A quinazoline compound, precursors, derivatives and uses thereof

Abstract

The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a quinazoline compound and precursors, derivatives and applications thereof. The quinazoline compound provided by the present application has excellent precursor chemical stability and in-vivo metabolic stability, and has an ideal imaging performance in a brain glioma model, thereby providing more reliable molecular imaging data for precise diagnosis of brain glioma and other cancers and diagnosis and treatment of neuroinflammation-related diseases, and having a good clinical transformation potential.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a quinazoline compound, its precursors, derivatives, and applications. Background Technology

[0002] Glioblastoma (GBM), as the most aggressive malignant tumor of the central nervous system, is difficult to eradicate surgically due to the diffuse infiltration of tumor cells into the surrounding brain parenchyma. Conventional imaging cannot accurately define the boundaries, and the median survival of patients is only about 15 months (Lancet Oncol. 2025, 26(12): 1665-1675). Currently, the clinical gold standard, magnetic resonance imaging (MRI), has limitations in differentiating radiation necrosis from tumor recurrence (J Clin Neurosci., 2025, 133:111036). Positron emission tomography (PET) can provide unique pathophysiological information at the molecular level and is considered a key technology to compensate for the shortcomings of MRI and achieve precise diagnosis and treatment of GBM. However, existing mainstream probes such as [¹ 8 F]FDG has high brain baseline, [¹] 8 Amino acid probes such as F]FET lack specificity (Eur J Radiol. 2023, 159:110658). Therefore, there is an urgent need to develop novel PET probes with high targeting and high stability.

[0003] 18 kDa translocator protein (TSPO) is a protein located on the outer mitochondrial membrane and is involved in various cellular functions, including steroid biosynthesis, cholesterol metabolism, cell proliferation, and apoptosis. It is overexpressed in neuroinflammation and various tumors (Eur J Nucl Med Mol Imaging. 2021, 49(1):174-185). In high-grade gliomas, TSPO is highly expressed while it is lowly expressed in normal brain tissue, making it an ideal target for glioma PET imaging (Acta Neuropathol Commun., 2023, 11(1): 75).

[0004] As a classic TSPO tracer, [¹¹C]PK11195 is widely used in neuroinflammatory imaging, but its low binding affinity and short half-life (20.4 min) of ¹¹C radionuclides limit its clinical application. Meanwhile, [¹¹C]PK11195... 8 F]PBR06 and [¹ 8 F]DPA-714 is a representative of [¹ 8The second-generation TSPO probe labeled with [F] showed higher binding affinity than the first generation (JNucl Med, 2011, 52: 107-114; 2012, 53: 287-294), but its widespread application was greatly limited because its ligand binding ability was severely affected by the rs6971 polymorphism of the TSPO gene. Subsequent third-generation probes […]. 18 F]GE180 has shown potential in various neurological diseases and gliomas, and more importantly, its ligand binding ability is not affected by rs6971 polymorphism (Eur J Nucl Med Mol Imaging. 2017, 44(13): 2230-2238); 11 C]ER176 also maintains high binding affinity for all genotypes, and its affinity is higher than [ 11 C]PBR28 (J Nucl Med. 2017, 58(2):320-325).

[0005] Our team previously developed [¹¹C]ER176 as a lead compound. 8 F] Labeling the TSPO-targeting probe[¹ 8 F]BIBD239 and its deuterated derivatives[¹ 8 F]BIBD239-2d, used for precise imaging of gliomas (CN202110674565.8; Mol. Pharmaceutics, 2022, 19(7), 2351-2366; New J Chem., 2025, 49(3): 1100-1109; Mol. Pharmaceutics, 2025, 22, 6339-6348). Evaluation showed that these two probes have excellent TSPO binding affinity (nM level) and good intracranial metabolic stability, and have the potential for precise localization of intracranial gliomas.

[0006] However, subsequent studies revealed the following pressing issues with this series of probes: First, the labeling precursors exhibit poor chemical stability, easily deliquescing and deteriorating during aliquoting and storage, making long-term storage unsuitable. Second, sulfonates (OMs) are prone to degradation during fluorination labeling, resulting in low labeling yields and susceptibility of product radiochemical purity to degradation products. Furthermore, the metabolic instability of the flexible side chains easily induces in vivo defluorination of the probes, leading to increased bone uptake and non-specific signal interference, affecting image clarity and the accuracy of quantitative analysis. Therefore, based on these core issues of precursor chemical instability and side-chain metabolic instability, a novel PET probe targeting TSPO is urgently needed. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a quinazoline compound, its precursor, derivatives, and applications. The quinazoline compound provided by this invention exhibits excellent precursor chemical stability and in vivo metabolic stability, and demonstrates promising imaging performance in glioma models. This provides more reliable molecular imaging data for the accurate diagnosis of gliomas and other cancers, as well as the treatment of neuroinflammatory diseases, and possesses significant potential for clinical translation.

[0008] In a first aspect, the present invention provides a quinazoline precursor having a structure as shown in Formula I or Formula II:

[0009] Formula I;

[0010] Formula II; Where X is selected from C or N; It is selected from any one of substituted or unsubstituted benzene rings, substituted or unsubstituted pyridine rings, substituted or unsubstituted pyrimidine rings, substituted or unsubstituted pyridazine rings, or substituted or unsubstituted pyrazine rings; R1 is selected from H or substituted or unsubstituted C1-C6 alkyl groups; R2 is selected from substituted or unsubstituted leaving groups; Selected from any one of substituted or unsubstituted divalent cycloalkyl, substituted or unsubstituted divalent bridged cycloalkyl, and substituted or unsubstituted divalent spirocycloalkyl; Selected from any one of substituted or unsubstituted divalent nitrogen-containing heterocyclic alkyl groups, substituted or unsubstituted divalent nitrogen-containing bridged cyclic alkyl groups, and substituted or unsubstituted divalent nitrogen-containing spirocyclic alkyl groups; When the group described above contains a substituent, the substituent is Cl or F.

[0011] The alkyl groups in C1-C6 can be methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.

[0012] The quinazoline precursors provided by this invention exhibit excellent chemical stability, showing no significant deterioration or degradation for more than 12 consecutive weeks in chemical stability tests. Even when stored in solution, no significant deterioration was found, which greatly facilitates subsequent drug repackaging, automated probe labeling, parallel quality control, and long-distance transportation.

[0013] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent cycloalkyl group is selected from any one of substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, and substituted or unsubstituted cyclohexyl.

[0014] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent bridged cycloalkyl group is selected from any one of substituted or unsubstituted bicyclo[1.1.0]butyl, substituted or unsubstituted bicyclo[1.1.1]pentyl, substituted or unsubstituted bicyclo[2.1.0]pentyl, substituted or unsubstituted bicyclo[2.1.1]hexyl, 2-oxabicyclo[2.1.1]hexyl, and substituted or unsubstituted bicyclo[2.2.0]hexyl.

[0015] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent spirocycloalkyl group is selected from any one of substituted or unsubstituted spiro[2.2]pentyl, substituted or unsubstituted spiro[2.3]hexyl, substituted or unsubstituted spiro[2.4]heptyl, substituted or unsubstituted spiro[3.3]heptyl, and substituted or unsubstituted spiro[3.4]octyl.

