WO2023207746A1 - Asymmetric donor-receptor type near-infrared region ii probe molecule, method for preparing same, and use thereof - Google Patents
Asymmetric donor-receptor type near-infrared region ii probe molecule, method for preparing same, and use thereof Download PDFInfo
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- WO2023207746A1 WO2023207746A1 PCT/CN2023/089455 CN2023089455W WO2023207746A1 WO 2023207746 A1 WO2023207746 A1 WO 2023207746A1 CN 2023089455 W CN2023089455 W CN 2023089455W WO 2023207746 A1 WO2023207746 A1 WO 2023207746A1
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- alkyl
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- integer
- carboxyl
- amino
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
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- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
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Definitions
- the invention belongs to the field of organic fluorescent probes and relates to asymmetric donor-acceptor (D-A) type near-infrared second-region probe molecules and their preparation methods and applications.
- D-A asymmetric donor-acceptor
- Imaging is a science that uses imaging technology to display specific molecules at the tissue, cellular and subcellular levels, and conducts qualitative and quantitative research on the observation of physiological and pathological conditions in vivo. In order to explore the occurrence, development and transformation of diseases, and evaluate the effectiveness of drugs It serves as a bridge between molecular biology and clinical medicine. Imaging methods used clinically include Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and computer X-ray tomography (Computerized Tomography, CT), ultrasound imaging (Ultrasound, US) and optical imaging (Optical Imaging, OI).
- MRI Magnetic Resonance Imaging
- PET Positron Emission Tomography
- SPECT Single Photon Emission Computed Tomography
- CT Computer X-ray tomography
- CT Computer X-ray tomography
- ultrasound imaging Ultrasound, US
- OI optical imaging
- optical imaging Compared with traditional imaging methods, optical imaging has the advantages of high sensitivity, high resolution, high contrast, real-time feedback, no ionizing radiation, and simple equipment. It has become one of the rapidly developing and widely used imaging technologies in the field of biological imaging.
- the optical imaging area can be specifically divided into visible light area (400-700nm), near-infrared first area (NIR-I, 700-900nm) and near-infrared second area (NIR-II, 900-1700nm).
- NIR-I fluorescent dyes indocyanine green (ICG) and methylene blue (MB) have been approved for clinical use by the U.S. Food and Drug Administration (FDA) and have made contributions to clinical diagnosis. They are mainly used for cardiovascular angiography. , lymphography, gastrointestinal imaging and tumor resection surgery to assist surgeons in diagnosis and treatment. Although NIR-I imaging has achieved good results, it is still limited by the penetration depth.
- NIR-II near-infrared II region
- SBR signal-to-noise ratio
- NIR-II probes mainly include inorganic materials (carbon nanotubes, quantum dots and rare earth-doped nanoparticles) conjugated polymers and organic small molecules.
- inorganic materials and conjugated polymer fluorophores have poor pharmacokinetics and poor biocompatibility, which limits their clinical application.
- the technical purpose of the present invention is to provide a type of near-infrared second-region (NIR-II) probe that is easier to metabolize and can be effectively used for whole-body vascular imaging, lymphatic imaging, disease diagnosis and detection, tumor imaging, surgical navigation, etc.
- NIR-II near-infrared second-region
- the present invention provides a type of asymmetric donor-acceptor type NIR-II probe molecule, which is represented by the following general formula 1:
- Ring A is selected from B and B' are each independently selected from
- X is S, O, Se or NR 5 ;
- R 1 is selected from
- R 2 is selected from
- R 6 and R 7 are each independently selected from H, hydroxyl, amino (-NH 2 ), carboxyl (-COOH), halogen, carboxyl C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, substituted or unsubstituted C6-C12 aryl or 5-12 membered heteroaryl containing heteroatoms selected from N, O, S (when the aryl or heteroaryl is substituted , the substituent is selected from C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylsilyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, Aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl or halogenated C 1 -C
- Y 2 is selected from S, O, Se and NR 5 ;
- Y is S, O, Se or NR 5 ;
- Y 1 is CR 5 or N
- D is selected from the following groups:
- substituents of the C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group and C 1 -C 8 alkyl silicon group are selected from the group consisting of hydroxyl, amino, alkynyl, azido, mercapto, and aldehyde groups.
- R 10 to R 46 are each independently selected from Where R"' is C 1 -C 8 alkylene.
- the probe molecule of general formula 1 can be selected from the group consisting of general formulas I, II, III and IV:
- a set of B and B' are respectively selected from as well as
- X is S
- R 1 is selected from
- R 2 is selected from
- R 3 and R 4 are each independently H or -(CH 2 )n 3 -COOCH 2 CH 2 Si(CH 3 ) 3 , where n 3 is an integer from 1 to 10; D is selected from the following groups:
- substituents of the C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group and C 1 -C 8 alkyl silicon group are selected from the group consisting of hydroxyl, amino, alkynyl, azido, mercapto, and aldehyde groups.
- the probe molecule is selected from the following compounds:
- halogen refers to fluorine, chlorine, bromine or iodine.
- C 1 -C 12 alkyl refers to a straight-chain or branched saturated hydrocarbon group having 1 to 12 carbon atoms in the chain, including without limitation methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl, tert-butyl, etc.
- the meanings of C 1 -C 8 alkyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl are deduced by analogy.
- alkoxy refers to the group obtained by connecting the end of the alkyl group with oxygen, for example, methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butyl, n-hexyloxy, etc.
- C 1 -C 8 alkylsilyl is a group of the structure RaRbRcSi-, where at least one of Ra, Rb and Rc is a C 1 -C 8 alkyl group and the remainder is hydrogen, for example, trimethylsilane , triethylsilane.
- sulfonate refers to -SO3H .
- amino refers to -NH2 .
- C6-C12 aryl refers to an aryl group having 6 to 12 ring carbon atoms, including without limitation phenyl, naphthyl, and the like.
- 5-12 membered heteroaryl refers to an aromatic cyclic group having 5 to 12 ring atoms and containing heteroatoms selected from N, O, and S, including, but not limited to, furyl, thienyl, Thiopyryl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, benzofuranyl, benzothienyl, benzothiopyranyl, indolyl, benzotriazolyl, benzopyridine base, Pyridofuryl, pyridopyrrolyl, etc.
- Heterocyclyl refers to a cyclic group containing one or more saturated and/or partially saturated rings and including 3 to 10 ring atoms, in which one or more ring atoms are selected from heteroatoms of nitrogen, oxygen or sulfur, and the remaining rings
- the atom is carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, etc.
- the present invention provides a method for preparing the above-mentioned probe molecule, as shown in the following reaction scheme, the method includes:
- R’ is boric acid or borate ester, tin salt
- Step 1 Compound 1 and compound 2 undergo Suzuki reaction to obtain compound 3;
- Step 2 Compound 3 is reduced to obtain compound 4;
- Step 3 Compound 4 is reacted with N-sulfenylanilide (PNSO) to obtain a compound of general formula I; or
- Step 3' Compound 4 is reacted with compound (5-2), (5-3) or (5-4) to form Schiff base to obtain compounds of general formula II, III or IV respectively.
- each step operates as follows:
- Step 1 Weigh compound 1 and catalyst tetrakis(triphenylphosphine)palladium in the reaction flask, replace the nitrogen, add toluene and potassium carbonate aqueous solution to dissolve, replace the nitrogen, stir the system, slowly add the toluene solution of compound 2 dropwise to react, After the reaction is completed, purify to obtain compound 3;
- Step 2 Dissolve compound 3 in a dichloromethane and methanol solution system, and add an appropriate amount of zinc powder and ammonium chloride aqueous solution under ice bath conditions.
- the reaction conditions are from 0°C to room temperature, and the reaction is carried out. After the reaction is completed, the compound is purified to obtain compound 4; as well as
- Step 3 After step 2, weigh compound 4 into the reaction flask, replace the nitrogen, add the solvent pyridine and replace the nitrogen again, then add N-sulfenylanilide (PNSO), replace the nitrogen, and add trimethylsilyl chloride (TMSCl ), carry out the reaction, and purify after the reaction is completed to obtain the compound of general formula I; or
- Step 3' After step 2, weigh compound 4, and weigh compound (5-2), (5-3) or (5-4) into the reaction bottle, replace nitrogen, add acetic acid solution to dissolve, replace nitrogen, Carry out the reaction and purify after the reaction is completed to obtain compounds of general formula II, III or IV respectively.
- step 1 the molar ratio of compound 1: compound 2: potassium carbonate and tetrakis(triphenylphosphine)palladium is 1:1:1.2:0.05, the reaction temperature is 110°C, and the reaction time is 12 -24h.
- step 2 in the dichloromethane and methanol solution system, the volume ratio of dichloromethane to methanol is 10:1, and the reaction time is 4 hours.
- step 3 the reaction temperature is 80°C and the reaction time is 12-16h.
- the reaction temperature is 110°C and the reaction time is 12-16h.
- the present invention provides the use of the probe molecule in the preparation of a developer.
- the developer can be used for in vitro quantitative detection and in vivo imaging in biological tissues and samples, as well as for indication quantification of non-biological tissues.
- the developer can be used for in vivo fluorescence imaging to guide tumor resection, such as in vivo imaging and fluorescence imaging of caries animals to guide tumor resection in tumor-bearing mice; the developer can be used to image the blood circulation system, lymphatic vessels and lymph nodes of caries animals. imaging, tumor blood vessel imaging, thrombus imaging and cerebral blood vessel imaging; the developer can be used for imaging of necrotic tissue, such as imaging of muscle necrosis tissue induced by absolute ethanol in carious animals.
- the contrast agent may be used for whole body vascular imaging, bone imaging, or lymphatic imaging.
- the imaging agent can be used for tumor imaging.
- the contrast agent may be used for surgical navigation.
- the present invention provides the use of the probe molecule in preparing a photothermal therapeutic agent.
- the photothermal therapeutic agent is used for the treatment of tumors.
- the method of use is as follows: after administration, the developer reaches a designated site (for example, a tumor tissue) and accumulates, and then is irradiated with a laser. Heat to kill tumor cells.
- a designated site for example, a tumor tissue
- the present invention provides the use of the probe molecule in preparing tumor diagnostic reagents.
- Yet another aspect of the present invention relates to a developer comprising the above-mentioned probe molecule.
- This application provides a series of asymmetric donor-acceptor (DA) type NIR-II probes, whose emission spectra can also reach the NIR-II region.
- DA asymmetric donor-acceptor
- the DA structure of the probe of the present application has reduced molecular weight and is easier to chemically modify and metabolize. It can be used for whole-body vascular imaging, lymphatic imaging, disease diagnosis and detection, tumor imaging, surgical navigation, etc. in animal models. , and is expected to be used for human whole body vascular imaging, lymphatic imaging, disease diagnosis and detection, tumor imaging and surgical navigation, etc.
- Figure 1 shows the UV absorption spectra of compounds Ia and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k).
- Figure 2 shows the fluorescence emission spectra of compounds Ia and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k).
- Figure 3 shows the biodistribution diagram of compound Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) in the body of normal mice at 1400nm in the second near-infrared region at different time points.
- Figure 4 shows the imaging of compound Ib (2k, 10k) in tumor mice, which can be used for long-term window fluorescence imaging tumor resection surgery.
- the dotted box indicates the tumor location.
- Figure 5 shows, a: imaging of compound Ib (10k) in the mouse lymphatic system, b: detectable fluorescence signal intensity of four lymphatic vessels.
- Figure 6 shows the heating curve of compound Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) under 808nm laser.
- D-A type near-infrared second-region probe molecules of the present invention are described. These examples are for illustrative purposes and are not intended to limit the scope of the invention.
- Dissolve intermediate compound 3a 200 mg, 0.189 mmol in a dichloromethane and methanol solution system (the volume ratio of dichloromethane to methanol is 10:1), add zinc powder (1583.05 mg, 22.68 mmol) and Ammonium chloride (363.95mg, 6.804mmol) aqueous solution.
- the reaction conditions range from 0°C to room temperature, and the reaction time is about 4 hours.
- the P groups in the Ib structure can each represent H or PEG chains (provided that the two Ps are not H at the same time), such as the following five compounds, where Ib 0.5K 2 means that the structure contains 2 PEGs with a molecular weight of 0.5kDa chain, Ib 2K 2 means that the structure contains 2 PEG chains with a molecular weight of 2kDa, Ib 2K means that the structure contains 1 PEG chain with a molecular weight of 2kDa, Ib 5K means that the structure contains 1 PEG chain with a molecular weight of 5kDa, Ib 10K Indicates that the structure contains a PEG chain with a molecular weight of 10kDa. Their calculated and measured molecular weights are as follows. ]
- Ib 2K 2 calculated MW: about 4868. Measured: about 4807
- Dissolve intermediate compound 2c 200mg, 0.170mmol in a dichloromethane and methanol solution system (the volume ratio of dichloromethane to methanol is 10:1), add zinc powder (1333.96mg, 20.4mmol) and Ammonium chloride (327.36mg, 6.12mmol) aqueous solution.
- the reaction conditions range from 0°C to room temperature, and the reaction time is about 4 hours.
