Cyclopentenone derivatives and their use as antibiotics

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use as a drug, in particular as an antibiotic. The present invention also relates to a pharmaceutical composition comprising said compound of formula (I) and at least one pharmaceutically acceptable excipient. The present invention further relates to a process for preparing a compound of formula (I'). [Formula 1] TIFF2023554322000083.tif2618(I) [Case 2] TIFF2023554322000084.tif2517(I')

Description

[Technical Field]

[0001] This invention relates to the use of cyclopentenone derivatives as drugs, particularly as antibiotics. The invention also relates to novel cyclopentenone derivatives and methods for preparing them. [Background technology]

[0002] Infectious diseases are the leading cause of morbidity and mortality worldwide. In particular, many pathogens are becoming increasingly resistant to widely used antibiotics, posing a major public health problem. The WHO estimates that resistance to available antibiotics could lead to 10 million deaths by 2050. One prime example of this type of resistant bacterium is MRSA (methicine-resistant Staphylococcus aureus). Therefore, a new class of antibiotics effective against a wide range of bacteria is needed. In particular, antibiotics that show selectivity against Gram-negative bacteria are required. Therefore, the inventors investigated cyclopentanone derivatives for use as drugs with broad-spectrum biological activity. In their search for a new class of antibiotics, the inventors surprisingly discovered that the cyclopentanone derivative of formula (I) exhibits strong activity against bacteria, particularly Gram-negative bacteria. The cyclopentenone derivatives disclosed herein have simple chemical structures and are not found in the catalog of traditional antibiotics used in clinics. These molecules are easily accessible and cost-effective. Through their structure, the molecules allow access to various structural analogues and antibiotic combinations, which can provide solutions in difficult-to-treat infection cases. [Overview of the Initiative]

[0003] In a first embodiment, the present invention relates to the following formula (I) for use as a drug: [ka] (I) (wherein X is O or NH, R is H, optionally substituted aryl, C(=O)-C1-C6 alkyl, C(=O)-O-C1-C6 alkyl or Si(C1-C6 alkyl)3, R 2 is H or CH2OR 4 and R 4 is H, C1-C6 alkyl, optionally substituted C1-C6 alkylaryl or C(=O)R 5 and R 5 is optionally substituted aryl or optionally substituted heterocycle, or R 1 and R 2 together represent an optionally substituted heterocycle, R 3 is optionally substituted aryl or optionally substituted heteroaryl) of the compound, and any isomers, diastereoisomers, enantiomers and mixtures thereof, and any pharmaceutically acceptable salts and / or solvates thereof, provided that R 3 and the X-R 1 groups are in the trans position, relates to a compound.

[0004] In a second aspect, the present invention relates to a compound of formula (I) as listed in claims 11, 12 and 13 or a pharmaceutically acceptable salt and / or solvate thereof. In a third aspect, the present invention relates to a method for preparing the compound of formula (I) as described above. In a fourth aspect, the present invention relates to a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. The present invention also relates to the above pharmaceutical composition for use as a drug.

[0005] Definition As used herein, the term "stereoisomer" refers to configurational isomers and more particularly optical isomers. In this invention, optical isomers arise particularly from differences in the spatial positions of substituents on chiral carbon atoms. Optical isomers that are not mirror images of each other are called "diastereoisomers," while optical isomers that are mirror images that cannot be superimposed are called "enantiomers." An equimolar mixture of two enantiomers of a chiral compound is called a racemic mixture or racemate.

[0006] As used herein, the term "pharmaceutically acceptable" is intended to mean a compound or material for pharmaceutical use that is useful in the preparation of pharmaceutical compositions and is generally safe and non-toxic. As used herein, the term “pharmaceutically acceptable salt and / or solvate” refers to a salt and / or solvate of a compound that is pharmaceutically acceptable as defined above and has the pharmacological activity of the corresponding compound. Pharmaceutically acceptable salts are: (1) Acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; or with organic acids, such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L25 tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid and trifluoroacetic acid, and (2) Includes base addition salts formed when an acid proton present in the compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or when it is coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. Acceptable solvates for therapeutic use of the compounds of the present invention include conventional solvates, such as those formed in the final stage of preparation of the compounds of the present invention in the presence of a solvent. Examples include solvates formed in the presence of water (these solvates are also called hydrates) or ethanol. As used in this invention, the term "halogen" refers to a fluorine, bromine, chlorine, or iodine atom.

[0007] As used herein, the term "C1-C6 alkyl" refers to a linear or branched monovalent saturated hydrocarbon chain containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, etc. As used herein, the term “heterocycle” refers to a non-aromatic, saturated or unsaturated monocyclic or polycyclic (including condensed, bridging, or spirocycle) ring containing preferably 5 to 10, particularly 5 or 6, atoms, the ring consisting of carbon atoms and one or more, preferably 1 to 4, more preferably 1 or 2, heteroatoms, such as nitrogen, oxygen, or sulfur atoms, with the remainder being carbon atoms. Heterocycles include, in particular, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, thiazepanyl, benzimidazolonyl, or formula: [ka] It can be coumarin.

[0008] As used herein, the term "aryl" refers to an aromatic hydrocarbon group that preferably comprises 6 to 14 carbon atoms and includes one or more fused rings, such as a phenyl, naphthyl, or phenanthryl group. Advantageously, this is a phenyl group. As used herein, the term "C1-C6 alkylaryl" refers to the alkyl group defined above that is substituted with the aryl group defined above. An example of a "C1-C6 alkylaryl" is the benzyl group.

[0009] As used herein, the term “heteroaryl” refers to an aromatic group comprising one or more, particularly one or two, fused hydrocarbon rings, wherein one or more, particularly one to four, preferably one or two carbon atoms, are each replaced by heteroatoms selected from sulfur, oxygen, and nitrogen atoms, and preferably selected from oxygen and nitrogen atoms. This may be furyl, thienyl, pyrrolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl, or indolyl. Preferably, this is thienyl, thiazolyl, or indolyl.

[0010] When a group is said to be "may be substituted," it means that the group may be substituted with one or more substituents, typically 1 to 3 substituents, including halogens, C1-C6 alkyls, C3-C7 cycloalkyls, C1-C6 haloalkyls, oxo, and NRs. a R b COR c CO2R d CONR e R f , OR g And may be selected from CN, R a ~R g These substituents are independently H or C1-C6 alkyl. In some embodiments, the two substituents may together form a heterocycle. For example, the phenyl group may be substituted with two substituents that together form a heterocycle, such as 1,3-dioxolane. As used herein, the term "C3-C7 cycloalkyl" refers to a saturated hydrocarbon ring containing 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. As used herein, the term "pharmaceutical composition" refers to a composition having preventive and therapeutic properties against bacterial infections. The expression "treatment" is intended to apply to all types of animals, preferably mammals, and more preferably humans. In the case of treatment of non-human animals, it refers to veterinary treatment. [Modes for carrying out the invention]

[0011] Detailed explanation Compound of formula (I) The compound of formula (I) is represented by the following formula: [ka] (I) (In the formula, X is either O or NH. R 1 is H, an optionally substituted aryl, a C(=O)-C1-C6 alkyl, a C(=O)-O-C1-C6 alkyl, or Si(C1-C6 alkyl)3. R 2 is H or CH2OR 4 And R 4 is H, C1-C6 alkyl, optionally substituted C1-C6 alkylaryl, or C(=O)R 5 And R 5 is either a substituted aryl or a substituted heteroalgebra, or R 1 and R 2 This represents a complex ring that may be substituted together, R 3 (is an aryl or heteroaryl that may be substituted.) Compounds of, and all stereoisomers, diastereoisomers, enantiomers and mixtures thereof, and all pharmaceutically acceptable salts and / or solvates thereof, provided that R 3 and XR 1 This indicates a compound in which the group is in the trans position.

[0012] The compound of formula (I) may be in the form of a mixture of stereoisomers, particularly a racemic mixture thereof. The compound of formula (I) may be in the form of a stereoisomer or a mixture of stereoisomers, such as a mixture of enantiomers, such as a racemic mixture. Preferably, the compound is in the form of a racemic mixture of one diastereoisomer as illustrated in this application. The compounds of formula (I) may be represented herein as specific stereoisomers, but such representations encompass all of their stereoisomers, except R 3 and XR 1 It should be understood that the base is in the transform position.

[0013] In some embodiments, substituent R 2 CH2OR 4 Represents R 4 is H, C1-C6 alkyl, optionally substituted C1-C6 alkylaryl, or C(=O)R 5 And R 5 is an optionally substituted aryl or optionally substituted heterocycle. In some embodiments, R 4 H, or possibly be substituted benzyl or C(=O)R 5 And R 5 R is a phenyl or coumarin group that may be substituted. Therefore, for example, R 4 is H or the following base [ka] It may represent one of the following.

[0014] In some preferred embodiments, R 2 represents H or CH2OH. In some preferred embodiments, R 1 is H, an optionally substituted phenyl, C(=O)-methyl, C(=O)-O-tert-butyl, or tert-butyldimethylsilyl group. Preferably, R 1 R is H, C(=O)-methyl, or aryl, and the aryl is either unsubstituted or substituted with one or more groups selected from halogen, C1-C6 haloalkyl, O-C1-C6 alkyl, and C1-C6 alkyl. In particular, R 1If it is an aryl group, it is either unsubstituted or substituted with one or two groups independently selected from halogens, CF3 groups, and OMe groups.

[0015] In some embodiments, X is an NH group. When X is an NH group, R 1 This is preferably the arrow defined above. In some embodiments, X is an oxygen atom. When X is an oxygen atom, R 1 Preferably, it is H or C(=O)-methyl, more preferably H. To have an advantage, R 1 The compound is H or C(=O)-C1-C6 alkyl, preferably H or C(=O)-methyl, and more preferably H. In some other embodiments, R 1 and R 2 These together represent a heterocycle, such as ethylene oxide or 1,3-dioxolane, which is either unsubstituted or substituted with one oxo or C3-C7 cycloalkyl, such as cyclohexyl. In some embodiments, R 1 R is H or C(=O)-C1-C6 alkyl, preferably H or C(=O)-methyl, 2 is H or CH2OH, X is O, R 3 The aryl group, preferably phenyl, may be substituted with one or two groups selected from halogens, fluorine, especially Cl, C1-C6 alkyl and O-C1-C6 alkyl, especially methyl, or with two substituents that together form a 1,3-dioxolane.

