Near-infrared fluorescent probe for active targeting of fibroblast growth factor receptor and preparation method and application thereof

Abstract

The present invention provides a near-infrared fluorescent probe for active targeting of fibroblast growth factor receptors and a preparation method and application thereof, and relates to the technical field of specific molecular targeted diagnostic reagents. The near-infrared fluorescent probe for active targeting of fibroblast growth factor receptors of the present invention can be quickly cleared in normal tissues and stays in the tumor site for a long time, thereby achieving the effect of in vivo diagnosis, having certain clinical application prospects, and being applied to clinical intraoperative navigation.

Description

Technical Field

[0001] The present invention relates to the technical field of specific molecular targeted diagnostic reagents, and in particular to a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptors, and a preparation method and application thereof. Background Art

[0002] Currently, surgery, radiotherapy, and chemotherapy are the most common treatments for malignant tumors. Compared with chemotherapy and radiotherapy, surgery can effectively remove tumor tissue. However, due to the lack of effective tumor tissue visualization technology and subtle morphological differences, it is challenging to distinguish between malignant lesions and healthy tissue. In addition, during the resection of cancerous tumors, more than 70% of patients will have residual positive margins, which will lead to tumor recurrence, with a recurrence rate as high as 20-42%. Therefore, during surgery, there is an urgent need for more powerful strategies to help surgeons identify and locate tiny malignant lesions.

[0003] With the development of molecular imaging, various diagnostic equipment, such as ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI) and single photon / positron emission tomography (PET-CT) have become increasingly mature. Although these technologies can provide preoperative diagnosis for clinical surgery, they still cannot achieve accurate tumor tissue localization. Moreover, these devices have disadvantages such as being bulky and highly radioactive, which greatly limits their application in surgery.

[0004] Near-infrared fluorescence imaging, with a wavelength between 650 and 900 nm, has the advantages of high spatial resolution, low background interference, strong tissue penetration, little damage, and low cost. During surgery, it can provide real-time guidance to surgeons, locate tiny malignant lesions, and achieve precise resection.

[0005] Indocyanine green (ICG) is the world's first generation fluorescent contrast agent approved by the FDA. It mainly works through passive targeting (EPR effect) and is a broad-spectrum tumor-targeted fluorescent probe. It is widely used in fluorescence-guided surgical resection of liver cancer, sentinel lymph nodes, cervical cancer, etc., and has important clinical value. However, its low luminescence efficiency, dose limitation, rapid blood circulation clearance, liver and intestine metabolism, high false positive rate, and limited tumor targeting ability have seriously restricted its application in gastrointestinal tumors. Therefore, small molecule fluorescent probes that are specifically targeted by kidney metabolism have been developed. Specific targeted fluorescent probes can actively target tumor tissues, greatly reduce false positive rates, and help surgeons effectively remove tumor-positive lesions while retaining as much normal tissue as possible to achieve precise tumor resection surgery.

[0006] Fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) are a typical class of receptor tyrosine kinases, which are closely related to the occurrence and development of many diseases such as lung cancer, liver cancer, intrahepatic bile duct cancer, breast cancer, gastric cancer, uterine cancer and bladder cancer. In 5-10% of human cancers, fibroblast growth factor receptors (FGFR) are abnormally activated through single nucleotide variation, gene fusion and copy number amplification. In urothelial carcinoma and intrahepatic bile duct cancer, this probability increases to 10-30%. Specific targeted near-infrared fluorescent probes designed for fibroblast growth factor receptors can be used in fluorescence-guided surgery to accurately remove tumor tissues. They have important clinical application value and are used in clinical tumor surgery for fluorescence-guided tumor surgical resection.

[0007] In summary, with the development of medical imaging technology, the application prospects of near-infrared fluorescence imaging technology in tumor surgery are broad. The development of specific tumor-targeted fluorescent probes will further improve the success rate of tumor surgery, reduce the postoperative recurrence rate, and prolong the survival of patients.

[0008] In view of this, the present invention is proposed. Summary of the invention

[0009] The purpose of the present invention is to provide a near-infrared fluorescent probe for active targeting of fibroblast growth factor receptors and its preparation method and application. The near-infrared fluorescent probe of the present invention can be quickly cleared in normal tissues and stays in the tumor site for a long time, thereby achieving the function of in vivo diagnosis, having certain clinical application prospects, and can be applied to clinical intraoperative navigation. And the compound represented by formula I of the present invention can maintain or enhance the fluorescence of the dye.

[0010] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

[0011] In a first aspect, the present invention provides a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptors, wherein the near-infrared fluorescent probe comprises a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0012]

[0013] Formula I;

[0014] Among them, the L group is a connecting group, the L group is selected from a polyethylene glycol chain and / or a polyglycine chain, and m is 0 or 1; the Y group is a dye molecule group having a fluorescence excitation and emission spectrum in the near-infrared range.

[0015] Preferably, the Y group has a structure as shown in Formula II:

[0016]

[0017] Formula II;

[0018] Among them, R 1 Group and R 2 The groups are each independently selected from , n is 3 or 4;

[0019] Wherein the Z group is selected from or ; and the S atom or O atom in the Z group is connected to the cyclohexene ring in one side of the Y group, and the carbonyl side in the Z group is connected to the L group or directly connected to the N atom of the compound shown in formula I.

[0020] Preferably, the L group has a structure as shown in formula L1 or L2:

[0021] ;

[0022] Wherein, p and q are each independently selected from integers between 1 and 4; and one side of the carbonyl group of the L group is connected to the N atom of the compound shown in Formula I, and one side of the amino group is connected to the Y group.

