Carborane polyfunctional derivative as well as preparation method and application thereof

Abstract

The invention discloses a carborane polyfunctional derivative, and a preparation method and application thereof. The invention provides a compound as shown in a formula I or a salt thereof. The carborane derivative provided by the invention simultaneously contains three bond types of B-C, B-N and B-O, and has a good application prospect in preparation of multi-effect candidate drugs with targeted delivery, boron neutron capture therapy and fluorescence development functions, the preparation method is simple and convenient to operate, the ligand is cheap and easy to obtain, and accurate modification of product structure diversity can be realized.

Description

Technical Field

[0001] This invention relates to a carborane multifunctionalized derivative, its preparation method, and its application. Specifically, it relates to a carborane derivative with selective trifunctionalization at the B(5, 9, 10) site, its preparation method, and its application. Background Technology

[0002] closo-C2B 10 H 12 Carboranes are icosahedral cage-like boron-rich compounds composed of carbon, boron, and hydrogen, and are three-dimensional aromatic analogs of benzene compounds. Carboranes possess rigid structures, high boron content, high thermal and chemical stability, and low toxicity. Due to these characteristics, carboranes are widely used as structural unit cells in many fields such as coordination chemistry, materials chemistry, medicinal chemistry, and supramolecular chemistry, and have received particular attention in recent years for their application in boron neutron capture therapy (BNCT) for cancer treatment.

[0003] In recent years, although significant progress has been made in the direct selective modification of BH bonds in carboranes, the modification groups are still limited, mostly concentrated on nonpolar substituents such as aryl and alkyl groups, while there are few reports on the introduction of nitrogen-containing heterocyclic structures, and the positions and types of substituents are limited. On the other hand, in the existing reports on coupling reactions involving halocarboranes catalyzed by transition metals, very few involve multifunctionalization modifications and the introduction of polar functional groups.

[0004] Among the common polar functional groups in drug molecules, amine groups and nitrogen-containing heterocycles are important components. Currently reported methods for modifying the BN bond of carboranes include: 1) catalysis by noble metals such as rhodium or iridium, via carboxyl group guidance, to achieve amidation of the B(4) site of ortho-carboranes; 2) palladium catalysis with silver salts as additives to achieve amination of the B(9) site of ortho- or meta-carboranes; and 3) palladium catalysis with sterically hindered biarylphosphine ligands to achieve amination of brominated carboranes at the B(9) site. However, these methods are still mainly limited to the introduction of a single amine group and cannot achieve multi-site functionalization modification. Therefore, developing efficient transition metal catalytic systems and constructing multi-site modified carborane functional structures is crucial for designing and synthesizing novel targeted boron neutron capture therapeutic drugs. Summary of the Invention

[0005] The technical problem this invention aims to solve is to overcome the deficiency of limited multi-site functionalization modification of carboranes in existing technologies, and to provide a multi-functionalized carborane derivative, its preparation method, and its applications. The carborane derivative provided in this application simultaneously contains BC, BN, and BO bond types, and has promising applications in the preparation of multifunctional drug candidates with targeted delivery, boron neutron capture therapy (BNCT), and fluorescence imaging functions. Its preparation method is simple, the ligands are inexpensive and readily available, and it enables precise modification to achieve diverse product structures.

[0006] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0007] This invention provides a compound as shown in Formula I or a salt thereof.

[0008] ;

[0009] in, middle," "The site is CH, and the other sites are BH;"

[0010] X is either N or CH;

[0011] n is 1, 2, 3 or 4;

[0012] R 1 For H;

[0013] Or, R 1 and Linked together to form 5-20 membered heteroaryl groups or bound by one or more R groups 1-1 Substituted 5-20 heteroaryl groups;

[0014] Each R 1-1 Independently halogenated, -CN, -OTBS, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or with one or more R 1-1-1 Substituted C1-C6 alkyl groups Or by one or more R 1-1-3 Substituted C2-C6 alkenyl groups;

[0015] Each R 1-1-1 Independently -OH, halogen, or -CN;

[0016] R 1-1-2 Independently, it is a C1-C6 alkyl group;

[0017] Each R 1-1-3 Independently ;

[0018] R 1-1-3-1 It is a C1-C6 alkyl group;

[0019] R 2 H, halogen, -CN, -OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, with one or more R 2-2 Substituted C1-C6 alkyl groups, with one or more R 2-3 Substituted C1-C6 alkoxy groups, with one or more R 2-4 Substituted C2-C6 alkenyl, -N(R) 2-6 ) (R 2-7 )or ;

[0020] R 2-1 It is a C1-C6 alkyl group;

[0021] Each R 2-2 Independently halogen, -N(R) 2-2-1 ) (R 2-2-2 )or ;

[0022] R 2-2-1 and R 2-2-2 Independently H or -Boc;

[0023] R 2-2-3 It is a C1-C6 alkyl, a 5-20 membered heteroaryl, or is surrounded by one or more R 2-2-3-a Substituted 5-20 heteroaryl groups;

[0024] Each R 2-2-3-a Independently oxygenated, C6-C 20 aryl or aryl with one or more R 2-2-3-b Replacement C6-C 20 Aryl;

[0025] Each R 2-2-3-b Independently, it is a C1-C6 alkyl or C1-C6 alkoxy group;

[0026] Each R 2-3 It can be halogen, -CN, or -OH independently;

[0027] Each R 2-4 Independently for C6-C 20 Aryl;

[0028] R 2-5 It is a 5-20 quinone heteroaryl group or is surrounded by one or more R groups. 2-5-1 Substituted 5-20 heteroaryl groups;

[0029] Each R 2-5-1 Independently, it is a C1-C6 alkyl or C1-C6 alkoxy group;

[0030] R 2-6 and R 2-7 Independently, it is H, C1-C6 alkyl, or C1-C6 alkoxy;

[0031] R 2-8 It consists of 5-20 heteroaryl groups;

[0032] R 2-9 It is a C1-C6 alkyl group or is composed of one or more R groups. 2-9-1 Substituted C1-C6 alkyl groups;

[0033] Each R 2-9-1 Independently ;

[0034] R 2-9-1-1 It is a C1-C6 alkyl group;

[0035] or,

[0036] Two or more R 2 Connected together with Together they form C6-C 20 aryl, 5-20 quinone heteroaryl, with one or more R 2-10 Substituted 5-20 heteroaryl groups;

[0037] Each R 2-10 It is an independent oxygen-producing agent.

[0038] In some embodiments of the present invention, n is 1, 2 or 3.

[0039] In some embodiments of the present invention, X is CH2.

[0040] In some embodiments of the invention, each of the halogens is independently F, Cl, Br or I, preferably F or Cl.

[0041] In some embodiments of the invention, each of the C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl, ethyl, or isopropyl.

[0042] In some embodiments of the present invention, each of the C1-C6 alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy.

[0043] In some embodiments of the present invention, each of the C2-C6 alkenyl groups is independently vinyl, allyl, or butenyl.

[0044] In some embodiments of the present invention, each of the 5-20 member heteroaryl groups is independently... , , , , , , or .

[0045] In some embodiments of the present invention, each of the C6-C 20 The aryl group can be phenyl, naphthyl, or... .

[0046] In some embodiments of the present invention, the compound shown in Formula I is a compound shown in Formula I-1 or a compound shown in Formula I-2.

[0047] or ;

[0048] Among them, X and R 1-1 R 2 , n independently as described in any embodiment of the present invention.

[0049] In some embodiments of the present invention, the compound as shown in Formula I is selected from any one of the following:

[0050] , , , ,

[0051] , , , ,

[0052] , , , ,

[0053] , , , ,

[0054] , , , ,

[0055] , , , ,

[0056] , , ,

[0057] , , , ,

[0058] , , and .

[0059] The present invention also provides a method for preparing a compound of formula I as described in any embodiment of the present invention, comprising the following steps: in an organic solvent, under the action of a palladium catalyst, a ligand and a basic reagent, a compound of formula II reacts with a compound of formula III to generate a compound of formula I;

[0060] ;

[0061] Among them, R A -OH, -Br, or R a It is a C1-C6 alkyl group; R b It is C2-C6 alkenyl or C2-C6 alkynyl;

[0062] Y represents a halogen;

[0063] X, R 1 and R 2 Independently as described in any embodiment of the present invention.

[0064] In some embodiments of the present invention, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl.

[0065] In some embodiments of the present invention, the C2-C6 alkenyl group is vinyl, allyl, or butenyl, preferably allyl.

[0066] In some embodiments of the present invention, the C2-C6 alkynyl group is ethynyl, propynyl or butynyl, preferably propynyl.

[0067] In some embodiments of the present invention, the halogen is Br or I, preferably Br.

[0068] In some embodiments of the present invention, R A It can be -OH, -Br, acetoxy, allyloxy, or propyneoxy.

[0069] In some embodiments of the present invention, the compound as shown in Formula II is selected from any one of the following:

[0070] , , , and .

[0071] In some embodiments of the present invention, the compound as shown in Formula III is selected from any one of the following:

[0072] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0073] In some embodiments of the present invention, the organic solvent is selected from one or more of the conventional solvents for this type of reaction in the art, such as ether solvents, aromatic solvents and amide solvents; the ether solvent is preferably 1,4-dioxane; the aromatic solvent is preferably toluene; the amide solvent is preferably N,N-dimethylformamide; more preferably, the organic solvent is 0.1M 1,4-dioxane.

[0074] In some embodiments of the present invention, the palladium catalyst is palladium acetate.

[0075] In some embodiments of the present invention, the ligand is a phosphorus ligand; the phosphorus ligand is, for example, (2,4,5-trimethoxyphenyl)phosphine, tris(2,-methoxyphenyl)phosphine, tris(2,5-dimethoxyphenyl)phosphine, tris(2,4,5-triethoxyphenyl)phosphine, tris(2,4,6-trimethoxyphenyl)phosphine, tri-tert-butylphosphine, cyclohexyldi-tert-butylphosphine, n-butyldi(1-adamantyl)phosphine, bis(cyclohexylphosphine)ferrocene, preferably (2,4,5-trimethoxyphenyl)phosphine.

[0076] In some embodiments of the present invention, the alkaline reagent is selected from one or more of alkali metal carbonates, alkali metal phosphates, and alkali metal alkoxides; the alkali metal carbonate is, for example, potassium carbonate, rubidium carbonate, or cesium carbonate; the alkali metal phosphate is, for example, potassium phosphate; the alkali metal alkoxide is, for example, potassium tert-butoxide; preferably, the alkaline reagent is rubidium carbonate; preferably, the alkaline reagent is rubidium carbonate.

[0077] In some embodiments of the present invention, the molar volume ratio of the compound as shown in Formula II to the organic solvent is 0.05 mmol / mL to 1 mmol / mL, preferably 0.1 mmol / mL.

[0078] In some embodiments of the present invention, the molar ratio of the compound shown in Formula II to the compound shown in Formula III is 1:(1-3), preferably 1:1.1, 1:2.5, 1:1.25 or 1:2.

[0079] In some embodiments of the present invention, the molar ratio of the compound as shown in Formula II to the palladium catalyst is 1:(0.05-0.2), preferably 1:0.1 or 1:0.15.

[0080] In some embodiments of the present invention, the molar ratio of the compound as shown in Formula II to the ligand is 1:(0.1-0.4), preferably 1:0.2 or 1:0.3.

[0081] In some embodiments of the present invention, the molar ratio of the compound as shown in Formula II to the basic reagent is 1:(2-5), preferably 1:3 or 1:4.5.

[0082] In some embodiments of the present invention, the reaction temperature is 50°C-130°C, preferably 120°C.

[0083] In some embodiments of the present invention, the reaction is carried out under the protection of an inert gas or nitrogen, preferably under the protection of nitrogen.

[0084] In some embodiments of the present invention, the post-processing of the reaction includes the following steps: concentration and column chromatography separation; the column chromatography separation can be performed using conventional column chromatography methods for this type of reaction in the art (e.g., petroleum ether: ethyl acetate = 5:1).

[0085] The present invention also provides the use of a compound of Formula I or a salt thereof, as described in any embodiment of the present invention, in the preparation of a BNCT prodrug.

[0086] In some embodiments of the present invention, the BNCT precursor drug is a BNCT precursor drug with enzyme-responsive fluorescence imaging function; the enzyme is, for example, alkaline phosphatase (ALP).

[0087] The present invention also provides a compound of formula II or a salt thereof as described in any embodiment of the present invention.

[0088] ;

[0089] Among them, Y and R A Independently as described in any embodiment of the present invention.

[0090] The present invention also provides a method for preparing a compound as shown in formula II-OH, which includes the following steps: in a solvent, under the action of a metal reagent and an acid, a compound as shown in formula II-1 reacts with hydrogen peroxide to generate a compound as shown in formula II-OH;

[0091] ;

[0092] Wherein, Y is as described in any embodiment of the present invention.

[0093] In some embodiments of the present invention, the solvent is a fluorinated alcohol solvent, such as hexafluoroisopropanol (HFIP); preferably, the concentration of the fluorinated alcohol solvent is 0.2M.

[0094] In some embodiments of the present invention, the metal reagent is a transition metal salt, such as Mn(OTf)2, Cu(OTf)2 or Cu(CH3CN)4PF6.

[0095] In some embodiments of the present invention, the acid is trifluoromethanesulfonic acid or trifluoroacetic acid, preferably trifluoromethanesulfonic acid.

