Fused tricyclic compound, preparation method therefor, and use thereof

Abstract

The present invention relates to a fused tricyclic compound, a preparation method therefor, and use thereof. The compound has an SARM1 inhibitory effect and can be used for treating neurodegenerative diseases.

Description

A fused tricyclic compound, its preparation method and application

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese patent applications CN202510372353.2 filed on March 26, 2025, CN202510570137.9 filed on April 30, 2025, and CN202510833090.0 filed on June 20, 2025, the contents of which are incorporated herein by reference in their entirety and for all purposes. Technical Field

[0003] This invention belongs to the pharmaceutical field, specifically relating to a fused tricyclic compound, its preparation method, and its application. Background Technology

[0004] Axon degeneration is closely related to the occurrence and development of neurological diseases. Wallerian degeneration is a major pathway of axon degeneration; also known as secondary degeneration, it refers to the process by which nerve fibers distal to a nerve axon degrade after the axon is severed due to trauma. This process involves two key proteins: nicotinamide adenine dinucleotide (NAD). + synthases NMNAT2 and NAD + The hydrolase SARM1 (Sterile alpha and Toll / interleukin-1 receptor motif-containing 1) is the main executor molecule in this neurodegradation process, and 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. + With low levels of nicotinamide mononucleotide (NMN), SARM1 remains at a low activity level. When neurons are damaged, NMNAT2 transport along the axon stops, and NMNAT2 rapidly degrades, leading to an increase in NMN levels and NAD. + The levels begin to decrease; this period is called the axonal degenerative latency period, and NMN and NAD levels... + Changes in this lead to the activation of SARM1, which in turn causes Ca... 2+ Influx, calpain activation, and ATP depletion, along with the accumulation of ROS, lead to axonal degeneration. Numerous studies have reported the protective effects of SARM1 knockout or inhibition 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, Parkinson's, multiple sclerosis, amyotrophic sclerosis, and Huntington's disease are very limited, with no truly effective cures. Current treatments primarily focus on symptomatic relief, failing to halt disease progression or provide a cure. Furthermore, with an aging population, the incidence of neurodegenerative diseases is steadily increasing. Therefore, there is an urgent need to develop more effective drugs to help slow disease progression, improve patients' quality of life, and even halt disease development in its early stages. Summary of the Invention

[0007] The first aspect of the present invention provides a compound of formula (I), or a stereoisomer thereof, a tautomer thereof, a polymorph thereof, a solvate thereof, a hydrate thereof, an N-oxide thereof, an isotopically labeled compound thereof, a metabolite thereof, an ester thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0008] in, Indicates a single bond or a double bond;

[0009] Selected from "#1" and "#2" represent two carbon atoms on the fused bond between ring C and ring B, respectively shown as carbon atom #1 and carbon atom #2;

[0010] X1, X2, X3, and X4 are each independently selected from CH or N;

[0011] Ring A is optionally substituted by one, two or three substituents, each independently selected from halogens, C1-6 alkyl groups or C1-6 haloalkyl groups;

[0012] Y1 and Y2 are each independently selected from CH2, NH, S, or O; m is selected from 1 or 2; and the structural fragments At most one of Y1 and Y2 is selected from NH, S or O, and the rest are CH2;

[0013] Ring B is optionally substituted by one, two or three substituents, each independently selected from halogens, C1-6 alkyl groups or C1-6 haloalkyl groups;

[0014] R1 is selected from H or C1-6 alkyl;

[0015] R2 and R3 are each independently selected from H or halogens;

[0016] Alternatively, R1 and R2 together with the atoms they are attached to form a 5-7 membered heterocyclic group, which has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from oxygen or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms.

[0017] Ring D is selected from C6-10 aryl or 5-10 heteroaryl;

[0018] Each R4 is independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or, two adjacent R4s together with the atoms they are attached to form a 5-6 membered heterocyclic group, the 5-6 membered heterocyclic group having one or two heteroatoms selected from nitrogen, oxygen, or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms;

[0019] n is selected from 0, 1, 2, 3, 4 or 5.

[0020] In some implementations, at least one of X1, X2, X3, and X4 is selected from N.

[0021] In some implementations, at least one of X1, X2, X3, and X4 is selected from N and at most two of them are selected from N.

[0022] In some implementations, X1, X3, and X4 are all CH, and X2 is N; or, X1 and X4 are all CH, and X2 and X3 are both N; or, X1 and X2 are both N, and X3 and X4 are all CH.

[0023] In some implementations, X1, X3, and X4 are all CH, and X2 is N.

[0024] In some embodiments, ring A is optionally substituted by one or two (preferably one) substituents, each independently selected from halogens, C1-4 alkyl groups, or C1-4 haloalkyl groups.

[0025] In some embodiments, ring A may optionally be substituted with one substituent selected from F, Cl, methyl, or trifluoromethyl.

[0026] In some embodiments, ring A may optionally be substituted with one substituent selected from F or methyl.

[0027] In some implementations, ring A is not replaced.

[0028] In some embodiments, Y1 and Y2 are each independently selected from CH2, NH, or O, and the structural fragments At most one of Y1 and Y2 is selected from NH or O, and the rest are CH2.

[0029] In some implementations, Y1 and Y2 are each independently selected from CH2 or O, and the structural fragments At most one of Y1 and Y2 is selected from O, and the rest are CH2.

[0030] In some implementations, Y1 is O and Y2 is CH2.

[0031] In some implementations, m is selected from 1 or 2.

[0032] In some implementations, m is 1.

[0033] In some implementations, structural fragments Selected from #A-CH2-CH2-CH2-, #AO-CH2-CH2-, #A-CH2-O-CH2-, #A-NH-CH2-CH2-, #A-CH2-NH-CH2-, #AO-CH2-, #A-CH2-O-, wherein the bond identified by "#A" is connected to ring A.

[0034] In some implementations, structural fragments Selected from #AO-CH2-CH2- and #AO-CH2-, wherein the bond identified by "#A" is connected to ring A.

[0035] In some implementations, structural fragments Selected from #AO-CH2-, where the bond identified by "#A" is connected to ring A.

[0036] In some embodiments, ring B is optionally substituted by one or two substituents, each independently selected from halogens, C1-4 alkyl groups, or C1-4 haloalkyl groups.

[0037] In some embodiments, ring B is optionally substituted with one or two substituents, each independently selected from F, Cl, methyl, ethyl, trifluoromethyl, or trifluoroethyl.

[0038] In some embodiments, ring B is optionally substituted with one or two methyl groups.

[0039] In some implementations, ring B is unsubstituted.

[0040] In some implementations, Selected from

[0041] In some implementations, for

[0042] In some implementations, Selected from

[0043] In some implementations, Selected from

[0044] In some implementations, for

[0045] In some embodiments, R1 is selected from H or C1-4 alkyl;

[0046] R2 and R3 are each independently selected from H or halogens;

[0047] Alternatively, R1 and R2 together with the atoms they are attached to form a 5-7 member monocyclic heterocyclic group, which has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from oxygen or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms.

[0048] In some implementations, R1 is H;

[0049] R2 and R3 are each independently selected from H or F;

[0050] Alternatively, R1 and R2 together with the atoms they are attached to form a 5-6 member monocyclic heterocyclic group, which has one nitrogen heteroatom and 0 or 1 oxygen heteroatom and 0 sulfur heteroatom, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms.

[0051] In some implementations, R1, R2, and R3 are all H.

[0052] In some embodiments, R3 is selected from H, and R1 and R2 together with the atoms attached to them form a 5-6 member monocyclic heterocyclic group having one nitrogen heteroatom and 0 or 1 oxygen heteroatom and 0 sulfur heteroatom, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms.

[0053] In some embodiments, R3 is selected from H, and R1 and R2 together with the atoms attached to them form a 5-6 member monocyclic heterocyclic group, the 5-6 member monocyclic heterocyclic group having 1 nitrogen heteroatom and 0 heteroatoms selected from oxygen or sulfur.

[0054] In some implementations, structural fragments for

[0055] In some implementations, structural fragments Selected from

[0056] In some implementations, structural fragments Selected from

[0057] In some implementations, structural fragments Selected from

[0058] In some implementations, structural fragments Selected from

[0059] In some implementations, structural fragments Selected from

[0060] In some implementations, structural fragments Selected from

[0061] In some implementations, structural fragments Selected from

[0062] In some implementations, structural fragments Selected from

[0063] In some embodiments, ring D is selected from phenyl or 5-6-membered heteroaryl groups.

[0064] In some embodiments, ring D is selected from phenyl or 6-membered heteroaryl.

[0065] In some embodiments, ring D is selected from phenyl or 6-membered heteroaryl; the heteroatom of the 6-membered heteroaryl is nitrogen, and the number of heteroatoms is 1 or 2 (preferably 1).

[0066] In some embodiments, ring D is selected from phenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl.

[0067] In some embodiments, ring D is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, or thiophene.

[0068] In some embodiments, ring D is selected from phenyl, pyridyl, pyrimidinyl, or pyridazinyl.

[0069] In some embodiments, ring D is selected from phenyl, pyridyl, and thiophene.

[0070] In some embodiments, ring D is selected from phenyl or pyridyl.

[0071] In some embodiments, each R4 is independently selected from hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy; or, two adjacent R4s together with the atoms they are attached to form a 5-6 membered monocyclic heterocyclic group, the 5-6 membered monocyclic heterocyclic group having one or two heteroatoms selected from nitrogen or oxygen and zero sulfur heteroatoms, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms.

[0072] In some embodiments, each R4 is independently selected from hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy; or, two adjacent R4s together with the atoms they are attached to form a 5-membered monocyclic heterocyclic group, the 5-membered monocyclic heterocyclic group having 1 or 2 (preferably 2) oxygen heteroatoms and 0 heteroatoms selected from nitrogen or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms.

[0073] In some embodiments, each R4 is independently selected from hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy.

[0074] In some embodiments, two adjacent R4 atoms together with the atoms they are connected to form a 5-membered monocyclic heterocyclic group, the 5-membered monocyclic heterocyclic group having 1 or 2 (preferably 2) oxygen heteroatoms and 0 heteroatoms selected from nitrogen or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms.

[0075] In some implementations, each R4 is independently selected from hydrogen, halogen, or cyano.

[0076] In some implementations, each R4 is independently selected from halogens (preferably F or Cl).

[0077] In some embodiments, each R4 is independently selected from hydrogen, F, Cl, cyano, or two adjacent R4s are formed together with the atoms they are bonded to. in This indicates the fusion site with ring D.

[0078] In some implementations, each R4 is independently selected from hydrogen, F, Cl, or cyano.

[0079] In some implementations, each R4 is independently selected from F, Cl, or cyano.

[0080] In some implementations, each R4 is independently selected from halogens (e.g., F, Cl) or cyano groups.

[0081] In some implementations, n is selected from 0, 1, 2 or 3.

[0082] In some implementations, n is selected from 1, 2, or 3.

[0083] In some implementations, n is selected from 2 or 3.

[0084] In some implementations, each R4 is independently selected from halogens (e.g., F, Cl); and / or, n is selected from 1, 2, or 3.

[0085] In some implementations, each R4 is independently selected from F, Cl; and / or, n is selected from 2 or 3.

[0086] In some implementations, Selected from Wherein W1, W2, W3, W4 and W5 are each independently selected from CH or N; preferably, 0, 1, 2 or 3 of W1, W2, W3, W4 and W5 are N; preferably, 0, 1 or 2 of W1, W2, W3, W4 and W5 are N; preferably, 0 or 1 of W1, W2, W3, W4 and W5 are N; preferably, W1, W2, W3, W4 and W5 are all CH; preferably, W2 is N, and W1, W3, W4 and W5 are all CH, or W4 is N, and W1, W2, W3 and W5 are all CH.

[0087] In some implementations, Selected from Wherein, W1, W2, W3, W4, and W5 are as defined above; when W1, W2, W3, W4, and W5 are all CH; n is selected from 2 or 3, and at least one R4 (e.g., F) is connected to W2 or W4; preferably, when n is selected from 2, R4 is connected to W2 and W4, or R4 is connected to W2 and W3; preferably, when n is selected from 3, R4 is connected to W2, W3, and W4; preferably, when R4 is connected to W2 and / or W4, R4 is F, and when R4 is connected to W3, R4 is Cl or CN (preferably Cl).

[0088] In some implementations, Selected from Wherein, W1, W2, W3, W4, and W5 are as defined above; when W2 is N, and W1, W3, W4, and W5 are all CH, or when W4 is N, and W1, W2, W3, and W5 are all CH, n is selected from 1 or 2, and at least one R4 is connected to W3; preferably, when n is selected from 1, R4 (e.g., F or Cl) is connected to W3; preferably, when n is selected from 2, and W2 is N, and W1, W3, W4, and W5 are all CH, R4 is connected to W3 and W4, or, when n is selected from 2, and W4 is N, and W1, W2, W3, and W5 are all CH, R4 is connected to W2 and W3; preferably, when R4 is connected to W2 or W4, R4 is F, and when R4 is connected to W3, R4 is F or Cl (preferably Cl).

[0089] In some implementations, Selected from Wherein n is selected from 1, 2 or 3, preferably n is selected from 2 or 3; preferably, at least one R4 is connected to the meta position of the phenyl group; preferably, when n is 2, R4 is connected to the meta and para positions of the phenyl group respectively or both are connected to the meta position of the phenyl group; preferably, when n is 3, R4 is connected to the meta and para positions of the phenyl group; preferably, when R4 is connected to the meta position of the phenyl group, R4 is F, and when R4 is connected to the para position of the phenyl group, R4 is Cl or CN (preferably Cl).

[0090] In some implementations, Selected from Wherein n is selected from 1, 2 or 3, preferably n is selected from 1 or 2; preferably, at least one R4 is connected to the 6th position of pyridine; preferably, when n is 1, R4 is connected to the 6th position of pyridine; preferably, when n is 2, R4 is connected to the 5th and 6th positions of pyridine; preferably, when R4 is connected to the 5th position of pyridine, R4 is selected from F; when R4 is connected to the 6th position of pyridine, R4 is selected from F or Cl (preferably Cl).

[0091] In some implementations, Selected from

[0092] In some implementations, Selected from

[0093] In some implementations, Selected from

[0094] In some implementations, Selected from In some implementations, Selected from In some implementations, Selected from In some implementations, Selected from In some implementations, Selected from In some implementations, Selected from In some implementations, Selected from

[0095] In some implementations, Selected from

[0096] In some implementations, Selected from

[0097] In some implementations, Selected from

[0098] In some implementations, Selected from

[0099] In some implementations, Selected from

[0100] In some embodiments, the compound of formula (I) is as shown in formula (I-1):

[0101] Wherein, X1, X2, X3, X4, Y1, Y2, m, n, R1, R2, R3, R4, ring A, ring B, ring C, ring D, #1, and #2 are as defined in any of the embodiments described herein.

[0102] In some embodiments, the compound of formula (I) is as shown in formula (I-2):

[0103] Wherein, X1, X2, X3, X4, Y1, Y2, m, n, R1, R2, R3, R4, ring A, ring B, ring C, ring D, #1, and #2 are as defined in any of the embodiments described herein.

[0104] In some embodiments, the compound of formula (I) is as shown in formula (I-3):

[0105] Wherein, X1, X2, X3, X4, Y1, Y2, m, n, R1, R2, R3, R4, ring A, ring B, ring C, ring D, #1, and #2 are as defined in any of the embodiments described herein.

[0106] In some embodiments, the compound of formula (I) is as shown in formula (II-1):

[0107] Wherein, n, R1, R2, R3, R4, ring A, ring B, ring C, ring D, #1, and #2 are as defined in any of the embodiments described herein.

[0108] In some embodiments, the compound of formula (I) is as shown in formula (II-2):

[0109] Wherein, n, R1, R2, R3, R4, ring A, ring B, ring C, ring D, #1, and #2 are as defined in any of the embodiments described herein.

[0110] In some embodiments, the compound of formula (I) is as shown in formula (III-1):

[0111] Wherein, n, R1, R2, R3, R4, W1, W2, W3, W4, W5, ring A, ring B, ring C, ring D, #1, and #2 are defined in any of the embodiments described in this paper.

[0112] In some embodiments, the compound of formula (I), or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is selected from:

[0113] In some embodiments, the compound of formula (I), or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is selected from:

[0114] In some embodiments, the compound of formula (I), or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is selected from:

[0115] In some embodiments, the compound of formula (I), or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is selected from:

[0116] A second aspect of the present invention provides a 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, said compound being selected from:

[0117] In some embodiments, the compound of the present invention, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is selected from:

[0118] In some embodiments, the compounds of the present invention are selected from:

[0119] In some embodiments, the compound of the present invention, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is selected from:

[0120] In some embodiments, the compound of the present invention, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is selected from:

[0121] In some embodiments, the compound of the present invention, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is selected from:

[0122] Any embodiment of any aspect of the present invention may be combined with other embodiments, provided that they do not contradict each other. Furthermore, any technical feature in any embodiment of any aspect of the present invention may be applied to the same technical feature in other embodiments, provided that they do not contradict each other.

[0123] A third aspect of the invention provides the aforementioned 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, for inhibiting SARM1 or as a SARM1 inhibitor.

[0124] A fourth aspect of the present invention provides a pharmaceutical composition comprising the compound described herein, 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 some embodiments, the compound described herein, 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.

[0125] A fifth aspect of the present invention provides a method for treating or preventing a disease, comprising the following steps:

[0126] The therapeutic or preventive effective amount 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 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 (i) an individual suffering from a condition characterized by axonal degeneration or (ii) an individual at risk of developing a condition characterized by axonal degeneration.

[0127] A sixth aspect of the invention provides a method for treating or preventing axonal degeneration, comprising administering to an individual in need a therapeutic or preventative amount of the compound of the 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, or a pharmaceutical composition of the invention.

[0128] The seventh aspect of the invention provides a method for treating or preventing a disease or condition characterized by axonal degeneration, comprising administering to an individual in need a therapeutic or preventative amount of the compound of the 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, or a pharmaceutical composition of the invention.

[0129] The eighth aspect of the invention provides the use of the compound described herein, 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 described herein, in the preparation of a medicament for the treatment or prevention of axonal degeneration.

[0130] The ninth aspect of the invention provides the use of the compounds described herein, or their stereoisomers, tautomers, polymorphs, solvates, hydrates, N-oxides, isotopically labeled compounds, metabolites, esters, prodrugs, pharmaceutically acceptable salts, or pharmaceutical compositions described herein, in the preparation of medicaments for the treatment or prevention of diseases or conditions characterized by axonal degeneration.