- Dissolve intermediate compound 2d 200 mg, 0.188 mmol in a dichloromethane and methanol solution system (the volume ratio of dichloromethane to methanol is 10:1), add zinc powder (1475.20 mg, 22.56 mmol) and Ammonium chloride (362.02mg, 6.768mmol) aqueous solution.
- the reaction conditions range from 0°C to room temperature, and the reaction time is about 4 hours.
- Dissolve intermediate compound 2f 200mg, 0.311mmol in a dichloromethane and methanol solution system (the volume ratio of dichloromethane to methanol is 10:1), add zinc powder (2438.86mg, 37.32mmol) and Ammonium chloride (598.87mg, 11.196mmol) aqueous solution.
- the reaction conditions range from 0°C to room temperature, and the reaction time is about 4 hours.
- mice used in the experiment were purchased after approval from the Shanghai Experimental Animal Center.
- the animal experiments were carried out in accordance with the Shanghai Drug Research Institute of the Chinese Academy of Sciences. Conducted in accordance with Institute Animal Care and Use Committee (IACUC) guidelines.
- IACUC Institute Animal Care and Use Committee
- the experiments used 6-week-old normal Balb/c female mice.
- Ib 0.5k 2 , 2k 2 , 2k, 5k, 10k
- PBS 0.5k 2 , 2k 2 , 2k, 5k, 10k
- a near-infrared second-zone camera was used to study in vivo imaging, excited by an 808nm laser, with a power of 220mW/cm 2 and a 1400nm long-pass filter.
- the results are shown in Figure 3.
- the fluorescence intensity is concentrated in the liver, intestines and blood vessels, indicating that the probe is metabolized by the liver and intestines and has a long blood circulation time, and can be used for vascular imaging and detection of vascular function.
- the probe has obvious absorption in the tibia and spine of mice and can be used for bone imaging in mice and related imaging of bone diseases.
- mice used in the experiments were purchased with approval from the Shanghai Laboratory Animal Center, and the animal experiments were conducted in accordance with the guidelines of the Animal Care and Use Committee (IACUC) of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
- IACUC Animal Care and Use Committee
- Take 6-week-old Balb/c female mice and inoculate mouse-derived breast cancer cells 4T1 into the subcutaneous parts of their hind legs. After tumor formation, use a vernier caliper to measure the diameter of the tumor. According to the formula, tumor volume V (length ⁇ width 2 ) / 2. Calculate the tumor volume and wait until the tumor grows to 150mm. 3.
- the results are shown in Figure 4.
- the mouse tumor tissue showed high absorption, and the contrast gradually increased over time, allowing long-term window fluorescence imaging tumor resection surgery.
- mice used in the experiments were purchased with approval from the Shanghai Laboratory Animal Center, and the animal experiments were conducted in accordance with the guidelines of the Animal Care and Use Committee (IACUC) of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
- IACUC Animal Care and Use Committee
- Take a 6-week-old normal Balb/c female mouse inject the probe Ib (10k) between the toes of the mouse's right limb, and gently massage the injection site to allow faster diffusion.
- the results are shown in Figure 5a.
- the mouse is placed in the near-infrared second-zone imaging system, two lymph nodes on the right side of the mouse can be seen.
- Using a high-magnification imaging device four lymphatic vessels can be clearly seen.
- the fluorescence intensity distribution diagram of the straight section contains the signals of the four lymphatic vessels, as shown in Figure 5b.
- the imaging results show that the probe has high quantum yield and biological The high degree of utilization indicates that it can be used for imaging research on lymphatic system-related diseases and has the potential for clinical translation.
- the probe Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) and configure it into a 100uM aqueous solution. Place it under an 808nm laser with a power of 1W/cm 2 for 5 minutes. Use an infrared camera to record the temperature every 30s. The temperature rise curve of the probe was obtained. The results in Figure 6 show that the probes all have photothermal effects and can be used for photothermal therapy.
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Abstract
Provided are an asymmetric donor-receptor type near-infrared region II probe molecule, a method for preparing same, and use thereof. The probe molecule is represented by the following general formula (1). The emission spectrum of the probe molecule can reach an NIR-II region, and compared with a probe with a D-A-D structure, a D-A structure of the probe reduces the molecular weight, such that the probe is easier for chemical modification and metabolism, and can be used for whole-body angiography, lymphatic imaging, diagnosis and detection of diseases, tumor imaging, surgical navigation, and the like.
Description
本发明属于有机荧光探针领域，涉及不对称的供体-受体(D-A)型近红外二区探针分子及其制备方法和应用。The invention belongs to the field of organic fluorescent probes and relates to asymmetric donor-acceptor (D-A) type near-infrared second-region probe molecules and their preparation methods and applications.
分子影像学是利用影像技术显示组织、细胞和亚细胞水平的特定分子，对活体生理和病理状态下的观察，进行定性和定量研究的科学，为探索疾病的发生、发展和转化，评价药物的疗效，起到连接分子生物学和临床医学之间的桥梁作用。临床上使用的成像手段包括核磁共振成像(Magnetic Resonance Imaging,MRI)、正电子发射断层扫描成像(Positron Emission Tomography,PET)、单光子发射型计算机断层成像(Single Photon Emission Computed Tomography,SPECT)、计算机X射线断层成像(Computerized Tomography,CT)、超声成像(Ultrasound,US)以及光学成像(Optical Imaging，OI)。Molecular imaging is a science that uses imaging technology to display specific molecules at the tissue, cellular and subcellular levels, and conducts qualitative and quantitative research on the observation of physiological and pathological conditions in vivo. In order to explore the occurrence, development and transformation of diseases, and evaluate the effectiveness of drugs It serves as a bridge between molecular biology and clinical medicine. Imaging methods used clinically include Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and computer X-ray tomography (Computerized Tomography, CT), ultrasound imaging (Ultrasound, US) and optical imaging (Optical Imaging, OI).
与传统成像手段相比，光学成像具有高灵敏度、高分辨率、高对比度、实时反馈、无电离辐射、设备简单等优点，成为了生物成像领域发展迅速、应用广泛的成像技术之一。光学成像区域可具体分为可见光区域(400-700nm)、近红外一区(NIR-I,700-900nm)和近红外二区(NIR-II,900-1700nm)。Compared with traditional imaging methods, optical imaging has the advantages of high sensitivity, high resolution, high contrast, real-time feedback, no ionizing radiation, and simple equipment. It has become one of the rapidly developing and widely used imaging technologies in the field of biological imaging. The optical imaging area can be specifically divided into visible light area (400-700nm), near-infrared first area (NIR-I, 700-900nm) and near-infrared second area (NIR-II, 900-1700nm).
目前，近红外一区(NIR-I,700-900nm)荧光成像在临床上得到了广泛的应用。NIR-I荧光染料吲哚菁绿(ICG)和亚甲蓝(MB)被美国食品和药品监督管理局(FDA)批准用于临床，在临床诊断上做出了贡献，主要用于心血管造影、淋巴造影、胃肠造影以及肿瘤切除手术等，协助外科医生的诊断和治疗。虽然NIR-I成像取得了不错的成果，但仍受到穿透深度的限制。At present, near-infrared first region (NIR-I, 700-900nm) fluorescence imaging has been widely used clinically. NIR-I fluorescent dyes indocyanine green (ICG) and methylene blue (MB) have been approved for clinical use by the U.S. Food and Drug Administration (FDA) and have made contributions to clinical diagnosis. They are mainly used for cardiovascular angiography. , lymphography, gastrointestinal imaging and tumor resection surgery to assist surgeons in diagnosis and treatment. Although NIR-I imaging has achieved good results, it is still limited by the penetration depth.
研究发现，近红外二区(NIR-II,1000-1700nm)在活体成像方面显示出优越的成像性能，由于降低了组织的吸收、散射和自荧光增加了成像分辨率和组织穿透深度，显示出更高的穿透深度、分辨率和信噪比(SBR)。Research has found that the near-infrared II region (NIR-II, 1000-1700nm) shows superior imaging performance in in vivo imaging. It reduces tissue absorption, scattering and autofluorescence, increases imaging resolution and tissue penetration depth, showing that Produces higher penetration depth, resolution and signal-to-noise ratio (SBR).
NIR-II探针主要包括无机材料(碳纳米管、量子点和稀土掺杂的纳米颗粒)共轭聚合物和有机小分子。然而无机材料与共轭聚合物荧光团具有较差的药代动力学，生物相容性差，这限制了它们在临床上的应用。而有机小分子探针，特别是供体-受体-供体(D-A-D)型结构的小分子，由于分子量小、结构明确、代谢快、生物相容性好，获得了更大的优势，具有临床转换的潜力。NIR-II probes mainly include inorganic materials (carbon nanotubes, quantum dots and rare earth-doped nanoparticles) conjugated polymers and organic small molecules. However, inorganic materials and conjugated polymer fluorophores have poor pharmacokinetics and poor biocompatibility, which limits their clinical application. Organic small molecule probes, especially small molecules with a donor-acceptor-donor (D-A-D) structure, have gained greater advantages due to their small molecular weight, clear structure, fast metabolism, and good biocompatibility. Potential for clinical translation.
发明内容Contents of the invention
本发明的技术目的是提供一类近红外二区(NIR-II)探针，其更易代谢，可以有效地用于全身血管成像、淋巴成像、疾病的诊断与检测、肿瘤成像及手术导航等。
The technical purpose of the present invention is to provide a type of near-infrared second-region (NIR-II) probe that is easier to metabolize and can be effectively used for whole-body vascular imaging, lymphatic imaging, disease diagnosis and detection, tumor imaging, surgical navigation, etc.
