Method for synthesizing an iodoaryl or astatidoaryl compound using an arylsulfonium salt

Abstract

In the present invention, the inventors have successfully developed arylsulfonium salts, particularly triarylsulfonium salts and dibenzothiophenium salts, and have developed new uses for such arylsulfonium salts. These compounds have the advantage of having a thioaryl group as a leaving group, by which all by-products can be separated from the radiolabeled product. Therefore, the aforementioned compounds are useful tools in a method for synthesizing iodoaryl or astataryl compounds, particularly radiolabeled iodoaryl or radiolabeled astataryl compounds. The present invention relates to a method for synthesizing an iodoaryl or astataryl compound, respectively, which comprises reacting an arylsulfonium compound with an iodide salt or an astatide salt. The present invention also relates to such arylsulfonium compounds. The present invention also relates to a method for synthesizing an iodine-labeled biomolecule or an astatine-labeled biomolecule and / or a vector using the aforementioned iodoaryl or astataryl compound.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing an iodoaryl or astataryl compound, respectively, including the respective reactions of an arylsulfonium compound with an iodide salt or an astatide salt. The present invention also relates to an arylsulfonium compound and the like. The present invention also relates to a method for synthesizing an iodoaryl or astataryl biomolecule and / or vector using the aforementioned iodoaryl and astataryl compounds.

Background Art

[0002] Among all radioactive substances for each medical purpose, heavy halogens show realistic potential, regardless of analysis or treatment. On the other hand, iodine is used for 123 I (t 1 / 2 = 13.2 h) for SPECT analysis, 124 I (t 1 / 2 = 4.18 d) for PET analysis, 125 I (t 1 / 2 = 59.9 d) for Auger electron therapy, and 131 I (t 1 / 2 = 8 h) for β-therapy (Ferris et al., J. Label. Compd. Radiopharm. 2021, 64, 92-108), etc., showing several radioisotopes used in clinical applications. On the other hand, astatine-211 (t 1 / 2 = 7.2 h) has recently emerged as one of the few alpha emitters showing decay characteristics (intermediate half-life, emission of one alpha particle at 5.7 or 7.4 MeV) suitable for targeted alpha therapy (TAT) (Eychenne et al., Pharmaceutics 2021, 13, 906-956), i.e., the treatment of small tumors or disseminated metastases and the separation of cancer cells, in an increasingly popular manner (Makvandi et al, Targ. Oncol. 2018,13, 189-203).

[0003] General knowledge in the synthetic chemistry of iodine has enabled the development of methods of radioiodination based mainly on typical electrophilic or nucleophilic substitution reactions that form radioactive halogenoaryl compounds. Iodine and astatine are adjacent in the periodic table, and they exhibit similar physicochemical properties. Therefore, the radiochemistry of iodine can often be applied to astatination as well. Nevertheless, radiolabeling methods are scarcely available and have long been limited to halogen deprotonation, halogen diazotization, nucleophilic halogen (or isotope) exchange, or electrophilic halogen demetallation (mainly from stannylated precursors), with the latter emerging as the standard method (Eychenne et al, Biomedical Sciences. Elsevier, 2021, p. B9780128229606000000). However, even if these conventional methods have allowed access to radioiodinated and radioastatined compounds, there are limitations in the development of new radiopharmaceuticals due to drawbacks such as the formation of by-products, the presence of non-radioiodinated analogs inseparable from the radiolabeled products, the use of toxic precursors, and / or the need for time-consuming purification steps.

[0004] In recent years, 211 interest in At has increased, contributing to an improved understanding of astatine reactivity (Guerard et al., Acc. Chem. Res. 2021, 54, 3264-3275). As a result, new methodologies for astatination of target compounds have been developed. In particular, in recent years, the At + species required for electrophilic reactions has been found to be relatively high in At -For the stability of the species, new research has been conducted on a nucleophilic approach rather than an electrophilic approach (Guerard et al., Chem. Eur. J. 2016, 22, 12332 - 12339; Reilly et al., Org. Lett. 2018, 20, 1752 - 1755). In particular, aromatic nucleophilic substitution of aryliodonium salts for the preparation of radioactive iodine or newly emerged astatination precursors has an efficient and reliable approach for labeling monoclonal antibodies (Guerard et al., Bioorg. Med. Chem. 2017, 25, 5975 - 5980; Navarro et al., Bioorg. Med. Chem. 2019, 27, 167 - 174). While this approach is a substantial advancement compared to the conventional electrophilic destannylation reaction, there is still room for improvement. In fact, the regioselectivity of the reaction strongly depends on the nature of the substituents of the aryliodonium precursor, and only strongly activated compounds (i.e., electron - deficient compounds) can suppress the formation of by - products and result in high regioselectivity, subsequently effectively leading to a high radiochemical yield (RCY). As a result, the application of aryliodonium salts has been limited to the production of electron - rich radioiodinated aryl compounds and astatinated aryl compounds. Recently, the low regioselectivity has been solved by using aryliodonium ylides, which is a similar classification of precursors that does not cause this regioselectivity problem and improves the RCY from electron - rich precursors to electron - deficient precursors (Maingueneau et al., Chem. Eur. J. 2022, 28, e202104169). Nevertheless, aryliodonium ylides and aryliodonium salts are included in the iodoaryl pattern and lead to the formation of inseparable 127 I - iodinated analogs by reaction or decomposition. As a result, the limitation of this class of precursors is that the molar activity is not optimal, which can have an adverse effect on the imaging and therapeutic effects of the resulting radiopharmaceuticals.

[0005] On the one hand, arylsulfonium salts have been used as precursors for the radiofluorination of aromatic compounds containing deactivated and activated aryl rings (Mu et al., Eur. J. Org. Chem. 2012, 889-892).

[0006] However, there is still a need for an improved method for synthesizing iodoaryl and astataryl compounds, particularly radioiodoaryl and radioastataryl compounds, which not only shows high efficiency in terms of RCY compared to previously reported procedures but also shows high efficiency in terms of chemical and radiochemical purity.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

[0008] In this study, the inventors successfully developed a method for synthesizing iodoaryl or astataryl compounds using arylsulfonium salts, particularly triarylsulfonium salts and dibenzothiophenium salts. These arylsulfonium salts have the advantage of having a thioaryl group as a leaving group, by which all by-products can be separated from the iodo-labeled or astatine-labeled products. Therefore, the aforementioned compounds are useful tools in the method for synthesizing iodoaryl or astataryl compounds, particularly radioiodoaryl or radioastataryl compounds. [Means for Solving the Problems]

[0009] In a general aspect, the present invention provides a method for synthesizing an iodoaryl compound or an astataryl compound, respectively, comprising a reaction between an arylsulfonium compound and an iodide salt or an astatine salt, wherein the arylsulfonium compound has the formula (I):

[0010]

Chem.

[0011]

Chem.

[0012] [Chemical formula] wherein R 10 is H or C1-C4 alkoxycarbonyl; R 3 is selected from H, C1-C6 alkyl, and C1-C6 alkoxy; R 4 and R 5 are independently selected from H, C1-C6 alkyl, and C1-C6 alkoxy; Y is a monovalent anion; and the dashed line represents a single bond or its absence.

[0013] The present invention also relates to compounds of general formula (I).

[0014] [Chemical formula] wherein Ar is C6-C10 aryl or C5-C10 heteroaryl; R 1 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, CN, NO 2 , CHO, OH, N=C=O, N=C=S, NR 6 R 7 (R 6 and R 7 are independently H or C1-C6 alkyl), C(O)NHR 8 (R 8 is H or C1-C6 alkyl), and C(O)OR 9 (R 9 is selected from H, C1-C6 alkyl, and N-succinimidyl), the aforementioned C1-C6 alkyl group is optionally substituted with N 3 or the following formula,

[0015] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, CN, NO 2 , CHO, OH, N=C=O, N=C=S, NR 6 R 7 (R 6 and R 7 are independently H or C1-C6 alkyl), C(O)NHR 8 (R 8 is H or C1-C6 alkyl), and C(O)OR 9 (R 9 is selected from H, C1-C6 alkyl and N-succinimidyl), and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 or the following formula,

[0016]

Chemical formula

Mode for Carrying Out the Invention

[0017] [Method for Synthesizing Iodoaryl or Astatidoaryl Compound] [Reaction of Arylsulfonium Compound with Iodide Salt or Astatine Salt] As detailed above, the present invention relates to a method for synthesizing an iodoaryl or astatidoaryl compound, particularly an astatidoaryl compound, which comprises reacting an arylsulfonium compound with an iodide salt or an astatine salt, respectively, particularly an astatine salt. The arylsulfonium compound has the formula (I):

[0018]

Chemical Formula

[0019] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; in particular, R 1 is selected from H, C1-C6 alkyl, halogen, CN, NO 2 and CHO, and the aforementioned C1-C6 alkyl group is N 3 or is optionally substituted with the following formula,

[0020] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; more particularly, R 1 is selected from H, C1-C4 alkyl, halogen, CN, NO 2 and CHO, and the aforementioned C1-C4 alkyl group is N 3 or is optionally substituted with the following formula,

[0021] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; still more particularly, R 1 is selected from H, C1-C2 alkyl, F, Cl, CN, NO 2 and CHO, and the aforementioned C1-C2 alkyl group is N 3 or is optionally substituted with the following formula,

[0022] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; even more particularly, R1 is selected from H, methyl, Cl, CN, NO 2 and CHO, and the aforementioned methyl group is optionally substituted with N 3 or the following formula,

[0023] [Chemical formula] wherein R 10 is tert-butyloxycarbonyl; R 2 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, CN, NO 2 , CHO, OH, N=C=O, N=C=S, NR 6 R 7 (R 6 and R 7 are independently H or C1-C6 alkyl), C(O)NHR 8 (R 8 is H or C1-C6 alkyl), and C(O)OR 9 (R 9 is selected from H, C1-C6 alkyl and N-succinimidyl), and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 or the following formula,

[0024] [Chemical formula] wherein R 10 is H or C1-C4 alkoxycarbonyl; in particular, H, C1-C6 alkyl, halogen, CN, NO 2 and CHO, and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 or the following formula,

[0025] [Chemical formula] wherein R 10 is H or C1-C4 alkoxycarbonyl; more particularly, R 2is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and halogen; still more particularly, R 2 is H; R 3 is selected from H, C1-C6 alkyl and C1-C6 alkoxy; particularly, R 3 is selected from H, C1-C4 alkyl and C1-C4 alkoxy; more particularly, R 3 is selected from H, C1-C2 alkyl and C1-C2 alkoxy; still more particularly, R 3 is selected from H, methyl and methoxy; R 4 and R 5 are independently selected from H, C1-C6 alkyl and C1-C6 alkoxy; particularly, R 4 and R 5 are H or C1-C6 alkoxy; more particularly, R 4 and R 5 are independently H or C1-C4 alkoxy; still more particularly, R 4 and R 5 are independently H or C1-C2 alkoxy; even more particularly, R 4 and R 5 are H or methoxy; Y is a monovalent anion; particularly, Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF 4 selected from; more particularly, Y is TfO; and the dashed line represents a single bond or its absence.

