Compounds, methods of making the same, and use in diagnostic agents

Abstract

The application discloses a compound, a preparation method thereof and application of the compound in a diagnostic agent, and belongs to the technical field of medical imaging. The application specifically discloses a compound as shown in the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a mixture thereof, which can significantly improve plasma exposure, has high bioavailability, can prolong an in-vivo imaging time window, has the advantages of long-acting and low-dose imaging, and has good clearance characteristics and low tissue residual risk, so that free Gd 3+ is released, hidden dangers are reduced, and a long-acting, low-dose and high-safety magnetic resonance contrast solution is provided for the clinic.

Description

Technical Field

[0001] This invention belongs to the field of medical imaging technology, specifically relating to a compound, its preparation method, and its application in diagnostic agents. Background Technology

[0002] Gadolinium (III)-based contrast agents (GBCAs) are widely used clinically in magnetic resonance imaging (MRI). Once in the body, gadolinium-containing chelates significantly shorten the relaxation time of protons in tissues, thereby enhancing the clarity and contrast of MRI images and improving lesion detection rates. They provide more diagnostically valuable information than plain scans for the localization and characterization of lesions in the brain, spinal cord, and central nervous system. They are also used for MRI of the abdomen, chest, pelvis, limbs, and other human tissues, as well as for renal function assessment. Compared to other contrast agents, gadolinium contrast agents offer high tissue resolution and good safety.

[0003] Currently available gadolinium contrast agents all contain a nine-coordinate gadolinium ion [Gd(III)], which can coordinate with an octardate polyaminocarboxylic acid ligand and a water molecule. According to the ligand structure, they can be divided into two types: linear and macrocyclic. There are six linear gadolinium contrast agents: gadopentetate diglucamine (Magnevist), gadodiamine (Omniscan), gadofosylamine, gadoxetate disodium (Primovist), gadobutrol diglucamine (MultiHance), and gadofosyltetrate trisodium. There are three macrocyclic gadolinium contrast agents: gadoteric acid dimeglumine (Dotarem), gadoteryl alcohol (ProHance), and gadobutrol (Gadovist). Most GBCAs are passively distributed extracellularly in vivo and are mainly excreted through the kidneys, while some contrast agents (such as disodium gadoxetate and gadobutrazol) also have hepatocyte uptake properties and can be used for liver-specific imaging.

[0004] To improve the imaging performance of gadolinium contrast agents, existing technologies mainly employ two strategies: one is to increase the number of inner-layer water molecules (q), i.e., to increase the number of water molecules directly coordinated with Gd(III), thereby significantly enhancing relaxation efficiency; the other is to slow down the rotational diffusion of the molecule, by increasing the molecular volume or introducing protein-binding groups to reduce the rotational-dependent time of the molecule, thereby improving the relaxation rate. Furthermore, the stability of the chelate is also a key factor in the design of GBCAs, because free Gd... 3+ Ions have potential toxicity, and their safety is particularly prominent for patients with impaired kidney function.

[0005] Although existing gadolinium contrast agents are widely used in clinical practice, several shortcomings remain. First, some agents have low relaxation rates, requiring higher dosages to achieve optimal imaging results, thus increasing the medication burden on patients. Second, the pharmacokinetic characteristics of existing GBCAs still need optimization; for example, achieving a balance between high imaging efficiency and rapid excretion in terms of distribution and clearance is challenging. Furthermore, some gadolinium contrast agents exhibit relatively poor stability, potentially leading to trace amounts of free Gd. 3+ Released, thus bringing potential security risks.

[0006] In terms of structural design, existing gadolinium contrast agent ligands are mostly based on single metal ion chelation, achieving gadolinium ion coordination stability through linear or macrocyclic structures. In recent years, researchers have attempted to improve relaxation rate and in vivo exposure by constructing multimeric structures. For example, existing patents CN110035996B and CN107667096B report similar nitrogen-centered dendritic gadolinium chelate structures (such as compounds in Comparative Example 2 and Comparative Example 3). However, these compounds with nitrogen atoms as the structural center have the following shortcomings: (1) The tetrahedral spatial configuration of the nitrogen center results in insufficient spatial symmetry of the four chelating arms, affecting the overall structural rigidity of the molecule; (2) The nitrogen center structure is relatively flexible and prone to conformational changes in vivo, increasing the risk of non-specific protein binding; (3) The steric hindrance effect between chelating arms is uneven, which may affect the relaxation efficiency of each arm. Developing a multimeric gadolinium chelate with better structural rigidity and symmetry is an important direction for further improving relaxation efficiency and pharmacokinetic performance.

[0007] Therefore, there is still a need in clinical practice to develop a gadolinium contrast agent with higher relaxation rate, better pharmacokinetic characteristics, good in vivo clearance performance, and higher coordination stability. Summary of the Invention

[0008] The purpose of this invention is to provide a compound, its preparation method, and its application in diagnostic agents. This compound can significantly increase plasma exposure and prolong the imaging time window at equal or lower doses, thereby achieving long-acting, low-dose magnetic resonance imaging while reducing tissue residue and free Gd. 3+ To mitigate risks and overcome the shortcomings of existing contrast agents, such as short imaging time, strong dose dependence, and insufficient safety.

[0009] In a first aspect, the present invention provides a compound as shown in formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof: ; in, R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, carboxyl, ester, amide, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, ether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 3-6 cycloalkyl or phenyl; R3 is selected from hydrogen or C. 1-4 alkyl.

[0010] Furthermore, R1 is selected from C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, carboxyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 alkyl; R3 is selected from hydrogen.

