Application of Boron Dipyrromethene Derivatives in Antitumor and Antibacterial Therapy

Abstract

Bioactive compounds and methods for their preparation are provided that can be used for diagnostic and therapeutic purposes, particularly as photosensitizers for PDT of cancer, infectious diseases, and other hyperproliferative diseases, as well as for fluorescent diagnosis and PDT treatment of non-tumor conditions such as arthritis, inflammatory diseases, viral or bacterial infections, and dermatological, otolaryngological, ophthalmological, or urological disorders. Because the compounds also exhibit toxicity to targets (tumor cells, bacteria, and inflammation-related cells) in the absence of light, these bioactive compounds can also be used for light-independent treatment of such conditions. Also included are methods for synthesizing boron dipyrromethene complex structures incorporating substituted 2,3,5,6-tetrafluorophenyl-dipyrromethene (2,3,5,6-tetrafluorophenyl-dipyrrin) units or substituted 3-nitrophenyl-dipyrromethene (3-nitrophenyl-dipyrrin) units. Amphiphilic compounds with enhanced antitumor and antibacterial effects are also provided. In particular, this is achieved by substitution with bromine atoms and sugar groups.

Description

Technical Field

[0001] (Cross - reference to related applications claiming priority) This application claims priority based on U.S. Patent Application No. 62 / 930,933, entitled "Application of Boron Dipyrromethene Derivatives to Antitumor and Antibacterial Therapy," filed on November 5, 2019, the entire content of which is hereby expressly incorporated by reference as part of this disclosure.

[0002] (Technical Field) This disclosure relates to the chemistry of bioactive compounds. More specifically, it relates to certain boron dipyrromethene complexes that can be used in the treatment of tumor diseases, as well as bacterial infections and other diseases. The action of these boron dipyrromethene complexes against tumor cells and bacteria can be enhanced by light, and thus they can also be used as photosensitizers for a wide range of light irradiation therapies such as photodynamic therapy (PDT) of cancer, infections, and other diseases.

Background Art

[0003] Cancer is one of the leading causes of death worldwide. Although many treatment approaches are known, there is still a need for new active substances and treatment methods that can be applied to tumors that cannot be effectively treated by conventional chemotherapeutic drugs. One of these new treatment approaches is photodynamic therapy (PDT).

[0004] PDT is currently being investigated for various medical applications (Non-Patent Document 1) and is well-known as a treatment method for destroying tumors (Non-Patent Document 2). Photodynamic therapy uses light and photosensitizers (dyes) to obtain the desired medical effect. Many naturally occurring dyes, as well as synthetic dyes, have been evaluated as potential photosensitizers for PDT. Perhaps the most widely studied class of photosensitizers is the tetrapyrrole macrocyclic compounds. Among them, especially porphyrins and chlorins, their PDT efficacy has been tested. However, there is always interest in the structures of new photosensitizers such as not only metal complexes but also other dyes like boron dipyrromethene (BODIPY). Since these BODIPYs were originally invented and used as fluorescent dyes and labels, their potential for PDT is limited in itself, and chemical modification is essential for their adoption as photosensitizers.

[0005] The photodynamic effect is confirmed only when the three necessary elements of photosensitizer, light, and oxygen (present in cells) coexist simultaneously (Non-Patent Document 1). As a result, PDT itself becomes a local treatment as opposed to the systemic action of chemotherapeutic drugs. This local treatment by PDT mainly limits its efficacy to local tumors, but recent reports have also suggested a systemic immunomodulatory effect of PDT (Non-Patent Document 3).

[0006] Another application area of PDT is antibacterial PDT, which applies photosensitizers and light to local bacterial infections. Bacteria are generally classified into two main groups, namely Gram-positive bacteria and Gram-negative bacteria, based on different characteristics and outer membrane structures. Different dyes are used for antibacterial PDT than for tumor treatment. Although amphiphilic photosensitizers have been proven to be the most effective in anti-tumor PDT, more hydrophilic and water-soluble dyes are generally used in antibacterial PDT (Non-Patent Document 4). In particular, for Gram-negative bacteria, water-soluble and positively charged photosensitizers are used (Non-Patent Document 4).

Prior Art Documents

Non-Patent Documents

[0007] [Non-Patent Document 1] B. W. Henderson, T. J. Dougherty, Photodynamic therapy, basic principles and clinical applications, New York: Marcel Dekker, 1992. [Non-Patent Document 2] J. G. Moser, Photodynamic tumor therapy. 2nd and 3rd generation photosensitizers, Amsterdam: Harwood Academic Publishers, 1998. [Non-Patent Document 3] J. W. Kleinovink, P. B. van Driel, T. J. Snoeks, N. Prokopi, M. F. Fransen, L. J. Cruz, L. Mezzanotte, A. Chan, C. W. Lowik, F. Ossendorp, <<Combination of Photodynamic Therapy and Specific Immunotherapy Efficiently Eradicates Established Tumors>>, Clin. Cancer Res., no 22, pp. 1459-1468, 2016. [Non-Patent Document 4] T. Maisch, <<Strategies to optimize photosensitizers for photodynamic inactivation of bacteria>> J. Photochem. Photobiol. B, 150, pp. 2-10, 2015. [Non-Patent Document 5] A. Treibs, F. H. Kreuzer, <<Difluorboryl-Komplexe von Di- und Tripyrrylmethenen>>, Justus Liebigs Ann. Chem., 718, pp. 208-223, 1968.

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

[28] Hexaphyrin Systems, Org. Lett., 21, pp. 5417-5420, 2019. [Non-Patent Document 13] C. S. Gutsche, M. Ortwerth, S. Grafe, K. J. Flanagan, M. O. Senge, H.-U. Reissig, N. Kulak, A. Wiehe, <<Nucleophilic Aromatic Substitution on Penta-fluoro-phenyl-Substituted Dipyrranes and Tetrapyrroles as a Route to Multifunctionalized Chromophores for Potential Application in Photodynamic Therapy>>, Chem. Eur. J. 22, pp. 13953-13964, 2016. [Non-Patent Document 14] B. F. Hohlfeld, K. J. Flanagan, N. Kulak, M. O. Senge, M. Christmann, A. Wiehe, <<Synthesis of Porphyrinoids, BODIPYs, and (Dipyrrinato)-ruthenium(II) Complexes from Prefunctionalized Dipyrromethanes>>, Eur. J. Org. Chem., pp. 4020-4033, 2019. [Non-Patent Document 15] C. S. Gutsche, B. F. Hohlfeld, K. J. Flanagan, M. O. Senge, N. Kulak, A. Wiehe, <<Sequential Nucleophilic Substitution of the α-Pyrrole and p-ArylPositions of meso-Pentafluorophenyl-Substituted BODIPYs>>, Eur. J. Org. Chem., pp. 3187-3196, 2017.

Summary of the Invention

Means for Solving the Problems

[0008] Embodiments include bioactive compounds that can be used as photosensitizers for a wide range of applications, including photodynamic therapy (PDT) for cancer, infectious diseases, and other disorders. One of the limitations of current PDT is that the treatment effect is local because light needs to be delivered to the treatment site. This could be overcome by compounds that act as photosensitizers but also exhibit light-dependent toxicity, for example, against tumor cells or bacteria. Thus, the structures described herein act as photosensitizers but can also be used for systemic treatment due to, for example, their light-dependent toxicity against tumor cells or bacteria. Furthermore, due to their light absorption and light emission properties, these compounds can also be used for diagnostic purposes, for example, by detecting their fluorescence.

[0009] Embodiments include chemically stable boron dipyrromethene complexes that are useful for various medical applications such as photodynamic therapy. However, these compounds can also be used for the treatment of tumors and other disorders without the need to project light, thereby enabling systemic treatment.

[0010] Embodiments include a boron dipyrromethene complex structure that can be used in the photodynamic therapy of tumors and other hyperproliferative diseases, dermatological disorders, viral or bacterial infections, otolaryngological disorders, ophthalmological disorders, or urological disorders, which is combined with a substituted 2,3,5,6-tetrafluorophenyl-dipyrromethene (2,3,5,6-tetrafluorophenyl-dipyrrin) unit or a substituted 3-nitrophenyl-dipyrromethene (3-nitrophenyl-dipyrrin) unit. Also, these compounds can be used in the treatment of tumors and other hyperproliferative diseases, dermatological disorders, viral or bacterial infections, otolaryngological disorders, ophthalmological disorders, or urological disorders without the need to project light. Furthermore, these compounds can also be used in light-based diagnosis of tumors, hyperproliferative diseases, dermatological disorders, bacterial infections, otolaryngological disorders, ophthalmological disorders, or urological disorders. Also, these compounds can be used for fluorescence diagnosis and PDT treatment of non-tumor symptoms such as arthritis and similar inflammatory diseases.

[0011] Embodiments include amphiphilic compounds that can be used in the PDT treatment of tumors, dermatological disorders, viral or bacterial infections, otolaryngological disorders, ophthalmological disorders, or urological disorders, and can also be used in the treatment of tumors, dermatological disorders, viral or bacterial infections, otolaryngological disorders, ophthalmological disorders, or urological disorders without the need to project light.

[0012] Embodiments include pharmaceutically acceptable formulations for the bioactive compounds described herein, such as liposomal formulations, for injecting to avoid undesirable effects such as precipitation at the injection site or pharmacokinetic delay of the compound.

[0013] Briefly, the embodiments include bioactive compounds that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infectious diseases, and other hyperproliferative diseases, as well as for fluorescence diagnosis and PDT treatment of non-tumor symptoms such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, otolaryngological, ophthalmological, or urological disorders, and methods for obtaining the bioactive compounds. Since the compounds also exhibit toxicity to targets (tumor cells, bacteria, inflammation-related cells) without light, these bioactive compounds can also be used for light-independent treatment of such symptoms. The embodiments also include methods for synthesizing boron dipyrromethene structures conjugated with a substituted 2,3,5,6-tetrafluorophenyl-dipyrromethene (2,3,5,6-tetrafluorophenyl-dipyrin) unit or a substituted 3-nitrophenyl-dipyrromethene (3-nitrophenyl-dipyrin) unit. These dipyrromethenes (dipyrins) can have various substituents at the 4-position, allowing for fine-tuning of their biological properties or amphiphilic / hydrophilic properties. The embodiments also include compounds with enhanced antitumor and antibacterial effects. In particular, this is achieved by substitution with bromine atoms and sugar groups.

[0014] The above and other subjects, features, and advantages of the present invention will become apparent from the following description read in conjunction with the accompanying drawings.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0016] Embodiments include bioactive compounds that can be used as photosensitizers for a wide range of light irradiation therapies such as PDT for cancer, hyperproliferative diseases, dermatological disorders, viral or bacterial infections, otolaryngological disorders, ophthalmic disorders, and / or urological disorders. Due to their light-independent toxicity, they can also be used for the treatment of such diseases that do not require light administration. The compounds disclosed herein have the advantage that they can be easily manufactured and characterized and can be further functionalized to enhance activity, stability, or enable new applications. Embodiments also include methods of adapting the compounds for a desired use and increasing the selectivity of the target tissue and thereby the therapeutic effect. The compounds described herein increase the effectiveness of the bioactive compounds compared to prior art compounds by combining with PDT and traditional chemotherapeutic agents or antibacterial treatments and by increasing the selectivity of the target tissue over healthy surrounding tissue due to the molecular structure adapted according to specific uses and the customized pharmacodynamic behavior.

[0017] Embodiments include bioactive compounds that are boron dipyrromethene complex structures conjugated with substituted 2,3,5,6-tetrafluorophenyl-dipyrromethene (2,3,5,6-tetrafluorophenyl-dipyrin) units, or substituted 3-nitrophenyl-dipyrromethene (3-nitrophenyl-dipyrin) units, which can be used for various medical conditions and treatments, among which can be used in PDT. Furthermore, these compounds can be used for the fluorescence diagnosis and treatment of non-tumor conditions such as arthritis and similar inflammatory diseases, expanding their uses.

[0018] To obtain novel compounds, embodiments use substituted dipyrromethanes (dipyrans), which are converted to the corresponding boron dipyrromethenes (dipyrins). The conversion is effected by treating the corresponding dipyrromethane (dipyran) with a suitable oxidizing agent followed by treatment with a base and boron trifluoride etherate (Non-Patent Document 5). In certain embodiments, 2,3,4,5,6-pentafluorophenyl-dipyrromethane or 4-fluoro-3-nitrophenyl-dipyrromethane is treated with a suitable nucleophile to afford 4-substituted 2,3,5,6-tetrafluorophenyl-dipyrromethane or 4-substituted-3-nitrophenyl-dipyrromethane, which are then converted to boron dipyrromethenes.

[0019] Alternatively, 2,3,4,5,6-pentafluorophenyl-dipyrromethane or 4-fluoro-3-nitrophenyl-dipyrromethane is first converted to boron dipyrromethenes. This complex is modified by nucleophilic aromatic substitution at the 4-position of the phenyl ring with a suitable nucleophile, specifically a nucleophile having an oxygen, nitrogen, or sulfur with a glycosyl group.

[0020] In a particularly preferred embodiment of the present invention, the nucleophile is a sugar thiol compound, such as galactosylthiol or glucosylthiol.

[0021] In another step, the boron dipyrromethenes are modified with 1 or 2 bromine atoms at the 2- and 6-positions, respectively. Such substitution can advantageously affect the photophysical properties of the compound, such as increasing the quantum yield of singlet oxygen. The compounds modified in this way exhibit higher antitumor and antibacterial effects (see the following examples).

[0022] In a particularly preferred embodiment of the present invention, the boron dipyrromethenes are substituted with only one bromine atom. Such compounds exhibit high antibacterial activity.

[0023] A preferred starting material for the synthesis of the boron dipyrromethene complexes described herein can be dipyrromethane (dipyran), which can be readily obtained from the condensation reaction of pyrrole and aldehyde (Non-Patent Document 6). Suitable methods for this condensation have been long known in the art (Non-Patent Document 6). Dipyrromethane (dipyran) can then be modified with a nucleophile according to the literature (Non-Patent Document 7). Dipyrromethane (dipyran) can be converted to the corresponding boron dipyrromethene, whether or not it is modified with a nucleophile (Non-Patent Documents 5, 7, 8). The pyrrole used for the condensation to dipyrromethane may or may not be substituted with a methyl group. In a preferred embodiment, the pyrrole is 2,4-dimethylpyrrole. Substitution of boron dipyrromethene with bromine, for example NBS, proceeds more slowly and with a lower equivalent of NBS to achieve monosubstitution in DCM (Non-Patent Documents 9, 10), or more rapidly and with a greater number of equivalents of NBS to achieve disubstitution in hexafluoroisopropanol (Non-Patent Document 11). Modification of boron dipyrromethene with a sugar group can be achieved by substituting the para-fluorine atom of a 2,3,4,5,6-pentafluorophenyl or 4-fluoro-3-nitrophenyl-substituted group with a suitable sugar nucleophile described in the literature for other pentafluorophenyl-substituted compounds, such as galactosylthiol or glucosylthiol (Non-Patent Document 12).

[0024] The synthesis of the compounds described herein is illustrated in the following examples.

[0025] Example 1 shows the synthesis of substituted boron dipyrromethene complexes, including amino- and glyco-substituted boron dipyrromethenes. The latter examples showed how they can be synthesized by substitution of the para-fluorine atom with a sugar thiol. Furthermore, it was exemplified that substitution with a specific nucleophile can be carried out on 1,3,5,7-tetramethyl and non-alkylated boron dipyrromethenes.

[0026] Example 2 shows the synthesis of bromine-substituted boron dipyrromethene. This illustrates that mono-substitution and di-substitution can be achieved by carefully selecting the reaction parameters (solvent, molar equivalent of NBS).

[0027] Specifically substituted boron dipyrromethene complexes as described herein are suitable for use in the chemotherapy of cancer and other (excessive) hyperproliferative diseases, and infections, as well as for the photodynamic therapy of those diseases, infections, and conditions.

[0028] In some embodiments, treatment is achieved by first incorporating the boron dipyrromethene into a pharmaceutically acceptable application vehicle (e.g., an ethanol solution, a liposomal formulation, or other pharmaceutical formulation) to deliver the derivative to a specific treatment site. After administering the derivative in the vehicle to the treatment area, sufficient time is required for the complex to preferentially accumulate in the diseased tissue and exert its effect. In the case of PDT treatment, the treatment area is irradiated with light of an appropriate wavelength and sufficient power to activate the boron dipyrromethene complex, inducing necrosis or apoptosis of the cells of the diseased tissue. Due to its amphiphilic nature, the chemically stable boron dipyrromethene complex of the present invention can be prepared in various pharmaceutically acceptable and active formulations for various administration methods, such as for injection. In one embodiment, such amphiphilic compounds are formulated into liposomes. This liposomal formulation can be injected avoiding undesirable effects such as precipitation at the injection site or delayed pharmacokinetics.

[0029] Determination of the dark toxicity (DT) and phototoxicity (Example 3) of boron dipyrromethene as described in the present disclosure in cell culture tests on HT29 tumor cell lines and other cell lines shows excellent properties of the compounds for use in PDT (Examples 3.1 - 3.11).

[0030] The data of Examples 3.1 to 3.11 show the results of photodynamic therapy with the compounds described in the present disclosure in model cell lines (J774A.1, macrophage cell line) particularly related to arthritis, indicating the usefulness of the disclosed boron dipyrromethene complexes in the diagnosis and treatment of arthritis and similar inflammatory diseases.

