Compound for recognizing α-synuclein aggregate, and use thereof

Abstract

A compound specifically binding to an α-synuclein aggregate, and a preparation method therefor and the use thereof. Specifically, the compound binding to the α-synuclein aggregate comprises compounds as shown in formula A or sub-general formulas thereof, or stereoisomers, pharmaceutically acceptable salts, solvates or stable isotope variants thereof. The compound is a small molecule tracer, which can specifically recognize the α-synuclein aggregate, and can be used for the preparation of a drug for the treatment or diagnosis of neurodegenerative diseases (such as Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy and progressive muscular atrophy) related to the α-synuclein aggregate and other misfolded proteins.

Description

A compound for identifying alpha-synuclein aggregates and its use

[0001] Cross-references

[0002] This application claims priority to Chinese invention patent application 202410121172.8 with a filing date of January 29, 2024, Chinese invention patent application 202410121133.8 with a filing date of January 29, 2024, and Chinese invention patent application 202410209817.3 with a filing date of February 26, 2024. Technical Field

[0003] The present invention relates to the field of medicine, and in particular to a compound that specifically recognizes α-synuclein aggregates and uses thereof. Background Art

[0004] Neurodegenerative diseases (NDs) are age-related disorders and include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), muscular dystrophy, and progressive supranuclear palsy (PSP). These disorders are characterized by progressive neuronal loss and degeneration. Currently, over 57 million NDs are diagnosed worldwide. With the increasing aging of the global population, the number of NDs is projected to triple by the middle of the 21st century, resulting in a significant medical and public health burden. However, there are currently no drugs that can cure NDs, and clinical medications can only alleviate or slow the symptoms of the disease. NDs have a long lifespan, with pathological changes occurring for decades before clinical symptoms appear, during which patients have already lost most of their neurons. Given the non-renewable nature of neurons, diagnosing and treating NDs at an early stage is an effective approach to improving the efficacy of ND treatment.

[0005] Abnormal protein aggregation is a common pathological change in ND and is also the most important early diagnostic biomarker for ND. Under physiological conditions, these proteins exist as disordered monomers, but under pathological conditions, they form ordered β-sheet structures and gradually aggregate into oligomers and fibrils. In AD, amyloid β (Aβ) forms amyloid plaques (APs) outside the cell, which are mainly deposited in the cortex, subcortical regions, and brainstem. At the same time, another pathological protein, Tau, can fibrillate and form neurofibrillary tangles (NFTs) that are deposited in the entorhinal cortex, hippocampus, and basal cortex. In PD, α-synuclein (α-syn) forms Lewy bodies and Lewy neurites, which appear in tissues and organs such as the substantia nigra, striatum, brainstem, and olfactory bulb.

[0006] Positron emission tomography (PET) and single-photon emission tomography (SPECT) are non-invasive imaging methods that can examine brain structure and function and investigate the pathological progression and pathogenesis of ND. These techniques incorporate radionuclides into small molecule tracers, which can target disease-associated proteins within the body. The positrons or alpha photons emitted by these radionuclides can be detected and located by the imaging probe. A processor and image reconstruction software calculate the tracer's uptake and spatial distribution within the body, thereby inferring changes in brain function and structure. These techniques have high spatial resolution, with PET visualization and quantification resolution reaching 3 mm.

[0007] Detecting α-syn aggregates in the brain using PET and SPECT techniques is of great significance for the early diagnosis of synucleinopathies. Synucleinopathies include PD, DLB, and MSA. PD patients develop abnormal neural inclusions in the brain, called Lewy bodies (LBs) and Lewy neurites (LNs), primarily found in the substantia nigra and striatum. DLB patients also have a large number of LBs and LNs in the cerebral cortex. Unlike PD and DLB, α-syn aggregates in the brains of MSA patients are rarely found in neurons, but rather in the cytoplasm of oligodendrocytes and neurons, forming glial cytoplasmic inclusions (GCIs). These pathological changes occur early in the course of synucleinopathies and are closely related to the progression of the disease. Therefore, imaging these misfolded α-syn through brain imaging techniques can achieve early diagnosis of the disease, which is of great significance for the treatment of the disease and the development of new drugs.

[0008] However, existing PET tracers have weak protein binding activity and poor in vivo imaging capabilities, which cannot meet the needs of clinical imaging. Therefore, there is an urgent need to develop a compound that can specifically recognize α-syn aggregates to facilitate the early diagnosis and treatment of neurodegenerative diseases related to α-synuclein aggregates, such as PD, DLB, and MSA.

[0009] SUMMARY OF THE INVENTION

[0010] To solve the above problems, the present invention provides a compound with strong binding ability to α-synuclein aggregates, which can be used to prepare preparations or preparation compositions for treating or diagnosing neurodegenerative diseases associated with α-synuclein aggregates and other misfolded proteins after binding to the target protein.

[0011] In the first aspect of the present invention, a compound that specifically recognizes α-synuclein aggregates is provided, wherein the compound is a compound represented by formula A, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotope variant thereof.

[0012] The variables are as defined herein.

[0013] Specifically, the first aspect of the present invention provides a compound of the following formula, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotope variant thereof,

[0014] wherein each variable is as generally or specifically defined herein.

[0015] The second aspect of the present invention provides a composition for specifically recognizing α-synuclein aggregates, the composition comprising

[0016] a. a compound as described in the first aspect of the present invention; and optionally

[0017] b. Pharmaceutically acceptable carrier.

[0018] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention and the composition described in the second aspect of the present invention in the preparation of a drug for treating or diagnosing neurodegenerative diseases associated with α-synuclein aggregates and other misfolded protein aggregates.

[0019] A fourth aspect of the present invention provides a method for detecting α-synuclein aggregates in a subject, comprising the following steps:

[0020] (A) administering to the subject a safe and effective amount of the compound according to the first aspect of the present invention or the composition according to the second aspect of the present invention; and

[0021] (B) detecting the binding of the compound or composition to α-synuclein aggregates in the subject.

[0022] In a preferred embodiment, the detection in step (B) is performed by imaging technology, preferably by the following imaging technology: positron emission tomography, single photon emission computed tomography, near-infrared brain function imaging, or a combination thereof.

[0023] In another preferred embodiment, the subject suffers from or is suspected of suffering from a neurodegenerative disease associated with α-synuclein aggregates or other misfolded protein aggregates.

[0024] In another preferred embodiment, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, multiple system atrophy, muscular dystrophy, Lewy body dementia, Alzheimer's disease, progressive supranuclear palsy or amyotrophic lateral sclerosis.

[0025] The fifth aspect of the present invention provides a use of the compound according to the first aspect of the present invention and the composition according to the second aspect of the present invention in preparing a kit for detecting the content of α-synuclein aggregates and other misfolded protein aggregates. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG1 shows an immunofluorescence staining diagram showing co-localization of the compound of the present application with α-syn aggregates in primary neurons.

[0027] Figure 2 shows immunofluorescence staining of the co-localization of the compounds of the present application with α-syn aggregates in the brain of PFF mice (top: Examples 1, 2, 3, 7, 11, 16, 26, and 38 refer to Examples II-1, II-2, II-3, II-7, II-11, II-16, II-26, and II-38, respectively).

[0028] Figure 3 shows immunofluorescence staining of the co-localization of the compounds of the present application with α-syn aggregates in the brains of PD patients (upper figure: Examples 1, 2, 11, and 26 refer to Examples I-1, I-2, I-11, and I-26, respectively; lower figure: Examples 1, 16, and 19 refer to Examples II-1, II-16, and II-19, respectively).

[0029] Figure 4 shows immunofluorescence staining of the co-localization of the compound of the present application with α-syn aggregates in the brain of PFF mice after intravenous injection of the compound of the present application into PFF mice (upper figure: Examples 1 and 2 refer to Examples I-1 and I-2, respectively; lower figure: Examples 1 and 16 refer to Examples II-1 and II-16, respectively).

[0030] FIG5A and FIG5B show the autoradiographic (ARG) patterns of the compound of the present application in brain slices of mice and PD patients, respectively.

[0031] FIG6A shows PET imaging of the compound 18F FD4 of the present application in PFF-injected rats.

[0032] FIG6B shows PET imaging of the compound 18F FD4 of the present application in PFF-injected marmosets.

[0033] FIG6C shows the PET imaging of the compound FD17 of the present application in PFF-injected rats.

[0034] FIG6D shows PET imaging of the compound FD17 of the present application in PFF-injected marmosets.

[0035] FIG6E shows PET imaging of the present compound FA35 in PFF-injected rats.

[0036] FIG6F shows PET imaging of the present compound FA23 in PFF-injected rats.

[0037] FIG7 shows PET images of human subjects treated with 18F FD4 compound.

[0038] FIG8 shows PET images of human subjects receiving C0505.

[0039] Detailed Description of the Invention

[0040] After extensive and lengthy research and extensive screening, the inventors have developed, for the first time, a compound that specifically recognizes α-synuclein aggregates, including compounds represented by Formula A and its various sub-formulas, or stereoisomers, pharmaceutically acceptable salts, solvates, or stable isotopic variants thereof. The compounds of this application can be used as detection reagents to detect the content of α-synuclein aggregates and other pathological aggregated proteins in in vitro samples, or to prepare reagents for treating or diagnosing neurodegenerative diseases associated with pathological aggregated proteins such as α-synuclein aggregates (such as Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Alzheimer's disease, and amyotrophic lateral sclerosis), and have very promising application prospects.

[0041] the term

[0042] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0043] As used herein, the term "alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon group consisting solely of carbon and hydrogen atoms. For example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms or a range of carbon atoms having any different numerical values ​​therein, for example, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

[0044] As used herein, the term "alkylene" refers to a divalent group obtained by removing a hydrogen atom from an alkyl group as described above, such as methylene (-CH2-), ethylene (-CH2CH2-), and the like.

[0045] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond, for example, "C 2-6"Alkenyl" refers to an alkenyl group having 2-6 (e.g., 2, 3, 4, 5, or 6) carbon atoms or a range of carbon atoms having any different numerical values ​​therein, such as C 2-4 Alkenyl, C 2-3 Alkenyl, C 2-5 Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0046] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 2-6 "Alkynyl" refers to an alkynyl group having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms or a range of carbon atoms having any different numerical values ​​therein, such as C 2-4 Alkynyl, C 2-3 Alkynyl, C 2-5 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0047] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group composed of carbon and hydrogen atoms, such as "C 3-8 "Cycloalkyl" refers to a cycloalkyl group containing 3-8 (e.g., 3, 4, 5, 6, 7 or 8) carbon atoms or a range of carbon atoms having any different numerical values, preferably C 3-6 Cycloalkyl. The cycloalkyl group may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like, or a bicyclic ring, such as a bridged ring or a spiro ring, preferably a monocyclic ring.

[0048] As used herein, the term "haloalkyl" refers to a group in which one or more hydrogen atoms in the alkyl group described above are replaced by the same or different halogen atoms. 1-6 Alkyl" or "C 1-6 "Haloalkyl" is used interchangeably, preferably halogenated C 1-4 Examples of alkyl and halogenated alkyl groups include, but are not limited to, -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (eg, -CF3-, -CF2CF3), and the like.

[0049] As used herein, the term "alkoxy" refers to a group of the formula -OR z or -R z '-OR z group, where R z is an alkyl group as defined herein, R z ' is an alkylene group, preferably -C 1-4 Alkoxy or -OC 1-4Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, -CH2O-CH3, -CH2CH2-O-CH3, -CH2-O-CH2CH3, and the like.

[0050] As used herein, the term "haloalkoxy" refers to a group obtained by replacing one or more hydrogen atoms in the alkoxy group as described above with the same or different halogen atoms, preferably -C 1-4 Haloalkoxy or -OC 1-4 Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 2-fluoroethoxy, and the like.

[0051] As used herein, the term "halohydroxyalkoxy" refers to a group obtained by replacing one or more hydrogen atoms in the haloalkoxy group described above with a hydroxy group, preferably -C 1-4 Halogenated hydroxyalkoxy or -OC 1-4 Halogenated hydroxyalkyl, more preferably -C 1-4 Examples of haloalkoxy groups include, but are not limited to,

[0052] As used herein, the term "alkylamino" refers to a group of the formula -NR y R x group, where R y and R x are each independently H or alkyl as defined herein, and R y and R x Not H at the same time, that is, the alkylamino group can be a monoalkylamino group or a dialkylamino group, preferably -NHC 1-4 Alkyl or -N(C 1-4 Examples of alkylamino groups include, but are not limited to, -NH-methyl, NH-ethyl, -N-dimethyl, -N-diethyl, and the like.

[0053] As used herein, the term "haloalkylamino" refers to a group in which one or more hydrogen atoms in an alkylamino group as described above are replaced by the same or different halogen atoms, preferably -NHC 1-4 Alkyl or -N(C 1-4 alkyl) 2， The alkyl groups are each independently substituted by one or more halogens, preferably by one or more F and / or Cl.

[0054] As used herein, the term "halohydroxyalkylamino" refers to a group obtained by replacing one or more hydrogen atoms in the haloalkylamino group as described above with a hydroxyl group, preferably a -C 1-4 Examples of haloalkylamino groups include, but are not limited to,

[0055] As used herein, the term "halogen" refers to halogen and its isotopes, including but not limited to F, 18 F, Cl, 32 Cl, Br, I.

[0056] As used herein, the term "amino" refers to -NH2.

[0057] As used herein, the term "carboxyl" refers to -COOH.

[0058] As used herein, the term "ester group" refers to -COOR w , where R w Can be independently selected from the following groups: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl; preferably -C(O)OC 1-6 Examples of ester groups include, but are not limited to, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH2CH(CH3)2, and the like.

[0059] As used herein, the term "acyl" refers to -COR w , where R w Can be independently selected from the following groups: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl; preferably -C(O)C 1-6 Examples of acyl groups include, but are not limited to, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH2CH(CH3)2, and the like.

[0060] As used herein, the term "amido" refers to -CONR v R v ', where R v and R v R may be independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl. v and R v ' can be the same or different. Preferably R v and R v 'Independently selected from hydrogen and C 1-6 Alkyl, i.e. amide, is selected from -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6Examples of amide groups include, but are not limited to, -CONH2, -CONHCH3, -CON(CH3)2, and the like.

[0061] As used herein, the term "sulfonamide" refers to -SO2NR v R v ' or R v SO2NR v '-, where R v and R v R may be independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl. v and R v ' can be the same or different. Preferably R v and R v 'Independently selected from hydrogen and C 1-6 Alkyl, i.e. amide, is selected from -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -NHSO2-C 1-6 Alkyl, -N(C 1-6 Alkyl)-SO2-C 1-6 Examples of sulfonamide groups include, but are not limited to, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, CH3SO2NH-, CH3SO2NCH3-, and the like.

[0062] As used herein, the term "heterocyclyl" refers to a fully saturated or partially saturated monocyclic, bicyclic or polycyclic cyclic group containing one or more heteroatoms selected from N, S or O in the ring backbone, for example, "3-12 membered heterocyclyl", "3-8 membered heterocyclyl", "4-8 membered heterocyclyl", "5-8 membered heterocyclyl" and "6-8 membered heterocyclyl" refer to groups having 3-12 ring members, 3-8 ring members, 4-8 ring members, 5-8 ring members and 6-8 ring members, respectively. The nitrogen or sulfur atom of the heterocyclyl may be oxidized, and the nitrogen atom may be quaternized. The heterocyclyl may be attached to the residue of any heteroatom or carbon atom of the ring or ring system. For the compounds of the present invention, a monocyclic 3-8 membered saturated heterocyclyl is preferred, such as a monocyclic 4-8 membered saturated heterocyclyl, a monocyclic 5-8 membered saturated heterocyclyl or a monocyclic 6-8 membered saturated heterocyclyl. Monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl, and tetrahydro-1,1-dioxythiophene. Polycyclic heterocyclic groups include, but are not limited to, spirocyclic, fused, and bridged heterocyclic groups, wherein the spirocyclic, fused, and bridged heterocyclic groups are optionally linked to other groups via single bonds, or further linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0063] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic or polycyclic groups), for example, "C 6- 12 "Aryl" refers to an aromatic cyclic hydrocarbon group having 6 to 12 (6, 7, 8, 9, 10, 11 or 12) ring carbon atoms, "C 6- 10 "Aryl" refers to an aromatic cyclic hydrocarbon group with 6-10 (6, 7, 8, 9, 10) ring carbon atoms. Among them, when containing two or more aromatic rings (such as bicyclic rings, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). Examples of aryl groups (especially monocyclic and bicyclic groups) include but are not limited to: phenyl, biphenyl or naphthyl. The aryl group can be fused with the heterocyclic group through a single bond or any two adjacent ring carbon atoms, for example: benzotetrahydrofuranyl, chromanyl, benzodioxanyl, wait.

[0064] As used herein, the term "heteroaryl" refers to an aromatic cyclic group (including monocyclic, bicyclic or polycyclic groups) whose ring skeleton contains 1, 2, 3 or 4 heteroatoms selected from N, S or O, for example, "5-12 membered heteroaryl" refers to a monocyclic, bicyclic or tricyclic group having 5 to 12 (5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, and "5-10 membered heteroaryl", "5-8 membered heteroaryl" and "6-10 membered heteroaryl" refer to a monocyclic or bicyclic group having 5 to 10 (5, 6, 7, 8, 9, 10, 11 or 12), 5-8 or 6-10 ring atoms, respectively. Examples of heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furanyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza Base, diazepine Acridinium, etc.

[0065] As used herein, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Specific substituents are those described above or as appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specified group at any substitutable position on the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0066] Unless otherwise specified, the groups of the present invention may be substituted by substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl, amino, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C2-6 alkynyl, -C 1-6 Alkoxy, 3-12 membered heterocyclic group, C3-C 12 Cycloalkyl, 5-10 membered heteroaryl and -C 6-10 Aryl.

[0067] As used herein, "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0068] The term "plurality" herein refers to a positive integer of 2, 3, 4, 5 or more.

[0069] As used herein, the terms "α-synuclein aggregates," "α-syn aggregates," and "α-syn fibrils" are synonymous.

[0070] As used herein, the terms "pathologically aggregated protein" and "misfolded protein" are synonymous.

[0071] As used herein, "compounds of the present invention" refers to compounds represented by formula (A) and its various sub-formulas, and also includes stereoisomers, optical isomers, pharmaceutically acceptable salts, crystalline forms, isotopic derivatives, prodrugs, metabolites, solvates, or hydrates thereof.

[0072] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0073] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0074] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0075] As used herein, the term "solvate" refers to a complex formed by coordination of the compound represented by formula (A) and its various sub-formulas with solvent molecules to form a specific ratio.

[0076] As used herein, the term "safe and effective amount" refers to an amount of a compound sufficient to treat or diagnose a disease without causing serious side effects.

[0077] As used herein, the term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels suitable for human use and of sufficient purity and low toxicity. "Compatibility" as used herein refers to the ability of the components of the composition to be compatible with the compounds of the invention, and with each other, without significantly reducing the efficacy of the compounds.

[0078] Compounds of the present invention

[0079] Unless otherwise indicated, the structural formulae described herein are intended to include all stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, cis-trans isomers, or conformational isomers are all within the scope of the present invention.

[0080] The compounds of the present invention may contain cis-trans isomers, one or more chiral carbon atoms, and may therefore give rise to stereoisomeric forms as cis-trans isomers, chiral isomers, enantiomers, diastereomers and other combinations thereof.

[0081] Cis-trans isomerism refers to the phenomenon of diastereoisomerism that occurs due to the different spatial arrangements of groups within a compound's molecules due to factors restricting free rotation. This restriction is generally caused by the presence of functional groups in the organic compound structure that cannot rotate freely, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing this type of isomerism, such as alkenes, azo compounds, and alicyclic hydrocarbons, are considered cis-trans isomers. The cis form refers to the presence of ligands of the same type in adjacent positions, typically designated "cis" or "cis-"; the trans form refers to the presence of ligands of the same type in diagonal positions, typically designated "trans" or "trans-."

[0082] Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates, mixtures of enantiomers in any proportion, or optically pure forms thereof. It should be noted that, in the case where the compounds of the present invention contain only one chiral center, the reference to the racemate herein is equivalent to a reference to both enantiomers thereof, and those skilled in the art can prepare the individual enantiomers based on the disclosure of the specification and conventional means in the art.

[0083] The compounds of the present invention may be prepared using racemates, cis-trans isomers, chiral isomers, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0084] Conventional techniques for preparing / isolating individual optical isomers (i.e., cis-trans isomers and chiral / enantiomers) include chiral synthesis from appropriate cis-trans or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography.

[0085] If a synthesis of a specific stereoisomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting stereomixture and removal of the chiral auxiliary to obtain a pure cis-trans monomer, chiral monomer, or mixed stereoisomer. If the molecule contains a cis-trans isomeric center, pure cis- or trans-forms can be obtained by purification via column chromatography (normal-phase silica gel or reverse-phase high-performance liquid chromatography). Furthermore, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomers.

[0086] The present invention also includes isotopically labeled compounds (i.e., isotopic derivatives) that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes in the isotopic derivatives of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The isotopic derivatives of the compounds of the present invention are all within the protection scope of the present invention.

[0087] In some embodiments, the compounds of the present invention are isotopes of 18 F-labeled compounds, such as those shown in some representative examples of the present invention. It should be noted that although some of the example compounds of the present application have not been isotopically labeled, those skilled in the art can prepare isotope-labeled forms of the compounds based on the content disclosed in this application, such as 18F-labeled forms, and these compounds are also covered by this application.

[0088] In some embodiments, the compounds of the present invention may be 3H-labeled compounds and 14 C-labeled compounds that are useful in drug and substrate tissue distribution experiments. 3 H) and carbon- 14 (Right now 14 C) Labeled compounds are easier to prepare and detect and are the first choice among isotopes.

[0089] In some embodiments, the compounds of the present invention may have heavier isotope substitutions, such as deuterium, i.e., 2H. Due to its good metabolic stability, it has advantages in certain therapies, such as increasing half-life in the body or reducing dosage. Therefore, it may be preferred in some cases.

[0090] Isotopically labeled compounds can be prepared in the usual manner by substituting a readily available isotopically labeled reagent for a non-isotopic reagent using the disclosed exemplified schemes.

[0091] The metabolites of the compounds represented by formula (A) and its various sub-general formulas and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the compounds represented by formula (A) and its various sub-general formulas and their pharmaceutically acceptable salts in vivo, are also included in the scope of protection of the present invention.

[0092] Specifically, the present invention provides the following compound embodiments:

[0093] Embodiment 1: A compound represented by formula A, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotope variant thereof,

[0094] in,

[0095] X, Y and U are independently selected from CH and N, and when any one of them is CH, the hydrogen atom on the CH may be replaced by R1;

[0096] W is selected from CH and N;

[0097] Z is selected from CH2, NH, O and S;

[0098] L is selected from -CH=CH- and -C≡C-, and when n is greater than 1, -(L) n - L's that are identical or different from each other form a chain;

[0099] Ring A is selected from C 6-8 Cycloalkanes, C 6-12 aromatic rings, 6-10 membered heteroaromatic rings and 6-8 membered heterocyclic rings;

[0100] Ring B is selected from C 6-12 Aromatic ring, C 4-8 Cycloalkanes, 5-10 membered heteroaromatic rings and 4-8 membered heterocycles;

[0101] M is a directly connected bond or a 4-8 membered heterocyclic ring;

[0102] R1 is independently selected from the group consisting of: deuterium, tritium, hydroxyl, amino, halogen, nitro, cyano, -COOH, -C 1-6 Alkyl, -C 2- 6-alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SO2-C 1-6 Alkyl, acyl, ester, amide, sulfonamide, -NH-C 3-8 Cycloalkyl, -N(C 1-6 Alkyl)(C 3-8 Cycloalkyl), -C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl,

[0103] Among them, -C in R1 1-6 Alkyl or C as part of a group 1-6 Alkyl, -C 3-8Cycloalkyl or -C as part of a group 3-8 The cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents, each of which is independently selected from deuterium, tritium, -OC 1-6 Alkyl, -C 1-6 Alkyl, halogen, hydroxy, oxo, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -O-(3-6 membered heterocyclic group), -O-(p-toluenesulfonyl), and the two substituents attached to the same C atom optionally form a 3-6 membered heterocyclic ring with the C atom to which they are attached;

[0104] R2 and R3 are each independently selected from the group consisting of: deuterium, tritium, hydroxyl, amino, halogen, nitro, cyano, -COOH, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SO2-C 1-6 Alkyl, acyl, ester, amide, sulfonamide, -NH-C 3-8 Cycloalkyl, -N(C 1-6 Alkyl)(C 3-8 Cycloalkyl), -C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl and C 6-12 Aryl, in which -C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl and C 6-12 Each aryl group is independently optionally substituted by halogen, hydroxy, -OC 1-6 Alkyl, -NHC 1-6 Alkyl or -N(C 1-6 alkyl)2 substituted,

[0105] The -C in R2 and R3 1-6 Alkyl or C as part of other groups or substituents 1-6 The alkyl group is optionally substituted with one or more substituents each independently selected from the group consisting of deuterium, tritium, halogen, hydroxy, -O-(3-6 membered heterocyclyl), -O-(p-toluenesulfonyl);

[0106] n is an integer from 0 to 3;

[0107] p is an integer from 1 to 4;

[0108] q and t are each independently selected from an integer from 0 to 5;

[0109] wherein the heteroaryl and heterocyclyl groups each independently contain 1, 2, 3 or 4 heteroatoms selected from N, S or O; and

[0110] Each occurrence of halogen is optionally an isotopic form thereof, and each occurrence of the ....

[0111] Embodiment 2: The compound according to the preceding embodiment, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotopic variant thereof, wherein the acyl group, the ester group, the amide group, the sulfonamide group is selected from -CO-C 1-6 Alkyl, -C(O)OC 1- 6-alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHCO-C 1-6 Alkyl, -N(C 1-6 alkyl)-CO-C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -NHSO2-C 1-6 Alkyl, -N(C 1-6 Alkyl)-SO2-C 1-6 Alkyl, and depending on the substituent (such as R1, R2 or R3), the -C 1-6 The alkyl group is optionally substituted with corresponding substituents as defined in the preceding embodiments.

[0112] Embodiment 3: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein W is selected from CH and N; and Z is selected from O and S.

[0113] Embodiment 4: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein X, Y and U are all CH, or one or two of X, Y and U are N and the rest are CH.

[0114] Embodiment 5: The compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein the fused ring comprising X, Y, U, W and Z is selected from:

[0115] Embodiment 6: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein p is an integer from 1 to 2, preferably p is 1.

[0116] Embodiment 7.1: A compound according to any of the preceding Embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein R1 can be halogen, nitro or cyano, such as halogen and nitro, such as F, Br, NO2.

[0117] Embodiment 7.2: A compound according to any of the preceding Embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein R1 can be hydroxy or -OC 1-6 Alkyl, where -C 1-6 The alkyl group is optionally substituted by one or more substituents, for example, by one or two substituents, and the substituents are as defined in Embodiment 1, for example, each independently selected from halogen, hydroxyl, -O-(3-6 membered heterocyclyl), -O-(p-toluenesulfonyl), wherein the halogen is preferably F or 18F, and wherein the -O-(3-6 membered heterocyclyl) is preferably -O-THP.