[0011] Furthermore, R1 is selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, carboxyl, C 1-2 Hydroxyalkyl, C 1-2 Carboxyalkyl, C 1-2 Mercaptoalkyl, mercaptoether, or phenyl; R2 is selected from hydrogen or isobutyl; R3 is selected from hydrogen.

[0012] Furthermore, R1 is selected from methyl, trifluoromethyl, hydroxymethyl, mercaptomethyl, carboxyl, carboxymethyl, carboxyethyl, hydroxyethyl, 1-hydroxyethyl, methylthioethyl, or phenyl; R2 is selected from hydrogen or isobutyl; R3 is selected from hydrogen.

[0013] Furthermore, the above compounds are selected from: , , , , , , , , , , , , , , or .

[0014] In a second aspect, the present invention provides a compound as shown in formula (II), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof: ; in, R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, carboxyl, ester, amide, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, ether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 3-6 cycloalkyl or phenyl; R3 is selected from hydrogen or C. 1-4 alkyl.

[0015] Furthermore, the above compounds are selected from: , , , , , , , , , , , , , , or .

[0016] Furthermore, the hydrogen in any of the above-mentioned compound structures can be replaced by one or more deuterium atoms.

[0017] Thirdly, the present invention provides a method for preparing the compound of formula (II) above, comprising: Compound d and compound e were condensed to obtain compound f, and compound f was further deprotected to obtain compound (II); ; R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, carboxyl, ester, amide, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, ether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 3-6 cycloalkyl or phenyl; R3 is selected from hydrogen or C. 1-4 alkyl; R1' is the protection form of R1 or R1; R4 is selected from methyl, tert-butyl, or benzyl.

[0018] Fourthly, this application provides a method for preparing the compound of formula (I) above, comprising: Compound of formula (I) was prepared by chelation reaction of the above compound (II); ; R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, carboxyl, ester, amide, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, ether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C3-6 cycloalkyl or phenyl; R3 is selected from hydrogen or C. 1-4 alkyl.

[0019] Fifthly, the present invention provides the use of the compound of formula (I) above, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, or the compound of formula (II) above, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, in the preparation of a diagnostic agent.

[0020] Furthermore, the aforementioned diagnostic agent is a magnetic resonance imaging contrast agent.

[0021] Preferably, the contrast agent is used for enhanced imaging of blood vessels.

[0022] Furthermore, the aforementioned diagnostic agent is used for contrast enhancement on magnetic resonance imaging (MRI) of systemic diseases in mammals, preferably for contrast enhancement on MRI of central nervous system diseases. Further, the mammal includes humans; the systemic aspect includes, but is not limited to, the central nervous system, abdomen, chest, blood vessels, bones, and muscles; the central nervous system includes, but is not limited to, the brain and spinal cord. The blood vessels include, but are not limited to, cerebral blood vessels. The abdomen includes, but is not limited to, the liver and kidneys.

[0023] In a sixth aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, or a compound of formula (II) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable carrier and / or excipient; preferably, the pharmaceutical composition is in the form of a lyophilized powder or a ready-to-use injection.

[0024] The compound names corresponding to the English abbreviations mentioned in this invention are: EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0025] HOBT: 1-Hydroxybenzotriazole.

[0026] Pd / C: Palladium on carbon.

[0027] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate.

[0028] TFA: Trifluoroacetic acid.

[0029] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0030] Compared with the prior art, the present invention has the following beneficial effects: 1. The gadolinium chelate and its salts of the present invention exhibit significantly higher relaxation (r1) in in vitro pure water and plasma than the comparative compounds, demonstrating greater potential for MRI contrast enhancement and providing a basis for achieving stronger signals or reduced-dose equivalent imaging at the same dose.

[0031] 2. The pharmacokinetic AUC and C0.05 of the gadolinium chelate and its salt in vivo according to the present invention. max It is higher, especially at equimolar doses, plasma exposure is about 8-10 times higher than the commercially available control, and it has higher bioavailability; in addition, it can maintain a higher peak signal even when the dose is at least halved, achieving "reduced dose without reduced effect", and the signal persistence window is extended by 1 time, with rapid elution within 2 hours and tissue residue close to the background, combining the advantages of long-lasting imaging and low exudation safety.

[0032] 3. The gadolinium chelates and their salts of the present invention also have good scavenging properties and low risk of tissue residue, thereby reducing free Gd. 3+ This approach aims to eliminate potential risks and provide a long-lasting, low-dose, and highly safe magnetic resonance imaging (MRI) contrast solution for clinical use.

[0033] 4. Compared to the comparative compounds, the compounds of this invention use a benzene ring as the structural center (core), rather than the traditional connection method using a nitrogen atom or a tetrazolium heterocycle as the structural center. The benzene ring core has better structural rigidity and symmetry, which helps the molecule maintain a more stable conformation in vivo, reduces non-specific protein binding, and thus increases plasma exposure and imaging time window. At the same time, the benzene ring central structure allows the four gadolinium chelate arms to be more evenly distributed in space, which is beneficial to improving the overall relaxation efficiency of the molecule. Attached Figure Description

[0034] Figure 1 MRI images of cerebral blood vessels in mice before and after administration of compounds 1-2 and compound 8; Figure 2 The graph shows the Δ signal intensity-time curves of cerebral blood vessels in mice after administration of compounds 1-2 and compound 8. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to embodiments and experimental examples. The embodiments and experimental examples of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Any equivalent substitutions made in the art based on the content disclosed in the present invention shall fall within the protection scope of the present invention.