[0016] In some embodiments, the compound of formula (I) is R 1 H is O, X is O, R 2 H is R 3 This is a compound as disclosed herein. In some embodiments, the compound of formula (I) is the following formula (I'): [ka] (I') (In the formula, R 3 (The details are disclosed above or below.) It corresponds to. The compound of formula (I') was found to be highly effective against Gram-negative bacteria. The compound of formula (I') may be advantageously selective for Gram-negative bacteria. In some embodiments of compounds of formula (I) or (I'), R 3 This is a heteroaryl selected particularly from thienyl, thiazolyl, or indolyl, wherein the indolyl may be substituted with an alkyl group, such as methyl.

[0017] In some preferred embodiments of the compounds of formula (I) or (I'), R 3 R is one or more groups, preferably 1 to 3, independently selected from halogens, C1-C6 haloalkyls, C1-C6 alkyls, O-C1-C6 alkyls, and CN, or an aryl group, such as phenyl, naphthyl, or anthracenyl, preferably phenyl, which may be substituted with two substituents that together form a heterocycle, such as 1,3-dioxolane. Advantageously, 3 This represents a phenyl group which may be substituted with one or two groups selected from halogens, particularly F or Cl, C1-C6 alkyl and O-C1-C6 alkyl, particularly methyl, or with two substituents that together form a 1,3-dioxolane.

[0018] In a preferred embodiment, the compound of formula (I) is as follows: [ka] TIFF0007840959000007.tif76132 TIFF0007840959000008.tif76150 TIFF0007840959000009.tif32133 TIFF0007840959000010.tif28124 TIFF0007840959000011.tif59129 TIFF0007840959000012.tif33124 TIFF0007840959000013.tif27118 TIFF0007840959000014.tif4090 TIFF0007840959000015.tif50139 TIFF0007840959000016.tif51106 Selected from TIFF0007840959000017.tif5166 and its pharmaceutically acceptable salts and / or solvates.

[0019] More preferably, the compound of formula (I) is: [ka] The following are selected from pharmaceutically acceptable salts and / or solvates thereof.

[0020] More preferably, the compound of formula (I) is: [ka] The following are selected from pharmaceutically acceptable salts and / or solvates thereof.

[0021] More preferably, the compound of formula (I) is: [ka] The following are selected from pharmaceutically acceptable salts and / or solvates thereof.

[0022] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salts and / or solvates are preferably the following: [ka] It is not one of the compounds.

[0023] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is any of the compounds disclosed in the Examples section, i.e., any of compounds (Ia) to (Im). The present invention relates to formula (I): [ka] (I) (In the formula, X is either O or NH. R 1 is H, optionally substituted aryl, C(=O)-C1-C6 alkyl, C(=O)-O-C1-C6 alkyl, or Si(C1-C6 alkyl)3, R 2 CH2OR 4 And R 4 H, or possibly substituted C1-C6 alkylaryl or C(=O)R 5 And R 5 is an optionally substituted aryl or optionally substituted hetero ring, R 3 (is an aryl or heteroaryl that may be substituted.) Compounds of, and all stereoisomers, diastereoisomers, enantiomers and mixtures thereof, and all pharmaceutically acceptable salts and / or solvates thereof, provided that R 3 and XR 1 The group is in the trans position, provided that the compound is as follows: [ka] Regarding compounds that are not compounds.

[0024] In particular, the present invention relates to the compounds If, Ih, Ig, and Ii disclosed in the Examples section. The present invention also relates to compound (Ic) disclosed in the Examples section. Method for preparing the compound of formula (I) The present invention relates to a method for preparing a compound of formula (I) above, in which X is an oxygen atom, or a pharmaceutically acceptable salt and / or solvate thereof, comprising the following steps: (i) Equation (II): [ka] (II) (In the formula, R 2 and R 3 (As defined above) A step of reacting the compound with a C1-C6 alcohol and optionally a Lewis acid under heating, (ii) If necessary, the step of isolating the diastereoisomer of formula (I). Regarding methods including

[0025] Preferably, the compound of formula (II) is as follows: [ka] Selected from.

[0026] Compounds of formula (II) can be obtained using suitable substituents according to methods described in the literature. For example, compounds of formula (II-A) can be obtained starting from furan or 2-fluoraldehyde according to the method described in Wang, H.-Y.; Yang, K.; Bennett, SR; Guo, S.-r.; Tang, W. Angew. Chem. Int. Ed. 2015, 54, 8756-8759, and compounds of formula (II-B) can be obtained starting from hydroxymethylfurfural according to the method described in Rajmohan, R.; Gayathri, S.; Vairaprakash, P. RSC Adv. 2015, 5, 100401-100407. Optionally, additional steps of protection / deprotection and / or functionalization, as well as are well known to those skilled in the art, may be performed on the substituent R described above. 2 and R 3 This may be performed before step (i) in order to obtain the compound of formula (II) using [the specified method].

[0027] The reaction in step (i) is carried out in the presence of a C1-C6 alcohol, such as methanol, ethanol, propanol, butanol, or a mixture thereof, preferably tert-butanol. Advantageously, the C1-C6 alcohol is mixed with water. For example, step (i) is carried out in the presence of a tert-butanol / water mixture in a ratio of 1:1 to 10:1, preferably 5:1. The reaction is preferably carried out under an inert atmosphere, such as a nitrogen (N2) or argon (Ar) atmosphere. The reaction is preferably carried out at a temperature of 18°C ​​to 250°C, preferably 80°C to 100°C. Heating can be achieved under conventional conditions or using microwaves. Preferably, the reaction is carried out using microwaves, which can reduce the reaction time to one-tenth.

[0028] Advantageously, step (i) is carried out in the presence of a Lewis acid, preferably one selected from the group consisting of DyCl3, Dy(OTf)3, Fe(OTf)3, FeCl3.6H2O, ZnCl2, CuCl2, Sc(OTf)3, and combinations thereof. More preferably, the Lewis acid is DyCl3. In step (i), X is an oxygen atom, and R 1 H is R 2 and R 3 A compound of formula (I) is obtained, where the above definition is given. Therefore, the preparation method is R 1 To replace H at the position with another group defined above, an additional functionalization step, well known to those skilled in the art, may be included between step (i) and step (ii).

[0029] The resulting final compound can be isolated, i.e., separated, from the reaction medium in step (ii) by methods well known to those skilled in the art, for example, by extraction, evaporation of the solvent, or by precipitation or crystallization (followed by filtration). The compounds may also be purified as needed by methods well known to those skilled in the art, for example, by recrystallization, distillation, chromatography on a silica gel column, or high-performance liquid chromatography (HPLC). According to another embodiment, the present invention relates to a method for preparing a compound of formula (I) above, or a pharmaceutically acceptable salt and / or solvate thereof, wherein X is an NH group, comprising the following steps: (i) Equation (II) [ka] (II) (In the formula, R 2 and R 3 (As defined above) A step of reacting the compound with a C1-C6 alcohol and optionally a Lewis acid under heating, (ii) If necessary, the step of isolating the diastereoisomer of formula (I). Regarding methods including

[0030] The conditions for processes (I') and (ii') are as defined above for processes (i) and (ii).

[0031] According to a preferred embodiment, the present invention relates to a method for preparing a compound of formula (I') or a pharmaceutically acceptable salt and / or solvate thereof, comprising the following steps: (a) Equation (II-B) [ka] (II-B) (In the formula, R 2 and R 3 (As defined above) A step of reacting the compound with a C1-C6 alcohol and optionally a Lewis acid under microwave heating, (b) If necessary, the step of isolating the diastereoisomer of formula (I). Regarding methods including Preferably, the reaction in step (a) is carried out in the presence of a tert-butanol / water mixture in a ratio of 1:1 to 10:1, preferably 5:1. The reaction is preferably carried out under an inert atmosphere, such as a nitrogen (N2) or argon (Ar) atmosphere. The reaction is preferably carried out at a temperature of 80°C to 100°C, more preferably 100°C. Advantageously, step (a) is carried out in the presence of a Lewis acid, preferably one selected from the group consisting of DyCl3, Dy(OTf)3, Fe(OTf)3, FeCl3.6H2O, ZnCl2, CuCl2, Sc(OTf)3, and combinations thereof. More preferably, the Lewis acid is DyCl3.

[0032] The resulting final compound of formula (I') can be separated from the reaction medium in step (b) by methods well known to those skilled in the art, for example, by extraction, evaporation of the solvent, or by precipitation or crystallization (followed by filtration). The compound can also be purified as needed by methods well known to those skilled in the art, for example, by recrystallization, distillation, chromatography on a silica gel column, or high-performance liquid chromatography (HPLC).

[0033] Pharmaceutical composition The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) disclosed herein or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions of the present invention may be administered orally or parenterally (e.g., subcutaneously, intramuscularly, intravenously), preferably orally or intravenously. The active ingredient may be administered to animals, preferably mammals including humans, in a dosage unit form mixed with a conventional pharmaceutical carrier. For oral administration, the pharmaceutical composition may be in solid or liquid (liquid or suspension) form.

[0034] The solid composition may be in the form of tablets, gelatin capsules, powders, granules, etc. In tablets, the active ingredient may be mixed with a pharmaceutical vehicle, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc., before compression. The tablets may be further coated with sucrose in particular or with other suitable materials, or treated in a manner that provides extended or delayed activity. In powders or granules, the active ingredient may be mixed or granulated with a dispersant, wetting agent or suspending agent and a flavor enhancer or sweetener. In gelatin capsules, the active ingredient may be introduced into soft or hard gelatin capsules in the form of a powder or granules as described above, or in the form of a liquid composition as described later. The liquid composition may contain the active ingredient together with a sweetener, flavor enhancer, or suitable colorant in a solvent, such as water. The liquid composition may also be obtained by suspending or dissolving the powder or granules in a liquid, such as water, juice, or milk, as described above. This may be, for example, a syrup or elixir. For parenteral administration, the composition may be in the form of an aqueous suspension or solution that may contain a suspending agent and / or a wetting agent. The composition is preferably sterile. It may be in the form of an isotonic solution (especially compared to blood). The compounds of the present invention can be used in pharmaceutical compositions in doses ranging from 0.01 mg to 1000 mg per day, administered once daily or several times throughout the day, for example, twice daily. The daily dose is preferably 5 mg to 500 mg, and more preferably 10 mg to 200 mg. However, there may be cases where doses outside these ranges are necessary, which will be recognized by those skilled in the art.

