7-((5-membered heterocyclic ring)methyl)-8-carboxylic acid-benzo-cyclic borate derivative and its use

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 a Chinese patent application filed with the China National Intellectual Property Administration on July 5, 2022, with an application number of 202210784531.9 and an invention title of "7-((5-membered heterocyclic ring)methyl)-8-carboxylic acid-benzo cyclic borate derivative and its use", and a Chinese patent application filed with the China National Intellectual Property Administration on June 21, 2023, with an application number of 202310747738.3 and an invention title of "7-((5-membered heterocyclic ring)methyl)-8-carboxylic acid-benzo cyclic borate derivative and its use", and the entire content thereof is incorporated herein by reference.

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

Background Art

[0003] Currently, the most widely used antibiotics in clinical practice are β-lactam antibiotics such as penicillins, cephalosporins, carbapenems, and monocyclics. Among them, carbapenem antibiotics, as atypical β-lactam antibiotics, have the broadest antibacterial spectrum and the strongest bactericidal power, making them important antibacterial drugs for treating severe bacterial infections clinically and also being called 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 that are resistant to carbapenem are regarded as the most dangerous superbugs, and since there are not enough safe and effective therapeutic drugs developed for them, they have attracted global attention and continuous vigilance. The main drug resistance mechanism of β-lactam antibiotics such as carbapenem antibiotics is that β-lactamase produced by the pathogenic bacteria themselves hydrolyzes the core pharmacophore of the β-lactam ring, resulting in the loss of antibacterial activity of β-lactam antibiotics. Based on the differences in their structures and catalytic mechanisms, β-lactamases are divided into metallo-β-lactamases (MBLs) and serine β-lactamases (SBLs). Since the exchange and transfer of genetic materials of drug resistance genes occur between the same or different pathogenic bacterial species, resistant bacteria co-expressing MBLs and SBLs keep emerging and spreading, posing a great threat to human life and health.

[0004] The combined use of β-lactam antibiotics and β-lactamase inhibitors is one of the most important measures for treating drug-resistant bacterial infections in clinical trials. Currently, six types of serine-β-lactamase (SBL) inhibitors, including clavulanic acid, sulbactam, tazobactam, avibactam, vaborbactam, and relebactam, have been clinically approved and have good clinical therapeutic effects against drug-resistant bacteria producing SBL. However, these commercially available SBL inhibitors have no effect on drug-resistant bacteria producing MBL, and there is still no drug that acts on drug-resistant bacteria producing MBL clinically. According to MBL / SBL dual inhibitors, hydrolysis of β-lactam antibiotics by MBLs and SBLs can be simultaneously blocked. Therefore, such inhibitors not only restore the effectiveness of β-lactam antibiotics against drug-resistant bacteria producing MBL or SBL but are also effective against drug-resistant bacteria producing both MBLs and SBLs. However, due to the different structures and catalytic mechanisms of MBLs and SBLs, the development of MBL / SBL dual inhibitors has become a major challenge, and there is still no inhibitor approved for clinical use so far. Therefore, in order to provide candidate compounds for new drug research to overcome drug-resistant bacteria of β-lactam antibiotics such as carbapenem antibiotics targeting MBL / SBL, the development of MBL / SBL dual inhibitors with higher activity and a broad-spectrum capable of drug discovery is desired.

Summary of the Invention

[0005] The present invention aims to provide 7-((5-membered heterocyclic ring)methyl)-8-carboxylic acid-benzo cyclic borate derivatives and their use as inhibitors of MBL and SBL.

[0006] According to the present invention, there is provided a compound represented by the following formula (I), or a salt, a conformational isomer, or an optical isomer thereof.

Chemical formula

[0007] Furthermore, n is 0, 1, 2, 3, 4 or 5, R1 is selected from the group consisting of hydrogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a halogen, a hydroxy group, an amino group, a nitro group, a carboxy group, a cyano group, and SR9, Ring A is a 5-membered unsaturated heterocyclic ring (wherein 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 each of R2, R3, R4, and R5 is independently absent, hydrogen, halogen, hydroxy group, amino group, nitro group, carboxy 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- to 6-membered cycloalkyl group, substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, substituted or unsubstituted 5- to 6-membered aryl group, substituted or unsubstituted 5- to 6-membered heteroaryl group, and -COR 10 selected from the group consisting of alternatively, the groups at any adjacent sites among R2, R3, R4, and R5 are linked so as to form a substituted or unsubstituted 3- to 6-membered cycloalkyl group, a substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 6-membered aryl group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group; R6 and R7 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C4 alkyl group, C1-C4 alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group, and cyano group; R8 is selected from the group consisting of hydrogen, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, amide 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; R9 is a 5-membered unsaturated heterocyclic group having one or more heteroatoms selected from the group consisting of N, O, and S; R 10 is selected from the group consisting of amino group, 4- to 5-membered heterocycloalkyl group, and 4- to 5-membered heterocycloalkyl group substituted with an amino group; The substituent of the alkyl group is selected from the group consisting of halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, guanidyl group, quaternary ammonium salt, sulfonamide group, and substituted or unsubstituted 4- to 6-membered heterocycloalkyl group. 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 group, C1-C4 aliphatic amine group, C1-C4 alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, guanidyl group, and sulfonamide group. The heteroatoms of the heterocycloalkyl group and heteroaryl group are N, O, or S, and the number of the heteroatoms is 1 or 2. One or more hydrogen atoms of the amino group may be further substituted with a C1-C4 alkyl group, C1-C4 aliphatic amine group, or sulfonamide group.

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

Chemical formula

[0009] Furthermore, R 10 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,

Chemical formula

[0011] Furthermore, when ring A is

Chemical formula

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

[0015] Furthermore, the compound is represented by formula (VI-1), or [Chemical Formula] (In the formula, R3 and R4 are defined as described above.) Alternatively, the compound is represented by formula (VI-2), or [Chemical Formula] (wherein R4 and R5 are defined as described above.) or the compound is represented by formula (VI-3),

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0016] Furthermore, the groups at any adjacent sites among R2, R3, R4, and R5 are linked so as to form a substituted or unsubstituted phenyl group, tetrahydropyrrole group, pyridyl group, or pyrimidine group.

[0017] Furthermore, the groups at any adjacent sites among R2, R3, R4, and R5 are linked so as to form the following group and condensed with ring A.

Chemical formula

[0018] Furthermore, the R 11 is selected from the group consisting of hydrogen, a sulfonamide group, an amide group, a C1-C4 aliphatic amine group, a C1-C4 alkyl group, and a C1-C4 alkoxy group, alternatively, R 11 forms a guanidinyl group together with the N atom linked thereto.

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

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0020] According to the present invention, there is further provided the use of the above-described compound, or a salt thereof, a conformational isomer thereof or an enantiomer thereof, in the production of an inhibitor of metallo-β-lactamase and / or serine-β-lactamase.

[0021] According to the present invention, there is provided the use of the above-described compound, or a salt thereof, a conformational isomer thereof or an enantiomer thereof, in the production of an antibacterial agent, preferably, the antibacterial agent is an agent that acts on drug-resistant bacteria, more preferably, the agent that acts on drug-resistant bacteria is an agent that acts on β-lactam antibiotic-resistant bacteria.

[0022] According to the present invention, there is further provided a pharmaceutical product which is a preparation prepared by using the above-described compound, or a salt, conformational isomer or optical isomer thereof as an active ingredient and adding a pharmaceutically acceptable additive or auxiliary component.