[0026] As used herein, the term "TfO" refers to the trifluoromethanesulfonate group of the formula: CF 3 SO 3 and is also called triflate.

[0027] As used herein, the term "TsO" refers to the formula: CH 3 C 6 H 4 SO3 refers to the para-toluenesulfonate group, also called tosylate.

[0028] As used herein, the term "MsO" refers to the following formula: CH 3 SO 3 refers to the methanesulfonate group, also called mesylate.

[0029] In one embodiment, when Ar is phenyl, R 1 is not H.

[0030] In one embodiment, R 2 is H.

[0031] In one embodiment, the dashed line is absent and R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl.

[0032] In one embodiment, the dashed line represents a single bond and R 3 , R 4 and R 5 are H.

[0033] In one embodiment, the dashed line represents a single bond, R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl, and R 4 and R 5 are C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy.

[0034] In one embodiment, Ar is phenyl and R 2 is H.

[0035] In one embodiment, Ar is pyridinyl, particularly pyridin-3-yl, and R 1 and R 2 are H.

[0036] In one embodiment, there is no dashed line and Ar is phenyl.

[0037] In one embodiment, the dashed line represents a single bond and Ar is phenyl.

[0038] In one embodiment, the dashed line represents a single bond and Ar is pyridinyl, particularly pyridin-3-yl.

[0039] In one embodiment, there is no dashed line and R 3 is C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy, and Ar is phenyl.

[0040] In one embodiment, the dashed line represents a single bond and R 3 , R 4 and R 5 are H and Ar is phenyl.

[0041] In one embodiment, the dashed line represents a single bond and R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl, R 4 and R 5 are C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy, and Ar is phenyl.

[0042] In one embodiment, the dashed line represents a single bond and R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl, R 4 and R 5 are C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy, and Ar is pyridinyl, particularly pyridin-3-yl.

[0043] In one embodiment, there is no dashed line and R 3is C1-C6 alkyl, especially C1-C4 alkyl, more especially C1-C2 alkyl, still more especially methyl, Ar is phenyl, R 2 is H.

[0044] In one embodiment, the dashed line represents a single bond, R 3 , R 4 and R 5 are H, Ar is phenyl, R 2 is H.

[0045] In one embodiment, the dashed line represents a single bond, R 3 is C1-C6 alkyl, especially C1-C4 alkyl, more especially C1-C2 alkyl, still more especially methyl, R 4 and R 5 are C1-C6 alkoxy, especially C1-C4 alkoxy, more especially C1-C2 alkoxy, still more especially methoxy, Ar is phenyl, R 2 is H.

[0046] In one embodiment, the dashed line represents a single bond, R 3 is C1-C6 alkyl, especially C1-C4 alkyl, more especially C1-C2 alkyl, still more especially methyl, R 4 and R 5 are C1-C6 alkoxy, especially C1-C4 alkoxy, more especially C1-C2 alkoxy, still more especially methoxy, Ar is pyridinyl, especially pyridin-3-yl, R 1 and R 2 are H.

[0047] In one embodiment, the arylsulfonium compound in the method of the present invention has the formula (I-a):

[0048]

Chemical formula

[0049] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (I-b):

[0050]

Chemical formula

[0051] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (I-c):

[0052]

Chemical formula

[0053] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (I-d):

[0054]

Chemical formula

[0055] In a specific embodiment, the arylsulfonium compound in the method of the present invention is one in which Ar is phenyl. In this embodiment, the arylsulfonium compound in the method of the present invention has the formula (II):

[0056]

Chemical formula

[0057] In one embodiment, the arylsulfonium compound in the method of the present invention has the formula (II-a):

[0058]

Chemical formula

[0059] In a specific embodiment, the arylsulfonium compound in the method of the present invention is one in which Ar is phenyl. In this embodiment, the arylsulfonium compound in the method of the present invention has the formula (III):

[0060]

Chemical formula

[0061] In one embodiment, the arylsulfonium compound in the method of the present invention has the formula (III-a):

[0062] [Chemical formula] In the formula, R 3 , R 4 , R 5 and Y are as defined in formula (I).

[0063] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (III-b):

[0064] [Chemical formula] In the formula, R 3 , R 4 , R 5 and Y are as defined in formula (I).

[0065] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (III-c):

[0066] [Chemical formula] In the formula, R 3 , R 4 , R 5 and Y are as defined in formula (I).

[0067] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (III-d):

[0068] [Chemical formula] In the formula, Y is as defined in formula (I).

[0069] In a specific embodiment, the arylsulfonium compound in the method of the present invention has no dashed line in formula (I). In this embodiment, the arylsulfonium compound in the method of the present invention is of formula (IV):

[0070] [Chemical formula] In the formula, Ar, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined in formula (I).

[0071] The specific arylsulfonium compound in formula (IV) is such that Ar, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined below: Ar is phenyl or pyridinyl, and in particular Ar is phenyl; R 1 is selected from C1-C6 alkyl, halogen, CN and NO 2 ; in particular, R 1 is selected from C1-C4 alkyl, F, Cl, Br, CN and NO 2 ; more particularly, R 1 is selected from C1-C2 alkyl, F, Cl, CN and NO 2 ; still more particularly, R 1 is selected from methyl, Cl, CN and NO 2 ; even more particularly, R 1 is p-methyl, o-methyl, p-Cl and p-NO 2 ; R 2 is H; R 3 is C1-C6 alkyl; in particular, R 3 is C1-C4 alkyl; more particularly, R 3 is C1-C2 alkyl; still more particularly, R 3 is methyl; R 4 and R 5 are H; Y is a monovalent anion, and in particular, Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF4 selected from; more particularly, Y is TfO.

[0072] In one embodiment, the arylsulfonium compound in the method of the present invention has the formula (IV-a):

[0073]

Chemical formula

[0074] In one embodiment, the arylsulfonium compound in the method of the present invention has the formula (IV-b):

[0075]

Chemical formula

[0076] In one embodiment, the arylsulfonium compound in the method of the present invention has the formula (IV-c):

[0077]

Chemical formula

[0078] In a particular embodiment, the broken line in formula (I) of the arylsulfonium compound in the method of the present invention represents a single bond. In this embodiment, the arylsulfonium compound in the method of the present invention has the formula (V):

[0079] [Chemical formula] In the formula, Ar, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined in formula (I).

[0080] The specific arylsulfonium compound in formula (V) is such that Ar, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined below: Ar is phenyl or pyridinyl, particularly Ar is phenyl or pyridin-3-yl; more particularly, Ar is phenyl; R 1 is selected from C1-C6 alkyl, halogen, CN, NO 2 and CHO, and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 or the following formula,

[0081] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; particularly, R 1 is selected from C1-C4 alkyl, F, Cl, Br, CN, NO 2 and CHO, and the aforementioned C1-C4 alkyl group is optionally substituted with N 3 or the following formula,

[0082] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; more particularly, R 1 is selected from C1-C2 alkyl, F, Cl, CN, NO 2 and CHO, and the aforementioned C1-C2 alkyl group is optionally substituted with N 3or is optionally replaced by the following formula,

[0083] [Chemical formula] wherein R 10 is C1-C4 alkoxycarbonyl; still more particularly, R 1 is selected from methyl, Cl, CN, NO 2 and CHO, and the aforementioned methyl group is N 3 or is optionally replaced by the following formula,

[0084] [Chemical formula] wherein R 10 is t-butyloxycarbonyl; R 2 is H; R 3 is H or C1-C6 alkyl; particularly, R 3 is H or C1-C4 alkyl; still more particularly, R 3 is H or C1-C2 alkyl; still more particularly, R 3 is H or methyl; R 4 and R 5 are independently H or C1-C6 alkoxy; particularly, R 4 and R 5 are independently H or C1-C4 alkoxy; still more particularly, R 4 and R 5 are independently H or C1-C2 alkoxy; still more particularly, R 4 and R 5 are independently H or methoxy; and Y is a monovalent anion; particularly, Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF 4 selected from; still more particularly, Y is TfO.

