Cyclopentenone derivatives and their use as antibiotics - Patents.com

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] The present invention relates to the use of cyclopentenone derivatives as drugs, especially as antibiotics. The present invention also relates to new cyclopentanone derivatives and methods for their preparation. [Background technology]

[0002] Infectious diseases are a major cause of morbidity and mortality worldwide. In particular, many pathogenic bacteria are becoming increasingly resistant to known and widely used antibiotics, posing a major public health problem. The WHO has indicated that resistance to available antibiotics will result in 10 million deaths by 2050. One representative example of this type of resistant bacteria is MRSA (Methylin-resistant Staphylococcus Aureus). Therefore, there is a need for new classes of antibiotics that are effective against a wide range of bacteria, and in particular, antibiotics that exhibit selectivity against Gram-negative bacteria. Therefore, the present inventors investigated cyclopentanone derivatives for use as drugs with a wide range of biological activities. In searching for a new class of antibiotics, the present inventors surprisingly discovered that the cyclopentanone derivatives of formula (I) exhibit potent activity against bacteria, particularly Gram-negative bacteria. The cyclopentenone derivatives disclosed herein have a simple chemical structure and are not present in the catalog of traditional antibiotics used in clinics. Access to these molecules is easy and cost-effective. Through their structure, the molecules allow access to a variety of structural analogs and antibiotic combinations, which can provide solutions in difficult-to-treat infection cases. Summary of the Invention

[0003] In a first aspect, the present invention provides a compound of formula (I) below for use as a medicament: [ka] (I) (In the formula, X is 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), 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 an optionally substituted aryl or an optionally substituted heterocycle, or R 1 and R 2 together represent an optionally substituted heterocycle, R 3 is an optionally substituted aryl or an optionally substituted heteroaryl and all isomers, diastereoisomers, enantiomers and mixtures thereof, and all pharmaceutically acceptable salts and / or solvates thereof, with the proviso that R 3 and XR 1 The group is in the trans position.

[0004] In a second aspect, the present invention relates to compounds of formula (I) as recited in claims 11, 12 and 13 or pharmaceutically acceptable salts and / or solvates thereof. In a third aspect, the present invention relates to a process for the preparation of compounds of formula (I) 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 medicament.

[0005] definition As used herein, the term "stereoisomer" refers to configurational stereoisomers and more particularly optical isomers. In the present invention, optical isomers arise in particular from differences in the positions in space of the substituents of the chiral carbon atoms. Optical isomers that are not mirror images of one another are called "diastereoisomers" and optical isomers that are non-superimposable mirror images are called "enantiomers." An equimolar mixture of two enantiomers of a chiral compound is called a racemic mixture or a racemate.

[0006] The term "pharmaceutically acceptable" as used herein is intended to mean compounds or materials for pharmaceutical use that are useful in the preparation of pharmaceutical compositions and are generally safe and non-toxic. As used herein, the term "pharmaceutically acceptable salts and / or solvates" refers to salts and / or solvates of compounds that are pharmaceutically acceptable, as defined above, and that possess the pharmacological activity of the corresponding compound. Pharmaceutically acceptable salts include: (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; (2) Includes base addition salts formed when an acid proton present in the compound is replaced with a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. 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 invention include conventional solvates, such as those formed during the final stage of the preparation of the compounds of the invention in the presence of a solvent, for example, solvates in the presence of water (these solvates are also called hydrates) or ethanol. As used herein, the term "halogen" refers to a fluorine, bromine, chlorine or iodine atom.

[0007] The term "C1-C6 alkyl" as used herein refers to a straight or branched monovalent saturated hydrocarbon chain containing from 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, and the like. The term "heterocycle" as used herein refers to a non-aromatic, saturated or unsaturated, monocyclic or polycyclic ring (including fused, bridged or spiro rings) preferably containing 5 to 10, especially 5 or 6, atoms in the ring, the atoms of the ring consisting of carbon atoms and one or more, advantageously 1 to 4, more advantageously 1 or 2 heteroatoms such as nitrogen, oxygen or sulfur atoms, the remainder being carbon atoms. Heterocycles include, inter alia, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, thiazepanyl, benzimidazolonyl or a ring of the formula: [ka] It may be a coumarin of the formula:

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

[0009] The term "heteroaryl" as used herein refers to an aromatic group containing one or several, especially one or two, fused hydrocarbon rings, in which one or several, especially one to four, and preferably one or two, carbon atoms are each replaced by a heteroatom selected from sulfur, oxygen, and nitrogen, preferably oxygen and nitrogen. It may be furyl, thienyl, pyrrolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl, or indolyl. Preferably, it is thienyl, thiazolyl, or indolyl.