一方面，本发明提供一类不对称的供体-受体型NIR-II探针分子，其由以下通式1表示：
On the one hand, the present invention provides a type of asymmetric donor-acceptor type NIR-II probe molecule, which is represented by the following general formula 1:
On the one hand, the present invention provides a type of asymmetric donor-acceptor type NIR-II probe molecule, which is represented by the following general formula 1:
在以上通式1中，In the above general formula 1,
环A选自B和B’各自独立地选自
Ring A is selected from B and B' are each independently selected from
X为S、O、Se或NR5；X is S, O, Se or NR 5 ;
R1选自
R 1 is selected from
R2选自
R 2 is selected from
其中，R6和R7各自独立地选自H、羟基、氨基(-NH2)、羧基(-COOH)、卤素、羧基C1-C7烷基、C1-C8烷基、C1-C8烷氧基、取代或未取代的C6-C12芳基或者5-12元含有选自N、O、S的杂原子的杂芳基(当所述芳基或杂芳基被取代时，取代基选自C1-C8烷基、C1-C8烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基或卤代C1-C8烷基)、-(CH2)n1-(OCH2CH2)n2-R((n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基(-CHO)、羧基、巯基(-SH)、炔基(-C≡CH)、叠氮基(-N3)、卤素、
及)；Among them, R 6 and R 7 are each independently selected from H, hydroxyl, amino (-NH 2 ), carboxyl (-COOH), halogen, carboxyl C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, substituted or unsubstituted C6-C12 aryl or 5-12 membered heteroaryl containing heteroatoms selected from N, O, S (when the aryl or heteroaryl is substituted , the substituent is selected from C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylsilyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, Aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl or halogenated C 1 -C 8 alkyl), -(CH 2 )n 1 -(OCH 2 CH 2 )n 2 -R((n 1 =an integer of 0-10, n 2 =an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino , hydroxyl group, methoxy group, aldehyde group (-CHO), carboxyl group, sulfhydryl group (-SH), alkynyl group (-C≡CH), azido group (-N 3 ), halogen, and );
R8和R9各自独立地选自H、羟基、氨基、羧基、卤素、羧基C1-C7烷基、C1-C8烷基、C1-C8烷氧基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)，或者R8和R9与其相连接的C一起形成5-10元含选自N、O和S的杂原子的杂环基；R 8 and R 9 are each independently selected from H, hydroxyl, amino, carboxyl, halogen, carboxyl C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy , aldehyde group, carboxyl group, mercapto group, alkynyl group, azide group, halogen, and ), or R 8 and R 9 together with the C to which they are connected form a 5-10 membered heterocyclic group containing heteroatoms selected from N, O and S;
Y2选自S、O、Se和NR5；Y 2 is selected from S, O, Se and NR 5 ;
R5选自H、C1-C12烷基、C1-C12烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、酰基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)；R 5 is selected from H, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 8 alkylsilyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl , aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, acyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl, halo Substituting C 1 -C 8 alkyl, -(CH 2 ) n 1 -(OCH 2 CH 2 )n 2 -R (n 1 =an integer of 0-10, n 2 =an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azido, halogen, and );
R3和R4各自独立地选自H、C1-C12烷基、C1-C12烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、酰基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)、-(CH2)n3-COOCH2CH2Si(CH3)3(n3为1-10的整数)、取代或未取代的C6-C12芳基或5-12元含有选自N、O、S的杂原子的杂芳基(当所述芳基或杂芳基被取代时，取代基选自C1-C8烷基、C1-C8烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基或卤代C1-C8烷基)；R 3 and R 4 are each independently selected from H, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 8 alkylsilyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, acyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, mercapto C 1 - C 8 alkyl, halogenated C 1 -C 8 alkyl, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000 , R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azido, halogen, and ), -(CH 2 )n 3 -COOCH 2 CH 2 Si(CH 3 ) 3 (n 3 is an integer from 1 to 10), substituted or unsubstituted C6-C12 aryl group or 5-12 yuan containing selected from N , heteroaryl group of heteroatoms of O and S (when the aryl group or heteroaryl group is substituted, the substituent is selected from C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylsilyl group, hydroxyl C 1 -C 8 alkyl group, amino C 1 -C 8 alkyl group, aldehyde group C 1 -C 8 alkyl group, carboxyl group C 1 -C 8 alkyl group, sulfonic acid group C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl or halogenated C 1 -C 8 alkyl);
Y为S、O、Se或NR5；Y is S, O, Se or NR 5 ;
Y1为CR5或N；Y 1 is CR 5 or N;
R5选自H、C1-C12烷基、C1-C12烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、酰基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、
羧基、巯基、炔基、叠氮基、卤素、及)；R 5 is selected from H, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 8 alkylsilyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl , aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, acyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl, halo Substituting C 1 -C 8 alkyl, -(CH 2 ) n 1 -(OCH 2 CH 2 )n 2 -R (n 1 =an integer of 0-10, n 2 =an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde group, Carboxyl, mercapto, alkynyl, azide, halogen, and );
D选自如下基团：
D is selected from the following groups:
D is selected from the following groups:
其中，R10至R46各自独立选自H、取代或未取代的C1-C12烷基、取代或未取代的C1-C12烷氧基、取代或未取代的C1-C8烷基硅基、氨基、卤素、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、
及)、-(CH2)n2-COOCH2CH2Si(CH3)3(n2为1-10的整数)、-(CH2)n4-CONHCH2CH2SO3H(n4为0-10的整数)；Wherein, R 10 to R 46 are each independently selected from H, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 1 -C 8 Alkylsilyl group, amino group, halogen, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer from 0 to 10, n 2 = an integer from 1 to 1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azido, halogen, and ), -(CH 2 )n 2 -COOCH 2 CH 2 Si(CH 3 ) 3 (n 2 is an integer from 1 to 10), -(CH 2 )n 4 -CONHCH 2 CH 2 SO 3 H (n 4 is an integer from 0 to 10);
其中，所述C1-C12烷基、C1-C12烷氧基和C1-C8烷基硅基的取代基选自羟基、氨基、炔基、叠氮基、巯基、醛基、羧基、磺酸基、卤素、RaOC(＝O)-、RaC(＝O)O-、RaNHC(＝O)-和吡咯烷二酮-NH-，其中Ra选自C1-C8烷基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、磺酸基C1-C8烷基、炔基C1-C8烷基、叠氮基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基和-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮、卤素、及)；Wherein, the substituents of the C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group and C 1 -C 8 alkyl silicon group are selected from the group consisting of hydroxyl, amino, alkynyl, azido, mercapto, and aldehyde groups. , carboxyl, sulfonic acid group, halogen, Ra OC(=O)-, Ra C(=O)O-, Ra NHC(=O)-, and pyrrolidinedione-NH-, where Ra is selected from C 1 -C 8 alkyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, alkynyl C 1 -C 8 alkyl, azido C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl, halo C 1 -C 8 alkyl and -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy , aldehyde group, carboxyl group, sulfhydryl group, alkynyl group, azide, halogen, and );
或者，R10至R46各自独立地选自其中R’和R”选自C1-C8亚烷基，C为H、环状RGD肽c(RGDyk)、c(RGDfk)、c(RADyk)、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)、(CH2CH2O)n2-R(n2＝1-1000的整数，R为C1-C8烷基)、多肽前列腺特异性模抗原多肽分子(PSMA)基团(所述PSMA可包括PSMA-617、PSMA-11、PSMA-1007)、奥曲肽基团、单糖及多糖基团(其中，单糖可选自葡萄糖、半乳糖、果糖、阿拉伯糖、鼠李糖、核糖、乳糖及麦芽糖，多糖可为环糊精)；D选自含有Fv段的分子，例如，D为单抗、双抗、或scFv；Alternatively, R 10 to R 46 are each independently selected from Wherein R' and R" are selected from C 1 -C 8 alkylene, C is H, cyclic RGD peptide c(RGDyk), c(RGDfk), c(RADyk), -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, Thiol, alkynyl, azide, halogen, and ), (CH 2 CH 2 O) n2 -R (n 2 = an integer of 1-1000, R is a C 1 -C 8 alkyl group), polypeptide prostate-specific model antigen polypeptide molecule (PSMA) group (the PSMA Can include PSMA-617, PSMA-11, PSMA-1007), octreotide group, monosaccharide and polysaccharide group (wherein, the monosaccharide can be selected from glucose, galactose, fructose, arabinose, rhamnose, ribose, lactose and maltose, the polysaccharide can be cyclodextrin); D is selected from molecules containing Fv segments, for example, D is a monoclonal antibody, a double antibody, or scFv;
或者，R10至R46各自独立地选自
其中R”’为C1-C8亚烷基。Alternatively, R 10 to R 46 are each independently selected from Where R"' is C 1 -C 8 alkylene.
在具体实施方式中，所述通式1的探针分子可选自通式I、II、III和IV：
In specific embodiments, the probe molecule of general formula 1 can be selected from the group consisting of general formulas I, II, III and IV:
In specific embodiments, the probe molecule of general formula 1 can be selected from the group consisting of general formulas I, II, III and IV:
在以上通式I、II、III和IV中，各取代基的定义分别如上文所定义。In the above general formulas I, II, III and IV, the definitions of each substituent are as defined above respectively.
在具体实施方式中，在通式1中，In a specific embodiment, in general formula 1,
环A为
Ring A is
一组B和B’分别选自以及
A set of B and B' are respectively selected from as well as
X为S；X is S;
R1选自
R 1 is selected from
R2选自
R 2 is selected from
其中，R6和R7各自独立地选自H、羟基、氨基(-NH2)、羧基(-NH2)、卤素、羧基C1-C7烷基、C1-C8烷基、C1-C8烷氧基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基(-CHO)、
羧基、巯基(-SH)、炔基(-C≡CH)、叠氮基(-N3)、卤素、及)；Among them, R 6 and R 7 are each independently selected from H, hydroxyl, amino (-NH 2 ), carboxyl (-NH 2 ), halogen, carboxyl C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -(CH 2 ) n 1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer from 0 to 10, n 2 = an integer from 1 to 1000, R is selected from C 1 - C 8 alkyl, amino, hydroxyl, methoxy, aldehyde (-CHO), Carboxyl group, mercapto group (-SH), alkynyl group (-C≡CH), azide group (-N 3 ), halogen, and );
R8和R9各自独立地选自H、羟基、氨基、羧基、卤素、羧基C1-C7烷基、C1-C8烷基、C1-C8烷氧基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数，n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)，或者R8和R9与其相邻的C形成5-10元含O的杂环基；R 8 and R 9 are each independently selected from H, hydroxyl, amino, carboxyl, halogen, carboxyl C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy , aldehyde group, carboxyl group, mercapto group, alkynyl group, azide group, halogen, and ), or R 8 and R 9 and their adjacent C form a 5-10 membered O-containing heterocyclic group;
R3和R4各自独立地为H或-(CH2)n3-COOCH2CH2Si(CH3)3，其中n3为1-10的整数；D选自如下基团：
R 3 and R 4 are each independently H or -(CH 2 )n 3 -COOCH 2 CH 2 Si(CH 3 ) 3 , where n 3 is an integer from 1 to 10; D is selected from the following groups:
R 3 and R 4 are each independently H or -(CH 2 )n 3 -COOCH 2 CH 2 Si(CH 3 ) 3 , where n 3 is an integer from 1 to 10; D is selected from the following groups:
其中，R10、R11、R14、R15、R45和R46各自独立地选自H、取代或未取代的C1-C12烷基、取代或未取代的C1-C12烷氧基、取代或未取代的C1-C8烷基硅基、氨基、卤素、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数，n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)、-(CH2)n2-COOCH2CH2Si(CH3)3(n2为1-10的整数)、-(CH2)n4-CONHCH2CH2SO3H(n4为0-10的整数)；Wherein, R 10 , R 11 , R 14 , R 15 , R 45 and R 46 are each independently selected from H, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 1 -C 12 alkyl Oxygen group, substituted or unsubstituted C 1 -C 8 alkylsilyl group, amino group, halogen, -(CH 2 ) n 1 -(OCH 2 CH 2 )n 2 -R(n 1 =an integer from 0 to 10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azide, halogen, and ), -(CH 2 )n 2 -COOCH 2 CH 2 Si(CH 3 ) 3 (n 2 is an integer from 1 to 10), -(CH 2 )n 4 -CONHCH 2 CH 2 SO 3 H (n 4 is an integer from 0 to 10);
其中，所述C1-C12烷基、C1-C12烷氧基和C1-C8烷基硅基的取代基选自羟基、氨基、炔基、叠氮基、巯基、醛基、羧基、磺酸基、卤素、RaOC(＝O)-、RaC(＝O)O-、RaNHC(＝O)-和吡咯烷二酮-NH-，其中Ra选自C1-C8烷基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、磺酸基C1-C8烷基、炔基C1-C8烷基、叠氮基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基和-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧
基、巯基、炔基、叠氮基、卤素、)；Wherein, the substituents of the C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group and C 1 -C 8 alkyl silicon group are selected from the group consisting of hydroxyl, amino, alkynyl, azido, mercapto, and aldehyde groups. , carboxyl, sulfonic acid group, halogen, Ra OC(=O)-, Ra C(=O)O-, Ra NHC(=O)-, and pyrrolidinedione-NH-, where Ra is selected from C 1 -C 8 alkyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, alkynyl C 1 -C 8 alkyl, azido C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl, halo C 1 -C 8 alkyl and -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy , aldehyde group, carboxyl group group, mercapto group, alkynyl group, azide group, halogen, );
或者，R10、R11、R14、R15、R45和R46各自独立地选自其中R’和R”选自C1-C8亚烷基，C为H或-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)，D选自含有Fv段的分子，例如，D为单抗、双抗、或scFv。Alternatively, R 10 , R 11 , R 14 , R 15 , R 45 and R 46 are each independently selected from Wherein R' and R" are selected from C 1 -C 8 alkylene, C is H or -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azide, halogen, and ), D is selected from molecules containing Fv segments, for example, D is a monoclonal antibody, bisclonal antibody, or scFv.
在具体实施方式中，所述探针分子选自以下各化合物：
In specific embodiments, the probe molecule is selected from the following compounds:
In specific embodiments, the probe molecule is selected from the following compounds:
术语“卤素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“C1-C12烷基”是指链上具有1至12个碳原子的直链或支链饱和烃基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。C1-C8烷基、C1-C6烷基、C1-C4烷基的含义以此类推。The term "C 1 -C 12 alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 12 carbon atoms in the chain, including without limitation methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl, tert-butyl, etc. The meanings of C 1 -C 8 alkyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl are deduced by analogy.
术语“烷氧基”是指上述烷基末端连接氧所得的基团，例如，甲氧基、乙氧基、正丙氧基、仲丁氧基、叔丁基、正己氧基等。The term "alkoxy" refers to the group obtained by connecting the end of the alkyl group with oxygen, for example, methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butyl, n-hexyloxy, etc.
术语“C1-C8烷基硅基”为结构RaRbRcSi-，其中，Ra、Rb和Rc中至少有一个为C1-C8烷基，其余为氢的基团，例如，三甲基硅烷、三乙基硅烷。The term "C 1 -C 8 alkylsilyl" is a group of the structure RaRbRcSi-, where at least one of Ra, Rb and Rc is a C 1 -C 8 alkyl group and the remainder is hydrogen, for example, trimethylsilane , triethylsilane.
术语“磺酸基”是指-SO3H。The term "sulfonate" refers to -SO3H .
术语“氨基”是指-NH2。The term "amino" refers to -NH2 .
术语“羧基”是指-COOH。The term "carboxy" refers to -COOH.
术语“C6-C12芳基”是指具有6至12个环碳原子的芳基，非限制性地包括苯基、萘基等。The term "C6-C12 aryl" refers to an aryl group having 6 to 12 ring carbon atoms, including without limitation phenyl, naphthyl, and the like.
术语“5-12元杂芳基”是指具有5至12个环原子且含有选自N、O、S的杂原子的芳香性环状基团，非限制性地包括呋喃基、噻吩基、噻喃基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、苯并呋喃基、苯并噻吩基、苯并噻喃基、吲哚基、苯并三唑基、苯并吡啶基、
吡啶并呋喃基、吡啶并吡咯基等。The term "5-12 membered heteroaryl" refers to an aromatic cyclic group having 5 to 12 ring atoms and containing heteroatoms selected from N, O, and S, including, but not limited to, furyl, thienyl, Thiopyryl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, benzofuranyl, benzothienyl, benzothiopyranyl, indolyl, benzotriazolyl, benzopyridine base, Pyridofuryl, pyridopyrrolyl, etc.