[0016] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent nitrogen-containing heterocyclic alkyl group is selected from any one of the following: substituted or unsubstituted nitrogen-containing heterocyclic propane, substituted or unsubstituted nitrogen-containing heterocyclic butane, substituted or unsubstituted 3-cyclopropylazetane, substituted or unsubstituted 3-cyclobutylazetane, substituted or unsubstituted nitrogen-containing heterocyclic pentane, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted triazole, substituted or unsubstituted oxazolidinone, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazolidinone, and substituted or unsubstituted piperazine.

[0017] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent nitrogen-containing bridged cycloalkyl group is selected from any one of azirbicyclo[2.1.1]hexyl, substituted or unsubstituted azirbicyclo[3.1.0]hexyl, substituted or unsubstituted azirbicyclo[3.1.1]heptyl, substituted or unsubstituted azirbicyclo[3.2.1]octyl, and substituted or unsubstituted octahydropyrrolo[3,4-c]pyrrole.

[0018] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent nitrogen-containing spirocycloalkyl group is selected from any one of 1-azaspiro[2.3]hexyl, 4-azaspiro[2.3]hexyl, 4,5-diazaspiro[2.3]hexyl, 5-azaspiro[2.3]hexyl, 1-oxa-5-azaspiro[2.3]hexyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[4.4]nonyl, and 2,7-diazaspiro[4.4]nonane-1-one.

[0019] In a preferred embodiment of the present invention, X is selected from N.

[0020] As a preferred technical solution of the present invention Selected from .

[0021] As a preferred technical solution of the present invention Selected from .

[0022] As a preferred embodiment of the present invention, the leaving group includes any one of methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, acetoxy, cyano, and halogen.

[0023] Secondly, the present invention provides a quinazoline compound and its derivatives, said derivatives comprising one or more of pharmaceutically acceptable salts, diastereomers, tautomers, hydrates, solvates, and crystals, said quinazoline compound having a structure as shown in Formula I or Formula II:

[0024] Formula I;

[0025] Formula II; Where X is selected from C or N; It is selected from any one of substituted or unsubstituted benzene rings, substituted or unsubstituted pyridine rings, substituted or unsubstituted pyrimidine rings, substituted or unsubstituted pyridazine rings, or substituted or unsubstituted pyrazine rings; R1 is selected from H or substituted or unsubstituted C1-C6 alkyl groups; R2 is selected from... 19 F or 18 F; Selected from any one of substituted or unsubstituted divalent cycloalkyl, substituted or unsubstituted divalent bridged cycloalkyl, and substituted or unsubstituted divalent spirocycloalkyl; Selected from any one of substituted or unsubstituted divalent nitrogen-containing heterocyclic alkyl groups, substituted or unsubstituted divalent nitrogen-containing bridged cyclic alkyl groups, and substituted or unsubstituted divalent nitrogen-containing spirocyclic alkyl groups; When the group described above contains a substituent, the substituent is Cl or F.

[0026] The quinazoline compounds and their derivatives provided by this invention have high affinity for TSPO and exhibit excellent in vitro and in vivo metabolic stability and superior glioma imaging performance. They provide a more reliable molecular tool for the accurate diagnosis of gliomas of different grades and the treatment of neuroinflammatory diseases, and offer important imaging data for promoting the development of personalized medicine. Specifically: The quinazoline compounds provided by this invention combine the general rules of brain imaging agents (molecular weight not exceeding 500, electrically neutral, highly lipid-soluble, and easy to label, store, and transport precursors, etc.) and address the technical shortcomings of existing ER176 and BIBD series compounds, where flexible side chains are prone to defluorination or degradation due to excessive freedom. A rigid regulation strategy is proposed: based on the principle of bioisosterism, a series of rigid ring structures (Ri or Rj) are introduced to constrain the original flexible chain segments, effectively restricting the free rotation of the original chiral center. This results in a class of rigid ring-derived quinazoline derivatives that significantly improve metabolic stability while maintaining target affinity. Simultaneously, by selecting bicyclic structures with specific chirality (such as the BCP backbone), the configuration of the chiral key pharmacophore of ER176 is simulated to maintain or even enhance the binding affinity for TSPO. Therefore, the quinazoline compounds and their derivatives provided by this invention exhibit high metabolic stability in PBS buffer and animal serum while maintaining high affinity for TSPO, effectively inhibiting in vivo defluorination. PET-CT imaging shows that the compounds provided by this invention... 18 F-labeled quinazoline compounds accurately accumulated in the tumor region in a mouse orthotopic glioma model, with low radioactive uptake by the normal brain tissue background and clear tumor boundaries, demonstrating their potential as PET tracers for gliomas. They also provide new molecular imaging data for precision diagnosis and treatment of neuroinflammatory diseases such as Alzheimer's disease, multiple sclerosis, and stroke, showing good potential for clinical translation.

[0027] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent cycloalkyl group is selected from any one of substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, and substituted or unsubstituted cyclohexyl.

[0028] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent bridged cycloalkyl group is selected from any one of substituted or unsubstituted bicyclo[1.1.0]butyl, substituted or unsubstituted bicyclo[1.1.1]pentyl, substituted or unsubstituted bicyclo[2.1.0]pentyl, substituted or unsubstituted bicyclo[2.1.1]hexyl, 2-oxabicyclo[2.1.1]hexyl, and substituted or unsubstituted bicyclo[2.2.0]hexyl.

[0029] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent spirocycloalkyl group is selected from any one of substituted or unsubstituted spiro[2.2]pentyl, substituted or unsubstituted spiro[2.3]hexyl, substituted or unsubstituted spiro[2.4]heptyl, substituted or unsubstituted spiro[3.3]heptyl, and substituted or unsubstituted spiro[3.4]octyl.

[0030] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent nitrogen-containing heterocyclic alkyl group is selected from any one of the following: substituted or unsubstituted nitrogen-containing heterocyclic propane, substituted or unsubstituted nitrogen-containing heterocyclic butane, substituted or unsubstituted 3-cyclopropylazetane, substituted or unsubstituted 3-cyclobutylazetane, substituted or unsubstituted nitrogen-containing heterocyclic pentane, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted triazole, substituted or unsubstituted oxazolidinone, substituted or unsubstituted oxadiazole, substituted or unsubstituted isoxazolidinone, and substituted or unsubstituted piperazine.

[0031] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent nitrogen-containing bridged cycloalkyl group is selected from any one of azirbicyclo[2.1.1]hexyl, substituted or unsubstituted azirbicyclo[3.1.0]hexyl, substituted or unsubstituted azirbicyclo[3.1.1]heptyl, substituted or unsubstituted azirbicyclo[3.2.1]octyl, and substituted or unsubstituted octahydropyrrolo[3,4-c]pyrrole.