[0131] The tenth aspect of the present invention provides the compounds described herein, or their stereoisomers, tautomers, polymorphs, solvates, hydrates, N-oxides, isotopically labeled compounds, metabolites, esters, prodrugs, pharmaceutically acceptable salts, or pharmaceutical compositions described herein, for the treatment or prevention of axonal degeneration, or for the treatment or prevention of a disease or condition characterized by axonal degeneration.

[0132] In some implementations, the condition or ailment characterized by axonal degeneration is a neurodegenerative disease, an eye disease, or a peripheral neuropathy.

[0133] In some embodiments, the neurodegenerative disease is preferably Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic sclerosis, or Huntington's disease.

[0134] In some implementations, the eye disease is glaucoma.

[0135] The compounds described in this invention can be synthesized using common chemical synthesis knowledge familiar to those skilled in the art, or various similar known methods in the art. The separation and purification of the products can be achieved using standard procedures known to those skilled in the art.

[0136] Terminology Definition

[0137] The various terms and phrases used in this invention have their general meanings known to those skilled in the art. Nevertheless, this invention still intends to provide a more detailed description and explanation of these terms and phrases. In the event of any inconsistency between the terms and phrases mentioned and their known meanings, the meanings expressed in this invention shall prevail.

[0138] When the compound name used in this invention is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0139] In the structural formula of this invention, the imidazole-containing fragment can undergo tautomerism, for example:

[0140] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: salts formed by addition to inorganic or organic acids, salts containing acidic protons present on the parent compound but surrounded by metal ions, or salts forming coordination compounds with organic bases.

[0141] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer 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-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0142] Unless otherwise specified, 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, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0143] The term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms of the same number but with a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include, but are not limited to, hydrogen isotopes, such as... 2 H, 3 H; carbon isotopes, for example 11 C, 13 C and 14 C; Chlorine isotopes, for example 36 Cl; fluorine isotopes, for example 18 F; Iodine isotopes, for example 123 I and 125 I; nitrogen isotopes, for example 13 N and 15 N; oxygen isotopes, for example 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0144] The term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compounds disclosed in this invention. Prodrugs become active compounds only under biological conditions, or they do not have or only have low activity in their unreacted forms. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0145] The term "ester" refers to esters that can undergo hydrolysis in vivo, including those that readily decompose within 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.

[0146] The compounds of this invention may exist as solvates (such as hydrates), wherein the compounds of this application contain a solvent, such as water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the solvent may be stoichiometric or non-stoichiometric.

[0147] This invention covers all possible crystalline forms or polymorphs of the compound, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0148] The term "N-oxide" refers to a compound in which at least one nitrogen atom is oxidized to form an oxide containing an amine moiety (i.e., an oxide of a tertiary amine group). Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized to an oxide; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form 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, by converting nitrogen atoms (e.g., trivalent nitrogen) to the corresponding N-oxide form through known methods such as treatment with an oxidizing agent.

[0149] In this invention, the purpose of the pharmaceutical composition is to promote drug delivery to organisms, facilitate the absorption of active ingredients, and thus exert biological activity. The carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycerol, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, and lanolin. The excipients refer to additives in the pharmaceutical preparation other than the active ingredient. They are stable, have no incompatibilities with the active ingredient, do not produce side effects, do not affect efficacy, are not easily deformed, cracked, moldy, or infested by insects at room temperature, are harmless to the human body, have no physiological effects, do not produce chemical or physical reactions with the active ingredient, and do not affect the content determination of the active ingredient. Examples of excipients include binders, fillers, disintegrants, and lubricants in tablets; wine, vinegar, and medicinal juice in traditional Chinese medicine pills; the base portion in semi-solid preparations such as ointments and creams; and preservatives, antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, osmotic pressure regulators, and colorants in liquid preparations.

[0150] In this invention, the pharmaceutical composition can be formulated 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 inhalers, sprays, etc. The pharmaceutical composition or suitable dosage form may contain 0.01 mg to 1000 mg of the compound described in this invention, or its stereoisomers, tautomers, polymorphs, solvates, hydrates, N-oxides, isotope-labeled compounds, metabolites, esters, prodrugs, or pharmaceutically acceptable salts, preferably 0.1 mg to 800 mg, preferably 0.5-500 mg, more preferably 0.5-350 mg, and particularly preferably 1-250 mg.

[0151] The term "individual" includes humans or non-human animals. Exemplary human individuals include individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. The term "non-human animal" in this 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.).

[0152] The term "treatment" aims to alleviate, reduce, improve, or eliminate a targeted disease state or symptom. A subject is successfully "treated" if, in accordance with the methods described herein, a therapeutic amount of the compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is received and one or more indications and symptoms show an observable and / or detectable reduction or improvement. It should also be understood that treatment of the disease state or symptom includes not only complete treatment but also the achievement of some biological or medically relevant outcome without achieving complete treatment.

[0153] The term "prevention" aims to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms before the onset of the relevant medication. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, reducing the risk of a subject developing a specific disease or disease-related symptoms after the administration of the relevant medication, or lessening the severity of subsequently occurring related symptoms, can be considered as "prevention" of the onset or development of the disease.

[0154] The term "effective amount" refers to an amount sufficient to achieve the desired therapeutic or preventative effect, such as an amount that alleviates symptoms associated with a disease to be treated, or an amount that effectively prevents, stops, or delays the onset of a disease. Determining such an effective amount is within the capabilities of someone skilled in the art.

[0155] It should also be noted that the dosage and method of administration of the compounds of this invention depend on many factors, including the patient's age, weight, sex, natural health condition, nutritional status, the activity intensity of the compound, the time of administration, metabolic rate, the severity of the disease, and the subjective judgment of the treating physician. The preferred dosage is between 0.01 and 100 mg / kg body weight / day.

[0156] The terms “optionally substituted” or “optionally substituted with…” indicate that a ring may or may not be substituted, encompassing both the presence and absence of substituents. For example, ring A is optionally substituted by 1, 2, or 3 substituents, each independently selected from halogens, C1-6 alkyl groups, or C1-6 haloalkyl groups, indicating that the number of substituents on ring A can be 0, 1, 2, or 3, wherein the substituents are selected from the set of groups: halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups; wherein: (i) when the number is 0, ring A remains unsubstituted; (ii) when the number is 1, ring A is substituted by a single substituent; (iii) when the number is 2 or 3, the substituents may be the same or different from the set of groups; in particular, “ring A is unsubstituted” means that the number of substituents on ring A is 0, i.e., ring A is unsubstituted.

[0157] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0158] When a substituent is shown to be a bond that passes through the ring and connects two atoms (“floating bond”), such a substituent may be bonded to any cyclic atom in the substituted ring, unless otherwise stated. In cases where a substituted hydrogen atom is shown to be carried by a substituted ring member, the substituted hydrogen atom is substantially substituted (i.e., not present) when the floating bond is bonded to that substituted ring member.

[0159] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0160] The term "alkyl" refers to a straight-chain or branched monovalent saturated aliphatic hydrocarbon, which can be considered as a group obtained by losing one hydrogen atom from an alkane. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight-chain or branched group with 1 to 6 carbon atoms, including "C". 2-6 Alkyl", C 2-5 "alkyl" and "C" 1-4 Alkyl group. "C" 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. The term "C" 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0161] The term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above. For example, C 1-6Alkoxy groups, specific examples of which include, but are not limited to, methoxy, ethoxy, propoxy, or butoxy groups.

[0162] The term "halogenated" refers to the substitution of a modified group by one or more halogens, such as 1, 2, 3, 4, 5, or 6 halogens. For example, "C 1-6 "Halogenated alkyl" refers to C as defined above. 1-6 The alkyl group is substituted with one or more halogens, including but not limited to CF3, CHF2, CH2F, or CF2CF3.

[0163] The term "fusion" refers to two or more ring structures sharing two adjacent ring atoms.

[0164] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 12 (suitably 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 6, or 5 to 6) ring carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. In some embodiments, cycloalkyl includes aryl-fused cycloalkyl, provided that the entire ring system is non-aromatic.

[0165] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic (including but not limited to bicyclic and tricyclic) cyclic structure, preferably having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, and sulfur. The heterocyclic group can be connected to the rest of the molecule via any one of its carbon or nitrogen atoms (if present). Specifically, a 3-12 membered heterocyclic group is a group having a total of 3-12 (e.g., 3-10, 3-8, 3-7, 3-6, 4-11, 4-9, 4-7, 4-6, 5-12, 5-6, 6-10, 6-9, 6-8, 7-11, or 8-12) carbon atoms and heteroatoms in the ring. Examples that can be listed include, but are not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and dioxolinyl. Heterocyclic groups include heteroaryl fused heterocyclic groups or cycloalkyl groups, as well as aryl fused heterocyclic groups, provided that the entire ring system is non-aromatic.

[0166] The term "aryl" refers to a fully carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C 6-10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.

[0167] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups can be benzofused. Examples of heteroaryl groups include, but are not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thiophene, oxazolyl, furanyl, pyrroloyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazole, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzoisothiazolyl, imidazole-pyridyl, quinolinyl, indolyl, pyrrolopyridazinyl, and benzofuran. The following are listed: benzothiophene, indazole, benzoxazolyl, benzoisoxazolyl, quinazolinyl, pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridyl, triazolopyridyl, isoquinolinyl, benzimidazolyl, cyclolinyl, indoleyl, phthalazinyl, isoindolyl, pteridinyl, purineyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthidyl, or furanolopyridyl, etc. Detailed Implementation

[0168] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products. In conventional synthetic methods and in the synthetic examples of compounds and intermediates of this invention, the abbreviations have the following meanings: EA: Ethyl acetate; PE: Petroleum ether; DCM: Dichloromethane; DMF: N,N-Dimethylformamide; NBS: N-bromosuccinimide; SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride; LDA: Lithium diisopropylamino; MTBE: Methyl tert-butyl ether; LiHMDS: Bistrimethylsilylaminolithium; DIEA: N,N-Diisopropylethylamine; T3P: 1-Propylphosphine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; TFA: Trifluoroacetic acid; TCFH: N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate; NMI: N-methylimidazolium; ACN: Acetonitrile; Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene.

[0169] Synthesis of intermediates

[0170] Synthesis of compound INT-1

[0171] Step 1: Potassium carbonate (11281.2 mg, 79.99 mmol) and 4-bromobutyronitrile (3.9 mL, 38.45 mmol) were added to a DMF (30 mL) solution of compound INT-1-1 (5000 mg, 32.00 mmol), and the mixture was stirred at 25 °C for 18 hours. The reaction solution was quenched with ammonium chloride aqueous solution (200 mL), extracted with EA (100 mL × 3), the organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound INT-1-2.

[0172] Step 2: Add the following to a 25 mL solution of compound INT-1-2 (4300 mg, 18.55 mmol) in DMF at 0 °C. t BuOK (4247.7 mg, 37.10 mmol) was added and the reaction was stirred at 0 °C for 3 hours. The reaction solution was quenched with ammonium chloride aqueous solution (200 mL), extracted with EA (100 mL × 3), the organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 4:1) to obtain compound INT-1-3.

[0173] Step 3: Hydrazine hydrochloride (4410.7 mg, 63.10 mmol) was added to an ethanol (10 mL) solution of compound INT-1-3 (2500 mg, 12.62 mmol), and the mixture was stirred at 80 °C for 18 hours. The reaction solution was quenched with ammonium chloride aqueous solution (50 mL), extracted with EA (50 mL × 3), the organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound INT-1. MS (ESI, pos.ion) m / z: 203.1 [M+1] + .

[0174] Synthesis of compound INT-2

[0175] Step 1: Dissolve compound INT-2-1 (1 g, 5.61 mmol) in acetonitrile (20 mL), add compound INT-2-0, and stir at 95 °C for 3 hours to obtain a brown solution. Cool to room temperature and concentrate under reduced pressure to remove the solvent. Purify the crude product by silica gel column chromatography (silica, petroleum ether: ethyl acetate = 20 / 1-10 / 1) to obtain compound INT-2-2.

[0176] Step 2: Compound INT-2-2 (50 mg, 0.21 mmol) and lithium hydroxide monohydrate (30 mg, 0.71 mmol) were dissolved in tetrahydrofuran (1 mL) and water (1 mL). The mixture was stirred at 25 °C for 2 hours to obtain a brown solution. The reaction mixture was adjusted to pH 2 with 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound INT-2.

[0177] Synthesis of compound INT-3

[0178] Step 1: Under nitrogen protection, compound INT-3-0 (2195.7 mg, 5.72 mmol) was added to a solution of compound INT-3-1 (800 mg, 4.76 mmol) in acetonitrile (10 mL), and the mixture was stirred at 90 °C for 18 hours. The reaction solution was quenched with ammonium chloride aqueous solution (100 mL), extracted with EA (100 mL × 3), the organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 4:1) to obtain compound INT-3-2.

[0179] Step 2: Hydrogen chloride (4 mL, 16.00 mmol, 4 M in dioxane) was added to a DCM (2 mL) solution of compound INT-3-2 (200 mg, 0.74 mmol), and the mixture was stirred at 25 °C for 3 hours. The reaction solution was quenched with ammonium chloride aqueous solution (50 mL), extracted with EA (50 mL × 3), the organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound INT-3. MS (ESI, pos.ion) m / z: 202.2 [M+1] + .

[0180] Synthesis of compound INT-4

[0181] Step 1: Compound INT-4-1 (500 mg, 1.18 mmol), diphenylmethyleneimine (475 mg, 2.59 mmol), cesium carbonate (852 mg, 2.59 mmol), and methanesulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (75 mg, 0.13 mmol) were dissolved in dioxane (5 mL). The solution was stirred at 100 °C for 18 hours under nitrogen protection to obtain a brown solution. The solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (silica, petroleum ether: ethyl acetate = 1 / 1-2 / 1) to obtain compound INT-4-2.

[0182] Step 2: Compound INT-4-2 (439 mg, 0.88 mmol), hydroxylamine hydrochloride (75 mg, 1.07 mmol), and sodium acetate (110 mg, 1.33 mmol) were dissolved in methanol (5 mL), and stirred at 25 °C for 18 hours to obtain a yellow solid. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography (silica, dichloromethane:methanol = 20 / 1-10 / 1) to obtain compound INT-4.

[0183] Synthesis of compound INT-5

[0184] Step 1: Dissolve compound INT-5-1 (46g, 364.75mmol) in MeOH (460mL). Add NBS (130g, 730.38mmol) at 0℃ and react at 25℃ for 2 hours. Concentrate the reaction solution under reduced pressure to remove most of the MeOH. Add EA (200mL), then pour the mixture into a saturated Na2SO3 (200mL) aqueous solution. Extract with EA (100mL × 3). Wash the organic phase with saturated NaCl solution, dry to anhydrous Na2SO4, and concentrate under reduced pressure to obtain compound INT-5-2.

[0185] Step 2: Dissolve compound INT-5-2 (93g, 327.57mmol) in H2O (900mL), add Na2SO3 (82g, 650.59mmol), and react at 90℃ for 24h. TLC monitoring showed that approximately half of the starting material had reacted. Add more Na2SO3 (82g, 650.59mmol), and react at 90℃ for another 24h. Cool the reaction solution to room temperature and then filter to obtain compound INT-5-3.

[0186] Step 3: Compound INT-5-3 (58.8 g, 286.81 mmol) was dissolved in DMF (600 mL). NaH (15 g, 375 mmol) was added at 0 °C, and the reaction was carried out for 0.5 h under nitrogen protection at 0 °C. Then, SEMCl (62 mL, 342.5 mmol) was added dropwise to the reaction solution at 0 °C, and the reaction was carried out at 25 °C for 1.5 h. The reaction solution was slowly poured into ice water (1.5 L), extracted with EA (300 mL × 3), the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (SiO2, EA:PE = 0%–12%) to obtain compound INT-5-4.

[0187] Step 4: Dissolve compound INT-5-4 (120 g, 357.92 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (159.7 g, 715.98 mmol) in 1,4-dioxane (2400 mL), add Cs2CO3 (174.9 g, 536.8 mmol) and palladium catalyst (CAS: 1599466-85-9, 16.23 g, 19.09 mmol), and react at 110 °C under nitrogen protection for 48 h. The reaction solution was poured into water (1.5 L), concentrated under reduced pressure to remove most of the 1,4-dioxane, and then extracted with EA (600 mL × 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (SiO2, EA:PE = 0%–65%) to obtain compound INT-5-5.

[0188] Step 5: Under nitrogen protection at 0℃, LiAlH4 (9.72 g, 256.13 mmol) was added to a reaction flask containing THF (400 mL). Then, compound INT-5-5 (45 g, 128.04 mmol) was dissolved in THF (400 mL), and the reaction was carried out at -15℃ under nitrogen protection for 0.5 h. The THF solution of compound INT-5-5 was then slowly added dropwise to the reaction flask over 30 min. The reaction was carried out at -15℃ under nitrogen protection for 15 min. The reaction was quenched with H2O (9.7 mL), 15% NaOH solution (9.7 mL), and H2O (29.1 mL), then EA (1.3 L) was added, and the mixture was stirred at 25℃ for 1 h. The mixture was then filtered and concentrated under reduced pressure to obtain compound INT-5-6.

[0189] Step Six: Dissolve compound INT-5-6 (38 g, 117.49 mmol) in THF (380 mL), add potassium tert-butoxide (26.36 g, 234.92 mmol), and react at 50 °C under nitrogen protection for 1.5 h. Pour the reaction solution into H2O (500 mL), then extract with EA (300 mL × 2). Wash the organic phase with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (SiO2, MeOH:DCM = 0%–3%) to obtain compound INT-5-7.

[0190] Step 7: Dissolve compound INT-5-7 (17g, 56.02mmol) in THF (170mL), and add LDA (48mL, 96mmol, 2M in THF) dropwise under nitrogen protection at -65℃. React at -65℃ for 0.5h. Dissolve tetrabromomethane (20.45g, 61.67mmol) in THF (15mL), and then add it dropwise to the reaction solution. React at -65℃ under nitrogen protection for 20min. Quench the reaction with saturated ammonium chloride aqueous solution (200mL), then extract with EA (100mL×2). Wash the organic phase with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (SiO2, MeOH:DCM = 0%–3%). Then, slurry the product with MTBE to obtain compound INT-5. MS (ESI, pos.ion) m / z: 382.0\384.0 [M+1] + .