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

[0024] According to the present invention, there is further provided the use of a combination of the above-described compound, or a salt, conformational isomer or optical isomer thereof, and an antibiotic in the manufacture of an antibacterial agent. Preferably, the antibacterial agent is a drug that acts on drug-resistant bacteria and / or the antibiotic is a β-lactam antibiotic. More preferably, the drug that acts on drug-resistant bacteria is a drug that acts on 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 the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0027] Unless otherwise specified, for the definitions of the terms used in the present invention, the initial definitions provided by the groups or terms in this specification apply to the groups or terms throughout the specification. For terms not specifically defined in this specification, they have the meanings understood by those skilled in the art based on the disclosure and context.

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

[0029] In the present invention, the said "substitution" means that a hydrogen atom in a molecule is substituted by another different atom or molecule.

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

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

[0032] In the present invention, "halogen" refers to fluorine, chlorine, bromine and iodine. In the present invention, the "amide group" includes formamide group, acetamide group, propionylamide group, etc. In the present invention, the "quaternary ammonium salt" is

Chemical formula

[0033] In the present invention, the "cycloalkyl group" refers to a saturated or partially saturated non-aromatic cyclic group having 3 to 8 carbon atoms, no ring-constituting heteroatoms, and having a monocyclic or polycyclic (including fused rings, bridged rings, and spiro rings). Examples of the cycloalkyl group include an adamantyl group, a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, and a cyclooctyl group. Examples of the cycloalkyl group including a polydicycloalkyl ring system include a dicyclohexyl group, a dicyclopentyl group, a dicyclooctyl group, etc. Below,

Chemical formula

Chemical formula

[0034] In the present invention, the "heterocycloalkyl group" refers to a saturated or partially saturated non-aromatic cyclic group having a monocyclic or polycyclic (including fused rings, bridged rings, and spiro rings) containing at least one heteroatom. Here, the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of the heterocycloalkyl group include

Chemical formula

[0035] In the present invention, the "aryl group" refers to an aromatic unsaturated group having 5 to 8 carbon atoms, no ring-constituting heteroatoms, and having a monocyclic or polycyclic (including fused rings, bridged rings, and spiro rings), for example, a phenyl group, an anthracene group, a naphthyl group,

Chemical formula

[0036] In the present invention, the "heteroaryl group" refers to an aromatic unsaturated ring having a monocyclic or polycyclic ring (including fused rings, bridged rings, and spiro rings) containing at least one heteroatom. Here, the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. For example, a furyl group, a thienyl group, a pyrrolyl group, a pyridyl group, a pyrazinyl group, a pyrazolyl group, an indazolyl group can be mentioned, and furthermore,

Chemical formula

[0037] In the present invention, the unsaturated heterocyclic ring refers to a heterocyclic ring containing at least one double bond, and may be a heteroaryl group or a heterocycloalkyl group.

[0038] In the present invention,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0039] According to the present invention, 7-((5-membered heterocyclic ring)methyl)-8-carboxylic acid-benzo cyclic borate derivatives are provided. The derivatives according to the present invention have good broad-spectrum inhibitory activity against both metallo-β-lactamases (MBLs) and serine-β-lactamases (SBLs) commonly seen in clinical practice, and are used for preparing antibacterial agents, particularly antibacterial agents acting against drug-resistant bacteria, as inhibitors of MBL and / or SBL. In addition, the derivatives according to the present invention have good antibacterial activity against various β-lactam antibiotic-resistant bacteria when used in combination with β-lactamase-based antibiotics. The derivatives according to the present invention have great potential in the preparation of double broad-spectrum antibacterial spectrum inhibitors of MBL and SBL and antibacterial drugs that overcome β-lactam antibiotic-resistant bacteria. According to the present invention, a new option is provided for the use of antibacterial agents, and various future applications can be expected.

[0040] According to the above content of the present invention, it is obvious that according to the general technical knowledge and common means in the art, various other forms of modifications, substitutions or changes may be made without departing from the basic technical idea of the present invention.

[0041] Hereinafter, the above content of the present invention will be further described in more detail in an exemplary form with reference to specific embodiments. However, it should not be understood that the scope of the above subject matter of the present invention is limited only to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention.

Embodiments for Carrying out the Invention

[0042] The raw materials and devices 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

Chemical formula

[0044] Here, the abbreviations of related reagents and the names of chemical formulas are as follows. That is, DIEA: N,N - diisopropylethylamine; NBS: N - bromosuccinimide; TFA: trifluoroacetic acid; TFAA: trifluoroacetic anhydride; 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 dropped into 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 temperature was maintained at 0 °C - 5 °C. After the dropping was completed, the ice bath was removed, and the reaction solution was stirred overnight. Subsequently, the reaction solution 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 a yield of 99%. 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 calculated for C 10 H 11 BrO3[M + H] + 259.0, found: 259.0 and 261.0.

[0046] Intermediate a2 (10.36 g, 40 mmol, 1 eq) was dissolved in a 250 mL eggplant-shaped flask containing a mixed solvent of EtOH / H2O (3 / 2, v / v, 48 mL), and KOH (8 M, 21.28 g, 380 mmol, 9.5 eq) was added in several portions. The reaction mixture was stirred at room temperature until it became clear. The reaction mixture was heated to 80 °C and refluxed for 4 hours. After observing the completion of the reaction by TLC, the reaction mixture was cooled to room temperature, and the pH was adjusted to 3 - 4 with 2N 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 a yield of 94%. 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 performing N2 substitution three times, 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 the reaction mixture was cooled to room temperature, the pH was adjusted to 6 - 7 with saturated NaHCO3, and extracted with EA (60 mL × 3). The organic layers were combined, washed with saturated NaCl (60 mL × 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 a yield of 45%. 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: m / z calculated for C 11 H 11 BrO3[M+H]+ 271.0, found: 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. It was concentrated under reduced pressure to remove CCl4 and purified by column chromatography (PE / EA = 300:1 - 170:1, v / v) to obtain the key intermediate a5 (8.28 g, pale yellow solid) in 80% yield. ESI-MS: m / z calculated for C 11 H 10 Br2O3[M+H] + 348.9 Measured value: 348.9.

Example

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

Chem.

[0050] Here, the abbreviations of related reagents and the names of chemical formulas are as follows. That is, K2CO3: Potassium carbonate; DMF: N,N-Dimethylformamide; pdCl2(dppf): [1,1-Bis(diphenylphosphino)ferrocene]palladium dichloride; Et3N: Triethylamine; dppe: 1,2-Bis(triphenylphosphine)ethane; pinBH: Pinacol borane; [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.

Chem.

[0052] The intermediate a6 (1.18 mmol, 1.0 eq), potassium trifluoroethylene borate (1.42 mmol, 1.2 eq) and Pd(dppf)2Cl2 (0.05 mmol, 0.04 eq) were dissolved in a mixed solvent of 20 ml 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 heterogeneous reaction mixture changed to a pale amber color and became slightly turbid. After observing the completion of the reaction by TLC, the orange reaction mixture was cooled to 50 °C, water (20 mL) and ethyl acetate (20 ml) were added. The biphasic reaction mixture was cooled to room temperature, filtered, and washed with ethyl acetate (10 mL × 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 an 81% yield. ESI-MS: m / z calculated for C 15 H16 N3O3[M+H]+ = 286.1, Measured value: 286.1.

