethoxy, haloethoxy, halopropoxy, and halobutoxy.

[0164] In certain embodiments, R is selected from F, Cl, Br, I, OH, CN, =0, methyl, ethyl, n-propyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0165] In certain embodiments, R is selected from F, Cl, Br, OH, =0, methyl, ethyl, monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0166] In certain embodiments, said R is selected from OH, -CH3 and =O.

[0167] In certain embodiments, the structural unit Selected from p is selected from 0, 1 and 2, q is selected from 0, 1, 2, 3, 4 and 5, Selected from single bonds and double bonds.

[0168] In certain embodiments, the structural unit Selected from

[0169] In certain embodiments, the structural unit Selected from p is selected from 0, 1 and 2, q is selected from 0, 1, 2, 3, 4 and 5, is selected from a single bond and a double bond, and R is as defined in the present invention.

[0170] In certain embodiments, the structural unit Selected from

[0171] In certain embodiments, the structural unit Selected from

[0172] In certain embodiments, the structural unit Selected from

[0173] In certain embodiments, the structural unit Selected from

[0174] In certain embodiments, the structural unit for Wherein "*" is connected to ring B.

[0175] In certain embodiments, the structural unit for Wherein "*" is connected to ring B.

[0176] In certain embodiments, the structural unit Selected from Wherein "*" is connected to ring B.

[0177] In certain embodiments, the structural unit Selected from Wherein "*" is connected to ring B.

[0178] In certain embodiments, the structural unit Selected from Wherein "*" is connected to ring B.

[0179] In certain embodiments, the structural unit Selected from Wherein "*" is connected to ring B.

[0180] In certain embodiments, W and Ring B, together with the atoms to which they are attached, form a 7-9 membered heterocyclyl.

[0181] In certain embodiments, W and ring B together with the atoms to which they are attached form a 7-membered heterocyclic group; preferably, the 7-membered heterocyclic group is selected from Wherein "*" is fused with ring B; More preferably, 7 heterocyclic groups are selected from Wherein "*" is fused to ring B.

[0182] In certain embodiments, W and ring B together with the atoms to which they are attached form an 8-9 membered heterocyclic group; preferably, the 8-9 membered heterocyclic group is selected from Wherein "*" is fused with ring B.

[0183] In certain embodiments, said L1 is absent.

[0184] In certain embodiments, L1 is selected from -CH2-, -CH2CH2-, =CH-, -NH-, and -O-.

[0185] In certain embodiments, said L1 is -CH2-.

[0186] In certain embodiments, the R4 is selected from halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Halogenated alkoxy.

[0187] In certain embodiments, R4 is selected from F, Cl, Br, I, -OH, -CN, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, halomethyl, haloethyl, halopropyl, halobutyl, halomethoxy, haloethoxy, halopropoxy, and halobutoxy.

[0188] In certain embodiments, the R4 is selected from F, Cl, Br, -OH, -CN, -NH2, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0189] In certain embodiments, said R4 is selected from F, Cl, -OH, -CN, -NH2, methyl and trifluoromethyl.

[0190] In certain embodiments, said R4 is selected from F, Cl and CN.

[0191] In certain embodiments, the ring C is selected from C6-C 10 Aryl, 5-10 membered heteroaryl, C 3-8 cyclyl, 4-6 membered heterocyclyl and 5-8 membered heterocyclyl.

[0192] In certain embodiments, the ring C is selected from phenyl, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl.

[0193] In certain embodiments, the ring C is selected from phenyl, thienyl, thiazolyl, pyridinyl, 1,3-benzodioxolyl, and benzodioxolyl.

[0194] In certain embodiments, the ring C is selected from phenyl, thienyl, thiazolyl, pyridinyl, and benzodicyclopentyl.

[0195] In certain embodiments, the ring C is selected from phenyl, thienyl, thiazolyl, and pyridinyl.

[0196] In certain embodiments, the ring C is selected from phenyl and pyridinyl.

[0197] In certain embodiments, the structural unit Selected from

[0198] In certain embodiments, the structural unit Selected from

[0199] In certain embodiments, the structural unit Selected from wherein n and R4 are as defined in the present invention.

[0200] In certain embodiments, the structural unit Selected from

[0201] In certain embodiments, the structural unit Selected from

[0202] In certain embodiments, the structural unit Selected from

[0203] In certain embodiments, the structural unit Selected from

[0204] In certain embodiments, in the compound represented by formula (I),

[0205] is selected from single bonds and double bonds;

[0206] Z is selected from O and S;

[0207] L1 is selected from -C 1-3 Alkylene-, =CH-, -NH- and -O-, or L1 is absent;

[0208] Ring A is selected from phenyl, 5-6 membered heteroaryl, C 4-8 Cycyl and 4-8 membered heterocyclic groups;

[0209] Ring B is selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl;

[0210] Ring C is selected from C6-C 10 Aryl, 5-12 membered heteroaryl, C 3-12 Cycyl and 4-10 membered heterocyclic groups;

[0211] Ring E is selected from 5-6 membered heteroaryl;

[0212] R1 is selected from H, OH, halogen, C 1-3 Alkyl and C 1-3 alkyl halide;

[0213] R2 is selected from H, OH, halogen, CN, NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and -O-C1-6 haloalkyl;

[0214] R3 is selected from H, C 1-6 Alkyl and -C(=O)C 1-6 alkyl;

[0215] W is selected from -C(R5R6)-, -CR5=, -C(=CH2)- and -NR5-, wherein R5 is selected from H and OH; or

[0216] W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclic group, said 4-6 membered heterocyclic group being optionally substituted with 1, 2, 3, 4 or 5 R; or

[0217] W and ring B together with the atoms to which they are attached form a 6-10 membered heterocyclic group, which is optionally substituted with 1, 2, 3, 4 or 5 R;

[0218] R4 is selected from halogen, CN, preferably halogen;

[0219] R6 is selected from H and C 1-6 alkyl;

[0220] R7 is selected from H, halogen and C 1-6 alkyl;

[0221] R is selected from halogen, OH and =O;

[0222] m is selected from 0 and 1;

[0223] n is selected from 0, 1, 2 and 3;

[0224] r, s, and t are each independently 0, 1, or 2, preferably 0 or 1.

[0225] In certain embodiments, in the compound represented by formula (I),

[0226] is selected from single bonds and double bonds;

[0227] Z is selected from O and S;

[0228] L1 is selected from -C 1-3 Alkylene-, =CH-, -NH- and -O-, or L1 is absent;

[0229] Ring A is selected from phenyl, 5-6 membered heteroaryl, C 4-8 Cycyl and 4-8 membered heterocyclic groups;

[0230] Ring B is selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl;

[0231] Ring C is selected from C6-C 10 Aryl, 5-12 membered heteroaryl, C 3-12 Cycyl and 4-10 membered heterocyclic groups;

[0232] Ring E is selected from 5-6 membered heteroaryl;

[0233] R1 is selected from H, OH, halogen, C 1-3 Alkyl and C 1-3 alkyl halide;

[0234] R2 is selected from H, OH, halogen, CN, NH2, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy and -O-C1-6 haloalkyl;

[0235] R3 is selected from H, C 1-6 Alkyl and -C(=O)C 1-6 alkyl;

[0236] W is selected from -C(R5R6)-, -CR5=, -C(=CH2)- and -NR5-, wherein R5 is selected from H and OH; or

[0237] W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 R;

[0238] R4 is selected from halogen, CN, preferably halogen;

[0239] R6 is selected from H and C 1-6 alkyl;

[0240] R7 is selected from H, halogen and C 1-6 alkyl;

[0241] R is selected from halogen, OH and =O;

[0242] m is selected from 0 and 1;

[0243] n is selected from 0, 1, 2 and 3;

[0244] r, s, and t are each independently 0, 1, or 2, preferably 0 or 1.

[0245] In certain embodiments, Select from single bonds.

[0246] In certain embodiments, Z is selected from O.

[0247] In certain embodiments, L1 is selected from -C 1-3 Alkylene-, =CH-, -NH- and -O-.

[0248] In certain embodiments, L1 is selected from -C 1-3 Alkylene-.

[0249] In certain embodiments, Ring A is selected from phenyl, 6-membered heteroaryl, C6 cyclyl, 6-7 membered heterocyclyl.

[0250] In certain embodiments, Ring A is selected from phenyl, 6-7 membered heterocyclyl.

[0251] In certain embodiments, Ring B is selected from 5-membered heteroaryl and 5-membered heterocyclyl.

[0252] In certain embodiments, Ring B is selected from a 5-membered heteroaryl.

[0253] In certain embodiments, ring C is selected from C 6-10 aryl, 5-12 membered heteroaryl and 4-10 membered heterocyclyl.

[0254] In certain embodiments, Ring C is selected from phenyl, 5-6 membered heteroaryl, 5-10 membered heterocyclyl (eg, 9-10 membered heterocyclyl).

[0255] In certain embodiments, Ring C is selected from phenyl, 6-membered heteroaryl.

[0256] In certain embodiments, phenyl or pyridinyl.

[0257] In certain embodiments, Ring E is selected from 6-membered heteroaryl.

[0258] In certain embodiments, R1 is H or OH.

[0259] In certain embodiments, R1 is H.

[0260] In certain embodiments, R2 is selected from H, OH, halogen, CN, NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -OC 1-6 Haloalkyl and -C 1-6 Alkylene-C 1-6 Alkoxy.

[0261] In certain embodiments, R2 is selected from H, halogen, CN, NH2, C 1-6 Alkyl or -C 1-6 Alkylene-C 1-6 Alkoxy.

[0262] In certain embodiments, R2 is selected from H, NH2.

[0263] In certain embodiments, R2 is H, halogen, NH2 or C 1-6 alkyl.

[0264] In certain embodiments, R3 is selected from H.

[0265] In certain embodiments, W is selected from -C(R5R6)-, -C(=CH2)-, wherein R5 is selected from H and OH; or W and R3 and the atoms to which they are attached form a 4-6 membered heterocyclyl, said 4-6 membered heterocyclyl being optionally substituted with 1, 2, 3, 4 or 5 R; or W and ring B and the atoms to which they are attached form a 7-9 membered heterocyclyl, said 7-9 membered heterocyclyl being optionally substituted with 1, 2, 3, 4 or 5 R.

[0266] In certain embodiments, W is selected from -C(R5R6)-, -C(=CH2)-, wherein R5 is selected from H; or W and R3 and the atoms to which they are attached form a 4-6 membered heterocyclic group, which is optionally substituted with 1, 2, 3, 4 or 5 R.

[0267] In certain embodiments, W is selected from -C(R5R6)-, wherein R5 is selected from H; or W and R3 together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 Rs.

[0268] In certain embodiments, R6 is selected from H.

[0269] In certain embodiments, R7 is selected from H.

[0270] In certain embodiments, R is selected from halogen, OH, ═O, C 1-6 alkyl.

[0271] In certain embodiments, R is selected from OH, ═O, and C 1-6 alkyl.

[0272] In certain embodiments, m is selected from 1.

[0273] In certain embodiments, n is selected from 1, 2, or 3.

[0274] In certain embodiments, r, s, and t are each independently zero.

[0275] In certain embodiments, the compound of formula (I) is selected from the compound of formula (IA),

[0276] in,

[0277] is selected from single bonds and double bonds;

[0278] p is selected from 0, 1 and 2; q is selected from 0, 1, 2, 3, 4 and 5;

[0279] Z, L1, Ring A, Ring B, Ring C, Ring E, R1, R2, R4, R7, R, n, r, s and t are as defined in the present invention.

[0280] In certain embodiments, in the compound represented by formula (IA), the structural unit The definition of is as described in the present invention.

[0281] In certain embodiments, the compound of formula (I) is selected from the compound of formula (IB),

[0282] in,

[0283] is selected from single bonds and double bonds;

[0284] Z, L1, Ring A, Ring B, Ring C, Ring E, R1, R2, R4, R7, W, n, r, s and t are as defined in the present invention.

[0285] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-1),

[0286] in,

[0287] is selected from single bonds and double bonds;

[0288] p is selected from 0, 1 and 2; q is selected from 0, 1, 2, 3, 4 and 5;

[0289] L1, Ring A, Ring B, Ring C, R1, R2, R4, R7, R, n, r, s and t are as defined in the present invention.

[0290] In certain embodiments, in the compound represented by formula (I-1), the structural unit The definition of is as described in the present invention.

[0291] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-2),

[0292] in,

[0293] L1, Ring A, Ring B, Ring C, R1, R2, R4, R7, W, n, r, s and t are as defined in the present invention.

[0294] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-3)

[0295] in,

[0296] is selected from single bonds and double bonds;

[0297] p is selected from 0, 1 and 2;

[0298] q is selected from 0, 1, 2, 3, 4 and 5;

[0299] Ring C, R4, R and n are as defined herein.

[0300] In certain embodiments, in the compound represented by formula (I-3), the structural unit The definition of is as described in the present invention.

[0301] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-4)

[0302] in,

[0303] L1, Ring A, Ring B, Ring C, R1, R2, R4, R7, n, r, s and t are as defined in the present invention.

[0304] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-5)

[0305] is selected from single bonds and double bonds;

[0306] p is selected from 0, 1 and 2; q is selected from 0, 1, 2, 3, 4 and 5;

[0307] Y1 and Y2 are each independently selected from CH and N, preferably, Y1 is N, Y2 is CH, or Y1 is CH, Y2 is N;

[0308] L1, Ring A, Ring B, Ring C, R1, R2, R4, R7, R, n, r, s and t are as defined in the present invention.

[0309] In certain embodiments, in the compound represented by formula (I-5), the structural unit The definition of is as described in the present invention. In certain embodiments, in the compound represented by formula (I-5), ring C is phenyl or pyridyl.

[0310] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-6)

[0311] in,

[0312] Y1 and Y2 are each independently selected from CH and N;

[0313] L1, Ring A, Ring B, Ring C, R1, R2, R4, R7, n, r, s and t are as defined in the present invention.

[0314] In certain embodiments, in the compound of formula (I-6), Y1 is N, and Y2 is CH. In certain embodiments, in the compound of formula (I-6), Y1 is CH, and Y2 is N.

[0315] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-7)

[0316] in

[0317] is selected from single bonds and double bonds;

[0318] p is selected from 0, 1 and 2; q is selected from 0, 1, 2, 3, 4 and 5;

[0319] M1, M2 and M3 are each independently C, CH or N; preferably M1, M2 and M3 are each independently CH or N;

[0320] Y1 and Y2 are each independently selected from CH and N;

[0321] L1, Ring A, Ring C, R1, R2, R4, R7, R, n, r, s and t are as defined in the present invention.

[0322] In certain embodiments, in the compound represented by formula (I-7), the structural unit The definition of is as described in the present invention.

[0323] In certain embodiments, in the compound of formula (I-7), Y1 is N, and Y2 is CH. In certain embodiments, in the compound of formula (I-7), Y1 is CH, and Y2 is N.

[0324] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-8)

[0325] in

[0326] is selected from single bonds and double bonds;

[0327] M1, M2 and M3 are each independently C, CH or N; preferably M1, M2 and M3 are each independently CH or N;

[0328] Y1 and Y2 are each independently selected from CH and N;

[0329] L1, Ring A, Ring C, R1, R2, R4, R7, W, n, r, s and t are as defined in the present invention.

[0330] In certain embodiments, in the compound of formula (I-8), Y1 is N, and Y2 is CH. In certain embodiments, in the compound of formula (I-8), Y1 is CH, and Y2 is N.

[0331] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-9)

[0332] in,

[0333] is selected from single bonds and double bonds;

[0334] p is selected from 1 and 2; q is selected from 0, 1, 2, 3, 4 and 5;

[0335] V is selected from CH, CR4 and N;

[0336] Y1 and Y2 are each independently selected from CH and N;

[0337] Ring A, R1, R2, R4, R, n and s are as defined in the present invention.

[0338] In certain embodiments, the structural unit in the compound represented by formula (I-9) The definition of is as described in the present invention.

[0339] In certain embodiments, in the compound of formula (I-9), Y1 is N, and Y2 is CH. In certain embodiments, in the compound of formula (I-9), Y1 is CH, and Y2 is N.

[0340] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-10)

[0341] in

[0342] V is selected from CH, CR4 and N;

[0343] Y1 and Y2 are each independently selected from CH and N;

[0344] Ring A, R1, R2, R4, n and s are as defined in the present invention.

[0345] In certain embodiments, in the compound of formula (I-10), Y1 is N and Y2 is CH. In certain embodiments, in the compound of formula (I-10), Y1 is CH and Y2 is N.

[0346] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-9')

[0347] In certain embodiments, the compound represented by formula (I) is selected from the compound represented by formula (I-10')

[0348] In certain embodiments, the compound represented by formula (I) is selected from the structures represented by formula (II-A) to (II-P):

[0349] In certain embodiments, the compound represented by formula (I) is selected from the structures represented by formula (II-1) to (II-11):

[0350] In certain embodiments, the compound represented by formula (I) is selected from the structures represented by formula (III-1) to (III-5):

[0351] In certain embodiments, the compound of formula (I) is selected from:

[0352] The second aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. In certain embodiments, the compound of the present invention, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, is present in an effective amount.

[0353] A third aspect of the present invention provides a method for treating or preventing a disease, comprising the following steps:

[0354] A therapeutically or prophylactically effective amount of a compound of the present invention, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotopically labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention is administered to an individual who (i) suffers from a condition characterized by axonal degeneration or (ii) is at risk of suffering from a condition characterized by axonal degeneration.

[0355] The fourth aspect of the present invention provides a method for treating or preventing axonal degeneration, which comprises administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound of the present invention, or a stereoisomer thereof, or a tautomer 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 of the present invention.

[0356] The fifth aspect of the present invention provides a method for treating or preventing a disease or condition characterized by axonal degeneration, which comprises administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound of the present invention, or a stereoisomer thereof, or a tautomer 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 of the present invention.

[0357] The sixth aspect of the present invention provides the use of the compound of the present invention, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention in the preparation of a drug for treating or preventing axonal degeneration.

[0358] The seventh aspect of the present invention provides the use of the compound of the present invention, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention in the preparation of a medicament for treating or preventing a disease or condition characterized by axonal degeneration.

[0359] The eighth aspect of the present invention provides a compound of the present invention, or a stereoisomer thereof, or a tautomer 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 of the present invention, for use in treating or preventing axonal degeneration, or for treating or preventing a disorder or condition characterized by axonal degeneration.

[0360] In certain embodiments, the disorder or condition characterized by axonal degeneration is a neurodegenerative disease or a peripheral neuropathy.

[0361] In certain embodiments, the neurodegenerative disease is preferably Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic sclerosis or Huntington's disease.

[0362] The compounds of the present invention can be synthesized by conventional chemical synthesis knowledge familiar to those skilled in the art or by various methods similarly known in the art. Isolation and purification of the products can be achieved by standard procedures known to those skilled in the art.

[0363] Definition of terms

[0364] The various terms and phrases used in the present invention have general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases herein. If the mentioned terms and phrases are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

[0365] When the name of the compound used in the present invention is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0366] In the structural formula of the present invention, the fragment containing imidazole can undergo tautomerism, for example:

[0367] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or organic acids, or coordination compounds formed by the substitution of acidic protons present in the parent compound with metal ions or organic bases.

[0368] As used herein, the term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0369] Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and diastereomeric pairs.

