Diaryl piperazine compound and application thereof in neurodegenerative diseases and heart-related diseases

Abstract

The invention relates to the technical field of radiopharmaceutical chemistry and clinical nuclear medicine, and particularly provides a diaryl piperazine compound capable of detecting neurodegenerative diseases and heart-related diseases and a derivative of the diaryl piperazine compound. The compound has high affinity to aggregated beta-folded proteins such as pathological beta-amyloid protein, immunoglobulin light chain aggregate, transthyretin aggregate and the like, and has a structure as shown in a general formula I. After being labeled by radionuclides, the compound and the derivative thereof can be used for nuclear medicine clinical diagnosis of patients with amyloid protein deposition characteristics including neurodegenerative diseases and heart amyloid protein diseases. Compound with structure as shown in general formula I: # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine. Specifically, it relates to a diarylpiperazine compound having high affinity for amyloid protein, and its preparation and application. Background Art

[0002] Modern molecular imaging techniques, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, are highly sensitive molecular imaging techniques. They achieve in-vivo imaging by specifically binding a tracer labeled with a positron or single photon radionuclide to a biomarker, and can quantitatively analyze the trace concentration of the radioactive tracer in the body, thereby achieving non-invasive localization at the molecular level. The information provided by PET and SPECT is of great value for the detection of biomarkers in patients, and can better monitor the location and degree of pathological changes at different stages. In recent years, it has been affirmed by clinical trials.

[0003] Amyloidosis is a disease caused by the accumulation of abnormally folded proteins in tissues, and the symptoms depend on the location of amyloid protein accumulation. The kidneys and heart are the most common affected organs, and the lesions can also involve the nervous system, gastrointestinal tract and accessory organs, glands (thyroid, adrenal, pancreas in diabetic patients), musculoskeletal system, eyes, oral cavity, etc.

[0004] Neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, etc., among which AD is the most common type. AD is an age-related, progressive and irreversible disease, with clinical manifestations such as memory loss, progressive intellectual decline, language disorders, personality and behavior changes, etc., ultimately affecting daily life. One of its most important pathological features is the presence of Aβ plaques formed by the aggregation of β-amyloid (Aβ) protein in the brain. The deposition of Aβ plaques begins 10 - 20 years before the onset of symptoms. The "A / T / N" framework for AD diagnosis research proposed in 2018 reconfirmed the extremely high specificity of Aβ plaques for AD, and a positive Aβ plaque detection has a high probability of suffering from AD. Developing diagnostic drugs for AD and achieving early diagnosis of AD at the preclinical stage may be able to intervene in the disease before irreversible neuronal damage occurs, effectively delaying the disease process and reducing the social medical and economic burden.

[0005] Currently, many tracers have entered the clinical stage. For example, the Aβ-PET tracers that have been approved by the US FDA for AD clinical diagnosis are 18 F-labeled stilbene derivatives 18 F]Florbetapir and 18 F]Florbetaben, and thioflavin T derivatives18 F]Flutemetamol, but these compounds have non-specific binding in the white matter region of the brain. 11 C-labeled Pittsburgh Compound B ( 11 C-PiB) is limited in its application due to 11 the short half-life of 123 I]IMPY was the first SPECT imaging agent to enter the clinical stage, but it could not be practically applied due to its poor in vivo stability. Therefore, the development of 18 F-labeled Aβ plaque imaging agents and the reduction of non-specific binding in the brain have become a hot topic in AD diagnostic research.

[0006] Cardiac amyloidosis (CA) is caused by the misfolding of abnormal precursor proteins to form amyloid fibrils deposited in the extracellular space of cardiomyocytes. Clinically, it mainly presents as restrictive cardiomyopathy and heart failure. More than 95% of amyloidosis involving the heart is caused by immunoglobulin light chain type CA (AL-CA) and transthyretin type CA (ATTR-CA). The latter is divided into mutant (ATTRv) and wild-type (ATTRwt) according to whether there is a gene mutation. AL originates from the overproduction of immunoglobulin light chains due to the expansion of clonal plasma cells and is a disease with rapid progression and high mortality. The median survival time of patients with AL-CA is only 6 months after diagnosis. ATTR-CA is caused by the dissociation and misfolding of transthyretin, and the median survival time after diagnosis is about 5 years. Developing early diagnostic drugs for CA is one of the important means to extend the lifespan of CA patients.

[0007] Currently, it is known that there is local and dense calcification in the myocardial tissue with ATTR deposition, so radioactive bone tracers 99m Tc]PYP / DPD / HMDP have been proven to have clinical value in diagnosing ATTR pathology. 11 C]PiB, 18 F]Florbetapir, 18 F]Florbetaben and 18 F]Flutemetamol were initially used to diagnose AD because they can specifically bind to the β-sheet structure in amyloid proteins, showing promise in diagnosing CA. However, their high signal accumulation in the liver may cause radioactive signal sparsity artifacts, thus interfering with the observation of lesions in the inferior wall of the heart, especially affecting the examination of patients with mild amyloid deposition. Therefore, there is still a need to further screen nuclear medicine PET imaging agents with high affinity, high selectivity for AL and ATTR aggregates, and excellent pharmacokinetic properties. Summary of the Invention

[0008] The object of the present invention is to provide a diarylpiperazine compound and its derivatives capable of detecting neurodegenerative diseases and heart-related diseases, and the compound has a high affinity for aggregating β-sheet amyloid proteins such as pathological β-amyloid protein, immunoglobulin light chain aggregates, and transthyretin aggregates. After being labeled with a radionuclide, the compound and its derivatives can be used for the nuclear medicine clinical diagnosis of patients with amyloid deposition characteristics, including neurodegenerative diseases and cardiac amyloid diseases.

[0009] In a first aspect, the diarylpiperazine compound provided by the present invention has the structure of the following general formula I:

[0010]

[0011] wherein Ar1 represents

[0012] Ar2 represents

[0013] R1 and R2 each independently represent H, 123 / 125 / 127 I, -NH((CH2) m 11 / 12 CH3), -N((CH2) m 11 / 12 CH3)2,

[0014] -O 11 / 12 CH3, -(OCH2CH2) m R3, wherein R3 is 18 / 19 F, and m is any integer between 0 and 6.

[0015] In some embodiments, the diarylpiperazine compound is selected from the following compounds:

[0016]

[0017] wherein both I and F can simultaneously refer to their isotopes such as: 123 / 125 / 127 I and 18 / 19 F;

[0018] In a second aspect, the present invention further provides derivatives of the above-mentioned diarylpiperazine compound, which are pharmaceutically acceptable salts, esters or amide compounds of the diarylpiperazine compound in the first aspect.

[0019] In a third aspect, the present invention further provides a diagnostic or detection reagent for amyloid proteins in neurodegenerative diseases or heart-related diseases, the active ingredient of which is the diarylpiperazine compound described in the first aspect above, and / or the derivative described in the second aspect above.

[0020] In some embodiments, the diseases include but are not limited to Alzheimer's disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, myocardial infarction, ischemia, heart failure, coronary heart disease, cardiac amyloidosis.

[0021] In a fourth aspect, the present invention further provides the use of the diarylpiperazine compound of the first aspect above and / or its derivative in the preparation of a nuclear medicine imaging agent.

[0022] Specifically, the nuclear medicine imaging agent is a PET or SPECT imaging agent.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] The diarylpiperazine compound provided by the present invention has a high affinity for amyloid proteins, including Aβ, AL, and ATTR proteins. After being labeled with a suitable radioisotope, it can be used for nuclear medicine imaging, and is particularly suitable for the diagnosis of neurodegenerative diseases with Aβ protein deposition characteristics including AD and heart-related diseases with AL and ATTR protein deposition characteristics including CA. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a schematic diagram of the synthesis process of the compounds in Examples 1-19 of the present invention, and the reaction reagents and conditions involved are:

[0026] (a) Ethylene glycol, 120 °C, 12 hours; (b) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, 12 hours; (c) n-hexabutylditin, tetrakis(triphenylphosphine)palladium, toluene, 110 °C, under nitrogen protection, 12 hours; (d) Na 125 I, 3% hydrogen peroxide, 1M hydrochloric acid, room temperature, 15 minutes; (e) trimethylamine, trifluoroacetic anhydride, dichloromethane, room temperature, 0.5 hours; (f) tetrabutylammonium fluoride, tetrahydrofuran, 60 °C, 2 hours; (g) 18 F - K 222 / K2CO3, acetonitrile, 60 °C, 10 minutes; (h) 1M hydrochloric acid, tetrahydrofuran, 90 °C, 6 hours; (i) ethylene glycol, 90 °C, 12 hours; (j) triethylamine, tetrahydrofuran, 55 °C, 12 hours; (k) 18F - , tetrabutylammonium bicarbonate, Cu(OTf)2(Py)4, n-butanol, N,N-dimethylacetamide, 110 °C, 20 minutes.

[0027] Figure 2 Schematic diagram of the synthesis process of the compounds of Examples 19-31 of the present invention, and the reaction reagents and conditions involved are:

[0028] (a) Di-tert-butyl dicarbonate, 4-dimethylaminopyridine, triethylamine, tetrahydrofuran, 90 °C, 5 hours; (b) ethylene glycol, 90 °C, 12 hours; (c) ethylene glycol, 120 °C, 12 hours; (d) 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, 12 hours; (e) 1M hydrochloric acid, tetrahydrofuran, 90 °C, 6 hours; (f) bis(pinacolato)diboron, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, potassium acetate, dioxane, 110 °C, under nitrogen protection, 12 hours; (g) n-hexabutylditin, tetrakis(triphenylphosphine)palladium, toluene, 110 °C, under nitrogen protection, 12 hours; (h)(1) 18 F - , tetrabutylammonium bicarbonate, Cu(OTf)2(Py)4, n-butanol, N,N-dimethylacetamide, 110 °C, 20 minutes; (2) 1M hydrochloric acid, acetonitrile, 90 °C, 10 minutes; (i) Na 125 I, 3% hydrogen peroxide, 1M hydrochloric acid, room temperature, 15 minutes.

[0029] Figure 3 Schematic diagram of the synthesis process of the compounds of Examples 32-41 of the present invention, and the reaction reagents and conditions involved are:

[0030] (a) Cesium carbonate, N,N-dimethylformamide, 110 °C, 12 hours; (b) 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, 12 hours; (c) p-toluenesulfonyl chloride, triethylamine, dichloromethane, 40 °C, 12 hours; (d) tetrabutylammonium fluoride, tetrahydrofuran, 60 °C, 2 hours; (e) 18 F - , K 222 / K2CO3, acetonitrile, 100 °C, 10 minutes; (f) tert-butyldimethylchlorosilane, imidazole, acetonitrile, 50 °C, 6 hours; (g) cesium carbonate, N,N-dimethylformamide, 110 °C, 12 hours.

[0031] Figure 4 Schematic diagram of the synthesis process of the compounds of Examples 42-51 of the present invention, and the reaction reagents and conditions involved are:

[0032] (a) Ethylene glycol, 120 °C, 12 h; (b) 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, 12 h; (c) 1 M boron tribromide, dichloromethane, -78 °C, 12 h; (d) tert-Butyldimethylchlorosilane, imidazole, acetonitrile, 50 °C, 6 h; (e) Di-tert-butyl dicarbonate, 4-dimethylaminopyridine, triethylamine, tetrahydrofuran, 90 °C, 5 h; (f) Tetrabutylammonium fluoride, tetrahydrofuran, 60 °C, 2 h; (g) Cesium carbonate, N,N-dimethylformamide, 110 °C, 12 h; (h) p-Toluenesulfonyl chloride, triethylamine, dichloromethane, 40 °C, 12 h; (i) 1 M hydrochloric acid, tetrahydrofuran, 90 °C, 6 h; (j)(1) 18 F - , K 222 / K2CO3, acetonitrile, 100 °C, 10 min; (2) 1 M hydrochloric acid, acetonitrile, 90 °C, 10 min.

[0033] Figure 5 Schematic diagram of the synthesis process of the compounds of Examples 52-61 of the present invention, and the reaction reagents and conditions involved are as follows:

[0034] (a) 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, 12 h; (b) 1 M boron tribromide, dichloromethane, -78 °C, 12 h; (c) Cesium carbonate, N,N-dimethylformamide, 110 °C, 12 h; (d) p-Toluenesulfonyl chloride, triethylamine, dichloromethane, 40 °C, 12 h; (e) Tetrabutylammonium fluoride, tetrahydrofuran, 60 °C, 2 h; (f) 18 F - , K 222 / K2CO3, acetonitrile, 100 °C, 10 min.