[0096] In some embodiments of the present invention, the molar volume ratio of the compound as shown in Formula II-1 to the solvent is 1 mmol / mL to 5 mmol / mL, preferably 2 mmol / mL.

[0097] In some embodiments of the present invention, the molar ratio of the compound as shown in Formula II-1 to the hydrogen peroxide is 1:(10-20), preferably 1:14.

[0098] In some embodiments of the present invention, the molar ratio of the compound as shown in Formula II-1 to the metal reagent is 1:(0.5-3), preferably 1:1.

[0099] In some embodiments of the present invention, the molar ratio of the compound as shown in Formula II-1 to the acid is 1:(4-20), preferably 1:6.

[0100] In some embodiments of the present invention, the hydrogen peroxide is added in 2-5 portions during the reaction, for example, 2, 3 or 4 times; preferably, the hydrogen peroxide is added once every 12 hours.

[0101] In some embodiments of the present invention, the reaction temperature is 90°C-120°C, preferably 90°C.

[0102] In some embodiments of the present invention, the post-processing of the reaction includes the following steps: neutralization (preferably using a saturated sodium bicarbonate solution), extraction (preferably using dichloromethane), drying (preferably using anhydrous MgSO4), concentration, and column chromatography separation.

[0103] In this invention, It is a meta-carborane, in which " "The site is CH, and the other sites are BH."

[0104] In this invention, room temperature refers to ambient temperature, such as 15℃-35℃.

[0105] In this invention, the "" in the structural segment "" indicates that the structural fragment is connected to other fragments in the molecule through this site. If there is no specific site, it means that any one or more sites in the structural fragment are connected to other fragments in the molecule.

[0106] In this invention, "each of" refers to any embodiment of the invention. For example, "each of the C1-C6 alkyl" refers to "C1-C6 alkyl" mentioned in any embodiment of the invention, which can be an unsubstituted C1-C6 alkyl or a substituted C1-C6 alkyl. The term "a plurality of" means 2, 3, 4 or 5.

[0107] The term "salt" refers to the salt obtained by reacting a compound with an acid or a base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid (e.g., TFA) in a suitable inert solvent.

[0108] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0109] The term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as described above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, pentoxy, etc.

[0110] The term "alkenyl" refers to a straight-chain or branched, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C2-C6) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bond.

[0111] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 20 A cyclic group consisting solely of carbon atoms, which may be monocyclic or polycyclic, with at least one ring possessing aromaticity. Aryl groups include, but are not limited to, phenyl, naphthyl, or... .

[0112] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5-20), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with at least one ring possessing aromaticity. Heteroaryl groups are attached to the remainder of the molecule via carbon atoms or heteroatoms; they can be attached to the remainder of the molecule via a ring with heteroatoms or a ring without heteroatoms; heteroaryl groups include, but are not limited to, those with and without heteroatoms. , , , , , , or .

[0113] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0114] The reagents and raw materials used in this invention are all commercially available.

[0115] The positive and progressive effects of this invention are as follows:

[0116] (1) This invention provides a novel B(5, 9, 10) three-point functionalized metacarborane derivative and its preparation method. The derivative contains three bond types: BC, BN, and BO. It has good application prospects in the preparation of multifunctional candidate drugs with targeted delivery, boron neutron capture therapy (BNCT) and fluorescence imaging functions.

[0117] (2) The method for preparing carborane derivatives provided by the present invention is simple to operate, the ligands are inexpensive and readily available, and can achieve precise modification of product structure diversity. Attached Figure Description

[0118] Figure 1 The X-ray structure diagram of the product in Example 7 is shown below.

[0119] Figure 2 The image shows the X-ray structure of the product in Example 10.

[0120] Figure 3 Comparison of the UV absorption spectra of probe C in application example 2 with probe C and ALP of the same concentration after incubation in Tris buffer at 37 °C for 30 min;

[0121] Figure 4 The image shows the fluorescence changes of probe C before and after incubation with ALP. Detailed Implementation

[0122] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0123] Example 1

[0124] 5-OH-9,10-Br2-m-CB was synthesized using 9,10-Br2-m-CB (prepared according to J. Am. Chem. Soc. 2016, 138, 9081-9084) as the starting material. The reaction conditions were optimized, as shown in the table below:

[0125]

[0126] In a 100 mL dry Schlenk flask, 9,10-Br2-m-CB (1.0 mmol, 1.0 equiv, 302 mg), Mn(OTf)2 (1.0 mmol, 1.0 equivalent, 355.1 mg), HFIP (5 mL, 0.2 M), HOTf (900.5 mg, 6.0 mmol, 6.0 equiv), and H2O2 (0.5 mL, 5.0 mmol, 5.0 equiv) were added sequentially. The Schlenk flask was tightened and placed in a 90 °C oil bath with stirring. Every 12 h, 3 equiv of H2O2 (0.3 mL, 3.0 mmol, 3.0 equivalent) was added three times. After the reaction was complete, the reaction solution was cooled to room temperature, and the reaction was monitored using TLC. After the reaction was monitored to be complete by TLC, it was neutralized with saturated NaHCO3, extracted with DCM, dried over anhydrous MgSO4, concentrated under vacuum, and separated by column chromatography (petroleum ether:ethyl acetate = 8:1) to give the target compound as a white powder (129.3 mg, 41%). The compound was obtained by... 1 H, 11 B. 11 B{ 1 H} and 13 C{ 1 The structure of 5-OH-9,10-Br2-m-CB was verified by NMR spectroscopy and high-resolution mass spectrometry (HRMS). Structural identity was also confirmed by single-crystal X-ray diffraction experiments.

[0127] Table 1 shows the reaction results of different metal reagents:

[0128] Table 1

[0129]

[0130] Note: Separation yield; b The solvent is nonafluorotert-butanol, and the reaction temperature is 120℃;

[0131] Example 2

[0132] Using compounds 5-OH-9,10-Br2-m-CB and 3,5-difluoroaniline as templates, the reaction conditions were optimized, as shown in the table below:

[0133]

[0134] Based on this, further optimization of the ligand, base, organic solvent, and reaction temperature was conducted. The optimal conditions for synthesizing the product were determined to be as follows: 1.0 equivalent of 5-OH-9,10-Br2-m-CB (a1), 1.1 equivalent of aniline (b1), 10 mol% Pd(OAc)2, 20 mol% ligand, 3.0 equivalent of rubidium carbonate, 120℃, reaction in 1,4-dioxane (0.1 M) for 12 hours, yield of %. The compound was obtained by... 1 H, 11 B. 11 B Target { 1 H} and 13 C{ 1 The structure of the five-membered fused ring product was verified by NMR spectroscopy and high-resolution mass spectrometry (HRMS). Structural identity was also confirmed by single-crystal X-ray diffraction experiments.

[0135] Table 2

[0136]

[0137] Note: a Fluorine spectrum yield, with trifluoromethylbenzene as an internal standard;

[0138] Molar amounts: a1 (0.05 mmol), b1 (0.055 mmol), Pd(OAc)2 (0.005 mmol), ligand (0.01 mmol), Dioxane (0.5 mL), alkali (0.15 mmol) in a nitrogen atmosphere;

[0139] Ligand structure:

[0140] .

[0141] 1 H NMR (400 MHz, Acetone) δ 6.40 (dd, J = 11.0, 2.0 Hz, 1H), 6.15 –6.10 (m, 1H), 3.71 (s, 1H), 3.35 (s, 1H).

[0142] 13 C NMR (151 MHz, Acetone) δ 165.75 (d, 1 J C-F = 239.9, 3 J C-F 9.4 Hz), 165.65 (d, 1 J C-F = 240.0, 3 J C-F8.7 Hz), 164.80 (d, 2 J C-F = 16.4 Hz), 96.52 (d, 2 J C-F = 22.2 Hz),90.93 (dd, 2 J C-F = 27.3, 26.8 Hz), 54.48, 38.19.

[0143] 19 19F NMR (376 MHz, Acetone) δ -105.64, -114.78.

[0144] 11 11B NMR (128 MHz, Acetone) δ 6.55(s, 1B), 3.63(s, 1B), -2.48(s, 1B), -9.62 (d, J = 162.7 Hz, 1B), -17.16 (d, J = 157.2 Hz, 2B), -19.52 (d, J =166.2 Hz, 2B), -24.99 (d, J = 186.5 Hz, 1B), -26.43 (d, J = 181.5 Hz, 1B).

[0145] 11 11B NMR (128 MHz, Acetone) δ 6.56(s, 1B), 3.64(s, 1B), -2.48(s, 1B), -9.63(s, 1B), -17.14(s, 2B), -19.55(s, 2B), -24.99(s, 1B), -26.48(s, 1B).

[0146] HR-MS (EI) for C8H 13 10 B2 11 B8F2NO [M] m / z [M] + : calculated: 285.1968,found: 285.1970.

[0147] Example 3

[0148]

[0149] Method for preparing B(5, 9, 10) trisubstituted compounds: In a dry 10 mL Schlenk tube, 5-OAc-9,10-Br2-m-CB a2 (36.0 mg, 0.1 mmol, 1 equiv), 4-fluoroindole b2 (33.8 mg, 0.25 mmol, 2.5 equiv), palladium acetate (2.2 mg, 0.01 mmol, 10 mol%), tris(2,4,5-trimethoxyphenyl)phosphine ligand (10.6 mg, 0.02 mmol, 20 mol%), and rubidium carbonate (69.3 mg, 0.3 mmol, 3.0 equiv) were added sequentially. The cap was immediately tightened. The system was purged with nitrogen three times. Dry 1,4-dioxane (1.0 mL, 0.1 M) was added as a solvent. The reaction mixture was then transferred to an oil bath at 120 °C and stirred for 12 minutes. h, the reaction solution was cooled to room temperature, and the reaction was monitored by TLC (petroleum ether:EtOAc = 4:1, Rf = 0.34). After the reaction was complete as monitored by TLC, it was concentrated under vacuum and separated by column chromatography (petroleum ether:EtOAc = 5:1) to give the target compound (16.9 mg, 58%).

[0150] 1 H NMR (400 MHz, CDCl3) δ 7.26-7.21 (m, 2H), 6.83 (dd, J = 11.3, 7.5Hz, 1H), 6.66 (d, J = 2.9 Hz, 1H), 3.33 (s, 1H), 2.85 (s, 1H).

[0151] 13 C{ 1 H} NMR (151 MHz, CDCl3) δ 156.93 (d, J = 250.9 Hz), 127.24,123.46 (d, J = 7.2 Hz), 106.29 (d, J = 19.9 Hz), 102.24, 52.63, 38.77.

[0152] 19 F{ 1 H} NMR (376 MHz, CDCl3) δ -121.37.

[0153] 11B NMR (128 MHz, CDCl3) δ 7.55 (s, 1B), 3.60 (s, 1B), 1.87 (s, 1B), -7.94 (d, J = 168.7 Hz, 1B), -16.68 (d, J = 143.8 Hz, 2B), -19.71 (d, J =167.4 Hz, 2B), -24.30 (d, J = 182.18 Hz, 1B), -24.93 (d, J = 179.34 Hz, 1B).

[0154] 11 B{ 1 H} NMR (128 MHz, CDCl3) δ 7.62 (s, 1B), 3.65 (s, 1B), 1.92 (s,1B), -7.93 (s, 1B), -16.75 (s, 1B), -17.64 (s, 1B), -19.80 (s, 2B), -24.33(s, 1B), -24.96(s, 1B).

[0155] HR-MS (ESI) for C 10 H 14 10 B2 11 B8NOF [M] m / z [M] + : calculated: 292.2135, found: 292.2136.

[0156] Preparation of 5-OAc-9,10-Br2-m-CB:

[0157]

[0158] In a dry 25 mL Schlenk tube, 5-OH-9,10-Br2-m-CB (155.4 mg, 0.5 mmol, 1 equiv), DCM (5.0 mL, 0.1 M), acetic anhydride (125.0 mg, 1.0 mmol, 2 equiv), and pyridine (142.1 mg, 2.0 mmol, 4 equiv) were added sequentially. The cap was immediately tightened, and the mixture was stirred at room temperature for 0.5 h. The mixture was then transferred to an oil bath at 90 °C and reacted for 8 h. Complete substrate conversion was monitored by TLC (petroleum ether: EtOAc = 4:1, R...). f= 0.62 for 4-4b). After the reaction was completed, the product was concentrated under vacuum and separated by column chromatography (petroleum ether: EtOAc = 20:1) to give a white solid (167.5 mg, 95%).

[0159] 1 H NMR (400 MHz, CDCl3) δ 4.16 (s, 1H), 2.91 (s, 1H), 2.16 (s, 1H).

[0160] 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 169.95, 52.68, 42.87, 22.46.

[0161] 11 B NMR (128 MHz, CDCl3) δ 2.35 (s, 1B), -7.95 (s, 3B), -13.87 (d, J =173.9 Hz, 2B), -16.43 (d, J = 173.6 Hz, 2B), -22.96 (d, J = 186.0 Hz, 2B).

[0162] 11 B{ 1 H} NMR (128 MHz, CDCl3) δ 2.35 (s, 1B), -7.93 (s, 3B), -13.90 (s, 2B), -16.48 (s, 2B), -23.03 (s, 2B).