[0031] The figures of Example 4 (4.1 to 4.11) show the effects of the boron dipyrromethenes described herein on bacteria, the Gram-positive bacterium Staphylococcus aureus and the Gram-negative bacterium Pseudomonas aeruginosa, indicating that these compounds can also be used for the treatment of bacterial infections. As seen in the examples, the selected compounds (4.1, 4.2, 4.4 to 4.10) show high antibacterial activity against Staphylococcus aureus even in the absence of light (at a maximum concentration of 100 μmol tested), and in particular, the compounds are non-toxic to cells in the absence of light on the other hand, thus exemplifying these main appropriates in systemic treatment (see Example 3). Also, some compounds can be specifically active against bacteria and show only low toxicity in cells (see Example 4.5 compared to Example 3.12).

[0032] The following examples provide a complete and illustrative disclosure and description of the method for producing the boron dipyrromethene complexes of the present invention to those skilled in the art, are presented to show their chemotherapeutic and photodynamic activities, and are not intended to limit the scope of what the inventors regard as the present invention. Although efforts have been made to be accurate with respect to the numerical values used (for example, amounts, temperatures, etc.), some experimental errors and deviations should be taken into account. Also, although the best efforts have been made to name the compounds with systematic IUPAC names, the basic reference is the structural formula given based on experimental spectroscopic data.

[0033] All reactions were carried out in standard round-bottom flasks. Air-sensitive reactions were performed under an argon gas protective atmosphere. DCM, n-pentane, and methanol were purchased and used as received. Other solvents were purchased and distilled under reduced pressure. The purchased chemicals were used as received without further purification. Liquid reagents were added via syringe. The reactions were monitored by thin-layer chromatography ((Merck, TLC silica gel l60 F 254 ), visualized under UV light (254 nm and 366 nm). Flash column chromatography was performed on silica gel (Fluka silica gel 60M, 40 - 63 μm). NMR spectra were recorded on JEOL ECX400, JEOL ECP500, Bruker Avance500, JEOL ECZ600, and Bruker Avance700. A number of signals were assigned as follows: s = singlet, br s = broad singlet, d = doublet, t = triplet, dd = doublet of doublets, dt = doublet of triplets, dq = doublet of quartets, tt = triplet of triplets, ddd = doublet of doublets of doublets, ddt = doublet of doublets of triplets, sept = septet, m = multiplet, mc = center multiplet. Chemical shifts are reported relative to CDCl3( 1 H: δ = 7.26 ppm, 13 C: δ = 77.2 ppm), CD2Cl2( 1 H: δ = 5.32 ppm, 13 C: δ = 53.8 ppm), THF-d8( 1 H: δ = 3.58 ppm, 13 C: δ = 67.6 ppm), and DMSO-d6( 1 H: δ = 2.50 ppm, 13 C: δ = 39.5 ppm). All 13The 13C NMR spectra were proton-decoupled and the coupling constants are given in Hertz (Hz). Two-dimensional spectra (COSY, HMBC, and HMQC) were measured for detailed peak assignment. HRMS analysis was performed on an Agilent Technologies 6210 ESI-TOF (electrospray ionization, time-of-flight) instrument. The UV / Vis spectra were recorded in a quartz cuvette (length 1 cm) with a SPECORD S300 UV / Vis spectrometer (Analytic Jena). The specified melting points were recorded on a Reichert Thermovar apparatus and were not corrected.

[0034] Para-amino-substituted 1,3,5,7-tetramethyl BODIPY, 8-pentafluorophenyl-1,3,5,7-tetramethyl BODPY (Non-Patent Document 8), para-alkoxy-substituted BODIPY, 8-pentafluorophenyl BODIPY (Non-Patent Document 7), para-amino-substituted BODIPYs (Non-Patent Document 13), para-4-amino-3-nitrophenyl-substituted BODIPY, 4-fluoro-3-nitrophenyl BODIPY (Non-Patent Document 14), and para-amino-substituted BODIPY (Non-Patent Document 15) were prepared according to the literature.

[0035] (Example 1) (Preparation of Substituted Boron Dipyrromethene) (1.1 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) [Chemical Structure]

[0036] 4-Fluoro-3-nitrobenzaldehyde (500 mg, 2.96 mmol) was dissolved in 35 mL of dichloromethane (DCM). 2,4-Dimethylpyrrole (900 μL, 8.87 mmol) and trifluoroacetic acid (37 μL, 0.48 mmol) were added, and the mixture was stirred at room temperature for 2.5 h. After the indicated time, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (671 mg, 2.96 mmol) was added, and the mixture was stirred at room temperature for an additional 1 h. Then, N,N-diisopropylethylamine (5.8 mL, 34.10 mmol) and BF3·OEt2 (5.8 mL, 45.70 mmol) were added, and the mixture was stirred at room temperature for 1.5 h. Water was added, and the mixture was extracted several times with DCM. The combined organic phases were washed again with water, concentrated (to about half the volume), and filtered through a glass frit packed with silica gel (DCM). The filtrate was dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by column chromatography (silica gel, n-hexane / EtOAc = 9 / 1, v / v) to give the product as an orange-green solid (536 mg, 47%).

[0037] Mp: 171~175 °C 1 1H NMR (500 MHz, CDCl3): δ (ppm) = 1.43 (s, 6H, Me), 2.56 (s, 6H, Me), 6.03 (s, 2H, H pyrrole ), 7.47 (dd, J = 10.3, 8.5 Hz, 1H, Ar-H meta ), 7.60 (ddd, J = 8.5, 4.1, 2.2 Hz, 1H, Ar-H ortho ), 8.05 (dd, J = 6.9, 2.3 Hz, 1H, Ar-H ortho )

[0038] 13 13C NMR (126 MHz, CDCl3): δ (ppm) = 14.8 (Me), 15.2 (Me), 119.7 (d, J C-F = 21.1 Hz, Ar-C meta ), 122.2 (CH pyrrole ), 126.5 (d, J C-F = 2.4 Hz, Ar-C ortho ), 131.1 (C pyrrole)、132.1*, 135.7 (d, J C-F = 8.5 Hz, Ar-C ortho )、136.7 (C meso )、138.1 (d, J C-F = 8.0 Hz)*、142.4 (C pyrrole )、155.79 (d, J C,F = 268.0 Hz, Ar-C para )、157.1 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0039] 19 19F NMR (376 Hz, CDCl3): δ (ppm) = -111.85 (s, 1F, CF), -145.85~-146.23 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 19 H 18 BF3N3O2 + [M + H] + : 388.1439, found: 388.1438. UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 507 [4.77]

[0040] General procedure for substitution with amines: Dissolve BODIPY in DCM, DMF, or DMSO and add the corresponding amine. Stir the mixture at room temperature for the indicated time. Then, dilute the mixture with EtOAc and wash it several times with water. Dry the organic layer over Na2SO4, filter, and evaporate to dryness. Purify the crude product by column chromatography.

[0041] (1.2 8-[4-(N-butylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0042] 8-[4-(N-Butylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared according to the general synthetic procedure. 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (116 mg, 0.30 mmol) and n-butylamine (0.6 mL, 5.99 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 90 minutes. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 2, v / v) to give the product as an orange solid (116 mg, 88%).

[0043] Mp: 133~139 °C 1 H NMR (500 MHz, CDCl3): δ (ppm) = 1.02 (t, J = 7.4 Hz, 3H, Me butyl ), 1.49~1.58 (m, 8H, CH2+Me), 1.75~1.81 (m, 2H, CH2), 2.55 (s, 3H, Me), 3.36 (td, J = 7.2, 4.7 Hz, 2H, CH2), 6.00 (s, 2H, H pyrrole ), 7.00 (d, J = 8.8 Hz, 1H, Ar-H meta ), 7.31 (dd, J = 8.8, 2.1 Hz, 1H, Ar-H ortho ), 8.13 (d, J = 2.1 Hz, 1H, Ar-H ortho ), 8.14~8.16 (m, 1H, NH)

[0044] 13 C NMR (126 MHz, CDCl3): δ (ppm) = 13.9 (Me butyl ), 14.8 (Me), 15.4 (Me), 20.4 (CH2), 31.1 (CH2), 43.1 (CH2), 114.9 (Ar-C meta ), 120.1 (C meso ), 121.4*, 121.6 (CH pyrrole), 126.9 (Ar-C ortho ), 131.9 (C pyrrole ), 136.1 (Ar-C ortho ), 139.4*, 142.8 (C pyrrole ), 145.6 (Ar-C para ), 156.1 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0045] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -145.60~-146.69 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 23 H 27 BF2N4O2Na + [M + Na] + : 463.2087, found: 463.2120, m / z calcd. for C 23 H 27 BF2N4O2K + [M + K] + : 479.1827, found: 479.1856, m / z calcd. for C 46 H 54 B2F4N8O4Na + [2M + Na] + : 903.4282, found: 903.4319 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 505 [4.75]

[0046] (1.3 8-[4-(N-2-hydroxyethylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0047] According to the general synthesis procedure, 8-[4-(N-2-hydroxyethylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (100 mg, 0.26 mmol) and ethanolamine (0.3 mL, 5.17 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 24 hours. The crude product was purified by column chromatography (silica gel, EtOAc) to obtain the product as an orange solid (96 mg, 87%).

[0048] Mp: 170~175 °C 1 H NMR (500 MHz, THF-d8): δ (ppm) = 1.57 (s, 6H, Me), 2.49 (s, 6H, Me), 3.48~3.51 (m, 2H, CH2), 3.80~3.83 (m, 2H, CH2), 4.23 (t, J = 4.9 Hz, 1H, OH), 6.04 (s, 2H, H pyrrole )、7.24 (d, J = 8.8 Hz, 1H, Ar-H meta )、7.42 (dd, J = 8.7, 2.2 Hz, 1H, Ar-H ortho )、8.15 (d, J = 2.2 Hz, 1H, Ar-H ortho )、8.41 (t, J = 5.3 Hz, 1H, NH)

[0049] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.9 (Me), 14.9 (Me), 43.8 (CH2), 112.3 (C meso )、116.5 (Ar-C meta )、121.2 (CH pyrrole )、127.9 (Ar-C ortho )、132.0 (C pyrrole )、133.2*, 136.6 (Ar-C ortho )、141.1*, 142.1 (C pyrrole )、146.9 (Ar-Cpara )、154.9 (C pyrrole ) These signals could not be accurately assigned to the corresponding carbon atoms. These are Ar-C of the aryl moiety ipso and Ar-C nitro and belong to

[0050] 19 19F NMR (376 MHz, THF-d8): δ (ppm) = -145.98~-146.84 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 21 H 23 BF2N4O3Na + [M + Na] + : 451.1723, found: 451.1789, m / z calcd. for C 42 H 46 B2F4N8O6Na + [2M + Na] + : 879.3555, found: 879.3647 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 505 [4.54]

[0051] (1.4 8-[3-Nitro-4-(N-2-prop-2-enylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chemical formula

[0052] 8-[3-Nitro-4-(N-2-propen-2-ylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared according to the general synthetic procedure. 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (132 mg, 0.34 mmol) and allylamine (0.3 mL, 3.40 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 24 h. The crude product was purified by column chromatography (silica gel, n-hexane / EtOAc = 9 / 1, v / v) to give the product as an orange solid (124 mg, 86%).

[0053] Mp: 176~179 °C 1 1H NMR (500 MHz, CDCl3): δ (ppm) = 1.53 (s, 6H, Me), 2.54 (s, 6H, Me), 4.05 (t, J = 5.0 Hz, 2H, CH2), 5.29~5.36 (m, 2H, H2C=CH-), 5.95~6.02 (m, 3H, H pyrrole +H2C=CH-), 6.98 (d, J = 8.8 Hz, 1H, Ar-H meta ), 7.30 (dd, J = 8.8, 2.2 Hz, 1H, Ar-H ortho ), 8.14 (d, J = 2.1 Hz, 1H, Ar-H ortho ), 8.28 (t, J = 5.8 Hz, 1H, NH)

[0054] 13 13C NMR (126 MHz, CDCl3): δ (ppm) = 14.7 (Me), 15.3 (Me), 45.6 (CH2), 115.2 (Ar-C meta ), 117.7 (H2C=CH-), 121.6 (CH pyrrole ), 121.8*, 126.8 (Ar-C ortho ), 131.9 (C pyrrole ), 132.1 (C meso ), 132.7 (H2C=CH-), 136.0 (Ar-C ortho ), 139.2*, 142.7 (C pyrrole ), 145.3 (Ar-Cpara )、156.1 (C pyrrole ) These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C of the aryl moiety ipso and Ar-C nitro .

[0055] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -145.57~-146.59 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 22 H 23 BF2N4O2Na + [M + Na] + : 447.1774, found: 447.1796, m / z calcd. for C 22 H 23 BF2N4O2K + [M + K] + : 463.1514, found: 463.1543, m / z calcd. for C 44 H 46 B2F4N8O4Na + [2M + Na] + : 871.3656, found: 871.3699, m / z calcd. for C 44 H 46 B2F4N8O4K + [2M + K] + : 887.3396, found: 887.3442 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 504 [4.83]

[0056] (1.5 8-[3-Nitro-4-(N-2-prop-2-ynylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0057] According to the general synthesis procedure, 8-[3-nitro-4-(N-2-prop-2-ynylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (116 mg, 0.30 mmol) and propargylamine (0.4 mL, 5.99 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 24 h. The crude product was purified by column chromatography (silica gel, n-hexane / EtOAc = 9 / 1, v / v) to give the product as an orange solid (56 mg, 44%).

[0058] Mp: 130~135 °C 1 H NMR (500 MHz, CDCl3): δ (ppm) = 1.51 (s, 6H, Me), 2.34 (t, J = 2.5 Hz, 1H, CH), 2.55 (s, 6H, Me), 4.20 (dd, J = 5.7, 2.5 Hz, 2H, CH2), 6.00 (s, 2H, H pyrrole )、7.12 (d, J = 8.7 Hz, 1H, Ar-H meta )、7.40 (dd, J = 8.7, 2.1 Hz, 1H, Ar-H ortho )、8.17 (d, J = 2.1 Hz, 1H, Ar-H ortho )、8.23 (t, J = 5.6 Hz, 1H, NH)

[0059] 13 C NMR (126 MHz, CDCl3): δ (ppm) = 14.8 (Me), 15.3 (Me), 32.97 (CH2), 72.99 (CH), 78.4 (C), 115.1 (Ar-C meta )、121.7*, 122.9 (CH pyrrole )、126.9 (Ar-C ortho )、131.8 (C meso )、132.9 (C pyrrole )、136.1 (Ar-C ortho )、138.9*, 142.8 (C pyrrole), 144.3 (Ar-C para ), 156.3 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0060] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -145.56~-146.60 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 22 H 21 BF2N4O2Na + [M + Na] + : 445.1618, found: 445.1634, m / z calcd. for C 22 H 21 BF2N4O2Na + [M + K] + : 461.1357, found: 461.1492, m / z calcd. for C 44 H 42 B2F4N8O4Na + [2M + Na] + : 867.3343, found: 867.3348 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 505 [4.47]

[0061] (1.6 8-[4-(N-6-methoxy-6-oxohexylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chemical formula

[0062] 8-[4-(N-6-Methoxy-6-oxohexylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared according to the general synthetic procedure. 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (200 mg, 0.52 mmol), methyl 6-aminohexanoate hydrochloride (939 mg, 5.17 mmol), and N,N-diisopropylamine (1.8 mL, 10.33 mmol) were dissolved in 20 mL of DCM. The mixture was stirred for 72 h. The crude product was purified by column chromatography (silica gel, n-hexane / EtOAc = 9 / 1, v / v, then n-hexane / EtOAc = 4 / 1, v / v) to give the product as an orange solid (80 mg, 30%).

[0063] Mp: 123~125 °C 1 1H NMR (500 MHz, CDCl3): δ (ppm) = 1.49~1.57 (m, 8H, Me + CH2), 1.70~1.76 (m, 2H, CH2), 1.77~1.83 (m, 2H, CH2), 2.36 (t, J = 7.4 Hz, 2H, CH2), 2.54 (s, 6H, Me), 3.36 (td, J = 7.1, 5.0 Hz, 2H, CH2), 3.67 (s, 3H, Me OMe ), 5.99 (s, 2H, H pyrrole ), 6.98 (d, J = 8.8 Hz, 1H, Ar-H meta ), 7.31 (dd, J = 8.7, 2.2 Hz, 1H, Ar-H ortho ), 8.11~8.14 (m, 2H, Ar-H ortho +NH)

[0064] 13 13C NMR (126 MHz, CDCl3): δ (ppm) = 14.7 (Me), 15.3 (Me), 24.6 (CH2), 26.7 (CH2), 28.7 (CH2), 33.9 (CH2), 43.1 (CH2), 51.7 (Me OMe ), 114.8 (Ar-C meta ), 121.5*, 121.6 (CHpyrrole ), 126.9 (Ar-C ortho ), 131.9 (C pyrrole ), 131.9 (C meso ), 136.1 (Ar-C ortho ), 139.3*, 142.7 (C pyrrole ), 145.5 (Ar-C para ), 156.1 (C pyrrole ), 173.95 (CO) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to the Ar-C ipso and Ar-C nitro of the aryl moiety.

[0065] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -145.57~-146.63 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 26 H 31 BFN4O4 + [M - F] + : 493.2417, found: 493.2410, m / z calcd. for C 26 H 31 BF2N4O4Na + [M + Na] + : 535.2299, found: 535.2298 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 504 [4.66]

[0066] (1.78-[4-(N,N-dibutylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chemical Structure

[0067] 8-[4-(N,N-Dibutylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared according to the general synthetic procedure. 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (200 mg, 0.52 mmol) and N,N-dibutylamine (1.60 mL, 9.66 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 24 h. The crude product was purified by column chromatography (silica gel, n-hexane / EtOAc = 9 / 1, v / v) to give the product as an orange solid (90 mg, 35%).