[0191] Synthesis of compound INT-6

[0192] Step 1: Dissolve compound INT-6-1 (1 g, 4.94 mmol) and DMF (0.01 mL, 0.1 mmol) in DCM (10 mL). Add 2-chloro-2-oxoacetyl chloride (0.85 mL, 9.87 mmol) dropwise at 0 °C. React at 25 °C under nitrogen protection for 1.5 h. Concentrate the reaction solution directly under reduced pressure to obtain compound INT-6-2.

[0193] Step 2: Compound INT-6-2 (1 g, 4.98 mmol) was dissolved in DCM (3 mL), and then added dropwise to ammonia (5 mL) and THF (5 mL) under nitrogen protection at 0 °C. The reaction mixture was reacted at 25 °C for 1 h. The reaction solution was poured into H2O (30 mL), and then extracted with DCM (20 mL × 2). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound INT-6. MS (ESI, pos.ion) m / z: 202.0 [M+1] + .

[0194] Synthesis of compound INT-7

[0195] Compound INT-7-1 (18.5 g, 186.62 mmol) was dissolved in THF (380 mL). Under nitrogen protection at 0 °C, n-BuLi (150 mL, 375 mmol, 2.5 M in hexane) was added dropwise, and the reaction was carried out at 0 °C for 1 h. The reaction solution was cooled to -40 °C, and then 4-(bromomethyl)-1-chloro-2-fluorobenzene (40.87 g, 182.89 mmol) was added dropwise to the reaction solution, and the reaction was carried out at -40 °C under nitrogen protection for 1 h. The temperature was then slowly increased to 25 °C, and the reaction was carried out under nitrogen protection for 18 h. The reaction was quenched with a saturated ammonium chloride aqueous solution (300 mL), and then extracted with EA (100 mL × 3). The organic phase was washed with a saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (SiO₂, MeOH:DCM = 0%–2%) to obtain compound INT-7. MS(ESI,pos.ion)m / z:242.1[M+1] + .

[0196] Synthesis of compound INT-8

[0197] Step 1: 4000 mg (21.6 mmol) of tert-butyl 2-oxopyrrolidine-1-carboxylate was dissolved in 15 mL of THF. Under a nitrogen atmosphere, 28 mL of LiHMDS (28.07 mmol) was added at -78 °C, and the reaction was maintained at -78 °C with stirring for 1 h. INT-8-1 (4830 mg (21.6 mmol)) was dissolved in 10 mL of THF and added to the reaction system, followed by stirring at -78 °C for 3 h. The reaction was confirmed to be complete by TLC. The reaction solution was quenched with ice water, extracted with EA, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (SiO2, PE:EA = 3:1) to obtain compound INT-8-2.

[0198] Step 2: Dissolve compound INT-8-2 (550 mg, 1.68 mmol) in dichloromethane (2 ml), add hydrogen chloride-ethyl acetate solution (1.5 ml), and react at room temperature for 1.5 hours. After the reaction is complete, adjust the pH of the reaction mixture to 10 with 10% NaOH. Pour the reaction mixture into water (10 ml) and extract with DCM (10 × 3 ml). Wash the organic layer with brine, dry with Na2SO4, filter and concentrate under reduced pressure to obtain compound INT-8, which can be used directly in the next reaction. MS (ESI, pos.ion) m / z: 228.0 [M+1] + .

[0199] Example 1

[0200] Step 1: Dissolve compound 1-1 (500 mg, 3.16 mmol) in THF (6 ml), add sodium hydroxide (253 mg, 6.32 mmol) at 0 °C, and react at 25 °C for half an hour. Add compound 1-2 (702 mg, 3.16 mmol), and react at 25 °C for another 3 hours. Quench the reaction solution with ice water (20 ml), extract with EA (20 ml × 3), wash the organic phase with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 10:1) to obtain compound 1-3.

[0201] Step 2: Compounds 1-3 (500 mg, 1.66 mmol) and lithium chloride (285.60 mg, 6.66 mmol) were dissolved in dimethyl sulfoxide (5 ml) and reacted at 120 °C for 18 h under nitrogen protection. The reaction solution was quenched with ice water (20 ml), extracted with EA (20 ml × 3), the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compounds 1-4.

[0202] Step 3: Dissolve compounds 1-4 (400 mg, 1.75 mmol) in hydrobromic acid solution (5 ml) and react at 50 °C for 18 h under nitrogen protection. Concentrate the reaction solution under reduced pressure to obtain compounds 1-5, which are used directly in the next step without purification.

[0203] Step 4: Compounds 1-5 (300 mg, 0.97 mmol), compound INT-1 (236 mg, 1.16 mmol), N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (324 mg, 1.16 mmol), and N-methylimidazole (238.62 mg, 2.91 mmol) were dissolved in N,N-dimethylacetamide (5 ml) and reacted at 25 °C for 18 h under nitrogen protection. The reaction solution was quenched with ice water (20 ml), extracted with EA (20 ml × 3), the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 1:2) to obtain compounds 1-6.

[0204] Step 5: Compounds 1-6 (150 mg, 0.30 mmol) were dissolved in N,N-dimethylacetamide (2 mL), and cesium carbonate (198.86 mg, 0.61 mmol) was added. The reaction mixture was reacted at 85 °C for 18 h under nitrogen protection. The reaction solution was quenched with water (10 mL), extracted with DCM (10 mL × 3), and the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (SiO₂, DCM:MeOH = 20:1) to obtain compound 1. MS (ESI, pos.ion) m / z: 413.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 10.75 (s, 1H), 7.77 (d, J = 8.5Hz, 1H), 7.46-7.24 (m, 1H), 7.10-7.05 (m, 1H), 7.02 (br d,J=8.4Hz,1H),6.96-6.88(m,1H),6.61(s,1H),4.51(br t,J=6.3Hz,1H),3.77(br t,J=6.5Hz,2H),3.62-3.52(m,2H),3.37-3.34(m,2H),2.69-2.58(m,2H),2.23(br s,2H).

[0205] Example 2

[0206] Compound INT-1 (91.6 mg, 0.43 mmol), DIEA (0.21 mL, 1.17 mmol), and T3P (373.2 mg, 0.59 mmol) were added to a DMF (2 mL) solution of compound INT-2 (90 mg, 0.39 mmol). The reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was quenched with ammonium chloride aqueous solution (20 mL), extracted with EA (30 mL × 3), the organic phase was washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 1:2) to give compound 2. MS (ESI, pos.ion) m / z: 403.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ=10.04-10.71(m,1H),8.34(s,1H),8.29(d,J=5.3Hz,1H),8.20-8.25(m,1H),7.93 (d,J=5.3Hz,1H),7.57-7.68(m,3H),6.96(d,J=15.8Hz,1H),4.28(t,J=5.0Hz,2H),2.91(t,J=5.1Hz,2H).

[0207] Example 3

[0208] Compound INT-1 (110.4 mg, 0.52 mmol) and DIEA (0.25 mL, 1.39 mmol) were added to a DMF (2 mL) solution of compound INT-3 (100 mg, 0.47 mmol), followed by T3P (449.6 mg, 0.71 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction solution was quenched with ammonium chloride aqueous solution (30 mL), extracted with EA (30 mL × 3), and the organic phase was washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 1:2) to give compound 3. MS (ESI, pos.ion) m / z: 386.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ=13.35(br s,1H),10.35(br s,1H),8.59(br s,1H),8.22-8.37(m,3H),7.78-8.01(m,1H),7.67(br d,J=15.0Hz,1H),7.02(br d, J=15.3Hz, 1H), 4.29 (br t, J=4.0Hz, 2H), 2.91 (br t, J=4.5Hz, 2H).

[0209] Example 4

[0210] Step 1: Compound INT-2-2 (700 mg, 2.98 mmol) and palladium on carbon (70 mg, 0.07 mmol) were dissolved in methanol (10 mL). The mixture was stirred at 25 °C for 18 hours under a hydrogen atmosphere to obtain a brown solution. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding compound 4-1, which was used directly in the next reaction step.

[0211] Step 2: Compound 4-1 (680 mg, 2.87 mmol) and lithium hydroxide monohydrate (269 mg, 6.35 mmol) were dissolved in tetrahydrofuran (4 mL) and water (5 mL). The mixture was stirred at 25 °C for 4 hours to obtain a brown solution. After the reaction was complete, the reaction mixture was adjusted to pH 2 with 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate (10 mL × 3), and the combined organic layers were washed with brine (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-2.

[0212] Step 3: Compound INT-5 (500 mg, 1.18 mmol), diphenylmethyleneimine (475 mg, 2.59 mmol), cesium carbonate (852 mg, 2.59 mmol), and methanesulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (75 mg, 0.13 mmol) were dissolved in 1,4-dioxane (5 mL). The solution was stirred at 100 °C for 18 hours under nitrogen protection to obtain a brown solution. The solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (silica, petroleum ether: ethyl acetate = 1 / 1-2 / 1) to obtain compound 4-3.

[0213] Step 4: Compound 4-3 (439 mg, 0.88 mmol), hydroxylamine hydrochloride (75 mg, 1.07 mmol), and sodium acetate (110 mg, 1.33 mmol) were dissolved in methanol (5 mL), and stirred at 25 °C for 18 hours to obtain a yellow solid. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the crude product was purified by silica gel column chromatography (silica, dichloromethane:methanol = 20 / 1-10 / 1) to obtain compound 4-4.

[0214] Step 5: Compound 4-4 (100 mg, 0.30 mmol), compound 4-2 (70 mg, 0.26 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (173 mg, 0.45 mmol), and N,N-diisopropylethylamine (118 mg, 0.90 mmol) were dissolved in N,N-dimethylformamide (4 mL). The mixture was stirred at 25 °C for 1 hour to obtain a brown solution. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (silica, dichloromethane:methanol = 20 / 1-10 / 1) to obtain compound 4-5.

[0215] Step Six: Compounds 4-5 (130 mg, 0.23 mmol) and trifluoroacetic acid (2 mL, 25.87 mmol) were dissolved in DCM (2 mL) and stirred at 25 °C for 6 hours to obtain a brown solution. The solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by high performance liquid chromatography to obtain compound 4. MS m / z (ESI): 391.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6)δ=12.49-11.95(m,1H),11.51(br s,1H),8.12-8.02(m,2H),7.74-7.17(m,3H),5.50 -5.31(m,2H),2.96(br s,2H),2.82-2.69(m,2H).

[0216] Example 5

[0217] Step 1: Under nitrogen protection, isopropyl magnesium chloride (13.97 mL, 2 M dissolved in THF) was added dropwise to a THF solution of compound 5-1 (5000 mg, 23.29 mmol) at 0 °C (100 mL), maintaining the internal reaction temperature at 5 °C. The solution was stirred at 0 °C for 1 hour. DMF (3.68 mL, 46.57 mmol) was added dropwise to the reaction, maintaining the internal reaction temperature below 10 °C, and the reaction was stirred at 25 °C for 18 hours. The reaction solution was quenched with an ammonium chloride aqueous solution (100 mL), extracted with EA (100 mL × 3), the organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 5-2.

[0218] Step 2: Under nitrogen protection, methyl (triphenylphosphono)acetate (2925.4 mg, 8.57 mmol) was added to a 20 mL solution of compound 5-2 (1200 mg, 7.15 mmol) in acetonitrile. The mixture was stirred at 90 °C for 18 hours. The reaction solution was quenched with 50 mL of ammonium chloride aqueous solution, extracted with EA (50 mL × 3), washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 4:1) to obtain compound 5-3.

[0219] Step 3: Add nickel(II) hexahydrate (450.3 mg, 1.8 mmol) and NaBH4 (219 mg, 5.69 mmol) to a THF (2 mL) solution of compound 5-3 (430 mg, 1.89 mmol), and stir at 25 °C for 2 hours. Quench the reaction solution with ammonium chloride aqueous solution (30 mL), extract with EA (30 mL × 3), wash the organic phase with saturated NaCl solution (30 mL), dry with anhydrous Na2SO4, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 4:1) to obtain compound 5-4.

[0220] Step 4: LiOH (65 mg, 1.52 mmol) was added to a THF (2 mL) / water (1 mL) solution of compound 5-4 (250 mg, 0.48 mmol), and the mixture was stirred at 25 °C for 2 hours. The pH of the reaction solution was adjusted to 6-7 with dilute hydrochloric acid aqueous solution, extracted with EA (50 mL × 3), the organic phase was washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 5-5.

[0221] Step 5: Add HATU (175.7 mg, 0.45 mmol), DIEA (0.20 mL, 1.12 mmol), and compound INT-4 (123 mg, 0.37 mmol) to a DMF (3 mL) solution of compound 5-5 (80 mg, 0.37 mmol), and stir the reaction mixture at 50 °C for 18 hours. Quench the reaction solution with ammonium chloride aqueous solution (50 mL), extract with EA (50 mL × 3), wash the organic phase with saturated NaCl solution (30 mL), dry with anhydrous Na2SO4, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 1:1) to obtain compound 5-6.

[0222] Step Six: Add TFA (1 mL) to a DCM (2 mL) solution of compounds 5-6 (170 mg, 0.32 mmol) and stir the reaction mixture at 25 °C for 3 hours. Quench the reaction solution with NaHCO3 aqueous solution (30 mL), extract with EA (50 mL × 3), wash the organic phase with saturated NaCl solution (30 mL), dry with anhydrous Na2SO4, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 1:2) to obtain compound 5. MS (ESI, pos.ion) m / z: 374.0 [M+1] + . 1HNMR(400MHz, DMSO-d6)δ=11.97-12.39(m,1H),11.36-11.55(m,1H),8.19-8.26(m,1H),8.02-8.10(m,2H ),7.88-7.96(m,1H),7.16-7.72(m,1H),5.45(s,1H),5.35(s,1H),2.95-3.04(m,2H),2.73-2.84(m,2H).

[0223] Example 6

[0224] Step 1: At 25°C, compound 6-1 (100 mg, 0.67 mmol) was dissolved in DCM (2 mL), and methyl triphenyl-λ5-phosphonoacetate (239.5 mg, 0.70 mmol) was added. The mixture was stirred at 25°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound 6-2.

[0225] Step 2: At 25°C, compound 6-2 (950 mg, 4.69 mmol) was dissolved in MeOH (10 mL). The reaction mixture was cooled to 0°C, and nickel chloride hexahydrate (11369.4 mg, 46.88 mmol) and sodium borohydride (5428.8 mg, 140.64 mmol) were slowly added. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with EA (15 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain compound 6-3.

[0226] Step 3: At 25°C, compound 6-3 (950 mg, 4.64 mmol) was dissolved in 5 mL of THF, and 2 mL of an aqueous solution of sodium hydroxide (378.8 mg, 9.28 mmol) was added. The reaction mixture was heated to 40°C and stirred for 18 hours. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 6 with 1 N HCl. The aqueous layer was extracted with EA (15 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain compound 6-4.

[0227] Step 4: At 25°C, compound 6-4 (29.9 mg, 0.16 mmol) was dissolved in DMF (2 mL), and HATU (73.06 mg, 0.19 mmol), DIEA (62.00 mg, 0.47 mmol), and compound INT-4 (50 mg, 0.16 mmol) were added. The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with EA (5 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 6-5.

[0228] Step 5: At 25°C, compound 6-5 (50 mg, 0.10 mmol) was dissolved in DCM (3 mL), and TFA (0.75 mL) was added. The mixture was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to obtain compound 6. MS (ESI, pos.ion) m / z: 361.0 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ=12.46-11.98(m,1H),11.58-11.38(m,1H),8.10-8.02(m,2H),7.74-7.17(m ,1H),6.95-6.91(m,1H),6.80-6.75(m,1H),5.48-5.31(m,2H),3.13-3.05(m,2H),2.78-2.70(m,2H).

[0229] Example 7

[0230] Step 1: At 25°C, compound 7-1 (2 g, 17.48 mmol) and trichloroisocyanuric acid (4.14 g, 17.48 mmol) were dissolved in DCM (40 mL). The mixture was cooled to 15°C, and AlCl3 (11.89 g, 87.39 mmol) was slowly added. The mixture was stirred at 15°C for 18 hours. The reaction solution was poured into 100 mL of ice-cold 1N HCl and extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 100:1) to obtain compound 7-2.

[0231] Step 2: Compound 7-2 (1 g, 4.78 mmol) was dissolved in DCM (20 mL) at 25 °C, and methyl triphenyl-λ5-phosphonoacetate (1.71 g, 5.01 mmol) was added. The mixture was stirred at 25 °C for 18 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 20:1) to obtain compound 7-3.

[0232] Step 3: At 25°C, compound 7-3 (400 mg, 1.97 mmol) was dissolved in THF (5 mL). The reaction mixture was cooled to 0°C, and nickel chloride hexahydrate (469.1 mg, 1.93 mmol) and sodium borohydride (224.0 mg, 5.80 mmol) were slowly added. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with EA (15 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain compound 7-4.

[0233] Step 4: At 25°C, compound 7-4 (400 mg, 1.95 mmol) was dissolved in THF (5 mL), and an aqueous solution of sodium hydroxide (159.53 mg, 3.91 mmol) (2 mL) was added. The reaction mixture was heated to 40°C and stirred for 18 hours. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 6 with 1N HCl. The aqueous layer was extracted with EA (15 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain compound 7-5.

[0234] Step 5: At 25°C, compound 7-5 (71.8 mg, 0.38 mmol) was dissolved in MeCN (3 mL), and compounds INT-4 (120 mg, 0.37 mmol), TCFH (126.8 mg, 0.44 mmol), and NMI (123.7 mg, 1.48 mmol) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with EA (5 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 7-6.

[0235] Step Six: At 25°C, compound 7-6 (40 mg, 0.05 mmol) was dissolved in DCM (3 mL), and TFA (0.75 mL) was added. The mixture was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified to obtain compound 7. MS (ESI, pos.ion) m / z: 361.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ = 12.52-12.00 (m, 1H), 11.66-11.39 (m, 1H), 8.12-8.05 (m, 2H), 7.36 (d, J = 1.3Hz, 1H), 7.27-7.16(m,1H),6.91(s,1H),,5.52-5.51(m,1H),5.51-5.34(m,1H),3.16-3.08(m,2H),2.82-2.71(m,2H).

[0236] Example 8

[0237] Step 1: Compound 8-1 (3 g, 16.82 mmol) was dissolved in methanol (20 mL). Sodium borohydride (1.29 g, 33.65 mmol) was added at 0 °C. The reaction mixture was heated to 25 °C and stirred for 3 hours to obtain a brown solution. The reaction mixture was slowly poured into a saturated ice-cold aqueous solution of ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The extract was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (silica, petroleum ether: ethyl acetate = 10 / 1-5 / 1) to obtain compound 8-2.