[0035] Figure 6 Schematic diagram of the synthesis process of the compounds of Examples 62-64 of the present invention, and the reaction reagents and conditions involved are as follows:

[0036] (a) 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, 12 h; (b) n-Hexabutylditin, tetrakistriphenylphosphinepalladium, toluene, 110 °C, under nitrogen protection, 12 h; (c) Iodine, dichloromethane, room temperature; (d) Na 125 I, 3% hydrogen peroxide, 1 M hydrochloric acid, room temperature, 15 min;

[0037] Figure 7 Schematic diagram of the synthesis process of the compounds of Examples 65 - 73 of the present invention, wherein the reaction reagents and conditions involved are as follows:

[0038] (a) 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, for 12 hours; (b) 1 M boron tribromide, dichloromethane, -78 °C, for 12 hours; (c) (R)-2,2-Dimethyl-1,3-dioxolan-4-yl methyl p-toluenesulfonate, cesium fluoride, N,N-dimethylformamide, 65 °C, for 12 hours; (d) 1 M hydrochloric acid, tetrahydrofuran, 90 °C, for 1 hour; (e) p-Toluenesulfonyl chloride, pyridine, at room temperature; (f) 3,4-Dihydropyran, pyridinium p-toluenesulfonate, dichloromethane, at room temperature, for 12 hours; (g) (1) Tetrabutylammonium fluoride, tetrahydrofuran, 90 °C, for 2 hours; (2) 1 M hydrochloric acid, 90 °C, for 1 hour; (h) ((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene)bis(4-methylbenzenesulfonate), cesium carbonate, N,N-dimethylformamide, 80 °C, for 2 hours; (i) (1) 18 F - ,K 222 / K2CO3, acetonitrile, 110 °C, for 8 minutes; (2) 1 M hydrochloric acid, acetonitrile, 90 °C, for 5 minutes.

[0039] Figure 8 Schematic diagram of the synthesis process of the compounds of Examples 74 - 77 of the present invention, wherein the reaction reagents and conditions involved are as follows:

[0040] (a) Ethylene glycol, 120 °C, for 12 hours; (b) 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, for 12 hours; (c) Trimethylamine, trifluoroacetic anhydride, dichloromethane, at room temperature, for 0.5 hour; (d) Tetrabutylammonium fluoride, tetrahydrofuran, 60 °C, for 2 hours; (e) 18 F - ,K 222 / K2CO3, acetonitrile, 60 °C, for 10 minutes.

[0041] Figure 9 Schematic diagram of the synthesis process of the compounds of Examples 78 - 84 of the present invention, wherein the reaction reagents and conditions involved are as follows:

[0042] (a) Ethylene glycol, 120 °C, for 12 hours; (b) n-Hexabutylditin, tetrakis(triphenylphosphine)palladium, toluene, 110 °C, under nitrogen protection, for 12 hours; (c) Na 125 I, 3% hydrogen peroxide, 1 M hydrochloric acid, at room temperature, for 15 minutes.

[0043] Figure 10 Schematic diagram of the synthesis process of the compounds of Examples 85 - 91 of the present invention, and the reaction reagents and conditions involved are as follows:

[0044] (a) Ethylene glycol, 120 °C, 12 hours; (b) 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, 12 hours; (c) Trimethylamine, trifluoroacetic anhydride, dichloromethane, room temperature, 0.5 hour; (d) Tetrabutylammonium fluoride, tetrahydrofuran, 60 °C, 2 hours.

[0045] Figure 11 Schematic diagram of the synthesis process of the compounds of Examples 85 - 91 of the present invention, and the reaction reagents and conditions involved are as follows:

[0046] (a) Ethylene glycol, 120 °C, 12 hours; (b) 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium(0), potassium tert-butoxide, dioxane, 110 °C, under nitrogen protection, 12 hours; (c) n-Hexabutylditin, tetrakis(triphenylphosphine)palladium, toluene, 110 °C, under nitrogen protection, 12 hours; (d) Iodine, dichloromethane, room temperature; (e) Na 125 I, 3% hydrogen peroxide, 1 M hydrochloric acid, room temperature, 15 minutes.

[0047] Figure 12 For the autoradiography results of the probe labeled with 125 I or 18 F on the brain tissue sections of AD patients (female, 102 years old, temporal lobe; female, 91 years old, temporal lobe; female, 95 years old, frontal lobe; male, 86 years old, frontal lobe).

[0048] Figure 13 For the autoradiography results of the probe labeled with 125 I or 18 F on the myocardial tissue sections of CA patients and healthy volunteers (female, 68 years old; male, 77 years old; female, 84 years old; female, 71 years old).

[0049] Figure 14 For the determination of the IC 18 F] betazine as the radioactive ligand, fluorobenzetazine cold ligand and compound 2 - 3 as inhibitors on the brain tissue sections of AD patients in Example 104 of the present invention 50 value. Where case 1 refers to the test results on section F97 (female, 97 years old, temporal lobe), and case 2 refers to the test results on section F87 (female, 87 years old, temporal lobe).

[0050] Figure 15 In Example 104 of the present invention, 125 Compound 2 labeled with 50 I was used as a radioligand, and Compounds 2, 12, 35, and 77 were inhibitors for IC

[0051] Figure 16 , Figure 17 , Figure 18 , Figure 19 , Figure 20 and Figure 21 were respectively the dynamic PET / CT imaging results of 18 F]12, 18 F]35, 18 F]60, 18 F]61, 18 F]73 and 18 F]77 in normal rats. On the left were the PET / CT fusion images of the rat brain at different time points (from left to right: transverse section, sagittal section, and coronal section) and the maximum signal intensity projection map (MIP) of the whole body transverse section at 60 - 70 min. On the right were the time - activity curves (TAC) in different organs. Detailed Embodiments

[0052] To facilitate the understanding of the present invention, the following further illustrates the implementation process of the present invention with specific implementation examples. These descriptions are only for further explaining the features and advantages of the present invention, rather than limiting the claims of the invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the scope of protection of the present invention.

[0053] Example 1: Synthesis of Compound 1

[0054]

[0055] 2 - Chlorobenzothiazole (3.4 g, 0.02 mol) and piperazine (8.6 g, 0.1 mol) were dissolved in 5 mL of ethylene glycol, and then heated under an oil bath at 120 °C for 12 hours. After the reaction was completed, saturated sodium bicarbonate was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered by suction. After removing dichloromethane from the filtrate by vacuum distillation, column chromatography separation was carried out with the volume ratio of the eluent dichloromethane:methanol = 4:1 to obtain a white solid, which was directly used in the next step without identification.

[0056] Example 2: Synthesis of Compound 2

[0057]

[0058] According to the method of Example 1, using intermediate compound 1 and 2,5-diiodopyridine as raw materials, Compound 2 was synthesized to obtain 246.3 mg of a white solid with a yield of 26.7%. The structure is as follows: 1 H NMR(600MHz,DMSO-d6)δ8.27(t,J=2.7Hz,1H),7.82–7.72(m,2H),7.44(dd,J=8.2,3.3Hz,1H),7.25(dd,J=9.3,6.1Hz,1H),7.05(t,J=7.6Hz,1H),6.79(dd,J=8.9,3.3Hz,1H),3.64–3.62(m,8H). 13 C NMR(151MHz,DMSO-d6)δ168.66,158.02,153.40,152.92,145.54,130.93,126.55,121.87,121.76,119.21,110.61,78.67,47.98,44.35.

[0059] Example 3: Synthesis of Compound 3

[0060]

[0061] According to the method of Example 1, using intermediate compound 1 and 2-bromo-5-fluoropyridine as raw materials, Compound 3 was synthesized to obtain 160.5 mg of a yellow solid with a yield of 58.3%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ8.07(s,1H),7.61(d,J=7.9Hz,1H),7.58(d,J=10.4Hz,1H),7.32–7.27(m,2H),7.09(t,J=7.5Hz,1H),6.66(d,J=9.2Hz,1H),3.78–3.73(m,4H),3.66–3.61(m,4H). 13 C NMR(151MHz,Chloroform-d)δ168.80,156.07,154.96(d,J=234.05Hz),152.57,134.95(d,J=24.16Hz),130.75,126.22,125.29(d,J=19.63Hz),121.77,120.87,119.33,108.19,48.11,45.63.

[0062] Example 4: Synthesis of Compound 4

[0063]

[0064] According to the method of Example 1, using 2-chlorothiazolo[4,5-c]pyridine and piperazine as raw materials to synthesize Compound 4, obtaining a white solid. Without identification, directly proceed to the next reaction.

[0065] Example 5: Synthesis of Compound 5

[0066]

[0067] Dissolve intermediate compound 1 (219.8 mg, 1.0 mmol), p-fluorobromobenzene (175.5 mg, 1.0 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (60.3 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (53.4 mg, 0.05 mmol), and potassium tert-butoxide (337.3 mg, 3.0 mmol) in 10 mL of dioxane, under nitrogen protection, then heat to reflux at 110 °C in an oil bath for 12 hours. After the reaction is completed, remove dioxane by distillation under reduced pressure, add dichloromethane, filter by suction. After removing dichloromethane from the filtrate by distillation under reduced pressure, separate by column chromatography, and the volume ratio of the eluent is petroleum ether:ethyl acetate = 3:1, obtaining 131.47 mg of a white solid with a yield of 42.0%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.61(d,J=8.0Hz,2H),7.32(t,J=7.7Hz,1H),7.11(t,J=7.6Hz,1H),7.03–6.96(m,2H),6.93(dd,J=9.1,4.7Hz,2H),3.83(s,4H),3.27–3.20(m,4H). 13 C NMR(151MHz,Chloroform-d)δ168.37,158.62,155.73(d,J=152.6Hz),148.88,130.85,126.85,122.77,120.87,119.35,118.93(d,J=7.7Hz),115.85(d,J=21.9Hz),50.63,48.51. 19 F NMR(565MHz,Chloroform-d)δ-123.72.

[0068] Example 6: Synthesis of Compound 6

[0069]

[0070] According to the method of Example 5, using intermediate compound 1 and 1,4-diiodobenzene as raw materials to synthesize compound 6, 747.4 mg of yellow solid was obtained with a yield of 35.5%. The structure is as follows: 1 H NMR(600MHz,Trifluoroacetic acid-d)δ8.08(d,J=8.9Hz,2H),7.86(d,J=8.2Hz,1H),7.73(q,J=9.6,8.8Hz,2H),7.67–7.60(m,1H),7.45(d,J=8.9Hz,2H),4.58(s,4H),4.27(s,4H). 13 C NMR(151MHz,Trifluoroaceticacid-d)δ168.87,141.20,139.11,137.04,129.60,127.05,122.28,121.87,121.41,114.77,97.55,54.68,47.73.

[0071] Example 7: Synthesis of compound 7

[0072]

[0073] According to the method of Example 5, using intermediate compound 4 and 2,5-diiodopyridine as raw materials to synthesize compound 7, 198.0 mg of white solid was obtained with a yield of 29.8%. The structure is as follows: 1 H NMR(600MHz,Trifluoroacetic acid-d)δ9.26(s,1H),8.66(s,1H),8.57(d,J=6.2Hz,1H),8.40(d,J=9.6Hz,1H),8.30(s,1H),7.26(d,J=9.6Hz,1H),4.41(s,4H),4.29(s,4H). 13 C NMR(151MHz,Trifluoroacetic acid-d)δ173.09,154.23,151.83,147.97,146.20,140.12,133.28,129.73,121.39,113.38,74.30,46.12,45.01.

[0074] Example 8: Synthesis of labeled precursor compound 8

[0075]

[0076] Intermediate compound 2 (63.3 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (23.4 mg, 0.02 mmol) and n-hexabutylditin (0.32 g, 0.55 mmol) were dissolved in 10 mL of toluene. Under nitrogen protection, the reaction was carried out at 110 °C for 12 hours. After the reaction was completed, toluene was removed by distillation under reduced pressure. Then, dichloromethane was added, and the mixture was filtered by suction. After the filtrate was concentrated by distillation under reduced pressure to remove dichloromethane, column chromatography was performed with a developing solvent of petroleum ether:ethyl acetate = 3:1. A white oily product (40.6 mg) was obtained with a yield of 46.3%. The structure is as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.59 (dd, J = 17.2, 7.9 Hz, 3H), 7.34–7.26 (m, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 3.76 (s, 8H), 1.65 (t, J = 7.9 Hz, 6H), 1.36 (t, J = 7.7 Hz, 6H), 1.45–1.09 (m, 6H), 0.89 (t, J = 7.7 Hz, 9H).

[0077] Example 9: Synthesis of labeled precursor compound 9

[0078]

[0079] According to the method of Example 8, compound 9 was synthesized using intermediate compound 7 as the raw material, and a white oily product (44.3 mg) was obtained with a yield of 29.7%. The structure is as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 8.28 (d, J = 5.4 Hz, 1H), 8.17 (s, 1H), 7.75–7.63 (m, 2H), 6.79 (d, J = 9.2 Hz, 1H), 3.86 (s, 8H), 1.67–1.47 (m, 6H), 1.39–1.22 (m, 6H), 1.10–1.03 (m, 6H), 0.93–0.86 (m, 9H).

[0080] Example 10: Synthesis of compound 10

[0081]

[0082] According to the method of Example 5, compound 10 was synthesized using intermediate compound 1 and 2-bromopyridine-N-oxide as the raw materials, and a white oily product was obtained. Without identification, it was directly used for the next reaction.