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

[0054] The intermediate a8 (0.70 mmol, 1 eq) was dissolved in 10 ml of 1,4-dioxane solution, 6N HCl (10 ml) was added, and the mixture was heated to 100 °C and refluxed for 2 hours. After the completion of the reaction was detected by TCL, it was concentrated under reduced pressure under vacuum, and the residue was recrystallized to obtain the target compound 1 (83 mg) in a 43% yield. 1 1H 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: m / z calculated for C 12 H 13 BN3O4[M+H] + = 274.1, Measured value: 274.1.

[0055] The synthesis and characterization of the target compound 2 are as follows.

Chemical formula

[0056] The synthesis and characterization of the target compound 13 are as follows.

Chemical Structure

[0057] Synthesis and characterization of the target compound 14:

Chemical Structure

[0058] Synthesis and characterization of target compound 15:

Chem.

[0059] Synthesis and characterization of target compound 16:

Chem.

[0060] Synthesis and characterization of the target compound 17:

Chem.

[0061] Synthesis and characterization of the target compound 18:

Chem.

[0062] Synthesis and characterization of target compound 19:

Chem.

[0063] Synthesis and characterization of target compound 20:

Chem.

[0064] Synthesis and characterization of target compound 21:

Chem.

[0065] Synthesis and characterization of target compound 22:

Chem.

[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

Example

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

Chem.

[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 h. After observing the completion of the reaction by TLC, the reaction mixture was concentrated to obtain crude product a9. ESI-MS: m / z calculated for C 22 H 31 BN3O5[M] + = 428.2, found: 428.2.

[0072] The obtained crude product a9 was dissolved in a 5 mL 1,4 - dioxane solution, 6N HCl (5 mL) was added, and the mixture was heated to 100 °C and refluxed for 2 h. After observing the completion of the reaction by TLC, it was concentrated under reduced pressure under vacuum, and target compound 3 (26 mg) was obtained in a 21% yield by preparative liquid chromatography. 11H 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 Calculated for C 13 H 15 BN3O4 [M] + = 288.1, found: 288.2.

Example

[0073] Synthesis of target compounds 4 - 12 The synthetic routes of target compounds 4 - 12 are as follows.

Chem.

[0074] Synthesis of intermediate a10: At 0 °C, NaN3 (260 mg, 4 mmol) was added to a mixed solution of intermediate a5 (696 mg, 2 mmol) in acetone (21 ml) and water (7 ml), and the reaction was carried out at room temperature for 1 hour. After observing the completion of the reaction by TLC, it 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 99% yield. MS calculated 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:

Chem.

[0076] Intermediate a11 (400 mg, 1.06 mmol), potassium trifluoroethylene borate (171 mg, 1.27 mmol), 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 completion of the reaction was observed by TLC, it was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phases were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, evaporated under reduced pressure under vacuum to remove the solvent, and then purified by silica gel chromatography to obtain intermediate a12 (316 mg, 0.97 mmol) in a 91% yield. MS calculated for (C 18 H 21 N3O3): 327.2; MS (ESI, positive) measured: (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 for 16 h under a nitrogen atmosphere. After completion of the reaction was observed by TLC, the reaction mixture was concentrated under reduced pressure, and after silica gel column chromatography, intermediate a13 (356 mg, 0.78 mmol) was obtained in an 81% yield. MS calculated for (C 24 H 34 BN3O5): 455.3; MS (ESI, positive) found: (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 h. After completion of the reaction was observed by TLC, the reaction mixture was concentrated under reduced pressure under vacuum, and the residue was recrystallized to obtain the target compound 4 (45 mg, 0.14 mmol) in a 43% yield. 1 1H 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 calculated for (C 15 H 18 BN3O4): 315.1; MS (ESI, positive) found: (M + H + ): 316.1.

[0079] Synthesis and characterization of the target compound 5:

Chemical Structure

[0080] Synthesis and characterization of target compound 6:

Chem.

[0081] Synthesis and characterization of target compound 7:

Chem.

[0082] Synthesis and characterization of the target compound 8:

Chemical formula

[0083] Synthesis and characterization of the target compound 9:

Chemical formula

[0084] Synthesis and characterization of target compound 10:

Chemical Structure

[0085] Compound a14 (1.05 g, 5.0 mmol) and a15 (528 mg, 5.0 mmol) were dissolved in DMF solution (2.5 ml), Et3N (1.4 ml, 10.0 mmol) was added, and the mixture was reacted overnight at room temperature. After observing the completion of the reaction 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 then purified by silica gel column chromatography to obtain alkynyl intermediate a16 (433 mg, 2.05 mmol, 41%). MS calculated for (C 10 H 17 N3O2): 211.1, MS (ESI, positive) found: (M + H + ): 212.1.

[0086] The specific synthesis method of target compound 4 was followed, except that intermediate a16 synthesized in place of 1 - pentyl was used. The overall yield of the five - step reaction was 8%. 11H 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 calculated for (C 15 H 19 BN6O4 + ): 359.2; MS (ESI, positive) measured: (M + H + ): 359.2.

[0087] Synthesis and characterization of target compound 11:

Chem.

[0088] Synthesis and characterization of target compound 12:

Chem.

Example

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

Chemical formula

[0090] Here, the abbreviations of related reagents and the names of chemical formulas are as follows. That is, 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(diphenylphosphino)ferrocene]palladium dichloride; 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: Isobutylboronic 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 a DMF solution (150 ml), and N2 substitution was performed three times. Subsequently, it was transferred to an oil bath at 100 °C and reacted for 16 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to 6 - 7 with 2N hydrochloric acid solution, and extracted with EA (40 mL × 3). The organic layers were combined, washed with saturated NaCl (50 mL × 2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and then purified by column chromatography (DCM / MeOH = 200:1 - 50:1, v / v) to obtain a18 (792 mg, brown solid) in a yield of 60%. ESI-MS: m / z calculated for C 16 H 15 N3O5[M - H] + 328.1, found: 328.1.

[0092] Intermediate a18 (658 mg, 2 mmol, 1 eq) was dissolved in a 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, stirring was continued at room temperature for 2 hours, and concentrated under reduced pressure to obtain a yellow solid, which was directly used in the next step.

[0093] The solid obtained by concentration under reduced pressure was dissolved in a 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 stirring was continued overnight. After the raw materials had completely reacted, the reaction solution was washed with HCl (0.2N, 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, light yellow solid). 11H 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)(+)-pinandiol diboronato (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 a 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. It was filtered through diatomaceous earth to remove insoluble substances. The filter cake was washed with EA, the filtrates were combined, and extracted with EA (30 mL × 2). The organic layers were combined, washed with saturated NaCl (30 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 a21 (312 mg, colorless oil) in a 45% yield. ESI-MS: m / z calculated for C 25 H 30 BN3O5[M+H] + 464.2, found: 464.2.

[0095] Ultra-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 round-bottom flask that had been purged with N2 three times, transferred to a cold trap at -78 °C, and stirred for 20 minutes. CH2I2 (967 μL, 12 mmol, 12 eq) was slowly added dropwise. When about half of it had been added dropwise, the precipitation of a white solid was observed. After the addition was complete, stirring was continued for 30 minutes. Subsequently, intermediate a21 (463 mg, 1 mmol, 1 eq) was dissolved in ultra-dehydrated DCM (2 mL), slowly added dropwise to the reaction solution, 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 × 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 (8:1 - 4:1, v / v)) to obtain intermediate a22 (248 mg, yellow oil) in a yield of 52%. ESI-MS: m / z calculated for C 26 H 32 BN3O5[M+H] + 478.3, found: 478.3; [M+Na] + 500.2, found: 500.3.

