7-((5-membered heterocyclic)methyl)-8-carboxylic acid-benzocyclic borate derivatives and their uses

Abstract

The present invention provides a 7-((5-membered heterocyclic ring)methyl)-8-carboxylic acid-benzo cyclic borate derivative represented by the following formula (I) and its use. This derivative has good inhibitory activity with a broad spectrum against metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) commonly found in clinics, and can be used in the preparation of antibacterial drugs, especially drugs acting against drug-resistant bacteria, as inhibitors of MBL and / or SBL enzymes. In addition, by combining this derivative with β-lactam antibiotics, it has good antibacterial activity against various β-lactam antibiotic-resistant bacteria, has great potential in the preparation of drugs for overcoming double broad-spectrum inhibitors of MBL and SBL and β-lactam antibiotic-resistant bacteria, provides new options for the use of antibacterial drugs, and various future applications can be expected. JPEG2025521595000121.jpg3273

Description

[Technical Field]

[0001] cross reference This application claims priority based on the Chinese patent application filed with the China National Intellectual Property Administration on July 5, 2022, application number 202210784531.9, title of invention "7-((5-membered heterocyclic)methyl)-8-carboxylic acid-benzocyclic borate derivatives and uses thereof", and the Chinese patent application filed with the China National Intellectual Property Administration on June 21, 2023, application number 202310747738.3, title of invention "7-((5-membered heterocyclic)methyl)-8-carboxylic acid-benzocyclic borate derivatives and uses thereof", the entire contents of which are incorporated herein by reference.

[0002] Technical field The present invention relates to the pharmaceutical technology, and more specifically to 7-((5-membered heterocyclic)methyl)-8-carboxylic acid-benzocyclic borate derivatives, and their use as metallo-β-lactamase and serine-β-lactamase inhibitors. [Background technology]

[0003] Currently, the most widely used antibiotics in clinical practice are β-lactam antibiotics such as penicillins, cephalosporins, carbapenems, and monocyclic antibiotics. Among these, carbapenem antibiotics, as atypical β-lactam antibiotics, have the broadest antibacterial spectrum and the strongest bactericidal activity, making them important antimicrobial agents for treating serious bacterial infections in clinical practice and often referred to as the "last line of defense" against bacterial infections. However, the problem of drug resistance to β-lactam antibiotics is becoming increasingly serious. In the list of drug-resistant bacteria published by the World Health Organization (WHO) in 2017, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae, which are resistant to carbapenems, were listed as the most dangerous superbags, and because safe and effective treatments for them have not been sufficiently developed, they are attracting attention and vigilance worldwide. The main mechanism of drug resistance to β-lactam antibiotics, such as carbapenems, is that β-lactamases produced by the pathogen itself hydrolyze the core pharmacophore of the β-lactam ring, rendering the β-lactam antibiotic inactive. Based on differences in their structure and catalytic mechanism, β-lactamases are classified into metallo-β-lactamases (MBLs) and serine β-lactamases (SBLs). Because the exchange and transfer of resistance gene genetic material occurs between the same or different pathogen species, resistant bacteria co-expressing MBLs and SBLs are emerging and spreading, posing a major threat to human life and health.

[0004] The combination of β-lactam antibiotics and β-lactamase inhibitors is one of the most important strategies for treating drug-resistant bacterial infections in clinical trials. Currently, six serine-β-lactamase (SBL) inhibitors, including clavulanic acid, sulbactam, tazobactam, avibactam, vaborbactam, and relebactam, are clinically approved and have shown good clinical efficacy against SBL-producing drug-resistant bacteria. However, these commercially available SBL inhibitors are ineffective against MBL-producing drug-resistant bacteria, and there are currently no drugs that act clinically against MBL-producing drug-resistant bacteria. MBL / SBL dual inhibitors can simultaneously inhibit the hydrolysis of β-lactam antibiotics by MBLs and SBLs. Therefore, such inhibitors not only restore the effectiveness of β-lactam antibiotics against drug-resistant bacteria that produce either MBLs or SBLs, but are also effective against drug-resistant bacteria that produce both MBLs and SBLs. However, because MBLs and SBLs have different structures and catalytic mechanisms, the development of MBL / SBL dual inhibitors is a significant challenge, and no inhibitors have yet been approved for clinical use. Consequently, there is a need for the development of MBL / SBL dual inhibitors with higher activity and a broader spectrum of drug discovery potential, in order to provide candidate compounds for new drug research targeting MBLs / SBLs and overcoming drug resistance to β-lactam antibiotics such as carbapenems. [Overview of the project]

[0005] The present invention aims to provide 7-((5-membered heterocyclic)methyl)-8-carboxylic acid-benzocyclic borate derivatives, as well as applications as inhibitors of MBL and SBL.

[0006] The present invention provides a compound represented by the following formula (I), a salt thereof, a conformational isomer thereof, or an optical isomer thereof. [ka] [In the formula, n is an integer from 0 to 5. R1 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C8 alkyl groups, C1-C8 alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, and SR9. Ring A is a 5-membered unsaturated hetero ring (where X, Y, Z, W, and U are each independently chosen from the groups C, CR8, and N), R2, R3, R4, and R5 are substituents on ring A, and R2, R3, R4, and R5 can independently be: absent, hydrogen, halogen, hydroxyl group, amino group, nitro group, carboxyl group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C1-C8 alkyl group, substituted or unsubstituted C2-C8 alkynyl group, C1-C8 alkoxy group, substituted or unsubstituted 3-8 membered cycloalkyl group, substituted or unsubstituted 4-8 membered heterocycloalkyl group, substituted or unsubstituted 5-8 membered aryl group, substituted or unsubstituted 5-8 membered heteroaryl group, and -COR 10 Selected from the group consisting of, Alternatively, any adjacent group in R2, R3, R4, and R5 may be linked to a substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 4-8 membered heterocycloalkyl group, a substituted or unsubstituted 5-8 membered aryl group, or a substituted or unsubstituted 5-8 membered heteroaryl group. R6 and R7 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C8 alkyl groups, C1-C8 alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, and cyano groups. R8 is selected from the group consisting of hydrogen, halogen, hydroxyl group, amino group, nitro group, carboxyl group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C1-C8 alkyl groups, C1-C8 alkoxy groups, substituted or unsubstituted 3- to 8-membered cycloalkyl groups, substituted or unsubstituted 4- to 8-membered heterocycloalkyl groups, substituted or unsubstituted 5- to 8-membered aryl groups, and substituted or unsubstituted 5- to 8-membered heteroaryl groups. R9 is a 5-membered unsaturated heterocyclic group. R 10 This is selected from the group consisting of an amino group, a 4-8 member heterocycloalkyl group, and a 4-8 member heterocycloalkyl group substituted with an amino group. The substituents of the alkyl group are selected from the group consisting of halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, guanidyl groups, quaternary ammonium salts, sulfonamide groups, and substituted or unsubstituted 4- to 8-membered heterocycloalkyl groups. The substituents of the alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are selected from the group consisting of C1-C8 alkyl groups, C1-C8 aliphatic amine groups, C1-C8 alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, guanidyl groups, and sulfonamide groups. The heteroatoms of the heterocycloalkyl group and heteroaryl group are N, O, or S, and the number of heteroatoms is 1, 2, 3, 4, or 5. One or more hydrogen atoms of the amino group may be further substituted with a C1-C8 alkyl group, a C1-C8 aliphatic amine group, or a sulfonamide group.

[0007] moreover, n is 0, 1, 2, 3, 4, or 5. R1 is selected from the group consisting of hydrogen, C1-C4 alkyl groups, C1-C4 alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, and SR9. Ring A is a 5-membered unsaturated hetero ring (where X is C, CR8, or N, Y is N, Z is C, CR8, or N, W is C or N, and U is C or N), R2, R3, R4, and R5 are substituents on ring A, and R2, R3, R4, and R5 can independently be: absent, hydrogen, halogen, hydroxyl group, amino group, nitro group, carboxyl group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C1-C4 alkyl group, substituted or unsubstituted C2-C4 alkynyl group, C1-C4 alkoxy group, substituted or unsubstituted 3-6 membered cycloalkyl group, substituted or unsubstituted 4-6 membered heterocycloalkyl group, substituted or unsubstituted 5-6 membered aryl group, substituted or unsubstituted 5-6 membered heteroaryl group, and -COR 10 Selected from the group consisting of, Alternatively, any adjacent group in R2, R3, R4, and R5 may be linked to a substituted or unsubstituted 3-6 membered cycloalkyl group, a substituted or unsubstituted 4-6 membered heterocycloalkyl group, a substituted or unsubstituted 5-6 membered aryl group, or a substituted or unsubstituted 5-6 membered heteroaryl group. R6 and R7 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl groups, C1-C4 alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, and cyano groups. R8 is selected from the group consisting of hydrogen, halogen, hydroxyl group, amino group, nitro group, carboxyl group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C1-C4 alkyl groups, C1-C4 alkoxy groups, substituted or unsubstituted 3-6 membered cycloalkyl groups, substituted or unsubstituted 4-6 membered heterocycloalkyl groups, substituted or unsubstituted 5-6 membered aryl groups, and substituted or unsubstituted 5-6 membered heteroaryl groups. R9 is a five-membered unsaturated heterocyclic group having one or more heteroatoms selected from the group consisting of N, O, and S. R 10 This is selected from the group consisting of an amino group, a 4-5 member heterocycloalkyl group, and a 4-5 member heterocycloalkyl group substituted with an amino group. The substituents of the alkyl group are selected from the group consisting of halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, guanidyl groups, quaternary ammonium salts, sulfonamide groups, and substituted or unsubstituted 4-6 membered heterocycloalkyl groups. The substituents of the alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are selected from the group consisting of C1-C4 alkyl groups, C1-C4 aliphatic amine groups, C1-C4 alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, guanidyl groups, and sulfonamide groups. The heteroatoms of the heterocycloalkyl group and heteroaryl group are N, O, or S, and the number of heteroatoms is 1 or 2. One or more hydrogen atoms of the amino group may be further substituted with a C1-C4 alkyl group, a C1-C4 aliphatic amine group, or a sulfonamide group.

[0008] Furthermore, R9 has a structure represented by the following formula. [ka]

[0009] Furthermore, R 10 The group is selected from the group consisting of an amino group, a 4- to 5-membered nitrogen-containing heterocycloalkyl group, and a 4- to 5-membered nitrogen-containing heterocycloalkyl group substituted with an amino group.

[0010] Furthermore, R 10 is an amino group, [ka] That is the case.

[0011] Furthermore, ring A is [ka] That is the case.

[0012] Furthermore, the compound is represented by formula (II). [ka] (In the formula, n, ring A, X, Y, Z, W, U, R1, R2, R3, R4, and R5 are defined as described above.)

[0013] Furthermore, the compound may be represented by formula (III), [ka] (In the formula, rings A, X, Y, Z, W, U, R1, R2, R3, R4, and R5 are defined as described above.) Alternatively, the compound may be represented by formula (IV). [ka] (In the formula, rings A, X, Y, Z, W, U, R2, R3, R4, and R5 are defined as described above.)

[0014] Furthermore, the compound is represented by formula (V). [ka] (In the formula, rings A, X, Y, Z, W, U, R2, R3, R4, and R5 are defined as described above.)

[0015] Furthermore, the compound may be represented by formula (VI-1), [ka] (In the formula, R3 and R4 are defined as described above.) Alternatively, the compound may be represented by formula (VI-2), [ka] (In the formula, R4 and R5 are defined as described above.) Alternatively, the compound may be represented by formula (VI-3), [ka] (In the formula, R2 and R4 are defined as described above.) Alternatively, the compound may be represented by formula (VI-4), [ka] (In the formula, R2, R3, and R4 are defined as described above.) Alternatively, the compound may be represented by formula (VI-5), [ka] (In the formula, R2, R4, and R5 are defined as described above.) Alternatively, the compound may be represented by formula (VI-6), [ka] (In the formula, R2, R3, R4, and R5 are defined as described above.) Alternatively, the compound may be represented by formula (VI-7), [ka] Alternatively, the compound may be represented by formula (VI-8). [ka] (In the formula, R2, R3, R4, and R5 are defined as above, R 81 , R 82each independently selected from the group consisting of hydrogen, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, amido group, quaternary ammonium salt, substituted or unsubstituted C1-C4 alkyl group, C1-C4 alkoxy group, substituted or unsubstituted 3- to 6-membered cycloalkyl group, substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, substituted or unsubstituted 5- to 6-membered aryl group, and substituted or unsubstituted 5- to 6-membered heteroaryl group, the substituent of said alkyl group is selected from the group consisting of halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, guanidinyl group, quaternary ammonium salt, and substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, the substituent of said cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group is selected from the group consisting of C1-C4 alkyl group, C1-C4 alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group and cyano group, the heteroatom in said heterocycloalkyl group and heteroaryl group is N, O or S, and the number of said heteroatoms is 1 or 2.)

[0016] furthermore, any adjacent groups in R2, R3, R4 and R5 are linked to form a substituted or unsubstituted phenyl group, tetrahydropyrrolyl group, pyridyl group or pyrimidine group.

[0017] furthermore, any adjacent groups in R2, R3, R4 and R5 are linked to form the following group and condensed with ring A.

Chemical Formula

[0018] Furthermore, the R 11 This is selected from the group consisting of hydrogen, sulfonamide groups, amide groups, C1-C4 aliphatic amine groups, C1-C4 alkyl groups, and C1-C4 alkoxy groups. Alternatively, R 11 It forms a guanidinyl group together with the N atom bonded to it.

[0019] Furthermore, the aforementioned compound is one of the following compounds. [ka] [ka] [ka] [ka] [ka]

[0020] The present invention further provides the use of the above-mentioned compounds, their salts, conformational isomers, or optical isomers in the production of inhibitors of metallo-β-lactamase and / or serine-β-lactamase.

[0021] According to the present invention, the use of the above-mentioned compound, its salt, its conformational isomer, or its optical isomer is provided in the production of an antimicrobial agent. Preferably, the antibacterial agent is a drug that acts against drug-resistant bacteria. More preferably, the drug that acts against the drug-resistant bacteria is a drug that acts against β-lactam antibiotic-resistant bacteria.

[0022] The present invention further provides pharmaceuticals which are formulations prepared by using the above-mentioned compound, or a salt thereof, its conformational isomer, or its optical isomer as an active ingredient, and adding pharmaceutically acceptable additives or auxiliary components.

[0023] According to the present invention, a pharmaceutical composition comprising the above-mentioned compound, or a salt thereof, a conformational isomer thereof, or an optical isomer thereof, and an antibiotic is further provided. Preferably, the antibiotic is a β-lactam antibiotic. More preferably, the antibiotic is meropenem.

[0024] The present invention further provides for the combined use of the above-mentioned compound, or a salt thereof, its conformational isomer, or its optical isomer, with an antibiotic in the production of an antimicrobial agent. Preferably, the antibacterial agent is a drug that acts against drug-resistant bacteria, and / or the antibiotic is a β-lactam antibiotic. More preferably, the drug acting against the drug-resistant bacteria is a drug acting against β-lactam antibiotic-resistant bacteria, and / or the antibiotic is one or more selected from the group consisting of meropenem, imipenem, and cefepime.

[0025] The metallo-β-lactamases include clinically relevant metallo-β-lactamases such as NDM-1, NDM-5, IMP-1, IMP-4, VIM-1, and VIM-2. The serine-β-lactamases include clinically relevant serine-β-lactamases such as KPC-2, TEM-1, SHV-12, CTX-M-14, AmpC, and OXA-48.

[0026] The compounds and derivatives in this invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Columbus, OH) naming system.

[0027] With regard to the definitions of terms used in this invention, unless otherwise specified, the initial definitions provided in a base or term herein apply to the base or term throughout the entire specification. Terms not specifically defined herein are to be understood by those skilled in the art based on the disclosure and context.

[0028] In this invention, the structure of the compound refers to a structure that can exist stably.

[0029] In this invention, "substitution" refers to a situation where a hydrogen atom in a molecule is replaced by another different atom or molecule.