[0083] Example 11: Synthesis of labeled precursor compound 11

[0084]

[0085] Compound 10 (156.1 mg, 0.5 mmol) was dissolved in 3 mL of dichloromethane. Then, trimethylamine (1.5 mL, 3 mmol) and trifluoroacetic anhydride (315.7 mg, 1.5 mmol) were successively added to the reaction solution, and the mixture was stirred at room temperature for half an hour. After the reaction was completed, 3 mL of water was added. After the aqueous phase was removed by distillation under reduced pressure, ether was added for ultrasonic washing, and centrifugation was performed to obtain 153.6 mg of a white solid in the lower layer, with a yield of 65.8%. The structure is as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (t, J = 8.1 Hz, 1H), 7.76 (dd, J = 8.1, 1.3 Hz, 1H), 7.45 (dd, J = 8.2, 1.1 Hz, 1H), 7.30–7.23 (m, 1H), 7.11 (dd, J = 8.2, 7.0 Hz, 2H), 7.06 (td, J = 7.6, 1.2 Hz, 1H), 3.77 (dd, J = 6.6, 3.8 Hz, 4H), 3.67 (dd, J = 6.5, 3.8 Hz, 4H), 3.48 (s, 9H).

[0086] Example 12: Synthesis of Compound 12

[0087]

[0088] The labeled precursor compound 11 (46.8 mg, 0.1 mmol) and tetrabutylammonium fluoride (1 M, 1.0 mL, 1.0 mmol) were dissolved in 5 mL of tetrahydrofuran, and the reaction was carried out at 60 °C for 2 hours. After the reaction was completed, column chromatography was performed with the eluent ratio of petroleum ether:ethyl acetate = 2:1 to obtain 21.8 mg of a white solid, with a yield of 46.6%. The structure is as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.61 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 8.7 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.45 (d, J = 8.3 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 3.75–3.69 (m, 8H). 1313C NMR (151 MHz, Chloroform-d) δ 168.72, 162.87 (d, J = 237.0 Hz), 157.99 (d, J = 15.9 Hz), 152.62, 142.27 (d, J = 7.9 Hz), 130.81, 126.23, 121.80, 120.89, 119.37, 103.04 (d, J = 4.3 Hz), 97.01 (d, J = 37.6 Hz), 47.92, 44.50. 19 19F NMR (565 MHz, Chloroform-d) δ -68.10.

[0089] Example 13: Synthesis of Compound 13

[0090]

[0091] According to the method of Example 5, using intermediate compound 1 and 3-bromopyridine-N-oxide as raw materials, Compound 13 was synthesized to obtain a white solid. Without identification, it was directly subjected to the next reaction.

[0092] Example 14: Synthesis of Labeled Precursor Compound 14

[0093]

[0094] According to the method of Example 11, using intermediate compound 13 as the raw material, the labeled precursor compound 14 was synthesized to obtain 52.9 mg of a white solid with a yield of 44.7%. The structure is as follows: 1 1H NMR (600 MHz, Chloroform-d) δ 7.96 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), 7.33–7.26 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 3.84–3.70 (m, 8H), 3.21–3.08 (m, 9H).

[0095] Example 15: Synthesis of Compound 15

[0096]

[0097] According to the method of Example 12, using the labeled precursor compound 14 as the raw material, Compound 15 was synthesized to obtain 19.8 mg of a white solid with a yield of 61.0%. The structure is as follows: 11H NMR (400 MHz, DMSO-d6) δ 7.86 (dd, J = 3.2, 1.8 Hz, 1H), 7.75 (dd, J = 7.9, 1.3 Hz, 1H), 7.63 (ddd, J = 8.9, 7.0, 3.2 Hz, 1H), 7.45 (dd, J = 8.2, 1.1 Hz, 1H), 7.25 (td, J = 7.6, 1.3 Hz, 1H), 7.10–7.00 (m, 2H), 3.82–3.60 (m, 4H), 3.37–3.20 (m, 4H). 13 13C NMR (151 MHz, DMSO-d6) δ 168.62, 157.61 (d, J = 244.1 Hz), 152.92, 145.86 (d, J = 3.0 Hz), 134.90 (d, J = 15.0 Hz), 131.02, 130.50 (d, J = 7.5 Hz), 126.57, 121.95, 121.78, 119.28, 109.7 (d, J = 39.4 Hz), 48.59, 48.17. 19 19F NMR (376 MHz, DMSO-d6) δ -80.12.

[0098] Example 16: Synthesis of Compound 16

[0099]

[0100] Dissolve 6-(4-Boc-1-piperazinyl)pyridine-3-boronic acid pinacol ester (1.2 g, 3.1 mmol) in 10 mL of tetrahydrofuran, adjust the pH to 2 with 1 M hydrochloric acid, then heat under reflux in an oil bath at 90 °C for 6 hours. After the reaction is completed, remove tetrahydrofuran by distillation under reduced pressure, add water, and extract three times with dichloromethane. Collect the organic phase, dry it over anhydrous sodium sulfate, filter by suction, and remove dichloromethane from the filtrate by distillation under reduced pressure to obtain a white solid. Without identification, directly proceed to the next step of the reaction.

[0101] Example 17: Synthesis of Compound 17

[0102]

[0103] According to the method of Example 16, using 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester as the raw material to synthesize Compound 17, a white solid was obtained. Without identification, directly proceed to the next step of the reaction.

[0104] Example 18: Synthesis of Labeled Precursor Compound 18

[0105]

[0106] Intermediate compound 1 (219.3 mg, 1.0 mmol) and intermediate compound 16 (291.4 mg, 1.0 mmol) were dissolved in 2 mL of ethylene glycol, and then the reaction was heated in an oil bath at 90 °C for 12 hours. After the reaction was completed, saturated sodium bicarbonate was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered by suction. After the dichloromethane was removed from the filtrate by vacuum distillation, column chromatography was carried out with the eluent of petroleum ether:ethyl acetate = 7:3 to obtain 134.8 mg of a white solid with a yield of 32.0%. The structure is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 1.9 Hz, 1H), 7.87 (dd, J = 8.5, 1.9 Hz, 1H), 7.66–7.55 (m, 2H), 7.31 (ddd, J = 8.2, 7.3, 1.3 Hz, 1H), 7.10 (td, J = 7.6, 1.2 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 3.86–3.72 (m, 8H), 1.33 (s, 12H).

[0107] Example 19: Synthesis of labeled precursor compound 19

[0108]

[0109] Intermediate compound 1 (220.1 mg, 1.0 mmol), intermediate compound 17 (290.4 mg, 1.0 mmol) and triethylamine (151.5 mg, 1.5 mmol) were dissolved in 10 mL of tetrahydrofuran, and then the reaction was heated in an oil bath at 55 °C for 12 hours. After the reaction was completed, tetrahydrofuran was removed by vacuum distillation, and column chromatography was carried out with the eluent of petroleum ether:ethyl acetate = 9:1 to obtain 120.7 mg of a white solid with a yield of 28.6%. The structure is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.79–7.68 (m, 2H), 7.65–7.56 (m, 2H), 7.36–7.27 (m, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.97–6.87 (m, 2H), 3.80 (s, 4H), 3.50–3.34 (m, 4H), 1.32 (s, 12H).

[0110] The schematic diagrams of the synthesis processes of the compounds in Examples 1-19 above are shown in Figure 1 .

[0111] Example 20: Synthesis of compound 20

[0112]

[0113] 6-Bromo-N-methylpyridin-3-amine (927.1 mg, 5.0 mmol), di-tert-butyl dicarbonate (4.4 g, 20.0 mmol), 4-dimethylaminopyridine (66.2 mg, 0.5 mmol), and triethylamine (506.2 mg, 5.0 mmol) were dissolved in 15 mL of tetrahydrofuran and reacted at 90 °C for 5 hours. After the reaction was completed, tetrahydrofuran was removed by distillation under reduced pressure, and column chromatography was performed with a developing solvent ratio of petroleum ether:ethyl acetate = 3:1 to obtain 333.2 mg of a white solid. Without identification, it was directly used for the next reaction.

[0114] Example 21: Synthesis of Compound 21

[0115]

[0116] Intermediate compound 20 (572.0 mg, 2.0 mmol) and piperazine (863.2 mg, 10.0 mmol) were dissolved in 5 mL of ethylene glycol, and then the reaction was heated in an oil bath at 90 °C for 12 hours. After the reaction was completed, saturated sodium bicarbonate was added, and the mixture was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated by distillation under reduced pressure to remove dichloromethane, followed by column chromatography with methanol as the developing solvent to obtain 348.6 mg of a white solid with a yield of 59.7%. The structure is as follows: 1 H NMR (400 MHz, Chloroform-d) δ8.15–7.97 (m, 1H), 7.36 (d, J = 22.4 Hz, 1H), 6.60 (dd, J = 9.0, 3.3 Hz, 1H), 3.75–3.62 (m, 4H), 3.19 (d, J = 3.2 Hz, 4H), 3.18–3.11 (m, 3H), 1.24 (s, 9H).

[0117] Example 22: Synthesis of Compound 22

[0118]

[0119] According to the method of Example 1, 2-chloro-6-fluorobenzothiazole and piperazine were used as raw materials to synthesize Compound 22, obtaining 1.1 g of a white solid with a yield of 96.7%. The structure is as follows: 1 H NMR (600 MHz, Chloroform-d) δ7.45 (dd, J = 8.8, 4.7 Hz, 1H), 7.29 (dd, J = 8.2, 2.6 Hz, 1H), 7.00 (td, J = 9.0, 2.7 Hz, 1H), 3.60–3.56 (m, 4H), 3.01–2.98 (m, 4H), 1.96 (s, 1H).

[0120] Example 23: Synthesis of Compound 23

[0121]

[0122] According to the method of Example 1, using 2-chloro-6-bromobenzothiazole and piperazine as raw materials to synthesize Compound 23, 1.3 g of white solid was obtained with a yield of 85.8%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.70(d,J=1.3Hz,1H),7.38(d,J=1.4Hz,2H),3.62–3.57(m,4H),3.03–2.97(m,4H),1.66(s,1H).

[0123] Example 24: Synthesis of Compound 24

[0124]

[0125] According to the method of Example 5, using Intermediate Compound 20 and Intermediate Compound 22 as raw materials to synthesize Compound 24, 188.9 mg of white solid was obtained with a yield of 79.2%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ8.08(s,1H),7.48(dd,J=8.8,4.7Hz,1H),7.39(s,1H),7.32(dd,J=8.1,2.6Hz,1H),7.02(td,J=8.9,2.6Hz,1H),6.66(d,J=8.9Hz,1H),3.74–3.72(m,4H),3.71–3.68(m,4H),3.20(s,3H),1.42(s,9H).

[0126] Example 25: Synthesis of Compound 25

[0127]

[0128] According to the method of Example 5, using Intermediate Compound 20 and Intermediate Compound 23 as raw materials to synthesize Compound 25, 238.0 mg of white solid was obtained with a yield of 82.4%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ8.08(d,J=2.6Hz,1H),7.74–7.68(m,1H),7.39(dd,J=2.4,1.1Hz,2H),7.25(d,J=0.9Hz,1H),6.67(d,J=8.9Hz,1H),3.78–3.67(m,8H),3.20(d,J=1.0Hz,3H),1.42(s,9H).

[0129] Example 26: Synthesis of Compound 26

[0130]

[0131] According to the method of Example 21, using intermediate compound 21 and 2-chloro-6-iodobenzothiazole as raw materials, compound 26 was synthesized to obtain 48.0 mg of a white solid with a yield of 4.6%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ8.08(d,J=2.7Hz,1H),7.89(d,J=1.7Hz,1H),7.56(dd,J=8.5,1.7Hz,1H),7.42(s,1H),7.30(d,J=8.5Hz,1H),6.66(d,J=9.0Hz,1H),3.81–3.62(m,8H),3.20(s,3H),1.42(s,9H).

[0132] Example 27: Synthesis of Compound 27

[0133]

[0134] According to the method of Example 16, using intermediate compound 24 as the raw material, compound 27 was synthesized to obtain 56.2 mg of a white solid with a yield of 68.9%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=3.0Hz,1H),7.47(dd,J=8.9,4.7Hz,1H),7.31(dd,J=8.2,2.6Hz,1H),7.01(td,J=9.0,2.7Hz,1H),6.95(dd,J=8.9,3.0Hz,1H),6.66(d,J=8.8Hz,1H),3.75–3.70(m,4H),3.54–3.48(m,4H),2.81(s,3H). 13 C NMR(101MHz,Chloroform-d)δ168.55,158.25(d,J=240.3Hz),153.92,149.19,139.27,132.58,131.52(d,J=10.6Hz),123.56,119.66(d,J=8.7Hz),113.78(d,J=23.6Hz),109.90,107.57(d,J=27.0Hz),48.29,46.72,31.47. 19 F NMR(376MHz,Chloroform-d)δ-121.16.

[0135] Example 28: Synthesis of Compound 28

[0136]

[0137] According to the method of Example 16, using intermediate compound 25 as the raw material, compound 28 was synthesized to obtain 253.8 mg of a white solid. Without identification, it was directly subjected to the next reaction.

[0138] Example 29: Synthesis of Compound 29

[0139]

[0140] According to the method of Example 16, using intermediate compound 26 as the raw material, compound 29 was synthesized to obtain 24.8 mg of a white solid with a yield of 55.0%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ7.87(t,J=1.9Hz,1H),7.73(t,J=2.4Hz,1H),7.55(dt,J=8.5,1.9Hz,1H),7.28(dd,J=8.6,1.8Hz,1H),6.94(dt,J=8.9,2.4Hz,1H),6.65(dd,J=8.9,1.8Hz,1H),3.74(t,J=6.0Hz,4H),3.50(t,J=6.0Hz,4H),2.81(s,3H). 13 C NMR(151MHz,Chloroform-d)δ168.89,155.03,152.41,140.29,136.68,133.42,132.63,129.71,124.23,121.73,111.07,83.88,49.46,46.71,31.93.