[0036] The technical concept of this invention lies in breaking through the design inertia of traditional "flexible multi-core" connections and proposing a new strategy of "rigid node confinement and spatial dispersion". Existing technologies usually pursue increased molecular size while neglecting the influence of the internal spatial arrangement of the molecule on relaxation properties. The inventors of this invention keenly realized that by introducing a benzene ring core with a highly π-conjugated system and fixed bond angles, the four Gd³⁺ centers can be effectively isolated in space and their specific geometric configurations can be fixed.

[0037] This invention provides a compound of formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof: ; in, R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, carboxyl, ester, amide, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, ether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 3-6 cycloalkyl or phenyl; R3 is selected from hydrogen or C. 1-4 alkyl.

[0038] The core design of this invention is as follows: (1) A benzene ring is used as the structural center (mother nucleus) of the tetramer. The planar six-membered rigid structure of the benzene ring allows the four gadolinium chelating arms to be symmetrically distributed in space. Compared with the tetrahedral configuration of the nitrogen center, it has better spatial symmetry and structural rigidity; (2) The four outer chelating arms are connected through the 1,2,4,5-tetrasubstituted sites of the benzene ring to maximize the symmetry advantage of the benzene ring; (3) The connecting arms are diazaalkyl structural units connected by amide bonds. While maintaining an appropriate chain length, hydrogen bond donors and acceptors are introduced to enhance the water solubility and biocompatibility of the molecule; (4) The R1 substituent is located at the α position of the connecting arm. By introducing substituents with different properties (such as hydroxyl, carboxyl, mercapto, alkyl, etc.), the hydrophilic-hydrophobic balance and protein binding characteristics of the molecule are adjusted to achieve fine regulation of pharmacokinetic behavior. The above design makes the compound of this invention significantly superior to the existing nitrogen-centered tetramer structure in key performance indicators such as relaxation rate, plasma exposure, imaging time window and clearance rate.

[0039] The structure-activity relationship study in this application shows that the magnetic resonance imaging performance of the compound is closely related to the rigidity of the molecular structure, steric hindrance, and the properties of the functional groups. The tetrameric structure with a benzene ring as the rigid parent core is the core basis for achieving high relaxation rate and excellent pharmacokinetic properties. Based on this, the modification of peripheral substituents plays a crucial regulatory role in performance optimization. Specifically: The benzene ring core is formed by four 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid gadolinium complexes (abbreviated as: DOTA-Gd). 3+ The chelating units are arranged and fixed in a spatially ordered manner, which effectively suppresses the rotation within the molecule and the excessive proximity of the Gd³⁺ center, thereby reducing the "magnetic shielding effect" caused by the dipole-dipole interaction between paramagnetic ions. This makes it easier for the molecule to adopt an extended conformation in solution, significantly improving the longitudinal relaxation rate (r1). At the same time, this rigid cage structure exhibits good stability in the physiological environment, reducing the risk of release of free Gd³⁺.

[0040] In the modification of substituents around the benzene ring, studies have found that introducing flexible chains of specific lengths or polar functional groups (such as the hydroxyl group in Example 1, the thiol group in Example 4, and the methylthio group in Example 5) can moderately regulate the balance between lipophilicity and water solubility of the molecule without compromising its overall rigidity, thereby affecting its distribution and clearance behavior in vivo. For example, the carboxyethyl group introduced in Example 8 not only enhances the water solubility of the molecule but also helps maintain its high exposure level (AUC) in plasma, while promoting its rapid clearance through the kidneys, achieving a synergy between "long-lasting imaging" and "low tissue residue". In addition, in some examples (such as compounds 5 and 8), the binding characteristics of the molecule to plasma proteins were further optimized by introducing oxygen- or sulfur-containing polar side chains, thereby extending the effective imaging time window while maintaining a high Cmax (peak plasma concentration).

[0041] Overall, the structure-activity relationship of this application exhibits a clear "structure determines performance" principle: the benzene ring core provides rigidity and spatial framework, the DOTA-Gd³⁺ unit ensures relaxation efficiency, and the peripheral substituents finely regulate pharmacokinetic behavior. The three work synergistically to achieve the comprehensive advantages of high relaxation rate, high bioavailability, long-lasting imaging, and high safety.

[0042] The structure of the compound in the embodiments of this invention is determined by nuclear magnetic resonance (NMR). 1 Determined by ¹H NMR or LC-MS.

[0043] In this invention, "room temperature" refers to 10–35°C.

[0044] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.

[0045] The synthesis methods described in Examples 1-8 below are exemplary. Those skilled in the art can prepare other compounds within the scope of the claims of this application by replacing the corresponding starting materials and using the same or similar synthesis strategies, based on the synthesis route.

[0046] Example 1: Preparation of Compound 1 [7,10-bis(carboxymethyl)-4-[8-hydroxy-3,6-dioxane-1-(2,4,5-tris{8-hydroxy-3,6-dioxane-7-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-2,5-diazaoct-1-yl}phenyl)-2,5-diazaoct-7-yl]-1,4,7,10-tetraazacyclododecane-1-yl]tetragadolinium acetate (compound 1) The synthesis route is as follows: Step 1: Synthesis of Compound 1a 5.67 g (35.17 mmol, 1.00 eq.) O-tert-butyl-serine, 14.65 g (123.10 mmol, 3.50 eq.) KBr and 47.43 g (281.36 mmol, 8.00 eq.) HBr (48%) were added to a 250 ml three-necked flask containing 57 ml of drinking water. The reaction system was stirred and cooled to 0 °C.