[0085] In one embodiment, the arylsulfonium compound in the method of the present invention has the formula (V-a):

[0086]

Chemical formula

[0087] In a particular embodiment, the arylsulfonium compound in the method of the present invention has the formula (V-I):

[0088]

Chemical formula

[0089] For a specific arylsulfonium compound in formula (V-I), Ar, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined below: Ar is phenyl or pyridinyl, and in particular Ar is phenyl; R 1 is selected from C1-C6 alkyl, halogen, CN and NO 2 , and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 ; in particular, R 1 is selected from C1-C4 alkyl, F, Cl, Br, CN and NO 2 , and the aforementioned C1-C4 alkyl group is optionally substituted with N 3 ; more particularly, R 1 is selected from C1-C2 alkyl, F, Cl, CN and NO 2 and the aforementioned C1-C2 alkyl group is substituted with N3 is optionally replaced; more particularly, R 1 is selected from methyl, Cl, CN and NO 2 and the aforementioned methyl group is optionally replaced by N 3 ; R 2 is H; Y is a monovalent anion; in particular, Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF 4 and is selected from; more particularly, Y is TfO.

[0090] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (V-I-a):

[0091]

Chemical formula

[0092] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (V-I-b):

[0093]

Chemical formula

[0094] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (V-I-c):

[0095]

Chemical formula

[0096] In certain embodiments, the arylsulfonium compound in the method of the present invention has the formula (V-II):

[0097]

Chemical formula

[0098] For a specific arylsulfonium compound in formula (V-II), Ar, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined below: Ar is phenyl or pyridinyl, particularly Ar is phenyl or pyridin-3-yl; more particularly, Ar is phenyl; R 1 is selected from H, C1-C6 alkyl, halogen, CN, NO 2 and CHO, and the aforementioned C1-C6 alkyl group is optionally substituted with the following formula,

[0099]

Chemical formula

[0100]

Chemical formula

[0101]

Chemical formula

[0102]

Chemical formula

[0103]

Chemical formula

[0104] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (V-II-a):

[0105]

Chemical formula

[0106] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (V-II-b):

[0107]

Chemical formula

[0108] In one embodiment, the arylsulfonium compound in the method of the present invention is of formula (V-II-c):

[0109]

Chemical formula

[0110] Certain preferred arylsulfonium compounds in the method of the present invention are shown in Table 1 below.

[0111]

Table 1-1

[0112]

Table 1-2

[0113]

Table 1-3

[0114] In a specific preferred embodiment, the arylsulfonium compound in the method of the present invention is selected from Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 in Table 1 above.

[0115] In one embodiment of the method of the present invention, the iodoaryl or astataryl compound has the formula (VI).

[0116]

Chemical formula

[0117] In one embodiment, X is a radioactive substance. In particular, X is 123 I, 124 I, 125 I, 131 I, 209 At, and 211 At, selected from the group consisting of. More particularly, X is 125 I or 211 At. Still more particularly, X is 211 At.

[0118] In another embodiment of the method of the present invention, the iodide salt and the astatine salt have the formula (VII).

[0119]

Chemical formula

[0120] In one embodiment, X is a radioactive substance. In particular, X is 123 I, 124 I, 125 I and 211 selected from the group consisting of At. More particularly, X is 125 I or 211 At. Still more particularly, X is 211 At.

[0121] In one embodiment, X is 125 I.

[0122] In one embodiment, X is 211 At.

[0123] In one embodiment of the method of the present invention, the reaction defined above is carried out in a solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, water, ethanol, methanol, acetone, and mixtures thereof. In particular, the reaction defined above is carried out in a solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, water, and mixtures thereof. More particularly, the reaction defined above is carried out in a solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, acetonitrile, water, and mixtures thereof. Still more particularly, the reaction defined above is carried out in a solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, water, and mixtures thereof. Even more particularly, the reaction defined above is carried out in a solvent selected from the group consisting of 1,2-dimethoxyethane, toluene, tetrahydrofuran, and mixtures thereof.

[0124] In one embodiment of the method of the present invention, the reaction defined above is carried out in the presence of a base. In particular, the base is NaOH, KOH, LiOH, CsOH, K 2 CO 3、 Na 2 CO 3、 Cs 2 CO 3 and is selected from the group consisting of mixtures thereof. More particularly, the base is NaOH, KOH, K 2 CO 3、 Na 2 CO 3 and mixtures thereof. Still more particularly, the base is selected from NaOH or K 2 CO 3 selected from.

[0125] In one embodiment of the method of the present invention, the reaction defined above is carried out at a temperature included between 60 °C and 140 °C, particularly between 70 °C and 130 °C, more particularly between 80 °C and 120 °C. In a particular embodiment, in the case of iodination, the reaction is carried out at a temperature included between 90 °C and 110 °C, particularly at 100 °C. In another particular embodiment, in the case of the astatination of the arylsulfonium compound of formula (II), the reaction is carried out at a temperature included between 80 °C and 100 °C, particularly at 90 °C. In another particular embodiment, in the case of the astatination of the arylsulfonium compound of formula (III), the reaction is carried out at a temperature included between 100 °C and 120 °C, particularly at 110 °C.

[0126] 〔Step of reducing astatine〕 In one embodiment, the method of the above invention includes a step of reducing astatine. In one embodiment, the reduction is carried out in a solution. The solution may be selected from alcohols such as acetonitrile, chloroform, methanol, N,N-dimethylformamide, water, and mixtures thereof. In particular, the solvent may be acetonitrile, a mixture of acetonitrile and water, or chloroform.

[0127] In a particular embodiment, the reduction step includes the following steps: i) Prepare a solution of astatine and a solvent as defined above (e.g., in the reduction step), particularly acetonitrile; and ii) Mix the solution obtained in step i) with a solution containing a reducing agent, preferably an aqueous solution, thereby obtaining a solution of an astatide salt.

[0128] In another embodiment, the reduction step includes the following steps: i) Prepare a solution of astatine and a solvent as defined above, particularly acetonitrile; ii) Evaporate and dry step i) under a stream of N 2 gas; and iii) Mix the obtained dry residue of astatine with a solution containing a reducing agent, particularly an aqueous solution.

[0129] In one embodiment, the astatide salt is an astatide salt of formula (V) as defined above.

[0130] In one embodiment, the reduction step is carried out with a reducing agent selected from the group consisting of dithiothreitol (DTT), Na 2 SO 3 、Na 2 S 2 O 5 、ascorbate, cysteine, triphenylphosphine, and hydrazine. In particular, the reducing agent is dithiothreitol.

[0131] In a particular embodiment, the method of the present invention includes the following steps: a) In the case of astatination, the step of reducing astatine as defined above, thereby obtaining an astatide salt; b) Reacting any of the arylsulfonium compounds of formula (I) or embodiments of the arylsulfonium compound of formula (I) as defined above with the aforementioned astatide salt or iodide salt, particularly an astatide salt, thereby obtaining an astatoaryl or iodoaryl compound of formula (IV) as defined above, particularly an astatoaryl compound; c) Optionally, a purification step in which an astataryl or iodoaryl compound of formula (IV), in particular an astataryl compound, is extracted with a solvent.

[0132] [Compound of formula (I)] The present invention also relates to compounds having formula (I):

[0133] [Chemical formula] wherein Ar is aryl having 6 to 10 carbon atoms or heteroaryl having 5 to 10 carbon atoms; in particular, Ar is phenyl or pyridinyl; more particularly, Ar is phenyl or pyridin-3-yl; still more particularly, Ar is phenyl; R 1 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, CN, NO 2 , CHO, N=C=O, N=C=S, NR 6 R 7 (R 6 and R 7 are independently H or C1-C6 alkyl), C(O)NHR 8 (R 8 is H or C1-C6 alkyl), and C(O)OR 9 (R 9 is selected from H, C1-C6 alkyl and N-succinimidyl), and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 or the following formula,

[0134] [Chemical formula] wherein R 10 is H or C1-C4 alkoxycarbonyl; in particular, R 1 is selected from C1-C6 alkyl, halogen, CN, NO 2 and CHO, and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 or the following formula,

[0135] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; more particularly, R 1 is selected from C1-C4 alkyl, halogen, CN, NO 2 and CHO, and the aforementioned C1-C4 alkyl group is optionally substituted with N 3 or the following formula,

[0136] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; still more particularly, R 1 is selected from C1-C2 alkyl, F, Cl, CN, NO 2 and CHO, and the aforementioned C1-C2 alkyl group is optionally substituted with N 3 or the following formula,

[0137] [Chemical formula] In the formula, R 10 is H or C1-C4 alkoxycarbonyl; even more particularly, R 1 is p-methyl, o-methyl, Cl, CN, NO 2 , m-CHO, CH 2 N 3 and the following formula,

[0138] [Chemical formula] In the formula, R 10 is t-butyloxycarbonyl; for example, R 1 is p-methyl, o-methyl, m-CHO, CH 2 N 3 and the following formula,

[0139] [Chemical formula] In the formula, R 10 is t-butyloxycarbonyl; R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, CN, NO 2 , CHO, OH, N=C=O, N=C=S, NR 6 R 7 (R 6 and R 7 are independently H or C1-C6 alkyl), C(O)NHR 8 (R 8 is H or C1-C6 alkyl), and C(O)OR 9 (R 9 is selected from H, C1-C6 alkyl, and N-succinimidyl), and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 or the following formula,

[0140]

Chemical formula

[0141]

Chemical formula

[0142] In one embodiment, the compound of the present invention is a compound of formula (I), Ar, R 1 , R2 , R 3 , R 4 , R 5 and Y are as defined above, However: R 1、 R 2 , R 3 , R 4 and R 5 will not all be H; When there is no dashed line and Ar is phenyl, R 3 is not H; When there is no dashed line, R 2 is H, Ar is phenyl, R 3 is methoxy, R 4 and R 5 are H, then R 1 is not H, methoxy or methoxycarbonyl; When there is no dashed line, R 2 is H, Ar is phenyl, R 3 and R 4 are methoxy, R 5 is H, then R 1 is not H; When there is no dashed line, R 2 is H, Ar is phenyl, R 3 is methoxy, R 4 and R 5 are H, and Y is PF 6 then R 1 is not methyl; When the dashed line is a single bond, Ar is phenyl or pyridinyl, and R 3 , R 4 and R 5 are H, then R 1 is not methyl or halogen; When the dashed line is a single bond, Ar is phenyl, R 3 is methyl, R 4 and R 5 are methoxy, then R 1 is not p-methyl, m-methyl, m-methoxy, m-Br, p-CF 3 , p-CHO or o-C(O)OtBu; and The dashed line is a single bond, Ar is pyridinyl, and R 3 is methyl, and R 4 and R 5 are methoxy, then R 1 is not H.