[0141] Example 30: Synthesis of Labeled Precursor Compound 30

[0142]

[0143] Intermediate compound 25 (103 mg, 0.2 mmol), bis(pinacolato)diboron (57.6 mg, 0.22 mmol), dichlorobis[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (7.3 mg, 0.01 mmol) and potassium acetate (70.3 mg, 0.7 mmol) were dissolved in 10 mL of dioxane, protected by nitrogen, and then heated under reflux in an oil bath at 110 °C for 12 hours. After the reaction was completed, dioxane was removed by distillation under reduced pressure, dichloromethane was added, and the mixture was filtered by suction. After dichloromethane was removed from the filtrate by distillation under reduced pressure, column chromatography was performed with a developing solvent having a volume ratio of petroleum ether:ethyl acetate = 2:3 to obtain 107.7 mg of a white solid with a yield of 97.1%. The structure is as follows: 1 H NMR (600 MHz, Chloroform-d) δ 8.09 (s, 2H), 7.76 (d, J = 6.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.51–7.33 (m, 1H), 6.69 (s, 1H), 3.85–3.66 (m, 8H), 3.22 (s, 3H), 1.44 (s, 9H), 1.35 (s, 12H).

[0144] Example 31: Synthesis of labeled precursor compound 31

[0145]

[0146] According to the method of Example 8, compound 31 was synthesized using intermediate compound 28 as the raw material to obtain 37.0 mg of a yellow solid with a yield of 62.8%. The structure is as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.75 (d, J = 3.0 Hz, 1H), 7.68 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 7.8, 1.0 Hz, 1H), 6.97 (dd, J = 8.9, 2.8 Hz, 1H), 6.68 (dd, J = 8.8, 1.7 Hz, 1H), 3.77 (dd, J = 6.3, 4.1 Hz, 4H), 3.53 (dd, J = 6.4, 4.0 Hz, 4H), 2.83 (s, 3H), 1.54 (t, J = 7.7 Hz, 6H), 1.33 (q, J = 7.4 Hz, 6H), 1.12–1.01 (m, 6H), 0.88 (t, J = 7.3 Hz, 9H).

[0147] Schematic diagrams of the synthesis processes of the compounds in Examples 20 - 31 above are shown in Figure 2 .

[0148] Example 32: Synthesis of compound 32

[0149]

[0150] 2-Bromo-5-hydroxypyridine (2.1 g, 12.1 mmol), 2-bromoethanol (5.0 g, 40 mmol) and cesium carbonate (4.0 g, 36 mmol) were dissolved in 12 mL of N,N-dimethylformamide, and then the reaction was heated in an oil bath at 110 °C for 12 hours. After the reaction was completed, N,N-dimethylformamide was removed by distillation under reduced pressure. Dichloromethane was added, and the mixture was filtered by suction. After dichloromethane was removed from the filtrate by distillation under reduced pressure, column chromatography was carried out with a developing solvent volume ratio of petroleum ether:ethyl acetate = 9:1 to obtain 2.2 g of a white solid. Without identification, it was directly used for the next reaction.

[0151] Example 33: Synthesis of Compound 33

[0152]

[0153] According to the method of Example 5, Compound 33 was synthesized using intermediate compound 1 and intermediate compound 32 as raw materials to obtain a white solid. Without identification, it was directly used for the next reaction.

[0154] Example 34: Synthesis of Labeled Precursor Compound 34

[0155]

[0156] Intermediate compound 33 (150.0 mg, 0.48 mmol), p-toluenesulfonyl chloride (200.1 mg, 1.0 mmol) and triethylamine (125.2 mg, 1.2 mmol) were dissolved in 10 mL of dichloromethane, and then the reaction was heated in an oil bath at 40 °C for 12 hours. After the reaction was completed, dichloromethane was removed by distillation under reduced pressure, and column chromatography was carried out with a developing solvent volume ratio of petroleum ether:ethyl acetate = 4:1 to obtain 98.8 mg of a white solid with a yield of 40.8%. The structure is as follows: 1 H NMR (600 MHz, DMSO-d6) δ 7.80–7.72 (m, 4H), 7.44 (d, J = 7.8 Hz, 3H), 7.27–7.23 (m, 1H), 7.19 (dd, J = 9.2, 3.1 Hz, 1H), 7.07–7.02 (m, 1H), 6.83 (d, J = 9.2 Hz, 1H), 4.26 (d, J = 4.5 Hz, 2H), 4.13–4.08 (m, 2H), 3.63 (t, J = 6.5 Hz, 4H), 3.51 (t, J = 6.9 Hz, 4H), 2.38 (s, 3H).

[0157] Example 35: Synthesis of Compound 35

[0158]

[0159] According to the method of Example 12, using the labeled precursor compound 34 as the raw material to synthesize compound 35, 28.1 mg of white solid was obtained with a yield of 78.2%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ7.97(d,J=3.0Hz,1H),7.61(dd,J=7.9,1.3Hz,1H),7.57(d,J=8.1Hz,1H),7.30(ddd,J=8.3,7.3,1.3Hz,1H),7.22(s,1H),7.09(ddd,J=8.2,7.4,1.1Hz,1H),6.70(d,J=9.1Hz,1H),4.82–4.64(m,2H),4.24–4.15(m,2H),3.77(t,J=6.5Hz,4H),3.62(t,J=6.4Hz,4H). 13 C NMR(151MHz,DMSO-d6)δ168.72,154.65,152.89,148.41,142.16,134.47,130.91,126.56,121.87,121.77,119.18,109.26,82.79(d,J=166.9Hz),68.73(d,J=19.5Hz),48.17,45.67. 19 F NMR(565MHz,DMSO-d6)δ-222.06.

[0160] Example 36: Synthesis of compound 36

[0161]

[0162] Dissolve 4-bromophenol (1.7 g, 10 mmol), tert-butyldimethylchlorosilane (3.8 g, 25 mmol) and imidazole (2.7 g, 40 mmol) in 15 mL of acetonitrile, then heat under reflux in an oil bath at 50 °C for 6 hours. After the reaction is completed, remove acetonitrile by distillation under reduced pressure, add dichloromethane, filter by suction. After removing dichloromethane from the filtrate by distillation under reduced pressure, perform column chromatography separation with the volume ratio of the eluent being petroleum ether:ethyl acetate = 9:1 to obtain 1.5 g of colorless oily liquid with a yield of 52.4%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.36–7.28(m,2H),6.70(d,J=8.8Hz,2H),0.96(s,9H),0.17(s,6H).

[0163] Example 37: Synthesis of compound 37

[0164]

[0165] According to the method of Example 5, using intermediate compound 1 and intermediate compound 36 as raw materials to synthesize compound 37, 302.2 mg of white solid was obtained with a yield of 14.1%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.60(dd,J=14.4,8.0Hz,2H),7.31(t,J=7.6Hz,1H),7.10(t,J=7.6Hz,1H),6.87(d,J=8.3Hz,2H),6.78(d,J=8.8Hz,2H),3.80(s,4H),3.20(s,4H),0.98(s,9H),0.17(d,J=1.4Hz,6H).

[0166] Example 38: Synthesis of compound 38

[0167]

[0168] According to the method of Example 12, using intermediate compound 37 as raw material to synthesize compound 38, 57.3 mg of white solid was obtained with a yield of 40.0%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.64–7.55(m,2H),7.34–7.28(m,1H),7.10(t,J=7.7Hz,1H),6.91(s,2H),6.79(d,J=8.7Hz,2H),3.81(s,4H),3.19(s,4H).

[0169] Example 39: Synthesis of compound 39

[0170]

[0171] According to the method of Example 32, using intermediate compound 38 and 2-bromoethanol as raw materials to synthesize compound 39, 70.3 mg of white solid was obtained with a yield of 42.0%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=7.6Hz,2H),7.32(d,J=8.5Hz,2H),7.11(s,1H),6.93(d,J=39.8Hz,3H),4.05(d,J=5.1Hz,2H),3.94(s,2H),3.83(s,4H),3.23(s,4H).

[0172] Example 40: Synthesis of labeled precursor compound 40

[0173]

[0174] According to the method of Example 34, using intermediate compound 39 and p-toluenesulfonyl chloride as raw materials to synthesize the labeled precursor compound 40, 54.3 mg of white solid was obtained with a yield of 63.2%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ7.83–7.79(m,2H),7.63–7.55(m,2H),7.32(dd,J=20.0,7.9Hz,3H),7.10(t,J=7.6Hz,1H),6.90(s,2H),6.75(d,J=8.8Hz,2H),4.37–4.29(m,2H),4.16–4.07(m,2H),3.80(s,4H),3.20(s,4H),2.44(s,3H).

[0175] Example 41: Synthesis of compound 41

[0176]

[0177] According to the method of Example 12, using the labeled precursor compound 40 as the raw material to synthesize compound 41, 24.4 mg of white solid was obtained with a yield of 66.7%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.59(dd,J=11.8,8.0Hz,2H),7.30(t,J=7.7Hz,1H),7.09(t,J=7.5Hz,1H),6.95(d,J=8.8Hz,2H),6.89(d,J=9.1Hz,2H),4.73(dt,J=47.4,4.2Hz,2H),4.17(dt,J=27.9,4.2Hz,2H),3.80(t,J=5.2Hz,4H),3.21(t,J=5.2Hz,4H). 13 C NMR(151MHz,DMSO-d6)δ168.67,152.97,152.81,145.91,130.98,126.55,121.87,121.76,119.22,118.73,115.72,82.81(d,J=166.4Hz),67.90(d,J=19.3Hz),49.87,48.57. 19 F NMR(565MHz,DMSO-d6)δ-221.88.

[0178] For the schematic diagrams of the synthesis processes of the compounds in Examples 32 - 41 above, see Figure 3 .

[0179] Example 42: Synthesis of compound 42

[0180]

[0181] According to the method of Example 1, 2-chloro-6-methoxybenzothiazole and piperazine were used as raw materials to synthesize Compound 42, and 1.2 g of white solid was obtained with a yield of 76.3%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.46(d,J=8.8Hz,1H),7.15(d,J=2.6Hz,1H),6.90(dd,J=8.8,2.6Hz,1H),3.82(s,3H),3.59(t,J=4.8Hz,4H),3.01(t,J=4.8Hz,4H),2.03(s,1H).

[0182] Example 43: Synthesis of Compound 43

[0183]

[0184] According to the method of Example 5, Intermediate Compound 20 and Intermediate Compound 42 were used as raw materials to synthesize Compound 43, and 1.4 g of white solid was obtained with a yield of 59.8%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J=2.7Hz,1H),7.50(d,J=8.8Hz,1H),7.43(s,1H),7.17(d,J=2.6Hz,1H),6.92(dd,J=8.8,2.6Hz,1H),6.68(d,J=8.9Hz,1H),3.83(s,3H),3.72(s,8H),3.22(s,3H),1.44(s,9H).

[0185] Example 44: Synthesis of Compound 44

[0186]

[0187] Intermediate Compound 43 (910.2 mg, 2 mmol) was dissolved in 10 mL of dichloromethane. At -78 °C, BBr3 (1 M, 20 mL, 20 mmol) was slowly added dropwise, and then the reaction was carried out at room temperature for 12 hours. After the reaction was completed, 20 mL of deionized water was slowly added dropwise in an ice-water bath, and ammonia water was added to adjust the pH to neutral. Filtration was carried out to obtain a white solid. Without identification, it was directly used for the next reaction.

[0188] Example 45: Synthesis of Compound 45

[0189]

[0190] According to the method of Example 36, using intermediate compound 44 as the raw material to synthesize compound 45, 104.5 mg of white solid was obtained with a yield of 48.8%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ7.74(s,1H),7.42(d,J=8.7Hz,1H),7.10(d,J=2.2Hz,1H),6.98(d,J=5.9Hz,1H),6.82(dd,J=8.6,2.2Hz,1H),6.69(d,J=8.9Hz,1H),3.74(s,4H),3.53(s,4H),2.83(s,3H),0.99(s,9H),0.19(s,6H).

[0191] Example 46: Synthesis of compound 46

[0192]

[0193] According to the method of Example 20, using intermediate compound 45 as the raw material to synthesize compound 46, 135.9 mg of white solid was obtained with a yield of 89.4%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ8.08(s,1H),7.43(d,J=8.7Hz,2H),7.10(d,J=2.3Hz,1H),6.83(dd,J=8.7,2.3Hz,1H),6.67(d,J=9.0Hz,1H),3.77–3.66(m,8H),3.21(s,3H),1.43(s,9H),0.99(s,9H),0.19(s,6H).

[0194] Example 47: Synthesis of compound 47

[0195]

[0196] According to the method of Example 12, using intermediate compound 46 as the raw material to synthesize compound 47, 85.4 mg of white solid was obtained with a yield of 89.6%. The structure is as follows: 11H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.74 (dd, J = 8.6, 2.5 Hz, 1H), 3.64 (t, J = 3.8 Hz, 4H), 3.60 (t, J = 3.8 Hz, 4H), 3.12 (s, 3H), 1.41 (s, 9H).