[0032] As a preferred embodiment of the present invention, the substituted or unsubstituted divalent nitrogen-containing spirocycloalkyl group is selected from any one of 1-azaspiro[2.3]hexyl, 4-azaspiro[2.3]hexyl, 4,5-diazaspiro[2.3]hexyl, 5-azaspiro[2.3]hexyl, 1-oxa-5-azaspiro[2.3]hexyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[4.4]nonyl, and 2,7-diazaspiro[4.4]nonane-1-one.

[0033] In a preferred embodiment of the present invention, X is selected from N.

[0034] As a preferred technical solution of the present invention Selected from .

[0035] As a preferred technical solution of the present invention Selected from .

[0036] As a preferred embodiment of the present invention, the quinazoline compounds and their derivatives include any one or more of the following compounds:

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043] .

[0044] Thirdly, the present invention provides a pharmaceutical composition comprising any one or more of the quinazoline compounds and their derivatives described in the second aspect.

[0045] Fourthly, the present invention provides the use of quinazoline precursors as described in the first aspect, or quinazoline compounds and their derivatives as described in the second aspect, or pharmaceutical compositions as described in the third aspect, in the preparation of medicaments for diagnosing diseases characterized by changes in 18 kDa translocase proteins.

[0046] As a preferred embodiment of the present invention, the diseases characterized by changes in 18 kDa translosin include cancer and neuroinflammatory diseases. The cancers include glioma, breast cancer, prostate cancer, thyroid cancer, colorectal cancer, lung cancer, head and neck squamous cell carcinoma, ovarian cancer, skin cancer, melanoma, and meningioma. The neuroinflammatory diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke.

[0047] Fifthly, the present invention provides an imaging agent or kit comprising one or more of the quinazoline compounds and their derivatives described in the second aspect, or a pharmaceutical composition described in the third aspect.

[0048] The technical solution provided by the embodiments of the present invention has the following advantages compared with the prior art: The quinazoline compounds provided by this invention have excellent precursor chemical stability and in vivo metabolic stability, and exhibit ideal imaging performance in glioma models. They provide more reliable molecular imaging data for the accurate diagnosis of gliomas and other cancers, as well as the diagnosis and treatment of neuroinflammatory diseases, and have good potential for clinical translation. Attached Figure Description

[0049] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0050] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0051] Figure 1 Here is a high-resolution mass spectrum of the quinazoline compound prepared in Example 1; Figure 2 The high-resolution mass spectrum of the quinazoline compound prepared in Example 2 is shown below. Figure 3 Here is a high-resolution mass spectrum of the quinazoline compound prepared in Example 3; Figure 4 Here is a high-resolution mass spectrum of the quinazoline compound prepared in Example 4; Figure 5 Here is a high-resolution mass spectrum of the quinazoline compound prepared in Example 5; Figure 6 Here is a high-resolution mass spectrum of the quinazoline compound prepared in Example 6; Figure 7 For Example 7, [ 18 120-minute dynamic PET-CT imaging of Quinazoline-RRS-1 in a GL261 mouse glioma model. Detailed Implementation

[0052] To better understand the above-mentioned objectives, features, and advantages of the present invention, the solutions of the present invention will be further described below. It should be noted that, unless otherwise specified, the embodiments of the present invention and the features thereof can be combined with each other.

[0053] Many specific details are set forth in the following description in order to provide a full understanding of the invention, but the invention may also be practiced in other ways different from those described herein; obviously, the embodiments in the specification are only some embodiments of the invention, and not all embodiments.

[0054] Example 1 This embodiment provides a quinazoline compound, its precursor, and its preparation method. The preparation process is shown below:

[0055] The specific preparation method includes the following steps: (1) 2-Aminobenzamide (3.27 g, 24.05 mmol) was added to diethyl oxalate (30 mL), stirred at 185 °C, and monitored by TLC. After 14 h, the reaction was stopped, and a light brown crude product precipitated upon cooling. The product was filtered, and the filter cake was washed with cold ethyl acetate / petroleum ether (1 / 10) to obtain a white solid pure compound 1, 3.55 g, with a yield of 67.7%. Theoretical calculation by high-resolution mass spectrometry (HRMS): C11H10N2NaO3+, 241.0589 [M+Na]+; Measured value: 241.0063.

[0056] (2) Under nitrogen protection, compound 1 (1.42 g, 6.52 mmol) was dissolved in toluene (35 mL), and phosphorus tribromooxyphosphate (2.24 g, 7.82 mmol) was added sequentially. N,N -Diisopropylethylamine (1.85 g, 14.34 mmol), refluxed for 9 h. After the reaction was stopped, the solvent was removed, ice water (40 mL) was added and ultrasonically mixed, extracted with ethyl acetate, and the organic phase was washed successively with saturated sodium bicarbonate solution (40 mL) and saturated brine (40 mL). The organic phases were combined, dried, concentrated, and purified by rapid column chromatography to give a pale yellow solid compound 2, 1.16 g, yield 63.6%. HRMS theoretical calculation: C11H10BrN2O2+, 280.9920 [M+H]+; bromine isotope peak; measured value: 280.9117.

[0057] (3) Under nitrogen protection, compound 2 (0.96 g, 3.41 mmol) was dissolved in ultra-dry 1,4-dioxane (20 mL), and 2-chlorophenylboronic acid (2.14 g, 13.65 mmol), sodium acetate (1.12 g, 13.65 mmol) and tetrakis(triphenylphosphine)palladium (0.2 g, 0.17 mmol) were added. The reaction was carried out at 80 °C and monitored by TLC. After 8 h, the reaction was stopped, the solvent was removed by rotary evaporation, water (20 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated, and then subjected to rapid column chromatography to obtain a pale yellow solid compound 3, 0.75 g, with a yield of 70.2%. HRMS theoretical value: C17H14ClN2O2+, 313.0743 [M+H]+; Measured value: 313.0105.

[0058] (4) Compound 3 (0.26 g, 0.83 mmol) was dissolved in ethanol (10 mL), and sodium hydroxide solution (0.17 g, 4.25 mmol, dissolved in 1 mL water) was added. The mixture was stirred at room temperature and monitored by TLC. The reaction was stopped after 6 h. After removing the solvent by rotary evaporation, water (4 mL) was added. The pH of the system was adjusted to 2 by adding dilute hydrochloric acid, and a solid precipitated. The solid was filtered and dried to obtain a light yellow solid compound 4, 0.23 g, with a yield of 97.6%. HRMS theoretical calculation: C15H10ClN2O2+, 285.0425 [M+H]+; Measured value: 284.8599.

[0059] (5) Under nitrogen protection, compound 4 (142 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (10 mL), and 3-hydroxymethylazacyclobutane (53 mg, 0.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol), 1-hydroxybenzotriazole (HOBt, 34 mg, 0.25 mmol) and triethylamine (152 mg, 1.5 mmol) were added sequentially. The reaction was carried out at room temperature, and the starting material was consumed after 9 h. After the reaction was stopped, the reaction solution was washed with water (10 mL × 2), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the mixture was separated by rapid column chromatography to obtain a white solid 1-1:123 mg, with a yield of 69.7%. HRMS theoretical calculation: C19H17ClN3O2+, 354.1004 [M+H]+; Measured value: 354.0692.