[0163] HR-MS (ESI) for C4H 12 10 B2 11 B8O2 79 Br 81 Br [M] m / z [MH] - : calculated:359.0103, found: 359.0118

[0164] Example 4

[0165]

[0166] Method for preparing B(5, 9, 10) trisubstituted compounds: In a dry 10 mL Schlenk tube, 5-allyl-9,10-Br2-m-CB (35.8 mg, 0.1 mmol, 1 equiv), isopropyl 4-aminobenzoate (44.8 mg, 0.25 mmol, 2.5 equiv), palladium acetate (2.2 mg, 0.01 mmol, 10 mol%), tris(2,4,5-trimethoxyphenyl)phosphine ligand (10.6 mg, 0.02 mmol, 20 mol%), and rubidium carbonate (69.3 mg, 0.3 mmol, 3.0 equiv) were added sequentially. The cap was immediately tightened. The system was purged with nitrogen three times. Dry 1,4-dioxane (1.0 mL, 0.1 M) was added as a solvent. The reaction mixture was then transferred to an oil bath at 120 °C and stirred for 12 minutes. h, the reaction solution was cooled to room temperature, and the reaction was monitored by TLC. After the reaction was complete as monitored by TLC, it was concentrated under vacuum and separated by column chromatography to obtain the target compound (9.0 mg, 14%).

[0167] 1 H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.36 (t, J = 75.2 Hz, 1H), 3.16 (s, 1H), 2.65 (s, 1H).

[0168] 19 F NMR (376 MHz, CDCl3) δ -79.37.

[0169] 11 B NMR (128 MHz, CDCl3) δ 6.08 (s, 1B), 3.70 (s, 1B), -0.61 (s, 1B), -9.41 (d, J = 163.8 Hz, 1B), -17.13 (d, J = 180.5 Hz, 2B), -19.12 (d, J =185.6 Hz, 2B), -25.17 (d, J = 184.1 Hz, 1B), -26.56 (d, J = 173.6 Hz, 1B).

[0170] 11B NMR (128 MHz, CDCl3) δ 6.10 (s, 1B), 3.72 (s, 1B), -0.54 (s, 1B), -9.46 (s, 1B), -16.95 (s, 2B), -19.20 (s, 2B), -25.35 (s, 1B), -26.65 (s,1B).

[0171] HR-MS (ESI) for C9H 15 10 B2 11 B8NO2F2[M] m / z [M+H] - : calculated: 316.2147, found: 316.2125.

[0172] Preparation of 5-allyl-9,10-Br2-m-CB:

[0173]

[0174] In a dry 10 mL Schlenk tube, 5-OH-9,10-Br2-m-CB (164.7 mg, 0.5 mmol, 1 equiv) and KOH (74.2 mg, 1.0 mmol, 2 equiv) were added sequentially. The tube was purged with nitrogen three times. Acetone (5.0 mL, 0.1 M) and 3-bromopropene (181.5 mg, 1.5 mmol, 3 equiv) were then added. The tube was immediately capped and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction was then transferred to an oil bath at 120 °C and allowed to proceed for 8 h. Complete substrate conversion was monitored by TLC (petroleum ether: EtOAc = 4:1, R...). f =0.57 for 4-6b). After the reaction was completed, the mixture was concentrated under vacuum and separated by column chromatography (petroleum ether: EtOAc = 20:1) to give a white solid 4-6b (58.9 mg, 32%).

[0175] 1 H NMR (400 MHz, CDCl3) δ 5.91 (ddt, J = 17.1, 10.3, 5.0 Hz, 1H), 5.29 (dd, J = 17.2, 1.8 Hz, 1H), 5.14 (dd, J = 10.4, 1.6 Hz, 1H), 4.45 (d, J = 4.9Hz, 2H), 3.14 (s, 1H), 2.74 (s, 1H).

[0176] 13 C{1 1H NMR (101 MHz, CDCl3) δ 135.26, 116.03, 70.03, 52.21, 37.85.

[0177] 11 11B NMR (128 MHz, CDCl3) δ 6.14(s, 1B), -6.72(s, 1B), -8.53(s, 2B), -14.99 (d, J = 172.4 Hz, 2B), -17.08 (d, J = 177.8 Hz, 2B), -23.43 (d, J =185.5 Hz, 2B).

[0178] 11 11B{ 1 1H} NMR (128 MHz, CDCl3) δ 6.17(s, 1B), -7.41(s, 1B), -8.59(s,2B), -15.02(s, 2B), -17.14(s, 2B), -23.47(s, 2B).

[0179] HR-MS (EI) C5H 14 10 B2 11 B8OBr2[M] m / z [M] + : calculated: 358.0392, found:358.0392.

[0180] Example 5

[0181]

[0182] Method for preparing B(5, 9, 10) trisubstituted compounds: In a dry 10 mL Schlenk tube, 5-propynyl-9,10-Br2-m-CB (35.6 mg, 0.1 mmol, 1 equiv), isopropyl 4-aminobenzoate (22.4 mg, 0.125 mmol, 1.25 equiv), palladium acetate (2.2 mg, 0.01 mmol, 10 mol%), tris(2,4,5-trimethoxyphenyl)phosphine ligand (10.6 mg, 0.02 mmol, 20 mol%), and rubidium carbonate (69.3 mg, 0.3 mmol, 3.0 equiv) were added sequentially. The cap was immediately tightened. The system was purged with nitrogen three times. Dry 1,4-dioxane (1.0 mL, 0.1 M) was added as a solvent. The reaction mixture was then transferred to 120 °C. The mixture was stirred in an oil bath at ℃ for 12 h, and the reaction solution was cooled to room temperature. The reaction was monitored by TLC. After the reaction was complete as monitored by TLC, the mixture was concentrated under vacuum and separated by column chromatography to obtain the target compound (7.1 mg, 11%).

[0183] 1 H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.36 (t, J = 75.2 Hz, 1H), 3.16 (s, 1H), 2.65 (s, 1H).

[0184] 19 F NMR (376 MHz, CDCl3) δ -79.37.

[0185] 11 B NMR (128 MHz, CDCl3) δ 6.08 (s, 1B), 3.70 (s, 1B), -0.61 (s, 1B), -9.41 (d, J = 163.8 Hz, 1B), -17.13 (d, J = 180.5 Hz, 2B), -19.12 (d, J =185.6 Hz, 2B), -25.17 (d, J = 184.1 Hz, 1B), -26.56 (d, J = 173.6 Hz, 1B).

[0186] 11B NMR (128 MHz, CDCl3) δ 6.10 (s, 1B), 3.72 (s, 1B), -0.54 (s, 1B), -9.46 (s, 1B), -16.95 (s, 2B), -19.20 (s, 2B), -25.35 (s, 1B), -26.65 (s,1B).

[0187] HR-MS (ESI) for C9H 15 10 B2 11 B8NO2F2[M] m / z [M+H] - : calculated: 316.2147, found: 316.2125.

[0188] Preparation of 5-propynyl-9,10-Br2-m-CB:

[0189]

[0190] In a dry 25 mL Schlenk tube, 5-OH-9,10-Br2-m-CB (159.8 mg, 0.5 mmol, 1 equiv) and KOH (56.1 mg, 1.0 mmol, 2 equiv) were added sequentially. The tube was purged with nitrogen three times. Acetone (5.0 mL, 0.1 M) and 3-bromopropyne (178.4 mg, 1.5 mmol, 3 equiv) were then added. The tube was immediately capped and stirred at room temperature for 0.5 h. The mixture was then transferred to an oil bath at 120 °C and reacted for 8 h. Complete substrate conversion was monitored by TLC (petroleum ether: EtOAc = 4:1, R...). f = 0.60 for 4-5b). After the reaction was completed, the mixture was concentrated under vacuum and separated by column chromatography (petroleum ether: EtOAc = 20:1) to give a white solid 4-5b (86.6 mg, 48%).

[0191] 1 H NMR (400 MHz, CDCl3) δ 4.57 (s, 2H), 3.38 (s, 1H), 2.78 (s, 1H), 2.44 (s, 1H).

[0192] 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 80.37, 74.65, 56.75, 52.20, 38.91.

[0193] 11 11B NMR (128 MHz, CDCl3) δ 5.83 (s, 1B), -6.57 (s, 1B), -8.42 (s, 2B), -14.93 (d, J = 162.3 Hz, 2B), -17.11 (d, J = 162.3 Hz, 2B), -23.24 (d, J = 185.8 Hz, 2B).

[0194] 11 11B{ 1 1H} NMR (128 MHz, CDCl3) δ 5.81(s, 1B), -7.26 (s, 1B), -8.46 (s, 2B), -14.93 (s, 2B), -17.13 (s, 2B), -23.25 (s, 2B).

[0195] HR-MS (ESI) for C5H 12 10 11B2 11 11B8Br2O [M] m / z [M+H] + : calculated: 356.0238, found: 356.0215

[0196] Example 6

[0197]

[0198] Method for preparing B(5, 9, 10) trisubstituted compounds: In a dry 10 mL Schlenk tube, 5,9,10-Br2-m-CB (38.1 mg, 0.1 mmol, 1 equiv), methyl 4-indolecarboxylate (35.0 mg, 0.2 mmol, 2.0 equiv), palladium acetate (3.3 mg, 0.015 mmol, 15 mol%), tris(2-methoxyphenyl)phosphine ligand (10.6 mg, 0.03 mmol, 30 mol%), potassium phosphate (95.5 mg, 0.45 mmol, 4.5 equiv), and 4A MS (4A molecular sieve, 50 mg / 0.1 mmol) were added sequentially. The cap was immediately tightened. The system was purged with nitrogen three times. Dry 1,4-dioxane (1.0 mL, 0.1 M) was added as a solvent. The reaction solution was then transferred to 100 mL. The mixture was stirred in an oil bath at ℃ for 12 h, and the reaction solution was cooled to room temperature. The reaction was monitored by TLC. After the reaction was complete as monitored by TLC, the mixture was concentrated under vacuum and separated by column chromatography to obtain the target compound (23.0 mg, 69%).

[0199] 1 H NMR (400 MHz, Acetone-d6) δ 7.83 (d, J = 7.3 Hz, 1H), 7.47 (d, J =2.9 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H), 6.94 (s, 1H), 5.22 (s, 1H), 3.96 (s,1H), 3.93 (s, 3H), 3.61 (s, 1H).

[0200] 13 C{ 1 H} NMR (151 MHz, Acetone-d6) δ 168.57, 159.82, 130.34, 130.30,125.19, 124.43, 122.43, 121.69, 107.52, 55.30, 51.72, 39.15.

[0201] 11B NMR (193 MHz, Acetone-d6) δ 8.25(s, 1B), 3.42(s, 1B), 1.66(s, 1B), -7.93 (d, J = 163.6 Hz, 1B), -17.34 (d, J = 137.0 Hz, 2B), -19.97 (d, J =161.6 Hz, 2B), -23.63 (d, J = 203.0 Hz, 1B), -24.68 (d, J = 203.8 Hz, 1B).

[0202] 11 B{ 1 H} NMR (193 MHz, Acetone-d6) δ 8.26(s, 1B), 3.42(s, 1B), 1.67(s,1B), -7.94(s, 1B), -17.05(s, 1B), -17.63(s, 1B), -20.00(s, 2B), -23.59(s,1B), -24.75(s, 1B).

[0203] HR-MS (ESI) for C 12 H 17 10 B2 11 B8NO3[M] m / z [M+H] + : calculated: 332.2284,found: 332.2301.

[0204] Preparation of 5, 9, 10-Br2-m-CB:

[0205]

[0206] In a 100 mL dry Schlenk flask, m-CB (548 mg, 3.8 mmol) was added, purged three times with nitrogen, followed by 10 mL of DCM solution, and then 5 mL of DCE solution containing Br2 (1.336 g, 2.2 equiv). AlCl3 (101.3 mg, 0.2 equiv) was added at -78 °C (dry ice / acetone bath). The Schlenk flask was screwed tightly shut and placed in a 100 °C oil bath with stirring for 1 h. After the reaction was complete, the reaction solution was cooled to room temperature, and the reaction was monitored by TLC. After the reaction was complete according to TLC, Rf = 0.64 (petroleum ether: EtOAc = 4:1). The solution was quenched with saturated NaS2O3, extracted with DCM, dried over anhydrous MgSO4, concentrated under vacuum, and separated by column chromatography to obtain the target compound as a white solid (0.9153 g, 80%).

[0207] 1 H NMR (400 MHz, CDCl3) δ 3.48 (s, 1H), 3.10 (s, 1H).

[0208] 13 C{ 1 H} NMR (151 MHz, CDCl3) δ 54.71, 46.65.

[0209] 11 B NMR (193 MHz, CDCl3) δ -3.81(s, 1B), -6.06(s, 3B), -11.99 (d, J =175.6 Hz, 2B), -14.58 (d, J = 173.7 Hz, 2B), -21.67 (d, J = 187.2 Hz, 2B).

[0210] 11 B{ 1 H} NMR (193 MHz, CDCl3) δ -3.82(s, 1B), -5.98(s, 3B), -12.00(s,2B), -14.58(s, 2B), -21.66(s, 2B).