[0010] When a group is said to be "optionally substituted," it is meant that the group is optionally substituted with one or more substituents, typically 1 to 3 substituents, such as halogen, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, oxo, NR a R b , C.O.R. c , CO2R d ,CONR e R f , OR g and CN, and R a ~R g are each independently H or C-C alkyl. In some embodiments, two substituents may be joined together to form a heterocycle. For example, a phenyl group may be substituted with two substituents that together form a heterocycle, such as 1,3-dioxolane. The term "C3-C7 cycloalkyl" as used herein refers to a saturated hydrocarbon ring containing from 3 to 7 carbons, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. As used herein, the term "pharmaceutical composition" refers to a composition that has prophylactic and therapeutic properties against bacterial infections. The expression "treatment" is intended to refer to animals of any type, preferably mammals, more preferably humans. In the case of treatment of non-human animals, veterinary treatment is referred to. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description Compounds of formula (I) The compound of formula (I) has the following formula: [ka] (I) (In the formula, X is 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), 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 an optionally substituted aryl or an optionally substituted heterocycle, or R 1 and R 2 together represent an optionally substituted heterocycle, R 3 is an optionally substituted aryl or an optionally substituted heteroaryl and all stereoisomers, diastereoisomers, enantiomers and mixtures thereof, and all pharmaceutically acceptable salts and / or solvates thereof, with the proviso that R 3 and XR 1 The compound is shown in which the groups are in the trans position.

[0012] The compounds of formula (I) may be in the form of a mixture of stereoisomers, in particular a racemic mixture thereof. The compounds 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 compounds are in the form of a racemic mixture of one diastereoisomer exemplified in the present application. Although the compounds of formula (I) may be represented hereinafter as particular stereoisomers, such representations include all stereoisomers thereof, with the proviso that R 3 and XR 1 It is to be understood that the groups are in the trans position.

[0013] In some embodiments, the substituent R 2 is 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 an optionally substituted heterocycle. In some embodiments, R 4 is H, optionally substituted benzyl or C(=O)R 5 and R 5 is an optionally substituted phenyl or coumarin group. Thus, for example, R 4 is H or the following group: [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, optionally substituted phenyl, C(=O)-methyl, C(=O)-O-tert-butyl or tert-butyldimethylsilyl group. 1 is H, C(=O)-methyl or aryl, said aryl being 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 1When is aryl, it is unsubstituted or substituted with one or two groups independently selected from halogen, CF3 groups, and OMe groups.

[0015] In some embodiments, X is NH. When X is an NH group, R 1 is preferably aryl as defined above. In some embodiments, X is an oxygen atom. When X is an oxygen atom, R 1 is preferably H or C(=O)-methyl, more preferably H. Advantageously, R 1 is H or C(=O)-C1-C6 alkyl, preferably H or C(=O)-methyl, more preferably H. In some other embodiments, R 1 and R 2 together represent a heterocycle, such as ethylene oxide or 1,3 dioxolane, which is unsubstituted or substituted with one oxo or C3-C7 cycloalkyl, such as cyclohexyl. In some embodiments, R 1 is H or C(=O)-C1-C6 alkyl, preferably H or C(=O)-methyl, and R 2 is H or CHOH, X is O, and R 3 is aryl, preferably phenyl, optionally substituted with one or two groups selected from halogen, fluorine, especially Cl, C-C alkyl and O-C-C alkyl, especially methyl, or with two substituents which together form a 1,3-dioxolane.

[0016] In some embodiments, the compound of formula (I) is R 1 is H, X is O, and R 2 is H and R 3 is a compound wherein: In some embodiments, the compound of formula (I) has the following formula (I'): [ka] (I') (In the formula, R 3 is as disclosed above or below) Corresponds to. Compounds of formula (I') have been found to be highly effective against gram-negative bacteria. Compounds of formula (I') may advantageously be selective for gram-negative bacteria. In some embodiments of compounds of Formula (I) or (I'), R 3 is in particular heteroaryl selected from thienyl, thiazolyl or indolyl, said indolyl being optionally substituted with an alkyl group, for example methyl.

[0017] In some preferred embodiments of compounds of formula (I) or (I'), R 3 is aryl, such as phenyl, naphthyl or anthracenyl, preferably phenyl, optionally substituted with one or more, preferably 1 to 3, groups independently selected from halogen, C1-C6 haloalkyl, C1-C6 alkyl, O-C1-C6 alkyl and CN, or with two substituents which together form a heterocyclic ring, such as 1,3-dioxolane. Advantageously, R 3 represents phenyl optionally substituted with one or two groups selected from halogen, in particular F or Cl, C1-C6 alkyl and O-C1-C6 alkyl, in particular methyl, or with two substituents which together form a 1,3-dioxolane.