[0023] In a second aspect, the present invention provides a method for preparing a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptors, the preparation method comprising method one and method two:

[0024] Method 1: When m is 1, the method for preparing the near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor comprises the following steps:

[0025] (1) In the presence of a condensing agent and a base, N1 -(3,5-dimethoxyphenyl)- N2 -Isopropyl- N1 -[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethylenediamine and a compound having an L group and an amino protecting group undergo a condensation reaction to obtain an intermediate A;

[0026] (2) intermediate A undergoes a deprotection reaction to obtain intermediate B;

[0027] (3) In the presence of a condensing agent and a base, the intermediate B and the compound having a Y group undergo a condensation reaction to obtain a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor as shown in Formula I;

[0028] Method 2: When m is 0, the method for preparing the near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor comprises the following steps:

[0029] In the presence of a condensing agent and a base,N1 -(3,5-dimethoxyphenyl)- N2 -Isopropyl- N1 -[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethylenediamine and a compound having a Y group undergo a condensation reaction to obtain a near-infrared fluorescent probe for actively targeting a fibroblast growth factor receptor as shown in formula I.

[0030] Preferably, in step (1) of method 1, the compound having an L group has a structure as shown in formula L10 or L20:

[0031]

[0032] Wherein, X represents a protecting group of an amino group, and p and q are each independently selected from an integer between 1 and 4.

[0033] Preferably, in step (1) of method 1, the condensing agent is HATU.

[0034] Preferably, in step (1) of method 1, the base is selected from triethylamine and / or diisopropylethylamine.

[0035] Preferably, in step (1) of method one, the condensation reaction is carried out in the presence of a polar solvent, and the polar solvent is selected from any one of dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone, or a combination of at least two thereof.

[0036] Preferably, in step (1) of method 1, the molar ratio of N1-(3,5-dimethoxyphenyl)-N2-isopropyl-N1-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethylenediamine: compound having an L group and an amino protecting group: condensing agent: base: polar solvent is 1:(1~1.2):(1~4):(1~6):(5~20).

[0037] Preferably, in step (1) of method 1, the temperature of the condensation reaction is 20-30° C., and the time of the condensation reaction is 0.5-2 h.

[0038] Preferably, in step (1) of method 1, the condensation reaction further includes the following post-treatment steps:

[0039] The reaction solution obtained after the condensation reaction is dropped into water to obtain a suspension; the suspension is then extracted with an organic solvent, dried and concentrated to obtain an intermediate A.

[0040] Preferably, in step (2) of method 1, the deprotection reaction is carried out in the presence of an acid.

[0041] Preferably, in step (2) of method 1, the acid is trifluoroacetic acid.

[0042] Preferably, in step (2) of method 1, the molar ratio of the intermediate A to the acid is 1:(1-10).

[0043] Preferably, in step (2) of method 1, the temperature of the deprotection reaction is 20-30° C., and the time of the deprotection reaction is 20-40 min.

[0044] Preferably, in step (3) of method 1, the condensing agent is HATU.

[0045] Preferably, in step (3) of method 1, the base is selected from triethylamine and / or N,N- Diisopropylethylamine.

[0046] Preferably, in step (3) of method 1, the condensation reaction is carried out in the presence of a polar solvent, and the polar solvent is selected from any one of dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone, or a combination of at least two thereof.

[0047] Preferably, in step (3) of method 1, the molar ratio of the intermediate B, the compound having a Y group, the condensing agent, the base and the polar solvent is 1:(1-1.2):(1-4):(1-6):(5-20).

[0048] Preferably, in step (3) of method 1, the temperature of the condensation reaction is 20-30° C., and the time of the condensation reaction is 0.5-2 h.

[0049] Preferably, in method 2, the condensing agent is HATU.

[0050] Preferably, in method 2, the base is selected from triethylamine and / or N,N- Diisopropylethylamine.

[0051] Preferably, in method 2, the condensation reaction is carried out in the presence of a polar solvent, and the polar solvent is selected from dimethylformamide, dimethyl sulfoxide or N -Methylpyrrolidone, any one or a combination of at least two thereof.

[0052] Preferably, in method 2, the N1 -(3,5-dimethoxyphenyl)- N2 -Isopropyl- N1 The molar ratio of -[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethylenediamine, the compound having a Y group, the condensing agent, the base and the polar solvent is 1:(1~1.2):(1~4):(1~6):(5~20).

[0053] Preferably, in method 2, the temperature of the condensation reaction is 20-30° C., and the time of the condensation reaction is 0.5-2 h.

[0054] In a third aspect, the present invention provides a use of a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor as described in the first aspect in the preparation of a fluorescent contrast agent.

[0055] Preferably, the fluorescent contrast agent includes a fluorescent contrast agent for tumor diagnosis.

[0056] Preferably, the tumor comprises any one of lung cancer, pancreatic cancer, colorectal cancer or ovarian cancer.

[0057] Compared with the prior art, the present invention has the following beneficial effects:

[0058] (1) The near-infrared fluorescent probe for actively targeting fibroblast growth factor provided by the present invention can be prepared by a simple chemical synthesis method.

[0059] (2) The targeting probe described in the present invention has the advantages of active tumor targeting capability, good water solubility, long tumor retention time, and no accumulation in normal tissues. It has potential application in the field of fluorescence-guided tumor surgical resection during clinical surgery. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0061] Figure 1 This is the absorption spectra of the near-infrared fluorescent probes NY-FGF-031~NY-FGF-037 prepared in Examples 1~5.

[0062] Figure 2 The fluorescence spectra of the near-infrared fluorescent probes NY-FGF-031~NY-FGF-037 prepared in Examples 1~5.

[0063] Figure 3 These are in vivo imaging images of the near-infrared fluorescent probes NY-FGF-031 to NY-FGF-037 prepared in Examples 1 to 5 in mice bearing lung cancer HCC827.