[0060] (6) Under ice-salt bath conditions, compound 1-1 (95 mg, 0.27 mmol) was dissolved in dichloromethane (8 mL), and triethylamine (57 mg, 0.56 mmol) was added. The mixture was stirred thoroughly for 10 min, followed by slow injection of methanesulfonyl chloride (93 mg, 0.81 mmol). The reaction was stirred and monitored by TLC. The starting material reacted completely within 5 min. After the reaction was stopped, the mixture was washed with water (10 mL), the organic phase was dried, and the filtrate was concentrated and separated by rapid column chromatography to obtain 105 mg of pale yellow solid 1-2 (which is the precursor of the quinazoline compound), with a yield of 90.3%. HRMS theoretical calculation: C20H19ClN3O4S+, 432.0779 [M+H]+; Measured value: 432.0296.

[0061] (7) Under nitrogen protection, compounds 1-2 (73 mg, 0.17 mmol) were dissolved in ultra-dry tetrahydrofuran (6 mL), and excess tetrabutylammonium fluoride (specification: 1M tetrahydrofuran solution, 0.6 mL) was added. The mixture was stirred thoroughly at 35 °C, and monitored by TLC. After 2 h, the starting material was completely consumed. The reaction was stopped, the solvent was removed by rotary evaporation, and an appropriate amount of dichloromethane was added. The mixture was washed twice with water. The organic phase was dried by rotary evaporation and separated by rapid column chromatography to obtain 50 mg of white solid, which was the quinazoline compound, named Quinazoline-RRS-1, with a yield of 83.5%.

[0062] High-resolution mass spectra as follows Figure 1 As shown, the theoretical HRMS value is: C19H16ClFN3O+, 356.0960 [M+H]+; the measured value is: 356.0777.

[0063] 1 H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 8.5 Hz, 1H), 8.03-7.91 (m, 1H), 7.67 (m, 2H), 7.61-7.40 (m, 4H), 4.81 (t, J = 9.5 Hz, 1H), 4.68 (d, J = 5.9Hz, 1H), 4.59-4.47 (m, 2H), 4.41 (t, J = 9.5 Hz, 1H), 4.20-4.08 (m, 1H), 3.05(m, 1H).

[0064] 13 C NMR (75 MHz, CDCl3) δ 167.49, 167.17, 150.97, 135.70, 134.48,132.77, 130.99, 130.08, 129.29, 128.69, 126.95, 123.40, 85.14, 82.89, 60.43,56.04, 53.46, 50.29, 29.71, 29.18.

[0065] Example 2 This embodiment provides a quinazoline compound, its precursor, and its preparation method. The preparation process is shown below:

[0066] The specific preparation method includes the following steps: (1) Under nitrogen protection, tert-butyl trans-3-hydroxymethylcyclobutylcarbamate (1 g, 4.98 mmol) was dissolved in anhydrous dichloromethane (12 mL), and excess trifluoroacetic acid (2.5 mL) was added. The reaction was carried out at room temperature, and the starting material was completely reacted after 3 h. After the reaction was stopped, the solvent and trifluoroacetic acid were evaporated, and the solvent was added again for separation by rapid column chromatography to obtain a colorless viscous oil of 2-1,469 mg, with a yield of 93.3%.

[0067] (2) Under nitrogen protection, compound 4 (227 mg, 0.8 mmol) was dissolved in anhydrous dichloromethane (15 mL), and trans-3-aminocyclobutane-methanol (compound 2-1, 97 mg, 0.96 mmol), EDCI (460 mg, 2.4 mmol), HOBt (55 mg, 0.4 mmol), and triethylamine (242 mg, 2.4 mmol) were added sequentially. The reaction was carried out at room temperature, and the reactants were consumed after 14 h. After the reaction was stopped, the reaction solution was washed twice with water, the organic phase was dried, the solvent was removed by rotary evaporation, and the mixture was separated by rapid column chromatography to obtain a pale yellow viscous oily substance 2-2, 226 mg, with a yield of 77.1%. HRMS theoretical calculation: C20H19ClN3O2+, 368.1160 [M+H]+; measured value: 368.1022.

[0068] (3) Compound 2-2 (150 mg, 0.41 mmol) was dissolved in anhydrous dichloromethane (10 mL), and 3,4-dihydro-2H-pyran (104 mg, 1.23 mmol) and pyridine 4-methylbenzenesulfonic acid (53 mg, 0.21 mmol) were added. The mixture was stirred at room temperature for 3.5 h until the starting material was completely reacted. After the reaction was stopped, the mixture was washed with water, dried, and the organic phase was concentrated and separated by rapid column chromatography to obtain a colorless oily compound 2-3, 159 mg, with a yield of 86.0%. HRMS theoretical calculation: C25H27ClN3O3+, 452.1735 [M+H]+; Measured value: 452.1601.

[0069] (4) Under ice bath conditions, compound 2-3 (135 mg, 0.30 mmol) was dissolved in ultra-dry DMF (8 mL), and sodium hydride (36 mg (60%), 0.90 mmol) and methyl iodide (128 mg, 0.90 mmol) were added sequentially. The reaction was carried out in an ice bath at room temperature. TLC monitoring showed that the starting material disappeared after 1.5 h. After the reaction was stopped, the reaction was quenched with ice water, and after removing the solvent, the product was separated by rapid column chromatography to obtain a colorless oily substance 2-4, 117 mg, with a yield of 83.9%. HRMS theoretical calculation: C26H29ClN3O3+, 466.1892[M+H]+; measured value: 466.1426.

[0070] (5) Compound 2-4 (100 mg, 0.22 mmol) was dissolved in 10 mL of anhydrous ethanol, and pyridine 4-methylbenzenesulfonic acid (28 mg, 0.11 mmol) was added. The mixture was stirred at 35 °C, and the reaction proceeded completely after 1.5 h. The ethanol was removed by rotary evaporation, and an appropriate amount of dichloromethane was added. The mixture was washed twice with water, and the organic phase was dried and concentrated. The mixture was then separated by rapid column chromatography to obtain a colorless oily compound 2-5, 80 mg, with a yield of 95.5%. HRMS theoretical calculation: C21H21ClN3O2+, 382.1317 [M+H]+; Measured value: 382.0919.

[0071] (6) Under ice-salt bath conditions, compound 2-5 (70 mg, 0.18 mmol) was dissolved in anhydrous dichloromethane (5 mL), and triethylamine (37 mg, 0.36 mmol) was added. After thorough stirring and cooling, methanesulfonyl chloride (62 mg, 0.54 mmol) was slowly injected. The reaction was carried out at this temperature, and TLC monitoring showed that the starting material reacted completely within 10 min. After the reaction was stopped, the mixture was washed with water, the organic phase was dried, and the filtrate was concentrated and separated by rapid column chromatography to obtain 68 mg of a pale yellow oily compound 2-6 (i.e., the precursor of the quinazoline compound), with a yield of 81.7%. HRMS theoretical calculation: C22H23ClN3O4S+, 460.1092 [M+H]+; measured value: 460.0454.