[0238] Step 2: Compound 8-2 (2.8 g, 15.52 mmol) was dissolved in dichloromethane (20 mL), and phosphorus tribromide (1.97 mL, 20.18 mmol) was added. The mixture was stirred at 25 °C for 2 hours to obtain a brown solution. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 3), the organic layers were combined, washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (silica, petroleum ether:ethyl acetate = 20 / 1-10 / 1) to obtain compound 8-3.

[0239] Step 3: Hexahydropyridin-2-one (0.82 g, 8.20 mmol) was added to a 100 mL three-necked round-bottom flask. Under nitrogen protection, n-butyllithium (6.56 mL, 16.40 mmol) was added at 0 °C, and the reaction was stirred at 0 °C for 0.5 h. The reaction mixture was cooled to -40 °C, and then compound 8-3 (2 g, 8.20 mmol) was added. The reaction mixture was stirred at -40 °C for 0.5 h, then heated to 25 °C and stirred for 18 h. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by high-performance liquid chromatography to obtain compound 8-4.

[0240] Step 4: Compound 8-4 (150 mg, 0.57 mmol), compound INT-5 (262 mg, 0.68 mmol), cesium carbonate (559 mg, 1.70 mmol), tris(dibenzylacetone)dipalladium (105 mg, 0.11 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (100 mg, 0.17 mmol) were dissolved in 1,4-dioxane (5 mL). The mixture was reacted at 130 °C (microwave) for 2 hours under a nitrogen atmosphere to obtain a brown solution. The solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (silica, dichloromethane:methanol = 20 / 1-10 / 1) to obtain compound 8-5.

[0241] Step 5: The solution of compound 8-5 (200 mg, 0.24 mmol) and trifluoroacetic acid (0.5 mL, 6.47 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 3 hours to obtain a brown solution. The solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by high-performance liquid chromatography to obtain compound 8. MS m / z (ESI): 431.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 12.98-12.17 (m, 1H), 8.14 (br d,J=2.8Hz,2H),7.91-7.33(m,1H),7.30(d,J=8.5Hz,2H),5.48(m,2H),4.06-3.89(m,2H),3.31-3.26(m,1H),3.09-2.96(m,2H),2.02 -1.77(m,3H),1.57-1.44(m,1H).

[0242] Example 9

[0243] Step 1: Compound INT-2 (45 mg, 0.20 mmol), compound INT-4 (75 mg, 0.23 mmol), (2,4-dimethyl-2,4-diazapentane-3-methylene)chlorohexafluoro-λ5-phosphoramide (77 mg, 0.27 mmol), and 1-methylimidazole (56 mg, 0.68 mmol) were dissolved in ACN (3 mL) and stirred at 50 °C for 6 hours to obtain a brown solution. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 3), the organic layers were combined, washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (silica, dichloromethane:methanol = 20 / 1-10 / 1) to obtain compound 9-1.

[0244] Step 2: Compound 9-1 (90 mg, 0.17 mmol) and TFA (0.5 mL, 0.57 mmol) were dissolved in DCM (1 mL) and stirred at 25 °C for 6 hours to obtain a brown solution. The reaction mixture was concentrated under vacuum. The crude product was purified by high performance liquid chromatography to obtain compound 9. MS m / z (ESI): 389.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ=12.06(br s,1H),11.24(m,1H),8.40-8.25(m,2H),8.14-7.78(m,1H),7.75-7.62(m,3H),6.97(d,J=15.8Hz,1H),5.65(s,2H).

[0245] Example 10

[0246] Step 1: Dissolve 1-Boc-2-piperidinone (0.55 mL, 3.01 mmol) in THF (5 mL), cool to -78 °C, and slowly add diisopropylaminolithium (2.85 mL, 5.70 mmol) to the reaction solution. React at -78 °C for 30 minutes. Then, slowly add compound 10-1 (500 mg, 2.83 mmol) dropwise to the reaction solution, and react at -78 °C for 1 hour. After the reaction is complete, quench with ice-cold saturated ammonium chloride solution, extract with EA, wash the organic phase with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 20:80) to obtain compound 10-2.

[0247] Step 2: Compound 10-2 (120 mg, 0.44 mmol), compound INT-5 (187 mg, 0.46 mmol), tris(dibenzylene-BASE-acetone)dipalladium (84 mg, 0.09 mmol), cesium carbonate (290 mg, 0.89 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (105 mg, 0.18 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 125 °C for 2 h under nitrogen protection. The reaction solution was quenched with ice water, extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 95:5) to obtain compound 10-3.

[0248] Step 3: Compound 10-3 (120 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL, 1.45 mmol) was added to the reaction solution. The reaction was carried out at 25 °C for 1 h. The reaction solution was quenched with ice-cold sodium bicarbonate solution, extracted with dichloromethane, washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified to obtain compound 10. MS (ESI, pos.ion) m / z: 429.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ=12.62-12.38(m,1H),8.12-8.06(m,2H),7.74(s,1H),7.52(d,J=8.5Hz,3H),5.46(s,2H),4.16-4.08(m,2H),2.87(br s,2H),2.00-1.93(m,2H).

[0249] Example 11

[0250] Step 1: Compound INT-5-5 (1.6 g, 4.55 mmol) was dissolved in THF (15 mL). Methylmagnesium bromide (25 mL, 75 mmol, 3 M in THF) was added dropwise under nitrogen protection at 0 °C. The reaction was continued at 25 °C under nitrogen protection for 0.5 h. Then, the reaction was continued at 66 °C under nitrogen protection for 1 h. The reaction was quenched with ammonium chloride aqueous solution (50 mL), then extracted with EA (30 mL × 2). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain compound 11-1.

[0251] Step 2: Compound 11-1 (2.1 g, 5.97 mmol) was dissolved in THF (25 mL), and potassium tert-butoxide (1.34 g, 11.94 mmol) was added. The reaction was carried out at 55 °C under nitrogen protection for 1 h. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL), and then extracted with EA (30 mL × 2). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (SiO2, MeOH:DCM = 0%–5%) to obtain compound 11-2.

[0252] Step 3: Compound 11-2 (1 g, 2.81 mmol) was dissolved in THF (15 mL), and LDA (2.6 mL, 5.2 mmol, 2 M in THF) was added dropwise under nitrogen protection at -65 °C. The reaction was carried out at -65 °C for 0.5 h. Tetrabromomethane (1.1 g, 3.32 mmol) was dissolved in THF (2 mL), and then added dropwise to the reaction solution. The reaction was carried out at -65 °C under nitrogen protection for 15 min. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL), and then extracted with EA (30 mL × 2). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (SiO2, MeOH:DCM = 0%–3%) to obtain compound 11-3.

[0253] Step 4: Compound 11-3 (200 mg, 0.49 mmol) and compound INT-6 (148 mg, 0.73 mmol) were dissolved in 1,4-dioxane (3 mL). Cs₂CO₃ (318 mg, 0.98 mmol), Xantphos (113 mg, 0.2 mmol), and palladium catalyst (CAS: 51364-51-3, 90 mg, 0.1 mmol) were added. The mixture was reacted under nitrogen protection at 135 °C for 3 h using microwave. The reaction solution was directly filtered, the filter cake was washed with EA, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (SiO₂, MeOH:DCM = 0%–3%) to obtain compound 11-4.

[0254] Step 5: Dissolve compound 11-4 (50 mg, 0.06 mmol) in DCM (1 mL), add TFA (1 mL), and react at 25 °C for 3 h. Concentrate the reaction solution under reduced pressure, then dissolve in water (10 mL) and EA (10 mL), and adjust the pH to 8. Extract with EA (10 mL × 3), dry the organic phase with anhydrous Na₂SO₄, concentrate under reduced pressure, and purify the crude product to obtain compound 11. MS (ESI, pos.ion) m / z: 401.1 [M+1] + . 1 H NMR (400MHz, METHANOL-d4) δ = 8.09-7.97 (m, 2H), 7.46 (d, J = 5.0Hz, 1H), 7.39 (t, J = 8.0Hz, 1H), 7.21 (d, J = 10.4Hz, 1H), 7.11 (d, J = 8.3Hz, 1H), 3.05 (t, J = 7.4Hz, 2H), 2.79 (t, J = 7.5Hz, 2H), 1.66 (s, 6H).

[0255] Example 12

[0256] Step 1: Compound 11-3 (200 mg, 0.49 mmol) and compound INT-7 (155 mg, 0.64 mmol) were dissolved in 1,4-dioxane (3 mL). Cs₂CO₃ (320 mg, 0.98 mmol), Xantphos (113 mg, 0.2 mmol), and palladium catalyst (CAS: 51364-51-3, 90 mg, 0.1 mmol) were added. The mixture was reacted under nitrogen protection at 135 °C for 5 h using microwave. The reaction solution was directly filtered, the filter cake was washed with EA, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (SiO₂, MeOH:DCM = 0%–3%) to obtain compound 12-1.

[0257] Step 2: Compound 12-1 (70 mg, 0.12 mmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The reaction mixture was reacted at 25 °C for 3 h. The reaction solution was concentrated under reduced pressure, then dissolved in water (10 mL) and EA (10 mL), and the pH was adjusted to 8. Extraction was performed with EA (15 mL × 3). The organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified to obtain compound 12. MS (ESI, pos.ion) m / z: 441.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ=12.62-12.30(m,1H),8.07(m,2H),7.72(d,J=5.0Hz,0.62H),7.52(t,J=8.0Hz,1H),7.37(br d,J=10.5Hz,1H),7.29(d,J=5.0Hz,0.34H),7.16(br d,J=8.3Hz,1H),4.01-3.87(m,2H),3.30-3.26(m,1H),2.99-2.88(m,1H),2 .85-2.75(m,1H),1.97-1.72(m,3H),1.70-1.55(m,6H),1.55-1.45(m,1H).

[0258] Example 13

[0259] Step 1: Compound 11-3 (100 mg, 0.22 mmol) and compound INT-8 (58 mg, 0.25 mmol) were dissolved in 1,4-dioxane (3 mL). Cs₂CO₃ (160 mg, 0.49 mmol), Xantphos (56 mg, 0.1 mmol), and palladium catalyst (CAS: 51364-51-3, 45 mg, 0.05 mmol) were added. The reaction mixture was reacted at 125 °C under nitrogen protection for 12 h. The reaction solution was directly concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (SiO₂, MeOH:DCM = 0%–5%) to obtain compound 13-1.

[0260] Step 2: Compound 13-1 (80 mg, 0.14 mmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The reaction mixture was reacted at 25 °C for 2 h. The reaction solution was concentrated under reduced pressure, then dissolved in water (15 mL) and EA (15 mL), and the pH was adjusted to 8. Extraction was performed with EA (15 mL × 3). The organic phase was dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified to obtain compound 13. MS (ESI, pos.ion) m / z: 427.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ=12.54-12.22(m,1H),8.11-8.05(m,2H),7.78(d,J= 5.0Hz,0.64H),7.53(t,J=8.1Hz,1H),7.40(d,J=10.5Hz,1H),7.28(d,J=4.8H z,0.30H),7.19(dd,J=1.5,8.3Hz,1H),3.98-3.75(m,2H),3.18-3.08(m,2H) ,2.85-2.75(m,1H),2.19-2.09(m,1H),1.89-1.78(m,1H),1.70-1.53(m,6H).

[0261] Example 14

[0262] Step 1: Dissolve compound INT-5-5 (2000 mg, 5.68 mmol) in toluene (25 mL). Under nitrogen protection at -65 °C, add DIBAL-H (6.8 mL, 6.80 mmol, 1 M) dropwise and react for 1.5 h under nitrogen protection at -65 °C. Quench the reaction with saturated potassium sodium tartrate solution (70 mL), then extract with EA (50 mL × 3). The organic phase is then treated with saturated potassium sodium tartrate solution.

[0263] The product was washed with NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH:DCM = 0%–3%) to obtain compound 14-2.

[0264] Step 2: Compound 14-2 (1.08 g, 3.36 mmol) was dissolved in THF (15 mL). Under nitrogen protection at -65 °C, MeLi (3.4 mL, 4.08 mmol, 1.2 M) was added dropwise. The reaction was carried out for 1.5 h under nitrogen protection at -65 °C. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL), and then extracted with EA (30 mL × 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 0%–3%) to obtain compound 14-3.

[0265] Step 3: Compound 14-3 (790 mg, 2.34 mmol) was dissolved in THF (10 mL), and potassium tert-butoxide (526 mg, 4.68 mmol) was added. The reaction was carried out at 55 °C under nitrogen protection for 1 h. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL), and then extracted with EA (30 mL × 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 0%–3%) to obtain compound 14-4.

[0266] Step 4: Compound 14-4 (442 mg, 1.38 mmol) was dissolved in THF (5 mL), and LDA (1.2 mL, 2.4 mmol, 2 M in THF) was added dropwise under nitrogen protection at -65 °C. The reaction was carried out at -65 °C for 0.5 h. Tetrabromomethane (552 mg, 1.66 mmol) was dissolved in THF (2 mL) and then added dropwise to the reaction solution. The reaction was carried out at -65 °C under nitrogen protection for 20 min. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL), and then extracted with EA (30 mL × 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 0%–3%) to obtain compound 14-5.

[0267] Step 5: Compound 14-5 (120 mg, 0.30 mmol) and compound INT-7 (87 mg, 0.36 mmol) were dissolved in 1,4-dioxane (3 mL). Cs₂CO₃ (194 mg, 0.60 mmol), Xantphos (34 mg, 0.06 mmol), and palladium catalyst (CAS: 51364-51-3, 27 mg, 0.03 mmol) were added. The mixture was reacted under nitrogen protection at 135 °C for 3 h using microwave. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 0%–5%) to obtain compound 14-6.

[0268] Step Six: Compound 14-6 (72 mg, 0.13 mmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The reaction mixture was reacted at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure, then dissolved in water (10 mL) and EA (10 mL), and the pH was adjusted to 8. Extraction was performed with EA (10 mL × 3). The organic phase was dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified to obtain compound 14. MS (ESI, pos.ion) m / z: 427.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6)δ=12.62-12.30(m,1H),8.15-8.07(m,2H),7.72-7.68(m,2H),7.52-7.43(m,1H),7.37-7.28(m,1H),5.23-5.19(m, 1H),4.01-3.87(m,2H),3.30-3.26(m,1H),2.99-2.88(m,1H),2.85-2 .75(m,1H),1.97-1.72(m,3H),1.70-1.55(m,3H),1.55-1.45(m,1H).

[0269] Example 15

[0270] Step 1: Compound 14-5 (120 mg, 0.30 mmol) and compound INT-8 (82 mg, 0.36 mmol) were dissolved in 1,4-dioxane (3 mL). Cs₂CO₃ (194 mg, 0.64 mmol), Xantphos (34 mg, 0.06 mmol), and palladium catalyst (CAS: 51364-51-3, 27 mg, 0.03 mmol) were added. The mixture was reacted under nitrogen protection at 135 °C for 3 h using microwave. The reaction solution was directly concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (SiO₂, MeOH:DCM = 0%–5%) to obtain compound 15-1.

[0271] Step 2: Compound 15-1 (68 mg, 0.125 mmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The reaction mixture was reacted at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure, then dissolved in water (10 mL) and EA (10 mL), and the pH was adjusted to 8. Extraction was performed with EA (10 mL × 3). The organic phase was dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by integral preparation to obtain compound 15. MS (ESI, pos.ion) m / z: 413.1 [M+1] + .

[0272] 1 H NMR(400MHz, DMSO-d6)δ=12.76-12.30(m,1H),8.13-8.07(m,2H),7.73-7.68(m,2H),7.56-7.51(m,1H),7.40-7.36(m, 1H),5.25-5.20(m,1H),4.08-3.81(m,2H),3.28-3.02(m,2H),2.72-2.61(m,1H),2.21-1.98(m,2H),1.82-1.73(m,3H).

[0273] Example 16

[0274] Compound 7-5 (141.4 mg, 0.74 mmol) was dissolved in DMF (5 mL) at 25 °C, and T3P (566.1 mg, 0.89 mmol), DIEA (292.9 mg, 2.23 mmol), and compound INT-1 (150.0 mg, 0.74 mmol) were added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with EA (5 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by reverse-phase chromatography to give compound 16. MS (ESI, pos.ion) m / z: 375.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.30 (s, 1H), 8.25 (br d, J = 5.0Hz, 1H), 7.94-7.80 (m, 1H), 7.32 (d, J = 1.5Hz, 1H), 6.88 (s, 1H), 4.23 (br t,J=4.9Hz,2H),3.08(t,J=7.0Hz,2H),2.79-2.73(m,2H),2.68(br t,J=6.9Hz,2H).

[0275] Example 17

[0276] Compound 6-4 (47.1 mg, 0.25 mmol) was dissolved in DMF (5 mL) at 25 °C, and T3P (235.8 mg, 0.37 mmol), DIEA (97.6 mg, 0.74 mmol), and compound INT-1 (50.0 mg, 0.16 mmol) were added. The reaction mixture was stirred at 25 °C for 11 hours. The reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with EA (5 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by reverse-phase chromatography to give compound 17. MS (ESI, pos.ion) m / z: 375.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 13.64-12.81 (m, 1H), 10.14-9.93 (m, 1H), 8.32 (s, 1H), 8.27 (d, J = 5.0Hz, 1H), 7.89 (br d,J=4.8Hz,1H),6.95(d,J=3.8Hz,1H),6.79(d,J=3.8Hz,1H),4.25(t,J=4.9Hz,2H),3.07(t,J=7.1Hz,2H),2.79(br t,J=4.9Hz,2H),2.71-2.64(m,2H).

[0277] Example 18

[0278] Step 1: Compound 18-1 (500 mg, 2.48 mmol) was dissolved in THF (2 ml). Under a nitrogen atmosphere, LDA (1.5 ml, 2.98 mmol) was added at -78 °C, and the reaction was maintained at -78 °C with stirring for 0.5 h. 3-Fluoro-4-chlorobenzyl bromide (610 mg, 2.73 mmol) was dissolved in THF (2 ml) and added to the reaction system, followed by stirring at -78 °C for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was quenched with ice water, extracted with EA, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 18-2.