[0068] Mp: 95~99 °C 1 1H NMR (500 MHz, CDCl3): δ (ppm) = 0.87 (t, J = 7.4 Hz, 6H, Me butyl ), 1.25~1.32 (m, 4H, CH2), 1.50~1.56 (m, 10H, CH2 + Me), 2.55 (s, 6H, Me), 3.20 (t, J = 7.3 Hz, 4H, CH2), 6.00 (s, 2H, H pyrrole ), 7.28 (br s, 2H, Ar-H meta + Ar-H ortho ), 7.65 (t, J = 1.2 Hz, 1H, Ar-H ortho )

[0069] 13 13C NMR (126 MHz, CDCl3): δ (ppm) = 13.9 (Me butyl ), 14.8 (Me), 14.99 (Me), 20.2 (CH2), 29.5 (CH2), 52.2 (CH2), 121.7 (CH pyrrole ), 122.6 (Ar-C meta ), 126.3 (Ar-C ortho ), 131.7 (C pyrrole ), 132.7 (Ar-C ortho ), 138.96*, 142.1*, 142.8 (C pyrrole ), 144.9 (Ar-C para ), 156.2 (C pyrrole) *These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0070] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -145.61~-146.64 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 27 H 35 BF2N4O2Na + [M + Na] + : 519.2713, found: 519.2713 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 505 [4.62]

[0071] (1.8 8-[4-(N-1-hydroxymethyl-2-hydroxyethylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0072] According to the general synthesis procedure, 8-[4-(N-1-hydroxymethyl-2-hydroxyethylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (200 mg, 0.52 mmol) and 2-amino-1,3-dihydroxypropane (706 mg, 7.75 mmol) were dissolved in 20 mL of DMSO. The mixture was stirred for 24 h. The crude product was purified by column chromatography (silica gel, EtOAc) to give the product as an orange-green solid (40 mg, 23%).

[0073] Mp: 110~116 °C 1 1H NMR (500 MHz, THF-d8): δ (ppm) = 1.58 (s, 6H, Me), 2.48 (s, 6H, Me), 3.72~3.76 (m, 2H, CH2), 3.80~3.82 (m, 3H, CH2+CH), 4.25 (br s, 2H, OH), 6.04 (s, 2H, H pyrrole )、7.33 (d, J = 8.9 Hz, 1H, Ar-H meta )、7.39 (dd, J = 8.8, 2.1 Hz, 1H, Ar-H ortho )、8.14 (d, J = 2.0 Hz, 1H, Ar-H ortho )、8.59 (d, J = 7.3 Hz, 1H, NH)

[0074] 13 13C NMR (126 MHz, THF-d8): δ (ppm) = 14.7 (Me), 15.5 (Me), 56.9 (CH), 61.5 (CH2), 116.9 (Ar-C meta )、122.0 (CH pyrrole )、122.1*, 127.8 (Ar-C ortho )、132.9 (C pyrrole )、133.2*, 136.7 (Ar-C ortho )、141.2 (C meso )、143.5 (C pyrrole )、146.5 (Ar-C para)、156.5(C pyrrole ) These signals could not be accurately assigned to the corresponding carbon atoms. They belong to Ar-C in the aryl moiety ipso and Ar-C nitro .

[0075] 19 19F NMR (376 MHz, THF-d8): δ (ppm) = -146.71~-147.02 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 22 H 25 BFN4O4 + [M - F] + : 439.1947, found: 439.1957, m / z calcd. for C 22 H 26 BF2N4O4 + [M + H] + : 459.2010, found: 459.2016, m / z calcd. for C 22 H 25 BF2N4O4Na + [M + Na] + : 481.1829, found: 481.1837, m / z calcd. for C 22 H 25 BF2N4O4K + [M + K] + : 497.1569, found: 497.1575 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 501 [4.80]

[0076] (1.98-[4-(N-prop-2-ynylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chemical formula

[0077] According to the general synthesis procedure, 8-[4-(N-prop-2-ynylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-Pentafluorophenyl-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 8)) (200 mg, 0.48 mmol) and propargylamine (0.31 mL, 4.83 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 24 hours. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 9, v / v) to obtain the product as an orange solid (53 mg, 23%).

[0078] Mp: 215~221 °C 1 H NMR (500 MHz, CDCl3): δ (ppm) = 1.66 (s, 6H, Me), 2.27~2.28 (m, 1H, CH), 2.56 (s, 6H, Me), 4.22 (br s, 2H, CH2), 6.02 (s, 2H, H pyrrole )

[0079] 13 C NMR (126 MHz, CDCl3): δ (ppm) = 13.6 (Me), 14.9 (Me), 35.8 (CH2), 72.9 (C), 121.95 (CH pyrrole ), 131.8 (C pyrrole ), 133.8 (Ar-C para ), 142.1 (C pyrrole ), 157.1 (C pyrrole ).

[0080] 19 F NMR (376 MHz, CDCl3): δ (ppm) = -142.41 (d, J = 18.8 Hz, 2F, CF meta ), -145.89~-146.15 (m c , 2F, BF2), -157.16 (d, J = 18.0 Hz, 2F, CF ortho ) HRMS(ESI-TOF): m / z calcd. for C 22 H 18 BF6N3Na + [M+Na] + : 472.1390, found: 472.1407, m / z calcd. for C 22 H 18 BF6N3K + [M+K] + : 488.1130, found: 488.1130, m / z calcd. for C 44 H 36 B2F 12 N6Na + [2M+Na] + : 921.2888, found: 921.2910 UV / Vis(DCM): λ max (nm)[log(ε / Lmol -1 cm -1 )]=515[4.72]

[0081] (1.10 8-[4-(N-2-hydroxyethylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0082] 8-[4-(N-2-Hydroxyethylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared according to the general synthesis procedure. 8-Pentafluorophenyl-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 8)) (200 mg, 0.48 mmol) and ethanolamine (0.50 mL, 8.93 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 4 hours. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 1, v / v) to obtain the product as an orange-green solid (81 mg, 41%).

[0083] Mp: 154~157 °C 1 H NMR (500 MHz, THF-d8): δ (ppm) = 1.70 (s, 6H, Me), 2.49 (s, 6H, Me), 3.52 - 3.56 (m, 2H, CH2), 3.69 (t, J = 5.5 Hz, 2H, CH2), 4.06 (br s, 1H, OH), 5.57 (s, 1H, NH), 6.09 (s, 2H, H pyrrole )

[0084] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.8 (Me), 14.8 (Me), 48.7 (CH2), 62.2 (CH2), 100.03 (t, J C-F = 19.8 Hz, Ar-C ipso )、122.5 (CH pyrrole )、126.5 (C meso )、131.4~131.6 (m, Ar-C para )、132.95 (C pyrrole )、139.03 (dd, J C-F = 242.1, 25.0 Hz, Ar-C meta )、142.9 (C pyrrole )、145.27 (ddt, J C-F = 242.3, 8.6, 4.1 Hz, Ar-C ortho )、157.8 (C pyrrole )

[0085] 19 19F NMR (376 MHz, THF-d8): δ (ppm) = -145.87 (d, J = 17.7 Hz, 2F, CF meta ), -146.58~-146.84 (m C , 2F, BF2), -161.12 (d, J = 18.3 Hz, 2F, CF ortho ) HRMS (ESI-TOF): m / z calcd. for C 21 H 20 BF6N3ONa + [M+Na] + : 478.1496, found: 478.1524, m / z calcd. for C 21 H 20 BF6N3OK + [M+K] + : 494.1235, found: 494.1267, m / z calcd. for C 42 H 40 B2F 12 N6O2Na + [2M+Na] + : 933.3099, found: 933.3149 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 515 [4.89]

[0086] General procedure for substitution with thiocarbohydrates: The BODIPY was dissolved in DMF and the corresponding thiocarbohydrate was added. The mixture was stirred at room temperature for the indicated time. Then, 5 mL of water was added and evaporated to dryness. The crude product was purified by column chromatography and recrystallization.

[0087] (1.11 8-[3-Nitro-4-(1'-thio-β-D-glucosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chemical Structure

[0088] According to the general synthesis procedure, 8-[3-nitro-4-(1'-thio-β-D-glucosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (100 mg, 0.26 mmol) and sodium 1'-thio-β-D-glucoside (67 mg, 0.31 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 15 minutes. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 6 / 1, v / v) and recrystallization (DCM + a few drops of MeOH / n-hexane) to obtain the product as an orange solid (67 mg, 46%).

[0089] Mp: 158~163 °C 1 H NMR (600 MHz, THF-d8): δ (ppm) = 1.48 (d, J = 6.6 Hz, 6H, Me), 2.50 (s, 6H, Me), 3.31~3.37 (m, 3H, 2'-H + 3'-H + 4'-H), 3.42 (ddd, J = 8.9, 5.9, 2.5 Hz, 1H, 5'-H), 3.57~3.60 (m, 4H, 6'-H + THF), 3.81 (dd, J = 12.0, 2.5 Hz, 1H, 6'-H), 3.88 (br s, 1H, OH), 4.61 (br s, 1H, OH), 4.84 br s, 1H, OH), 4.88~4.89 (m, 1H, 1'-H), 5.07 (br s, 1H, OH), 6.07 (d, J = 3.6 Hz, 2H, H pyrrole )、7.65 (dd, J = 8.3, 2.0 Hz, 1H, Ar-H ortho )、8.12 (d, J = 8.3 Hz, 1H, Ar-H meta )、8.23 (d, J = 1.9 Hz, 1H, Ar-H ortho )

[0090] 1313C NMR (151 MHz, THF-d8): δ (ppm) = 14.4 (Me), 15.1 (Me), 62.7 (6’-C), 70.9 (4’-C), 73.6 (2’-C), 79.9 (3’-C), 81.9 (5’-C), 86.4 (1’-C), 121.99 (CH pyrrole ), 126.3 (Ar-C ortho ), 130.7 (Ar-C meta ), 131.9 (C pyrrole ), 132.9 (Ar-C para ), 134.3 (Ar-C ort-ho ), 138.1*, 139.3*, 143.2 (C pyrrole ), 148.0 (C meso ), 156.7 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0091] 19 19F NMR (376 MHz, THF-d8): δ (ppm) = -146.71~-146.89 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 25 H 30 N3O7S + [M - BF2 + H] + : 516.1799, found: 516.1802, m / z calcd. for C 25 H 28 BF2N3O7SNa + [M + Na] + : 586.1601, found: 586.1614 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 382 [3.58], 503 [4.52]

[0092] (1.12 8-[3-Nitro-4-(1'-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) [Chemical formula]

[0093] According to the general synthesis procedure, 8-[3-nitro-4-(1'-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Fluoro-3-nitrophenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (100 mg, 0.26 mmol) and sodium 1'-thio-β-D-galactoside (68 mg, 0.31 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 15 minutes. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 9 / 1, v / v) and recrystallization (DCM + a few drops of MeOH / n-hexane) to obtain the product as an orange-red solid (116 mg, 80%).

[0094] Mp: 151~158 °C 1 H NMR (500 MHz, THF-d8): δ (ppm) = 1.48 (d, J = 5.3 Hz, 6H, Me), 2.50 (s, 6H, Me), 3.46 (d, J = 8.4 Hz, 1H, 3'-H), 3.64~3.67 (m, 2H, 5'-H + 6'-H), 3.70~3.74 (m, 2H, 2'-H + 6'-H), 3.89 (br s, 1H, 4'-H), 4.00 (br s, 1H, OH), 4.53 (br s, 1H, OH), 4.79 (d, J = 9.7 Hz, 1H, 1'-H), 4.89 (br s, 1H, OH), 6.06 (s, 2H, H pyrrole ), 7.62 (dd, J = 8.3, 1.9 Hz, 1H, Ar-H ortho ), 8.19 (d, J = 8.4 Hz, 1H, Ar-H meta ), 8.21 (d, J = 1.9 Hz, 1H, Ar-H ortho ),

[0095] 13 13C NMR (126 MHz, THF-d8): δ (ppm) = 14.8 (Me), 15.4 (Me), 62.7 (6'-C), 70.1 (4'-C), 70.9 (2'-C), 79.6 (3'-C), 80.95 (5'-C), 87.3 (1'-C), 122.6 (CH pyrrole ), 126.3 (Ar-C ortho ), 131.5 (Ar-C meta ), 133.2 (C pyrrole ), 134.4 (Ar-C ortho ), 138.5*, 139.7 (Ar-C para ), 143.5*, 143.6 (C pyrrole ), 148.5 (C meso ), 157.1 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0096] 19 19F NMR (376 MHz, THF-d8): δ (ppm) = -146.68~-146.94 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 25 H 30 N3O7S + [M - BF2 + H] + : 516.1799, found: 516.1836, m / z calcd. for C 25 H 28 BF2N3O7SNa + [M + Na] + : 586.1601, found: 586.1642, m / z calcd. for C 25 H 28 BF2N3O7SK + [M + K] + : 602.1341, found: 602.1380 UV / Vis (MeOH): λ max(nm)[log(ε / Lmol -1 cm -1 )]=359[3.89], 502[4.77]

[0097] (1.13 8-[2,3,5,6-Tetrafluoro-4-(1'-thio-β-D-glucosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0098] According to the general synthetic procedure, 8-[2,3,5,6-tetrafluoro-4-(1'-thio-β-D-glucosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-Pentafluorophenyl-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 8)) (100 mg, 0.24 mmol) and sodium 1'-thio-β-D-glucoside (63 mg, 0.29 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 30 minutes. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 6 / 1, v / v) and recrystallization (DCM + a few drops of MeOH / n-hexane) to obtain the product as an orange solid (98 mg, 69%).

[0099] Mp: 180~183 °C 11H NMR (500 MHz, THF-d8): δ (ppm) = 1.66 (s, 6H, Me), 2.51 (s, 6H, Me), 3.16 - 3.20 (m, 1H, 3’-H), 3.25 - 3.29 (m, 2H, 2’-H + 5’-H), 3.43 (dd, J = 7.2, 4.9 Hz, 1H, 4’-H), 3.50 (ddd, J = 11.7, 7.1, 5.1 Hz, 1H, 6’-H), 3.63 (ddd, J = 11.5, 4.8, 2.7 Hz, 1H, 6’-H), 4.50 (s, 1H, OH), 4.77 (s, 1H, OH), 4.88 (d, J = 8.6 Hz, 1H, 1’-H), 4.97 (s, 1H, OH), 6.12 (s, 2H, H pyrrole ).

[0100] 13 13C NMR (126 MHz, THF-d8): δ (ppm) = 13.9 (Me), 14.8 (Me), 62.9 (6’-C), 71.5 (2’-C), 76.2 (4’-C), 79.98 (3’-C), 82.7 (5’-C), 85.8 (1’-C), 119.4 (Ar-C ipso ), 122.9 (CH pyrrole ), 125.0 (Ar-C para ), 131.8 (C pyrrole ), 142.95 (C pyrrole ), 158.5 (C pyrrole )

[0101] 19 19F NMR (376 MHz, THF-d8): δ (ppm) = -132.29 - -132.39 (m, 2F, CF ortho ), -142.89 (dd, J = 24.8, 11.1 Hz, 2F, CF meta ), -146.50 - -146.75 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 25 H 26 BF6N2O5S + [M + H] + : 591.1554, found: 591.1565, m / z calcd. for C 25 H 25 BF6N2O5SNa +[M+Na] + : 613.1374, found: 613.1390, m / z calcd. for C 25 H 25 BF6N2O5SK + [M+K] + : 629.1113, found: 629.1137, m / z calcd. for C 50 H 50 B2F 12 N6O 10 S2Na + [2M+Na] + : 1203.2855, found: 1203.2887 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 513 [4.72]

[0102] (1.14 8-[2,3,5,6-tetrafluoro-4-(1'-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0103] 8-[2,3,5,6-Tetrafluoro-4-(1’-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared according to the general synthetic procedure. 8-Pentafluorophenyl-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 8)) (200 mg, 0.48 mmol) and sodium 1’-thio-β-D-galactoside (126 mg, 0.58 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 20 minutes. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 9 / 1, v / v) and recrystallization (DCM + a few drops of MeOH / n-hexane) to obtain the product as a red solid (130 mg, 46%).