[0064] Figure 4These are in vivo imaging images of the near-infrared fluorescent probes NY-FGF-031, NY-FGF-035 and NY-FGF-037 prepared in Examples 1, 3 and 5 in mice bearing colorectal cancer HCT116.

[0065] Figure 5 These are in vivo imaging images of the near-infrared fluorescent probes NY-FGF-033, NY-FGF-035, NY-FGF-036 and NY-FGF-037 prepared in Examples 2 to 5 in mice bearing ovarian cancer SKOV-3.

[0066] Figure 6 These are in vivo imaging images of the near-infrared fluorescent probes NY-FGF-031 to NY-FGF-037 prepared in Examples 1 to 5 in mice bearing pancreatic cancer PANC-1. DETAILED DESCRIPTION

[0067] Unless otherwise defined herein, scientific and technological terms used in conjunction with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the case of any potential ambiguity, the definitions provided herein take precedence over any dictionary or external definitions. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms is non-limiting.

[0068] It should be noted that specific details are described in the following description to facilitate a full understanding of the present invention. However, the present invention can be implemented in a variety of other ways different from those described herein, and those skilled in the art can make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0069] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0070] In a first aspect, the present invention provides a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptors, wherein the near-infrared fluorescent probe comprises a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0071]

[0072] Formula I;

[0073] Among them, the L group is a connecting group, and the L group is selected from a polyethylene glycol chain and / or a polyglycine chain; m is 0 or 1; and the Y group is a dye molecule group having a fluorescence excitation and emission spectrum in the near-infrared range.

[0074] It should be noted that when m is 0, it means that there is no connecting group L, and the Y group is directly connected to the N atom. The structural formula of the compound shown in Formula I is as follows:

[0075] .

[0076] It should be noted that when m is 1, it represents the presence of a linking group L, and the Erdafitinib small molecule group and the dye molecule group are connected via the linking group L. The structural formula of the compound shown in Formula I is as follows:

[0077] .

[0078] Among them, Erdafitinib small molecule compound is used as a targeting ligand to design and synthesize a specific tumor-targeted fluorescent probe, which has important clinical application value. The near-infrared fluorescent probe of the present invention can be quickly cleared in normal tissues and stay in the tumor site for a long time, thereby achieving the role of in vivo diagnosis, having certain clinical application prospects, and being used in clinical intraoperative navigation.

[0079] It should be noted that "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt of a compound represented by Formula I, which is relatively non-toxic and harmless to the patient, and the side effects caused by the salt do not impair the beneficial effects of the compound. Pharmaceutically acceptable metal salts can be prepared using a base. Alkali metal salts or alkaline earth metal salts are obtained by dissolving the compound in an excess of an alkali metal basic compound or an alkaline earth metal basic compound solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, the preparation of sodium salts, potassium salts or calcium salts as metal salts is suitable for pharmaceutical use, but the present invention is not limited thereto.

[0080] As an optional embodiment, the Y group has a structure as shown in Formula II:

[0081]

[0082] Formula II;

[0083] Among them, R 1 Group and R 2 The groups are each independently selected from , n is 3 or 4;

[0084] Wherein the Z group is selected from or ; and the S atom or O atom in the Z group is connected to the cyclohexene ring in one side of the Y group, and the carbonyl side in the Z group is connected to the L group or directly connected to the N atom of the compound shown in formula I.

[0085] As an optional embodiment, the Y group has a structure as shown in Formula II-1 or Formula II-2:

[0086]

[0087] Formula II-1;

[0088]

[0089] Formula II-2.

[0090] As an optional embodiment, the L group has a structure as shown in formula L1 or L2:

[0091] ;

[0092] Wherein, p and q are each independently selected from integers between 1 and 4, for example, 1, 2, 3, 4; and one side of the carbonyl group of the L group is connected to the N atom of the compound shown in Formula I, and one side of the amino group is connected to the Y group.

[0093] In a second aspect, the present invention provides a method for preparing a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor as described in the first aspect, wherein the preparation method comprises any one of the following methods 1 and 2.

[0094] As an optional implementation, method 1 refers to the case where m=1, which is specifically as follows:

[0095] When m is 1, the method for preparing the near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor comprises the following steps:

[0096] (1) In the presence of a condensing agent and a base, N1 -(3,5-dimethoxyphenyl)- N2 -Isopropyl- N1 -[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethylenediamine and a compound having an L group and an amino protecting group undergo a condensation reaction to obtain an intermediate A;

[0097] (2) intermediate A undergoes a deprotection reaction to obtain intermediate B;

[0098] (3) In the presence of a condensing agent and a base, the intermediate B and the compound having a Y group undergo a condensation reaction to obtain a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor as shown in formula I.

[0099] As an optional embodiment, in step (1) of method 1, the compound having an L group has a structure as shown in formula L10 or L20:

[0100]

[0101] Wherein, X represents a protecting group of an amino group, and p and q are each independently selected from an integer between 1 and 4.

[0102] As an optional implementation, the route flow of step (1) of method 1 is as follows:

[0103] .

[0104] As an optional embodiment, in step (1) of method 1, the condensing agent is HATU.

[0105] As an optional embodiment, in step (1) of method 1, the base is selected from triethylamine and / or diisopropylethylamine.

[0106] As an optional embodiment, in step (1) of method 1, the condensation reaction is carried out in the presence of a polar solvent, and the polar solvent is selected from dimethylformamide, dimethyl sulfoxide or N -Methylpyrrolidone, any one or a combination of at least two thereof.