[0018] In a preferred embodiment, the compound of formula (I) is: [ka] TIFF2023554322000008.tif76132 TIFF2023554322000009.tif76150 TIFF2023554322000010.tif32133 TIFF2023554322000011.tif28124 TIFF2023554322000012.tif59129 TIFF2023554322000013.tif33124 TIFF2023554322000014.tif27118 TIFF2023554322000015.tif4090 TIFF2023554322000016.tif50139 TIFF2023554322000017.tif51106 TIFF2023554322000018.tif5166 and pharmaceutically acceptable salts and / or solvates thereof.

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

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

[0021] Even more preferably, the compound of formula (I) is: [ka] and pharmaceutically acceptable salts and / or solvates thereof.

[0022] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is preferably: [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)-(Im). The present invention relates to a compound of formula (I): [ka] (I) (In the formula, X is 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), R 2 is CH2OR 4 and R 4 is H, optionally substituted C1-C6 alkylaryl or C(=O)R 5 and R 5 is an optionally substituted aryl or an optionally substituted heterocycle, R 3 is an optionally substituted aryl or an optionally substituted heteroaryl and all stereoisomers, diastereoisomers, enantiomers and mixtures thereof, and all pharmaceutically acceptable salts and / or solvates thereof, with the proviso that R 3 and XR 1 groups are in the trans position, provided that said compound has: [ka] The compound is not

[0024] In particular, the present invention relates to compounds If, Ih, Ig and Ii disclosed in the Examples section. The present invention also relates to compound (Ic) disclosed in the Examples section. Process for preparing compounds of formula (I) The present invention provides a process for preparing a compound of the above formula (I) wherein X is an oxygen atom, or a pharmaceutically acceptable salt and / or solvate thereof, comprising the steps of: (i) Formula (II): [ka] (II) (In the formula, R 2 and R 3 is as defined above) in the presence of a C1-C6 alcohol and optionally a Lewis acid under heating; (ii) optionally isolating the diastereoisomers of formula (I) The present invention relates to a method comprising:

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

[0026] The compound of formula (II) can be obtained by using suitable substituents according to the method described in the literature.For example, the compound of formula (II-A) can be obtained by starting from furan or 2-furaldehyde 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 the compound of formula (II-B) can be obtained by 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 well known to those skilled in the art may be carried out to modify the above-mentioned substituents R 2 and R 3 may be carried out before step (i) to obtain the compound of formula (II).

[0027] The reaction of 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 mixture of tert-butanol / water 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 between 18°C ​​and 250°C, preferably between 80°C and 100°C. Heating can be achieved under conventional conditions or using microwaves. Preferably, the reaction is carried out in a microwave, which can reduce the reaction time by a factor of 10.

[0028] Advantageously, step (i) is carried out in the presence of a Lewis acid, preferably selected from the group consisting of DyCl, Dy(OTf), Fe(OTf), FeCl.6H0, ZnCl, CuCl, Sc(OTf), and combinations thereof. More preferably, the Lewis acid is DyCl. Step (i) provides a compound in which X is an oxygen atom and R 1 is H and R 2 and R 3 A compound of formula (I) is obtained, wherein Therefore, the preparation method is 1 An additional step of functionalization well known to those skilled in the art may be included between steps (i) and (ii) to replace H at position with another group as defined above.

[0029] The final compound obtained may be isolated, ie 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, if necessary, by methods well known to those skilled in the art, for example, by recrystallization, by distillation, by chromatography on a silica gel column or by high performance liquid chromatography (HPLC). According to another embodiment, the present invention provides a process for preparing a compound of formula (I) above, wherein X is an NH group, or a pharmaceutically acceptable salt and / or solvate thereof, comprising the following steps: (i) Formula (II) [ka] (II) (In the formula, R 2 and R 3 is as defined above) in the presence of a C1-C6 alcohol and optionally a Lewis acid under heating; (ii) optionally isolating the diastereoisomers of formula (I) The present invention relates to a method comprising:

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

[0031] According to a preferred embodiment, the present invention provides a method for preparing a compound of formula (I') above or a pharmaceutically acceptable salt and / or solvate thereof, comprising the steps of: (a) Formula (II-B) [ka] (II-B) (In the formula, R 2 and R 3 is as defined above) in the presence of a C1-C6 alcohol and optionally a Lewis acid under microwave heating; (b) optionally isolating the diastereoisomers of formula (I) The present invention relates to a method comprising: Preferably, the reaction of step (a) is carried out in the presence of a mixture of tert-butanol / water 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 (N) 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 selected from the group consisting of DyCl, Dy(OTf), Fe(OTf), FeCl.6H0, ZnCl, CuCl, Sc(OTf), and combinations thereof. More preferably, the Lewis acid is DyCl.

[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, if necessary, by methods well known to those skilled in the art, for example by recrystallization, by distillation, by chromatography on a silica gel column or by high performance liquid chromatography (HPLC).