[0197] Example 48: Synthesis of Compound 48

[0198]

[0199] According to the method of Example 32, using intermediate compound 47 and 2-[2-(2-chloroethoxy)ethoxy]ethanol as raw materials, compound 48 was synthesized to obtain a white solid. Without identification, it was directly subjected to the next reaction.

[0200] Example 49: Synthesis of Labeled Precursor Compound 49

[0201]

[0202] According to the method of Example 34, using intermediate compound 48 as the raw material, labeled precursor compound 49 was synthesized to obtain 48.7 mg of a white solid with a yield of 64.3%. The structure is as follows: 1 1H NMR (400 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.46 (dd, J = 9.2, 2.7 Hz, 1H), 7.38 (dd, J = 8.5, 3.2 Hz, 3H), 7.29 (d, J = 2.6 Hz, 1H), 6.92 (dd, J = 8.8, 2.6 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 4.10 (q, J = 4.3 Hz, 4H), 3.80–3.76 (m, 2H), 3.69 (s, 8H), 3.65–3.59 (m, 4H), 3.54 (dd, J = 6.0, 3.1 Hz, 2H), 3.17 (s, 3H), 2.39 (s, 3H), 1.48 (s, 9H).

[0203] Example 50: Synthesis of Compound 50

[0204]

[0205] According to the method of Example 12, using the labeled precursor compound 49 as the raw material to synthesize compound 50, 22.4 mg of white solid was obtained with a yield of 64.3%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ8.09(s,1H),7.48(d,J=8.7Hz,1H),7.43(s,1H),7.20(s,1H),6.94(d,J=8.8Hz,1H),6.68(d,J=9.0Hz,1H),4.63–4.52(m,2H),4.16(t,J=4.1Hz,2H),3.90–3.85(m,2H),3.80–3.67(m,14H),3.22(s,3H),1.44(s,9H).

[0206] Example 51: Synthesis of compound 51

[0207]

[0208] According to the method of Example 16, using the intermediate compound 50 as the raw material to synthesize compound 51, 12.7 mg of white solid was obtained with a yield of 46.3%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.76(d,J=3.0Hz,1H),7.47(d,J=8.8Hz,1H),7.19(d,J=2.6Hz,1H),7.15(dd,J=9.2,2.8Hz,1H),6.94(dd,J=8.8,2.7Hz,1H),6.78(d,J=9.0Hz,1H),4.57(dt,J=47.7,4.1Hz,2H),4.15(t,J=4.6Hz,2H),3.87(t,J=4.8Hz,2H),3.76(ddt,J=12.5,9.9,4.3Hz,10H),3.61(t,J=5.3Hz,4H),2.85(s,3H). 19 FNMR(376MHz,Chloroform-d)δ-222.75.

[0209] For the schematic diagrams of the synthesis processes of the compounds in Examples 42 - 51 above, see Figure 4 .

[0210] Example 52: Synthesis of compound 52

[0211]

[0212] According to the method of Example 5, using intermediate compound 42 and 2-bromopyridine as raw materials to synthesize compound 52, 1.0 g of white solid was obtained, and the yield was 53.2%. The structure is as follows: 1 H NMR(400MHz,Chloroform-d)δ8.23(d,J=4.9Hz,1H),7.53(d,J=7.7Hz,1H),7.49(d,J=8.8Hz,1H),7.17(d,J=2.6Hz,1H),6.92(dd,J=8.8,2.6Hz,1H),6.70(t,J=10.3Hz,2H),3.83(s,3H),3.73(s,8H).

[0213] Example 53: Synthesis of compound 53

[0214]

[0215] According to the method of Example 5, using intermediate compound 42 and 2-chloropyrimidine as raw materials to synthesize compound 53, 0.8 g of white solid was obtained, and the yield was 45.8%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ8.35(d,J=4.7Hz,2H),7.51(d,J=8.8Hz,1H),7.16(d,J=2.6Hz,1H),6.92(dd,J=8.8,2.6Hz,1H),6.56(t,J=4.7Hz,1H),4.01(t,J=4.74Hz,4H),3.83(t,J=12.6Hz,3H),3.69(t,J=5.3Hz,4H).

[0216] Example 54: Synthesis of compound 54

[0217]

[0218] According to the method of Example 44, using intermediate compound 52 as the raw material to synthesize compound 54, a white solid was obtained. Without identification, it was directly subjected to the next reaction.

[0219] Example 55: Synthesis of compound 55

[0220]

[0221] According to the method of Example 44, using intermediate compound 53 as the raw material to synthesize compound 55, a white solid was obtained. Without identification, it was directly subjected to the next reaction.

[0222] Example 56: Synthesis of compound 56

[0223]

[0224] According to the method of Example 32, using intermediate compound 54 and 2-bromoethanol as raw materials to synthesize compound 56, 225.4 mg of white solid was obtained with a yield of 63.5%. The structure is as follows: 1 H NMR(600MHz,DMSO-d6)δ8.18–8.12(m,1H),7.61–7.55(m,1H),7.43(d,J=2.6Hz,1H),7.39(d,J=8.8Hz,1H),6.90(dd,J=7.9,3.7Hz,2H),6.69(dd,J=7.1,4.9Hz,1H),4.87(t,J=5.5Hz,1H),3.98(t,J=5.0Hz,2H),3.73–3.70(m,2H),3.68–3.66(m,4H),3.62–3.61(m,4H).

[0225] Example 57: Synthesis of compound 57

[0226]

[0227] According to the method of Example 32, using intermediate compound 55 and 2-bromoethanol as raw materials to synthesize compound 57, 278.9 mg of white solid was obtained with a yield of 62.7%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ8.35(d,J=4.7Hz,2H),7.53(d,J=8.8Hz,1H),7.19(d,J=2.6Hz,1H),6.94(dd,J=8.8,2.6Hz,1H),6.57(t,J=4.7Hz,1H),4.10(t,J=4.5Hz,2H),4.00(s,4H),3.98(t,J=4.4Hz,2H),3.71(s,4H).

[0228] Example 58: Synthesis of labeled precursor compound 58

[0229]

[0230] According to the method of Example 34, using intermediate compound 56 as raw material to synthesize labeled precursor compound 58, 78.5 mg of white solid was obtained with a yield of 48.9%. The structure is as follows: 11H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.6 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.80 (dd, J = 8.7, 2.5 Hz, 1H), 6.69 (t, J = 6.2 Hz, 1H), 4.33 (s, 2H), 4.16 (s, 2H), 3.66 (s, 4H), 3.63 (s, 4H), 2.41 (s, 3H).

[0231] Example 59: Synthesis of Labeled Precursor Compound 59

[0232]

[0233] According to the method of Example 34, using intermediate compound 57 as the raw material to synthesize labeled precursor compound 59, 58.3 mg of white solid was obtained, and the yield was 52.5%. The structure is as follows: 1 1H NMR (600 MHz, Chloroform-d) δ 8.36 (d, J = 4.7 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.50 (s, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 2.5 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.57 (t, J = 4.8 Hz, 1H), 4.37 (t, J = 4.7 Hz, 2H), 4.17 (t, J = 4.8 Hz, 2H), 4.02 (s, 4H), 3.72 (s, 4H), 2.45 (s, 3H).

[0234] Example 60: Synthesis of Compound 60

[0235]

[0236] According to the method of Example 12, using labeled precursor compound 58 as the raw material to synthesize compound 60, 28.7 mg of white solid was obtained, and the yield was 59.0%. The structure is as follows: 11H NMR (600 MHz, Chloroform-d) δ 8.22 (d, J = 5.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.20 (s, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.70 (t, J = 7.9 Hz, 2H), 4.76 (d, J = 47.4 Hz, 2H), 4.23 (d, J = 24.8 Hz, 2H), 3.72 (s, 8H). 13 13C NMR (151 MHz, Chloroform-d) δ 167.73, 159.07, 153.99, 148.03, 147.44, 137.89, 131.83, 119.78, 114.53, 114.07, 107.51, 106.74, 82.08 (d, J = 171.2 Hz), 68.19 (d, J = 21.0 Hz), 48.14, 44.86.

[0237] Example 61: Synthesis of Compound 61

[0238]

[0239] According to the method of Example 12, using the labeled precursor compound 59 as the raw material, Compound 61 was synthesized to obtain 14.6 mg of a white solid with a yield of 68.4%. The structure is as follows: 1 1H NMR (600 MHz, Chloroform-d) δ 8.34 (d, J = 4.7 Hz, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 6.94 (dd, J = 8.8, 2.6 Hz, 1H), 6.55 (t, J = 4.7 Hz, 1H), 4.75 (dt, J = 47.5, 4.1 Hz, 2H), 4.22 (dt, J = 27.9, 4.2 Hz, 2H), 3.99 (t, J = 5.3 Hz, 4H), 3.68 (t, J = 5.3 Hz, 4H). 13 13C NMR (101 MHz, Chloroform-d) δ 167.76, 161.63, 157.92, 153.99, 147.32, 131.72, 119.75, 114.52, 110.63, 106.72, 82.09 (d, J = 170.5 Hz), 68.17 (d, J = 20.2 Hz), 48.33, 43.21. 19 19F NMR (376 MHz, Chloroform-d) δ -223.62.

[0240] Schematic diagram of the synthesis process of the compounds in Examples 52 - 61 is shown in Figure 5 。

[0241] Example 62: Synthesis of Compound 62

[0242]

[0243] According to the method of Example 5, using intermediate compound 1 and 2 - chloro - 5 - bromobenzothiazole as raw materials, Compound 62 was synthesized to obtain a white solid. Without identification, it was directly used for the next reaction.

[0244] Example 63: Synthesis of Labeled Precursor Compound 63

[0245]

[0246] According to the method of Example 8, using intermediate compound 62 as the raw material, the labeled precursor compound 63 was synthesized to obtain 28.7 mg of a white solid with a yield of 62.9%. The structure is as follows: 1 H NMR(400MHz,Chloroform - d)δ7.73(s,1H),7.61(t,J=8.6Hz,3H),7.32(t,J=7.7Hz,1H),7.19(d,J=7.9Hz,1H),7.12(t,J=7.6Hz,1H),3.82(s,8H),1.89(t,J=8.0Hz,6H),1.67(q,J=8.5Hz,6H),1.31–0.98(m,6H),0.88–0.79(m,9H).

[0247] Example 64: Synthesis of Compound 64

[0248]

[0249] The labeled precursor compound 63 (64.2 mg, 0.10 mmol) and iodine (50.1 mg, 0.2 mmol) were dissolved in 10 mL of dichloromethane, and then reacted at room temperature for 1 hour. After the reaction was completed, dichloromethane was removed by distillation under reduced pressure, and then separated by column chromatography. The volume ratio of the eluent was petroleum ether:ethyl acetate = 1:1, to obtain 37.2 mg of a white solid with a yield of 78.0%. The structure is as follows: 1 H NMR(400MHz,Chloroform - d)δ7.94(d,J=1.6Hz,1H),7.68–7.60(m,2H),7.41(dd,J=8.2,1.6Hz,1H),7.35(dd,J=8.3,5.5Hz,2H),7.15(t,J=7.6Hz,1H),3.85(s,8H). 1313C NMR (101 MHz, Chloroform-d) δ 168.76, 168.32, 153.76, 144.15, 130.62, 130.46, 128.47, 126.60, 122.45, 122.30, 121.00, 119.35, 92.31, 77.30, 48.08, 47.82.

[0250] Schematic diagrams of the synthesis processes of the compounds in Examples 62 - 64 are shown in Figure 6 .

[0251] Example 65: Synthesis of Compound 65

[0252]

[0253] According to the method of Example 1, using intermediate compound 1 and 2-bromo-5-methoxypyridine as raw materials to synthesize Compound 65, obtaining a white solid. Without identification, directly proceed to the next reaction.

[0254] Example 66: Synthesis of Compound 66

[0255]

[0256] According to the method of Example 44, using intermediate compound 65 as the raw material to synthesize Compound 66, obtaining 423.5 mg of a white solid. The structure is as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.81–7.75 (m, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.31–7.27 (m, 1H), 7.13–7.06 (m, 2H), 6.81 (d, J = 9.0 Hz, 1H), 3.69–3.64 (m, 4H), 3.50–3.46 (m, 4H).

[0257] Example 67: Synthesis of Compound 67

[0258]

[0259] The intermediate compound 66 (312.2 mg, 1 mmol) and (R)-2,2-dimethyl-1,3-dioxolan-4-yl methyl p-toluenesulfonate (858.9 mg, 3 mmol) were dissolved in 10 mL of N,N-dimethylformamide. Cesium fluoride (455.7 mg, 3 mmol) was added under stirring, and the reaction was heated in an oil bath at 65 °C for 12 hours. After the reaction was completed, N,N-dimethylformamide was removed by distillation under reduced pressure. Dichloromethane was added, and the mixture was filtered by suction. Dichloromethane was removed by distillation under reduced pressure, and column chromatography was carried out with the volume ratio of the eluent being petroleum ether:ethyl acetate = 3:1 to obtain 156.8 mg of a yellow solid with a yield of 35.5%. The structure is as follows: 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (d, J = 2.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.25 (s, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.47 (p, J = 5.8 Hz, 1H), 4.16 (dd, J = 8.4, 6.6 Hz, 1H), 4.04 (dd, J = 9.5, 5.7 Hz, 1H), 3.94 (dd, J = 9.5, 5.4 Hz, 1H), 3.88 (dd, J = 8.4, 6.0 Hz, 1H), 3.79 (s, 4H), 3.64 (s, 4H), 1.25 (s, 6H).