[0107] As an optional implementation, in step (1) of method 1, the N1 -(3,5-dimethoxyphenyl)- N2 -Isopropyl- N1 The molar ratio of -[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethylenediamine: the compound having an L group and an amino protecting group: the condensing agent: the base: the polar solvent is 1:(1-1.2):(1-4):(1-6):(5-20);

[0108] Here, “1~1.2” can be, for example, 1, 1.05, 1.1, 1.15, 1.2, etc.;

[0109] Among them, "1~4" can be, for example, 1, 1.5, 2, 2.5, 3, 3.5, 4, etc.;

[0110] Among them, "1~6" can be, for example, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, etc.;

[0111] Among them, "5~20" can be, for example, 5, 7, 10, 12, 14, 15, 16, 18, 20, etc.

[0112] As an optional embodiment, the temperature of the condensation reaction in step (1) of method one is 20-30°C, for example, 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, 30°C, etc., and the time of the condensation reaction is 0.5-2 h, for example, 0.5 h, 0.6 h, 0.8 h, 1 h, 1.2 h, 1.4 h, 1.6 h, 1.8 h, 2 h, etc.

[0113] As an optional embodiment, in step (1) of method 1, the condensation reaction further includes the following post-treatment steps:

[0114] The reaction solution obtained after the condensation reaction is dropped into water to obtain a suspension; the suspension is then extracted with an organic solvent, dried and concentrated to obtain an intermediate A.

[0115] As an optional embodiment, in step (2) of method 1, the deprotection reaction is carried out in the presence of an acid.

[0116] As an optional implementation, the route flow of step (2) of method 1 is as follows:

[0117] .

[0118] As an optional embodiment, in step (2) of method 1, the acid is trifluoroacetic acid.

[0119] As an optional embodiment, in step (2) of method one, the molar ratio of the intermediate A to the acid is 1:(1-10), for example, it can be 1:1, 1:2, 1:4, 1:6, 1:8, 1:10, etc.

[0120] As an optional embodiment, in step (2) of method one, the temperature of the deprotection reaction is 20-30°C, for example, 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, 30°C, etc., and the time of the deprotection reaction is 20-40 min, for example, 20 min, 22 min, 24 min, 26 min, 28 min, 30 min, 32 min, 34 min, 36 min, 38 min, 40 min, etc.

[0121] As an optional embodiment, in step (3) of method 1, the condensing agent is HATU.

[0122] As an optional embodiment, in step (3) of method 1, the base is selected from triethylamine and / or N,N- Diisopropylethylamine.

[0123] As an optional embodiment, in step (3) of method 1, the condensation reaction is carried out in the presence of a polar solvent, and the polar solvent is selected from dimethylformamide, dimethyl sulfoxide or N -Methylpyrrolidone, any one or a combination of at least two thereof.

[0124] As an optional embodiment, in step (3) of method 1, the molar ratio of the intermediate B, the compound having a Y group, the condensing agent, the base and the polar solvent is 1:(1-1.2):(1-4):(1-6):(5-20);

[0125] Here, “1~1.2” can be, for example, 1, 1.05, 1.1, 1.15, 1.2, etc.;

[0126] Among them, "1~4" can be, for example, 1, 1.5, 2, 2.5, 3, 3.5, 4, etc.;

[0127] Among them, "1~6" can be, for example, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, etc.;

[0128] Among them, "5~20" can be, for example, 5, 7, 10, 12, 14, 15, 16, 18, 20, etc.

[0129] As an optional embodiment, in step (3) of method one, the temperature of the condensation reaction is 20-30°C, for example, 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, 30°C, etc., and the time of the condensation reaction is 0.5-2 h, for example, 0.5 h, 0.6 h, 0.8 h, 1 h, 1.2 h, 1.4 h, 1.6 h, 1.8 h, 2 h, etc.

[0130] As an optional implementation, method 1 refers to the case where m=0, which is specifically as follows:

[0131] Method 2: When m is 0, the method for preparing the near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor comprises the following steps:

[0132] In the presence of a condensing agent and a base, N1 -(3,5-dimethoxyphenyl)- N2 -Isopropyl- N1 -[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethylenediamine and a compound having a Y group undergo a condensation reaction to obtain a near-infrared fluorescent probe for actively targeting a fibroblast growth factor receptor as shown in formula I.

[0133] As an optional implementation, the route flow of step (3) of method 1 is as follows:

[0134] .

[0135] As an optional embodiment, in method 2, the condensation agent is HATU.

[0136] As an optional embodiment, in method 2, the base is selected from triethylamine and / or N,N- Diisopropylethylamine.

[0137] As an optional embodiment, in method 2, the condensation reaction is carried out in the presence of a polar solvent, and the polar solvent is selected from dimethylformamide, dimethyl sulfoxide or N -Methylpyrrolidone, any one or a combination of at least two thereof.

[0138] As an optional implementation, in method 2, the N1 -(3,5-dimethoxyphenyl)- N2 -Isopropyl- N1 The molar ratio of -[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-1,2-ethylenediamine, the compound having a Y group, the condensing agent, the base and the polar solvent is 1:(1-1.2):(1-4):(1-6):(5-20);

[0139] Here, “1~1.2” can be, for example, 1, 1.05, 1.1, 1.15, 1.2, etc.;

[0140] Among them, "1~4" can be, for example, 1, 1.5, 2, 2.5, 3, 3.5, 4, etc.;

[0141] Among them, "1~6" can be, for example, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, etc.;

[0142] Among them, "5~20" can be, for example, 5, 7, 10, 12, 14, 15, 16, 18, 20, etc.

[0143] As an optional embodiment, in method 2, the temperature of the condensation reaction is 20-30°C, for example, it can be 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, 30°C, etc., and the time of the condensation reaction is 0.5-2 h, for example, it can be 0.5h, 0.6 h, 0.8 h, 1 h, 1.2 h, 1.4 h, 1.6 h, 1.8 h, 2 h, etc.

[0144] In a third aspect, the present invention provides a use of a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor as described in the first aspect in the preparation of a fluorescent contrast agent.