[0035] According to certain embodiments, the compound of formula (I) or its pharmaceutically acceptable salts and / or solvates are present in a pharmaceutical composition in capsule form. This can be encapsulated within polymeric surfactant micelles or liposomes, where the polymeric surfactant is, for example, polysorbate, e.g., polysorbate 80. Such encapsulation can be carried out according to methods well known to those skilled in the art, particularly those described in Gasser, G. et al., J. Am. Chem. Soc. 2020, 142, 6066-6084. Encapsulation is particularly useful for controlling, targeting, and / or extending the release of the compound of formula (I) within the body of the subject requiring it. In particular, encapsulation can improve the bioavailability of the compound of formula (I) or its pharmaceutically acceptable salts and / or solvates, or the pharmaceutical composition, by increasing its apparent water solubility. Therefore, parenteral injection is facilitated.

[0036] treatment The present invention relates to compounds of formula (I) disclosed herein above, or pharmaceutically acceptable salts and / or solvates thereof, or pharmaceutical compositions according to the present invention, for use as drugs, particularly for the treatment of bacterial infections. The present invention relates to the use of compounds of formula (I) according to the present invention, or pharmaceutically acceptable salts and / or solvates thereof, or pharmaceutical compositions according to the present invention, for the manufacture of drugs, and in particular for the treatment of bacterial infections. The present invention also relates to the use of compounds of formula (I) according to the present invention, or pharmaceutically acceptable salts and / or solvates thereof, or pharmaceutical compositions containing them, for the treatment of bacterial infections. The present invention also relates to a method for treating a bacterial infection, comprising administering an effective amount of a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present invention, to a person in need thereof.

[0037] In preferred embodiments, the compounds of formula (I) according to the present invention, or pharmaceutically acceptable salts and / or solvates thereof, or pharmaceutical compositions are useful for treating bacterial infections, such as bacterial infections associated with resistant pathogenic Gram-negative or Gram-positive bacteria. In other words, the compounds of formula (I) according to the present invention, or pharmaceutically acceptable salts and / or solvates thereof, or pharmaceutical compositions are useful as antibiotics, particularly broad-spectrum antibiotics, especially as antibiotics against resistant pathogenic Gram-negative or Gram-positive bacteria. The compounds of formula (I) according to the present invention, or pharmaceutically acceptable salts and / or solvates thereof, or pharmaceutical compositions may be useful in treating bacterial infections associated with drug-resistant pathogenic bacteria involved in urogenital, respiratory, digestive, neuronal, and skin infections.

[0038] Therefore, according to this embodiment, the compound of formula (I) is preferably the following [ka] Furthermore, from the pharmaceutically acceptable salts and / or solubles thereof, more preferably the following [ka] They may also be selected from pharmaceutically acceptable salts and / or solubles thereof.

[0039] For example, bacterial infections can be induced by resistant Gram-negative bacteria selected from Eschericha coli, Enterobacter cloacae, and Acinetobacter baumanii, or by resistant Gram-positive bacteria, such as Staphylococcus aureus.

[0040] Preferably, when the compound of formula (I) is used to treat bacterial infections associated with resistant Gram-negative bacteria, R 1 represents H, R 2 is H or CH2OR 4 Represents R 4is preferably H or C1-C6 alkyl, and X and R 3 are as defined above. More preferably, R 1 represents H, R 2 represents H or CH2OH, X represents O, and R 3 is as defined above. Even more preferably, according to this embodiment, the compound of formula (I) is as follows:

Chemical formula

[0043] [Figure 1] Kirby-Bauer disk diffusion susceptibility testing of Staphylococcus aureus ATCC25923 with compounds Ia, Ib, and Ic at 12.5, 25, 50, and 100 μg, and reference gentamicin at 10 μg; left: graph showing the diameter of the inhibition zone as a function of each sample; right: photographs of petri dishes illustrating the inhibition zones for Ic at 12.5, 25, 50, and 100 μg. [Figure 2] Kirby-Bauer disk diffusion susceptibility testing of Enterobacter cloaca ATCC13047 with compounds Ia and Ib at 12.5, 25, 50, and 100 μg, and reference gentamicin at 10 μg; left: graph showing the diameter of the inhibition zone as a function of each sample; right: photographs of petri dishes illustrating the inhibition zones for Ia at 12.5, 25, 50, and 100 μg. [Figure 3] Kirby-Bauer disk diffusion susceptibility testing of Acinetobacter baumannii ATCC19606 with compounds Ib and Ic at 12.5, 25, 50, and 100 μg, and reference gentamicin at 10 μg; left: graph showing the diameter of the inhibition zone as a function of each sample; right: photograph of petri dishes illustrating the inhibition zones for Ib and Ic at 12.5, 25, 50, and 100 μg. [Figure 4] Kirby-Bauer disk diffusion susceptibility testing of *Escherichia coli* ATCC25922 with compounds Ia and Ib at 12.5, 25, 50, and 100 μg, and reference gentamicin at 10 μg; left: graph showing the diameter of the inhibition zone as a function of each sample; right: photographs of petri dishes illustrating the inhibition zones for Ia at 12.5, 25, 50, and 100 μg. [Examples]

[0044] 1) Synthesis Materials, apparatus and methods The reactions were carried out under an argon atmosphere using oven-dried glassware. All separations were performed under flash chromatography conditions on silica gel (Redi Sep pre-packed column, 230-400 mesh) at medium pressure (20 psi) using CombiFlash Companion, or by preparative HPLC. The reactions were monitored by thin-layer chromatography on Merck silica gel plates (60 F254 aluminum sheets) visualized by UV light and by spraying vanillin (15%) + sulfuric acid (2.5%) in EtOH followed by heating. Reagent-grade chemicals were obtained from various commercial suppliers and used as received. Microwave-assisted reactions were carried out in a 300-microwave reactor using borosilicate glass standard vials G10. A sealed reaction vessel was used. The reaction temperature was monitored with an external sensor and maintained throughout each experiment.

[0045] 1 ¹H NMR (500 or 300 MHz) and ¹³C NMR (125 or 75 MHz) spectra were recorded at 298 K on a Bruker Avance spectrometer unless otherwise specified. Chemical shifts are shown in ppm(δ) and refer to the internal solvent signal. Multiplicity is expressed as follows: s (singlet), brs (broad singlet), d (doublet), t (triplet), q (quadraplet), dd (doublet of doublets), m (multiplet). The bonding constant J is expressed in Hz. Carbon multiplicity was determined by the DEPT135 experiment.

[0046] Infrared spectra (IR) were recorded using a Perkin-Elmer FT-IR system with a Dura SamplIR II diamond window. The data is reported in reciprocal centimeters (cm⁻¹). High-resolution mass spectrometry (HRMS) was performed using electrospray ionization (ESI) and time-of-flight (TOF) analyzers in positive or negative ion detection mode.

[0047] Synthesis of intermediates (Fran-2-yl)phenylmethanol [ka] To a solution of 2-fluoraldehyde (500 mg, 5.20 mmol, 1 equivalent) in anhydrous Et2O (15 mL), phenylmagnesium bromide (1 M solution in Et2O, 6.76 mL, 6.76 mmol, 1.3 equivalents) was added at 0°C under argon. The reaction mixture was stirred from 0°C to room temperature for 2 hours, and then quenched by adding saturated NH4Cl aqueous solution (20 mL). The aqueous layer was extracted three times with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane / Â:100:0~70:30) to obtain the desired carbinol (900 mg, quantified) as a pale yellow oil. Rf(n-heptane / Â 70:30):0.42.

[0048] The spectral data matches that of the compound (CAS number [60907-91-7]) previously described in the literature (D'Auria, M. Heterocycles 2000, 52, 185-194). 1 H NMR (CDCl3, 500.2 MHz) δ 7.45 (bd, J = 7.8 Hz, 2H), 7.40-7.37 (m, 3H), 7.33 (bt, J = 7.8 Hz, 2H), 6.32 (dd, J = 3.2, 1.8 Hz, 1H), 6.12 (d, J = 3.2 Hz, 1H), 5.84 (bs, 1H), 2.38 (bs, 1H). 13C NMR (CDCl3, 75.5 MHz) δ 156.1 (C), 142.7 (CH), 140.9 (C), 128.6 (CH), 128.2 (CH), 126.7 (CH), 110.4 (CH), 107.6 (CH), 70.3 (CH). (4-chlorophenyl)(furan-2-yl)methanol [ka] To a solution of 2-fluoraldehyde (500 mg, 5.20 mmol, 1 equivalent) in anhydrous Et2O (15 mL), 4-chlorophenylmagnesium bromide (1 M solution in Et2O, 6.76 mL, 6.76 mmol, 1.3 equivalents) was added at 0°C under argon. The reaction mixture was stirred from 0°C to room temperature for 2 hours, and then quenched by adding saturated NH4Cl aqueous solution (20 mL). The aqueous layer was extracted three times with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography on silica gel (n-heptane / Âi: 100:0~70:30) to obtain the desired carbinol (1.08 g, quantified) as a pale yellow oil. Rf(n-heptane / Âi 70:30): 0.48.