[0279] Step 2: Dissolve compound 18-2 (240 mg, 0.68 mmol) in dichloromethane (2 ml), add hydrogen chloride-ethyl acetate solution (2 ml), and react at room temperature for 2 hours. After the reaction is complete, adjust the pH of the reaction mixture to 10 with 10% NaOH. Pour the reaction mixture into water (10 ml) and extract with DCM (10 × 3 ml). Wash the organic layer with brine, dry with Na2SO4, filter and concentrate under reduced pressure to obtain compound 18-3, which can be used directly in the next step.

[0280] Step 3: Compound INT-5 (235 mg, 0.62 mmol), compound 18-3 (124 g, 0.49 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (71.4 mg, 0.12 mmol), cesium carbonate (402 mg, 1.23 mmol), and Pd2(dba)3 (56 mg, 0.06 mmol) were dissolved in 1,4-dioxane (5 ml), and the mixture was microwaved at 130 °C for 2 hours under nitrogen atmosphere. The reaction solution was quenched with ice water, extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 18-4.

[0281] Step 4: Compound 18-4 (250 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was quenched with water (10 mL), and the pH of the reaction mixture was adjusted to 10 with 10% NaOH. The mixture was separated by DCM (40 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 18. MS (ESI, pos.ion) m / z: 415.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ: 12.1-13.0 (m, 1H), 8.0-8.2 (m, 2H), 7.50 (br t, 1H, J = 8.1Hz), 7.35 (br dd,1H,J=6.1,9.4Hz),7.27(d,1H,J=4.5Hz),7.1-7.2(m,1H),5.3-5.5(m,2H),4. 6-4.7(m,1H),4.0-4.2(m,2H),3.8-4.0(m,2H),3.2-3.3(m,1H),3.1-3.2(m,1H).

[0282] Example 19

[0283] Step 1: Dissolve 2-methylpropyl-2-yl-oxohexahydropyridine-1-carboxylate (0.66 mL, 3.63 mmol) in tetrahydrofuran (5 mL). Add bis(trimethylsilylaminolithium) (4.84 mL, 4.84 mmol) dropwise to the solution at -78 °C. After reacting at -78 °C for half an hour, add compound 19-1 (500 mg, 2.42 mmol) to the reaction solution at -78 °C and react for another half hour. After the reaction is complete, quench the reaction solution with ice-cold ammonium chloride aqueous solution, add an appropriate amount of EA, filter, extract the filtrate with EA again, wash the organic phase with saturated NaCl solution, and dry with anhydrous Na₂SO₄.

[0284] The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 80:20) to obtain compound 19-2.

[0285] Step 2: Compound 19-2 (180 mg, 0.53 mmol) was dissolved in dichloromethane (2 mL). 4M 1,4-dioxane hydrochloric acid solution (3 mL) was added to the reaction solution at 0 °C, and the reaction was carried out at 25 °C for 1.5 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified to obtain compound 19-3.

[0286] Step 3: Compound 19-3 (85 mg, 0.36 mmol), compound INT-5 (159 mg, 0.40 mmol), Pd2(dba)3 (66 mg, 0.07 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (85 mg, 0.15 mmol), and cesium carbonate (237 mg, 0.73 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction was carried out under nitrogen protection and microwaved at 130 °C for 2 hours. After the reaction was completed, the reaction solution was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 95:5) to obtain compound 19-4.

[0287] Step 4: Compound 19-4 (140 mg, 0.19 mmol) was dissolved in dichloromethane (1.5 mL). Trifluoroacetic acid (1 mL) was added to the reaction solution at 0 °C, and the reaction was carried out at 25 °C for 0.5 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified to obtain compound 19. MS (ESI, pos.ion) m / z: 396.1 [M+1] + . 1H NMR(400MHz, DMSO-d6)δ=12.73-12.23(m,1H),8.36-8.30(m,1H),8.15(s,1H),8.12 -8.03(m,2H),7.78(dd,J=2.0,8.0Hz,1H),7.47(s,1H),5.50-5.35(m,2H),3.96(br d,J=17.5Hz,2H),3.23(br d,J=9.0Hz,1H),2.99-2.94(m,1H),2.87-2.81(m,1H),1.96-1.89(m,1H),1.86-1.77(m,2H),1.54-1.46(m,1H).

[0288] Example 20

[0289] Step 1: Under nitrogen protection, LiHMDS (2.4 mL, 1 M) was added to a tetrahydrofuran (3 mL) solution of 2-methylpropyl-2-yl-2-oxohexahydropyridine-1-carboxylate (930.9 mg, 4.63 mmol) at -78 °C. The mixture was kept at -78 °C for 20 minutes, and then compound 20-1 (500 mg, 2.31 mmol) was added dropwise. The mixture was stirred at -78 °C for 1.5 hours. The reaction solution was quenched with an aqueous solution of ammonium chloride (30 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to give compound 20-2.

[0290] Step 2: Add hydrogen chloride solution (7 mL, 28.00 mmol, 2 M) to a dichloromethane (3 mL) solution of compound 20-2 (650 mg, 1.86 mmol) and stir at 25 °C for 2 hours. Adjust the pH of the reaction solution to 8 with sodium bicarbonate aqueous solution (50 mL), extract with ethyl acetate (50 mL × 3), wash the organic phase with saturated sodium chloride solution (50 mL), dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 4:1) to obtain compound 20-3.

[0291] Step 3: Compound INT-5 (144.9 mg, 0.36 mmol), Xantphos Pd G4 (31.8 mg, 0.03 mmol), and cesium carbonate (215.4 mg, 0.65 mmol) were added to a 2 mL solution of 1,4-dioxane containing compound 20-3 (80 mg, 0.33 mmol). The mixture was stirred at 130 °C for 18 hours under nitrogen protection. The reaction solution was quenched with 10 mL of ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL × 3), washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 20-4.

[0292] Step 4: Add 1 mL of trifluoroacetic acid to a 2 mL solution of compound 20-4 (85 mg, 0.15 mmol) in dichloromethane, and stir the reaction mixture at 25 °C for 3 hours. Quench the reaction solution with 10 mL of sodium bicarbonate aqueous solution, extract with ethyl acetate (20 mL × 3), wash the organic phase with 30 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:EA = 1:9) to obtain compound 20. MS (ESI, pos.ion) m / z: 404.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ=12.29-12.67(m,1H),8.04-8.12(m,2H),7.87(t,J=7.6Hz,1H),7.67-7.75(m,1H),7.36(d,J=8.0Hz,1H) ,7.23-7.30(m,1H),5.34-5.52(m,2H),3.89-4.10(m,2H),3.01-3.10(m,1H),2.87-2.94(m,1H),2.54-2.63(m,1H),1.89-1.99(m,

[0293] 1H),1.75-1.88(m,2H),1.45-1.57(m,1H).

[0294] Example 21

[0295] Step 1: Compound 21-1 (250 mg, 1.49 mmol) and 1-(tert-butoxycarbonyl)-2-piperidinone (0.32 mL, 1.79 mmol) were dissolved in tetrahydrofuran (5 mL). Potassium tert-butoxide (134 mg, 1.19 mmol) was slowly added to the solution at 0 °C, and the reaction was maintained at 60 °C for 3 hours. After the reaction was complete, the reaction solution was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 80:20) to obtain compound 21-2.

[0296] Step 2: Compound 21-2 (260 mg, 0.69 mmol) was dissolved in dichloromethane (2 mL). 4M 1,4-dioxane hydrochloric acid solution (3 mL) was added to the reaction solution at 0 °C, and the reaction was carried out at 25 °C for 1 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified to obtain compound 21-3.

[0297] Step 3: Compound 21-3 (100 mg, 0.38 mmol), compound INT-5 (169 mg, 0.42 mmol), Pd2(dba)3 (70 mg, 0.08 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (89 mg, 0.15 mmol), and cesium carbonate (250 mg, 0.77 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction was carried out under nitrogen protection and microwaved at 130 °C for 2 hours. After the reaction was completed, the reaction solution was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 95:5) to obtain compound 21-4.

[0298] Step 4: Compound 21-4 (120 mg, 0.18 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added to the reaction solution at 0 °C, and the reaction was carried out at 25 °C for 1 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified to obtain compound 21. MS (ESI, pos.ion) m / z: 412.1 [M+1] + . 1H NMR (400MHz, DMSO-d6)δ=12.90-12.29(m,1H),8.52-8.43(m,1H),8.09(br s,3H),7.78(br s,1H),7.63-7.31(m,1H),5.55-5.40(m,2H),4.13(br s,2H),2.93-2.83(m,2H),1.97(br s,2H).

[0299] Example 22:

[0300] Step 1: 1-(tert-butoxycarbonyl)-2-piperidinone (754 mg, 3.78 mmol) was dissolved in THF (5 mL). Under a nitrogen atmosphere, LiHMDS (6.3 mL, 6.3 mmol) was added at -78 °C, and the reaction was maintained at -78 °C with stirring for 0.5 h. Compound 22-1 (500 mg, 3.15 mmol) was dissolved in THF (5 mL) and added to the reaction system, and the mixture was stirred at -78 °C for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was quenched with ice water, extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain 22-2.

[0301] Step 2: Compound 22-2 (300 mg, 0.84 mmol) and 2,4-dimethylaminopyridine (5.2 mg, 0.04 mmol) were dissolved in DCM (5 mL). Acetic anhydride (88 μL, 0.93 mmol) was added at 0 °C under a nitrogen atmosphere. The reaction was maintained at 25 °C with stirring for 3 h. The reaction was monitored by TLC to ensure complete reaction. The reaction solution was quenched with ice water, extracted with EA, and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 22-3.

[0302] Step 3: Dissolve compound 22-3 (160 mg, 0.47 mmol) in dichloromethane (2 ml), add hydrogen chloride-ethyl acetate solution (1 ml), and react at room temperature for 2 hours. After the reaction is complete, adjust the pH of the reaction mixture to 10 with 10% NaOH. Pour the reaction mixture into water (10 ml) and extract with DCM (10 × 3 ml). Wash the organic layer with brine, dry with Na2SO4, filter and concentrate under reduced pressure to obtain compound 22-4, which can be used directly in the next step.

[0303] Step 4: Compound INT-5 (100 mg, 0.26 mmol), compound 22-4 (67 g, 0.28 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (30 mg, 0.05 mmol), cesium carbonate (255 mg, 0.79 mmol), and Pd2(dba)3 (24 mg, 0.03 mmol) were dissolved in 1,4-dioxane (2 ml), and the mixture was microwaved at 130 °C for 2 hours under nitrogen atmosphere. The reaction solution was quenched with ice water, extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 22-5.

[0304] Step 5: Dissolve compound 22-5 (70 mg, 0.12 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 1 hour. Quench the reaction solution with water (10 mL), adjust the pH of the reaction mixture to 10 with 10% NaOH, separate the liquid-liquid chromatography (DCM) (40 mL), wash the organic phase with saturated brine (10 mL), dry with anhydrous Na₂SO₄, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound 22. MS (ESI, pos.ion) m / z: 411.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ:δ12.8-12.9(m,1H),8.09(m,3H),7.7-7.8(m,1H), 7.7-7.7(m,1H),7.6-7.6(m,1H),7.4-7.4(m,1H),5.4-5.6(m,2H),4.12(br d, 2H, J = 2.3Hz), 2.87 (br t, 2H, J = 4.9Hz), 1.96 (br s, 2H).

[0305] Example 23

[0306] Step 1: 1-(tert-Butoxycarbonyl)-2-piperidinone (774 mg, 3.89 mmol) and compound 23-1 (500 mg, 3.53 mmol) were dissolved in THF (5 mL). Under a nitrogen atmosphere, potassium tert-butoxide (341.9 mmol, 2.83 mmol) was slowly added at 0 °C, and the reaction was maintained at 60 °C with stirring for 5 h. The reaction was monitored by TLC to ensure complete reaction. The reaction solution was quenched with ice water, extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 23-2.

[0307] Step 2: Dissolve compound 23-2 (240 mg, 0.3 mmol) in dichloromethane (1 ml), add hydrogen chloride-ethyl acetate solution (1 ml), and react at room temperature for 1 hour. After the reaction is complete, adjust the pH of the reaction mixture to 10 with 10% NaOH. Pour the reaction mixture into water (10 ml) and extract with DCM (10 × 3 ml). Wash the organic layer with brine, dry with Na2SO4, filter and concentrate under reduced pressure to obtain compound 23-3, which can be used directly in the next step.

[0308] Step 3: Compound INT-5 (110 mg, 0.29 mmol), compound 23-3 (70 g, 0.31 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (33 mg, 0.06 mmol), cesium carbonate (281 mg, 0.86 mmol), and Pd2(dba)3 (26.3 mg, 0.03 mmol) were dissolved in 1,4-dioxane (3 ml), and the mixture was microwaved at 130 °C for 3 hours under nitrogen atmosphere. The reaction solution was quenched with ice water, extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 23-4.

[0309] Step 4: Compound 23-4 (50 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was reacted at room temperature for 3 hours. The reaction solution was quenched with water (10 mL), and the pH of the reaction mixture was adjusted to 10 with 10% NaOH. The mixture was separated by DCM (40 mL), and the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 23. MS (ESI, pos.ion) m / z: 394.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ: 8.57 (d, 1H, J = 2.3Hz), 8.22 (s, 2H), 7.99 (br d, 1H, J = 2.5Hz), 7.80 (s, 2H), 7.60 (d, 1H, J = 8.4Hz), 5.60 (s, 2H), 4.15 (br d,2H,J=5.9Hz),2.9-2.9(m,2H),2.0-2.1(m,2H).

[0310] Example 24

[0311] Step 1: 1-(tert-Butoxycarbonyl)-2-piperidinone (800 mg, 4.02 mmol) was dissolved in THF (5 mL). Under a nitrogen atmosphere, LiHMDS (8 mL, 8.03 mmol) was added at -78 °C, and the reaction was maintained at -78 °C with stirring for 0.5 h. Compound 24-1 (500 mg, 4.02 mmol) was dissolved in THF (5 mL) and added to the reaction system, and the mixture was stirred at -78 °C for 3 h. The reaction was confirmed to be complete by TLC. The reaction solution was quenched with ice water, extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 24-2.

[0312] Step 2: Dissolve compound 24-2 (70 mg, 0.23 mmol) in dichloromethane (1 ml), add hydrogen chloride-ethyl acetate solution (1 ml), and react at room temperature for 1 hour. After the reaction is complete, adjust the pH of the reaction mixture to 10 with 10% NaOH. Pour the reaction mixture into water (10 ml) and extract with DCM (10 × 3 ml). Wash the organic layer with brine, dry with Na2SO4, filter and concentrate under reduced pressure to obtain compound 24-3, which can be used directly in the next step.

[0313] Step 3: Compound INT-5 (60 mg, 0.16 mmol), compound 24-3 (33 g, 0.16 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (18 mg, 0.03 mmol), cesium carbonate (153 mg, 0.47 mmol), and Pd2(dba)3 (14.3 mg, 0.02 mmol) were dissolved in 1,4-dioxane (3 ml), and the mixture was microwaved at 130 °C for 3 hours under nitrogen atmosphere. The reaction solution was quenched with ice water, extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 24-4.

[0314] Step 4: Compound 24-4 (40 mg, 0.08 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was reacted at room temperature for 18 hours. The reaction solution was quenched with water (10 mL), and the pH of the reaction mixture was adjusted to 10 with 10% NaOH. The mixture was separated by dichloromethane chromatography (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 24. MS (ESI, pos.ion) m / z: 378.2 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ:12.47(s,1H),8.44(s,1H),8.0-8.2(m,3H),7.8-7.8(m,1H),7.31(br d,2H,J=7.8Hz),5.4-5.6(m,2H),4.0-4.2(m,2H),2.86(br s,2H),1.97(br s,2H).

[0315] Example 25

[0316] Step 1: Under nitrogen protection, LDA (13.28 mL, 26.55 mmol) was added to a tetrahydrofuran (30 mL) solution of 2-methylpropyl-2-yl-2-oxohexahydropyridine-1-carboxylate (3206.7 mg, 15.93 mmol). The mixture was kept at -78 °C for 20 minutes, and then compound 25-1 (2000 mg, 13.28 mmol) was added dropwise. The mixture was stirred at -78 °C for 1.5 hours. The reaction solution was quenched with ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 25-2.

[0317] Step 2: Compound INT-5 (99.7 mg, 0.25 mmol), Xantphos Pd G4 (20 mg, 0.02 mmol), and cesium carbonate (134.5 mg, 0.41 mmol) were added to a 1,4-dioxane (2 mL) solution of compound 25-2 (50 mg, 0.21 mmol). The mixture was stirred at 130 °C for 18 hours under a nitrogen atmosphere. The reaction solution was quenched with an aqueous solution of ammonium chloride (10 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 25-3.

[0318] Step 3: Add 1 mL of trifluoroacetic acid to a 2 mL solution of compound 25-3 (65 mg, 0.12 mmol) in dichloromethane, and stir the reaction mixture at 25 °C for 3 hours. Quench the reaction solution with 10 mL of sodium bicarbonate aqueous solution, extract with ethyl acetate (10 mL × 3), wash the organic phase with 10 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:EA = 1:9) to obtain compound 25. MS (ESI, pos.ion) m / z: 402.1 [M+1] + .1 H NMR (400MHz, DMSO-d6) δ=12.21-12.59(m,1H),8.02-8.10(m,2H),7.81-7.88(m,1H),7.44(br d,J=10.6Hz,1H),7.33(br d,J=8.3Hz,1H),7.26(br d,J=4.4Hz,1H),6.87(t,J=4.1Hz,1H),5.35-5.46(m,2H),4.11-4.26(m,2H),3.69-3.80(m,2H),2.55-2.61(m,2H).

[0319] Example 26

[0320] Step 1: Potassium tert-butoxide (483.4 mg, 4.27 mmol) and 2-methylpropyl-2-yl-oxohexahydropyridine-1-carboxylate (1430.8 mg, 7.11 mmol) were added to a tetrahydrofuran (4 mL) solution of compound 26-1 (350 mg, 2.32 mmol), and the mixture was stirred at 60 °C for 1.5 h. The reaction solution was quenched with ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 26-2.

[0321] Step 2: Hydrogen chloride (3 mL, 2 M) was added to a dichloromethane (2 mL) solution of compound 26-2 (580 mg, 1.50 mmol), and the mixture was stirred at 25 °C for 2 hours. The reaction solution was adjusted to pH 8 with sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 4:1) to obtain compound 26-3.