[0370] As used herein, the term "isotopically labeled compound" refers to a compound in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, hydrogen isotopes such as 2 H, 3 H; carbon isotopes such as 11 C, 13 C and 14 C; chlorine isotopes such as 36 Cl; fluorine isotopes such as 18 F; iodine isotopes such as 123 I and 125 I; Nitrogen isotopes such as 13 N and 15 N; oxygen isotopes such as 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0371] As used in the present invention, the term "prodrug" refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound disclosed herein. Prodrugs are active compounds that react only under biological conditions, or they do not have or only have relatively low activity in their unreactive form. Prodrugs can generally be prepared using known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0372] The term "ester" refers to esters that are hydrolyzed in vivo and includes those that readily decompose in the human body and separate from the parent compound. The hydroxyl-containing compounds of the present invention can form esters with organic or inorganic acids, or the carboxyl-containing compounds of the present invention can form esters with alcohols such as methanol, ethanol, or propanol.

[0373] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present application contain a solvent, such as water, methanol, or ethanol, as a structural element of the crystal lattice of the compound. The amount of the solvent may be present in a stoichiometric or non-stoichiometric ratio.

[0374] The present invention encompasses all possible crystalline forms or polymorphs of the compounds, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0375] As used herein, the term "N-oxide" refers to a compound containing an amine oxide moiety (i.e., an oxide of a tertiary amine group) formed by oxidation of at least one nitrogen atom in the compound. Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of nitrogen-containing heterocycles and tertiary amines are well known to those skilled in the art, for example, a nitrogen atom (e.g., trivalent nitrogen) can be converted to the corresponding N-oxide form by known methods such as treatment with an oxidizing agent.

[0376] In the present invention, the purpose of the pharmaceutical composition is to promote administration to an organism, facilitate the absorption of the active ingredient, and thus exert its biological activity. The carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, and lanolin. The excipients refer to additives other than the main drug in a pharmaceutical preparation. They are stable in nature, have no incompatibility with the main drug, do not produce side effects, do not affect the efficacy, are not easily deformed, cracked, molded, or damaged by insects at room temperature, are harmless to the human body, have no physiological effects, do not chemically or physically interact with the main drug, and do not affect the content determination of the main drug. For example, adhesives, fillers, disintegrants, and lubricants in tablets; wine, vinegar, and medicinal juice in Chinese medicine pills; the matrix part in semi-solid preparations such as ointments and creams; preservatives, antioxidants, flavoring agents, fragrances, cosolvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants, etc. in liquid preparations can all be called excipients.

[0377] In the present invention, the pharmaceutical composition can be prepared into various suitable dosage forms according to the route of administration, such as tablets, capsules, granules, oral solutions, oral suspensions, oral emulsions, powders, tinctures, syrups, injections, suppositories, ointments, creams, pastes, ophthalmic preparations, pills, implants, aerosols, powder sprays, sprays, etc. The pharmaceutical composition or suitable dosage form can contain 0.01 mg to 1000 mg of the compound of the present invention, or its stereoisomers, or tautomers, or polymorphs, or solvates, or hydrates, or N-oxides, or isotope-labeled compounds, or metabolites, or esters, or prodrugs, or pharmaceutically acceptable salts thereof, preferably 0.1 mg to 800 mg, preferably 0.5-500 mg, more preferably 0.5 to 350 mg, and particularly preferably 1-250 mg.

[0378] As used herein, the term "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from a disease (e.g., a disease described herein) (referred to as a patient) or normal individuals. The term "non-human animal" in the present disclosure includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0379] As used herein, the term "treatment" is intended to alleviate, alleviate, improve, or eliminate the disease state or condition being treated. If a subject receives a therapeutic amount of the compound, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to the methods described herein, and the subject exhibits an observable and / or detectable decrease or improvement in one or more signs and symptoms, then the subject is successfully "treated." It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also includes achieving some biologically or medically relevant results while not achieving complete treatment.

[0380] As used herein, the term "prevention" is intended to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms, provided that the disease or disease-related symptoms have not yet appeared before the administration of the relevant drug. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, if the administration of the relevant drug can reduce the risk of a subject developing a particular disease or disease-related symptom, or reduce the severity of related symptoms that later appear, it can be considered to have "prevented" the onset or development of the disease.

[0381] As used herein, the term "effective amount" refers to an amount sufficient to achieve a desired therapeutic or preventive effect, for example, an amount that alleviates the symptoms associated with the disease to be treated, or an amount that is effective in preventing, arresting, or delaying the onset of the disease. Determining such an effective amount is within the capabilities of those skilled in the art.

[0382] It should also be noted that the dosage and method of use of the compounds of this invention depend on many factors, including the patient's age, weight, sex, natural health, nutritional status, the potency of the compound, time of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. The preferred dosage is between 0.01 and 100 mg / kg body weight / day.

[0383] As used herein, the term "optionally substituted" means that it may be substituted or may not be substituted.

[0384] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0385] As used in the present invention, the term "C 1-6 "Alkyl" refers to a linear or branched monovalent saturated hydrocarbon group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms. 1-6 Alkyl groups include C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, etc., specific examples include but are not limited to methyl, ethyl, propyl, butyl, pentyl or hexyl, etc.

[0386] As used herein, the term "C 1-6 "Alkylene" refers to a straight or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms. 1-6 Alkylene includes C 1-5 Alkylene, C 1-4 Alkylene, C 1-3 Specific examples include, but are not limited to, methylene, ethylene, propylene, or isopropylene.

[0387] As used in the present invention, the term "C 1-6 "Alkoxy" refers to -OC 1-6 Alkoxy, that is, C 1-6 The group obtained by connecting the carbon atom on the alkyl group with the oxygen atom, C 1-6 Alkoxy groups include C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy, etc., specific examples include but are not limited to methoxy, ethoxy, propoxy or butoxy, etc.

[0388] As used herein, the term "halo" means that the group it modifies is substituted by one or more halogens, for example, 1, 2, 3, 4, 5 or 6 halogens. For example, "C 1-6 "Haloalkyl" refers to a C 1-6 The alkyl group is substituted by one or more halogens, specific examples of which include but are not limited to CF3, CHF2, CH2F or CF2CF3.

[0389] As used herein, the term "C6-C 10 "Aryl" refers to an unsaturated aromatic carbocyclic group having a conjugated π electron system and consisting of 6 to 10 (e.g., 6, 7, 8, 9 or 10) carbon atoms and having a single ring or two or more condensed rings. Specific examples include, but are not limited to, phenyl, naphthyl, and anthracenyl.

[0390] As used herein, the term "5-12 membered heteroaryl" refers to a group having a conjugated π electron system consisting of 5 to 12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, including monocyclic heteroaromatic rings and polycyclic heteroaromatic rings, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. 5-12 membered heteroaryl includes 5-10 membered, 5-9 membered, 6-9 membered, 5-6 membered heteroaryl, and the like, and specific examples include, but are not limited to, imidazolyl, thiazolyl, pyridyl, thienyl, or furyl. "5 membered nitrogen-containing heteroaryl" refers to a group wherein 1, 2, 3, or 4 of the ring atoms are N heteroatoms and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized or oxidized.

[0391] As used in the present invention, the term "C 3-12 "Cyclic group" refers to a saturated cyclic hydrocarbon group or a partially unsaturated or cyclic hydrocarbon group consisting of 3 to 12 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms. 3-12 The ring group includes C 3-10 Cyclic group, C 4-8 Cyclic group, C 4-6 Cyclic group, C 4-7 Cyclic group, C 5-6 Cyclic group, C 5-7 Cyclic or C 6-7 Cyclic group, etc. 3-12 The cyclic group includes monocyclic, bicyclic or polycyclic rings, including spirocyclic, fused or bridged rings. Specific examples include but are not limited to cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl or 1,4-cyclohexadienyl.

[0392] As used in the present invention, the term "C 3-7"Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 7 (such as 3, 4, 5, 6 or 7) carbon atoms. 3-7 Cycloalkyl groups include C 4-6 Cycloalkyl, C 4-7 Cycloalkyl, C 5-6 Cycloalkyl, C 5-7 Cycloalkyl or C 6-7 Cycloalkyl, etc. 3-7 Cycloalkyl includes monocyclic, bicyclic or polycyclic rings, including spirocyclic, fused or bridged rings. 3-7 Specific examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, or cyclohexyl.

[0393] As used in the present invention, "4-10 membered heterocyclyl" refers to a saturated or partially unsaturated cyclic group consisting of 4 to 10 (such as 4, 5, 6, 7, 8, 9 or 10) ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. The 4-10 membered heterocyclyl includes 4-8, 4-6, 5-6, 8-10, 9-10 membered heterocyclyl and the like. The 4-10 membered heterocyclyl includes a monocyclic, bicyclic or polycyclic ring, including a spirocyclic, a cyclic or a bridged ring. The 4-10 membered heterocyclyl includes a monocyclic ring that is a heterocyclic ring and at least one of the fused rings containing a bicyclic or tricyclic ring is a heterocyclic ring, for example Specific examples of 4-10 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, 2,3-dihydrofuranyl, or 3,4-dihydro-2H-pyranyl.

[0394] As used herein, the term "3-7 membered heterocycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 7 (e.g., 3, 4, 5, 6, or 7) ring atoms, of which 1, 2, 3, or 4 are heteroatoms and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. Specific examples of 3-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, or pyrrolidinyl.

[0395] As used in the present invention, "*" indicates that the C atom at that location is a chiral carbon atom, unless otherwise specified. Beneficial effects:

[0396] The compounds of the present invention are effective in inhibiting the SARM1 enzyme. DETAILED DESCRIPTION

[0397] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0398] Instruments and reagents

[0399] NMR was measured using a Bruker Avance III 400 NMR spectrometer, and the chemical shift (δ) was measured at 10 -6 The unit is ppm. The solvent is deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0400] MS was measured using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B).

[0401] High-performance liquid chromatography (HPLC) assay conditions: Gilson GX-281, C18 column (10 μM, 19 mm x 250 mm), UV detection at 220 and 254 nm, elution with a gradient of 5–95% acetonitrile (containing 0.05% (v / v) formic acid or ammonium bicarbonate) over 15 min.

[0402] Reverse phase purification was performed using the Biotage Isolera Rapid Purification System.

[0403] Thin layer chromatography separation and purification were performed using thin layer chromatography silica gel plates (aluminum plates (20 cm x 20 cm x 1 mm) produced by Meck, or GF 254 produced in Yantai).

[0404] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0405] Reaction monitoring is usually performed by TLC or LC-MS. Common developing solvent systems include: dichloromethane / methanol, n-hexane / ethyl acetate, petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0406] The silica gel used in column chromatography is generally 100-200 mesh. Common eluent systems include dichloromethane / methanol and petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0407] The reagents and solvents of the present invention were purchased from Aldrich Chemical Company, Anage, Adamas, Leyan, J&K Technology, Shanghai Bid Pharmaceutical Technology Co., Ltd., Yaoshi Technology, and Shanghai Titan Technology Co., Ltd.

[0408] Chiral HPLC analysis was performed using a Waters UPC2 analytical SFC (SFC-H) high performance liquid chromatograph.

[0409] Chiral preparation was performed using a WATERS 150 preparative SFC (SFC-26) preparative chromatograph.

[0410] Reversed phase column model SW040 / SW080Bonded Series C18, Changzhou Santai.

[0411] In conventional synthesis methods and synthesis examples of compounds and intermediates of the present invention, the meanings of the abbreviations are shown in Table 1 below.

[0412] Table 1

[0413] Synthesis of intermediate a

[0414] Method 1

[0415] Step 1: At 0°C, add 6-bromoisoquinoline (25 g, 120.16 mmol, Bidler, batch number CPU905) and sodium nitrite (18.22 g, 180.24 mmol) to a solution of concentrated sulfuric acid (60 mL). The mixture was allowed to warm to room temperature and stirred at room temperature for 16 h. LC-MS indicated that the reaction of the starting materials was complete. The mixture was quenched by adding 500 mL of water under ice-bath conditions and the pH was adjusted to 7 with 4 M NaOH solution. A large amount of solid precipitated during the reaction. Filter and collect the filter cake, slurry it with water (500 mL x 2), and then filter and collect the filter cake. The filter cake was dried under reduced pressure to obtain intermediate a-1. LC-MS (ESI): m / z = 253.0 / 255.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.28 (s, 1H), 8.65 (d, J = 6.0Hz, 1H), 7.94 (d, J = 8.8Hz, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.45 (d, J = 6.0Hz, 1H).

[0416] Step 2: Intermediate a-1 (2.00 g, 7.90 mmol) was dissolved in N-methylpyrrolidone (40 mL) at room temperature, and 2,4-dimethoxybenzylamine (2.64 g, 15.81 mmol, Anaiji, batch number: 7MRKRRET) was added. The reaction was then heated to 120°C and stirred for 3 hours. LC-MS showed complete reaction. The reaction mixture was cooled to room temperature and extracted with water (50 mL) and ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 5), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (0 / 100 (v / v) to 40 / 60 (v / v)) to obtain intermediate a-2. 1 H NMR (400MHz, CDCl3) δ9.48(t,J=6.0Hz,1H),9.02(s,1H),8.53(d,J=6.0Hz,1H),8.34(d,J=6.0Hz,1H),8.10(d,J=9.6Hz,1H),7.40(d,J = 9.6Hz, 1H), 7.19 (d, J = 8.0Hz, 1H), 6.62 (d, J = 2.4Hz, 1H), 6.48 (dd, J = 8.8, 2.4Hz, 1H), 4.66 (d, J = 6.0Hz, 2H), 3.86 (s, 3H), 3.74 (s, 3H).

[0417] Step 3: Add intermediate a-2 (2.4 g, 7.07 mmol) and 10% palladium on carbon (0.25 g, 2.35 mmol) to methanol (50 mL) at room temperature. Replace the mixture with hydrogen (15 psi) three times and allow to react at room temperature for 3 hours. LC-MS monitored the reaction completion. The reaction solution was filtered and concentrated to yield intermediate a-3. LC-MS (ESI): m / z = 310.2 [M+H] + .

[0418] Step 4: At room temperature, intermediate a-3 (200 mg, 0.65 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C, and triphosgene (289 mg, 0.98 mmol) was added. The reaction solution was warmed to room temperature and stirred overnight. LC-MS showed that the starting material was completely reacted. Water (20 mL) and ethyl acetate (20 mL × 2) were added to the reaction solution for extraction. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 10 / 90 (v / v)) to obtain intermediate a-4. LC-MS (ESI): m / z = 336.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.52(s,1H),9.75(s,1H),8.58(d,J=6.8Hz,1H),8.42(d,J=6.7Hz,1H),8.23(d,J=8.8Hz,1H),7.89(d, J=8.8Hz,1H),7.06(d,J=8.4Hz,1H),6.59(d,J=2.3Hz,1H),6.46(dd,J=8.4,2.4Hz,1H),5.09(s,2H),3.81(s,3H),3.73(s,3H).

[0419] Step 5: To a reaction flask at room temperature, add intermediate a-4 (1.00 g, 2.98 mmol) and phosphorus oxybromide (4.27 g, 14.91 mmol). The mixture is then heated to 110°C and stirred for 3 hours. LC-MS indicates complete reaction of the starting material. The mixture is cooled to room temperature and slowly added to a saturated sodium bicarbonate solution. The solution is concentrated, dissolved in DMF, and the insoluble material is filtered off. The filtrate is purified by reverse phase chromatography (Phase A: 0.5% aqueous ammonium bicarbonate, Phase B: acetonitrile, gradient: 2% to 95% B) to afford intermediate a-5. 1 H NMR (400MHz, DMSO-d6) δ9.35 (s, 1H), 8.60 (d, J = 5.7Hz, 1H), 8.16 (d, J = 5.7Hz, 1H), 7.91 (d, J = 8.8Hz, 1H), 7.82 (d, J = 8.7Hz, 1H).

[0420] Step 6: Dissolve a-5 (195 mg, 0.79 mmol) in dichloromethane (5 mL) at room temperature, cool to 0°C, and add triethylamine (0.27 mL, 0.98 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.17 mL, 0.94 mmol, Anaiji). The reaction mixture was warmed to room temperature and stirred overnight. LC-MS indicated complete reaction. Water (20 mL) and ethyl acetate (20 mL x 2) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 10 / 90 (v / v)) to yield intermediate a. LC-MS (ESI): m / z = 378.0, 380.0 [M+H] + .

[0421] Method 2

[0422] Step 1: Dissolve intermediate a-3 (6.40 g, 20.69 mmol) in formic acid (60 mL) at room temperature. Heat the reaction mixture to 100°C and stir for 2 hours. LC-MS indicates complete reaction. Cool the reaction mixture to room temperature and concentrate. Remove most of the formic acid, then dissolve in dichloromethane. Adjust the mixture to alkalinity with triethylamine. Concentrate the solution and purify by silica gel column chromatography (methanol / dichloromethane (0 / 100 to 10 / 90)) to obtain intermediate a-6. LC-MS (ESI): m / z = 170.0 [M+H] + .

[0423] Step 2: Dissolve intermediate a-6 (2.68 g, 15.82 mmol) in DMF (50 mL) at room temperature, cool to 0°C, and add N,N-diisopropylethylamine (5.11 g, 39.55 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (3.96 g, 23.73 mmol). The reaction mixture is heated to 80°C and stirred for 3 hours. LC-MS indicates complete reaction. Water (50 mL) and ethyl acetate (50 mL x 2) are added to the reaction mixture for extraction. The organic phase is washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 5 / 95 (v / v)) to afford intermediate a-7. LC-MS (ESI): m / z = 300.2 [M+H] + .

[0424] Step 3: At room temperature, intermediate a-7 (2.12 g, 7.08 mmol) was dissolved in tetrahydrofuran (40 mL), cooled to -78°C, and lithium diisopropylamide (7.08 mL, 14.16 mmol) was slowly added dropwise. The reaction mixture was stirred at -78°C for 0.5 hour, followed by the dropwise addition of a solution of carbon tetrabromide (4.70 g, 14.16 mmol) in tetrahydrofuran (20 mL). The reaction mixture was then stirred at the same temperature for 1 hour. LC-MS indicated complete reaction. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with water (50 mL) and ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 3 / 97 (v / v)) to yield intermediate a. LC-MS(ESI): m / z=378.0 / 380.0[M+H] + .

[0425] Synthesis of intermediate b

[0426] At room temperature, intermediate a-3 (3.36 g, 10.86 mmol) was dissolved in methanol (40 mL), and cyanogen bromide (1.73 g, 16.29 mmol) was added. The reaction mixture was heated to 60°C and stirred for 3 hours. LC-MS showed that the starting material had reacted completely. The reaction mixture was cooled to room temperature and slowly added to a 1 mol / L aqueous sodium hydroxide solution. The insoluble matter was filtered off, and the filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 5 / 95 (v / v)) to obtain intermediate b. LC-MS (ESI): m / z = 335.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.17(s,1H),8.40(d,J=5.7Hz,1H),7.98(d,J=5.7Hz,1H),7.56(d,J=8.6Hz,1H),7.49(d,J=8 .6Hz,1H),6.75–6.67(m,3H),6.64–6.57(m,1H),6.46–6.36(m,1H),5.26(s,2H),3.85(s,3H),3.71(d,J=6.2Hz,3H).