[0030] In this invention, the minimum and maximum number of carbon atoms in a hydrocarbon group are represented by a prefix. For example, the prefix C a~b An alkyl group represents any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C 1~4 An alkyl group refers to an alkyl group containing 1 to 4 carbon atoms. 1~4 An "alkoxy group" refers to an alkoxy group that contains 1 to 4 carbon atoms.

[0031] In this invention, "alkyl group" refers to an aliphatic hydrocarbon group, that is, a saturated hydrocarbon group. The alkyl portion may be a linear alkyl group or a branched alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups.

[0032] In this invention, "halogen" refers to fluorine, chlorine, bromine, and iodine. In this invention, the term "amide group" includes formamide group, acetamide group, propionylamide group, and the like. In this invention, "quaternary ammonium salt" is, [ka] That is the case.

[0033] In this invention, "cycloalkyl group" refers to a saturated or partially saturated non-aromatic cyclic group having 3 to 8 carbon atoms, no ring-forming heteroatoms, and being monocyclic or polycyclic (including fused rings, crosslinking rings, and spiro rings). Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cyclooctyl groups. Examples of cycloalkyl groups including polydicycloalkyl ring systems include dicyclohexyl, dicyclopentyl, and dicyclooctyl groups. Below, [ka] dicyclohexyl group and [ka] We will use two types of dicycloalkyl polycyclic structures of the dicyclohexyl group as examples for naming.

[0034] In this invention, "heterocycloalkyl group" refers to a saturated or partially saturated non-aromatic cyclic group having a monocyclic or polycyclic (including fused rings, bridging rings, and spiro rings) containing at least one heteroatom. Here, a heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of heterocycloalkyl groups include: [ka] These are some examples.

[0035] In this invention, "aryl group" refers to an aromatic unsaturated group having 5 to 8 carbon atoms, no ring-forming heteroatoms, and being monocyclic or polycyclic (including fused rings, bridging rings, and spiro rings), such as a phenyl group, anthracene group, naphthyl group, [ka] This refers to...

[0036] In this invention, "heteroaryl group" refers to an aromatic unsaturated ring having a monocyclic or polycyclic (including fused rings, bridging rings, and spiro rings) containing at least one heteroatom. Here, a heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Examples include the furyl group, thienyl group, pyrrolyl group, pyridyl group, pyrazinyl group, pyrazolyl group, and indazolyl group, and further, [ka] These are some examples.

[0037] In this invention, an unsaturated heterocycle refers to a heterocycle containing at least one double bond, and may be a heteroaryl group or a heterocycloalkyl group.

[0038] In this invention, [ka] In a structure represented by , if n is 0, then the structure is [ka] Therefore, if n is 1, its structure is [ka] When n is 2, the structure is [ka] However, we can infer from this. In this invention, "salt" refers to a "pharmaceutically acceptable salt."

[0039] The present invention provides 7-((5-membered heterocyclic)methyl)-8-carboxylic acid-benzocyclic borate derivatives. These derivatives exhibit good broad-spectrum inhibitory activity against both commonly encountered metallo-β-lactamases (MBLs) and serine β-lactamases (SBLs), and are used to prepare antimicrobial agents, particularly those acting against drug-resistant bacteria, as inhibitors of MBLs and / or SBLs. Furthermore, when used in combination with β-lactamase antibiotics, these derivatives exhibit good antimicrobial activity against various β-lactam antibiotic-resistant bacteria. The derivatives possess great potential for the preparation of dual broad-spectrum antimicrobial inhibitors of MBLs and SBLs, as well as antimicrobial agents that overcome β-lactam antibiotic resistance. The present invention provides new options for the use of antimicrobial agents and is expected to have various applications in the future.

[0040] As described above, it is clear that, in accordance with the general technical knowledge and conventional means of the art, it is possible to make various other forms of modifications, substitutions, or changes without departing from the basic technical concept of the present invention.

[0041] The above-mentioned aspects of the present invention will be described in more detail below in illustrative form with reference to specific embodiments. However, this should not be understood as limiting the scope of the subject matter of the present invention to the following examples only. All technologies realized based on the above-mentioned aspects of the present invention fall within the scope of the present invention. [Modes for carrying out the invention]

[0042] The raw materials and apparatus used in the specific embodiments of the present invention are all known products and can be obtained by purchasing commercially available products.

[0043] 1. Synthesis of important intermediate a5 [ka]

[0044] Here, the abbreviations and chemical formula names of the related reagents are as follows: DIEA: N,N-diisopropylethylamine; NBS: N-bromosuccinimide; TFA: trifluoroacetic acid; TFAA: anhydrous trifluoroacetic acid; KOH: potassium hydroxide; DCM: dichloromethane; EtOH: ethanol; Acetone: acetone; DMF: N,N-dimethylformamide; AIBN: azobisisobutyronitrile; CCl4: carbon tetrachloride.

[0045] The specific synthesis method is as follows: A solution of NBS (7.12 g, 40 mmol, 1 eq) in DCM (340 mL) was added dropwise to a solution of starting material a1 (7.2 g, 40 mmol, 1 eq) and DIEA (600 μL, 4 mmol, 0.1 eq) in DCM (50 mL), and the mixture was maintained at a temperature of 0°C to 5°C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (PE / EA = 60:1-30:1, v / v) to obtain intermediate a2 (10.26 g, colorless oil) in 99% yield. 1 H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 4.46 (q, J= 7.1 Hz, 2H), 2.52 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H). ESI-MS: m / z calculation C 10 H 11 BrO3[M+H] + 259.0, measured values: 259.0 and 261.0.

[0046] Intermediate a2 (10.36 g, 40 mmol, 1 eq) was dissolved in a 250 mL round-bottom flask containing a mixed solvent of EtOH / H2O (3 / 2, v / v, 48 mL). KOH (8 M, 21.28 g, 380 mmol, 9.5 eq) was added in several batches, and the mixture was stirred at room temperature until the reaction mixture became clear. The reaction mixture was heated to 80 °C and refluxed for 4 hours. After confirmation of the completion of the reaction by TLC, the reaction mixture was cooled to room temperature, and the pH was adjusted to 3-4 with 2 N hydrochloric acid solution. Next, a large amount of white solid was precipitated, filtered, and the filter cake was washed with water, collected, and dried in a vacuum dryer to obtain intermediate a3 (8.69 g, white solid) in 94% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J = 8.1 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 2.47 (s, 3H).

[0047] Under ice bath conditions, intermediate a3 (6 g, 26 mmol, 1 eq) was dissolved in a 250 mL two-necked flask containing trifluoroacetic acid (36 mL) and DMF (26 mL). After three N2 substitutions, acetone (19.5 mL) and TFAA (26 mL) were slowly added dropwise. After the addition was complete, the reaction mixture was transferred to an oil bath (100 °C) and reacted overnight. After cooling the reaction mixture to room temperature, the pH was adjusted to 6-7 with saturated NaHCO3 and extracted with EA (60 mL x 3). The organic layers were combined, washed with saturated NaCl (60 mL x 2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 80:1-10:1, v / v) to obtain intermediate a4 (3.17 g, orange solid) in 45% yield. 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 2.64 (s, 3H), 1.75 (s, 6H).ESI-MS: C for m / z calculation 11 H 11 BrO3[M+H]+ 271.0, measured values: 271.0 and 273.0.

[0048] Intermediate a4 (8.14 g, 30 mmol, 1 eq), NBS (8.01 g, 45 mmol, 1.5 eq), and AIBN (8.14 g, 30 mmol, 1 eq) were placed in a reaction flask, dissolved in CCl4 (30 mL), and refluxed at 80°C for 4 hours. The mixture was concentrated under reduced pressure to remove CCl4, and purified by column chromatography (PE / EA = 300:1-170:1, v / v) to obtain the important intermediate a5 (8.28 g, pale yellow solid) in 80% yield. ESI-MS: m / z calculation C 11 H 10 Br2O3[M+H] + 348.9 Measured value: 348.9. [Examples]

[0049] Synthesis of target compounds 1, 2, and 13-26 The synthesis routes for target compounds 1, 2, and 13-26 are as follows. [ka]

[0050] Here, the abbreviations and chemical formula names of the related reagents are as follows: K2CO3: Potassium carbonate; DMF: N,N-dimethylformamide; pdCl2(dppf): [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride; Et3N: Triethylamine; dppe: 1,2-bis(triphenylphosphine)ethane; pinBH: Pinacolborane; [IrCl(COD)]2: 1,5-Cyclooctadiene iridium chloride; DCM: Dichloromethane; HCl: Hydrochloric acid; Dioxane: 1,4-Dioxane.

[0051] The synthesis and characterization of target compound 1 are as follows. [ka] Under nitrogen gas protection at 0°C, K2CO3 (5.74 mmol, 2.0 eq) was added to a solution of 2H-1,2,3-triazole (4.3 mmol, 1.5 eq) in DMF (10 ml), and a5 (2.87 mmol, 1.0 eq) in DMF (10 ml) was slowly added dropwise to the mixture. After the addition was complete, the mixture was left at room temperature and stirred overnight. After confirming the completion of the reaction by TLC, the reaction mixture was charged into water and extracted with ethyl acetate (20 ml x 3). The organic phase was combined, washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated. After silica gel column chromatography, the intermediate 5-((2H-1,2,3-triazole-2-yl)methyl)-8-bromo-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (a6, 423 mg, white solid) was obtained in 44% yield. ESI-MS: C for m / z calculation 13 H 13 BrN3O3[M+H]+ = 338.0, measured values: 338.0 and 340.1.

[0052] Intermediate a6 (1.18 mmol, 1.0 eq), potassium trifluoroethyleneborate (1.42 mmol, 1.2 eq), and Pd(dppf)2Cl2 (0.05 mmol, 0.04 eq) were dissolved in 20 ml of a mixed solvent of n-propanol and water (7:3, v / v). The mixture was purged with nitrogen gas at room temperature, Et3N (1.77 mmol, 1.5 eq) was added, and the reaction mixture was heated to 100°C. When the temperature reached 70°C, the orange multiphase reaction mixture changed to a pale amber color and became slightly cloudy. After confirmation of the completion of the reaction by TLC, the orange reaction mixture was cooled to 50°C, and water (20 mL) and ethyl acetate (20 ml) were added. The two-phase reaction mixture was cooled to room temperature, filtered, and washed with ethyl acetate (10 mL x 2). The organic layer was washed with water (60 mL), concentrated, and then purified by column chromatography to obtain 5-((2H-1,2,3-triazol-2-yl)methyl)-2,2-dimethyl-8-vinyl-4H-benzo[d][1,3]dioxin-4-one (a7, 274 mg, colorless oily compound) in 81% yield. ESI-MS: m / z calculation C 15 H16 N3O3[M+H]+ = 286.1, Measured value: 286.1.

[0053] Under nitrogen gas protection, a 10 mL solution of dichloromethane containing [IrCl(cod)]2 (0.02 mmol, 0.02 eq), dppe (0.04 mmol, 0.04 eq), pinacolborane (1.15 mmol, 1.2 eq), and a7 (0.96 mmol, 1 eq) was added to a two-necked flask and stirred at room temperature for 18 hours. After confirmation of reaction completion by TLC, the reaction mixture was concentrated and purified by column chromatography to obtain 5-(2H-1,2,3-triazole-2-yl)methyl)-2,2-dimethyl-8-(2-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)ethyl)-4Hbenzo[d][1,3]dioxin-4-one (a8, 290 mg) in 73% yield. ESI-MS: m / z calculation C 21 H 29 BN3O5[M+H] + = 414.2, Measured value: 414.2.

[0054] Intermediate a8 (0.70 mmol, 1 eq) was dissolved in 10 ml of 1,4-dioxane solution, 6NHCl (10 ml) was added, and the mixture was heated to 100°C and refluxed for 2 hours. After detecting the end of the reaction by TCL, the mixture was concentrated under reduced pressure under vacuum, and the residue was recrystallized to obtain target compound 1 (83 mg) in 43% yield. 1 H NMR (400 MHz, CD3OD) δ 7.78 - 7.65 (m, 3H), 7.17 (d, J = 7.8 Hz, 1H), 5.84 (s, 2H), 2.72 (t, J = 7.9 Hz, 2H), 1.07 (t, J= 7.9 Hz, 2H). ESI-MS: C for m / z calculation 12 H 13 BN3O4[M+H] + = 274.1, Measured value: 274.1.

[0055] The synthesis and characterization of target compound 2 are as follows. [ka] Under nitrogen gas protection at 0°C, K2CO3 (5.74 mmol, 2.0 eq) was added to a solution of 2H-1,2,3-triazole (4.3 mmol, 1.5 eq) in DMF (10 ml), and a5 (2.87 mmol, 1.0 eq) in DMF (10 ml) was slowly added dropwise to the mixture. After the addition was complete, the mixture was left at room temperature and stirred overnight. After confirmation of the completion of the reaction by TLC, the reaction mixture was charged into water and extracted with ethyl acetate (20 ml x 3). The organic phase was combined, washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography to obtain 5-((1H-1,2,3-triazole-1-yl)methyl)-8-bromo-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (507 mg, white solid) in 52% yield. ESI-MS: C for m / z calculation 13 H 13 BrN3O3[M+H]+ = 338.0, measured values: 338.0 and 340.1. The remaining three steps of synthesis were carried out in the same manner as for target compound 1. The total yield of the three steps was 19%. 1 H NMR (400 MHz, CD3OD) δ 7.76 - 7.64 (m, 3H), 7.13 (d, J = 7.4 Hz, 1H), 5.85 (s, 2H), 2.70 (t, J = 7.8 Hz, 2H), 1.05 (t, J= 7.9 Hz, 2H). ESI-MS: C for m / z calculation 12 H 13 BN3O4[M+H] + = 274.1, Measured value: 274.0.

[0056] The synthesis and characterization of target compound 13 are as follows. [ka] Under nitrogen gas protection at 0°C, K2CO3 (3.0 mmol, 2.0 eq) was added to a solution of 4H-1,2,4-triazole (2.25 mmol, 1.5 eq) in DMF (10 ml), and a solution of a5 (1.5 mmol, 1.0 eq) in DMF (10 ml) was slowly added dropwise to the mixture. After the addition was complete, the mixture was left at room temperature and stirred overnight. After confirming the completion of the reaction by TLC, the reaction mixture was charged into water and extracted with ethyl acetate (20 ml x 3). The organic phase was combined, washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography to obtain 5-((1H-1,2,4-triazole-1-yl)methyl)-8-bromo-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (a6, 362 mg, white solid) in 71% yield. ESI-MS: C for m / z calculation 13 H 13 BrN3O3[M+H]+ = 338.0, measured values: 338.0 and 340.1. The remaining three steps of synthesis were carried out in the same manner as for target compound 1. The total yield of the three steps was 11%. 1 H NMR (400 MHz, CD3OD) δ 7.72 (d, J = 1.4 Hz, 2H), 7.12 - 6.90 (m, 2H), 6.09 (s, 2H), 2.64 (t, J = 7.2 Hz, 2H), 0.65 (t, J = 7.2 Hz, 2H). ESI-MS: m / z calculation in C 12 H 13 BN3O4[M+H] + = 274.1, Measured value: 274.1.

[0057] Synthesis and characterization of target compound 14: [ka] The synthesis method was the same as that for target compound 1, except that 1H-pyrazole was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 16%. 1H NMR (400 MHz, CD3OD) δ 7.65-7.35 (m, 2H), 7.26 - 7.15 (m, 2H), 6.91 (m, 1H), 6.09 (s, 2H), 2.63 (t, J = 7.6 Hz, 2H), 1.02 (t, J = 7.6 Hz, 2H). ESI-MS: m / z calculation C 13 H 13 BN2O4[M+H] + = 273.1, Measured value: 273.1.

[0058] Synthesis and characterization of target compound 15: [ka] The synthesis method was the same as that for target compound 1, except that 4-fluoro-1H-pyrazole was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 21%. 1 H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 4.5 Hz, 1H), 7.40 (d, J = 4.1 Hz, 1H), 7.18 (dd, J = 16.4, 7.6 Hz, 1H), 5.43 (s, 2H), 2.73 (t, J = 7.9 Hz, 2H), 1.08 (t, J = 7.9 Hz, 2H). ESI-MS: m / z calculation C 13 H 13 BFN2O4[M+H] + = 291.1, Measured value: 291.2.