[0260] Example 68: Synthesis of Compound 68

[0261]

[0262] The intermediate compound 67 (150.0 mg, 0.35 mmol) was dissolved in 10 mL of tetrahydrofuran. 1 M HCl was added to adjust the pH to 1, and the reaction was carried out at 90 °C for 1 hour. After the reaction was completed, deionized water was added, and the mixture was filtered by suction to obtain 98.4 mg of a yellow solid. The structure is as follows: 11H NMR (600 MHz, DMSO-d6) δ 7.92 (d, J = 3.0 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.35–7.26 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 3.97 (dd, J = 9.9, 4.1 Hz, 1H), 3.84 (dd, J = 9.8, 6.2 Hz, 1H), 3.79–3.73 (m, 1H), 3.71–3.64 (m, 4H), 3.58–3.53 (m, 4H), 3.43 (d, J = 5.4 Hz, 2H).

[0263] Example 69: Synthesis of Compound 69

[0264]

[0265] Intermediate Compound 68 (77.2 mg, 0.2 mmol) and p-toluenesulfonyl chloride (76.0 mg, 0.4 mmol) were dissolved in 10 mL of pyridine and reacted at room temperature for 12 hours. After the reaction was completed, pyridine was removed by distillation under reduced pressure, and column chromatography was performed with a developing solvent of petroleum ether:ethyl acetate = 3:1 to obtain 35.6 mg of a white solid with a yield of 26.4%. The structure is as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 7.87 (d, J = 2.9 Hz, 1H), 7.81 (t, J = 9.1 Hz, 2H), 7.61 (dd, J = 10.8, 8.1 Hz, 2H), 7.35–7.30 (m, 3H), 7.17 (dd, J = 9.1, 2.8 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 9.2 Hz, 1H), 4.24 -4.17 (m, 3H), 3.98 (d, J = 4.3 Hz, 2H), 3.82–3.76 (m, 4H), 3.67–3.59 (m, 4H), 2.44 (s, 3H).

[0266] Example 70: Synthesis of Labeled Precursor Compound 70

[0267]

[0268] The intermediate compound 69 (54.0 mg, 0.1 mmol), 3,4-dihydropyran (84.1 mg, 1 mmol), and pyridinium 4-methylbenzenesulfonate (50.2 mg, 0.2 mmol) were dissolved in anhydrous dichloromethane and reacted at room temperature for 12 hours. After the reaction was completed, dichloromethane was removed by distillation under reduced pressure, and column chromatography was performed with a developing solvent volume ratio of petroleum ether:ethyl acetate = 3:1 to obtain 28.4 mg of a white solid with a yield of 26.4%. Without identification, it was directly subjected to the next reaction.

[0269] Example 71: Synthesis of Compound 71

[0270]

[0271] The labeled precursor compound 70 (62.4 mg, 0.1 mmol) and tetrabutylammonium fluoride (1 M, 1 mL, 1 mmol) were dissolved in 5 mL of tetrahydrofuran and reacted at 90 °C for 2 hours. After the reaction was completed, 1 M HCl was added to adjust the pH to 1, and the reaction was continued at 90 °C for 1 hour. After the reaction was completed, the pH was adjusted to neutral with ammonia water, and filtration was performed to obtain 15.6 mg of a white solid with a yield of 40.2%.

[0272] Example 72: Synthesis of the Labeled Precursor Compound 72

[0273]

[0274] The intermediate compound 66 (312.1 mg, 1 mmol), ((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (705.8 mg, 1.5 mmol), and potassium carbonate (690.5 mg, 3 mmol) were dissolved in 2 mL of N,N-dimethylformamide and reacted at 80 °C for 2 hours. After the reaction was completed, N,N-dimethylformamide was removed by distillation under reduced pressure, and column chromatography was performed with a developing solvent volume ratio of petroleum ether:ethyl acetate = 3:1 to obtain 129.7 mg of a white solid with a yield of 21.3%. The structure is as follows: 11H NMR (600 MHz, Chloroform-d) δ 7.89 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.31 (dd, J = 19.5, 7.9 Hz, 3H), 7.20 (dd, J = 11.5, 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 4.22 (dd, J = 10.5, 4.1 Hz, 1H), 4.17 (dd, J = 11.2, 3.9 Hz, 2H), 4.15–4.12 (m, 1H), 4.09 (dd, J = 9.6, 4.9 Hz, 1H), 4.00 (dd, J = 9.7, 4.4 Hz, 1H), 3.79 (d, J = 16.4 Hz, 4H), 3.62 (s, 4H), 2.43 (s, 3H), 1.38 (d, J = 18.0 Hz, 6H).

[0275] Example 73: Synthesis of Compound 73

[0276]

[0277] The labeled precursor compound 72 (125.0 mg, 0.2 mmol) and tetrabutylammonium fluoride (1 M, 2 mL, 2 mmol) were dissolved in 5 mL of tetrahydrofuran and reacted at 90 °C for 1 hour. After the reaction was completed, 1 M HCl was added to adjust the pH to 1, and the reaction was continued at 90 °C for 1 hour. After the reaction was completed, ammonia water was used to adjust the pH to neutral, and the mixture was filtered by suction to obtain 45.3 mg of a white solid with a yield of 54.2%. The structure is as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 7.92 (d, J = 2.7 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 9.1, 2.8 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 5.18–5.07 (m, 2H), 4.51 (ddd, J = 46.9, 9.1, 3.6 Hz, 1H), 4.39 (dt, J = 48.3, 8.0 Hz, 1H), 4.04 (dd, J = 9.7, 4.3 Hz, 1H), 3.90–3.85 (m, 1H), 3.81 (s, 2H), 3.71–3.65 (m, 4H), 3.58–3.53 (m, 4H). 19 19F NMR (565 MHz, DMSO-d6) δ -226.20.

[0278] The schematic diagram of the synthesis process of the compounds in Examples 65 - 73 is shown in Figure 7 .

[0279] Example 74: Synthesis of Compound 74

[0280]

[0281] According to the method of Example 1, using 2 - chlorobenzoxazole and piperazine as raw materials to synthesize Compound 74, 478.9 mg of white solid was obtained, with a yield of 67.8%. The structure is as follows: 1 H NMR(400MHz,Chloroform - d)δ7.36(d,J = 7.7Hz,1H),7.26(s,1H),7.16(t,J = 7.5Hz,1H),7.02(t,J = 7.2Hz,1H),3.68(s,4H),3.00(s,4H),1.80(s,1H).

[0282] Example 75: Synthesis of Compound 75

[0283]

[0284] According to the method of Example 5, using intermediate Compound 74 and 2 - bromopyridine - N - oxide as raw materials to synthesize Compound 75, 256.4 mg of white solid was obtained, with a yield of 45.0%. The structure is as follows: 1 H NMR(600MHz,Chloroform - d)δ8.22(d,J = 6.3Hz,1H),7.39(d,J = 7.7Hz,1H),7.29(d,J = 7.9Hz,2H),7.19(t,J = 7.3Hz,1H),7.05(t,J = 7.4Hz,1H),6.95(t,J = 6.2Hz,1H),6.90(d,J = 8.1Hz,1H),3.96(s,4H),3.53(s,4H).

[0285] Example 76: Synthesis of Labeled Precursor Compound 76

[0286]

[0287] According to the method of Example 11, using intermediate Compound 75 as raw material to synthesize labeled precursor Compound 76, 68.9 mg of white solid was obtained, with a yield of 33.2%. The structure is as follows: 11H NMR (600 MHz, Chloroform-d) δ 7.79 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.25–7.17 (m, 2H), 7.08 (t, J = 7.7 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 3.90–3.83 (m, 4H), 3.78 (s, 9H), 3.77–3.74 (m, 4H).

[0288] Example 77: Synthesis of Compound 77

[0289]

[0290] According to the method of Example 12, Compound 77 was synthesized using the labeled precursor compound 76 as the raw material, and 12.6 mg of white solid was obtained with a yield of 46.2%. The structure is as follows: 1 1H NMR (600 MHz, Chloroform-d) δ 7.59 (q, J = 8.2 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.51–6.46 (m, 1H), 6.27–6.21 (m, 1H), 3.86–3.80 (m, 4H), 3.73–3.69 (m, 4H). 19 19F NMR (565 MHz, Chloroform-d) δ -68.11.

[0291] The schematic diagrams of the synthesis processes of the compounds in Examples 74 - 77 above are shown in Figure 8 .

[0292] Example 78: Synthesis of Compound 78

[0293]

[0294] According to the method of Example 1, Compound 78 was synthesized using 7-chloroimidazo[1,2-a]pyridine and piperazine as the raw materials, and 848.4 mg of yellow solid was obtained with a yield of 84.0%. The structure is as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 6.6 Hz, 1H), 7.70 (s, 1H), 7.40 (s, 1H), 6.88 (d, J = 7.0 Hz, 1H), 6.79 (s, 1H), 3.46 (s, 4H), 2.92 (s, 4H).

[0295] Example 79: Synthesis of Compound 79

[0296]

[0297] According to the method of Example 1, using intermediate compound 78 and 2,5-diiodopyridine as raw materials to synthesize compound 79, 132.1 mg of yellow solid was obtained with a yield of 32.6%. The structure is as follows: 1 H NMR(400MHz,Methol-d4)δ8.37(d,J=7.8Hz,1H),8.27(s,1H),7.79(d,J=9.2Hz,1H),7.72(s,1H),7.52(s,1H),7.12(d,J=6.0Hz,1H),6.82(s,1H),6.76(d,J=8.8Hz,1H),3.73(s,4H),3.31(s,4H). 13 C NMR(151MHz,Methanol-d4)δ161.44,153.68,151.01,147.14,127.95,125.13,112.20,110.60,108.40,92.65,75.51,62.95,46.54,44.56.

[0298] Example 80: Synthesis of compound 80

[0299]

[0300] According to the method of Example 1, using 6-bromopyrazolo[1,5-a]pyrimidine and piperazine as raw materials to synthesize compound 80, 568.4 mg of yellow solid was obtained with a yield of 56.7%. The structure is as follows: 1 H NMR(400MHz,DMSO-dδ8.65(d,J=2.7Hz,1H),8.53–8.37(m,1H),8.01(d,J=2.5Hz,1H),6.60(d,J=2.4Hz,1H),3.03(t,J=5.0Hz,4H),2.87(d,J=5.2Hz,4H).

[0301] Example 81: Synthesis of compound 81

[0302]

[0303] According to the method of Example 1, using intermediate compound 80 and 2,5-diiodopyridine as raw materials to synthesize compound 81, 50.1 mg of white solid was obtained with a yield of 6.2%. The structure is as follows:: 11H NMR (600 MHz, Trifluoroacetic acid-d) δ 8.34 (s, 1H), 8.10 (s, 1H), 7.49 (s, 1H), 7.37 (s, 2H), 6.46–6.17 (m, 2H), 3.19 (s, 4H), 2.91 (s, 4H). 13 13C NMR (151 MHz, Trifluoroacetic acid-d) δ 153.75, 151.09, 148.42, 140.78, 140.63, 138.32, 136.69, 136.59, 119.25, 97.36, 72.78, 46.50, 44.89.

[0304] Example 82: Synthesis of Compound 82

[0305]

[0306] According to the method of Example 1, using 6-chloroimidazo[1,2-b]pyridazine and piperazine as raw materials to synthesize Compound 82, 358.3 mg of yellow solid was obtained with a yield of 91.2%. The structure is as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J = 9.9 Hz, 1H), 7.68 (d, J = 1.1 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 6.81 (d, J = 9.9 Hz, 1H), 3.51–3.46 (m, 4H), 3.06–3.01 (m, 4H), 2.23 (s, 1H).

[0307] Example 83: Synthesis of Compound 83

[0308]

[0309] According to the method of Example 1, using intermediate Compound 82 and 2,5-diiodopyridine as raw materials to synthesize Compound 83, 257.1 mg of yellow solid was obtained with a yield of 62.1%. The structure is as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 8.26 (d, J = 2.3 Hz, 1H), 7.88 (s, 1H), 7.83 (d, J = 10.0 Hz, 1H), 7.77 (dd, J = 8.9, 2.3 Hz, 1H), 7.46 (s, 1H), 7.17 (d, J = 9.9 Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 3.59 (dd, J = 7.0, 3.4 Hz, 4H), 3.53 (dd, J = 6.4, 3.5 Hz, 4H). 1313C NMR(151MHz,DMSO-d6)δ158.24,155.38,153.38,145.42,136.36,132.17,126.45,117.03,111.20,110.51,63.34,45.74,44.47.