[0072] (7) Under nitrogen protection, compound 2-6 (60 mg, 0.13 mmol) was dissolved in ultra-dry tetrahydrofuran (5 mL), and excess tetrabutylammonium fluoride (0.5 mL, 1M THF solution) was added. The reaction was carried out at 35 °C, and the reaction was monitored by TLC. The starting material was completely consumed after 1.5 h. The reaction was stopped, the solvent was removed by rotary evaporation, an appropriate amount of dichloromethane was added, and the mixture was washed twice with water. The organic phase was dried by rotary evaporation, and the mixture was separated by rapid column chromatography to obtain 43 mg of colorless oil, which was the quinazoline compound, named Quinazoline-RRS-2, with a yield of 87.0%.

[0073] High-resolution mass spectra as follows Figure 2 As shown, the theoretical HRMS value is: C21H20ClFN3O+, 384.1273 [M+H]+; the measured value is: 384.1069.

[0074] 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 8.5 Hz, 1H), 7.97 (dd, J =10.8, 4.1 Hz, 1H), 7.67 (dd, J = 12.9, 7.6 Hz, 2H), 7.61-7.43 (m, 4H), 4.42 (m, 1H), 4.34-4.20 (m, 1H), 3.14 (s, 2H), 2.95 (s, 1H), 2.40-2.03 (m, 6H).

[0075] 13 C NMR (75 MHz, CDCl3) δ 167.84, 166.98, 158.34, 150.57, 135.49,134.82, 132.64, 131.13-130.67, 130.03, 129.12, 128.73, 127.00, 123.13, 86.17,83.95, 49.53, 45.09, 31.43, 29.58, 28.09, 22.70.

[0076] Example 3 This embodiment provides a quinazoline compound, its precursor, and its preparation method. The preparation process is shown below:

[0077] The specific preparation method includes the following steps: (1) Under nitrogen protection, compound 4 (170 mg, 0.6 mmol) was dissolved in anhydrous dichloromethane (12 mL), and (3-amino-1-bicyclo[1.1.1]pentyl)methanol (107 mg, 0.72 mmol), EDCI (345 mg, 1.8 mmol), HOBt (40 mg, 0.3 mmol) and triethylamine (182 mg, 1.8 mmol) were added sequentially. The reaction was carried out at room temperature for 10 h. After the reaction was stopped, the reaction solution was washed twice with water, the organic phase was dried, the solvent was removed by rotary evaporation, and the mixture was separated by rapid column chromatography to obtain a light yellow viscous oily compound 3-1, 156 mg, with a yield of 68.8%. The theoretical HRMS value of C21H19ClN3O2+ was 380.1160 [M+H]+; the measured value was 380.1002.

[0078] (2) Compound 3-1 (140 mg, 0.37 mmol) was dissolved in anhydrous dichloromethane (10 mL), and 3,4-dihydro-2H-pyran (124 mg, 1.48 mmol) and pyridine 4-methylbenzenesulfonic acid (50 mg, 0.20 mmol) were added. The mixture was stirred at room temperature for 3 h until the starting material was completely reacted. After the reaction was stopped, the mixture was washed twice with water, dried, and the organic phase was concentrated and separated by rapid column chromatography to obtain a colorless oily compound 3-2, 139 mg, with a yield of 81.1%. The theoretical HRMS value of C26H27ClN3O3+ was 464.1735 [M+H]+; the measured value was 464.1640.

[0079] (3) Under ice bath conditions, compound 3-2 (130 mg, 0.28 mmol) was dissolved in ultra-dry DMF (10 mL), and sodium hydride (34 mg, 0.85 mmol) and iodomethane (121 mg, 0.85 mmol) were added sequentially. The reaction was carried out in an ice bath at room temperature for 3 h until the reaction was complete. After the reaction was stopped, the mixture was quenched with ice water, and after removing the solvent, it was separated by rapid column chromatography to obtain a colorless oily compound 3-3, 109 mg, with a yield of 81.9%. HRMS theoretical calculation: C27H29ClN3O3+, 478.1892 [M+H]+; measured value: 478.1919.

[0080] (4) The procedure was the same as that used for the synthesis of compounds 2-5 in Example 2. Compound 3-3 (100 mg, 0.21 mmol) was dissolved in anhydrous ethanol (10 mL), and pyridine 4-methylbenzenesulfonic acid (28 mg, 0.11 mmol) was added. The reaction was carried out at 35 °C. After post-treatment, the mixture was separated by rapid column chromatography to obtain a white solid compound 3-4, 78 mg, with a yield of 94.1%. The theoretical HRMS value of C22H21ClN3O2+ was 394.1317 [M+H]+; the measured value was 394.0743.

[0081] (5) The procedure was the same as that used for the synthesis of compounds 2-6 in Example 2. Compounds 3-4 (70 mg, 0.18 mmol) were dissolved in anhydrous dichloromethane (5 mL) and reacted in an ice-salt bath. After post-treatment, the mixture was separated by column chromatography to obtain a pale yellow oily compound 3-5, 75 mg, with a yield of 87.5%. The theoretical HRMS value of C23H23ClN3O4S+ was 472.1092 [M+H]+; the measured value was 472.0787.

[0082] (6) Under nitrogen protection, compound 3-5 (65 mg, 0.14 mmol) was dissolved in ultra-dry tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (0.5 mL, 1 M THF solution) was added. The reaction was carried out at 35 °C for 2 h until complete. After stopping the reaction, THF was removed by rotary evaporation, and an appropriate amount of dichloromethane was added. The organic phase was washed with water and dried. After separation by rapid column chromatography, 49 mg of white solid was obtained, which was the quinazoline compound, named Quinazoline-RRS-3, with a yield of 89.3%.

[0083] High-resolution mass spectra as follows Figure 3 As shown, the theoretical HRMS value is: C22H20ClFN3O+, 396.1273 [M+H]+; the measured value is: 396.0782.

[0084] 1 H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 8.6 Hz, 1H), 7.97 (dd, J =10.3, 4.1 Hz, 1H), 7.66 (t, J = 7.0 Hz, 2H), 7.51 (m, 4H), 4.34 (s, 1H), 4.18 (s, 1H), 3.13 (s, 2H), 2.95 (s, 1H), 1.74 (s, 6H).

[0085] 13 C NMR (75 MHz, CDCl3) δ 168.04, 166.86, 159.17, 158.89, 150.04,134.96, 130.88, 129.87, 128.85, 127.14, 123.20, 82.60, 80.39, 52.17, 51.67,35.09, 34.21, 33.22, 31.93, 30.48, 29.69, 29.46, 28.34, 27.91, 27.22, 25.86,25.13, 24.74, 22.70, 20.16, 17.97, 14.34, 13.91, 13.58.