[0033] Pharmaceutical Composition The present invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) as disclosed herein above 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 intended for oral or parenteral (e.g., subcutaneous, intramuscular, or intravenous) administration, preferably oral or intravenous administration. The active ingredient may be administered to animals, preferably mammals including humans, in dosage unit forms mixed with a conventional pharmaceutical carrier. For oral administration, the pharmaceutical composition may be in solid or liquid (solution or suspension) form.

[0034] Solid compositions 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. Tablets may further be coated, especially with sucrose or other suitable materials, or may be treated in such a way as to have extended or delayed activity. In powders or granules, the active ingredient may be mixed or granulated with dispersing agents, wetting agents, or suspending agents, and with flavor correctors or sweeteners. In gelatin capsules, the active ingredient may be introduced into soft or hard gelatin capsules in the form of powders or granules, as described above, or in the form of a liquid composition, as described below. Liquid compositions can contain the active ingredient in a solvent, such as water, together with a sweetener, a taste enhancer, or a suitable colorant. Liquid compositions can also be obtained by suspending or dissolving the powder or granules described above in a liquid, such as water, juice, milk, etc. This can be, for example, a syrup or elixir. For parenteral administration, the composition may be in the form of an aqueous suspension or solution which may contain suspending agents and / or wetting agents. The composition is advantageously sterile. It may be in the form of an isotonic solution (especially compared to blood). The compounds of the present invention may be used in pharmaceutical compositions in doses ranging from 0.01 mg to 1000 mg per day, administered either once a day or in several doses throughout the day, for example, twice a day. The daily dose is preferably comprised between 5 mg and 500 mg, more preferably between 10 mg and 200 mg. However, it may be necessary to use doses outside these ranges, as will be recognized by those skilled in the art.

[0035] According to certain embodiments, the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is present in a pharmaceutical composition in the form of a capsule. It may be encapsulated in a polymeric surfactant micelle or liposome, where the polymeric surfactant is, for example, a polysorbate, e.g., polysorbate 80. Such encapsulation may be performed according to methods well known to those skilled in the art, particularly the method described in Gasser, G. et al., J. Am. Chem. Soc. 2020, 142, 6066-6084. Encapsulation is particularly useful for controlled, targeted, and / or extended release of the compound of formula (I) in the body of a subject in need thereof. In particular, encapsulation can improve the bioavailability of the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate, or pharmaceutical composition of the present invention, by increasing its apparent aqueous solubility. This can facilitate parenteral injection.

[0036] treatment The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as disclosed herein above, or a pharmaceutical composition according to the invention, for use as a medicament, in particular for the treatment of bacterial infections. The present invention relates to the use of a compound of formula (I) according to the invention or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament, in particular for the treatment of bacterial infections. The present invention also relates to the use of a compound of formula (I) according to the invention or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising same, for the treatment of bacterial infections. The present invention also relates to a method for treating a bacterial infection, which method comprises administering to a person in need thereof 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.

[0037] According to a preferred embodiment, the compound of formula (I) according to the present invention or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition, is useful for treating bacterial infections, for example bacterial infections associated with resistant pathogenic Gram-negative or Gram-positive bacteria. In other respects, the compound of formula (I) according to the present invention or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition, is useful as an antibiotic, especially a broad-spectrum antibiotic, and in particular as an antibiotic against resistant pathogenic Gram-negative or Gram-positive bacteria. The compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, or pharmaceutical compositions according to the present invention may be useful in the treatment of bacterial infections associated with resistant pathogenic bacteria involved in urogenital, respiratory, gastrointestinal, neuronal and skin infections.

[0038] Thus, according to this embodiment, the compound of formula (I) is preferably [ka] and pharmaceutically acceptable salts and / or solvates thereof, more preferably [ka] and pharmaceutically acceptable salts and / or solvates thereof.

[0039] For example, the bacterial infection may be caused by a resistant pathogenic Gram-negative bacterium selected from Eschericha coli, Enterobacter cloacae, Acinetobacter baumannii, or by a resistant pathogenic Gram-positive bacterium, such as Staphylococcus aureus.

[0040] Preferably, when the compound of formula (I) is used for the treatment of bacterial infections associated with resistant pathogenic Gram-negative bacteria, R 1 represents H, and R 2 is H or CH2OR 4 represents R 4is preferably H or C1-C6 alkyl, and X and R 3 is as defined above. More preferably, R 1 represents H, and R 2 represents H or CH2OH, X represents O, R 3 is as defined above. Even more preferably, according to this embodiment, the compound of formula (I) is [ka] and pharmaceutically acceptable salts and / or solvates thereof, in particular [ka] and pharmaceutically acceptable salts and / or solvates thereof.