[0104] Mp: 213~216 °C 1 1H NMR (500 MHz, THF-d8): δ (ppm) = 1.66 (s, 6H, Me), 2.51 (s, 6H, Me), 3.37 (ddd, J = 9.2, 6.3, 3.3 Hz, 1H, 3’-H), 3.43 (dd, J = 6.6, 6.0 Hz, 1H, 5’-H), 3.47 (dd, J = 10.6, 5.6 Hz, 1H, 6’-H), 3.56~3.61 (m, 2H, 4’-H + 6’-H), 3.66 (t, J = 5.5 Hz, 1H, OH), 3.82 (t, J = 3.3 Hz, 1H, 2’-H), 3.95 (d, J = 4.1 Hz, 1H, OH), 4.39 (d, J = 6.3 Hz, 1H, OH), 4.76~4.77 (m, 1H, 1’-H), 4.79 (d, 1H, OH), 6.12 (s, 2H, H pyrrole )

[0105] 13 13C NMR (126 MHz, THF-d8): δ (ppm) = 13.9 (Me), 14.8 (Me), 62.0 (6’-C), 70.0 (2’-C), 73.3 (4’-C), 76.5 (3’-C), 81.3 (5’-C), 86.3 (1’-C), 115.0 (Ar-C ipso ), 122.9 (CH pyrrole )、125.1 (Cmeso )、131.8 (C pyrrole )、131.9 (Ar-C para )、142.97 (C pyrrole )、158.5 (C pyrrole )

[0106] 19 F NMR (376 MHz, THF-d8): δ (ppm) = -131.26 (dd, J = 25.4, 11.7 Hz, 2F, CF ortho )、-142.24 (dd, J = 25.5, 11.7 Hz 2F, CF meta )、-145.71~ -145.96 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 25 H 25 BF6N2O5SNa + [M + Na] + : 613.1374, found: 613.1402 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 ) = 513 [4.54]

[0107] (1.15 8-[3-Nitro-4-(1’-thio-β-D-glucopyranosyl)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0108] According to the general synthesis procedure, 8-[3-nitro-4-(1’-thio-β-D-glucosyl)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Fluoro-3-nitrophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 14)) (100 mg, 0.36 mmol) and sodium 1’-thio-β-D-glucoside (79 mg, 0.36 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 15 minutes. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 6 / 1, v / v) and recrystallization (DCM + a few drops of MeOH / n-hexane) to obtain the product as an orange-red solid (140 mg, 91%).

[0109] Mp: >250 °C 1 1H-NMR (500 MHz, DMSO-d6): δ (ppm) = 3.19~3.21 (m, 1H, 4’-H), 3.27~3.33 (m, 2H, 2’-H + 3’-H), 3.42~3.48 (m, 2H, 5’-H + 6’-H), 3.73 (d, J = 10.4 Hz, 1H, 6’-H), 4.63 (br s, 1H, OH), 4.98 (d, J = 9.3 Hz, 1H, 1’-H), 5.13 (br s, 1H, OH), 5.26 (br s, 1H, OH), 5.67 (br s, 1H, OH), 6.72 (dd, J = 4.3, 1.9 Hz, 2H, H pyrrole )、7.18 (d, J = 4.2 Hz, 2H, H pyrrole )、7.92 (dd, J = 8.5, 2.0 Hz, 1H, Ar-H ortho )、8.01 (d, J = 8.5 Hz, 1H, Ar-H meta )、8.19 (s, 2H, H pyrrole )、8.39 (d, J = 2.0 Hz, 1H, Ar-H ortho )

[0110] 13 13C-NMR (126 MHz, DMSO-d6): δ (ppm) = 60.9 (6’-C), 69.7 (4’-C), 72.4 (2’-C), 78.2 (3’-C), 81.1 (5’-C), 84.4 (1’-C), 119.7 (Cpyrrole )、127.5 (Ar-C ortho )、129.8 (Ar-C para )、128.95 (Ar-C meta )、131.8 (C pyrrole )、134.1 (C pyrrole )、135.3 (Ar-C ortho )、138.8*, 143.6*, 145.0 (C pyrrole )、145.7 (C meso ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety. 19F-NMR (376 MHz, DMSO-d6): δ (ppm) = -141.06~-141.29 (mc, 2F, BF2)

[0111] HRMS (ESI-TOF): m / z calcd. for C 21 H 20 BF2N3O7SNa + [M+Na] + : 530.0975, found: 530.0988 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 373 [4.24], 504 [4.68]

[0112] (1.16 8-[3-Nitro-4-(1’-thio-β-D-galactosyl)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0113] According to the general synthesis procedure, 8-[3-nitro-4-(1’-thio-β-D-galactosyl)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Fluoro-3-nitrophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 14)) (100 mg, 0.30 mmol) and sodium 1’-thio-β-D-galactoside (79 mg, 0.36 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 15 minutes. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 6 / 1, v / v) and recrystallization (DCM + a few drops of MeOH / n-hexane) to obtain the product as an orange-red solid (125 mg, 82%).

[0114] Mp: 221~225 °C 1 1H-NMR (600 MHz, DMSO-d6): δ (ppm) = 3.44~3.46 (m, 1H, 3’-H), 3.54 (d, J = 5.9 Hz, 2H, 6’-H), 3.63 (t, J = 9.1 Hz, 1H, 2’-H), 3.68 (t, J = 6.0 Hz, 1H, 5’-H), 3.78~3.79 (m, 1H, 4’-H), 4.64 (br s, 1H, OH), 4.73 (br s, 1H, OH), 4.92 (d, J = 9.7 Hz, 1’-H), 5.04 (br s, 1H, OH), 5.50 (br s, 1H, OH), 6.71~6.72 (m, 2H, H pyrrole )、7.17 (d, J = 4.2 Hz, 2H, H pyrrole )、7.92 (dd, J = 8.4, 2.1 Hz, 1H, Ar-H ortho )、8.05 (d, J = 8.5 Hz, 1H, Ar-H meta )、8.17 (s, 2H, H pyrrole )、8.38 (d, J = 2.1 Hz, 1H, Ar-H ortho )

[0115] 1313C-NMR (151 MHz, DMSO-d6): δ (ppm) = 60.6 (6’-C), 68.4 (4’-C), 69.0 (2’-C), 74.7 (3’-C), 79.4 (5’-C), 85.0 (1’-C), 119.8 (C pyrrole ), 127.5 (Ar-C ortho ), 128.8 (Ar-C para ), 128.99 (Ar-C meta ), 131.8 (C pyrrole ), 134.1 (C pyrrole ), 135.2 (Ar-C ortho ), 139.1*, 143.6*, 145.5 (C pyrrole ), 145.8 (C meso ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0116] 19 19F-NMR (376 MHz, DMSO-d6): δ (ppm) = -141.12~-141.35 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 21 H 20 BF2N3O7SNa + [M+Na] + : 530.0975, found: 530.0985, m / z calcd. for C 21 H 20 BF2N3O7SK + [M+K] + : 546.0715, found: 546.0712 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 371 [4.14], 503 [4.57]

[0117] (1.17 8-[2,3,5,6-Tetrafluoro-4-(1'-thio-β-D-glucosyl)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0118] According to the general synthetic procedure, 8-[2,3,5,6-tetrafluoro-4-(1'-thio-β-D-glucosyl)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-Pentafluorophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 7)) (100 mg, 0.28 mmol) and sodium 1'-thio-β-D-glucoside (73 mg, 0.34 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 15 minutes. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 8 / 1, v / v) and recrystallization (DCM + a few drops of MeOH / n-hexane) to obtain the product as an orange-red solid (130 mg, 88%).

[0119] Mp: 100~109 °C 1 H NMR(500 MHz, THF-d6): δ(ppm) = 3.21~3.26 (m, 2H, 2'-H + 5'-H), 3.27~3.30 (m, 2H, 3'-H + 4'-H), 3.46~3.51 (m, 1H, 6'-H), 3.72~3.75 (m, 1H, 6'-H), 4.43 (s, 1H, OH), 4.82 (s, 1H, OH), 4.93 (d, J = 9.0 Hz, 1H, 1'-H), 6.60~6.61 (m, 2H, H pyrrole )、7.05 (s, 2H, H pyrrole )、8.04 (s, 2H, H pyrrole )

[0120] 1313C NMR (126 MHz, THF-d6): δ (ppm) = 63.2 (6’-C), 71.8 (2’-C), 76.1 (4’-C), 80.1 (3’-C), 82.8 (5’-C), 85.8 (1’-C), 120.5 (C pyrrole ), 131.8 (C pyrrole ), 136.0 (C pyrrole ), 147.8 (C pyrrole )

[0121] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -133.29 (dd, J = 23.5, 10.6 Hz, 2F, CF ortho ), -140.54~-140.63 (m, 2F, CF meta ), -145.33~-145.56 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 21 H 17 BF5N2O5S + [M - F] + : 515.0866, found: 515.0844, m / z calcd. for C 21 H 17 BF6N2O5SNa + [M + Na] + : 557.0748, found: 557.0729 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 356 [3.84], 513 [4.58]

[0122] (1.18 8-[2,3,5,6-Tetrafluoro-4-(1’-thio-β-D-galactosyl)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0123] 8-[2,3,5,6-Tetrafluoro-4-(1'-thio-β-D-galactosyl)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared according to the general synthetic procedure. 8-Pentafluorophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 7)) (100 mg, 0.28 mmol) and sodium 1'-thio-β-D-galactoside (73 mg, 0.34 mmol) were dissolved in 5 mL of DMF. The mixture was stirred for 15 minutes. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 8 / 1, v / v) and recrystallization (DCM + a few drops of MeOH / n-hexane) to obtain the product as an orange-red solid (91 mg, 61%).

[0124] Mp: 110~115 °C 1 H NMR (600 MHz, THF-d6): δ (ppm) = 3.39 (dd, J = 8.7, 4.1 Hz, 1H, 3'-H), 3.45 (dd, J = 5.9, 5.6 Hz, 1H, 5'-H), 3.60~3.63 (m, 3H, 4'-H + 6'-H), 3.73 (br s, 1H, OH), 3.82 (br s, 1H, 2'-H), 3.99 (br s, 1H, OH), 4.43 (br s, 1H, OH), 4.86 (dd, J = 9.5, 4.8 Hz, 2H, 1'-H + OH), 6.60 (s, 2H, H pyrrole )、7.04 (s, 2H, H pyrrole )、8.04 (s, 2H, H pyrrole )

[0125] 13 C NMR (151 MHz, THF-d6): δ (ppm) = 62.0 (6'-C), 69.9 (2'-C), 72.9 (4'-C), 76.2 (3'-C), 81.1 (5'-C), 86.1 (1'-C), 112.86 (t, J C-F = 18.7 Hz, Ar-C ipso )、116.61 (t, J C-F = 20.3 Hz, Ar-C para )、120.2 (C pyrrole )、131.0 (C meso)、131.4 (C pyrrole )、135.6 (C pyrrole )、144.73 (ddt, J C-F = 250.2, 15.8, 4.5 Hz, Ar-C meta )、147.4 (C pyrrole )、147.95 (ddt, J C-F = 245.5, 13.1, 4.5 Hz, Ar-C ortho )

[0126] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -133.09 (dd, J = 24.7, 10.6 Hz, 2F, CF ortho )、-140.54~-140.74 (m, 2F, CF meta )、-145.40~-145.62 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 21 H 17 BF5N2O5S + [M - F] + : 515.0866、found: 515.0856、m / z calcd. for C 21 H 17 BF6N2O5SNa + [M + Na] + : 557.0748、found: 557.0749、m / z calcd. for C 42 H 34 B2F 12 N4O 10 S2Na + [2M + Na] + : 1091.1603、found: 1091.1615 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 352 [3.69]、513 [4.45]

[0127] (1.19 8-(4-Butyloxy-2,3,5,6-tetrafluorophenyl)]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) [Chemical]

[0128] 5-(Butyloxy-2,3,5,6-tetrafluorophenyl)dipyrromethane (prepared according to literature (Non-Patent Document 7)) (843 mg, 2.33 mmol) was dissolved in 40 mL of DCM. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (534 mg, 2.33 mmol, suspended in 5 mL of DCM) was added, and the reaction mixture was stirred at room temperature for 5 minutes. After the indicated time, N,N-Diisopropylethylamine (3.60 ml, 21.17 mmol) was added and stirred for 15 minutes. Then, BF3·OEt2 (2.80 ml, 21.17 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 20 minutes to 1 hour. Water was added to the mixture, and it was extracted several times with DCM. The combined organic phases were washed with water. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 1 / 1, v / v) to obtain the product as a dark red-tinged green solid (203 mg, 11%).

[0129] 1 H NMR (500 MHz, CDCl3): δ (ppm) = 1.01 (t, J = 7.4 Hz, 3H, Me), 1.52 - 1.58 (m, 2H, CH2), 1.80 - 1.86 (m, 2H, CH2), 4.38 (t, J = 6.5 Hz, 2H, CH2), 6.55 (d, J = 4.0 Hz, 2H, H pyrrole )、6.85 (d, J = 4.0 Hz, 2H, H pyrrole )、7.95 (s, 2H, H pyrrole )

[0130] 13 C NMR (500 MHz, CDCl3): δ (ppm) = 13.8 (Me), 18.9 (CH2), 32.1 (CH2), 75.4 (CH2), 105.64 (t, J C-F = 18.1 Hz, Ar-C ipso )、119.6 (C pyrrole )、130.8 (C pyrrole )、131.1 (Ar-Cpara )、135.3 (C pyrrole )、141.14 (dd, J C-F = 249.4, 19.1 Hz, Ar - C meta )、144.73 (dd, J C-F = 251.2, 19.4 Hz, Ar - C ortho )、146.2 (C pyrrole )

[0131] 19 F NMR (376 MHz, CDCl3): δ (ppm) = - 138.19 (d, J = 16.4 Hz, 2F, Ar - CF meta )、- 144.66 ~ - 144.89 (m c , 2F, BF2) - 153.63 (d, J = 23.4 Hz, 2F, Ar - CF ortho ) HRMS (ESI - TOF): m / z calcd. for C 19 H 15 BF6N2ONa + [M + Na] + : 435.1074、found: 435.1107、m / z calcd. for C 38 H 30 BF 12 N4O2Na + [2M + Na] + : 847.2255、found: 847.2309 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 348 [4.03]、517 [4.73]

[0132] (Example 2) (Preparation of Bromo - Substituted Boron Dipyrromethene) General procedure for the halogenation of 1,3,5,7 - tetramethyl BODIPY: The BODIPY was dissolved in 1,1,1,3,3,3 - hexafluoroisopropanol (HFIP), and N - bromosuccinimide (NBS) was added. The mixture was stirred at room temperature for the indicated time. Then, the reaction mixture was diluted with EtOAc and washed several times with water. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by column chromatography.

[0133] (2.1 2,6 - Dibromo - 8 - (4 - fluorophenyl - 3 - nitrophenyl) - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - boron - 3a,4a - diaza - s - indacene) [Chemical Structure]

[0134] According to the general synthetic procedure, 2,6 - dibromo - 8 - (4 - fluorophenyl - 3 - nitrophenyl) - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - boron - 3a,4a - diaza - s - indacene was prepared. 8 - (4 - fluorophenyl - 3 - nitrophenyl) - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - boron - 3a,4a - diaza - s - indacene (60 mg, 0.16 mmol) and NBS (66 mg, 0.37 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n - hexane = 1 / 4, v / v) to give the product as a red - tinged green solid (48 mg, 57%).

[0135] Mp: >250 °C 1 1H NMR (500 MHz, THF - d8): δ (ppm) = 1.48 (s, 6H, Me), 2.58 (s, 6H, Me), 7.71 (dd, J = 10.8, 8.5 Hz, 1H, Ar - H meta )、7.81 (ddd, J = 8.5, 4.2, 2.2 Hz, 1H, Ar - H ortho )、8.30 (dd, J = 7.0, 2.3 Hz, 1H, Ar - H ortho )

[0136] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.96 (Me), 14.7 (Me), 112.6 - 122.7 (m, CBr), 120.99 (d, J C-F = 20.9 Hz, Ar-C meta )、127.9 (d, J C-F = 2.1 Hz, Ar-C ortho )、131.4 (C pyrrole )、132.2 *, 136.9 (d, J C-F = 9.3 Hz, Ar-C ortho )、139.9 *, 141.2 (C pyrrole )、155.7 (C pyrrole )、157.10 (d, J C-F = 266.0 Hz, Ar-C para ). * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0137] 19 F NMR (376 MHz, THF-d8): δ (ppm) = -117.54 (s, 1F, CF), -146.26 - -146.51 (m c , 2F, BF2) UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 538 [4.66]

[0138] (2.2 2,6 - Dibromo - 8 - pentafluorophenyl - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene)

Chemical Structure

[0139] According to the general synthesis procedure, 2,6-dibromo-8-pentafluorophenyl-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-Pentafluorophenyl-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 8)) (100 mg, 0.24 mmol) and NBS (107 mg, 0.60 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 9, v / v) to obtain the product as an orange-red solid (85 mg, 62%).

[0140] Mp: >250 °C 1 1H NMR (500 MHz, CDCl3): δ (ppm) = 1.62 (s, 6H, Me), 2.63 (s, 6H, Me)

[0141] 13 13C NMR (126 MHz, CDCl3): δ (ppm) = 13.1 (Me), 14.1 (Me), 113.2 (CBr), 114.0 (Ar-C ipso )、121.2 (C meso )、130.2 (C pyrrole )、139.1 (C pyrrole )、156.6 (C pyrrole )

[0142] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -138.79~-138.87 (m, 2F, CF meta )、-145.62~-145.87 (m c , 2F, BF2)、-148.83 (t, J = 20.8 Hz, 1F, CF para )、-158.36~-158.49 (m, 2F, CF meta ) HRMS (ESI-TOF): m / z calcd. for C 19 H 11 BF7N2 - [M - H] -:570.9255, found:570.9248 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 551 [4.79]

[0143] (2.3 2,6 - Dibromo - 8 - [4 - (N - butylamino) - 3 - nitrophenyl] - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene)

Chem.

[0144] According to the general synthetic procedure, 2,6 - dibromo - 8 - [4 - (N - butylamino) - 3 - nitrophenyl] - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene was prepared. 8 - [4 - (N - butylamino) - 3 - nitrophenyl] - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene (95 mg, 0.22 mmol) and NBS (96 mg, 0.54 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n - hexane = 1 / 9, v / v) to obtain the product as a red solid (81 mg, 63%).