[0049] The spectral data matches that of the compound previously described in the reference (E. Riva, S. Gagliardi, M. Martinelli, D. Passarella, D. Vigo, A. Rencurosi, Tetrahedron 2010, 66, 3242-3247) (CAS number [143747-66-4]). 1H NMR (CDCl3, 300.2 MHz) δ 7.39 (dd, J = 1.8, 0.8 Hz, 1H), 7.37-7.34 (m, 4H), 6.33 (dd, J = 3.5, 1.8 Hz, 1H), 6.12 (ddd, J = 3.5, 0.8, 0.8 Hz, 1H), 5.81 (bd, J = 3.3 Hz, 1H), 2.44 (bd, J = 3.3 Hz, 1H). 13 C NMR (CDCl3, 75.5 MHz) δ 155.6 (C), 142.9 (CH), 139.3 (C), 134.0 (C), 128.8 (CH), 128.1 (CH), 110.4 (CH), 107.7 (CH), 69.6 (CH). IR (n / cm -1 ) 3343, 1596, 1491, 1407, 1225, 1186, 1141, 1089, 1010, 813, 765, 738. HRMS (ESI+) C 12 H8OCl [M+H-H2O] + Calculated value: 191.0264, Measured value: 191.0263.

[0050] (2-chlorophenyl)(furan-2-yl)methanol [ka] To a solution of furan (2.20 mL, 30.0 mmol, 2.0 equivalents) in anhydrous Et2O (60 mL), n-butyllithium (2.5 M solution in hexane, 7.2 mL, 17.9 mmol, 1.2 equivalents) was added dropwise at 0°C under argon. The reaction mixture was stirred at 0°C for 1 hour and at room temperature for 15 minutes. The mixture was then cooled to -78°C, and 2-chlorobenzaldehyde (2.10 g, 14.9 mmol, 1.0 equivalent) in anhydrous THF (10 mL) was slowly added. The reaction mixture was stirred at -78°C for 2 hours and at room temperature for 1 hour. The mixture was then quenched by adding saturated aqueous NH4Cl (20 mL). The aqueous layer was extracted three times with ethyl acetate (3 × 60 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum to obtain crude carbinol (2.99 g, 96%), which was used without further purification.

[0051] The spectral data matches that of the compound (CAS number [60907-97-3]) previously described in the literature (MB Plutschack, PH Seeberger, K. Gilmore, Organic Letters 2017, 19, 30-33). 1 H NMR (CDCl3, 500.2 MHz) δ 7.68 (dd, J = 7.7, 1.9 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.36-7.32 (m, 2H), 7.26 (td, J = 7.9, 1.9 Hz, 1H), 6.31 (dd, J = 3.3, 1.8 Hz, 1H), 6.22 (bd, J = 3.1 Hz, 1H), 6.08 (d, J = 3.3 Hz, 1H), 2.59 (bd, J = 3.1 Hz, 1H).

[0052] (5-(hydroxymethyl)furan-2-yl)(phenyl)methanol [ka] To a solution of 5-(hydroxymethyl)furfural (1.00 g, 7.93 mmol, 1.0 equivalent) in anhydrous THF (0.25 M), a solution of phenylmagnesium bromide (1.0 M solution in Et2O, 19.8 mL, 19.8 mmol, 2.5 equivalents) was added at 0°C. The reaction mixture was stirred from 0°C to room temperature for 2 hours. The mixture was then quenched with 0.1 M hydrogen chloride solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (10-60% Â / heptane) on silica gel to obtain the desired compound (1.25 g, 77%) as a pale yellow oil. Rf 0.24 (50% Â / heptane).

[0053] 1 H-NMR (acetone-d6, 300 MHz) δ 7.48 -7.44 (m, 2H), 7.37 - 7.28 (m, 3H), 6.16 (d, 1H, J = 3.0 Hz), 6.03 (d, 1H, J = 3.0 Hz), 5.75 (d, 1H, J = 13C-NMR (acetone-d6, 75 MHz) δ 157.8 (C), 156.0 (C), 143.5 (C), 128.9 (CH), 128.2 (CH), 127.5 (CH), 108.2 (CH), 108.0 (CH), 70.3 (CH), 57.4 (CH2); IR (ν / cm-1) 3351, 2866, 1494, 1452, 1365, 1189, 1012, 791, 745, 699; HRMS (ESI) m / z = 187.0757, calculated value of C12H11O2 [M-H2O+H]+: 187.0759.

[0054] (4-Fluorophenyl)(5-(Hydroxymethyl)furan-2-yl)methanol [ka] To a solution of 5-(hydroxymethyl)furfural (450 mg, 3.56 mmol, 1.0 equivalent) in anhydrous THF (0.25 M), a solution of 4-fluorophenylmagnesium bromide (1.0 M solution in THF, 12.5 mL, 12.5 mmol, 3.5 equivalents) was added at 0°C. The reaction mixture was stirred from 0°C to room temperature for 2 hours. The mixture was then quenched with 0.1 M hydrogen chloride solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (10-60% Â / heptane) on silica gel to obtain the desired compound (766 mg, 77%) as a pale yellow solid. Rf 0.46 (60% Â / heptane). Mp: 95-98°C.

[0055] 1 H-NMR (acetone-d6, 300 MHz) δ 7.51-7.47 (m, 2H), 7.13-7.07 (m, 2H), 6.18 (d, J = 3.2 Hz, 1H), 6.06 (d, J = 3.2 Hz, 1H), 5.78 (d, J = 4.8 Hz, 1H), 5.02 (d, J = 4.8 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H), 4.19 (t, J = 6.0 Hz, 1H); 13 C-NMR (acetone-d6, 75 MHz) δ 163.0 (d, JCF = 240 Hz, C), 157.5 (C), 156.0 (CH), 139.6 (CH) , 129.4 (d, JCF = 9 Hz, CH), 115.5 (d, JCF = 21 Hz, CH), 108.2 (CH), 108.1 (CH), 69.6 (CH), 57.3 (CH2); 19F-NMR (acetone-d6, 282 MHz): 60.4; IR (ν / cm-1): 3324, 1604, 1508, 1414, 1221, 1185, 1157, 1011, 843, 800, 777; HRMS (ESI): m / z = 205.0655, calculated value of C12H10O2F [M-H2O+H]+: 205.0665.

[0056] (5-(hydroxymethyl)furan-2-yl)(4-methoxyphenyl)methanol [ka] To a solution of 5-(hydroxymethyl)furfural (600 mg, 4.76 mmol, 1.0 equivalent) in anhydrous THF (0.25 M), a solution of 4-methoxyphenylmagnesium bromide (1.0 M solution in THF, 16.7 mL, 16.7 mmol, 3.5 equivalents) was added at 0°C. The reaction mixture was stirred from 0°C to room temperature for 2 hours. The mixture was then quenched with 0.1 M hydrogen chloride solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (10-60% Â / heptane) on silica gel to obtain the desired compound (1.11 g, 99%) as a pale yellow oil. Rf 0.47 (70% Â / heptane).

[0057] 1 H-NMR (acetone-d6, 300 MHz) δ 7.35 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.16 (d, J = 3.0 Hz, 1H), 6.03 (d, J = 3.0 Hz, 1H), 5.70 (d, J = 4.8 Hz, 1H), 4.81 (d, J = 4.8 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 4.16 (t, J = 6.0 Hz, 1H), 3.78 (s, 3H); 13C-NMR (acetone-d6, 75 MHz) δ160.0 (C), 158.1 (C), 155.8 (C), 135.6 (C), 128.7 (CH), 114.2 (CH), 108.1 (CH), 107.7 (CH), 70.0 (CH), 57.4 (CH2), 55.5 (CH3); IR (ν / cm-1) 3356, 1611, 1512, 1463, 1303, 1247, 1173, 1012, 838, 800, 781; HRMS (ESI): m / z = 217.0863, C13H13O3 Calculated value of [M-H2O+H]+: 217.0865.

[0058] Benzo[d][1,3]dioxol-5-yl(5-(hydroxymethyl)furan-2-yl)methanol [ka] To a magnesium (462 mg, 19.0 mmol, 6.0 equivalents) suspension in anhydrous THF (0.20 M), a few drops of 5-bromo-1,3-benzodioxole and 1,2-dibromoethane were added under argon. The reaction mixture was heated for 2 minutes to initiate the reaction, and 5-bromo-1,3-benzodioxole (2.55 g, 12.7 mmol, 4.0 equivalents) was added dropwise. After refluxing under argon for 2 hours, the mixture was cooled to 0°C, and a solution of 5-(hydroxymethyl)furfural (400 mg, 3.17 mol, 1.0 equivalent) in THF was added dropwise. After stirring from 0°C to room temperature for 2 hours, the reaction was quenched with saturated NH4Cl solution. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (10-60% Â / heptane) on silica gel to obtain the desired compound (262 mg, 33%) as a pale yellow solid. Rf 0.24 (50% Â / heptane). Mp: 90-92°C.

[0059] 1H-NMR (acetone-d6, 300 MHz) δ 6.96 (d, J = 1.5 Hz, 1H), 6.93 (dd, J = 8.0, 1.5 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.17 (d, J = 3.0 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H), 5.97 (s, 2H), 5.68 (d, J = 4.6 Hz, 1H), 4.86 (d, J = 4.6 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H), 4.14 (t, J = 6.0 Hz, 1H); 13 C-NMR (acetone-d6, 75 MHz) δ 157.8 (C), 155.9 (C), 148.5 (C), 147.8 (C), 137.6 (C), 120.9 (CH), 108.5 (CH), 108.2 (CH), 108.0 (CH), 107.7 (CH), 101.9 (CH2), 70.1 (CH), 57.3 (CH2); IR (ν / cm-1) 3329, 1502, 1488, 1443, 1242, 1095, 1036, 1011, 928, 868, 776; HRMS (ESI): m / z = 231.0665, C13H11O4 Calculated value of [M-H2O+H]+: 231.0657.