[0059] Synthesis and characterization of target compound 16: [ka] The synthesis method was the same as that for target compound 1, except that 4-(trifluoromethyl)-1H-pyrazole was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 17%. 1H NMR (400 MHz, CD3OD) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.23 (d, J = 7.7 Hz, 1H), 6.53 (br s, 1H), 5.56 (s, 2H), 2.74 (t, J = 7.9 Hz, 2H), 1.08 (t, J = 7.9 Hz, 2H). ESI-MS: m / z calculation C 14 H 12 BFN2O4[M+H] + 341.1, Measured value: 341.2; [M+Na] + 363.1, Measured value: 363.2.

[0060] Synthesis and characterization of target compound 17: [ka] The synthesis method was the same as that for target compound 1, except that 4-cyanopyrazole was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 19%. 1 H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.75 (s, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.55 (m, 1H), 5.58 (s, 2H), 2.72 (t, J = 7.8 Hz, 2H), 1.06 (t, J = 7.8 Hz, 2H). ESI-MS: m / z calculation C 14 H 12 BN3O4[M+H] + 298.1, Measured value: 298.1.

[0061] Synthesis and characterization of target compound 18: [ka] The synthesis method was the same as that for target compound 1, except that 3-cyanopyrazole was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 18%. 1H NMR (400 MHz, CD3OD) δ 7.82-7.77 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 6.52 (m, 1H), 5.58 (s, 2H), 2.74 (t, J = 7.8 Hz, 2H), 1.08 (t, J= 7.8 Hz, 2H). ESI-MS: m / z calculation C 14 H 12 BN3O4[M+H] + 298.1, Measured value: 298.1.

[0062] Synthesis and characterization of target compound 19: [ka] The synthesis method was the same as that for target compound 1, except that 1H-pyrazole-4-formamide was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 15%. 1 H NMR (400 MHz, CD3OD) δ 8.83 (s, 1H), 7.82 (s, 1H), 7.79 (s br, 2H), 7.26 (d, J = 7.8 Hz, 1H), 6.56 (s br, 1H), 5.56 (s, 2H), 2.74 (t, J = 7.9 Hz, 2H), 1.08 (t, J = 7.9 Hz, 2H). ESI-MS: m / z calculation C 14 H 14 BN3O5[M+H] + 316.1, Measured value: 316.1.

[0063] Synthesis and characterization of target compound 20: [ka] The synthesis method was the same as that for target compound 1, except that 1H-pyrazole-3-formamide was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 16%. 1H NMR (400 MHz, CD3OD) δ 8.22 (s, 2H), 7.83 (m, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.96-6.88 (m, 2H), 5.56 (s, 2H), 2.76 (t, J = 7.8 Hz, 2H), 1.09 (t, J = 7.8 Hz, 2H). ESI-MS: m / z calculation C 14 H 14 BN3O5[M+H] + 316.1, Measured value: 316.1.

[0064] Synthesis and characterization of target compound 21: [ka] The synthesis method was the same as that for target compound 1, except that 4-(Boc-aminomethyl)pyrazole was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 16%. 1 H NMR (400 MHz, CD3OD) δ 7.77 (d, J= 9.9 Hz, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 5.53 (s, 2H), 4.03 (s, 2H), 2.72 (t, J = 7.9 Hz, 2H), 1.06 (t, J= 7.9 Hz, 2H). ESI-MS: C for m / z calculation 14 H 16 BN3O4[M+H] + 302.1, Measured value: 302.1.

[0065] Synthesis and characterization of target compound 22: [ka] The synthesis method was the same as that for target compound 1, except that 1H-indazole was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 17%. 1H NMR (400 MHz, CD3OD)δ 8.08 (d, J = 1.0 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.43 - 7.45 (m, 1H), 7.35 -7.39 (m, 1H), 7.15 - 7.19 (m, 1H), 7.05 (d, J = 7.9 Hz, 1H), 5.81 (s, 2H), 2.69 (t, J = 7.9 Hz, 2H), 1.05 (t, J = 7.9 Hz, 2H). ESI-MS: m / z calculated for C 17 H 15 BN2O4[M+H] + 323.1, found: 323.4; [M+Na] + 345.1, found: 345.1.

[0066] Synthesis and characterization of target compound 23:

Chemical Structure

[0067] Synthesis and characterization of target compound 24:

Chemical Structure

[0068] Synthesis and characterization of target compound 25:

Chemical Structure

[0069] Synthesis and characterization of target compound 26:

Chemical Structure

[0070] Synthesis of target compound 3 Synthesis and characterization of target compound 3: [ka]

[0071] a8 (0.44 mmol, 1.0 eq) and iodomethane (CH3I, 0.44 mmol) were added to a 25 mL capped tube and stirred at 80°C for 24 hours. After confirmation of reaction completion by TLC, the reaction mixture was concentrated to obtain crude product a9. ESI-MS: m / z calculation C 22 H 31 BN3O5[M] + = 428.2, Measured value: 428.2.

[0072] The obtained crude product a9 was dissolved in 5 mL of 1,4-dioxane solution, 5 mL of 6N HCl was added, and the mixture was heated to 100°C and refluxed for 2 hours. After confirmation of the completion of the reaction by TLC, the mixture was concentrated under vacuum and reduced pressure, and the target compound 3 (26 mg) was obtained in 21% yield by preparative liquid-phase chromatography. 1H NMR (400 MHz, CD3OD) δ 7.83-7.71 (m, 3H), 7.23 (d, J = 7.8 Hz, 1H), 5.88 (s, 2H), 4.12 (s, 3H), 2.73 (t, J = 7.8 Hz, 2H), 1.08 (t, J = 7.8 Hz, 2H). ESI-MS: m / z calcd for C 13 H 15 BN3O4[M] + = 288.1, found: 288.2. [Examples]

[0073] Synthesis of target compounds 4 to 12 The synthetic route of target compounds 4 to 12 is as follows. [Chemical Formula] Herein, the abbreviations and chemical formulas of the related reagents are the same as those described above, and the rest are as follows. NaN3: sodium azide; t-BuOH: tert-butanol; CuSO4: copper(II) sulfate.

[0074] Synthesis of intermediate a10: At 0°C, NaN3 (260 mg, 4 mmol) was added into a mixed solution of intermediate a5 (696 mg, 2 mmol) in acetone (21 mL) and water (7 mL), and the reaction was allowed to proceed at room temperature for 1 hour. After the completion of the reaction was observed by TLC, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, and distilled under reduced pressure to obtain intermediate a10 (pale yellow solid, 620 mg, 1.98 mmol) in a yield of 99%. MS calcd for (C 19 H 23 BrN4O5): 310.0, 313.0; MS (ESI, positive) found: (M-N2+H + ): 287.0, 289.0.

[0075] Synthesis and characterization of target compound 4: [Chemical Formula] Intermediate a10 (542 mg, 1.74 mmol), 1-pentyl (324 mg, 1.91 mmol), anhydrous CuSO4 (27.7 mg, 0.174 mmol), and sodium ascorbate (172 mg, 0.87 mmol) were dissolved in a mixed solvent of tert-butanol (12 ml) and water (12 ml) and reacted overnight at room temperature. After confirmation of reaction completion by TLC, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound a11 (501 mg, 1.32 mmol) in 76% yield. MS calculation (C 16 H 18 BrN3O3): 379.1, 381.1; MS (ESI, positive) Measurement value: (M+ H + ): 380.1, 382.1.

[0076] Intermediate a11 (400 mg, 1.06 mmol), potassium trifluoroethyleneborate (171 mg, 1.27 mmol), and Pd(dppf)Cl2 (31 mg, 0.042 mmol) were dissolved in a mixed solvent of n-propanol (12.5 ml) and water (5 ml). Et3N (0.24 ml, 1.59 mmol) was added under a nitrogen atmosphere, and the mixture was reacted at 100°C for 5 hours. After confirmation of reaction completion by TLC, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was combined, washed with saturated NaCl, dried over anhydrous Na2SO4, and the solvent was removed by reduced-pressure evaporation under vacuum. The mixture was then purified by silica gel chromatography to obtain intermediate a12 (316 mg, 0.97 mmol) in 91% yield. MS calculation (C 18 H 21 N3O3): 327.2; MS (ESI, positive) Measurement value: (M+ H + ): 328.2.

[0077] Intermediate a12 (316 mg, 0.97 mmol), PinBH (0.18 ml, 1.16 mmol), dppe (23.2 mg, 0.066 mmol), and [IrCl(COD)]2 (19.5 mg, 0.029 mmol) were dissolved in anhydrous dichloromethane (5.2 ml) and reacted at room temperature under a nitrogen atmosphere for 16 hours. After confirmation of reaction completion by TLC, the reaction mixture was concentrated under reduced pressure, and intermediate a13 (356 mg, 0.78 mmol) was obtained in 81% yield after silica gel column chromatography. MS calculation (C 24 H 34 BN3O5): 455.3; MS (ESI, positive) Measurement value: (M+ H + ): 456.3.

[0078] 6NHCl (4 ml) was added to a dioxane solution (4 ml) of intermediate a13 (149 mg, 0.33 mmol), and the mixture was heated to 100°C and refluxed for 2 hours. After confirmation of the completion of the reaction by TLC, the reaction mixture was concentrated under vacuum and reduced pressure, and the residue was recrystallized to obtain the target compound 4 (45 mg, 0.14 mmol) in 43% yield. 1 H NMR (600 MHz, CD3OD) δ 7.83-6.87 (m, 2H), 6.42-5.73 (m, 3H), 2.61 (qm, 4H), 1.79 -1.22 (m, 3H), 0.93 (t, J = 9.1 Hz, 3H). MS calculation (C 15 H 18 BN3O4): 315.1; MS (ESI, positive) Measurement value: (M+ H + ): 316.1.

[0079] Synthesis and characterization of target compound 5: [ka] The synthesis method was the same as that for target compound 4, except that 1-(propyl-2-alkynyl-1-yl)pyrrolidine was used instead of 1-pentyl. The total yield for the five steps was 22%. 1H NMR (600 MHz, CD3OD) δ 7.81 - 6.89 (m, 2H), 6.40 -6.33 (m, 1H), 5.84 (s, 2H), 2.72 (t, J = 7.8 Hz, 2H), 2.60-2.45 (m, 4H), 1.71- 1.49 (m, 4H), 0.98 (t, J = 7.8 Hz, 2H). (C 17 H 21 BN4O4): 356.2; MS (ESI, positive) Measurement value: (M+ H + ): 356.2.

[0080] Synthesis and characterization of target compound 6: [ka] The synthesis method was the same as that for target compound 4, except that hexinenitrile was used instead of 1-pentyl nitrile. The total yield for the five steps was 20%. 1 H NMR (600 MHz, CD3OD) δ 7.76 (s, 1H), 7.28- 6.92 (m, 2H), 5.87 (s, 2H), 2.73 (t, J = 7.8 Hz, 2H), 2.52-2.46 (m, 2H), 1.99- 1.78 (m, 4H), 0.98 (t, J = 7.8 Hz, 2H). MS calculation (C 16 H 17 BN4O4): 341.1; MS (ESI, positive) Measurement value: (M+ H + ): 341.1.

[0081] Synthesis and characterization of target compound 7: [ka] The synthesis method was the same as that for target compound 4, except that N-Boc-aminopropion was used instead of 1-pentyl. The total yield for the five steps was 11%. 1H NMR (400 MHz, CD3OD) δ 8.17-7.76 (m, 1H), 7.27 (m, 1H), 6.86 - 6.45 (m, 1H), 6.20-5.68 (m, 2H), 4.30-4.15 (m, 2H), 2.93-2.57(m ,2H), 1.27-0.91(m, 2H);MS (ESI, positive) Measured value:(M+ H + ): 303.1.

[0082] Synthesis and characterization of target compound 8: [ka] The synthesis method was the same as that for target compound 4, except that N-Boc-butylene-1-amine was used instead of 1-pentyl. The total yield for the five steps was 9%. 1 H NMR (400 MHz, CD3OD) δ 7.84 (s, 1H), 7.27 (d, J = 7.6 Hz, 1H), 6.87-6.67 (m, 1H), 5.76 (m, 2H), 3.28-3.22 (m, 2H), 3.10-3.03 (m, 2H), 2.92-2.57 (m, 2H), 1.28-0.90 (m, 2H). MS calculation (C 14 H 18 N4O4 + ): 317.1; MS (ESI, positive) Measured value: (M): 317.1.

[0083] Synthesis and characterization of target compound 9: [ka] The synthesis method was the same as that for target compound 4, except that N-Boc-pentin-1-amine was used instead of 1-pentyl. The total yield for the five steps was 9%. 1H NMR (400 MHz, CD3OD) δ 8.23-7.81 (m, 1H), 7.31 (m, 1H), 6.92-6.56 (m, 1H), 6.20-5.68 (m, 2H), 3.08-2.58 (m, 6H), 2.17-1.92 (m, 2H), 1.23-0.89 (m, 2H). MS: m / z calcd. for C 15 H 20 BN4O4 + [M] 331.2, found: 331.2.

[0084] Synthesis and characterization of target compound 10:

化

[0085] Compound a14 (1.05 g, 5.0 mmol) and a15 (528 mg, 5.0 mmol) were dissolved in a DMF solution (2.5 ml), Et3N (1.4 ml, 10.0 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction was observed by TLC, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layers were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain alkynyl intermediate a16 (433 mg, 2.05 mmol, 41%). MS calcd. for (C 10 H 17 N3O2): 211.1, MS (ESI, positive) found: (M+H + ): 212.1.

[0086] The procedure was the same as the specific synthesis method for target compound 4, except that intermediate a16 synthesized in place of 1-pentyl was used. The overall yield over five steps was 8%. 1H NMR (400 MHz, CD3OD) δ 7.89-7.71 (m, 1H), 7.41-7.14 (m, 1H), 6.79-6.44 (m, 1H), 6.10-5.67 (m, 2H), 3.28-3.20 (m, 2H), 3.12-3.02 (m, 2H), 2.91-2.53 (m, 2H), 1.24-0.91 (m, 2H). MS calculation (C 15 H 19 BN6O4 + ): 359.2; MS (ESI, positive) Measurement value: (M+ H + ): 359.2.

[0087] Synthesis and characterization of target compound 11: [ka] The synthesis method was the same as that for target compound 4, except that 1-(Boc-amino)-4-ethynylcyclohexane was used instead of 1-pentyl. The total yield for the five steps was 19%. 1 H NMR (400 MHz, CD3OD) δ 8.21 - 8.00 (m, 1H), 7.40 - 7.20 (m, 1H), 6.91 - 6.54 (m, 1H), 6.18 - 5.76 (m, 2H), 3.26 - 3.10 (m, 1H), 2.99 - 2.59 (m, 3H), 2.20 (m, 4H), 1.69 - 1.51 (m, 4H), 1.24-0.91 (m, 2H). MS calculation (C 18 H 24 BN4O4 + ): 331.2; MS (ESI, positive) Measured value: (M+ H + ): 331.2.

[0088] Synthesis and characterization of target compound 12: [ka] The synthesis method was the same as that for target compound 4, except that phenylacetylene was used instead of 1-pentyl. The total yield for the five steps was 21%. 1 H NMR (400 MHz, CD3OD) δ 7.91 - 7.79 (m, 3H), 7.62 - 7.50 (m, 3H), 7.28 (d, J = 7.8 Hz, 1H), 6.87 - 6.79 (m, 1H), 5.88 (s, 2H), 2.78 (t, J= 7.8 Hz, 2H), 1.08 (t, J= 7.8 Hz, 2H). MS calculation (C 18 H 16 BN3O4 + ): 350.1; MS (ESI, positive) Measured value: (M+ H + ): 350.1. [Examples]

[0089] Synthesis of target compounds 27-28 Synthesis and characterization of target compound 27: [ka]

[0090] Here, the abbreviations and chemical formula names of the related reagents are as follows: Pd(Oac)2: Palladium acetate; P(o-toly)3: Tri(o-toluene)phosphine; CHCl3: Trichloromethane; TEA: Triethylamine; DMF: N,N-dimethylformamide; B2(+)pinanediol)2: Bis[(+)-pinanediol]; TFA: Trifluoroacetic acid; TES: Triethylsilane; pdCl2(dppf): [1,1-Bis(diphenylphosphine)ferrocene]palladium chloride; KOAc: Potassium acetate; Dioxane: 1,4-Dioxane; Et2Zn: Diethylzinc; CH2I2: Diiodomethane; DCM: Dichloromethane; NaOH: Sodium hydroxide; TFA: Trifluoroacetic acid; TES: Triethylsilane; i-BuB(OH)2: Isobutylboric acid.