[0145] Mp: 191~194 °C 1 1H NMR (500 MHz, THF - d8): δ (ppm) = 1.02 (t, J = 7.4 Hz, 3H, Me butyl )、1.49~1.55 (m, 2H, CH2)、1.59 (s, 6H, Me)、1.75~1.79 (m, 2H, CH2)、2.56 (s, 6H, Me)、3.45 (td, J = 7.3, 5.4 Hz, 1H, CH2)、7.27 (d, J = 8.8 Hz, 1H, Ar - H meta )、7.43 (dd, J = 8.7, 2.1 Hz, 1H, Ar - H ortho)、8.18 (d, J = 2.2 Hz, 1H, Ar-H ortho )、8.26 (t, J = 5.5 Hz, 1H, NH)

[0146] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.9 (Me)、14.3 (Me)、14.9 (Me butyl )、21.3 (CH2)、32.1 (CH2)、43.8 (CH2)、112.3 (CBr)、116.5 (Ar-C meta )、121.1 (C meso )、127.9 (Ar-C ortho )、132.0 (C pyrrole )、133.2*、136.6 (Ar-C ortho )、141.1 (C pyrrole )、146.9 (Ar-C para )、154.9 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0147] 19 F NMR (376 MHz, THF-d8): δ (ppm) = -145.98~-146.84 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 23 H 25 BBr2F2N4O2Na + [M+Na] + : 621.0277, found: 621.0314, m / z calcd. for C 46 H 50 B2Br4F4N8O4Na + [2M+Na] + : 1219.0662, found: 1219.0712 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 397 [4.19], 533 [4.87]

[0148] (2.4 2,6-dibromo-8-[4-(N-2-hydroxyethylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0149] According to the general synthetic procedure, 2,6-dibromo-8-[4-(N-2-hydroxyethylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(N-2-hydroxyethylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (90 mg, 0.21 mmol) and NBS (94 mg, 0.53 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 4 / 1, v / v) to obtain the product as a red solid (39 mg, 32%).

[0150] Mp: >250 °C 1 1H NMR (500 MHz, THF-d8): δ (ppm) = 1.59 (s, 6H, Me), 2.56 (s, 6H, Me), 3.52 (t, J = 5.4 Hz, 2H, CH2), 3.82 (t, J = 5.4 Hz, 2H, CH2), 7.30 (d, J = 8.8 Hz, 1H, Ar-H meta ), 7.42 (dd, J = 8.8, 2.2 Hz, 1H, Ar-H ortho ), 8.17 (d, J = 2.1 Hz, 1H, Ar-H ortho )

[0151] 13 13C NMR (126 MHz, THF-d8): δ (ppm) = 13.9 (Me), 14.9 (Me), 46.2 (CH2), 60.7 (CH2), 112.2 (CBr), 116.7 (Ar-C meta), 121.2*, 127.8 (Ar-C ortho ), 132.0 (C pyrrole ), 133.3*, 136.5 (Ar-C ortho ), 141.1 (C pyrrole ), 142.1 (Ar-C para ), 154.8 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro of the aryl moiety.

[0152] 19 F NMR (376 MHz, THF-d8): δ (ppm) = -146.26~-146.57 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 21 H 21 BBr2F2N4O3Na + [M+Na] + : 608.9913, found: 608.9924, m / z calcd. for C 21 H 21 BBr2F2N4O3K + [M+K] + : 624.9653, found: 624.9670, m / z calcd. for C 42 H 42 B2Br4F4N8O6K + [2M+K] + : 1210.9674, found: 1210.9682 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 401 [3.76], 528 [4.36]

[0153] (2.5 2,6-Dibromo-8-[3-nitro-4-(N-2-prop-2-enylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) [Chemistry]

[0154] According to the general synthesis procedure, 2,6-dibromo-8-[3-nitro-4-(N-2-prop-2-enylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[3-Nitro-4-(N-2-prop-2-enylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (87 mg, 0.21 mmol) and NBS (91 mg, 0.51 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 9, v / v) to obtain the product as a red solid (53 mg, 44%).

[0155] Mp: 209~214 °C 1 H NMR (500 MHz, THF-d8): δ (ppm) = 1.58 (m, 6H, Me), 2.56 (s, 6H, Me), 4.12~4.15 (m, 2H, CH2), 5.23 (ddd, J = 10.4, 1.5 Hz, 1H, H2C=CH-), 5.31 (ddd, J = 17.2, 1.6 Hz, 1H, H2C=CH-), 6.01 (ddt, J = 17.2, 10.1, 4.9 Hz, 1H, H2C=CH-), 7.20 (d, J = 8.8 Hz, 1H, Ar-H meta )、7.41 (dd, J = 8.8, 2.1 Hz, 1H, Ar-H ortho )、8.19 (d, J = 2.2 Hz, 1H, Ar-H ortho )、8.45 (t, J = 5.9 Hz, 1H, NH)

[0156] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.9 (Me), 14.8 (Me), 46.1 (CH2), 112.3 (CBr), 116.9 (H2C=CH-), 117.0 (Ar-C meta )、121.5*, 127.7 (Ar-C ortho)、131.99 (C pyrrole )、133.5 *, 134.9 (H2C=CH-), 136.4 (Ar-C ortho )、141.1 (C pyrrole )、142.1 (C meso )、146.8 (Ar-C para )、154.9 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0157] 19 19F NMR (376 MHz, THF-d8): δ (ppm) = -146.27~-146.56 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 22 H 21 BBr2FN4O2 + [M - F] + : 563.0082, found: 563.0083, m / z calcd. for C 22 H 21 BBr2F2N4O2Na + [M + Na] + : 604.9964, found: 604.9968, m / z calcd. for C 22 H 21 BBr2F2N4O2K + [M + K] + : 620.9703, found: 620.9707, m / z calcd. for C 44 H 42 B2Br4F4N8O4Na + [2M + Na] + : 1187.0036, found: 1187.0044 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 399 [4.17], 528 [4.85]

[0158] (2.6 2,6-Dibromo-8-[3-nitro-4-(N-2-prop-2-ynylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) [Chemical formula]

[0159] According to the general synthetic procedure, 2,6-dibromo-8-[3-nitro-4-(N-2-prop-2-ynylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[3-Nitro-4-(N-2-prop-2-ynylamino)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (90 mg, 0.21 mmol) and NBS (95 mg, 0.53 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 9, v / v) to obtain the product as a red solid (35 mg, 28%).

[0160] Mp: 229~235 °C 1 1H NMR (500 MHz, THF-d8): δ (ppm) = 1.57 (m, 6H, Me), 2.56 (s, 6H, Me), 2.76 (t, J = 2.4 Hz, 1H, CH), 4.30 (dd, J = 5.9, 2.5 Hz, 2H, CH2), 7.36 (d, J = 8.8 Hz, 1H, Ar-H meta ), 7.50 (dd, J = 8.8, 2.1 Hz, 1H, Ar-H ortho ), 8.21 (d, J = 2.2 Hz, 1H, Ar-H ortho ), 8.43 (t, J = 5.9 Hz, 1H, NH)

[0161] 1313C NMR (126 MHz, THF-d8): δ (ppm) = 13.99 (Me), 14.8 (Me), 33.2 (CH2), 73.5 (CH), 80.2 (C), 112.4 (CBr), 117.1 (Ar-C meta ), 122.5 *, 127.7 (Ar-C ortho ), 131.98 (C pyrrole ), 134.1 *, 136.4 (Ar-C ortho ), 141.2 (C pyrrole ), 141.9 (C meso ), 145.9 (Ar-C para ), 154.95 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0162] 19 19F NMR (376 MHz, THF-d8): δ (ppm) = -146.27~-146.56 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 22 H 19 BBr2FN4O2 + [M - F] + : 560.9926, found: 560.9975, m / z calcd. for C 22 H 19 BBr2F2N4O2Na + [M + Na] + : 602.9808, found: 602.9862, m / z calcd. for C 22 H 19 BBr2F2N4O2K + [M + K] + : 618.9547, found: 618.9608, m / z calcd. for C 44 H 38 B2Br4F4N8O4Na + [2M + Na] + : 1182.9723, found: 1182.9824 UV / Vis (DCM): λmax (nm)[log(ε / Lmol -1 cm -1 )]=397[4.25], 533[4.87]

[0163] (2.7 2,6-Dibromo-8-[4-(N-6-methoxy-6-oxohexylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) [Chemical formula]

[0164] According to the general synthesis procedure, 2,6-dibromo-8-[4-(N-6-methoxy-6-oxohexylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(N-6-methoxy-6-oxohexylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (95 mg, 0.19 mmol) and NBS (83 mg, 0.46 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 9, v / v) to obtain the product as a red solid (67 mg, 54%).

[0165] Mp: 152~155 °C 1 H NMR(500MHz,THF-d8): δ(ppm)=1.48~1.54(m, 2H, CH2), 1.59(s, 6H, Me), 1.67~1.71(m, 2H, CH2), 1.76~1.82(m, 2H, CH2), 2.33(t, J = 7.3Hz, 2H, CH2), 2.56(s, 6H, Me), 3.46(td, J = 7.3, 5.6Hz, 2H, CH2), 3.60(s, 3H, Me OMe )、7.27(d, J = 8.8Hz, 1H, Ar-H meta )、7.43(dd, J = 8.8, 2.2Hz, 1H, Ar-Hortho ), 8.18 (d, J = 2.1 Hz, 1H, Ar-H ortho ), 8.27 (t, J = 5.5 Hz, 1H, NH)

[0166] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.9 (Me), 14.9 (Me), 25.98 (CH2), 27.6 (CH2), 29.4 (CH2), 34.3 (CH2), 43.9 (CH2), 51.5 (Me OMe ), 112.6 (CBr), 116.5 (Ar-C meta ), 121.2 *, 127.9 (Ar-C ortho ), 132.0 (C pyrrole ), 133.2 *, 136.6 (Ar-C ortho ), 141.1 (C pyrrole ), 142.1 (C meso ), 146.9 (Ar-C para ), 154.9 (C pyrrole ), 173.8 (CO) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0167] 19 F NMR (376 MHz, THF-d8): δ (ppm) = -146.25~-146.56 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 26 H 29 BBr2F2N4O4Na + [M+Na] + : 693.0488, found: 693.0503, m / z calcd. for C 26 H 29 BBr2F2N4O4K + [M+K] + : 709.0228, found: 709.0235, m / z calcd. for C 52 H 58 B2Br4F4N8O8Na +[2M + Na] + : 1363.1085, found: 1363.1112 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 404 [4.19], 532 [4.87]

[0168] (2.8 2,6 - dibromo - 8 - [4 - (N,N - dibutylamino) - 3 - nitrophenyl] - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene)

Chem.

[0169] According to the general synthetic procedure, 2,6 - dibromo - 8 - [4 - (N,N - dibutylamino) - 3 - nitrophenyl] - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene was prepared. 8 - [4 - (N,N - dibutylamino) - 3 - nitrophenyl] - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene (90 mg, 0.18 mmol) and NBS (80 mg, 0.45 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n - hexane = 1 / 9, v / v) to obtain the product as a red solid (68 mg, 57%).

[0170] Mp: 157 - 159 °C 1 H NMR (500 MHz, THF - d8): δ (ppm) = 0.89 (t, J = 7.3 Hz, 6H, Me butyl )、1.28 - 1.35 (m, 4H, CH2)、1.53 - 1.59 (m, 10H, Me + CH2)、2.56 (s, 6H, Me)、3.25 (t, J = 7.1 Hz, 4H, CH2)、7.39 (dd, J = 8.7, 2.0 Hz, 1H, Ar - H meta )、7.46 (dd, J = 8.7, 1.4 Hz, 1H, Ar - Hortho ), 7.77 (d, J = 2.0 Hz, 1H, Ar-H ortho )

[0171] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.99 (Me butyl ), 14.3 (Me), 14.6 (Me), 21.0 (CH2), 30.6 (CH2), 52.8 (CH2), 112.3 - 112.4 (m, CBr), 123.7 (Ar-C meta ), 125.4 *, 127.2 (Ar-C ortho ), 131.8 (C pyrrole ), 133.2 (Ar-C ortho ), 141.1 (C pyrrole ), 141.7 (C meso ), 143.9 *, 146.4 (Ar-C para ), 154.97 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0172] 19 F NMR (376 MHz, THF-d8): δ (ppm) = -146.31 - -146.52 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 27 H 34 BBr2F2N4O2 + [M + H] + : 655.1084, found: 655.1087, m / z calcd. for C 27 H 33 BBr2F2N4O2Na + [M + Na] + : 677.0903, found: 677.0899, m / z calcd. for C 54 H 66 B2Br4F4N8O4Na + [2M + Na] + : 1331.1914, found: 1331.1930 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 389 [4.03], 533 [4.86]

[0173] (2.9 2,6 - dibromo - 8 - [4 - (N - 1 - hydroxymethyl - 2 - hydroxyethylamino) - 3 - nitrophenyl] - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene)

Chem.

[0174] According to the general synthetic procedure, 2,6 - dibromo - 8 - [4 - (N - 1 - hydroxymethyl - 2 - hydroxyethylamino) - 3 - nitrophenyl] - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene was prepared. 8 - [4 - (N - 1 - hydroxymethyl - 2 - hydroxyethylamino) - 3 - nitrophenyl] - 1,3,5,7 - tetramethyl - 4,4 - difluoro - 4 - bora - 3a,4a - diaza - s - indacene (94 mg, 0.21 mmol) and NBS (91 mg, 0.51 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n - hexane = 9 / 1, v / v) to obtain the product as a red solid (61 mg, 48%).

[0175] Mp: >250 °C 1 1H NMR (500 MHz, THF - d8): δ (ppm) = 1.61 (s, 6H, Me), 2.56 (s, 6H, Me), 3.73 - 3.78 (m, 2H, CH2), 3.81 - 3.84 (m, 3H, CH2 + CH), 4.28 (t, J = 5.1 Hz, 2H, OH), 7.39 - 7.40 (m, 2H, Ar - H meta + Ar - H ortho )、8.17 (dd, J = 1.5, 1.0 Hz, 1H, Ar - H ortho)、8.65(d, J = 7.8 Hz, 1H, NH)

[0176] 13 C NMR(126 MHz, THF-d8): δ(ppm) = 13.9 (Me), 14.9 (Me), 56.96 (CH), 61.6 (CH2), 112.2~112.3 (m c , CBr), 117.3 (Ar-C meta ), 121.0*, 127.9 (Ar-C ortho ), 132.0 (C pyrrole ), 133.2*, 136.3 (Ar-C ortho ), 141.1 (C pyrrole ), 142.2 (C meso ), 146.8 (Ar-C para ), 154.8 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0177] 19 F NMR(376 MHz, THF-d8): δ(ppm) = -146.12~ -146.72 (m c , 2F, BF2) HRMS(ESI-TOF): m / z calcd. for C 22 H 23 BBr2FN4O4 + [M - F] + : 597.0137, found: 597.0165, m / z calcd. for C 22 H 23 BBr2F2N4O4Na + [M + Na] + : 639.0019, found: 639.0050 UV / Vis(MeOH): λ max (nm)[log(ε / Lmol -1 cm -1 )] = 402[4.03], 528[4.72]

[0178] (2.10 2,6-Dibromo-8-[4-(N-butylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) [Chemical Structure]

[0179] According to the general synthetic procedure, 2,6-dibromo-8-[4-(N-butylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(N-butylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 8)) (95 mg, 0.20 mmol) and NBS (91 mg, 0.51 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 9, v / v) to obtain the product as a red solid (68 mg, 54%).

[0180] Mp: 133~135 °C 1 1H NMR (500 MHz, THF-d8): δ (ppm) = 0.96 (t, J = 7.4 Hz, 3H, Me butyl )、1.39~1.46 (m, 2H, CH2)、1.61~1.67 (m, 2H, CH2)、1.73 (s, 6H, Me)、2.57 (s, 6H, Me)、3.45~3.50 (m, 2H, CH2)、5.83 (s, 1H, NH)

[0181] 13 13C NMR (126 MHz, THF-d8): δ (ppm) = 13.1 (Me)、14.0 (Me), 14.3 (Me butyl )、20.9 (CH2)、33.9 (CH2)、45.96 (CH2)、98.61 (t, J C-F = 19.9 Hz, Ar-C ipso)、112.9~112.99(m, CBr)、127.5(C meso )、131.9(Ar-C para )、132.0(C pyrrole )、138.82(dd, J C-F =241.3, 26.0Hz, Ar-C meta )、140.5(C pyrrole )、145.26(dd, J C-F =242.0, 11.9Hz, Ar-C ortho )、156.2(C pyrrole )

[0182] 19 19F NMR(376MHz, CDCl3): δ(ppm)= -145.65(d, J = 17.6Hz, 2F, CF meta )、-146.17~ -146.42(m c , 2F, BF2)、-161.13(d, J = 17.6Hz, 2F, CF meta ) HRMS(ESI-TOF): m / z calcd. for C 23 H 22 BBr2F6N3Na + [M + Na] + : 648.0049、found: 648.0058、m / z calcd. for C 46 H 44 B2Br4F 12 N6Na + [2M + Na] + : 1237.0207、found: 1237.0221 UV / Vis(DCM): λ max (nm)[log(ε / Lmol -1 cm -1 )]= 391[4.12]、545[4.93]

[0183] (2.11 2,6-Dibromo-8-[4-(N-prop-2-ynylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0184] According to the general synthesis procedure, 2,6-dibromo-8-[4-(N-prop-2-ynylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(N-prop-2-ynylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (87 mg, 0.19 mmol) and NBS (86 mg, 0.48 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 9, v / v) to obtain the product as a green solid (54 mg, 44%).