杂环基是指含有一个或多个饱和和/或部分饱和环且包括3至10个环原子的环状基，其中一个或多个环原子选自氮、氧或硫的杂原子，其余环原子为碳；例如，环氧丙烷基、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基等。Heterocyclyl refers to a cyclic group containing one or more saturated and/or partially saturated rings and including 3 to 10 ring atoms, in which one or more ring atoms are selected from heteroatoms of nitrogen, oxygen or sulfur, and the remaining rings The atom is carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, etc.
另一方面，本发明提供上述探针分子的制备方法，如以下反应路线所示，所述方法包括：
On the other hand, the present invention provides a method for preparing the above-mentioned probe molecule, as shown in the following reaction scheme, the method includes:
On the other hand, the present invention provides a method for preparing the above-mentioned probe molecule, as shown in the following reaction scheme, the method includes:
在以上反应式中，各取代基的定义分别如上文所定义；R’为硼酸或硼酸酯，锡盐；In the above reaction formula, the definitions of each substituent are as defined above; R’ is boric acid or borate ester, tin salt;
步骤1：化合物1与化合物2经Suzuki反应得到化合物3；Step 1: Compound 1 and compound 2 undergo Suzuki reaction to obtain compound 3;
步骤2：化合物3经还原反应得到化合物4；以及Step 2: Compound 3 is reduced to obtain compound 4; and
步骤3：化合物4与N-亚磺酰苯胺(PNSO)进行成环反应得到通式I的化合物；或者Step 3: Compound 4 is reacted with N-sulfenylanilide (PNSO) to obtain a compound of general formula I; or
步骤3’：化合物4与化合物(5-2)、(5-3)或(5-4)进行生成Schiff碱的反应，分别得到通式II、III或IV的化合物。Step 3': Compound 4 is reacted with compound (5-2), (5-3) or (5-4) to form Schiff base to obtain compounds of general formula II, III or IV respectively.
特别地，各步骤如下操作：Specifically, each step operates as follows:
步骤1：称取化合物1与催化剂四(三苯基膦)钯于反应瓶，置换氮气，加入甲苯与碳酸钾水溶液溶解，置换氮气，将体系搅拌，缓慢滴加化合物2的甲苯溶液进行反应，反应结束后进行提纯，得到化合物3；Step 1: Weigh compound 1 and catalyst tetrakis(triphenylphosphine)palladium in the reaction flask, replace the nitrogen, add toluene and potassium carbonate aqueous solution to dissolve, replace the nitrogen, stir the system, slowly add the toluene solution of compound 2 dropwise to react, After the reaction is completed, purify to obtain compound 3;
步骤2：将化合物3溶于二氯甲烷与甲醇溶液体系，在冰浴条件下加入适量锌粉与氯化铵水溶液。反应条件从0℃至室温，进行反应，反应结束后进行提纯，得到化合物4；
以及Step 2: Dissolve compound 3 in a dichloromethane and methanol solution system, and add an appropriate amount of zinc powder and ammonium chloride aqueous solution under ice bath conditions. The reaction conditions are from 0°C to room temperature, and the reaction is carried out. After the reaction is completed, the compound is purified to obtain compound 4; as well as
步骤3：在步骤2之后，称取化合物4于反应瓶，置换氮气，加入溶剂吡啶后再次置换氮气，随后加入N-亚磺酰苯胺(PNSO)，置换氮气，加入三甲基氯硅烷(TMSCl)，进行反应，反应结束后进行提纯，得到通式I的化合物；或者Step 3: After step 2, weigh compound 4 into the reaction flask, replace the nitrogen, add the solvent pyridine and replace the nitrogen again, then add N-sulfenylanilide (PNSO), replace the nitrogen, and add trimethylsilyl chloride (TMSCl ), carry out the reaction, and purify after the reaction is completed to obtain the compound of general formula I; or
步骤3’：在步骤2之后，称取化合物4，以及称取化合物(5-2)、(5-3)或(5-4)于反应瓶，置换氮气后加入醋酸溶液溶解，置换氮气，进行反应，反应结束后进行提纯，分别得到通式II、III或IV的化合物。Step 3': After step 2, weigh compound 4, and weigh compound (5-2), (5-3) or (5-4) into the reaction bottle, replace nitrogen, add acetic acid solution to dissolve, replace nitrogen, Carry out the reaction and purify after the reaction is completed to obtain compounds of general formula II, III or IV respectively.
在具体实施方式中，在步骤1中，化合物1：化合物2：碳酸钾、四(三苯基膦)钯的摩尔比为1:1:1.2:0.05，反应温度为110℃，反应时间为12-24h。In a specific embodiment, in step 1, the molar ratio of compound 1: compound 2: potassium carbonate and tetrakis(triphenylphosphine)palladium is 1:1:1.2:0.05, the reaction temperature is 110°C, and the reaction time is 12 -24h.
在具体实施方式中，在步骤2中，在二氯甲烷与甲醇溶液体系中，二氯甲烷与甲醇体积比为10:1，反应时间为4h。In a specific embodiment, in step 2, in the dichloromethane and methanol solution system, the volume ratio of dichloromethane to methanol is 10:1, and the reaction time is 4 hours.
在具体实施方式中，在步骤3中，反应温度为80℃，反应时间为12-16h。In a specific embodiment, in step 3, the reaction temperature is 80°C and the reaction time is 12-16h.
在具体实施方式中，在步骤3’中，反应温度为110℃，反应时间为12-16h。In a specific embodiment, in step 3', the reaction temperature is 110°C and the reaction time is 12-16h.
再一方面，本发明提供所述探针分子在制备显影剂中的用途。In yet another aspect, the present invention provides the use of the probe molecule in the preparation of a developer.
所述显影剂可以用于在生物组织及样品中进行体外定量检测和体内成像以及非生物组织的指示定量。例如，所述显影剂可以用于活体荧光成像指导肿瘤切除，例如龋齿类动物活体成像及荧光成像指导荷瘤鼠肿瘤切除；所述显影剂可用于龋齿类动物血液循环系统成像、淋巴管及淋巴结成像、肿瘤血管成像、血栓成像及脑血管成像；所述显影剂可用于坏死组织成像，例如龋齿类动物无水乙醇诱导的肌肉坏死组织成像。The developer can be used for in vitro quantitative detection and in vivo imaging in biological tissues and samples, as well as for indication quantification of non-biological tissues. For example, the developer can be used for in vivo fluorescence imaging to guide tumor resection, such as in vivo imaging and fluorescence imaging of caries animals to guide tumor resection in tumor-bearing mice; the developer can be used to image the blood circulation system, lymphatic vessels and lymph nodes of caries animals. imaging, tumor blood vessel imaging, thrombus imaging and cerebral blood vessel imaging; the developer can be used for imaging of necrotic tissue, such as imaging of muscle necrosis tissue induced by absolute ethanol in carious animals.
在具体实施方式中，所述显影剂可用于全身血管成像、骨成像或淋巴成像。In specific embodiments, the contrast agent may be used for whole body vascular imaging, bone imaging, or lymphatic imaging.
在具体实施方式中，所述显影剂可用于肿瘤成像。In specific embodiments, the imaging agent can be used for tumor imaging.
在具体实施方式中，所述显影剂可用于手术导航。In specific embodiments, the contrast agent may be used for surgical navigation.
又一方面，本发明提供所述探针分子在制备光热治疗剂中的用途，特别地，所述光热治疗剂用于肿瘤的治疗。In another aspect, the present invention provides the use of the probe molecule in preparing a photothermal therapeutic agent. In particular, the photothermal therapeutic agent is used for the treatment of tumors.
在具体实施方式中，在所述探针分作为光热治疗剂时，使用方法如下：显影剂经给药后到达指定部位(例如为肿瘤组织)聚集，随后给予激光照射，通过显影剂产生的热以达到杀死肿瘤细胞的目的。In a specific embodiment, when the probe is used as a photothermal therapeutic agent, the method of use is as follows: after administration, the developer reaches a designated site (for example, a tumor tissue) and accumulates, and then is irradiated with a laser. Heat to kill tumor cells.
又一方面，本发明提供所述探针分子在制备肿瘤诊断试剂中的用途。In another aspect, the present invention provides the use of the probe molecule in preparing tumor diagnostic reagents.
本发明又一方面涉及一种显影剂，其包含上述探针分子。Yet another aspect of the present invention relates to a developer comprising the above-mentioned probe molecule.
本申请提供了一系列不对称的供体-受体(D-A)型NIR-II探针，其发射光谱也能到达NIR-II区域。与D-A-D结构的探针相比，本申请探针的D-A结构减少了分子量，更容易化学修饰及代谢，可以对动物模型全身血管成像、淋巴成像、疾病的诊断与检测、肿瘤成像及手术导航等，并且预期可用于人类全身血管成像、淋巴成像、疾病的诊断与检测、肿瘤成像及手术导航等。
This application provides a series of asymmetric donor-acceptor (DA) type NIR-II probes, whose emission spectra can also reach the NIR-II region. Compared with probes with a DAD structure, the DA structure of the probe of the present application has reduced molecular weight and is easier to chemically modify and metabolize. It can be used for whole-body vascular imaging, lymphatic imaging, disease diagnosis and detection, tumor imaging, surgical navigation, etc. in animal models. , and is expected to be used for human whole body vascular imaging, lymphatic imaging, disease diagnosis and detection, tumor imaging and surgical navigation, etc.
图1为化合物Ia和Ib(0.5k2,2k2,2k,5k,10k)的紫外吸收光谱。Figure 1 shows the UV absorption spectra of compounds Ia and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k).
图2为化合物Ia和Ib(0.5k2,2k2,2k,5k,10k)的荧光发射光谱。Figure 2 shows the fluorescence emission spectra of compounds Ia and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k).
图3为化合物Ib(0.5k2,2k2,2k,5k,10k)在正常小鼠体内近红外二区1400nm在不同时间点的生物分布图。Figure 3 shows the biodistribution diagram of compound Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) in the body of normal mice at 1400nm in the second near-infrared region at different time points.
图4为化合物Ib(2k,10k)在肿瘤小鼠中的成像，可用于长时间窗口的荧光成像肿瘤切除手术，虚线框指示肿瘤位置。Figure 4 shows the imaging of compound Ib (2k, 10k) in tumor mice, which can be used for long-term window fluorescence imaging tumor resection surgery. The dotted box indicates the tumor location.
图5示出，a：化合物Ib(10k)在小鼠淋巴系统中的成像，b：可检测的4根淋巴管的荧光信号强度。Figure 5 shows, a: imaging of compound Ib (10k) in the mouse lymphatic system, b: detectable fluorescence signal intensity of four lymphatic vessels.
图6为化合物Ib(0.5k2,2k2,2k,5k,10k)在808nm激光下的升温曲线。Figure 6 shows the heating curve of compound Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) under 808nm laser.
以下实施方法中，对本发明的部分D-A型近红外二区探针分子进行阐述。这些实施例为解释说明目的，不用于限制本发明的范围。In the following implementation method, some D-A type near-infrared second-region probe molecules of the present invention are described. These examples are for illustrative purposes and are not intended to limit the scope of the invention.
实施例Example
实施例1：化合物Ia的合成
Example 1: Synthesis of Compound Ia
Example 1: Synthesis of Compound Ia
取化合物1a(500mg,0.912mmol)与催化剂四(三苯基膦)钯(52.7mg,0.046mmol)于反应瓶，置换氮气，在氮气条件下加入甲苯(约10ml)与碳酸钾溶液(151.26mg,1.09mmol，溶于2ml水中，反应体系甲苯：水体积比约为5:1)，置换氮气，将反应置于110℃搅拌下缓慢滴加化合物2a的甲苯溶液(652.89mg,0.912mmol)，110℃加热回流反应12-16h。TLC检测反应完全后，将反应冷却至室温，旋蒸除去大部分甲苯，将剩余反应液用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，无水硫酸镁干燥，过滤，旋干大部分溶剂，加入硅胶拌样过柱，得到化合物3a 241.04mg，粗产率为25％。
Take compound 1a (500 mg, 0.912 mmol) and the catalyst tetrakis (triphenylphosphine) palladium (52.7 mg, 0.046 mmol) in the reaction flask, replace the nitrogen, and add toluene (about 10 ml) and potassium carbonate solution (151.26 mg) under nitrogen conditions , 1.09mmol, dissolved in 2ml of water, the reaction system toluene: water volume ratio is about 5:1), replace nitrogen, place the reaction at 110°C and slowly add the toluene solution of compound 2a (652.89mg, 0.912mmol) under stirring, Heat and reflux at 110°C for 12-16 hours. After TLC detects that the reaction is complete, cool the reaction to room temperature, remove most of the toluene by rotary evaporation, extract the remaining reaction solution with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, and spin to dryness Most of the solvent was added to silica gel and the sample was passed through the column to obtain 241.04 mg of compound 3a with a crude yield of 25%.