[0091] At room temperature, intermediate a17 (1.35 g, 4 mmol, 1 eq), acrylic acid (864 mg, 12 mmol, 3 eq), Pd(OAC)2 (179 mg, 0.8 mmol, 0.2 eq), P(o-toly)3 (486 mg, 1.6 mmol, 0.4 eq), and Et3N (1.67 ml, 12 mmol, 3 eq) were dissolved in DMF solution (150 ml), and N2 substitution was performed three times. Subsequently, the mixture was transferred to an oil bath at 100 °C and reacted for 16 hours. After cooling the reaction mixture to room temperature, the pH was adjusted to 6-7 with 2N hydrochloric acid solution, and the mixture was extracted with EA (40 mL x 3). The organic layers were combined, washed with saturated NaCl (50 mL x 2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 200:1-50:1, v / v) to obtain a18 (792 mg, brown solid) in 60% yield. ESI-MS: m / z calculation C 16 H 15 N3O5[MH] + 328.1, Measured value: 328.1.

[0092] Intermediate a18 (658 mg, 2 mmol, 1 eq) was dissolved in CHCl3 solution (3 mL), pre-cooled in an ice bath at 0°C for 5 minutes, and then Br2 (118 μL, 2.3 mmol, 1.15 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred continuously at room temperature for 2 hours and concentrated under reduced pressure to obtain a yellow solid, which was used directly in the next step.

[0093] The solid obtained by concentration under reduced pressure was dissolved in DMF solution (2 mL), pre-cooled in an ice bath at 0°C for 5 minutes, and then Et3N (556 μL, 4 mmol, 2 eq) was slowly added dropwise. After the addition was complete, the ice bath was removed and the mixture was stirred overnight. After the starting materials had completely reacted, the reaction solution was washed with HCl (0.2 N, 50 mL) and H2O (30 mL) and extracted with EA (40 mL × 3). The organic layers were combined, washed with saturated NaCl (40 mL × 2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and then purified by column chromatography (PE / EA = 10:1-4:1, v / v) to obtain intermediate a20 (473 mg, pale yellow solid). 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.2 Hz, 1H), 7.73 (s, 2H), 7.12 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.20 (s, 2H), 6.15 (d, J = 8.4 Hz, 1H), 1.76 (s, 6H).

[0094] Intermediate a20 (546 mg, 1.5 mmol, 1.0 eq), bis(1S,2S,3R,5S)(+)-pinanediol diboronate (823 mg, 2.3 mmol, 1.5 eq), PdCl2(dppf) (110 mg, 0.15 mmol, 0.1 eq), and KOAc (294 mg, 3 mmol, 2 eq) were dissolved in 1,4-dioxane solution (5 mL) at room temperature, and N2 substitution was performed three times. Subsequently, the mixture was heated to 60°C and reacted for 2 hours. Insoluble substances were removed by filtration through diatomaceous earth. The filtration cake was washed with EA, the filtrate was combined, and extracted with EA (30 mL x 2). The organic layers were combined, washed with saturated NaCl (30 mL x 2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 10:1-4:1, v / v) to obtain intermediate a21 (312 mg, colorless oil) in 45% yield. ESI-MS: m / z calculation C 25 H 30 BN3O5[M+H] + 464.2, Measured value: 464.2.

[0095] Super-dehydrated DCM (10 ml) and Et2Zn (8 ml, 1 M hexane solution, 8 mmol, 8.0 eq) were added to a 50 ml two-necked lasso that had been substituted with N2 three times, and the mixture was transferred to a cold trap at -78°C and stirred for 20 minutes. CH2I2 (967 L, 12 mmol, 12 eq) was slowly added dropwise, and a white solid precipitate was observed when about half of the mixture had been added. After the addition was complete, stirring was continued for 30 minutes. Subsequently, intermediate a21 (463 mg, 1 mmol, 1 eq) was dissolved in super-dehydrated DCM (2 mL) and slowly added dropwise to the reaction solution. The mixture was gradually heated to room temperature and stirred overnight. After the completion of the reaction was observed by TLC, the reaction solution was quenched with saturated NH4Cl solution (40 mL) and extracted with EA (40 mL x 3). The organic layers were combined, washed with saturated NaCl (40 mL x 2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (PE / EA (8:1-4:1, v / v)) to obtain intermediate a22 (248 mg, yellow oily substance) in 52% yield. ESI-MS: m / z calculation C 26 H 32 BN3O5[M+H] + 478.3, Measured value: 478.3; [M+Na] + 500.2, Measured value: 500.3.

[0096] Intermediate a22 (248 mg, 0.52 mmol, 1 eq) was dissolved in 1,4-dioxane solution (3 mL), 3NNaOH solution (3 mL) was added, and the mixture was stirred at room temperature for 2 hours. Subsequently, the reaction solution was transferred to an ice bath, and TES (300 mg), TFA (5 mL), and i-BuB(OH)2 (150 mg) were added sequentially. The resulting pale yellow reaction solution was stirred at room temperature for 2 hours. After confirmation of the completion of the reaction by TLC, the solution was purified by column chromatography (DCM / MeOH, 50:1-10:1, v / v) to obtain the target compound 27 (120 mg, white solid) in 28% yield. 1 1H NMR (400 MHz, CD3OD) )δ 7.57 (s, 2H), 6.88 (d, J = 7.7 Hz, 1H), 5.95 (d, J= 7.8 Hz, 1H), 5.72 (d, J = 15.7 Hz, 1H), 5.62 (d, J = 15.3 Hz, 1H), 1.67 (td, J = 8.4, 3.7 Hz, 1H), 0.70 - 0.75 (m, 1H), 0.31 - 0.34 (m, 1H), 0.18 - 0.25 (m, 1H). ESI-MS: C for m / z calculation 13 H 12 BN3O4[M+H] + 286.1, Measured value: 286.1; [M+Na] + 308.1, Measured value: 308.1.

[0097] Synthesis and characterization of target compound 28: [ka] According to the synthesis method for compound 27 described above, compound 28 (82 mg, white solid) was finally obtained using 5-(1H-1,2,3-triazol-1-yl)methyl)-8-bromo-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one as a starting material. 1 H NMR (400 MHz, CD3OD) δ 7.97 (br s, 1H), 7.63 (br s, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.37 (d, J = 7.7 Hz, 1H), 5.69 (d, J = 14.6 Hz, 1H), 5.52 (d, J = 14.5 Hz, 1H), 1.72 - 1.77 (m, 1H), 0.78 (ddd, J = 10.3, 8.0, 2.6 Hz, 1H), 0.38 - 0.41 (m, 1H), 0.27 - 0.33 (m, 1H). ESI-MS: C for m / z calculation 13 H 12 BN3O4[M+H] + 286.1, Measured value: 286.1; [M+Na] +308.1, Measured value: 308.1. [Examples]

[0098] Synthesis of target compound 29 Synthesis and characterization of target compound 29: [ka]

[0099] Here, the abbreviations and chemical formula names of the related reagents are as follows: Zn: Zinc powder; DIBAL-H: Diisobutylaluminum hydride; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium; THF: Tetrahydrofuran; n-BuLi: n-butyllithium; DCM: Dichloromethane; MeMgBr: Magnesium methylbromide; NaOH: Sodium hydroxide; Dioxane: 1,4-Dioxane; TFA: Trifluoroacetic acid; TES: Triethylsilane; i-BuB(OH)2: Isobutylboric acid.

[0100] At room temperature, zinc powder (Zn, 2.4 g, 75 mmol) and a24 (50 mg, 0.37 mmol) were added to super-dehydrated THF (15 mL), then DIBAL-H (0.5 mL, 0.75 mmol, dissolved in 1.5 M toluene) was added and the mixture was stirred for 5 minutes. The remaining compound a24 (4.05 g, 15 mmol) was dissolved in super-dehydrated THF (15 mL) and slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was heated to 50°C, stirred for 1 hour, and then cooled to room temperature. Under the protection of nitrogen gas, the supernatant was added to a reaction mixture of intermediate a23 (3.87 g, 11.6 mmol) and Pd(t-Bu3P)2 (176 mg, 0.344 mmol) in super-dehydrated THF (50 mL). The mixture was stirred at room temperature for 1 hour to concentrate the reaction mixture, and then purified by column chromatography (PE / EA, 8:1-4:1, v / v) to obtain a yellow oily substance a25 (2.35 g) in 45% yield. ESI-MS: m / z calculation C 24 H 30 BN3O5[M+H] + 353.2, Measured value: 352.2.

[0101] Under the protection of nitrogen gas, a25 (2.34 g, 5.18 mmol) and chloroiodomethane (0.49 mL, 6.73 mmol) dissolved in super-dehydrated THF (20 mL) were added to a 50 mL two-necked flask. After pre-cooling at -100°C (ethanol / liquid nitrogen system) for 20 minutes, a solution of n-butyllithium in n-hexane (2.7 mL, 6.73 mmol, 2.5 M) was slowly added dropwise along the flask wall and continued for 30 minutes. During this process, the reaction solution was observed to gradually change to yellow, and then to a pale yellow. After the dropwise addition was complete, the mixture was stirred at -100°C for 30 minutes. A solution of anhydrous zinc chloride in tetrahydrofuran (5.2 mL, 5.2 mmol, 1 M) was added dropwise along the flask wall over 30 minutes. After the dropwise addition was complete, the reaction was continued at -100°C for 30 minutes. Subsequently, the mixture was gradually heated to room temperature and allowed to react overnight. After confirming the completion of the reaction by TLC, the sample was washed with saturated NaCl (40 mL x 2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography PE / EA (8:1-4:1, v / v) to obtain a yellow oily substance a26 (1.08 g) in 41% yield. ESI-MS: m / z calculation C 25 H 31 BClN3O5[M+H] + 500.1, Measured value: 500.1.

[0102] At -78°C, magnesium methylbromide (1.03 mL, 3.1 mmol, 3M THF solution) was slowly added dropwise to a super-dehydrated THF solution of compound a26 (1.03 g, 2.06 mmol) (10 mL). The reaction mixture was gradually heated to room temperature and stirred for 18 hours. After confirmation of reaction completion by TLC, the reaction mixture was quenched with saturated NH4Cl solution (40 mL) and extracted with EA (40 mL x 3). The organic layers were combined, washed with saturated NaCl (40 mL x 2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography to obtain a yellow oily substance a27 (454 mg) in 46% yield. ESI-MS: m / z calculation C 26 H 34 BClN3O5[M+H] +480.2, Measured value: 480.2.

[0103] Intermediate a27 (249 mg, 0.52 mmol) was dissolved in 1,4-dioxane (3 mL), and 3NNaOH solution (3 mL) was added, followed by stirring at room temperature for 2 hours. Subsequently, the reaction solution was transferred to an ice bath, and TES (300 mg), TFA (5 mL), and i-BuB(OH)2 (150 mg) were added sequentially. The resulting pale yellow reaction solution was stirred at room temperature for 2 hours. After confirmation of the completion of the reaction by TLC, the solution was purified by column chromatography DCM / MeOH (50:1-10:1, v / v) to obtain the target compound 29 (49 mg) as a white solid in 33% yield. 1 H NMR (400 MHz, CD3OD) δ 7.96 (br s, 1H), 7.68 (s, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H), 5.67(d, J = 14.6 Hz, 1H), 5.56 (d, J = 14.5 Hz, 1H), 2.53-2.45 (m, 2H), 2.01-1.98 (m, 1H), 0.98 (d, J = 7.2 Hz, 2H). ESI-MS: C for m / z calculation 13 H 14 BN3O4[M+H] + 288.1, Measured value: 288.1. [Examples]

[0104] Synthesis of target compound 30 Synthesis and characterization of target compound 30: [ka] Here, the abbreviations and chemical formula names of the related reagents are as follows: MeOH: methanol; K2CO3: potassium carbonate; DMF: N,N-dimethylformamide; NaOH: sodium hydroxide; Dioxane: 1,4-dioxane; TFA: trifluoroacetic acid; TES: triethylsilane; i-BuB(OH)2: isobutylboric acid.

[0105] At room temperature, MeOH (61 μL, 1.5 mmol) and K2CO3 (552 mg, 4 mmol) were sequentially added to a solution of intermediate a26 (500 mg, 1.0 mmol) in DMF (6 mL). The reaction solution was heated to 50°C and stirred for 1 hour. After confirmation of reaction completion by TLC, the reaction solution was quenched with saturated NH4Cl solution (40 mL) and extracted with EA (40 mL × 3). The organic layers were combined, washed with saturated NaCl (40 mL × 2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography PE / EA (8:1-4:1) to obtain compound a28 (345 mg) in 70% yield. ESI-MS: m / z calculation C 26 H 34 BN3O6[M+H] + 496.2, Measured value: 496.2.

[0106] Using compound a28, the target compound 30 (66 mg, white solid) was synthesized in 36% yield according to the synthesis method of compound 29. ESI-MS: m / z calculation C 13 H 14 BN3O5[M+H] + 304.1, Measured value: 304.1. [Examples]

[0107] Synthesis of target compounds 31-75 Synthesis and characterization of target compound 31: The synthesis method was the same as that for target compound 1, except that 4-nitro-1H-pyrazole was used instead of 2H-1,2,3-triazole. The total yield for the four steps was 12%. 1 H NMR (400 MHz, CD3OD): δ 8.52 - 8.39 (m, 1H), 8.18 - 8.05 (m, 1H), 7.30 - 7.20 (m, 1H), 6.73 - 6.35 (m, 1H), 5.86 - 5.46 (m, 2H), 2.90 - 2.56 (m, 2H), 1.11-0.63 (m, 2H).

[0108] Synthesis and characterization of target compound 32: [ka] Compound 32a (10 mmol, 830 mg) was dissolved in tetrahydrofuran (THF, 30 mL), di-tert-butyl dicarbonate (11 mmol, 2.4 g) was added, and then saturated sodium bicarbonate solution (5.5 mL) was added. The mixture was allowed to react at room temperature for 24 hours. After confirmation of the completion of the reaction by TLC, the mixture was extracted with ethyl acetate, evaporated to remove the solvent, and n-hexane was added to form a slurry. Intermediate 32b (1.7 g) was obtained in 93% yield.

[0109] Compound 32 was synthesized using intermediate 32b (1.5 mmol, 275 mg) as a starting material, according to the synthesis method for target compound 1. 1 H NMR (400 MHz, CD3OD): δ 7.88 - 7.83 (m, 1H), 7.67 - 7.53 (m, 1H), 7.25 - 7.16 (m, 1H), 6.62 - 6.30 (m, 1H), 5.86 - 5.46 (m, 2H), 3.15 - 2.35 (m, 2H), 1.30 - 0.48 (m, 2H).

[0110] Synthesis and characterization of target compound 33: [ka] Intermediate 32c (1.2 mmol, 543 mg) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was reacted at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the excess solvent was evaporated and removed to obtain the crude product of intermediate 33c.

[0111] Intermediate 33c, N-Boc-bromoethylamine (1.5 mmol, 248 mg), was dissolved in dichloromethane (2 mL), and triethylamine (2.26 mmol, 0.32 mL) was added. The mixture was then reacted at 50°C for 2 hours. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The solvent was removed by evaporation. After column chromatography, intermediate 33d (145 mg) was obtained.

[0112] Compound 33 was synthesized using intermediate 33d (1.5 mmol, 275 mg) as a starting material, according to the synthesis method for target compound 1. 1 H NMR (400 MHz, CD3OD): δ 7.92 - 7.82 (m, 1H), 7.77 - 7.66 (m, 1H), 7.37 - 7.17 (m, 1H), 6.84 - 6.28 (m, 1H), 5.93 - 5.48 (m, 2H), 3.62 - 3.45 (m, 2H), 3.28 - 3.21 (m, 2H), 2.88 - 2.55 (m, 2H), 1.25 - 0.86 (m, 2H).