[0185] Mp: 184~188 °C 1 H NMR (500 MHz, THF-d8): δ (ppm) = 1.72 (s, 6H, Me), 2.58 (s, 6H, Me), 2.72 (t, J = 2.4 Hz, 1H, CH), 4.19~4.21 (m, 2H, CH2), 6.20~6.23 (s, 1H, NH)

[0186] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.1 (Me), 14.1 (Me), 35.6 (CH2), 73.5 (C), 81.0 (CH), 101.20 (t, J C-F = 18.7 Hz, Ar-C ipso )、113.0~113.1 (m, CBr)、127.1 (C meso )、130.8~131.0 (m, Ar-C para )、131.8 (C pyrrole )、139.85 (ddd, J C-F = 242.5, 15.8, 10.5 Hz, Ar-C meta )、140.5 (C pyrrole )、145.03 (dd, J C-F = 244.1, 16.7 Hz, Ar-Cortho ), 156.4 (C pyrrole )

[0187] 19 F NMR (376 MHz, CDCl3): δ (ppm) = -145.33 (d, J = 14.5 Hz, 2F, CF meta ), -146.14~-146.29 (m c , 2F, BF2), -158.57 (d, J = 15.4 Hz, 2F, CF meta ) HRMS (ESI-TOF): m / z calcd. for C 22 H 15 BBr2F6N3 - [M - H] - : 605.9615, found: 605.9587 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 391 [3.97], 546 [4.76]

[0188] (2.12 2,6-Dibromo-8-[4-(N-2-hydroxyethylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0189] According to the general synthesis procedure, 2,6-dibromo-8-[4-(N-2-hydroxyethylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(N-2-hydroxyethylamino)-2,3,5,6-tetrafluorophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (94 mg, 0.21 mmol) and NBS (92 mg, 0.52 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 9, v / v) to obtain the product as a red solid (56 mg, 44%).

[0190] Mp: 103~108 °C 1 H NMR (500 MHz, THF-d8): δ (ppm) = 1.73 (s, 6H, Me), 2.57 (s, 6H, Me), 3.54~3.58 (m, 2H, CH2), 3.69~3.72 (m, 2H, CH2), 4.05 (t, J = 5.2 Hz, 1H, OH), 5.71~5.74 (NH)

[0191] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.2 (Me), 14.0 (Me), 48.7 (CH2), 62.3 (CH2), 112.9~113.0 (m, CBr), 124.7 (C meso ), 132.0 (Ar-C para ), 132.0 (C pyrrole ), 140.5 (C pyrrole ), 156.2 (C pyrrole )

[0192] 19 F NMR (376 MHz, CDCl3): δ (ppm) = -145.76 (d, J = 15.7 Hz, 2F, CF meta ), -146.21~-146.38 (m c , 2F, BF2), -160.61 (d, J = 15.4 Hz, 2F, CF meta ) HRMS (ESI-TOF): m / z calculated for C 24 H 18 BBr2F6N3ONa + [M + Na] + : 635.9686, found: 635.9687, m / z calculated for C 24 H 18 BBr2F6N3OK + [M + K] + : 651.9425, found: 651.9436, m / z calculated for C 48 H 36 B2Br4F 12 N6O2Na + [2M + Na] + : 1248.9479, found: 1248.9480 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 391 [4.03], 546 [4.83]

[0193] (2,6-dibromo-8-[3-nitro-4-(1'-thio-β-D-glucosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) [Chemical formula]

[0194] According to the general synthetic procedure, 2,6-dibromo-8-[3-nitro-4-(1'-thio-β-D-glucosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[3-Nitro-4-(1'-thio-β-D-glucosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (100 mg, 0.18 mmol) and NBS (79 mg, 0.44 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 9 / 1, v / v) to obtain the product as a reddish-brown solid (44 mg, 35%).

[0195] Mp: >250 °C 1 H NMR (500 MHz, THF-d8): δ (ppm) = 1.50 (d, J = 6.1 Hz, 6H, Me), 2.57 (s, 6H, Me), 3.34 - 3.38 (m, 3H, 2'-H + 3'-H + 4'-H), 3.43 (ddd, J = 8.6, 5.7, 2.1 Hz, 1H, 5'-H), 3.56 (d, J = 7.1 Hz, 1H, 6'-H), 3.81 (dd, J = 11.9, 2.5 Hz, 1H, 6'-H), 4.57 (br s, 1H, OH), 4.81 (br s, 1H, OH), 4.90 - 4.92 (m, 1H, 1'-H), 5.06 (br s, 1H, OH), 7.66 (dd, J = 8.3, 2.0 Hz, 1H, Ar-H meta )、8.16 (d, J = 8.3 Hz, 1H, Ar-H ortho )、8.26 (d, J = 2.0 Hz, 1H, Ar-H ortho )

[0196] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.9 (Me), 14.8 (Me), 63.1 (6'-C), 71.3 (4'-C), 73.96 (2'-C), 80.3 (3'-C), 83.3 (5'-C), 86.6 (1'-C), 112.6 (CBr), 126.6 (Ar-C ortho )、131.5 (Ar-C meta), 132.4 (C pyrrole ), 134.3 (Ar-C ortho ), 139.3 (Ar-C para ), 140.5*, 141.2 (C pyrrole ), 141.3*, 148.5 (C meso ), 155.4 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro of the aryl moiety.

[0197] 19 19F NMR (376 MHz, THF-d8): δ (ppm) = -146.22~-146.46 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 25 H 26 BBr2F2N3O7SNa + [M+Na] + : 743.9791, found: 743.9789 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 372 [4.04], 530 [4.72]

[0198] (2.14 2,6-Dibromo-8-[3-nitro-4-(1'-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chemical Structure

[0199] According to the general synthesis procedure, 2,6-dibromo-8-[3-nitro-4-(1’-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[3-Nitro-4-(1’-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (100 mg, 0.18 mmol) and NBS (79 mg, 0.44 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 9 / 1, v / v) to obtain the product as a red solid (58 mg, 45%).

[0200] Mp: >250 °C 1 H NMR (500 MHz, DMSO-d6): δ (ppm) = 1.40 (s, 6H, Me), 2.47 (s, 6H, Me), 3.39 - 3.46 (m, 3H, 3’-H + 6’-H), 3.54 - 3.62 (m, 3H, 2’-H + 5’-H), 3.72 (br s, 1H, 4’-H), 4.90 (d, J = 9.4 Hz, 1H, 1’-H), 7.73 (d, J = 7.0 Hz, 1H, Ar-H ortho )、8.03 (d, J = 8.0 Hz, 1H, Ar-H meta )、8.27 (br s, 1H, Ar-H ortho )

[0201] 13 C NMR (126 MHz, DMSO-d6): δ (ppm) = 13.5 (Me), 14.1 (Me), 60.3 (6’-C), 68.2 (4’-C), 69.1 (2’-C), 74.6 (3’-C), 79.2 (5’-C), 84.9 (1’-C), 111.5 - 111.6 (m, CBr), 125.4 (Ar-C ortho )、129.9*, 130.1 (Ar-C meta )、130.3 (C pyrrole )、133.3 (Ar-C ortho )、136.99*, 139.4 (Ar-C para )、140.2 (C pyrrole)、146.8 (C meso )、153.7 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0202] 19 19F NMR (376 MHz, DMSO-d6): δ (ppm) = -143.15~-143.36 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 25 H 26 BBr2F2N3O7SNa + [M+Na] + : 743.9791, found: 743.9849 UV / Vis (MeOH): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 371 [4.08], 530 [4.80]

[0203] (2.15 2,6-Dibromo-8-[2,3,5,6-tetrafluoro-4-(1’-thio-β-D-glucopyranosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chemical formula

[0204] According to the general synthesis procedure, 2,6-dibromo-8-[2,3,5,6-tetrafluoro-4-(1’-thio-β-D-glucosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[2,3,5,6-Tetrafluoro-4-(1’-thio-β-D-glucosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (100 mg, 0.17 mmol) and NBS (75 mg, 0.42 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 9 / 1, v / v) to obtain the product as a dark yellow solid (79 mg, 62%).

[0205] Mp: 162~169 °C 1 1H NMR (500 MHz, THF-d8): δ (ppm) = 1.69 (s, 6H, Me), 2.58 (s, 6H, Me), 3.21 (dd, J = 5.4, 2.6 Hz, 1H, 5’-H), 3.26~3.29 (m, 2H, 2’-H + 3’-H + 4’-H), 3.50 (dd, J = 11.7, 5.3 Hz, 1H, 6’-H), 3.67 (dd, J = 11.7, 2.6 Hz, 1H, 6’-H), 4.89~4.90 (m, 1H, 1’-H), 4.91 (s, 1H, OH)

[0206] 13 13C NMR (126 MHz, THF-d8): δ (ppm) = 13.3 (Me), 14.1 (Me), 62.9 (6’-C), 71.5 (2’-C), 76.3 (4’-C), 79.97 (3’-C), 82.9 (5’-C), 85.7 (1’-C), 113.4 (CBr), 117.1 (Ar-C ipso ), 130.9 (C pyrrole ), 140.6 (C pyrrole ), 157.0 (C pyrrole )

[0207] 1919F NMR (376 MHz, THF-d8): δ (ppm) = -131.51 (dd, J = 24.2, 10.3 Hz, 2F, CF ortho ), -142.80 (dd, J = 24.1, 10.7 Hz, 2F, CF meta ), -146.07~-146.32 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 25 H 23 BBr2F6N2O5SNa + [M + Na] + : 770.9563、found: 770.9560、m / z calcd. for C 50 H 46 B2Br4F 12 N4O 10 S2Na + [2M + Na] + : 1518.9235、found: 1518.9218 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 544 [4.63]

[0208] (2.16 2,6-dibromo-8-[2,3,5,6-tetrafluoro-4-(1'-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0209] According to the general synthesis procedure, 2,6-dibromo-8-[2,3,5,6-tetrafluoro-4-(1'-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[2,3,5,6-Tetrafluoro-4-(1'-thio-β-D-galactosyl)phenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (100 mg, 0.17 mmol) and NBS (75 mg, 0.42 mmol) were dissolved in 2 mL of HFIP. The mixture was stirred for 1 minute. The crude product was purified by column chromatography (silica gel, DCM / MeOH = 9 / 1, v / v) to obtain the product as a dark yellow solid (73 mg, 58%).

[0210] Mp: 173~180 °C 1 H NMR (500 MHz, THF-d8): δ (ppm) = 1.68 (s, 6H, Me), 2.58 (s, 6H, Me), 3.38 (dd, J = 8.5, 3.7 Hz, 1H, 3'-H), 3.45 (t, J = 6.0 Hz, 1H, 5'-H), 3.47 (dd, J = 10.6, 5.6 Hz, 1H, 6'-H), 3.50 (dd, J = 10.6, 6.0 Hz, 1H, 6'-H), 3.59~3.61 (m, 2H, 4'-H, 6'-H), 3.83 (d, J = 2.7 Hz, 1H, 2'-H), 4.79 (d, J = 9.3 Hz, 1H, 1'-H)

[0211] 13 C NMR (126 MHz, THF-d8): δ (ppm) = 13.3 (Me), 14.1 (Me), 62.1 (6'-C), 70.0 (2'-C), 73.4 (4'-C), 76.5 (3'-C), 81.4 (5'-C), 86.2 (1'-C), 113.3~113.4 (m, CBr), 114.00 (t, J C-F = 18.3 Hz, Ar-C ipso )、116.90 (t, J C-F = 20.6 Hz, Ar-C para )、125.9 (C meso )、130.9 (C pyrrole )、140.6 (Cpyrrole ), 144.33 (dd, J C-F = 247.6, 18.1 Hz, Ar-C meta ), 149.27 (dd, J C-F = 246.0, 14.9 Hz, Ar-C ortho ), 157.0 (C pyrrole )

[0212] 19 F NMR (376 MHz, THF-d8): δ (ppm) = -131.09 (dd, J = 25.2, 11.9 Hz, 2F, CF ortho ), -142.89 (dd, J = 24.3, 10.8 Hz, 2F, CF meta ), -146.07~-146.32 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 25 H 23 BBr2F6N2O5SNa + [M + Na] + : 770.9563, found: 770.9550, m / z calcd. for C 50 H 46 B2Br4F 12 N4O 10 S2Na + [2M + Na] + : 1518.9235, found: 1518.9208 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 393 [3.96], 544 [4.83]

[0213] (2.17 2-Bromo-8-pentafluorophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene

Chem.

Chem.

[0214] 8-Pentafluorophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 7)) (257 mg, 0.72 mmol) was dissolved in 6 mL of DCM. NBS (286 mg, 1.61 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. Then, the reaction mixture was diluted with EtOAc and washed several times with water. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 2 / 1, v / v) to give 2,6-dibromo-8-pentafluorophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (31 mg, 8%) as a greenish red solid, and 2-bromo-8-pentafluorophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (148 mg, 47%) as a red solid.

[0215] 2,6-Dibromo-8-pentafluorophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene: 1 1H NMR (400 MHz, CDCl3): δ (ppm) = 6.54 (s, 2H, H pyrrole )、7.89 (s, 2H, H pyrrole )

[0216] 13 13C NMR (126 MHz, CDCl3): δ (ppm) = 107.1 (t, J C-F = 17.6 Hz, Ar-C ipso )、108.95~109.0 (m, C Br )、128.9 (Ar-C para )、130.6 (C pyrrole )、134.9 (C pyrrole )、138.1 (dd, J C-F = 254.9, 6.2 Hz, Ar-C meta )、144.5 (dd, J C-F = 253.2, 8.4 Hz, Ar-Cortho ) 147.0 (C pyrrole )

[0217] 19 FNMR (376 MHz, CDCl3): δ (ppm) = -136.30 (d, J = 19.3 Hz, 2F, CF meta )、-144.63~-144.85 (m c , 2F, BF2)、-148.23 (t, J = 20.8 Hz, CF para )、-158.58 (t, J = 19.0 Hz (m, 2F, CF ortho )

[0218] 2-Bromo-8-pentafluorophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene: M.P. (°C): 141~146 1 H NMR (700 MHz, CDCl3): δ (ppm) = 6.63~6.64 (m, 1H, H pyrrole )、6.77 (s, 1H, H pyrrole )、6.88 (d, J = 4.5 Hz, 1H, H pyrrole )、7.82 (s, 1H, H pyrrole )、8.05 (s, 1H, H pyrrole )

[0219] 13 C NMR (176 MHz, CDCl3): δ (ppm) = 107.5~107.7 (m, Ar-C ipso +CBr)、121.1 (C pyrrole )、129.2 (C pyrrole )、129.2 (Ar-C para )、132.1 (C pyrrole )、134.2 (C pyrrole )、135.7 (C pyrrole )、138.0 (ddd, J C-F = 255.2, 28.7, 5.2 Hz, Ar-C meta )、144.6 (dd, J C-F = 253.0, 10.9 Hz, Ar-C ortho ) 144.8 (C pyrrole )、149.1 (C pyrrole )

[0220] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -140.15 (dt, J = 21.0, 5.5 Hz, 2F, CF meta ), -144.51~-144.73 (m c , 2F, BF2), -153.67 (tt, J = 20.7, 2.9 Hz, 1F, CF para ), -162.35~-162.50 (m, 2F, CF ortho ) HRMS (ESI-TOF): m / z calcd. for C 15 H5BBrF6N2 + [M - F] + : 416.9628, found: 416.9636, m / z calcd. for C 15 H5BBrF7N2Na + [M + Na] + : 458.9510, found: 458.9516 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 536 [4.75]

[0221] General procedure for the halogenation of BODIPY: Dissolve BODIPY in DCM and add NBS. Stir the mixture at room temperature for the indicated time. Then, dilute the reaction mixture with EtOAc and wash it several times with water. Dry the organic layer over Na2SO4, filter it, and evaporate to dryness. Purify the crude product by column chromatography.

[0222] (2.18 2-Bromo-8-(4-fluoro-3-nitrophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0223] According to the general synthesis procedure, 2-bromo-8-(4-fluoro-3-nitrophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Fluoro-3-nitrophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 14)) (100 mg, 0.30 mmol) and NBS (129 mg, 0.75 mmol) were dissolved in 5 mL of DCM. The mixture was stirred for 3 hours. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 1 / 1, v / v) to obtain the product as a red-tinged green solid (79 mg, 64%).

[0224] M.P. (°C): 165 - 167 1 1H-NMR (700 MHz, CDCl3): δ (ppm) = 6.66 - 6.67 (m, 1H, H pyrrole ), 6.81 (s, 1H, H pyrrole ), 6.93 (d, J = 4.4 Hz, 1H, H pyrrole ), 7.53 (dd, J = 10.1, 8.5 Hz, 1H, Ar-H meta ), 7.83 - 7.85 (m, 2H, H pyrrole , Ar-H ortho ), 8.06 (s, 1H, H pyrrole ), 8.27 (dd, J = 6.8, 2.3 Hz, 1H, Ar-H ortho )

[0225] 13 13C-NMR (176 MHz, CDCl3): δ (ppm) = 107.2 (CBr), 119.5 (d, J C-F = 21.4 Hz, Ar-C meta ), 120.8 (C pyrrole ), 127.8 (Ar-C ortho ), 129.8 (C pyrrole ), 130.1*, 132.6 (C pyrrole ), 134.0 (C pyrrole ), 135.3 (C pyrrole ), 136.9 (d, J C-F = 9.1 Hz, Ar-C ortho ), 137.7 (d, J C-F=8.2Hz)*, 142.0 (C meso ), 143.96 (C pyrrole ), 147.98 (C pyrrole ), 156.89 (d, J C,F =271.0Hz, Ar-C para ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0226] 19 19F-NMR (376 MHz, CDCl3): δ (ppm) = -116.83 (s, 1F, CF), -144.18~-144.63 (m, 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 15 H8BBrF3N3O2Na + [M+Na] + : 431.9737, found 431.9743 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 527 [4.69]

[0227] (2.19 2,6-Dibromo-8-(4-fluorophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chemical Structure

[0228] According to the general synthesis procedure, 2,6-dibromo-8-(4-fluoro-3-nitrophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Fluoro-3-nitrophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 14)) (50 mg, 0.15 mmol) and NBS (67 mg, 0.38 mmol) were dissolved in 5 mL of DCM. The mixture was stirred for 4 days. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 1 / 1, v / v) to obtain the product as a dark yellow solid (15 mg, 20%).