取中间体化合物3a(200mg,0.189mmol)溶于二氯甲烷与甲醇溶液体系(二氯甲烷与甲醇体积比为10:1)，在冰浴条件下加入锌粉(1583.05mg,22.68mmol)与氯化铵(363.95mg,6.804mmol)水溶液。反应条件从0℃至室温，反应时间约为4h。旋干大部分溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，用无水硫酸镁干燥，过滤，旋干除去溶剂，得到化合物4a，直接用于下一步反应。Dissolve intermediate compound 3a (200 mg, 0.189 mmol) in a dichloromethane and methanol solution system (the volume ratio of dichloromethane to methanol is 10:1), add zinc powder (1583.05 mg, 22.68 mmol) and Ammonium chloride (363.95mg, 6.804mmol) aqueous solution. The reaction conditions range from 0°C to room temperature, and the reaction time is about 4 hours. Spin most of the solvent dry, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, spin dry to remove the solvent, and obtain compound 4a, which is directly used in the next reaction.
取化合物4a(100mg,0.109mmol)与噻吩偶姻(36.45mg,0.164mmol)溶于醋酸，置换氮气，将反应置于110℃反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物Ia，102.34mg，产率为85％。Dissolve compound 4a (100 mg, 0.109 mmol) and thienoin (36.45 mg, 0.164 mmol) in acetic acid, replace with nitrogen, and place the reaction at 110°C for 12-16 hours. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain compound Ia, 102.34 mg, with a yield of 85%.
1H NMR(400MHz,CDCl3)δ7.99(d,J＝6.6Hz,1H),7.70(d,J＝6.8Hz,1H),7.66–7.53(m,6H),7.33(dd,J＝4.8,1.8Hz,1H),7.20(ddd,J＝20.3,6.8,4.8Hz,3H),7.07–6.99(m,2H),7.00(d,J＝0.9Hz,7H),4.02(t,J＝9.9Hz,2H),3.16(s,1H),2.88(tt,J＝9.8,0.8Hz,4H),2.65–2.56(m,4H),0.94(t,J＝9.9Hz,2H),0.08(s,6H),0.04(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.99 (d, J＝6.6Hz, 1H), 7.70 (d, J＝6.8Hz, 1H), 7.66–7.53 (m, 6H), 7.33 (dd, J＝ 4.8,1.8Hz,1H),7.20(ddd,J＝20.3,6.8,4.8Hz,3H),7.07–6.99(m,2H),7.00(d,J＝0.9Hz,7H),4.02(t,J ＝9.9Hz,2H),3.16(s,1H),2.88(tt,J＝9.8,0.8Hz,4H),2.65–2.56(m,4H),0.94(t,J＝9.9Hz,2H),0.08 (s,6H),0.04(s,6H).
13C NMR(101MHz,CDCl3)δ147.92,146.89,145.86,143.67,138.35,131.86,129.39,129.13,129.08,128.75,128.10,127.61,127.60,127.58,127.01,126.71,126.43,117.00,112.85,66.11,64.64,53.57,34.60,30.21,30.14,8.77,6.15. 13 C NMR (101MHz, CDCl 3 ) δ147.92,146.89,145.86,143.67,138.35,131.86,129.39,129.13,129.08,128.75,128.10,127.61,127.60,127.58,127.01 ,126.71,126.43,117.00,112.85,66.11,64.64 ,53.57,34.60,30.21,30.14,8.77,6.15.
MALDI-TOF-MS:计算M.W:1103.26.实测:约1103.281MALDI-TOF-MS: Calculated M.W: 1103.26. Measured: approximately 1103.281
实施例2：化合物Ib的合成
Example 2: Synthesis of Compound Ib
Example 2: Synthesis of Compound Ib
取化合物Ia(100mg,0.091mmol)溶于20ml二氯甲烷，在冰浴条件下滴加体积约5ml左右的三氟乙酸(TFA)，反应温度从0℃至室温，反应时间约为6h。TLC监测反应结束后，
旋蒸除去二氯甲烷和三氟乙酸，得到中间体化合物2a，为墨绿色粉末，产率为98％。Dissolve compound Ia (100 mg, 0.091 mmol) in 20 ml of methylene chloride, add trifluoroacetic acid (TFA) with a volume of about 5 ml dropwise under ice bath conditions, the reaction temperature is from 0°C to room temperature, and the reaction time is about 6 hours. After the reaction was monitored by TLC, Dichloromethane and trifluoroacetic acid were removed by rotary evaporation to obtain intermediate compound 2a as a dark green powder with a yield of 98%.
取中间体化合物2b(10mg,0.011mmol)、N-羟基丁二酰亚胺(NHS,25.32mg,0.22mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,25.30mg,0.1322mmol)于反应瓶，加入干燥的二甲亚砜作为溶剂，置换氮气，室温搅拌2h后，将相应长度的NH2-PEG链(M.W.550，15.125mg，0.0275mmol；M.W.2000，55mg，0.0275mmol；M.W.5000，82.5mg，0.0165mmol；M.W.10000，165mg，0.0165mmol)分别加入至反应瓶中，室温条件下反应8h。反应结束用透析袋透析，而后采用C18反向柱纯化。最终产物Ib经MALDI-TOF-MS确认。[Ib结构中的P基团可各自代表H或PEG链(前提是两个P不同时为H)，如以下5种化合物，其中Ib 0.5K2表示结构中包含2条分子量为0.5kDa的PEG链，Ib 2K2表示结构中包含2条分子量为2kDa的PEG链，Ib 2K表示结构中包含1条分子量为2kDa的PEG链，Ib 5K表示结构中包含1条分子量为5kDa的PEG链，Ib 10K表示结构中包含1条分子量为10kDa的PEG链，它们的计算和实测分子量分别如下。]Take intermediate compound 2b (10mg, 0.011mmol), N-hydroxysuccinimide (NHS, 25.32mg, 0.22mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (EDCI, 25.30 mg, 0.1322 mmol) was added to the reaction flask, dry dimethyl sulfoxide was added as the solvent, replaced with nitrogen, and after stirring at room temperature for 2 hours, the corresponding length of NH 2 -PEG chain (MW550, 15.125 mg, 0.0275 mmol; MW2000, 55mg, 0.0275mmol; MW5000, 82.5mg, 0.0165mmol; MW10000, 165mg, 0.0165mmol) were added to the reaction bottle respectively, and reacted at room temperature for 8 hours. At the end of the reaction, the reaction was dialyzed with a dialysis bag, and then purified using a C18 reverse column. The final product Ib was confirmed by MALDI-TOF-MS. [The P groups in the Ib structure can each represent H or PEG chains (provided that the two Ps are not H at the same time), such as the following five compounds, where Ib 0.5K 2 means that the structure contains 2 PEGs with a molecular weight of 0.5kDa chain, Ib 2K 2 means that the structure contains 2 PEG chains with a molecular weight of 2kDa, Ib 2K means that the structure contains 1 PEG chain with a molecular weight of 2kDa, Ib 5K means that the structure contains 1 PEG chain with a molecular weight of 5kDa, Ib 10K Indicates that the structure contains a PEG chain with a molecular weight of 10kDa. Their calculated and measured molecular weights are as follows. ]
MALDI-TOF-MS:MALDI-TOF-MS:
Ib 0.5K2,计算M.W:约1968.实测:约2142Ib 0.5K 2 , calculated MW: about 1968. Measured: about 2142
Ib 2K2,计算M.W:约4868.实测:约4807Ib 2K 2 , calculated MW: about 4868. Measured: about 4807
Ib 2K,计算M.W:约2886.实测:约2912Ib 2K, calculated M.W: about 2886. Measured: about 2912
Ib 5K,计算M.W:约5886.实测:约5898Ib 5K, calculated M.W: about 5886. Measured: about 5898
Ib 10K,计算M.W:约10886.实测:约10983Ib 10K, calculated M.W: about 10886. Measured: about 10983
实施例3：化合物Ic的合成
Example 3: Synthesis of Compound Ic
Example 3: Synthesis of Compound Ic
取化合物1c(500mg,0.753mmol)与催化剂四(三苯基膦)钯(43.51mg,0.038mmol)于反应瓶，置换氮气，在氮气条件下加入甲苯(约10ml)与碳酸钾溶液(124.89mg,0.904mmol，溶于2ml水中，反应体系甲苯：水体积比约为5:1)，置换氮气，将反应置于110℃搅拌下缓慢滴加化合物2a的甲苯溶液(539.07mg,0.753mmol)，110℃加热回流反应12-16h。TLC检测反应完全后，将反应冷却至室温，旋蒸除去大部分甲苯，将剩余反应液用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，无水硫酸镁干燥，过滤，旋干大部分溶剂，加入硅胶拌样过柱，得到化合物2c，220.87mg，粗产率为25％。
Take compound 1c (500mg, 0.753mmol) and the catalyst tetrakis(triphenylphosphine)palladium (43.51mg, 0.038mmol) in the reaction flask, replace the nitrogen, and add toluene (about 10ml) and potassium carbonate solution (124.89mg) under nitrogen conditions , 0.904mmol, dissolved in 2ml of water, the reaction system toluene: water volume ratio is about 5:1), replace nitrogen, place the reaction at 110°C and slowly add the toluene solution of compound 2a (539.07mg, 0.753mmol) under stirring, Heat and reflux at 110°C for 12-16 hours. After TLC detects that the reaction is complete, cool the reaction to room temperature, remove most of the toluene by rotary evaporation, extract the remaining reaction solution with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, and spin to dryness Most of the solvent was added to silica gel and the sample was passed through the column to obtain compound 2c, 220.87 mg, with a crude yield of 25%.
取中间体化合物2c(200mg,0.170mmol)溶于二氯甲烷与甲醇溶液体系(二氯甲烷与甲醇体积比为10:1)，在冰浴条件下加入锌粉(1333.96mg,20.4mmol)与氯化铵(327.36mg,6.12mmol)水溶液。反应条件从0℃至室温，反应时间约为4h。旋干大部分溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，用无水硫酸镁干燥，过滤，旋干除去溶剂，得到化合物3c，直接用于下一步反应。Dissolve intermediate compound 2c (200mg, 0.170mmol) in a dichloromethane and methanol solution system (the volume ratio of dichloromethane to methanol is 10:1), add zinc powder (1333.96mg, 20.4mmol) and Ammonium chloride (327.36mg, 6.12mmol) aqueous solution. The reaction conditions range from 0°C to room temperature, and the reaction time is about 4 hours. Spin most of the solvent dry, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, spin dry to remove the solvent, and obtain compound 3c, which is directly used in the next reaction.
取化合物3c(100mg,0.097mmol)与噻吩偶姻(32.41mg,0.146mmol)溶于醋酸，置换氮气，将反应置于110℃反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物Ic，100.53mg，产率为85％。Dissolve compound 3c (100 mg, 0.097 mmol) and thienoin (32.41 mg, 0.146 mmol) in acetic acid, replace with nitrogen, and place the reaction at 110°C for 12-16 hours. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain compound Ic, 100.53 mg, with a yield of 85%.
实施例4：化合物Id的合成
Example 4: Synthesis of Compound Id
Example 4: Synthesis of Compound Id
取化合物1a(500mg,0.912mmol)与催化剂四(三苯基膦)钯(52.7mg,0.046mmol)于反应瓶，置换氮气，在氮气条件下加入甲苯(约10ml)与碳酸钾溶液(151.26mg,1.09mmol，溶于2ml水中，反应体系甲苯：水体积比约为5:1)，置换氮气，将反应置于110℃搅拌下缓慢滴加化合物1d的甲苯溶液(657.04mg,0.912mmol)，110℃加热回流反应12-16h。TLC检测反应完全后,将反应冷却至室温，旋蒸除去大部分甲苯，将剩余反应液用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，无水硫酸镁干燥，过滤，旋干大部分溶剂，加入硅胶拌样过柱，得到化合物2d，242.20mg，粗产率为25％。Take compound 1a (500 mg, 0.912 mmol) and the catalyst tetrakis (triphenylphosphine) palladium (52.7 mg, 0.046 mmol) in the reaction flask, replace the nitrogen, and add toluene (about 10 ml) and potassium carbonate solution (151.26 mg) under nitrogen conditions , 1.09mmol, dissolved in 2ml of water, the reaction system toluene: water volume ratio is about 5:1), replace nitrogen, place the reaction at 110°C and slowly add the toluene solution of compound 1d (657.04mg, 0.912mmol) under stirring, Heat and reflux at 110°C for 12-16 hours. After TLC detects that the reaction is complete, cool the reaction to room temperature, remove most of the toluene by rotary evaporation, extract the remaining reaction solution with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, and spin to dryness Most of the solvent was added to silica gel and the sample was passed through the column to obtain compound 2d, 242.20 mg, with a crude yield of 25%.
取中间体化合物2d(200mg,0.188mmol)溶于二氯甲烷与甲醇溶液体系(二氯甲烷与甲醇体积比为10:1)，在冰浴条件下加入锌粉(1475.20mg,22.56mmol)与氯化铵(362.02mg,6.768mmol)水溶液。反应条件从0℃至室温，反应时间约为4h。旋干大部分溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，用无水硫酸镁干燥，过滤，旋干除去溶剂，得到化合物3d，直接用于下一步反应。Dissolve intermediate compound 2d (200 mg, 0.188 mmol) in a dichloromethane and methanol solution system (the volume ratio of dichloromethane to methanol is 10:1), add zinc powder (1475.20 mg, 22.56 mmol) and Ammonium chloride (362.02mg, 6.768mmol) aqueous solution. The reaction conditions range from 0°C to room temperature, and the reaction time is about 4 hours. Spin most of the solvent to dryness, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, spin dry to remove the solvent, and obtain compound 3d, which is directly used in the next reaction.