[0145] As an optional embodiment, the fluorescent contrast agent includes a fluorescent contrast agent for tumor diagnosis.

[0146] As an optional embodiment, the tumor includes any one of lung cancer, pancreatic cancer, colorectal cancer or ovarian cancer.

[0147] The present invention is further described below by way of examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or directly purchased from the market.

[0148] The materials and sources used in the following examples are shown in Table 1 below:

[0149] Table 1

[0150]

[0151] Example 1

[0152] This embodiment provides a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptors. The near-infrared fluorescent probe (hereinafter referred to as compound NY-FGF-031) has a structure as shown below:

[0153]

[0154] The synthetic route of the compound NY-FGF-031 is as follows:

[0155]

[0156] The preparation method of the compound NY-FGF-031 is as follows:

[0157] Erdafitinib (10 mg, 1.0 eq), S0456-Der-01 (22.71 mg, 1.0 eq), 2-(7-azatriazene)- N,N,N''N' -Tetramethyluronium hexafluorophosphate (HATU, 25.54 mg, 3.0 eq), N,N -Diisopropylethylamine (19.50 μL, 5.0 eq), react at room temperature in the dark for 1 h, monitor the reaction by HPLC, and after the reaction is complete, purify by preparative liquid phase, and freeze-dry the target fraction to obtain green solid NY-FGF-031.

[0158] The structure was confirmed by mass spectrometry, H-NMR and C-NMR spectra:

[0159] <h2 style=";text-align:left;direction:ltr">[M-2H] / 2-= 720.9;<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0160] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (600 MHz, DMSO) δ 9.06 (s, 1H), 8.66 (s, 1H), 8.31 (d, J = 7.0 Hz, 1H), 7.83 (dd, J = 19.5, 11.6 Hz, 3H), 7.63 (d, J = 0.8 Hz, 3H), 7.60-7.58 (m, 2H), 7.31 (d, J = 7.6 Hz, 4H), 7.27 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.50 (d, J = 2.2 Hz, 2H), 6.41 (dd, J = 6.7, 4.6 Hz, 2H), 6.21(d, J = 14.2 Hz, 3H), 4.11 (s, 5H), 3.95 (s, 5H), 2.71 (s, 5H), 2.58 (dd, J =16.7, 9.8 Hz, 8H), 1.74 (s, 12H), 1.27 (s, 12H), 1.20 (s, 3H), 1.04 (d, J =6.8 Hz, 2H), 0.99 (d, J = 6.5 Hz, 7H);<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0161] <h2 style=";text-align:left;direction:ltr"> 13C NMR (151 MHz, DMSO) δ 213.83, 171.96, 163.56, 162.03, 161.95,158.96, 158.94, 158.90, 158.69, 158.57, 148.07, 145.52, 142.49, 141.31,141.30, 140.72, 140.32, 140.11, 138.82, 136.28, 135.96, 132.05, 130.86,126.61, 122.54, 120.04, 116.50, 114.97, 110.82, 103.64, 101.07, 101.05,99.77, 97.72, 88.42, 69.88, 55.85, 55.60, 51.09, 48.92, 48.12, 44.04, 44.03,40.49, 40.38, 40.24, 40.10, 39.96, 39.82, 39.68, 39.54, 35.37, 35.27, 35.03,34.94, 30.46, 27.60, 27.51, 26.30, 24.25, 22.80, 21.23, 20.57, 18.53, 17.18,9.45, 9.18, 2.62.

[0162] Example 2

[0163] This embodiment provides a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptors. The near-infrared fluorescent probe (hereinafter referred to as compound NY-FGF-033) has a structure as shown below:

[0164]

[0165] The synthetic route of the compound NY-FGF-033 is as follows:

[0166]

[0167] The preparation method of the compound NY-FGF-033 is as follows:

[0168] (1) Erdafitinib (10 mg, 1.0 eq), Boc-PEG4-COOH (8.18 mg, 1.0 eq), HATU (25.54 mg, 3.0 eq), N,N-Diisopropylethylamine (19.50ul, 5.0eq) was reacted at room temperature for 1 h and monitored by TLC. After the reaction was complete, the reaction solution was dropped into water and extracted with ethyl acetate. The organic layers were combined and concentrated, and 0.1 mL of trifluoroacetic acid was added to react at room temperature for 30 min to remove Boc. The reaction was also monitored by TLC. After the reaction was complete, the reaction solution was evaporated to dryness and purified to obtain the intermediate 1.

[0169] (2) The synthetic method of reference compound NY-FGF-031 is different from that of Example 1 in that erdafitinib is replaced by the intermediate 1, and S0456-Der-01 is replaced by the S0456-Der-02. After preparative liquid phase purification and lyophilization, the target compound NY-FGF-033 is obtained as a green solid.

[0170] The structure of the green solid was confirmed by mass spectrometry, H-NMR spectrum, and C-NMR spectrum:

[0171] [M-2H] / 2- = 801.3.