[0096] Intermediate a22 (248 mg, 0.52 mmol, 1 eq) was dissolved in a 1,4-dioxane solution (3 mL), 3N NaOH (3 ml) solution 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 sequentially added. The resulting pale yellow reaction solution was continuously stirred at room temperature for 2 hours. After the completion of the reaction was observed by TLC, it was purified by column chromatography (DCM / MeOH, 50:1 - 10:1, v / v) to obtain the target compound 27 (120 mg, white solid) in a yield of 28%. 1 H 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: Calculated for C 13 H 12 BN3O4 [M+H] + 286.1, found: 286.1; [M+Na] + 308.1, found: 308.1.

[0097] Synthesis and characterization of the target compound 28: [Chemical formula] According to the synthesis method of the above compound 27, using 5-(1H-1,2,3-triazol-1-yl)methyl)-8-bromo-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one as the raw material, finally compound 28 (82 mg, white solid) was obtained. 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: Calculated for C 13 H 12 BN3O4 [M+H] + 286.1, found: 286.1; [M+Na] +308.1, Measured value: 308.1.

Example

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

Chemical formula

[0099] Here, the abbreviations of related reagents and the names of chemical formulas are as follows. That is, 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: methylmagnesium bromide; NaOH: sodium hydroxide; Dioxane: 1,4-dioxane; TFA: trifluoroacetic acid; TES: triethylsilane; i-BuB(OH)2: isobutylboronic acid.

[0100] At room temperature, zinc powder (Zn, 2.4 g, 75 mmol) and a24 (50 mg, 0.37 mmol) were added to ultra-dehydrated THF (15 mL), and then DIBAL-H (0.5 mL, 0.75 mmol, dissolved in toluene at 1.5 M) was added, and the mixture was stirred for 5 minutes. The remaining compound a24 (4.05 g, 15 mmol) was dissolved in ultra-dehydrated THF (15 mL) and slowly added dropwise to the reaction solution. After the addition was completed, 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 solution of intermediate a23 (3.87 g, 11.6 mmol) and Pd(t-Bu3P)2 (176 mg, 0.344 mmol) in ultra-dehydrated THF (50 mL), stirred at room temperature for 1 hour, the reaction solution was concentrated, 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 a yield of 45%. ESI-MS: m / z calculated for 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) dissolved in ultra-dehydrated THF (20 mL) and chloriodomethane (0.49 mL, 6.73 mmol) were added to a 50 mL two-necked flask, pre-cooled at -100 °C (ethanol / liquid nitrogen system) for 20 minutes, and then a solution of n-butyllithium in n-hexane (2.7 mL, 6.73 mmol, 2.5 M) was slowly added dropwise along the wall of the flask, and the dropping was continued for 30 minutes. During this process, the reaction solution was gradually observed to change to yellow and then to pale yellow. After the dropping was completed, stirring was continued 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 wall of the flask over 30 minutes. After the dropping was completed, the reaction was continued at -100 °C for 30 minutes. Subsequently, it was gradually heated to room temperature and reacted overnight. After the completion of the reaction was observed by TLC, it was washed with saturated NaCl (40 mL×2), dried over anhydrous Na2SO4, concentrated under reduced pressure, and then purified by column chromatography with PE / EA (8:1 - 4:1, v / v) to obtain yellow oil a26 (1.08 g) in a yield of 41%. ESI-MS: m / z calculated for C 25 H 31 BClN3O5[M+H] + 500.1, found: 500.1.

[0102] At -78 °C, methylmagnesium bromide (1.03 mL, 3.1 mmol, 3 M THF solution) was slowly added dropwise into a solution of compound a26 (1.03 g, 2.06 mmol) in ultra-dehydrated THF (10 mL), and the reaction mixture was gradually warmed to room temperature and stirred for 18 hours. 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×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 to obtain yellow oily substance a27 (454 mg) in a yield of 46%. ESI-MS: m / z calculated for 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), 3N NaOH (3 mL) solution 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 continuously stirred at room temperature for 2 hours. After observing the completion of the reaction by TLC, it 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 a 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: m / z calculated for C 13 H 14 BN3O4[M + H] + 288.1, Measured value: 288.1.

Example

[0104] Synthesis of target compound 30 Synthesis and characterization of target compound 30:

Chemical formula

[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 observing the completion of the reaction 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 then purified by column chromatography PE / EA (8:1 - 4:1) to obtain compound a28 (345 mg) in a 70% yield. ESI-MS: m / z calculated for C 26 H 34 BN3O6[M + H] + 496.2, found: 496.2.

[0106] Using compound a28, according to the synthetic method of the above compound 29, the target compound 30 (66 mg, white solid) was synthesized in a 36% yield. ESI-MS: m / z calculated for C 13 H 14 BN3O5[M + H] + 304.1, found: 304.1.

Example

[0107] Synthesis of target compounds 31 - 75 Synthesis and characterization of target compound 31: The same procedure as the specific synthetic method of target compound 1 was followed, except that 4-nitro-1H-pyrazole was used instead of 2H-1,2,3-triazole. The total yield of 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: [Chemical formula] Compound 32a (10 mmol, 830 mg) was dissolved in tetrahydrofuran (THF, 30 mL), and di-tert-butyl dicarbonate (11 mmol, 2.4 g) was added. Then, saturated sodium bicarbonate solution (5.5 mL) was added. The reaction was carried out at room temperature for 24 hours. After observing the completion of the reaction by TLC, it was extracted with ethyl acetate, evaporated to remove the solvent, and n-hexane was added to form a slurry to obtain intermediate 32b (1.7 g) in a yield of 93%.

[0109] Using intermediate 32b (1.5 mmol, 275 mg) as the raw material, compound 32 was synthesized according to the synthesis method of 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: [Chemical formula] Intermediate 32c (1.2 mmol, 543 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. Then, the reaction was carried out at room temperature for 2 hours. After observing the completion of the reaction by TLC, the excess solvent was evaporated to remove, and a crude product of intermediate 33c was obtained.

[0111] Intermediate 33c, N-Boc-bromoethylamine (1.5 mmol, 248 mg) was dissolved in dichloromethane (2 mL). After adding triethylamine (2.26 mmol, 0.32 mL), the mixture was reacted at 50 °C for 2 hours. After observing the completion of the reaction by TLC, it 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] Using Intermediate 33d (1.5 mmol, 275 mg) as the raw material, Compound 33 was synthesized according to the synthesis method of the 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:

Chemical formula

[0114] Intermediate 34c and Intermediate 33c (1.13 mmol, 528 mg) were dissolved in pyridine (7 mL), triethylamine (2.26 mmol, 0.32 mL) was added, and the reaction was carried out overnight at room temperature. After observing the completion of the reaction by TLC, the excess solvent was removed by evaporation. The residual solid was redissolved in dichloromethane, washed with 1N 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] Using Intermediate 34d (0.56 mmol, 300 mg) as a raw material, Compound 34 was synthesized according to the synthesis method of the 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 the target compound 35:

Chemical formula

[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 reaction was carried out overnight at 75 °C under an argon gas atmosphere. After observing the completion of the reaction by TLC, it was cooled to room temperature, the reaction solution was quenched with saturated sodium sulfate, anhydrous sodium sulfate was added and filtered, and the excess solvent was removed by evaporation to obtain a crude product of Intermediate 35c.