[0047] 2.55 g (36.91 mmol, 1.05 eq.) of NaNO2 was dissolved in 26 ml of drinking water and added dropwise to the reaction system. The internal temperature was controlled at 0±5℃ during the dropwise addition. After the dropwise addition was completed, the mixture was stirred at 0±5℃ for 4 hours and monitored by TLC. After the reaction was completed, the mixture was extracted with 113 ml of ethyl acetate, washed with 113 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6.81 g (86%, 30.24 mmol) of intermediate compound 1a.

[0048] LC-MS (ESI-): m / z = 223.1 (MH) - .

[0049] Step 2: Synthesis of Compound 1b 4.51 g (22.37 mmol, 1.05 eq.) glycine benzyl ester hydrochloride, 4.79 g (21.30 mmol, 1.00 eq.) compound 1a, 6.12 g (31.95 mmol, 1.50 eq.) EDCI and 4.32 g (31.95 mmol, 1.5 eq.) HOBT were added to a 500 mL three-necked flask containing 100 mL of dichloromethane solvent. The reaction system was stirred and cooled to 0 °C under nitrogen protection. Then, 8.25 g (63.90 mmol, 3.0 eq.) of N,N-diisopropylethylamine was added dropwise to the reaction flask. The reaction mixture was then brought to room temperature and stirred overnight.

[0050] After the reaction was completed by TLC monitoring, the reaction system was washed twice with 1 L of water, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain 6.58 g (83%, 17.68 mmol) of intermediate compound 1b.

[0051] LC-MS(ESI+): m / z=316.0(Mt-Bu+H) + .

[0052] Step 3: Synthesis of compound 1c 5.63 g (15.13 mmol, 1.00 eq.) of compound 1b and 7.79 g (15.13 mmol, 1.00 eq.) of 2,2',2”-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tritert-butyl ester were dissolved in 389 mL of acetonitrile. Then, 6.27 g (45.39 mmol, 3.00 eq.) of potassium carbonate and 0.23 g (1.51 mmol, 0.10 eq.) of sodium iodide were added. The reaction system was stirred and heated to 60 °C under nitrogen protection and stirred overnight. After the reaction was completed by TLC monitoring, the mixture was filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain 6.83 g (56%, 8.47 mmol) of intermediate compound 1c.

[0053] LC-MS(ESI+): m / z=806.8(M+H) + .

[0054] Step 4: Synthesis of Compound 1d 5.76 g (7.15 mmol, 1.00 eq.) of compound 1c, 2.77 g (1.43 mmol, 0.20 eq.) of 10% Pd / C (containing 55% water) and 230 ml of isopropanol were added to a hydrogenation reactor. The reactor was purged with hydrogen three times, pressurized to P=1.00 MPa, heated to 100℃ and reacted for 8 h. Heating was stopped, the reactor was cooled, the gas was vented, the reactor was opened, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain 4.25 g (83%, 5.93 mmol) of intermediate compound 1d.

[0055] LC-MS (ESI-): m / z = 714.5 (MH) - .

[0056] Step 5: Synthesis of compound 1f 3.52 g (4.92 mmol, 12.00 eq.) of compound 1d, 2.18 g (5.74 mmol, 14.00 eq.) of HATU and 205 ml of N,N-dimethylacetamide were added to a 500 mL three-necked flask. The reaction system was stirred and cooled to 0 °C under nitrogen protection. Then, 1.59 g (12.30 mmol, 30.00 eq.) of N,N-diisopropylethylamine dissolved in 82 ml of N,N-dimethylacetamide was added. After stirring the resulting reaction mixture at 0-5°C for 30 min, 79.7 mg (0.41 mmol, 1.00 eq.) of compound 1e was added, and the reaction was continued with stirring at room temperature. After the reaction was completed, 3 L of purified water was added to the reaction solution, and stirring was continued. 2 L of dichloromethane was added for extraction, and the organic phase was collected. The organic phase was washed three times with 2 L of saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, crude product 1f was obtained. This crude product did not require further characterization and was directly used in the next chemical step.

[0057] LC-MS(ESI+): m / z(z=2)=1493.0(M+2H) 2+ m / z (z = 3) = 995.7 (M + 3H) 3+ m / z (z = 4) = 747.0 (M + 4H) 4+ .

[0058] Step Six: Synthesis of 1g of Compound The crude product (1f) obtained in the previous step was treated with TFA (120 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain an oil, which was separated by reversed-phase preparative chromatography to give 1 g of intermediate compound (162.7 mg, overall yield of the two-step chemical reaction was 19%, 0.08 mmol).

[0059] LC-MS(ESI+): m / z(z=2)=1044.5 (M+2H) 2+ m / z (z = 3) = 696.7 (M + 3H) 3+ m / z (z = 4) = 522.8 (M + 4H) 4+ .

[0060] Step 7: Synthesis of Compound 1 150.0 mg (0.07 mmol, 1.00 eq.) of compound 1 g was dissolved in 150 ml of purified water. After adding 50.8 mg (0.14 mmol, 2.00 eq.) of Gd2O3, the reaction mixture was heated to 90-100 °C and stirred for 5 h. The reaction solution was then cooled to room temperature and lyophilized. The crude product was separated by reverse preparative chromatography to obtain 130.2 mg (67%, 0.05 mmol) of compound 1 with a purity of 98.6%.

[0061] LC-MS(ESI+): m / z(z=2)=1354.3(M+2H) 2+ m / z (z = 3) = 903.2 (M + 3H) 3+ m / z (z = 4) = 677.7 (M + 4H) 4+ .