[0143] In one embodiment, when Ar is phenyl, R 1 is not H.

[0144] In one embodiment, R 2 is not H.

[0145] In one embodiment, there is no dashed line and R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl.

[0146] In one embodiment, the dashed line represents a single bond and R 3 , R 4 and R 5 are H.

[0147] In one embodiment, the dashed line represents a single bond, R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl, and R 4 and R 5 are C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy.

[0148] In one embodiment, Ar is phenyl and R 2 is H.

[0149] In one embodiment, Ar is pyridinyl, particularly pyridin-3-yl, and R 1 and R 2 are H.

[0150] In one embodiment, there is no dashed line and Ar is phenyl.

[0151] In one embodiment, the dashed line represents a single bond and Ar is phenyl.

[0152] In one embodiment, the dashed line represents a single bond and Ar is pyridinyl, particularly pyridin-3-yl.

[0153] In one embodiment, the dashed line is absent, R 3 is C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy, and Ar is phenyl.

[0154] In one embodiment, the dashed line represents a single bond, R 3 , R 4 and R 5 are H, and Ar is phenyl.

[0155] In one embodiment, the dashed line represents a single bond, R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl, R 4 and R 5 are C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy, and Ar is phenyl.

[0156] In one embodiment, the dashed line represents a single bond, R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl, R 4 and R 5 are C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy, and Ar is pyridinyl, particularly pyridin-3-yl.

[0157] In one embodiment, the dashed line is absent, R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl, Ar is phenyl, and R 2 is H.

[0158] In one embodiment, the dashed line represents a single bond, and R 3 , R 4 and R 5 are H, Ar is phenyl, and R 2 is H.

[0159] In one embodiment, the dashed line represents a single bond, and R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl, R 4 and R 5 are C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy, Ar is phenyl, and R 2 is H.

[0160] In one embodiment, the dashed line represents a single bond, and R 3 is C1-C6 alkyl, particularly C1-C4 alkyl, more particularly C1-C2 alkyl, still more particularly methyl, R 4 and R 5 are C1-C6 alkoxy, particularly C1-C4 alkoxy, more particularly C1-C2 alkoxy, still more particularly methoxy, Ar is pyridinyl, particularly pyridin-3-yl, and R 1 and R 2 are H.

[0161] In one embodiment, the compound of the present invention is such that R 3 is selected from C1-C6 alkyl and C1-C6 alkoxy and there is no dashed line.

[0162] In one embodiment, the compound of the present invention has the formula (I-a):

[0163]

Chemical formula

[0164] In one embodiment, the compound of the present invention has the formula (I-b):

[0165]

Chemical formula

[0166] In one embodiment, the compound of the present invention has the formula (I-c):

[0167]

Chemical formula

[0168] In one embodiment, the compound of the present invention has the formula (I-d):

[0169]

Chemical formula

[0170] In certain embodiments, the arylsulfonium compound in the method of the present invention is one in which Ar is phenyl. In this embodiment, the arylsulfonium compound in the method of the present invention has the formula (II):

[0171] [Chemical formula] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined in formula (I).

[0172] In one embodiment, the compound of the present invention has the formula (II-a):

[0173] [Chemical formula] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined in formula (I).

[0174] In a particular embodiment, the compound of the present invention is such that Ar is phenyl. In this embodiment, the compound of the present invention has the formula (III):

[0175] [Chemical formula] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined in formula (I).

[0176] In one embodiment, the compound of the present invention has the formula (III-a):

[0177] [Chemical formula] In the formula, R 3 , R 4 , R 5 and Y are as defined in formula (I).

[0178] In one embodiment, the compound of the present invention has the formula (III-b):

[0179]

Chemical formula

[0180] In one embodiment, the compound of the present invention has the formula (III-c):

[0181]

Chemical formula

[0182] In one embodiment, the compound of the present invention has the formula (III-d):

[0183]

Chemical formula

[0184] In a particular embodiment, the compound of the present invention has no dashed line in formula (I). In this embodiment, the compound of the present invention has the formula (IV):

[0185]

Chemical formula

[0186] Particular compounds in formula (IV) are Ar, R 1 , R 2 , R3 , R 4 , R 5 and Y are as defined below: Ar is phenyl or pyridinyl, particularly Ar is phenyl; R 1 is selected from C1-C6 alkyl, halogen, CN and NO 2 ; particularly, R 1 is selected from C1-C4 alkyl, F, Cl, Br, CN and NO 2 ; more particularly, R 1 is selected from C1-C2 alkyl, F, Cl, CN and NO 2 ; still more particularly, R 1 is selected from methyl, Cl, CN and NO 2 ; even more particularly, R 1 is p-methyl, o-methyl, p-Cl and p-NO 2 ; R 2 is H; R 3 is C1-C6 alkyl; particularly, R 3 is C1-C4 alkyl; more particularly, R 3 is C1-C2 alkyl; still more particularly, R 3 is methyl; R 4 and R 5 are H; and Y is a monovalent anion, particularly, Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF 4 selected from; more particularly, Y is TfO.

[0187] In one embodiment, the compound of the present invention is of formula (IV-c):

[0188]

Chemical formula

[0189] In one embodiment, the compound of the present invention is of formula (IV-d):

[0190]

Chemical formula

[0191] In certain embodiments, the compound of the present invention is such that the dashed line in formula (I) represents a single bond. In this embodiment, the compound of the present invention is of formula (V):

[0192]

Chemical formula

[0193] For certain compounds in formula (V), Ar, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined below: Ar is phenyl or pyridinyl, particularly Ar is phenyl or pyridin-3-yl; more particularly, Ar is phenyl; R 1 is selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, CN, NO 2 and CHO, and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 or the following formula,

[0194]

Chemical formula

[0195]

Chemical formula

[0196]

Chemical formula

[0197]

Chemical formula

[0198]

Chemical formula

[0199]

Chemical formula

[0200] In one embodiment, the compound of the present invention has the formula (V-a):

[0201]

Chemical formula

[0202] In a particular embodiment, the compound of the present invention has the formula (V-I):

[0203]

Chemical formula

[0204] For specific compounds in formula (V-I), Ar, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined below: Ar is phenyl or pyridinyl, and in particular Ar is phenyl or pyridin-3-yl; more particularly, Ar is phenyl; R 1 is selected from C1-C6 alkyl, halogen, CN and NO 2 , and the aforementioned C1-C6 alkyl group is optionally substituted with N 3 ; in particular, R 1 is selected from C1-C4 alkyl, F, Cl, Br, CN and NO 2 , and the aforementioned C1-C4 alkyl group is optionally substituted with N 3is optionally replaced; more particularly, R 1 is C1-C2 alkyl, F, Cl, CN and NO 2 selected from, and the aforementioned C1-C2 alkyl group is N 3 optionally substituted; still more particularly, R 1 is methyl, Cl, CN and NO 2 selected from, and the aforementioned methyl group is N 3 optionally substituted; even more particularly, R 1 is CN, NO 2 and CH 2 N 3 selected from; R 2 is H; Y is a monovalent anion; in particular, Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF 4 selected from; more particularly, Y is TfO; provided that when Ar is phenyl, R 1 is not p-methyl or halogen.

[0205] In certain embodiments, the compounds of the invention are of formula (V-I-b):

[0206]

Chemical formula

[0207] Particular compounds of formula (V-I-b) are those where R 1 and Y are as defined below.

[0208] R 1 is selected from C1-C6 alkyl, halogen, CN and NO 2 and the aforementioned C1-C6 alkyl group is N 3 optionally substituted; in particular, R 1 is C1-C4 alkyl, F, Cl, Br, CN and NO 2selected from, and the alkyl groups of C1-C4 described above are N 3 optionally substituted; more particularly, R 1 is C1-C2 alkyl, F, Cl, CN and NO 2 selected from, and the alkyl groups of C1-C2 described above are N 3 optionally substituted; still more particularly, R 1 is methyl, Cl, CN and NO 2 selected from, and the methyl group described above is N 3 optionally substituted; Y is a monovalent anion; Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF 4 ; more particularly Y is TfO; provided that R 1 is not p-methyl or Cl.

[0209] In one embodiment, the compound of the present invention is of formula (V-I-c):

[0210]

Chemical formula

[0211] In a particular embodiment, the compound of the present invention is of formula (V-II):

[0212]

Chemical formula

[0213] Particular compounds in formula (V-II) are Ar, R 1 , R 2 , R 3 , R 4 , R5 and Y is as defined below: Ar is phenyl or pyridinyl, in particular Ar is phenyl or pyridin-3-yl; more particularly, Ar is phenyl; R 1 is selected from C1-C6 alkyl, halogen, CN, NO 2 and CHO, and the aforementioned C1-C6 alkyl group is optionally substituted with the following formula,

[0214]

Chemical formula

[0215]

Chemical formula

[0216]

Chemical formula

[0217]

Chemical formula

[0218] [Chemical formula] wherein R 10 is t-butyloxycarbonyl; for example, R 1 is m-CHO and is selected from the following formulae,

[0219] [Chemical formula] wherein R 10 is t-butyloxycarbonyl; R 2 is H; R 3 is C1-C6 alkyl; particularly, R 3 is C1-C4 alkyl; more particularly, R 3 is C1-C2 alkyl; still more particularly, R 3 is methyl; R 4 and R 5 are C1-C6 alkoxy; particularly, R 4 and R 5 are C1-C4 alkoxy; more particularly, R 4 and R 5 are C1-C2 alkoxy; still more particularly, R 4 and R 5 are methoxy; Y is a monovalent anion; particularly, Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF 4 selected therefrom; more particularly, Y is TfO; provided that when Ar is phenyl, R is methyl, and R and R are methoxy, R is p-methyl, m-methyl, m-methoxy, m-Br, p-CF 3, it is not p-CHO or o-C(O)OtBu.