[0041] Preferably, when the compound of formula (I) is used for the treatment of bacterial infections associated with resistant pathogenic Gram-positive bacteria, R 1 represents H or C(=O)-C1-C6 alkyl, R 2 is H or CH2OR 4 represents R 4 is preferably H or C1-C6 alkyl, X is an oxygen atom, and R 3 is as defined above. More preferably, R 1 represents H or C(=O)-methyl, R 2 represents H or CHOH, X is an oxygen atom, and R 3 is as defined above. Even more preferably, according to this embodiment, the compound of formula (I) is [ka] and pharmaceutically acceptable salts and / or solvates thereof.

[0042] According to certain embodiments, the compounds of formula (I) may be selective for resistant pathogenic Gram-negative bacteria, meaning that the compounds of formula (I) may be active against resistant pathogenic Gram-negative bacteria while otherwise being inactive against resistant pathogenic Gram-positive bacteria or other pathogenic microorganisms. [Brief explanation of the drawings]

[0043] [Figure 1] Kirby-Bauer disk diffusion susceptibility test against Staphylococcus aureus ATCC25923 with 12.5, 25, 50 and 100 μg of compounds Ia, Ib and Ic and 10 μg of reference gentamicin; Left: Graph representing the diameter of the zone of inhibition as a function of the respective sample; Right: Photograph of a Petri dish illustrating the zone of inhibition with 12.5, 25, 50 and 100 μg of Ic. [Figure 2] Kirby-Bauer disk diffusion susceptibility test against Enterobacter cloacae ATCC 13047 with 12.5, 25, 50, and 100 μg of compounds Ia and Ib and 10 μg of reference gentamicin; Left: Graph representing the diameter of the zone of inhibition as a function of the respective sample; Right: Photograph of a Petri dish illustrating the zone of inhibition with 12.5, 25, 50, and 100 μg of Ia. [Figure 3] Kirby-Bauer disk diffusion susceptibility test against Acinetobacter baumannii ATCC 19606 with 12.5, 25, 50, and 100 μg of compounds Ib and Ic and 10 μg of reference gentamicin; Left: Graph representing the diameter of the zone of inhibition as a function of the respective sample; Right: Photograph of a Petri dish illustrating the zone of inhibition with 12.5, 25, 50, and 100 μg of Ib and Ic. [Figure 4] Kirby-Bauer disk diffusion susceptibility test against E. coli ATCC25922 with 12.5, 25, 50 and 100 μg of compounds Ia and Ib and 10 μg of reference gentamicin; Left: Graph representing the diameter of the zone of inhibition as a function of the respective sample; Right: Photograph of a Petri dish illustrating the zone of inhibition with 12.5, 25, 50 and 100 μg of Ia. [Example]

[0044] 1) Synthesis Materials, Devices and Methods 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 prepacked columns, 230-400 mesh) using a CombiFlash Companion at medium pressure (20 psi) or by preparative HPLC. Reactions were monitored by UV light and by thin-layer chromatography on Merck silica gel plates (60 F254 aluminum sheets), visualized by spraying with vanillin (15%) and 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 Microwave 300 microwave reactor using borosilicate glass standard vials G10. A sealed reaction vessel was used. The reaction temperature was monitored by an external sensor and maintained throughout each experiment.

[0045] 1 H NMR (500 or 300 MHz) and C NMR (125 or 75 MHz) spectra were recorded at 298 K on a Bruker Avance spectrometer unless otherwise stated. Chemical shifts are given in ppm (δ) and are referenced to the internal solvent signal. Multiplicities are indicated as follows: s (singlet), brs (broad singlet), d (doublet), t (triplet), q (quadruplet), dd (doublet of doublets), m (multiplet). Coupling constants J are given in Hz. Carbon multiplicities were determined by DEPT135 experiments.

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

[0047] Synthesis of intermediates (Furan-2-yl)phenylmethanol [ka] To a solution of 2-furaldehyde (500 mg, 5.20 mmol, 1 equiv.) in anhydrous EtO (15 mL) at 0 °C under argon was added phenylmagnesium bromide (1 M solution in EtO, 6.76 mL, 6.76 mmol, 1.3 equiv.). The reaction mixture was stirred from 0 °C to room temperature for 2 h and then quenched by the addition of saturated aqueous NH4Cl (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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 70:30) to afford the desired carbinol (900 mg, quantitative) as a pale yellow oil. Rf (n-heptane / EtOAc 70:30): 0.42.

[0048] The spectral data are consistent with a compound previously described in the literature (D'Auria, M. Heterocycles 2000, 52, 185-194) (CAS number [60907-91-7]). 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-furaldehyde (500 mg, 5.20 mmol, 1 equiv.) in anhydrous EtO (15 mL) at 0 °C under argon was added 4-chlorophenylmagnesium bromide (1 M solution in EtO, 6.76 mL, 6.76 mmol, 1.3 equiv.). The reaction mixture was stirred from 0 °C to room temperature for 2 h and then quenched by the addition of saturated aqueous NH4Cl (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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 70:30) to give the desired carbinol (1.08 g, quantitative) as a pale yellow oil. Rf (n-heptane / EtOAc 70:30): 0.48.