取化合物3d(100mg,0.108mmol)与噻吩偶姻(36.01mg,0.162mmol)溶于醋酸，置换氮气，将反应置于110℃反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸
至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物Id，101.87mg，产率为85％。Dissolve compound 3d (100 mg, 0.108 mmol) and thienoin (36.01 mg, 0.162 mmol) in acetic acid, replace with nitrogen, and place the reaction at 110°C for 12-16 hours. After the reaction is completed, the reaction is cooled to room temperature, and the reaction liquid is evaporated Use a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, add silica gel and mix the sample through the column to obtain compound Id, 101.87 mg, the yield is 85%.
实施例5：化合物Ie的合成
Example 5: Synthesis of Compound Ie
Example 5: Synthesis of Compound Ie
取化合物4a(100mg,0.109mmol)与化合物1e(88.37mg,0.164mmol)溶于醋酸，置换氮气，将反应置于110℃反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物Ie，131.67mg，产率为85％。Dissolve compound 4a (100mg, 0.109mmol) and compound 1e (88.37mg, 0.164mmol) in acetic acid, replace with nitrogen, and place the reaction at 110°C for 12-16h. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain compound Ie, 131.67 mg, with a yield of 85%.
实施例6：化合物If的合成
Example 6: Synthesis of Compound If
Example 6: Synthesis of Compound If
取化合物1a(500mg,0.912mmol)与催化剂四(三苯基膦)钯(52.7mg,0.046mmol)
于反应瓶，置换氮气，在氮气条件下加入甲苯(约10ml)与碳酸钾溶液(151.26mg,1.09mmol，溶于2ml水中，反应体系甲苯：水体积比约为5:1)，置换氮气，将反应置于110℃搅拌下缓慢滴加化合物1f的甲苯溶液(274.65mg,0.912mmol)，110℃加热回流反应12-16h。TLC检测反应完全后,将反应冷却至室温，旋蒸除去大部分甲苯，将剩余反应液用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，无水硫酸镁干燥，过滤，旋干大部分溶剂，加入硅胶拌样过柱，得到化合物2f 146.48mg，粗产率为25％。Take compound 1a (500mg, 0.912mmol) and catalyst tetrakis(triphenylphosphine)palladium (52.7mg, 0.046mmol) In the reaction bottle, replace the nitrogen, add toluene (about 10ml) and potassium carbonate solution (151.26mg, 1.09mmol, dissolved in 2ml of water, the volume ratio of toluene: water in the reaction system is about 5:1) under nitrogen conditions, replace the nitrogen, The reaction was stirred at 110°C and the toluene solution of compound 1f (274.65mg, 0.912mmol) was slowly added dropwise, and the reaction was heated to reflux at 110°C for 12-16h. After TLC detects that the reaction is complete, cool the reaction to room temperature, remove most of the toluene by rotary evaporation, extract the remaining reaction solution with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, and spin to dryness Most of the solvent was added to silica gel and the sample was passed through the column to obtain 146.48 mg of compound 2f with a crude yield of 25%.
取中间体化合物2f(200mg,0.311mmol)溶于二氯甲烷与甲醇溶液体系(二氯甲烷与甲醇体积比为10:1)，在冰浴条件下加入锌粉(2438.86mg,37.32mmol)与氯化铵(598.87mg,11.196mmol)水溶液。反应条件从0℃至室温，反应时间约为4h。旋干大部分溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，用无水硫酸镁干燥，过滤，旋干除去溶剂，得到化合物3f，直接用于下一步反应。Dissolve intermediate compound 2f (200mg, 0.311mmol) in a dichloromethane and methanol solution system (the volume ratio of dichloromethane to methanol is 10:1), add zinc powder (2438.86mg, 37.32mmol) and Ammonium chloride (598.87mg, 11.196mmol) aqueous solution. The reaction conditions range from 0°C to room temperature, and the reaction time is about 4 hours. Spin most of the solvent dry, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, spin dry to remove the solvent, and obtain compound 3f, which is directly used in the next reaction.
取化合物3f(100mg,0.199mmol)与噻吩偶姻(66.46mg,0.299mmol)溶于醋酸，置换氮气，将反应置于110℃反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物If，116.35mg，产率为85％。Dissolve compound 3f (100 mg, 0.199 mmol) and thienoin (66.46 mg, 0.299 mmol) in acetic acid, replace with nitrogen, and place the reaction at 110°C for 12-16 hours. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain compound If, 116.35 mg, with a yield of 85%.
实施例7：化合物Ig的合成
Example 7: Synthesis of Compound Ig
Example 7: Synthesis of Compound Ig
取中间体化合物2b(10mg,0.011mmol)、N-羟基丁二酰亚胺(NHS,25.32mg,0.22mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,25.30mg,0.1322mmol)于反应瓶，加入干燥的二甲亚砜作为溶剂，置换氮气，室温反应6h。反应结束后除去溶剂，加入硅胶拌样过柱，得到化合物Ig，9.03mg，产率为75％。Take intermediate compound 2b (10mg, 0.011mmol), N-hydroxysuccinimide (NHS, 25.32mg, 0.22mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (EDCI, 25.30 mg, 0.1322 mmol) was added to the reaction bottle, dry dimethyl sulfoxide was added as the solvent, nitrogen was replaced, and the reaction was carried out at room temperature for 6 hours. After the reaction, the solvent was removed, silica gel was added, and the sample was passed through the column to obtain compound Ig, 9.03 mg, with a yield of 75%.
实施例8：化合物Ih的合成
Example 8: Synthesis of Compound Ih
Example 8: Synthesis of Compound Ih
取中间体化合物2b(10mg,0.011mmol)和化合物1h(27.533mg,0.22mmol)于反应瓶，加入干燥二甲亚砜作为溶剂，置换氮气，随后加入38μl N,N-二异丙基丙胺(28.43mg,0.22mmol)，反应体系搅拌2min后加入HBTU(62.58mg,0.165mmol)。在室温条件下反应12-16h。反应结束后，加入水搅拌1h淬灭，随后除去溶剂，用半制备高效液相质谱分离纯化得到Ih，产率约为90％。Take intermediate compound 2b (10mg, 0.011mmol) and compound 1h (27.533mg, 0.22mmol) in the reaction bottle, add dry dimethyl sulfoxide as the solvent, replace the nitrogen, and then add 38μl N,N-diisopropylpropylamine ( 28.43 mg, 0.22 mmol), the reaction system was stirred for 2 min and then HBTU (62.58 mg, 0.165 mmol) was added. React at room temperature for 12-16h. After the reaction was completed, water was added and stirred for 1 hour to quench, and then the solvent was removed, and Ih was separated and purified by semi-preparative high performance liquid chromatography mass spectrometry with a yield of about 90%.
实施例9：化合物Ii的合成
Example 9: Synthesis of Compound II
Example 9: Synthesis of Compound II
取化合物1i(500mg,0.637mmol)与催化剂四(三苯基膦)钯(36.98mg,0.032mmol)于反应瓶，置换氮气，在氮气条件下加入甲苯(约10ml)与碳酸钾溶液(151.26mg,1.09mmol，溶于2ml水中，反应体系甲苯：水体积比约为5:1)，置换氮气，将反应置于110℃搅拌下缓慢滴加化合物2a的甲苯溶液(456.02mg,0.637mmol)，110℃加热回流反应12-16h。TLC检测反应完全后,将反应冷却至室温，旋蒸除去大部分甲苯，将剩余反应液用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，无水硫酸镁干燥，过滤，旋干大部分溶剂，加入硅胶拌样过柱，得到化合物2i，205.99mg，粗产率为25％。Take compound 1i (500mg, 0.637mmol) and catalyst tetrakis(triphenylphosphine)palladium (36.98mg, 0.032mmol) in the reaction flask, replace the nitrogen, and add toluene (about 10ml) and potassium carbonate solution (151.26mg) under nitrogen conditions , 1.09mmol, dissolved in 2ml of water, the reaction system toluene: water volume ratio is about 5:1), replace nitrogen, place the reaction at 110°C and slowly add the toluene solution of compound 2a (456.02mg, 0.637mmol) under stirring, Heat and reflux at 110°C for 12-16 hours. After TLC detects that the reaction is complete, cool the reaction to room temperature, remove most of the toluene by rotary evaporation, extract the remaining reaction solution with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, and spin to dryness Most of the solvent was added to silica gel and the sample was passed through the column to obtain compound 2i, 205.99 mg, with a crude yield of 25%.
取中间体化合物2i(200mg,0.155mmol)溶于二氯甲烷与甲醇溶液体系(二氯甲烷与甲醇体积比为10:1)，在冰浴条件下加入锌粉(1216.25mg,18.6mmol)与氯化铵(298.47mg,5.58mmol)水溶液。反应条件从0℃至室温，反应时间约为4h。旋干大部分溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，用无水硫酸镁干燥，过滤，旋干除去溶剂，得到化合物3i，直接用于下一步反应。Dissolve intermediate compound 2i (200 mg, 0.155 mmol) in a dichloromethane and methanol solution system (the volume ratio of dichloromethane to methanol is 10:1), add zinc powder (1216.25 mg, 18.6 mmol) and Ammonium chloride (298.47mg, 5.58mmol) aqueous solution. The reaction conditions range from 0°C to room temperature, and the reaction time is about 4 hours. Spin most of the solvent dry, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, spin dry to remove the solvent, and obtain compound 3i, which is directly used in the next reaction.
取化合物3i(100mg,0.087mmol)与噻吩偶姻(28.90mg,0.13mmol)溶于醋酸，置换氮气，将反应置于110℃反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物Ii，98.12mg，产率为85％。Dissolve compound 3i (100 mg, 0.087 mmol) and thienoin (28.90 mg, 0.13 mmol) in acetic acid, replace with nitrogen, and place the reaction at 110°C for 12-16 hours. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain compound II, 98.12 mg, with a yield of 85%.
实施例10：化合物Ij的合成
Example 10: Synthesis of Compound Ij
Example 10: Synthesis of Compound Ij
取化合物4a(100mg,0.109mmol)与化合物1j(34.48mg,0.164mmol)溶于醋酸，置换氮气，将反应置于110℃反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物Ij，101.22mg，产率为85％。Dissolve compound 4a (100mg, 0.109mmol) and compound 1j (34.48mg, 0.164mmol) in acetic acid, replace with nitrogen, and place the reaction at 110°C for 12-16h. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain compound Ij, 101.22 mg, with a yield of 85%.
实施例11：化合物Ik的合成
Example 11: Synthesis of Compound Ik
Example 11: Synthesis of Compound Ik
取化合物4a(100mg,0.109mmol)与化合物1k(34.80mg,0.164mmol)溶于醋酸，置换氮气，将反应置于110℃反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物Ik，101.41mg，产率为85％。Dissolve compound 4a (100 mg, 0.109 mmol) and compound 1k (34.80 mg, 0.164 mmol) in acetic acid, replace with nitrogen, and place the reaction at 110°C for 12-16 hours. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain compound Ik, 101.41 mg, with a yield of 85%.
实施例12：化合物Il的合成
Example 12: Synthesis of Compound Il
Example 12: Synthesis of Compound Il
取化合物4a(100mg,0.109mmol)与化合物1l(34.80mg,0.164mmol)溶于醋酸，置换氮气，将反应置于110℃反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物Il 99.36mg，产率为85％。Dissolve compound 4a (100mg, 0.109mmol) and compound 1l (34.80mg, 0.164mmol) in acetic acid, replace with nitrogen, and place the reaction at 110°C for 12-16h. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain 99.36 mg of compound I1, with a yield of 85%.
实施例13：化合物Im的合成
Example 13: Synthesis of Compound Im
Example 13: Synthesis of Compound Im
取化合物4a(100mg,0.109mmol)于反应瓶，置换氮气，加入溶剂吡啶后再次置换氮气，随后加入N-亚磺酰苯胺(151.71mg,1.09mmol)再次换氮气，加入三甲基氯硅烷(118.42mg,1.09mmol)，将反应置于80℃下反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物Im，41.26mg，产率为40％。Take compound 4a (100 mg, 0.109 mmol) in the reaction flask, replace the nitrogen, add the solvent pyridine and replace the nitrogen again, then add N-sulfenylanilide (151.71 mg, 1.09 mmol) and replace the nitrogen again, add trimethylsilyl chloride ( 118.42mg, 1.09mmol), and the reaction was placed at 80°C for 12-16h. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain compound Im, 41.26 mg, with a yield of 40%.