[0427] Synthesis of intermediate c

[0428] Step 1: To a solution of N-methylpyrrolidone (20 mL) at room temperature, add intermediate a-1 (1 g, 3.95 mmol), potassium ferrocyanide (2.91 g, 7.90 mmol), and cuprous iodide (0.75 g, 3.95 mmol). The atmosphere was purged with nitrogen three times, and the reaction mixture was heated to 120°C and stirred for 16 h in a sealed chamber. LC-MS indicated complete reaction. After cooling the reaction mixture to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with water (100 mL x 2) and saturated brine (100 mL). The organic phase was collected and concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (1 / 100 v / v to 1 / 1 v / v)) to yield intermediate c-1.

[0429] Step 2: To a solution of N-methylpyrrolidone (3 mL) at room temperature were added intermediate c-1 (130 mg, 0.65 mmol), hydrazine hydrochloride (134.13 mg, 1.96 mmol), and N,N-diisopropylethylamine (253.09 mg, 1.96 mmol). The reaction mixture was heated to 130°C and stirred for 30 min under microwave conditions. LC-MS indicated complete reaction of the starting materials. After cooling the reaction mixture to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 4). The organic phase was washed with saturated brine (20 mL) and collected. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (1 / 100 (v / v) to 1 / 15 (v / v)) to obtain intermediate c. LC-MS (ESI): m / z = 185.0 [M+H] + .

[0430] Synthesis of intermediate d

[0431] Step 1: Under an ice bath, add methyl 2-imidazolecarboxylate (5 g, 39.65 mmol) to acetonitrile (100 mL). Then, add dropwise NBS dissolved in acetonitrile (100 mL) to the reaction mixture. The atmosphere was purged with nitrogen three times. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. LCMS indicated complete consumption of the starting material, and intermediate d-1 was detected. The reaction mixture was concentrated in vacuo to afford the crude product, which was then purified on a silica gel column using ethyl acetate / petroleum ether (1 / 100 to 1 / 1) as the eluent to afford intermediate d-1. LC-MS (ESI): m / z = 204.8 [M+H]+.

[0432] Step 2: To an anhydrous dichloromethane (100 mL) solution at room temperature were added intermediate d-1 (6.7 g, 32.68 mmol) and triethylamine (13.59 mL, 98.04 mmol). The reaction mixture was cooled to 0°C in an ice-salt bath. SEMCl (11.59 mL, 65.36 mmol) was added dropwise at 0°C. The mixture was warmed to room temperature and stirred for 16 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) confirmed the disappearance of the starting material. The reaction mixture was diluted with water (100 mL x 3), and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography using ethyl acetate / petroleum ether (1 / 100 to 1 / 10) as the eluent to obtain intermediate d-2. LC-MS (ESI): m / z = 335.0 [M+H]+.

[0433] Step 3: To a solution of 1,2-dioxane (15 mL) and water (0.8 mL) was added intermediate d-2, 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.82 g, 8.17 mmol), Pd(dppf)Cl2 (0.30 g, 0.41 mmol), and cesium carbonate (3.99 g, 12.26 mmol) at room temperature. The atmosphere was replaced with nitrogen three times and stirred at 130°C under a nitrogen atmosphere for 24 hours. LC-MS indicated the formation of the product. The reaction mixture was diluted with aqueous solution (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel chromatography using ethyl acetate / petroleum ether (1 / 100 to 1 / 1) to afford intermediate d-3. LC-MS (ESI): m / z=352.1[M+H]+.

[0434] Step 4: To an anhydrous tetrahydrofuran (15 mL) solution was added intermediate d-3 (840 mg, 2.39 mmol) and lithium aluminum tetrahydride (136.06 mg, 3.59 mmol) under ice-cooling. The reaction mixture was stirred at 0°C for 1 h. LC-MS indicated the formation of the product. The solution was diluted with ethyl acetate (100 mL), and the organic layer was extracted with water (100 mL) and ethyl acetate (100 mL x 2). The organic phase was concentrated in vacuo to obtain the crude product, which was then purified by silica gel chromatography using dichloromethane / methanol (1 / 100 to 1 / 20) as the eluent to afford intermediate d-4. LC-MS (ESI): m / z = 324.2 [M+H]+.

[0435] Step 5: To an anhydrous tetrahydrofuran (15 mL) solution at room temperature were added intermediate d-4 (970 mg, 3.00 mmol) and potassium tert-butoxide (0.92 mL, 7.50 mmol). The mixture was stirred at 40°C under a nitrogen atmosphere for 16 hours. LC-MS analysis revealed the product. The reaction mixture was diluted with aqueous solution (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by silica gel chromatography using ethyl acetate / petroleum ether (1 / 100 to 1 / 1) as the eluent to afford intermediate d-5. LC-MS (ESI): m / z = 304.0 [M+H]+.

[0436] Step 6: At room temperature, add intermediate d-5 (540 mg, 1.78 mmol) to anhydrous tetrahydrofuran (20 mL). The reaction mixture is cooled to -50°C, and LDA (1.78 mL, 3.56 mmol) is slowly added dropwise to the reaction mixture. The reaction is maintained at -50°C for 1 hour. A solution of carbon tetrabromide (1180.33 mg, 3.56 mmol) in tetrahydrofuran (1 mL) is slowly added dropwise to the reaction mixture. The reaction is continued at -50°C with stirring for 1 hour. LC-MS indicates the formation of the product. The reaction mixture is diluted with aqueous solution (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases are washed with saturated NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product is then purified by silica gel chromatography using ethyl acetate / petroleum ether (1 / 100 to 1 / 2) to afford intermediate d. LC-MS (ESI): m / z=382.0[M+H]+.

[0437] Synthesis of intermediate e

[0438] Step 1: A mixture of intermediate a-1 (2 g, 7.90 mmol), sodium hydroxide (3 g, 75.00 mmol), and water (50 mL) was stirred at 100°C for 2 hours. After completion of the reaction, the reaction mixture was filtered through a Buchner funnel, and the filter cake was collected and dried to afford crude intermediate e-1. LC-MS (ESI): m / z = 191.0 [M+H]+.

[0439] Step 2: Intermediate e-1 (1.2 g, 6.31 mmol), palladium hydroxide (0.1 g, 0.71 mmol), ethanol (15 mL), and glacial acetic acid (15 mL) were stirred at 25°C under a hydrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was filtered through a Buchner funnel, and the filter cake was collected and dried to afford crude intermediate e-2. LC-MS (ESI): m / z = 161.0 [M+H]+.

[0440] Step 3: A mixture of intermediate e-2 (1.5 g, 3.28 mmol), triethoxymethane (1.46 g, 9.83 mmol), pyridinium-1-4-methylbenzenesulfonate (0.82 g, 3.24 mmol), and toluene (20 mL) was stirred at 100°C under nitrogen for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 3) to afford intermediate e-3. LC-MS (ESI): m / z = 170.9 [M+H]+.

[0441] Step 4: A mixture of intermediate e-3 (245 mg, 1.44 mmol), DMF (10 mL), sodium 2-methylpropan-2-ol (138.36 mg, 1.44 mmol), and 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (996.10 mg, 2.88 mmol) was stirred at 25°C under nitrogen for 2 hours. The reaction mixture was filtered through a Buchner funnel, and the filtrate was concentrated under reduced pressure to provide intermediate e. LC-MS (ESI): m / z = 296.9 [M+H]. 1 H NMR (400MHz, DMSO) δ9.47(d,J=0.6Hz,1H),8.70(d,J=5.7Hz,1H),8.19(d,J=5.7Hz,1H),8.17–8.10(m,2H).

[0442] Synthesis of intermediate f

[0443] A mixture of intermediate e-2 (1 g, 2.19 mmol), (imidazol-1-yl)(imidazol-3-yl)formimine (0.70 g, 4.37 mmol), pyridin-1-ium 4-methylbenzenesulfonate (0.55 g, 2.19 mmol), and DMF (15 mL) was stirred at 75°C for 3 hours under nitrogen. After completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (dichloromethane / methanol = 93 / 7) to afford intermediate f. LC-MS (ESI): m / z = 186.0 [M+H]+.

[0444] Example 1 Preparation of Compound 1

[0445] Step 1: Dissolve ethyl 2-oxopiperidine-3-carboxylate (5 g, 29.21 mmol) in ethanol (50 mL) at room temperature. Under nitrogen, add sodium ethoxide (11.42 mL, 29.21 mmol). Stir at room temperature for 15 minutes, then add 4-chlorobenzyl bromide (6.00 g, 29.21 mmol). The reaction mixture is stirred at room temperature overnight. LC-MS indicates complete reaction. The reaction mixture is quenched with saturated aqueous ammonium chloride and extracted with water (50 mL) and ethyl acetate (50 mL x 2). The organic phase is washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (0 / 100 (v / v) to 30 / 70 (v / v)) to afford Intermediate 1-1. LC-MS (ESI): m / z = 296.0 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.25–7.15(m,4H),5.99(s,1H),4.31–4.15(m,2H),3.57(d,J=13.5Hz,1H),3.30–3.16(m,1H),3.12– 2.94(m,2H),2.13–2.03(m,1H),1.88–1.76(m,1H),1.73(dd,J=13.3,2.8Hz,1H),1.62–1.51(m,1H),1.29(t,J=7.1Hz,3H).

[0446] Step 2: Dissolve intermediate 1-1 (3 g, 10.14 mmol) in methanol (20 mL) and water (20 mL) at room temperature, cool to 0°C, add sodium hydroxide (2.43 g, 60.84 mmol), and stir the reaction mixture overnight. LC-MS indicated complete reaction. Concentrate the reaction mixture to remove methanol, adjust the pH to 4 with 1 mol / L hydrochloric acid, and extract with water (50 mL) and ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to yield intermediate 1-2. LC-MS (ESI): m / z = 268.0 [M+H] + .

[0447] Step 3: Dissolve Intermediate 1-2 (2.72 g, 10.16 mmol) in ethyl acetate (50 mL) at room temperature and heat to 90°C with stirring under reflux for 3 hours. LC-MS indicated complete reaction. The reaction mixture was cooled to room temperature and concentrated to afford Intermediate 1-3. LC-MS (ESI): m / z = 224.0 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.18(d,J=8.4Hz,2H),7.07(d,J=8.3Hz,2H),6.52(s,1H),3.30–3.11(m, 3H),2.63(m,1H),2.51–2.38(m,1H),1.81–1.63(m,2H),1.63–1.53(m,1H),1.41–1.28(m,1H).

[0448] Step 4: Intermediate a (55 mg, 0.15 mmol) and intermediate 1-3 (39 mg, 0.17 mmol) were placed in a microwave vial at room temperature and dissolved in 1,4-dioxane (2 mL). Cesium carbonate (118 mg, 0.36 mmol), Xantphos (34 mg, 0.06 mmol), and tris(dibenzylideneacetone)dipalladium (27 mg, 0.03 mmol) were added. After nitrogen purging, the reaction mixture was heated to 130°C using a microwave synthesizer for 45 minutes. LC-MS indicated complete reaction. Water (30 mL) and ethyl acetate (30 mL x 2) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 10 / 90 (v / v)) to afford intermediate 1-4. LC-MS (ESI): m / z = 521.2 [M+H] + .

[0449] Step 5: Intermediate 1-4 (100 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. LC-MS indicated complete reaction. The reaction mixture was concentrated, dissolved in DMF, and purified by HPLC (Phase A: 0.1% FA in H2O, Phase B: ACN) to afford compound 1. LC-MS (ESI): m / z = 391.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),9.28(s,1H),8.53(d,J=5.6Hz,1H),8.32(s,1H),8.15(brs,1H),7.93–7.85(m,1H),7.84 -7.78(m,1H),7.40–7.29(m,4H),4.27–4.10(m,2H),3.05–2.95(m,1H),2. 89–2.80(m,1H),2.59–2.50(m,1H),2.04–1.78(m,3H),1.562–1.48(m,1H).

[0450] Example 2 Preparation of Compound 2

[0451] Step 1: To dichloromethane (50 mL) was added pyrrolidin-2-one (5 g, 58.8 mmol, Anaiji, batch number: 0LGHRSDQ), N,N-diisopropylethylamine (30.4 g, 235 mmol), 4-dimethylaminopyridine (1.44 g, 11.8 mmol), and Boc2O (25.6 g, 118 mmol). The mixture was allowed to react at room temperature for 16 hours. TLC (petroleum ether / tetrahydrofuran = 3 / 1) showed complete consumption of the pyrrolidin-2-one, with the formation of a new, less polar spot. The reaction solution was concentrated and purified by silica gel column chromatography (0-25% tetrahydrofuran / petroleum ether) to afford Intermediate 2-1. 1 H NMR (400MHz, DMSO-d6) δ: 3.64 (t, J = 7.1 Hz, 2H), 2.40 (t, J = 8.0 Hz, 2H), 1.90 (m, 2H), 1.45 (s, 9H).

[0452] Step 2: To tetrahydrofuran (50 mL) was added intermediate 2-1 (5.00 g, 27.0 mmol) at room temperature. The mixture was cooled to -78°C under nitrogen atmosphere. A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (29.7 mL, 29.7 mmol) was added and stirred for 1 hour. Then, p-chlorobenzyl bromide (5.82 g, 28.3 mmol) dissolved in tetrahydrofuran (25 mL) was added dropwise to the reaction system. The mixture was reacted at -78°C for 3 hours. TLC (petroleum ether / tetrahydrofuran = 2 / 1) showed complete consumption of intermediate 2-1, with the formation of a new, more polar spot. The reaction mixture was quenched with saturated ammonium chloride (50 mL) at room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-25% tetrahydrofuran / petroleum ether) to afford intermediate 2-2. LC-MS(ESI): m / z=254.1[M+H-56] + .

[0453] Step 3: To dioxane (10 mL) was added Intermediate 2-2 (400 mg, 1.29 mmol), followed by dioxane hydrochloride (5 mL) at room temperature. The reaction was allowed to react for 1 hour. LC-MS confirmed the completion of the reaction. The reaction solution was quenched with saturated sodium bicarbonate (15 mL) at room temperature, diluted with water (15 mL), and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate 2-3.

[0454] Step 4: To toluene (1 mL) at room temperature, intermediate a (36 mg, 0.10 mmol), intermediate 2-3 (29.9 mg, 0.14 mmol), cuprous iodide (1.81 mg, 0.01 mmol), (1R,2R)-(-)-N,N-dimethylcyclohexane-1,2-diamine (2.71 mg, 0.02 mmol), and cesium carbonate (93.0 mg, 0.29 mmol) were added. The mixture was replaced with nitrogen three times and heated to 110°C for 3 hours. The reaction was complete as monitored by LC-MS. The reaction solution was cooled, filtered, concentrated, and purified by thin-layer chromatography (petroleum ether:tetrahydrofuran (0.5% triethylamine) = 2:3) to afford intermediate 2-4. LC-MS (ESI): m / z = 507.2 [M+H] + .

[0455] Step 5: To tetrahydrofuran (2 mL) was added intermediate 2-4 (58 mg, 0.11 mmol) and 70% pyridine hydrofluoric acid solution (4 mL) at room temperature. The reaction was allowed to react for 1 hour. LC-MS monitored the reaction completion. The reaction solution was concentrated, and the crude product was separated and purified by HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: H2O (0.05% NH3.H2O v / v)-ACN; B(ACN)%: 36%-76%, 9 min) and lyophilized to obtain compound 2. LC-MS (ESI): m / z = 377.0 [M+H] + . 1 H NMR(400MHz,CD3OD)δ:9.27(s,1H),8.51(d,J=5.9Hz,1H),8.41(d,J=6.2Hz,1H),7.92(s,2H),7.32(s,4H),4.1 5-3.98(m,2H),3.32-3.26(m,1H),3.23-3.13(m,1H),2.95-2.86(m,1H),2.40-2.30(m,1H),2.10-1.99(m,1H).

[0456] Example 3 Preparation of Compound 3

[0457] Step 1: Pyrrolidone-2-one (1.1 g, 6.94 mmol, Anaiji, batch number: 0LGHRSDQ) was dissolved in toluene (5 mL), and TFAA (1.05 mL, 7.57 mmol) was added at 0°C. After 1 hour, the reaction solution was concentrated, and an appropriate amount of toluene was added to the residue, and the mixture was re-concentrated. The above operation was repeated twice. The obtained colorless oily compound was re-dissolved in THF (3 mL) together with 3-chloro-4-fluorobenzaldehyde (1 g, 6.31 mmol, Bid Pharmaceuticals). 1M t-BuOK (8.20 mL, 8.20 mmol) in THF was slowly added to the system at 0°C. After the addition was complete, the resulting mixture was heated to 55°C in an oil bath and stirred for an additional hour. LC-MS showed the formation of the target product. Water (30 mL) was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 3-1. LC-MS (ESI): m / z = 226.0 [M+H] + .

[0458] Step 2: Intermediate 3-1 (1.2 g, 5.32 mmol) was dissolved in ethyl acetate (20 mL) and 10% palladium on carbon (280 mg, 2.66 mmol) was added. The resulting reaction system was purged with hydrogen three times and stirred at room temperature for 3 hours. LC-MS monitoring indicated the formation of the desired product. The reaction solution was filtered, the filtrate was concentrated, and purified by HPLC (ACN / H2O / 0.1% HCOOH) to afford Intermediate 3-2. LC-MS (ESI): m / z = 228.0 [M+H] + .

[0459] Step 3: Intermediate 3-2 (80 mg, 0.35 mmol), intermediate a (132.9 mg, 0.35 mmol), Pd2(dba)3 (32.18 mg, 0.035 mmol), XantPhos (40.67 mg, 0.07 mmol), and cesium carbonate (229 mg, 0.7 mmol) were dissolved in dioxane (10 mL). The resulting reaction system was purged with nitrogen three times and stirred at 100°C for 18 hours. LC-MS showed that the reaction was complete. The mixture was directly concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1 (v / v)) to obtain intermediate 3-3. LC-MS (ESI): m / z = 525.2 [M+H] + .

[0460] Step 4: Intermediate 3-3 (180 mg, 0.34 mmol) was dissolved in dioxane (5 mL), and 4M HCl / EA (7 mL, 28.00 mmol) was added. The resulting mixture was microwaved at 80°C for 1 hour. LC-MS monitoring showed complete consumption of the starting material. The reaction solution was directly concentrated, and the residue was added to water (10 mL). The pH was adjusted to 7-8 with saturated NaHCO₃. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were concentrated to give the crude product, which was further purified by HPLC (ACN / H₂O / 0.1% HCOOH) to give compound 3. LC-MS (ESI): m / z = 395.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ12.83(s,1H),9.29(s,1H),8.52(d,J=6.0Hz,1H),8.26–8.06(m,1H),7.94–7.78(m,2H),7.62-7.53(m,1H),7 .45–7.27(m,2H),4.18-4.06(m,1H),4.00-3.89(m,1H),3.25-3.12(m,2H),2.90–2.78(m,1H),2.25-2.14(m,1H),1.99-1.86(m,1H).

[0461] Example 4 Preparation of Compound 4

[0462] Step 1: Dissolve 3,5-difluoro-4-chlorobenzaldehyde (2 g, 11.33 mmol, Bidex Pharmaceuticals, batch number: CNA149) in methanol (50 mL). Add NaBH4 (430 mg, 11.33 mmol) in portions at 0°C. The resulting mixture is stirred at 0°C for 30 minutes. LC-MS monitoring indicates the formation of the desired product. The system is quenched by the addition of saturated ammonium chloride (20 mL). Excess methanol is removed by concentration, and the residue is washed with ethyl acetate (30 mL x 3). The combined organic phases are washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain the crude product, Intermediate 4-1. LC-MS (ESI): m / z = 161.0 [M+H-18] + .