[0211] HR-MS (EI) for C2H9 10 B2 11 B8Br3[M] m / z [M] + : calculated: 380.9242, found: 380.9139

[0212] Example 7

[0213] Method for preparing B(5, 9, 10) trisubstituted compounds: 5-OH-9,10-Br2-m-CB (31.8 mg, 0.1 mmol, 1 equiv), an amino compound (0.11 mmol, 1.1 equiv), palladium acetate (2.2 mg, 0.01 mmol, 10 mol%), tris(2,4,5-trimethoxyphenyl)phosphine ligand (10.6 mg, 0.02 mmol, 20 mol%), and rubidium carbonate (69.3 mg, 0.3 mmol, 3.0 equiv) were added sequentially to a dry 10 mL Schlenk tube. The cap was immediately tightened. The system was purged with nitrogen three times. Dry 1,4-dioxane (1.0 mL, 0.1 M) was added as a solvent. The reaction solution was then transferred to an oil bath at 120 °C and stirred for 12 h. The reaction solution was cooled to room temperature, and the reaction was monitored by TLC. After the reaction was monitored by TLC until complete, the mixture was concentrated under vacuum and separated by column chromatography. The results of obtaining the target compound are shown below:

[0214]

[0215]

[0216] 1 H NMR (400 MHz, MeOD) δ 7.29 (d, J = 7.2 Hz, 1H), 7.09 – 7.05 (m,1H), 6.81 (d, J = 8.0 Hz, 1H), 6.66 – 6.62 (m, 1H), 3.52 (s, 1H), 3.19 (s,1H).

[0217] 13 C NMR (101 MHz, MeOD) δ 163.80, 130.87, 128.87, 117.12, 113.79, 55.00, 39.50.

[0218] 11B NMR (128 MHz, MeOD) δ 5.76 (s, 1B), 3.81 (s, 1B), 0.08 (s, 1B), -9.20 (d, J = 163.2 Hz, 1B), -17.32(d, J = 166.1 Hz, 2B), -19.44 (d, J = 177.5Hz, 2B), -25.48 (d, J = 191.1 Hz, 1B), -27.64(d, J = 185.0 Hz, 1B).

[0219] 11 B NMR (128 MHz, MeOD) δ 5.77(s, 1B), 3.81(s, 1B), 0.08(s, 1B), -9.21(s, 1B), -17.26(s, 2B), -19.49(s, 2B), -25.50(s, 1B), -26.97(s, 1B).

[0220] HR-MS (ESI) for C8H 15 10 B2 11 B8NO [M] m / z [M+H] + : calculated: 250.2230,found: 250.2234.

[0221]

[0222] 1 H NMR (400 MHz, Acetone) δ 7.53 (s, 1H), 7.35 (dd, J = 8.5, 2.1 Hz,1H), 6.90 (d, J = 8.5 Hz, 1H), 3.73 (s, 1H), 3.37 (s, 1H).

[0223] 13 C NMR (151 MHz, Acetone) δ 166.26, 127.57, 127.01(q, 1 J C-F = 270.5,269.2 Hz), 125.95 (q, 3 J C-F = 4.1, 2.8 Hz), 117.57 (q, 2 J C-F= 31.4, 28.8 Hz),112.91, 54.83, 38.45.

[0224] 11 B NMR (128 MHz, Acetone) δ 11.62(s, 1B), 8.87(s, 1B), 4.40(s, 1B), -4.56 (d, J = 161.8 Hz, 1B), -11.88 (d, J = 145.6 Hz, 2B), -14.20 (d, J =160.0 Hz, 2B), -19.87 (d, J = 193.8 Hz, 1B) , -21.38 (d, J = 194.7 Hz, 1B).

[0225] 11 B NMR (128 MHz, Acetone) δ 6.43(s, 1B), 3.67(s, 1B), -0.81(s, 1B), -9.79(s, 1B), -16.94(s, 2B), -19.43(s, 2B), -25.07(s, 1B), -26.67(s, 1B).

[0226] 19 F NMR (376 MHz, Acetone) δ -55.06.

[0227] HR-MS (EI) for C 18 H 22 10 B2 11 B8N2[M] m / z [M] + : calculated: 317.2031, found:317.2033.

[0228]

[0229] 1 H NMR (400 MHz, Acetone) δ 7.94 (d, J = 2.0 Hz, 1H), 7.77 (dd, J =8.5, 2.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.24 (s, 1H), 5.15 (hept, J = 6.3Hz, 1H), 3.71 (s, 1H), 3.35 (s, 1H), 1.33 (s, 3H), 1.31 (s, 3H).

[0230] 13 C{ 1 H} NMR (101 MHz, Acetone) δ 167.50, 167.11, 132.66, 130.98,118.82, 112.71, 67.30, 54.95, 54.81, 38.45, 22.31.

[0231] 11 B NMR (128 MHz, Acetone) δ 6.58 (s, 1B), 3.71 (s, 1B), -0.67 (s,1B), -9.65 (d, J = 163.9 Hz 1B), -17.32 (d, J = 222.1 Hz, 2B), -19.97 (d, J =162.5 Hz, 2B), -25.19 (d, J = 193.0 Hz, 1B), -26.63 (d, J = 176.3 Hz, 1B).

[0232] 11 B{ 1 H} NMR (128 MHz, Acetone) δ 6.59 (s, 1B), 3.72 (s, 1B), -0.68 (s,1B), -9.66 (s, 1B), -17.15 (s, 2B), -19.51 (s, 2B), -25.21 (s, 1B), -26.61(s, 1B).

[0233] HR-MS (EI) for C 12 H 21 10 B2 11 B8NO3[M] m / z [M] + : calculated: 335.2525,found: 335.2530.

[0234]

[0235] 1 H NMR (400 MHz, Acetone) δ 6.40 (dd, J = 11.0, 2.0 Hz, 1H), 6.15 –6.10 (m, 1H), 3.71 (s, 1H), 3.35 (s, 1H).

[0236] 13 C NMR (151 MHz, Acetone) δ 165.75 (d, 1 J C-F = 239.9, 3 J C-F 9.4 Hz), 165.65(d, 1 J C-F = 240.0, 3 J C-F 8.7 Hz), 164.80 (d, 2 J C-F = 16.4 Hz), 96.52 (d, 2 J C-F = 22.2 Hz),90.93 (dd, 2 J C-F = 27.3, 26.8 Hz), 54.48, 38.19.

[0237] 19 F NMR (376 MHz, Acetone) δ -105.64, -114.78.

[0238] 11 B NMR (128 MHz, Acetone) δ 6.55(s, 1B), 3.63(s, 1B), -2.48(s, 1B), -9.62 (d, J = 162.7 Hz, 1B), -17.16 (d, J = 157.2 Hz, 2B), -19.52 (d, J =166.2 Hz, 2B), -24.99 (d, J = 186.5 Hz, 1B), -26.43 (d, J = 181.5 Hz, 1B).

[0239] 11 B NMR (128 MHz, Acetone) δ 6.56(s, 1B), 3.64(s, 1B), -2.48(s, 1B), -9.63(s, 1B), -17.14(s, 2B), -19.55(s, 2B), -24.99(s, 1B), -26.48(s, 1B).

[0240] HR-MS (EI) for C8H 13 10 B2 11 B8F2NO [M] m / z [M] +: Calculated: 285.1968, Found: 285.1970.

[0241]

[0242] [[ID=`6]] 19 F{ 1 H} NMR (565 MHz, CDCl3) δ -60.63, -62.70.

[0243] 11 B NMR (193 MHz, CDCl3) δ 5.63 (s, 1B), 2.73 (s, 1B), -1.45 (s, 1B), -9.61 (d, J = 167.8 Hz, 1B), -15.74 (d, J = 210.3 Hz, 1B), -18.10 (d, J = 184.7 Hz, 1B), -18.97 (d, J = 153.91 Hz, 2B), -24.60 (d, J = 187.8 Hz, 1B), -25.95 (d, J = 180.1 Hz, 1B).

[0244] <` 11 B{ [[ID=`8]] 1 H} NMR (193 MHz, CDCl3) δ 5.59 (s, 1B), 2.71 (s, 1B), -1.45 (s, 1B), -9.57 (s, 1B), -15.54 (s, 1B), -16.85 (s, 1B), -18.11 (s, 1B), -18.83 (s, 1B), -24.46 (s, 1B), -25.84 (s, 1B).

[0245] HR-MS (EI) for C 10 H 13 10 B2 11 B8NOF6[M] m / z [M] + : Calculated: 385.1905, Found: 385.1911.

[0246] X-ray structure is as Figure 1 。

[0247]

[0248] 1H NMR (400 MHz, Acetone-d6) δ 7.41 – 7.23 (m, 2H), 3.85 (s, 3H),3.59 (s, 1H), 3.24 (s, 1H).

[0249] 13 C{ 1 H} NMR (151 MHz, Acetone-d6) δ 168.25, 158.85, 131.23, 128.43,119.26, 53.17, 51.42, 36.87.

[0250] 11 B NMR (128 MHz, Acetone-d6) δ 6.33(s, 1B), 2.08(s, 1B), 0.52(s, 1B),-10.10 (d, J = 161.7 Hz, 1B), -15.20 – -19.95 (4B), -25.04 (d, J = 162.7 Hz,1B), -26.78 (d, J = 143.5 Hz, 1B).

[0251] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 6.35(s, 1B), 2.10(s, 1B), 0.53(s,1B), -10.11(s, 1B), -15.86(s, 1B), -17.25(s, 1B), -18.50(s, 1B), -19.34(s,1B), -25.13(s, 1B), -26.28(s, 1B).

[0252] HR-MS (ESI) for C 10 H 16 10 B2 11 B8NO3Cl [M] m / z [M+H] + : calculated: 342.1895,found: 342.1917.

[0253]

[0254] 1H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.70(d, J = 8.6 Hz, 1H), 6.36 (t, J = 75.2 Hz, 1H), 3.16 (s, 1H), 2.65 (s, 1H).

[0255] 19 F NMR (376 MHz, CDCl3) δ -79.37.

[0256] 11 B NMR (128 MHz, CDCl3) δ 6.08 (s, 1B), 3.70 (s, 1B), -0.61 (s, 1B),-9.41 (d, J = 163.8 Hz, 1B), -17.13 (d, J = 180.5 Hz, 2B), -19.12 (d, J =185.6 Hz, 2B), -25.17 (d, J = 184.1 Hz, 1B), -26.56 (d, J = 173.6 Hz, 1B).

[0257] 11 B NMR (128 MHz, CDCl3) δ 6.10 (s, 1B), 3.72 (s, 1B), -0.54 (s, 1B),-9.46 (s, 1B), -16.95 (s, 2B), -19.20 (s, 2B), -25.35 (s, 1B), -26.65 (s,1B).

[0258] HR-MS (ESI) for C9H 15 10 B2 11 B8NO2F2[M] m / z [M+H] - : calculated: 316.2147,found: 316.2125.

[0259]

[0260] 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.69 (dd, J = 8.5, 2.2 Hz,1H), 6.87 (d, J = 8.6 Hz, 1H), 5.01 (s, 1H), 3.28 (s, 1H), 3.04 (s, 3H), 2.76(s, 1H).

[0261] 13 C{ 1 H} NMR (151 MHz, CDCl3) δ 165.52, 130.17, 128.61, 127.74, 112.61,45.17.

[0262] 11 B NMR (193 MHz, DCl3) δ 5.94(s, 1B), 3.27(s, 1B), 1.08(s, 1B), 9.65(m, 1B), 11.78(m, 4B), 25.24(m, 2B).

[0263] 11 B{ 1 H} NMR (193 MHz, CDCl3) δ 5.29(s, 1B), 3.25(s, 1B), 1.12(s, 1B),9.47(s, 2B), -16.76(s, 2B), -18.99(s, 2B), -25.66(s, 1B).

[0264] HR-MS (EI) for C9H 17 10 B2 11 B8NSO3[M] m / z [M] + : calculated: 328.2005,found:328.1906.

[0265]

[0266] 1H NMR (400 MHz, CDCl3) δ 7.24(s, 1H), 7.07–6.99(m, 2H), 5.08(t, , J =7.2 Hz 1H), 4.52(s, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.36(s, 1H), 3.06 (d, J =6.3 Hz, 2H), 2.81(s, 1H), 1.43 – 1.41 (m, 9H), 1.21 (t, J = 6.1 Hz, 3H).

[0267] 13 C NMR (151 MHz, CDCl3) δ 171.07, 154.12, 130.69, 128.97, 128.91,78.95, 60.38, 53.54, 37.83, 37.15, 28.68, 27.30, 13.10.

[0268] 11 B NMR (128 MHz, CDCl3) δ 7.06(s, 1B), 2.48(s, 1B), 0.25(s, 1B), -8.16(s, 1B), -16.30(s, 4B), -24.13(s, 2B).

[0269] 11 B{ 1 H} NMR (128 MHz, CDCl3) δ 7.30(s, 1B), 2.27(s, 1B), 0.40(s, 1B),-7.25(s, 1B), -16.66(s, 4B), -24.45(s, 2B).

[0270] HR-MS (ESI) for C 18 H 32 10 B2 11 B8N2O5[M] m / z [M+H] + : calculated: 465.3387,found: 465.3404.

[0271]

[0272] 11H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.2 Hz, 1H), 6.61 (d, J = 7.3Hz, 1H), 3.89 (s, 3H), 3.24 (s, 1H), 2.71 (s, 1H), 2.52 (s, 3H).