[0062] Example 2: Preparation of Compound 2 {4-[7-carboxy-3,6-dioxonyl-1-(2,4,5-tris{7-carboxy-3,6-dioxonyl-7-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-2,5-diazaheptane-1-yl}phenyl)-2,5-diazaheptane-7-yl]-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl}tetragadolinium acetate (compound 2) The preparation method is the same as that in Example 1, except that 1b in Example 1 is replaced with intermediate 2b to obtain compound 2. The synthesis yield in step seven is 60% and the purity is 99.0%.

[0063] LC-MS(ESI+): m / z(z=2)=1382.3(M+2H) 2+ m / z (z = 3) = 921.8 (M + 3H) 3+ m / z (z = 4) = 691.6 (M + 4H) 4+ .

[0064] The synthetic route for compound 2b is as follows: Step 1: Synthesis of compound 2b-1 14.63 g (72.54 mmol, 1.05 eq.) glycine benzyl ester hydrochloride, 11.07 g (69.09 mmol, 1.00 eq.) mono-tert-butyl malonate, 19.87 g (103.64 mmol, 1.5 eq.) EDCI and 14.00 g (103.64 mmol, 1.5 eq.) HOBT were added to a 1 L three-necked flask containing 221 mL of dichloromethane solvent. The reaction system was stirred and cooled to 0 °C under nitrogen protection. Then, 26.75 g (207.27 mmol, 3.0 eq.) of N,N-diisopropylethylamine was added dropwise to the reaction flask. The reaction mixture was then brought to room temperature and stirred overnight.

[0065] After the reaction was completed by TLC monitoring, the reaction system was washed twice with 1 L of water, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain 18.05 g (85%, 58.73 mmol) of intermediate compound 2b-1.

[0066] LC-MS(ESI+): m / z=252.1(Mt-Bu+H) + .

[0067] Step 2: Synthesis of compound 2b 15.41 g (50.14 mmol, 1.00 eq.) of compound 2b-1, 8.40 g (55.15 mmol, 1.10 eq.) of DBU and 154 mL of tetrahydrofuran were added to a 500 mL three-necked flask and stirred until cooled to 0 ± 5 °C.

[0068] 17.46 g (52.65 mmol, 1.05 eq.) of carbon tetrabromide was dissolved in 200 mL of tetrahydrofuran and added dropwise to the reaction system. The internal temperature was controlled at 0±5℃ during the dropwise addition. After the dropwise addition was completed, the mixture was stirred at 0±5℃ for 2 hours and monitored by TLC. After the reaction was completed, 250 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was stirred and allowed to rise naturally to room temperature. 500 mL of dichloromethane was added for extraction and separation. The aqueous phase was extracted again with 250 mL of dichloromethane. The organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain 10.26 g (53%, 26.57 mmol) of intermediate compound 2b.

[0069] LC-MS(ESI+): m / z=330.0(Mt-Bu+H) + .

[0070] Example 3: Preparation of Compound 3 [7,10-bis(carboxymethyl)-4-[3,6-dioxane-1-(2,4,5-tris{3,6-dioxane-7-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-2,5-diazaoct-1-yl}phenyl)-2,5-diazaoct-7-yl]-1,4,7,10-tetraazacyclododecane-1-yl]tetragadolinium acetate (compound 3) The preparation method is the same as that in Example 1, except that 1b in Example 1 is replaced with intermediate 3b to obtain compound 3. The synthesis yield in step seven is 72% and the purity is 98.4%.

[0071] LC-MS(ESI+): m / z(z=2)=1322.3(M+2H) 2+ m / z (z = 3) = 881.9 (M + 3H) 3+ m / z (z = 4) = 661.7 (M + 4H) 4+ .

[0072] The synthetic route for compound 3b is as follows: ; 53.73 g (159.25 mmol, 0.91 eq.) glycine benzyl ester p-toluenesulfonate and 19.48 g (192.50 mmol, 1.10 eq.) triethylamine were added to a 3L three-necked flask containing 1L of dichloromethane solvent. The mixture was stirred and cooled to -5-0℃. Then, 30.00 g (175.00 mmol, 1.00 eq.) of 2-bromopropionyl chloride was added dropwise to the reaction flask while maintaining the internal temperature at -5-0℃. After the addition was complete, the reaction mixture was allowed to react at -5-0℃ for 1 h. Finally, the reaction mixture was allowed to rise to room temperature and reacted for 3 h. After the reaction was completed by TLC monitoring, the reaction system was washed once with 1 L of water, once with 300 ml of 5% dilute hydrochloric acid, twice with 300 ml of saturated sodium bicarbonate, and twice with 300 ml of drinking water. The organic phase was dried with anhydrous sodium sulfate and subjected to silica gel column chromatography to obtain 36.50 g (76%, 121.61 mmol) of compound 3b.

[0073] LC-MS(ESI+): m / z=300.0(M+H) + Example 4: Preparation of Compound 4 [7,10-bis(carboxymethyl)-4-[3,6-dioxane-8-mercapto-1-(2,4,5-tris{3,6-dioxane-8-mercapto-7-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-2,5-diazaoct-1-yl}phenyl)-2,5-diazaoct-7-yl]-1,4,7,10-tetraazacyclododecane-1-yl]tetragadolinium acetate (compound 4) The preparation method is the same as that in Example 1, except that O-tert-butyl-serine in Example 1 is replaced with S-tert-butyl-DL-cysteine ​​hydrochloride to obtain compound 4. The synthesis yield in step seven is 68%, and the purity is 98.1%.

[0074] LC-MS(ESI+): m / z(z=2)=1386.3(M+2H) 2+ m / z (z = 3) = 924.5 (M + 3H) 3+ m / z (z = 4) = 693.6 (M + 4H) 4+ .