[0463] Step 2: Intermediate 4-1 (1.5 g, 8.4 mmol) was dissolved in DCM (35 mL). Triethylamine (2.33 mL, 16.8 mmol) and MsCl (0.72 mL, 9.24 mmol) were added at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. LC-MS monitoring indicated the reaction was complete. Water (30 mL) was added to the reaction solution, the DCM phase was separated, and the aqueous phase was extracted with DCM (10 mL x 3). The combined organic phases were washed once with saturated NaHCO3 and once with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, Intermediate 4-2. LC-MS (ESI): m / z = 161.0 [M+H-96] + .

[0464] Step 3: Ethyl 2-oxopyrrolidine-3-carboxylate (900 mg, 5.73 mmol, Bidex Pharmaceuticals, Batch No. CNZ287) was dissolved in ethanol (30 mL). A 20 wt% NaOEt solution in ethanol (2.24 mL, 5.73 mmol) was added. After 30 minutes, a solution of Intermediate 4-2 (2.2 g, 8.59 mmol) in ethanol (3 mL) was added. The resulting mixture was stirred at room temperature for 3 hours. LC-MS monitoring indicated the reaction was complete. Water (30 mL) was added to the reaction solution, and the excess ethanol was removed by vortexing. The residue was extracted with ethyl acetate (20 mL x 3). The combined organic phases were concentrated and separated by silica gel column chromatography (DCM:MeOH = 20:1 (v / v)) to afford Intermediate 4-3. LC-MS (ESI): m / z = 318.0 [M+H] + .

[0465] Step 4: Intermediate 4-3 (500 mg, 1.57 mmol) and LiCl (113.41 mg, 2.68 mmol) were dissolved in DMSO (10 mL), and water (0.09 mL, 5.19 mmol) was added. The resulting mixture was stirred at 180°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The system was cooled to room temperature, and water (50 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were separated by silica gel column chromatography (DCM:MeOH = 30:1 (v / v)) to obtain intermediate 4-4. LC-MS (ESI): m / z = 246.0 [M+H] + .

[0466] Step 5: Intermediate 4-4 (84.4 mg, 0.34 mmol), intermediate a (130 mg, 0.34 mmol), Pd2(dba)3 (31.46 mg, 0.034 mmol), XantPhos (39.76 mg, 0.068 mmol), and cesium carbonate (223.9 mg, 0.68 mmol) were dissolved in dioxane (5 mL). The resulting reaction system was purged with nitrogen three times and stirred at 100°C for 18 hours. LC-MS monitoring showed that the reaction was complete. The mixture was directly concentrated, and the residue was separated by silica gel column chromatography (DCM:MeOH = 30:1 (v / v)) to obtain intermediate 4-5. LC-MS (ESI): m / z = 543.2 [M+H] + .

[0467] Step 6: Intermediate 4-5 (170 mg, 0.31 mmol) was dissolved in dioxane (5 mL), and 4M HCl / EA (7 mL, 28.00 mmol) was added. The resulting mixture was microwaved at 80°C for 1 hour. LC-MS monitoring showed complete consumption of the starting material. The reaction solution was directly concentrated, and water (10 mL) was added to the residue. The pH was adjusted to 7-8 with saturated NaHCO₃. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were concentrated to give the crude product, which was further purified by HPLC (ACN / H₂O / 0.1% HCOOH) to give compound 4. LC-MS (ESI): m / z = 413.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),9.28(s,1H),8.52(d,J=6.0Hz,1H),8.18-8.10(m,1H),7.94–7.77(m,2H),7. 39-7.31(m,2H),4.22-4.09(m,1H),4.02-3.91(m,1H),3.30–3.16(m,2H),2.93–2.81(m,1H),2.30-2.18(m,1H),2.0 -1.87(m,1H).

[0468] Example 5 Preparation of Compound 5

[0469] Step 1: Dissolve 3-fluoro-4-chlorobenzyl alcohol (2.0 g, 12.46 mmol, Adamas, batch number: P2138624) in dichloromethane (20 mL) at room temperature. After cooling in an ice-water bath, slowly add triphenylphosphine (3.92 g, 14.95 mmol) and carbon tetrabromide (4.96 g, 14.95 mmol). The reaction mixture is stirred at room temperature for 3 hours. TLC monitoring indicates complete reaction. The reaction mixture is concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (0 / 100 v / v to 10 / 90 v / v)) to obtain intermediate 5-1. 1 H NMR (400MHz, CDCl3) δ7.37 (t, J = 7.9 Hz, 1H), 7.19 (dd, J = 9.5, 2.0 Hz, 1H), 7.12 (dd, J = 8.2, 1.6 Hz, 1H), 4.42 (s, 2H).

[0470] Step 2: Dissolve ethyl 2-oxopyrrolidine-3-carboxylate (500 mg, 3.18 mmol, Bidex Pharmaceuticals, Batch No. CNZ287) in ethanol (10 mL) at room temperature. Add sodium ethoxide (1.24 mL, 3.18 mmol). Stir at room temperature for 15 minutes, then add Intermediate 5-1 (711 mg, 3.18 mmol). The reaction mixture is stirred at room temperature overnight. LC-MS monitoring indicates complete reaction. The reaction mixture is quenched with saturated aqueous ammonium chloride solution, then extracted with water (20 mL) and ethyl acetate (20 mL x 2). The organic phase is washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. Purification by silica gel column chromatography (methanol / dichloromethane (0 / 100 v / v to 3 / 97 v / v)) affords Intermediate 5-2. LC-MS (ESI): m / z = 300.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.50(t,J=8.1Hz,1H),7.26(dd,J=10.7,1.8Hz,1H),7.10(dd,J=8.3,1.5Hz,1H),4.21–4 .02(m,2H),3.20–3.08(m,2H),3.08–2.95(m,1H),2.89–2.70(m,1H),2.36–2.26(m,1H),2.07–1.98(m,1H),1.25–1.09(m,3H).

[0471] Step 3: At room temperature, intermediate 5-2 (800 mg, 2.67 mmol) was dissolved in ethanol (10 mL) and water (5 mL). The temperature was lowered to 0°C and sodium hydroxide (641 mg, 16.01 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. LC-MS monitoring showed that the reaction of the starting material was complete. The reaction mixture was concentrated to remove ethanol, and the pH was adjusted to 4 with 1 mol / L hydrochloric acid. Water (30 mL) and ethyl acetate (30 mL x 2) were added for extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 5-3. LC-MS (ESI): m / z = 272.0 [M+H] + .

[0472] Step 4: Dissolve intermediate 5-3 (600 mg, 2.21 mmol) in ethyl acetate (10 mL) at room temperature, heat to 90°C, and reflux with stirring for 3 hours. LC-MS monitoring indicated complete reaction. The reaction mixture was cooled to room temperature and concentrated to afford intermediate 5-4. LC-MS (ESI): m / z = 228.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.67(s,1H),7.49(t,J=8.1Hz,1H),7.32(dd,J=10.7,1.7Hz,1H),7.12(dd,J=8.2, 1.2Hz,1H),3.14–3.04(m,2H),3.03–2.94(m,1H),2.62–2.53(m,2H),2.04–1.91(m,1H),1.70–1.54(m,1H).

[0473] Step 5: Intermediate 5-4 (57 mg, 0.25 mmol) and intermediate a (80 mg, 0.21 mmol) were placed in a microwave vial at room temperature and dissolved in 1,4-dioxane (2 mL). Cesium carbonate (172 mg, 0.53 mmol), Xantphos (49 mg, 0.08 mmol), and tris(dibenzylideneacetone)dipalladium (39 mg, 0.04 mmol) were then added. After nitrogen purging, the reaction mixture was heated to 130°C using a microwave synthesizer for 60 minutes. LC-MS monitoring indicated complete reaction. Water (30 mL) and ethyl acetate (30 mL x 2) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The mixture was then purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 v / v to 3 / 97 v / v)) to afford intermediate 5-5. LC-MS (ESI): m / z = 525.2 [M+H] + .

[0474] Step 6: Intermediate 5-5 (230 mg, 0.44 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS monitoring indicated that the reaction was complete. The reaction mixture was concentrated to obtain product A, which was then dissolved in DMF and purified by HPLC (Phase A: 0.1% FA in H2O, Phase B: ACN) to obtain compound 5. LC-MS (ESI): m / z = 395.0 [M+H] + . 1 HNMR(400MHz, DMSO-d6)δ12.92(s,1H),9.41(s,1H),8.55(d,J=5.9Hz,1H),8.26(s,1H),8.00–7.90(m,2H),7.56–7.50(m,1H),7.44–7.38(m,1H) ,7.20(dd,J=8.3,2.0Hz,1H),4.18–4.09(m,1H),4.02-3.92(m,1H),3.2 5–3.16(m,2H),2.91–2.81(m,1H),2.27–2.18(m,1H),1.99–1.87(m,1H).

[0475] Example 6 Preparation of Compound 6

[0476] Step 1: Dissolve ethyl 2-oxopyrrolidine-3-carboxylate (500 mg, 3.18 mmol, Bidex Pharmaceuticals, Batch No. CNZ287) in ethanol (10 mL) at room temperature. Add sodium ethoxide (1.24 mL, 3.18 mmol) and stir at room temperature for 15 minutes. Then, add 3,4-dichlorobenzyl bromide (763 mg, 3.18 mmol). The reaction mixture is stirred at room temperature overnight. LC-MS monitoring indicates complete reaction. The reaction mixture is quenched with saturated aqueous ammonium chloride and extracted with water (20 mL) and ethyl acetate (20 mL x 2). The organic phase is washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. Purification by silica gel column chromatography (methanol / dichloromethane (0 / 100 v / v to 3 / 97 v / v)) provides Intermediate 6-1. LC-MS (ESI): m / z = 316.0 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.34(dd,J=5.1,3.1Hz,2H),7.09(dd,J=8.3,2.0Hz,1H),6.27(s,1H),4.23(q,J=7.1Hz,2H),3 .44–3.33(m,1H),3.25–3.14(m,2H),3.04–2.94(m,1H),2.55–2.46(m,1H),2.16–2.02(m,1H),1.29(t,J=7.1Hz,3H).

[0477] Step 2: Dissolve intermediate 6-1 (820 mg, 2.59 mmol) in ethanol (10 mL) and water (5 mL) at room temperature, cool to 0°C, and add sodium hydroxide (519 mg, 12.97 mmol). The reaction mixture is stirred at room temperature for 3 hours. LC-MS monitoring shows that the reaction is complete. The reaction mixture is concentrated to remove ethanol, and the pH is adjusted to 4 with 1 mol / L hydrochloric acid. Water (30 mL) and ethyl acetate (30 mL x 2) are then added for extraction. The organic phase is washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain intermediate 6-2. LC-MS (ESI): m / z = 288.0 [M+H] + .

[0478] Step 3: Dissolve intermediate 6-2 (730 mg, 2.53 mmol) in ethyl acetate (10 mL) at room temperature, heat to 90°C, and reflux with stirring for 3 hours. LC-MS monitoring indicated complete reaction. The reaction mixture was cooled to room temperature and concentrated to afford crude intermediate 6-3. LC-MS (ESI): m / z = 244.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.67(s,1H),7.54(d,J=8.4Hz,2H),7.25(dd,J=8.2,1.9Hz,1H),3.1 3–3.01(m,2H),3.01–2.92(m,1H),2.64–2.53(m,2H),2.02–1.90(m,1H),1.69–1.55(m,1H).

[0479] Step 4: Intermediate a (100 mg, 0.26 mmol) and intermediate 6-3 (77 mg, 0.32 mmol) were placed in a microwave vial at room temperature. 1,4-dioxane (2 mL) was added for dissolution. Cesium carbonate (215 mg, 0.66 mmol), Xantphos (61 mg, 0.11 mmol), and tris(dibenzylideneacetone)dipalladium (48 mg, 0.05 mmol) were then added. After nitrogen purging, the reaction mixture was heated to 130°C using a microwave synthesizer for 60 minutes. LC-MS monitoring indicated complete reaction. Water (30 mL) and ethyl acetate (30 mL x 2) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 3 / 97 (v / v)) to afford intermediate 6-4. LC-MS (ESI): m / z = 541.2 [M+H] + .

[0480] Step 5: Intermediate 6-4 (220 mg, 0.41 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. LC-MS monitoring indicated complete reaction. The reaction mixture was concentrated, dissolved in DMF, and purified by HPLC (Phase A: 0.1% FA in H2O, Phase B: ACN) to afford compound 6. LC-MS (ESI): m / z = 411.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.94(br s,1H),9.42(s,1H),8.55(d,J=5.9Hz,1H),8.27(s,1H),8.00–7.88(m,2H),7.64(d,J=1.6Hz,1H),7.59(d,J=8.2Hz,1H),7.39– 7.29(m,1H),4.20–4.08(m,1H),4.02–3.91(m,1H),3.23–3.13(m,2H),2.91–2.81(m,1H),2.28–2.17(m,1H),2.00–1.86(m,1H).

[0481] Example 7 Synthesis of Compound 7

[0482] Step 1: Dissolve ethyl 2-oxopyrrolidine-3-carboxylate (500 mg, 3.18 mmol, Bidex Pharmaceuticals, Batch No. CNZ287) in ethanol (10 mL) at room temperature. Add sodium ethoxide (1.24 mL, 3.18 mmol). Stir at room temperature for 15 minutes, then add 5-bromomethyl-2-chloro-3-fluoropyridine (714 mg, 3.18 mmol). Stir the reaction mixture overnight at room temperature. LC-MS monitoring indicated complete reaction. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with water (20 mL) and ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. Purification by silica gel column chromatography (methanol / dichloromethane (0 / 100 v / v to 3 / 97 v / v)) afforded Intermediate 7-1. LC-MS (ESI): m / z = 301.0 [M+H] + .

[0483] Step 2: Dissolve intermediate 7-1 (580 mg, 1.93 mmol) in ethanol (10 mL) and water (5 mL) at room temperature, cool to 0°C, then add sodium hydroxide (309 mg, 7.72 mmol). Stir the reaction mixture at room temperature for 3 hours. LC-MS monitoring indicated complete reaction. Concentrate the reaction mixture to remove ethanol, adjust the pH to 4 with 1 mol / L hydrochloric acid, and extract with water (30 mL) and ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield intermediate 7-2. LC-MS (ESI): m / z = 273.0 [M+H] + .

[0484] Step 3: Dissolve intermediate 7-2 (450 mg, 1.65 mmol) in ethyl acetate (10 mL) at room temperature, heat to 100°C, and reflux with stirring overnight. LC-MS monitoring indicated complete reaction of the starting material. The reaction solution was cooled to room temperature, concentrated, and purified by silica gel column chromatography using methanol / dichloromethane (0 / 100 (v / v) to 3 / 97 (v / v)) to obtain intermediate 7-3. LC-MS (ESI): m / z = 229.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.19 (s, 1H), 7.89 (dd, J = 9.8, 1.8Hz, 1H), 7.68 (s, 1H), 3.13–3. 07(m,2H),3.07–2.97(m,1H),2.69–2.57(m,2H),2.07–1.96(m,1H),1.71–1.59(m,1H).

[0485] Step 4: Intermediate a (100 mg, 0.26 mmol) and intermediate 7-3 (73 mg, 0.32 mmol) were placed in a microwave vial at room temperature. 1,4-dioxane (2 mL) was added for dissolution. Cesium carbonate (215 mg, 0.66 mmol), Xantphos (61 mg, 0.11 mmol), and tris(dibenzylideneacetone)dipalladium (48 mg, 0.05 mmol) were then added. After nitrogen purging, the reaction mixture was heated to 130°C using a microwave synthesizer for 60 minutes. LC-MS monitoring indicated complete reaction. Water (30 mL) and ethyl acetate (30 mL x 2) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 3 / 97 (v / v)) to afford intermediate 7-4. LC-MS (ESI): m / z = 526.2 [M+H] + .

[0486] Step 5: Intermediate 7-4 (60 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS monitoring indicated complete reaction. The reaction mixture was concentrated, dissolved in DMF, and purified by HPLC (Phase A: 0.1% FA in H2O, Phase B: ACN) to afford compound 7. LC-MS (ESI): m / z = 396.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),9.28(s,1H),8.52(d,J=5.6Hz,1H),8.29(s,1H),8.13(d,J=5.8Hz,1H),8.00(d,J=8.4Hz,1H), 7.91–7.79(m,2H),4.22–4.11(m,1H),4.02-3.92(m,1H),3.30–3.18(m,2H),2.98-2.89(m,1H),2.31–2.21(m,1H),2.01–1.90(m,1H).

[0487] Example 8 Preparation of Compound 8

[0488] Step 1: Dissolve 3-(4-chlorophenyl)propanoic acid (500 mg, 2.71 mmol, Bis-Phase, Batch No. CNZ584) in dichloromethane (10 mL) at room temperature, cool to 0°C, and add oxalyl chloride (1.16 mL, 13.54 mmol). Then, warm to room temperature and stir for 2 hours. TLC monitoring indicated complete reaction. The reaction solution was concentrated to yield Intermediate 8-1.

[0489] Step 2: Intermediate b (100 mg, 0.30 mmol) was dissolved in DMF (3 mL) at room temperature and cooled to 0°C. Sodium hydride (18 mg, 0.45 mmol, 60% purity) was added and stirred for 30 minutes. Intermediate 8-1 (73 mg, 0.36 mmol) was then added. The reaction mixture was then warmed to room temperature and stirred for 3 hours. LC-MS monitoring indicated complete reaction. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with water (20 mL) and ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 5 / 95 (v / v)) to afford Intermediate 8-2. LC-MS (ESI): m / z = 501.0 [M+H] + .

[0490] Step 3: Intermediate 8-2 (60 mg, 0.12 mmol) was dissolved in 1,2-dichloroethane (3 mL) and trifluoroacetic acid (1 mL) at room temperature, heated to 60°C, and stirred for 0.5 h. LC-MS monitoring indicated complete reaction. The reaction solution was concentrated, dissolved in DMF, and purified by HPLC (Phase A: 0.1% FA in H2O, Phase B: ACN) to afford compound 8. LC-MS (ESI): m / z = 351.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.95(s,1H),12.00(s,1H),9.58(s,1H),8.60(d,J=6.2Hz,1H),8 .33(s,1H),8.02(s,2H),7.40–7.30(m,4H),2.98(t,J=7.4Hz,2H),2.83(t,J=7.4Hz,2H).

[0491] Example 9 Preparation of Compound 9

[0492] Step 1: To a solution of dichloromethane (5 mL) at room temperature, add 3-(4-chloro-3-fluorophenyl)propanoic acid (200 mg, 0.99 mmol, Bismuth, Batch CQY874) and oxalyl chloride (626.43 mg, 4.94 mmol). Stir at room temperature for 2 h. TLC (ethyl acetate / petroleum ether = 20 / 1) indicates complete reaction. The reaction mixture is concentrated under reduced pressure to yield Intermediate 9-1.

[0493] Step 2: Under ice-cooling conditions, intermediate b (100 mg, 0.30 mmol) was added to a solution of N,N-dimethylformamide (2 mL), followed by the slow addition of sodium hydride (23.92 mg, 0.60 mmol, 60% purity). The reaction mixture was stirred at 0°C for 0.5 h. Intermediate 9-1 was then slowly added dropwise, and the resulting reaction mixture was stirred at room temperature for 2 h. LC-MS monitoring indicated complete reaction of the starting material. Water (10 mL) was slowly added dropwise under ice-cooling conditions, followed by extraction with ethyl acetate (20 mL x 3). The organic phase was concentrated in vacuo to yield the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (1 / 100 (v / v) to 1 / 10 (v / v)) to yield intermediate 9-2. LC-MS (ESI): m / z = 519.2 [M+H] + .