[0172] 1H NMR (600 MHz, DMSO) δ 9.07 (s, 1H), 8.68 (dd, J = 20.9, 10.5 Hz,3H), 8.30 (d, J = 6.3 Hz, 1H), 8.01 (t, J = 5.6 (J = 5.6), Jdd , 8. 18 Hz, 1H), 7.77 (s, 2H), 7.64 (d, J = 9.0 Hz, 2H), 7.54 (dd, J = 9.3, 2.6Hz, 1H), 7.49-7.30 (m, 2H-), 7.24 (d, J. 4 = 2.5 4.6). 5H), 4.34(s, 5H), 4.18-4.09 (m, 1H), 4.07-3.84 (m, 6H), 3.75 (d, J = 5.7 Hz, 7H), 3.67(t, J = 6.7 Hz, 2H-3), 4.72 (2H, 4.52). 3.47–3.43 (m, 7H), 3.41–3.31 (m, 5H),3.16 (d, J = 5.7 Hz, 2H), 2.98 (t, J = 7.1 Hz, 2H), 2.65 (dd, J = 2.9, J = 8.3Hz, Hz, 2H), 2.02 (d, J = 7.1 Hz, 4H), 1.86–1.75 (m,2H), 1.69 (s, 12H), 1.06 (t, J = 5.5 Hz, 7H)。

[0173] 13C NMR (151 MHz, DMSO) δ 172.42, 171.07, 170.09, 162.02, 159.22, 158.97, 158.71, 158.46, 155.79, 150.23, 147.90, 145.42, 142.77, 140.85,139.97, 138.91, 136.22, 134.34, 132.24, 129.96, 126.63, 122.13, 120.23,118.68, 118.35, 116.43, 114.53, 112.62, 110.72, 9.93, 39.79, 39.65, 39.51, 39.07, 38.07, 35.91, 33.67, 33.24, 27.85, 26.32, 28.70, 29.98, 30.77, 31.10, 33.70, 33.24, 27.85, 26.32, 28.70, 29.98, 30.77, 33.24, 28.70, 29.98, 33.70, 33.24, 28.70, 29.98 23.68,21.27, 21.08, 20.60.

[0174] Example 3

[0175] This embodiment provides a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptors. The near-infrared fluorescent probe (hereinafter referred to as compound NY-FGF-035) has a structure as shown below:

[0176]

[0177] The synthetic route of the compound NY-FGF-035 is as follows:

[0178]

[0179] The preparation method of the compound NY-FGF-035 is as follows:

[0180] The synthesis method refers to Example 2, the difference from Example 2 is that S0456-Der-02 is replaced by the above-mentioned S0456-Der-01.

[0181] The structure was confirmed by mass spectrometry, H-NMR and C-NMR:

[0182] [M-2H] / 2-= 845.5。

[0183] 1 H NMR (600 MHz, DMSO) δ 9.02 (s, 1H), 8.60 (d, J = 3.6 Hz, 1H),8.27-8.22 (m, 1H), 7.91-7.75 (m, 6H), 7.67-7.56 (m, 6H), 7.48 (dd, J = 9.2,2.6 Hz, 1H), 7.31 (dd, J = 22.1, 5.5 Hz, 4H), 7.22 (d, J = 8.6 Hz, 3H), 7.04(d, J = 8.5 Hz, 2H), 6.54-6.36 (m, 4H), 6.21 (d, J = 14.2 Hz, 2H), 4.19-4.06(m, 7H), 3.94 (s, 7H), 3.12 (dd, J = 11.5, 5.8 Hz, 3H), 2.71 (d, J = 5.6 Hz,8H), 2.66 (d, J = 6.7 Hz, 3H), 2.30-2.22 (m, 3H), 2.03-1.86 (m, 4H), 1.74 (s,12H), 1.35-1.21 (m, 18H), 1.06 (dd, J = 16.3, 6.7 Hz, 9H)。

[0184] 13C NMR (151 MHz, DMSO) δ 210.68, 197.20, 196.56, 184.91, 171.97,171.93, 171.73, 171.03, 168.89, 161.94, 161.12, 158.91, 146.82, 145.60,142.48, 141.30, 140.71, 138.97, 138.54, 136.19, 131.64, 130.53, 130.28,126.62, 122.51, 120.06, 116.59, 114.89, 114.85, 103.53, 101.04, 97.48, 71.61,70.23, 70.21, 70.20, 70.14, 69.96, 69.50, 69.36, 67.39, 55.82, 51.11, 48.94,40.50, 40.38, 40.24, 40.10, 39.97, 39.83, 39.69, 39.55, 37.71, 37.11, 33.69,30.72, 27.59, 26.33, 24.23, 24.22, 22.85, 21.30, 14.44, 13.73, 13.57.

[0185] Example 4

[0186] This embodiment provides a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptors. The near-infrared fluorescent probe (hereinafter referred to as compound NY-FGF-036) has a structure as shown below:

[0187]

[0188] The synthetic route of the compound NY-FGF-036 is as follows:

[0189]

[0190] The preparation method of the compound NY-FGF-036 is as follows:

[0191] The synthesis method refers to NY-FGF-033, which is different from Example 2 in that (tert-butyloxycarbonyl)glycylglycylglycine is used instead of 5,8,11,14-tetraoxa-2-azaheptadecanedioic acid-1-tert-butyl ester.

[0192] The structure was confirmed by mass spectrometry, H-NMR and C-NMR:

[0193] [M-2H] / 2-= 763.3。

[0194] 1 H NMR (600 MHz, DMSO) δ 9.03 (s, 1H), 8.70 (d, J = 14.0 Hz, 2H),8.63 (s, 1H), 8.31-8.25 (m, 2H), 8.22 (dd, J = 7.5, 4.4 Hz, 1H), 8.00 (dd, J= 18.5, 13.3 Hz, 1H), 7.91-7.81 (m, 2H), 7.77 (d, J = 1.0 Hz, 3H), 7.64 (d, J= 8.2 Hz, 3H), 7.48 (dd, J = 9.3, 2.5 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.27(d, J = 2.5 Hz, 1H), 6.57-6.46 (m, 5H), 6.42 (t, J = 2.1 Hz, 1H), 4.33 (d, J= 6.2 Hz, 6H), 4.10-3.99 (m, 4H), 3.94 (s, 5H), 3.01 (t, J = 7.0 Hz, 3H),2.63 (dd, J = 25.8, 19.4 Hz, 11H), 2.07-1.99 (m, 5H), 1.87-1.75 (m, 3H), 1.69(s, 16H), 1.07 (dd, J = 11.6, 6.9 Hz, 7H)。

[0195] 13C NMR (151 MHz, DMSO) δ 172.44, 170.62, 169.72, 169.40, 168.80,161.99, 155.60, 149.81, 148.00, 145.54, 145.35, 142.73, 140.85, 140.13,138.71, 136.12, 134.35, 131.91, 129.84, 126.60, 120.24, 119.45, 110.72,103.76, 102.44, 97.78, 97.77, 88.69, 83.72, 33.01, 27.85,26.33, 23.74, 21.14, 20.40, 11.16, 4.55.