[0118] Embodiment 7.3: A compound according to any of the preceding embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein R1 can be amino, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHCO-C 1-6 Alkyl, -N(C 1-6 alkyl)-CO-C 1-6 Alkyl, -NHSO2-C 1-6 Alkyl, -N(C 1-6 Alkyl)-SO2-C 1-6 Alkyl, -NH-C 3-8 Cycloalkyl, -N(C 1-6 Alkyl)(C 3-8 Cycloalkyl), for example, R1 can be -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHCO-C 1-6 Alkyl or -N(C 1-6 alkyl)-CO-C 1-6 alkyl,

[0119] Among them -C 1-6 The alkyl group is optionally substituted by one or more substituents, for example, by one or two substituents, and the substituents are as defined in Embodiment 1, for example, each independently selected from halogen, hydroxyl, -O-(3-6 membered heterocyclyl), -O-(p-toluenesulfonyl), wherein the halogen is preferably F or 18F, and wherein the -O-(3-6 membered heterocyclyl) is preferably -O-THP.

[0120] Embodiment 7.4: A compound according to any of the preceding embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein R1 can be -COOH, -SO2-C 1-6 Alkyl, -CO-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHCO-C 1-6 Alkyl, -N(C 1- 6-alkyl)-CO-C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -NHSO2-C 1-6 Alkyl or -N(C 1-6 Alkyl)-SO2-C 1-6 Alkyl, for example, R1 can be -COOH or -NHCO-C 1-6 alkyl,

[0121] Among them -C 1-6 The alkyl group is optionally substituted by one or more substituents, for example, by one or two substituents, and the substituents are as defined in Embodiment 1, for example, each independently selected from halogen, hydroxyl, -O-(3-6 membered heterocyclyl), -O-(p-toluenesulfonyl), wherein the halogen is preferably F or 18F, and wherein the -O-(3-6 membered heterocyclyl) is preferably -O-THP.

[0122] Embodiment 7.5: A compound according to any of the preceding Embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein R1 can be -C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl, for example, R1 can be -C 3-6 Cycloalkyl, 5-8 membered heterocyclyl or 5-6 membered heteroaryl, such as 5-8 membered heterocyclyl; each independently optionally substituted by one or more substituents, the substituents being as defined in Embodiment 1, such as each independently selected from -OC 1-6 Alkyl, -C 1-6 Alkyl, halogen, hydroxy, oxo, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2.

[0123] Embodiment 7.6: A compound according to any of the preceding embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein each R1 is independently selected from: halogen, nitro, hydroxy, -OC1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -COOH, -NHCO-C 1-6 Alkyl, -N(C 1-6 alkyl)-CO-C 1-6 Alkyl and 5-8 membered heterocyclic group, wherein -C 1-6 Alkyl or C as part of a group 1-6 The alkyl and 5-8 membered heterocyclic groups are each independently optionally substituted by one or more, for example, 1-2 substituents, each of which is independently selected from deuterium, tritium, -OC 1-6 Alkyl, -C 1-6 Alkyl, halogen, hydroxy, oxo, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -O-(3-6 membered heterocyclyl), -O-(p-toluenesulfonyl), wherein the halogen present in R1 is optionally in an isotopic form, such as 18F.

[0124] Embodiment 7.7: A compound according to any of the preceding Embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein each R1 is independently selected from halogen, nitro, hydroxy, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 1-6 Halogenated hydroxyalkyl, -O- substituted by O-(3-6 membered heterocyclic group) and / or -O-(p-toluenesulfonyl) 1-6 Alkyl, -NHC 1-6 Alkyl, -NHC 1-6 Haloalkyl, -NHC 1-6 Halogenated hydroxyalkyl, -NH- substituted by O-(3-6 membered heterocyclic group) and / or -O-(p-toluenesulfonyl) 1-6 Alkyl, -N(C 1-6 Alkyl)2, -COOH, -NHCO-C 1-6 Alkyl, -N(C 1- 6-alkyl)-CO-C 1-6 Alkyl and 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by 1 or more, for example 1-2 substituents, each of which is independently selected from deuterium, tritium, -OC 1-6 Alkyl, -C 1-6 Alkyl, halogen, hydroxy, oxo, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,

[0125] Preferably R1 is selected from -OC 1-6 Halogenated hydroxyalkyl and -NHC1-6 Halogenated hydroxyalkyl;

[0126] More preferably, R1 is selected from -OC 1-6 Halogenated hydroxyalkyl;

[0127] The halogen present in R1 is optionally in an isotopic form, for example 18F.

[0128] Embodiment 7.8: A compound according to any of the preceding Embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein p is 2, one of R1 is selected from H and halogen, and the other is selected from hydroxy, -OC 1- 6-alkyl, -O-methyl, -OC 1-6 Haloalkyl, -OC 1-6 Halogenated hydroxyalkyl, NH2, -NHC 1-6 Alkyl, -NHCH3, -NHC 1- 6-haloalkyl, -NHC 1-6 Halogenated hydroxyalkyl, -N(C 1-6 Alkyl)2, -N(CH3)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 Haloalkyl), -N(C 1-6 Alkyl)(C 1-6 Halogenated hydroxyalkyl), -N(CH3)(C 1-6 Halogenated hydroxyalkyl), -N(C 1-6 Halogenated alkyl) (C 1-6 Haloalkyl), -N(C 1-6 Halogenated alkyl) (C 1-6 Halogenated hydroxyalkyl), -NH(C 3-8 Cycloalkyl), -N(C 3-8 Cycloalkyl)(C 1-6 Alkyl), -N(C 3-8 Cycloalkyl)(CH3), -N(C 3-8 Cycloalkyl)(C 1-6 Haloalkyl), -N(C 3-8 Cycloalkyl)(C 1-6 wherein the alkyl group is optionally substituted with 1 to 3 -O-(3-6 membered heterocyclyl) or -O-(p-toluenesulfonyl).

[0129] Embodiment 7.9: A compound according to any of the preceding Embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein p is 1, R1 is selected from -OC 1-6 Haloalkyl, -OC 1-6 Halogenated hydroxyalkyl, -N(C 1-6 Alkyl)(C1-6 Haloalkyl), -N(C 1-6 Alkyl)(C 1-6 Halogenated hydroxyalkyl), -N(C 1-6 Halogenated alkyl) (C 1-6 Haloalkyl), -N(C 1-6 Halogenated alkyl) (C 1-6 Halogenated hydroxyalkyl), -N(C 3-8 Cycloalkyl)(C 1-6 Haloalkyl), -N(C 3-8 Cycloalkyl)(C 1-6 halohydroxyalkyl).

[0130] Embodiment 7.10: A compound according to any of the preceding Embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate, or stable isotopic variant thereof, wherein each R1 is independently selected from: F, Br,

[0131] Embodiment 7.11: A compound according to any preceding Embodiment 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate, or stable isotopic variant thereof, wherein each R1 is independently selected from:

[0132] Embodiment 7.12: A compound according to any preceding Embodiment 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate, or stable isotopic variant thereof, wherein each R1 is independently selected from:

[0133] Embodiment 7.13: A compound according to any of the preceding Embodiments 1-6, or a stereoisomer, pharmaceutically acceptable salt, solvate, or stable isotopic variant thereof, wherein R1 is selected from -OC 1-6 Halogenated hydroxyalkyl and -NHC 1-6 Halogenated hydroxyalkyl, such as -OC 1-6 Halogenated hydroxyalkyl, specifically selected from

[0134] Embodiment 7.14: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate, or stable isotopic variant thereof, wherein p is 1, and R is at an adjacent ring carbon atom to Y; or p is 2, and R is attached to adjacent ring carbon atoms to Y and Y, respectively, or R is attached to a ring carbon atom between X and Y, respectively;

[0135] Preferably, p is 1 and R1 is located at an ortho-ring carbon atom relative to Y.

[0136] Embodiment 7.15: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein when R1 carries both hydroxyl and halogen, the hydroxyl and halogen are attached to different backbone atoms, such as C 1-6 The alkyl groups are attached to different carbon atoms, preferably adjacent carbon atoms.

[0137] Embodiment 8.1: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein: n=0.

[0138] Embodiment 8.2: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein: n is 1, and L is -CH=CH-, or L is -C≡C-.

[0139] Embodiment 8.3: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein n is 2 and (L)2 is -CH=CH-CH=CH-, -CH=CH-C≡C-, -C≡C-CH=CH- or -C≡CC≡C-, preferably -CH=CH-CH=CH- or -CH=CH-C≡C-.

[0140] Embodiment 8.4: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein n is 3 and (L)3 is -CH=CH-CH=CH-CH=CH-, -CH=CH-CH=CH-C≡C-, -CH=CH-C≡C-CH=CH-, -C≡C-CH=CH-CH=CH-, -CH=CH-C≡CC≡C-, -C≡C-CH=CH-C≡C- or -C≡CC≡C-CH=CH-, preferably -CH=CH-CH=CH-CH=CH-CH=CH-, -CH=CH-CH=CH-C≡C-, -CH=CH-C≡C-CH=CH- or -CH=CH-C≡CC≡C-.

[0141] Embodiment 9: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein formula (A) has the following sub-formula:

[0142] Embodiment 10.1: A compound according to any of the preceding Embodiments 1-9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring A is C 6-12 Aromatic rings, such as C6-10 Aromatic rings, such as benzene rings.

[0143] Embodiment 10.2: A compound according to any of the preceding embodiments 1-9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein ring A is a 6-10 membered heteroaromatic ring, such as a 6 membered heteroaromatic ring containing 1 or 2 nitrogen heteroatoms, such as

[0144] Embodiment 10.3: A compound according to any of the preceding embodiments 1-9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring A is a 6-8 membered heterocycle, for example a 6 membered heterocycle containing 1 or 2 nitrogen heteroatoms, for example

[0145] Embodiment 10.4: A compound according to any of the preceding Embodiments 1-9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring A is selected from C 6-12 Aromatic ring, 6-10 membered heteroaromatic ring and 6-8 membered heterocyclic ring, for example, ring A is selected from C 6-10 Aromatic ring, 6-8 membered heteroaromatic ring and 6-8 membered heterocyclic ring, for example, ring A is selected from benzene ring and 6-membered heteroaromatic ring or 6-membered heterocyclic ring containing 1 or 2 nitrogen heteroatoms, for example, ring A is selected from benzene ring and 6-membered heteroaromatic ring containing 1 or 2 nitrogen heteroatoms, for example, A is selected from Preferably, ring A is selected from

[0146] Embodiment 10.5: A compound according to any of the preceding Embodiments 1-9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring A is selected from C 6-8 Aromatic ring, 6-8 membered heteroaromatic ring, for example, ring A is selected from

[0147] Embodiment 10.6: A compound according to any of the preceding Embodiments 1-9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring A is selected from C 6-8 Aromatic ring, 6-8 membered heteroaromatic ring, for example, ring A is selected from

[0148] Embodiment 10.7: A compound according to any of the preceding Embodiments 1-9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring A is selected from C 6-8 Aromatic ring, 6-8 membered heteroaromatic ring, for example, ring A is selected from

[0149] Embodiment 10.8: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein A is attached to the remainder of the molecule through a ring carbon atom, or when ring A is a heterocycle, may also be attached to the remainder of the molecule through a ring heteroatom.

[0150] Embodiment 11.1: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein ring A is optionally substituted with 0-5 of said substituents R2, for example, q is 0-4, 0-3, 0-2, 0-1, 1, preferably q is 0.

[0151] Embodiment 11.2: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring A is optionally substituted with 1 R2 selected from the group consisting of halogen, nitro, cyano and halogen-substituted -C 1-6 Alkyl is preferably selected from halogen, nitro and cyano, more preferably R2 is selected from halogen or its isotope, for example R2 is selected from F and 18F.

[0152] Embodiment 12.1: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring B is selected from C 6-12 Aromatic rings, such as C 6-10 An aromatic ring, such as a benzene ring or a naphthalene ring.

[0153] Embodiment 12.2: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein ring B is selected from a 5-10 membered heteroaromatic ring, such as a 5-8 membered heteroaromatic ring, and further such as a 5-6 membered heteroaromatic ring containing 1-3, such as 1-2, heteroatoms selected from nitrogen, oxygen and sulfur; for example, B is selected from

[0154] Embodiment 12.3: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring B is selected from C 6-12 Aromatic rings and 5-10 membered heteroaromatic rings, such as C 6-10 Aromatic rings and 5-8 membered heteroaromatic rings, for example, ring B is selected from benzene rings, naphthalene rings and 5-6 membered heteroaromatic rings containing 1-3, for example 1-2, heteroatoms selected from nitrogen, oxygen and sulfur, for example, B is selected from

[0155] Preferably, ring B is selected from

[0156] Embodiment 12.4: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring B is selected from a benzene ring, a 5-8 membered heteroaromatic ring, for example, Ring B is selected from

[0157] Or for example, ring B is selected from

[0158] Alternatively, ring B is a 6-membered heteroaromatic ring containing 2 or 3 heteroatoms selected from N, S or O, for example

[0159] Embodiment 13.1: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein ring B is optionally substituted with 0-5 of said substituents R3, for example, t is 0-4, 0-3, 0-2, 0-1, 0, 1-2, preferably t is 1.

[0160] Embodiment 13.2: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring B is optionally substituted with 1 or 2 R3, R3 being selected from hydroxy, amino, halogen, nitro, cyano, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 3-8 Cycloalkyl, 5-8 membered heterocyclic group and C 6-10 Aryl; wherein the -C 3-8 Cycloalkyl, 5-8 membered heterocyclic group and C 6-10 Aryl is preferably -C 3-6 Cycloalkyl, 5-7 membered heterocyclic group and C6 aryl, each independently optionally substituted by halogen, hydroxyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl or -N(C 1-6 alkyl)2 substituted;

[0161] The -C that appears in R3 1-6 The alkyl group is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of deuterium, tritium, halogen, hydroxy, -O-(3-6 membered heterocyclyl) and -O-(p-toluenesulfonyl), such as deuterium, tritium, halogen and hydroxy, such as halogen or an isotope thereof (e.g., F or 18F), and hydroxy.

[0162] Embodiment 13.3: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring B is optionally substituted with 1 or 2 R3, R3 being selected from hydroxy, amino, halogen, nitro, cyano, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2, 5-7 membered heterocyclic group and C6 aryl; wherein the 5-7 membered heterocyclic group and C6 aryl are each independently optionally replaced by -NHC 1-6 Alkyl or -N(C 1-6 alkyl)2 substituted;

[0163] The -C that appears in R3 1-6 The alkyl group is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen or an isotope thereof (eg, F or 18 F), and hydroxy.

[0164] Embodiment 13.4: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring B is optionally substituted with 1 or 2 R3, R3 being selected from the group consisting of: hydroxy, amino, F, Br, nitro, cyano, -O-CH3, -NHCH3, -N(CH3)2,

[0165] Embodiment 13.5: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring B is substituted with one substituent R3 selected from -NHC 1-6 Alkyl, for example -NHCH3.

[0166] Embodiment 14.1: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein M is a 6-8 membered nitrogen-containing heterocycle, such as a 6 membered nitrogen-containing heterocycle, such as

[0167] Embodiment 14.2: A compound according to any preceding embodiment, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein n is 0 and M is a 6-membered nitrogen-containing heterocycle, for example

[0168] Embodiment 15: A compound according to any of Embodiments 1-9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, having the following formula:

[0169] wherein each group and variable are as defined in the corresponding embodiment above, specifically

[0170] R1 is selected from halogen, nitro, hydroxy, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 1-6 Halogenated hydroxyalkyl, -O- substituted by O-(3-6 membered heterocyclic group) and / or -O-(p-toluenesulfonyl) 1-6 Alkyl, -NHC 1-6 Alkyl, -NHC 1-6 Haloalkyl, -NHC 1-6 Halogenated hydroxyalkyl, -NH- substituted by O-(3-6 membered heterocyclic group) and / or -O-(p-toluenesulfonyl) 1-6 Alkyl, -N(C 1- 6 alkyl) 2, -COOH, -NHCO-C 1-6 Alkyl, -N(C 1-6 alkyl)-CO-C 1-6 Alkyl and 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by one or more substituents, each of which is independently selected from deuterium, tritium, -OC 1-6 Alkyl, -C 1- 6 alkyl, halogen, hydroxy, oxo, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2, wherein the halogen present in R1 is optionally in an isotopic form, for example 18F;

[0171] Ring A is selected from C 6-12 aromatic rings and 6-10 membered heteroaromatic rings;

[0172] Ring B is selected from C 6-12 aromatic rings and 5-10 membered heteroaromatic rings;

[0173] R3 is selected from hydroxy, amino, halogen, nitro, cyano, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl) 2, 4-7 membered heterocyclic group;

[0174] t is an integer from 0 to 2,

[0175] wherein the heteroaryl and heterocyclyl groups each independently contain 1, 2 or 3 heteroatoms selected from N, S or O; and

[0176] wherein each occurrence of halogen is optionally in its isotopic form, and the carbon atoms in the substituents and / or the hydrogen atoms thereon are optionally in their isotopic forms;

[0177] Embodiment 15.1: A compound according to Embodiment 15, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein:

[0178] R1 is selected from -OC 1-6 Halogenated hydroxyalkyl and -NHC 1-6 Halogenated hydroxyalkyl, preferably R1 is selected from -OC 1-6 Halogenated hydroxyalkyl;

[0179] Ring A is selected from a benzene ring and a 6-membered heteroaromatic ring containing 1 or 2 nitrogen heteroatoms;

[0180] Ring B is selected from a benzene ring and a 5-6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur;

[0181] R3 is selected from -NHC 1-6 alkyl;

[0182] t is 1;

[0183] Each occurrence of halogen is preferably F or 18F, and the carbon atoms and / or hydrogen atoms in the substituents are optionally in their isotopic forms.

[0184] Embodiment 15.2: A compound of the formula: or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof,

[0185] in:

[0186] R1 is selected from hydroxyl, -OC 1-6 Alkyl, -O-methyl, -OC 1-6 Haloalkyl, -OC 1-6 Halogenated hydroxyalkyl, NH2, -NHC 1- 6-alkyl, -NHCH3, -NHC 1-6 Haloalkyl, -NHC 1-6 Halogenated hydroxyalkyl, -N(C 1-6 Alkyl)2, -N(CH3)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 Haloalkyl), -N(C 1-6 Alkyl)(C 1-6 Halogenated hydroxyalkyl), -N(CH3)(C 1-6 Halogenated hydroxyalkyl), -N(C 1- 6-halogenated alkyl)(C 1-6 Haloalkyl), -N(C 1-6 Halogenated alkyl) (C 1-6 Halogenated hydroxyalkyl), -NH(C 3-8 Cycloalkyl), -N(C3-8 Cycloalkyl)(C 1-6 Alkyl), -N(C 3-8 Cycloalkyl)(CH3), -N(C 3-8 Cycloalkyl)(C 1-6 Haloalkyl), -N(C 3-8 Cycloalkyl)(C 1-6 halohydroxyalkyl), wherein the alkyl group is optionally substituted with 1-3 -O-(3-6 membered heterocyclyl) or -O-(p-toluenesulfonyl);

[0187] Ring A is

[0188] Ring B is selected from C 6-12 Aromatic ring, C 4-8 Cycloalkanes, 5-8 membered heteroaromatic rings and 4-8 membered heterocyclic rings;

[0189] R3 is selected from deuterium, tritium, hydroxyl, amino, halogen, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, methylsulfone, C 2-6 Acyl, C 2-6 Ester group, C 2-6 Amide, C 2-6 Sulfonamide, C 1-6 Halogenated hydroxyalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl.

[0190] t is an integer from 0 to 5;

[0191] wherein each occurrence of halogen is optionally in an isotopic form.

[0192] Embodiment 16: A compound according to any of Embodiments 1-9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, having the following formula:

[0193] wherein each group and variable are as defined in the corresponding embodiment above, specifically

[0194] R1 is selected from halogen, nitro, hydroxy, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 1-6Halogenated hydroxyalkyl, -O- substituted by O-(3-6 membered heterocyclic group) and / or -O-(p-toluenesulfonyl) 1-6 Alkyl, -NHC 1-6 Alkyl, -NHC 1-6 Haloalkyl, -NHC 1-6 Halogenated hydroxyalkyl, -NH- substituted by O-(3-6 membered heterocyclic group) and / or -O-(p-toluenesulfonyl) 1-6 Alkyl, -N(C 1- 6 alkyl) 2, -COOH, -NHCO-C 1-6 Alkyl, -N(C 1-6 alkyl)-CO-C 1-6 Alkyl and 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by one or more substituents, each of which is independently selected from deuterium, tritium, -OC 1-6 Alkyl, -C 1- 6 alkyl, halogen, hydroxy, oxo, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,

[0195] Ring A is selected from C 6-12 aromatic rings and 6-10 membered heteroaromatic rings;

[0196] Ring B is selected from C 6-12 aromatic rings and 5-10 membered heteroaromatic rings;

[0197] R3 is selected from hydroxy, amino, halogen, nitro, cyano, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1- 6 alkyl) 2, 5-7 membered heterocyclic group and C6 aryl; wherein the 5-7 membered heterocyclic group and C6 aryl are each independently optionally replaced by -NHC 1- 6-alkyl or -N(C 1-6 alkyl)2, wherein the -C 1-6 The alkyl group is optionally substituted with 1 or 2 substituents each independently selected from halogen or halogen isotopes (e.g., F or 18F) and hydroxy;

[0198] t is an integer from 0 to 2,

[0199] wherein the heteroaryl and heterocyclyl groups each independently contain 1, 2 or 3 heteroatoms selected from N, S or O; and

[0200] Each occurrence of halogen is optionally an isotopic form thereof, and each occurrence of the ....

[0201] Embodiment 16.1: A compound according to Embodiment 16, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein

[0202] R1 is selected from -OC 1-6 Halogenated hydroxyalkyl and -NHC 1-6 Halogenated hydroxyalkyl, preferably R1 is selected from -OC 1-6 Halogenated hydroxyalkyl,

[0203] Ring A is selected from a benzene ring and a 6-membered heteroaromatic ring containing 1 or 2 nitrogen heteroatoms;

[0204] Ring B is selected from a benzene ring and a 5-6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur;

[0205] R3 is selected from -NHC 1-6 alkyl;

[0206] t is 1;

[0207] Each occurrence of halogen is preferably F or 18F, and the carbon atoms and / or hydrogen atoms in the substituents are optionally in their isotopic forms.

[0208] Embodiment 16.2: A compound according to Embodiment 16, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof,

[0209] in

[0210] R1 is selected from -OC 1-6 Haloalkyl, -OC 1-6 Halogenated hydroxyalkyl, -N(C 1-6 Alkyl)(C 1-6 Haloalkyl), -N(C 1-6 Alkyl)(C 1-6 Halogenated hydroxyalkyl), -N(C 1-6 Halogenated alkyl) (C 1-6 Haloalkyl), -N(C 1-6 Halogenated alkyl) (C 1-6 Halogenated hydroxyalkyl), -N(C 3-8 Cycloalkyl)(C 1-6 Haloalkyl), -N(C 3-8 Cycloalkyl)(C 1-6 halohydroxyalkyl);

[0211] Ring A is

[0212] Ring B is selected from a 6-membered heteroaromatic ring;

[0213] R3 is selected from deuterium, tritium, hydroxyl, amino, halogen, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6-hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, methylsulfone, C 2-6 Acyl, C 2-6 Ester group, C 2-6 Amide, C 2-6 Sulfonamide, C 1-6 Halogenated hydroxyalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl.

[0214] t is an integer from 0 to 5;

[0215] wherein each occurrence of halogen is optionally in an isotopic form.

[0216] Embodiment 16.3: A compound according to Embodiment 16, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein:

[0217] Ring A is

[0218] Ring B is selected from C 6-12 Aromatic ring, C 4-8 Cycloalkanes, 5-8 membered heteroaromatic rings;

[0219] R1 is selected from the group consisting of: deuterium, tritium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, C 1-6 Alkylamino, halogen, C 1-6 Halogenated alkoxy, C 1-6 Haloalkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Acyl, nitro, cyano, carboxyl, C 2-6 Ester group, amino group, C 2-6 Amide, -SO2CH3, C 2-6 Sulfonamide; wherein the C 1- 6 alkyl, C 1-6 Alkoxy and C 1-6 The hydrogen atoms on the alkylamino group may be optionally replaced by 1 to 3 groups selected from C 1-6 Alkoxy, C 1-6Alkyl, halogen, hydroxyl, OTHP, -O-(3-6 membered heterocyclic group), -O-(p-toluenesulfonyl) group substitution, and when two substituents are on the same C atom, they can form a 3-6 membered heterocyclic ring together with the C atom to which they are connected;

[0220] R3 is selected from: deuterium, tritium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, C 1-6 Alkylamino, halogen, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Acyl, nitro, cyano, carboxyl, C 2-6 Ester group, amino group, C 2-6 Amide, -SO2CH3, C 2-6 Sulfonamide; wherein said C 1-6 Alkoxy and C 1-6 The alkylamino group is optionally substituted with 1 to 3 substituents selected from halogen, hydroxy, OTHP, -O-(3-6 membered heterocyclyl), and -O-(p-toluenesulfonyl);

[0221] wherein the heteroaryl, heteroaromatic ring, heterocyclic group and heterocyclic ring each independently contain 1, 2, 3 or 4 heteroatoms selected from N, S or O;

[0222] The halogen includes isotopes thereof.

[0223] It should be noted that, in any one of the above-mentioned implementation plans 15 to 16.3, the specific examples of each variable are as illustrated in the above-mentioned corresponding implementation plans.

[0224] Embodiment 17: A compound according to any of the preceding embodiments, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein the isotopic variant comprises an atom selected from 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl; preferably comprises 18F.

[0225] Embodiment 18: A compound or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof selected from:

[0226] In a more specific embodiment, the compound of the present invention is selected from the following compounds and stereoisomers thereof, or pharmaceutically acceptable salts or solvates thereof:

[0227] In other embodiments, some compounds of formula A of the present invention may also be defined as follows:

[0228] or a pharmaceutically acceptable salt or solvate thereof,

[0229] Wherein, X and Y are independently selected from CH or N; and when X or Y is CH, the hydrogen atom on CH can be replaced by R b or R c replace;

[0230] W is selected from CH, or N;

[0231] W and Z are each independently selected from CH2, NH, O or S;

[0232] Ring A is selected from the group consisting of a 4-8 membered saturated cycloalkane, a benzene ring, a 5-8 membered heteroaromatic ring, and a 4-8 membered heterocyclic ring;

[0233] Ring B is selected from the following groups: naphthalene ring, biphenyl, 4-8 membered saturated cycloalkane, benzene ring, 5-8 membered heteroaromatic ring, 4-8 membered heterocyclic ring;

[0234] 0, 1, 2, 3, 4 or 5 hydrogen atoms on the ring A or ring B are substituted by a substituent selected from the group consisting of deuterium, tritium, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated hydroxyalkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, C 1-6 Alkylamino, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Haloalkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Acyl, C 1-6 Hydroxyalkyl, nitro, cyano, carboxyl, C 2-6 Ester group, amino group, C 2-6 Amide, methyl sulfone, C 2-6 Sulfonamide group;

[0235] R b and R c Each independently selected from the group consisting of deuterium, tritium, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated hydroxyalkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, C 1-6Alkylamino, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Haloalkylamino, C 1-6 Halogenated hydroxyalkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Acyl, C 1-6 Hydroxyalkyl, nitro, cyano, carboxyl, C 2-6 Ester group, amino group, C 2-6 Amide, methyl sulfone, C 2-6 Sulfonamide, or JR '; wherein the C 1-6 0, 1, 2 or 3 hydrogen atoms on the alkoxy group can be replaced by R d and R e Substituted, the R d and R e Each independently selected from the following group: C 1-6 Alkoxy, halogen, hydroxy, TsO, OTHP, -O-(3-6 membered heterocyclic group), -O-(p-toluenesulfonyl), and when R d and R e When substituted on the same C atom, R d 、R e It can form a 3-6 membered heterocyclic ring with the C atom it is connected to; J is O or NR a ; R a Selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-8 membered cycloalkyl; R' is selected from the following group: hydrogen, methyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Halogenated alkyl, wherein the C 1-6 0, 1, 2 or 3 hydrogen atoms on the alkyl group may be substituted by -O-(3-6 membered heterocyclyl) or -O-(p-toluenesulfonyl);

[0236] The heteroaryl, heteroaromatic ring, heterocyclic group and heterocyclic ring each independently contain 1, 2, 3 or 4 heteroatoms selected from N, S or O;

[0237] The halogen includes isotopes thereof.