[0220] In one embodiment, the compound of the present invention has the formula (V-II-a):

[0221]

Chemical formula

[0222] In one embodiment, the compound of the present invention has the formula (V-II-b):

[0223]

Chemical formula

[0224] In one embodiment, the compound of the present invention has the formula (V-II-c):

[0225]

Chemical formula

[0226] Certain preferred arylsulfonium compounds in the method of the present invention are shown in Table 2 below.

[0227]

Table 2-1

[0228]

Table 2-2

[0229] The compounds of the present invention can be prepared in various ways using reactions known to those skilled in the art, particularly as described in the examples.

[0230] [Radioactive labeling step] The present invention also relates to a method for synthesizing an iodine-labeled biomolecule or an astatine-labeled biomolecule and / or a vector, comprising the following steps: (i) Synthesize an iodoaryl or astataryl compound according to the method of the present invention; (ii) React the aforementioned iodoaryl or astataryl compound with a biomolecule and / or a vector having a functional group that reacts with the aforementioned iodoaryl or astataryl compound.

[0231] [Definitions] The following definitions and explanations relate to terms used throughout the present application, including both the specification and the claims.

[0232] Unless otherwise specified, references to the compounds of the present invention in this specification mean the compounds referred to, as well as their pharmaceutically acceptable salts and solvates.

[0233] When describing the compounds of the present invention, the terms used are construed according to the following definitions, unless otherwise specified.

[0234] As used herein, the term "unsubstituted" means that a radical, group or residue has no substituents. The term "substituted" means that a radical, group or residue has one or more substituents.

[0235] The term "halo" or "halogen" refers to an atom of Group 17 (halogens) of the periodic table, and particularly includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) atoms. Preferred halogen atoms in the context of the present invention are fluorine and chlorine, with chlorine being particularly preferred.

[0236] The term "alkyl", by itself or as part of another substituent, refers to a hydrocarbyl group of the formula C n H 2n+1 where n is a number of 1 or greater. Thus, an alkyl group may contain one or more carbon atoms and generally, according to the present invention, may contain from 1 to 12 carbon atoms, more preferably from 1 to 8 carbon atoms, still more preferably from 1 to 6 carbon atoms. An alkyl group in the context of the present invention may be straight-chain or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, neohexyl, isohexyl, sec-hexyl, and tert-hexyl. Examples of specific alkyl groups in the context of the present invention include methyl, ethyl, n-propyl, n-butyl and tert-butyl.

[0237] The term "haloalkyl" refers to an alkyl group as defined above having one or more hydrogens replaced by a halogen as defined above, either alone or in combination. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like. A specific example of a haloalkyl group according to the present invention is trifluoromethyl.

[0238] As used herein, the term "heteroatom" refers to any atom that is not carbon or hydrogen. Non-limiting examples of such heteroatoms include nitrogen, oxygen, sulfur, and phosphorus. Preferred heteroatoms according to the present invention are nitrogen, oxygen and sulfur.

[0239] As used herein, the term "aryl" refers to a polyunsaturated aromatic hydrocarbyl group having a single ring (e.g., phenyl) or a ring in which a plurality of aromatic rings are fused (e.g., naphthyl), typically containing 5 to 12 atoms; preferably 6 to 10 atoms, and at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, 1-naphthyl (or naphthalen-1-yl), 2-naphthyl (or naphthalen-2-yl), anthracenyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl. A preferred example of the aryl group in the present invention is phenyl.

[0240] As used herein, the term "heteroaryl" when used by itself or as part of another group refers to a ring system containing an aromatic ring of 5 to 12 carbon atoms or 1 to 2 rings in which each ring typically contains 5 to 6 atoms and at least one is an aromatic ring and the rings are fused to each other, wherein one or more carbon atoms of these rings are replaced by oxygen, nitrogen and / or sulfur atoms, and the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may be optionally quaternized. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, furanyl, benzofuranyl, pyrrolinyl, indolyl, thiophenyl, benzothiophenyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiazolyl, and benzothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl and tetrazolyl. An example of a specific heteroaryl group according to the present invention is pyridinyl.

[0241] As used herein, the term "astatination" refers to the synthesis of an astataryl compound according to the present invention, particularly a compound of formula (IV) wherein X is At, particularly 211 At.

[0242] The compounds of the present invention include all polymorphs and crystal habits thereof, prodrugs and their isomers (including optical isomers, geometric isomers and tautomers), and isotopically labeled compounds of the present invention as defined herein.

[0243] The present invention will be better understood by reference to the following examples and figures. These examples represent specific embodiments of the present invention and do not limit the scope of the present invention.

Examples

[0244] [Abbreviations] DCM: Dichloromethane DBTO: Dibenzothiophene S-oxide DMSO: Dimethyl sulfoxide DPEphos: Bis[(2-diphenylphosphino)phenyl]ether EDTA: Ethylenediaminetetraacetic acid equiv.: Equivalent HPLC: High performance liquid chromatography NCS: N-Chlorosuccinimide NMR: Nuclear magnetic resonance ppm: Parts per million RCY: Radiochemical yield TFA: Trifluoroacetic acid TFSA: Trifluoromethanesulfonic acid THF: Tetrahydrofuran TLC: Thin layer chromatography t R : Retention time UV: Ultraviolet

[0245] [Synthesis] 1. Materials and equipment All commercially available reagents, solvents and chromatography reagents were purchased from Sigma-Aldrich, Fisher Scientific, TCI, VWR or Fluorochem.

[0246] 1 H and13 The 13C NMR spectra were recorded on a Bruker AC spectrometer at 400( 1 H) and 100( 13 C) MHz. Chemical shifts (δ) are reported in parts per million (ppm) relative to deuterated solvent CDCl 3 : 7.26 ppm, DMSO-d6: 2.50 ppm, CD 3 CN: 1.94 ppm (CD 3 ) 2 CO: 2.50 ppm. All deuterated solvents were purchased from Sigma Aldrich. Multiplicities are represented by the symbols s (singlet), d (doublet), t (triplet), m (multiplet).

[0247] The reaction was monitored by thin layer chromatography (TLC) using a 60 F254 silica gel plate on an aluminum support (Merck) and visualized with a UV lamp (254 nm). Purification was carried out using a Puriflash 600 (Interchim) with a 30 μm silica prepacked column.

[0248] The yield of radioTLC was evaluated by elution of an aliquot attached to the TLC plate. The eluent was hexane / ethyl acetate 1 / 1. After elution, the plate was read using a Cyclone phosphorimager scanner (Perkin Elmer).

[0249] Non-radioactive 127I-Analog compounds were also analyzed on the same HPLC system, and the retention times detected by a UV detector were used as a reference for the identification of radioiodinated and astatined analog compounds. Since astatine and iodine have similar polarities, the difference in retention times between astatined products and iodinated products was small. The radioiodination reaction and the astatination reaction were analyzed on two different HPLC systems with the same configuration to explain some of the observed retention differences. HPLC analysis was performed on a Waters Alliance e2695 system equipped with a FlowStar LB 513 Radio Flow Detector or a Beta-RAM 5 Radio-HPLC detector (LabLogic). A = H 2 O containing 0.05% TFA, B = CH 3 CN.

[0250] Analysis conditions: C 18 Using a column (Spherisorb ODS2 5μm, 4.6mm×25cm, Waters), the flow rate was set at 1.50 mL / min, and the following gradient was performed: t = 0: A 60%, B 40%; t = 7 min: A 30%, B 70%; t = 15 min: B 100%. UV-Vis detection was performed using an HPLC PDA detector set at 254 nm, and radiation detection was performed using a Berthold radioflowstar LB513 detector.

[0251] 2. Synthesis of Triarylsulfonium Salts and Dibenzothiophenium Salts 2.1. General Procedure 1 for the Synthesis of Triarylsulfonium Salts A diarylthioether precursor was prepared from an aryl iodide derivative having a selected substituent. Subsequently, the corresponding triarylsulfonium salt was obtained.

[0252]

Chemical Structure

[0253] An aryl iodide derivative (1 eq.), sodium tert-butoxide (2 eq.), copper(I) iodide (0.1 eq.) and neocuproine (0.1 eq.) were added to 6 mL of toluene and sealed. The mixture was stirred for 5 minutes under an argon atmosphere, and then 4-methoxybenzenethiol (2 eq.) was added. Thereafter, the solution was further purged with argon for 10 minutes and heated at 110 °C for 24 hours. After monitoring by TLC and completion of the reaction, the cooled mixture was filtered through celite. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash chromatography on silica gel using heptane / AcOEt as the eluent.

[0254] Step 2: Synthesis of triarylsulfonium salt (adapted from Sander et al., Sci. Rep. 2015, 5, 9941) To a solution of the diarylthioether derivative (1 equiv.) obtained in Step 1 above in bromobenzene (5 mL), copper(II) benzoate (0.05 eq.) and diphenyliodonium trifluoromethanesulfonate (1.1 eq.) were added. Thereafter, the solution was purged with argon for 5 minutes and heated at 125 °C for about 16 hours. After completion of the reaction, the resulting residue was purified by flash chromatography on silica gel using DCM / MeOH as a gradient.