[0310] Example 84: Synthesis of the labeled precursor compound 84

[0311]

[0312] According to the method of Example 8, using the intermediate compound 83 as the raw material, the labeled precursor compound 84 was synthesized to obtain 257.1 mg of a yellow solid with a yield of 62.1%. The structure is as follows: 1 1H NMR(400MHz,Chloroform-d)δ8.21(s,1H),7.82–7.63(m,2H),7.63–7.51(m,1H),7.52–7.38(m,2H),6.87(d,J = 9.3Hz,1H),6.73(d,J = 8.3Hz,1H),3.72(t,J = 6.6,4H),3.64(t,J = 6.6,4H),1.53(t,J = 8.7Hz,6H),1.39–1.27(m,6H),1.08–1.00(m,6H),0.89(t,J = 7.3Hz,9H).

[0313] For the schematic diagrams of the synthesis processes of the compounds in Examples 78 - 84 above, see Figure 9 .

[0314] Example 85: Synthesis of compound 85

[0315]

[0316] According to the method of Example 1, using 2-chloro-1,5-naphthyridine and piperazine as raw materials, compound 85 was synthesized to obtain 341.7 mg of a yellow solid with a yield of 79.7%. Without identification, it was directly used for the next reaction.

[0317] Example 86: Synthesis of compound 86

[0318]

[0319] According to the method of Example 1, using 2-chloroquinoxaline and piperazine as raw materials, compound 86 was synthesized, 432.8 mg, with a yield of 81.3%. Without identification, it was directly used for the next reaction.

[0320] Example 87: Synthesis of compound 87

[0321]

[0322] According to the method of Example 1, using intermediate compound 85 and 2,5-diiodopyridine as raw materials to synthesize compound 87, 70.9 mg of yellow solid was obtained, and the yield was 16.8%. The structure is as follows: 1 H NMR(600MHz,DMSO-d6)δ8.59(dd,J=4.0,1.9Hz,1H),8.30(t,J=1.9Hz,1H),8.09(d,J=9.3Hz,1H),7.95(d,J=8.4Hz,1H),7.81(dt,J=9.0,2.0Hz,1H),7.56–7.49(m,2H),6.82(d,J=8.9Hz,1H),3.88–3.81(m,4H),3.65(dd,J=7.2,4.1Hz,4H). 13 C NMR(151MHz,DMSO-d6)δ158.24,157.27,153.38,146.54,145.40,143.22,140.31,138.65,133.89,125.08,114.14,110.44,78.35,44.68,44.57.

[0323] Example 88: Synthesis of compound 88

[0324]

[0325] According to the method of Example 1, using intermediate compound 86 and 2,5-diiodopyridine as raw materials to synthesize compound 88, 120.4 mg of yellow solid was obtained, and the yield was 35.3%. The structure is as follows: 1 H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.26(d,J=2.3Hz,1H),7.84–7.74(m,2H),7.62–7.51(m,2H),7.41–7.33(m,1H),6.78(d,J=9.0Hz,1H),3.94–3.77(m,4H),3.71–3.56(m,4H). 13 C NMR(151MHz,DMSO-d6)δ158.18,153.39,152.50,145.42,141.53,137.44,136.82,130.55,128.93,126.56,124.98,110.45,78.42,44.56,44.12.

[0326] Example 89: Synthesis of compound 89

[0327]

[0328] According to the method of Example 5, using intermediate compound 85 and 3-bromopyridine-N-oxide as raw materials to synthesize compound 89, 128.9 mg of white solid was obtained with a yield of 42.0%. Without identification, the next reaction was carried out directly.

[0329] Example 90: Synthesis of labeled precursor compound 90

[0330]

[0331] According to the method of Example 11, using intermediate compound 89 as raw material to synthesize labeled precursor compound 90, 198.3 mg of white solid was obtained with a yield of 35.8%. Without identification, the next reaction was carried out directly.

[0332] Example 91: Synthesis of compound 91

[0333]

[0334] According to the method of Example 12, using labeled precursor compound 90 as raw material to synthesize compound 91, 14.1 mg of yellow solid was obtained with a yield of 65.2%. The structure is as follows: 1 H NMR(400MHz,Methanol-d4)δ8.52(d,J=4.6Hz,1H),8.04(d,J=8.9Hz,2H),7.83(s,1H),7.67–7.60(m,1H),7.59–7.52(m,1H),7.47(d,J=9.4Hz,1H),6.96(dd,J=9.0,3.0Hz,1H),3.95(t,J=5.2Hz,4H),3.31–3.30(m,4H). 13 C NMR(101MHz,Methanol-d4)δ157.81(d,J=234.32Hz),157.34,146.06,145.53,143.92,139.40,137.06,135.21,133.99(d,J=14.14Hz),130.33(d,J=7.07Hz),124.44,113.78,139.06(d,J=38.38Hz),49.10,44.71. 19 F NMR(376MHz,Methanol-d4)δ-82.41.

[0335] Example 92: Synthesis of compound 92

[0336]

[0337] According to the method of Example 1, using 2,5-dibromopyridine and piperazine as raw materials to synthesize Compound 92, 538 mg of white solid was obtained, with a yield of 42.1%. Without identification, the next reaction was carried out directly.

[0338] Example 93: Synthesis of Compound 93

[0339]

[0340] According to the method of Example 1, using 2-bromopyridine and piperazine as raw materials to synthesize Compound 93, 1.3 g of colorless oily liquid was obtained, with a yield of 48.7%. Without identification, the next reaction was carried out directly.

[0341] Example 94: Synthesis of Compound 94

[0342]

[0343] According to the method of Example 1, using intermediate Compound 93 and 2,5-dibromopyridine as raw materials to synthesize Compound 94, 256.4 mg of white solid was obtained, with a yield of 44.2%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ8.29(d,J=5.9Hz,2H),8.22(d,J=2.1Hz,1H),7.58(dd,J=9.0,2.4Hz,1H),6.74–6.68(m,2H),6.58(d,J=9.0Hz,1H),3.72–3.68(m,4H),3.50(dd,J=9.7,4.5Hz,4H).

[0344] Example 95: Synthesis of Compound 95

[0345]

[0346] According to the method of Example 5, using intermediate Compound 92 and iodobenzene as raw materials to synthesize Compound 95, 216.1 mg of white solid was obtained, with a yield of 68.1%. Without identification, the next reaction was carried out directly.

[0347] Example 96: Synthesis of Compound 96

[0348]

[0349] According to the method of Example 8, using intermediate Compound 94 as raw material to synthesize the labeled precursor Compound 96, 24.5 mg of light yellow oily liquid was obtained, with a yield of 33.5%. The structure is as follows: 11H NMR (600 MHz, Chloroform-d) δ 8.23–8.20 (m, 1H), 8.20 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.54–7.48 (m, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.68–6.63 (m, 1H), 3.71 (s, 8H), 1.53 (dt, J = 15.7, 7.7 Hz, 6H), 1.33 (dp, J = 21.9, 7.3 Hz, 6H), 1.10–0.98 (m, 6H), 0.88 (t, J = 7.3 Hz, 9H).

[0350] Example 97: Synthesis of Compound 97

[0351]

[0352] According to the method of Example 8, using intermediate compound 95 as the raw material, the labeled precursor compound 97 was synthesized to obtain 45.3 mg of a white solid with a yield of 47.6%. The structure is as follows: 1 1H NMR (600 MHz, Chloroform-d) δ 8.19 (d, J = 17.6 Hz, 1H), 7.41 (d, J = 5.0 Hz, 1H), 7.28 (t, J = 7.9 Hz, 2H), 6.96 (d, J = 7.8 Hz, 2H), 6.89 (t, J = 6.9 Hz, 1H), 6.73 (d, J = 17.3 Hz, 1H), 3.71 (s, 4H), 3.32 (s, 4H), 1.52 (dd, J = 16.2, 8.3 Hz, 6H), 1.41–1.27 (m, 6H), 1.04 (s, 6H), 0.89 (dtd, J = 22.5, 7.3, 1.2 Hz, 9H).

[0353] Example 98: Synthesis of Compound 98

[0354]

[0355] According to the method of Example 64, using the labeled precursor compound 96 as the raw material, compound 98 was synthesized to obtain 23.6 mg of a white solid with a yield of 57.8%. The structure is as follows: 1 1H NMR (600 MHz, Chloroform-d) δ 8.36–8.31 (m, 1H), 8.22 (d, J = 4.7 Hz, 1H), 7.70 (dd, J = 10.0, 1.0 Hz, 1H), 7.55 (s, 1H), 6.76–6.65 (m, 2H), 6.53 (d, J = 8.9 Hz, 1H), 3.70 (d, J = 12.7 Hz, 8H).

[0356] Example 99: Synthesis of Compound 99

[0357]

[0358] According to the method of Example 64, Compound 99 was synthesized using the labeled precursor compound 97 as the raw material, and 33.4 mg of white solid was obtained with a yield of 89.5%. The structure is as follows: 1 H NMR(600MHz,Chloroform-d)δ8.34(s,1H),7.70(d,J=11.0Hz,1H),7.54(d,J=8.7Hz,1H),7.31(d,J=8.2Hz,1H),6.97(d,J=43.5Hz,2H),6.72(d,J=7.0Hz,1H),6.55(q,J=8.9,8.4Hz,1H),3.81–3.63(m,4H),3.37–3.24(m,4H).

[0359] For the schematic diagrams of the synthesis processes of the compounds in the above Examples 92 - 99, see Figure 10 。

[0360] Example 100: 125 I and 18 Preparation of F-Labeled Compounds

[0361] I. Experimental Procedures

[0362] (a) Preparation of Compounds 125 I]2, 125 I]7, 125 I]29, 125 I]64, 125 I]83, 125 I]98 and 125 I]99

[0363] Dissolve 0.01 mg of the labeled precursor compound (which are labeled precursor compounds 8, 9, 31, 63, 84, 96 or 97 respectively) in 100 μL of ethanol, add approximately 100 μCi of Na 125 I solution, 50 μL of hydrochloric acid (1 M) and 100 μL of 3% hydrogen peroxide solution, react at room temperature for 15 minutes, add NaHCO3 to adjust the pH to neutral. Then separate and purify by HPLC, and the separation conditions are: Venusil MPC18 chromatographic column (5 μm, 4.6 mm×250 mm), collect the eluent of the target product stream.

[0364] (b) Preparation of Compounds 18 F]3 and 18 F]5

[0365] [ 18 F]F - The ions were concentrated on the QMA column and 1 mL of eluent (containing 6.8 mg TBAB, methanol solution) was used to 18 F]F - Elute from the QMA column. Take about 20mCi of fluoride ion solution and add it to a 10mL glass reaction tube, heat it in a 120℃ metal bath, and continuously blow dry with N2 to ensure that the reaction system is dry. Dissolve 4.0mg of labeled precursor compound 18 or labeled precursor compound 19 and 7.0mg of Cu(OTf)2(Py)4 in 100μL of anhydrous n-butanol and 200μL of anhydrous N,N-dimethylacetamide, and transfer the solution to a flask containing [ 18 F]F - The mixture was purified by a pre-treated Sep-Pak C18 solid phase extraction column, and the column was rinsed with 20 mL of deionized water to remove unreacted 18 F]F - The column was eluted with 1 mL of anhydrous acetonitrile to elute the labeled compound and the labeled precursor compound adsorbed on the column, concentrated and purified by HPLC, separation conditions: Venusil MP C18 reverse column (10 μm, 10 mm × 250 mm), and the effluent of the target product was collected.

[0366] (c) Compound [ 18 Preparation of F]27

[0367] [ 18 F]F - The ions were concentrated on the QMA column and 1 mL of eluent (containing 6.8 mg TBAB, methanol solution) was used to 18 F]F - Elute from the QMA column. Take about 20mCi of fluoride ion solution and add it to a 10mL glass reaction tube, heat it in a 120℃ metal bath, and continuously blow N2 to dry it to ensure that the reaction system is dry. Dissolve 4.0mg of the labeled precursor compound 30 and 7.0mg of Cu(OTf)2(Py)4 in 100μL of anhydrous n-butanol and 200μL of anhydrous N,N-dimethylacetamide, and transfer the solution to a flask containing [ 18 F]F - The mixture was purified by a pre-treated Sep-Pak C18 solid phase extraction column, and the column was rinsed with 20 mL of deionized water to remove unreacted 18 F]F- and inorganic salts. The column was rinsed with 1 mL of anhydrous acetonitrile, and the labeled compounds and labeled precursor compounds adsorbed on the column were eluted into a 10 mL glass reaction tube. 200 μL of hydrochloric acid (1 M) was added, and the mixture was heated in a metal bath at 90 °C for 3 minutes. Saturated aqueous NaHCO3 solution was added to adjust the pH to neutral. Then, it was separated and purified by HPLC. Separation conditions: Venusil MP C18 reverse column (10 μm, 10 mm × 250 mm), and the effluent of the target product was collected.

[0368] (d) Compound 18 F]35, 18 F]41, 18 F]60 and 18 Preparation of

[0369] 18 F]F - ion was enriched on the QMA column, and 1 mL of eluent (containing 13 mg of Kryptofix-2.2.2, 1.1 mg of K2CO3, acetonitrile / water = 4 / 1) was used to 18 F]F - elute it from the QMA column. Approximately 20 mCi of fluoride ion solution was added to a 10 mL glass reaction tube, heated in a metal bath at 120 °C, and continuously purged with N2 until dry to ensure that the reaction system was anhydrous. 2.0 mg of the labeled precursor compound (labeled precursor compounds 34, 40, 58, or 59 respectively) was dissolved in 500 μL of anhydrous acetonitrile, and this solution was transferred to the glass reaction tube containing 18 F]F - . The reaction was heated at 100 °C for 10 minutes. After cooling, it was separated and purified by HPLC. Separation conditions: Venusil MP C18 reverse column (10 μm, 10 mm × 250 mm), and the effluent of the target product was collected.