[0229] M.P. (°C): 170~179 1 H-NMR (700 MHz, CDCl3): δ (ppm) = 6.88 (s, 2H, H pyrrole )、7.54 (dd, J = 10.0, 8.6 Hz, 1H, Ar-H meta )、7.82 (ddd, J = 8.6, 4.1, 2.3 Hz, 1H, Ar-H ortho )、7.91 (s, 2H, H pyrrole )、8.26 (dd, J = 6.8, 2.3 Hz, 1H, Ar-H ortho )

[0230] 13 C-NMR (176 MHz, CDCl3): δ (ppm) = 108.5~108.6 (m, CBr), 119.7 (d, J C-F = 21.2 Hz, Ar-C meta )、127.8 (Ar-C ortho )、130.7 (C pyrrole )、131.1*, 134.5 (C pyrrole )、136.8 (d, J C-F = 9.3 Hz, Ar-C ortho )、137.8 (d, J C-F = 6.6 Hz)*、141.7 (C meso )、146.1 (C pyrrole )、157.06 (d, J = 271.7 Hz, Ar-C para) These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0231] 19 19F-NMR (376 MHz, CDCl3): δ (ppm) = -111.98 (s, 1F, CF), -144.36~-144.98 (m, 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 15 H7BBr2F3N3O2 - [M] - : 488.8935, found: 488.8920 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 554 [4.78]

[0232] (2.20 2-Bromo-8-[4-(N-butylamino)-3-nitrophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chemical formula

[0233] According to the general synthetic procedure, 2-bromo-8-[4-(N-butylamino)-3-nitrophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(N-butylamino)-3-nitrophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 14)) (100 mg, 0.26 mmol) and NBS (116 mg, 0.65 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 3 hours. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 4 / 1, v / v) to obtain the product as a red solid (58 mg, 48%).

[0234] Mp: 129~132 °C 1 1H-NMR (500 MHz, THF-d8): δ (ppm) = 1.02 (t, J = 7.4 Hz, 3H, Me), 1.48 - 1.55 (m, 2H, CH2), 1.75 - 1.80 (m, 2H, CH2), 3.48 - 3.52 (m, 2H, CH2), 6.68 (d, J = 4.3 Hz, 1H, H pyrrole ), 7.07 (s, 1H, H pyrrole ), 7.18 (d, J = 4.1 Hz, 1H, H pyrrole ), 7.23 (d, J = 9.0 Hz, 1H, Ar-H meta ), 7.80 (dd, J = 8.9, 2.2 Hz, 1H, Ar-H ortho ), 7.89 (s, 1H, H pyrrole ), 8.06 (s, 1H, H pyrrole ), 8.46 - 8.48 (m, 1H, NH), 8.49 (d, J = 2.2 Hz, 1H, Ar-H ortho )

[0235] 13 13C-NMR (126 MHz, THF-d8): δ (ppm) = 14.3 (Me), 21.2 (CH2), 32.0 (CH2), 43.8 (CH2), 106.3 (CBr), 115.7 (Ar-C meta ), 120.5*, 121.1 (C pyrrole ), 130.1 (C pyrrole ), 131.1 (Ar-C ortho ), 133.1 (C pyrrole ), 133.2*, 135.0 (C pyrrole ), 136.2 (C pyrrole ), 138.7 (Ar-C ortho ), 142.5 (C pyrrole ), 146.5 (Ar-C para ), 147.0 (C pyrrole ), 148.0 (C meso )) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0236] 19F-NMR (376 MHz, THF-d8): δ (ppm) = -145.44~-145.66 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 19 H 18 BBrF2N4O2Na + [M + Na] + : 485.0566, found: 485.0548 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 518 [4.73]

[0237] (2.21 2-Bromo-8-[4-(N-cyclohexylamino)-3-nitrophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0238] According to the general synthesis procedure, 2-bromo-8-[4-(N-cyclohexylamino)-3-nitrophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(N-cyclohexylamino)-3-nitrophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 14)) (60 mg, 0.15 mmol) and NBS (65 mg, 0.37 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 3 hours. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 4 / 1, v / v) to obtain the product as a red solid (44 mg, 62%).

[0239] Mp: 207~213 °C 1 1H-NMR (500 MHz, CD2Cl2): δ (ppm) = 1.32~1.40 (m, 1H, CH axial ), 1.43~1.52 (m, 4H, CH equat.), 1.67~1.72 (m, 1H, CH equat. ), 1.81~1.87 (m, 2H, CH axial ), 2.10 - 2.13 (m, 2H, CH axial ), 3.62~3.69 (m, 1H, CH), 6.66 (d, J = 4.6Hz, 1H, H pyrrole ), 6.99 (s, 1H, H pyrrole ), 7.08 (d, J = 9.0Hz, 1H, Ar - H meta ), 7.12 (d, J = 4.4Hz, 1H, H pyrrole ), 7.67 (dd, J = 9.0, 2.2Hz, 1H, Ar - H ortho ), 7.75 (s, 1H, H pyrrole ), 7.98 (s, 1H, H pyrrole ), 8.42~8.43 (m, 1H, NH), 8.46 (d, J = 2.2Hz, 1H, Ar - H ortho )

[0240] 13 C - NMR (126MHz, CD2Cl2): δ (ppm) = 24.9 (CH2), 25.9 (CH2), 32.96 (CH2), 52.0 (CH), 106.0 (CBr), 115.4 (Ar - C meta ), 119.98 (C pyrrole ), 120.2*, 129.7 (C pyrrole ), 130.7 (Ar - C ortho ), 132.0 (C pyrrole ), 132.7*, 134.2 (C pyrrole ), 135.4 (C pyrrole ), 137.96 (Ar - C ortho ), 141.6 (C pyrrole ), 145.8 (Ar - C para ), 145.9 (C pyrrole ), 146.6 (C meso ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar - C ipso and Ar - C nitro in the aryl moiety.

[0241] 19F-NMR (376 MHz, CD2Cl2): δ (ppm) = -145.01~-145.23 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 21 H 19 BBrF2N4O2 - [M-H] - : 487.0758, found: 487.0747 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 518 [4.55]

[0242] (2.22 2-Bromo-8-[3-nitro-4-(N-prop-2-enylamino)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0243] According to the general synthesis procedure, 2-bromo-8-[3-nitro-4-(N-prop-2-enylamino)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[3-Nitro-4-(N-prop-2-enylamino)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 15)) (95 mg, 0.26 mmol) and NBS (115 mg, 0.65 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 3 hours. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 4 / 1, v / v) to obtain the product as a red solid (35 mg, 30%).

[0244] Mp: 160~162 °C 1H-NMR(500 MHz, THF-d8): δ(ppm) = 4.16~4.18 (m, 2H, CH2), 5.23~5.26 (m, 1H, H2C=CH-), 5.32~5.37 (m, 1H, H2C=CH-), 6.01 (ddt, J = 17.2, 10.1, 4.9 Hz, 1H, H2C=CH-), 6.67 (d, J = 4.5 Hz, 1H, H pyrrole ), 7.06 (s, 1H, H pyrrole ), 7.16~7.18 (m, 2H, H pyrrole + Ar-H meta ), 7.79 (dd, J = 9.0, 2.2 Hz, 1H, Ar-H ortho ), 7.89 (s, 1H, H pyrrole ), 8.06 (s, 1H, H pyrrole ), 8.50 (d, J = 2.2 Hz, 1H, Ar-H ortho ), 8.66 (t, J = 6.2 Hz, 1H, NH)

[0245] 13 C-NMR(126 MHz, THF-d8): δ(ppm) = 46.7 (CH2), 106.4 (CBr), 116.1 (Ar-C meta ), 117.1 (H2C=CH-), 120.5 (C pyrrole ), 121.4*, 130.1 (C pyrrole ), 130.97 (Ar-C ortho ), 133.25 (C pyrrole ), 133.33*, 134.8 (H2C=CH-), 135.0 (C pyrrole ), 136.2 (C pyrrole ), 138.5 (Ar-C ortho ), 142.6 (C pyrrole ), 146.4 (Ar-C para ), 147.1 (C pyrrole ), 147.9 (C meso ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0246] 19F-NMR (376 MHz, THF-d8): δ (ppm) = -145.43~-145.66 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 18 H 14 BBrF2N4O2Na + [M + Na] + : 469.0253, found: 469.0262 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 519 [4.64]

[0247] (2.23 2-Bromo-8-[4-(N-6-methoxy-6-oxohexylamino)-3-nitrophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0248] According to the general synthetic procedure, 2-bromo-8-[4-(N-6-methoxy-6-oxohexylamino)-3-nitrophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(N-6-methoxy-6-oxohexylamino)-3-nitrophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 14)) (90 mg, 0.20 mmol) and NBS (87 mg, 0.49 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 3 hours. The crude product was purified by column chromatography (silica gel, DCM) to obtain the product as a red solid (35 mg, 30%).

[0249] M.P. (°C): 77~80 1H-NMR (500 MHz, THF-d8): δ (ppm) = 1.48~1.54 (m, 2H, CH2), 1.67~1.71 (m, 2H, CH2), 1.77~1.83 (m, 2H, CH2), 2.33 (t, J = 7.4 Hz, 2H, CH2), 3.50~3.53 (m, 2H, CH2), 3.60 (s, 3H, Me), 6.68 (d, J = 4.3 Hz, 1H, H pyrrole ), 7.07 (s, 1H, H pyrrole ), 7.18 (d, J = 4.3 Hz, 1H, H pyrrole ), 7.23 (d, J = 9.0 Hz, 1H, Ar-H meta ), 7.80 (dd, J = 8.9, 2.2 Hz, 1H, Ar-H ortho ), 7.89 (s, 1H, H pyrrole ), 8.06 (s, 1H, H pyrrole ), 8.49 (d, J = 2.2 Hz, 1H, Ar-H ortho ), 8.49~8.52 (m, 1H, NH)

[0250] 13 C-NMR (126 MHz, THF-d8): δ (ppm) = 25.6 (CH2), 27.5 (CH2), 29.6 (CH2), 34.4 (CH2), 43.9 (CH2), 51.5 (Me), 106.3 (CBr), 115.7 (Ar-C meta ), 120.5 (C pyrrole ), 121.1*, 130.1 (C pyrrole ), 131.1 (Ar-C ortho ), 133.1 (C pyrrole ), 133.2*, 134.99 (C pyrrole ), 136.2 (C pyrrole ), 138.7 (Ar-C ortho ), 142.5 (C pyrrole ), 146.5 (Ar-C para ), 147.0 (C pyrrole ), 147.99 (C meso ), 173.8 (CO) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to Ar-C ipso and Ar-C nitro in the aryl moiety.

[0251] 19 F-NMR (376 MHz, THF-d8): δ (ppm) = -145.42~-145.64 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 22 H 22 BBrFN4O4 + [M - F] + : 517.0888, found: 517.0894, m / z calcd. for C 22 H 22 BBrF2N4O4Na + [M + Na] + : 557.0778, found: 557.0809, m / z calcd. for C 22 H 22 BBrF2N4O4K + [M + K] + : 573.0517, found: 573.0542, m / z calcd. for C 44 H 44 B2Br2F4N8O8Na + [2M + Na] + : 1093.1668, found: 1093.1669 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 517[4.74]

[0252] (2.24 2-Bromo-8-[4-(N-prop-2-ynylamino)-2,3,5,6-tetrafluorophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0253] According to the general synthesis procedure, 2-bromo-8-[4-(N-prop-2-ynylamino)-2,3,5,6-tetrafluorophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(N-prop-2-ynylamino)-2,3,5,6-tetrafluorophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 13)) (100 mg, 0.25 mmol) and NBS (113 mg, 0.64 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 1.5 hours. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 1 / 1, v / v) to obtain the product as a green solid (75 mg, 63%).

[0254] Mp: 80~82 °C 1 1H NMR (500 MHz, THF-d6): δ (ppm) = 2.74 (t, J = 2.4 Hz, 1H, CH), 4.22~4.24 (m, 2H, CH2), 6.36 (s, 1H, NH), 6.67 (d, J = 4.3 Hz, 1H, H pyrrole )、7.07 (s, 1H, H pyrrole )、7.15 (d, J = 4.2 Hz, 1H, H pyrrole )、7.94 (s, 1H, H pyrrole )、8.13 (s, 1H, H pyrrole )

[0255] 13 13C NMR (126 MHz, THF-d6): δ (ppm) = 35.3 (CH2), 73.3 (CH), 81.6 (C), 99.97 (t, J C-F = 18.3 Hz, Ar-C ipso )、107.1~107.2 (m, CBr)、121.5 (C pyrrole )、130.4 (C pyrrole )、130.9~131.1 (m, Ar-C para )、132.7 (C meso )、133.6 (C pyrrole )、135.6 (C pyrrole )、137.4 (C pyrrole )、138.63 (dd, J C-F=235.0, 22.2Hz, Ar-C meta )、144.5(C pyrrole )、138.63(dd, J C-F =235.0, 22.2Hz)、145.91(dd, J C-F =246.2, 12.2Hz, Ar-C ortho )、149.6(C pyrrole )

[0256] 19 19F NMR(376MHz, CDCl3): δ(ppm) = -142.07(d, J = 17.7Hz, 2F, CF meta )、-145.46~ -145.68(m c , 2F, BF2)、-159.92(d, J = 17.9Hz, 2F, CF ortho ) HRMS(ESI-TOF): m / z calcd. for C 18 H9BBrF6N3Na + [M + Na] + : 493.9869、found: 493.9886 UV / Vis(DCM): λ max (nm)[log(ε / Lmol -1 cm -1 )] = 389[4.05]、536[4.63]

[0257] (2.25 2-Bromo-8-(4-butoxy-2,3,5,6-tetrafluorophenyl)]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0258] According to the general synthesis procedure, 2-bromo-8-(4-butoxy-2,3,5,6-tetrafluorophenyl)]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-(4-Butoxy-2,3,5,6-tetrafluorophenyl)]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (100 mg, 0.24 mmol) and NBS (108 mg, 0.61 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 1 hour. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 1 / 2, v / v) to obtain the product as a red-tinged green solid (63 mg, 53%).

[0259] Mp: 114~116 °C 1 1H NMR (500 MHz, THF-d6): δ (ppm) = 1.01 (t, J = 7.4 Hz, 1H, Me), 1.52~1.59 (m, 2H, CH2), 1.80~1.85 (m, 2H, CH2), 4.40 (t, J = 6.4 Hz, 2H, CH2), 6.69 (d, J = 4.4 Hz, 1H, H pyrrole )、7.07 (s, 1H, H pyrrole )、7.15 (d, J = 4.4 Hz, 1H, H pyrrole )、8.01 (s, 1H, H pyrrole )、8.19 (s, 1H, H pyrrole )

[0260] 13 13C NMR (126 MHz, THF-d6): δ (ppm) = 14.2 (Me), 19.9 (CH2), 33.0 (CH2), 76.4 (CH2), 106.2~106.5 (m, Ar-C ipso )、107.6~107.7 (m, CBr), 121.9 (C pyrrole )、128.9 (Ar-C para )、130.3 (C pyrrole )、131.3 (C meso )、133.6 (C pyrrole )、135.4 (C pyrrole )、137.2 (C pyrrole )、141.26 (dd, J C-F=70.4, 13.8 Hz, Ar-C meta ), 144.3 (C pyrrole ), 138.63 (dd, J C-F =235.0, 22.2 Hz), 145.91 (dd, J C-F =253.0, 10.5 Hz, Ar-C ortho ), 150.5 (C pyrrole )

[0261] 19 19F NMR (376 MHz, CDCl3): δ (ppm) = -141.26 (d, J = 19.1 Hz, 2F, CF meta ), -145.42~-145.64 (m c , 2F, BF2), -157.18 (d, J = 17.3 Hz, 2F, CF ortho ) HRMS (ESI-TOF): m / z calcd. for C 19 H 14 BBrF6N2ONa + [M+Na] + : 513.0179、found: 513.0196、m / z calcd. for C 19 H 14 BBrF6N2OK + [M+K] + : 530.9898、found: 530.9988 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 368 [4.11]、536 [4.71]

[0262] (2.25 2-Bromo-8-[4-(prop-2-enyloxy)-2,3,5,6-tetrafluorophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0263] According to the general synthesis procedure, 2-bromo-8-[4-(prop-2-enyloxy)-2,3,5,6-tetrafluorophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(Prop-2-enyloxy)-2,3,5,6-tetrafluorophenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 7)) (100 mg, 0.25 mmol) and NBS (112 mg, 0.63 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 1 hour. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 1 / 1, v / v) to obtain the product as a red-tinged green solid (37 mg, 31%).