[0060] (4-Chlorophenyl)(5-(Hydroxymethyl)furan-2-yl)methanol [ka] To a solution of hydroxymethylfurfural (HMF) (500 mg, 3.96 mmol, 1 equivalent) in anhydrous THF (15 mL), magnesium 4-fluorophenyl bromide (1 M solution in Et2O, 9.90 mL, 6.76 mmol, 2.5 equivalents) was added at 0°C under argon. The reaction mixture was stirred from 0°C to room temperature for 2 hours. The mixture was then quenched by adding 1 M aqueous HCl (15 mL). The aqueous layer was extracted three times with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / Ã:100:0~50:50) on silica gel to obtain the desired biscarbinol (773 mg, 82%) as a pale yellow solid. Rf(n-heptane / Ã 50:50):0.31. 1 H-NMR (acetone-d 6, 300.2 MHz) δ 7.47 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.18 (d, J = 3.2 Hz, 1H), 6.07 (d, J = 3.2 Hz, 1H), 5.78 (d, J = 4.8 Hz, 1H), 5.09 (d, J = 4.8 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H), 4.20 (t, J = 5.8 Hz, 1H). 13 C-NMR (acetone-d6, 75.5 MHz) δ157.2 (C), 156.2 (C), 142.4 (C), 133.4 (C), 129.2 (CH), 129.0 (CH), 108.3 (CH), 108.2 (CH), 69.6 (CH), 57.3 (CH2).IR (ν / cm -1 ) 3350, 2871, 1666, 1490, 1408, 1189, 1089, 1013, 843, 799, 774. HRMS (ESI+): m / z = 221.0364, C 12 H 10 O2Cl [M+H-H2O] + Calculated value: 221.0369.

[0061] (Fran-2-yl)(4-methoxyphenyl)methanol [ka] To a solution of 4-bromoanisole (500 mg, 2.67 mmol, 1.0 equivalent) in anhydrous THF (15 mL), n-butyllithium (1.6 M solution in hexane, 1.8 mL, 2.94 mmol, 1.1 equivalent) was added dropwise at -78°C under argon. The reaction mixture was stirred at -78°C for 30 minutes, and flualdehyde (0.23 mL, 2.81 mmol, 1.05 equivalent) was added. The reaction mixture was stirred at -78°C for 2 hours, and quenched with saturated NH4Cl solution (10 mL). The aqueous layer was extracted three times with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / siRNA: 100:0~60:40) on silica gel to obtain the desired compound (443 mg, 81%) as a pale orange oil. Rf(n-heptane / siRNA 70:30): 0.27.

[0062] The spectral data matches that of the compound previously described in the reference (Nandy, SK; Liu, J.; Padmapriya, AA Tetrahedron Lett. 2008, 49, 2469-2471) (CAS number [100518-86-3]). 1 H NMR (CDCl3, 500 MHz): 7.39 (bs, 1H), 7.36 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.32-6.31 (m, 1H), 6.12 (d, J = 3.3 Hz, 1H), 5.79 (d, J = 3.3 Hz, 1H), 3.81 (s, 3H). IR (ν / cm- 1): 1739, 1610, 1511, 1463, 1303, 1248, 1175, 1032, 838, 742. HRMS (ESI): m / z = 187.0751, C 12 H 11 O2[M-H2O+H] + Calculated value: 187.0759.

[0063] (Fran-2-yl)(3-methoxyphenyl)methanol [ka] Furfural (150 mg, 1.56 mmol, 1.0 equivalent), 3-methoxybenzeneboric acid (474 ​​mg, 3.12 mmol, 2.0 equivalents), acetylacetonate dicarbonyl rhodium (I) (12 mg, 0.04 mmol, 3 mol%) and 1,1'-ferrocenediyl-bis(diphenylphosphine) (26 mg, 0.04 mmol, 3 mol%) were dissolved in DME (5 mL) and water (3 mL) under argon. The reaction mixture was stirred at 80°C for 16 hours. The aqueous layer was extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / ethyl acetate) on silica gel. The residue was further purified by flash chromatography (n-heptane / ÃO:100:0~40:60) on silica gel to obtain the desired compound (278 mg, 87%) as a pale orange oil. Rf(n-heptane / ÃO 70:30):0.27.

[0064] The spectral data matches that of the compound previously described in the reference (DeBerardinis, AM; Turlington, M.; Ko, J.; Sole, L.; Pu, LJ Org. Chem. 2010, 75, 2836-2850) (CAS number [944523-02-8]). 1H NMR (CDCl3, 300 MHz): δ 7.39 (dd, J = 1.8, 0.9 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.02-6.99 (m, 2H), 6.88-6.84 (m, 1H), 6.32 (dd, J = 3.0, 1.8 Hz, 1H), 6.14 (dd, J = 3.0, 0.9 Hz, 1H), 5.81 (bs, 1H), 3.81 (s, 3H). 13 C NMR (CDCl3, 75 MHz): δ 159.9 (C), 155.9 (C), 142.7 (CH), 142.6 (C), 129.6 (CH), 119.0 (CH), 113.8 (CH), 112.0 (CH), 110.4 (CH), 107.6 (CH), 70.2 (CH), 55.4 (CH3). IR (ν / cm- 1 ): 3419, 1585, 1489, 1464, 1454, 1434, 1255, 1143, 1037, 1009, 882, 748, 694. HRMS (ESI): m / z = 187.0737, C 12 H 11 O2[M-H2O+H] + Calculated value: 187.0759.

[0065] (Furan-2-yl)(naphthalene-2-yl)methanol [ka] To a solution of 2-bromonaphthalene (600 mg, 2.90 mmol, 1.0 equivalent) in anhydrous THF (25 mL), n-butyllithium (1.6 M solution in hexane, 4.0 mL, 6.37 mmol, 2.2 equivalents) was added dropwise at -78°C under argon. The reaction mixture was stirred at -78°C for 30 minutes, and flualdehyde (0.31 mL, 3.77 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at -78°C for 3 hours, and quenched with saturated NH4Cl aqueous solution (10 mL). The aqueous layer was extracted three times with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / Âi:100:0~30:70) on silica gel to obtain the desired compound (309 mg, 48%) as a pale orange oil. Rf(n-heptane / Âi 50:50):0.39.

[0066] The spectral data matches that of the compound previously described in the reference (Kuriyama, M.; Shimazawa, R.; Shirai, RJ Org. Chem. 2008, 73, 1597-1600) (CAS number [944649-38-1]). 1 H NMR (acetone-d6, 300 MHz): δ 8.01 (s, 1H), 7.92-7.86 (m, 3H), 7.60 (dd, J = 1.7, 8.6 Hz, 1H), 7.58-7.45 (m, 3H), 6.36 (dd, J = 3.3, 1.7 Hz, 1H), 6.23 (dd, J = 3.3, 0.7 Hz, 1H), 6.01 (d, J = 4.5 Hz, 1H), 5.15 (d, J = 4.5 Hz, 1H). 13C NMR (acetone-d6, 75 MHz): δ 158.3 (C), 143.0 (CH), 141.0 (C), 134.2 (C), 133.9 (C), 128.8 (CH), 128.5 (CH), 128.3 (CH), 126.9 (CH), 126.6 (CH), 125.9 (CH), 125.8 (CH), 110.9 (CH), 107.4 (CH), 70.3 (CH). IR (ν / cm- 1 ): 3371, 1738, 1602, 1508, 1365, 1217, 1142, 1122, 1010, 782, 742. HRMS (ESI): m / z = 207.0814, C 15 H 11 O [M-H2O+H] + Calculated value: 207.0810.

[0067] (Furan-2-yl)(naphthalene-1-yl)methanol [ka] Furfural (250 mg, 2.60 mmol, 1.0 equivalent), 1-Naphthaleneboric acid (895 mg, 5.20 mmol, 2.0 equivalent), Acetylacetonate dicarbonyl rhodium (I) (20 mg, 0.08 mmol, 3 mol%) and 1,1'-ferrocendiyl-bis(diphenylphosphine) (43 mg, 0.08 mmol, 3 mol%) were dissolved in DME (6 mL) and water (4 mL) under argon. The reaction mixture was stirred at 80°C for 16 hours. The aqueous layer was extracted three times with ethyl acetate (15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / ethyl acetate) on silica gel. The residue was further purified by flash chromatography (n-heptane / Ã:100:0~50:50) on silica gel to obtain the desired compound (450 mg, 77%) as a pale yellow oil. Rf(n-heptane / Ã 50:50):0.48.

[0068] The spectral data matches that of the compound previously described in the reference (Duan, W.; Ma, Y.; He, F.; Zhao, L.; Chen, J.; Song, C. Tetrahedron Asym. 2013, 24, 241-248) (CAS number [873974-71-1]). 1 H NMR (acetone-d6, 300 MHz): δ 8.16-8.13 (m, 1H), 7.93-7.85 (m, 2H), 7.81 (d, J = 7.3 Hz, 1H), 7.55-7.44 (m, 4H), 6.55 (d, J = 4.6 Hz, 1H), 6.32 (dd, J = 3.3, 1.9 Hz, 1H), 6.13 (d, J = 3.3 Hz, 1H), 5.13 (d, J = 4.6 Hz, 1H). 13 C NMR (acetone-d6, 75 MHz): δ 158.2 (C), 142.8 (CH), 138.8 (C), 134.8 (C), 131.7 (C), 129.4 (CH), 128.9 (CH), 126.6 (CH), 126.3 (CH), 126.2 (CH), 125.2 (CH), 124.9 (CH), 111.0 (CH), 107.8 (CH), 67.7 (CH). IR (ν / cm- 1 ): 3379, 3051, 1757, 1687, 1598, 1510, 1220, 1173, 1141, 1054, 1010, 783. HRMS (ESI): m / z = 207.0815, C 15 H 11 O [M-H2O+H] + Calculated value: 207.0810.

[0069] Synthesis of the compound of formula (I) General means A A suitable intermediate (1 equivalent) solution in a t-BuOH / H2O 5:1 (0.1M) mixture was mixed with DyCl3 (10 mol%). The reaction mixture was heated under MW radiation at 100°C for 1.5 hours. After cooling to room temperature, the mixture was quenched with saturated NaHCO3 solution. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (heptane / ethyl acetate) on silica gel.