[0049] The spectral data are consistent with a previously described compound (CAS number [143747-66-4]) in the literature (E. Riva, S. Gagliardi, M. Martinelli, D. Passarella, D. Vigo, A. Rencurosi, Tetrahedron 2010, 66, 3242-3247). 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 equiv) in anhydrous EtO (60 mL) was added n-butyllithium (2.5 M solution in hexanes, 7.2 mL, 17.9 mmol, 1.2 equiv) dropwise at 0 °C under argon. The reaction mixture was stirred at 0 °C for 1 h and at room temperature for 15 min. The mixture was then cooled to -78 °C, and 2-chlorobenzaldehyde (2.10 g, 14.9 mmol, 1.0 equiv) in anhydrous THF (10 mL) was slowly added, and the reaction mixture was stirred at -78 °C for 2 h and at room temperature for 1 h. The mixture was then quenched by the addition of saturated aqueous NH Cl (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 in vacuo to give the crude carbinol (2.99 g, 96%), which was used without further purification.

[0051] The spectral data are consistent with a previously described compound (CAS number [60907-97-3]) 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 equiv.) in anhydrous THF (0.25 M) at 0 °C was added phenylmagnesium bromide solution (1.0 M solution in EtO, 19.8 mL, 19.8 mmol, 2.5 equiv.). The reaction mixture was stirred from 0 °C to room temperature for 2 h. 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 in vacuo. The residue was purified by flash chromatography on silica gel (10–60% EtOAc / heptane) to give the desired compound (1.25 g, 77%) as a pale yellow oil. Rf 0.24 (50% EtOAc / 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 (CH); IR (ν / cm-1) 3351, 2866, 1494, 1452, 1365, 1189, 1012, 791, 745, 699; HRMS (ESI) m / z = 187.0757, calculated for 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 equiv) in anhydrous THF (0.25 M) at 0 °C was added 4-fluorophenylmagnesium bromide solution (1.0 M solution in THF, 12.5 mL, 12.5 mmol, 3.5 equiv). The reaction mixture was stirred from 0 °C to room temperature for 2 h. 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 in vacuo. The residue was purified by flash chromatography on silica gel (10-60% EtOAc / heptane) to give the desired compound (766 mg, 77%) as a pale yellow solid. Rf 0.46 (60% EtOAc / 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 for 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 equiv.) in anhydrous THF (0.25 M) at 0 °C was added 4-methoxyphenylmagnesium bromide solution (1.0 M solution in THF, 16.7 mL, 16.7 mmol, 3.5 equiv.). The reaction mixture was stirred from 0 °C to room temperature for 2 h. 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 in vacuo. The residue was purified by flash chromatography on silica gel (10–60% EtOAc / heptane) to give the desired compound (1.11 g, 99%) as a pale yellow oil. Rf 0.47 (70% EtOAc / 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 suspension of magnesium (462 mg, 19.0 mmol, 6.0 equiv) in anhydrous THF (0.20 M) under argon, 5-bromo-1,3-benzodioxole and a few drops of 1,2-dibromoethane were added. The reaction mixture was warmed for 2 min to initiate the reaction, and 5-bromo-1,3-benzodioxole (2.55 g, 12.7 mmol, 4.0 equiv) was added dropwise. After refluxing under argon for 2 h, the mixture was cooled to 0 °C, and a solution of 5-(hydroxymethyl)furfural (400 mg, 3.17 mol, 1.0 equiv) in THF was added dropwise. After stirring from 0 °C to room temperature for 2 h, 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 in vacuo. The residue was purified by flash chromatography on silica gel (10-60% EtOAc / heptane) to give the desired compound (262 mg, 33%) as a pale yellow solid. Rf 0.24 (50% EtOAc / 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 equiv.) in anhydrous THF (15 mL) at 0 °C under argon, 4-fluorophenylmagnesium bromide (1 M solution in EtO, 9.90 mL, 6.76 mmol, 2.5 equiv.) was added. The reaction mixture was stirred from 0 °C to room temperature for 2 h. The mixture was then quenched by the addition of 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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 50:50) to afford the desired biscarbinol (773 mg, 82%) as a pale yellow solid. Rf (n-heptane / EtOAc 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] (Furan-2-yl)(4-methoxyphenyl)methanol [ka] To a solution of 4-bromoanisole (500 mg, 2.67 mmol, 1.0 equiv) in anhydrous THF (15 mL) was added n-butyllithium (1.6 M solution in hexanes, 1.8 mL, 2.94 mmol, 1.1 equiv) dropwise at −78° C. under argon. The reaction mixture was stirred at −78° C. for 30 minutes, and furaldehyde (0.23 mL, 2.81 mmol, 1.05 equiv) 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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 60:40) to give the desired compound (443 mg, 81%) as a pale orange oil. Rf (n-heptane / EtOAc 70:30): 0.27.