[0113] Synthesis and characterization of target compound 34: [ka] Tert-butanol (1.9 mmol, 0.18 ml) was dissolved in anhydrous dichloromethane (3 ml), cooled to 0°C, and then chlorosulfonyl isocyanate (1.5 mmol, 0.15 ml) was slowly added. The reaction was carried out at 0°C for 2 hours. Next, the solvent was removed by evaporation to obtain the crude product of intermediate 34c.

[0114] Intermediate 34c and intermediate 33c (1.13 mmol, 528 mg) were dissolved in pyridine (7 mL), and triethylamine (2.26 mmol, 0.32 mL) was added and the mixture was reacted overnight at room temperature. After confirming the completion of the reaction by TLC, the excess solvent was removed by evaporation. The residual solid was redissolved in dichloromethane, washed with 1 N HCl, then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. After column chromatography, intermediate 34d (300 mg, yield 50%) was obtained.

[0115] Compound 34 was synthesized using intermediate 34d (0.56 mmol, 300 mg) as a starting material, according to the synthesis method for target compound 1. 1 H NMR (400 MHz, CD3OD): δ 8.00 - 7.77 (m, 1H), 7.68 - 7.62 (m, 1H), 7.37 - 7.16 (m, 1H), 6.58 - 6.36 (m , 1H), 6.15 - 5.48 (m, 2H), 2.92 - 2.51 (m, 2H), 1.16 - 0.59 (m, 2H).

[0116] Synthesis and characterization of target compound 35: [ka]

[0117] 4-cyanopyrazole (10 mmol, 930 mg) was dissolved in anhydrous tetrahydrofuran (75 mL), lithium aluminum hydride (30 mmol, 1.14 g) was added, and the mixture was reacted overnight at 75°C under an argon gas atmosphere. After confirmation of the completion of the reaction by TLC, the mixture was cooled to room temperature, the reaction solution was quenched with saturated sodium sulfate, anhydrous sodium sulfate was added, and the mixture was filtered. The excess solvent was removed by evaporation to obtain the crude product of intermediate 35c.

[0118] Using intermediate 35c as a starting material, intermediate 35d was obtained according to the same synthesis method as for intermediate a6. Next, 35e was synthesized according to the same synthesis method as for intermediate a7.

[0119] Compound 35e (3 mmol, 1.24 mg) was dissolved in DCM (5 mL), and trifluoroacetic acid (5 mL) was added and the mixture was reacted at room temperature for 2 hours. After the completion of the reaction was observed by TLC, the solvent was removed by evaporation to obtain the crude product of intermediate 35f.

[0120] Using intermediate 35f as a starting material, intermediate 35g (200mg) was synthesized according to the same synthesis method as for intermediate 33d. Using intermediate 35g as a starting material, compound 35 was synthesized according to the synthesis method for target compound 1. ESI-MS: [M+H + ]: 345.2.

[0121] Synthesis and characterization of target compound 36: [ka] Intermediate 36a was obtained using intermediate 35f as a starting material, following the same synthetic method as for intermediate 34d. Using intermediate 36a (1.29 mmol, 505 mg) as a starting material, and intermediate 36a (1 mmol, 517 mg) as a starting material, target compound 36 (300 mg) was synthesized following the same synthetic method as for compound 1. 1 H NMR (400 MHz, CD3OD): δ 8.18 - 7.62 (m, 2H), 7.45 - 7.11 (m, 1H), 6.89 - 6.20 (m, 1H), 6.01 - 5.44 (m, 2H), 4.22 - 3.96 (m, 2H), 2.93 - 2.49 (m, 2H), 1.28 - 0.61 (m, 2H).

[0122] Synthesis and characterization of target compound 37: [ka] Intermediate 35f and compound 37a (1.95 mmol, 560 mg) were dissolved in tetrahydrofuran (8 mL), triethylamine (3.9 mmol, 0.57 mL) was added, and the mixture was heated to 50°C and reacted overnight. After confirmation of the completion of the reaction by TLC, the mixture was cooled to room temperature, extracted with ethyl acetate and water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was removed by evaporation, and intermediate 37b (144 mg) was obtained after column chromatography.

[0123] Intermediate 8d (80 mg, yield 45%) was synthesized using intermediate 37b (0.26 mmol, 144 mg) as a starting material, following the same synthesis method as for intermediate 1d.

[0124] Using intermediate 8d (0.12 mmol, 80 mg) as a starting material, target compound 37 was synthesized according to the same synthesis method as for compound 1. ESI-MS: [M+H + ]: 344.2.

[0125] Synthesis and characterization of target compound 38: Using intermediate 33c as a starting material, target compound 38 (50 mg) was synthesized according to the same synthesis method as for compound 38. 1 H NMR (400 MHz, CD3OD): δ 8.02 - 7.53 (m, 2H), 7.39 - 7.09 (m, 1H), 6.69 - 6.11 (m, 1H), 5.91 - 5.38 (m, 2H), 3.37 - 3.23 (m, 2H), 2.82 - 2.46 (m, 2H), 1.15 - 0.57 (m, 2H).

[0126] Synthesis and characterization of target compound 39: [ka] 4-Acetamino-1H-pyrrole (10 mmol, 1.1 g) was dissolved in acetonitrile (60 mL), and PMBCl (10 mmol, 1.36 mL) and potassium carbonate (20 mmol, 2.76 g) were added. The mixture was heated to 85°C and reacted overnight. After the reaction was complete, TLC confirmed that the reaction was finished. The mixture was then cooled to room temperature, extracted with ethyl acetate and water, and the solvent was removed by evaporation. Column chromatography yielded intermediate 39b (2.25 g, 98% yield).

[0127] Intermediate 39b (9.8 mmol, 2.25 g) was dissolved in anhydrous methanol (45 mL), cooled to 0°C, and then sodium borohydride (19.6 mmol, 741 mg) was added. The reaction was then allowed to proceed at 0°C for 3 hours. After the reaction was complete, TLC confirmed that the reaction was finished. The reaction mixture was then quenched with saturated ammonium chloride, extracted with ethyl acetate and water, and the solvent was removed by evaporation to obtain intermediate 39c (2 g, yield 88%).

[0128] Next, intermediate 39c (8.61 mmol, 2 g) and DPPA (13 mmol, 2.8 mL) were dissolved in anhydrous tetrahydrofuran (22 mL), cooled to 0°C, and DBU (13 mmol, 1.97 mL) was added. The mixture was then reacted overnight at room temperature under an argon gas atmosphere. After confirmation of the completion of the reaction by TLC, the mixture was extracted with ethyl acetate and water, the solvent was removed by evaporation, and column chromatography analysis was performed to obtain intermediate 39d (1.3 g, yield 59%).

[0129] Next, intermediate 39d (5.1 mmol, 1.3 g) was dissolved in methanol, 10% Pd / C (300 mg) was added, and the mixture was reacted overnight under a hydrogen gas atmosphere. After confirmation of the completion of the reaction by TLC, the mixture was filtered, and the excess solvent was removed by evaporation to obtain the crude product of intermediate 39e.

[0130] Intermediate 39 g (750 mg) was synthesized using intermediate 39f as a starting material, following the same synthetic method as for intermediate 35c. Target compound 39 (100 mg) was synthesized using intermediate 39 g (3.55 mmol, 750 mg) as a starting material, following the same synthetic method as for compound 1. ¹H NMR (400 MHz, CD3OD): δ 8.04 - 7.61 (m, 2H), 7.38 - 7.09 (m, 1H), 6.63 - 6.24 (m, 1H), 5.96 - 5.44 (m, 2H), 4.62 - 4.45 (m, 1H), 2.94 - 2.42 (m, 2H), 1.68 - 1.65 (m, 3H), 1.18 - 0.60 (m, 2H).

[0131] Synthesis and characterization of target compound 40: [ka] Intermediate 40a (2.1 g, yield 98%) was synthesized using 4-cyanopyrazole as a starting material, following the same synthetic method as for intermediate 39b. 40a (9.8 mmol, 2.1 g) was dissolved in anhydrous tetrahydrofuran (20 mL), tetraisopropyl titanate (12 mmol, 7.2 mL) was added, and after cooling to -78°C, magnesium ethyl bromide (1.0 mmol, THF solution) (24.5 mmol, 24.5 mL) was added. The mixture was stirred for 30 minutes, heated to room temperature, and stirred for 1 hour. Then, ethyl boron trifluoride ether (19.6 mmol, 2.5 mL) was added, and the mixture was reacted at room temperature for 16 hours. After detection by LC-MS until the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride, saturated sodium bicarbonate was added, and the mixture was extracted with dichloromethane and water. The solvent was removed by evaporation to obtain the crude product of intermediate 40b.

[0132] 40b was dissolved in methylene chloride (40 mL), and di-tert-butyl dicarbonate (10 mmol, 2.2 g) and triethylamine (15 mmol, 2.1 mL) were added and the mixture was reacted overnight at room temperature. After confirming the completion of the reaction by TLC, the excess solvent was removed by evaporation, and intermediate 40c (1.2 g) was obtained after column chromatography.

[0133] Intermediate 40d (650 mg, yield 83%) was synthesized using intermediate 40c (3.5 mmol, 1.2 g) as a starting material, following the same synthesis method as for intermediate 39f. Intermediate 40e (498 mg, yield 35%) was synthesized using intermediate 40d (2.91 mmol, 650 mg) as a starting material, following the same synthesis method as for intermediate 40c.

[0134] Compound 40 (100 mg) was synthesized using 40e (1 mmol, 492 mg) as a starting material, according to the synthesis method for target compound 1. 1 H NMR (400 MHz, CD3OD): δ 7.90 - 7.72 (m, 1H), 7.72 - 7.49 (m, 1H), 7.34 - 7.14 (m, 1H), 6.63 - 6.14 (m, 1H), 5.87-5.45 (m, 2H), 2.96 - 2.48 (m, 2H), 1.35 - 1.24 (m, 2H), 1.17 (t, J = 7.0 Hz, 2H), 1.11 - 0.65 (m, 2H).

[0135] Synthesis and characterization of target compound 41: [ka] Intermediate a10 (2 mmol, 625 mg), compound 41a (2.2 mmol, 400 mg), anhydrous copper sulfate (0.2 mmol, 32 mg), and sodium ascorbate (1 mmol, 198 mg) were dissolved in tert-butanol (14 mL) and water (14 mL) and reacted overnight at room temperature. After confirmation of reaction completion by TLC, the mixture was extracted with ethyl acetate, the solvent was removed by evaporation, and column chromatography analysis was performed to obtain intermediate 41b (880 mg, yield 89%).

[0136] Using intermediate 41b (1.78 mmol, 880 mg) as a starting material, compound 41 (300 mg, yield 69%) was synthesized according to the synthesis method for target compound 1. 1 H NMR (400 MHz, CD3OD): δ 7.96 - 7.76 (m, 1H), 7.33-7.21 (m, 1H), 6.80 - 6.45 (m, 1H), 6.12 - 5.70 (m, 2H), 2.90 - 2.51 (m, 2H), 1.49 - 1.27 (m, 4H), 1.24 - 0.86 (m, 2H).

[0137] Synthesis and characterization of target compound 42: (1H-pyrazole-3-yl)methylamine was used as a starting material, and target compound 42 (300 mg) was synthesized according to the synthesis method for target compound 1. The total yield in the 5 steps was 15%. 1 H NMR (400 MHz, CD3OD): δ 7.78 - 7.58 (m, 1H), 7.30 - 7.06 (m, 1H), 6.63 - 6.15 (m, 2H), 5.84-5.43 (m, 2H), 4.12 (s, 2H), 3.08 - 2.43 (m, 2H), 1.42 - 0.60 (m, 2H).

[0138] Synthesis and characterization of target compound 43: [ka] Compound 43a (10 mmol, 1.12 g) was dissolved in dichloromethane (30 mL), di-tert-butyl dicarbonate (11 mmol, 2.4 g), DMAP (1 mmol, 122 mg), and triethylamine (15 mmol, 3 mL), and the mixture was reacted overnight at room temperature. After confirming the completion of the reaction by TLC, the solvent was removed by evaporation, and intermediate 43b (1.71 g, 81%) was obtained by column chromatography.

[0139] Intermediate 43b (8.1 mmol, 1.71 g) was dissolved in anhydrous dichloromethane (10 mL), triethylamine (8.1 mmol, 1.3 mL) was added, the mixture was cooled to 0°C, and methanesulfonyl chloride (8.9 mmol, 0.9 mL) was added. The mixture was then reacted at room temperature for 2 hours. After confirmation of the completion of the reaction by TLC, the solvent was removed by evaporation to obtain the crude product of intermediate 43c.

[0140] Intermediate 43c was dissolved in N,N-dimethylformamide (16 mL), sodium azide (24 mmol, 1.56 g) was added, and the mixture was heated to 70°C and reacted for 4-5 hours. After confirming the completion of the reaction by TLC, the mixture was extracted with ethyl acetate and water, the solvent was removed by evaporation, and intermediate 43d (1.2 g) was obtained by column chromatography.

[0141] Compound 43 (115 mg) was synthesized using 43d as a raw material, according to the synthesis method for target compound 39. 1 H NMR (400 MHz, CD3OD): δ 8.15 - 7.52 (m, 2H), 7.34 - 7.06 (m, 1H), 6.85 - 6.14 (m, 1H), 5.90 - 5.38 (m, 2H), 3.15 - 2.98 (m, 2H), 2.88 - 2.47 (m, 4H), 1.27 - 0.46 (m, 2H).

[0142] Synthesis and characterization of target compound 44: [ka]

[0143] 44a (42 mmol, 11 g) was dissolved in tetrahydrofuran (84 mL), and di-tert-butyl dicarbonate (168 mmol, 37 g), tert-butanol (84 mL), and DMAP (2.1 mmol, 257 mg) were added. The mixture was heated to 60°C and reacted overnight. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature, and intermediate 44b (7 g, yield 43%) was obtained by column chromatography.

[0144] Intermediate 44c (4g, yield 47%) was synthesized using intermediate 44b (18 mmol, 7 g) as a starting material, following the synthesis method for intermediate a5.

[0145] Compound 44d (20 mmol, 2 g) was dissolved in DMF (20 mL), imidazole (40 mmol, 4.2 g), DMAP (2 mmol, 244 mg), and TBCl (28 mmol, 4.2 g) were added, and the mixture was allowed to react overnight at 40°C. After confirmation of the completion of the reaction by TLC, the mixture was cooled to room temperature, extracted with ethyl ether and water, the solvent was removed by evaporation, and the mixture was mixed with n-pentane to form a slurry. The slurry was filtered to obtain intermediate 44e (4 g, yield 93%).

[0146] Intermediate 44e (646 mg, 3 mmol) was dissolved in anhydrous DMF (30 mL), cooled to 0°C, sodium hydride (4.5 mmol, 108 mg) was added and stirred for 10 minutes, then intermediate 44c (4.5 mmol, 2 g) was added and the mixture was reacted overnight at room temperature under an argon gas atmosphere. After confirmation of reaction completion by TLC, the reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, the solvent was removed by evaporation, and intermediate 44f (377 mg, yield 21%) was obtained after column chromatography.

[0147] Using intermediate 44f (0.63 mmol, 377 mg) as a starting material, compound 44 (20 mg) was synthesized according to the synthesis method for target compound 1. 1H NMR (400 MHz, CD3OD): δ 7.71 - 7.12 (m, 1H), 7.01-6.65(m, 1H), 4.81-4.23 (m, 2H), 3.77-3.51 (m, 1H), 3.27 - 3.07 (m, 1H), 2.95 - 2.20 (m, 4H), 1.31 - 0.49 (m, 2H).

[0148] Synthesis and characterization of target compound 45: [ka]

[0149] Intermediate 44f (6.66 mmol, 4 g) was dissolved in tetrahydrofuran (70 mL), TBAF (20 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After confirmation of the completion of the reaction by TLC, the reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the solvent was removed by evaporation to obtain intermediate 45a (1.7 g, yield 52%).