[0273] 13 13C{ 1 1H} NMR (101 MHz, CDCl3) δ 170.04, 163.69, 140.39, 133.87, 120.13,53.31, 51.27, 38.48, 23.59.

[0274] 11 11B NMR (128 MHz, CDCl3) δ 6.21 (s, 1B), 3.48 (s, 1B), -0.75 (s, 1B),-9.27 (d, J = 164.2 Hz, 1B), -16.75 (d, J = 198.6 Hz, 2B), -18.97 (d, J =188.2 Hz, 2B), -25.09 (d, J = 178.0 Hz, 1B), -26.51 (d, J = 186.5 Hz, 1B).

[0275] 11 11B{ 1 1H} NMR (128 MHz, CDCl3) δ 6.24 (s, 1B), 3.50 (s, 1B), -0.73 (s,1B), -9.28 (s, 1B), -16.78 (s, 2B), -19.06 (s, 2B), -25.14 (s, 1B), -26.57(s, 1B).

[0276] [[ID=1NMR (ESI) for C 11 1H 19 10 2B2 11 8NO3[M] m / z [M+H] + : calculated: 322.2441,found: 322.2446.

[0277] Example 8

[0278] Method for preparing B(5, 9, 10) trisubstituted compounds: 5-OH-9,10-Br2-m-CB (31.8 mg, 0.1 mmol, 1 equiv), an amino compound (0.11 mmol, 1.1 equiv), palladium acetate (2.2 mg, 0.01 mmol, 10 mol%), tris(2,4,5-trimethoxyphenyl)phosphine ligand (10.6 mg, 0.02 mmol, 20 mol%), and rubidium carbonate (69.3 mg, 0.3 mmol, 3.0 equiv) were added sequentially to a dry 10 mL Schlenk tube. The cap was immediately tightened. The system was purged with nitrogen three times. Dry 1,4-dioxane (1.0 mL, 0.1 M) was added as a solvent. The reaction solution was then transferred to an oil bath at 120 °C and stirred for 12 h. The reaction solution was cooled to room temperature, and the reaction was monitored by TLC. After the reaction was monitored by TLC until complete, the mixture was concentrated under vacuum and separated by column chromatography to obtain the target compound. The results are shown below:

[0279]

[0280]

[0281] Silica gel column chromatography (petroleum ether: EtOAc = 5:1) yielded a white solid product (20.2 mg, 61%). f = 0.39 (Petroleum ether: EtOAc = 4:1)

[0282] 1 H NMR (400 MHz, Acetone-d6) δ 7.23 (s, 1H), 7.07 (s, 1H), 5.82 (s,1H), 4.77 (s, 1H), 3.70 (s, 1H), 3.34 (s, 1H), 2.36 (d, J = 2.0 Hz, 3H).

[0283] 13 C{ 1 H} NMR (151 MHz, Acetone-d6) δ 161.20, 134.34, 133.26, 128.20 (q, 2 J C-F = 29.0, 28.4 Hz), 126.54(q, 1 J C-F = 273.1, 272.1 Hz), 122.62, 109.83, 54.78,38.44, 18.59.

[0284] 19 F{ 1 H} NMR (376 MHz, Acetone-d6) δ -61.69.

[0285] 11 B NMR (128 MHz, Acetone-d6) δ 6.43 (s, 1B), 3.90 (s, 1B), -0.76 (s,1B), -9.89 (d, J = 162.3 Hz, 1B), -17.05 (d, J = 148.6 Hz, 2B), -19.45 (d,J = 165.4 Hz, 2B), -25.26 (d, J = 207.7 Hz, 1B), -27.60 (d, J = 200.1 Hz, 1B).

[0286] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 6.45 (s, 1B), 3.91 (s, 1B), -0.77(s, 1B), -9.95 (s, 1B), -17.13 (s, 2B), -19.56 (s, 2B), -25.30 (s, 1B), -27.03 (s, 1B).

[0287] HR-MS (SI) for C 10 H 16 10 B2 11 B8NOF3[M] m / z [M+Na] + : calculated: 333.2224, found: 333.2239.

[0288]

[0289] Silica gel column chromatography (petroleum ether: EtOAc = 5:1) yielded a white solid product (28.0 mg, 93%). f = 0.26 (Petroleum ether: EtOAc = 5:1)

[0290] 1H NMR (400 MHz, Acetone-d6) δ 7.79 (d, J = 8.3 Hz, 1H), 7.71 (d, J =8.1 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.35 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H),7.19 (d, J = 8.7 Hz, 1H), 7.15 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 3.67 (s, 1H),3.30 (s, 1H).

[0291] 13 C{ 1 H} NMR (151 MHz, Acetone-d6) δ 161.91, 137.05, 129.37, 128.89,128.06, 126.75, 126.47, 121.62, 117.62, 54.54, 38.21.

[0292] 11 B NMR (128 MHz, Acetone-d6) δ 6.43(s, 1B), 3.56(s, 1B), -0.33(s,1B), -9.82 (d, J = 161.9 Hz, 1B), -16.93 (d, J = 168.5 Hz, 2B), -19.38 (d, J= 168.5 Hz, 2B), -25.73 (d, J = 166.5 Hz, 1B), -26.92 (d, J = 137.5 Hz, 1B).

[0293] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 6.43(s, 1B), 3.57(s, 1B), -0.33(s,1B), -9.80(s, 1B), -16.94(s, 2B), -19.37(s, 2B), -25.81(s, 1B), -26.76(s,1B).

[0294] HR-MS (EI) for C 12 H 17 10 B2 11 B8NO [M] m / z [M] +: calculated: 299.2313, found: 299.2315.

[0295]

[0296] The product was obtained as a white solid (25.8 mg, 85%) by silica gel column chromatography (petroleum ether: EtOAc = 5:1). f = 0.33 (Petroleum ether: EtOAc = 5:1)

[0297] 1 H NMR (400 MHz, Acetone-d6) δ 8.29 – 8.09 (m, 1H), 7.95 – 7.65 (m,1H), 7.56 – 7.30 (m, 3H), 7.18 (d, J = 8.0 Hz, 1H), 6.37 (s, 1H), 3.66 (s,1H), 3.31 (s,1H).

[0298] 13 C{ 1 H} NMR (101 MHz, Acetone-d6) δ 159.69, 134.98, 129.22, 128.78,125.85, 124.45, 123.98, 122.83, 122.81, 116.43, 54.13, 38.01.

[0299] 11 B NMR (128 MHz, Acetone-d6) δ 6.41(s, 1B), 3.70(s, 1B), 0.40(s, 1B), -10.04 (d, J = 162.7 Hz, 1B), -17.01 (d, J = 163.4 Hz, 2B), -19.49 (d, J =167.3 Hz, 2B), -25.84 (d, J = 168.5 Hz, 1B), -27.12 (d, J = 162.3 Hz, 1B).

[0300] 11 B{ 1H} NMR (128 MHz, Acetone-d6) δ 6.41(s, 1B), 3.70(s, 1B), 0.39(s,1B), -10.04(s, 1B), -17.02(s, 2B), -19.51(s, 2B), -25.90(s, 1B), -27.08(s,1B).

[0301] HR-MS (EI) for C 12 H 17 10 B2 11 B8NO [M] m / z [M] + : calculated: 299.2313, found: 299.2315.

[0302] Example 9

[0303] Method for preparing B(5, 9, 10) trisubstituted compounds: In a dry 10 mL Schlenk tube, 5-OH-9,10-Br2-m-CB (31.8 mg, 0.1 mmol, 1 equiv), an amino compound containing heteroatoms or pharmacophores (0.11 mmol, 1.1 equiv), palladium acetate (2.2 mg, 0.01 mmol, 10 mol%), tris(2,4,5-trimethoxyphenyl)phosphine ligand (10.6 mg, 0.02 mmol, 20 mol%), and rubidium carbonate (69.3 mg, 0.3 mmol, 3.0 equiv) were added sequentially. The cap was immediately tightened. The system was purged with nitrogen three times. Dry 1,4-dioxane (1.0 mL, 0.1 M) was added as a solvent. The reaction mixture was then transferred to an oil bath at 120 °C and stirred for 12 minutes. h, the reaction solution was cooled to room temperature, and the reaction was monitored by TLC. After the reaction was complete as monitored by TLC, it was concentrated under vacuum and separated by column chromatography to obtain the target compound. The results are shown below:

[0304]

[0305]

[0306] 1 H NMR (400 MHz, Acetone-d6) δ 9.05 (s, 1H), 7.43 (s, 2H), 5.97 (s,1H), 4.80 (s, 1H), 3.71 (s, 1H), 3.36 (s, 1H).

[0307] 13 C{ 1 H} NMR (151 MHz, Acetone-d6) δ 157.00, 155.95, 152.74, 128.74,112.42, 54.96, 38.30.

[0308] 11 B NMR (128 MHz, Acetone-d6) δ 6.61(s, 1B), 3.86(s, 1B), 0.02(s, 1B),-9.75 (d, J = 163.6 Hz, 1B), -16.99 (d, J = 167.9 Hz, 1B), -19.50 (d, J =170.0 Hz, 1B), -25.49 (d, J = 173.2 Hz, 1B), -27.37(d, J = 152.8 Hz, 1B).

[0309] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 6.69(s, 1B), 3.93(s, 1B), 0.10(s,1B), -9.73(s, 1B), -17.00(s, 2B), -19.49(s, 2B), -25.55(s, 1B), -26.75(s,1B).

[0310] HR-MS (ESI) for C9H 14 10 B2 11 B8N2OS [M] m / z [M+H] + : calculated: 307.1903,found: 307.1919.

[0311]

[0312] 1 H NMR (400 MHz, MeOD) δ 7.51 (d, J = 7.4 Hz, 1H), 7.18 (d, J = 7.4Hz, 1H), 5.28 (s, 2H), 3.66 (s, 1H), 3.32 (s, 1H).

[0313] 13 C{ 1H} NMR (101 MHz, MeOD) δ 174.90, 157.99, 132.74, 129.68, 124.39,113.67, 68.52, 56.00, 40.90.

[0314] 11 B NMR (128 MHz, MeOD) δ 5.50 (s, 1B), 3.89 (s, 1B), -0.73 (s, 1B), -9.65 (d, J = 163.3 Hz, 1B), -16.94 (d, J = 155.0 Hz, 2B), -19.17 (d, J =159.2 Hz, 2B), -25.01 (d, J = 193.2 Hz, 1B), -26.47 (d, J = 182.6 Hz, 1B).

[0315] 11 B{ 1 H} NMR (128 MHz, MeOD) δ 5.48 (s, 1B), 3.87 (s, 1B), -0.75 (s,1B), -9.72 (s, 1B), -16.98 (s, 2B), -19.25 (s, 2B), -25.02 (s, 1B), -26.57(s, 1B).

[0316] HR-MS (ESI) for C 10 H 15 10 B2 11 B8NO3[M] m / z [M+H] + : calculated: 306.2128,found: 306.2130.

[0317]

[0318] 1 H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.38 (d, J = 5.8 Hz, 1H), 7.73(d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.8 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 5.58(s, 1H), 3.08 (s, 1H), 2.66 (s, 1H), -0.41 (s, 9H).

[0319] 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 158.63, 145.84, 141.61, 136.39, 133.65,121.20, 118.12, 114.38, 52.48, 36.36, 0.89.

[0320] 11 B NMR (128 MHz, CDCl3) δ 4.36(s, 1B), 2.91(s, 1B), -0.51(s, 1B), -10.09 (d, J = 164.6 Hz, 1B), -17.1 (d, J = 178.3 Hz, 2B), -19.35 (d, J =164.8 Hz, 2B), -25.72 (d, J = 160.9 Hz, 1B), -26.77 (d, J = 108.6 Hz, 1B).

[0321] 11 B{ 1 H} NMR (128 MHz, CDCl3) δ 4.35(s, 1B), 2.90(s, 1B), -0.54(s, 1B),-10.15(s, 1B), -17.02(s, 2B), -19.34(s, 2B), -25.83(s, 1B), -26.81(s, 1B).

[0322] HR-MS (ESI) for C 11 H 16 10 B2 11 B8N2O [M] m / z [M] + : calculated: 311.2353,found: 311.2363.

[0323]

[0324] 1 H NMR (400 MHz, Acetone-d6) δ 9.05 (s, 1H), 7.43 (s, 2H), 5.97 (s,1H), 4.80 (s, 1H), 3.71 (s, 1H), 3.36 (s, 1H).

[0325] 13 C{ 1H} NMR (151 MHz, Acetone-d6) δ 157.00, 155.95, 152.74, 128.74,112.42, 54.96, 38.30.

[0326] 11 B NMR (128 MHz, Acetone-d6) δ 6.61(s, 1B), 3.86(s, 1B), 0.02(s, 1B),-9.75 (d, J = 163.6 Hz, 1B), -16.99 (d, J = 167.9 Hz, 1B), -19.50 (d, J =170.0 Hz, 1B), -25.49 (d, J = 173.2 Hz, 1B), -27.37(d, J = 152.8 Hz, 1B).

[0327] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 6.69(s, 1B), 3.93(s, 1B), 0.10(s,1B), -9.73(s, 1B), -17.00(s, 2B), -19.49(s, 2B), -25.55(s, 1B), -26.75(s,1B).

[0328] HR-MS (ESI) for C9H 14 10 B2 11 B8N2OS [M] m / z [M+H] + : calculated: 307.1903,found: 307.1919.