实施例14：化合物In的合成
Example 14: Synthesis of Compound In
Example 14: Synthesis of Compound In
取化合物3d(100mg,0.108mmol)于反应瓶，置换氮气，加入溶剂吡啶后再次置换氮气，随后加入N-亚磺酰苯胺(150.31mg,1.08mmol)再次换氮气，加入三甲基氯硅烷(117.33mg,1.08mmol)，将反应置于80℃下反应12-16h。反应结束后，将反应冷却至室温，将反应液旋蒸至少量溶剂，用乙酸乙酯萃取，合并有机相，用水和饱和食盐水洗涤，随后无水硫酸镁干燥，过滤，旋干，加入硅胶拌样过柱，得到化合物In，41.10mg，产率为40％。Take compound 3d (100 mg, 0.108 mmol) in the reaction flask, replace the nitrogen, add the solvent pyridine and replace the nitrogen again, then add N-sulfenylanilide (150.31 mg, 1.08 mmol) and replace the nitrogen again, add trimethylsilyl chloride ( 117.33mg, 1.08mmol), and the reaction was placed at 80°C for 12-16h. After the reaction is completed, cool the reaction to room temperature, evaporate the reaction solution to a small amount of solvent, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine, then dry over anhydrous magnesium sulfate, filter, spin dry, and add silica gel The sample was stirred and passed through the column to obtain compound In, 41.10 mg, with a yield of 40%.
实验例Experimental example
实验例1：化合物Ia和Ib(0.5k2,2k2,2k,5k,10k)的紫外吸收光谱Experimental Example 1: UV absorption spectra of compounds Ia and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k)
将Ia溶解在四氢呋喃中，Ib(0.5k2,2k2,2k,5k,10k)溶解在去离子水中。由UV2600(SHIMADZU)紫外分光光度计、1cm石英比色皿测定，记录波长范围为550-1000nm，化合物Ia和Ib(0.5k2,2k2,2k,5k,10k)的吸收峰值在740nm左右(图1)。Dissolve Ia in tetrahydrofuran and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) in deionized water. Measured by UV2600 (SHIMADZU) UV spectrophotometer and 1cm quartz cuvette, the recording wavelength range is 550-1000nm. The absorption peaks of compounds Ia and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) are around 740nm ( figure 1).
实验例2：化合物Ia和Ib(0.5k2,2k2,2k,5k,10k)的荧光发射光谱Experimental Example 2: Fluorescence emission spectra of compounds Ia and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k)
将Ia溶解在四氢呋喃中，Ib(0.5k2,2k2,2k,5k,10k)溶解在去离子水中。由荧光光谱仪(IHR320,HORIBA SCIENTIFIC)、808nm激光器、1cm石英比色皿测定，记录波长范围为850-1500nm，化合物Ia和Ib(0.5k2,2k2,2k,5k,10k)发射峰落在近红外二区900-1400nm，聚乙二醇化的水溶性探针Ib(0.5k2,2k2,2k,5k,10k)发射有略微的红移现象(图2)。Dissolve Ia in tetrahydrofuran and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) in deionized water. It is measured by a fluorescence spectrometer (IHR320, HORIBA SCIENTIFIC), 808nm laser, and 1cm quartz cuvette. The recording wavelength range is 850-1500nm. The emission peaks of compounds Ia and Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) fall on In the second near-infrared region 900-1400nm, the emission of the PEGylated water-soluble probe Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) has a slight red shift (Figure 2).
实验例3：化合物Ib(0.5k2,2k2,2k,5k,10k)在正常小鼠体内生物分布图Experimental Example 3: Biodistribution map of compound Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) in normal mice
实验所用小鼠由上海实验动物中心批准后购买，动物实验根据中国科学院上海药物研
究所动物保护和使用委员会(IACUC)指导方针进行。实验使用的是6周的正常的Balb/c雌性小鼠。Ib(0.5k2,2k2,2k,5k,10k)溶解在PBS中，经尾静脉注射至小鼠体内。用近红外二区相机研究体内成像，808nm激光器激发，功率为220mW/cm2，滤光片为1400nm长通滤光片。The mice used in the experiment were purchased after approval from the Shanghai Experimental Animal Center. The animal experiments were carried out in accordance with the Shanghai Drug Research Institute of the Chinese Academy of Sciences. Conducted in accordance with Institute Animal Care and Use Committee (IACUC) guidelines. The experiments used 6-week-old normal Balb/c female mice. Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) was dissolved in PBS and injected into mice through the tail vein. A near-infrared second-zone camera was used to study in vivo imaging, excited by an 808nm laser, with a power of 220mW/cm 2 and a 1400nm long-pass filter.
结果如图3所示，荧光强度集中在肝脏、肠道以及血管，表明探针经肝肠代谢，具有长的血液循环时间，可用于血管成像以及血管功能的检测。另外，探针在小鼠的胫骨和脊柱有明显的吸收，可用于小鼠骨成像以及骨疾病的相关成像。The results are shown in Figure 3. The fluorescence intensity is concentrated in the liver, intestines and blood vessels, indicating that the probe is metabolized by the liver and intestines and has a long blood circulation time, and can be used for vascular imaging and detection of vascular function. In addition, the probe has obvious absorption in the tibia and spine of mice and can be used for bone imaging in mice and related imaging of bone diseases.
实验例4：化合物Ib(2k,10k)在肿瘤小鼠中的成像Experimental Example 4: Imaging of compound Ib (2k, 10k) in tumor mice
实验所用小鼠由上海实验动物中心批准后购买，动物实验根据中国科学院上海药物研究所动物保护和使用委员会(IACUC)指导方针进行。取6周的Balb/c雌性小鼠，在其后腿皮下部位接种肿瘤鼠源乳腺癌细胞4T1，成瘤后用游标卡尺测量肿瘤径线长度，根据公式肿瘤体积V＝(长×宽2)/2计算肿瘤体积，待肿瘤长至150mm3后使用，尾静脉注射Ib(2k,10k)用于NIR-II活体成像，使用808nm激光器激发，功率220mW/cm2，1000nm长通滤光片。The mice used in the experiments were purchased with approval from the Shanghai Laboratory Animal Center, and the animal experiments were conducted in accordance with the guidelines of the Animal Care and Use Committee (IACUC) of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Take 6-week-old Balb/c female mice and inoculate mouse-derived breast cancer cells 4T1 into the subcutaneous parts of their hind legs. After tumor formation, use a vernier caliper to measure the diameter of the tumor. According to the formula, tumor volume V = (length × width 2 ) / 2. Calculate the tumor volume and wait until the tumor grows to 150mm. 3. Inject Ib (2k, 10k) into the tail vein for NIR-II in vivo imaging. Use an 808nm laser for excitation, a power of 220mW/cm 2 and a 1000nm long-pass filter.
结果如图4所示，小鼠肿瘤组织呈现出高吸收，随着时间的推移对比度也逐渐增加，可以实现长时间窗口的荧光成像肿瘤切除手术。The results are shown in Figure 4. The mouse tumor tissue showed high absorption, and the contrast gradually increased over time, allowing long-term window fluorescence imaging tumor resection surgery.
实验例5：化合物Ib(10k)在小鼠淋巴系统中的成像Experimental Example 5: Imaging of compound Ib (10k) in mouse lymphatic system
实验所用小鼠由上海实验动物中心批准后购买，动物实验根据中国科学院上海药物研究所动物保护和使用委员会(IACUC)指导方针进行。取6周正常的Balb/c雌性小鼠，将探针Ib(10k)注射于小鼠右肢趾间，轻轻按摩注射部位，使其能更快的扩散。结果如图5a，将小鼠置于近红外二区成像系统，能看到小鼠右侧两个淋巴结。使用高倍成像装置，能清晰得看到四根淋巴管，其中直线截面的荧光强度分布图，包含四根淋巴管的信号，如图5b，成像结果说明该探针的具有量子产率高、生物利用度高的特点，说明能用于淋巴系统相关疾病的成像研究，并具有临床转化的潜力。The mice used in the experiments were purchased with approval from the Shanghai Laboratory Animal Center, and the animal experiments were conducted in accordance with the guidelines of the Animal Care and Use Committee (IACUC) of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Take a 6-week-old normal Balb/c female mouse, inject the probe Ib (10k) between the toes of the mouse's right limb, and gently massage the injection site to allow faster diffusion. The results are shown in Figure 5a. When the mouse is placed in the near-infrared second-zone imaging system, two lymph nodes on the right side of the mouse can be seen. Using a high-magnification imaging device, four lymphatic vessels can be clearly seen. The fluorescence intensity distribution diagram of the straight section contains the signals of the four lymphatic vessels, as shown in Figure 5b. The imaging results show that the probe has high quantum yield and biological The high degree of utilization indicates that it can be used for imaging research on lymphatic system-related diseases and has the potential for clinical translation.
实验例6：探针Ib(0.5k2,2k2,2k,5k,10k)在808nm激光下的升温曲线。Experimental Example 6: Temperature rising curve of probe Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) under 808nm laser.
取探针Ib(0.5k2,2k2,2k,5k,10k)配置成100uM的水溶液，将其置于功率为1W/cm2的808nm激光下照射5min，利用红外相机每30s记录下温度，得到了探针的升温曲线。图6结果显示探针均具有光热效果，可以用于光热治疗。
Take the probe Ib (0.5k 2 , 2k 2 , 2k, 5k, 10k) and configure it into a 100uM aqueous solution. Place it under an 808nm laser with a power of 1W/cm 2 for 5 minutes. Use an infrared camera to record the temperature every 30s. The temperature rise curve of the probe was obtained. The results in Figure 6 show that the probes all have photothermal effects and can be used for photothermal therapy.