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

[0119] Compound 35e (3 mmol, 1.24 mg) was dissolved in DCM (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was reacted at room temperature for 2 hours. After 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 the raw material, intermediate 35g (200 mg) was synthesized according to the same synthetic method as intermediate 33d. Using intermediate 35g as the raw material, compound 35 was synthesized according to the synthetic method of the target compound 1. ESI-MS: [M+H + : 345.2.

[0121] Synthesis and characterization of the target compound 36:

Chemical formula

[0122] Synthesis and characterization of the target compound 37:

Chemical formula

[0123] Using intermediate 37b (0.26 mmol, 144 mg) as the starting material, intermediate 8d (80 mg, yield 45%) was synthesized according to the same synthetic method as intermediate 1d.

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

[0125] Synthesis and characterization of the target compound 38: Using intermediate 33c as the starting material, the target compound 38 (50 mg) was synthesized according to the same synthetic method as 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 the target compound 39:

Chemical Structure

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

[0128] Subsequently, 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, DBU (13 mmol, 1.97 mL) was added, and then reacted overnight at room temperature under an argon gas atmosphere. After it was observed by TLC that the reaction was complete, it 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 it was observed by TLC that the reaction was complete, it was filtered, and the excess solvent was removed by evaporation to obtain a crude product of intermediate 39e.

[0130] Using intermediate 39f as the raw material, intermediate 39g (750 mg) was synthesized according to the same synthetic method as intermediate 35c. Using intermediate 39g (3.55 mmol, 750 mg) as the raw material, the target compound 39 (100 mg) was synthesized according to the same synthetic method as 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:

Chemical Structure

[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, followed by reacting overnight at room temperature. After observing 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] Using intermediate 40c (3.5 mmol, 1.2 g) as the raw material, intermediate 40d (650 mg, yield 83%) was synthesized according to the same synthetic method as intermediate 39f. Using intermediate 40d (2.91 mmol, 650 mg) as the raw material, intermediate 40e (498 mg, yield 35%) was synthesized according to the same synthetic method as intermediate 40c.

[0134] Using 40e (1 mmol, 492 mg) as the raw material, compound 40 (100 mg) was synthesized according to the synthetic method of the 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 the target compound 41:

Chemical formula

[0136] Using Intermediate 41b (1.78 mmol, 880 mg) as a raw material, Compound 41 (300 mg, yield 69%) was synthesized according to the synthesis method of the 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 the target compound 42: (1H-Pyrazol-3-yl)methylamine was used as a raw material, and the target compound 42 (300 mg) was synthesized according to the synthesis method of the target compound 1. The total yield of the five 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 the target compound 43:

Chemical formula

[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, cooled to 0 °C, and methanesulfonyl chloride (8.9 mmol, 0.9 mL) was added. Then it was reacted at room temperature for 2 hours. After observing 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, then heated to 70 °C and reacted for 4 - 5 hours. After observing the completion of the reaction by TLC, it was extracted with ethyl acetate and water, the solvent was removed by evaporation, and intermediate 43d (1.2 g) was obtained after column chromatography.

[0141] Using 43d as the raw material, compound 43 (115 mg) was synthesized according to the synthetic method of the 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 the target compound 44:

Chemical formula

[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 observing the completion of the reaction by TLC, it was cooled to room temperature, and after column chromatography, intermediate 44b (7 g, yield 43%) was obtained.

[0144] Using intermediate 44b (18 mmol, 7 g) as a raw material, intermediate 44c (4 g, yield 47%) was synthesized according to the synthetic method of intermediate a5.

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

[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 reaction was carried out overnight at room temperature under an argon gas atmosphere. After observing the completion of the reaction by TLC, the reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, the solvent was removed by evaporation, and after column chromatography, intermediate 44f (377 mg, yield 21%) was obtained.

[0147] Using intermediate 44f (0.63 mmol, 377 mg) as a raw material, compound 44 (20 mg) was synthesized according to the synthetic method of the target compound 1. 11H 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 the Target Compound 45: [Chemical formula]

[0149] The 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 observing the completion of the reaction by TLC, the reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the solvent was removed by evaporation to obtain the intermediate 45a (1.7 g, yield 52%).

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

[0151] The intermediate 45d was dissolved in methanol (6 mL), di-tert-butyl dicarbonate (0.9 mmol, 200 mg) and triethylamine (0.9 mmol, 0.3 mL) were added, and the mixture was reacted at room temperature overnight. After observing the 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, the intermediate 45e (635 mg) was obtained.

[0152] Using 45e (1.08 mmol, 635 mg) as the raw material, target compound 45 (20 mg) was synthesized according to the synthesis method of the target compound. 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:

Chemical formula

[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, then di-tert-butyl dicarbonate (10 mmol, 2.2 g) was added, and the reaction was carried out overnight at room temperature. After observing the completion of the reaction by TLC, extraction was performed 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 tetrakis(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 and reacted for 3 hours under an argon gas atmosphere. After observing the completion of the reaction by TLC, it 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 the starting material, target compound 46 (40 mg) was synthesized according to the synthetic method of 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:

Chemical formula

[0158] Using compound 47a (2.42 mmol, 439 mg) as the starting material, target compound 47 (100 mg) was synthesized according to the synthetic method of 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:

Chemical formula

[0160] Using N-BOC-4-pentyn-1-amine (2.2 mmol, 420 mg) as the starting material, intermediate 48b (706 mg, yield 72%) was synthesized according to the synthetic method of intermediate 41b. Using intermediate 48b (1.43 mmol, 706 mg) as the starting material, compound 48 (60 mg) was synthesized according to the synthetic method of target compound 37. 11H 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: [Chemical formula]

[0162] Using Intermediate 47c (1.77 mmol, 781 mg) as the raw material, Intermediate 49a was synthesized according to the synthesis method of Intermediate 33c. Using Intermediate 49a as the raw material, Intermediate 49b was synthesized according to the synthesis method of Intermediate 37b. Using 49b (0.5 mmol, 289 mg) as the raw material, Target Compound 49 (30 mg) was synthesized according to the synthesis method of Target Compound 1. 1 1H 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: [Chemical formula]

[0164] Using Intermediate 43i (0.47 mmol, 203 mg) as the raw material, Target Compound 50 (50 mg) was synthesized according to the synthesis method of Target Compound 48. 11H 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 the target compound 51:

Chemical formula

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

Chemical formula

[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 reaction was carried out at room temperature overnight under an argon gas atmosphere. After observing the completion of the reaction by TLC, extraction was performed with ethyl acetate and water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the excess solvent was removed by evaporation. After column chromatography, intermediate 52b (1.03 g, yield 48%) was obtained.

[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 sequentially added. The mixture was heated to 100 °C under an argon gas atmosphere and reacted for 14 hours. After completion of the reaction was observed by TLC, the mixture was cooled to room temperature, extracted with ethyl acetate and water, the solvent was removed by evaporation, mixed with n-pentane to form a slurry, and intermediate 52c (772 mg, yield 60%) was obtained.

[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, and the reaction was carried out at 0 °C for 2 - 3 hours. After completion of the reaction was observed 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, triethylamine (1.12 mL) was added, and the reaction was carried out overnight at room temperature. After completion of the reaction was observed 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[(+)-pinandiolato]diboron (2 mmol, 720 mg), Pd(dppf)Cl2 (0.13 mmol, 98 mg), and potassium acetate (5.4 mmol, 526 mg) were sequentially added. The mixture was heated to 60 °C under an argon gas atmosphere and reacted for 2 hours. After completion of the reaction was observed by TLC, the mixture was cooled to room temperature, extracted with ethyl acetate and water, the excess solvent was removed by evaporation, and intermediate 52f (300 mg, 37%) was obtained after column chromatography. Using intermediate 52f (0.5 mmol, 300 mg) as the starting material, the 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:

Chem.