[0329]

[0330] 1 H NMR (400 MHz, Acetone-d6) δ 8.10 (s, 1H), 7.39 (d, J = 8.5 Hz,1H), 6.90 (d, J = 8.5 Hz, 1H), 5.98 (s, 1H) , 4.89 (s, 1H), 3.71 (s, 1H),3.36 (s, 1H).

[0331] 13 C{ 1H} NMR (151 MHz, Acetone-d6) δ 163.54, 152.75, 150.60, 131.06,121.35, 119.99, 111.75, 54.40, 38.01.

[0332] 11 B NMR (128 MHz, Acetone-d6) δ 6.46 (s, 1B), 3.93 (s, 1B), -2.04 (s,1B), -9.87 (d, J = 163.0 Hz, 1B), -17.02 (d, J = 163.6 Hz, 2B), -19.45 (d, J= 165.0 Hz, 2B), -25.37 (d, J = 185.5 Hz, 1B), -27.51 (d, J = 177.4 Hz, 1B).

[0333] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 6.42 (s, 1B), 3.89 (s, 1B), -2.07(s, 1B), -9.87 (s, 1B), -17.04 (s, 2B), -19.47 (s, 2B), -25.32 (s, 1B), -26.82 (s, 1B).

[0334] HR-MS (ESI) for C9H 14 10 B2 11 B8N2O2[M] m / z [M] + : calculated: 291.2131,found: 291.2134.

[0335]

[0336] 1 H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.6Hz, 1H), 3.64 (s, 1H), 3.32 (s, 1H).

[0337] 13 C{ 1H}NMR (151 MHz, MeOD) δ 157.56, 155.09, 134.21, 130.85, 108.60, 55.05, 39.49.

[0338] 11 B NMR (128 MHz, MeOD) δ 5.10(s, 1B), 3.44(s, 1B), 0.02(s, 1B), -9.83(d, J = 161.3 Hz, 1B), -17.09 (d, J = 175.0 Hz, 2B), -19.30 (d, J = 189.4). Hz, 2B), -25.56 (d, J = 173.9 Hz, 1B), -26.89 (d, J = 167.0 Hz, 1B).

[0339] 11 B{ 1 H}NMR (128 MHz, MeOD) δ 5.19(s,1B), 3.50(s,1B), 0.07(s,1B), -9.90(s,1B), -17.22(s,1B), -19.59(s,2B), -25.72(s,1B), -26.92(s, 25). 1B).

[0340] HR-MS (ESI) for C8H 13 10 B2 11 B8N3OS [M] m / z [M+H] + : calculated: 308.1855,found:

[0341]

[0342] 1 H NMR (400 MHz, MeOD) δ 7.40(d, J = 4.6 Hz, 1H), 7.23–7.21(m,1H), 3.69(s,1H), 3.35(s,1H).

[0343] 13 C{ 1 H}NMR (151 MHz, MeOD) δ 130.97, 130.90, 122.94, 54.29, 38.33.

[0344] 19F{ 1 H} NMR (376 MHz, MeOD) δ -91.26.

[0345] 11 B NMR (128 MHz, MeOD) δ 5.19(s, 1B), 3.50(s, 1B), -1.36(s, 1B), -10.03 (d, J = 162.2 Hz, 1B), -16.88 (d, J = 187.8 Hz, 2B), -19.09 (d, J =178.9 Hz, 2B), -24.76 (d, J = 228.2 Hz, 1B), -26.43(d, J = 198.8 Hz, 1B).

[0346] 11 B{ 1 H} NMR (128 MHz, MeOD) δ 5.30(s, 1B), 3.59(s, 1B), -1.27(s, 1B),-9.96(s, 1B), -16.83(s, 2B), -19.16(s, 2B), -24.58(s, 1B), -26.62(s, 1B).

[0347] HR-MS (ESI) for C7H 13 10 B2 11 B8N2OF [M] m / z [M] + : calculated: 269.2088,found: 269.2091.

[0348]

[0349] 1 H NMR (400 MHz, Acetone-d6) δ 7.23 – 6.92 (m, 16H), 6.82 (dd, J =8.3, 2.0 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 3.17 (s, 1H), 2.67 (s, 1H).

[0350] 13 C{ 1H} NMR (151 MHz, Acetone-d6) δ 162.27, 162.19, 145.72, 145.62,145.57, 143.23, 139.16, 133.97, 132.28, 132.14, 132.04, 131.91, 128.37,128.32, 128.27, 126.95, 126.65, 126.57, 112.49, 112.41, 53.06, 38.35.

[0351] 11 B NMR (128 MHz, Acetone-d6) δ 6.49(s, 1B), 3.67(s, 1B), -0.23(s,1B), -9.74 (d, J = 165.9 Hz, 1B), -16.89(d, J = 154.8 Hz, 2B), -19.81(d, J =177.4 Hz, 2B), -27.44 (d, J = 207.4 Hz, 2B).

[0352] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 6.53 (s, 1B), 3.69 (s, 1B), -0.19(s, 1B), -9.74 (s, 1B), -17.38 (s, 2B), -19.73 (s, 2B), -25.76 (s, 1B), -27.42 (s, 1B).

[0353] HR-MS (ESI) for C 28 H 29 10 B2 11 B8NO [M] m / z [M] + : calculated: 504.3325,found: 504.3309.

[0354]

[0355] 1H NMR (400 MHz, DMSO) δ 8.29 (d, J = 9.2 Hz, 1H), 8.06 (s, 1H), 7.97– 7.71 (m, 5H), 7.62 (d, J = 8.8 Hz, 1H), 7.23 (s, 1H), 4.35 (s, 2H), 3.46(s, 1H).

[0356] 13 C{ 1 H} NMR (151 MHz, DMSO) δ 159.06, 133.03, 132.70, 129.16, 128.87,126.83, 126.35, 125.97, 125.35, 123.90, 123.69, 123.39, 122.85, 122.44,119.31, 116.02, 55.22, 38.71.

[0357] 11 B NMR (128 MHz, DMSO) δ 6.39(s, 1B), 3.91(s, 1B), 0.39(s, 1B), -9.28(s, 1B), -17.23(s, 4B), -24.95(s, 2B).

[0358] 11 B{ 1 H} NMR (128 MHz, DMSO) δ 6.90(s, 1B), 3.63(s, 1B), 0.08(s, 1B), -9.51(s, 1B), -18.56(s, 4B), -26.85(s, 2B).

[0359] HR-MS (ESI) for C 18 H 20 10 B2 11 B8NO [M] m / z [M+H] + : calculated: 374.2543,found: 374.2516.

[0360]

[0361] 1H NMR (400 MHz, MeOD) δ 8.36 (d, J = 5.4 Hz, 1H), 7.66 (s, 1H), 7.33(s, 1H), 7.13 (d, J = 2.5 Hz, 1H), 7.03 – 6.81 (m, 2H), 6.56 (d, J = 5.5 Hz,1H), 4.01 (s, 6H), 3.60 (s, 1H), 3.26 (s, 1H).

[0362] 13 C{ 1 H} NMR (151 MHz, MeOD) δ 162.85, 160.43, 153.31, 149.66, 148.22,145.72, 144.50, 134.01, 122.03, 120.46, 115.94, 112.88, 105.96, 102.53,99.48, 63.35, 55.09, 55.05, 53.82, 38.17, 23.85.

[0363] 11 B NMR (128 MHz, MeOD) δ 9.49, (s, 1B) 7.91(s, 1B), 3.32(s, 1B), -5.34(s, 1B), -15.13(s, 4B), -22.16(s, 2B).

[0364] 11 B{ 1 H} NMR (128 MHz, MeOD) δ 9.49(s, 1B), 7.91(s, 1B), 3.32(s, 1B), -5.27(s, 1B), -12.95(s, 2B), -15.77(s, 2B), -22.63(s, 2B).

[0365] HR-MS (ESI) for C 19 H 24 10 B2 11 B8N2O4[M] m / z [M+H] + : calculated: 453.2812,found: 453.2838.

[0366]

[0367] 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 7.04 (d, J = 9.7 Hz, 1H), 6.95(d, J = 8.2 Hz, 1H), 6.61 (d, J = 3.6 Hz, 1H), 6.50 (s, 1H), 6.40 (s, 2H),6.06 – 5.87 (m, 2H) , 5.71 (dd, J = 5.8, 1.9 Hz, 1H), 4.38 – 4.32 (m, 2H),4.20 (dd, J = 9.4, 2.3 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H),3.57 – 3.46 (m, 2H), 3.34 (s, 1H), 3.33 – 3.22 (m, 1H), 2.92 (s, 1H), 2.79(s, 1H).

[0368] 13 C{ 1 H} NMR (151 MHz, CDCl3) δ 177.34, 171.82, 153.25, 148.20, 147.00,138.84, 131.25, 129.71, 126.51, 126.46, 109.67, 107.78, 105.53, 105.48,101.33, 72.46, 70.49, 60.87, 56.21, 56.18, 45.37, 44.13, 40.79, 39.77, 39.73,38.83.

[0369] 11 B NMR (193 MHz, CDCl3) δ 6.68 (s, 1B), 2.37 (s, 1B), -0.10 (s, 1B),-8.54 (s, 1B), -16.03 (s, 2B), -18.28 (s, 2B), -23.71 (s, 2B).

[0370] 11 B{ 1 H} NMR (193 MHz, CDCl3) δ 6.79 (s, 1B), 2.46 (s, 1B), 0.06 (s,1B), -8.40 (s, 1B), -16.34 (s, 2B), -18.44 (s, 2B), -25.28 (s, 2B).

[0371] HR-MS (EI) C 32 H 37 10 B3 11 B7NO 10 [M] m / z [M+H] + : calculated:703.3535, found:703.3543.

[0372]

[0373] 1 H NMR (400 MHz, DMSO) δ 8.37 (dd, J = 4.9, 1.9 Hz, 1H), 7.36 (d, J =2.0 Hz, 1H), 7.03 (dd, J = 7.3, 4.9 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.38 –6.28 (m, 1H), 6.19 (d, J = 8.0 Hz, 1H), 4.19 (q, J = 7.4 Hz, 2H), 3.94 (q, J= 7.1 Hz, 2H), 3.86 (s, 1H), 3.59 (s, 1H), 2.72 (s, 3H), 2.68 – 2.58 (m, 2H),1.23 (s, 2H), 1.11 (t, J = 7.1 Hz, 3H).

[0374] 13 C{ 1 H} NMR (151 MHz, DMSO) δ 171.44, 156.26, 148.50, 137.41, 130.13,122.53, 120.67, 60.40, 53.96, 43.78, 37.48, 33.64, 14.44.

[0375] 11 B NMR (128 MHz, DMSO) δ 6.75(s, 1B), 2.92(s, 1B), -0.01(s, 1B), -9.84(s, 1B), -17.57(s, 4B), -24.33(s, 2B).

[0376] 11 B{ 1H} NMR (128 MHz, DMSO) δ 11.48(s, 1B), 7.61(s, 1B), 5.19(s, 1B), -4.28(s, 1B), -12.04(s, 4B), -20.13(s, 2B).

[0377] HR-MS (ESI) for C 20 H 30 10 B2 11 B8N4O4[M] m / z [M+Na] + : calculated: 521.3162, found: 521.3171.

[0378] Example 10

[0379] Method for preparing B(5, 9, 10) trisubstituted compounds: In a dry 10 mL Schlenk tube, 5-OH-9,10-Br2-m-CB (31.8 mg, 0.1 mmol, 1 equiv), an indole substrate (0.11 mmol, 1.1 equiv), palladium acetate (2.2 mg, 0.01 mmol, 10 mol%), tris(2,4,5-trimethoxyphenyl)phosphine ligand (10.6 mg, 0.02 mmol, 20 mol%), and rubidium carbonate (69.3 mg, 0.3 mmol, 3.0 equiv) were added sequentially. The cap was immediately tightened. The system was purged with nitrogen three times. Dry 1,4-dioxane (1.0 mL, 0.1 M) was added as a solvent. The reaction mixture was then transferred to an oil bath at 120 °C and stirred for 12 minutes. h, the reaction solution was cooled to room temperature, and the reaction was monitored by TLC. After the reaction was complete as monitored by TLC, it was concentrated under vacuum and separated by column chromatography to obtain the target compound. The results are shown below:

[0380]

[0381]

[0382] 1 H NMR (400 MHz, Acetone-d6) δ 7.38 (d, J = 3.0 Hz, 1H), 7.33 (dd, J= 11.6, 7.1 Hz, 1H), 6.50 (s, 1H), 5.30 (s, 1H), 3.99 (s, 1H), 3.64 (s, 1H).

[0383] 13 C{1 H} NMR (151 MHz, Acetone-d6) δ 154.34, 148.59 (q, 1 J = 235.2, 18.2Hz)148.19 (q, 1 J = 242.1 Hz, 16.7), , 129.86 (d, 3 J = 7.2 Hz), 120.63 (d, 3 J =7.9 Hz),107.53 (d, 2 J = 21.7 Hz), 106.26, 55.21, 38.98.

[0384] 19 F{ 1 H} NMR (376 MHz, Acetone-d6) δ -140.93 (d, J = 20.4 Hz), -149.96(d, J = 20.7 Hz).