[0070] (4S*,5R*)-4-hydroxy-5-phenyl-cyclopenta-2-en-1-one (Ia) [ka] To a solution of (furan-2-yl)phenylmethanol (1.06 mg, 6.08 mmol, 1 equivalent) in t-BuOH / H2O 5:1 (0.077 M solution, 65 mL and 13 mL respectively), Dy(OTf)3 (371 mg, 0.61 mmol, 10 mol%) was added, and the reaction mixture was immediately placed in an oil bath preheated to 80°C. The resulting reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature and injected into a saturated NaHCO3 aqueous solution. This mixture was extracted three times with diethyl oxide (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / Â100:0~50:50) on silica gel to obtain the desired substituted cyclopentenone Ia (850 mg, 80%) as a pale yellow oil. Rf(n-heptane / alkyl 40:60):0.17.

[0071] The spectral data matches that of the compound previously described in the literature (Ulbrich, K.; Kreitmeier, P.; Reiser, O. Synlett 2010, 2037-2040.) (CAS number [70951-36-9]). 1H NMR (CDCl3, 500.2 MHz) δ 7.61 (dd, J = 5.7, 2.2 Hz, 1H), 7.35 (dd, J = 7.5, 7.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 2H), 6.32 (dd, J = 5.7, 1.4 Hz, 1H), 4.97 (bs, 1H), 3.45 (bd, J = 2.8 Hz, 1H), 2.57 (bs, 1H). 13 C-NMR (CDCl3, 75.5 MHz) δ 206.3 (CO), 162.7 (CH), 136.9 (C), 134.0 (CH), 128.9 (CH), 128.4 (CH), 127.5 (CH), 78.7 (CH), 62.0 (CH).

[0072] (4S*,5R*)-5-(4-chlorophenyl)-4-hydroxycyclopenta-2-en-1-one(Ib) [ka] To a solution of (4-chlorophenyl)(furan-2-yl)methanol (340 mg, 1.63 mmol, 1 equivalent) in t-BuOH / H2O 5:1 (0.077 M solution, 18 mL and 3.6 mL respectively), Dy(OTf)3 (99.4 mg, 0.16 mmol, 10 mol%) was added, and the reaction mixture was immediately placed in an oil bath preheated to 80°C. The resulting reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature and injected into a saturated NaHCO3 aqueous solution. This mixture was extracted three times with diethyl oxide (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / ethyl:100:0~50:50) on silica gel to obtain the desired substituted cyclopentenone Ib (242 mg, 71%) as a pale yellow solid. Rf(n-heptane / ا 50:50): 0.25.

[0073] The spectral data matches that of the compound previously described in the reference (Schober, L.; Sako, M.; Takizawa, S.; Groger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154.) (CAS number [2470798-26-4]). 1 H NMR (CDCl3, 500.2 MHz) δ 7.63 (dd, J = 5.8, 2.2 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.35 (dd, J = 5.8, 1.4 Hz, 1H), 4.98 (bs, 1H), 3.45 (bd, J = 3.0 Hz, 1H), 2.26 (bs, 1H). 13 C-NMR (CDCl3, 75.5 MHz) δ 204.8 (CO), 161.8 (CH), 135.3 (C), 134.5 (CH), 133.6 (C), 129.8 (CH), 129.2 (CH), 78.9 (CH), 61.5 (CH). IR (ν / cm -1 ) 3395, 1698, 1590, 1492, 1409, 1338, 1182, 1161, 1091, 1033, 1014, 878, 814, 775. HRMS (ESI+): m / z = 209.0361, C 11 H 10 O2Cl [M+H] + Calculated value: 209.0369.

[0074] (4S*,5R*)-5-(2-chlorophenyl)-4-hydroxycyclopenta-2-en-1-one(Ic) [ka] To a solution of (2-chlorophenyl)(furan-2-yl)methanol (342 mg, 1.64 mmol, 1 equivalent) in t-BuOH / H2O 5:1 (0.077 M solution, 18 mL and 3.6 mL respectively), Dy(OTf)3 (99.4 mg, 0.16 mmol, 10 mol%) was added, and the reaction mixture was immediately placed in an oil bath preheated to 80°C. The resulting reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature and injected into a saturated NaHCO3 aqueous solution. This mixture was extracted three times with diethyl oxide (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / ethyl:100:0~50:50) on silica gel to obtain the desired substituted cyclopentenone Ic (236 mg, 69%) as a pale yellow solid. Rf(n-heptane / Â 50:50): 0.30. 1 H NMR (CDCl3, 500.2 MHz) δ 7.60 (dd, J = 5.8, 2.2 Hz, 1H), 7.43-7.40 (m, 1H), 7.29-7.25 (m, 2H), 7.15-7.11 (m, 1H), 6.41 (dd, J = 5.8, 1.4 Hz, 1H), 5.15 (bs, 1H), 3.77 (bd, J = 3.0 Hz, 1H), 2.39 (bs, 1H). 13 C-NMR (CDCl3, 75.5 MHz) δ 204.0 (CO), 160.8 (CH), 134.9 (C), 134.7 (CH), 134.2 (C), 131.6 (CH), 130.2 (CH), 129.2 (CH), 127.4 (CH), 78.1 (CH), 61.4 (CH). IR (ν / cm -1 ) 3404, 1705, 1475, 1444, 1338, 1161, 1107, 1055, 753. HRMS (ESI+): m / z = 209.0375, C 11 H 10 O2Cl [M+H] + Calculated value: 209.0369.

[0075] (4S*,5R*)-5-(4-chlorophenyl)-4-hydroxy-4-(hydroxymethyl)-cyclopenta-2-en-1-one (Id) [ka] This compound was prepared according to general method A using biscarbinol (4-chlorophenyl)[5-(hydroxymethyl)furan-2-yl]methanol (100 mg, 0.42 mmol, 1 equivalent). 1 H NMR (CDCl3, 300.2 MHz) δ 7.56 (d, J = 5.9 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.38 (d, J = 5.9 Hz, 1H), 3.81 (s, 1H), 3.32 (s, 2H), 1.67 (bs, 1H). 13 C-NMR (CDCl3, 75.5 MHz) δ 204.7 (CO), 162.6 (CH), 134.5 (CH), 134.0 (C), 132.5 (C), 131.1 (CH), 129.2 (CH), 82.0 (C), 66.8 (CH2), 62.6 (CH). IR (ν / cm -1 ) 3404, 2926, 1702, 1592, 1493, 1409, 1339, 1217, 1170, 1091, 1034, 1016, 880. HRMS (ESI+): m / z = 239.0479, C 12 H 12 O3Cl [M+H] + Calculated value: 239.0475.

[0076] (4S*,5R*)-4-acetoxy-5-phenylcyclopenta-2-en-1-one (Ie) [ka] To a solution of (4S*,5R*)-4-hydroxy-5-phenyl-cyclopenta-2-en-1-one (39 mg, 0.22 mmol, 1 equivalent) in acetic anhydride (1.5 mL), toluene-4-sulfonic acid monohydrate (2.3 mg, 0.02 mmol, 10 mol%) was added at 0°C, and the mixture was heated to room temperature for 4 hours. Then, silica gel (500 mg) was added, and the acetic anhydride was removed under reduced pressure to obtain a solid sample, which was then packed into a column chromatograph. The crude product was purified on silica gel (eluent: n-heptane / Âi 0:100~3:7) to obtain the title compound Ie (38 mg, yield 79%) as a colorless oil. Rf (n-heptane / Âi 20:80): 0.38.

[0077] 1 H NMR (CDCl3, 500.2 MHz) δ 7.69 (dd, J = 5.8, 2.3 Hz, 1H), 7.35 (dd, J = 7.3, 7.3 Hz, 2H), 7.29 (dd, J = 7.3, 7.3 Hz, 1H), 7.15 (d, J = 7.3 Hz, 2H), 6.45 (d, J = 5.8 Hz, 1H), 5.93 (bs, 1H), 3.59 (d, J = 2.3 Hz, 1H), 2.11 (s, 3H). 13 C-NMR (CDCl3, 75.5 MHz) δ 204.0 (CO), 170.3 (CO2), 158.3 (CH), 136.2 (C), 136.1 (CH), 128.9 (CH), 128.1 (CH), 127.6 (CH), 79.4 (CH), 57.6 (CH), 20.8 (CH3). IR (ν / cm -1 ) 3062, 3039, 2943, 1739, 1721, 1498, 1454, 1373, 1325, 1229, 1111, 1078, 1027, 977, 931, 910. HRMS (ESI+): m / z = 217.0855, C 13 H 13 O3[M+H] + Calculated value: 217.0865.

[0078] 4-Hydroxy-4-(hydroxymethyl)-5-phenylcyclopenta-2-en-1-one (If) [ka] This compound was prepared according to general method A using 50 mg of (5-(hydroxymethyl)furan-2-yl)(phenyl)methanol (0.25 mmol, 1 equivalent). After flash chromatography (toluene / acetone: 80:20~70:30), If (26 mg, yield 51%, dr 95:5) was obtained as a pale yellow oil. Rf 0.39 (40% acetone / toluene). 1 H-NMR (CDCl3, 300 MHz) δ 7.53 (d, J = 5.8 Hz, 1H), 7.39-7.30 (m, 3H), 7.22-7.16 (m, 2H), 6.40 (d, J = 5.8 Hz, 1H), 3.85 (s, 1H), 3.42-3.33 (m, 2H); 13 IR (ν / cm-1) 3401, 2924, 1699, 1497, 1453, 1338, 1170, 1079, 1033, 925, 814, 739, 699; HRMS (ESI): m / z = 205.0876, C12H13O3 Calculated value of [M+H]+: 205.0865.