[0150] Intermediate 45c (610 mg) was synthesized using intermediate 45a (3.48 mmol, 1.7 g) as a starting material, following the synthesis method for intermediate 43d. 45c (0.84 mmol, 610 mg) was dissolved in tetrahydrofuran (12 mL) and water (3 mL), and triphenylphosphine (1.26 mmol, 480 mg) was added. The mixture was reacted overnight at room temperature. After confirmation of reaction completion by TLC, the solvent was removed by evaporation to obtain the crude product of intermediate 45d.

[0151] Intermediate 45d was dissolved in methanol (6 mL), and di-tert-butyl dicarbonate (0.9 mmol, 200 mg) and triethylamine (0.9 mmol, 0.3 mL) were added and the mixture was reacted overnight at room temperature. After confirming completion of the reaction by TLC, the solvent was removed by evaporation. DCM was added to redissolve the residue, washed with saturated ammonium chloride, and the solvent was removed by evaporation. After column chromatography, intermediate 45e (635 mg) was obtained.

[0152] Using 45e (1.08 mmol, 635 mg) as a starting material, target compound 45 (20 mg) was synthesized according to the synthesis method of target compound 1. 1 H NMR (400 MHz, CD3OD): δ 7.42 - 7.07 (m, 1H), 7.07 - 6.58 (m, 1H), 5.27-5.04 (m, 1H), 4.76 - 4.26 (m, 1H), 4.15 - 3.63 (m, 2H), 3.51-3.30 (m, 1H), 3.09 - 2.38 (m, 4H), 1.41 - 0.36 (m, 2H).

[0153] Synthesis and characterization of target compound 46: [ka]

[0154] Compound 46a (10 mmol, 1.05 mL) was dissolved in tetrahydrofuran (20 mL) and water (47.5 mL), saturated sodium bicarbonate (1.5 mL) was added, and then di-tert-butyl dicarbonate (10 mmol, 2.2 g) was added. The mixture was reacted overnight at room temperature. After confirming the completion of the reaction by TLC, the mixture was extracted with dichloromethane, and the solvent was removed by evaporation to obtain intermediate 46b.

[0155] Intermediate 46b (5.4 mmol, 990 mg), compound 46c (2.7 mmol, 844 mg), cuprous iodide (0.11 mmol, 21 mg), and tetra(triphenylphosphine)palladium (0.22 mmol, 250 mg) were dissolved in DMF (6 mL), triethylamine (4.3 mmol) was added, and the mixture was heated to 100 °C under an argon gas atmosphere and reacted for 3 hours. After confirmation of the completion of the reaction by TLC, the mixture was cooled to room temperature, the reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate and water, the solvent was removed by evaporation, and intermediate 46d (748 mg, yield 55%) was obtained after column chromatography.

[0156] Using compound 46d (1 mmol, 250 mg) as a starting material, target compound 46 (40 mg) was synthesized according to the synthesis method for target compound 1. 1 H NMR (400 MHz, CD3OD): δ 8.46 - 7.53 (m, 2H), 7.31-7.15 (m, 1H), 6.71 - 6.05 (m, 1H), 5.97 - 5.44 (m, 2H), 2.94 - 2.45 (m, 2H), 1.42 (s, 6H), 1.11 - 0.64 (m, 2H).

[0157] Synthesis and characterization of target compound 47: [ka]

[0158] Using compound 47a (2.42 mmol, 439 mg) as a starting material, target compound 47 (100 mg) was synthesized according to the synthesis method for target compound 41. 1 H NMR (400 MHz, CD3OD): δ 8.10 - 7.60 (m, 1H), 7.56 - 7.11 (m, 1H), 7.06 - 6.33 (m, 1H), 6.23 - 5.35 (m, 2H), 4.52 - 4.14 (m, 5H), 2.95 - 2.53 (m, 1H),1.99-1.76(m, 1H), 1.47 - 0.65 (m, 2H).

[0159] Synthesis and characterization of target compound 48: [ka]

[0160] Using N-BOC-4-pentin-1-amine (2.2 mmol, 420 mg) as a starting material, intermediate 48b (706 mg, yield 72%) was synthesized according to the synthesis method of intermediate 41b. Using intermediate 48b (1.43 mmol, 706 mg) as a starting material, compound 48 (60 mg) was synthesized according to the synthesis method of target compound 37. 1H NMR (400 MHz, CD3OD): δ 8.06 - 7.67 (m, 1H), 7.43 - 7.07 (m, 1H), 6.87 - 6.41 (m, 1H), 6.10 - 5.58 (m, 2H), 3.18-3.09 (m, 2H), 2.83 - 2.46 (m, 4H), 2.06 - 1.71 (m, 2H), 1.22 - 0.56 (m, 2H).

[0161] Synthesis and characterization of target compound 49: [ka]

[0162] Intermediate 49a was synthesized using intermediate 47c (1.77 mmol, 781 mg) as a starting material, following the synthesis method for intermediate 33c. Intermediate 49b was synthesized using intermediate 49a as a starting material, following the synthesis method for intermediate 37b. Target compound 49 (30 mg) was synthesized using 49b (0.5 mmol, 289 mg) as a starting material, following the synthesis method for target compound 1. 1 H NMR (400 MHz, CD3OD): δ 7.98 - 7.69 (m, 1H), 7.36 - 7.10 (m, 1H), 6.77 - 6.43 (m, 1H), 6.13-5.67 (m, 2H), 4.50 (t, J = 8.2 Hz, 2H), 4.32 - 3.98 (m, 3H), 2.94 - 2.52 (m, 2H), 1.12 - 0.60 (m, 2H).

[0163] Synthesis and characterization of target compound 50: [ka]

[0164] Using intermediate 43i (0.47 mmol, 203 mg) as a starting material, target compound 50 (50 mg) was synthesized according to the synthesis method for target compound 48. 1H NMR (400 MHz, CD3OD): δ 8.01 - 7.54 (m, 1H), 7.40 - 7.08 (m, 1H), 6.70 - 6.11 (m, 1H), 5.90 - 5.41 (m, 2H), 3.36 - 3.23 (m, 2H), 2.85 - 2.45 (m, 2H), 1.16 - 0.57 (m, 2H).

[0165] Synthesis and characterization of target compound 51: [ka] Using 51a as a raw material, target compound 51 was synthesized according to the synthesis method for target compound 36. ESI-MS:[M+H + ]:396.1.

[0166] Synthesis and characterization of target compound 52: [ka]

[0167] Compound 52a (5.7 mmol, 1.2 g) and intermediate a5 (5.7 mmol, 2 g) were dissolved in anhydrous DMF (17 mL), cesium carbonate (6.84 mmol, 2.23 g) was added, and the mixture was reacted overnight at room temperature under an argon gas atmosphere. After confirmation of the completion of the reaction by TLC, the mixture was extracted with ethyl acetate and water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, excess solvent was removed by evaporation, and intermediate 52b (1.03 g, yield 48%) was obtained after column chromatography.

[0168] 52b (1.03 g, 2.72 mmol) was dissolved in anhydrous DMF (14 mL), and acrylic acid (4.1 mmol, 0.29 mL), palladium acetate (0.14 mmol, 31 mg), P(o-tolyl)3 (0.28 mmol, 83 mg), and triethylamine (8.1 mmol, 1.1 mL) were added sequentially. The mixture was heated to 100 °C under an argon gas atmosphere and reacted for 14 hours. After confirmation of the completion of the reaction by TLC, the mixture was cooled to room temperature, extracted with ethyl acetate and water, the solvent was removed by evaporation, and the mixture was mixed with n-pentane to obtain a slurry, which yielded intermediate 52c (772 mg, yield 60%).

[0169] Intermediate 52c (1.64 mmol, 772 mg) was dissolved in chloroform (18 mL), cooled to 0°C, and bromine (2 mmol, 110 μL) was slowly added dropwise. The reaction was allowed to proceed at 0°C for 2-3 hours. After confirmation of the completion of the reaction by TLC, the excess solvent was removed by evaporation to obtain the crude product of intermediate 52d.

[0170] Intermediate 52d was dissolved in DMF (6 mL), cooled to 0°C, and triethylamine (1.12 mL) was added and the mixture was reacted overnight at room temperature. After confirmation of the completion of the reaction by TLC, the mixture was extracted with ethyl acetate and water, the solvent was removed by evaporation, and intermediate 52e (676 mg) was obtained after column chromatography.

[0171] Intermediate 52e (1.34 mmol, 676 mg) was dissolved in 1,4-dioxane (7 mL), and bis[(+)-pinandiolate]diborone (2 mmol, 720 mg), Pd(dppf)Cl2 (0.13 mmol, 98 mg), and potassium acetate (5.4 mmol, 526 mg) were added sequentially. The mixture was heated to 60°C under an argon gas atmosphere and reacted for 2 hours. After confirmation of the completion of the reaction by TLC, the mixture was cooled to room temperature, extracted with ethyl acetate and water, and the excess solvent was removed by evaporation. After column chromatography, intermediate 52f (300 mg, 37%) was obtained. Using intermediate 52f (0.5 mmol, 300 mg) as a starting material, target compound 52 was synthesized according to the synthesis method of compound 1. ESI-MS:[M+H + ]:312.1.

[0172] Synthesis and characterization of target compounds 53 and 54: [ka]

[0173] Diethylzinc (4.4 mmol, 4.45 mL) was dissolved in anhydrous DCM (3.5 mL), cooled to -78°C, and then diiodomethane (6.6 mmol, 0.59 mL) was added. After stirring for 30 minutes, a solution of 52f (334 mg, 0.55 mmol) in DCM (2.5 mL) was added. The mixture was slowly heated to room temperature and then reacted for 24 hours. After confirming completion of the reaction by TLC, the solvent was removed by evaporation to obtain the crude intermediates 53a and 54a.

[0174] Intermediates 53a and 54a were dissolved in DCM (3 mL), triethylamine (0.3 mL) and di-tert-butyl dicarbonate (138 mg) were added, and the mixture was reacted at room temperature for 1 hour. After confirming the completion of the reaction by TLC, the excess solvent was removed by evaporation, and intermediates 53b (142 mg) and 54d (65 mg) were obtained after column chromatography.

[0175] Target compound 53 (30 mg) was synthesized from intermediate 53b (0.23 mmol, 142 mg) according to the synthesis method for target compound 1. 1 H NMR (400 MHz, CD3OD): δ 7.74 - 7.38 (m, 1H), 6.99 - 6.41 (m, 1H), 6.41 - 6.16 (m, 1H), 6.07 - 5.36 (m, 1H), 4.49-4.29 (m, 4H), 2.23 - 1.54 (m, 2H), 1.15 - 0.76 (m, 1H), 0.75 - 0.47 (m, 1H).

[0176] Target compound 54 (10 mg) was synthesized from intermediate 54b (0.1 mmol, 65 mg) according to the synthesis method for target compound 1. ESI-MS:[M+H + ]:326.1.

[0177] Synthesis and characterization of target compound 55: Compound 55 was synthesized using 7H-pyrazolopyrimidine instead of 2H-1,2,3-triazole, following the synthesis method for target compound 1. The total yield for the four steps was 9%. 1 H NMR (400 MHz, Methanol-d4) δ 9.02 (d, J= 11.0 Hz, 1H), 8.81 (d, J = 25.7 Hz, 1H), 7.54 (d, J = 29.2 Hz, 1H), 7.11 (d, J = 23.0 Hz, 1H), 6.76 (d, 11.0 Hz, 1H), 6.34 - 5.80 (m, 3H), 2.86 - 2.42 (m, 2H), 2.11 (d, J = 65.1 Hz, 1H), 1.72 (m, 1H). 16 H 14 BN3O4[M+H] + 324.1, Measured value: 324.1.

[0178] Synthesis and characterization of 56 target compounds: Using intermediate 52b as a starting material, compound 56 (30 mg) was synthesized according to the synthesis method for target compound 1. 1 1H NMR 1 H NMR (400 MHz, D2O) δ 7.48 (d, J = 15.0 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 5.45 (s, 2H), 4.42 (d, J = 15.8 Hz, 4H), 2.73 (t, J = 8.0 Hz, 2H), 1.06 (t, J = 7.8 Hz, 2H). ESI-MS: C for m / z calculation 15 H 17 BN3O4[M+H] + 314.1, Measured value: 314.1.

[0179] Synthesis and characterization of target compound 57: [ka] Compound 57 (40 mg) was synthesized using compound 57a as a raw material, according to the synthesis method for target compound 36. 1 1H NMR 1 H NMR (400 MHz, MeOD) δ 7.44 (s, 1H), 7.34 - 7.15 (m, 2H), 5.61 (d, J = 66.5 Hz, 3H), 4.40 (s, 4H), 2.75 (t, J = 8.0 Hz, 2H), 1.09 (t, J = 7.8 Hz, 2H). ESI-MS: m / z calculation C 15 H 18 BN4O6S [M+H] + 393.1, Measured value: 393.1.

[0180] Synthesis and characterization of target compound 58: [ka] Compound 58 (78 mg) was synthesized using compound 57b as a raw material, following the synthesis method for target compound 37. 1 H NMR (400 MHz, MeOD) δ 7.61 - 7.48 (m, 1H), 7.17 (m, 1H), 6.31 (m, 1H), 5.87 - 5.49 (m, 2H), 4.66 - 4.28 (m, 4H), 2.91 - 2.52 (m, 2H), 1.12 - 0.66 (m, 2H). ESI-MS: m / z calculation C 16 H 19 BN5O4[M+H] + 356.1, Measured value: 356.1.

[0181] Synthesis and characterization of target compound 59: Compound 59 was synthesized using tert-butyl(4-ethynylphenyl)carbamate as a starting material, according to the synthesis method for target compound 4. 1H NMR (400 MHz, MeOD) δ 8.33 - 8.16 (m, 1H), 8.04 - 7.88 (m, 2H), 7.44 (q, J = 8.6 Hz, 2H), 7.24 (dd, J = 27.3, 7.7 Hz, 1H), 6.81 - 6.43 (m, 1H), 6.17 - 5.77 (m, 2H), 2.87 - 2.53 (m, 2H), 1.12 - 0.68 (m, 2H). ESI-MS: C for m / z calculation 18 H 18 BN4O4[M+H] + 365.1, Measured value: 365.2.

[0182] Synthesis and characterization of target compound 60: Compound 60 was synthesized using tert-butyl(4-ethynylpyridine)carbamate as a starting material, according to the synthesis method for target compound 4. 1 H NMR (400 MHz, MeOD) δ 8.45 - 8.00 (m, 3H), 7.43 - 6.93 (m, 2H), 6.84 - 6.52 (m, 1H), 6.15 - 5.75 (m, 2H), 2.90 - 2.52 (m, 2H), 1.23 - 0.72 (m, 2H). ESI-MS: m / z calculation C 17 H 17 BN5O4[M+H] + 366.1, Measured value: 366.1.

[0183] Synthesis and characterization of target compound 61: Compound 61 was synthesized using tert-butyl(5-ethynylpyrimidinyl)carbamate as a starting material, according to the synthesis method for target compound 4. 1 H NMR (400 MHz, MeOD) δ 9.06 - 8.89 (m, 2H), 8.36 - 8.11 (m, 1H), 7.36 - 7.14 (m, 1H), 6.80 - 6.54 (m, 1H), 6.15 - 5.75 (m, 2H), 2.91 - 2.54 (m, 2H), 1.21 - 0.89 (m, 2H). ESI-MS: m / z calculation C16 H 16 BN6O4[M+H] + 367.1, Measured value: 367.1.

[0184] Synthesis and characterization of target compound 62: Compound 62 was synthesized using 4-ethynylbenzenesulfonamide as a starting material, according to the synthesis method for target compound 4. 1 H NMR (400 MHz, MeOD) δ 8.42 - 8.28 (m, 1H), 8.06 - 7.20 (m, 5H), 6.77 - 6.48 (m, 1H), 6.14 - 5.78 (m, 2H), 2.88 - 2.58 (m, 2H), 1.37 - 1.04 (m, 2H). ESI-MS: m / z calculation C 18 H 18 BN4O6[M+H] + 429.1, Measured value: 429.1.