[0075] Example 5: Preparation of Compound 5 [4,7-bis(carboxymethyl)-10-[6,9-dioxane-11-(2,4,5-tris{6,9-dioxane-5-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-7,10-diaza-2-thia-undecane-11-yl}phenyl)-7,10-diaza-2-thia-undecane-5-yl]-1,4,7,10-tetraazacyclododecane-1-yl]tetragadolinium acetate (compound 5) The preparation method is the same as that in Example 1, except that O-tert-butyl-serine in Example 1 is replaced with DL-methionine to obtain compound 5. The synthesis yield in step seven is 72%, and the purity is 98.4%.

[0076] LC-MS(ESI+): m / z(z=2)=1442.3(M+2H) 2+ m / z (z = 3) = 961.9 (M + 3H) 3+ m / z (z = 4) = 721.7 (M + 4H) 4+ .

[0077] Example 6: Preparation of Compound 6 [4,7-bis(carboxymethyl)-10-[8-hydroxy-3,6-dioxane-1-(2,4,5-tris{8-hydroxy-3,6-dioxane-7-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-2,5-diazanon-1-yl}phenyl)-2,5-diazanon-7-yl]-1,4,7,10-tetraazacyclododecane-1-yl]tetragadolinium acetate (compound 6) The preparation method is the same as that in Example 1, except that O-tert-butyl-serine in Example 1 is replaced with O-tert-butyl-DL-threonine to obtain compound 6. The synthesis yield in step seven is 80%, and the purity is 98.5%.

[0078] LC-MS(ESI+): m / z(z=2)=1382.3(M+2H) 2+ m / z (z = 3) = 921.9 (M + 3H) 3+ m / z (z = 4) = 691.7 (M + 4H) 4+ .

[0079] Example 7: Preparation of Compound 7 {10-[8-carboxy-3,6-dioxonyl-1-(2,4,5-tris{8-carboxy-3,6-dioxonyl-7-[4,7,10-tris(carboxylmethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-2,5-diazaoct-1-yl}phenyl)-2,5-diazaoct-7-yl]-4,7-bis(carboxylmethyl)-1,4,7,10-tetraazacyclododecane-1-yl}tetragadolinium acetate (compound 7) The preparation method is the same as that in Example 1, except that O-tert-butyl-serine in Example 1 is replaced with 2-amino-4-[(2-methylprop-2-yl)oxy]-4-oxonylbutyric acid to obtain compound 7. The synthesis yield of step seven is 69%, and the purity is 98.7%.

[0080] The structure of 2-amino-4-[(2-methylprop-2-yl)oxy]-4-oxonylbutyric acid is: .

[0081] LC-MS (ESI+): m / z (z=2)=1410.3 (M+2H) 2+ m / z (z = 3) = 940.5 (M + 3H) 3+ m / z (z = 4) = 705.6 (M + 4H) 4+ .

[0082] Example 8: Preparation of Compound 8 {10-[9-carboxy-3,6-dioxonyl-1-(2,4,5-tris{9-carboxy-3,6-dioxonyl-7-[4,7,10-tris(carboxylmethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-2,5-diazanon-1-yl}phenyl)-2,5-diazanon-7-yl]-4,7-bis(carboxylmethyl)-1,4,7,10-tetraazacyclododecane-1-yl}tetragadolinium acetate (compound 8) The preparation method is the same as that in Example 1, except that O-tert-butyl-serine in Example 1 is replaced with DL-glutamic acid-5-tert-butyl ester to obtain compound 8. The synthesis yield in step seven is 73% and the purity is 98.9%.

[0083] LC-MS(ESI+): m / z(z=2)=1438.3(M+2H) 2+ m / z (z = 3) = 959.2 (M + 3H) 3+ m / z (z = 4) = 719.7 (M + 4H) 4+ .

[0084] The intermediates and their mass spectrometry data included in the above embodiments are shown in the table below: Comparative Example 1: Gadovist (purchased from Anaiji Chemical, purity over 98%) (Comparative Example 1) Comparative Example 2: (Comparative Example 2) The compound of Example 6 was prepared according to the preparation method in Example 6 of patent CN110035996B, and is used as Comparative Example 2 of this application. Finally, it was purified by reversed-phase preparative chromatography and dried to obtain the target Comparative Example 2 compound with a purity of 98.1%. The structure was consistent with the analysis, and the LC-MS (ESI+) of the main product was: m / z (z=2) = 1373.4 (M+2H). 2+ m / z (z=3) = 916.0 (M+3H) 3+ The chemical structure of the product is the same as that of Comparative Example 2 above.

[0085] Comparative Example 3: (Comparative Example 3) The compound of Example 3 was prepared according to the preparation method in Example 3 of patent CN107667096B, and is used as Comparative Example 3 of this application. Finally, it was purified by reversed-phase preparative chromatography and dried to obtain the target Comparative Example 3 compound with a purity of 98.5%. The structure was consistent with the analysis, and the LC-MS (ESI+) of the main product was: m / z (z=2) = 1290.5 (M+2H). 2+ m / z (z=3) = 860.9 (M+3H) 3+ The chemical structure of the product is the same as that of Comparative Example 3 above.

[0086] Experimental Example 1: Relaxation Measurement 1. Instruments Meishi Medical 7.0T Small Animal Magnetic Resonance Imaging System.

[0087] 2. Preparation of test samples At room temperature, using pure water and human blood plasma as matrices, the compounds of the examples and comparative examples were prepared into test samples with concentrations of 1.0, 0.75, 0.6, 0.5, 0.4, and 0.25 mmol Gd / L, respectively. The samples were sonicated for 2 min to remove air bubbles, centrifuged to ensure the liquid level was consistent, sealed to prevent evaporation, and placed in a honeycomb array sample holder in order of concentration for later use.