[0086] Example 4 This embodiment provides a quinazoline compound, its precursor, and its preparation method. The preparation process is shown below:

[0087] The specific preparation method includes the following steps: (1) Under nitrogen protection, compound 4 (200 mg, 0.7 mmol) was dissolved in anhydrous dichloromethane (15 mL), and (1-(aminomethyl)cyclobutyl)methanol (97 mg, 0.84 mmol), EDCI (402 mg, 2.1 mmol), HOBt (47 mg, 0.35 mmol) and triethylamine (212 mg, 2.1 mmol) were added sequentially. The reaction was carried out at room temperature for 12 h. After the reaction was stopped, the reaction solution was washed twice with water, the organic phase was dried, and the mixture was separated by rapid column chromatography to obtain a light yellow oily compound 4-1, 187 mg, with a yield of 70.1%. HRMS theoretical calculation: C21H21ClN3O2+, 382.1317 [M+H]+; measured value: 382.1155.

[0088] (2) The procedure was the same as that used for the synthesis of compound 3-2 in Example 3. Compound 4-1 (160 mg, 0.42 mmol) was dissolved in anhydrous dichloromethane. After post-treatment, the compound 4-2 was separated by rapid column chromatography to obtain a colorless, viscous oily compound 4-2, 162 mg, with a yield of 83.0%. HRMS theoretical calculation: C26H29ClN3O3+, 466.1892 [M+H]+; measured value: 466.1635.

[0089] (3) The procedure was the same as that used for the synthesis of compound 3-3 in Example 3. Compound 4-2 (150 mg, 0.28 mmol) was dissolved in ultradry DMF (10 mL) and reacted under ice bath conditions. After post-treatment, the colorless oily compound 4-3, 117 mg, was obtained by column chromatography, with a yield of 87.3%. HRMS theoretical calculation: C27H31ClN3O3+, 480.2048 [M+H]+; measured value: 480.1822.

[0090] (4) The procedure was the same as that used for the synthesis of compounds 3-4 in Example 3. Compound 4-3 (105 mg, 0.22 mmol) was dissolved in anhydrous ethanol and reacted at 35 °C. After post-treatment, column chromatography yielded 80 mg of a colorless oily compound 4-4, with a yield of 92.0%. HRMS theoretical calculation: C22H23ClN3O2+, 396.1473 [M+H]+; measured value: 396.1244.

[0091] (5) The procedure was the same as that used for the synthesis of compounds 3-5 in Example 3. Compound 4-4 (65 mg, 0.16 mmol) was dissolved in anhydrous dichloromethane and reacted in an ice-salt bath. After post-treatment, the product was separated by column chromatography to obtain 61 mg of a pale yellow oily compound 4-5 (i.e., the precursor of the quinazoline compound), with a yield of 81.1%. HRMS theoretical calculation: C23H25ClN3O4S+, 474.1249 [M+H]+; measured value: 474.0948.

[0092] (6) Under nitrogen protection, compound 4-5 (55 mg, 0.12 mmol) was dissolved in ultra-dry tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (0.4 mL, 1 M THF solution) was added. The reaction was carried out at 35 °C for 3 h until complete. After stopping the reaction, THF was removed by rotary evaporation, and dichloromethane (8 mL) was added. The organic phase was washed with water and dried. After separation by rapid column chromatography, 41 mg of colorless oil was obtained, which was the quinazoline compound, named Quinazoline-RRS-4, with a yield of 86.1%.

[0093] High-resolution mass spectra as follows Figure 4 As shown, the theoretical HRMS value is: C22H22ClFN3O+, 398.1430 [M+H]+; the measured value is: 398.0936.

[0094] 1 H NMR (300 MHz, CDCl3) δ 8.19-8.09 (m, 1H), 7.90 (t, J = 6.8 Hz, 1H), 7.60 (dd, J = 13.3, 8.1 Hz, 2H), 7.54-7.37 (m, 4H), 4.59 (s, 0.5H), 4.42 (m,1H), 4.26 (s, 0.5H), 3.65 (dd, J = 33.4, 21.8 Hz, 2H), 3.15 (s, 1H), 2.98 (s,2H), 1.97-1.67 (m, 6H).

[0095] 13C NMR (75 MHz, CDCl3) δ 173.19, 167.42, 167.15, 147.24, 139.32,138.96, 137.47, 134.93, 134.23, 131.03, 130.37, 130.18, 129.77, 128.84,128.40, 128.13, 126.96, 121.71, 60.44, 53.37, 51.92, 45.35, 43.34, 43.07,31.94, 31.45, 30.20, 29.99, 28.83, 27.61, 26.82, 25.45, 22.71, 14.14.

[0096] Example 5 This embodiment provides a quinazoline compound, its precursor, and its preparation method. The preparation process is shown below:

[0097] The specific preparation method includes the following steps: (1) Under nitrogen protection, compound 4 (114 mg, 0.4 mmol) was dissolved in anhydrous dichloromethane (10 mL), and then added sequentially ( R 3-pyrrolidine-3-methanol (49 mg, 0.48 mmol), EDCI (229 mg, 1.2 mmol), HOBt (27 mg, 0.2 mmol), and triethylamine (121 mg, 1.2 mmol) were reacted at room temperature for 8.5 h. After the reaction was stopped, the reaction solution was washed twice with water, the organic phase was dried, and the mixture was separated by rapid column chromatography to obtain a white solid compound 5-1, 108 mg, in 73.4% yield. HRMS theoretical value: C20H19ClN3O2+, 368.1160 [M+H]+; measured value: 368.1001.

[0098] (2) Under ice-salt bath conditions, compound 5-1 (90 mg, 0.25 mmol) was dissolved in anhydrous dichloromethane (8 mL), and triethylamine (51 mg, 0.50 mmol) was added. After thorough stirring, methanesulfonyl chloride (72 mg, 0.63 mmol) was slowly injected. TLC monitoring showed that compound 5-1 was completely consumed within 5 min after the addition. After the reaction was stopped, the mixture was washed once with water, the organic phase was dried, and the filtrate was concentrated and separated by rapid column chromatography to obtain 99 mg of a pale yellow solid compound 5-2 (i.e., the precursor of the quinazoline compound), with a yield of 89.6%. HRMS theoretical calculation: C21H21ClN3O4S+, 446.0936 [M+H]+; measured value: 446.0604.

[0099] (3) Under nitrogen protection, compound 5-2 (80 mg, 0.18 mmol) was dissolved in ultra-dry tetrahydrofuran (8 mL), and tetrabutylammonium fluoride (0.5 mL, 1M THF solution) was added. The reaction was carried out at 35 °C for 2 h until complete. After stopping the reaction, THF was removed by rotary evaporation, and an appropriate amount of dichloromethane was added. After washing with water, the organic phase was dried and separated by rapid column chromatography to obtain 41 mg of white solid, which was the quinazoline compound, named Quinazoline-RRS-5, with a yield of 86.1%.

[0100] High-resolution mass spectra as follows Figure 5 As shown, the theoretical HRMS value is: C20H18ClFN3O+, 370.1117 [M+H]+; the measured value is: 370.0684.

[0101] 1 H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 7.5 Hz, 1H), 7.92 (s, 1H), 7.62(s, 2H), 7.56-7.35 (m, 4H), 4.20 (s, 1H), 3.88 (d, J = 14.2 Hz, 1H), 3.71 (s, 1H), 3.53 (s, 1H), 2.99 (s, 1H), 2.90 (d, J = 7.4 Hz, 1H), 2.69 (s, 1H), 2.13(s, 1H), 1.80 (s, 1H).