[0062] The spectral data is consistent with a compound (CAS number [100518-86-3]) previously described in the literature (Nandy, SK; Liu, J.; Padmapriya, AA Tetrahedron Lett. 2008, 49, 2469-2471). 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] (Furan-2-yl)(3-methoxyphenyl)methanol [ka] Furfural (150 mg, 1.56 mmol, 1.0 equiv.), 3-methoxybenzeneboronic acid (474 ​​mg, 3.12 mmol, 2.0 equiv.), acetylacetonate dicarbonyl rhodium (I) 1,1'-Ferrocenediyl-bis(diphenylphosphine) (26 mg, 0.04 mmol, 3 mol%) (12 mg, 0.04 mmol, 3 mol%) was dissolved in DME (5 mL) and water (3 mL) under argon. The reaction mixture was stirred at 80 °C for 16 h. 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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / ethyl acetate). The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 40:60) to give the desired compound (278 mg, 87%) as a pale orange oil. Rf (n-heptane / EtOAc 70:30): 0.27.

[0064] The spectral data is consistent with a compound previously described in the literature (CAS number [944523-02-8]) (DeBerardinis, A. M.; Turlington, M.; Ko, J.; Sole, L.; Pu, L. J. Org. Chem. 2010, 75, 2836-2850). 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)(naphthalen-2-yl)methanol [ka] To a solution of 2-bromonaphthalene (600 mg, 2.90 mmol, 1.0 equiv) in anhydrous THF (25 mL) at −78° C. under argon was added n-butyllithium (4.0 mL of a 1.6 M solution in hexanes, 6.37 mmol, 2.2 equiv) dropwise. The reaction mixture was stirred at −78° C. for 30 minutes, and furaldehyde (0.31 mL, 3.77 mmol, 1.3 equiv) was added. The reaction mixture was stirred at −78° C. for 3 hours and quenched with saturated aqueous NH4Cl (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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 30:70) to give the desired compound (309 mg, 48%) as a pale orange oil. Rf (n-heptane / EtOAc 50:50): 0.39.

[0066] The spectral data are consistent with a compound (CAS number [944649-38-1]) previously described in the literature (Kuriyama, M.; Shimazawa, R.; Shirai, RJ Org. Chem. 2008, 73, 1597-1600). 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-HO+H] + Calculated value: 207.0810.

[0067] (Furan-2-yl)(naphthalen-1-yl)methanol [ka] Furfural (250 mg, 2.60 mmol, 1.0 equiv.), 1-naphthaleneboronic acid (895 mg, 5.20 mmol, 2.0 equiv.), acetylacetonate dicarbonylrhodium (I) 1,1'-Ferrocenediyl-bis(diphenylphosphine) (43 mg, 0.08 mmol, 3 mol%) (20 mg, 0.08 mmol, 3 mol%) was dissolved in DME (6 mL) and water (4 mL) under argon. The reaction mixture was stirred at 80 °C for 16 h. 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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / ethyl acetate). The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 50:50) to give the desired compound (450 mg, 77%) as a pale yellow oil. Rf (n-heptane / EtOAc 50:50): 0.48.

[0068] The spectral data are consistent with a previously described compound (CAS number [873974-71-1]) in the literature (Duan, W.; Ma, Y.; He, F.; Zhao, L.; Chen, J.; Song, C. Tetrahedron Asym. 2013, 24, 241-248). 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-HO+H] + Calculated value: 207.0810.

[0069] Synthesis of Compounds of Formula (I) General means A To a solution of the appropriate intermediate (1 equivalent) in a 5:1 (0.1 M) mixture of t-BuOH / HO was added DyCl (10 mol%). The reaction mixture was heated at 100°C under MW radiation for 1.5 hours. After cooling to room temperature, the mixture was quenched with saturated NaHCO 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 in vacuo. The residue was purified by flash chromatography on silica gel (heptane / ethyl acetate).

[0070] (4S*,5R*)-4-Hydroxy-5-phenyl-cyclopent-2-en-1-one (Ia) [ka] To a solution of (furan-2-yl)phenylmethanol (1.06 mg, 6.08 mmol, 1 equiv.) in t-BuOH / HO 5:1 (0.077 M solution, 65 mL and 13 mL, respectively), Dy(OTf) (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 to 80 °C for 18 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO solution. This mixture was extracted three times with diethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 50:50) to afford the desired substituted cyclopentenone Ia (850 mg, 80%) as a pale yellow oil. Rf (n-heptane / EtOAc 40:60): 0.17.