[0238] In a preferred embodiment, the ring A is selected from the following groups: 6-8 membered aromatic rings, 5-8 membered heteroaromatic rings; preferably, the ring A is selected from the following groups:

[0239] In a preferred embodiment, the ring B is selected from the following group: a benzene ring, a 5-8 membered heteroaromatic ring; preferably, the ring B is selected from the following group:

[0240] In a preferred embodiment, the R b is hydrogen or halogen, R c For W-R',

[0241] Where W is O or NR a , R a Selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-8 membered cycloalkyl;

[0242] R' is selected from the following group: hydrogen, methyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Halogenated alkyl, wherein the C 1-6 0, 1, 2 or 3 hydrogen atoms on the alkyl group may be substituted by -O-(3-6 membered heterocyclyl) or -O-(p-toluenesulfonyl);

[0243] Preferably, R c Select from the following groups:

[0244] In a preferred embodiment, the compound includes a compound as shown in Formula I', or a pharmaceutically acceptable salt or solvate thereof,

[0245] Where J is O or NR a ; R a Selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-8 membered cycloalkyl;

[0246] R' is selected from the group consisting of hydrogen, methyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C substituted by hydroxy 1-6 Halogenated alkyl, wherein the C 1-6 0, 1, 2 or 3 hydrogen atoms on the alkyl group may be substituted by -O-(3-6 membered heterocyclyl) or -O-(p-toluenesulfonyl);

[0247] Ring A is

[0248] Ring B is as defined in claim 1.

[0249] In other embodiments, some compounds of formula A of the present invention may also be defined as follows:

[0250] or a pharmaceutically acceptable salt or solvate thereof,

[0251] wherein X and Y are independently selected from CH or N; and when X or Y is CH, the hydrogen atom on CH may be replaced by R;

[0252] Z is selected from CH2, O, NH or S;

[0253] n is 1, 2, or 3;

[0254] Ring A is selected from the group consisting of a 6-8 membered saturated cycloalkane, a benzene ring, a 5-8 membered heteroaromatic ring, and a 6-8 membered heterocyclic ring;

[0255] Ring B is selected from the group consisting of a naphthalene ring, a biphenyl ring, a benzene ring, a 4-8 membered saturated cycloalkane, a 5-membered heteroaromatic ring (such as pyridine), and a 7-8 membered heteroaromatic ring;

[0256] R is selected from the group consisting of deuterium, tritium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, C 1-6 Alkylamino, halogen, C 1-6 Halogenated alkoxy, C 1-6 Haloalkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Acyl, nitro, cyano, carboxyl, C 2-6 Ester group, amino group, C 2-6 Amide, methyl sulfone, C 2-6 Sulfonamide; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 0, 1, 2 or 3 hydrogen atoms on the alkylamino group can be replaced by R b or R c Substituted, the R b and R c Each independently selected from the following group: C 1-6 Alkoxy, C 1-6 Alkyl, halogen, hydroxyl, TsO, OTHP, -O-(3-6 membered heterocyclic group), -O-(p-toluenesulfonyl), and when R b and R c When substituted on the same C atom, R b 、R c The C atom to which it is connected can form a 3-6 membered heterocyclic ring;

[0257] R a Selected from the group consisting of deuterium, tritium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, C 1-6 Alkylamino, halogen, C2-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Acyl, nitro, cyano, carboxyl, C 2-6 Ester group, amino group, C 2-6 Amide, methyl sulfone, C 2-6 Sulfonamide; wherein the C 1-6 Alkoxy and C 1-6 0, 1, 2 or 3 hydrogen atoms on the alkylamino group may be substituted by a substituent selected from the group consisting of halogen, hydroxy, TsO, OTHP, -O-(3-6 membered heterocyclyl), -O-(p-toluenesulfonyl);

[0258] Unless otherwise specified, 0, 1, 2, 3, 4 or 5 hydrogen atoms on the above groups may be further substituted by a substituent selected from the group consisting of deuterium, tritium, hydroxyl, halogen, C 1-6 Alkoxy, C 1-6 Halogenated hydroxyalkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Haloalkylamino, C 1-6 Halogenated hydroxyalkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, acyl, C 1-6 Hydroxyalkyl, nitro, cyano, carboxyl, ester, amino, amide, methylsulfone, sulfonamide;

[0259] The heteroaryl, heteroaromatic ring, heterocyclic group and heterocyclic ring each independently contain 1, 2, 3 or 4 heteroatoms selected from N, S or O;

[0260] The halogen includes isotopes thereof.

[0261] In another preferred embodiment, the -O-(3-6 membered heterocyclyl) is -O-(tetrahydropyranyl).

[0262] In a preferred embodiment, the ring A is selected from the following group: 6-8 membered aromatic rings, 5-8 membered heteroaromatic rings; preferably, the ring A is selected from the following group:

[0263] In a preferred embodiment, the ring B is selected from the following group: a benzene ring, a 5-8 membered heteroaromatic ring; preferably, the ring B is selected from the following group:

[0264] In a preferred embodiment, the R is selected from the following group:

[0265] In a preferred embodiment, the compound includes a compound as shown in Formula I', or a pharmaceutically acceptable salt or solvate thereof,

[0266] Among them, ring B, R and R a The definition of is as above.

[0267] In other embodiments, some compounds of formula A of the present invention may also be defined as follows:

[0268] or a pharmaceutically acceptable salt or solvate thereof,

[0269] wherein X and Y are independently selected from CH or N;

[0270] Z is selected from CH2, O, NH or S;

[0271] n is 1, 2, or 3;

[0272] Ring A is selected from the group consisting of a 6-8 membered saturated cycloalkane, a benzene ring, a 5-8 membered heteroaromatic ring, and a 6-8 membered heterocyclic ring;

[0273] Ring B is a 6-membered heteroaromatic ring;

[0274] 0, 1, 2, 3, 4 or 5 hydrogen atoms on the ring A or ring B are substituted by a substituent selected from the group consisting of deuterium, tritium, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated hydroxyalkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, C 1-6 Alkylamino, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Haloalkylamino, C 1-6 Halogenated hydroxyalkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, acyl, C 1-6 Hydroxyalkyl, nitro, cyano, carboxyl, C 2-6 Ester group, amino group, C 2-6 Amide, methyl sulfone, C 2-6 Sulfonamide group;

[0275] R is selected from the group consisting of deuterium, tritium, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, C 1-6 Alkylamino, halogen, C 1-6 Halogenated alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 2-6 Acyl, C 1-6 Hydroxyalkyl, nitro, cyano, carboxyl, C 2-6 Ester group, amino group, C 2-6 Amide, methyl sulfone, C 2-6 Sulfonamide; wherein the C 1-6 Alkoxy and C 1-6 0, 1, 2 or 3 hydrogen atoms on the alkylamino group can be replaced by R b or R c Substituted, the R b and R c Each independently selected from the following group: C 1-6 Alkoxy, halogen, hydroxyl, TsO, OTHP, and when R b and R c When substituted on the same C atom, R b 、R c The C atom to which it is connected can form a 3-6 membered heterocyclic ring;

[0276] The heteroaryl, heteroaromatic ring, heterocyclic group and heterocyclic ring each independently contain 1, 2, 3 or 4 heteroatoms selected from N, S or O;

[0277] The halogen includes isotopes thereof.

[0278] In a preferred embodiment, the ring A is selected from the following group:

[0279] In a preferred embodiment, the ring B is a 6-membered heteroaryl group containing 2 or 3 heteroatoms selected from N, S or O;

[0280] Preferably, ring B is selected from the group consisting of:

[0281] In a preferred embodiment, the R is W-R',

[0282] Where W is O or NR a ; the R a Select from the following group: C 1-6 Alkyl, C 1-6 Haloalkyl, 3-8 membered cycloalkyl;

[0283] R' is C substituted by hydroxyl 1-6 Halogenated alkyl is preferably selected from the group consisting of:

[0284] In a preferred embodiment, the compound includes a compound as shown in Formula I', or a pharmaceutically acceptable salt or solvate thereof,

[0285] Where W is O or NR a , R a Select from the following group: C 1-6 Alkyl, C 1-6 Haloalkyl, 3-8 membered cycloalkyl;

[0286] R' is selected from the following group: C substituted by hydroxyl 1-6 Haloalkyl, unsubstituted C 1-6 alkyl halide;

[0287] Ring B is as defined above.

[0288] It should be noted that, for the compounds of formula (I), (II) and (III), in addition to the definitions above, each substituent therein may have the general, specific or preferred meaning defined above for the corresponding substituent in formula (A), and the technical solutions formed by these substituents or any combination thereof are also covered by the present invention.

[0289] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one.

[0290] The main advantages of the present invention are:

[0291] The compound of the present application has a novel structure and can specifically recognize α-synuclein aggregates. It can be used to prepare drugs for the treatment or diagnosis of neurodegenerative diseases associated with α-synuclein aggregates and other misfolded proteins, and has great clinical significance.

[0292] Pharmaceutical compositions and methods of administration

[0293] Since the compounds of the present invention can recognize α-synuclein aggregates and are used to treat or diagnose neurodegenerative diseases associated with α-synuclein aggregates and other pathological aggregated proteins (such as Parkinson's disease, Lewy body dementia, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, etc.), the compounds of the present invention and their stereoisomers, optical isomers, pharmaceutically acceptable salts, crystalline forms, isotopic derivatives, prodrugs, metabolites, solvates, or hydrates thereof, as well as pharmaceutical compositions containing the compounds of the present invention as the main active ingredient, can be used as drugs for treating (stabilizing, alleviating, or curing) or diagnosing neurodegenerative diseases associated with α-synuclein aggregates and other pathological aggregated proteins (such as Parkinson's disease, Lewy body dementia, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, progressive muscular dystrophy, etc.).

[0294] The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable excipient or carrier. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0295] Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0296] The administration of the compound or pharmaceutical composition of the present invention includes, but is not limited to, intravenous injection.

[0297] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0298] Preparation method

[0299] In one aspect, the present application provides a method for preparing a compound of formula (A-1), comprising the following steps:

[0300] Method 1: R1 is not hydroxyl, amino, C 1-6 Halogenated hydroxyalkoxy, C 1-6 Halogenated hydroxyalkylamino, C 1-6 Haloalkoxy or C 1- When 6 haloalkylamino groups are present,

[0301] wherein X, Y, U, Z, W, Ring A and Ring B are as defined above;

[0302] Method 2: R1 is an optionally substituted hydroxyl group or an optionally substituted amino group and the substituent is C 1-6 Alkyl or C 3-8 When cycloalkyl,

[0303] wherein X, Y, U, Z, W, Ring A and Ring B are as defined above;

[0304] Method 3: R1 is substituted C 1-6 Alkoxy or substituted C 1-6 Alkylamino, and the substituent is selected from halogen and OH,

[0305] wherein R' is selected from -C 1-6 Alkyl and C 1-6 alkyl halide;

[0306] R" is selected from C 1-6 alkyl halide;

[0307] R a Selected from H or -C 1-6 alkyl;

[0308] X, Y, U, Z, W, Ring A and Ring B are as defined above;

[0309] Method 4: R1 is substituted C 1-6 Alkoxy or substituted C 1-6 When alkylamino and the substituent is selected from halogen, -O-(p-toluenesulfonyl), -O-(3-6 membered heterocyclic group),

[0310] where R b C 1-6 Alkyl, wherein 0, 1, 2, 3, 4 or 5 hydrogen atoms are substituted by a substituent selected from the group consisting of halogen, -O-(p-toluenesulfonyl), and -O-(3-6 membered heterocyclyl);

[0311] R a Selected from H or -C 1-6 alkyl;

[0312] X, Y, U, Z, W, Ring A and Ring B are as defined above.

[0313] In this regard, when the compound of formula (A) is defined as formula (I) shown in the above description, its corresponding preparation method can also be expressed as follows:

[0314] Method 1.R b Not hydroxyl, amino, C 1-6 Halogenated hydroxyalkoxy, C 1-6 Halogenated hydroxyalkylamino, C 1-6 Haloalkoxy or C 1-6 When haloalkylamino

[0315] R c , X, U, Z, W, Ring A and Ring B are as defined above;

[0316] Method 2.R b When hydroxyl or amino

[0317] Wherein, R3 is C1-6 alkyl or C1-6 cycloalkyl;

[0318] R c, X, U, Z, W, Ring A and Ring B are as defined above;

[0319] Method 3.R b C 1-6 Halogenated hydroxyalkoxy or C 1-6 Halogenated hydroxyalkylamino

[0320] Wherein, said R1 is selected from the following group: C 1-6 Alkyl, C 1-6 Haloalkyl, 3-8 membered cycloalkyl;

[0321] Said R2 is selected from the following group: C 1-6 alkyl halide;

[0322] R3, R c , J, X, U, Z, W, Ring A and Ring B are as defined above;

[0323] Method 4.R b C 1-6 Haloalkoxy or C 1-6 When haloalkylamino

[0324] Wherein, R4 is selected from the following group: C 1-6 alkyl, and the C 1-6 0, 1, 2, 3, 4 or 5 hydrogen atoms on the alkoxy group are substituted by a substituent selected from the group consisting of halogen, -O-(p-toluenesulfonyl), and -O-(3-6 membered heterocyclyl);

[0325] R3, R c , J, X, U, Z, W, Ring A and Ring B are as defined above.

[0326] On the other hand, the present application provides a method for preparing a compound as shown in formula (A-2), comprising the following method:

[0327] Method 1: When R1 is not hydroxyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated hydroxyalkoxy or C 1-6 When halogenated hydroxyalkylamino group,

[0328] Wherein, the definitions of X, Y, U, W, Z, n, Ring A and Ring B are as described above;

[0329] Method 2: When R1 is hydroxyl,

[0330] Among them, R c Selected from: C 1-6 haloalkyl; X, Y, U, W, Z, n, ring A and ring B are as defined above;

[0331] Method 3: When R1 is C 1-6 Halogenated hydroxyalkoxy or C 1-6 Halogenated hydroxyalkylamino

[0332] Wherein, R' is selected from the following group: C 1-6 Alkyl and C 1-6 alkyl halide;

[0333] R" is selected from the following group: C 1-6 alkyl halide;

[0334] R a Selected from H or -C 1-6 alkyl;

[0335] X, Y, U, W, Z, n, Ring A and Ring B are as defined above;

[0336] Method 4: R1 is C 1-6 Alkoxy, and the C 1-6 The alkoxy group is optionally substituted by 1 to 5 substituents selected from the group consisting of halogen, -O-(p-toluenesulfonyl), -O-(3-6 membered heterocyclyl),

[0337] Among them, the R b Select from the following group: C 1-6 Alkyl, wherein 0, 1, 2, 3, 4 or 5 hydrogen atoms are substituted by a substituent selected from the group consisting of halogen, -O-(p-toluenesulfonyl), and -O-(3-6 membered heterocyclyl);

[0338] W, U, X, Y, Z, n, ring A and ring B are as defined above.

[0339] In this regard, when the compound of formula (A) is defined as formula (II) or formula (III) shown in the above description, its corresponding preparation method can also be expressed as follows:

[0340] Method 1: When R is not hydroxyl, C 1-6 Hydroxyalkoxy, C 1-6 Halogenated hydroxyalkoxy or C 1-6 When halogenated hydroxyalkylamino group,

[0341] Wherein, the definitions of X, Y, Z, n, Ring A and Ring B are as described above;

[0342] Method 2: When R is hydroxyl,

[0343] Wherein, R' is selected from: C 1-6haloalkyl; X, Y, Z, n, ring A and ring B are as defined above;

[0344] Method 3: When R is C 1-6 Halogenated hydroxyalkoxy or C 1-6 Halogenated hydroxyalkylamino

[0345] Wherein, W is O, S or NH;

[0346] Said R1 is selected from the following group: C 1-6 Alkyl, C 1-6 Haloalkyl, 3-8 membered cycloalkyl;

[0347] Said R2 is selected from the following group: C 1-6 alkyl halide;

[0348] The definitions of X, Y, Z, n, ring A and ring B are as described above;

[0349] Method 4: R is C 1-6 Alkoxy, and the C 1-6 0, 1, 2, 3, 4 or 5 hydrogen atoms on the alkoxy group are substituted by a substituent selected from the group consisting of halogen, -O-(p-toluenesulfonyl), -O-(3-6 membered heterocyclyl),

[0350] Wherein, said R4 is selected from the following group: C 1-6 alkyl, and the C 1-6 0, 1, 2, 3, 4 or 5 hydrogen atoms on the alkoxy group are substituted by a substituent selected from the group consisting of halogen, -O-(p-toluenesulfonyl), and -O-(3-6 membered heterocyclyl);

[0351] W, X, Y, Z, n, ring A and ring B are as defined above.

[0352] Abbreviations Ts: p-Toluenesulfonyl THP: Tetrahydropyranyl Ex-vivo: In vitro

[0353] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods for which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are weight percentages and parts by weight. Known starting materials of the present invention can be synthesized using methods known in the art or purchased from commercially available products of multiple reagent companies. The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry.

[0354] Example I-1: Preparation of Compound I-1

[0355] Synthesis route of compound I-1:

[0356] Step 1: Preparation of intermediate Ia-1

[0357] 6-Methoxy-2-bromobenzothiazole (537 mg, 3 mmol) and 2-fluoro-5-pyridineboronic acid (423 mg, 3 mmol) were dissolved in 15 mL of a solvent (1,4-dioxane:H2O = 4:1). K2CO3 (1.24 g, 9 mmol) and Pd(dppf)Cl2 (219 mg, 0.3 mmol) were added, and the mixture was reacted at 80°C for 8 h under N2 protection. The reaction solution was then poured into 100 mL of saturated NH4Cl solution, extracted three times with ethyl acetate, washed three times with brine, dried over anhydrous sodium sulfate, and purified by column chromatography to afford Ia-1 as a light yellow solid in a 49% yield. ESI-MS (positive): 261.0 [M+1]. + .

[0358] Step 2: Preparation of Intermediate Ib-1

[0359] 1-tert-Butyloxycarbonylpiperazine (373 mg, 2 mmol), 4-bromo-2-(methylamino)pyridine (357 mg, 2 mmol), Cs2CO3 (1.96 g, 6 mmol), Pd2(dba)3 (36 mg, 0.04 mmol), and XantPhos (70 mg, 0.12 mmol) were placed in a round-bottom flask. 10 mL of THF was added, and the mixture was reacted at 80°C for 12 h under N2 protection. After the reaction, the THF was removed by vacuum distillation, and the product was dissolved in 20 mL of ethyl acetate, washed three times with brine, dried over anhydrous sodium sulfate, and purified by column chromatography. The purified product was dissolved in 20 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, followed by stirring at room temperature for 2 h. The solvent was removed by vacuum distillation to obtain intermediate Ib-1 as a yellow solid in a 57% yield. ESI-MS (positive): 193.1 [M+1]. + .

[0360] Step 3: Preparation of intermediate Ic-1

[0361] Intermediates Ia-1 (0.2 mmol) and Ib-1 (0.2 mmol) were dissolved in 1 mL of NMP, and DIPEA (200 μL, 1 mmol) was added. The mixture was microwaved at 180°C for 4 h under N₂ protection. After the reaction, 10 mL of water was added, followed by extraction with 20 mL of ethyl acetate. The mixture was washed three times with brine, dried over anhydrous sodium sulfate, and purified by column chromatography to afford Ic-1 as a pale yellow solid in 50% yield. ESI-MS (positive): 432.8 [M+1]. + .

[0362] Step 4: Preparation of intermediate Id-1

[0363] Intermediate Ic-1 (0.1 mmol) was dissolved in 0.3 mL of dichloromethane and the solution was cooled to -78°C. BBr3 (0.3 mL, 1 M in DCM) was then added dropwise and allowed to react at room temperature for 12 h. After the reaction, the reaction solution was poured into 5 mL of water and extracted with 20 mL of ethyl acetate. The mixture was washed three times with brine, dried over anhydrous sodium sulfate, and evaporated to dryness to afford Intermediate Id-1 as a yellow solid in 81% yield. ESI-MS (positive): 418.9 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ12.14–11.98(m,1H),9.82(s,1H),8.74(d,J=2.5Hz,1H) ,8.13(dd,J=9.0,2.5Hz,1H),7.78(d,J=8.8Hz,1H),7.66(t,J=6.3Hz,1H),7.56( d,J=5.2Hz,1H),7.38(d,J=2.4Hz,1H),7.01–6.92(m,2H),6.61(dd,J=7.6,2.5H z,1H),5.92(s,1H),3.88–3.79(m,4H),3.76–3.71(m,4H),2.86(d,J=4.8Hz,3H).

[0364] Step 5: Preparation of product I-1

[0365] Intermediate Id-1 (0.05 mmol) was dissolved in 0.5 mL of DMF, and KCO (20 mg, 0.15 mmol) and epifluoropropane (8 μL, 0.1 mmol) were added. The solution was reacted at 80°C for 4 h. After completion of the reaction, the reaction mixture was purified by column chromatography to obtain the final product I-1 as a pale yellow solid in a 61% yield. ESI-MS (positive): 495.0 [M+1]. + . 1H NMR (400MHz, DMSO-d6) δ12.07(s,1H),8.78(d,J=2.6Hz,1H),8.16(dd,J=9.0,2.6Hz,1H),7.8 7(d,J=8.9Hz,1H),7.75-7.63(m,2H),7.58(d,J=5.6Hz,1H),7.12(dd,J=8.9,2.6Hz,1H),6.99 (d,J=9.1Hz,1H),6.61(dd,J=7.7,2.5Hz,1H),5.92(s,1H),4.58(dd,J=9.5,4.3Hz,1H),4.52 –4.39(m,1H),4.13-4.01(m,3H),3.88-3.83(m,4H),3.76-3.72(m,4H),2.86(d,J=4.7Hz,3H).

[0366] Example I-2: Preparation of Compound I-2

[0367] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-2-(methylamino)pyridine. Compound I-2 was obtained as a yellow solid in a yield of 21%. ESI-MS (positive): 495.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.77(d,J=2.5Hz,1H),8.42(s,1H),8.14(dd,J=9.0,2.5 Hz,1H),8.01(dd,J=9.8,2.7Hz,1H),7.87(d,J=8.9Hz,1H),7.71(d,J=2.6Hz,1H ),7.26(d,J=2.7Hz,1H),7.15-6.99(m,3H),4.62–4.58(m,1H),4.50-4.41(m,1H ), 4.14-4.02 (m, 3H), 3.82 (t, J = 5.0Hz, 4H), 3.14 (t, J = 5.0Hz, 4H), 2.91 (s, 3H).

[0368] Example I-3: Preparation of Compound I-3

[0369] The synthesis method of Example I-1 was used, except that 2-fluoro-5-pyridineboronic acid was replaced with 3-fluoro-6-pyridineboronic acid and 4-bromo-2-(methylamino)pyridine was replaced with 2-bromopyridine. Compound I-3 was obtained as a pale yellow solid in a 5% yield. ESI-MS (positive): 466.1 [M+1] + .1 H NMR (400MHz, DMSO-d6) δ8.45 (d, J = 2.9 Hz, 1H), 8.15-8.05 (m, 2H), 7.89 (d, J = 8. 9Hz,1H),7.82-7.75(m,1H),7.70(d,J=2.6Hz,1H),7.53(dd,J=9.0,2.9Hz,1H) ,7.18-7.08(m,2H),6.82(t,J=6.3Hz,1H),4.58(dd,J=9.6,4.3Hz,1H),4.46(d d,J=9.9,4.8Hz,1H),4.14-4.01(m,3H),3.78-3.74(m,4H),3.59-3.55(m,4H).

[0370] Example I-4: Preparation of Compound I-4

[0371] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 4-bromo-2-(dimethylamino)pyridine. Compound I-4 was obtained as a yellow solid in an 11% yield. ESI-MS (positive): 509.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),8.78(d,J=2.5Hz,1H),8.16(dd,J=8.9,2.5Hz,1H ),7.87(d,J=8.9Hz,1H),7.75-7.66(m,2H),7.12(dd,J=8.9,2.5Hz,1H),7.00(d,J=9.0H z,1H),6.66(dd,J=7.6,2.3Hz,1H),5.96(d,J=2.3Hz,1H),4.58(dd,J=9.6,4.3Hz,1H),4 .51-4.41(m,1H),4.15-4.02(m,3H),3.87-3.82(m,4H),3.81-3.76(m,4H),3.13(s,6H).

[0372] Example I-5: Preparation of Compound I-5

[0373] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 2-bromopyrazine. Compound I-5 was obtained as a brown solid in a 15% yield. ESI-MS (positive): 467.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.77(d,J=2.6Hz,1H),8.38(s,1H),8.19-8.11(m,2H),7.92-7.84(m,2H),7.71(d,J=2.6Hz,1H),7.12(dd,J=8.9,2 .6Hz,1H),7.04(d,J=9.1Hz,1H),4.58(dd,J=9.5,4.2Hz,1H),4.51-4.38(m,1H),4.16-4.02(m,3H),3.83-3.79(m,4H),3.75-3.71(m,4H).

[0374] Example I-6: Preparation of Compound I-6

[0375] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-3-(methylamino)pyridine. Compound I-6 was obtained as a yellow solid in a 22% yield. ESI-MS (positive): 495.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.78 (d, J=2.5Hz, 1H), 8.16 (dd, J=8.9, 2.7Hz, 1H), 7.87 (d, J= 8.9Hz,1H),7.80-7.75(m,1H),7.71(d,J=2.6Hz,1H),7.61-7.43(m,1H),7.13(dd,J=8. 9,2.6Hz,1H),7.09-7.04(m,1H),6.98-6.90(m,1H),4.58(dd,J=9.5,4.3Hz,1H),4.50- 4.39(m,1H),4.13-4.02(m,3H),3.84(t,J=4.8Hz,4H),3.38-3.30(m,4H),2.80(s,3H).

[0376] Example I-7: Preparation of Compound I-7

[0377] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-pyrimidine. Compound I-7 was obtained as a brown solid in a 9% yield. ESI-MS (positive): 467.0 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ8.81-8.75(m,1H),8.66-8.53(m,3H),8.19-8.11(m,1H),7.92-7.83(m,1H),7.75-7.67(m,1H ),7.19-7.03(m,2H),4.66-4.53(m,1H),4.51-4.42(m,1H),4.09-4.03(m,3H),3.87-3.81(m,4H),3.48-3.40(m,4H).