[0173] Diethylzinc (4.4 mmol, 4.45 mL) was dissolved in anhydrous DCM (3.5 mL), cooled to -78 °C, then diiodomethane (6.6 mmol, 0.59 ml) was added. After stirring for 30 minutes, a DCM (2.5 ml) solution of 52f (334 mg, 0.55 mmol) was added. After slowly heating to room temperature, the reaction was carried out for 24 hours. After observing the completion of the reaction by TLC, the solvent was removed by evaporation to obtain the crude products of 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 reaction was carried out at room temperature for 1 hour. After observing 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 of 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 of target compound 1. ESI-MS: [M+H + :326.1.

[0177] Synthesis and Characterization of Target Compound 55: Compound 55 was synthesized according to the synthesis method of Target Compound 1 using 7H-pyrazolopyrimidine instead of 2H-1,2,3-triazole. The total yield of 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). ESI-MS: m / z calculated for C 16 H 14 BN3O4[M+H] + 324.1, found: 324.1.

[0178] Synthesis and Characterization of Target Compound 56: Using Intermediate 52b as the raw material, Compound 56 (30 mg) was synthesized according to the synthesis method of Target Compound 1. 1 H 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: m / z calculated for C 15 H 17 BN3O4[M+H] + 314.1, found: 314.1.

[0179] Synthesis and Characterization of Target Compound 57:

Chemical Structure

[0180] Synthesis and characterization of the target compound 58:

Chemical Structure

[0181] Synthesis and characterization of the target compound 59: Using tert-butyl (4-ethynylphenyl) carbamate as a raw material, compound 59 was synthesized according to the synthesis method of the target compound 4. 11H 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: m / z calculated for C 18 H 18 BN4O4[M+H] + 365.1, found: 365.2.

[0182] Synthesis and characterization of target compound 60: Using tert-butyl (4-ethynylpyridine) carbamate as the raw material, compound 60 was synthesized according to the synthesis method of target compound 4. 1 1H 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 calculated for C 17 H 17 BN5O4[M+H] + 366.1, found: 366.1.

[0183] Synthesis and characterization of target compound 61: Using tert-butyl (5-ethynyl-pyrimidinyl) carbamate as the raw material, compound 61 was synthesized according to the synthesis method of target compound 4. 1 1H 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 calculated for C16 H 16 BN6O4[M+H] + 367.1, Measured value: 367.1.

[0184] Synthesis and characterization of target compound 62: Using 4-ethynylbenzenesulfonamide as the raw material, compound 62 was synthesized according to the synthesis method of 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 calculated for C 18 H 18 BN4O6[M+H] + 429.1, Measured value: 429.1.

[0185] Synthesis and characterization of target compound 63: Using tert-butyl (4-ethynylbenzyl) carbamate as the raw material, compound 63 was synthesized according to the synthesis method of 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: m / z calculated for C 18 H 18 BN4O6[M+H] + 379.1, Measured value: 379.2.

[0186] Synthesis and characterization of target compound 64:

Chemical Structure

[0187] Synthesis and characterization of the target compound 65: Using tert-butyl (4-ethynylphenylethyl) carbamate as the raw material, compound 65 was synthesized according to the synthesis method of the 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 the target compound 66: Compound 66 was synthesized according to the synthesis method of the 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 calculated for C 15 H 17 BN3O4[M+H] + 314.1, found: 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:

Chemical Structure

[0191] Under a nitrogen 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 a DMF (10 mL) solution and stirred at 80 °C overnight. After observing the completion of the reaction by TLC, the reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, concentrated, and then 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 at room temperature to a solution of zinc powder (6.6 mmol, 429 mg) and a borate compound (0.3 mmol, 75 mg) in anhydrous tetrahydrofuran (5 mL). After stirring the mixture for 5 minutes, a solution of the borate 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 was mixed with a solution of compound 68a (1.1 mmol, 620 mg) and Pd(t-Bu3P)2 (0.03 mmol, 14 mg) in THF (8 mL), and the reaction was carried out for 1 hour under a N2 atmosphere. After concentration, it was directly purified by silica gel chromatography to obtain compound 68b (627 mg, yield 82%). ESI-MS: calculated m / z for C 37 H 55 BN3O9[M + H] + 696.4, found: 696.4.

[0193] Under an argon gas atmosphere, a solution of DCM (2 mmol, 170 mg) in THF (4 mL) 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 solution of compound 68b (0.8 mmol, 550 mg) in THF (3 mL) was added dropwise. The mixture was gradually heated to room temperature and stirred overnight, and then spin-dried to obtain compound 68c. ESI-MS: calculated m / z for C 38 H 56 BClN3O9[M + H] + 744.4, found: 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, it 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, 6 N HCl (3 mL) was added, and the mixture was heated to 100 °C and refluxed for 2 hours. After the completion of the reaction was observed by TLC, it was concentrated under reduced pressure, 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: m / z calculated for C 16 H 17 BN5O4S2[M + H] + 418.1, found: 418.1.

[0196] Synthesis and characterization of the target compound 69:

Chemical Structure

[0197] Compound 69a (0.09 mmol, 70 mg) was dissolved in 3 mL of 1,4-dioxane solution. After adding 6N HCl (3 mL), the mixture was heated to 100 °C and refluxed for 2 hours. After observing the completion of the reaction by TLC, it was concentrated under reduced pressure 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: m / z calculated for C 15 H 19 BN3O5[M+H] + 332.1, found: 332.2.

[0198] Synthesis and characterization of the target compound 70:

Chemical Structure

[0199] Synthesis and characterization of target compound 71: Using 3-cyanopyrrole as the raw material, compound 71 was synthesized according to the synthesis method of target compound 1. The total yield of the four steps was 12%. 1 1H 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: [Chemical formula]

[0201] Compound 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. DMF was added under a N2 atmosphere and the reaction was carried out at 80 °C overnight. After observing the completion of the reaction by TLC, it 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 then purified by silica gel column chromatography to obtain compound 72b (807 mg, yield 62%).

[0202] TFA (2.3 mL) was added dropwise to a solution of compound 72b (1.85 mmol, 807 mg) in DCM at room temperature, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction was observed 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 reaction was carried out at room temperature for 3 hours. 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 concentrated under reduced pressure. Then, it was purified by silica gel column chromatography to obtain compound 72d (639 mg, yield 69%).

[0204] Using compound 72d (1.20 mmol, 639 mg) as the starting material, compound 72 was synthesized according to the synthesis method of the 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 the target compound 73:

Chemical Structure

[0206] Using compound 73a as a raw material, compound 73 was synthesized according to the synthesis method of the 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 calculated for C 16 H 18 BN4O5[M+H] + 357.1, found: 357.1.

[0207] Synthesis and characterization of the target compound 74:

Chem.

[0208] Synthesis and characterization of the target compound 75:

Chem.

[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 stirred at room temperature for 17 hours. It was spin-dried and purified by column to obtain compound 75c (800 mg, yield 70%). Using compound 75c as the raw material, compound 75 was synthesized according to the synthesis method of the 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 calculated for C 17 H 22 BN4O4[M+H] + 357.2, found: 357.1.