[0494] Step 3: To a solution of 1,2-dichloroethane (2 mL) and TFA (1 mL) at room temperature was added intermediate 9-2 (79.37 mg, 0.20 mmol). The reaction mixture was heated to 60°C and stirred for 1 h. LC-MS monitoring indicated complete reaction of the starting material. The reaction mixture was purified by HPLC under acidic conditions (Phase A: 0.1% FA / H2O; Phase B: ACN) to afford compound 9. LC-MS (ESI): m / z = 369.0 [M+H] + .

[0495] 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),11.90(s,1H),9.28(s,1H),8.52(d,J=5.7Hz,1H),8.14(s,1H),8.06(d,J=5.7Hz,1H),7.88–7.76(m,2H),7.54 -7.49(m,1H),7.41–7.33(m,1H),7.20–7.14(m,1H),3.00(t,J=7.3Hz,2H),2.83(t,J=7.4Hz,2H).

[0496] Example 10 Preparation of Compound 10

[0497] Step 1: To a solution of toluene (10 mL) and water (0.5 mL) at room temperature were added 5-bromo-2-chloro-3-fluoropyridine (200 mg, 0.95 mmol, Bidler, Batch: DLY954), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (644.62 mg, 2.85 mmol, Bidler, Batch: CGU883), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (61.37 mg, 0.1 mmol), and potassium phosphate (605.22 mg, 2.85 mmol). The atmosphere was flushed with nitrogen three times and the reaction was heated to 80°C in a microwave oven with stirring for 40 min. LC-MS monitoring indicated complete reaction of the starting material. After the reaction mixture was cooled to room temperature, ethyl acetate (50 mL) was added, and the mixture was washed with water (50 mL x 2) and saturated brine (100 mL). The organic phase was collected and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (1 / 100 (v / v) to 1 / 8 (v / v)) to obtain Intermediate 10-1. LC-MS (ESI): m / z = 230.0 [M+H] + .

[0498] Step 2: To anhydrous tetrahydrofuran (20 mL) at room temperature, add intermediate 10-1 (700 mg, 3.05 mmol) and then rhodium on carbon (31 mg, 9.15 mmol). The reaction was stirred at room temperature under a hydrogen atmosphere for 2 h. LC-MS monitoring indicated complete reaction. The reaction solution was filtered and the filtrate was concentrated under vacuum to obtain crude intermediate 10-2. LC-MS (ESI): m / z = 232.0 [M+H] + .

[0499] Step 3: To a solution of ethanol (5 mL), water (5 mL), and tetrahydrofuran (1.5 mL) at room temperature, intermediate 10-2 (500 mg, 2.16 mmol) and LiOH (271.70 mg, 6.48 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. LC-MS monitoring indicated that the starting material was completely reacted. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was separated, washed with saturated NaCl solution, and then concentrated in vacuo. The product was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (1 / 100 (v / v) to 1 / 1 (v / v)) to afford intermediate 10-3. LC-MS (ESI): m / z = 204.0 [M+H] + .

[0500] Step 4: To a solution of dichloromethane (5 mL) at room temperature, add Intermediate 10-3 (200 mg, 0.99 mmol) and oxalyl chloride (626.43 mg, 4.94 mmol). Stir at room temperature for 2 h. TLC (ethyl acetate / petroleum ether = 20 / 1 (v / v)) monitoring indicated complete reaction. The reaction mixture was then concentrated under reduced pressure to yield crude Intermediate 10-4.

[0501] Step 5: Under ice-cooling, intermediate b (100 mg, 0.30 mmol) was added to a solution of N,N-dimethylformamide (2 mL), followed by the slow addition of sodium hydride (23.92 mg, 0.60 mmol, 60% purity). The reaction mixture was stirred at 0°C for 0.5 h. Intermediate 10-4 was then added, and the resulting reaction mixture was stirred at room temperature for 2 h. LC-MS indicated complete reaction. Water (10 mL) was slowly added dropwise under ice-cooling, followed by extraction with ethyl acetate (20 mL x 3). The organic phase was concentrated in vacuo to afford the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (1 / 100 v / v to 1 / 10 v / v)) to afford intermediate 10-5. LC-MS (ESI): m / z = 520.0 [M+H] + .

[0502] Step 6: To a solution of 1,2-dichloroethane (2 mL) and TFA (1 mL) at room temperature was added intermediate 10-5 (79.37 mg, 0.20 mmol). The reaction mixture was heated to 60°C and stirred for 1 h. LC-MS monitoring indicated complete reaction of the starting material. The reaction mixture was purified by HPLC under acidic conditions (Phase A: 0.1% FA / H2O; Phase B: ACN) to afford compound 10. LC-MS (ESI): m / z = 370.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.64(br s,1H),11.89(br s,1H),9.27(s,1H),8.52(d,J=5.7Hz,1H),8.30–8.18(m,2H),8.08(brs,1H),7.95(d d,J=9.7,1.7Hz,1H),7.87–7.75(m,2H),3.06(t,J=7.4Hz,2H),2.88(t,J=7.3Hz,2H).

[0503] Example 11 Preparation of Compound 11

[0504] Step 1: Dissolve 2-(4-chlorophenyl)ethan-1-ol (5.00 g, 31.93 mmol, Bidler, Batch No. CMZ071) in dichloromethane (50 mL) at room temperature. Add triphenylphosphine (9.21 g, 35.12 mmol), imidazole (2.61 g, 38.31 mmol), and iodine (8.91 g, 35.12 mmol) under ice-water cooling. The reaction was stirred at room temperature for 2 hours. TLC monitoring indicated complete reaction. Water (50 mL) and dichloromethane (50 mL × 2) were added to the reaction solution for extraction. The organic phase was washed with aqueous sodium thiosulfate (50 mL × 2) and saturated brine (50 mL × 5), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The mixture was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (0 / 100 (v / v) to 10 / 90 (v / v)) to afford Intermediate 11-1. 1 H NMR (400MHz, DMSO-d6) δ7.37 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 3.46 (t, J = 7.3 Hz, 2H), 3.12 (t, J = 7.3 Hz, 2H).

[0505] Step 2: Dissolve triethyl phosphoacetate (3.00 g, 13.38 mmol, Bidler, Batch No. DLY849) in tetrahydrofuran (40 mL) at room temperature and cool to 0°C. Add potassium tert-butoxide (1.95 g, 17.40 mmol) and stir for 0.5 hours before adding Intermediate 11-1 (3.74 g, 14.05 mmol). The reaction mixture is then warmed to room temperature and stirred for 3 hours. LC-MS monitoring indicates complete reaction. The reaction mixture is quenched with saturated aqueous ammonium chloride and extracted with water (40 mL) and ethyl acetate (40 mL x 2). The organic phase is washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. Purification by silica gel column chromatography (ethyl acetate / petroleum ether (0 / 100 (v / v) to 30 / 70 (v / v)) affords Intermediate 11-2. LC-MS (ESI): m / z = 363.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.28–7.25(m,2H),7.18–7.08(m,2H),4.30–4.07(m,6H),3.02–2.87(m,1H) ,2.78–2.67(m,1H),2.65–2.52(m,1H),2.38–2.23(m,1H),2.22–2.06(m,1H),1.40–1.27(m,9H).

[0506] Step 3: Intermediate 11-2 (2.60 g, 7.17 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL) at room temperature. Potassium carbonate (2.97 g, 21.50 mmol) and aqueous formaldehyde (5.82 g, 71.67 mmol) were added. The reaction mixture was heated to 70°C and stirred for 3 hours. LC-MS monitoring indicated complete reaction. Water (20 mL) and ethyl acetate (30 mL × 2) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (0 / 100 (v / v) to 20 / 80 (v / v)) to afford Intermediate 11-3. LC-MS (ESI): m / z = 239.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.21–7.11(m,2H),7.08–6.97(m,2H),6.08(d,J=1.2Hz,1H),5.40(dd,J=2.5,1.2Hz, 1H), 4.15 (q, J = 7.1Hz, 2H), 2.69 (dd, J = 9.1, 6.5Hz, 2H), 2.51 (dd, J = 9.2, 6.4Hz, 2H), 1.24 (t, J = 7.1Hz, 3H).

[0507] Step 4: Intermediate 11-3 (1.40 g, 5.86 mmol) was dissolved in ethanol (20 mL) and water (10 mL) at room temperature. After cooling to 0°C, lithium hydroxide (0.70 g, 29.32 mmol) was added. The reaction solution was then warmed to room temperature and stirred for 3 hours. LC-MS monitoring showed that the starting material had reacted completely. The reaction solution was concentrated to remove ethanol, and the pH was adjusted to 4 with 1 mol / L hydrochloric acid. Water (20 mL) and ethyl acetate (20 mL × 2) were added for extraction. The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 11-4. LC-MS (ESI): m / z = 209.0 [MH] - . 1 H NMR(400MHz,DMSO-d6)δ12.51(s,1H),7.36–7.29(m,2H),7.22(d,J=8.4Hz,2H),6 .03(d,J=1.4Hz,1H),5.55(d,J=1.3Hz,1H),2.82–2.65(m,2H),2.52–2.48(m,2H).

[0508] Step 5: Dissolve Intermediate 11-4 (500 mg, 2.37 mmol) in hydrobromic acid (10 mL, 33% wt in AcOH) at room temperature. Stir the reaction mixture for 3 hours. TLC monitoring indicates complete reaction. Concentrate the reaction mixture to yield Intermediate 11-5. 1 H NMR(400MHz,DMSO-d6)δ12.65(s,1H),7.38–7.31(m,2H),7.26–7.19(m,2H), 3.74–3.60(m,2H),2.76–2.66(m,1H),2.66–2.56(m,2H),1.96–1.70(m,2H).

[0509] Step 6: Dissolve Intermediate 11-5 (200 mg, 0.69 mmol) in dichloromethane (5 mL) at room temperature. Cool in an ice-water bath and add oxalyl chloride (0.29 mL, 3.43 mmol). Then, warm the reaction mixture to room temperature and stir for 3 hours. TLC monitoring indicates complete reaction. Concentrate the reaction mixture to obtain Intermediate 11-6.

[0510] Step 7: Intermediate b (100 mg, 0.30 mmol) was dissolved in DMF (3 mL) at room temperature and cooled to 0°C. Sodium hydride (18 mg, 0.45 mmol, 60% purity) was added and stirred for 30 minutes. Intermediate 11-6 (111 mg, 0.36 mmol) was then added. The reaction mixture was then heated to 90°C and stirred for 3 hours. LC-MS monitoring indicated complete reaction of the starting material. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. Water (20 mL) and ethyl acetate (20 mL x 2) were then added for extraction. The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (0 / 100 (v / v) to 5 / 95 (v / v)) to afford Intermediate 11-7. LC-MS (ESI): m / z = 527.2 [M+H] + .

[0511] Step 8: Intermediate 11-7 (115 mg, 0.22 mmol) was dissolved in 1,2-dichloroethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature, heated to 60°C, and stirred for 0.5 hours. LC-MS monitoring indicated complete reaction. The reaction solution was concentrated, dissolved in DMF, and purified by HPLC (Phase A: 0.1% FA in H2O, Phase B: ACN) to afford compound 11. LC-MS (ESI): m / z = 377.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.81(br s,1H),11.89(br s,1H),9.29(s,1H),8.53(d,J=5.7Hz,1H),8.15(s,1H),7.90–7.78(m,2H),7.37–7.32(m ,2H),7.31–7.26(m,2H),6.17(s,1H),5.67(s,1H),2.84–2.77(m,2H),2.74–2.65(m,2H).

[0512] Examples 12 and 13 Synthesis of Compounds 12 and 13

[0513] To a solution of N,N-dimethylformamide (0.5 mL) at room temperature were added 3-(4-chlorophenyl)propionic acid (40 mg, 0.22 mmol, Bidler, Batch No. CNZ584), intermediate c (48.11 mg, 0.26 mmol), triethylamine (65.92 mg, 0.65 mmol), and HATU (99.09 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by HPLC under alkaline conditions (Phase A: 10 mM NH4HCO3 / H2O, Phase B: ACN) to afford Compounds 12 and 13.

[0514] Compound 12: LC-MS (ESI): m / z = 351.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.88(s,1H),10.54(s,1H),9.33(s,1H),8.69(d,J=5.6Hz,1H),8.23(d,J=5.3Hz,1 H), 7.83 (d, J = 8.8Hz, 1H), 7.58 (d, J = 8.9Hz, 1H), 7.36 (m, 4H), 2.98 (t, J = 7.9Hz, 2H), 2.75 (t, J = 7.5Hz, 2H).

[0515] Compound 13: LC-MS (ESI): m / z = 351.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.57 (d, J = 5.3Hz, 1H), 8.09 (d, J = 5.3Hz, 1H), 7.82–7. 68 (m, 3H), 7.37 (s, 4H), 7.08 (d, J = 9.1Hz, 1H), 3.61 (d, J = 7.5Hz, 2H), 3.05 (t, J = 7.5Hz, 2H).

[0516] Example 14 Synthesis of Compound 14

[0517] Step 1: Dissolve 3,5-difluoro-4-chlorobenzaldehyde (1.0 g, 5.66 mmol, Bidler, DQU774) in methanol (10 mL) at room temperature. Slowly add sodium borohydride (0.21 g, 5.66 mmol) at 0-10°C and stir at 0-10°C for 1 hour. LC-MS indicates complete reaction. Extract the reaction mixture with water (30 mL) and ethyl acetate (30 mL x 2). The organic phase is washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the crude product is purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to afford Intermediate 14-1.

[0518] Step 2: Dissolve Intermediate 14-1 (900 mg, 5.04 mmol) in dichloromethane (20 mL) at room temperature. After cooling in an ice-water bath, slowly add phosphorus tribromide (2.04 g, 7.56 mmol, Titan, P2169731). Stir the reaction mixture at room temperature for 1 hour. TLC indicated complete reaction. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (0-5% ethyl acetate / petroleum ether) to afford Intermediate 14-2.

[0519] Step 3: Ethyl 2-oxopiperidine-3-carboxylate (921 mg, 3.82 mmol, Bidex, CMY580) was dissolved in ethanol (10 mL) at room temperature. Sodium ethoxide (432 mg, 6.36 mmol, Anaiji, WMEZRRRM) was added and stirred at room temperature for 15 minutes. Intermediate 14-2 (500 mg, 3.18 mmol) was then added and the reaction mixture was stirred at room temperature overnight. LC-MS indicated that the reaction was complete. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with water (30 mL) and ethyl acetate (30 mL × 2). The organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (0-35% ethyl acetate / petroleum ether) to obtain Intermediate 14-3. LC-MS (ESI): m / z = 332.2 [M+H] + .

[0520] Step 4: Intermediate 14-3 (550 mg, 1.88 mmol) was dissolved in ethanol (10 mL) and water (5 mL) at room temperature. Sodium hydroxide (199 mg, 4.97 mmol, Titan, P2468807) was added and the reaction mixture was stirred at room temperature for 3 hours. LC-MS showed that the starting material was completely reacted. The reaction mixture was concentrated to remove ethanol, and the pH was adjusted to 4 with 1 mol / L hydrochloric acid. Water (30 mL) and ethyl acetate (30 mL x 2) were added for extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude intermediate 14-4. LC-MS (ESI): m / z = 304.0 [M+H] + .

[0521] Step 5: Dissolve Intermediate 14-4 (480 mg, 1.58 mmol) in ethyl acetate (20 mL) at room temperature, heat to 90°C, and reflux with stirring for 3 hours. LC-MS indicated complete reaction. The reaction mixture was cooled to room temperature and concentrated to afford crude Intermediate 14-5. LC-MS (ESI): m / z = 260.0 [M+H] + .

[0522] Step 6: Intermediate 14-5 (76 mg, 0.29 mmol) and intermediate a (100 mg, 0.26 mmol) were placed in a microwave tube at room temperature. 1,4-Dioxane (4 mL) was added to dissolve the mixture. Cesium carbonate (258 mg, 0.79 mmol, Titanium, P2299073), Xantphos (61 mg, 0.11 mmol, Titanium, P2168097), and tris(dibenzylideneacetone)dipalladium (48 mg, 0.05 mmol, Titanium, P2437515) were then added. The reaction mixture was purged with nitrogen and heated to 130°C in a microwave synthesizer for 60 minutes. LC-MS indicated complete reaction. Water (30 mL) and ethyl acetate (30 mL x 2) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was separated and purified by silica gel column chromatography (0-60% ethyl acetate / petroleum ether) to obtain Intermediate 14-6. LC-MS (ESI): m / z = 557.2 [M+H] + .

[0523] Step 7: Intermediate 14-6 (100 mg, 0.28 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated complete reaction of the starting material. The reaction mixture was concentrated, and the residue was dissolved in DMF and purified by HPLC (Waters-CORTECS-C18-2.7 μm-4.6*30 mm, B: 30%-95%, 8 min, A: 0.1% FA in H2O, B: ACN) to afford compound 14. LC-MS (ESI): m / z = 427.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.19-12.89(m,1H),9.30(s,1H),8.53(d,J=5.6Hz,1H),8.16(d,J=5.7Hz,1H),7.93–7.81(m,2H),7.33(d,J=8 .5Hz,2H),4.30-4.10(m,2H),3.33-3.26(m,1H),3.20-3.05(m,1H),2.86(dd,J=13.8,8.4Hz,1H),2.05-1.81(m,3H),1.62-1.50(m,1H).

[0524] Example 15 Synthesis of Compound 15

[0525] Step 1: 3-Fluoro-4-chlorobenzyl alcohol (1.0 g, 6.23 mmol, Titan, P2138624) was dissolved in dichloromethane (20 mL) at room temperature. After cooling in an ice-water bath, triphenylphosphine (1.96 g, 7.48 mmol, Anaiji, 06EUGEPR) and carbon tetrabromide (4.96 g, 14.95 mmol, Titan, P2330286) were slowly added. The reaction mixture was stirred at room temperature for 3 hours. TLC showed that the reaction of the starting material was complete. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (100 / 0 (v / v)) to obtain intermediate 15-1.

[0526] Step 2: Dissolve ethyl 2-oxopiperidine-3-carboxylate (850 mg, 4.96 mmol, Bidex, CMY580) in ethanol (10 mL) at room temperature. Add sodium ethoxide (372 mg, 5.46 mmol, Anaiji, L0D8REUC). Stir at room temperature for 15 minutes, then add Intermediate 15-1 (1.10 g, 4.96 mmol). Stir the mixture overnight. LC-MS indicated complete reaction. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with water (30 mL) and ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol (100 / 0 (v / v) to 95 / 5 (v / v)) to afford Intermediate 15-2. LC-MS (ESI): m / z = 314.0 [M+H] + .

[0527] Step 3: Dissolve Intermediate 15-2 (590 mg, 1.88 mmol) in ethanol (10 mL) and water (5 mL) at room temperature, cool to 0°C, and then add sodium hydroxide (451 mg, 11.28 mmol, Titan, P2468807). The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed that the starting material was completely reacted. The reaction mixture was concentrated to remove ethanol, and the pH was adjusted to 4 with 1 mol / L hydrochloric acid. Water (30 mL) and ethyl acetate (30 mL x 2) were added for extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain crude Intermediate 15-3. LC-MS (ESI): m / z = 286.0 [M+H] + .