[0255] [Compound 1] (4-Methoxyphenyl)(p-tolyl)sulfane

[0256] [Chemical formula] (4-Methoxyphenyl)(p-tolyl)sulfane was prepared from 1-iodo-4-methylbenzene (500 mg, 2.29 mmol) according to Step 1 of General Procedure 1 and obtained as a colorless solid (396 mg, 75%).

[0257] 1 H NMR (400 MHz, DMSO-d 6): δ (ppm) 7.31 - 7.38 (m, 2H), 7.05 - 7.16 (m, 4H), 6.93 - 7.01 (m, 2H), 3.76 (s, 3H), 2.25 (s, 3H). 13 C NMR (100 MHz, DMSO - d 6 ): δ (ppm) 159.3, 135.9, 134.2, 133.5, 129.8, 128.9, 124.3, 115.2, 55.2, 20.4.

[0258] (4 - Methoxyphenyl)(phenyl)(p - tolyl)sulfonium trifluoromethanesulfonate (1)

[0259]

Chemical Structure

[0260] 1 H NMR (400 MHz, DMSO - d6): δ (ppm) 7.71 - 7.87 (m, 7H), 7.65 - 7.71 (m, 2H), 7.55 - 7.62 (m, 2H), 7.28 - 7.36 (m, 2H), 3.92 (s, 3H), 2.55 (s, 3H). 13 C NMR (100 MHz, DMSO - d6): δ (ppm) 163.8, 145.0, 133.8, 133.6, 131.7, 131.1, 130.8, 130.4, 126.3, 122.4, 116.9, 114.3, 56.09, 20.9. MS (ESI + ): m / z = 307.2 [M - OTf] +

[0261] [Compound 2] (4-Methoxyphenyl)(o-tosyl)sulfane

[0262]

Chem.

[0263] 1 H NMR (400 MHz, DMSO-d 6 ): δ (ppm) 7.30 - 7.35 (m, 2H), 7.21 - 7.27 (m, 1H), 7.07.-7.16 (m, 2H), 6.97 - 7.03 (m, 2H), 6.86 - 6.91 (m, 1H), 3.78 (s, 3H), 2.31 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ): δ (ppm) 159.3, 136.3, 136.2, 134.4, 130.2, 128.5, 126.7, 126.3, 123, 115.3, 55.2, 19.7.

[0264] (4-Methoxyphenyl)(phenyl)(o-tosyl)sulfonium trifluoromethanesulfonate (2)

[0265]

Chem.

[0266] 11H NMR (400 MHz, DMSO-d6): δ (ppm) 7.60 - 7.81 (m, 8H), 7.46 - 7.54 (m, 2H), 7.18 - 7.26 (m, 2H), 7.08 - 7.15 (m, 1H), 3.92 (s, 3H), 2.55 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6): δ (ppm) 164.8, 140.3, 134.4, 134.3, 133.8, 133.15, 131.6, 130.7, 129.6, 129.0, 124.2, 124.0, 117.55, 113.32, 56.18, 19.76. MS (ESI + ): m / z = 307.2 [M - OTf] +

[0267] [Compound 3] (4-Chlorophenyl)(4-methoxyphenyl)sulfane

[0268] [Chemical Structure] (4-Chlorophenyl)(4-methoxyphenyl)sulfane was prepared from 1-chloro-2-iodobenzene (1.0 g, 4.19 mmol) according to Step 1 of General Procedure 1 and obtained as a white powder (705 mg, 67%).

[0269] 1 1H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.39 - 7.46 (m, 2H), 7.18 - 7.25 (m, 2H), 7.06 - 7.13 (m, 2H), 6.89 - 6.96 (m, 2H), 3.84 (s, 3H). 13 13C NMR (100 MHz, CDCl 3 ): δ (ppm) 160.0, 137.3, 135.4, 131.6, 129.3, 129, 123.8, 115.1, 55.3.

[0270] (4-Chlorophenyl)(4-methoxyphenyl)(phenyl)sulfonium trifluoromethanesulfonate (3)

[0271] [Chemical formula] Compound 3 was prepared from (4-chlorophenyl)(4-methoxyphenyl)sulfane (100 mg, 3.98 mmol) according to Step 2 of General Procedure 1 and obtained as an orange oil (146 mg, 77%).

[0272] 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 7.73 - 7.90 (m, 10H), 7.28 - 7.38 (m, 3H), 3.88 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm) 164.0, 139.2, 134.1, 133.9, 132.5, 131.2, 131.1, 121.1, 130.79, 126.02, 125.0, 116.9, 113.8, 56.1. MS (ESI + ): m / z = 327.1 [M - OTf] +

[0273] [Compound 4] (4-Methoxyphenyl)(4-nitrophenyl)sulfane

[0274] [Chemical formula] (4-Methoxyphenyl)(4-nitrophenyl)sulfane was prepared from 1-iodo-4-nitrobenzene (300 mg, 1.15 mmol) according to Step 1 of General Procedure 1 and obtained as a yellow solid (189 mg, 60%).

[0275] 1 H NMR (400 MHz, CDCl 3): δ (ppm) 8.02 - 8.06 (m, 2H), 7.47 - 7.51 (m, 2H), 7.07 - 7.11 (m, 2H), 6.97 - 7.01 (m, 2H), 3.87 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ (ppm) 161.1, 150.0, 145.0, 137.1, 125.6, 123.9, 120.2, 115.6, 55.4.

[0276] (4 - Methoxyphenyl)(4 - nitrophenyl)(phenyl)sulfonium trifluoromethanesulfonate (4)

[0277]

Chem.

[0278] 1 H NMR (400 MHz, DMSO - d6): δ (ppm) 8.45 - 8.43 (m, 2H), 7.90 - 7.92 (m, 2H), 7.69 - 7.83 (m, 7H), 7.20 - 7.22 (m, 2H), 3.90 (s, 3H). 13 C NMR (100 MHz, DMSO - d6): δ (ppm) 165.8, 150.8, 135.1, 134.4, 133.0, 132.1, 132.0, 131.3, 126.2, 124.6, 117.9, 111.7, 56.4. MS (ESI + ): m / z = 338.2 [M - OTf] + , 825.2 [2M - OTf] + .

[0279] 2.2.5 General procedure 2 (LG B) for the synthesis of dibenzothiophenium salts with 2.2.5H-dibenzo[b,d]thiophen-5-ylidene as the leaving group Sulfonium salts were prepared from dibenzothiophene S-oxide and the corresponding functionalized aryl compounds (Xu et al., Angew. Chem. Int. Ed. 2020, 59, 1956-1960).

[0280] [Chemical formula]

[0281] An arene (0.50 mmol, 1.0 equiv.) and dry MeCN (2.0 mL, c = 0.25 M) were charged into a 10 mL nitrogen-filled Schlenk tube equipped with a magnetic stir bar at 25 °C. After cooling to -40 °C (acetonitrile / dry ice bath), trifluoromethanesulfonic acid (1.0 - 2.0 mmol, 2.0 - 4.0 equiv.) and trifluoroacetic anhydride (209 μL, 315 mg, 1.50 mmol, 3.0 equiv.) were added to the stirred reaction mixture. Subsequently, dibenzothiophene S-oxide (DBTO) (0.75 mmol, 1.5 equiv.) was added portionwise to the stirred reaction mixture over 1 minute. After the addition, the reaction mixture was stirred at -40 °C for 1 hour. Subsequently, the Schlenk tube was removed from the cold bath and warmed to 25 °C in air. After stirring at 25 °C for an additional 1 hour, the reaction mixture was diluted with DCM (10 mL) and poured into saturated aqueous NaHCO 3 (10 mL). The mixture was concentrated under reduced pressure to remove most of the MeCN solvent, and the residue was diluted with 20 mL of DCM and 10 mL of water. The mixture was poured into a separatory funnel and the layers were separated. The DCM layer was collected, and the aqueous layer was further extracted with DCM (4 × ca. 30 mL). The combined DCM layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel.

[0282] [Compound 5] 5-(4-Methylphenyl)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (5)

[0283]

Chem.

[0284] [Compound 6] 5-(4-Chlorophenyl)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (6)

[0285]

Chem.

[0286] [Compound 7] 5-(4-Cyanophenyl)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (7)

[0287]

Chem.

[0288] 11H NMR (400 MHz, DMSO-d6): δ (ppm) 8.69 (d, J = 1.9 Hz, 1H), 8.60 (d, J = 7.7 Hz, 2H), 8.40 - 8.29 (m, 3H), 8.02 (t, J = 7.6 Hz, 2H), 7.77 (t, J = 7.8 Hz, 2H), 7.57 (dd, J = 8.7, 1.9 Hz, 1H). 19 19F NMR (376 MHz, DMSO-d6): δ (ppm) - 77.81.

[0289] [Compound 8] 5-(4-Nitrophenyl)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (8)

[0290]

Chem.

[0291] 1 1H NMR (400 MHz, CD 3 CN): δ (ppm) 8.35 (dd, J = 7.9, 0.6 Hz, 2H), 8.08 (d, J = 8.1 Hz, 2H), 7.95 (td, J = 7.8, 1.0 Hz, 2H), 7.77 - 7.68 (m, 2H), 7.62 - 7.52 (m, 4H).

[0292] [Compound 9] 5-(4-(Azidomethyl)phenyl)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (9)

[0293]

Chem.

[0294] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.96 (dd, J = 11.7, 4.4 Hz, 4H), 7.63 (td, J = 7.7, 1.0 Hz, 2H), 7.49 - 7.35 (m, 4H), 7.23 (d, J = 8.6 Hz, 2H), 7.03 (s, 1H), 4.20 (s, 2H). 19 F NMR (376 MHz, CDCl 3 ): δ (ppm) -78.20. MS (ESI+): 316.8 [M - OTf] + .