[0322] Step 3: Under nitrogen protection, compound 26-3 (38.9 mg, 0.15 mmol), Pd2(dba3 (11.7 mg, 0.01 mmol), Xantphos (14.7 mg, 0.03 mmol), and cesium carbonate (82.7 mg, 0.25 mmol) were added to a 1,4-dioxane (2 mL) solution of compound INT-5 (50 mg, 0.13 mmol). The mixture was stirred at 135 °C for 2 hours under microwave conditions. The reaction solution was quenched with ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 26-4.

[0323] Step 4: Add 1 mL of trifluoroacetic acid to a 2 mL solution of compound 26-4 (40 mg, 0.07 mmol) in dichloromethane, and stir the reaction mixture at 25 °C for 3 hours. Quench the reaction solution with 10 mL of sodium bicarbonate aqueous solution, extract with ethyl acetate (20 mL × 3), wash the organic phase with 10 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:EA = 1:5) to obtain compound 26. MS (ESI, pos.ion) m / z: 420.1 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ=12.52-12.87(m,1H),8.11-8.17(m,2H),7.78(s,1H),7.64( s,1H),7.61(s,1H),7.31-7.40(m,1H),5.42-5.59(m,2H),4.06-4.20(m,2H),2.89(br t,J=5.4Hz,2H),1.94-2.02(m,2H).

[0324] Example 27

[0325] Step 1: Compound 27-1 (1.3 g, 7.02 mmol) was dissolved in THF (5 mL), and LiHMDS (13.9 mL, 1 M in THF) was added dropwise at -65 °C. The reaction was carried out under nitrogen protection at -65 °C for 0.5 h. Then, compound 27-2 (1 g, 6.31 mmol) was dissolved in THF (3 mL), and added dropwise to the above reaction solution at -65 °C. The reaction was carried out under nitrogen protection at -65 °C for another 4.5 h. The reaction was quenched with saturated ammonium chloride solution (50 mL), and then extracted with EA (30 mL × 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE = 0%–25%) to obtain compound 27-3.

[0326] Step 2: Compound 27-3 (580 mg, 1.69 mmol) and DMAP (11 mg, 0.09 mmol) were dissolved in DCM (5 mL). Acetic anhydride (0.2 mL, 2.12 mmol) was dissolved in DCM (2 mL) and added dropwise to the above solution at 0 °C. The reaction was carried out at 25 °C under nitrogen protection for 12 h. The reaction was quenched with saturated sodium bicarbonate solution (30 mL), and then extracted with DCM (20 mL × 2). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 0%–2%) to obtain compound 27-4.

[0327] Step 3: Dissolve compound 27-4 (500 mg, 1.3 mmol) in EA (2 mL), add HCl / EA (2 mL, 4 M in EA) dropwise, and react at 25 °C under nitrogen protection for 2 h. Quench the reaction with saturated aqueous sodium bicarbonate solution and adjust the pH to 8. Then extract with EA (20 mL × 3). Wash the organic phase with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (MeOH:DCM = 0%–2%) to obtain compound 27-5.

[0328] Step 4: Compound INT-5 (100 mg, 0.26 mmol) and compound 27-5 (89 mg, 0.31 mmol) were dissolved in 1,4-dioxane (3 mL). Cs₂CO₃ (298 mg, 0.91 mmol), Xtanphos (30 mg, 0.05 mmol), and Pd₂(dba)₃ (24 mg, 0.03 mmol) were added. The mixture was reacted under nitrogen protection at 130 °C for 1.5 h using microwave. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 0%–3%) to obtain compound 27-6.

[0329] Step 5: Dissolve compound 27-6 (50 mg, 0.09 mmol) in DCM (1 mL), add TFA (1 mL), and react at 25 °C for 2 h. Concentrate the reaction solution under reduced pressure, and then adjust the pH to approximately 8 with DIEA. Prepare and purify the crude product to obtain compound 27. MS (ESI, pos.ion) m / z: 397.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 12.76-12.30 (m, 1H), 8.13-8.07 (m, 2H), 7.73-7.68 (m, 2H), 7.56-7.51 (m, 1H), 7. 40-7.36(m,1H),7.30(d,J=4.8Hz,1H),5.54-5.39(m,2H),4.08(td,J=6.7,17.3Hz,2H),3.28-3.23(m,2H).

[0330] Example 28

[0331] Step 1: 1-(tert-Butoxycarbonyl)-2-pyrrolidone (1.3 mL, 7.62 mmol) was dissolved in tetrahydrofuran (10 mL). Bistrimethylsilylaminolithium (12 mL, 12.00 mmol) was added dropwise at -78 °C. After reacting at -78 °C for one hour, compound 28-1 (1 g, 5.66 mmol) was added to the reaction solution at -78 °C, and the reaction was maintained at -78 °C for 3 hours. After the reaction was complete, the reaction solution was quenched with ice-cold ammonium chloride aqueous solution. After adding an appropriate amount of EA, the solution was filtered. The filtrate was extracted again with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified to obtain compound 28-2.

[0332] Step 2: Compound 28-2 (85 mg, 0.33 mmol), compound INT-5 (161 mg, 0.40 mmol), Pd2(dba)3 (62 mg, 0.07 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (78 mg, 0.13 mmol), and cesium carbonate (217 mg, 0.67 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction was carried out under nitrogen protection and microwaved at 130 °C for 2 hours. After the reaction was completed, the reaction solution was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 99:1) to obtain compound 28-3.

[0333] Step 3: Compound 28-3 (120 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added to the reaction solution at 0 °C, and the reaction was carried out at 25 °C for 1 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified to obtain compound 28. MS (ESI, pos.ion) m / z: 415.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ=8.15-8.01(m,2H),7.53(br d,J=9.0Hz,2H),7.49-7.42(m,1H),7.39-7.31(m,1H),5.44(br s,2H),4.08(br d,J=5.4Hz,2H),3.43-3.33(m,2H).

[0334] Example 29

[0335] Step 1: Compound 29-1 (85 mg, 0.33 mmol), compound INT-5 (161 mg, 0.40 mmol), Pd2(dba)3 (62 mg, 0.07 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (78 mg, 0.13 mmol), and cesium carbonate (217 mg, 0.67 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction was carried out under nitrogen protection and microwaved at 130 °C for 2 hours. After the reaction was completed, the reaction solution was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 99:1) to obtain compound 29-2.

[0336] Step 2: Compound 29-2 (120 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added to the reaction solution at 0 °C, and the reaction was carried out at 25 °C for 1 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified to obtain compound 29. MS (ESI, pos.ion) m / z: 381.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ=12.72-12.27(m,1H),8.07(br s,2H),7.36(br s,5H),5.55-5.41(m,2H),4.07(br s,2H),3.29-3.22(m,2H).

[0337] Example 30

[0338] Step 1: Compound 30-1 (280 mg, 1.16 mmol) and nickel chloride (280 mg, 1.18 mmol) were dissolved in methanol (5 mL). Sodium borohydride (47 mg, 1.24 mmol) was slowly added to the solution at 0 °C, and the reaction was maintained at 0 °C for two hours. After the reaction was complete, 2 M HCl solution was added to the reaction solution until the pH reached 7-8. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 95:5) to obtain compound 30-2.

[0339] Step 2: Compound 30-2 (90 mg, 0.32 mmol), compound INT-5 (134 mg, 0.33 mmol), Pd2(dba)3 (61 mg, 0.07 mmol), Xantphos (76 mg, 0.13 mmol), and cesium carbonate (210 mg, 0.64 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction was carried out under nitrogen protection and microwaved at 130 °C for 3 hours. After the reaction was completed, the reaction solution was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 95:5) to obtain compound 30-3.

[0340] Step 3: Compound 30-3 (70 mg, 0.14 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added to the reaction solution at 0 °C, and the reaction was carried out at 25 °C for 1 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified to obtain compound 30. MS (ESI, pos.ion) m / z: 414.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ=12.04-11.46(m,1H),8.13(br d,J=1.0Hz,3H),7.45(dd,J=1.5,8.8Hz,1H),7.26-6.92(m,1H),5.50(br s,2H),4.28-4.17(m,1H),4.06-3.95(m,1H),3.32(br d,J=4.8Hz,1H),3.00(s,1H),2.91-2.82(m,1H),2.15-2.08(m,1H),2.05-1.97(m,2H),1.68-1.60(m,1H).

[0341] Example 31

[0342] Step 1: At 0°C, sodium borohydride (228.6 mg, 5.98 mmol) was added to an ethanol (10 mL) solution of compound 31-1 (1019 mg, 6.04 mmol), and the mixture was stirred at 25°C for 3 hours. The reaction solution was quenched with an aqueous solution of ammonium chloride (10 mL), extracted with ethyl acetate (50 mL × 3), washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 31-2.

[0343] Step 2: At 0°C, carbon tetrabromide (2224.6 mg, 6.64 mmol) and triphenylphosphine (1488.8 mg, 5.62 mmol) were added to a tetrahydrofuran solution of compound 31-2 (900 mg, 5.11 mmol). The reaction mixture was stirred at 25°C for 18 hours. The reaction solution was quenched with an aqueous solution of ammonium chloride (20 mL), extracted with ethyl acetate (40 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 31-3.

[0344] Step 3: At -78°C, LiHMDS (4.7 mL, 1 M) was added dropwise to a tetrahydrofuran (15 mL) solution of compound 31-4 (1700.1 mg, 8.45 mmol). The mixture was maintained at -78°C for 30 minutes. Then, a tetrahydrofuran (1 mL) solution of compound 31-3 (1000 mg, 4.22 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 1.5 hours. The reaction solution was quenched with an aqueous solution of ammonium chloride (20 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 31-5.

[0345] Step 4: Add a 1,4-dioxane solution (1 mL, 4 M) of hydrogen chloride to a 2 mL solution of compound 31-5 (1000 mg, 2.74 mmol) in dichloromethane. Stir the mixture at 25 °C for 2 hours. Adjust the pH of the reaction solution to approximately 8 with an aqueous sodium bicarbonate solution, extract with ethyl acetate (50 mL × 3), wash the organic phase with a saturated sodium chloride solution (30 mL), dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 31-6.

[0346] Step 5: Compound INT-5 (100 mg, 0.25 mmol), XantPhosPd G4 (24.2 mg, 0.02 mmol), and cesium carbonate (163.6 mg, 0.50 mmol) were added to a 2 mL solution of 1,4-dioxane (2 mL) of compound 31-6 (84.2 mg, 0.32 mmol). The mixture was stirred at 130 °C for 18 hours under a nitrogen atmosphere. The reaction solution was quenched with 20 mL of ammonium chloride aqueous solution, extracted with ethyl acetate (20 mL × 3), washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 31-8.

[0347] Step Six: Add 1 mL of trifluoroacetic acid to a 2 mL solution of compound 31-8 (80 mg, 0.15 mmol) in dichloromethane, and stir the reaction mixture at 25 °C for 3 hours. Quench the reaction solution with 20 mL of sodium bicarbonate aqueous solution, extract with 40 mL × 3 ethyl acetate, wash the organic phase with 20 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:EA = 1:9) to obtain compound 31. MS (ESI, pos.ion) m / z: 422.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ=12.29-12.66(m,1H),8.03-8.12(m,2H),7.44(br d,J=9.8Hz,2H),7.28(br d,J=2.5Hz,1H),5.34-5.52(m,2H),3.88-4.08(m,2H),3.35-3.40(m,1H),3.05-3.15(m,1 H), 2.90 (dd, J = 13.8, 8.3Hz, 1H), 1.90-2.01 (m, 1H), 1.78-1.89 (m, 2H), 1.46-1.59 (m, 1H).

[0348] Example 32

[0349] Step 1: Compound 32-2 (1387.5 mg, 6.89 mmol) and potassium tert-butoxide (311.9 mg, 2.76 mmol) were added to a tetrahydrofuran (10 mL) solution of compound 32-1 (440 mg, 3.48 mmol). The mixture was stirred at 60 °C for 2 hours. The reaction solution was quenched with ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 32-3.

[0350] Step 2: Add a 1,4-dioxane solution (1 mL, 4 M) of hydrogen chloride to a 2 mL solution of compound 32-3 (450 mg, 1.41 mmol) in dichloromethane. Stir the mixture at 25 °C for 2 hours. Adjust the pH of the reaction solution to approximately 8 with an aqueous sodium bicarbonate solution, extract with ethyl acetate (30 mL × 3), wash the organic phase with a saturated sodium chloride solution (30 mL), dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 1:1) to obtain compound 32-4.

[0351] Step 3: Add nickel(II) dichloride hexahydrate (232.3 mg, 0.97 mmol) and NaBH4 (149.7 mg, 3.91 mmol) to a THF (4 mL) solution of compound 32-4 (210 mg, 0.98 mmol). Stir the mixture at 0 °C for 2 hours. Quench the reaction solution with an aqueous solution of ammonium chloride (20 mL), extract with ethyl acetate (40 mL × 3), wash the organic phase with a saturated sodium chloride solution (30 mL), dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 1:1) to obtain compound 32-5.

[0352] Step 4: Compound 32-5 (54 mg, 0.25 mmol), Pd2(dba)3 (21.4 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol), and cesium carbonate (151.9 mg, 0.46 mmol) were added to a 1,4-dioxane (2 mL) solution of compound INT-5 (90 mg, 0.23 mmol). The mixture was stirred in a microwave at 135 °C for 2 hours under a nitrogen atmosphere. The reaction solution was quenched with ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 32-7.

[0353] Step 5: Add 1 mL of trifluoroacetic acid to a 2 mL solution of compound 32-7 (90 mg, 0.17 mmol) in dichloromethane, and stir the reaction mixture at 25 °C for 3 hours. Adjust the pH of the reaction solution to approximately 8 with 20 mL of sodium bicarbonate aqueous solution, extract with 40 mL × 3 ethyl acetate, wash the organic phase with 30 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:EA = 1:9) to obtain compound 32. MS (ESI, pos.ion) m / z: 380.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 12.33-12.69 (m, 1H), 8.05-8.12 (m, 2H), 7.91 (br t,J=8.0Hz,1H),7.25-7.78(m,1H),7.14(dd,J=8.4,2.4Hz,1H),5.35-5.52(m,2H),3.86-4.10(m,2H),3.20- 3.27(m,1H),2.92-3.01(m,1H),2.81-2.90(m,1H),1.89-2.00(m,1H),1.75-1.88(m,2H),1.44-1.57(m,1H).

[0354] Example 33

[0355] Step 1: Potassium tert-butoxide (339.6 mg, 3.00 mmol) and compound 33-2 (660 mg, 3.25 mmol) were added to a tetrahydrofuran (4 mL) solution of compound 33-1 (400 mg, 2.50 mmol) and stirred at 50 °C for 1.5 h. The reaction solution was quenched with ammonium chloride aqueous solution (80 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 33-3.

[0356] Step 2: Compound 33-3 (82.2 mg, 0.33 mmol), Pd2(dba)3 (23.7 mg, 0.03 mmol), Xantphos (30 mg, 0.05 mmol), and cesium carbonate (168.7 mg, 0.51 mmol) were added to a 1,4-dioxane (2 mL) solution of compound INT-5 (100 mg, 0.26 mmol). The mixture was stirred in a microwave at 130 °C for 2 hours under a nitrogen atmosphere. The reaction solution was quenched with an aqueous solution of ammonium chloride (30 mL), extracted with ethyl acetate (40 mL × 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 33-5.

[0357] Step 3: Add 1 mL of trifluoroacetic acid to a 2 mL solution of compound 33-5 (95 mg, 0.17 mmol) in dichloromethane, and stir the reaction mixture at 25 °C for 3 hours. Adjust the pH of the reaction solution to approximately 8 with 30 mL of sodium bicarbonate aqueous solution, extract with 50 mL × 3 ethyl acetate, wash the organic phase with 30 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:EA = 1:9) to obtain compound 33. MS (ESI, pos.ion) m / z: 413.1 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ=12.46-12.89(m,1H),8.12-8.18(m,2H),7.83-7.89(m,1H),7.58-7.67( m,2H),7.33-7.42(m,1H),6.85(s,1H),5.41-5.60(m,2H),4.46-4.57(m,2H),4.28-4.42(m,2H).

[0358] Example 34

[0359] Step 1: Compound INT-5 (100 mg, 0.26 mmol) and compound 34-1 (80 mg, 0.31 mmol) were dissolved in 1,4-dioxane (3 mL). Cs₂CO₃ (170 mg, 0.52 mmol), Xantphos (30 mg, 0.05 mmol), and Pd₂(dba)₃ (24 mg, 0.03 mmol) were added, and the mixture was reacted under nitrogen protection at 135 °C for 3 h using microwave. The reaction solution was poured into H₂O (30 mL) and EA (30 mL), filtered, and extracted with EA (30 mL × 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 0%–5%) to obtain compound 34-2.

[0360] Step 2: Compound 34-2 (55 mg, 0.10 mmol) was dissolved in DCM (1 mL), and TFA (1 mL) was added. The reaction mixture was reacted at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure and then purified to obtain compound 34. MS (ESI, pos.ion) m / z: 397.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.28-8.17 (m, 2H), 7.74 (br s,1H),7.53-7.40(m,2H),7.15-7.03(m,1H),6.84(s,1H),5.59(s,2H),4.56-4.47(m,2H),4.39-4.29(m,2H).

[0361] Example 35

[0362] Step 1: Compound 35-1 (600 mg, 2.98 mmol) and compound 35-2 (600 mg, 3.40 mmol) were dissolved in THF (15 mL), and potassium tert-butoxide (267 mg, 2.38 mmol) was added. The reaction was carried out at 50 °C under nitrogen protection for 12 h. H2O (30 mL) was added to the reaction solution, and then extracted with EA (20 mL × 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 0%–3%) to obtain compound 35-3.

[0363] Step 2: Compound INT-5 (100 mg, 0.26 mmol) and compound 35-3 (68 mg, 0.26 mmol) were dissolved in 1,4-dioxane (3 mL). Cs₂CO₃ (170 mg, 0.52 mmol), Xtanphos (30 mg, 0.05 mmol), and Pd₂(dba)₃ (48 mg, 0.05 mmol) were added, and the mixture was reacted under nitrogen protection at 130 °C for 3 h using microwave. The reaction solution was poured into H₂O (30 mL) and EA (30 mL), filtered, and extracted with EA (30 mL × 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM = 0%–5%), and further purified by preparative chromatography to obtain compound 35-4.