[0378] Example I-8: Preparation of Compound I-8

[0379] The synthesis method of Example I-1 was used, except that 2-fluoro-5-pyridineboronic acid was replaced with 3-fluoro-6-pyridineboronic acid. Compound I-8 was obtained as a yellow solid in a 20% yield. ESI-MS (positive): 495.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.04(s,1H),8.42(d,J=2.9Hz,1H),8.11(d,J=8.8Hz,1H),7.88(d,J= 8.9Hz,1H),7.70–7.63(m,2H),7.55(d,J=5.4Hz,1H),7.49(dd,J=8.9,2.9Hz,1H),7.12(dd,J= 8.9,2.6Hz,1H),6.65(dd,J=7.5,2.5Hz,1H),5.98–5.90(m,1H),4.63–4.52(m,1H),4.50–4.40 (m,1H),4.14–4.02(m,3H),3.76(t,J=5.0Hz,4H),3.58(t,J=5.3Hz,4H),2.87(d,J=4.8Hz,3H).

[0380] Example I-9: Preparation of Compound I-9

[0381] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 4-bromo-2-fluoro-pyridine. Compound I-9 was obtained as a yellow solid in a 6% yield. ESI-MS (positive): 408.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.81(s,1H),8.73(d,J=2.5Hz,1H),8.11(dd,J=9.0,2.5Hz,1H),7.84(d,J=6.1Hz,1H),7.78(d,J=8.8Hz,1H),7.38 (d,J=2.4Hz,1H),7.01(d,J=9.0Hz,1H),6.95(dd,J=8.8,2.5Hz,1H),6.88–6.78(m,1H),6.52(s,1H),3.83–3.77(m,4H),3.59–3.54(m,4H).

[0382] Example I-10: Preparation of Compound I-10

[0383] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-2-fluoro-pyridine. Compound I-10 was obtained as a yellow solid in an 11% yield. ESI-MS (positive): 408.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.81(s,1H),8.73(d,J=2.5Hz,1H),8.11(dd,J=9.0,2.5Hz,1H),7.92–7.86(m,1H),7.78(d,J=8.7Hz,1H),7. 71–7.64(m,1H),7.38(d,J=2.5Hz,1H),7.10–7.03(m,2H),6.96(dd,J=8.8,2.5Hz,1H),3.81(t,J=5.2Hz,4H),3.28(t,J=5.1Hz,4H).

[0384] Example I-11: Preparation of Compound I-11

[0385] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 4-bromo-pyridine. Compound I-11 was obtained as a yellow solid in a yield of 21%. ESI-MS (positive): 466.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.78(d,J=2.4Hz,1H),8.33–8.27(m,2H),8.17(dd,J=9.0,2.5Hz,1H),7.87(d,J=8.9Hz,1H),7.71(d,J=2.5Hz,1H) ,7.32–7.18(m,2H),7.13(dd,J=8.9,2.5Hz,1H),7.04–6.96(m,1H),4.63–4.53(m,1H),4.52–4.41(m,1H),4.16–4.01(m,3H),3.89(s,8H).

[0386] Example I-12: Preparation of Compound I-12

[0387] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 2-bromo-pyridine. Compound I-12 was obtained as a yellow solid in a 13% yield. ESI-MS (positive): 466.0 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ8.80–8.73(m,1H),8.16(dd,J=9.0,2.6Hz,1H),8.10(d,1H),7.91–7.81(m,2H),7.71(d,J=2.6Hz,1H),7.21(d,J=8.9Hz,1H), 7.12(dd,J=8.9,2.6Hz,1H),7.03(d,J=9.1Hz,1H),6.86(t,J=6.3Hz,1H),4 .64–4.52(m,1H),4.51–4.40(m,1H),4.15–4.01(m,3H),3.93–3.73(m,8H).

[0388] Example I-13: Preparation of Compound I-13

[0389] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 2-bromo-5-hydroxy-pyridine. Compound I-13 was obtained as a yellow solid in a 23% yield. ESI-MS (positive): 405.9 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.01(s,1H),8.74(d,J=2.5Hz,1H),8.17–8.09(m,1H),7.78(d,J=8.8Hz,1H),7.66(d,J=2.8Hz,1H),7.45(d,J =9.4Hz,1H),7.40–7.36(m,1H),7.13(d,J=9.4Hz,1H),7.04(d,J=9.1Hz,1H),6.98–6.94(m,1H),3.85–3.78(m,4H),3.63–3.57(m,4H).

[0390] Example I-14: Preparation of Compound I-14

[0391] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 2-bromo-5-hydroxy-pyridine. Compound I-14 was obtained as a yellow solid in a 2% yield. ESI-MS (positive): 484.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.77(s,1H),8.18–8.09(m,1H),7.81(d,J=8.8Hz,1H),7.67(d,J=2.9Hz,1H),7.42(d, J=9.4Hz,1H),7.15(d,J=8.9Hz,1H),7.10(d,J=9.4Hz,1H),7.04(d,J=9.1Hz,1H),3.83(t,J=5.3Hz,4H),3.66–3.57(m,4H).

[0392] Example I-15: Preparation of Compound I-15

[0393] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-2-dimethylamino-pyridine. Compound I-15 was obtained as a dark yellow solid in 8% yield. ESI-MS (positive): 433.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.76(s,1H),8.67(d,J=2.5Hz,1H),8.05(dd,J=9.0,2.5Hz,1H),7.96(d,J=9.7Hz,1H),7.71(d,J=8.8Hz,1H) ,7.33–7.26(m,2H),7.14(d,J=9.9Hz,1H),7.00(d,J=9.1Hz,1H),6.89(dd,J=8.8,2.5Hz,1H),3.78–3.71(m,4H),3.15–3.05(m,10H).

[0394] Example I-16: Preparation of Compound I-16

[0395] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 2-fluoro-5-pyridineboronic acid was replaced with 3-fluoro-6-pyridineboronic acid and 4-bromo-2-(methylamino)pyridine was replaced with 2-bromo-pyridine. Compound I-16 was obtained as a dark yellow solid in a 14% yield. ESI-MS (positive): 389.9 [M+1]. + . 1 H NMR(400MHz, DMSO-d6)δ9.83(s,1H),8.43(d,J=2.8Hz,1H),8.14–8.05(m,2H),7.90–7.77(m,2H),7.52(dd,J=8.9,2.9Hz,1H),7.3 6(d,J=2.4Hz,1H),7.22(d,J=9.0Hz,1H),6.96(dd,J=8.8,2.5Hz,1H),6.85(t,J=6.4Hz,1H),3.82–3.75(m,4H),3.60–3.54(m,4H).

[0396] Example I-17: Preparation of Compound I-17

[0397] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 4-bromo-2-dimethylamino-pyridine. Compound I-17 was obtained as a dark yellow solid in an 11% yield. ESI-MS (positive): 433.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.91(s,1H),9.83(s,1H),8.74(d,J=2.5Hz,1H),8.13(dd,J=9.0,2.6Hz,1H),7.78(d,J=8.7Hz,1H),7.70–7.64(m, 1H),7.38(d,J=2.5Hz,1H),7.02–6.90(m,2H),6.66(dd,J=7.4,2.4Hz,1H),5.96(s,1H),3.87–3.80(m,4H),3.79–3.76(m,4H),3.13(s,6H).

[0398] Example I-18: Preparation of Compound I-18

[0399] The synthesis method of intermediate Ic-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 2-bromo-5-hydroxy-pyridine. Compound I-18 was obtained as a yellow solid in a 35% yield. ESI-MS (positive): 420.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.15(d,J=8.9Hz,1H),7.91–7.83(m,1H),7.72–7.64(m,2H),7.43(d,J= 9.3Hz, 1H), 7.11 (d, J = 9.2Hz, 2H), 7.05 (d, J = 9.2Hz, 1H), 3.85 (s, 3H), 3.84–3.80 (m, 4H), 3.61–3.56 (m, 4H).

[0400] Example I-19: Preparation of Compound I-19

[0401] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 3-bromo-pyridine. Compound I-19 was obtained as a yellow solid in a yield of 21%. ESI-MS (positive): 466.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.81–8.74(m,1H),8.48(s,1H),8.23–8.11(m,2H),8.01(d,J=8.7Hz,1H),7.91–7.83(m,1H),7. 82–7.73(m,1H),7.73–7.68(m,1H),7.21–7.01(m,2H),4.64–4.40(m,2H),4.13–4.01(m,3H),3.86(s,4H),3.56(s,4H).

[0402] Example I-20: Preparation of Compound I-20

[0403] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-thiazole. Compound I-20 was obtained as a yellow solid in a 17% yield. ESI-MS (positive): 396.2 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ9.80(s,1H),8.77–8.69(m,1H),8.45(s,1H),8.11(dd,J=9.0,2.5Hz,1H),7.78(d,J=8.8Hz,1H),7.38( d,J=2.5Hz,1H),7.19(s,1H),7.06(d,J=9.0Hz,1H),6.95(dd,J=8.8,2.5Hz,1H),3.81(t,J=5.0Hz,4H),3.21(t,J=5.0Hz,4H).

[0404] Example I-21: Preparation of Compound I-21

[0405] The synthesis method of intermediate Ic-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-thiazole. Compound I-21 was obtained as a yellow solid in a 35% yield. ESI-MS (positive): 410.1 [M+1] + . 1H NMR(400MHz,Chloroform-d)δ8.72(s,1H),8.28(s,1H),8.13(d,J=9.0Hz,1H),7.82(d,J=9.0Hz,1H),7. 18(s,1H),7.10(s,1H),7.03–6.95(m,1H),6.70(d,J=9.0Hz,1H),3.84–3.75(m,8H),3.23–3.12(m,3H).

[0406] Example I-22: Preparation of Compound I-22

[0407] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 3-pyridine and epifluoropropane was replaced with 1-bromo-2-fluoro-ethane. Compound I-22 was obtained as a yellow solid in a 25% yield. ESI-MS (positive): 436.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.46(s,1H),8.24–8.11(m,2H),7.97–7.82(m,2H),7.75–7.60(m ,2H),7.18–7.01(m,2H),4.92–4.56(m,2H),4.43–4.10(m,2H),3.88–3.82(m,4H),3.56–3.45(m,4H).

[0408] Example I-23: Preparation of Compound I-23

[0409] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 2-fluoro-5-pyridineboronic acid was replaced with 4-fluorophenylboronic acid and 4-bromo-2-(methylamino)pyridine was replaced with 2-pyridine. Compound I-23 was obtained as a yellow solid in a 19% yield. ESI-MS (positive): 388.9 [M+1] + . 1H NMR(400MHz, DMSO-d6)δ9.78(s,1H),8.11(dd,J=5.7,1.9Hz,1H),7.94–7.78(m,3H),7.76(d,J=8.8Hz,1H),7.36(d,J=2.4Hz,1H),7.20( d, J=8.8Hz, 1H), 7.10 (d, J=8.9Hz, 2H), 6.94 (dd, J=8.8, 2.4Hz, 1H), 6.84 (t, J=6.4Hz, 1H), 3.76 (t, J=5.0Hz, 4H), 3.50 (t, J=5.3Hz, 4H).

[0410] Example I-24: Preparation of Compound I-24

[0411] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 2-fluoro-5-pyridineboronic acid was replaced with 4-fluorophenylboronic acid and 4-bromo-2-(methylamino)pyridine was replaced with 2-pyridine. Compound I-24 was obtained as a yellow solid in a 2% yield. ESI-MS (positive): 466.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.10(dd,J=5.6,1.8Hz,1H),7.90(d,J=8.6Hz,2H),7.86–7.76(m,2H) ,7.25–7.17(m,1H),7.16–7.07(m,3H),6.85(t,J=6.4Hz,1H),3.77(t,J=5.0Hz,4H),3.53(t,J=5.2Hz,4H).

[0412] Example I-25: Preparation of Compound I-25

[0413] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 4-bromophenylboronic acid. Compound I-25 was obtained as a yellow solid in a 19% yield. ESI-MS (positive): 466.8 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.80(s,1H),8.73(d,J=2.5Hz,1H),8.11(dd,J=9.0,2.5Hz,1H),7.78(d,J=8.7Hz,1H ),7.47–7.30(m,3H),7.04(d,J=9.1Hz,1H),7.01–6.90(m,3H),3.79(t,J=5.3Hz,4H),3.28(t,J=5.1Hz,4H).

[0414] Example I-26: Preparation of Compound I-26

[0415] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 4-bromopyridine. Compound I-26 was obtained as a yellow solid in a 22% yield. ESI-MS (positive): 489.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ13.42(s,1H),9.82(s,1H),8.75(d,J=2.5Hz,1H),8.29(d,J=7.0Hz,2H),8.14(dd,J=9.0 ,2.5Hz,1H),7.78(d,J=8.8Hz,1H),7.38(d,J=2.4Hz,1H),7.22(d,J=7.1Hz,2H),7.08–6.89(m,2H),3.88(s,8H).

[0416] Example I-27: Preparation of Compound I-27

[0417] The synthesis method of intermediate Ic-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 2-bromopyridine. Compound I-27 was obtained as a yellow solid in a 40% yield. ESI-MS (positive): 403.9 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ8.80(s,1H),8.29–8.14(m,2H),7.89(d,J=8.9Hz,1H),7.54(t,J=8.0Hz,1H),7 .34(s,1H),7.07(d,J=8.7,2.2Hz,1H),6.79–6.63(m,3H),3.89(s,3H),3.87–3.81(m,4H),3.76–3.71(m,4H).

[0418] Example I-28: Preparation of Compound I-28

[0419] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 2-bromopyridine. Compound I-28 was obtained as a yellow solid in a 35% yield. ESI-MS (positive): 389.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=2.4Hz,1H),8.16(dd,J=9.1,2.4Hz,1H),8.07(d,J=6.1Hz,1H),8.02(t,J=8. 3Hz,1H),7.79(d,J=8.8Hz,1H),7.42–7.37(m,2H),7.06(d,J=9.1Hz,1H),7.00–6.92(m,2H),3.93–3.81(m,8H).

[0420] Example I-29: Preparation of Compound I-29

[0421] The synthesis method of intermediate Ic-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 3-bromopyridine. Compound I-29 was obtained as a yellow solid in a 41% yield. ESI-MS (positive): 403.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=2.4Hz,1H),8.49(d,J=2.8Hz,1H),8.22–8.12(m,2H),7.99(dd,J=8.9,2.8Hz,1H),7.8 8(d,J=8.9Hz,1H),7.76(dd,J=8.9,5.1Hz,1H),7.69(d,J=2.5Hz,1H),7.19–6.90(m,2H),3.90–3.81(m,7H),3.54(t,4H).

[0422] Example I-30: Preparation of Compound I-30

[0423] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 3-bromopyridine. Compound I-30 was obtained as a yellow solid in a 40% yield. ESI-MS (positive): 389.9 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.84(s,1H),8.75(d,J=2.5Hz,1H),8.49(d,J=2.8Hz,1H),8.21(d,J=5.2Hz,1H),8.13(dd,J=9.0,2.5Hz,1H),8.04(dd,J=9 .2,2.7Hz,1H),7.83–7.75(m,2H),7.38(d,J=2.4Hz,1H),7.07(d,J=9.1H z,1H),6.96(dd,J=8.8,2.4Hz,1H),3.93–3.75(m,4H),3.64–3.53(m,4H).

[0424] Example I-31: Preparation of Compound I-31

[0425] The synthesis method for intermediate Ic-1 in Example I-1 was used, except that 6-methoxy-2-methylbenzothiazole was replaced with 6-dimethylamino-2-methylbenzothiazole and 4-bromo-2-(methylamino)pyridine was replaced with 2-bromopyridine. Compound I-31 was obtained as a yellow solid in a 37% yield. ESI-MS (positive): 417.0 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=2.5Hz,1H),8.15–8.04(m,2H),7.86(t,J=8.1Hz,1H),7.78(d,J=9.0Hz,1H),7.33(d,J=2. 6Hz, 1H), 7.22 (d, J = 9.0Hz, 1H), 7.05–6.95 (m, 2H), 6.86 (t, J = 6.5Hz, 1H), 3.87–3.81 (m, 4H), 3.79–3.74 (m, 4H), 2.99 (s, 6H).

[0426] Example I-32: Preparation of Compound I-32

[0427] The preparation route of compound I-32 is as follows:

[0428] Preparation of intermediate Ic-32:

[0429] Intermediate Ic-32 was prepared using the same method as for Intermediate Ic-1 in Example I-1, except that 6-methoxy-2-bromobenzothiazole was replaced with 6-amino-2-bromobenzothiazole, and 4-bromo-2-(methylamino)pyridine was replaced with 3-bromopyridine. Compound Ic-32 was obtained as a yellow solid in a 31% yield. ESI-MS (positive): 389.1 [M+1]. + .

[0430] Preparation of compound I-32:

[0431] Intermediate Ic-32 (73 mg, 0.2 mmol) was dissolved in 2 mL of NMP, and Cs2CO3 (195 mg, 0.6 mmol) and 1-bromo-2-fluoroethane (35 μL, 0.4 mmol) were added. The mixture was reacted at 100°C for 12 h. After completion of the reaction, the reaction solution was poured into 5 mL of water, extracted with 20 mL of ethyl acetate, washed three times with brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound I-32 as a yellow solid in a yield of 1.8%. ESI-MS (positive): 435.0 [M+1]. + . 1 H NMR(400MHz,DMSO-d6)δ8.88–8.67(m,1H),8.21–8.05(m,2H),7.87–7.60(m,2H ),7.29–6.74(m,6H),4.81–4.46(m,2H),4.01–3.66(m,8H),3.60–3.31(m,2H).

[0432] Example I-33: Preparation of Compound I-33

[0433] Using the synthesis method of Example I-32, except that 1-bromo-2-fluoroethane was replaced with epifluoropropane, compound I-33 was obtained as a yellow solid in a 5% yield. ESI-MS (positive): 465.1 [M+1] + . 1H NMR(400MHz, DMSO-d6)δ8.71(s,1H),8.10(d,J=6.8Hz,2H),7.86(t,J=8.1Hz,1H),7 .68(d,J=8.8Hz,1H),7.22(d,J=9.2Hz,1H),7.14(s,1H),7.01(d,J=8.9Hz,1H),6.91 –6.80(m,2H),4.55–4.44(m,1H),4.43–4.30(m,1H),3.97–3.92(m,1H),3.86–3.83(m ,4H),3.79–3.75(m,4H),3.21(dd,J=13.3,5.8Hz,1H),3.09(dd,J=13.2,6.3Hz,1H).

[0434] Example I-34: Preparation of Compound I-34

[0435] The synthesis method for intermediate Ic-1 in Example I-1 was used, except that 6-methoxy-2-bromobenzothiazole was replaced with 6-dimethylamino-2-bromobenzothiazole, and 4-bromo-2-(methylamino)pyridine was replaced with 2-bromo-5-methoxypyridine. Compound I-34 was obtained as a yellow solid in a 9% yield. ESI-MS (positive): 447.1 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),8.14–8.07(m,1H),7.87(s,1H),7.78(d,J=8.9Hz,1H),7.44–7.38( m,1H),7.33(s,1H),7.04–6.96(m,3H),3.76(s,3H),3.59–3.53(m,4H),3.08–3.01(m,4H),2.99(s,6H).

[0436] Example I-35: Preparation of Compound I-35

[0437] The synthesis method of Example I-1 was used, except that epifluoropropane was replaced with 1-bromo-2-fluoro-ethane. Compound I-35 was obtained as a yellow solid in a 12% yield. ESI-MS (positive): 465.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.78(d,J=2.5Hz,1H),8.15(dd,J=8.9,2.5Hz,1H),7.88(d,J=8 .9Hz,1H),7.75–7.65(m,2H),7.27–7.10(m,2H),7.00(d,J=9.1Hz,1H),6.50(dd,J=7.1, 2.4Hz,1H),5.90(d,J=2.4Hz,1H),4.87–4.82(m,1H),4.75–4.71(m,1H),4.37(t,J=3.8 Hz,1H),4.31–4.27(m,1H),3.87–3.77(m,4H),3.70–3.60(m,4H),2.83(d,J=4.8Hz,3H).

[0438] Example I-36: Preparation of Compound I-36

[0439] The synthesis method of intermediate Ic-1 in Example I-1 was used, except that 6-methoxy-2-bromobenzothiazole was replaced with 6-fluoro-2-methylbenzothiazole. Compound I-36 was obtained as a yellow solid in a 20% yield. ESI-MS (positive): 421.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),8.82(d,J=2.5Hz,1H),8.19(dd,J=9.0,2.6Hz,1H),8.10–7.92(m,2H),7.72–7.64(m,1H),7.58(d,J=5.3Hz,1 H),7.44–7.32(m,1H),7.00(d,J=9.0Hz,1H),6.61(dd,J=7.5,2.5Hz,1H), 5.92(s,1H),3.89–3.84(m,4H),3.77–3.71(m,4H),2.86(d,J=4.8Hz,3H).

[0440] Example I-37: Preparation of Compound I-37

[0441] The synthesis method of intermediate Ic-1 in Example I-1 was used, except that 6-methoxy-2-bromobenzothiazole was replaced with 6-dimethylamino-2-bromobenzothiazole and 4-bromo-2-(methylamino)pyridine was replaced with 4-bromo-2-fluoropyridine. Compound I-37 was obtained as a yellow solid in a 34% yield. ESI-MS (positive): 435.2 [M+1]. + . 1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.12(d,J=8.9Hz,1H),7.91–7.74(m,2H),7.36(s,1H),7.07 –6.95(m,2H),6.95–6.79(m,1H),6.53(s,1H),3.82–3.78(m,4H),3.31–3.29(m,4H),3.00(s,6H).

[0442] Example I-38: Preparation of Compound I-38

[0443] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromopyrimidine. Compound I-38 was obtained as a yellow solid in a 16% yield. ESI-MS (positive): 467.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.59(s,2H),8.48(d,J=2.9Hz,1H),8.10(d,J=8.8Hz,1H),7.89(d,J=8.9Hz,1H),7.70(d,J=2.6Hz,1H),7.57( dd,J=8.9,2.9Hz,1H),7.12(dd,J=8.9,2.6Hz,1H),4.63–4.52(m,1H),4. 51–4.41(m,1H),4.13–4.01(m,3H),3.62–3.53(m,4H),3.49–3.44(m,4H).

[0444] Example I-39: Preparation of Compound I-39

[0445] The synthesis method of Example I-1 was used except that 4-bromo-2-(methylamino)pyridine was replaced by 4-bromo- 2 ,N 6 -dimethylpyridine-2,6-diamine. Compound I-39 was obtained as a yellow solid with a yield of 10%. ESI-MS (positive): 524.3 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.77(d,J=2.5Hz,1H),8.16(dd,J=9.0, 2.6Hz,1H),7.87(d,J=8.9Hz,1H),7.71(d,J=2.5Hz,1H),7.12(dd,J=8.9,2.6H z,1H),7.03–6.86(m,3H),5.34(s,2H),4.64–4.52(m,1H),4.51–4.41(m,1H),4 .15–3.98(m,3H),3.86–3.79(m,4H),3.71–3.67(m,4H),2.80(d,J=4.5Hz,6H).

[0446] Example I-40: Preparation of Compound I-40

[0447] The synthesis method of Example I-32 was used, except that 1-bromo-2-fluoroethane was replaced with epifluoropropane and 4-bromo-2-(methylamino)pyridine was replaced with 2-bromopyridine. Compound I-40 was obtained as a yellow solid in a 7% yield. ESI-MS (positive): 494.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ12.17–11.96(m,1H),8.79–8.66(m,1H),8.14–8.07(m ,1H),7.72–7.62(m,2H),7.61–7.54(m,1H),7.15–7.10(m,1H),7.02–6.94(m, 1H),6.86(dd,J=8.9,2.3Hz,1H),6.62(dd,J=7.7,2.4Hz,1H),5.92(s,1H),4. 56–4.43(m,1H),4.43–4.31(m,1H),3.97–3.79(m,3H),2.86(d,J=4.7Hz,3H).

[0448] Example I-41: Preparation of Compound I-41

[0449] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-2-(pyrrolidin-1-yl)pyridine. Compound I-41 was obtained as a yellow solid in a 35% yield. ESI-MS (positive): 535.2 [M+1]. + . 1H NMR(400MHz, DMSO-d6)δ8.76(d,J=2.4Hz,1H),8.41(s,1H),8.13(dd,J=8.9,2.3H z,1H),8.00(dd,J=9.7,2.5Hz,1H),7.88(d,J=8.9Hz,1H),7.73(d,J=2.5Hz,1H), 7.25(d,J=2.6Hz,1H),7.14-6.97(m,3H),4.62–4.53(m,1H),4.50-4.40(m,1H),4 .13-4.00(m,3H),3.81(t,J=4.9Hz,4H),3.12(t,J=4.9Hz,4H),2.07–1.99(m,1H).

[0450] Example I-42: Preparation of Compound I-42

[0451] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-6-fluoro-2-(methylamino)pyridine. Compound I-42 was obtained as a yellow solid in a 24% yield. ESI-MS (positive): 513.2 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=2.5Hz,1H),8.43(s,1H),8.12(dd,J=9.0,2.5Hz,1H),8.00(d,J=9.8Hz,1H),7.86(d,J=8.9Hz,1H),7.73(d,J=2 .6Hz,1H),7.12-6.97(m,3H),4.61–4.52(m,1H),4.50-4.40(m,1H),4.15 -4.00(m,3H),3.81(t,J=4.9Hz,4H),3.12(t,J=4.9Hz,4H),2.94(s,3H).

[0452] Example I-43: Preparation of Compound I-43

[0453] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-2-(methylamino)pyridine and 2-fluoro-5-pyridineboronic acid was replaced with (2,6-difluoropyridin-3-yl)boronic acid. Compound I-43 was obtained as a yellow solid in a 27% yield. ESI-MS (positive): 437.1 [M+1]. + . 1H NMR (400MHz, DMSO-d6) δ9.83 (s, 1H), 8.41 (s, 1H), 8.14 (d, J = 9.0Hz, 1H), 8. 01(dd,J=9.8,2.7Hz,1H),7.85(d,J=8.9Hz,1H),7.70(d,J=2.6Hz,1H),7.25 (d,J=2.7Hz,1H),7.17-7.03(m,3H),4.61–4.52(m,1H),4.51-4.45(m,1H),4 .13-4.01(m,3H),3.81(t,J=5.1Hz,4H),3.23(t,J=5.1Hz,4H),2.97(s,3H).

[0454] Example I-44: Preparation of Compound I-44

[0455] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 6-methoxy-2-bromobenzothiazole was replaced with 6-methoxy-2-bromobenzoxazole, and 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-2-(methylamino)pyridine. Compound I-44 was obtained as a yellow solid in a 22% yield. ESI-MS (positive): 403.2 [M+1]. + . 1 H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.41(s,1H),8.13-8.00(m,2H),7.87-7.80(m,1H),7.72(d,J=2.6Hz ,1H),7.23(d,J=2.6Hz,1H),7.15-7.05(m,3H),3.82(t,J=5.1Hz,4H),3.21(t,J=5.1Hz,4H),2.93(s,3H).