[0185] Synthesis and characterization of target compound 63: Compound 63 was synthesized using tert-butyl(4-ethynylbenzyl)carbamate as a starting material, according to the synthesis method for target compound 4. 1 H NMR (400 MHz, MeOD) δ 8.47 - 8.29 (m, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.53 (dd, J = 8.5, 2.3 Hz, 2H), 7.31 - 7.20 (m, 1H), 6.84 - 6.51 (m, 1H), 6.13 - 5.78 (m, 2H), 4.14 (s, 2H), 2.89 - 2.57 (m, 2H), 1.10 - 0.70 (m, 2H). ESI-MS: C for m / z calculation 18 H 18 BN4O6[M+H] + 379.1, Measured value: 379.2.

[0186] Synthesis and characterization of target compound 64: [ka] Compound 64 was synthesized using compound 64a as a starting material, according to the synthesis method for target compound 37. 1 H NMR (400 MHz, MeOD) δ 8.51 - 8.38 (m, 1H), 7.83 (m, 2H), 7.44 (m, 2H), 7.35 - 7.25 (m, 1H), 6.71 (m, 1H), 6.16 - 5.83 (m, 2H), 4.46 (s, 2H), 2.89 - 2.59 (m, 2H), 1.12 - 0.70 (m, 2H).

[0187] Synthesis and characterization of target compound 65: Compound 65 was synthesized using tert-butyl(4-ethynylphenylethyl)carbamate as a starting material, according to the synthesis method for target compound 4. 1 H NMR (400 MHz, MeOD) δ 8.53 - 8.35 (m, 1H), 7.84 - 7.74 (m, 2H), 7.46 - 7.25 (m, 3H), 6.73 (dd, J = 66.6, 7.6 Hz, 1H), 6.16 - 5.82 (m, 2H), 3.20 (t, J = 7.8 Hz, 2H), 3.08 - 2.95 (t, J = 7.8 Hz, 2H), 2.91 - 2.60 (m, 2H), 1.14 - 0.72 (m, 2H).

[0188] Synthesis and characterization of target compound 66: Compound 66 was synthesized according to the synthesis method for target compound 56. 1 H NMR (400 MHz, MeOD) δ 7.51 - 7.21 (m, 2H), 6.82 - 6.48 (m, 1H), 5.84 - 5.39 (m, 2H), 4.37 (m,, 2H), 4.12 (d, 2H), 2.89 - 2.58 (m, 2H), 1.16 - 0.66 (m, 2H). ESI-MS: m / z calculation C 15 H 17 BN3O4[M+H] + 314.1, Measured value: 314.1.

[0189] Synthesis and characterization of target compound 67: Compound 67 was synthesized according to the synthesis method of target compound 58. 1 H NMR (400 MHz, MeOD) δ 7.52 - 7.18 (m, 2H), 6.69 - 6.24 (m, 1H), 5.88 - 5.42 (m, 2H), 4.63 - 4.31 (m, 4H), 2.88 - 2.57 (m, 2H), 1.12 - 0.67 (m, 2H).

[0190] Synthesis and characterization of target compound 68: [ka]

[0191] Under an N2 atmosphere, K2CO3 (2.25 mmol, 311 mg), 4-(Boc-aminomethyl)pyrazole (2.25 mmol / L, 443 mg), KI (0.02 mmol, 5 mg), and 44c (1.5 mmol, 700 mg) were dissolved in DMF (10 mL) solution and stirred overnight at 80°C. After confirming the completion of the reaction by TLC, the reaction mixture was charged into water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography to obtain compound 68a (670 mg, yield 77%).

[0192] DIBAL-H (0.33 mmol, 220 μL) was added dropwise to a solution of zinc powder (6.6 mmol, 429 mg) and borate ester compound (0.3 mmol, 75 mg) in anhydrous tetrahydrofuran (5 mL) at room temperature. The mixture was stirred for 5 minutes, and then a solution of borate ester compound (7.2 mmol, 720 mg) in anhydrous tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was heated to 50°C and stirred for 1.5 hours. The supernatant and compound 68a (1.1 mmol, 620 mg) and Pd(t-Bu3P)2 (0.03 mmol, 14 mg) in THF (8 mL) were mixed and reacted under an N2 atmosphere for 1 hour. After concentration, the mixture was purified by silica gel chromatography to obtain compound 68b (627 mg, yield 82%). ESI-MS: m / z calculation C 37 H 55 BN3O9[M+H] + 696.4, Measured value: 696.4.

[0193] Under an argon gas atmosphere, a 4 mL solution of DCM (2 mmol, 170 mg) in THF was cooled to -100°C, and n-BuLi (1.3 mmol, 512 μL) was slowly added dropwise. After stirring the mixture at this temperature for 30 minutes, a 3 mL solution of compound 68b (0.8 mmol, 550 mg) in THF was added dropwise. The mixture was gradually heated to room temperature and stirred overnight, then spin-dried to obtain compound 68c. ESI-MS: m / z calculation of C 38 H 56 BClN3O9[M+H] + 744.4, Measured value: 744.4.

[0194] Triethylamine (0.52 mmol, 52 mg) was added at room temperature to a solution of compound 68c (0.26 mmol, 190 mg) and 2-mercapto-1,3,4-thiadiazole (0.31 mmol, 36 mg) in DCM (2 mL). After stirring for 2 hours, the solution was diluted with DCM, washed with dilute hydrochloric acid and water, and concentrated to obtain compound 68d (50 mg, yield 23%).

[0195] Compound 68d (0.06 mmol, 50 mg) was dissolved in 3 mL of 1,4-dioxane solution, 3 mL of 6N HCl was added, and the mixture was heated to 100°C and refluxed for 2 hours. After confirmation of the reaction completion by TLC, the mixture was concentrated under vacuum and recrystallized from acetonitrile-methanol to obtain the target compound 68 (20 mg, yield 79%). 1 H NMR (400 MHz, MeOD) δ 9.25 (m, J= 3.7 Hz, 1H), 7.97 - 7.57 (m, 2H), 7.49 - 7.10 (m, 1H), 5.92 - 5.72 (m, 1H), 5.60 - 5.34 (m, 1H), 4.14 - 3.97 (m, 2H), 3.81 - 3.58 (m, 1H), 3.25 - 3.00 (m, 1H), 2.99 - 2.71 (m, 1H). ESI-MS: C for m / z calculation 16 H 17 BN5O4S2[M+H] + 418.1, Measured value: 418.1.

[0196] Synthesis and characterization of target compound 69: [ka] To a solution of compound 68c (0.27 mmol, 200 mg) in DMF (5 mL), MeOH (0.41 mmol, 13 mg) was added, followed by K2CO3 (1.1 mmol, 149 mg). The resulting mixture was stirred at 50°C for 1 hour, then diluted with ethyl acetate and washed with saturated NH4Cl and water. The organic layer was concentrated and dried, and then purified by column chromatography to obtain pure compound 69a (70 mg, yield 79%). ESI-MS: m / z calculation of C 39 H 59 BN3O 10 [M+H] + 740.4, Measured value: 740.4.

[0197] Compound 69a (0.09 mmol, 70 mg) was dissolved in 3 mL of 1,4-dioxane solution, and 3 mL of 6N HCl was added. The mixture was then heated to 100°C and refluxed for 2 hours. After confirmation of the reaction completion by TLC, the mixture was concentrated under vacuum and recrystallized from acetonitrile-methanol to obtain the target compound 69 (35 mg, yield 79%). 1 H NMR (400 MHz, MeOD) δ 7.83 - 7.56 (m, 2H), 7.32 - 7.10 (m, 1H), 6.56 - 6.25 (m, 1H), 5.81 - 5.41 (m, 2H), 4.05 (d, J = 17.5 Hz, 2H), 3.60 - 3.30 (m, 3H), 3.26 - 2.84 (m, 3H). ESI-MS: C for m / z calculation 15 H 19 BN3O5[M+H] + 332.1, Measured value: 332.2.

[0198] Synthesis and characterization of target compound 70: [ka] Compound 70a (1.73 mmol, 850 mg), N-Boc-bromoethylamine (426 mg, 1.9 mmol), and triethylamine (3.46 mmol, 350 mg) were dissolved in DMF (10 mL) at room temperature and reacted overnight at 50°C. After confirmation of reaction completion by TLC, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 70b (696 mg, yield 77%). Compound 70 (120 mg) was synthesized using 70b as a starting material according to the synthesis method for target compound 1. 1H NMR (400 MHz, MeOD) δ 7.58 - 7.44 (m, 1H), 7.26 - 7.12 (m, 1H), 6.47 (m, 1H), 5.70 - 5.47 (m, 1H), 4.64 (s, 4H), 3.83 (m, J = 14.4, 6.8 Hz, 2H), 3.48 (m, 2H), 2.87 - 2.52 (m, 2H), 1.11 - 0.58 (m, 2H).

[0199] Synthesis and characterization of target compound 71: Compound 71 was synthesized using 3-cyanopyrrole as a starting material, following the synthesis method for target compound 1. The total yield for the four steps was 12%. 1 H NMR (400 MHz, Methanol-d4) δ 7.37 (m, 1H), 7.24 - 7.19 (m, 1H), 6.76 (m, 1H), 6.63 - 6.53 (m, 1H), 6.44 - 6.37 (m, 1H), 5.30 (s, 2H), 2.73 (t, J = 8.0 Hz, 2H), 1.08 (t, J = 7.9 Hz, 2H).

[0200] Synthesis and characterization of target compound 72: [ka]

[0201] Compounds 72a (2.86 mmol), a5 (2.86 mol, 1.0 g), K2CO3 (593 mg, 4.29 mmol), and KI (0.03 mmol, 5 mg) were added to a two-necked flask at room temperature, and DMF was added under an N2 atmosphere. The mixture was reacted overnight at 80°C. After confirmation of reaction completion by TLC, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 72b (807 mg, yield 62%).

[0202] TFA (2.3 mL) was added dropwise to a DCM solution of compound 72b (1.85 mmol, 807 mg) at room temperature, and the mixture was stirred at room temperature for 3 hours. After confirmation of the completion of the reaction by TLC, the mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 72c (662 mg, 95%).

[0203] Compound 72c (1.75 mmol, 662 mg) and HBTU (2.1 mmol, 796 mg) were dissolved in DMF (7 mL) at room temperature. EtN(Pr-i)2 (5.25 mmol, 679 mg) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 3-N-tert-butoxycarbonylaminocyclobutylamine (2.1 mmol, 362 mg) was added, and the mixture was reacted at room temperature for 3 hours. After confirming the completion of the reaction by TLC, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 72d (639 mg, yield 69%).

[0204] Compound 72 was synthesized using compound 72d (1.20 mmol, 639 mg) as a starting material, according to the synthesis method for target compound 1. 1 H NMR (400 MHz, Methanol-d4) δ 8.13 - 7.93 (m, 1H), 7.91 - 7.76 (m, 1H), 7.15 (m, J1H), 6.57 - 6.12 (m, 1H), 5.80 - 5.36 (m, 2H), 4.33 - 4.22 (m, 2H), 3.98 - 3.50 (m, 3H), 2.74 (m, 2H), 0.96 (m, 2H).

[0205] Synthesis and characterization of target compound 73: [ka] Compound 70a (2.7 mmol, 1000 mg), KOCN (8.1 mmol, 656 mg), and ACOOH (5.4 mmol, 310 mg) were dissolved in dichloromethane (20 mL) and stirred overnight at room temperature. The mixture was spin-dried and purified by column chromatography to obtain the target compound 73a (1.1 g, yield 96%).

[0206] Compound 73 was synthesized using compound 73a as a starting material, according to the synthesis method for target compound 1. 1 H NMR (400 MHz, MeOD) δ 7.59 - 7.44 (m, 1H), 7.26 - 7.11 (m, 1H), 6.49 - 6.15 (m, 1H), 5.82 - 5.45 (m, 2H), 4.52 (m, 4H), 2.64 (m, 2H), 1.09 (t, 2H). ESI-MS: m / z calculation C 16 H 18 BN4O5[M+H] + 357.1, Measured value: 357.1.

[0207] Synthesis and characterization of target compound 74: [ka] Compound 70a (3 mmol, 1100 mg), aqueous formaldehyde solution (21 mmol, 1.7 g), and ACOOH (30 mmol, 1.8 ml) were dissolved in acetonitrile (20 ml), stirred at room temperature for 30 minutes, and then NaBH3CN (6 mmol, 377 mg) was added. Spin drying and purification by column chromatography yielded the target compound 74a (490 mg, yield 42%). Compound 74 was synthesized using compound 73a as a starting material, according to the synthesis method for target compound 1. ESI-MS: m / z calculation C 16 H 19 BN3O4[M+H] + 328.1, Measured value: 328.1.

[0208] Synthesis and characterization of target compound 75: [ka] Under 0°C and a nitrogen atmosphere, K2CO3 (4.32 mmol, 597 mg), pyrazole-3-carboxyaldehyde (75a, 2.88 mmol, 276 mg), and a5 (2.8 mmol, 1 g) were dissolved in DMF (10 mL) solution and stirred overnight at room temperature. After confirmation of reaction completion by TLC, the reaction mixture was charged into water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography to obtain a white solid 75b (903 mg, yield 86%).

[0209] Compound 75b (4.32 mmol, 597 mg), tert-butyl azetidine-3-carbamate (4.32 mmol, 597 mg), and 9 drops of acetic acid were dissolved in 24 mL of dichloromethane and refluxed for 1 hour. NaBH3CN (4.32 mmol / L, 597 mg) and 9 mL of ethanol were added and the mixture was stirred at room temperature for 17 hours. The mixture was spin-dried and purified by column chromatography to obtain compound 75c (800 mg, yield 70%). Compound 75 was synthesized using compound 75c as a starting material according to the synthesis method for target compound 1. 1 H NMR (400 MHz, MeOD) δ 7.86 (m, 1H), 7.77 - 7.67 (m, 1H), 7.30 - 7.19 (m, 1H), 6.83 (m, 1H), 6.29 - 6.18 (m, 1H), 5.84 - 5.28 (m, 3H), 4.47 - 3.82 (m, 6H), 3.55 - 3.27 (m, 2H). ESI-MS: m / z calculation C 17 H 22 BN4O4[M+H] + 357.2, Measured value: 357.1.

[0210] The beneficial effects of the present invention will be explained below with specific experimental examples. Experimental Example 1

[0211] Inhibitory activity of the compound of the present invention against MBL and SBL 1. Experimental Method The principle of activity measurement is that MBL and SBL enzymes catalyze the reaction with a fluorescent substrate to generate a fluorescent group, and the activity of the enzyme can be reflected by measuring the fluorescence intensity. Activity measurement was performed on a black 96-well microplate, with a total reaction system volume of 60 μL. The specific procedure is as follows.

[0212] (1) The test solid compound was prepared into a mother liquor with a concentration of 100 mM using DMSO. Next, the mother liquor was diluted to a 3.6 mM or 600 μM working solution using either MBL activity measurement buffer (20 mM Tris-HCl pH 7.5, 200 mM NaCl, 0.01% Triton X-100) or SBL activity measurement buffer (50 mM Phosphate, pH 7.0 or 50 mM HEPES, pH 7.2, 200 mM NaCl, 1 μg / ml BSA). Then, the working solution was diluted threefold with the test buffer to obtain 10 working solutions of different concentrations.

[0213] (2) Using the activity test buffer, the MBLs enzymes to be measured (including NDM-1, NDM-5, IMP-1, IMP-4, VIM-1, and VIM-2) and SBLs enzymes (including KPC-2, TEM-1, SHV-12, CTX-M-14, AmpC, and OXA-48) were prepared into enzyme solutions of appropriate concentrations.

[0214] (3) Using the test buffer, the fluorescent substrate FC-5 was prepared as a 30 μM substrate solution and set aside for use in the next step.

[0215] (4) 10 μL of the working solution of the compound obtained in step (1), 30 μL of the test buffer, and 10 μL of the enzyme solution were sequentially dispensed into a 96-well microplate and incubated at room temperature for 10 minutes.

[0216] (5) After incubation was complete, 10 μL of the fluorescent substrate solution was dispensed into each well of a 96-well microplate, and the change in fluorescence value was continuously measured for 6 minutes using a microplate reader under conditions of an excitation wavelength (λex) of 380 nm and an emission wavelength (λem) of 460 nm for fluorescence detection.