[0088] 3. Test methods Before the formal scan, after the gradient and radio frequency tests pass, the sample is placed at the center of the coil, and local shimming (based on the water peak) is performed until the linewidth is <30–50 Hz. A rapid localization image is acquired to ensure that the single-layer slice covers all samples. After confirmation, localization / tuning / matching / field modulation are performed, and the geometry of the coil and sample is recorded. T1 arrays of all concentration samples are acquired sequentially. The sequence parameters (IR-SE sequence) are as follows: Field of view (FOV) 80×80 mm²; matrix 128×128; thickness 3 mm; repetition time (TR) 3000 ms; echo time (TE) 7.5 ms; 8 TI arrays with times of 10, 300, 580, 860, 1150, 1400, 1700, and 2000 ms respectively; accumulation count 1; number of layers 1.

[0089] 4. Data Processing and Result Analysis Data processing: The average signal is taken within the circular ROI (avoiding the boundary by 1–2 pixels) for each sample, and T1 (m) is fitted. T1 is then converted to R1 = 1 / T1 (unit: s⁻¹; T1 needs to be converted to seconds). A univariate linear regression is performed on (R1, [C]): R1 = r1[C] + R10, and the resulting slope r1 is the relaxation rate of the compound (unit: mM).-1 s -1 ).

[0090] The relaxation properties of each compound measured in pure water and human plasma are shown in Table 1: Table 1. Relaxivity (mM) in water and human plasma -1 s -1 ) As shown in Table 1, the compounds of this application exhibit high relaxation rates (r1) in both water and human plasma. Compound 8 shows the highest relaxation rate, with r1 values ​​exceeding 10 in both water and human plasma, significantly superior to the comparative compounds, demonstrating its superior relaxation performance. These results indicate that the compounds of this application possess excellent relaxation performance and greater potential for MRI contrast enhancement, providing a basis for achieving stronger signals at the same dose or equivalent imaging with reduced dose.

[0091] Experimental Example 2: In vivo pharmacokinetic experiment in SD rats 1. Experimental animals SPF-grade male SD rats, 6-8 weeks old, weighing 180-250g, with 6 rats in each group, were randomly assigned to groups according to their weight and had free access to food and water.

[0092] 2. Administration Test samples: compounds from each example and comparative example; Administration method: Weigh the patient before administration. Calculate the dosage based on body weight at 0.1 mmol Gd / kg. Prepare the injection solution using 0.9% sodium chloride as the solvent. Prepare and use immediately. Administer intravenously.

[0093] 3. Sample collection and processing After blood was collected via the jugular vein, the blood samples were placed on ice. At least 150 µL of blood was collected per time point. The samples were temporarily placed on ice before centrifugation and the plasma was separated by centrifugation within one hour. The collected whole blood samples were placed in blood collection tubes containing anticoagulant (EDTA-K2) and centrifuged at 6800 g at 2-8ºC for 6 min. At least 75 µL of plasma was collected and stored in a -80ºC freezer for testing.

[0094] 4. Data Processing and Result Analysis Bioanalysis: An ICP-MS standard curve was established to detect the plasma concentration of gadolinium, with an upper limit of quantification of 20,000 ng / mL and a lower limit of quantification of 0.1 ng / mL. The accuracy of quality control samples was evaluated simultaneously with the analysis of the samples. The accuracy of more than 66% of the quality control samples was between 80-120%.

[0095] Data processing: Pharmacokinetic parameters, such as AUC, were calculated using WinNonlin based on blood drug concentration data at different time points. all AUC inf T 1 / 2 C max and T max When plotting plasma drug concentration-time curves, BLQ is always recorded as 0. When calculating pharmacokinetic parameters, the concentration before administration is calculated as 0; C max Previous BLQs (including "No peak") are calculated as 0; C max Subsequent BLQs (including "No peak") will not be included in the calculation.

[0096] The main pharmacokinetic parameters (Mean ± SD) of each compound in rats are shown in Table 2: Table 2. Pharmacokinetic parameters of gadolinium in plasma (Mean ± SD) As shown in Table 2, at equimolar gadolinium doses, the AUC of the compounds in the embodiments of this application in rats was... all and AUC inf All were significantly higher than the comparative compounds, approximately 8-10 times higher, indicating a significantly increased overall in vivo exposure level of the compounds in this application. Meanwhile, the C of the compounds in this application... max The value is approximately twice that of the comparative example, indicating that it can rapidly reach a high peak blood drug concentration after administration, which is beneficial for quickly producing a significant imaging enhancement effect. Furthermore, the half-life (T5) of the compound in this application... 1 / 2 The concentration of free Gd was significantly lower than that of the comparative compound, indicating a faster clearance rate in vivo. These results demonstrate that the compound of this application achieves high exposure and high peak concentration while exhibiting good clearance characteristics and a low risk of tissue residue, thereby reducing the risk of free Gd. 3+ Eliminate potential hazards and enhance safety.

[0097] Experimental Example 3: Evaluation of Magnetic Resonance Imaging (MRI) Results This study aims to evaluate the magnetic resonance efficacy of the compound in the examples and the comparative compound in mice, including the magnetic resonance enhancement effects on cerebral blood vessels, liver, kidneys and muscles, and their pharmacodynamic characteristics, through a single imaging test and pharmacodynamic test.

[0098] 1. Test materials Instrument: MedSci 7.0T Small Animal Magnetic Resonance Imaging System.