[0370] (c) Compound 18 F]12, 18 F]15 and 18 Preparation of

[0371] 18 F]F - ion was enriched on the QMA column, and 1 mL of eluent (containing 13 mg of Kryptofix-2.2.2, 1.1 mg of K2CO3, acetonitrile / water = 4 / 1) was used to 18 F]F - ​​Eluted from the QMA column. Take about 20 mCi of fluoride ion solution and add it to a 10 mL glass reaction tube. Heat it in a metal bath at 120 °C and continuously pass N2 to blow it dry to ensure that the reaction system is anhydrous. Dissolve 1.0 mg of the precursor compound for labeling (precursor compounds 11, 14 or 76 respectively) in 500 μL of anhydrous acetonitrile, and transfer this solution to a glass reaction tube containing 18 F]F - . Heat and react for 10 minutes at 60 °C. After cooling, separate and purify by HPLC. Separation conditions: Venusil MP C18 reverse column (10 μm, 10 mm × 250 mm), and collect the effluent of the target product.

[0372] (e) Preparation of compounds 18 F]51 and 18 F]73

[0373] 18 F]F - ions were enriched on the QMA column, and 18 F]F - was eluted from the QMA column. Take about 20 mCi of fluoride ion solution and add it to a 10 mL glass reaction tube. Heat it in a metal bath at 120 °C and continuously pass N2 to blow it dry to ensure that the reaction system is anhydrous. Dissolve 2.0 mg of the precursor compound for labeling (precursor compounds 50 or 72 respectively) in 500 μL of anhydrous acetonitrile, and transfer this solution to a glass reaction tube containing 18 F]F - . Heat and react for 10 minutes at 100 °C. Add 200 μL of hydrochloric acid (1 M), heat and react for 3 minutes in a metal bath at 90 °C, and add saturated aqueous NaHCO3 to adjust the pH to neutral. Then separate and purify by HPLC. Separation conditions: Venusil MP C18 reverse column (10 μm, 10 mm × 250 mm), and collect the effluent of the target product.

[0374] II. Experimental Results

[0375] 125 I]2, 18 F]3, 18 F]5, 125 I]7, 18 F]12, 18 F]15, 18 F]27, 125 I]29, 18 F]35, 18 ​​F]41, 18 F]51, 18 F]60, 18 F]61, 125 I]64, 18 F]73, 18 F]77, 125 I]83, 125 I]98 and 125 The labeling rates of I]99 are as follows. After separation and purification by HPLC, the radiochemical purities are all greater than 95%. The chromatographic column is a Venusil MP C18 reversed-phase column (5 μm, 4.6 mm × 250 mm or 10 μm, 10 mm × 250 mm), the mobile phase flow rate is 1 mL / min or 4 mL / min, and the radiochemical yields are shown in Table 1.

[0376] Table 1: Radiochemical Yields of Labeled Compounds

[0377]

[0378]

[0379] Example 101: Autoradiography Experiment

[0380] Incubate the labeled product (10% ethanol solution) at a certain concentration with tissue sections at room temperature for a certain period of time. After incubation, expose to a phosphor screen, and then scan and analyze the image with a storage phosphor screen system ( Plus, Perkin-Elmer, USA).

[0381] I. Experimental Procedures:

[0382] (1) Pretreat paraffin sections;

[0383] (2) Cover the tissue sections with 1 mL of a solution of I-labeled compound at 2 - 5 μCi / mL or F-labeled compound at 10 - 20 μCi / mL, and incubate at room temperature for 1 - 2 hours; 125 I-labeled or 18 F-labeled

[0384] (3) Rinse with 50% ethanol solution for 5 minutes;

[0385] (4) After air-drying, wrap with plastic wrap and expose to a phosphor screen for 24 hours ( 125 I-labeled compound) or 1 hour ( 18 F-labeled compound), and then scan and analyze the image with a storage phosphor screen system ( Plus, Perkin-Elmer, USA).

[0386] II. Experimental Results:

[0387] The experimental results are as follows Figure 12 and Figure 13 shown. It fully demonstrates that after the compounds 2, 5, 7, 12, 15, 35, 41, 60, 61, 64, 73, 77 of the present invention are labeled with radionuclides, they can recognize Aβ plaques on human brain tissue sections. After the compounds 2, 60, 61, 73 are labeled with radionuclides, they can recognize AL aggregates and ATTR aggregates on myocardial tissue sections. Preferably, the radionuclide 125 I-labeled compound 2 and the radionuclide 18 F-labeled compound 12 have excellent imaging effects in this series of compounds and can be used as preferred Aβ plaque imaging agents for AD in the brain and detection of AL and ATTR aggregates in heart-related diseases. These compounds have potential application prospects in clinical diagnosis.

[0388] Example 102: Biodistribution experiment in normal mice

[0389] I. Experimental steps:

[0390] Inject 5 - 10 μCi 18 F-labeled compound or 0.5 - 1 μCi 125 I-labeled compound (100 μL physiological saline solution containing 10% ethanol) into normal mice (ICR, male, 18 - 20 g, 3 - 4 weeks old) via the tail vein (n = 3). Dissect and remove the relevant organs at 2 minutes and 60 minutes after injection, and measure the wet weight and radioactivity count. The data is expressed as the percentage of radioactive dose per gram of organ (%ID / g).

[0391] II. Experimental results:

[0392] The experimental results are shown in Table 2. The probes 125 I]2, 18 F]12, 125 F]15, 125 F]35 and 18 F]41 of the present invention can all successfully cross the blood-brain barrier, have a certain retention in the brain at 2 minutes and can be cleared by normal mice. They meet the basic requirements of central nervous system PET imaging agents and have the potential to be developed into Aβ plaque imaging agents.

[0393] Table 2: Animal distribution results of some compounds in normal mice

[0394]

[0395]

[0396] Example 103: Determination of Aβ protein activity

[0397] I. Experimental Procedures

[0398] (1) Add 100 μL of radioactive ligand ( 125 I]IMPY, 1 μCi / mL), an ethanol solution of the compound to be tested (100 μL, containing compounds 2, 3, 5, 6, 7, 12, 15, 27, 29, 35, 41, 51, 60, 61, 64, 73, 77, 79, 81, 83, 87, 88, 91, 98, and 99) with a final concentration of 10 -5 M to 10 -11 M), 700 μL of BSA, and Aβ 1-42 aggregates (100 μL, containing Aβ protein with a final concentration of 1.9 μM) into a borosilicate glass test tube in sequence.

[0399] (2) Incubate statically at 37 °C for 2 hours.

[0400] (3) Filter and separate using an MP-48T cell harvester, and wash 3 times with 10% ethanol.

[0401] (4) Collect the glass fiber filter paper containing the 1-42 I ligand bound to Aβ 125 aggregates and place it at the bottom of the numbered counting tube, and measure the radioactivity count of each counting tube. The half-inhibitory constant (IC 50 ) is obtained by fitting calculation.

[0402] II. Experimental Results

[0403] The experimental results are shown in Table 3. Except for compounds 15, 77, and 91 with an Aβ 1-42 aggregate activity (IC 50 ) greater than 100 nM, compounds 2, 3, 5, 6, 7, 12, 27, 29, 35, 41, 51, 60, 61, 64, 73, 79, 81, 83, 87, 88, 98, and 99 all have an Aβ 1-42 aggregate activity (IC 50 ) less than 100 nM, indicating good binding ability to Aβ aggregates.

[0404] Table 3: Aβ Activity Test Results of Compounds 1-42 Activity Test Results

[0405]

[0406] Example 104: Determination of IC 50 Value of the Compound on Brain Tissue Sections of AD Patients

[0407] I. Experimental Procedures:

[0408] (1) Pre-treat the paraffin sections of AD human brains;

[0409] (2) Cover the AD human brain sections with 1 mL of 125 I-labeled compound 2 or 10 μCi / mL of 18 F-labeled compound flubetazine solution and stable cold ligand solutions of the test compounds at different concentrations, and incubate at room temperature for 1 - 2 hours;

[0410] (3) Rinse with 50% ethanol solution for 3 minutes;

[0411] (4) After air-drying, wrap with plastic wrap and expose to a phosphor screen for 10 hours. Scan and analyze the image using a storage phosphor screen system ( Plus, Perkin-Elmer, USA) to obtain the quantitative values (Digital Light Unit / mm 2 , DLU / mm 2 ) of Region of interests (ROIs). Fit a curve based on the values and the corresponding cold ligand concentrations, and the half-inhibitory constant (IC 50 ) is obtained through fitting calculation.

[0412] II. Experimental results:

[0413] Table 4: IC 50 values of the compounds on the brain tissue sections of AD patients

[0414]

[0415] The experimental results are as shown in Figure 14 - 15 , Table 4. Compounds 2, 3, 12, and 35 have high affinity for Aβ plaques in the brains of AD patients, and their IC 50 are all less than 60 nM, which is consistent with the results of in vitro autoradiography and in vitro Aβ protein activity tests, indicating that these compounds have the potential to be further developed into Aβ plaque imaging agents with clinical application value.

[0416] Example 105: PET / CT imaging of rodents

[0417] I. Experimental procedures

[0418] Inject 18 F]12 injection solution (5.3243 - 8.5803 MBq, 10% ethanol solution), 18 F]35 injection solution (7.8329 - 8.2103 MBq, 10% ethanol solution), 18 F]60 injection solution (6.6378 - 8.3176 MBq, 10% ethanol solution), 18F]61 (9.4461 - 7.2890 MBq, 10% ethanol solution), 18 F]73 (8.2436 MBq, 10% ethanol solution) or 18 F]77 (10.5265 - 13.6604 MBq, 10% ethanol solution) injection was intravenously injected into SD rats (1 - 3 rats per group, male) via the tail vein, and immediately started the PET dynamic scan for 0 - 60 min. During the acquisition process, anesthetic method of continuous inhalation of a mixed gas of isoflurane and air was used, and the gas flow rate was 1 - 2 L / min. After the PET data acquisition was completed, CT acquisition was performed to obtain anatomical information. The PET data was reconstructed by the 3D - OSEM method, and the dynamic data of SD rats was framed in the way of 15×60 s, 5×300 s and 1×600 s. The reconstructed data was imported into PMOD 4.1 software to complete the quantitative analysis of the data and export the PET images.

[0419] II. Experimental Results

[0420] As Figure 16 - 21 shown, 18 F]12, 18 F]35, 18 F]60, 18 F]61, 18 F]73 and 18 F]77 can all cross the blood - brain barrier of rodents, reach the peak brain uptake at 1.5 minutes, and are rapidly cleared in the brains of healthy rodents without obvious off - target binding. Their maximum brain uptake values and brain clearance rates are shown in Table 5. Among them, 18 F]12 has a high brain uptake value and a rapid brain clearance rate, and has a high affinity with Aβ aggregates, meeting the basic requirements of a central nervous system imaging agent, and is expected to be developed into a PET imaging agent for Aβ plaques with clinical value.

[0421] Table 5: Maximum brain uptake values Brain max and brain clearance rates Ratio

[0422] Compound <![CDATA[Brain max > Ratio <![CDATA 18 F]12]]> 2.30 4.60 <![CDATA 18 F]35]]> 1.74 2.49 <![CDATA 18 F]60]]> 0.84 2.00 <![CDATA 18 F]61]]> 1.70 2.33 <![CDATA 18 F]73]]> 0.89 3.56 <![CDATA 18 F]77]]> 2.74 4.03

[0423] Although the present invention has been described in detail with general descriptions and specific embodiments above, based on the present invention, some modifications or improvements can be made, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection of the present invention.

Claims

1. A diarylpiperazine compound, characterized in that, The compound has the structure of general formula I as follows: wherein Ar1 represents Ar2 represents R1 and R2 each independently represent H, 123 / 125 / 127 I, -NH((CH2) m 11 / 12 CH3), -N((CH2) m 11 / 12 CH3)2, -O 11 / 12 CH3, -(OCH2CH2) m R3, wherein R3 is 18 / 19 F, and m is any integer between 0 and 6.

2. The diarylpiperazine compound according to claim 1, wherein Selected from the following compounds: Among them, both I and F can simultaneously refer to their isotopes, such as: 123 / 125 / 127 I and 18 / 19 F.

3. A derivative of the diarylpiperazine compound according to claim 1 or 2, characterized in that, Including pharmaceutically acceptable salts, esters or amide compounds.

4. A diagnostic or detection reagent for amyloid in a neurodegenerative disease or a heart-related disease, characterized in that, Its active ingredient is the diarylpiperazine compound described in claim 1 or 2, and / or the derivative described in claim 3.

5. The diagnostic or detection reagent according to claim 4, wherein The diseases include Alzheimer's disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, myocardial infarction, myocardial ischemia, heart failure, coronary heart disease, cardiac amyloidosis.

6. Use of the diarylpiperazine compound described in claim 1 or 2, and / or the derivative described in claim 3 in the preparation of a nuclear medicine imaging agent.

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