[0456] Example I-45: Preparation of Compound I-45

[0457] The synthesis method of intermediate Id-1 in Example I-1 was used, except that 6-methoxy-2-bromobenzothiazole was replaced with 2-bromo-6-methoxythienyl[2,3-b]pyridine, and 4-bromo-2-(methylamino)pyridine was replaced with 5-bromo-2-(methylamino)pyridine. Compound I-45 was obtained as a yellow solid in a 13% yield. ESI-MS (positive): 419.2 [M+1]. + . 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.45(s,1H),7.78-7.66(m,3H),7.17-7.07(m ,2H),6.82-6.54(m,4H),3.81(t,J=5.0Hz,4H),3.25(t,J=5.0Hz,4H),2.90(s,3H).

[0458] Example I-46: Preparation of Compound I-46

[0459] Synthesis route of compound I-46:

[0460] Step 1: Preparation of intermediate Ie-1

[0461] Glycerol (1 g, 11 mmol) and 4-dimethylaminopyridine (DMAP) (335 mg, 2.75 mmol) were dissolved in pyridine (10 mL). p-Toluenesulfonyl chloride (TsCl) (4.4 g, 23 mmol) dissolved in pyridine (15 mL) was added dropwise at 0°C and allowed to react overnight at room temperature. After completion, the reaction solution was diluted with 100 mL of water and the pH was adjusted to acidic by dropwise addition of concentrated hydrochloric acid. The solution was extracted with DCM (100 mL x 5). The organic phase was washed with 1N HCl (100 mL) and then with water (100 mL). Finally, the product was purified by flash silica gel column chromatography (PE / EA) to obtain the product Ie-1 (2.8 g, 7 mmol) as a colorless oil in a 64% yield. MS-ESI: m / z 401 [M+H] + .

[0462] Step 2: Preparation of intermediate If-1

[0463] Ie-1 (1.2 g, 3 mmol) and 3,4-dihydropyran (DHP) (5.5 mL, 60 mmol) were dissolved in DCM (10 mL). Pyridinium p-toluenesulfonate (PPTS) (150 mg, 0.6 mmol) was added and allowed to react overnight at 40°C. After completion of the reaction, the reaction solution was concentrated and purified by flash silica gel column chromatography (PE / EA) to obtain the product If-1 (1.3 g, 2.7 mmol) as a light yellow oil in an 89% yield. MS-ESI: m / z 485 [M+H] + .

[0464] Step 3: Preparation of Product I-46

[0465] Id-2 (0.06 mmol), If-1 (0.29 mmol), and potassium carbonate (16 mg, 0.12 mmol) were added to DMF (0.5 mL) and reacted at 80°C for 2 h. After the reaction was complete, the product was purified by flash silica gel column chromatography (PE / EA) to obtain the product I-46 (3.8 mg, 0.006 mmol) as a yellow solid in a 69% yield. MS-ESI: m / z 731.2 [M+H] + .

[0466] Example I-47: Preparation of Compound I-47

[0467] Method 1:

[0468] 150mCi 18 F was enriched on a QMA column and washed with 0.6 mL of eluent (150 mg Kryptofix 222, 15 mg K2CO3 dissolved in 9 mL acetonitrile and 1 mL water). 18 F was eluted into a reaction flask; the solvent was dried by heating at 110°C for 20 min under high-purity nitrogen; 0.2 mg of oxirane-2-ylmethyl 4-methylbenzenesulfonate and 0.2 mL of acetonitrile were added to the reaction flask, and the mixture was reacted at 90°C for 10 min; the acetonitrile was evaporated to dryness, and 0.2 mL of DMF solvent and 0.5 mg of Id-2 were added, and the mixture was reacted at 130°C for 10 min; the mixture was separated and purified by HPLC (HPLC conditions: CAPCELL PAK C18 UG80 10 mm×250 mm, acetonitrile:water = 26:74, flow rate: 3 mL / min), the product was collected and subjected to solid-phase extraction on a C18 column, and the final product I-47 was obtained by elution with ethanol, with a labeling efficiency of 8%.

[0469] Method 2:

[0470] 150mCi 18 F was enriched on a QMA column and washed with 0.6 mL of eluent (150 mg Kryptofix 222, 15 mg K2CO3 dissolved in 9 mL acetonitrile and 1 mL water). 18 F was eluted into the reaction flask; the solvent was dried by heating at 110°C for 20 min under high-purity nitrogen; 0.5 mg of I-46 was added to the reaction flask and the reaction was carried out at 140°C for 10 min; then 0.2 mL of 2N hydrochloric acid 105 ℃The THP protecting group was removed after 8 min of reaction. The reaction solution was separated and purified by HPLC (HPLC conditions: CAPCELL PAK C18 UG80 10 mm × 250 mm, acetonitrile:water = 26:74, flow rate: 3 mL / min). The product was collected and subjected to solid-phase extraction using a C18 column. The final product I-47 was obtained by elution with ethanol. The labeling efficiency was 10%.

[0471] Example I-48: Preparation of Compound I-48

[0472] The synthetic method of Example I-47 was adopted, except that the intermediate was replaced by the corresponding starting material.

[0473] Example I-49: Preparation of Compound I-49

[0474] Synthesis route of compound I-49:

[0475] Step 1: Synthesis of the precursor I-49pre

[0476] Id-1 (0.06 mmol), diethylene glycol xylenesulfonic acid (0.29 mmol), and potassium carbonate (16 mg, 0.12 mmol) were added to DMF (0.5 mL) and reacted at 80°C for 2 h. After the reaction was complete, it was purified by flash silica gel column chromatography (PE / EA) to obtain the product I-49pre (3.8 mg, 0.006 mmol) as a yellow solid in 83% yield. MS-ESI: m / z 617.2 [M+H] + .

[0477] Step 2: Radiolabeling of I-49

[0478] 150mCi 18 F was enriched on a QMA column and washed with 0.6 mL of eluent (150 mg Kryptofix 222, 15 mg K2CO3 dissolved in 9 mL acetonitrile and 1 mL water). 18 F was eluted into a reaction flask; the solvent was dried by heating at 110°C for 20 min under high-purity nitrogen; 0.5 mg of I-49pre was added to the reaction flask, and the reaction was carried out at 140°C for 10 min; the reaction solution was separated and purified by HPLC (HPLC conditions: CAPCELL PAK C18 UG80 10 mm×250 mm, acetonitrile:water=29:71, flow rate: 3 mL / min), the product was collected and solid-phase extracted with a C18 column, and the final product I-49 was obtained by elution with ethanol, with a labeling efficiency of 18%.

[0479] Example I-50: Preparation of Compound I-50

[0480] Synthesis route of compound I-50:

[0481] Step 1: Synthesis of precursor I-50pre

[0482] The synthesis method is the same as that of Example I-43, except that 2-fluoro-5-boronic acid pyridine is replaced with 2-fluoro-5-boronic acid-6-fluoro-pyridine. MS-ESI: m / z 464.1 [M+H] + .

[0483] Step 2: Radiolabeling of I-50

[0484] 150mCi 18 F was enriched on a QMA column and washed with 0.6 mL of eluent (150 mg Kryptofix 222, 15 mg K2CO3 dissolved in 9 mL acetonitrile and 1 mL water). 18 F was eluted into the reaction flask; the solvent was dried by heating at 110°C for 20 min under high-purity nitrogen; 0.7 mg I-50pre, 140 ℃ The reaction was allowed to proceed for 10 min. The reaction solution was separated and purified by HPLC (HPLC conditions: CAPCELL PAK C18 UG80 10 mm × 250 mm, acetonitrile:water = 20:80, flow rate: 3 mL / min). The product was collected and subjected to solid-phase extraction using a C18 column. The final product I-50 was obtained by elution with ethanol. The labeling efficiency was 5%.

[0485] Example I-51: Preparation of Compound I-51

[0486] The synthesis method of Example I-1 was used, except that 4-bromo-2-(methylamino)pyridine was replaced with 4-bromopyridin-2-amine. Compound I-51 was obtained as a yellow solid in a 12% yield. ESI-MS (positive): 481.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.08(s,1H),8.77(s,1H),8.16(d,J=9.0Hz,1H),7.87(d,J=8.9Hz,1H),7.77–7.62(m,2H),7.42–6.91(m,4H) ,6.77–6.57(m,1H),6.17–5.94(m,1H),4.66–4.51(m,1H),4.51–4.37(m,1H),4.15–4.01(m,3H),3.87–3.83(m,4H),3.69–3.66(m,4H).

[0487] Example II-1: Preparation of Compound II-1

[0488] Synthesis route of compound II-1:

[0489] Step 1: Preparation of intermediate IIa-1

[0490] (6-Formylpyridin-3-yl)boronic acid (48 mg, 0.32 mmol), 5-bromo-2-(methylamino)pyridine (60 mg, 0.32 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (Pd(dppf)Cl2) (23 mg, 0.032 mmol), and potassium carbonate (138 mg, 0.96 mmol) were dissolved in 1,4-dioxane (2.4 mL) and water (0.6 mL). The mixture was reacted at 80°C overnight under nitrogen. After completion of the reaction, the product IIa-1 was purified by flash silica gel column chromatography using petroleum ether (PE) / ethyl acetate (EA) to obtain the product IIa-1 (42 mg, 0.2 mmol) as a yellow solid in a 61% yield. MS-ESI: m / z 214 [M+H] + .

[0491] Step 2: Preparation of Intermediate IIb-1

[0492] IIa-1 (42 mg, 0.2 mmol) and 6-methoxy-2-methylbenzothiazole (36 mg, 0.2 mmol) were dissolved in dimethyl sulfoxide (DMSO) (2 mL). Aqueous sodium hydroxide solution (1 g / mL) (32 μL, 0.8 mmol) was added and the mixture was allowed to react at 50°C for 2 h. After completion of the reaction, the product was purified by flash silica gel column chromatography (PE / EA) and flash C18 column chromatography (acetonitrile / water) to obtain the product IIb-1 (4 mg, 0.01 mmol) as an orange solid in a 5% yield. MS-ESI: m / z 375 [M+H] + .

[0493] Step 3: Preparation of intermediate IIc-1

[0494] IIb-1 (4 mg, 0.01 mmol) was dissolved in dichloromethane (DCM) (0.03 mL) under nitrogen protection. A 1 M solution of boron tribromide in dichloromethane (0.03 mL, 0.03 mmol) was added dropwise at -78°C. After stirring for 2 h, the mixture was returned to room temperature and allowed to react overnight. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate (50 mL) and extracted with EA (50 mL). The EA phase was washed with water (50 mL × 2) and then with saturated aqueous sodium chloride (50 mL). The product was dried over anhydrous sodium sulfate to obtain the product IIc-1 (3.6 mg, 0.01 mmol) as an orange solid in a 93% yield. MS-ESI: m / z 361 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.86 (s, 1H), 8.57 (d, J = 2.4Hz, 1H), 8.37 (d, J = 4.8, 1.9Hz, 1H), 8.09 (dd, J = 9.0, 2.4Hz, 1H), 7.82-7.72 (m, 2H),7.47(s,2H),7.41-7.34(m,2H),7.25(d,J=8.8Hz,1H),7.08(dd,J=7.2,4.9Hz,1H),6.96(dd,J=8.8,2.5Hz,1H),3.57(s,3H).

[0495] Step 4: Preparation of product II-1

[0496] IIc-1 (3.6 mg, 0.01 mmol) and potassium carbonate (4 mg, 0.03 mmol) were added to N,N-dimethylformamide (DMF) (0.1 mL), and epifluorohydrin (1.5 μL, 0.02 mmol) was added dropwise. The mixture was reacted at 80°C for 4 h. After the reaction was complete, the product was purified by high-performance liquid chromatography (HPLC) (acetonitrile / water) to obtain the product II-1 (0.9 mg, 0.002 mmol) as an orange solid in a yield of 21%. MS-ESI: m / z 437 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.98(d,J=2.4Hz,1H),8.42(s,1H),8.23-8.12(m,2 H),7.92(s,1H),7.89(d,J=8.5Hz,1H),7.84(d,J=8.2Hz,1H),7.74(d,J=2. 5Hz,1H),7.65(d,J=15.8Hz,1H),7.16(dd,J=8.9,2.6Hz,1H),7.00-6.86(m ,1H),4.63–4.52(m,1H),4.52-4.41(m,1H),4.17–4.02(m,3H),2.94(s,3H).

[0497] Isomer separation and characterization of compound II-1

[0498] Compound II-1 (100 mg, 0.23 mmol) was dissolved in MeOH:DCM = 1:1 (80 mL) and separated and purified by chiral SFC (chromatographic column: ChiralPak IH, 250×40 mm ID, 10 μm, mobile phase: A: CO2, B: MeOH (0.1% NH3.H2O), flow rate: 140 mL / min) to obtain yellow solid II-1A (shorter retention time, 40 mg, MS-ESI: m / z 437.1 [M+H]+) and yellow solid II-1B (longer retention time, 40 mg, MS-ESI: m / z 437.0 [M+H]+).

[0499] Single configuration compound I-1A (shorter retention time):

[0500] SFC analysis: retention time: 4.578 min, ee value>99.9% (chromatographic column: Chiral Pak IH, 100×3 mm ID, 3 μm, mobile phase: A: CO2, B: MeOH (0.1% DEA), flow rate: 2.0 mL / min).

[0501] 1HNMR(400MHz,DMSO-d6)δ8.93(d,J=2.3Hz,1H),8.48(d,J=2.5Hz,1H),8.06(dd,J=8.2 ,2.4Hz,1H),7.90(d,J=8.9Hz,1H),7.89–7.80(m,2H),7.76(d,J=8.2Hz,1H),7.73(d, J=2.6Hz,1H),7.61(d,J=15.9Hz,1H),6.57(d,J=8.8Hz,1H),5.53(d,J=5.1Hz,1H),4. 58(qd,J=9.6,4.2Hz,1H),4.52–4.40(m,1H),4.18–3.96(m,3H),2.83(d,J=4.8Hz,3H).

[0502] Single configuration compound I-1B (longer retention time):

[0503] SFC analysis: retention time: 5.744 min, ee value: 99.59% (chromatographic column: Chiral Pak IH, 100×3 mm ID, 3 μm, mobile phase: A: CO2, B: MeOH (0.1% DEA), flow rate: 2.0 mL / min).

[0504] 1 HNMR(400MHz,DMSO-d6)δ8.93(d,J=2.3Hz,1H),8.48(d,J=2.5Hz,1H),8.06(dd,J=8.2 ,2.4Hz,1H),7.90(d,J=8.9Hz,1H),7.89–7.80(m,2H),7.76(d,J=8.2Hz,1H),7.73(d, J=2.6Hz,1H),7.61(d,J=15.9Hz,1H),6.57(d,J=8.8Hz,1H),5.53(d,J=5.1Hz,1H),4. 58(qd,J=9.6,4.2Hz,1H),4.52–4.40(m,1H),4.18–3.96(m,3H),2.83(d,J=4.8Hz,3H).

[0505] Example II-2: Preparation of Compound II-2

[0506] Example II-2 is intermediate IIc-1, and its synthesis is detailed in Example II-1.

[0507] Example II-3: Preparation of Compound II-3

[0508] The synthesis method of Example 3 is the same as that of Intermediate IIc-1, except that (6-formylpyridin-3-yl)boronic acid is replaced with 4-boronic acid benzaldehyde, and 5-bromo-2-(methylamino)pyridine is replaced with 3-bromopyridine. The resulting product II-3 is a yellow solid with a yield of 26%. LC-MS (ESI) [M+H] + :331.0. 1 H NMR (400MHz, DMSO-d6) δ9.91(s,1H),9.09(d,J=2.4Hz,1H),8.73-8.66(m,1H),8.41(d,J=8.0Hz,1H),7.98-7.83(m,4H),7.79(d,J=8.8 Hz,1H),7.72(dd,J=8.0,5.0Hz,1H),7.65(d,J=16.2Hz,1H),7.57(d,J=16.3Hz,1H),7.38(d,J=2.5Hz,1H),6.98(dd,J=8.8,2.5Hz,1H).

[0509] Example II-4: Preparation of Compound II-4

[0510] Example II-4 was synthesized in the same manner as Intermediate IIc-1, except that (6-formylpyridin-3-yl)boronic acid was replaced with 4-boronic acid benzaldehyde. The resulting product II-4 was a yellow solid with a yield of 31%. LC-MS (ESI) [M+H] + :360.1. 1 H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.56–8.11(m,3H),7.84(s,2H),7.80–7.69(m,3H) ),7.57(dd,J=16.1,4.2Hz,2H),7.37(s,1H),7.08–6.88(m,2H),2.96(d,J=4.1Hz,3H).

[0511] Example II-5: Preparation of Compound II-5

[0512] Example II-5 was synthesized in the same manner as Example II-1, except that (6-formylpyridin-3-yl)boric acid was replaced with 4-boronic acid benzaldehyde, and 5-bromo-2-(methylamino)pyridine was replaced with 4-bromo-2-(methylamino)pyridine. The resulting product II-5 was a yellow solid with a yield of 12%. LC-MS (ESI) [M+H] + :436.0. 1H NMR (400MHz, DMSO-d6) δ8.03(d,J=6.6Hz,1H),7.97(d,J=8.2Hz,2H),7.94–7.86(m,3H),7.77–7.71(m,2H),7.65(d,J=16.2Hz, 1H),7.26(d,J=8.3Hz,2H),7.15(dd,J=8.9,2.6Hz,1H),4.64–4.53(m,1H),4.51–4.39(m,1H),4.16–4.02(m,3H),3.00(s,3H).

[0513] Example II-6: Preparation of Compound II-6

[0514] Example II-6 was synthesized in the same manner as Example II-1, except that (6-formylpyridin-3-yl)boric acid was replaced with 3-boronic acid benzaldehyde, and 5-bromo-2-(methylamino)pyridine was replaced with 4-bromo-2-(methylamino)pyridine. The resulting product II-6 was a yellow solid with a yield of 12%. LC-MS (ESI) [M+H] + :436.0. 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),8.07(d,J=6.8Hz,1H),7.96(d,J=7.3Hz,1 H),7.88(d,J=8.9Hz,1H),7.85–7.78(m,2H),7.77–7.69(m,2H),7.67–7.62(m,1 H),7.55–7.46(m,1H),7.34–7.29(m,1H),7.15(dd,J=8.9,2.5Hz,1H),7.10–7.0 0(m,1H),4.62–4.50(m,1H),4.48–4.37(m,1H),4.14–3.92(m,3H),3.02(s,3H).

[0515] Example II-7: Preparation of Compound II-7

[0516] Synthesis route of compound II-7:

[0517] Step 1: Preparation of Intermediate IId-1

[0518] Glycerol (1 g, 11 mmol) and 4-dimethylaminopyridine (DMAP) (335 mg, 2.75 mmol) were dissolved in pyridine (10 mL). p-Toluenesulfonyl chloride (TsCl) (4.4 g, 23 mmol) dissolved in pyridine (15 mL) was added dropwise at 0°C and allowed to react overnight at room temperature. After completion, the reaction solution was diluted with 100 mL of water and the pH was adjusted to acidic by dropwise addition of concentrated hydrochloric acid. The solution was extracted with DCM (100 mL x 5). The organic phase was washed with 1N HCl (100 mL) and then with water (100 mL). Finally, the product was purified by flash silica gel column chromatography (PE / EA) to obtain product IId-1 (2.8 g, 7 mmol) as a colorless oil in a 64% yield. MS-ESI: m / z 401 [M+H] + .

[0519] Step 2: Preparation of intermediate IIe-1

[0520] IId-1 (1.2 g, 3 mmol) and 3,4-dihydropyran (DHP) (5.5 mL, 60 mmol) were dissolved in DCM (10 mL). Pyridinium p-toluenesulfonate (PPTS) (150 mg, 0.6 mmol) was added and allowed to react at 40°C overnight. After the reaction was complete, the reaction solution was concentrated and purified by flash silica gel column chromatography (PE / EA) to obtain the product IIe-1 (1.3 g, 2.7 mmol) as a light yellow oil in 89% yield. MS-ESI: m / z 485 [M+H] + .

[0521] Step 3: Preparation of product II-7

[0522] IIc-1 (21 mg, 0.06 mmol), IIe-1 (140 mg, 0.29 mmol), and potassium carbonate (16 mg, 0.12 mmol) were added to DMF (0.5 mL) and reacted at 80°C for 2 h. After the reaction was complete, it was purified by flash silica gel column chromatography (PE / EA) to obtain the product II-7 (3.8 mg, 0.006 mmol) as a yellow solid in a 10% yield. MS-ESI: m / z 673 [M+H] + Example II-8: Preparation of Compound II-8

[0523] Method 1:

[0524] 150mCi 18 F was enriched on a QMA column and washed with 0.6 mL of eluent (150 mg 222, 15mg K2CO3 dissolved in 9mL acetonitrile and 1mL water)18 F was eluted into a reaction flask; the solvent was dried by heating at 110°C for 20 min under high-purity nitrogen; 0.2 mg of oxirane-2-ylmethyl 4-methylbenzenesulfonate and 0.2 mL of acetonitrile were added to the reaction flask, and the mixture was reacted at 90°C for 10 min; the acetonitrile was evaporated to dryness, and 0.2 mL of DMF solvent and 0.5 mg of IIc-1 were added, and the mixture was reacted at 130°C for 10 min; the mixture was separated and purified by HPLC (HPLC conditions: CAPCELL PAK C18 UG80 10 mm×250 mm, acetonitrile:water = 26:74, flow rate: 3 mL / min, peak elution time: 25 min), the product was collected and subjected to solid-phase extraction on a C18 column, and eluted with ethanol to obtain the final product II-8, with a labeling efficiency of 15%.

[0525] Method 2:

[0526] 150mCi 18 F was enriched on a QMA column and washed with 0.6 mL of eluent (150 mg Kryptofix 222, 15 mg K2CO3 dissolved in 9 mL acetonitrile and 1 mL water). 18 F was eluted into a reaction flask; the solvent was dried by heating at 110°C for 20 min under high-purity nitrogen; 0.5 mg of II-7 was added to the reaction flask and reacted at 140°C for 10 min; then 0.2 mL of 2N hydrochloric acid was added and reacted at 105°C for 8 min to remove the THP protecting group; the reaction solution was separated and purified by HPLC (HPLC conditions: CAPCELL PAK C18 UG80 10 mm×250 mm, acetonitrile:water = 26:74, flow rate: 3 mL / min, peak elution time: 25 min), the product was collected and subjected to solid-phase extraction on a C18 column, and eluted with ethanol to obtain the final product II-8, with a labeling efficiency of 13%.

[0527] According to a method similar to Example II-1, for example, using a ChiraPak IH column, a pair of enantiomers of Example II-8 can be separated: Enantiomer 1 and Enantiomer 2.

[0528] Example II-9: Preparation of Compound II-9

[0529] Example II-9 was synthesized in the same manner as Example II-1, except that 6-methoxy-2-methylbenzothiazole was replaced with 6-methoxy-2-methylbenzoxazole. The resulting product II-9 was a yellow solid with a yield of 10%. LC-MS (ESI) [M+H] + :421.2. 1H NMR (400MHz, DMSO-d6) δ9.01(d,J=2.4Hz,1H),8.41(s,1H),8.25–8.14(m,2H),7.89(d,J=8.2Hz,1H),7.80(d,J=16.0Hz,1H),7.67(d,J=8.7Hz ,1H),7.59(d,J=15.9Hz,1H),7.40(d,J=2.4Hz,1H),7.09–6.95(m,2H) ,4.65–4.52(m,1H),4.51–4.39(m,1H),4.15–4.01(m,3H),2.96(s,3H).

[0530] Example II-10: Preparation of Compound II-10

[0531] The synthesis method of Example II-10 is the same as that of Example II-1, except that 6-methoxy-2-methylbenzothiazole is replaced with 7-methoxy-2-methylbenzothiazole. The resulting product II-10 is a yellow solid with a yield of 19%. LC-MS (ESI) [M+H] + :437.2. 1 H NMR(400MHz, DMSO-d6)δ9.01(d,J=2.4Hz,1H),8.40(s,1H),8.26(d,J=9.2Hz,1H),8.19 (dd,J=8.2,2.5Hz,1H),8.01(d,J=8.8Hz,1H),7.93(d,J=15.9Hz,1H),7.88(d,J=8.2Hz ,1H),7.73(d,J=15.9Hz,1H),7.58(d,J=2.5Hz,1H),7.14(dd,J=8.8,2.5Hz,1H),7.04( d,J=9.3Hz,1H),4.64–4.53(m,1H),4.52–4.40(m,1H),4.16–4.04(m,3H),2.97(s,3H).

[0532] Example II-11: Preparation of Compound II-11

[0533] Example II-11 was synthesized in the same manner as Example II-1, except that (6-formylpyridin-3-yl)boronic acid was replaced with (6-formylpyridin-4-yl)boronic acid. The resulting product II-11 was a yellow solid with a yield of 17%. LC-MS (ESI) [M+H] + :437.2. 1H NMR(400MHz,DMSO-d6)δ8.70(d,J=5.4Hz,1H),8.58(s,1H),8.28(d,J=9.0Hz ,1H),8.24(s,1H),8.04(d,J=16.0Hz,1H),7.93(d,J=8.9Hz,1H),7.81–7.74 (m,2H),7.65(d,J=16.0Hz,1H),7.18(dd,J=8.9,2.5Hz,1H),6.97(d,J=9.1H z,1H),4.64–4.53(m,1H),4.51–4.41(m,1H),4.14–4.03(m,3H),2.97(s,3H).

[0534] Example II-12: Preparation of Compound II-12

[0535] Example II-12 was synthesized in the same manner as Example II-1, except that 5-bromo-2-(methylamino)pyridine was replaced with 4-bromo-2-(methylamino)pyridine. The resulting product II-12 was a yellow solid with a yield of 13%. LC-MS (ESI) [M+H] + :437.1. 1 HNMR(400MHz,DMSO-d6)δ9.11(s,1H),8.36–8.28(m,1H),8.08(d,J=6.5Hz,1H),8.03–7.89(m,3H),7.75(d,J=2.6Hz,1H),7.70(d,J =15.8Hz,1H),7.36–7.26(m,2H),7.17(dd,J=8.9,2.6Hz,1H),4.64–4.51(m,1H),4.51–4.41(m,1H),4.16–4.03(m,3H),3.00(s,3H).

[0536] Example II-13: Preparation of Compound II-13

[0537] Example II-13 was synthesized in the same manner as Intermediate IIb-1, except that 6-methoxy-2-methylbenzothiazole was replaced with 6-dimethylamino-2-methylbenzothiazole. The resulting product II-13 was a yellow solid with a yield of 12%. LC-MS (ESI) [M+H] + :388.2.

[0538] Example II-14: Preparation of Compound II-14

[0539] Example II-14 was synthesized in the same manner as Example II-1, except that 5-bromo-2-(methylamino)pyridine was replaced with 4-bromo-2-(methylamino)thiazole. The resulting product II-14 was a yellow solid with an 18% yield. LC-MS (ESI) [M+H] + :443.1. 1 HNMR(400MHz, DMSO-d6)δ9.12(d,J=2.2Hz,1H),8.25(dd,J=8.1,2.3Hz,1H),7.96–7.69(m,5H),7.61(d,J=15.9Hz,1 H),7.37(s,1H),7.16(dd,J=8.9,2.6Hz,1H),4.64–4.52(m,1H),4.51–4.40(m,1H),4.12–4.03(m,3H),2.91(s,3H).