[0217] (6) As a control, each experiment included a well without the compound added, and all measurements included three groups of duplicate experiments.

[0218] The residual activity concentration of the enzyme in each well was calculated using the following formula based on the change in fluorescence intensity measured by a microplate reader: Formula: Residual activity concentration (%) = (ΔF1) / (ΔF2) × 100 (where ΔF1 represents the change in fluorescence value of the well containing the test compound over a certain period of time, and ΔF2 represents the change in emission value of the control well without the compound over the same period of time). The processed data was fitted using GraphpadPrism5 software to determine the half-number inhibitory concentration (i.e., IC) of the enzyme. 50 The value was calculated.

[0219] 2. Experimental results The results of the inhibitory activity of the compounds of the present invention against MBL enzyme and SBL enzyme are shown in Tables 1 and 2 below.

[0220] [Table 1-1] [Table 1-2]

[0221] [Table 2-1] [Table 2-2]

[0222] The experimental results described above clearly demonstrate that the compounds of the present invention exhibit good broad-spectrum inhibitory activity against clinically important MBL enzymes (including NDM-1, NDM-5, IMP-1, IMP-4, VIM-1, and VIM-2). Among them, compound 62 showed inhibitory activity of less than 10 nmol against VIM-2, compounds 1, 2, 3, 4, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 29, 30, 31, 32, 33, 34, 36, 37, 38, 42, 44, 47, 49, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 70, 71, 72, 73 and 74 showed inhibitory activity at the nanomolar level (less than 1 μM) against NDM-1 and NDM-5, and compounds 4, 22, 28, 29, 30, 49 Compounds 55, 59, 60, 61, 62, 63, 64, 65, and 70 showed nanomolar (less than 1 μM) inhibitory activity against IMP-1 and / or IMP-4, and compounds 1, 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 28, 29, 30, 42, 44, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 70, 71, 72, 73, and 74 showed nanomolar (less than 1 μM) inhibitory activity against VIM-1 and / or VIM-2. Compared to existing inhibitors, such as tazobactam and avibactam, the compounds of the present invention showed better inhibitory activity against the test subject MBLs. Some of the compounds of the present invention showed MBL inhibitory activity equivalent to that of tanivolbactam, which is in the clinical evaluation process.

[0223] Similarly, the compounds of the present invention were found to exhibit good broad-spectrum inhibitory activity against clinically important SBL enzymes (including KPC-2, TEM-1, SHV-12, CTX-M-14, AmpC, and OXA-48). All compounds of the present invention showed nanomolar (less than 1 μM) inhibitory activity against KPC-2, TEM-1, CTX-M-14, and OXA-48, and were superior to the control drugs tazobactam and tanivolbactam. Among these, several compounds (e.g., 17, 18, 19, 59, 60, 61, 62, 63, 64, 70, 73, 74) showed activity against these four enzymes that was superior to or equivalent to avibactam. Compounds 1-69 and 75 of the present invention showed lower inhibitory activity against SHV-12 than avibactam and tazobactam, but were mostly equivalent to tanivolbactam. The inhibitory activity of compounds 70, 71, 72, 73, and 74 against SHV-12 was equivalent to that of avibactam and tazobactam, and superior to that of tanivolbactam. Compounds 1-58 showed lower inhibitory activity against AmpC than avibactam and tanivolbactam, but were mostly equivalent to that of tazobactam. Compounds 59, 60, 61, 62, 63, 64, 70, 73, and 74 showed equivalent inhibitory activity against AmpC than that of avibactam and tanivolbactam, and superior to that of tazobactam.

[0224] Based on the above, the compounds of the present invention exhibit good inhibitory activity against both MBL enzyme and SBL enzyme, and can be used to produce inhibitors that have a dual effect of inhibiting both MBL and SBL enzymes. Experimental Example 2

[0225] Antibacterial activity of the compound of the present invention in combination with meropenem 1. Test Method (1) Strain resuscitation: Strains stored in a -80°C refrigerator were resuscitated, streaked onto antibiotic-free LB plates using an inoculation loop, and incubated at 37°C for 18-20 hours.

[0226] (2) Dilution of the drug solution: Meropenem solid was weighed and dissolved in DMSO to prepare a mother liquor of 12.8 mg / ml. The mother liquor was diluted with CAMHB medium to a 512 μg / ml working solution. 100 μL of CAMHB was added to a clear 96-well plate, followed by 100 μL of meropenem working solution. Nine concentrations were then obtained by 2-fold dilution, with control wells set up where no meropenem was added. 2 μL of the compound at a concentration of 1 mg was added to each well.

[0227] (3) Dilution of bacterial solution: Single colonies were selected from the plate using an inoculation loop and suspended in physiological saline. OD600 was set to 0.08-0.13 (1 × 10⁻⁶). 8 The bacterial solution was adjusted to the equivalent of CFU / mL, diluted 100-fold with CAMHB, and 100 μL was added to each well. At this time, the concentrations of meropenem ranged from 0.25 to 128 μg / mL, and the concentration of the enzyme inhibitor was 10 μM.

[0228] (4) Static culture and result analysis: 96-well plates were incubated in a 37°C incubator for 16-20 hours. The experimental results were observed the following day, and the minimum concentration that could completely or significantly inhibit bacterial growth was defined as the minimum inhibitory concentration (MIC) of meropenam.

[0229] 2. Test results The antibacterial activity results of clinically isolated bacterial strains obtained by using the compound of the present invention in combination with meropenem are shown in Table 3 below.

[0230] [Table 3-1] [Table 3-2]

[0231] From the experimental results described above, it was revealed that when several compounds of the present invention are used in combination with meropenem, they exhibit good antibacterial activity against clinically isolated drug-resistant strains such as Klebsiella pneumoniae expressing KPC-2 and NDM-1, and Escherichia coli expressing IMP-1. For example, when compounds 1, 2, 7, 8, 9, 10, 13, 14, 16, 17, 21, 22, 23, 24, 31, 36, 37, 38, 39, 40, 41, 42, 43, 45, 48, 49, 50, 56, 57, 58, 63, 64, 66, 67, and 70 are used in combination with meropenem, the measured MIC values ​​against clinically isolated drug-resistant strains were 4 μg / ml or less. These compounds showed antibacterial activity against Klebsiella pneumoniae expressing KPC-2 that was equivalent to the control drugs avibactam and tanivolbactam. However, their antibacterial activity against Escherichia coli expressing IMP-1 and Klebsiella pneumoniae expressing NDM-1 was clearly superior to avibactam and equivalent to tanivolbactam.

[0232] As described above, the present invention provides a 7-((5-membered heterocyclic)methyl)-8-carboxylic acid-benzocyclic borate derivative. The derivative according to the present invention has good broad-spectrum inhibitory activity against metallo-β-lactamases (MBLs) and serine β-lactamases (SBLs) commonly found in clinical practice, and can be used as an inhibitor of MBLs and / or SBLs in the preparation of antimicrobial agents, particularly those that act against drug-resistant bacteria. Furthermore, when used in combination with β-lactam antibiotics, the derivative according to the present invention exhibits good antimicrobial activity against various β-lactam antibiotic-resistant bacteria. The derivative according to the present invention has great potential for dual broad-spectrum inhibitors of MBLs and SBLs and for the preparation of antimicrobial agents to overcome β-lactam antibiotic resistance. The present invention provides a new option for the use of antimicrobial agents and can be expected to have various applications in the future.

Claims

1. A compound represented by the following formula I, or a salt thereof, its conformational isomer, or its optical isomer. 【Chemistry 1】 [In the formula, n is an integer between 0 and 5. R １ C is hydrogen, substituted or unsubstituted. １ ~C ８ Alkyl alkyl group, C １ ~C ８ Alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, and SR ９ Selected from the group consisting of, Ring A is selected from the following group: 【Chemistry 2】 R ２ , R ３ , R ４ , R ５ are substituents on ring A, and R ２ , R ３ , R ４ , R ５ are each independently selected from the group consisting of absence, hydrogen, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, amido group, quaternary ammonium salt, substituted or unsubstituted C １ to C ８ alkyl group, substituted or unsubstituted C ２ to C ８ alkynyl group, C １ to C ８ alkoxy group, substituted or unsubstituted 3- to 8-membered cycloalkyl group, substituted or unsubstituted 4- to 8-membered heterocycloalkyl group, substituted or unsubstituted 5- to 8-membered aryl group, substituted or unsubstituted 5- to 8-membered heteroaryl group, and -COR １０ ​ Alternatively, R ２ , R ３ , R ４ , R ５ The groups at any adjacent site within the molecule are linked to a substituted or unsubstituted 3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 8-membered aryl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group. R ６ , R ７ It is hydrogen, R ９ It is a five-membered unsaturated heterocyclic group, R １０ This is selected from the group consisting of an amino group, a 4-8 membered heterocycloalkyl group, and a 4-8 membered heterocycloalkyl group substituted with an amino group. The substituents of the alkyl group are selected from the group consisting of halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, guanidyl groups, quaternary ammonium salts, sulfonamide groups, and substituted or unsubstituted 4- to 8-membered heterocycloalkyl groups. The substituents of the alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are C １ ~C ８ alkyl group, C １ ~C ８ Aliphatic amine group, C １ ~C ８ Selected from the group consisting of alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, guanidyl groups, and sulfonamide groups, The heteroatoms of the heterocycloalkyl group and heteroaryl group are N, O, or S, and the number of heteroatoms is 1, 2, 3, 4, or 5. One or more hydrogen atoms of the aforementioned amino group are further C １ ~C ８ alkyl group, C １ ~C ８ It may be substituted with an aliphatic amine group or a sulfonamide group.

2. n is 0, 1, 2, 3, 4, or 5. R １ is hydrogen, C １ ~C ４ alkyl group, C １ ~C ４ Alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, and SR ９ Selected from the group consisting of, Ring A is selected from the following group: 【Transformation 3】 R ２ , R ３ , R ４ , R ５ R is a substituent on ring A, ２ , R ３ , R ４ , R ５ Each of these independently represents: non-existent, hydrogen, halogen, hydroxyl group, amino group, nitro group, carboxyl group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C １ ~C ４ Alkyl, substituted, or unsubstituted C ２ ~C ４ Alkynyl group, C １ ~C ４ Alkoxy groups, substituted or unsubstituted 3-6 membered cycloalkyl groups, substituted or unsubstituted 4-6 membered heterocycloalkyl groups, substituted or unsubstituted 5-6 membered aryl groups, substituted or unsubstituted 5-6 membered heteroaryl groups, and -COR １０ Selected from the group consisting of, Alternatively, R ２ , R ３ , R ４ , R ５ The groups at any adjacent site within the molecule are linked to a substituted or unsubstituted 3-6 membered cycloalkyl group, a substituted or unsubstituted 4-6 membered heterocycloalkyl group, a substituted or unsubstituted 5-6 membered aryl group, or a substituted or unsubstituted 5-6 membered heteroaryl group. R ６ , R ７ It is hydrogen, R ９ It is a five-membered unsaturated heterocyclic group having one or more heteroatoms selected from the group consisting of N, O, and S. R １０ This is selected from the group consisting of an amino group, a 4-5 member heterocycloalkyl group, and a 4-5 member heterocycloalkyl group substituted with an amino group. The substituents of the alkyl group are selected from the group consisting of halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, guanidyl groups, quaternary ammonium salts, sulfonamide groups, and substituted or unsubstituted 4- to 6-membered heterocycloalkyl groups. The substituents of the alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are C １ ~C ４ alkyl group, C １ ~C ４ Aliphatic amine group, C １ ~C ４ Selected from the group consisting of alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, guanidyl groups, and sulfonamide groups, The heteroatoms of the heterocycloalkyl group and heteroaryl group are N, O, or S, and the number of heteroatoms is one or two. One or more hydrogen atoms of the aforementioned amino group are further C １ ~C ４ alkyl group, C １ ~C ４ The compound according to claim 1, or a salt thereof, its conformational isomer, or its optical isomer, which may be substituted with an aliphatic amine group or a sulfonamide group.

3. A compound according to claim 1, represented by the following formula III or formula IV, or a salt thereof, its conformational isomer, or its optical isomer: 【Chemistry 4】 (In the formula, rings A, X, Y, Z, W, U, R １ , R ２ , R ３ , R ４ , R ５ This is as defined in claim 1. 【Transformation 7】 (In the formula, rings A, X, Y, Z, W, U, R ２ , R ３ , R ４ , R ５ This is as defined in claim 1. 【Request Item 4】 【Chemistry 6】 (wherein ring A, X, Y, Z, W, U, R ２ , R ３ , R ４ , R ５ are as defined in claim 1.) The compound according to claim 3, or a salt thereof, a conformational isomer thereof, or an optical isomer thereof, wherein the compound is represented by the above formula (V).

5. The following are the compounds described in claim 1, or salts thereof, conformational isomers thereof, or optical isomers thereof: The compound is represented by the following formulas VI-1, VI-2, VI-3, VI-4, VI-5, VI-6, or VI-8. 【Transformation 7】 (In the formula, R ３ , R ４ (This is as defined in claim 1.) 【Transformation 8】 (In the formula, R ４ , R ５ (This is as defined in claim 1.) 【Chemistry 9】 (wherein R ２ , R ４ is as defined in claim 1.) 【Chemistry 10】 (In the formula, R ２ , R ３ , R ４ (This is as defined in claim 1.) 【Chemistry 11】 (In the formula, R ２ , R ４ , R ５ (This is as defined in claim 1.) 【Chemistry 12】 (In the formula, R ２ , R ３ , R ４ , R ５ (This is as defined in claim 1.) 【Chemistry 13】 (In the formula, R ２ , R ３ , R ４ , R ５ (As defined in claim 1.) The substituents of the alkyl group are selected from the group consisting of halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, cyano groups, guanidinyl groups, quaternary ammonium salts, and substituted or unsubstituted 4- to 6-membered heterocycloalkyl groups. The substituents of the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are C １ ~C ４ alkyl group, C １ ~C ４ Selected from the group consisting of alkoxy groups, halogens, hydroxyl groups, amino groups, nitro groups, carboxyl groups, and cyano groups, The heteroatoms of the heterocycloalkyl group and heteroaryl group are N, O, or S, and the number of heteroatoms is one or two. 【Request Item 6】 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 【Chemistry 16-4】 【Chemistry 16-5】 The compound according to any one of claims 1 to 5, wherein the compound is one of the above compounds, or a salt thereof, a conformational isomer thereof, or an optical isomer thereof.

7. Use of a compound according to any one of claims 1 to 5, a salt thereof, a conformational isomer thereof, or an optical isomer thereof in the production of a metallo-β-lactamase and / or serine β-lactamase inhibitor.

8. Use of a compound according to any one of claims 1 to 5, a salt thereof, a conformational isomer thereof, or an optical isomer thereof in the manufacture of an antimicrobial agent.

9. The use according to claim 8, wherein the antibacterial agent is a drug that acts against drug-resistant bacteria.

10. The use according to claim 9, wherein the drug that acts against the drug-resistant bacteria is a drug that acts against β-lactam antibiotic-resistant bacteria.

11. A pharmaceutical product comprising a compound described in any one of claims 1 to 5, a salt thereof, a conformational isomer thereof, or an optical isomer thereof, manufactured by adding a pharmaceutically acceptable additive or auxiliary component.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, a salt thereof, a conformational isomer thereof, or an optical isomer thereof, and an antibiotic.

13. The pharmaceutical composition according to claim 12, wherein the antibiotic is a β-lactam antibiotic.

14. The pharmaceutical composition according to claim 13, wherein the antibiotic is one or more selected from the group consisting of meropenem, imipenem, and cefepime.

15. The use of a compound according to any one of claims 1 to 5, a salt thereof, a conformational isomer thereof, or a photorotational isomer thereof in combination with an antibiotic in the manufacture of an antimicrobial agent.

16. The use according to claim 15, wherein the antibacterial agent is a drug that acts against drug-resistant bacteria, and / or the antibiotic is a β-lactam antibiotic.

17. The use according to claim 16, wherein the drug acting against the drug-resistant bacteria is a drug acting against β-lactam antibiotic-resistant bacteria, and / or the antibiotic is one or more selected from the group consisting of meropenem, imipenem, and cefepime.

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