Claims (10)
- 不对称的供体-受体型NIR-II探针分子，其由以下通式1表示：
Asymmetric donor-acceptor type NIR-II probe molecule, which is represented by the following general formula 1:
在以上通式1中，In the above general formula 1,环A选自B和B’各自独立地选自 Ring A is selected from B and B' are each independently selected fromX为S、O、Se或NR5；X is S, O, Se or NR 5 ;R1选自 R 1 is selected fromR2选自 R 2 is selected from其中，R6和R7各自独立地选自H、羟基、氨基(-NH2)、羧基(-COOH)、卤素、羧基C1-C7烷基、C1-C8烷基、C1-C8烷氧基、取代或未取代的C6-C12芳基或者5-12元含有选自N、O、S的杂原子的杂芳基(当所述芳基或杂芳基被取代时，取代基选自C1-C8烷基、C1-C8烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基或卤代C1-C8烷基)、-(CH2)n1-(OCH2CH2)n2-R((n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基(-CHO)、 羧基、巯基(-SH)、炔基(-C≡CH)、叠氮基(-N3)、卤素、及)；Among them, R 6 and R 7 are each independently selected from H, hydroxyl, amino (-NH 2 ), carboxyl (-COOH), halogen, carboxyl C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, substituted or unsubstituted C6-C12 aryl or 5-12 membered heteroaryl containing heteroatoms selected from N, O, S (when the aryl or heteroaryl is substituted , the substituent is selected from C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylsilyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, Aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl or halogenated C 1 -C 8 alkyl), -(CH 2 )n 1 -(OCH 2 CH 2 )n 2 -R((n 1 =an integer of 0-10, n 2 =an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino , hydroxyl group, methoxy group, aldehyde group (-CHO), Carboxyl group, mercapto group (-SH), alkynyl group (-C≡CH), azide group (-N 3 ), halogen, and );R8和R9各自独立地选自H、羟基、氨基、羧基、卤素、羧基C1-C7烷基、C1-C8烷基、C1-C8烷氧基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)，或者R8和R9与其相连接的C一起形成5-10元含选自N、O和S的杂原子的杂环基；R 8 and R 9 are each independently selected from H, hydroxyl, amino, carboxyl, halogen, carboxyl C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy , aldehyde group, carboxyl group, mercapto group, alkynyl group, azide group, halogen, and ), or R 8 and R 9 together with the C to which they are connected form a 5-10 membered heterocyclic group containing heteroatoms selected from N, O and S;Y2选自S、O、Se和NR5；Y 2 is selected from S, O, Se and NR 5 ;R5选自H、C1-C12烷基、C1-C12烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、酰基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)；R 5 is selected from H, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 8 alkylsilyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl , aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, acyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl, halo Substituting C 1 -C 8 alkyl, -(CH 2 ) n 1 -(OCH 2 CH 2 )n 2 -R (n 1 =an integer of 0-10, n 2 =an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azido, halogen, and );R3和R4各自独立地选自H、C1-C12烷基、C1-C12烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、酰基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)、-(CH2)n3-COOCH2CH2Si(CH3)3(n3为1-10的整数)、取代或未取代的C6-C12芳基或5-12元含有选自N、O、S的杂原子的杂芳基(当所述芳基或杂芳基被取代时，取代基选自C1-C8烷基、C1-C8烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基或卤代C1-C8烷基)；R 3 and R 4 are each independently selected from H, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 8 alkylsilyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, acyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, mercapto C 1 - C 8 alkyl, halogenated C 1 -C 8 alkyl, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000 , R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azido, halogen, and ), -(CH 2 )n 3 -COOCH 2 CH 2 Si(CH 3 ) 3 (n 3 is an integer from 1 to 10), substituted or unsubstituted C6-C12 aryl group or 5-12 yuan containing selected from N , heteroaryl group of heteroatoms of O and S (when the aryl group or heteroaryl group is substituted, the substituent is selected from C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylsilyl group, hydroxyl C 1 -C 8 alkyl group, amino C 1 -C 8 alkyl group, aldehyde group C 1 -C 8 alkyl group, carboxyl group C 1 -C 8 alkyl group, sulfonic acid group C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl or halogenated C 1 -C 8 alkyl);Y为S、O、Se或NR5；Y is S, O, Se or NR 5 ;Y1为CR5或N；Y 1 is CR 5 or N;R5选自H、C1-C12烷基、C1-C12烷氧基、C1-C8烷基硅基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、酰基C1-C8烷基、磺酸基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10 的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)；R 5 is selected from H, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 8 alkylsilyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl , aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, acyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl, halo Substituting C 1 -C 8 alkyl, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R(n 1 =0-10 an integer, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azido, halogen, and );D选自如下基团：
D is selected from the following groups:
其中，R10至R46各自独立选自H、取代或未取代的C1-C12烷基、取代或未取代的C1-C12烷氧基、取代或未取代的C1-C8烷基硅基、氨基、卤素、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、 及)、-(CH2)n2-COOCH2CH2Si(CH3)3(n2为1-10的整数)、-(CH2)n4-CONHCH2CH2SO3H(n4为0-10的整数)；Wherein, R 10 to R 46 are each independently selected from H, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 1 -C 8 Alkylsilyl group, amino group, halogen, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer from 0 to 10, n 2 = an integer from 1 to 1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azido, halogen, and ), -(CH 2 )n 2 -COOCH 2 CH 2 Si(CH 3 ) 3 (n 2 is an integer from 1 to 10), -(CH 2 )n 4 -CONHCH 2 CH 2 SO 3 H (n 4 is an integer from 0 to 10);其中，所述C1-C12烷基、C1-C12烷氧基和C1-C8烷基硅基的取代基选自羟基、氨基、炔基、叠氮基、巯基、醛基、羧基、磺酸基、卤素、RaOC(＝O)-、RaC(＝O)O-、RaNHC(＝O)-和吡咯烷二酮-NH-，其中Ra选自C1-C8烷基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、磺酸基C1-C8烷基、炔基C1-C8烷基、叠氮基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基和-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮、卤素、及)；Wherein, the substituents of the C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group and C 1 -C 8 alkyl silicon group are selected from the group consisting of hydroxyl, amino, alkynyl, azido, mercapto, and aldehyde groups. , carboxyl, sulfonic acid group, halogen, Ra OC(=O)-, Ra C(=O)O-, Ra NHC(=O)-, and pyrrolidinedione-NH-, where Ra is selected from C 1 -C 8 alkyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, alkynyl C 1 -C 8 alkyl, azido C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl, halo C 1 -C 8 alkyl and -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy , aldehyde group, carboxyl group, sulfhydryl group, alkynyl group, azide, halogen, and );或者，R10至R46各自独立地选自其中R’和R”选自C1-C8亚烷基，C为H、环状RGD肽c(RGDyk)、c(RGDfk)、c(RADyk)、或-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)、(CH2CH2O)n2-R(n2为1-1000的整数，R为C1-C8烷基)、多肽前列腺特异性模抗原多肽分子(PSMA)基团(所述PSMA可包括PSMA-617、PSMA-11、PSMA-1007)、奥曲肽基团、单糖及多糖基团(其中，单糖可选自葡萄糖、半乳糖、果糖、阿拉伯糖、鼠李糖、核糖、乳糖及麦芽糖，多糖可为环糊精)；D选自含有Fv段的分子，例如，D为单抗、双抗、或scFv；Alternatively, R 10 to R 46 are each independently selected from Wherein R' and R" are selected from C 1 -C 8 alkylene, C is H, cyclic RGD peptide c(RGDyk), c(RGDfk), c(RADyk), or -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl , mercapto, alkynyl, azide, halogen, and ), (CH 2 CH 2 O) n2 -R (n2 is an integer from 1 to 1000, R is C 1 -C 8 alkyl), polypeptide prostate-specific model antigen polypeptide molecule (PSMA) group (the PSMA can Including PSMA-617, PSMA-11, PSMA-1007), octreotide group, monosaccharide and polysaccharide groups (wherein, the monosaccharide can be selected from glucose, galactose, fructose, arabinose, rhamnose, ribose, lactose and Maltose, the polysaccharide can be cyclodextrin); D is selected from molecules containing Fv segments, for example, D is a monoclonal antibody, a double antibody, or scFv;或者，R10至R46各自独立地选自 其中R”’为C1-C8亚烷基。Alternatively, R 10 to R 46 are each independently selected from Where R"' is C 1 -C 8 alkylene. - 根据权利要求1所述的探针分子，其中，所述通式1的探针分子选自通式I、II、III和IV：
The probe molecule according to claim 1, wherein the probe molecule of general formula 1 is selected from the group consisting of general formulas I, II, III and IV:
在以上通式I、II、III和IV中，各取代基的定义分别如权利要求1中所定义。In the above general formulas I, II, III and IV, the definitions of each substituent are as defined in claim 1 respectively. - 根据权利要求1所述的探针分子，其中，在通式1中，The probe molecule according to claim 1, wherein in general formula 1,环A为 Ring A is一组B和B’分别选自以及 A set of B and B' are respectively selected from as well asX为S；X is S;R1选自 R 1 is selected fromR2选自 R 2 is selected from其中，R6和R7各自独立地选自H、羟基、氨基(-NH2)、羧基(-NH2)、卤素、羧基C1-C7烷基、C1-C8烷基、C1-C8烷氧基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10 的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基(-CHO)、羧基、巯基(-SH)、炔基(-C≡CH)、叠氮基(-N3)、卤素、及)；Among them, R 6 and R 7 are each independently selected from H, hydroxyl, amino (-NH 2 ), carboxyl (-NH 2 ), halogen, carboxyl C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R(n 1 =0-10 an integer, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl group, amino group, hydroxyl group, methoxy group, aldehyde group (-CHO), carboxyl group, mercapto group (-SH), alkynyl group (- C≡CH), azido (-N 3 ), halogen, and );R8和R9各自独立地选自H、羟基、氨基、羧基、卤素、羧基C1-C7烷基、C1-C8烷基、C1-C8烷氧基、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数，n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)，或者R8和R9与其相邻的C形成5-10元含O的杂环基；R 8 and R 9 are each independently selected from H, hydroxyl, amino, carboxyl, halogen, carboxyl C 1 -C 7 alkyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy , aldehyde group, carboxyl group, mercapto group, alkynyl group, azide group, halogen, and ), or R 8 and R 9 and their adjacent C form a 5-10 membered O-containing heterocyclic group;R3和R4各自独立地为H或-(CH2)n3-COOCH2CH2Si(CH3)3，其中n3为1-10的整数；D选自如下基团：
R 3 and R 4 are each independently H or -(CH 2 )n 3 -COOCH 2 CH 2 Si(CH 3 ) 3 , where n 3 is an integer from 1 to 10; D is selected from the following groups:
其中，R10、R11、R14、R15、R45和R46各自独立地选自H、取代或未取代的C1-C12烷基、取代或未取代的C1-C12烷氧基、取代或未取代的C1-C8烷基硅基、氨基、卤素、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数，n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)、-(CH2)n2-COOCH2CH2Si(CH3)3(n2为1-10的整数)、-(CH2)n4-CONHCH2CH2SO3H(n4为0-10的整数)；Wherein, R 10 , R 11 , R 14 , R 15 , R 45 and R 46 are each independently selected from H, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 1 -C 12 alkyl Oxygen group, substituted or unsubstituted C 1 -C 8 alkylsilyl group, amino group, halogen, -(CH 2 ) n 1 -(OCH 2 CH 2 )n 2 -R(n 1 =an integer from 0 to 10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azide, halogen, and ), -(CH 2 )n 2 -COOCH 2 CH 2 Si(CH 3 ) 3 (n 2 is an integer from 1 to 10), -(CH 2 )n 4 -CONHCH 2 CH 2 SO 3 H (n 4 is an integer from 0 to 10);其中，所述C1-C12烷基、C1-C12烷氧基和C1-C8烷基硅基的取代基选自羟基、氨基、炔基、叠氮基、巯基、醛基、羧基、磺酸基、卤素、RaOC(＝O)-、RaC(＝O)O-、RaNHC(＝O)-和吡咯烷二酮-NH-，其中Ra选自C1-C8烷基、羟基C1-C8烷基、氨基C1-C8烷基、醛基C1-C8烷基、羧基C1-C8烷基、磺酸基C1-C8烷基、炔基C1-C8烷基、叠氮基C1-C8烷基、巯基C1-C8烷基、卤代C1-C8烷基和-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧 基、巯基、炔基、叠氮基、卤素、)；Wherein, the substituents of the C 1 -C 12 alkyl group, C 1 -C 12 alkoxy group and C 1 -C 8 alkyl silicon group are selected from the group consisting of hydroxyl, amino, alkynyl, azido, mercapto, and aldehyde groups. , carboxyl, sulfonic acid group, halogen, Ra OC(=O)-, Ra C(=O)O-, Ra NHC(=O)-, and pyrrolidinedione-NH-, where Ra is selected from C 1 -C 8 alkyl, hydroxyl C 1 -C 8 alkyl, amino C 1 -C 8 alkyl, aldehyde C 1 -C 8 alkyl, carboxyl C 1 -C 8 alkyl, sulfonate C 1 -C 8 alkyl, alkynyl C 1 -C 8 alkyl, azido C 1 -C 8 alkyl, mercapto C 1 -C 8 alkyl, halo C 1 -C 8 alkyl and -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy , aldehyde group, carboxyl group group, mercapto group, alkynyl group, azide group, halogen, );或者，R10、R11、R14、R15、R45和R46各自独立地选自其中R’和R”选自C1-C8亚烷基，C为H、-(CH2)n1-(OCH2CH2)n2-R(n1＝0-10的整数,n2＝1-1000的整数，R选自C1-C8烷基、氨基、羟基、甲氧基、醛基、羧基、巯基、炔基、叠氮基、卤素、及)，D选自含有Fv段的分子，例如，D为单抗、双抗、或scFv。Alternatively, R 10 , R 11 , R 14 , R 15 , R 45 and R 46 are each independently selected from Wherein R' and R" are selected from C 1 -C 8 alkylene, C is H, -(CH 2 ) n1 -(OCH 2 CH 2 )n 2 -R (n 1 = an integer of 0-10, n 2 = an integer of 1-1000, R is selected from C 1 -C 8 alkyl, amino, hydroxyl, methoxy, aldehyde, carboxyl, mercapto, alkynyl, azide, halogen, and ), D is selected from molecules containing Fv segments, for example, D is a monoclonal antibody, bisclonal antibody, or scFv. - 根据权利要求1所述的探针分子，其中，所述探针分子选自以下各化合物：
The probe molecule according to claim 1, wherein the probe molecule is selected from the following compounds:
- 一种制备如权利要求1所述的探针分子的方法，如以下反应路线所示，所述方法包括：
A method for preparing the probe molecule as claimed in claim 1, as shown in the following reaction scheme, the method includes:
在以上反应式中，各取代基的定义分别如上文所定义；R’为硼酸或硼酸酯，锡盐；In the above reaction formula, the definitions of each substituent are as defined above; R’ is boric acid or borate ester, tin salt;步骤1：化合物1与化合物2经Suzuki反应得到化合物3；Step 1: Compound 1 and compound 2 undergo Suzuki reaction to obtain compound 3;步骤2：化合物3经还原反应得到化合物4；以及Step 2: Compound 3 is reduced to obtain compound 4; and步骤3：化合物4与N-亚磺酰苯胺(PNSO)进行成环反应得到通式I的化合物；或者Step 3: Compound 4 is reacted with N-sulfenylanilide (PNSO) to obtain a compound of general formula I; or步骤3’：化合物4与化合物(5-2)、(5-3)或(5-4)进行生成Schiff碱的反应，分别得到通式II、III或IV的化合物。Step 3': Compound 4 is reacted with compound (5-2), (5-3) or (5-4) to form Schiff base to obtain compounds of general formula II, III or IV respectively. - 如权利要求1-4中任一项所述的探针分子在制备显影剂中的用途。Use of the probe molecule according to any one of claims 1 to 4 in the preparation of a developer.
- 根据权利要求6所述的用途，其中，所述显影剂用于全身血管成像、骨成像或淋巴成像、肿瘤成像、或手术导航。The use according to claim 6, wherein the contrast agent is used for whole body vascular imaging, bone imaging or lymphatic imaging, tumor imaging, or surgical navigation.
- 如权利要求1-4中任一项所述的探针分子在制备光热治疗剂中的用途，特别地，所述光热治疗剂用于肿瘤的治疗。The use of the probe molecule according to any one of claims 1 to 4 in the preparation of a photothermal therapeutic agent, in particular, the photothermal therapeutic agent is used for the treatment of tumors.
- 如权利要求1-4中任一项所述的探针分子在制备肿瘤诊断试剂中的用途。The use of the probe molecule according to any one of claims 1 to 4 in the preparation of tumor diagnostic reagents.
- 一种显影剂，其包含如权利要求1-4中任一项所述的探针分子。 A developer comprising the probe molecule according to any one of claims 1-4.
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