[0364] Step 3: Compound 35-4 (68 mg, 0.12 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added. The mixture was reacted at 25 °C for 20 min. The reaction solution was concentrated under reduced pressure, and then purified to obtain compound 35. MS (ESI, pos.ion) m / z: 431.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.33-8.25 (m, 2H), 7.76 (d, J = 9.0Hz, 2H), 7.25-7.03 (m, 1H), 6.85 (s, 1H), 5.64 (br s, 2H), 4.58-4.51 (m, 2H), 4.37 (br d,J=4.5Hz,2H).

[0365] Example 36

[0366] Step 1: A tetrahydrofuran solution (3.9 mL, 1 M) of lithium bis(trimethylsilylamino)-lithium (10 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of compound 36-2 (1416.8 mg, 7.04 mmol) at -78 °C. The mixture was maintained at -78 °C for 20 minutes, followed by the dropwise addition of compound 36-1 (800 mg, 3.52 mmol). The mixture was stirred at -78 °C for 1.5 hours. The reaction mixture was quenched with an aqueous solution of ammonium chloride (30 mL), extracted with ethyl acetate (40 mL × 3), washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 36-3.

[0367] Step 2: Add a 1,4-dioxane solution (4 mL, 4 M) of hydrogen chloride to a dichloromethane (2 mL) solution of compound 36-3 (800 mg, 2.31 mmol). Stir the mixture at 25 °C for 2 hours. Adjust the pH of the reaction solution to approximately 8 with an aqueous sodium bicarbonate solution, extract with ethyl acetate (30 mL × 3), wash the organic phase with a saturated sodium chloride solution (30 mL), dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 1:1) to obtain compound 36-4.

[0368] Step 3: Compound 36-4 (63 mg, 0.25 mmol), Pd2(dba)3 (21.4 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol), and cesium carbonate (151.9 mg, 0.46 mmol) were added to a 1,4-dioxane (2 mL) solution of compound INT-5 (90 mg, 0.23 mmol). The mixture was stirred in a microwave at 130 °C for 2 hours under a nitrogen atmosphere. The reaction solution was quenched with ammonium chloride aqueous solution (40 mL), extracted with ethyl acetate (40 mL × 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 36-6.

[0369] Step 4: Add 1 mL of trifluoroacetic acid to a 2 mL solution of compound 36-6 (90 mg, 0.16 mmol) in dichloromethane, and stir the reaction mixture at 25 °C for 3 hours. Adjust the pH of the reaction solution to approximately 8 with 30 mL of sodium bicarbonate aqueous solution, extract with 30 mL × 3 ethyl acetate, wash the organic phase with 30 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:EA = 1:9) to obtain compound 36. MS (ESI, pos.ion) m / z: 415.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ=12.13-12.77(m,1H),8.05-8.11(m,2H),7.63-7.78(m,1H),7.28(dd,J=9.0,7.0Hz,2H),5.31-5.58(m,2H),3.97(br s,2H),3.26(br d,J=13.0Hz,1H),2.93-3.04(m,1H),2.77(dd,J=13.8,8.8Hz,1H),1.90-1.99(m,1H),1.75-1.88(m,2H),1.45-1.55(m,1H).

[0370] Example 37

[0371] Step 1: Compound 37-2 (1991.3 mg, 9.89 mmol) and potassium tert-butoxide (447.7 mg, 3.96 mmol) were added to a tetrahydrofuran (10 mL) solution of compound 37-1 (800 mg, 4.95 mmol). The mixture was stirred at 60 °C for 2 hours. The reaction solution was quenched with an aqueous solution of ammonium chloride (30 mL), extracted with ethyl acetate (50 mL × 3), washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain compound 37-3.

[0372] Step 2: Add a 1,4-dioxane solution (4 mL, 4 M) of hydrogen chloride to a 2 mL solution of compound 37-3 (530 mg, 1.41 mmol) in dichloromethane. Stir the mixture at 25 °C for 2 hours. Adjust the pH of the reaction solution to approximately 8 with an aqueous sodium bicarbonate solution, extract with ethyl acetate (40 mL × 3), wash the organic phase with a saturated sodium chloride solution (30 mL), dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA = 1:1) to obtain compound 37-4.

[0373] Step 3: Compound 37-4 (62.5 mg, 0.25 mmol), Pd2(dba)3 (21.4 mg, 0.02 mmol), Xantphos (27 mg, 0.05 mmol), and cesium carbonate (151.9 mg, 0.46 mmol) were added to a 2 mL solution of 1,4-dioxane (INT-5, 90 mg, 0.23 mmol). The mixture was stirred in a microwave at 130 °C for 2 hours under a nitrogen atmosphere. The reaction solution was quenched with an aqueous solution of ammonium chloride (30 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:EA = 1:1) to obtain compound 37-6.

[0374] Step 4: Add 1 mL of trifluoroacetic acid to a 2 mL solution of compound 37-6 (90 mg, 0.16 mmol) in dichloromethane, and stir the reaction mixture at 25 °C for 3 hours. Adjust the pH of the reaction solution to approximately 8 with 20 mL of sodium bicarbonate aqueous solution, extract with 30 mL × 3 ethyl acetate, wash the organic phase with 30 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:EA = 1:9) to obtain compound 37. MS (ESI, pos.ion) m / z: 413.1 [M+1] + . 1H NMR (400MHz, DMSO-d6)δ=12.37-12.88(m,1H),8.07-8.12(m,2H),7.71-7.74(m,1H),7.50-7.58(m,2H ),7.30(d,J=4.5Hz,1H),5.39-5.52(m,2H),4.05-4.18(m,2H),2.83-2.91(m,2H),1.91-2.01(m,2H).

[0375] Example 38

[0376] Step 1: Compound 38-1 (400 mg, 2.51 mmol) and tert-butyl 3-oxomorpholine-4-carboxylic acid ester (520 mg, 2.58 mmol) were dissolved in tetrahydrofuran (5 mL). Potassium tert-butoxide (226 mg, 2.01 mmol) was added at 0 °C, and the reaction was maintained at 55 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with water, extracted with an appropriate amount of ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified to obtain compound 38-2.

[0377] Step 2: Compound 38-2 (650 mg, 0.95 mmol) was dissolved in dichloromethane (4 mL), and 4 M hydrochloric acid 1,4-dioxane solution (8 mL) was added at 0 °C. The reaction mixture was then reacted at 25 °C for 0.5 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain compound 38-3.

[0378] Step 3: Compound 38-3 (90 mg, 0.35 mmol), compound INT-5 (75 mg, 0.19 mmol), cuprous iodide (16 mg, 0.08 mmol), N,N'-dimethylethylenediamine (16 mg, 0.18 mmol), and cesium carbonate (110 mg, 0.34 mmol) were dissolved in 1,4-dioxane (3 mL). The reaction was carried out under nitrogen protection and microwaved at 110 °C for 3 hours. After the reaction was completed, the reaction solution was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified to obtain compound 38-4.

[0379] Step 4: Compound 38-4 (120 mg, 0.22 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added at 0 °C. The reaction mixture was reacted at 25 °C for 1 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified to obtain compound 38. MS (ESI, pos.ion) m / z: 414.0 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ=8.68-8.58(m,1H),8.46-8.35(m,2H),8.35-8.26(m,1H), 8.07-7.92(m,1H),6.90(s,1H),5.70(s,2H),4.63-4.49(m,2H),4.44-4.30(m,2H).

[0380] Example 39

[0381] Step 1: Compound 39-1 (500 mg, 2.99 mmol) and tert-butyl-3-oxomorpholine-4-carboxylic acid ester (800 mg, 3.98 mmol) were dissolved in tetrahydrofuran (5 mL). Potassium tert-butoxide (350 mg, 3.12 mmol) was slowly added to the solution at 0 °C, and the reaction was maintained at 0 °C for 18 hours. After the reaction was complete, the reaction solution was diluted with water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA = 80:20) to obtain compound 39-2.

[0382] Step 2: Compound 39-2 (580 mg, 1.57 mmol) was dissolved in dichloromethane (3 mL), and 4 M 1,4-dioxane hydrochloric acid solution (6 mL) was added at 0 °C. The reaction mixture was then reacted at 25 °C for 1 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified to obtain compound 39-3.

[0383] Step 3: Compound 39-3 (30 mg, 0.11 mmol), compound INT-5 (50 mg, 0.12 mmol), cuprous iodide (5 mg, 0.03 mmol), N,N'-dimethylethylenediamine (5 mg, 0.06 mmol), and cesium carbonate (85 mg, 0.26 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction was carried out under nitrogen protection at 115 °C for 1 hour. After the reaction was completed, the reaction solution was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified to obtain compound 39-4.

[0384] Step 4: Compound 39-4 (17 mg, 0.03 mmol) was dissolved in dichloromethane (0.3 mL), and trifluoroacetic acid (0.3 mL) was added at 0 °C. The reaction mixture was reacted at 25 °C for 0.5 h. The reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified to obtain compound 39. MS (ESI, pos.ion) m / z: 422.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ = 12.87-12.36 (m, 1H), 8.24-8.00 (m, 2H), 7.84-7.77 (m, 2H), 7.35 -7.27(m,1H),6.92-6.83(m,1H),5.54-5.34(m,2H),4.65-4.52(m,2H),4.44-4.30(m,2H).

[0385] Example 40

[0386] Step 1: Compound 40-1 (170 mg, 0.44 mmol) and palladium on carbon (48 mg, 0.45 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction was carried out at 25 °C for 18 hours under hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, the filtrate was diluted with water and extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 40-2.

[0387] Step 2: Compound 40-2 (83 mg, 0.22 mmol), compound INT-5 (90 mg, 0.22 mmol), cuprous iodide (20 mg, 0.11 mmol), N,N'-dimethylethylenediamine (10 mg, 0.11 mmol), and cesium carbonate (150 mg, 0.46 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction was carried out under nitrogen protection at 115 °C for 2 hours. After the reaction was complete, the water in the reaction solution was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified to obtain compound 40-3.

[0388] Step 3: Compound 40-3 (25 mg, 0.04 mmol) was dissolved in dichloromethane (0.3 mL), and trifluoroacetic acid (0.3 mL) was added at 0 °C. The reaction was carried out at 25 °C for 0.5 h. After the reaction was complete, the reaction solution was neutralized to pH 7 with sodium bicarbonate aqueous solution in an ice bath. The reaction mixture was extracted with EA, the organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified to obtain compound 40. MS (ESI, pos.ion) m / z: 424.1 [M+1] + . 1 HNMR (400MHz, DMSO-d6)δ=8.65-8.03(m,2H),7.99-7.82(m,1H),7.28-7.18(m,2H),5.80-5.62(m,2 H),4.71-4.66(m,1H),4.27-4.15(m,2H),4.05-3.93(m,2H),3.50-3.42(m,1H),3.29-3.22(m,1H).

[0389] Other compounds of the present invention can be prepared by methods similar to those described in the above embodiments (with appropriate modifications if necessary).

[0390] Biological evaluation of compounds

[0391] Test Example 1: In vitro enzymatic inhibitory activity of the compounds of the present invention

[0392] 1. See Table 1 for reagents, consumables, and instruments.

[0393] Table 1

[0394] 2. Preparation of SAM-TIR lysate

[0395] NRK1-HEK293T cells were used at approximately 10 × 10⁻⁶ 6Cells / plate were seeded into 150 mm culture dishes containing 25 mL of growth medium. The following day, 15 μg of human SARM1 expression plasmid (SARM1408-724 expression plasmid and vector-control customized by Shenzhou Yiqiao) was premixed with 45 μL of X-tremeGENE 9 DNA transfection reagent and 750 μL of OptiMEM, and then this mixture was added directly to the cells for transfection. During transfection, 250 μL of 100 mM nicotinamide nucleoside was added to each dish to minimize the toxicity from SAM-TIR overexpression. Forty-eight hours after transfection, cells were washed three to four times with cold PBS and collected. Cells were resuspended in 0.5 mL of PBS containing protease inhibitors. Cell lysates were prepared by sonication. The lysate was centrifuged at 12,500 rpm for 10 minutes at 4 °C to remove cell debris. The protein concentration was determined by the quinoline carboxylic acid (BCA) method and used to normalize the lysate concentration. The aliquots of the supernatant were stored at -80 °C for later use.

[0396] 3. Experimental Procedure

[0397] 1) Use an Echo 650 to transfer the compound dilution to the assay plate;

[0398] 2) Add 10 μl of 2×SAM-TIR lysate to each well;

[0399] 3) Seal the test plate, centrifuge at 1000 rpm for 1 min, and incubate at 25℃ for 30 min;

[0400] 4) Add 10 μl of 2×NAD to each well;

[0401] 5) Centrifuge at 1000 rpm for 1 min, then incubate at 25℃ for 3 h;

[0402] 6) Add 40 μL of trichloroacetic acid to each well to terminate the reaction, mix and shake for 30 s, and centrifuge at 4000 rpm for 10 min;

[0403] 7) Take 40 μL of supernatant from each well and add an appropriate amount of ammonia to adjust the pH;

[0404] 8) Nicotinamide adenine dinucleotide (NAD) and adenosine diphosphate ribose (ADPR) were detected by HPLC-MS / MS.

[0405] 4. Data Analysis

[0406] 1) For each screening plate, calculate the mean data and standard deviation (SD) for DMSO (as negative control (VC)) and 100 μM control I-5 (as positive control (PC)).

[0407] 2) Percentage of inhibition of the compound

[0408] NAD: Inhibition rate = {(Signal of compound - Signal of negative control) / (Signal of positive control - Signal of negative control)} × 100%

[0409] ADPR: Inhibition rate = {1 - (Signal of compound - Signal of positive control) / (Signal of negative control - Signal of positive control)} × 100%

[0410] 3) The IC50 is calculated using the nonlinear regression equation of XLfit 5.3.1, as shown in the following formula:

[0411] Inhibition rate = Minimum value + (Maximum value - Minimum value) / (1 + 10^((LogIC50 - Log(compound concentration)) * slope coefficient))

[0412] Reference substance I-5, namely Yangshen compound Prepared according to method C of WO2022046606A1.

[0413] Conclusion: At least some of the compounds in this application have good inhibitory effects on SARM1 enzyme. The in vitro SARM1 activity data of some compounds are shown in Table 2.

[0414] Table 2 Note: A represents IC 50 <100nM, B represents 100nM <IC 50 <1000nM.

[0415] Test Example 2. hERG Test

[0416] 1. Test method:

[0417] The cells used in this experiment were HEK293 cell lines (#60187, provided by BPS, with P3-P23 cells used as substitutes for the experimental study) transfected with hERG cDNA and stably expressing the hERG channel. Cell culture was conducted in a medium containing the following components: MEM medium, 10% (v / v) inactivated fetal bovine serum, 1 mM sodium pyruvate, 500 μg / ml genimycin, 0.1 mM non-essential amino acids, and 100 U / ml penicillin / streptomycin. HEK293 hERG cells were grown in culture dishes containing the above medium and cultured at 37°C in a 5% CO2 incubator, passaged approximately three times per week, maintaining cell confluence between 40% and 80%. 24 to 48 hours before electrophysiological experiments, HEK293 hERG cells were transferred to slides pretreated with 0.05 mg / ml PDL and cultured at 1 × 10⁻⁶ cells / mL. 4Each cell type was placed in a 48-well plate and grown under the same culture medium and conditions. The density of HEK293 hERG cells on each round slide was required to ensure that the vast majority of cells were independent and singular. The extracellular fluid composition (mM) used in the hERG assay was as follows: 145 NaCl, 4 KCl, 2 CaCl2, 1 MgCl2, 10 glucose, and 10 HEPES (pH adjusted to 7.40 using NaOH). The intracellular fluid composition (mM) was as follows: 130 KCl, 2 MgCl2, 5 EGTA, 10 HEPES, and 5 Na2ATP (pH adjusted to 7.25 using KOH).

[0418] Electrophysiological experiments were performed using a manual patch-clamp system (HEKA EPC-10 signal amplifier and digital conversion system, HEKA Electronics, Germany) to record whole-cell currents. The specific testing method is described below: A circular slide with CHO hERG cells grown on its surface was placed in an electrophysiological recording chamber under an inverted microscope. The recording chamber was continuously perfused with extracellular fluid (approximately 1 ml per minute). The experiment employed standard whole-cell patch-clamp current recording techniques. Unless otherwise specified, experiments were conducted at normal room temperature (~25°C). Cells were clamped at -80 mV. The cell clamping voltage was depolarized to +30 mV to activate hERG potassium channels, and after 5 seconds, it was clamped again to -50 mV to eliminate inactivation and generate a tail current. The peak value of the tail current was used as the magnitude of the hERG current. After the hERG potassium current recorded in the above steps stabilized under continuous extracellular fluid perfusion in the recording chamber, the drug to be tested could be continuously perfused until the inhibitory effect of the drug on the hERG current reached a stable state. Generally, the overlap of the three most recent consecutive current recording lines is used as the standard for judging whether a stable state has been reached.

[0419] 2. Data Analysis

[0420] The dose-response curves of the test compounds were plotted with the %hERG inhibition rate on the vertical axis and the concentration of the test compounds on the horizontal axis, and the IC50 was calculated.

[0421] Conclusion: At least some of the compounds of this invention have no significant inhibitory effect on hERG, for example, compound 21 has an hERG IC50. 50 >30uM.

[0422] Test Example 3. Liver Microsomal Stability Test

[0423] 1. Test method:

[0424] Acetonitrile solutions of various liver microsomes and compounds were prepared using 100 mM phosphate buffer (pH 7.4) to create a stock solution, bringing the final concentration of the compounds in the reaction system to 1 μM. After mixing, 30 μL of each solution was aliquoted into new 96-well plates to form reaction groups (n=2) containing NADPH for 0, 5, 15, 30, and 45 min, and a control group (n=1) without NADPH for 0 and 45 min. The samples were pre-incubated at 37°C with shaking for 5 min. Then, 15 μL of NADPH was added to each sample to initiate the reaction, bringing the final NADPH concentration to 2 mM. For the control group without NADPH, 15 μL of phosphate buffer was added. After mixing, the samples were incubated for the corresponding time. The reaction was terminated with 200 μL of acetonitrile containing the internal standard (ice). The mixture was vortexed, centrifuged at 4000 rpm for 50 min at 4°C, and the supernatant was diluted with ultrapure water for UPLC-MS / MS analysis.

[0425] 2. Data Analysis

[0426] Plot the logarithm of the remaining percentage of the test substance against the incubation time, and calculate the elimination half-life of the test substance using T1 / 2 = 0.693 / K.