[0079] (5-(4-fluorophenyl)-4-hydroxy-4-(hydroxymethyl)cyclopenta-2-en-1-one(Ig) [ka] This compound was prepared according to general method A using 60 mg of (4-fluorophenyl)(5-(hydroxymethyl)furan-2-yl)methanol (0.3 mmol, 1 equivalent). After flash chromatography (heptane / ethyl acetate: 100:0~20:80), Ig (34 mg, yield 59%, dr=90:10) was obtained as a white solid. Rf 0.31 (60% ethyl acetate / heptane). MP: 111~113°C 1 H-NMR (acetone-d6300 MHz)δ7.57 (d, J = 5.9 Hz, 1H), 7.32-7.27 (m, 2H), 7.10-7.03 (m, 2H), 6.31 (d, J = 5.9 Hz, 1H), 4.80 (s, 1H), 3.81 (dd, J = 6.3, 4.8 Hz, 1H), 3.77 (s, 1H), 3.30 (dd, J = 10.8, 4.8 Hz, 1H), 3.16 (dd, J = 10.8, 6.3 Hz, 1H); 13 C-NMR(acetone-d6, 75 MHz) δ 204.3 (C), 163.7 (CH), 162.7 (d, JCF = 241 Hz, C), 134.1 (CH), 133.1 (d, JCF = 9 Hz, CH), 132.0 (C), 115.3 (d, JCF = 21 Hz, CH), 83.3 (C), 66.1 (CH2), 63.8 (CH); 19 F-NMR (acetone-d6, 282 MHz): 60.0; IR (ν / cm-1): 3418, 2919, 1704, 1606, 1510, 1225, 1162, 1035, 841, 812; HRMS (ESI): m / z = 223.0764, calculated value of C12H12FO3 [M+H]+: 223.0770.

[0080] 4-Hydroxy-4-(hydroxymethyl)-5-(4-methoxyphenyl)cyclopenta-2-en-1-one(Ih) [ka] This compound was prepared according to general method A using 70 mg of (5-(hydroxymethyl)furan-2-yl)(4-methoxyphenyl)methanol (0.3 mmol, 1 equivalent). After flash chromatography (heptane / ethyl acetate: 100:0~20:80), Ih (25 mg, yield 35%, dr 95: >5) was obtained as a pale yellow solid. MP: 134~136°C 1 H-NMR (CDCl3, 300 MHz) δ7.51 (d, J = 5.9 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.36 (d, J = 5.9 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 1H), 3.38-3.29 (m, 2H); 13 C-NMR (CDCl3, 75 MHz) δ 205.7 (C), 162.4 (CH), 159.3 (C), 134.7 (CH), 130.8 (CH), 125.9 (C), 114.7 (CH), 82.1 (C), 66.9 (CH2), 62.8 (CH), 55.4 (CH3); IR (ν / cm-1) 3411, 2934, 1703, 1612, 1514, 1250, 1180, 1087, 1033, 836; HRMS (ESI): m / z = 235.0972, Calculated value of C13H15O4 [M+H]+: 235.0970.

[0081] 5-(benzo[d][1,3]dioxol-5-yl)-4-hydroxy-4-(hydroxymethyl)cyclopenta-2-en-1-one(Ii) [ka] This compound was prepared according to general method A using 74.4 mg of benzo[d][1,3]dioxol-5-yl(5-(hydroxymethyl)furan-2-yl)methanol (0.30 mmol). After flash chromatography (heptane / ethyl acetate: 40:60~30:70), Ii (40.4 mg, yield 54%, dr>95:5) was obtained as a brown oily substance. Rf 0.29 (50% ethyl acetate / heptane). 1 H-NMR (CDCl3, 300 MHz) δ 7.52 (d, J = 5.8 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.60 (s, 1H), 6.33 (d, J = 5.8 Hz, 1H), 5.93 (s, 2H), 3.72 (s, 1H), 3.38-3.28 (m, 2H); 13 C-NMR (CDCl3, 75 MHz) δ 205.5 (C), 162.8 (CH), 148.1 (C), 147.3 (C), 134.3 (CH), 127.4 (C), 123.3 (CH), 109.8 (CH), 108.8 (CH), 101.3 (CH2), 82.0 (C), 66.9 (CH2), 63.0 (CH); IR (ν / cm-1) 3411, 2898, 1700, 1504, 1489, 1442, 1234, 1035, 929, 806, 733; HRMS (ESI): m / z = 249.0759, Calculated value of C13H13O5 [M+H]+: 249.0763.

[0082] (4S*,5R*)-4-hydroxy-5-(4-methoxyphenyl)cyclopenta-2-en-1-one(Ij) [ka] To a solution of (furan-2-yl)(4-methoxyphenyl)methanol (80 mg, 0.39 mmol, 1.0 equivalent) in t-BuOH / H2O 5:1 (0.068 M solution, 5 mL and 0.8 mL respectively), DyCl3 (10.5 mg, 0.04 mmol, 10 mol%) was added, and the reaction mixture was immediately placed in an oil bath preheated to 80°C. The resulting reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature and injected into a saturated NaHCO3 aqueous solution. This mixture was extracted three times with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / Âi:70:30~50:50) on silica gel to obtain the desired substituted cyclopentenone (18 mg, 23%) as a pale yellow oil. Rf(n-heptane / acetate 50:50): 0.20. 1 H NMR (CDCl3, 300 MHz): δ 7.61 (dd, J = 6.0, 2.1 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H,), 6.33 (dd, J = 6.0, 1.5 Hz, 1H), 4.96-4.95 (m, 1H), 3.80 (s, 3H), 3.41 (d, J = 3.0 Hz, 1H). 13 C NMR (CDCl3, 75 MHz): δ 205.6 (C), 161.5 (CH), 159.1 (C), 134.7 (CH), 129.5 (CH), 114.6 (CH), 79.3 (CH), 61.7 (CH), 55.5 (CH3). IR (ν / cm- 1 ): 3409, 1705, 1613, 1582, 1514, 1302, 1251, 1179, 1033, 825, 762. HRMS (ESI): m / z = 205.0865, C 12 H 13 O3[M+H] + Calculated value: 205.0865.

[0083] (4S*,5R*)-4-hydroxy-5-(3-methoxyphenyl)cyclopenta-2-en-1-one (Ik) [ka]

[0084] To a solution of (furan-2-yl)(3-methoxyphenyl)methanol (60 mg, 0.29 mmol, 1.0 equivalent) in t-BuOH / H2O 5:1 (0.082 M solution, 3 mL and 0.6 mL respectively), DyCl3 (7.9 mg, 0.03 mmol, 10 mol%) was added, and the reaction mixture was immediately placed in an oil bath preheated to 80°C. The resulting reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature and injected into a saturated NaHCO3 aqueous solution. This mixture was extracted three times with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / Âi:100:0~60:40) on silica gel to obtain the desired substituted cyclopentenone (42 mg, 70%) as a pale yellow oil. Rf(n-heptane / Â 50:50):0.33.

[0085] The spectral data matches that of the compound previously described in the reference (Schober, L.; Sako, M.; Takizawa, S.; Groger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154) (CAS number [2470798-31-1]). 1 H NMR (CDCl3, 300 MHz): δ 7.61 (dd, J = 5.7, 2.4 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.83 (ddd, J =8.0, 2.7, 1.2 Hz, 1H), 6.73-6.66 (m, 2H), 6.33 (dd, J = 5.7, 1.2 Hz, 1H), 4.98 (bs, 1H), 3.82 (s, 3H), 3.40 (d, J = 3.0 Hz, 1H).13 C NMR (CDCl3, 75 MHz): δ 205.2 (C), 161.8 (CH), 160.1 (C), 138.4 (C), 134.6 (CH), 130.1 (CH), 120.7 (CH), 114.4 (CH), 112.9 (CH), 79.1 (CH), 62.2 (CH), 55.4 (CH3). IR (ν / cm- 1 ): 3419, 2940, 1705, 1601, 1584, 1491, 1454, 1437, 1340, 1260, 1157, 1041, 782. HRMS (ESI): m / z = 205.0860, C 12 H 13 O3[M+H] + Calculated value: 205.0865.

[0086] (4S*,5R*)-4-hydroxy-5-(naphthalene-2-yl)cyclopenta-2-en-1-one(Il) [ka] To a solution of (furan-2-yl)(naphthalen-2-yl)methanol (80 mg, 0.36 mmol, 1.0 equivalent) in t-BuOH / H2O 5:1 (0.050 M solution, 6 mL and 1.2 mL respectively), DyCl3 (9.6 mg, 0.04 mmol, 10 mol%) was added, and the reaction mixture was immediately placed in an oil bath preheated to 80°C. The resulting reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature and injected into a saturated NaHCO3 aqueous solution. This mixture was extracted three times with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / Âi:100:0~40:60) on silica gel to obtain the desired substituted cyclopentenone (32 mg, 40%) as a pale orange oil. Rf(n-heptane / ا 50:50): 0.25.

[0087] The spectral data matches that of the compound previously described in the reference (Schober, L.; Sako, M.; Takizawa, S.; Groger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154) (CAS number [1612765-18-0]). 1 H NMR (CDCl3, 500 MHz): δ 7.81-7.74 (m, 3H), 7.56 (s, 1H), 7.50 (dd, J = 5.7, 2.4 Hz, 1H), 7.48-7.46 (m, 2H), 7.07 (dd, J = 8.4, 1.9 Hz, 1H), 6.24 (dd, J = 5.7, 1.5 Hz, 1H), 4.90 (bs, 1H), 3.49 (d, J = 2.9 Hz, 1H). 13 C NMR (CDCl3, 75 MHz): δ 205.8 (C), 162.2 (CH), 138.4 (C), 134.3 (CH), 134.2 (C), 133.5 (C), 132.7 (C), 128.9 (CH), 127.8 (CH), 126.5 (CH), 126.1 (CH), 125.8 (CH), 78.8 (CH), 62.3 (CH). IR (ν / cm- 1 ): 3387, 3054, 2919, 1696, 1633, 1599, 1508, 1336, 1156, 1106, 1032, 907, 813. HRMS (ESI): m / z = 225.0920, C 15 H 13 O2[M+H] + Calculated value: 225.0916.

[0088] (4S*,5R*)-4-hydroxy-5-(naphthalene-1-yl)cyclopenta-2-en-1-one(Im) [ka] To a solution of (furan-2-yl)(naphthalen-1-yl)methanol (100 mg, 0.45 mmol, 1.0 equivalent) in t-BuOH / H2O 5:1 (0.063 M solution, 6 mL and 1.2 mL respectively), DyCl3 (12 mg, 0.05 mmol, 10 mol%) was added, and the reaction mixture was immediately placed in an oil bath preheated to 80°C. The resulting reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature and injected into a saturated NaHCO3 aqueous solution. This mixture was extracted three times with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (n-heptane / Âi:100:0~50:50) on silica gel to obtain the desired substituted cyclopentenone (99 mg, 99%) as a pale orange oil. Rf(n-heptane / ا 50:50): 0.25.