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

[0211] Inhibitory activities of the compounds 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 of a fluorescent substrate to generate a fluorescent group, and the enzyme activity can be reflected by measuring the fluorescence intensity. The activity measurement was carried out on a black 96-well microplate, and the total reaction system was 60 μL. The specific operation procedure is as follows.

[0212] (1) The test solid compound was prepared into a stock solution with a concentration of 100 mM using DMSO. Next, the stock solution was diluted into working solutions of 3.6 mM or 600 μM using 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 solutions were serially diluted 3-fold with the test buffer to obtain 10 working solutions with different concentrations.

[0213] (2) Using the activity test buffer, the MBLs enzymes (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) to be measured were prepared into enzyme solutions with appropriate concentrations.

[0214] (3) Using the test buffer, the fluorescent substrate FC-5 was prepared into a 30 μM substrate solution and prepared 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 the incubation was completed, 10 μL of the fluorescent substrate solution was dispensed per well into the 96-well microplate, and the change in fluorescence value was continuously measured for 6 minutes using a microplate reader under the conditions that the excitation wavelength (λex) was 380 nm and the emission wavelength (λem) was 460 nm.

[0217] (6) As a control, wells without adding the compound were provided for each experiment, and triple replicate experiments were set up for all measurements.

[0218] From the change in fluorescence intensity measured by a microplate reader, the residual activity concentration of the enzyme in each well was calculated by the following formula. Formula: Residual activity concentration (%) = (ΔF1) / (ΔF2) × 100 (where ΔF1 represents the change in fluorescence value within a certain time in the well containing the test compound, and ΔF2 represents the change in luminescence value within the same time in the control well without adding the compound). The processed data was fitted with Graphpad Prism5 software, and the half inhibitory concentration of the enzyme (i.e., IC 50 value) was calculated.

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

[0220]

Table 1-1

Table 1-2

[0221]

Table 2-1

Table 2-2

[0222] From the above experimental results, it was revealed that the compounds of the present invention exhibit good inhibitory activity with a broad spectrum against clinically important MBLs 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, and 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. Compounds 4, 22, 28, 29, 30, 49, 55, 59, 60, 61, 62, 63, 64, 65 and 70 showed inhibitory activity at the nanomolar level (less than 1 μM) against IMP-1 and / or IMP-4. 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 inhibitory activity at the nanomolar level (less than 1 μM) against VIM-1 and / or VIM-2. Compared with existing inhibitors such as tazobactam and avibactam, the compounds of the present invention showed better inhibitory activity against the subject MBLs. Some compounds of the present invention showed MBL inhibitory activity equivalent to that of taniborbactam in the clinical evaluation process.

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

[0224] From the above, the compounds of the present invention have good inhibitory effects against both MBL enzymes and SBL enzymes, and can be used in the production of inhibitors having a dual effect of inhibiting MBL enzymes and SBL enzymes. Experimental Example 2

[0225] Antibacterial activity by the combined use of the compounds of the present invention and meropenem 1. Test method (1) Resuscitation of strains: The strains stored in a -80°C refrigerator were resuscitated, streaked on an antibiotic-free LB plate using an inoculation loop, and cultured 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 stock solution of 12.8 mg / ml. The stock solution was diluted with CAMHB medium to a working solution of 512 μg / ml. 100 μL of CAMHB was added to a transparent 96-well plate, and then 100 μL of the meropenem working solution was added. After that, nine concentrations were prepared by two-fold dilution, and a control well without added meropenem was set. 2 μL of a compound with a concentration of 1 mM was added to each well.

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

[0228] (4) Static culture and result analysis: The 96-well plate was placed in an incubator at 37°C and cultured for 16 - 20 hours. The experimental results were observed the next day, and the minimum concentration that could completely or significantly inhibit the growth of bacteria was defined as the minimum inhibitory concentration (MIC) of meropenem.

[0229] 2. Test results The antibacterial activity results of the clinical isolated strains by the combination of the compound of the present invention and meropenem are shown in Table 3 below.

[0230]

Table 3-1

Table 3-2

[0231] From the above experimental results, it was revealed that when some compounds of the present invention were used in combination with meropenem, they showed 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, 70 were used in combination with meropenem, the measured MIC values against clinically isolated drug-resistant strains were 4 μg / ml or less. These compounds had antibacterial activity against Klebsiella pneumoniae expressing KPC-2 equivalent to that of the control drugs avibactam and tazobactam, but their antibacterial activity against Escherichia coli expressing IMP-1 and Klebsiella pneumoniae expressing NDM-1 was clearly superior to that of avibactam and equivalent to that of tazobactam.

[0232] As described above, according to the present invention, 7-((5-membered heterocycle)methyl)-8-carboxylic acid-benzo cyclic borate derivatives are provided. The derivatives according to the present invention have good inhibitory activity with a broad spectrum against metallo-β-lactamases (MBLs) and serine-β-lactamases (SBLs) commonly found in clinical practice, and can be used for the preparation of antibacterial drugs, particularly drugs acting on drug-resistant bacteria, as inhibitors of MBL and / or SBL. In addition, the derivatives according to the present invention have good antibacterial activity against various β-lactam antibiotic-resistant bacteria when used in combination with β-lactam antibiotics. The derivatives according to the present invention have great potential for the preparation of antibacterial drugs to overcome double broad-spectrum inhibitors of MBL and SBL and β-lactam antibiotic-resistant bacteria. According to the present invention, new options are provided for the use of antibacterial drugs, and various future applications can be expected.

Claims

1. A compound represented by the following formula (I), or a salt thereof, a conformational isomer thereof, or an enantiomer thereof. 【Chemical 1】 [In the formula, n is an integer from 0 to 5, R １ is hydrogen, a substituted or unsubstituted C １ -C ８ alkyl group, C １ -C ８ alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, and SR ９ selected from the group consisting of, Ring A is a 5-membered unsaturated heterocyclic ring (where X, Y, Z, W, and U are each independently selected from the group consisting of C, CR ８ , and N), 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 absent, hydrogen, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C １ -C ８ alkyl group, substituted or unsubstituted C ２ -C ８ alkynyl group, C １ -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 selected from the group consisting of, Alternatively, R ２ 、R ３ 、R ４ 、R ５ The groups of any adjacent sites among R are linked so as to be 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 and R ７ are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted C １ to C ８ alkyl group, a C １ to C ８ alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group, and cyano group. R ８ is selected from the group consisting of hydrogen, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C １ to C ８ alkyl 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, and substituted or unsubstituted 5- to 8-membered heteroaryl group, R ９ is a 5-membered unsaturated heterocyclic group, R １０ is selected from the group consisting of an amino group, a 4- to 8-membered heterocycloalkyl group, and a 4- to 8-membered heterocycloalkyl group substituted with an amino group, the substituent of the alkyl group is selected from the group consisting of halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, guanidyl group, quaternary ammonium salt, sulfonamide group, and a substituted or unsubstituted 4- to 8-membered heterocycloalkyl group, The substituents of the alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are selected from the group consisting of C １ to C ８ alkyl group, C １ to C ８ aliphatic amine group, C １ to C ８ alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, guanidyl group, and sulfonamide group. the heteroatom of the heterocycloalkyl group and heteroaryl group is N, O or S, and the number of the heteroatoms is 1, 2, 3, 4 or 5, One or more hydrogen atoms of the amino group may further be substituted with a C １ -C ８ alkyl group, a C １ -C ８ aliphatic amine group, or a sulfonamide group.]