[0102] 13 C NMR (75 MHz, CDCl3) δ 169.10, 168.43, 167.81, 165.77, 165.13,157.76, 134.76, 132.75, 131.05, 130.49, 129.39, 129.05, 128.68, 127.01,123.23, 64.17, 53.46, 50.84, 48.82, 47.84, 45.64, 41.66, 39.75, 31.93, 29.83,29.23, 28.65, 27.21, 26.64, 24.94, 22.70.

[0103] Example 6 This embodiment provides a quinazoline compound, its precursor, and its preparation method. The preparation process is shown below:

[0104] The specific preparation method includes the following steps: (1) Under nitrogen protection, compound 4 (142 mg, 0.5 mmol) was dissolved in anhydrous dichloromethane (15 mL), and (1R,5S,6R)-3-azabicyclo[3.1.0]hexane-6-methanol (68 mg, 0.6 mmol), EDCI (287 mg, 1.5 mmol), HOBt (34 mg, 0.25 mmol) and triethylamine (152 mg, 1.5 mmol) were added sequentially. The reaction was carried out at room temperature for 15 h. After the reaction was stopped, the reaction solution was washed twice with water, the organic phase was dried, and the white solid 6-1 was obtained by rapid column chromatography, 127 mg, with a yield of 66.9%. HRMS theoretical calculation: C21H19ClN3O2+, 380.1160 [M+H]+; measured value: 380.0997.

[0105] (2) Under ice-salt bath conditions, compound 6-1 (85 mg, 0.22 mmol) was dissolved in anhydrous dichloromethane (8 mL), and triethylamine (66 mg, 0.66 mmol) was added. After thorough stirring, methanesulfonyl chloride (75 mg, 0.66 mmol) was slowly injected. TLC monitoring showed that the starting material was completely consumed within 5 min after the addition. After the reaction was stopped, the mixture was washed once with water, the organic phase was dried, and rapid column chromatography was used to separate 81 mg of a light yellow solid 6-2 (which is the precursor of the quinazoline compound), with a yield of 81.5%. HRMS theoretical calculation: C22H21ClN3O4S+, 458.0936 [M+H]+; measured value: 458.0666.

[0106] (3) Under nitrogen protection, compound 6-2 (70 mg, 0.18 mmol) was dissolved in ultra-dry tetrahydrofuran (8 mL), and tetrabutylammonium fluoride (0.5 mL, 1M THF solution) was added. The reaction was carried out at 35 °C for 2 h until complete. After stopping the reaction, THF was removed by rotary evaporation, and an appropriate amount of dichloromethane was added. After washing with water, the organic phase was dried and separated by rapid column chromatography to obtain 57 mg of white solid, which was the quinazoline compound, named Quinazoline-RRS-6, with a yield of 82.7%.

[0107] High-resolution mass spectra as follows Figure 6 As shown, the theoretical HRMS value is: C21H18ClFN3O+, 382.1117 [M+H]+; the measured value is: 382.0644.

[0108] 1H NMR (300 MHz, CDCl3) δ 8.19 (dd, J = 12.8, 6.8 Hz, 1H), 7.97 (t, J= 7.4 Hz, 1H), 7.67 (dd, J = 11.7, 7.2 Hz, 2H), 7.52 (m, 4H), 4.48 (m, 0.5H), 4.38 – 4.08 (m, 2.5H), 3.89 (m, 1H), 3.68 (mz, 2H), 1.67 (s, 2H), 1.26 (s, 1H).

[0109] 13 C NMR (75 MHz, CDCl3) δ 168.09, 165.74, 165.60, 157.56, 150.56,134.76, 134.73, 134.37, 132.75, 130.99, 129.23, 128.70, 127.04, 127.00,126.90, 123.24, 85.69, 83.47, 50.33, 50.18, 48.16, 48.13, 48.08, 1,22.56,22.23, 21.72, 21.63, 20.43, 20.02, 19.92.

[0110] Example 7 This embodiment provides a radioactive quinazoline compound and its preparation method, with the following labeling steps:

[0111] The specific preparation method includes the following steps: Take an appropriate activity level 18 F]F - The activated QMA column was rinsed with an aqueous solution to [ 18 F]F - Adsorbed onto a QMA column; then 1 mL K 2.2.2 / K2CO3 solution will [ 18 F]F - Elute to a 1 mL reaction flask, evaporate to remove water at 100°C under nitrogen purging, add acetonitrile (repeated three times) for azeotropic dehydration, and obtain [ 18 F]KF / K 2.2.2 Complex. Dissolve 1-2 (1.5 mg) of the quinazoline precursor in ultradry DMSO (1 mL), vortex to mix, and add the above [ 18 F]KF / K 2.2.2 In the complex, heat to 100°C and react for 10 min.

[0112] After the reaction was complete and cooled, the solution was diluted with water and passed through an Oasis HLB solid-phase extraction column. The column was then rinsed with 10 mL of water and air-pressed to dryness. 1 mL of ethanol was then used to extract the solution. 18 The crude product of Quinazoline-RRS-1 was eluted from an Oasis column. The ethanol solution of the eluted crude product was diluted with 1 mL of water and then purified by high-performance liquid chromatography (eluting agent: acetonitrile-0.1% formic acid aqueous solution) to obtain […]. 18 F]Quinazoline-RRS-1 pure product; finally, […] 18 The ethanol solution of [F]Quinazoline-RRS-1 was concentrated, diluted with physiological saline containing 5% ethanol (1 mL), and filtered through a sterile membrane to obtain a radioactive quinazoline compound, named [F]. 18 F]Quinazoline-RRS-1, for backup.

[0113] Example 8 This embodiment provides a radioactive quinazoline compound [ 18 [F]Quinazoline-RRS-2 and its preparation method, the labeling steps are as follows:

[0114] The preparation method is the same as in Example 7, except that quinazoline precursors 1-2 are replaced with quinazoline precursors 2-6.

[0115] Example 9 This embodiment provides a radioactive quinazoline compound [ 18 [F]Quinazoline-RRS-3 and its preparation method, the labeling steps are as follows:

[0116] The preparation method is the same as in Example 7, except that quinazoline precursors 1-2 are replaced with quinazoline precursors 3-5.

[0117] Example 10 This embodiment provides a radioactive quinazoline compound [ 18 [F]Quinazoline-RRS-4 and its preparation method, the labeling steps are as follows:

[0118] The preparation method is the same as in Example 7, except that quinazoline precursor 1-2 is replaced with quinazoline precursor 4-5.

[0119] Example 11 This embodiment provides a radioactive quinazoline compound [ 18 [F]Quinazoline-RRS-5 and its preparation method, the labeling steps are as follows:

[0120] The preparation method is the same as in Example 7, except that quinazoline precursor 1-2 is replaced with quinazoline precursor 5-2.