[0540] Example II-15: Preparation of Compound II-15

[0541] Example II-15 was synthesized in the same manner as Example II-1, except that 5-bromo-2-(methylamino)pyridine was replaced with 5-bromo-2-(methylamino)thiazole. The resulting product II-15 was a yellow solid with a yield of 22%. LC-MS (ESI) [M+H] + :443.0. 1 HNMR(400MHz, DMSO-d6)δ9.80(s,2H),8.87(d,J=2.4Hz,1H),8.17(s,1H),8.04(dd,J=8.1,2.5Hz,1H),7.94–7.81(m,3H),7.74(d,J=2 .6Hz,1H),7.64(d,J=15.8Hz,1H),7.16(dd,J=8.9,2.6Hz,1H),4.65–4.53(m,1H),4.51–4.39(m,1H),4.15–4.01(m,3H),3.65(s,3H).

[0542] Example II-16: Preparation of Compound II-16

[0543] Example II-16 was synthesized in the same manner as Example II-1, except that 5-bromo-2-(methylamino)pyridine was replaced with 4-bromo-N-methylaniline. The resulting product II-16 was a yellow solid with a yield of 7%. LC-MS (ESI) [M+H] + :436.1. 1H NMR (400MHz, DMSO-d6) δ8.92(d,J=2.6Hz,1H),8.40(s,1H),8.25-8.10(m,2H),7.90(s,1H),7.82(d,J=8.5Hz,1H),7.80(d,J=8.2Hz,1H),7.7 3(d,J=2.3Hz,2H),7.65(d,J=15.6Hz,2H),7.16(dd,J=8.9,2.6Hz,1H),7.00-6.86(m,1H),4.63-4.48(m,2H),4.15-4.03(m,3H),2.96(s,3H).

[0544] Example II-17: Preparation of Compound II-17

[0545] The synthesis method of Example II-17 is the same as that of Example II-14, except that the amount of epifluoropropane is increased threefold. The resulting product II-17 is a yellow solid with a yield of 4%. LC-MS (ESI) [M+H] + :519.1. 1 H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.26(s,1H),7.97–7.70(m,4H),7.66–7.58(m,1H),7. 47(d,J=4.9Hz,1H),7.17(s,1H),4.62–4.30(m,4H),4.20–4.01(m,6H),3.20–3.13(m,3H).

[0546] Example II-18: Preparation of Compound II-18

[0547] Example II-18 was synthesized in the same manner as Example II-1, except that (6-formylpyridin-3-yl)boronic acid was replaced with (6-formylpyrazin-3-yl)boronic acid. The resulting product II-18 was a yellow solid with a yield of 7%. LC-MS (ESI) [M+H] + :438.2. 1H NMR (400MHz, DMSO-d6) δ9.30–9.26(m,1H),8.97–8.90(m,1H),8.80–8.74(m,1H),8.41(d,J=9.2Hz,1H),7.99–7.88(m,2H),7.80–7. 65(m,2H),7.17(dd,J=8.9,2.6Hz,1H),6.91(d,J=9.2Hz,1H),4.64–4.54(m,1H),4.51–4.40(m,1H),4.15–4.03(m,3H),2.95(s,3H).

[0548] Example II-19: Preparation of Compound II-19

[0549] The synthesis method of Example II-19 is the same as that of Example II-1, except that epifluoropropane is replaced with 1-bromo-2-fluoroethane. The resulting product II-19 is a yellow solid with a yield of 27%. LC-MS (ESI) [M+H] + :407.1. 1 H NMR(400MHz, DMSO-d6)δ8.99(s,1H),8.41(s,1H),8.23–8.11(m,2H),7.96–7.81(m,3H),7.75(s,1H),7.65(d,J=15.8Hz,1H),7.18 (d,J=9.1Hz,1H),6.97(d,J=9.0Hz,1H),4.91–4.83(m,1H),4.80–4.72(m,1H),4.44–4.35(m,1H),4.34–4.29(m,1H),2.95(s,3H).

[0550] Example II-20: Preparation of Compound II-20

[0551] Example II-20 was synthesized in the same manner as Intermediate IIb-1, except that 6-methoxy-2-methylbenzothiazole was replaced with 6-nitro-2-methylbenzothiazole. The resulting product II-20 was a yellow solid with a yield of 12%. LC-MS (ESI) [M+H] + :390.1.

[0552] Example II-21: Preparation of Compound II-21

[0553] The synthesis method of Example II-21 is the same as that of Example II-1, except that epifluoropropane is replaced with 1-bromo-2-oxy-p-toluenesulfonyl-ethane. The obtained product II-21 is a yellow solid with a yield of 21%. LC-MS (ESI) [M+H] + :559.1.

[0554] Example II-22: Preparation of Compound II-22

[0555] 150mCi 18 F was enriched on a QMA column and washed with 0.6 mL of eluent (150 mg Kryptofix 222, 15 mg K2CO3 dissolved in 9 mL acetonitrile and 1 mL water). 18 F was eluted into a reaction flask; the solvent was dried by heating at 110°C for 20 minutes under high-purity nitrogen; 0.5 mg of the precursor compound II-21 was added to the reaction flask and reacted at 140°C for 10 minutes; the reaction solution was separated and purified by HPLC), the product was collected and solid-phase extracted with a C18 column, and the final product II-22 was obtained by elution with ethanol, with a labeling efficiency of 21%.

[0556] Example II-23: Preparation of Compound II-23

[0557] Example II-23 was synthesized in the same manner as Example II-2, except that 5-bromo-2-(methylamino)pyridine was replaced with 5-bromo-6-fluoro-2-(methylamino)pyridine. The resulting product II-23 was a brown solid with a yield of 9%. LC-MS (ESI) [M+H] + :379.1.

[0558] Example II-24: Preparation of Compound II-24

[0559] Example II-24 was synthesized in the same manner as Example II-1, except that 6-methoxy-2-methylbenzothiazole was replaced with 6-amino-2-methylbenzothiazole. The resulting product II-24 was a yellow solid with a yield of 3%. LC-MS (ESI) [M+H] + :437.2.

[0560] Example II-25: Preparation of Compound II-25

[0561] Synthesis route of compound II-25:

[0562] Step 1: Preparation of intermediate IIa-1'

[0563] (6-Formylpyridin-3-yl)boronic acid (48 mg, 0.32 mmol), 5-bromo-2-(methylamino)pyrimidine (60 mg, 0.32 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (Pd(dppf)Cl2) (23 mg, 0.032 mmol), and potassium carbonate (138 mg, 0.96 mmol) were dissolved in 1,4-dioxane (2.4 mL) and water (0.6 mL). The mixture was reacted at 80°C overnight under nitrogen protection. After completion of the reaction, the product IIa-1' was purified by flash silica gel column chromatography with petroleum ether (PE) / ethyl acetate (EA) to obtain the product IIa-1' (42 mg, 0.2 mmol) as a yellow solid in a 73% yield. MS-ESI: m / z 215.0 [M+H] + .

[0564] Step 2: Preparation of Intermediate IIb-1'

[0565] IIa-1' (42 mg, 0.2 mmol) and 6-methoxy-2-methylbenzothiazole (36 mg, 0.2 mmol) were dissolved in dimethyl sulfoxide (DMSO) (2 mL). Aqueous sodium hydroxide solution (1 g / mL) (32 μL, 0.8 mmol) was added and the mixture was allowed to react at 50°C for 2 h. After completion of the reaction, the product was purified by flash silica gel column chromatography (PE / EA) and flash C18 column chromatography (acetonitrile / water) to obtain the product IIb-1' (4 mg, 0.01 mmol) as an orange solid in an 11% yield. MS-ESI: m / z 376.1 [M+H] + .

[0566] Step 3: Preparation of intermediate IIc-1'

[0567] IIb-1' (4 mg, 0.01 mmol) was dissolved in dichloromethane (DCM) (0.03 mL) under nitrogen. A 1 M solution of boron tribromide in dichloromethane (0.03 mL, 0.03 mmol) was added dropwise at -78°C. The mixture was stirred for 2 h, then returned to room temperature and allowed to react overnight. The reaction solution was quenched by addition of saturated aqueous sodium bicarbonate (50 mL) and extracted with EA (50 mL). The EA phase was washed with water (50 mL x 2) and then with saturated aqueous sodium chloride (50 mL). The product was dried over anhydrous sodium sulfate to obtain product IIc-1' (3.6 mg, 0.01 mmol) as an orange solid in a 90% yield. MS-ESI: m / z 362.1 [M+H] + .

[0568] Step 4: Preparation of product II-25

[0569] IIc-1' (3.6 mg, 0.01 mmol) and potassium carbonate (4 mg, 0.03 mmol) were added to N,N-dimethylformamide (DMF) (0.1 mL), and epifluorohydrin (1.5 μL, 0.02 mmol) was added dropwise. The mixture was reacted at 80°C for 4 h. After the reaction was complete, the product I-1 was purified by high-performance liquid chromatography (HPLC) (acetonitrile / water) to obtain a yellow solid in a 7% yield. LC-MS (ESI) [M+H] + :438.1. 1 H NMR (400MHz, DMSO-d6) δ8.98(d,J=2.4Hz,1H),8.79(s,2H),8.17(dd,J=8.2,2.4Hz,1H),7.94–7.86(m,2H),7.84(d,J=8.3Hz,1H),7.74(d,J=2.6 Hz,1H),7.63(d,J=15.9Hz,1H),7.49(s,1H),7.16(dd,J=8.9,2.5Hz,1H ),4.64–4.53(m,1H),4.51–4.41(m,1H),4.15–4.04(m,3H),2.87(s,3H).

[0570] Example II-26: Preparation of Compound II-26

[0571] Example II-26 was synthesized in the same manner as Example II-25, except that 5-bromo-2-(methylamino)pyrimidine was replaced with 6-bromo-3-(methylamino)pyridazine. The resulting product II-26 was a yellow solid with a yield of 5%. LC-MS (ESI) [M+H] + :438.1. 1 HNMR(400MHz, DMSO-d6)δ9.26(d,J=2.3Hz,1H),8.42(dd,J=8.3,2.4Hz,1H),8.25(d,J=9.6Hz,1H),8.00–7.87(m,3H),7.75(d,J=2.5Hz,1H),7.68 (d,J=15.8Hz,1H),7.36(d,J=9.5Hz,1H),7.17(dd,J=8.9,2.6Hz,1H),4. 63–4.53(m,1H),4.51–4.42(m,1H),4.18–4.02(m,3H),3.05–2.98(m,3H).

[0572] Example II-27: Preparation of Compound II-27

[0573] Example II-27 was synthesized in the same manner as Example II-25, except that 5-bromo-2-(methylamino)pyrimidine was replaced with 5-bromo-2-(methylamino)pyrazine. The resulting product II-27 was a yellow solid with a yield of 7%. LC-MS (ESI) [M+H] + :438.1. 1 HNMR(400MHz,DMSO-d6)δ9.22(d,J=2.3Hz,1H),8.79–8.70(m,1H),8.37(dd,J=8.3,2.3Hz,1H),8.07–8.04(m,1H),7.93-7.79(m,3H),7.74(d,J=2 .6Hz,1H),7.63(d,J=15.9Hz,1H),7.43(s,1H),7.16(dd,J=8.9,2.6Hz,1 H),4.65–4.53(m,1H),4.52-4.41(m,1H),4.16-4.02(m,3H),2.88(s,3H).

[0574] Example II-28: Preparation of Compound II-28

[0575] 200mCi 18 F was enriched on a QMA column and washed with 0.7 mL of eluent (150 mg 222, 15 mg K2CO3, 9 mL acetonitrile, 1 mL water) 18 F was eluted into the reaction flask; high-purity nitrogen was introduced, and the solvent was evaporated by heating at 110°C for 20 minutes; 0.2 mL of acetonitrile and 0.2 mg of 2-oxirane-4-methylbenzenesulfonate were added to the reaction flask, and the reaction was set at 90°C for 10 minutes; the acetonitrile was evaporated on a rotary evaporator, and 0.2 mL of DMF solvent and 0.5 mg of IIc-1' were added, and the reaction was carried out at 130°C for 10 minutes; the mixture was separated and purified by HPLC (HPLC conditions: CAPCELL PAK C18 UG80 10 mm×250 mm, acetonitrile:water = 30:70, flow rate: 3 mL / min, peak elution time: 29 minutes), the product was collected and subjected to solid-phase extraction on a C18 column, and eluted with ethanol to obtain the final product II-28, with a labeling efficiency of 6%.

[0576] Example II-29: Preparation of Compound II-29

[0577] The labeling method is the same as that shown in Example II-28, except that the precursor IIc-1' is replaced by

[0578] Example III-1: Preparation of Compound III-1

[0579] Synthesis route of compound III-1:

[0580] Step 1: Preparation of intermediate 17

[0581] To a mixture of compound 15 (1.280 g, 4.51 mmol), compound 16 (1.5 g, 4.51 mmol), cesium carbonate (4.41 g, 13.53 mmol), palladium acetate (101 mg, 0.45 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (DPPF, 249 mg, 0.45 mmol) were added 1,4-dioxane (15 mL), ethanol (5 mL) and water (5 mL). The reaction mixture was reacted at 120 ° C for 3 hours under a nitrogen atmosphere. Afterwards, the reaction mixture was filtered and directly concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to give a white solid compound 17 (1.2 g, yield 73.5%). LCMS: m / z (ESI) = 363.6 [M + H] +

[0582] Step 2: Preparation of Intermediate 7

[0583] To a solution of compound 17 (1.2 g, 3.31 mmol) in dioxane (25 mL) were added pinacol diboronate (1.68 g, 6.62 mmol), Pd(dppf)Cl2 (242 mg, 0.33 mmol), and potassium acetate (973 mg, 9.93 mmol). The reaction mixture was stirred at 80°C for 15 hours. The reaction solution was then filtered and concentrated directly. The residue was then purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 7 as a gray solid (400 mg, 29.4% yield).

[0584] Step 3: Preparation of Intermediate 3

[0585] Compound 1 (5 g, 26.88 mmol) and compound 2 (4.8 g, 26.88) were dissolved in dimethyl sulfoxide (DMSO, 100 mL), and then 50% potassium hydroxide aqueous solution (100 mL) was slowly added dropwise and stirred at room temperature overnight. After the reaction was completed, a yellow precipitate was produced. The solid was collected by filtration and dried under reduced pressure to obtain white compound 3 (3.2 g, yield: 34%). LCMS: m / z (ESI) = 346.8 / 348.8 [M+H] +

[0586] Step 4: Preparation of Intermediate 4

[0587] At -78 ° C, to a solution of compound 3 (3.2 g, 9.25 mmol) in dichloromethane (100 mL) was added dropwise a 1 M solution of boron tribromide (BBr3) in dichloromethane (1 M, 92.5 mL, 92.5 mmol). After stirring at -78 ° C for 2 hours, the mixture was warmed to room temperature and stirred for 15 hours. The reaction solution was poured into ice water (500 mL), and then a saturated sodium bicarbonate solution was slowly added dropwise until the pH reached 8. The precipitate was collected by filtration to give compound 4 (2.4 g, 78% yield) as a yellow solid. 1 HNMR (400MHz, DMSO) δ8.76(d,J=2.4Hz,1H),8.12(dd,J=8.4,2.4Hz,1H),7.84(d,J=15.9Hz,1H),7.80(d,J=8 .8Hz,1H),7.70(t,J=13.1Hz,1H),7.51(d,J=15.9Hz,1H),7.35(d,J=2.3Hz,1H),6.97(dd,J=8.8,2.4Hz,1H).

[0588] Step 5: Preparation of Intermediate 6

[0589] To a solution of compound 4 (2.4 g, 7.2 mmol) in N,N-dimethylformamide (DMF, 30 mL) were added cesium carbonate (Cs2CO3, 2.98 g, 21.6 mmol) and compound 5 (2.74 g, 36 mmol). The reaction mixture was heated to 80°C and maintained for 4 hours. After cooling to room temperature, the reaction mixture was poured into ice water (100 mL), stirred for 10 minutes, and then filtered. The solid was collected and purified by flash column chromatography (dichloromethane:methanol=10:1) to give compound 6 (1.5 g, 51% yield) as a yellow solid. LCMS: m / z(ESI)=409.0[M+H]+

[0590] Step 6: Preparation of Intermediate 8

[0591] 1,4-dioxane (10 mL) and water (2 mL) were added to a mixture of compound 6 (300 mg, 0.73 mmol), compound 7 (300 mg, 0.73 mmol), Pd(dppf)Cl2 (51 mg, 0.07 mmol) and K2CO3 (294 mg, 2.16 mmol). The reaction mixture was stirred at 80 ° C for 15 hours under a nitrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give a yellow solid compound 8 (360 mg, yield 81%). LCMS: m / z (ESI) = 613.2 [M + H] +

[0592] Step 7: Preparation of Compound III-1

[0593] To a solution of compound 8 (360 mg, 0.59 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC (containing 0.05% trifluoroacetic acid) to obtain the trifluoroacetic acid salt of compound III-1 as a yellow solid (60 mg, 16.7% yield). LCMS: m / z (ESI) = 513.2 [M+H]+. 1 H NMR (400MHz, DMSO) δ9.12(d,J=2.0Hz,1H),9.01(d,J=2.0Hz,1H),8.37-8.3(m,2H),8.04(d,J=8.8Hz,1H),7.98-7.89(m,5H),7.75(d,J=3.5Hz,1H ),7.68(d,J=16Hz,1H),7.17(dd,J=8.8,2.4Hz,1H),6.69(d,J=7.2Hz,2H ),4.60-4.58(m,1H),4.57-4.50(m,1H),4.12-4.08(m,3H),2.77(s,3H).

[0594] Example III-2: Preparation of Compound III-2

[0595] Synthesis route of compound III-2:

[0596] Step 1: Preparation of Intermediate 3

[0597] Compound 1 (10.00 g, 65.33 mmol) and compound 2 (22.11 g, 78.40 mmol) were dissolved in dioxane (80 mL), followed by the addition of water (20 mL), Pd(dppf)Cl2 (1.00 g, 1.36 mmol), and K2CO3 (27.04 g, 196.00 mmol). The reaction mixture was then stirred at 80°C for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel flash column chromatography using (28% EtOAc in PE) as the eluent to obtain compound 3 (5 g, 29.00% yield) as a yellow solid. LCMS: m / z (ESI) = 338.6 [M+H] +

[0598] Step 2: Preparation of Intermediate 4

[0599] To a solution of compound 3 (5.00 g, 18.94 mmol) and compound 3A (14.58 g, 94.70 mmol) in toluene (50 mL) were added diisopropylethylamine (DIEA, 7.34 g, 56.82 mmol), tri-tert-butylphosphine tetrafluoroborate (1.09 g, 3.78 mmol), and Pd2(dba)3 (1.73 g, 1.89 mmol). The reaction mixture was then stirred at 100°C for 12 hours. The reaction mixture was then concentrated, and the residue was purified by flash column chromatography on silica gel using 30% EA in PE as the eluent to afford compound 4 (0.80 g, 12.46% yield) as a yellow solid. LCMS: m / z (ESI) = 338.6 [M+H] +

[0600] Step 3: Preparation of Compound III-2

[0601] To a solution of compound 4 (0.80 g, 2.36 mmol) and compound 5 (0.64 g, 2.83 mmol) in dioxane (8 mL) and water (2 mL) were added Pd(dppf)Cl2 (0.10 g, 0.14 mmol) and K2CO3 (0.97 g, 7.09 mmol). The reaction mixture was then stirred at 80°C for 2 hours. The reaction mixture was then concentrated to obtain a residue. The residue was purified by flash column chromatography on silica gel using 26% EtOAc in PE as the eluent to obtain the crude product. The crude product was then purified by preparative high-performance liquid chromatography (pre-HPLC) (instrument: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20AP UV detector; column: Ultimate XB-C18, 50×250 mm×10 μm; mobile phase A: H 2 O with FA (10 mmol / L); mobile phase B: CH 3 CN; gradient: B increased from 12% to 42% in 30 minutes, then maintained at 100% B for 3 minutes; flow rate: 20 mL / min; retention time Rt = 15.0 minutes; column temperature: 30° C.; wavelength: 214 nM, 254 nM) to obtain yellow solid compound III-2 (58.1 mg, yield: 6.8%). LCMS: m / z (ESI) = 362.4 [M+H] +.1H NMR (400MHz, DMSO) δ9.96(s,1H),8.99(d,J=2.0Hz,1H),8.64(d,J=2.4Hz,1H),8.19-8.14(m,2H),7.87(d,J= 16Hz,1H),7.82(d,J=8.8Hz,2H),7.59(d,J=16Hz,1H),7.40(d,J=2.4Hz,1H),7.00-6.96(m,2H),3.92(s,3H).

[0602] Example III-3: Preparation of Compound III-3

[0603] Synthesis route of compound III-3:

[0604] To a mixture of compound 8 (300 mg, 0.73 mmol), compound 9 (300 mg, 140 mmol), Pd(dppf)Cl2 (51 mg, 0.07 mmol) and K2CO3 (294 mg, 2.16 mmol) was added 1,4-dioxane (10 mL) and water (2 mL). Under a nitrogen atmosphere, the reaction mixture was heated to 80°C and maintained for 15 hours. The reaction solution was filtered and concentrated, and the resulting residue was purified by preparative high-performance liquid chromatography (containing 0.05% formic acid) to obtain a gray solid compound III-3 (63.0 mg, 18.0%). LCMS: m / z (ESI) = 477.2 [M+H]+. 1H NMR (400MHz, DMSO) δ8.96(d,J=2.4Hz,1H),8.58(d,J=6.8Hz,1H),8.09(dd,J=8.2,2.4Hz,1H) ,7.96(dd,J=8.8,2.4Hz,1H),7.93-7.82(m,2H),7.75(dd,J=14.4,5.4Hz,2H),7.62(d,J=15.8 Hz,1H),7.20-7.12(m,1H),6.57(d,J=8.8Hz,1H),5.51(d,J=9.2Hz,1H),4.58(d,J=12.8Hz,1H ),4.47(t,J=8.2Hz,1H),4.09(d,J=17.6Hz,3H),3.46(d,J=6.6Hz,4H),1.97(t,J=6.6Hz,4H).

[0605] Example III-4: Preparation of Compound III-4

[0606] Synthesis route of compound III-4:

[0607] To a mixture of compound 8 (300 mg, 0.73 mmol), compound 10 (122 mg, 0.73 mmol), Pd(dppf)Cl2 (51 mg, 0.07 mmol), and K2CO3 (294 mg, 2.16 mmol) was added 1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was heated to 80°C under a nitrogen atmosphere for 15 hours. The reaction mixture was then filtered and concentrated, and the resulting residue was purified by preparative HPLC (containing 0.05% formic acid) to afford compound III-4 as a yellow solid (78.0 mg, 23.5% yield). LCMS: m / z (ESI) = 452.2 [M+H]+. 1H NMR (400MHz, DMSO) δ9.11(d,J=2.4Hz,1H),8.38-8.31(m,3H),8.12(d,J=8.8Hz,2H),7.95(t,J=11.2Hz ,3H),7.72(dd,J=22.8,9.2Hz,2H),7.17(dd,J=8.8,2.6Hz,1H),4.61-4.43(m,3H),4.13-4.05(m,3H).

[0608] Example III-5: Preparation of Compound III-5

[0609] Synthesis route of compound III-5:

[0610] Step 1: Preparation of Intermediate 2

[0611] To a solution of compound 1 (25.00 g, 142.90 mmol) in tetrahydrofuran (450 mL) was added LDA (157 mmol, 157 mmol) at -78°C, and the reaction mixture was stirred at this temperature for 1 hour. Then, a solution of iodine (142.90 g, 142.90 mmol) in anhydrous tetrahydrofuran (50 mL) was added, and stirring was continued at -78°C for 1.5 hours. At this temperature, the reaction mixture was quenched with saturated aqueous sodium thiosulfate and extracted with ethyl acetate (3 times x 500 mL). The organic layers were combined, washed with saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by flash chromatography on silica gel using 18% EtOAc in PE as the eluent to obtain compound 2 (16 g, 37.2% yield) as a white solid. 1H NMR (400MHz, DMSO) δ8.31 (t, J=8.0Hz, 1H), 7.43-7.41 (d, J=8.0Hz, 1H).

[0612] Step 2: Preparation of Intermediate 4

[0613] To a solution of compound 2 (2.00 g, 6.64 mmol) and compound 3 (2.66 g, 7.97 mmol) in dioxane (20 mL) and water (4 mL) at 25°C were added Pd(dppf)Cl2 (0.20 g, 0.273 mmol) and K2CO3 (2.75 g, 19.9 mmol). The reaction mixture was then stirred at 80°C for 2 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by silica gel flash chromatography using (18% EtOAc in PE) as the eluent to obtain compound 4 (1.1 g, 43.47% yield) as a yellow solid. LCMS: m / z (ESI) = 326.0 [M-56+H] +

[0614] Step 3: Preparation of Intermediate 5

[0615] To a solution of compound 4 (1.10 g, 2.88 mmol) and compound 4A (2.22 g, 14.43 mmol) in toluene (20 mL) were added tri-tert-butylphosphine tetrafluoroborate (0.16 g, 0.57 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol) and diisopropylethylamine (DIEA, 1.11 g, 8.64 mmol) at 25 ° C. The reaction mixture was then stirred at 100 ° C for 12 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by silica gel flash chromatography using (30% EtOAc in PE) as eluent to obtain yellow solid compound 5 (0.78 g, 59.54% yield). LCMS:, m / z (ESI) = 400.4 [M-56 + H] +

[0616] Step 4: Preparation of Intermediate 7

[0617] To a solution of compound 5 (0.78 g, 1.71 mmol) and compound 6 (0.47 g, 2.05 mmol) in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl2 (0.20 g, 0.27 mmol) and K2CO3 (0.70 g, 5.13 mmol) at 25°C. The reaction mixture was then stirred at 80°C for 2 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by flash chromatography on silica gel using (22% EA in PE) as the eluent to obtain compound 7 (0.50 g, 61.72% yield) as a yellow solid. LCMS: m / z (ESI) = 478.6 [M+H]+.

[0618] Step 5: Preparation of compound III-5

[0619] Compound 7 (0.50 g, 1.04 mmol) was dissolved in HCl-dioxane solution (5 mL, 4 mmol / L) and stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (instrument: Shimadzu LH-40 liquid handler, Shimadzu LC-20AP pump, Shimadzu SPD-20AP UV detector; column: Ultimate XB-C18, 50 × 250 mm × 10 μm; mobile phase A: water containing formic acid (10 mmol / L); mobile phase B: acetonitrile; gradient: 18% to 48% phase B over 30 minutes, then hold at 100% phase B for 3 minutes; flow rate: 20 mL / min; retention time Rt = 12.5 min; column temperature: 30°C; detection wavelengths: 214 nm, 254 nm) to obtain compound III-5 (63.1 mg, 16.1% yield) as a yellow solid. LCMS: m / z (ESI) = 379.4 [M+H] + 1H NMR (400MHz, DMSO) δ9.99 (s, 1H), 8.33 (s, 1H), 8.14–8.10 (m, 1H), 7.86–7.68 (m, 4H), 7.54 (d, J = 16 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.00–6.98 (m, 1H), 6.90–6.86 (m, 1H), 6.57 (d, J = 8.8 Hz, 1H), 2.83 (d, J = 4.8 Hz, 3H). Example III-6: Preparation of Compound III-6

[0620] Synthesis route of compound III-6:

[0621] Referring to the synthesis method of II-1 in Example II-1, replacing 6-methoxy-2-methylbenzothiazole with II-1a, product III-6 (54 mg, yellow solid) was obtained. LC-MS (ESI): [M+1]+=536.1.