[0196] Example 5

[0197] This embodiment provides a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptors. The near-infrared fluorescent probe (hereinafter referred to as compound NY-FGF-037) has a structure as shown below:

[0198]

[0199] The synthetic route of the compound NY-FGF-037 is as follows:

[0200]

[0201] The preparation method of the compound NY-FGF-037 is as follows:

[0202] The synthesis method refers to NY-FGF-036, and the difference from Example 4 is that S0456-Der-01 replaces S0456-Der-02.

[0203] The structure was confirmed by mass spectrometry, H-NMR and C-NMR:

[0204] [M-2H] / 2- = 807.3.

[0205] 1H NMR (600 MHz, DMSO) δ 9.04 (s, 1H), 8.61 (d, J = 13.7 Hz, 1H),8.26 (d, J = 16.5 Hz, 1H), 8.15 (ddd, J = 18.3, 12.2, 5.5 Hz, 3H), 8.01 (t, J= 5.2 Hz, 1H), 7.84 (dd, J = 23.7, 19.4 Hz, 4H), 7.68 – 7.55 (m, 5H), 7.52 –7.43 (m, 1H), 7.32 (d, J = 8.3 Hz, 3H), 7.28 (d, J = 2.5 Hz, 1H), 7.23 (d, J= 8.5 Hz, 3H), 7.06 (dd, J = 16.8, 5.1 Hz, 3H), 6.50 (t, J = 7.1 Hz, 3H),6.43 (dd, J = 8.0, 5.9 Hz, 1H), 6.21 (d, J = 14.2 Hz, 2H), 3.75 (s, 6H), 2.80– 2.68 (m, 8H), 2.60 – 2.54 (m, 5H), 2.41 – 2.31 (m, 3H), 1.93 (s, 3H), 1.74(s, 11H), 1.26 (s, 16H), 1.14 – 1.04 (m, 8H)。

[0206] 13C NMR (151 MHz, DMSO) δ 213.83, 171.96, 163.56, 162.03, 161.95,158.96, 158.94, 158.90, 158.69, 158.57, 148.07, 145.52, 142.49, 141.31,141.30, 140.72, 140.32, 140.11, 138.82, 136.28, 135.96, 132.05, 130.86,126.61, 122.54, 120.04, 116.50, 114.97, 110.82, 103.64, 101.07, 101.05,99.77, 97.72, 88.42, 69.88, 55.85, 55.60, 51.09, 48.92, 48.12, 44.04, 44.03,40.49, 40.38, 40.24, 40.10, 39.96, 39.82, 39.68, 39.54, 35.37, 35.27, 35.03,34.94, 30.46, 27.60, 27.51, 26.30, 24.25, 22.80, 21.23, 20.57, 18.53, 17.18,9.45, 9.18, 2.62.

[0207] Test Example 1

[0208] UV and fluorescence testing

[0209] Test samples: the five compounds NY-FGF-31, NY-FGF-33, NY-FGF-35, NY-FGF-36 and NY-FGF-37 provided in Examples 1 to 5.

[0210] Test method:

[0211] (1) NY-FGF-31, NY-FGF-33, NY-FGF-35, NY-FGF-36 and NY-FGF-37 were prepared into an aqueous solution of about 10 nmol, and the absorption spectrum of each probe in the range of 500-1000 nm was measured using an ELISA reader (Thermo Fisher, Varioskan LUX);

[0212] (2) The fluorescence emission spectrum of each probe in the range of 800–900 nm was measured using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B).

[0213] Test results:

[0214] like Figure 1 As shown, the maximum absorption of compounds NY-EGF-31, NY-EGF-35 and NY-FGF-37 is about 770 nm, and that of compounds NY-EGF-33 and NY-EGF-36 is about 790 nm.

[0215] like Figure 2 As shown, the maximum emission spectra of compounds NY-EGF-31, NY-EGF-35 and NY-FGF-37 are about 820 nm, and those of compounds NY-EGF-33 and NY-EGF-36 are about 840 nm.

[0216] Test Example 2

[0217] In vivo imaging test of subcutaneous tumor-bearing mouse model (human lung cancer cells)

[0218] Test samples: the five compounds NY-FGF-31, NY-FGF-33, NY-FGF-35, NY-FGF-36 and NY-FGF-37 provided in Examples 1 to 5.

[0219] Test method: In the subcutaneous tumor HCC827 mouse model, NY-FGF series probes (10 nmol / mouse, 100 μL of glucose injection) were administered through the tail vein. After administration, fluorescence imaging was performed using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10 B) at 0 h (before administration), 6 h, 12 h, 24 h, 48 h, and 72 h, respectively.

[0220] Test results:

[0221] like Figure 3 As shown, (1) in mice bearing subcutaneous tumors of HCC827, NY-FGF-033 / NY-FGF-035 / NY-FGF-036 / NY-FGF-037 had stronger tumor fluorescence signals, while NY-FGF-031 had a weaker fluorescence signal at the tumor site; (2) NY-FGF-035 and NY-FGF-037 had a certain liver uptake; (3) NY-FGF-033 and NY-FGF-036 had better in vivo metabolic characteristics, with basically no liver accumulation. After 24 hours of administration, they showed obvious tumor fluorescence signals, and the NY-FGF-036 tumor fluorescence signal was stronger and lasted longer; (4) NY-FGF-033 and other series of probes have potential lung cancer tumor imaging capabilities and can be further studied and developed in order to be applied to clinical fluorescence-guided tumor surgical resection.