[0295] 2.3.2,4 - Dimethoxy - 8 - methyl - 5H - dibenzo[b,d]thiophen - 5 - ylium as the leaving group, General Procedure 3 (LG B) for the synthesis of dibenzothiophenium salts The dibenzothiophenium salts were prepared by the cyclization reaction of biaryl thioether precursors (Gendron et al., J. Am. Chem. Soc. 2018, 140, 11125 - 11132).

[0296]

Chemical Structure

[0297] Flame - dried, DPEphos (2 mol%), tris(dibenzylideneacetone)dipalladium(0) (1 mol%), and toluene were added to a three - necked round - bottom flask equipped with an argon inlet and a condenser (reaction concentration = 0.15 mol.L -1)。The resulting dark purple solution was stirred at room temperature for 10 minutes under an argon atmosphere, and then an aromatic halide (1 equiv.), 2-ethylhexyl 3-((3',5'-dimethoxy-5-methyl-[1,1'-biphenyl]-2-yl)thio)propanoate (1 equiv.), and potassium tert-butoxide (1.2 equiv.) were added. After the resulting mixture was filled with argon, it was placed in a preheating device maintained at 125 °C. The reaction was heated and refluxed for 15 minutes to 6 hours (determined by TLC). After cooling to room temperature, the mixture was filtered through a pad of Celite (registered trademark), and the cake was washed twice with toluene. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography.

[0298] Step 2: Synthesis of dibenzothiophenium salt To a round-bottom flask were added the biaryl thioether (1 equiv.) obtained in Step 1 and acetonitrile (reaction concentration = 0.125 mol·L -1 ). N-Chlorosuccinimide (1 equiv.) and bismuth(III) triflate (1 equiv.) were added thereto. The resulting solution was stirred at room temperature for 5 minutes to 2 hours (determined by TLC), and then quenched with EDTA (0.05 M saturated aqueous potassium carbonate solution, 4 equiv.). Thereafter, the crude reaction mixture was extracted three times with dichloromethane, and the combined organic layers were washed with a 1 M aqueous solution of sodium triflate (usually 10 - 30 mL). The combined organic layers were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by flash chromatography.

[0299] [Compound 10] 2,4-Dimethoxy-8-methyl-5-(p-tosyl)-5H-dibenzothieno[b,d]thiophen-5-ium trifluoromethanesulfonate (10)

[0300] [Chemical formula] Compound 10 was prepared in two steps from 1-iodo-4-methylbenzene (78 mg, 0.4 mmol) according to General Procedure 3 and obtained as a white solid (35 mg, 7%).

[0301] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.07 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 1.8 Hz, 2H), 7.28 (s, 1H), 6.54 (d, J = 2.0 Hz, 1H), 4.02 (s, 3H), 3.85 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H). 19 F NMR (376 MHz, DMSO): δ (ppm) -77.77. MS (ESI+): 349.9 [M] + .

[0302] [Compound 11] 5-(3-Formylphenyl)-2,4-dimethoxy-8-methyl-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (11)

[0303]

Chemical Structure

[0304] 1 H NMR (400 MHz, CDCl 3): δ (ppm) 9.92 (s, 1H), 8.09 - 8.00 (m, 5H), 7.85 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.66 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 3.98 (s, 4H), 3.81 (s, 4H), 2.33 (s, 3H). 19 F NMR (376 MHz, CDCl 3 ): δ (ppm) -78.20. MS (ESI+): 364.0 [M - OTf] + .

[0305] [Compound 12] 3 - ((1,2,3,3 - Tetrakis(tert - butoxycarbonyl)guanidino)methyl)iodobenzene

[0306]

Chem.

[0307] (Z) - 2,4 - Dimethoxy - 8 - methyl - 5 - (3 - ((1,2,3,3 - tetrakis(tert - butoxycarbonyl)guanidino)methyl)phenyl) - 5H - dibenzo[b,d]thiophen - 5 - ium trifluoromethanesulfonate (12)

[0308]

Chem.

[0309] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.17 - 7.95 (m, 2H), 7.70 - 7.60 (m, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.33 (d, J = 1.9 Hz, 2H), 7.28 (d, J = 1.8 Hz, 1H), 6.57 (dd, J = 8.8, 1.8 Hz, 1H), 4.93 (d, J = 24.9 Hz, 2H), 4.05 (s, 3H), 3.88 (s, 3H), 2.42 (s, 3H), 1.52 - 1.46 (s, 18H), 1.34 (s, 9H), 1.26 - 1.23 (S, 9H). 19 F NMR (376 MHz, CDCl 3 ): δ (ppm) -78.21. MS (ESI+): 807.2 [M - OTf] + .

[0310] [Compound 13] 2,4-Dimethoxy-8-methyl-5-(pyridin-3-yl)-5H-dibenz[b,d]thiophen-5-ium trifluoromethanesulfonate (13)

[0311]

Chemical Structure

[0312] [Compound 14] 5-(o-Tolyl)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (14)

[0313] [Chem.] Compound 14 was prepared from 2-iodobiphenyl (280 mg) according to F. Sirindil et al., Int. J. Mol. Sci. 2022, 23, 15481 and obtained as an off-white solid in 38% yield.

[0314] [Chem.] 1 H NMR (400 MHz, MeOD): δ (ppm) 8.58-8.39 (dd, J = 8.1, 0.5 Hz, 1H), 8.20 (dd, J = 8.1, 0.5 Hz, 1H), 8.10-7.91 (m, 1H), 7.88-7.72 (m, 1H), 7.70-7.57 (m, 1H), 7.35-7.19 (m, 1H), 6.75 (d, J = 8.2 Hz, 1H), 3.02 (s, 1H). 19 F NMR (376 MHz, MeOD) δ (ppm) -80.09.

[0315] [Radiochemistry] 1. Radiolabeling of Sulfonium Salts and Dibenzothiophenium Salts 211 At Radioisotope Labeling 1.1. Preparation Procedure of Nucleophilic At 211 Astatine was 209 produced by the Bi(α,2n) 211 At reaction at the ronax cyclotron facility and recovered from the irradiated target in chloroform or 0.1 N aqueous NaOH solution using a dry distillation protocol adapted from the procedure already reported by Lindegren et al., Appl. Radiat. Isot. 2001, 55, 157-160.

[0316] The chloroform astatine solution was dried under reduced pressure under a gentle nitrogen stream to obtain dry astatine, and 10 μL (10 mg / mL) of a DTT solution in CH 3 CN was added to form reactive species.

[0317] Various reducing agents (dithiothreitol (DTT), sodium sulfite, sodium metabisulfite) were tried for the preparation of astatides, but DTT was preferentially used.

[0318] Instead, after dry distillation 211 when astatine was recovered with 0.1 N aqueous NaOH solution, 211 the astatine solution was used as it was without evaporation and addition of a reducing agent.

[0319] General procedure 1 for 211 radioiodination of astatine with (4-methoxyphenyl)(phenyl)sulfonium as the leaving group (LG A)

[0320]

Chemical formula

[0321] For dibenzothiophenium salt (LG B) with 1.3.5H-dibenzo[b,d]thiophen-5-ium as the leaving group 211 General procedure 2 for At radioisotope labeling

[0322] [Chemical formula] To the reduced astatine prepared as described above, an arylsulfonium salt (3.0 μmol) in 1,2-dimethoxyethane (100 μL) was added, and the reaction mixture was heated at 110 °C for 20 minutes. An aliquot was taken out and attached to a silica gel TLC plate, eluted with an appropriate solvent (hexane / ethyl acetate 7 / 3), or diluted with a 1:1 water / MeCN mixed solvent for reverse-phase HPLC analysis (Table 6).

[0323] For dibenzothiophenium salt (LG C) with 1.4.2,4-dimethoxy-8-methyl-5H-dibenzo[b,d]thiophen-5-ium as the leaving group 211 General procedure 3 for At radioisotope labeling

[0324] [Chemical formula] To the reduced astatine prepared as described above, an arylsulfonium salt (3.0 μmol) in 1,2-dimethoxyethane (100 μL) was added, and the reaction mixture was heated at 90 °C for 30 minutes. An aliquot was taken out and applied to a silica gel TLC plate, eluted with an appropriate solvent (hexane / ethyl acetate 7 / 3), or diluted with a 1:1 water / MeCN mixed solvent for reverse-phase HPLC analysis (Table 6).

[0325] 2. 125 I Radioisotope Labeling of Sulfonium Salts and Dibenzothiophenium Salts 125 I] NaI is commercially available from Perkin Elmer at a radioactivity of 50 μCi / μL (1.85 MBq / mL) per volume in 10 -5 M NaOH solution and was diluted 10-fold with MeCN before use.

[0326] 2.1. General Procedure for 125 I Radioisotope Labeling of Sulfonium Salt (LG A) with (4-Methoxyphenyl)(phenyl)sulfonium as the Leaving Group To a sealed vial, K 222 (100 μL, 10 mg / mL) and K 2 CO 3 (2.7 μL, 0.5 M) were added to a commercially available -5 I] NaI solution in 10 125 M NaOH. The I - / K 222 / K 2 CO 3 solution was dried under reduced pressure, 250 μL of MeCN was added and azeotroped, and this step was repeated twice. Then, an arylsulfonium salt (3.0 μmol) dissolved in an appropriate solvent (100 μL) was added, and the reaction mixture was heated at 90 °C for 30 minutes. An aliquot was taken out and applied to a silica gel TLC plate, eluted with an appropriate solvent (hexane / ethyl acetate 1:1), or diluted with a 1:1 water / MeCN mixed solvent for reverse-phase HPLC analysis (Table 6).