[0099] Animals: Balb / c mice, 7-12 weeks old; single imaging test, males, 3 mice per group; time-dependent test, half males and half females, 2 mice per group.

[0100] Test samples: Take each compound and prepare injection solutions using 0.9% sodium chloride as solvent. Prepare and use immediately.

[0101] 2. Dosing regimen Single imaging test: All test samples were administered at an equivalent dose of 0.1 mmol Gd / kg.

[0102] Pharmacokinetic studies (time-dependent): Compound 1 was administered at 0.1 mmol Gd / kg; Compound 8 and Compound 2 were administered at a low dose of 0.04 mmol Gd / kg.

[0103] 3. Test methods Mice were fasted overnight before the examination and anesthetized with 1%-1.5% isoflurane gas at a ventilation rate of 0.8-1.0 L / minO2. After the mice were anesthetized, a tail vein access was established.

[0104] Cerebral angiography: Mice were fixed in a prone position in a magnetic resonance imaging (MRI) scanner, using a special head-mounted coil. After tuning and shimming, cerebral vascular MRA data were acquired before drug administration. Subsequently, the test substance was injected via the tail vein, and data were acquired after drug administration. Single-shot imaging test: Images were acquired before drug administration (pre) and immediately after drug administration. Pharmacokinetic test (time-dependent): Images were acquired before drug administration (pre) and at multiple time points, including 0.5 min, 5 min, 15 min, and 30 min after drug administration.

[0105] 4. Data Processing MRI angiography was performed using 3D CE-MRA sequences. The MRI images were analyzed and processed using ImageJ and MatLab software. The signal intensity (SI) of the target region (blood vessel) was measured, and the imaging effect was expressed as MRI Δ signal intensity, calculated using the following formula: MRI Δ signal intensity = (signal intensity after drug administration / signal intensity before drug administration) - 1.

[0106] 5. Results Analysis 5.1 Single Imaging Table 3. Δ signal intensity of cerebral blood vessels before and after drug administration (Mean±SD) Figure 1 The images of cerebral blood vessels in mice before and after administration of compounds 1-2 and compound 8 are shown in Table 3. As can be seen from the data, under the same dosage, compound 8 of this application achieved a significantly better cerebral vascular enhancement effect than the comparative compounds after administration. Its imaging effect had the highest brightness, sharp vascular edges, and no signal spillover, which was significantly better than the comparative compounds.

[0107] 5.2 Pharmacokinetics 5.2.1 Cerebrovascular Pharmacokinetics Table 4. Δ signal intensity of cerebral blood vessels on MRI (Mean ± SD) Figure 2 This is a mouse brain vascular MRI Δ signal intensity-time curve, from... Figure 2 As shown in the trend and the data in Table 4, at a lower dose (0.04 mmol Gd / kg), compound 8 of this application reached a signal enhancement peak of approximately 9.5 times at 0.5 min after administration, significantly higher than the comparative compound; and maintained a high signal intensity at 15 min, indicating a longer imaging window. Meanwhile, its signal intensity decreased to near the level of the comparative compound at 30 min, indicating rapid clearance in vivo with no significant retention. These results demonstrate that the compound of this application possesses the combined advantages of "high peak value, longer effective window, and rapid clearance," consistent with its pharmacokinetic experimental results.

[0108] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound of formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof: ； in, R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, carboxyl, ester, amide, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, ether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 3-6 cycloalkyl or phenyl; R3 is selected from hydrogen or C. 1-4 alkyl.

2. The compound according to claim 1, or its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof, characterized in that, R1 is selected from C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, carboxyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 alkyl; R3 is selected from hydrogen.

3. The compound according to claim 1, or its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof, characterized in that, R1 is selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, carboxyl, C 1-2 Hydroxyalkyl, C 1-2 Carboxyalkyl, C 1-2 Mercaptoalkyl, mercaptoether, or phenyl; R2 is selected from hydrogen or isobutyl; R3 is selected from hydrogen.

4. The compound according to any one of claims 1-3, or its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof, characterized in that, The compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

5. A compound as shown in formula (II), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof: ； in, R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, carboxyl, ester, amide, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, ether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 3-6 cycloalkyl or phenyl; R3 is selected from hydrogen or C. 1-4 alkyl.

6. The compound according to claim 5, or its stereoisomers, pharmaceutically acceptable salts, or mixtures thereof, characterized in that, The compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

7. A method for preparing a compound of formula (II) as described in claim 5 or 6, characterized in that, Includes the following steps: Compound d and compound e were condensed to obtain compound f, and compound f was further deprotected to obtain compound (II); ； in, R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, carboxyl, ester, amide, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, ether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 3-6 cycloalkyl or phenyl; R3 is selected from hydrogen or C. 1-4 alkyl; R1' is the protection form of R1 or R1; R4 is selected from methyl, tert-butyl, or benzyl.

8. A method for preparing a compound of formula (I) as described in any one of claims 1-4, characterized in that, Includes the following steps: Compound of formula (I) was prepared by chelation reaction; ； in, R1 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, carboxyl, ester, amide, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 1-4 Mercaptoalkyl, mercaptoether, ether, or phenyl; R2 is selected from hydrogen, deuterium, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Carboxyalkyl, C 3-6 cycloalkyl or phenyl; R3 is selected from hydrogen or C. 1-4 alkyl.

9. Use of the compound of any one of claims 1-4, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, or the compound of claim 5 or 6, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, in the preparation of a diagnostic agent.

10. A pharmaceutical composition comprising the compound of any one of claims 1-4, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, or the compound of claim 5 or 6, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable carrier and / or excipient.

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