[0089] The spectral data matches that of the compound previously described in the reference (Schober, L.; Sako, M.; Takizawa, S.; Groger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154) (CAS number [2470798-35-5]). 1 H NMR (CDCl3, 300 MHz): δ 7.91-7.86 (m, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.71-7.67 (m, 1H), 7.66 (dd, J = 5.8, 2.3 Hz, 1H), 7.53-7.47 (m, 2H), 7.43 (dd, J = 8.4, 7.1 Hz, 1H), 7.22 (dd, J = 7.1, 1.1 Hz, 1H), 6.48 (dd, J = 5.8, 1.4 Hz, 1H), 5.12 (bs, 1H), 4.07 (d, J = 2.8 Hz, 1H), 2.41 (bs, 1H). 13C NMR (CDCl3, 75 MHz): δ 205.8 (C), 162.1 (CH), 135.0 (CH), 134.4 (C), 133.5 (C), 132.1 (C), 129.3 (CH), 128.5 (CH), 127.3 (CH), 126.7 (CH), 126.0 (CH), 125.7 (CH), 123.6 (CH), 79.0 (CH), 60.5 (CH). IR (ν / cm- 1 ): 3405, 3051, 2920, 1699, 1595, 1510, 1397, 1337, 1158, 1106, 1026, 797, 776, 731. HRMS (ESI): m / z = 225.0913, C 15 H 13 O2[M+H] + Calculated value: 225.0916.

[0090] antibiotic activity Antibiotic activity against trans-configured racemic molecules was evaluated against a panel of pathogenic microorganisms. A. Inhibitory zone technology (Kirby-Bauer disk diffusion susceptibility test) Preparation of pre-inoculation materials Pathogenic bacteria were revived by streaking overnight at 30-37°C in 100 mm Petri dishes containing Luria-Bertani broth (LB, Difco, Thermo Fisher Scientific Inc.), trypsin soy broth (TSB, Difco, Thermo Fisher Scientific Inc.), and nutrient broth (NB, Difco, Thermo Fisher Scientific Inc.), as recommended by the ATCC protocol.

[0091] Preparation of inoculum For each pathogen, several colonies were collected in a loop, transferred to 5 ml of sterile NB medium, and incubated overnight at 30-37°C on a rotary shaker (130 rpm).

[0092] assay A 150 mm nutrient broth agar plate was swabbed with the inoculum and held for 15 minutes for absorption. Sterile 6 mm Whatman No. 1 disks were placed in the Petri dishes, and 12.5, 25, 50, and 100 μg of the test compounds in DMSO (10 mg / ml) were applied to the sterile disk papers. Gentamicin (10 μg), a standard drug, was used as a positive reference standard to determine the susceptibility of each bacterial species, and DMSO was used as a negative control. The plates were then incubated at 30 °C or 37 °C for 24 hours, and the inhibition diameters were measured. Compounds Ia - Ic were also tested for the following pathogenic bacteria to evaluate their inhibitory effectiveness by the Petri dish inhibition zone method: - Staphylococcus aureus ATCC25923 - Gram positive (test compounds Ia, Ib, and Ic) - Enterobacter cloacae ATCC13047 - Gram negative (test compounds Ia and Ib) - Acinetobacter baumannii ATCC19606 - Gram negative (test compounds Ib and Ic) - Escherichia coli ATCC25922 - Gram negative (test compounds Ia and Ib). This technique can visualize the potential to inhibit the growth of target pathogenic bacteria.

[0093] A dose - response study with each of the compounds at 12.5, 25, 50, and 100 μg was conducted by comparing the inhibition zones with 10 μg of gentamicin. The results are shown in Figures 1 - 4. All of the test products Ia, Ib, and / or Ic showed inhibitory activity against each of the test pathogenic bacteria. The best results were obtained against Gram - negative bacteria, especially Enterobacter cloacae, as represented in Figure 2. [[ID=二十二]]Compounds Ib, Ic, Ij, Ik, Il, Im, Ih, Ig, Ii, Id, and If were also tested for the following pathogenic bacteria to evaluate their inhibitory effectiveness by the Petri dish inhibition zone method: - Micrococcus luteus ATCC10240; - Bacillus subtilis ATCC6633; - Escherichia coli ATCC25922. The inhibitory growth percentage with 100 μg of each test compound was determined. The results are shown in the following table.

[0094]

Table 1

[0095] Preparation of inoculum material For each pathogen, several colonies were collected with a loop and transferred to 10 ml of sterile Mueller - Hinton Broth (Sigma) medium and incubated for several hours at 30 - 37 °C on a rotary shaker (130 rpm). The OD at 600 nm was measured and adjusted to 0.5 OD, and then the solution was diluted 400 - fold to obtain a suitable inoculum material.

[0096] Assay Antimicrobial susceptibility was performed by the broth microdilution method. The test was carried out with a final volume of 100 μL of Mueller - Hinton Broth (Sigma) medium and... 5Performed in 96-well plates at a final bacterial concentration of CUF / ml. The test compound was solubilized in dimethyl sulfoxide (DMSO) to obtain a stock solution of 10 mg / mL (then expressed in μM). The stock solution was diluted and tested from 100 μg / mL to 0.195 μg / mL. Compounds Ia - Ie were also tested against Staphylococcus aureus ATCC 25923 strain and Staphylococcus aureus BAA - 1766 (MRSA) strain (both Gram-positive) by using the screening method for MIC (Minimum Inhibitory Concentration) measurement.

[0097] This technique enables determination of the minimum concentration that completely inhibits the growth of the target pathogen. The following table shows that all of the products Ia - Ie exhibit good antibiotic activity. Good antibiotic activity was obtained with molecules Ic - Ie, and the MIC was 6.25 μg / mL.

Table 2

Chemical Structure

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[10] Compounds for use as described in any one of items [1] to [8] above and pharmaceutical compositions as described in item [9] above, for use in treating bacterial infections, such as genitourinary, respiratory, digestive, neuronal and skin infections.

[11] The following equation (I):

change

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change

[11] .

[13] The following formula:

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[14] A method for preparing a compound of formula (I') as defined in [5] or [6] above, or a pharmaceutically acceptable salt and / or solvate thereof, comprising the following steps: (a) Equation (II-B)

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[15] Step (a) is performed in the presence of a Lewis acid, preferably DyCl 3 , Dy(OTf) 3 Fe(OTf) 3 FeCl 3 .6H 2 O, ZnCl 2 CuCl 2 , Sc(OTf) 3 The method according to

[13] , carried out in the presence of a Lewis acid selected from the group consisting of combinations thereof.

Claims

1. Formula (I) below for preparing the drug: 【Chemistry 1】 (I) (In the formula, X is O, R 1 is H or C (=O)-C 1 -C 6 It is alkyl, R 2 is H or CH 2 OR 4 And R 4 H is, R 3 (These are phenyl, naphthyl, or benzodioxolyl groups, which may be substituted with one or more groups selected from halogens and O-C1-C6 alkyl groups, or with two substituents that together form a 1,3-dioxolane.) The compound (wherein in the compound, R 3 and X-R 1 groups are in the trans position), or any stereoisomer thereof (excluding compounds in which the R3 and X-R1 groups are not in the trans position), diastereoisomer (excluding compounds in which the R3 and X-R1 groups are not in the trans position), enantiomer or mixture, or use of any pharmaceutically acceptable salt or solvate thereof, wherein The use of the aforementioned drug is for treating bacterial infections, such as genitourinary, respiratory, digestive, neuronal, and skin infections.

2. R 1 The use according to claim 1, wherein is H or C(=O)-methyl.

3. The compound is given by the following formula (I'): 【Chemistry 2】 (I’) The use according to any one of claims 1 to 2, corresponding to the use described in claim 1 to 2.

4. R 3 However, halogens and O-C 1 -C 6 The use according to any one of claims 1 to 3, wherein the phenyl is substituted with one to three groups selected from alkyl groups, or with two substituents that together form a 1,3-dioxolane.

5. The compounds are as follows: 【Transformation 3】 The use according to claim 1, selected from the group consisting of the following.

6. The compounds are as follows: 【Chemistry 4】 The use according to claim 5, selected from the group consisting of the following.

7. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 6 and at least one pharmaceutically acceptable excipient.

8. The pharmaceutical composition according to claim 7, for use in treating bacterial infections, such as genitourinary, respiratory, digestive, neuronal, and skin infections.

9. The following equation (I): 【Transformation 6】 (I) (In the formula, X is O, R 1 is H or C (=O)-C 1 -C 6 It is alkyl, R 2 CH 2 OR 4 And R 4 H is, R 3 (These are phenyl, naphthyl, or benzodioxolyl groups, which may be substituted with one or more groups selected from halogens and O-C1-C6 alkyl groups, or with two substituents that together form a 1,3-dioxolane.) The compound (however, in the above compound, R 3 and X-R 1 A compound having a trans group, or any stereoisomer thereof (except for compounds in which the R3 and X-R1 groups are not in the trans position), diastereoisomers (except for compounds in which the R3 and X-R1 groups are not in the trans position), enantiomers or mixtures thereof, or any pharmaceutically acceptable salt or solvate thereof.

10. below: 【Transformation 8】 A compound according to claim 9, selected from the group consisting of the following.

11. The following formula: 【Chemistry 10】 A compound of [this].

12. A method for preparing a compound of formula (I') as defined in claim 3 or 4, or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps: (a) Equation (II-B) 【Chemistry 11】 (II-B) (In the formula, R 3 (This is as defined in claim 1 or 4.) The compound C 1 -C 6 A step of reacting in the presence of alcohol and, optionally, a Lewis acid, under microwave heating. (b) If necessary, the step of isolating diastereoisomers of formula (I') (excluding compounds in which R3 and OH groups are not in the trans position). A method that includes this.

13. The method according to claim 12, wherein step (a) is carried out in the presence of a Lewis acid.

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