[0327] 3. Results ​3.1. Aromatic compounds using a sulfonium salt (LG A) with (4-methoxyphenyl)(phenyl)sulfonium as a leaving group 211 At radioisotope labeling Aromatic compounds using a sulfonium salt (LG A) with (4-methoxyphenyl)(phenyl)sulfonium as a leaving group 211 At radioisotope labeling was carried out according to General Procedure 1. The radiochemical yield (RCY) was measured by HPLC of the crude product. The results are shown in Table 3 and Table 3b below.

[0328]

Table 3-1

[0329]

Table 3-2

[0330] 3.2. Aromatic compounds using a dibenzothiophenium salt (LG B) with 5H-dibenzo[b,d]thiophen-5-ium as a leaving group 211 At radioisotope labeling Aromatic compounds using a sulfonium salt (LG A) with (4-methoxyphenyl)(phenyl)sulfonium as a leaving group 211 At radioisotope labeling was carried out according to General Procedure 2. The results are shown in Table 4 below.

[0331]

Table 4-1

[0332] 3.3. Aromatic compounds using a dibenzothiophenium salt (LG C) with 2,4-dimethoxy-8-methyl-5H-dibenzo[b,d]thiophen-5-ium as a leaving group 211 At radioisotope labeling Aromatic compounds using a sulfonium salt (LG A) with (4-methoxyphenyl)(phenyl)sulfonium as a leaving group 211The At radiolabeling was carried out according to General Procedure 3. Starting from Compound 11, the corresponding 211 At radiolabeled product was obtained in 92% yield.

[0333] [Chemical Structure]

[0334] The results starting from Compounds 10, 11, and 13 are shown in Table 4b below.

[0335] [Table 4-2]

[0336] 3.4. Iodination of aromatic compounds using a sulfonium salt (LG A) with (4-methoxyphenyl)(phenyl)sulfonium as the leaving group 125 I radiolabeling (4-Methoxyphenyl)(phenyl)sulfonium as the leaving group of the sulfonium salt (LG A) for iodination of aromatic compounds 125 I radiolabeling was carried out according to General Procedure 4. The radiochemical yield (RCY) was measured by HPLC of the crude product. The results are shown in Table 5 and Table 5b below.

[0337] [Table 5-1]

[0338] [Table 5-2]

[0339] 3.5. Retention times of the expected products using non-radioactive iodinated reference compounds, radioactive iodinated compounds, and radioactive astatined compounds The retention times of the expected products of the non-radioactive iodinated reference compound, the radioactive iodinated compound, and the radioactive astatized compound obtained by HPLC analysis are summarized in Table 6 below.

[0340] [Table 6]

[0341] Radioactive labeling of aromatic compounds using dibenzothiophenium salt (LG B) with 3.6.5H-dibenzothiophen-5-ylium as the leaving group 125 I Radioactive labeling Radioactive labeling of aromatic compounds using dibenzothiophenium salt (LG B) with 5H-dibenzothiophen-5-ylium as the leaving group 125 I Radioactive labeling was carried out according to General Procedure 4. The results are shown in Table 7 below.

[0342] [Table 7]

Claims

1. A method for synthesizing an iodoaryl or astatoaryl compound, respectively, comprising a reaction of an arylsulfonium compound with an iodide salt or an astatine salt, wherein the arylsulfonium compound has the formula (I), 【Chemical 1】 wherein Ar is an aryl having 6 to 10 carbon atoms or a heteroaryl having 5 to 10 carbon atoms; R 1 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, CN, NO 2 , CHO, OH, N=C=O, N=C=S, NR 6 R 7 (R 6 and R 7 are independently H or C1-C6 alkyl), C(O)NHR 8 (R 8 is H or C1-C6 alkyl), and C(O)OR 9 (R 9 is selected from H, C1-C6 alkyl, and N-succinimidyl), The C1-C6 alkyl group is N 3 optionally substituted by N or the following formula, 【Chemical Formula 2】 In the formula, R 10 is H or an alkoxycarbonyl having 1 to 4 carbon atoms; R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, CN, NO 2 , CHO, OH, N=C=O, N=C=S, NR 6 R 7 (R 6 and R 7 are independently H or C1-C6 alkyl), C(O)NHR 8 (R 8 is H or C1-C6 alkyl), and C(O)OR 9 (R 9 is selected from H, C1-C6 alkyl, and N-succinimidyl), The C1-C6 alkyl group is N 3 optionally substituted by N or the following formula, [Chemical Formula 3] In the formula, R 10 is H or an alkoxycarbonyl having 1 to 4 carbon atoms; R 3 is selected from H, C1-C6 alkyl, and C1-C6 alkoxy; R 4 and R 5 are each independently selected from H, C1-C6 alkyl and C1-C6 alkoxy; Y is a monovalent anion; and the dashed line represents a single bond or its absence, the method.

2. The arylsulfonium compound has the formula (II): 【Chemical 4】 wherein R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined in claim 1, the method according to claim 1.

3. The arylsulfonium compound has the formula (IV): 【Chemical Formula 5】 wherein Ar, R 1 R 2 R 3 R 4 R 5 and Y are as defined in claim 1, the method according to claim 1.

4. The arylsulfonium compound has the formula (V): 【Chemical Formula 6】 wherein Ar, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined in claim 1, the method according to claim 1.

5. Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF 4 The method according to any one of claims 1 to 4, selected from

6. The iodoaryl or the astatoaryl compound has the formula (VI): 【Chemical Formula 7】 wherein X is I or At; and R 1 is the method according to any one of claims 1 to 5 as defined in claim 1.

7. The iodide salt or the astatide salt has the formula (VII): 【Chemical 8】 wherein A is selected from Na, K, Cs, tetraalkylammonium and tetraalkylphosphonium; and X is I or At, the method according to any one of claims 1 to 6.

8. X is a radioactive substance, the method according to claim 7.

9. X is 211 the method according to claim 7, which is At.

10. X is 125 the method according to claim 7, which is I.

11. A compound having the formula (I): 【Chemical Formula 9】 wherein Ar is an aryl having 6 to 10 carbon atoms or a heteroaryl having 5 to 10 carbon atoms; R 1 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, CN, NO 2 , CHO, OH, N=C=O, N=C=S, NR 6 R 7 (R 6 and R 7 are independently H or C1-C6 alkyl), C(O)NHR 8 (R 8 is H or C1-C6 alkyl), and C(O)OR 9 (R 9 is selected from H, C1-C6 alkyl and N-succinimidyl), The C1-C6 alkyl group is N 3 optionally substituted by N or the following formula, 【Chemical 10】 In the formula, R 10 is H or C1-C4 alkoxycarbonyl; R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, CN, NO 2 , CHO, OH, N=C=O, N=C=S, NR 6 R 7 (R 6 and R 7 are independently H or C1-C6 alkyl), C(O)NHR 8 (R 8 is H or C1-C6 alkyl), and C(O)OR 9 (R 9 is selected from H, C1-C6 alkyl and N-succinimidyl), and the C1-C6 alkyl group is optionally substituted with N 3 or the following formula, 【Chemical 11】 In the formula, R 10 is H or C1-C4 alkoxycarbonyl; R 3 is selected from H, C1-C6 alkyl and C1-C6 alkoxy; R 4 and R 5 are each independently selected from H, C1-C6 alkyl and C1-C6 alkoxy; Y is a monovalent anion; and the dashed line represents a single bond or its absence; However, when there is no dashed line and Ar is phenyl, R 3 is not H; The broken line is a single bond, Ar is phenyl, and R 3 , R 4 and R 5 are H, then R 1 is not p-methyl or halogen; and The broken line is a single bond, Ar is phenyl, R 3 is methyl, R 4 and R 5 are methoxy, a compound where R 1 is not p-methyl, m-methyl, m-methoxy, m-Br, p-CF 3 , p-CHO or o-C(O)OtBu.

12. having the formula (II): 【Chemical Formula 12】 wherein R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined in claim 11, a compound according to claim 11.

13. Y is TfO, CF 3 COO, TsO, MsO, Br, Cl, SO 4 and BF 4 The compound according to claim 11 or 12, selected from

14. (4-Methoxyphenyl)(phenyl)(p-tolyl)sulfonium trifluoromethanesulfonate; (4-methoxyphenyl)(phenyl)(o-tolyl)sulfonium trifluoromethanesulfonate; (4-chlorophenyl)(4-methoxyphenyl)(phenyl)sulfonium trifluoromethanesulfonate; 5-(4-chlorophenyl)-5H-dibenz[b,d]thiophen-5-ium trifluoromethanesulfonate; 5-(4-cyanophenyl)-5H-dibenz[b,d]thiophen-5-ium trifluoromethanesulfonate; 5-(4-nitrophenyl)-5H-dibenz[b,d]thiophen-5-ium trifluoromethanesulfonate; 5-(4-(azidomethyl)phenyl)-5H-dibenz[b,d]thiophen-5-ium trifluoromethanesulfonate; 5-(3-formylphenyl)-2,4-dimethoxy-8-methyl-5H-dibenz[b,d]thiophen-5-ium trifluoromethanesulfonate; and (Z)-2,4-dimethoxy-8-methyl-5-(3-((1,2,3,3-tetrakis(tert-butoxycarbonyl)guanidino)methyl)phenyl)-5H-dibenz[b,d]thiophen-5-ium trifluoromethanesulfonate: the compound according to claim 11, selected from the group consisting of.

15. A method for synthesizing an iodine-labeled biomolecule or an astatine-labeled biomolecule and / or a vector, comprising: (iii) synthesizing an iodoaryl or astataryl compound by the method according to any one of claims 1 to 10; (iv) reacting the iodoaryl or the astataryl compound with a biomolecule and / or a vector having a functional group reactive with the iodoaryl or the astataryl compound A method comprising.

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