[0121] Example 12 This embodiment provides a radioactive quinazoline compound [ 18 [F]Quinazoline-RRS-6 and its preparation method, the labeling steps are as follows:

[0122] The preparation method is the same as in Example 7, except that quinazoline precursor 1-2 is replaced with quinazoline precursor 6-2.

[0123] Performance Test 1 The chemical stability of the quinazoline precursors prepared in Examples 1-6 was tested.

[0124] Quinazoline precursors 1-2, 2-6, 3-5, 4-5, 5-2, and 6-2 were selected and stored at room temperature (~20°C), 4°C, and -20°C, respectively. Thin-layer chromatography (TLC) and high-resolution mass spectrometry (HRMS) were used to periodically monitor the degradation behavior (including hydrolysis to generate OH derivatives) and other possible deterioration of the compounds.

[0125] The results showed that, after monitoring the samples for more than 12 weeks, the precursor compounds did not undergo significant degradation or deterioration under all storage conditions. This indicates that the series of moderately rigid labeled precursors provided by this invention have good chemical stability and can meet the requirements of routine storage, precursor aliquoting, and subsequent radiolabeling experiments.

[0126] Performance Test 2 The in vitro stability of the radioactive quinazoline compounds prepared in Examples 7-12 was tested.

[0127] The results were evaluated in PBS buffer and mouse serum, respectively. 18F] In vitro stability of the labeled target probes. The radioactive quinazoline compounds prepared in Examples 7-12 were used as probes (180 μL, 16.2 MBq) and co-incubated in PBS buffer (1 mL) and mouse serum at 37°C. Samples of 20 μL were taken at 15 min, 30 min, 1 h, and 2 h, respectively. The degradation behavior of the probes was analyzed by radio-high performance liquid chromatography (Radio-HPLC), and the radiochemical purity (RCP) of the original probes was calculated by peak area integration. The stability results of each probe in PBS and mouse serum are shown in Table 1. Table 1

[0128] The experimental results showed that all probes exhibited excellent in vitro stability after incubation in PBS buffer and mouse serum for 2 hours, with no significant metabolites or degradation peaks observed, indicating their high in vitro stability.

[0129] Performance Test 3 The radioactive quinazoline compounds prepared in Examples 7-12 of this invention were used as probes to evaluate the intracranial glioma model in GL261 mice using PET imaging.

[0130] GL261 mouse intracranial model: GL261 cells (5×10⁻⁶) 5 (Number of tumor cells) were stereotactically implanted into the brain region of C57BL / 6 mice. Tumor formation was confirmed by in vivo imaging 7-10 days post-inoculation. Tumors were allowed to grow to the target size (5-15 mm). 3 After anesthetizing the animals with 1.5% isoflurane, the target probe (Examples 7-12, approximately 7.4 MBq) and the control probe were injected via the tail vein. 18 F]BIBD239 was used, and PET-CT dynamic scans were performed at 0.5 h, 1 h, and 2 h post-injection to obtain imaging information at different time points, assessing initial brain uptake, uptake data after blockade, tumor boundary clarity, and image contrast. A rigid registration method was used to align the obtained images to the mouse brain template space, and the spatial transformation parameters were applied to the PET images. Regions of interest were manually delineated using Amira 3.1 software.

[0131] Among them, the comparison probe [ 18 F]BIBD239 (prepared according to patent CN202110674565.8) was compared with the probes of each set of examples in parallel.

[0132] In addition, an inhibition experiment was conducted in this embodiment: mice were injected with an excessive amount of ER176 (as an inhibitor, purchased from Taoshu Biotechnology) via the tail vein 30 minutes before probe injection, and brain uptake was observed. During the scanning process, the mice were kept under anesthesia and their body temperature was maintained using a warm air heating pad.

[0133] The probe uptake data in the GL261 mouse model are shown in Table 2. Among them, the uptake data of the probe in Example 7... 18 F]Quinazoline-RRS-1 in a GL261 mouse glioma model: 120 min dynamic PET-CT imaging Figure 7 As shown.

[0134] Table 2

[0135] From Table 2 and Figure 7 It can be observed that in the GL261 mouse glioma model, the radioactive signal in the brain is mainly concentrated in the tumor area. After inhibition by the inhibitor, the brain uptake is significantly reduced, demonstrating the targeting selectivity of the probe of this invention. Simultaneously, the background radiation in normal brain tissue is low, while the uptake at the tumor site is significant, with clear contours and a clear contrast with the contralateral normal brain tissue. Furthermore, in Example 8... 18 [F] Initial brain uptake of Quinazoline-RRS-2 (1.63 %ID / mL) was superior to [ 18 F]BIBD239 was taken up by the brain and showed a relatively ideal clearance rate, demonstrating the potential to become an excellent glioma imaging agent.

[0136] Physicochemical property tests showed that the quinazoline precursors provided by this invention did not exhibit significant degradation after more than 12 weeks in chemical stability tests, maintaining stable chemical purity. This provides a guarantee for significantly improving the radiochemical purity of the subsequent radiolabeled products and greatly facilitates automated probe production, multi-batch quality control, and clinical transportation. Furthermore, the quinazoline compounds provided by this invention, as target probes, demonstrated excellent metabolic stability in PBS buffer and animal serum, maintaining a radiochemical purity of over 90% after 120 min of incubation. PET-CT imaging showed that the target probes exhibited ideal pharmacokinetic characteristics in the GL261 mouse glioma model: initial brain uptake was superior to analogs with the same parent nucleus structure, and the clearance rate from normal brain tissue was ideal. The radioactive signal accumulated in the tumor region, with low background in normal brain tissue, clear tumor boundaries, and a striking contrast with the contralateral normal brain tissue.

[0137] In summary, the quinazoline compounds provided by this invention possess excellent precursor chemical stability, metabolic stability, and relatively ideal glioma imaging performance, demonstrating potential as novel glioma PET imaging agents for clinical application. They provide visual guidance for subsequent targeted tumor therapy, promote substantial progress in the precise diagnosis of gliomas, and also provide key imaging data and new research tools for the precise diagnosis and treatment of a wider range of neuroinflammatory diseases (such as Alzheimer's disease, multiple sclerosis, and stroke).

[0138] It should be noted that, in this document, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0139] The above description is merely a specific embodiment of the present invention, enabling those skilled in the art to understand or implement the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention is not to be limited to the embodiments described herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A quinazoline precursor, characterized in that, The quinazoline precursor is selected from any one or more of the following compounds: 。 2. A quinazoline compound, characterized in that, The quinazoline compounds are selected from any one or more of the following compounds: 。 3. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises any one or more of the quinazoline compounds of claim 2.

4. The use of the quinazoline precursor of claim 1, the quinazoline compound of claim 2, or the pharmaceutical composition of claim 3 in the preparation of a medicament for diagnosing a disease characterized by changes in an 18 kDa transloin, wherein the disease characterized by changes in an 18 kDa transloin is glioma.

5. A developer, characterized in that, It includes any one or more of the quinazoline compounds of claim 2 or the pharmaceutical composition of claim 3.

6. A reagent kit, characterized in that, It includes any one or more of the quinazoline compounds of claim 2 or the pharmaceutical composition of claim 3.

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