[0264] Mp: 101~103 °C 1 H NMR (500 MHz, THF-d6): δ (ppm) = 4.89 (d, J = 5.9 Hz, 2H, CH2), 5.34 (dd, J = 10.4, 1.1 Hz, 1H, -HC=CH2), 5.48 (dd, J = 17.1, 1.5 Hz, 1H, -HC=CH2), 6.11 (ddt, J = 16.6, 10.9, 5.9 Hz, 1H, -HC=CH2), 6.70 (d, J = 4.3 Hz, 1H, H pyrrole )、7.06 (s, 1H, H pyrrole )、7.13 (d, J = 4.3 Hz, 1H, H pyrrole )、8.01 (s, 1H, H pyrrole )、8.19 (s, 1H, H pyrrole )

[0265] 13 C NMR (126 MHz, THF-d6): δ (ppm) = 76.7 (CH2), 106.74 (t, J C-F = 18.5 Hz, Ar-C ipso )、107.6~107.7 (m, CBr)、119.98 (-HC=CH2)、121.9 (C pyrrole )、130.3 (C pyrrole )、131.2 (C meso )、133.5 (C pyrrole )、133.7 (-HC=CH2)、135.4 (Cpyrrole )、137.2 (C pyrrole )、140.36 (dd, J C-F = 8.1, 3.4 Hz, Ar-C para )、142.60 (dd, J C-F = 242.4, 13.7 Hz, Ar-C meta )、145.4 (C pyrrole )、145.82 (dd, J C-F = 248.9, 19.3 Hz, Ar-C ortho )、150.6 (C pyrrole )

[0266] 19 F NMR (376 MHz, CDCl3): δ (ppm) = -141.18 (d, J = 18.1 Hz, 2F, CF meta )、-145.45~-145.67 (m c , 2F, BF2)、-156.46 (d, J = 18.3 Hz, 2F, CF ortho ) HRMS (ESI-TOF): m / z calcd. for C 18 H 10 BBrF6N2ONa + [M + Na] + : 498.9845、found: 498.9851 UV / Vis (DCM): λ max (nm) [log(ε / Lmol -1 cm -1 )] = 366 [4.05]、537 [4.66]

[0267] (2.26 2-Bromo-8-[4-(prop-2-ynyloxy)-2,3,5,6-tetrafluoro-phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0268] According to the general synthesis procedure, 2-bromo-8-[4-(prop-2-ynyloxy)-2,3,5,6-tetrafluoro-phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene was prepared. 8-[4-(Prop-2-ynyloxy)-2,3,5,6-tetrafluoro-phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (prepared according to the literature (Non-Patent Document 7)) (100 mg, 0.25 mmol) and NBS (113 mg, 0.64 mmol) were dissolved in 10 mL of DCM. The mixture was stirred for 1 hour. The crude product was purified by column chromatography (silica gel, DCM / n-hexane = 1 / 1, v / v) to obtain the product as a redish green solid (41 mg, 34%).

[0269] Mp: 139~141 °C 1 H NMR (500 MHz, THF-d6): δ (ppm) = 3.25 (t, J = 2.4 Hz, 1H, CH), 5.06 (d, J = 2.4 Hz, 2H, CH2), 6.70 (d, J = 4.3 Hz, 1H, H pyrrole )、7.07 (s, 1H, H pyrrole )、7.14 (d, J = 4.2 Hz, 1H, H pyrrole )、8.02 (s, 1H, H pyrrole )、8.20 (s, 1H, H pyrrole )

[0270] 13 C NMR (126 MHz, THF-d6): δ (ppm) = 63.1 (CH2), 78.2 (CH), 79.4 (C), 107.5~107.8 (m, CBr+Ar-C ipso )、121.97 (C pyrrole )、130.3 (C pyrrole )、131.0 (C meso )、133.5 (C pyrrole )、135.3 (C pyrrole )、137.1 (C pyrrole )、139.1~139.3 (m, Ar-C para )、142.92 (dd, J C-F = 248.7, 10.8 Hz, Ar-C meta)、145.5(C pyrrole )、145.76(dd,J C-F =248.0,13.2Hz,Ar-C ortho )、150.7(C pyrrole )

[0271] 19 19F NMR(376MHz,CDCl3):δ(ppm)=-140.98(d,J=19.7Hz,2F,CF meta )、-145.43~-145.65(m c ,2F,BF2)、-155.64(d,J=17.3Hz,2F,CF ortho ) HRMS(ESI-TOF):m / z calcd. for C 18 H8BBrF6N2ONa + [M+Na] + :496.9689、found:496.9686、m / z calcd. for C 18 H8BBrF6N2OK + [M+K] + :512.9428、found:512.9428、m / z calcd. for C 36 H 16 B2Br2F 12 N4O2Na + [2M+Na] + :968.9506、found:968.9496 UV / Vis(DCM):λ max (nm)[log(ε / Lmol -1 cm -1 )]=367[4.09]、537[4.73]

[0272] (2.27 2-Bromo-8-[4-(N-butylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)

Chem.

[0273] 8-[4-(N-butylamino)-3-nitrophenyl]-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (118 mg, 0.27 mmol) was dissolved in 5 mL of DCM. A solution of NBS (47 mg, 0.27 mmol) in 5 mL of DCM was added dropwise, and the mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with EtOAc and washed several times with water. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by column chromatography (silica gel, n-hexane / EtOAc = 9 / 1, v / v) to give the product (41 mg, 29%) as a pale orange solid.

[0274] 1 1H-NMR (500 MHz, THF-d8): δ (ppm) = 1.01 (t, J = 7.4 Hz, 3H, Me butyl ), 1.47~1.55 (m, 2H, CH2), 1.57 (s, 3H, Me), 1.59 (s, 3H, Me), 1.74~1.79 (m, 2H, CH2), 2.52 (s, 3H, Me), 2.53 (s, 3H, Me), 3.42~3.46 (m, 2H, CH2), 6.14 (s, 1H, H pyrrole ), 7.24 (d, J = 8.8 Hz, 1H, Ar-H meta ), 7.43 (dd, J = 8.8, 2.1 Hz, 1H, Ar-H ortho ), 8.16 (d, J = 2.1 Hz, 1H, Ar-H ortho ), 8.22 (t, J = 4.7 Hz, 1H, NH)

[0275] 13 13C-NMR (126 MHz, THF-d8): δ (ppm) = 13.6 (Me), 14.3 (Me butyl ), 14.5 (Me), 14.9 (Me), 15.7 (Me), 21.3 (CH2), 32.1 (CH2), 43.8 (CH2), 110.8~110.9 (m, CBr), 116.3 (Ar-C meta ), 121.7*, 123.3 (CH pyrrole ), 127.8 (Ar-C ortho ), 131.2 (C pyrrole ), 133.1*, 133.8 (C pyrrole)、136.8 (Ar-C ortho )、138.7 (C pyrrole )、141.5 (C pyrrole )、145.9 (C meso )、146.8 (Ar-C para )、151.9 (C pyrrole )、154.7 (C pyrrole ) * These signals could not be accurately assigned to the corresponding carbon atoms. These belong to the Ar-C ipso and Ar-C nitro of the aryl moiety.

[0276] 19 19F-NMR (376 MHz, THF-d8): δ (ppm) = -146.53~-146.77 (m c , 2F, BF2) HRMS (ESI-TOF): m / z calcd. for C 23 H 26 BBrF2N4O2Na + [M + Na] + : 541.1192, found: 541.1222, m / z calcd. for C 23 H 26 BBrF2N4O2K + [M + K] + : 559.0911, found: 559.0948 m / z calcd. for C 46 H 52 B2Br2F4N8O4Na + [2M + Na] + : 1061.2472, found: 1061.2518

[0277] (Example 3) (Cell tests of selected compounds in HT29 and other cell lines) The photosensitizing activity was determined in the following cell lines. - HT29 (human colon adenocarcinoma cell line) - L929 (mouse fibroblast cell line) - A431 (human epidermoid carcinoma cell line) - A253 (submandibular salivary gland, epidermal cell line) -CAL-27 (Human tongue squamous cell carcinoma cell line) -J774A.1 (Mouse BALB / c monocyte macrophage)

[0278] The cell lines were grown in DMEM supplemented with 10% heat-inactivated fetal calf serum (FCS, c.c.pro GmbH), 1% penicillin (1000 IU), and streptomycin (10000 μg / ml, c.c.pro GmbH). Cells were maintained as monolayer cultures in a humidified incubator (37 °C, 5% CO2 in air).

[0279] The photosensitizer stock solution (2 mM) was prepared in DMSO and stored in the dark at 4 °C. Further dilutions were made in phenol red-free DMEM medium supplemented with 10% FCS to obtain final photosensitizer concentrations of 2 or 10 μM, respectively.

[0280] After seeding the cells in microplates, prior to light exposure, the cells were incubated for 24 h in fresh medium (phenol red-free DMEM) containing 10% FCS and 2 or 10 μM of the photosensitizer. Before photosensitization, the cells were washed and the cell culture medium was replaced with phenol red-free DMEM and 10% FCS, and then irradiated at room temperature with a white light source at an approximate fluence rate of 100 mW / cm 2 (50 J / cm 2 ). Following irradiation, the cells were incubated in a humidified incubator (37 °C, 5% CO2 in air) for 24 h until cell viability assay.

[0281] Cell viability was evaluated by XTT assay. 500 mg of XTT (3’-[phenyl-amino-carbonyl]-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid sodium salt, Applichem GmbH) was dissolved in 500 ml of PBS buffer (Ca 2+ and Mg 2+It was dissolved in (excluding) and filter-sterilized. The solution was stored at -20°C in the dark until use. As an XTT activation reagent, a sterilized solution containing PMS (N-methyldibenzopyrazine methyl sulfate, Applichem GmbH) was required. 0.383 mg of PMS was dissolved in 1 ml of PBS buffer. The solution should be stored frozen and must not be exposed to light. The XTT reagent solution was thawed in a 37°C water bath, and the activation solution (PMS) was added promptly before use. To prepare sufficient reaction solution for one microplate (96 wells), 0.1 ml of the activation solution (PMS) was added to 5 ml of the XTT reagent. The medium in the microplate was replaced with phenol red-free RPMI and 10% FCS (100 μl) before adding 50 μl of the XTT reaction solution per well. The microplate was incubated at 37°C and 5% CO2 for 2 - 3 hours until an orange dye was formed. The microplate was gently shaken to evenly distribute the dye in the wells.

[0282] The absorbance of the samples at a wavelength of 490 nm was measured with a microplate reader (Infinite 200, Tecan Group Ltd.).

[0283] Examples 3.1 - 3.12 (shown in Figures 1 - 12 respectively) show the photodynamic activity of the selected compounds which are the subject of the present invention ("with litht" means phototoxicity). It should be noted that the compounds were also active against the macrophage cell line J774A.1. Since macrophages are involved in the inflammatory process, the compounds of the present invention can also be applied to the diagnosis and treatment of inflammatory diseases such as arthritis or otitis media.

[0284] (Example 4) (Antibacterial test) The microorganisms studied were the Gram-positive Staphylococcus aureus DSM11729 and the Gram-negative Pseudomonas aeruginosa DSM1117.

[0285] The cultured cells were suspended in sterile phosphate buffered saline (PBS) or sterile PBS supplemented with 10% sterile horse serum. The bacterial suspension was transferred to a sterile black well plate with a transparent bottom. The concentrations of the photosensitizers used in this study were as follows: 100 μM, 10 μM, and 1 μM.

[0286] After a 30-minute incubation period, the samples were exposed to white light at an output density and irradiation time that provided an energy fluence of approximately 100 J / cm 2 No laser light was exposed to the control plates without photosensitizer. The dark toxicity control samples were exposed only to the photosensitizer without any irradiation.

[0287] After irradiation, the samples were removed and resuspended in the culture medium. After sufficient incubation time, the colony forming units (CFU / ml) were counted.

[0288] Figures 13 - 24 of Examples 4.1 - 4.11 show the effects of boron dipyrromethene according to the present invention on bacteria, the gram-positive bacterium Staphylococcus aureus and the gram-negative bacterium Pseudomonas aeruginosa. As can be seen in the examples, the selected compounds (4.1, 4.2, 4.4 - 4.10) show high antibacterial activity against Staphylococcus aureus even in the absence of light (at the highest concentration tested, 100 μmol), and in particular, the compounds are non-toxic to cells in the absence of light on the other hand, thus illustrating these major appropriates in systemic therapy (see Example 3). Also, some compounds can be specifically active against bacteria and show only low toxicity in cells (see Example 4.5 compared to Example 3.12). In Examples 4.1, 4.2, and 4.5 - 4.11, antibacterial activity has been confirmed even in the presence of a complex medium (serum added). Examples 4.7 - 4.11 show the antibacterial effect of the compounds according to the present invention against the gram-negative bacterium Pseudomonas aeruginosa. Also, Examples 4.1 and 4.11 show the strong antibacterial activity of the compounds according to the present invention having only one bromine atom.

[0289] Preferred embodiments of the present invention have been described with reference to the accompanying examples, but the present invention is not limited to the exact embodiments, and it will be understood that various changes and modifications can be made by those skilled in the art without departing from the scope of the present invention as defined by the appended claims.

[0290] (Addendum) (Addendum 1) Formula 1, 2, 3, or 4 [Chemical formula] A boron dipyrromethene compound based on wherein X is at least one of O, NH, or S; R 1 is at least one of a carbohydrate moiety, a short-chain alkyl having 3 to 6 carbon atoms, propargyl, HO-CH2-CH2-, CH(CH2OH)2, CH2-CH(OH)-CH2OH, or CH(OH)-CH(OH)-CH3; R 2 is at least one of a hydrogen or bromine substituent (atom); A boron dipyrromethene compound.

[0291] (Addendum 2) The compound according to Addendum 1, or a pharmaceutically acceptable derivative thereof, for use in the treatment of tumors.

[0292] (Addendum 3) The compound according to Addendum 1, or a pharmaceutically acceptable derivative thereof, for use in photodynamic therapy.

[0293] (Addendum 4) The compound according to Addendum 1, or a pharmaceutically acceptable derivative thereof, for use in the treatment of at least one of tumors, dermatological disorders, viral infections, bacterial infections, otolaryngological disorders, ophthalmological disorders, or urological disorders.

[0294] (Addendum 5) The compound according to Appendix 1, or a pharmaceutically acceptable derivative thereof, for use in at least one of photodynamic therapy for tumors, dermatological disorders, viral infections, bacterial infections, otolaryngological disorders, ophthalmic disorders, or urological disorders.

[0295] (Appendix 6) Use of the compound according to Appendix 1, or a pharmaceutically acceptable derivative thereof, for the preparation of a pharmaceutical composition for tumor treatment or photodynamic therapy.

[0296] (Appendix 7) Use of the compound according to Appendix 1, or a pharmaceutically acceptable derivative thereof, for treatment or photodynamic therapy of arthritis and similar inflammatory diseases.

[0297] (Appendix 8) Use of the compound according to Appendix 1, or a pharmaceutically acceptable derivative thereof, for the diagnosis of arthritis and similar inflammatory diseases, or for the diagnosis of tumors.

[0298] (Appendix 9) The compound according to Appendix 1, or a pharmaceutically acceptable derivative thereof, when placed on the surface of a medical device.

[0299] (Appendix 10) A pharmaceutical composition comprising the compound according to Appendix 1, or a pharmaceutically acceptable derivative thereof, as an active ingredient.

[0300] (Appendix 11) The pharmaceutical composition according to Appendix 10, wherein the compound is complexed with a targeting agent.

[0301] (Appendix 12) The pharmaceutical composition according to Appendix 12, wherein the targeting agent is a peptide.

Claims

1. A boron dipyrromethene compound according to Formula 1, 2, 3, or 4 【Chemical Formula 1】 wherein X is at least one of O, NH, or S; a boron dipyrromethene compound. R １ is glucose, galactose, HO—CH ２ —CH ２ —, CH(CH ２ (OH)) ２ —, CH ２ —CH(OH)—CH ２ (OH), or CH(OH)—CH(OH)—CH ３ and R ２ is at least one of a hydrogen or bromine substituent (atom), The compound according to claim 1, wherein

2. 【Fig. 2】

3. The compound according to claim 1 or 2 for use in the treatment of tumors.

4. The compound according to claim 1 or 2 for use in photodynamic therapy.

5. The compound according to claim 1 or 2 for use in the treatment of at least one of tumors, dermatological disorders, viral infections, bacterial infections, otolaryngological disorders, ophthalmic disorders, or urological disorders.

6. The compound according to claim 1 or 2 for use in photodynamic therapy of at least one of tumors, dermatological disorders, viral infections, bacterial infections, otolaryngological disorders, ophthalmic disorders, or urological disorders.

7. Use of the compound according to claim 1 or 2 for the preparation of a pharmaceutical composition for tumor treatment or photodynamic therapy.

8. The compound according to claim 1 or 2 for use in the treatment or photodynamic therapy of arthritis and similar inflammatory diseases.

9. The compound according to claim 1 or 2 for use in the diagnosis of arthritis and similar inflammatory diseases or the diagnosis of tumors.

10. The compound according to claim 1 or 2 when placed on the surface of a medical device.

11. A pharmaceutical composition comprising the compound according to claim 1 or 2 as an active ingredient.

12. The pharmaceutical composition according to claim 11, wherein the compound is complexed with a targeting agent.

13. The pharmaceutical composition according to claim 12, wherein the targeting agent is a peptide. ​

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