[0528] Step 4: Dissolve Intermediate 15-3 (490 mg, 1.72 mmol) in ethyl acetate (10 mL) at room temperature, heat to 90°C, and reflux with stirring for 3 hours. LC-MS indicated complete reaction. The reaction mixture was cooled to room temperature and concentrated to afford crude Intermediate 15-4. LC-MS (ESI): m / z = 242.0 [M+H] + .

[0529] Step 5: Intermediate 15-4 (77 mg, 0.32 mmol) and intermediate a (100 mg, 0.26 mmol) were placed in a microwave vial at room temperature. 1,4-Dioxane (2 mL) was added to dissolve the mixture. Cesium carbonate (258 mg, 0.79 mmol, Titanium, P2299073), Xantphos (61 mg, 0.11 mmol, Titanium, P2168097), and tris(dibenzylideneacetone)dipalladium (48 mg, 0.05 mmol, Titanium, P2437515) were then added. The reaction mixture was purged with nitrogen and heated to 130°C in a microwave synthesizer for 60 minutes. LC-MS indicated complete reaction. Water (30 mL) and ethyl acetate (30 mL x 2) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol (100 / 0 (v / v) to 97 / 3 (v / v)) to obtain Intermediate 15-5. LC-MS (ESI): m / z = 539.2 [M+H] + .

[0530] Step 6: Intermediate 15-5 (150 mg, 0.28 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated that the starting material was completely reacted. The reaction mixture was concentrated, and the residue was dissolved in DMF and purified by HPLC (Waters-CORTECS-C18-2.7 μm-4.6*30 mm, B: 30%-95%, 8 min, A: 0.1% FA in H2O, B: ACN) to afford compound 15. LC-MS (ESI): m / z = 409.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.00(s,1H),9.34(s,1H),8.54(d,J=5.8Hz,1H),8.20( d,J=5.6Hz,1H),7.97-7.83(m,2H),7.53(t,J=8.1Hz,1H),7.40(dd,J=10.7,1.7H z,1H),7.19(dd,J=8.2,1.5Hz,1H),4.28–4.12(m,2H),3.32–3.27(m,1H),3.14– 3.02(m,1H),2.86(dd,J=13.8,8.6Hz,1H),2.06–1.78(m,3H),1.62–1.49(m,1H).

[0531] Example 16-17 Preparation of Compound 16-17

[0532] Step 1: Compound 4 (60 mg) was subjected to chiral separation (separation method: Waters UPC2 analytical SFC (SFC-H), ChiralCel OJ, 150×4.6 mm ID, 3 μm, Mobile phase: A for CO2 and B for Ethanol (0.05% DEA), Gradient: B 40%, Flow rate: 2.5 mL / min, Back pressure: 100 bar, Column temperature: 35°C, Wavelength: 220 nm, Cycle time: ~4 min) to give compound 16 (28.54 mg) and compound 17 (18.62 mg).

[0533] Compound 16: LC-MS (ESI): m / z = 413.0 [M+H] +. Retention time 2.240 min, 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),9.28(s,1H),8.52(d,J=5.7Hz,1H),8.14(s,1H),7.89-7.81(m,2H),7.36(d,J=8.4Hz,2H),4.2 1–4.11(m,1H),3.96(dd,J=17.3,9.2Hz,1H),3.30–3.16(m,2H),2.87(dd,J=13.6,8.7Hz,1H),2.30–2.17(m,1H),2.00–1.87(m,1H).

[0534] Compound 17: LC-MS (ESI): m / z = 413.0 [M+H] +. Retention time 2.875 min, 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),9.28(s,1H),8.52(d,J=5.7Hz,1H),8.18(s,1H),7.90-7.81(m,2H),7.36(d,J=8.4Hz ,2H),4.16(t,J=8.7Hz,1H),4.04–3.90(m,1H),3.30–3.16(m,2H),2.88-2.85(m,1H),2.28–2.18(m,1H),2.00–1.87(m,1H).

[0535] Example 18-19 Preparation of Compound 18-19

[0536] Step 1: The concentrated product A (64.5 mg) was subjected to chiral separation (separation method: WATERS150preparative SFC (SFC-26), ChiralCel OJ, 250×30mm ID5μm, Mobile phase: A for CO2 and B for Ethanol (0.1% NH3 H2O), Gradient: B 40%, Flow rate: 150mL / min, Back pressure: 100bar, Column temperature: 38℃, Wavelength: 220nm, Cycle time: ~5min) to give compound 18 (20.75mg) and compound 19 (26.5mg).

[0537] Compound 18: LC-MS (ESI): m / z = 395.2 [M+H] +. Retention time 2.667 min, 1 H NMR (400MHz, DMSO) δ12.83(s,1H),9.29(s,1H),8.52(d,J=4.9Hz,1H),8.13(d,J=5.7Hz,1H),7.91–7.81(m,2H),7.54(t,J=8.1Hz,1H),7.46–7. 40(m,1H),7.24–7.18(m,1H),4.20–4.09(m,1H),4.01–3.91(m,1H),3.2 6–3.16(m,2H),2.90–2.81(m,1H),2.26–2.16(m,1H),1.98–1.86(m,1H).

[0538] Compound 19: LC-MS (ESI): m / z = 395.2 [M+H] +. Retention time 4.007 min, 1 H NMR (400MHz, DMSO) δ12.96(s,1H),9.43(s,1H),8.56(d,J=5.9Hz,1H),8.27(s,1H),8.00–7.91(m,2H),7.54(t,J=8.1Hz,1H),7.43(d d,J=10.6,1.7Hz,1H),7.21(dd,J=8.2,1.5Hz,1H),4.19–4.09(m,1H),4.02-3.92(m,1H),3.25–3.16(m,2H),2.91–2.82(m,1H),2.28– 2.17(m,1H),2.00-1.87(m,1H).

[0539] Example 20 Synthesis of Compound 20

[0540] Step 1: Intermediate e (95 mg, 0.32 mmol), intermediate 5-4 (73.05 mg, 0.32 mmol), Pd2(dba)3 (58.77 mg, 0.06 mmol), Xantphos (55.70 mg, 0.10 mmol), Cs2CO3 (209.09 mg, 0.64 mmol), and 1,4-dioxane (12 mL) were stirred in a microwave oven at 130°C under nitrogen for 1.5 hours. After completion of the reaction, the solvent was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol = 93 / 7) to obtain intermediate 20-1. LC-MS (ESI): m / z = 428.1 [M+H] +

[0541] Step 2: A mixture of Intermediate 20-1 (150 mg, 0.35 mmol), LiOH (22.07 mg, 0.53 mmol), H2O (2 mL), and THF (4 mL) was stirred at 25°C under nitrogen for 2 hours. After the reaction, the solvent was removed in vacuo, and the crude product was purified by C18 (A: 10 mM NH4HCO3 / H2O B: ACN, 2%-30%) to afford Intermediate 20-2. LC-MS (ESI): m / z = 414.1 [M+H] + .

[0542] Step 3: A mixture of intermediate 20-2 (85 mg, 0.21 mmol), ethyl[di(propyl-2-yl)]amine (132.74 mg, 1.03 mmol), T4P (50% in ethyl acetate) (0.5 mL, 0.01 mmol) and tetrahydrofuran (10 mL) was stirred at 25°C under nitrogen for 16 hours. After the reaction, the solvent was removed by concentration under reduced pressure, and the crude product was purified by preparative HPLC (Waters-Xbridge-C18-5μm-30*150mm, A: 10mM NH4HCO3 / H2O B: ACN) to give compound 20. LC-MS (ESI): m / z = 395.9 [M+H]+, 1H NMR (400MHz, DMSO) δ9.45(s,1H),8.64(d,J=5.8Hz,1H),8.12(d,J=5.9Hz,1H),8.10(s,2H),7.54(t,J=8.1Hz,1H),7.40(dd,J=10.6,1.7Hz,1H) ,7.19(dd,J=8.2,1.4Hz,1H),4.16–4.07(m,1H),4.03-3.93(m,1H),3.2 1–3.11(m,2H),2.87–2.77(m,1H),2.24-2.14(m,1H),1.98-1.85(m,1H).

[0543] Example 21 Synthesis of Compound 21

[0544] Step 1: Intermediate e (60 mg, 0.20 mmol), intermediate 15-4 (73.05 mg, 0.32 mmol), Pd2(dba)3 (37.12 mg, 0.04 mmol), Xantphos (35.18 mg, 0.06 mmol), Cs2CO3 (132.06 mg, 0.41 mmol) and 1,4-dioxane (10 mL) were stirred in a microwave oven at 130°C under nitrogen protection for 1.5 hours. After the reaction was completed, the crude product was evaporated under reduced pressure and purified by preparative HPLC (Waters-Xbridge-C18-10μm-19*250mm, A: 10mM NH4HCO3 / H2O B: ACN) to give compound 21. LC-MS (ESI): m / z = 409.9 [M+H]+, 1 H NMR (400MHz, DMSO) δ9.46(s,1H),8.66(d,J=5.8Hz,1H),8.16–8.11(m,2H),8.08(d,J=8.9Hz,1H),7.52(t,J=8.1Hz,1H),7.38(dd,J=10.7,1.8Hz,1 H),7.17(dd,J=8.2,1.5Hz,1H),4.09-4.03(m,2H),3.29–3.23(m,1H),3. 07–2.97(m,1H),2.83–2.76(m,1H),2.04–1.80(m,3H),1.65–1.53(m,1H).

[0545] Example 22 Synthesis of Compound 22

[0546] Step 1: Intermediate f (80 mg, 0.43 mmol), 3-(4-chloro-3-fluorophenyl)propanoic acid (174.24 mg, 0.86 mmol), ethyldiisopropylamine (279.17 mg, 2.16 mmol), T4P (50% in ethyl acetate) (1 mL, 0.05 mmol), and tetrahydrofuran (10 mL) were stirred at 25°C under nitrogen for 16 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the crude product was purified by preparative HPLC (Waters-Xbridge-C18-10 μm-19*250 mm, A: 10 mM NH4HCO3 / H2O B: ACN) to give compound 22. LC-MS (ESI): m / z = 370.0 [M+H]+, 1 H NMR(400MHz,DMSO)δ11.96(br s,1H),9.43(s,1H),8.63(d,J=5.7Hz,1H),8.10–8.01(m,3H),7.51(t,J=8.1Hz,1H),7.37( dd,J=10.6,1.8Hz,1H),7.17(dd,J=8.4,1.8Hz,1H),2.99-2.94(m,2H),2.91-2.84(m,2H).

[0547] Example 23 Synthesis of Compound 23

[0548] Step 1: To a solution of 1,2-dioxane (3 mL) was added Intermediate d (150 mg, 0.39 mmol), 3-chloro-4-fluorophenylpropionamide (89.32 mg, 0.59 mmol), cesium carbonate (170.44 mg, 0.78 mmol), Pd2(dba)3 (47.90 mg, 0.08 mmol), and Xant Phos (60.54 mg, 0.16 mmol) at room temperature. The reaction mixture was purged with nitrogen three times and heated in a microwave oven at 130°C for 45 minutes under nitrogen protection. LCMS indicated the formation of the product. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated NaCl (30 mL), dried, and concentrated to afford the crude product, which was then purified by silica gel chromatography using dichloromethane / methanol (1 / 10) as the eluent to afford Intermediate 23-1. LC-MS (ESI): m / z=503.2[M+H]+.

[0549] Step 2: To a solution of dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature was added intermediate 23-1 (61 mg, 0.12 mmol). The reaction was stirred at 25°C for 2 h. LCMS indicated product formation. The reaction was concentrated in vacuo to afford the crude product, which was then subjected to preparative liquid chromatography (A: 10 mmol / L NaHCO in H2O B: ACN) to afford compound 23. LC-MS (ESI): m / z = 373.1 [M+H]+. 1 HNMR(DMSO-d6)δ:9.18(s,2H),8.12–7.99(m,2H),7.54–7.31(m,3H),7.17–7.10(m,1H),5.39(s,2H),2.95(t,J=7.3Hz,2H),2.73(t,J=7.3Hz,2H).

[0550] Example 24 Synthesis of Compound 24

[0551] Step 1: To a solution of 1,4-dioxane (3 mL) was added Intermediate d (100 mg, 0.26 mmol), Intermediate 5-4 (89.32 mg, 0.39 mmol), cesium carbonate (170.44 mg, 0.52 mmol), Pd2(dba)3 (47.90 mg, 0.05 mmol), and Xant Phos (60.54 mg, 0.10 mmol) at room temperature. The reaction mixture was purged with nitrogen three times and heated to 130°C in a microwave oven under nitrogen for 45 minutes. LCMS indicated the formation of the product. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated NaCl (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was then purified by silica gel chromatography using dichloromethane / methanol (1 / 10) as the eluent to afford Intermediate 23-1. LC-MS (ESI): m / z=529.2[M+H]+.

[0552] Step 2: To a solution of dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature was added intermediate 24-1 (140 mg, 0.26 mmol). The reaction was stirred at 25°C for 2 h. LCMS indicated the formation of the product. The reaction was concentrated in vacuo to afford the crude product, which was then purified using a reverse-phase column (3:2 = 0.1% formic acid in water:acetonitrile; 40 g C-18 column) to afford compound 24. LC-MS (ESI): m / z = 399.1 [M+H]+. 1HNMR(DMSO-d6)δ:12.26(s,1H),8.26(s,1H),8.07(d,J=6.1Hz,2H),7.52(t,J=8.1Hz,1H),7.39(dd,J=10.6,1.7Hz,1H),7.17(dd,J=8.2,1 .4Hz,1H),5.42(s,2H),3.95–3.86(m,1H),3.82–3.73(m,1H),3.17–3.08(m,2H),2.84–2.75(m,1H),2.20–2.08(m,1H),1.92–1.77(m,1H).

[0553] Example 25 Synthesis of Compound 25

[0554] Step 1: Intermediate d (150 mg, 0.39 mmol) and intermediate 15-4 (190 mg, 0.78 mmol) were placed in a microwave vial at room temperature. 1,4-Dioxane (2 mL) was added to dissolve the mixture. Cesium carbonate (383 mg, 1.18 mmol, Titanium, P2299073), Xantphos (91 mg, 0.16 mmol, Titanium, P2168097), and tris(dibenzylideneacetone)dipalladium (72 mg, 0.08 mmol, Titanium, P2437515) were then added. The reaction mixture was purged with nitrogen and heated to 130°C in a microwave synthesizer for 60 minutes. LC-MS indicated complete reaction. Water (30 mL) and ethyl acetate (30 mL x 2) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography using a dichloromethane / methanol (100 / 0 to 97 / 3) system to obtain Intermediate 25-1. LC-MS (ESI): m / z = 543.2 [M+H]+.

[0555] Step 2: Intermediate 25-1 (75 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) at room temperature, and the reaction was stirred at room temperature for 1 hour. LC-MS indicated complete reaction. The reaction mixture was concentrated, and the residue was dissolved in DMF and purified by prep-HPLC (Waters-CORTECS-C18-2.7 μm-4.6*30 mm, B: 0%-95%, 0.98 min, A: 0.1% FA in H2O, B: ACN) to afford compound 25. LC-MS (ESI): m / z = 413.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ12.89–12.18(m,1H),8.15–8.07(m,2H),7.88–7.68(m,1H ),7.51(t,J=8.1Hz,1H),7.36(dd,J=10.7,1.7Hz,1H),7.15(dd,J=8.2,1.4Hz,1H) ,5.55–5.37(m,2H),4.10–3.84(m,2H),3.27–3.20(m,1H),3.01–2.92(m,1H),2.81 (dd,J=13.7,8.7Hz,1H),1.98–1.87(m,1H),1.87–1.71(m,2H),1.57–1.43(m,1H).

[0556] Example 26-27 Synthesis of Compound 26-27

[0557] Step 1: Under ice, ethyl 2-oxotetrahydrofuran-3-carboxylate (5 g, 39.65 mmol) was added to a tetrahydrofuran (20 mL) solution. Sodium hydride (395 mg, 9.89 mmol, 60% in oil) and 3-fluoro-4-chlorobenzyl bromide (1.62 g, 7.25 mmol) were then added to the reaction mixture. The atmosphere was purged with nitrogen three times, and the reaction was heated to 80°C and stirred for 3 hours. LCMS indicated complete consumption of the starting material. The reaction mixture was diluted with aqueous solution (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was purified by silica gel chromatography using ethyl acetate / petroleum ether (1 / 100 to 1 / 10) as the eluent to afford Intermediate 26-1. LC-MS (ESI): m / z = 287.0 [M+H]+.

[0558] Step 2: To DMSO (6 mL) at room temperature, add Intermediate 26-1 (1.2 g, 4.19 mmol) and lithium chloride (1.77 g, 41.86 mmol). The reaction mixture was heated to 140°C and stirred for 16 hours. LCMS indicated complete consumption of the starting material. The solution was then diluted with ethyl acetate (20 mL) and washed with water (10 mL x 3). The organic layer was separated and concentrated in vacuo to afford the crude product, which was then purified by silica gel chromatography using ethyl acetate / petroleum ether (1 / 100 to 1 / 10) to afford Intermediate 26-2. LC-MS (ESI): m / z = 228.9 [M+H]+.

[0559] Step 3: To a solution of acetic acid (5 mL) and hydrogen bromide in acetic acid (0.65 mL, 3.94 mmol) was added intermediate 26-2 (450 mg, 1.97 mmol) at room temperature. The mixture was stirred at 50°C for 16 hours. LCMS indicated complete consumption of the starting material. The mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL x 3). The organic layer was separated and concentrated in vacuo to afford the crude product, which was then purified by silica gel chromatography using ethyl acetate / petroleum ether (1 / 100 to 1 / 2) as the eluent to afford intermediate 26-3. LC-MS (ESI): m / z = 309.0 [M+H]+.

[0560] Step 4: To a dichloromethane (2 mL) solution under ice, add Intermediate 26-3 (100 mg, 0.32 mmol) and oxalyl chloride (0.28 mL, 3.23 mmol). The reaction mixture was stirred at 25°C for 1 h. TLC (petroleum ether / ethyl acetate = 5 / 1) showed complete consumption of the starting material. The reaction mixture was directly concentrated to afford crude Intermediate 26-4.

[0561] Step 5: To an anhydrous DMF (2 mL) solution at room temperature, intermediate c (100 mg, 0.35 mmol) and sodium hydride (42.21 mg, 1.06 mmol, 60% in oil) were added. The mixture was stirred at 0°C under a nitrogen atmosphere for 0.5 h. Compound 26-4 was then added to the reaction mixture, and the reaction mixture was stirred at 80°C for 3 h. LCMS indicated complete consumption of the starting material. The reaction mixture was diluted with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was subjected to preparative liquid phase separation (A: 10 mmol / L NaHCO₃ in H₂O B: ACN) to afford Compounds 26 and 27.

[0562] Compound 26: LC-MS (ESI): m / z = 395.0 [M+H] +. 1 H NMR(DMSO-d6)δ:14.07(s,1H),9.36(s,1H),8.71(d,J=5.6Hz,1H),8.28–8.25(m,1H),8.21-8.17(m,1H),7.63(d,J=9.1Hz,1H),7.54(t,J=8.1 Hz,1H),7.46–7.39(m,1H),7.24–7.17(m,1H),3.94–3.87(m,2H),3.22 –3.05(m,2H),2.89–2.81(m,1H),2.24–2.14(m,1H),1.97–1.87(m,1H).