[0222] Test Example 3

[0223] In vivo imaging of subcutaneous tumor-bearing mouse model (human colorectal cancer cells)

[0224] Test samples: three compounds provided in Examples 1, 3 and 5, namely NY-FGF-31, NY-FGF-35 and NY-FGF-37.

[0225] Test method: In the subcutaneous tumor HCT116 mouse model, NY-FGF-031, NY-FGF-035, and NY-FGF-037 probes (10 nmol / mouse, 100 μL of glucose injection) were administered through the tail vein, and fluorescence imaging was performed using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) after administration, at 0 h (before administration), 6 h, 2 h, 24 h, 48 h, 72 h, 120 h, and 144 h, respectively.

[0226] Test results:

[0227] like Figure 4 As shown: (1) In subcutaneous HCT116 tumor-bearing mice, NY-FGF-031 / NY-FGF-035 / NY-FGF-037 had obvious tumor fluorescence signals, and the tumor imaging time exceeded 144 hours; (2) After administration, NY-FGF-031 / NY-FGF-035 / NY-FGF-037 was mainly excreted from the body through the kidneys, had better in vivo metabolic characteristics, and basically did not accumulate in the liver; (3) NY-FGF-031 and other series of probes have potential colorectal cancer tumor imaging capabilities and can be further studied and developed in order to be applied to clinical fluorescence-guided tumor surgical resection.

[0228] Test Example 4

[0229] In vivo imaging of subcutaneous tumor-bearing mouse model (human ovarian cancer cells)

[0230] Test samples: the four compounds NY-FGF-31, NY-FGF-33, NY-FGF-35, NY-FGF-36 and NY-FGF-37 provided in Examples 2 to 5.

[0231] Test method: In the subcutaneous tumor SKOV-3 mouse model, NY-FGF-033, NY-FGF-035, NY-FGF-036, and NY-FGF-037 probes (10 nmol / mouse, 100 μL of glucose injection) were administered through the tail vein, and fluorescence imaging was performed using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) after administration, at 0 h (before administration), 6 h, 12 h, 24 h, 48 h, and 72 h, respectively.

[0232] Test results:

[0233] like Figure 5As shown: (1) In subcutaneous SKOV-3 tumor-bearing mice, NY-FGF-033, NY-FGF-035, NY-FGF-036, and NY-FGF-037 had obvious tumor fluorescence signals, and the tumor imaging time exceeded 72 hours; (2) After administration, NY-FGF-035 and NY-FGF-037 had a certain liver uptake, and the fluorescence retention time in the liver was longer, while the probes NY-FGF-033 and NY-FGF-036 had better in vivo metabolic characteristics and basically no liver accumulation; (3) NY-FGF-033 and other series of probes have potential ovarian cancer tumor imaging capabilities and can be further researched and developed in order to be applied to clinical fluorescence-guided tumor surgical resection.

[0234] Test Example 5

[0235] In vivo imaging of subcutaneous tumor-bearing mouse model (human pancreatic cancer cells)

[0236] Test samples: the five compounds NY-FGF-31, NY-FGF-33, NY-FGF-35, NY-FGF-36 and NY-FGF-37 provided in Examples 1 to 5.

[0237] Test method: In the subcutaneous tumor PANC-1 mouse model, NY-FGF-031, NY-FGF-033, NY-FGF-035, NY-FGF-036, and NY-FGF-037 probes (10 nmol / mouse, 100 μL of glucose injection) were administered through the tail vein, and fluorescence imaging was performed using a surgical fluorescence imaging system (Nanjing Nuoyuan Medical Instrument Co., Ltd., 10B) after administration, at 0 h (before administration), 6 h, 12 h, 24 h, 48 h, and 72 h, respectively.

[0238] Test results:

[0239] like Figure 6 As shown: (1) In mice bearing subcutaneous PANC-1 tumors, NY-FGF-031, NY-FGF-033, NY-FGF-035, NY-FGF-036, and NY-FGF-037 had obvious tumor fluorescence signals, and the tumor imaging time exceeded 72 hours; (2) After administration, NY-FGF-031, NY-FGF-035, and NY-FGF-037 had a certain liver uptake, and the fluorescence retention time in the liver was longer, while the probes NY-FGF-033 and NY-FGF-036 had better in vivo metabolic characteristics and basically no liver accumulation; (3) NY-FGF-033 and other series of probes have potential pancreatic cancer tumor imaging capabilities and can be further studied and developed in order to be applied to clinical fluorescence-guided tumor surgical resection.

[0240] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor, characterized in that: The near-infrared fluorescent probe is selected from the following compounds: 。 2. A method for preparing a near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor according to claim 1, characterized in that: The preparation method is selected from the following synthetic routes: The synthetic route of NY-FGF-031 is: ； The synthetic route of NY-FGF-033 is: ； The synthetic route of NY-FGF-035 is: ； The synthetic route of NY-FGF-036 is: ； The synthetic route of NY-FGF-037 is: 。 3. Use of the near-infrared fluorescent probe for actively targeting fibroblast growth factor receptor according to claim 1 in the preparation of a fluorescent contrast agent.

4. The use according to claim 3, characterized in that: The fluorescent contrast agent is a fluorescent contrast agent for tumor diagnosis.

5. The use according to claim 4, characterized in that: The tumor is any one of lung cancer, pancreatic cancer, colorectal cancer or ovarian cancer.

Images