[0622] Example III-7: Preparation of Compound III-7

[0623] Synthesis route of compound III-7:

[0624] Step 1: Preparation of intermediate II-2b

[0625] 4-iodo-6-methoxypyridin-3-amine (5.10 g, 20.4 mmol) was dissolved in dichloromethane (50 mL), triethylamine (4.27 mL, 30.6 mmol) and acetyl chloride (1.74 mL, 24.5 mmol) were added under ice-bath cooling, and then stirred at room temperature for 1 hour. The reaction mixture was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated powder was washed with isopropyl ether and collected by filtration to obtain intermediate II-2b as a white solid (4.42 g, 74% yield). LC-MS (ESI): [M+1] + = 293.0.

[0626] Step 2: Preparation of intermediate II-2c

[0627] At room temperature, II-2b (1.32 g, 4.51 mmol), potassium sulfide (1.49 g, 13.5 mmol) and cuprous iodide (85.8 mg, 0.451 mmol) were dissolved in DMF (25 mL). The reaction solution was warmed to 90 ° C and stirred for 1 hour. Subsequently, the reaction solution was quenched with 1N hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 2: 1) to give II-2c (354 mg, yellow solid, 43.5% yield). LC-MS (ESI): [M+1] + = 181.0.

[0628] Steps 3, 4, and 5 were prepared by following the method of Example II-1, except that 6-methoxy-2-methylbenzothiazole was replaced with II-2c to obtain product III-7 (24 mg, yellow solid). LC-MS (ESI): [M+1]+ = 438.1.

[0629] Example III-8: Preparation of Compound III-8

[0630] Synthesis route of compound III-8:

[0631] Referring to the synthesis method of II-1 in Example II-1, replacing 6-methoxy-2-methylbenzothiazole with II-3a, product III-8 (28 mg, yellow solid) was obtained. LC-MS (ESI): [M+1]+ = 439.1. The synthesis of II-3a was carried out according to the method described in Chem. Pharm. Bull. 1958, 6, 334-338.

[0632] Example III-9: Preparation of Compound III-9

[0633] Synthesis route of compound III-9:

[0634] Step 1: Preparation of intermediate II-4b

[0635] Under nitrogen, II-4a (2.49 g, 15 mmol) was dissolved in dry tetrahydrofuran (70 mL) using a syringe and injected into a dry, single-necked flask. The solution was cooled to -78°C, and 25 mL of tert-butyllithium (1.5 M) was added dropwise over 15 minutes. The temperature was then raised to 0°C, and stirring was maintained for 2 hours. The reaction mixture was cooled to -78°C again, and iodine (9.52 g, 37.5 mmol, dissolved in 5 mL of dry tetrahydrofuran) was added. The reaction mixture was then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with an aqueous sodium thiosulfate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: dichloromethane / methanol 100 / 0 to 95 / 5). Intermediate II-4b (1.5 g, 34% yield) was obtained. LC-MS (ESI): [M+1]+ = 292.9.

[0636] Follow the synthesis method of III-7 in Example III-7 in the second, third, fourth, and fifth steps, replacing II-2b with II-4b, to obtain product III-9 (56 mg, yellow solid). LC-MS (ESI): [M+1]+ = 438.1.

[0637] Example III-10: Preparation of Compound III-10

[0638] Synthesis route of compound III-10:

[0639] Referring to the synthesis method of III-7 in Example III-7, II-2a was replaced with II-5a to obtain product III-10 (38 mg, yellow solid). LC-MS (ESI): [M+1]+=438.1.

[0640] Example III-11: Preparation of Compound III-11

[0641] Synthesis route of compound III-11:

[0642] Step 1: Preparation of intermediate II-6a

[0643] 1a-1 (2.13 g, 10 mmol) was dissolved in methanol (43 mL), and potassium carbonate (2.76 g, 20 mmol) was added to the mixture. A solution of dimethyl (1-diazo-2-oxo-propyl)-phosphonate (2.14 g, 11 mmol) in methanol (14 mL) was then added at room temperature, and the resulting mixture was stirred for 2 h. Subsequently, the mixture was poured into a 1 M sodium carbonate solution and extracted with ethyl acetate. The organics were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. After separation and purification by silica gel column chromatography, intermediate II-6a (1.29 g, 62%) was obtained as a yellow liquid. LC-MS (ESI): [M+1]+ = 210.1.

[0644] Step 2: Preparation of intermediate II-6c

[0645] In a 5 mL microwave tube, II-6a (142.3 mg, 0.68 mmol), II-6b (197.9 mg, 0.68 mmol), tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol), cuprous iodide (0.02 g, 0.05 mmol) and triethylamine (0.28 mL, 2.04 mmol) were added in acetonitrile (2.0 mL). The suspension was irradiated at 100 ° C for 5 minutes in a microwave reactor. After cooling to room temperature, the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography using n-hexane: dichloromethane (1:0-0:1) as eluent to give II-6c (53 mg, 21%) as a yellow solid. LC-MS (ESI): [M+1] + = 373.1.

[0646] The third and fourth steps were carried out according to the synthesis method in Example III-6 to obtain product III-11 (15 mg, yellow solid). LC-MS (ESI): [M+1]+ = 435.1.

[0647] Example III-12: Preparation of Compound III-12

[0648] Synthesis route of compound III-12:

[0649] Referring to the synthesis method of II-1 in Example II-1, 5-bromo-2-(methylamino)pyridine was replaced with II-7b to obtain product III-12 (63 mg, yellow solid). LC-MS (ESI): [M+1]+ = 454.2.

[0650] Example III-13: Preparation of Compound III-13

[0651] Synthesis route of compound III-13:

[0652] Step 1: Preparation of intermediate II-8b

[0653] Combine II-8a (4.68 g, 20 mmol), piperazine (7.83 mL, 100 mmol), cuprous iodide (76.18 mg, 0.4 mmol), 2-[(2,6-dimethylphenyl)amino]-2-oxoacetic acid (386 mg, 2 mmol), and sodium carbonate (5.3 g, 50 mmol) in a three-necked flask. Add N,N-dimethylformamide (35 mL) and replace the atmosphere with nitrogen. The temperature was raised to 100°C for the reaction. After completion of the reaction, the reaction solution was concentrated and then separated by column chromatography. Intermediate II-8b (1.5 g, 39%) was obtained. LC-MS (ESI): [M+1]+ = 193.1.

[0654] Step 2: Preparation of intermediate II-8c

[0655] Under a nitrogen atmosphere, II-7d (358 mg, 2 mmol), II-8b (375 mg, 1.95 mmol), and triethyl orthoformate (2.49 mL, 15 mmol) were dissolved in methanol (12 mL). The reaction mixture was heated to 70°C for 18 hours. After cooling to room temperature, the precipitate was filtered and washed with ether. The resulting solid was dried under high vacuum at room temperature. Intermediate II-8c (119 mg, 16% yield) was obtained. LC-MS (ESI): [M+1]+ = 382.2.

[0656] The third and fourth steps were carried out according to the synthesis method in Example III-6 to obtain product III-13 (23 mg, gray solid). LC-MS (ESI): [M+1]+=444.2.

[0657] Example III-14: Preparation of Compound III-14

[0658] The synthesis method of compound III-14 was similar to that of Example II-1, except that 5-bromo-2-(methylamino)pyridine was replaced with 2-hydroxy-5-bromopyridine to obtain product III-14 (56 mg, brownish-gray solid). LC-MS (ESI): [M+1]+ = 424.1.

[0659] Example III-15: Preparation of Compound III-15

[0660] The synthesis method of compound III-15 was similar to that of Example II-1, except that 5-bromo-2-(methylamino)pyridine was replaced with 5-bromo-2-cyanopyridine to obtain product III-15 (35 mg, yellow solid). LC-MS (ESI): [M+1]+ = 433.1.

[0661] Example III-16: Preparation of Compound III-16

[0662] The synthesis method of compound III-16 was similar to that of Example II-1, except that 6-methoxy-2-methylbenzothiazole was replaced with 2-methyl-benzothiazole-6-carboxylic acid to obtain product III-16 (78 mg, yellow solid). LC-MS (ESI): [M+1]+ = 389.1.

[0663] Example III-17: Preparation of Compound III-17

[0664] Synthesis route of compound III-17:

[0665] Step 1: Preparation of intermediate II-12c

[0666] To a dry tetrahydrofuran (5 mL) solution at room temperature were added II-12a (114.1 mg, 0.5 mmol), N-methylpiperazine (75 mg, 0.75 mmol), and K3PO4 (425 mg, 2.0 mmol), and the reaction mixture was purged with nitrogen for 15 minutes. Ruphos Pd G1 (81.7 mg, 0.1 mmol) was then added. The reaction mixture was further purged with argon for 5 minutes and then stirred at 80°C in a sealed tube for 24 hours. After completion of the reaction, the mixture was filtered through a pad of Celite, and the pad was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure and separated by column chromatography. Intermediate II-12c (28.5 mg, 23% yield) was obtained. LC-MS (ESI): [M+1]+ = 248.1.

[0667] Step 2: Preparation of compound III-17

[0668] Intermediates 1a-1 (24.6 mg, 0.115 mmol) and 11-12c (28.5 mg, 0.115 mmol) were dissolved in dimethyl sulfoxide (2 mL). 50% aqueous potassium hydroxide solution (1 mL) was slowly added dropwise and stirred at room temperature overnight. After the reaction was complete, a yellow solid precipitated. The mixture was filtered and the filter cake washed with water. The solid was collected and dried to afford product III-17 (35 mg, yellow solid, 68% yield). LC-MS (ESI): [M+1] = 443.2.

[0669] Example III-18: Preparation of Compound III-18

[0670] The synthesis method of compound III-18 was similar to that of Example III-17, except that N-methylpiperazine was replaced with 4-methylpiperazin-2-one to obtain product III-18 (12 mg, yellow solid). LC-MS (ESI): [M+1]+=457.2.

[0671] Example III-19: Preparation of Compound III-19

[0672] Synthesis route of compound III-19:

[0673] Step 1: Preparation of intermediate II-14c

[0674] At room temperature, 3-fluoropropionic acid II-14b (35.5 mg, 0.386 mmol) was dissolved in dichloromethane (4.0 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) hexafluorophosphate (293 mg, 0.77 mmol), N,N-diisopropylethylamine (127 μL, 0.77 mmol), and II-14a (63.4 mg, 0.386 mmol) were added. The reaction was allowed to proceed at room temperature for 40 minutes. After completion, the reaction was diluted with dichloromethane (100 mL), and the organic phase was washed sequentially with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 5 / 95). A pale yellow oil, II-4c (74 mg, yield: 80%), was obtained. LC-MS (ESI): [M+1]+=239.1

[0675] In the second step, referring to the synthesis method in Example III-17, II-12c was replaced with II-14c to obtain product III-19 (24 mg, yellow solid). LC-MS (ESI): [M+1]+=434.2.

[0676] Example III-20: Preparation of Compound III-20

[0677] Compound III-20 was synthesized by referring to the method of Example II-1, except that 5-bromo-2-(methylamino)pyridine was replaced with 7-bromo-N,N-dimethylnaphthalen-2-amine to obtain product III-20 (5.6 mg, gray solid). LC-MS (ESI): [M+1]+ = 500.2.

[0678] Example III-21: Preparation of Compound III-21

[0679] The synthesis of compound III-21 was carried out by referring to the synthesis method in Example III-17, except that N-methylpiperazine was replaced with 2-fluoroethylamine hydrochloride to obtain product III-21 (34 mg, yellow solid). LC-MS (ESI): [M+1]+=406.2.

[0680] Example III-22: Preparation of Compound III-22

[0681] Synthesis route of compound III-22:

[0682] Step 1: Preparation of intermediate II-17b

[0683] N-Bromosuccinimide (NBS, 585 mg, 3.29 mmol) was added to a solution of II-17a (323 mg, 3.29 mmol) in dimethylformamide (DMF, 17 mL). The reaction mixture was stirred at 30°C for 1 hour. The reaction solution was then concentrated and purified by silica gel flash chromatography (increasing the methanol ratio in ethyl acetate from 0% to 20%) to afford II-17b as a yellow solid (286 mg, 49% yield). LC-MS (ESI): [M+1] = 176.9.

[0684] Step 2: Preparation of Intermediate II-17d

[0685] II-17b (286 mg, 1.62 mmol), II-17c (244.5 mg, 1.62 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (118.5 mg, 0.162 mmol), and potassium carbonate (670 mg, 4.85 mmol) were dissolved in 1,4-dioxane (10 mL) and water (3 mL). The mixture was reacted at 80°C overnight under nitrogen. After completion of the reaction, the product was purified by flash silica gel column chromatography with petroleum ether (PE) / ethyl acetate (EA) to obtain the product II-17d (178 mg, 54% yield). LC-MS (ESI): [M+1]+ = 204.1.

[0686] Steps 3, 4, and 5 were carried out according to the synthesis method of Example II-1, except that 1a-1 was replaced with II-17d and epifluoropropane was replaced with fluoroethyl p-toluenesulfonate (II-17f) to obtain product III-22 (59 mg, yellow solid). LC-MS (ESI): [M+1]+ = 397.1.

[0687] Example III-23: Preparation of Compound III-23

[0688] Synthesis route of compound III-23:

[0689] Step 1: Synthesis of Precursor III-X

[0690] Id-38 (0.06 mmol), If-1 (0.29 mmol), and potassium carbonate (16 mg, 0.12 mmol) were added to DMF (0.5 mL) and reacted at 80°C for 2 h. After the reaction was complete, purification by flash silica gel column chromatography (PE / EA) afforded product III-X (3.8 mg, 0.006 mmol) as a yellow solid in a 57% yield. MS-ESI: m / z 703.2 [M+H] + .

[0691] Step 2: Synthesis of Precursor III-23

[0692] 150mCi 18 F was enriched on a QMA column and washed with 0.6 mL of eluent (150 mg Kryptofix 222, 15 mg K2CO3 dissolved in 9 mL acetonitrile and 1 mL water). 18F was eluted into a reaction flask; the solvent was dried by heating at 110°C for 20 min under high-purity nitrogen; 0.5 mg of IX was added to the reaction flask and the reaction was carried out at 140°C for 10 min; then 0.2 mL of 2N hydrochloric acid was added and the reaction was carried out at 105°C for 8 min to remove the THP protecting group; the reaction solution was separated and purified by HPLC (HPLC conditions: CAPCELL PAK C18 UG80 10 mm×250 mm, acetonitrile:water = 25:75, flow rate: 3 mL / min), the product was collected and subjected to solid-phase extraction on a C18 column, and the final product III-23 was obtained by elution with ethanol, with a labeling efficiency of 14%.

[0693] Reference Example 1: Preparation of Reference Compound 1

[0694] Synthesis route of reference compound 1:

[0695] Step 1: Preparation of intermediate 13

[0696] To a solution of compound 11 (4 g, 25.64 mmol) and compound 12 (3.6 g, 25.64 mmol) in 1,4-dioxane (100 mL) and water (20 mL) were added Pd(dppf)Cl2 (220 mg, 0.3 mmol) and K2CO3 (10.46 g, 76.92 mmol). The reaction mixture was heated to 80°C under nitrogen for 15 hours. After completion of the reaction, the reaction mixture was filtered and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 13 (800 mg, 14.3% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δ9.90 (s, 1H), 7.73 (d, J = 4.0Hz, 1H), 7.69-7.59 (m, 1H), 7.49 (t ,J=8.0Hz,1H),7.04(d,J=6.8Hz,1H),6.40(d,J=8.4Hz,1H),2.99(d,J=4.0Hz,3H).

[0697] Step 2: Preparation of reference compound 1

[0698] Compound 13 (600 mg, 2.75 mmol) and compound 14 (836 mg, 2.75 mmol) were dissolved in methanol (50 mL) and heated to 80°C for 15 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered. The solid was recrystallized from methanol, washed, and dried to yield reference compound 1 (60 mg, 4.3%) as a yellow solid. LCMS: m / z (ESI) = 378.2 [M+H]+. 1H NMR (400MHz, DMSO) δ8.45-8.41(m,2H),8.28(d,J=8.6Hz,1H),7.99(d,J=3.8Hz,1H),7.87(d,J=15.2Hz,2H),7.82-7.70(m,2H),7.49(t,J=7.8H z,1H),7.20(d,J=7.4Hz,1H),6.74(d,J=4.6Hz,1H),6.49(d,J=8.4Hz,1H),4.95(d,J=7.2Hz,2H),2.88(d,J=4.8Hz,3H),1.48(t,J=7.2Hz,3H).

[0699] Reference Example 2: Preparation of Reference Compound 2

[0700] The synthesis of reference compound 2 was carried out according to patent publication KR20190090448. Reference compound 2 was a yellow solid (61.7 mg). LCMS: m / z (ESI) = 435.6 [M+H] + . .

[0701] Biological test example 1: protein level activity test

[0702] Fluorescence and surface plasmon resonance (SPR) are commonly used assays for detecting interactions between small molecules and proteins. The applicant used these two methods to test the binding affinity of the example compounds to α-synuclein.

[0703] 1.1 Experimental methods:

[0704] (1) Preparation of α-syn:

[0705] The α-syn plasmid and the yeast N-acetyltransferase complex B plasmid were co-transformed into BL21(DE3) competent E. coli cells. The transformation medium was plated onto solid culture plates containing ampicillin and chloramphenicol (Gibco, Cat. No. 15140148) and cultured overnight at 37°C for plasmid transformation. A single colony was selected and plated in 20 ml of 2×YT medium (Sigma-Aldrich, 2× yeast extract tryptone medium containing the appropriate penicillin and chloramphenicol) at 37°C, 220 rpm, and cultured overnight. The culture was then inoculated into 1 L of 2×YT medium at a 1:100 ratio. After 1 hour (when the culture OD600 reached 0.8-1), 1 mM IPTG (isopropyl β-D-1-thiogalactopyranoside) was added and induced at 37°C for 4 hours. The E. coli were harvested by centrifugation (4°C, 4500 rpm, 20 minutes). Resuspend the harvested E. coli in 60-80 ml of bacterial lysis buffer (100 mM Tris-HCl, pH 8.0, 1 mM EDTA, 1 mM PMSF). Lyse the cells using high-pressure disruptor (4°C, 10 min). Centrifuge the cell lysate (4°C, 15,000 rpm, 25 min), and boil the supernatant in a water bath for 15 min. Centrifuge again (4°C, 15,000 rpm, 25 min), add streptomycin sulfate (20 mg / ml, wt / vol), and stir continuously at 4°C for 30 min. Centrifuge the lysate further (4°C, 15,000 rpm, 25 min), and adjust the pH of the supernatant to 3.5. Finally, centrifuge (4°C, 15,000 rpm, 25 min) and dialyze the supernatant overnight (4°C) into 25 mM Tris-HCl, pH 8.0.

[0706] First, an anion exchange column (Q column) was used for purification: the Q column was washed with Buffer B (25mM Tris-HCl, pH 8.0, 1M NaCl) and equilibrated with Buffer A (25mM Tris-HCl, pH 8.0) (5-10 column volumes). The protein dialyzate was filtered through a 0.22μm filter membrane and purified using a protein purification system. Load the sample onto the Q column, then wash away the unbound protein with Buffer A; set the gradient elution from 0-60% Buffer B over 40 min; use The eluate was collected by an automatic sampling system. Then, the protein was purified using a gel size exclusion column (Superdex 75): the target protein solution eluted from the Q column was collected, concentrated and filtered, and then loaded using a sample loop; the molecular sieve was eluted using D PBS buffer (Thermo Fisher Scientific, Cat. No. 14040117). The eluate was collected by an automatic sampling system to prepare pure α-synuclein monomers.

[0707] (2) Preparation of α-synuclein aggregates: α-syn protein monomers (200 μM, in 50 mM Tris, pH 7.5, 150 mM KCl buffer) were placed on a ThermoMixer shaker and incubated at 37°C, 900 rpm for 5-7 days to form amyloid fibrils. Finally, the mature α-syn fibril morphology was examined using transmission electron microscopy (TEM).

[0708] (3) SPR test method: The CMD 500 chip (GE) was cleaned with double distilled water, air-dried, and then the "d℃k" program was run to enter the biacore T200 instrument. Impurities were removed by the "desorb" program, and bubbles were removed by the "Prime" program. The incubated α-syn aggregates (5 mg / mL) were diluted with NaAc buffers with pH values ​​of 4.0, 4.5, 5.0, and 5.5 to 20 μg / mL samples, and injected for 60 seconds. After injection, the sample was eluted with NaOH, and the optimal coupling buffer was selected according to the coupling amount. 200 μL of chip activation solution was injected for 900 seconds to activate the carboxyl groups on the chip. The α-syn aggregates were diluted with NaAc buffer (pH = 4.0) to 50 μg / mL protein samples, and then the protein samples were injected for 110 seconds. This was repeated 10 times to allow the protein to fully couple with the chip. The blocking solution (GE original protein blocking solution) was injected for 900 seconds to block the unreacted carboxyl groups in the chip. The small molecule to be tested is diluted to different concentrations, and the "Kinetic" program in Biacore is run to inject samples in sequence. The binding force and kinetic map of the small molecule are exported using the system software.

[0709] (4) Fluorescence protein binding test: The small molecule was prepared into a 10mM stock solution with DMSO, and then diluted to 20μM with PBS, and then 7 gradient dilutions were performed (three times each dilution); 30μL of the test compound was added to a 384-well plate, 30μL of α-syn aggregates (Example I and Example III series: 1μM; Example II series: 3μM) were added to the experimental group, and an equal amount of PBS was added to the control group. The 384-well plate was shaken (50rpm) and incubated at room temperature for 1 hour; the maximum absorption and emission wavelengths of the small molecule were detected using an enzyme-labeled instrument, and the fluorescence value was detected at this wavelength. The fluorescence change value of the molecule at different concentrations was calculated by deducting the control group from the experimental group, and the binding affinity of the small molecule to the protein was calculated using the Saturation Binding module of GraphPad Prism.

[0710] 1.2 Experimental results:

[0711] Table 1 α-synuclein aggregate binding ability test results of the test compounds Note: A represents K d The value is less than 0.01-0.5 μM, B represents K d The value is between 0.5 and 2 μM, and C represents K d The value is between 2 and 10 μM, and D represents K d Values ​​are greater than 10 μM, and ND stands for not tested.

[0712] Biological Test Example 2: Immunofluorescence staining of α-syn aggregated primary neurons

[0713] 2.1 Experimental methods:

[0714] (1) Primary neuron culture: Place a glass slide in a 24-well plate, add poly-lysine solution, dissect SD mice that are 15-18 days pregnant, remove the left and right cerebral cortex of the fetus and place it in HBSS buffer containing HEPES. After the fetal cortical tissue is rinsed with HBSS buffer, the brain tissue is digested with activated papain and DNase, placed in a 37°C cell culture incubator, and gently flipped several times every 5 minutes. After digestion, filter with a 40μm cell strainer and rinse the filter with 15ml plating medium (10% FBS, 1% PS in DMEM (without pyruvate)). Centrifuge the cell solution at 900rpm for 5 minutes, resuspend with plating medium, and count the cells. Press 10-15×10 4 Plate the cells in 0.5 ml of plating medium per well. After 1-2 hours of incubation in a cell culture incubator, replace the medium with 1 ml of Neurobasal medium (containing 1% PS, B27 supplement, and 0.5 mM GlutaMAX) per well. Finally, culture the neurons in a cell culture incubator until they mature (7-10 days).

[0715] (2) Cell treatment: After primary neurons were cultured in vitro for 7-10 days, α-syn PFF was added to the culture medium at a final concentration of 100 nM. The treated neurons were cultured for an additional 30 days and then collected for sample preparation.

[0716] (3) Immunofluorescence staining: aspirate the stem cell culture medium, wash three times with PBS, and then add 0.3% Triton X-100 and incubate for 10 minutes; after washing with PBS, add 10% goat serum to block for 1 hour; after washing with PBS, add p-129-α-syn antibody (1:600, ab51253, Abcam) and incubate at 4°C overnight; after washing with PBS, add secondary antibody (1:1000, goat-anti-rabbit Alex Fluor 594 and goat-anti-mouse Alex Fluor 488, Invitrogen) and incubate at room temperature for 2 hours; finally, add the test compound and incubate at room temperature for 1 hour, wash with PBS, seal the slides, and photograph using a fluorescence microscope or laser confocal microscope (Olympus laser scanning confocal microscope FV3000).

[0717] 2.2 Experimental results:

[0718] The immunofluorescence staining results are shown in Figure 1. The series of compounds of the present application have green autofluorescence. The experimental results show that the fluorescence of the test compound can co-localize with the fluorescence signal of the pS129 antibody (pathological α-syn), indicating that the compounds of the present application can bind to α-syn aggregates in primary neurons, that is, the compounds of the present application can detect α-syn aggregates in primary neurons.

[0719] Biological Test Example 3: Immunofluorescence staining of PFF mouse brain slices

[0720] 3.1 Experimental methods:

[0721] (1) Construction of the protofibril (PFF) mouse model (i.e., PD mouse model): The mice were weighed and the injection dose of α-syn PFF was calculated (0.2 μg / g). Six-week-old mice were anesthetized and fixed on a stereotaxic instrument. The position of the mouse brain was adjusted so that it was symmetrical on the left and right. The hair on the mouse head was trimmed, and the scalp was cut to expose the skull. Under a microscope, the mouse brain was adjusted with the micrometer on the stereotaxic instrument so that it was flat and symmetrical in front, back, left and right. A hole was made in the dorsal striatum (dSTR) using a cranial puncture, and then α-syn PFF and PBS were injected into the bilateral brain regions of the mouse using a microinjection pump. The PD mice were cultured for 6 to 9 months after surgery, and the mice were killed and the brain tissue was obtained by dissection.

[0722] (2) Brain slice preparation: The brain tissue was fixed overnight with 4% paraformaldehyde solution, dehydrated with sucrose solution, and embedded in a tissue cryoembedding machine. The brain tissue was cut into 30 μm thick slices using a microtome (Leica CM1860), collected in cryoprotective solution (30% sucrose (w / v), 30% ethylene glycol (v / v) dissolved in PBS) and stored at -20°C for subsequent fluorescent staining and imaging.

[0723] (3) Immunofluorescence staining: The prepared brain slices were washed three times with PBS, incubated with 0.3% Triton X-100 for 10 min; washed three times with PBS, blocked with 10% goat serum for 1 h; washed three times with PBS, incubated with p-129-α-syn antibody (1:600, ab51253, Abcam) at 4°C overnight; washed three times with PBS, incubated with secondary antibodies (1:1000, goat-anti-rabbit Alex Fluor 594 and goat-anti-mouse Alex Fluor 488, Invitrogen) at room temperature for 2 h; washed three times with PBS, incubated with the test compound at room temperature for 1 h; washed three times with PBS, sealed and observed with a fluorescence microscope or laser confocal microscopy.