[0563] Compound 27: LC-MS (ESI): m / z = 395.0 [M+H] +. 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),9.20(s,1H),8.64(d,J=5.4Hz,1H),8.19(d,J=5.4Hz, 1H),7.63(d,J=8.9Hz,1H),7.48(d,J=9.0Hz,1H),7.41(t,J=8.1Hz,1H),7.28(dd,J=10.8,1 .9Hz,1H),7.07(dd,J=8.3,1.9Hz,1H),4.70-4.62(m,1H),4.58-4.98(m,1H),3.00(dd,J=13 .3,6.9Hz,1H),2.78-2.71(m,1H),2.66-2.62(m,1H),2.47-2.40(m,1H),2.18-2.08(m,1H).

[0564] Example 28-29 Synthesis of Compound 28-29

[0565] Step 1: To a solution of methyl 3-hydroxyisonicotinate (1.9 g, 12.41 mmol) in DMF (50 mL) were added 4-bromobutyronitrile (1.49 mL, 14.89 mmol) and potassium carbonate (4.29 g, 31.02 mmol), and the reaction was stirred at 25°C for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (60 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:2) to obtain Intermediate 28-1. LC-MS (ESI): m / z = 221.2 [M+H] + .

[0566] Step 2: Intermediate 28-1 (500 mg, 2.27 mmol) was dissolved in a solution of DMF (20 mL), cooled to 0 ° C, potassium tert-butoxide (509.51 mg, 4.54 mmol) dissolved in DMF (10 mL) was added to the mixture, and the reaction was stirred at 0 ° C for 1 hour. LCMS showed that the starting material was consumed and the target product was formed. The reaction mixture was adjusted to pH = 5 with saturated aqueous citric acid solution, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give a crude product. The crude product was slurried with acetonitrile (20 mL), and the suspension was separated by filtration. The filter cake was washed with acetonitrile (20 mL x 3) and then dried under reduced pressure to give compound 3. LC-MS (ESI): m / z = 189.1 [M + H]+ .

[0567] Step 3: To a solution of Intermediate 28-2 (200 mg, 1.06 mmol) in EtOH (10 mL) was added hydrazine hydrochloride (364 mg, 5.31 mmol) and the reaction was stirred at 80°C for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was cooled to room temperature, the mixture was filtered, and the filter cake was washed with MeOH (20 mL x 3). The filtrate was concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by reverse phase chromatography (Phenomenex Gemini 150 mm*25 mm*10 μm column (eluent: 30% to 60% (v / v) CH3CN and H2O with 0.1% NH4OH) to give Intermediate 28-3. LC-MS (ESI): m / z = 202.9 [M+H] + .

[0568] Step 4: To a solution of 3-(4-chloro-3-fluorophenyl)propanoic acid (60.12 mg, 0.30 mmol, Bidex Pharmaceuticals) in DMF (5 mL) was added CDI (52.92 mg, 0.33 mmol). The resulting mixture was stirred at room temperature for 1 hour, followed by the addition of Intermediate 28-3 (60 mg, 0.30 mmol) and stirring for an additional hour. LCMS indicated the formation of the desired product. The reaction mixture was added to water (50 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were concentrated to afford the crude product, which was further purified by Prep-HPLC (CAN / Water / 0.1% HCOOH) to afford Compounds 28 and 29. LC-MS (ESI): m / z = 387.0 [M+H] + .

[0569] Compound 28: 1 H NMR(400MHz,DMSO-d6)δ13.31(br s,1H),9.98(br s,1H),8.36-8.32(m,1H),8.29-8.25(m,1H),7.91-7.88(m,1H),7.53-7.49(m,1H),7.36-7.32(m,1H ),7.17-7.13(m,1H),4.23(t,J=4.8Hz,2H),2.96-2.92(m,2H),2.76-2.72(m,2H),2.68-2.64(m,2H).

[0570] Compound 29: 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.26-8.22(m,1H),8.06-8.02(m,1H),7.53-7.49(m,1H),7.43-7.39(m,1H) ),7.22-7.18(m,1H),6.62(s,2H),4.33-4.29(m,2H),3.51-3.48(m,2H),3.04-3.01(m,2H),2.81-2.77(m,2H).

[0571] Biological evaluation of compounds

[0572] Test Example 1: In vitro enzymatic inhibition activity

[0573] 1. Reagents, consumables, and instruments are listed in Table 2.

[0574] Table 2

[0575] 2. Preparation of SAM-TIR Lysate

[0576] NRK1-HEK293T cells were cultured at a density of approximately 10 × 10 6 Cells / plate were seeded into 150mm culture dishes containing 25mL of growth medium. The next day, 15μg of human SARM1 expression plasmid (SARM1408-724 expression plasmid and vector-control customized by Sino-Bio) was premixed with 45μL X-tremeGENE 9 DNA transfection reagent and 750μL OptiMEM, and then the mixture was added directly to the cells to transfect the cells. During transfection, 250μL of 100mM nicotinamide riboside was added to each dish to minimize the toxicity from SAM-TIR overexpression. 48 hours after transfection, the cells were washed three to four times with cold PBS and collected. The cells were resuspended in 0.5mL PBS containing protease inhibitors. Cell lysates were prepared by ultrasonic treatment. The lysate was centrifuged at 12500 rpm for 10 min at 4°C to remove cell debris, the protein concentration was determined by bicinchoninic acid (BCA) method and used to normalize the lysate concentration, and aliquots of the supernatant were stored at -80°C until use.

[0577] 3. Experimental Procedure

[0578] 1) Transfer compound dilutions to assay plates using the Echo 650.

[0579] 2) Add 10 μl of 2× SAM-TIR lysate to each well;

[0580] 3) Seal the test plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 30 min;

[0581] 4) Add 10 μl of 2×NAD to each well;

[0582] 5) Centrifuge at 1000 rpm for 1 min and incubate at 25°C for 3 h;

[0583] 6) Add 40 μL trichloroacetic acid to each well to terminate the reaction, mix and shake for 30 seconds, and centrifuge at 4000 rpm for 10 minutes;

[0584] 7) Take 40 μL of supernatant from each well and add appropriate amount of ammonia to adjust the pH;

[0585] 8) Nicotinamide adenine dinucleotide (NAD) and adenosine diphosphate ribose (ADPR) were detected by HPLC-MS / MS.

[0586] 4. Data Analysis

[0587] 1) For each screening plate, calculate the mean data and standard deviation (SD) of DMSO (as negative control (VC)) and 100 μM control I-5 (as positive control (PC))

[0588] 2) Inhibition percentage of the compound

[0589] NAD:

[0590] Inhibition rate = {(Signal of compound - Signal of negative control) / (Signal of positive control - Signal of negative control)}×100%

[0591] ADPR:

[0592] Inhibition rate = {1-(Signal of compound-Signal of positive control) / (Signal of negative control-Signal of positive control)}×100%

[0593] 3) Calculate IC using the nonlinear regression equation of XLfit 5.3.1 50 , the formula is as follows:

[0594] Inhibition rate = lowest value + (highest value - lowest value) / (1 + 10^((LogIC 50 -Log(compound concentration))*slope coefficient)

[0595] Control I-5 Prepared according to WO2022046606A1 method C.

[0596] Conclusion: At least some of the compounds of the present invention have a good inhibitory effect on the SARM1 enzyme. The SARM1 enzymatic activity data of some compounds are shown in Table 3.

[0597] Table 3 Note: A<150nM; 150nM≤B<500nM; 500nM≤C<1000nM; D≥1000nM.

[0598] Test Example 2: Kinetic Solubility Evaluation

[0599] Dissolve the test compound in DMSO to prepare a 10 mM stock solution. Prepare a 100 mM K2HPO4 solution by adding 8.71 g of K2HPO4 to 500 mL of deionized water. Prepare a 100 mM K2HPO4 solution by adding 2.05 g of potassium dihydrogen phosphate to 150 mL of deionized water. Combine 405 mL of 100 mM K2HPO4 and 95 mL of 100 mM KH2PO4. Adjust the pH of the mixture to 7.4 using a 100 mM K2HPO4 / KH2PO4 solution.

[0600] Using a 96-well plate, add 16 μL of a 10 mM compound stock solution to 784 μL of PBS buffer (n=3). Seal the plate and shake at 1000 rpm at 25°C for 1.5 hours. 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 acetonitrile-water solution containing an internal standard (1:1) and mix thoroughly. Then, dilute the solution with acetonitrile-water solution containing an internal standard (1:1) based on the compound's properties and its mass spectrometric response. Adjust the dilution factor based on solubility and UPLC-MS / MS signal response.

[0601] Conclusion: At least some of the compounds of the present application have good solubility in PBS buffer, for example, the solubility of compound 25 is >50 μg / mL.

[0602] Test Example 3: In vitro liver microsome stability evaluation

[0603] 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.

[0604] Conclusion: At least some of the compounds of the present application have good in vitro liver microsome stability. The test results of some compounds are shown in Table 4.

[0605] Table 4

[0606] Test Example 4: Evaluation of cell membrane permeability

[0607] Test compounds were diluted from a 10 mM stock solution to a 10 μM concentration in transport buffer (HBSS + BSA) and applied to the cell monolayer apically or basolaterally. 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.

[0608] Conclusion: It shows that at least some of the compounds of the present application have good cell membrane permeability and are not P-glycoprotein substrates. The test results of some compounds are shown in Table 5.

[0609] Table 5

[0610] Experimental Example 5: Pharmacokinetic Evaluation in Mice

[0611] Test compounds were dissolved in vehicle to prepare clear solutions or homogeneous suspensions. Three mice (CD1 mice) were administered 2 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 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after oral administration. Plasma samples were centrifuged, and the supernatant was collected for quantitative analysis by LC / MS / MS.

[0612] Conclusion: At least some of the compounds of the present application (e.g., compound 25) have excellent pharmacokinetic properties in mice (including but not limited to Cl (clearance rate), T 1 / 2 (half-life), C max (peak concentration), AUC (area under the drug-time curve), F (bioavailability), etc.) The test results of some compounds, such as the mouse PK properties of compound 25, are shown in Table 6.

[0613] Table 6 PK properties of compound 25 in mice

[0614] Test Example 6: In vivo brain penetration performance evaluation

[0615] Dissolve the test compound in vehicle to prepare a clear solution or homogenous suspension. Three mice (CD1 mice) per group were orally administered (PO) at a dose of 10 mg / kg. Plasma and cerebrospinal fluid were collected 1, 4, and 8 hours after oral administration and quantitatively analyzed by LC / MS / MS.

[0616] Conclusion: At least some of the compounds of this application have reached very high levels of Cmax and AUC in cerebrospinal fluid, and have good brain penetration performance in vivo. For example, the AUC of compound 25 is brain AUC plasma =0.71, indicating that the compound has very good brain penetration in vivo. Table 7 shows the plasma and cerebrospinal fluid PK data of compound 25 of the present invention.

[0617] Table 7 Plasma and cerebrospinal fluid PK of compound 25

[0618] Experimental Example 7: Neuronal Injury Model Based on Mouse Primary Neurons

[0619] Methods: Neocortices were dissected from the brains of newborn mice at DIV 0 (Day In Vitro 0), digested with 0.05% (w / v) trypsin / EDTA, and incubated at 37°C for 10 minutes. The resulting neurons were seeded in culture dishes pre-incubated with poly-D-lysine in Neurobasal / B-27 medium (Neurobasal medium supplemented with 1% (v / v) B-27, 2 mM glutamine, 100 U / ml penicillin, and 100 mg / ml streptomycin). Starting at DIV 3, half of the medium was replaced with fresh Neurobasal / B-27 medium every two days. At DIV 10, cultures were axotomized and treated with compounds. The day after axotomy, cells were fixed with 4% paraformaldehyde and immunofluorescently stained for TUJ1. Confocal imaging of axons was performed using a Zeiss LSM710 laser confocal microscope.

[0620] Conclusion: At least some of the compounds described herein have strong neuroprotective activity and can reduce axonal loss after axonal injury. For example, as shown in Figure 1, compared to the control compound I-5, compound 25 exhibits stronger neuroprotective activity at a lower concentration (0.3 μM), reducing axonal loss after axonal injury.

[0621] Experimental Example 8: Mouse Sciatic Nerve Axotomy (SNA) Model

[0622] Methods: Mice were anesthetized with isoflurane, and the skin of the right hind limb was shaved and disinfected with iodine. An incision was made between the knee and hip joints, and the gluteal muscles were carefully separated using a pair of sterile surgical scissors. The sciatic nerve was transected proximal to the thigh using a pair of sterile surgical scissors, and a 1-2 mm segment of the nerve was removed to prevent axonal regeneration into the distal stump. The gluteal muscle was then returned to its original anatomical position, and the overlying skin was reattached using surgical staples or sutures.

[0623] To examine neuromuscular junction (NMJ) denervation, tibialis anterior muscles were dissected from perfused animals and fixed overnight in 4% paraformaldehyde / PBS at 4°C. Immunohistochemical staining was then performed using antibodies against Neurofilament-L and Synapsin-1, as well as acetylcholine receptor (AchR) markers. Images were acquired using a Zeiss LSM710 laser confocal microscope.

[0624] Conclusion: At least some of the compounds of the present application can significantly protect axons from injury-induced axonal degeneration. For example, as shown in Figure 2, compound 25 can significantly protect axons from injury-induced axonal degeneration in mice.

[0625] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solutions of the present invention. They should all be included in the scope of the technical solutions claimed for protection by the present invention.

Claims

1. A compound represented by formula (I), or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, in, is selected from a single bond, a double bond and a triple bond; Z is selected from O and S; L1 is selected from -C 1-3 Alkylene-, =CH-, -NH- and -O-, or L1 is absent; Ring A is selected from phenyl, 5-6 membered heteroaryl, C 4-8 Cycyl and 4-8 membered heterocyclic group, preferably, ring A is selected from phenyl, dihydropyranyl, pyridyl, dihydropyridyl and oxepanyl; Ring B is selected from phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl; Ring C is selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 3-12 Cycyl and 4-10 membered heterocyclic groups; Ring E is selected from 5-6 membered heteroaryl and phenyl; R1 is selected from H, -OH, halogen, -NH2, -CN, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl, -C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl; R2 is selected from H, OH, halogen, -CN, -NH2, -NO2, -COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6 alkoxy, C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl, -C 1-6 Alkylene-C 1-6 Alkoxy, -C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl; R3 is selected from H, C 1-6 Alkyl and -C(=O)C 1-6 Alkyl, the C 1-6 Alkyl or -C(=O)C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogens, -OH, -NH2, -CN, -NO2 and -COOH; W is selected from -C(R5R6)-, -CR5=, -C(=CH2)- and -NR5-, wherein R5 is selected from H, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 haloalkoxy; or W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 R; Alternatively, W and ring B together with the atoms to which they are attached form a 6-10 membered heterocyclic group, which is optionally substituted with 1, 2, 3, 4 or 5 R; R4 is selected from halogen, OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; R6 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; R7 is selected from H, halogen, -OH, -NO2, -CN, -NH2, -COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6 haloalkyl, C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl, -C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl; R is selected from halogen, -OH, -CN, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; m is selected from 0 and 1; n is selected from 0, 1, 2, 3, 4 and 5, preferably 0, 1, 2 or 3; r, s, and t are each independently 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2, and more preferably 0 or 1.

2. The compound according to claim 1, or its stereoisomer, or its tautomer, 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 W is selected from -C(R5R6)-, -CR5=, -C(=CH2)- and -NR5-, or W and R3 form a 4-6 membered heterocyclic group with the atoms connected thereto, and the 4-6 membered heterocyclic group is optionally substituted by 1, 2, 3, 4 or 5 R; Preferably, W is selected from -C(R5R6)-, -C(=CH2)-, or W and R3 and the atoms to which they are connected form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted by 1, 2, 3, 4 or 5 R; Preferably, W is selected from -C(R5R6)-, -C(=CH2)-, or W and R3 and the atoms to which they are attached form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by 1, 2, 3, 4 or 5 R; Preferably, W is selected from -C(R5R6)-, or W and R3 together with the atoms to which they are attached form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by 1, 2, 3, 4 or 5 Rs.

3. The compound according to claim 1 or 2, or its stereoisomer, or its tautomer, 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 m is 1.

4. The compound according to any one of claims 1 to 3, or its stereoisomer, or its tautomer, 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 R1 is selected from H, -OH, halogen, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene -OH, -OC 1-4 Haloalkyl, -C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl; Preferably, R1 is selected from H, -OH, F, Cl, Br, I, -NH2, -CN, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, halomethyl, haloethyl, halopropyl, halobutyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Preferably, R1 is selected from H, -OH, F, Cl, Br, -NH2, -CN, -NO2, -COOH, methyl, ethyl, n-propyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl and hydroxyethyl; Preferably, R1 is selected from F, Cl, Br and I; Preferably, R1 is selected from -NH2, -CN, -NO2 and -COOH; Preferably, R1 is selected from methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl and hydroxyethyl; Preferably, R1 is selected from H and OH; Preferably, R1 is H.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, or its tautomer, 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 R2 is selected from H, -OH, halogen, -CN, -NH2, -NO2, -COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene -OH, -OC 1-4 Haloalkyl, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl; Preferably, R2 is selected from H, -OH, F, Cl, Br, I, -CN, -NH2, -NO2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, halomethyl, haloethyl, halopropyl, halobutyl, methoxy, ethoxy, propoxy, butoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, haloethoxy, halopropoxy, halobutoxy, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OCH2CH3, -CH2O(CH2)2CH3, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Preferably, R2 is selected from H, -OH, F, Cl, Br, -NH2, -CN, -NO2, -COOH, methyl, ethyl, n-propyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, -CH2OCH3, -(CH2)2OCH3 and -CH2OCH2CH3; Preferably, R2 is selected from H, Cl, -CN, -NH2, -CH3 and -CH2OCH3; Preferably, R2 is selected from H, NH2, -CH3 and -CH2OCH3; Preferably, R2 is selected from H, -CH3 and -CH2OCH3; Preferably, R2 is selected from H, NH2; Preferably, R2 is selected from H.

6. The compound according to any one of claims 1 to 5, or its stereoisomer, or its tautomer, 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 R7 is selected from H, halogen, -OH, -NO2, -CN, -NH2, -COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Alkylene -OH, -OC 1-4 Haloalkyl, -C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl; Preferably, R7 is selected from H, F, Cl, Br, I, -OH, -NO2, -CN, -NH2, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Preferably, R7 is selected from H, F, Cl, Br, I, -OH, -NO2, -CN, -NH2, -COOH, methyl, ethyl, methoxy and ethoxy; Preferably, R7 is selected from H, F, Cl, Br and CH3; Preferably, R7 is selected from H, F, Cl and Br; Preferably, R7 is selected from H.