2. n is 0, 1, 2, 3, 4 or 5, R １ is selected from the group consisting of hydrogen, C １ to C ４ alkyl group, C １ to C ４ alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, and SR ９ and is selected from the group consisting of Ring A is a 5-membered unsaturated heterocyclic ring (wherein X is C, CR ８ or N, Y is N, Z is C, CR ８ or N, W is C or N, and U is C or N), 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 absent, hydrogen, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C １ -C ４ alkyl group, substituted or unsubstituted C ２ -C ４ alkynyl group, C １ -C ４ 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, substituted or unsubstituted 5- to 6-membered heteroaryl group, and -COR １０ is selected from the group consisting of, Alternatively, R ２ , R ３ , R ４ , R ５ The groups of any adjacent sites among them are linked so as to be a substituted or unsubstituted 3- to 6-membered cycloalkyl group, a substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, a substituted or unsubstituted 5- to 6-membered aryl group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group, R ６ and R ７ are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted C １ -C ４ alkyl group, a C １ -C ４ alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group, and cyano group. R ８ is selected from the group consisting of hydrogen, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C １ to C ４ alkyl group, C １ to C ４ 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 R ９ is a 5-membered unsaturated heterocyclic group having one or more heteroatoms selected from the group consisting of N, O, and S, R １０ is selected from the group consisting of an amino group, a 4- to 5-membered heterocycloalkyl group, and a 4- to 5-membered heterocycloalkyl group substituted with an amino group, the substituent of the alkyl group is selected from the group consisting of halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, guanidyl group, quaternary ammonium salt, sulfonamide group, and a substituted or unsubstituted 4- to 6-membered heterocycloalkyl group, The substituents of the alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are selected from the group consisting of C １ to C ４ alkyl group, C １ to C ４ aliphatic amine group, C １ to C ４ alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, guanidyl group, and sulfonamide group. the heteroatom of the heterocycloalkyl group and heteroaryl group is N, O or S, and the number of the heteroatoms is 1 or 2, One or more hydrogen atoms of the amino group may further be C １ to C ４ alkyl group, C １ to C ４ aliphatic amine group, or sulfonamide group, and the compound according to claim 1, or a salt thereof, a conformational isomer thereof, or an optical isomer thereof, characterized in that it may be substituted therewith.

3. The ring A is [Chemical 2] The compound according to claim 1, or a salt thereof, a conformational isomer thereof, or an enantiomer thereof, characterized in that.

4. 【Figure 3】 (wherein n, ring A, X, Y, Z, W, U, R １ , R ２ , R ３ , R ４ , R ５ are as defined in any one of claims 1 to 3.) The compound according to claim 1, or a salt thereof, a conformational isomer thereof, or an enantiomer thereof, characterized in that the compound is represented by the above formula (II).

5. 【Fig. 4】 (wherein, ring A, X, Y, Z, W, U, R １ , R ２ , R ３ , R ４ , R ５ are as defined in any one of claims 1 to 3.) 【Chemical Formula 5】 (wherein ring A, X, Y, Z, W, U, R ２ , R ３ , R ４ , R ５ are as defined in any one of claims 1 to 3.) The compound according to claim 4, or a salt thereof, a conformational isomer thereof, or an enantiomer thereof, characterized in that the compound is represented by the above formula (III) or the compound is represented by the above formula (IV).

6. 【Fig. 6】 (wherein ring A, X, Y, Z, W, U, R ２ , R ３ , R ４ , R ５ are as defined in any one of claims 1 to 3.) The compound according to claim 5, or a salt thereof, a conformational isomer thereof, or an enantiomer thereof, characterized in that the compound is represented by the above formula (V).

7. The compound according to claim 1, or a salt thereof, a conformational isomer thereof, or an enantiomer thereof, characterized in that the compound is represented by the following formula (VI-1), or the compound is represented by the following formula (VI-2), or the compound is represented by the following formula (VI-3), or the compound is represented by the following formula (VI-4), or the compound is represented by the following formula (VI-5), or the compound is represented by the following formula (VI-6), or the compound is represented by the following formula (VI-7), or the compound is represented by the following formula (VI-8). 【Chemical Formula 7】 (wherein R ３ , R ４ is as defined in any one of claims 1 to 3.) [Chemical 8] (wherein R ４ , R ５ is as defined in any one of claims 1 to 3.) 【Chemical Formula 9】 (wherein R ２ , R ４ is as defined in any one of claims 1 to 3.) 【Chemical 10】 (wherein, R ２ , R ３ , R ４ is as defined in any one of claims 1 to 3.) 【Chemical Formula 11】 (wherein, R ２ , R ４ , R ５ is as defined in any one of claims 1 to 3.) 【Chemical 12】 (wherein R ２ , R ３ , R ４ , R ５ are as defined in any one of claims 1 to 3.). 【Chemical 13】 (wherein, R ２ , R ３ , R ４ , R ５ is defined by any one of claims 1 to 3, R ８１ 、R ８２ each independently represents hydrogen, halogen, hydroxy group, amino group, nitro group, carboxy group, cyano group, amide group, quaternary ammonium salt, substituted or unsubstituted C １ -C ４ alkyl group, C １ -C ４ 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, and is selected from the group consisting of The substituent of the 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 substituents of the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are C １ to C ４ alkyl group, C １ to C ４ alkoxy group, halogen, hydroxy group, amino group, nitro group, carboxy group, and cyano group, and are selected from the group consisting of The heteroatom of the heterocycloalkyl group and heteroaryl group is N, O or S, and the number of the heteroatoms is 1 or 2.

8. 【Fig. 14-1】 【Chemical Formula 14-2】 【Chemical 14-3】 【Chemical Formula 14-4】 【Chemical Formula 14-5】 The compound according to any one of claims 1 to 7, or a salt, conformational isomer or optical isomer thereof, characterized in that the compound is one of the above compounds.

9. Use of the compound according to any one of claims 1 to 8, or a salt, conformational isomer or optical isomer thereof, in the manufacture of a metallo-β-lactamase and / or serine β-lactamase inhibitor.

10. Use of the compound according to any one of claims 1 to 8, or a salt, conformational isomer or optical isomer thereof, in the manufacture of an antibacterial agent, preferably, the antibacterial agent is a drug that acts on drug-resistant bacteria, more preferably, the drug that acts on drug-resistant bacteria is a drug that acts on β-lactam antibiotic-resistant bacteria.

11. A pharmaceutical preparation characterized by comprising, as an active ingredient, the compound according to any one of claims 1 to 8, or a salt, conformational isomer or optical isomer thereof, and adding a pharmaceutically acceptable additive or auxiliary component.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a salt, conformational isomer or optical isomer thereof, and an antibiotic, preferably, the antibiotic is a β-lactam antibiotic, more preferably, the antibiotic is one or more selected from the group consisting of meropenem, imipenem, and cefepime.

13. Use of a combination of the compound according to any one of claims 1 to 8, or a salt, conformational isomer or optical isomer thereof, and an antibiotic in the manufacture of an antibacterial agent, preferably, the antibacterial agent is a drug that acts on drug-resistant bacteria, and / or the antibiotic is a β-lactam antibiotic. More preferably, the drug acting on the drug-resistant bacterium is a drug acting on a β-lactam antibiotic-resistant bacterium, and / or the antibiotic is one or more selected from the group consisting of meropenem, imipenem, and cefepime.

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