[0427] Conclusion: At least some of the compounds of the present invention have liver microsomal stability comparable to or even better than that of *Codonopsis pilosula* (e.g., compounds 4, 22, 26) (e.g., 8, 9, 10, 11, 31, 33, 35, 36, 37).

[0428] Test Example 4: Evaluation of Kinetic Solubility

[0429] 1. Testing Method

[0430] The test compound was dissolved in DMSO to prepare a 10 mM stock solution. 8.71 g of K₂HPO₄ was added to 500 mL of deionized water to prepare a 100 mM K₂HPO₄ solution. 2.05 g of potassium dihydrogen phosphate was added to 150 mL of deionized water to prepare a 100 mM potassium dihydrogen phosphate solution. 405 mL of 100 mM K₂HPO₄ and 95 mL of 100 mM KH₂PO₄ were mixed, and the pH of the mixture was adjusted to 7.4 using a 100 mM K₂HPO₄ / KH₂PO₄ solution. Using a 96-well plate, 16 μL of the 10 mM compound stock solution was added to 784 μL of PBS buffer (n = 3), the plate was sealed, and the plate was shaken at 1000 rpm for 1.5 h at 25 °C. After incubation, the solution was transferred to a filter plate. All samples were filtered. Take 5 μL of the filtrate and add it to 5 μL of DMSO and 490 μL of acetonitrile aqueous solution containing internal standard (1:1), and mix well. Then dilute with acetonitrile aqueous solution containing internal standard (1:1) according to the properties of the compound and its response in mass spectrometry. Adjust the dilution factor according to the solubility value and UPLC MS / MS signal response.

[0431] Conclusion: At least some of the compounds in this application have good solubility in PBS buffer, which is superior to that of the Yangshen compound.

[0432] Test Example 5: Pharmacokinetic Study in Mice

[0433] 1. Laboratory animals

[0434] Male CD-1 mice were divided into two groups: one receiving oral administration and the other receiving intravenous administration, with three mice in each group. Mice were fasted for 10-14 hours prior to administration, but had free access to water.

[0435] 2. Preparation of drug formulations

[0436] Weigh the test compound according to the dosage and prepare an appropriate concentration of the drug preparation. For intravenous injection, it is a clear solution; for oral administration, it is a clear solution or a homogeneous suspension.

[0437] 3. Animal drug administration and blood sample collection

[0438] Animals were administered the drug via intravenous injection and oral gavage. Blood samples were collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration, and at the same time after oral administration. Whole blood was centrifuged at 6800g for 6 minutes at 4°C, and the supernatant plasma was collected and stored at -80°C for analysis.

[0439] 4. Plasma sample testing

[0440] Dilute the DMSO stock solution of the analyte with methanol or acetonitrile to prepare a series of working solutions, add them to the blank plasma matrix, and prepare a standard curve and quality control samples. Take an appropriate volume of plasma sample and add an appropriate amount of methanol or acetonitrile containing internal standard according to the response to precipitate proteins. Centrifuge all samples at 4°C, 18000g for 10 min, and take an appropriate amount of supernatant for LC-MS / MS analysis.

[0441] 5. Parameter Calculation

[0442] Based on the test concentration, a blood drug concentration-time curve was plotted. Using WinNonlin software, pharmacokinetic parameters were calculated according to a non-compartmental model, including: half-life (T1 / 2), area under the curve (AUC0-t), clearance (CL), steady-state volume of distribution (Vss), and bioavailability (F).

[0443] Conclusion: At least some of the compounds in this application exhibit excellent pharmacokinetic properties in mice (including but not limited to Cl (clearance), T... 1 / 2 (half-life), C max (Peak concentration, AUC (area under the curve), F (bioavailability), etc.).

[0444] Test Example 6: In vivo brain penetration performance evaluation

[0445] Test method: The test compound was dissolved in a solvent to prepare a clear solution or homogeneous suspension. Three mice (male CD1 mice) were administered the compound orally (PO) at a dose of 10 mg / kg. Plasma and cerebrospinal fluid were collected at 1 h, 4 h, and 8 h after oral administration and quantitative analysis was performed by LC / MS / MS.

[0446] Conclusion: At least some of the compounds in this application have C60 in cerebrospinal fluid. max Both AUC and AUC reached very high levels, indicating good in vivo brain penetration performance.

[0447] Test Example 7: Neuronal Injury Model Based on Primary Mouse Neurons

[0448] 1. Testing method:

[0449] On DIV 0 (Day In Vitro 0, in vitro culture day 0), the neocortex was dissected from the brains of male C57BL / 6 mice and digested with 0.05% (w / v) trypsin / EDTA, incubated at 37°C for 10 minutes. The resulting neurons were seeded in pre-incubated poly-D-lysine cell culture dishes using 70% 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 from DIV 3, half of the medium was replaced with fresh Neurobasal / B-27 every two days. On DIV 10, axonal cleavage and compound administration were performed. The day after cleavage, cells were fixed with 4% paraformaldehyde and subjected to TUJ1 immunofluorescence staining. Confocal imaging of axons was performed using a Zeiss LSM710 laser confocal microscope.

[0450] Conclusion: At least some of the compounds in this application have strong neuronal protective activity and can reduce axonal loss after axonal injury.

[0451] Test Example 8: Mouse Sciatic Nerve Block (SNA) Model

[0452] Test method:

[0453] Male C57BL / 6 mice were anesthetized with isoflurane. The skin of their 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 severed near 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 muscles were then returned to their original anatomical position, and the overlying skin was reattached using surgical staples or sutures.

[0454] To examine the denervation of the neuromuscular junction (NMJ), the anterior tibial muscle was dissected from perfused animals and fixed overnight at 4°C with 4% paraformaldehyde / PBS. Immunohistochemical staining was then performed using Neurofilament-L antibody, Synapsin-1 antibody (Cell Signaling Technology), and an acetylcholine receptor (AchR) marker (Biotium). Finally, imaging was performed using a Zeiss LSM710 laser confocal microscope.

[0455] Conclusion: At least some of the compounds in this application can significantly protect axons from damage-induced axonal degeneration.

[0456] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. The compound of formula (I), or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound (preferably deuterium), metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, in, Indicates a single bond or a double bond; Selected from "#1" and "#2" represent two carbon atoms on the fused bond between ring C and ring B, respectively shown as carbon atom #1 and carbon atom #2; X1, X2, X3, and X4 are each independently selected from CH or N; Ring A is optionally substituted by one, two or three substituents, each independently selected from halogens, C1-6 alkyl groups or C1-6 haloalkyl groups; Y1 and Y2 are each independently selected from CH2, NH, S, or O; m is selected from 1 or 2; and the structural fragments At most one of Y1 and Y2 is selected from NH, S or O, and the rest are CH2; Ring B is optionally substituted by one, two or three substituents, each independently selected from halogens, C1-6 alkyl groups or C1-6 haloalkyl groups; R1 is selected from H or C1-6 alkyl; R2 and R3 are each independently selected from H or halogens; Alternatively, R1 and R2 together with the atoms they are attached to form a 5-7 membered heterocyclic group, which has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from oxygen or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms. Ring D is selected from C6-10 aryl or 5-10 heteroaryl; Each R4 is independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or, two adjacent R4s together with the atoms they are attached to form a 5-6 membered heterocyclic group, the 5-6 membered heterocyclic group having one or two heteroatoms selected from nitrogen, oxygen, or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms; n is selected from 0, 1, 2, 3, 4 or 5.

2. The compound, or its stereoisomer, its tautomer, its polymorph, its solvate, its hydrate, its N-oxide, its isotopically labeled compound, its metabolite, its ester, its prodrug, or its pharmaceutically acceptable salt, according to claim 1, wherein: At least one of X1, X2, X3, and X4 is selected from N; Preferably, at least one of X1, X2, X3, and X4 is selected from N, and at most two of them are selected from N; Preferably, X1, X3, and X4 are all CH, and X2 is N; or, X1 and X4 are both CH, and X2 and X3 are both N; or, X1 and X2 are both N, and X3 and X4 are both CH. More preferably, X1, X3 and X4 are all CH, and X2 is N.

3. The compound, or its stereoisomer, its tautomer, its polymorph, its solvate, its hydrate, its N-oxide, its isotopically labeled compound, its metabolite, its ester, its prodrug, or its pharmaceutically acceptable salt, according to claim 1 or 2, wherein: The ring A is optionally substituted by one or two (preferably one) substituents, each independently selected from halogens, C1-4 alkyl groups or C1-4 haloalkyl groups; Preferably, ring A is optionally substituted with one substituent selected from F, Cl, methyl, and trifluoromethyl; Preferably, ring A is optionally substituted with one substituent selected from F or methyl; Preferably, ring A is unsubstituted.

4. The compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, according to any one of claims 1-3, wherein: Y1 and Y2 are each independently selected from CH2, NH, or O, and the structural segments... In the structure, at most one of Y1 and Y2 is selected from NH or O, and the rest are CH2; preferably, Y1 and Y2 are each independently selected from CH2 or O, and the structural fragments At most one of Y1 and Y2 is selected from O, and the rest are CH2; preferably, Y1 is O and Y2 is CH2; and / or m is selected from 1 or 2; preferably, m is 1; and / or Preferably, structural fragments Selected from #A-CH2-CH2-CH2-, #AO-CH2-CH2-, #A-CH2-O-CH2-, #A-NH-CH2-CH2-, #A-CH2-NH-CH2-, #AO-CH2-, #A-CH2-O-, wherein the bond identified by "#A" is connected to ring A; Preferably, structural fragments Selected from #AO-CH2-CH2- and #AO-CH2-, wherein the bond identified by "#A" is connected to ring A; Preferably, structural fragments Selected from #AO-CH2-, where the bond identified by "#A" is connected to ring A.

5. The compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein: Ring B may optionally be substituted by one or two substituents, each independently selected from halogens, C1-4 alkyl groups, or C1-4 haloalkyl groups; Preferably, ring B is optionally substituted with one or two substituents, each independently selected from F, Cl, methyl, ethyl, trifluoromethyl or trifluoroethyl; Preferably, ring B is optionally substituted with one or two methyl groups; Preferably, ring B is unsubstituted.

6. The compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein: Selected from Preferably, for 7. The compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, according to any one of claims 1-6, wherein: Selected from Preferably, Selected from Preferably, for 8. The compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein: Preferably, R1 is selected from H or C1-4 alkyl groups; R2 and R3 are each independently selected from H or halogens; Alternatively, R1 and R2 together with the atoms they are attached to form a 5-7 member monocyclic heterocyclic group, which has 1 or 2 nitrogen heteroatoms and 0 or 1 heteroatoms selected from oxygen or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms. Preferably, R1 is H; R2 and R3 are each independently selected from H or F; Alternatively, R1 and R2 together with the atoms they are attached to form a 5-6 member monocyclic heterocyclic group, which has one nitrogen heteroatom and 0 or 1 oxygen heteroatom and 0 sulfur heteroatom, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms. Preferably, R1, R2, and R3 are all H; Preferably, R3 is selected from H, and R1 and R2 together with the atoms attached to them form a 5-6 member monocyclic heterocyclic group, wherein the 5-6 member monocyclic heterocyclic group has 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom and 0 sulfur heteroatom, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms; Preferably, R3 is selected from H, and R1 and R2 together with the atoms attached to them form a 5-6 member monocyclic heterocyclic group, wherein the 5-6 member monocyclic heterocyclic group has 1 nitrogen heteroatom and 0 heteroatoms selected from oxygen or sulfur; Preferably, structural fragments for 9. The compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, according to any one of claims 1-8, wherein: Structural fragments Selected from Preferably, structural fragments Selected from Preferably, structural fragments Selected from Preferably, structural fragments Selected from Preferably, structural fragments Selected from Preferred Preferably, structural fragments Selected from Preferably, structural fragments Selected from 10. The compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, according to any one of claims 1-9, wherein: Ring D is selected from phenyl or 5-6-membered heteroaryl groups; Preferably, ring D is selected from phenyl or 6-membered heteroaryl; the heteroatom of the 6-membered heteroaryl is nitrogen, and the number of heteroatoms is 1 or 2 (preferably 1); Preferably, ring D is selected from phenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl; Preferably, ring D is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or thiopheneyl; Preferably, ring D is selected from phenyl, pyridinyl, pyrimidinyl, or pyridazinyl; Preferably, ring D is selected from phenyl, pyridyl, and thiophene; More preferably, ring D is selected from phenyl or pyridyl.

11. The compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, according to any one of claims 1-10, wherein: Each R4 is independently selected from hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy; or, two adjacent R4s together with the atoms they are attached to form a 5-6 membered monocyclic heterocyclic group, the 5-6 membered monocyclic heterocyclic group having one or two heteroatoms selected from nitrogen or oxygen and zero sulfur heteroatoms, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms; Preferably, each R4 is independently selected from hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy; or, two adjacent R4s together with the atoms they are attached to form a 5-membered monocyclic heterocyclic group, wherein the 5-membered monocyclic heterocyclic group has 1 or 2 (preferably 2) oxygen heteroatoms and 0 heteroatoms selected from nitrogen or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms; Preferably, each R4 is independently selected from hydrogen, halogen, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy. Preferably, two adjacent R4 atoms together with the atoms they are connected to form a 5-membered monocyclic heterocyclic group, wherein the 5-membered monocyclic heterocyclic group has 1 or 2 (preferably 2) oxygen heteroatoms and 0 heteroatoms selected from nitrogen or sulfur, and the two adjacent atoms on its ring are not simultaneously selected from heteroatoms; Preferably, each R4 is independently selected from hydrogen, halogen, or cyano; Preferably, each R4 is independently selected from halogens (e.g., F, Cl) or cyano groups; Preferably, each R4 is independently selected from halogens (preferably F or Cl); Preferably, each R4 is independently selected from hydrogen, F, Cl, or cyano, or two adjacent R4s are formed together with the atoms they are attached to. in Indicates the confluence site with ring D; Preferably, each R4 is independently selected from hydrogen, F, Cl, or cyano; More preferably, each R4 is independently selected from F, Cl or cyano.

12. The compound, or its stereoisomer, its tautomer, its polymorph, its solvate, its hydrate, its N-oxide, its isotopically labeled compound, its metabolite, its ester, its prodrug, or its pharmaceutically acceptable salt, according to any one of claims 1-11, wherein: n is selected from 0, 1, 2, or 3; Preferably, n is selected from 1, 2, or 3; Preferably, n is selected from 2 or 3.

13. The compound, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, according to any one of claims 1-12, wherein: Selected from Wherein W1, W2, W3, W4, and W5 are each independently selected from CH or N; preferably, 0, 1, 2, or 3 of W1, W2, W3, W4, and W5 are N; preferably, 0, 1, or 2 of W1, W2, W3, W4, and W5 are N; preferably, 0 or 1 of W1, W2, W3, W4, and W5 are N; preferably, W1, W2, W3, W4, and W5 are all CH; preferably, W2 is N, and W1, W3, W4, and W5 are all CH, or W4 is N, and W1, W2, W3, and W5 are all CH. Preferably, Selected from Preferably, Selected from Preferably, Selected from Preferably, Selected from Preferably, Selected from Preferably, Selected from Preferred selection Preferred selection Preferred Preferred 14. The compound, or its stereoisomer, its tautomer, its polymorph, its solvate, its hydrate, its N-oxide, its isotopically labeled compound, its metabolite, its ester, its prodrug, or its pharmaceutically acceptable salt, according to any one of claims 1-13, wherein, The compound is shown as any one of formulas (I-1) to (I-3): Preferably, the compound of formula (I) is as shown in formula (II-1) or (II-2): Preferably, the compound of formula (I) is as shown in formula (III-1): Wherein, X1, X2, X3, X4, Y1, Y2, m, n, R1, R2, R3, R4, W1, W2, W3, W4, W5, ring A, ring B, ring C, ring D, #1, #2 are as defined in any one of claims 1-13.

15. The compound according to any one of claims 1-14, or its stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

16. A 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, wherein the compound is selected from:

17. The compound, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-16, for use in inhibiting SARM1 or as a SARM1 inhibitor.

18. A pharmaceutical composition comprising a compound according to any one of claims 1-17, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, a solvate thereof, a hydrate thereof, an N-oxide thereof, an isotopically labeled compound thereof, a metabolite thereof, an ester thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

19. A method for treating or preventing a disease, comprising the following steps: The therapeutic or preventive effective amount of any one of the compounds, stereoisomers, tautomers, polymorphs, solvates, hydrates, N-oxides, isotopically labeled compounds, metabolites, esters, prodrugs, pharmaceutically acceptable salts, or pharmaceutical compositions according to claim 18 shall be administered to (i) an individual suffering from a condition characterized by axonal degeneration or (ii) an individual at risk of developing a condition characterized by axonal degeneration.

20. A method of treating or preventing axonal degeneration, comprising administering to an individual in need a therapeutically or preventively effective amount of a compound, stereoisomer thereof, tautomer thereof, polymorph thereof, solvate thereof, hydrate thereof, N-oxide thereof, isotopically labeled thereof, metabolite thereof, ester thereof, prodrug thereof, pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claim 18.

21. A method for treating or preventing a disease or condition characterized by axonal degeneration, comprising administering to an individual in need a therapeutically or preventively effective amount of a compound, stereoisomer thereof, tautomer thereof, polymorph thereof, solvate thereof, hydrate thereof, N-oxide thereof, isotopically labeled thereof, metabolite thereof, ester thereof, prodrug thereof, pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claim 18; Preferably, the condition or symptom characterized by axonal degeneration is a neurodegenerative disease, an eye disease, or a peripheral neuropathy; Preferably, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic sclerosis, or Huntington's disease; Preferably, the eye disease is glaucoma.

22. Use of any compound, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claim 18, in the preparation of a medicament for the treatment or prevention of axonal degeneration; or in the preparation of a medicament for the treatment or prevention of a disease or condition characterized by axonal degeneration; Preferably, the condition or symptom characterized by axonal degeneration is a neurodegenerative disease, an eye disease, or a peripheral neuropathy; Preferably, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic sclerosis, or Huntington's disease; Preferably, the eye disease is glaucoma.

23. The compound, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, pharmaceutically acceptable salt thereof, or pharmaceutical composition according to any one of claims 1 to 17, for the treatment or prevention of axonal degeneration, or for the treatment or prevention of a disease or condition characterized by axonal degeneration; Preferably, the condition or symptom characterized by axonal degeneration is a neurodegenerative disease, an eye disease, or a peripheral neuropathy; Preferably, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic sclerosis, or Huntington's disease; Preferably, the eye disease is glaucoma.

Images