7. The compound according to any one of claims 1 to 6, or its stereoisomer, or its tautomer, 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 structural unit Selected from in, is selected from a single bond or a double bond; Z1 and Z2 are each independently selected from CH or N; V is selected from C, CH or N, preferably V is selected from C or N; T1, T2 and T3 are each independently selected from CH2, O, S and NH, preferably T1, T2 and T3 are each independently selected from CH2, O and NH; u is selected from 0, 1 and 2, preferably u is selected from 0 or 1; Preferably, the structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit Selected from More preferably, the structural unit Selected from More preferably, the structural unit Selected from 8. The compound according to any one of claims 1 to 7, or its stereoisomer, or its tautomer, 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 Ring B is selected from a 5-membered nitrogen-containing heteroaryl group and a 5-membered nitrogen-containing heterocycloalkenyl group; Preferably, ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl and dihydrotriazolyl; Preferably, ring B is selected from pyrrolyl, pyrazolyl, imidazolyl and oxazolyl; More preferably, ring B is selected from imidazolyl, pyrazolyl, oxazolyl.

9. The compound according to any one of claims 1 to 8, or its stereoisomer, or its tautomer, 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 ring E is a 6-membered nitrogen-containing heteroaryl group; Preferably, ring E is selected from pyridyl and pyridazinyl; More preferably, ring E is selected from pyridyl.

10. The compound according to any one of claims 1 to 9, or its stereoisomer, or its tautomer, 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 structural unit Selected from (Preferred ),in, Y1 and Y2 are each independently selected from CH and N, preferably, Y1 is N and Y2 is CH; or Y1 is CH and Y2 is N; or Y1 is N and Y2 is N; Preferably, Selected from in is selected from a single bond or a double bond; Z1 and Z2 are each independently selected from CH or N; V is selected from C, CH or N, preferably V is selected from C or N; T1, T2 and T3 are each independently selected from CH2, O and NH; u is selected from 0, 1 and 2, preferably u is selected from 0 or 1; Preferably, Selected from Preferably, Selected from Preferably, Selected from 11. The compound according to any one of claims 1 to 10, or its stereoisomer, or its tautomer, 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 structural unit Selected from in, is selected from a single bond or a double bond, Y1 and Y2 are each independently selected from CH and N, V ​​is selected from C, CH or N, preferably V is selected from C or N; U1 and U2 are each independently selected from O, N, NH or CH; W1 and W3 are selected from CH or N; W2 is selected from NH or O; Ring A is selected from phenyl, 5-6 membered heteroaryl, C 4-8 Ring A is preferably selected from phenyl, 6-membered heteroaryl, C 6-7 A phenyl group, a 6-7 membered heterocyclic group; more preferably, ring A is selected from a phenyl group, a 6-7 membered heterocyclic group; Preferably, the structural unit Selected from Preferably, the structural unit Selected from in Select a single bond or a double bond, connecting two One of them is a single key, and the other is a double bond; Y1 and Y2 are each independently selected from CH and N, Z1 and Z2 are each independently selected from CH or N; U1 and U2 are each independently selected from O, N, NH or CH; T1, T2 and T3 are each independently selected from CH2, O and NH; W1 and W3 are selected from CH or N; W2 is selected from NH or O; u is selected from 0 or 1; Preferred structural units Selected from Structural unit wherein, preferably, Y1 is selected from N, and Y2 is selected from CH; or Y1 is selected from N, and Y2 is selected from N; more preferably, Y1 is selected from N, and Y2 is selected from CH; preferably, Z1 is selected from CH, and Z2 is selected from CH; or Z1 is selected from N, and Z2 is selected from CH; or Z1 is selected from CH, and Z2 is selected from N; more preferably, Z1 is selected from CH, and Z2 is selected from CH; preferably, U1 is selected from N and CH, and U2 is selected from NH and O; or U1 is selected from NH and O, and U2 is selected from N and CH; more preferably, U1 is selected from N, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N; or U1 is selected from N, and U2 is selected from O; Structural unit wherein Y1 is preferably selected from N, Y2 is selected from CH; T1 is preferably selected from CH2, T2 is selected from O or NH, and T3 is selected from CH2; or T1 is selected from O, T1 and T3 are selected from CH2; U1 is preferably selected from N, U2 is selected from NH; or U1 is selected from NH, U2 is selected from N; the structural unit wherein Y1 is preferably selected from N, and Y2 is selected from CH; preferably T1 is selected from NH, and T3 is selected from CH2; or T1 is selected from CH2, and T3 is selected from NH; or T1 is selected from O, and T3 is selected from CH2; or T1 is selected from CH2, and T3 is selected from O; or T1 is selected from CH2, and T3 is selected from CH2; more preferably T1 is selected from O, and T3 is selected from CH2; preferably U1 is selected from N or CH, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N or CH; more preferably U1 is selected from N, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N; Structural unit In the above, Y1 is preferably selected from N, Y2 is preferably selected from CH; Z1 is preferably selected from CH, Z2 is preferably selected from CH; W1 is preferably selected from N, W2 is preferably selected from NH; Structural unit In the above, preferably Y1 is selected from N, Y2 is selected from CH; preferably Z1 is selected from CH, Z2 is selected from CH; preferably W1 is selected from N, W3 is selected from CH; Structural unit wherein Y1 is preferably selected from N, Y2 is selected from CH; T1 is preferably selected from O, T2 and T3 are selected from CH2; or T1 is selected from CH2, T2 is selected from O, T3 is selected from CH2; more preferably T1 is selected from O, T2 and T3 are selected from CH2; W1 is preferably selected from N, W2 is selected from NH; Structural unit wherein Y1 is preferably selected from N, Y2 is selected from CH; T1 is preferably selected from O, T3 is selected from CH2, or T1 is selected from CH2, T3 is selected from O; or T1 is selected from NH, T3 is selected from CH2; or T1 is selected from CH2, T3 is selected from NH; W1 is preferably selected from N, W2 is selected from NH; Structural unit wherein Y1 is preferably selected from N, and Y2 is selected from CH; Z1 is preferably selected from CH, and Z2 is selected from CH; U1 is preferably selected from N, and U2 is selected from NH; or U1 is selected from NH, and U2 is selected from N; more preferably U1 is selected from N, and U2 is selected from NH; Structural unit In the above, Y1 is preferably selected from N, Y2 is preferably selected from CH; T1 is preferably selected from CH2 or O, T2 is selected from CH2; preferably U1 is selected from N, U2 is selected from NH; or U1 is selected from NH, U2 is selected from N; more preferably U1 is selected from N, U2 is selected from NH; Structural unit wherein Y1 is preferably selected from N, Y2 is preferably selected from CH; T1 is preferably selected from O, T2 and T3 are preferably selected from CH2; W1 is preferably selected from N; More preferably, the structural unit Selected from Further preferred structural units Selected from Further preferred structural units Selected from Further preferred structural units Selected from 12. The compound according to any one of claims 1 to 11, or its stereoisomer, or its tautomer, 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 structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit Selected from 13. The compound according to any one of claims 1 to 12, or its stereoisomer, or its tautomer, 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 structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit for Preferably, the structural unit for 14. The compound according to any one of claims 1 to 13, or its stereoisomer, or its tautomer, 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 W is selected from -C(R5R6)-, -C(=CH2)- and -NR5-, wherein R5 and R6 are defined as in claim 1; Preferably, R5 is selected from H, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; R6 is selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; Preferably, R5 is selected from H, -OH, methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, butoxy, halomethyl, haloethyl, halopropyl, halobutyl, halomethoxy, haloethoxy, halopropoxy and halobutoxy; R6 is selected from H, methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, butoxy, halomethyl, haloethyl, halopropyl, halobutyl, halomethoxy, haloethoxy, halopropoxy and halobutoxy; Preferably, R5 is selected from H, -OH, methyl, methoxy, monofluoromethyl, difluoromethyl and trifluoromethyl; R6 is selected from H, methyl, ethyl, methoxy, monofluoromethyl, difluoromethyl and trifluoromethyl; Preferably, R5 is selected from H, -OH; R6 is selected from H; Preferably, R5 is selected from H; R6 is selected from H; Preferably, W is selected from -CH2-, -CH(OH)-, -C(=CH2)- and -NH-. Preferably, W is selected from -CH2- and -NH-; Preferably, W is selected from -CH2- and -C(=CH2)-; Preferably, W is selected from -CH2-.

15. The compound according to any one of claims 1 to 14, or its stereoisomer, or its tautomer, 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 R3 is selected from H, C 1-4 Alkyl and -C(=O)C 1-4 Alkyl, the C 1-4 Alkyl or -C(=O)C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogens -OH, -NH2, -CN, -NO2 and -COOH; Preferably, R3 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)(CH2)2CH3 and -C(=O)(CH2)3CH3; Preferably, R3 is selected from H, -CH3 and -C(=O)CH3; More preferably, R3 is H.

16. The compound according to any one of claims 1 to 15, or its stereoisomer, or its tautomer, 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 structural unit Selected from wherein the bond marked with "*" is connected to Ring B; Preferably, the structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit Selected from -C(=O)-CH2-, -NH-C(=O)-CH2-, -N(CH3)-C(=O)-CH2-, -N(C(=O)CH3)-C(=O)-CH2-, -N(CH3)-C(=O)-CH(OH)-, -NH-C(=O)-C(=CH2)- and -NH-C(=S)-CH2-; Preferably, the structural unit is -NH-C(=O)-CH2-; or, Structural unit for Wherein "*" is connected to ring B; Preferably, the structural unit Selected from *-C(=O)-CH2-, *-NH-C(=O)-CH2-, *-N(CH3)-C(=O)-CH2-, *-N(C(=O)CH3)-C(=O)-CH2-, *-N(CH3)-C(=O)-CH(OH)-, *-NH-C(=O)-C(=CH2)- and *-NH-C(=S)-CH2-, wherein "*" is connected to Ring B; More preferably, the structural unit It is *-NH-C(=O)-CH2-, wherein "*" is connected to ring B.

17. The compound according to any one of claims 1 to 16, or its stereoisomer, or its tautomer, 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 R is selected from halogen, OH, CN, =O, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; Preferably, R is selected from F, Cl, Br, I, OH, CN, =O, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, halomethyl, haloethyl, halopropyl, halobutyl, halomethoxy, haloethoxy, halopropoxy and halobutoxy; Preferably, R is selected from F, Cl, Br, I, OH, CN, =O, methyl, ethyl, n-propyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl and trifluoromethyl; Preferably, R is selected from F, Cl, Br, OH, =O, methyl, ethyl, monofluoromethyl, difluoromethyl and trifluoromethyl; Preferably, R is selected from OH, -CH3 and =O.

18. The compound according to any one of claims 1 to 17, or its stereoisomer, or its tautomer, 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 structural unit Selected from p is selected from 0, 1 and 2, q is selected from 0, 1, 2, 3, 4 and 5, is selected from single bonds and double bonds; Preferably Selected from Best Preferably, Selected from Preferably, Selected from Preferably, the structural unit Selected from More preferably, the structural unit Selected from or, Structural unit for Wherein "*" is connected to ring B; Preferably, the structural unit Selected from Wherein "*" is connected to ring B; Preferably, Selected from Wherein "*" is connected to ring B; Preferably, the structural unit Selected from Wherein "*" is connected to ring B; More preferably, the structural unit Selected from Wherein "*" is connected to ring B.

19. The compound according to any one of claims 1 to 18, or its stereoisomer, or its tautomer, 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 W and ring B form a 7-9 membered heterocyclic group with the atoms to which they are connected; Preferably, W and ring B together with the atoms to which they are attached form a 7-membered heterocyclic group, Preferably, the 7-membered heterocyclic group is selected from Wherein "*" is fused with ring B; Preferably, the heterocyclic group is selected from Wherein "*" is fused to ring B.

20. The compound according to any one of claims 1 to 19, or its stereoisomer, or its tautomer, 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 L1 is absent; or L1 is selected from -CH2-, -CH2CH2-, =CH-, -NH- and -O-; preferably, L1 is -CH2-.

21. The compound according to any one of claims 1 to 20, or its stereoisomer, or its tautomer, 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 R4 is selected from halogen, -OH, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 Haloalkoxy; Preferably, R4 is selected from F, Cl, Br, I, -OH, -CN, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, halomethyl, haloethyl, halopropyl, halobutyl, halomethoxy, haloethoxy, halopropoxy and halobutoxy; Preferably, R4 is selected from F, Cl, Br, -OH, -CN, -NH2, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl and trifluoromethyl; Preferably, R4 is selected from F, Cl, -OH, -CN, -NH2, methyl and trifluoromethyl; Preferably, R4 is selected from F, Cl and CN.

22. The compound according to any one of claims 1 to 21, or its stereoisomer, or its tautomer, 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 ring C is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycyl, 4-6 membered heterocyclyl and 5-8 membered heterocyclyl; Preferably, ring C is selected from phenyl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl; Further preferably, ring C is selected from phenyl, thienyl, thiazolyl, pyridyl, 1,3-benzodioxolyl and benzodioxolyl; Further preferably, ring C is selected from phenyl, thienyl, thiazolyl and pyridyl; Further preferably, ring C is selected from phenyl and pyridyl.

23. The compound according to any one of claims 1 to 22, or its stereoisomer, or its tautomer, 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 structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit Selected from More preferably, the structural unit Selected from More preferably, the structural unit Selected from 24. A compound according to any one of claims 1 to 23, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, in, Selected from single bonds and double bonds; preferably is selected from single bonds; Z is selected from O and S; preferably Z is selected from O; L1 is selected from -C 1-3 Alkylene-, =CH-, -NH- and -O-, or L1 is absent; preferably L1 is selected from -C 1-3 Alkylene-, =CH-, -NH- and -O-; more preferably L1 is selected from -C 1-3 Alkylene-; Ring A is selected from phenyl, 5-6 membered heteroaryl, C 4-8 A cyclic group and a 4-8 membered heterocyclic group; preferably, ring A is selected from phenyl, a 6-membered heteroaryl, a C6 cyclic group, a 6-7 membered heterocyclic group; more preferably, ring A is selected from phenyl, a 6-7 membered heterocyclic group; Ring B is selected from 5-6 membered heteroaryl and 5-6 membered heterocyclyl; preferably, ring B is selected from 5 membered heteroaryl and 5 membered heterocyclyl; more preferably, ring B is selected from 5 membered heteroaryl; Ring C is selected from C 6-10 Aryl, 5-12 membered heteroaryl, C 3-12 Cycyl and 4-10 membered heterocyclic group; preferably ring C is selected from C 6-10 aryl, 5-12 membered heteroaryl and 4-10 membered heterocyclyl; more preferably, ring C is selected from phenyl, 5-6 membered heteroaryl, 5-10 membered heterocyclyl (e.g. 9-10 membered heterocyclyl); further preferably, ring C is selected from phenyl and 6 membered heteroaryl; more preferably, ring C is phenyl or pyridyl; Ring E is selected from 5-6 membered heteroaryl; preferably, Ring E is selected from 6 membered heteroaryl; R1 is selected from H, OH, halogen, C 1-3 Alkyl and C 1-3 Haloalkyl, preferably H or OH, more preferably H; R2 is selected from H, OH, halogen, CN, NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -OC 1- 6 haloalkyl and -C 1-6 Alkylene-C 1-6 Alkoxy, preferably H, halogen, CN, NH2, C 1-6 Alkyl or -C 1-6 Alkylene-C 1-6 Alkoxy, more preferably H, NH2; R3 is selected from H, C 1-6 Alkyl and -C(=O)C 1-6 Alkyl, preferably H; W is selected from -C(R5R6)-, -CR5=, -C(=CH2)- and -NR5-, wherein R5 is selected from H and OH; or W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclic group, which is optionally substituted with 1, 2, 3, 4 or 5 R; or W and ring B together with the atoms to which they are attached form a 6-10 membered heterocyclic group, which is optionally substituted with 1, 2, 3, 4 or 5 R; Preferably W is selected from -C(R5R6)-, -C(=CH2)-, wherein R5 is selected from H and OH; or W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclic group, which is optionally substituted with 1, 2, 3, 4 or 5 R; or W and ring B together with the atoms to which they are attached form a 7-9 membered heterocyclic group, wherein the 7-9 membered heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 R; More preferably, W is selected from -C(R5R6)-, -C(=CH2)-, wherein R5 is selected from H; or W and R3 together with the atoms to which they are attached form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 R; It is further preferred that W is selected from -C(R5R6)-, wherein R5 is selected from H; or W and R3 together with the atoms to which they are attached form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted with 1, 2, 3, 4 or 5 R; R4 is selected from halogen, CN, preferably halogen; R6 is selected from H and C 1-6 Alkyl, preferably H; R7 is selected from H, halogen and C 1-6 Alkyl, preferably H; R is selected from halogen, OH, =O, C 1-6 Alkyl, preferably R is selected from OH, =O and C 1-6 alkyl; m is selected from 0 and 1, preferably 1; n is selected from 0, 1, 2 and 3, preferably 1, 2 or 3; r, s, and t are each independently 0, 1 or 2, preferably 0 or 1, and more preferably 0.

25. A compound according to any one of claims 1 to 24, or a stereoisomer thereof, or a tautomer 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 the compound represented by formula (IA), or The compound is selected from the compound represented by formula (IB), Preferably, (1) The compound is selected from the compound represented by formula (I-1), or The compound is selected from the compound represented by formula (I-2), More preferably, the compound is selected from the compound represented by formula (I-3) or The compound is selected from the compound represented by formula (I-4) or, (2) The compound is selected from the compound represented by formula (I-5) or The compound is selected from the compound represented by formula (I-6) or, (3) The compound is selected from the compound represented by formula (I-7) in is selected from single bonds and double bonds; M1, M2 and M3 are each independently C, CH or N; or The compound is selected from the compound represented by formula (I-8) in is selected from single bonds and double bonds; M1, M2 and M3 are each independently C, CH or N; or, (4) The compound is selected from the compound represented by formula (I-9') in, V is selected from CH and N; or The compound is selected from the compound represented by formula (I-10') in, V is selected from CH and N.

26. A compound according to any one of claims 1 to 25, or a stereoisomer thereof, or a tautomer 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, having a structure shown in formula (II-A) to (II-P): Preferably, it has a structure shown in formula (II-1) to (II-11): More preferably, the structures represented by formula (III-1) to (III-5) are:

27. The compound according to any one of claims 1 to 26, or its stereoisomer, or its tautomer, 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 is selected from:

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a stereoisomer thereof, or a tautomer 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, and one or more pharmaceutically acceptable carriers or excipients.

29. A method for treating or preventing a disease, comprising the following steps: A therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 27, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28 is administered to an individual (i) suffering from a condition characterized by axonal degeneration or (ii) at risk of suffering from a condition characterized by axonal degeneration.

30. A method for treating or preventing axonal degeneration, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 27, or a stereoisomer thereof, or a tautomer 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 28.

31. A method for treating or preventing a disorder or condition characterized by axonal degeneration, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 27, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28; Preferably, the disease or condition characterized by axonal degeneration is a neurodegenerative disease or a peripheral neuropathy; The neurodegenerative disease is preferably Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic sclerosis or Huntington's disease.

32. Use of a compound according to any one of claims 1 to 27, or a stereoisomer thereof, or a tautomer 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 28 in the preparation of a medicament for treating or preventing axonal degeneration; or in the preparation of a medicament for treating or preventing a disorder or condition characterized by axonal degeneration; Preferably, the disease or condition characterized by axonal degeneration is a neurodegenerative disease or a peripheral neuropathy; The neurodegenerative disease is preferably Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic sclerosis or Huntington's disease.

33. A compound according to any one of claims 1 to 27, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28, for use in treating or preventing axonal degeneration, or for treating or preventing a disorder or condition characterized by axonal degeneration; Preferably, the disease or condition characterized by axonal degeneration is a neurodegenerative disease or a peripheral neuropathy; The neurodegenerative disease is preferably Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic sclerosis or Huntington's disease.

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