[0724] 3.2 Experimental results:

[0725] The experimental results are shown in Figure 2. The autofluorescence signal of the preferred compound of the present application (also known as the tracer) is co-localized with the pS129 antibody (pathological α-syn) signal, and there is no other non-specific binding signal, indicating that the compound of the present application can specifically recognize pathological α-syn aggregates in brain tissue, verifying the ability of the compound of the present application to bind to α-syn aggregates in brain tissue.

[0726] Biological Test Example 4: Immunofluorescence staining of PD patient brain slices

[0727] 4.1 Experimental methods:

[0728] Brain tissue was obtained from an 86-year-old Asian female PD patient with a 14-year disease course within 12 hours of her death. Immunofluorescence staining was performed using the same method as that used for mouse brain slices in Biological Test Example 3.

[0729] 4.2 Experimental Results

[0730] The experimental results (Figure 3) show that the autofluorescence signal of the compound of the present application (also known as the tracer) colocalizes with the α-syn antibody signal, indicating that the compound of the present application can label pathological α-syn in patient brain slices. Combined with the immunofluorescence staining results of the above cells and mouse brain slices, it shows that the compound of the present application has good target binding ability in vitro.

[0731] Biological Test Example 5: Ex-vivo staining experiment of PFF mouse brain slices

[0732] 5.1 Experimental methods:

[0733] A PFF mouse model was constructed using the method described in Biological Test Example 3. 1 mg / kg of the test compound was injected into the mice via the tail vein. Two hours later, the mice were killed and the brain tissue was removed. Brain slices were prepared and subjected to immunofluorescence staining.

[0734] 5.2 Experimental Results

[0735] The experimental results are shown in FIG4 . The compound of the present application (also known as a tracer) can pass through the blood-brain barrier of mice and specifically recognize pathological α-syn in the mouse brain, indicating that it has good in vivo drugability.

[0736] Biological Test Example 6: Comparison of Compound Binding Activity to α-Syn, Aβ, and Tau

[0737] 6.1 Test compounds

[0738] Example II-1 compound, reference compound 1, reference compound 2, and prior art compound C0505: (Prepared according to WO2014 / 097474)

[0739] 6.2 Experimental methods

[0740] 1) The preparation method of α-synuclein aggregates refers to 1(1) of Activity Test Example 1.

[0741] 2) Expression and purification of human Tau protein

[0742] The genes encoding human tau proteins (containing amino acid sequences 266–391 (3R) and 297–391) were inserted into the pRK172 vector, respectively. The plasmids were transformed into competent Escherichia coli BL21(DE3) cells and cultured at 37°C to an OD600 of 0.8–1.2. Expression was induced by the addition of 1 mM IPTG (isopropyl β-D-1-thiogalactopyranoside) at 24°C for 16 hours. The cells were lysed in wash buffer (50 mM MES, pH 6.0, 10 mM EDTA, 10 mM DTT, 0.1 mM PMSF), followed by centrifugation and filtration. The protein was purified by SP column precipitation with ammonium sulfate, and the pellet was resuspended in phosphate buffer (pH 7.2–7.4) containing DTT (dithiothreitol) and further purified by Superdex 75 gel filtration. Each fraction was analyzed by SDS-PAGE, and the protein concentration was determined using a nanospectrophotometer (Winner 801). The purified protein was stored in phosphate buffer (pH 7.4) containing DTT, quickly frozen, and stored at -80°C.

[0743] 3) Preparation of Tau and Aβ fibrils

[0744] Preparation of Tau fibrils: 190 μM Tau monomer (commercially available, abcam, cat. no. ab246003) was dissolved in a buffer containing 10 mM phosphate buffer (PB, pH 6.0), 10 mM DTT, 200 mM MgCl2, and 0.02% NaN3, and incubated in a Corning 96-well black polystyrene microplate (Thermo) at 37°C with orbital shaking at 200 rpm for 48 hours using a FLUOstar Omega microplate reader (BMG LABTECH).

[0745] Preparation of Aβ fibrils: 200 μM Aβ(1-40,E22Δ) peptide was dissolved in a buffer containing 10 mM phosphate buffer (PB, pH 7.4), 100 mM NaCl, and 0.05% NaN 3 , shaken at 700 rpm in a ThermoMixer, and incubated at 37° C. for 7 days.

[0746] 4) Fluorescence binding experiment

[0747] 1 μM of the test compound was mixed with 1 μM of fibrils in a buffer containing 50 mM Tris (pH 7.5) and 150 mM KCl, and incubated at 25°C for 1 hour. The fluorescence signal of the mixture was then measured using a microplate reader. A control reaction without fibrils was also performed to assess nonspecific fluorescence. The results are shown in the table below.

[0748] 6.3 Experimental results

[0749] Binding activity Kd (μM) of representative compounds against α-Syn, Aβ and Tau

[0750] Compared with other reference compounds, the binding activity of the compound of Example II-1 of the present application to α-syn is significantly better than that to Aβ and Tau, indicating that the compound of the present invention has highly selective binding activity to α-syn.

[0751] Activity Test Example 7: Autoradiography (ARG) of Mouse and PD Patient Brain Slices

[0752] 7.1 Mouse model preparation

[0753] C57BL / 6J male mice (2 months old, 18-20 g, purchased from Shanghai Lingchang Biotechnology Co., Ltd.), 5 per cage, 12-h light-dark cycle, free access to food and water. Mice were anesthetized with a mixture of 0.5% isoflurane and 1% oxygen, and body temperature was maintained with a heating pad. α-Syn PFF (5 μg) was stereotaxically injected into the dorsal neostriatum (dSTR) of both hemispheres at the coordinates: AP ± 2.0 mm, ML + 0.2 mm, DV - 2.60 mm. A 10 μL microsyringe was used to infuse the first 0.5 μL at a rate of 0.5 μL / min, and the remaining 2 μL was then infused at a rate of 0.2 μL / min. Control animals received sterile PBS in the same manner. Mice were monitored regularly after postoperative recovery.

[0754] 7.2 Autoradiography (ARG)

[0755] Brain slices of the mouse model in 7.1 were prepared according to the method of Biological Test Example 3, and brain slices of PD patients were prepared according to the method of Biological Test Example 4. The brain slices were pre-incubated in PBS buffer for 30 minutes at 25°C, and then incubated with 10nM 18F-FD4 (Compound of Example II-8) in PBS buffer containing 20% ​​ethanol at 25°C for 1 hour. After rinsing with pre-cooled PBS buffer containing 20% ​​ethanol, the brain slices were dried and placed on an imaging plate and covered with a storage phosphor screen overnight. The plate was then scanned using a high-sensitivity imaging plate scanner (CR-35 Bio plus), and the images were analyzed using AutoRAD morphological quantitative analysis software. Non-specific and off-target binding of 18F-FD4 was eliminated by adding excess unlabeled FD4 (Compound of Example II-1) (10 μM for mouse brain, 2 μM for human brain) and MAO-A / B inhibitor (Clorgyline / Selegiline, 10 μM), respectively.

[0756] 7.3 Experimental Results

[0757] This experiment further evaluated the sensitivity of 18F-FD4 to α-syn aggregates in mouse and human brain slices. The results, as shown in Figures 5A and 5B, show that at a concentration of 10 nM, 18F-FD4 produced significant radioactive signals in brain slices of mice injected with α-syn PFFs and patients with Parkinson's disease (PD); while no signal was detected in brain slices of healthy individuals. Referring to the experimental method of Biological Test Example 3.1, antibody immunostaining (β-amyloid antibody: NAB228, Cell Signaling Technology; Tau antibody: AT8, BioLegend; α-syn antibody: ab138501, ab51253, Abcam) confirmed that the positive radioactive signal co-localized with α-syn aggregates, but not with Aβ and Tau aggregates. After adding an excess of unlabeled FD4, the radioactive signal completely disappeared, excluding the nonspecific binding of 18F-FD4. Furthermore, the radioactivity remained unchanged after the addition of MAO-A and MAO-B inhibitors, ruling out possible nonspecific binding of the targeted monoamine oxidase (MAO). These results support the potential of FD4 as a highly sensitive and selective PET imaging tracer for pathological α-syn aggregates.

[0758] Activity Test Example 8: PET imaging of the compounds of the present application in rodents, marmosets and human subjects

[0759] 8.1 Rat Model Preparation

[0760] Sprague Dawley female rats (10-12 weeks old, 250-350 g, purchased from Shanghai Lingchang Biotechnology Co., Ltd.), 3 per cage, were housed in a 12-hour light-dark cycle with free access to food and water. The rats were anesthetized with a mixture of Zoletil 50 (15 mg / kg) and xylazine hydrochloride (5 mg / kg). A heating pad was used to maintain their body temperature. α-Syn PFFs (18 μg) were stereotactically injected into the dorsal neostriatum (dSTR) of the left hemisphere at the coordinates: AP + 0.1 mm, ML - 2.5 mm, DV - 4.5 mm. A glass microelectrode was used to infuse the first 0.5 μL at a rate of 0.5 μL / min, followed by the remaining PFFs at a rate of 0.2 μL / min. Control animals received sterile PBS in the same manner. The rats were monitored regularly after recovery from surgery.

[0761] 8.2 Preparation of marmoset model

[0762] Marmosets (2 years old, 400-600 g) were housed at the Jiuting Experimental Center, Institute of Neuroscience. Marmosets were housed two per cage and maintained on a 12-h light-dark cycle with free access to food and water. The marmosets were anesthetized with a mixture of 0.5% isoflurane and 1% oxygen, and their body temperature was maintained using a heating pad. α-Syn PFFs (200 μg) were stereotaxically injected into the caudate nucleus and putamen of the right hemisphere. The coordinates of the caudate nucleus were: 9.5 mm interaural, 3 mm lateral, 7.6 mm deep, and the coordinates of the putamen were: 9.5 mm interaural, 6 mm lateral, 9.3 mm deep. A 10 μL microsyringe was used for infusion at a rate of 10 nL / sec. The marmosets were monitored regularly after postoperative recovery.

[0763] 8.3 Human Subjects

[0764] Fourteen subjects were enrolled in this study. All subjects or their legal guardians provided written informed consent in accordance with the Declaration of Helsinki before study entry. This study was approved by the Institutional Review Board (HIRB) of Huashan Hospital Affiliated to Fudan University (Approval No. (2024) Review No. (592)). This study was registered with the Chinese Clinical Trial Registry (Registration No.: ChiCTR2400093128).

[0765] Diagnoses were confirmed by three movement disorder experts, with PD diagnosed according to the 2015 Movement Disorder Society (MDS) criteria63 and MSA diagnosed according to the 2022 MDS criteria64, meeting the definition of clinically probable or clinically definite MSA. Healthy controls had no history of neurologic or psychiatric disorders; furthermore, they did not demonstrate any deficits on neurologic examination or pre-imaging assessment. Pre-imaging assessment included motor and cognitive assessments, complete blood count (CBC), urinalysis (UA), liver function tests (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), renal function tests (serum creatinine and blood urea nitrogen [BUN]), serum electrolyte analysis, and electrocardiogram (ECG). Vital signs were monitored at baseline and 10 and 30 minutes after injection. Two-week follow-up included repeated laboratory assessments and documentation of adverse events.

[0766] 8.4. PET Imaging in Rodents and Marmosets

[0767] The above-mentioned model rats and marmosets were anesthetized with 2.0-4.0% isoflurane during PET scanning. 18F-FD4 was injected via the tail vein at a dose of 1-1.5 mci / rat and 1.5-2.0 mci / marmoset. Dynamic PET scanning was performed for 90 minutes using a Siemens INVEON PET / CT scanner. CT attenuation correction was used during PET acquisition, and CT scanning lasted approximately 5 minutes. PET images were reconstructed using a filtered back projection algorithm with CT attenuation correction. The reconstructed pixel size was 0.2 mm × 0.2 mm × 0.8 mm, and image analysis was subsequently performed using PMOD software. Uptake in key brain regions was analyzed using the ROI method on the Inveon platform. Each experiment was performed twice in each group.

[0768] 8.5 PET Imaging of Human Subjects

[0769] 18F-FD4 imaging was performed in three-dimensional (3D) mode on a PET / CT scanner (u780 / UExplorer, United Imaging Healthcare, Shanghai, China) at Huashan Hospital of Fudan University in Shanghai. Each participant received a 6-8 mcI injection of 18F-FD4. Low-dose CT transmission was acquired before the PET scan for attenuation correction. Healthy controls underwent dynamic imaging 0-100 minutes after injection, while patients with PD and MSA underwent 20-minute PET imaging (60-80 minutes after injection). Image reconstruction was performed using the ordered subset expectation maximization 3D (OSEM 3D) method. In addition, all subjects who underwent 18F-FD4 PET / CT imaging also underwent a separate 3D T1 MRI scan using a Siemens MAGNETOM Prisma scanner.

[0770] 8.6 Experimental Results

[0771] Figure 6A shows PET imaging of PFF-injected rats (right striatum, 0.5 months) for 50-60 minutes, indicating that 18F-FD4 can effectively penetrate the blood-brain barrier and is enriched in the right striatum of α-syn model rats, indicating that this molecule can image α-syn PFFs around the striatum.

[0772] Figure 6B shows a schematic diagram of PET imaging of a PFF-injected marmoset (right striatum, 6 months old) over 50-60 minutes of imaging, along with a comparison of the Standardized Uptake Value Ratio (SUVR) of the right striatum and frontal cortex. This graphic demonstrates that F18-FD4 effectively crosses the blood-brain barrier and exhibits elevated uptake in the right striatum and frontal cortex of the α-syn model marmoset, indicating that the molecule can image α-syn aggregation around these brain regions.

[0773] Figure 6C shows PET imaging of PFF-injected rats (left striatum, 4 months) at 55-60 minutes of development, indicating that FD17 (Compound of Example II-29) can effectively penetrate the blood-brain barrier and has increased uptake in the bilateral striatum of α-syn model rats, and the signal in the left striatum is higher than that in the right striatum. This signal is consistent with the distribution of α-syn in the brain of the model rats, indicating that FD17 can effectively label α-syn.

[0774] Figure 6D shows PET imaging of a PFF-injected marmoset (right striatum, 5 months old) taken 50-60 minutes after development. This image demonstrates that FD17 effectively crosses the blood-brain barrier and accumulates in the striatum of the α-syn model marmoset, with higher uptake in the right striatum compared to the left. Meanwhile, uptake in the striatum of WT marmosets was not increased, indicating that this molecule can image α-syn pathology around the striatum.

[0775] Figure 6E shows PET imaging of PFF-injected rats (left striatum, 0.5 months) for 30 to 40 minutes, showing that FA35 (Compound of Example III-23) can effectively penetrate the blood-brain barrier and is enriched in the striatum of α-syn model rats, indicating that this molecule can image α-syn PFFs around the striatum.

[0776] Figure 6F shows PET imaging of PFF-injected rats (left striatum, 0.5 months) for 60-80 minutes, showing that FA23 (Example I-48 compound) can effectively penetrate the blood-brain barrier and is enriched in the striatum of α-syn model rats, indicating that this molecule can image α-syn PFF injected into the striatum.

[0777] Figure 7 shows PET imaging of a human subject treated with the 18F FD4 compound. 18F FD4 showed a significant increase in radioligand uptake, which can be observed at the midbrain level (indicated by the arrow). Nonspecific signal in the SN and SNc was minimal.

[0778] Figure 8 shows PET imaging of human subjects receiving the prior art compound C0505 (Endo et al., Imaging α-synuclein pathologies in animal models and patients with Parkinson's and related diseases, Neuron 112, 1-18, August 7, 2024). Although the total midbrain tracer uptake was higher in patients with PD / DLB, nonspecific signals were also observed in healthy volunteers (A). In addition, the SUVR values ​​of many PD / DLB cases were close to or even lower than those of healthy volunteers (B), indicating that C0505 is ineffective for PD / DLB imaging.

[0779] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound that specifically recognizes α-synuclein aggregates, characterized in that The compound is a compound represented by formula A, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotope variant thereof, in, X, Y and U are independently selected from CH and N, and when any one of them is CH, the hydrogen atom on the CH may be replaced by R1; W is selected from CH and N; Z is selected from CH2, NH, O and S; L is selected from -CH=CH- and -C≡C-, and when n is greater than 1, -(L) n - L's that are identical or different from each other form a chain; Ring A is selected from C 6-8 Cycloalkanes, C 6-12 aromatic rings, 6-10 membered heteroaromatic rings and 6-8 membered heterocyclic rings; Ring B is selected from C 4-8 Cycloalkanes, C 6-12 aromatic rings, 5-10 membered heteroaromatic rings and 4-8 membered heterocyclic rings; M is a directly connected bond or a 4-8 membered heterocyclic ring; R1 is independently selected from the group consisting of: deuterium, tritium, hydroxyl, amino, halogen, nitro, cyano, -COOH, -C 1-6 Alkyl, -C 2- 6-alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SO2-C 1-6 Alkyl, -CO-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHCO-C 1-6 Alkyl, -N(C 1-6 alkyl)-CO-C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -NHSO2-C 1-6 Alkyl, -N(C 1-6 Alkyl)-SO2-C 1-6 Alkyl, -NH-C 3-8 Cycloalkyl, -N(C 1-6 Alkyl)(C 3-8 Cycloalkyl), -C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl, Among them, -C in R1 1-6 Alkyl or C as part of a group 1-6 Alkyl, -C 3-8 Cycloalkyl or -C as part of a group 3-8 The cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents, each of which is independently selected from deuterium, tritium, -OC 1-6 Alkyl, -C 1-6 Alkyl, halogen, hydroxy, oxo, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -O-(3-6 membered heterocyclic group), -O-(p-toluenesulfonyl), and the two substituents attached to the same C atom optionally form a 3-6 membered heterocyclic ring with the C atom to which they are attached; R2 and R3 are each independently selected from the group consisting of: deuterium, tritium, hydroxyl, amino, halogen, nitro, cyano, -COOH, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SO2-C 1-6 Alkyl, -CO-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHCO-C 1-6 Alkyl, -N(C 1-6 alkyl)-CO-C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -NHSO2-C 1-6 Alkyl, -N(C 1-6 Alkyl)-SO2-C 1-6 Alkyl, -NH-C 3-8 Cycloalkyl, -N(C 1-6 Alkyl)(C 3-8 Cycloalkyl), -C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl and C 6-12 Aryl, in which -C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 5-10 membered heteroaryl and C 6-12 Each aryl group is independently optionally substituted by halogen, hydroxy, -OC 1-6 Alkyl, -NHC 1-6 Alkyl or -N(C 1-6 alkyl)2, wherein R3 appears -C 1-6 Alkyl or C as part of other groups or substituents 1-6 The alkyl group is optionally substituted with one or more substituents each independently selected from the group consisting of deuterium, tritium, halogen, hydroxy, -O-(3-6 membered heterocyclyl), -O-(p-toluenesulfonyl); n is an integer from 0 to 3; p is an integer from 1 to 4; q and t are each independently selected from an integer from 0 to 5; wherein the heteroaryl and heterocyclyl groups each independently contain 1, 2, 3 or 4 heteroatoms selected from N, S or O; and Each occurrence of halogen is optionally an isotopic form thereof, and each occurrence of the ....

2. The compound according to claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein W is selected from CH and N; and Z is selected from O and S.

3. The compound according to claim 1 or 2, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein X, Y and U are all CH, or one or two of X, Y and U are N and the rest are CH.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein the fused ring comprising X, Y, U, W and Z is selected from:

5. The compound according to any one of claims 1 to 4, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotopic variant thereof, wherein p is an integer from 1 to 2, and R1 is independently selected from the group consisting of: halogen, nitro, hydroxyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -COOH, -NHCO-C 1-6 Alkyl, -N(C 1-6 alkyl)-CO-C 1- 6-membered alkyl and 5-8-membered heterocyclic group, wherein -C in R1 1-6 Alkyl or C as part of a group 1-6 The alkyl and 5-8 membered heterocyclic groups are each independently optionally substituted by one or more, for example, 1-2 substituents, each of which is independently selected from deuterium, tritium, -OC 1-6 Alkyl, -C 1-6 Alkyl, halogen, hydroxy, oxo, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -O-(3-6 membered heterocyclyl), -O-(p-toluenesulfonyl), wherein the halogen present in R1 is optionally in an isotopic form, such as 18F.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotopic variant thereof, wherein p is an integer from 1 to 2, and R1 is independently selected from halogen, nitro, hydroxyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 1-6 Halogenated hydroxyalkyl, -O- substituted by O-(3-6 membered heterocyclic group) and / or -O-(p-toluenesulfonyl) 1-6 Alkyl, -NHC 1-6 Alkyl, -NHC 1-6 Haloalkyl, -NHC 1-6 Halogenated hydroxyalkyl, -NH- substituted by O-(3-6 membered heterocyclic group) and / or -O-(p-toluenesulfonyl) 1-6 Alkyl, -N(C 1-6 Alkyl)2, -COOH, -NHCO-C 1- 6-alkyl, -N(C 1-6 alkyl)-CO-C 1-6 Alkyl and 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by 1 or more, for example 1-2 substituents, each of which is independently selected from deuterium, tritium, -OC 1-6 Alkyl, -C 1-6 Alkyl, halogen, hydroxy, oxo, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, wherein the halogen present in R1 is optionally in an isotopic form, for example F18.

7. The compound according to any one of claims 1 to 6, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotopic variant thereof, wherein p is an integer from 1 to 2, and R1 is independently selected from the group consisting of: F, Br, 8. The compound according to any one of claims 1 to 7, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein p is 1, and R is located at an adjacent ring carbon atom of Y; or p is 2, and R is attached to adjacent ring carbon atoms of Y and Y, respectively, or R is attached to X and a ring carbon atom between X and Y, respectively.

9. The compound according to any one of claims 1 to 8, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein p is 1.

10. The compound according to any one of claims 1 to 9, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein R1 is each independently selected from 11. A compound according to any one of claims 1 to 10, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein n is not 0 and M is absent, and formula (A) has the following sub-formula:

12. The compound according to any one of claims 1 to 10, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein n is 0 and M is a 4-8 membered heterocycle, and formula (A) has the following sub-formula:

13. A compound according to any one of claims 1 to 11, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein n is 1, and L is -CH=CH-, or L is -C≡C-; or n is 2, and (L)2 is -CH=CH-CH=CH-, -CH=CH-C≡C-, -C≡C-CH=CH-, or -C≡CC≡C-, preferably -CH=CH-CH=CH- or -CH=CH-C≡C-; or n is 3, and (L)3 is -CH=CH-CH=CH-CH=CH-, -CH=CH-CH=CH-C≡C-, -CH=CH-C≡C-CH=CH-, -C≡C-CH=CH-CH=CH-, -CH=CH-C≡CC≡C-, -C ≡C-CH=CH-C≡C- or -C≡CC≡C-CH=CH-, preferably -CH=CH-CH=CH-CH=CH-, -CH=CH-CH=CH-C≡C-, -CH=CH-C≡C-CH=CH- or -CH=CH-C≡CC≡C-.

14. The compound according to any one of claims 1 to 13, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotopic variant thereof, wherein Ring A is selected from C 6-10 Aromatic ring, 6-8 membered heteroaromatic ring and 6-8 membered heterocyclic ring, for example, ring A is selected from benzene ring and 6-membered heteroaromatic ring or 6-membered heterocyclic ring containing 1 or 2 nitrogen heteroatoms, for example, A is selected from 15. The compound according to any one of claims 1 to 14, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotopic variant thereof, wherein ring A is selected from 16. A compound according to any one of claims 1 to 15, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein ring A is linked to the remainder of the molecule via a ring carbon atom, or when ring A is a heterocycle, may also be linked to the remainder of the molecule via a ring heteroatom.

17. The compound according to any one of claims 1 to 16, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotopic variant thereof, wherein Ring A is unsubstituted, or Ring A is substituted with one R2, R2 being selected from halogen, nitro, cyano and halogen-substituted -C 1-6 Alkyl, for example selected from halogen, nitro and cyano, for example R2 is selected from halogen or an isotope thereof, for example R2 is selected from F and 18F.

18. The compound according to any one of claims 1 to 17, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein ring B is selected from C 6-10 Aromatic rings and 5-8 membered heteroaromatic rings, for example, ring B is selected from benzene rings, naphthalene rings and 5-6 membered heteroaromatic rings containing 1-3, for example 1 or 2, heteroatoms selected from nitrogen, oxygen and sulfur, for example, B is selected from 19. The compound according to any one of claims 1 to 18, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein ring B is selected from 20. The compound according to any one of claims 1 to 19, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring B is optionally substituted with 1 or 2 R3, R3 being selected from hydroxy, amino, halogen, nitro, cyano, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 3-8 Cycloalkyl, 5-8 membered heterocyclic group and C 6-10 Aryl, the -C 3-8 Cycloalkyl, 5-8 membered heterocyclic group and C 6-10 Aryl is preferably -C 3-6 Cycloalkyl, 5-7 membered heterocyclic group and C6 aryl, each independently optionally substituted by halogen, hydroxyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl or -N(C 1-6 alkyl)2, wherein the -C 1-6 The alkyl group is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of deuterium, tritium, halogen, hydroxy, -O-(3-6 membered heterocyclyl) and -O-(p-toluenesulfonyl), preferably deuterium, tritium, halogen and hydroxy.

21. The compound according to any one of claims 1 to 20, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein Ring B is optionally substituted with 1 or 2 R3, R3 being selected from the group consisting of: hydroxy, amino, F, Br, nitro, cyano, -O-CH3, -NHCH3, -N(CH3 alkyl)2, 22. The compound according to any one of claims 1 to 21, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein ring B is replaced by -NHC 1-6 Alkyl substitution.

23. A compound according to any one of claims 1 to 22, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein t is 1.

24. A compound according to any one of claims 1 to 8 and 10 to 17, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, wherein M is a 6-8 membered nitrogen-containing heterocycle, such as a 6-membered nitrogen-containing heterocycle, such as 25. A compound according to any one of claims 1 to 24, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, comprising an isotope selected from the group consisting of 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, preferably comprising 18F.

26. A compound according to claim 1 or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, selected from:

27. The compound according to claim 26, which is selected from the following compounds and stereoisomers thereof, or pharmaceutically acceptable salts or solvates thereof:

28. A compound as defined in any one of claims 1 to 27, or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotope variant thereof, for use in the treatment or diagnosis of neurodegenerative diseases associated with α-synuclein aggregates and other misfolded protein aggregates.

29. A composition that specifically binds to α-synuclein aggregates, comprising a compound according to any one of claims 1 to 28 or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotope variant thereof, and one or more pharmaceutically acceptable carriers.

30. Use of a compound according to any one of claims 1 to 28 or a stereoisomer, pharmaceutically acceptable salt, solvate or stable isotopic variant thereof, or a composition according to claim 29, in the preparation of a medicament for the treatment or diagnosis of neurodegenerative diseases associated with α-synuclein aggregates and other misfolded protein aggregates.

31. The method according to claim 30, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, muscular dystrophy, progressive supranuclear palsy, preferably Parkinson's disease and muscular dystrophy.

32. A method for detecting α-synuclein aggregates in a subject, comprising the steps of: (A) administering to the subject a safe and effective amount of a compound according to any one of claims 1 to 28 or a composition according to claim 28; and (B) detecting the binding of the compound or composition to α-synuclein aggregates in the subject.

33. The method according to claim 32, characterized in that The detection in step (B) is performed by imaging technology, preferably by the following imaging technology: positron emission tomography, single photon emission tomography, near-infrared brain function imaging, optical imaging, or a combination thereof.

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