[0385] 11 B NMR (128 MHz, Acetone-d6) δ 7.95 (s, 1B), 3.32 (s, 1B), -0.00 (s,1B), -8.25 (d, J = 164.7 Hz, 1B), -13.89 – -18.69 (2B), -19.95 (d, J = 165.3Hz, 2B), -23.56 (d, J = 167.3 Hz, 1B), , -24.86 (d, J = 162.3 Hz, 1B).

[0386] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 8.02(s, 1B), 3.36(s, 1B), 0.03(s,1B), -8.25(s, 1B), -16.86(s, 1B), -17.10(s, 1B), -17.64(s, 1B), -20.01(s,1B), -23.67(s, 1B), -24.83(s, 1B).

[0387] HR-MS (ESI) for C 10 H 13 10 B2 11 B8NOF2[M] m / z [M+H]+ : calculated: 310.2041,found: 310.2055.

[0388]

[0389] 1 H NMR (400 MHz, Acetone-d6) δ 7.41 (dd, J = 7.9, 0.9 Hz, 1H), 7.20(d, J = 6.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 3.86 (s, 1H), 3.51 (s, 1H), 2.31(s, 3H).

[0390] 13 C{ 1 H} NMR (151 MHz, Acetone-d6) δ 159.87, 126.37, 125.70, 125.66,123.01, 120.66, 115.28, 54.82, 38.70, 10.47.

[0391] 11 B NMR (128 MHz, Acetone-d6) δ 7.97(s, 1B), 3.51(s, 1B), 2.15(s, 1B),-8.19 (d, J = 164.5 Hz, 1B), -17.73 (dd, J = 165.3, 101.8 Hz, 2B), -20.30 (d,J = 163.7 Hz, 2B), -24.23 (d, J = 158.8 Hz, 1B), -25.50 (d, J = 166.6 Hz,1B).

[0392] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 8.03(s, 1B), 3.55(s, 1B), 2.18(s,1B), -8.18(s, 1B), -17.41(s, 1B), -18.03(s, 1B), -20.37(s, 2B), -24.35(s,1B), -25.45(s, 1B).

[0393] HR-MS (ESI) for C 11 H 17 10 B211 B8NO [M] m / z [M] + : calculated: 288.2386,found: 288.2390.

[0394]

[0395] 1 H NMR (400 MHz, DMSO) δ 7.43 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 6.8Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 5.91 (s, 1H), 4.63 (t, J = 5.3 Hz, 1H),4.14 (s, 1H), 3.85 (s, 1H), 3.70 (td, J = 7.4, 5.2 Hz, 2H), 2.86 (t, J = 7.4Hz, 2H).

[0396] 13 C{ 1 H} NMR (151 MHz, DMSO) δ 158.24, 125.28, 124.45, 122.07, 119.56,117.82, 116.11, 61.68, 54.39, 37.79, 29.73.

[0397] 11 B NMR (128 MHz, DMSO) δ 8.22(s, 1B), 3.25(s, 1B), 2.09(s, 1B), -8.10(s, 1B), -18.60(s, 4B), -23.86(s, 2B).

[0398] 11 B{ 1 H} NMR (128 MHz, DMSO) δ 7.80(s, 1B), 3.24(s, 1B), 1.71(s, 1B), -8.20(s, 1B), -21.35(s, 4B), -24.72(s, 2B).

[0399] HR-MS (ESI) for C 12 H 29 10 B2 11 B8NO2[M] m / z [M+H] +: calculated: 318.2492,found: 318.2498.

[0400]

[0401] 1 H NMR (400 MHz, Acetone-d6) δ 7.60 (d, J = 3.0 Hz, 1H), 7.48 (d, J =7.1 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 6.66 (s, 1H), 4.02 (s, 1H), 3.67 (s,1H).

[0402] 13 C{ 1 H} NMR (151 MHz, Acetone-d6) δ 131.61, 126.94, 123.20, 119.81,104.49, 102.23, 55.70, 39.53.

[0403] 11 B NMR (128 MHz, Acetone-d6) δ 8.24(s, 1B), 3.26(s, 1B), 1.46(s, 1B),-7.98 (d, J = 166.7 Hz, 1B), -17.32 (d, J = 135.8 Hz, 2B), -19.92 (d, J =165.5 Hz, 2B), -23.36 (d, J = 176.2 Hz, 1B), -254.63 (d, J = 150.7 Hz, 1B).

[0404] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 8.20(s, 1B), 3.23(s, 1B), 1.43(s,1B), -8.01(s, 1B), -17.33(s, 2B), -19.94(s, 2B), -23.41(s, 1B), -24.58(s,1B).

[0405] HR-MS (ESI) for C 11 H 14 10 B2 11 B8N2O [M] m / z [M+H] +: calculated: 299.2182,found: 299.2196.

[0406]

[0407] 1 H NMR (400 MHz, CDCl3) δ 7.26-7.21 (m, 2H), 6.83 (dd, J = 11.3, 7.5Hz, 1H), 6.66 (d, J = 2.9 Hz, 1H), 3.33 (s, 1H), 2.85 (s, 1H).

[0408] 13 C{ 1 H} NMR (151 MHz, CDCl3) δ 156.93 (d, J = 250.9 Hz), 127.24,123.46 (d, J = 7.2 Hz), 106.29 (d, J = 19.9 Hz), 102.24, 52.63, 38.77.

[0409] 19 F{ 1 H} NMR (376 MHz, CDCl3) δ -121.37.

[0410] 11 B NMR (128 MHz, CDCl3) δ 7.55 (s, 1B), 3.60 (s, 1B), 1.87 (s, 1B), -7.94 (d, J = 168.7 Hz , 1B), -16.68 (d, J = 143.8 Hz , 2B), -19.71 (d, J =167.4 Hz , 2B), -24.30 (d, J = 182.18 Hz , 1B), -24.93 (d, J = 179.34 Hz ,1B).

[0411] 11 B{ 1 H} NMR (128 MHz, CDCl3) δ 7.62 (s, 1B), 3.65 (s, 1B), 1.92 (s,1B), -7.93 (s, 1B), -16.75 (s, 1B), -17.64 (s, 1B), -19.80 (s, 2B), -24.33(s, 1B), -24.96 (s, 1B).

[0412] HR-MS (ESI) for C 10 H 14 10 B2 11 B8NOF [M] m / z [M] + : calculated: 292.2135,found: 292.2136.

[0413]

[0414] 1 H NMR (400 MHz, Acetone-d6) δ 7.83 (d, J = 7.3 Hz, 1H), 7.47 (d, J =2.9 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H), 6.94 (s, 1H), 5.22 (s, 1H), 3.96 (s,1H), 3.93 (s, 3H), 3.61 (s, 1H).

[0415] 13 C{ 1 H} NMR (151 MHz, Acetone-d6) δ 168.57, 159.82, 130.34, 130.30,125.19, 124.43, 122.43, 121.69, 107.52, 55.30, 51.72, 39.15.

[0416] 11 B NMR (193 MHz, Acetone-d6) δ 8.25(s, 1B), 3.42(s, 1B), 1.66(s, 1B),-7.93 (d, J = 163.6 Hz, 1B), -17.34 (d, J = 137.0 Hz, 2B), -19.97 (d, J =161.6 Hz, 2B), -23.63 (d, J = 203.0 Hz, 1B), -24.68 (d, J = 203.8 Hz, 1B).

[0417] 11 B{ 11H NMR (193 MHz, Acetone-d6) δ 8.26(s, 1B), 3.42(s, 1B), 1.67(s,1B), -7.94(s, 1B), -17.05(s, 1B), -17.63(s, 1B), -20.00(s, 2B), -23.59(s,1B), -24.75(s, 1B).

[0418] HR-MS (ESI) for C 12 H 17 10 B2 11 B8NO3[M] m / z [M+H] + : calculated: 332.2284,found: 332.2301.

[0419] X-ray structure is as Figure 2 。

[0420]

[0421] 1 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 2.9 Hz, 1H), 7.08 (d, J = 2.1Hz, 1H), 7.03 (s, 1H), 6.52 (d, J = 2.8 Hz, 1H), 3.87 (s, 3H), 3.32 (s, 1H),2.84 (s, 1H).

[0422] 13 13C{ 1 1H} NMR (151 MHz, CDCl3) δ 177.14, 156.06, 153.55, 127.95, 124.49,112.99, 105.48, 102.97, 56.36, 52.46, 38.55.

[0423] 11 11B NMR (128 MHz, CDCl3) δ 7.80(s, 1B), 3.58(s, 1B), 2.14(s, 1B), -7.91 (d, J = 161.0 Hz, 1B), -16.94 (d, J = 142.2 Hz, 2B), -20.00 (d, J =168.9 Hz, 2B), -25.51 (d, J = 143.5 Hz, 2B).<00016

[0424] 11 B{ 1 H} NMR (128 MHz, CDCl3) δ 7.83(s, 1B), 3.60(s, 1B), 2.14(s, 1B),-8.02(s, 1B), -16.88(s, 1B), -17.68(s, 1B), -20.03(s, 2B), -25.28(s, 2B).

[0425] HR-MS (ESI) for C 11 H 17 10 B2 11 B8NO2[M] m / z [M+H] + : calculated: 304.2335,found: 304.2349.

[0426]

[0427] 1 H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 2.9 Hz, 1H), 7.02 (d, J = 1.9Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 6.48 (d, J = 3.0 Hz, 1H), 3.31 (s, 1H),2.83 (s, 1H), 1.03 (s, 9H), 0.22 (s, 6H).

[0428] 13 C{ 1 H} NMR (101 MHz, CDCl3) δ 149.53, 127.88, 124.83, 116.69, 109.85,105.38, 51.92, 38.58, 25.80, 18.15.

[0429] 11 B NMR (128 MHz, CDCl3) δ 7.68 (s, 1B), 3.56 (s, 1B), 2.13 (s, 1B), -8.03 (s, 1B), -17.03(s, 2B), -19.85 (s, 2B), -24.90 (s, 2B).

[0430] 11 B{ 1H} NMR (128 MHz, CDCl3) δ 7.79 (s, 1B), 3.62 (s, 1B), 2.22 (s,1B), -8.07 (d, J = 185.2 Hz, 1B), -17.35 (2B), -19.88 (d, J = 169.2 Hz, 2B),-25.46 (d, J = 180.6 Hz, 2B).

[0431] HR-MS (ESI) for C 16 H 29 10 B2 11 B8NO2Si [M] m / z [M+H] + : calculated: 404.3044,found: 404.3051.

[0432]

[0433] 1 H NMR (400 MHz, Acetone-d6) δ 7.86 (d, J = 15.9 Hz, 1H), 7.77 (s,1H), 7.61 (s, 1H), 7.39 (d, J = 3.0 Hz, 1H), 6.57 (d, J = 3.0 Hz, 1H), 6.49(d, J = 15.9 Hz, 1H), 3.96 (s, 1H), 3.74 (s, 3H), 3.62 (s, 1H).

[0434] 13 C{ 1 H} NMR (151 MHz, Acetone-d6) δ 168.16, 160.80, 148.64, 130.56,129.66, 128.40, 125.85, 122.79, 114.29, 106.61, 55.25, 51.43, 39.10.

[0435] 11 B NMR (128 MHz, Acetone-d6) δ 8.17 (s, 1B), 3.46 (s, 1B), 1.80 (s,1B), -8.14 (s, 1B), -17.79 (s, 2B), -20.27 (s, 2B), -25.02 (s, 2B).

[0436] 11 B{ 1 H} NMR (128 MHz, Acetone-d6) δ 8.16 (s, 1B), 3.45 (s, 1B), 1.78(s, 1B), -8.09 (d, J = 167.9 Hz, 1B), -18.26 (2B), -20.22 (d, J = 161.0 Hz, 2B), -25.01 (d, J = 152.8 Hz, 2B).

[0437] HR-MS (ESI) for C 14 H 19 10 B2 11 B8NO3[M] m / z [M+H] + : calculated: 358.2441, found: 358.2446.

[0438] Application Example 1

[0439] Step 1:

[0440]

[0441] In a dry 10 mL Schlenk tube, the trisubstituted cyclized product (159.8 mg, 0.5 mmol, 1 equiv) and KOH (56.1 mg, 1.0 mmol, 2 equiv) were added sequentially. After purging with nitrogen three times, acetone (5.0 mL, 0.1 M) and 3-bromopropyne (178.4 mg, 1.5 mmol, 3 equiv) were added. The cap was immediately tightened, and the mixture was stirred at room temperature for 0.5 h. Then, the mixture was transferred to an oil bath at 120 °C and reacted for 8 h.

[0442] Silica gel column chromatography (petroleum ether: EtOAc = 12:1 to 5:1) gave a white solid product (24.1 mg, 68%). Rf = 0.36 (petroleum ether: EtOAc = 6:1).

[0443] Step 2:

[0444]

[0445] Post-modification of the selectively trisubstituted cyclized product of carborane was performed to synthesize the potential BNCT drug RGDfK-m-CB. First, sodium azide (65.0 mg, 1.0 mmol, 5.0 equiv) and 1.2 mL of water were added to a 2 mL microcentrifuge tube equipped with a stir bar and placed in an ice-water bath. DCM (2.1 mL) and trifluoromethanesulfonic anhydride (34 μL, 0.2 mmol, 1.0 equiv) were then added, and the reaction was carried out at room temperature for 1 h. After washing the organic layer three times with water, the organic layer was collected to obtain trifluoromethanesulfonyl azide reaction solution 1.

[0446] Next, a stir bar, c-RGDfK (0.013 mmol, 8.4 mg, 1.0 equiv), CuSO4·5H2O (1.7 mg, 0.0052 mmol, 0.4 equiv), methanol (266 μL), and water (94 μL) were added sequentially to a clean 4 mL glass vial. Then, the organic phase from reaction solution 1 (1.0 mL, 0.056 mmol, 4.27 equiv) was added. The pH was adjusted to approximately 10.0 with potassium carbonate, and the reaction solution turned blue. After 3 h of reaction, HPLC analysis confirmed the completeness of the aqueous phase reaction. The product c-RGDfK-N3 was obtained by HPLC purification.

[0447] Finally, the stir bar, 4-7c (0.028 mmol, 1.0 mg, 1.0 equiv), CuSO4 (0.3 mg, 0.0014 mmol, equiv), VC (2.0 mg, 0.0112 mmol, 4.0 equiv), and c-RGDfK-N3 (3.0 mg, 0.0042 mmol, 1.5 equiv) were added to a 4 mL glass bottle, followed by DMSO (0.42 mL) and water (0.14 mL). The mixture was stirred at room temperature for 3 h. HPLC analysis confirmed that the aqueous phase reaction was complete. HPLC purification yielded 0.8 mg of a white solid RGDfK-m-CB, with a yield of 64%.

[0448] HR-MS (ESI) for C 39 H 55 10 B2 11 B8N 12 F3O8[M] m / z [M+H] + : calculated: 985.5299, found: 985.5361

[0449] Application Example 2:

[0450] To develop pleiotropic drug candidates with targeted delivery, boron neutron capture therapy (BNCT), and fluorescence or radioactive tracing capabilities, this study combines enzyme catalysis with fluorescence signal transduction. The active drug component is released via an ALP-mediated dephosphorylation reaction, while the on / off effect of fluorescent molecules enables real-time monitoring of the drug activation process. A fluorescently responsive precursor molecule with aggregation-induced emission (AIE) properties was successfully synthesized and confirmed by HPLC and ESI. This system uses alkaline phosphatase (ALP) as a response switch, catalyzing the hydrolysis and dephosphorylation reaction to achieve targeted tracking of potential drug molecules within tumor cells. Notably, during ALP hydrolysis monitoring, HPLC analysis revealed excessive hydrolysis of the precursor molecule, ultimately generating the target compound A.

[0451]

[0452] We verified the responsiveness of the fluorescent precursor C to ALP by measuring the absorbance changes before and after probe enzyme hydrolysis using a UV spectrophotometer. We found that the absorbance spectra of the same concentration of probe (10 μM) and ALP (2 U / mL) after incubation in Tris buffer (10 mM, pH 8.0) at 37 °C for 30 min were basically consistent with the absorbance spectrum of C itself. Figure 3 To more intuitively demonstrate the responsiveness of probe C to ALP, we used a fluorometer to test the changes in fluorescence before and after incubation with ALP to observe the probe's enzyme response. We used 310 nm as the excitation wavelength and tested the fluorescence changes of probe C using a fluorometer. It can be seen that the fluorescent probe C itself has low fluorescence (…). Figure 4 The fluorescence intensity of probe C after enzymatic hydrolysis (black line) is significantly enhanced compared to that of the probe itself (red line), reaching a peak at approximately 490 nm after incubation with ALP in Tris buffer (10 mM, pH 8.0) at 37°C for 30 min. Furthermore, when ALP was pre-incubated with the ALP inhibitor p-BTO (p-bromotetraimidazole oxalate) for 30 min, followed by incubation with the fluorescent probe for another 30 min, the enhancement in probe fluorescence intensity disappeared (blue line), indicating that inhibited ALP activity cannot hydrolyze the probe. This further demonstrates that C can serve as a novel probe for detecting ALP activity, exhibiting excellent applicability.

[0453] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A compound of Formula I, or a salt thereof, ； wherein In particular, the "B" sites are CH and the other sites are BH. In particular, the "B" sites are CH and the other sites are BH. X is N or CH; n is 1, 2, 3, or 4; R 1 is H; or R 1 with together form a 5-20 membered heteroaryl or a 5-20 membered heteroaryl substituted by one or more R 1-1 substituted 5-20 membered heteroaryl; Each R 1-1 Independently halogenated, -CN, -OTBS, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or with one or more R 1-1-1 Substituted C1-C6 alkyl groups Or by one or more R 1-1-3 Substituted C2-C6 alkenyl groups; Each R 1-1-1 Independently -OH, halogen, or -CN; R 1-1-2 independently C1-C6alkyl; each R is independently 1-1-3 independently ; R 1-1-3-1 Ci-C6-alkyl; R 2 H, halogen, -CN, -OH, , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C1-C6 alkyl substituted by one or more R 2-2 , C1-C6 alkoxy substituted by one or more R 2-3 , C2-C6 alkenyl substituted by one or more R 2-4 , C2-C6 alkenyl substituted by one or more R , -N(R 2-6 ) (R 2-7 ) or ; R 2-1 Ci-C6-alkyl; each R is independently halogen, -N(R 2-2 ) (R 2-2-1 ) or 2-2-2 ; and each R is independently halogen, -N(R ); R 2-2-1 and R 2-2-2 are independently H or -Boc; R 2-2-3 C1-C6 alkyl, 5-20 membered heteroaryl, or 5-20 membered heteroaryl substituted with one or more R 2-2-3-a substituted with one or more R Each R 2-2-3-a Independently oxygenated, C6-C 20 aryl or aryl with one or more R 2-2-3-b Replacement C6-C 20 Aryl; Each R 2-2-3-b Independently, it is a C1-C6 alkyl or C1-C6 alkoxy group; Each R 2-3 It can be halogen, -CN, or -OH independently; Each R 2-4 Independently for C6-C 20 Aryl; R 2-5 R is 5-20 membered heteroaryl or 5-20 membered heteroaryl substituted with one or more R 2-5-1 R is 5-20 membered heteroaryl or 5-20 membered heteroaryl substituted with one or more R Each R 2-5-1 Independently, it is a C1-C6 alkyl or C1-C6 alkoxy group; R 2-6 and R 2-7 independently H, C1-C6alkyl or C1-C6alkoxy; R 2-8 is 5-20 membered heteroaryl; R 2-9 C1-C6alkyl or C1-C6alkyl substituted by one or more R 2-9-1 substituted by one or more R each R is independently 2-9-1 independently ; R 2-9-1-1 Ci-C6-alkyl; or, two or more R 2 connected together with together form C6-C 20 aryl, 5-20 membered heteroaryl, 5-20 membered heteroaryl substituted with one or more R 2-10 substituted 5-20 membered heteroaryl; Each R 2-10 It is an independent oxygen-producing agent.

2. The compound of claim 1, or a salt thereof, wherein which satisfies one or more of the following conditions: (1) n is 1, 2, or 3; (2) X is CH2; (3) each of the halogens is independently F, Cl, Br, or I, preferably F or Cl; (4) each of the C1-C6 alkyl groups is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, preferably methyl, ethyl, or i-propyl; (5) each of the C1-C6 alkoxy groups is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy; (6) each of the C2-C6 alkenyl groups is independently vinyl, allyl, or butenyl; (7) each said 5-20 membered heteroaryl is independently , , , , , , or ; (8) each said C6-Ci8aryl is independently phenyl, naphthyl, or 20 aryl is independently phenyl, naphthyl, or .

3. The compound of claim 1 or 2, or a salt thereof, wherein the compound of Formula I is a compound of Formula I-1 or a compound of Formula I-2, or ; wherein X, R 1-1 , R 2 , n are independently as described in claim 1 or 2; preferably, the compound of Formula I is selected from any one of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , and .

4. A process for the preparation of a compound of formula I according to any one of claims 1 to 3, characterized in that which comprises the step of reacting a compound of Formula II with a compound of Formula III in the presence of a palladium catalyst, a ligand, and a basic reagent in an organic solvent to form a compound of Formula I; ； wherein R A is -OH, -Br, or ; R a is C1-C6alkyl; R b is C2-C6alkenyl or C2-C6alkynyl; Y is halogen; X, R 1 and R 2 independently of one another as in any one of claims 1 to 3.

5. The production method according to claim 4, wherein the preparation method satisfies one or more of the following conditions: (1) the C1-C6 alkyl group is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, preferably methyl; (2) the C2-C6 alkenyl group is vinyl, allyl, or butenyl, preferably allyl; (3) the C2-C6 alkynyl group is ethynyl, propargyl, or butynyl, preferably propargyl; (4) the halogen is Br or I, preferably Br; Preferably, R A is -OH, -Br, acetyloxy, allyloxy or propargyloxy.

6. The production method according to claim 4, wherein the compound of Formula II is selected from any one of the following: , , , and ; and / or, the compound of Formula III is selected from any one of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

7. The production method according to claim 4, wherein the preparation method satisfies one or more of the following conditions: (1) the organic solvent is selected from one or more of an ether solvent, an aromatic hydrocarbon solvent, and an amide solvent; the ether solvent is preferably 1,4-dioxane; the aromatic hydrocarbon solvent is preferably toluene; the amide solvent is preferably N,N-dimethylformamide; more preferably, the organic solvent is 0.1 M 1,4-dioxane; (2) the palladium catalyst is palladium acetate; (3) the ligand is a phosphorus ligand; the phosphorus ligand is, for example, (2,4,5-trimethoxyphenyl)phosphine, tri(2,-methoxyphenyl)phosphine, tri(2,5-dimethoxyphenyl)phosphine, tri(2,4,5-triethoxyphenyl)phosphine, tri(2,4,6-trimethoxyphenyl)phosphine, tri-tert-butylphosphine, cyclohexyldi-tert-butylphosphine, n-butylbis(1-adamantyl)phosphine, bis(cyclohexylphosphine)ferrocene, preferably (2,4,5-trimethoxyphenyl)phosphine; (4) the basic reagent is selected from one or more of an alkali metal carbonate, an alkali metal phosphate, and an alkali metal alcoholate; the alkali metal carbonate is, for example, potassium carbonate, rubidium carbonate, or cesium carbonate; the alkali metal phosphate is, for example, potassium phosphate; the alkali metal alcoholate is, for example, potassium tert-butoxide; preferably, the basic reagent is rubidium carbonate; preferably, the basic reagent is rubidium carbonate; (5) the molar volume ratio of the compound of formula II to the organic solvent is 0.05 mmol / mL-1 mmol / mL, preferably 0.1 mmol / mL; (6) the molar ratio of the compound of formula II to the compound of formula III is 1:(1-3), preferably 1:1.1, 1:2.5, 1:1.25 or 1:2; (7) the molar ratio of the compound of formula II to the palladium catalyst is 1:(0.05-0.2), preferably 1:0.1 or 1:0.15; (8) the molar ratio of the compound of formula II to the ligand is 1:(0.1-0.4), preferably 1:0.2 or 1:0.3; (9) the molar ratio of the compound of formula II to the basic reagent is 1:(2-5), preferably 1:3 or 1:4.5; (10) the reaction temperature is 50-130°C, preferably 120°C; (11) the reaction is carried out under inert gas or nitrogen protection, preferably under nitrogen protection; (12) the post-treatment of the reaction comprises the following steps: concentration, column chromatography separation.

8. Use of the compound of formula I or a salt thereof according to any one of claims 1-3 in the preparation of a BNCT prodrug; Preferably, the BNCT prodrug is a BNCT prodrug with fluorescence imaging function in response to an enzyme; the enzyme is, for example, alkaline phosphatase (ALP).

9. A compound of formula II or a salt thereof according to any one of claims 4-6, ； wherein Y and R A independently as any one of claims 4-6.

10. A method for preparing a compound of formula II-OH, characterized in that, which comprises the following steps: reacting the compound of formula II-1 with hydrogen peroxide to form the compound of formula II-OH in a solvent under the action of a metal reagent and an acid; ； wherein Y is as defined in any one of claims 4-6; Preferably, the preparation method of the compound of formula II-OH satisfies one or more of the following conditions: (1) the solvent is a fluorine-containing alcohol solvent, for example, hexafluoroisopropanol; preferably, the concentration of the fluorine-containing alcohol solvent is 0.2M; (2) the metal reagent is a transition metal salt, for example, Mn(OTf)2, Cu(OTf)2or Cu(CH3CN)4PF6; (3) the acid is triflic acid or trifluoroacetic acid, preferably triflic acid; (4) the molar volume ratio of the compound of formula II-1 to the solvent is 1 mmol / mL-5 mmol / mL, preferably 2 mmol / mL; (5) the molar ratio of the compound of formula II-1 to the hydrogen peroxide is 1:(10-20), preferably 1:14; (6) the molar ratio of the compound of formula II-1 to the metal reagent is 1:(0.5-3), preferably 1:1; (7) the molar ratio of the compound of formula II-1 to the acid is 1:(4-20), preferably 1:6; (8) in the reaction, the hydrogen peroxide is added 2-5 times, for example, 2 times, 3 times or 4 times; preferably, the hydrogen peroxide is supplemented every 12 h. (9) the reaction temperature of the reaction is 90-120°C, preferably 90°C; (10) the post-treatment of the reaction comprises the following steps: neutralization, extraction, drying, concentration and column chromatography separation.

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