[0071] The spectral data are consistent with 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-hydroxycyclopent-2-en-1-one (Ib) [ka] To a solution of (4-chlorophenyl)(furan-2-yl)methanol (340 mg, 1.63 mmol, 1 equiv.) in t-BuOH / HO 5:1 (18 mL and 3.6 mL, respectively, of a 0.077 M solution), Dy(OTf) (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 to 80 °C for 18 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO solution. This mixture was extracted three times with diethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 50:50) to afford the desired substituted cyclopentenone Ib (242 mg, 71%) as a pale yellow solid. Rf (n-heptane / EtOAc 50:50): 0.25.

[0073] The spectral data is consistent with a previously described compound (CAS number [2470798-26-4]) in the literature (Schober, L.; Sako, M.; Takizawa, S.; Groger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154.). 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-hydroxycyclopent-2-en-1-one (Ic) [ka] To a solution of (2-chlorophenyl)(furan-2-yl)methanol (342 mg, 1.64 mmol, 1 equiv.) in t-BuOH / HO 5:1 (18 mL and 3.6 mL, respectively, of a 0.077 M solution), Dy(OTf) (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 to 80 °C for 18 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO solution. This mixture was extracted three times with diethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 50:50) to afford the desired substituted cyclopentenone Ic (236 mg, 69%) as a pale yellow solid. Rf (n-heptane / EtOAc 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)-cyclopent-2-en-1-one (Id) [ka] This compound was prepared according to general procedure A using biscarbinol(4-chlorophenyl)[5-(hydroxymethyl)furan-2-yl]methanol (100 mg, 0.42 mmol, 1 equiv). 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-phenyl-cyclopent-2-en-1-one (Ie) [ka] To a solution of (4S,5R)-4-hydroxy-5-phenyl-cyclopent-2-en-1-one (39 mg, 0.22 mmol, 1 equiv.) in acetic anhydride (1.5 mL) was added toluene-4-sulfonic acid monohydrate (2.3 mg, 0.02 mmol, 10 mol%) at 0 °C, and the mixture was allowed to warm to room temperature for 4 h. Silica gel (500 mg) was then added, and the acetic anhydride was removed under reduced pressure to obtain a solid sample, which was then loaded onto a column for chromatography. The crude product was purified on silica gel (eluent: n-heptane / EtOAc 0:100 to 3:7) to give the title compound Ie (38 mg, 79% yield) as a colorless oil. Rf (n-heptane / EtOAc 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-phenylcyclopent-2-en-1-one (If) [ka] This compound was prepared according to general procedure A using 50 mg of (5-(hydroxymethyl)furan-2-yl)(phenyl)methanol (0.25 mmol, 1 equiv.). After flash chromatography (toluene / acetone: 80:20 to 70:30), If (26 mg, 51% yield, 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)cyclopent-2-en-1-one (Ig) [ka] This compound was prepared according to general procedure A using 60 mg of (4-fluorophenyl)(5-(hydroxymethyl)furan-2-yl)methanol (0.3 mmol, 1 equiv.). After flash chromatography (heptane / ethyl acetate: 100:0 to 20:80), Ig (34 mg, 59% yield, dr=90:10) was obtained as a white solid. Rf 0.31 (60% EtOAc / 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 for C12H12FO3 [M+H]+: 223.0770.

[0080] 4-Hydroxy-4-(hydroxymethyl)-5-(4-methoxyphenyl)cyclopent-2-en-1-one (Ih) [ka] This compound was prepared according to general procedure A using 70 mg of (5-(hydroxymethyl)furan-2-yl)(4-methoxyphenyl)methanol (0.3 mmol, 1 equiv.). After flash chromatography (heptane / ethyl acetate: 100:0 to 20:80), Ih (25 mg, 35% yield, 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)cyclopent-2-en-1-one (Ii) [ka] This compound was prepared according to general procedure 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 to 30:70), Ii (40.4 mg, 54% yield, dr > 95:5) was obtained as a brown oil. Rf 0.29 (50% EtOAc / 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)cyclopent-2-en-1-one (Ij) [ka] To a solution of (furan-2-yl)(4-methoxyphenyl)methanol (80 mg, 0.39 mmol, 1.0 equiv.) in t-BuOH / HO 5:1 (0.068 M solution, 5 mL and 0.8 mL, respectively), DyCl (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 to 80 °C for 18 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO 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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 70:30 to 50:50) to give the desired substituted cyclopentenone (18 mg, 23%) as a pale yellow oil. Rf (n-heptane / EtOAc 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)cyclopent-2-en-1-one (Ik) [ka]

[0084] To a solution of (furan-2-yl)(3-methoxyphenyl)methanol (60 mg, 0.29 mmol, 1.0 equiv.) in t-BuOH / HO 5:1 (0.082 M solution, 3 mL and 0.6 mL, respectively), DyCl (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 to 80 °C for 18 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO 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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 60:40) to afford the desired substituted cyclopentenone (42 mg, 70%) as a pale yellow oil. Rf (n-heptane / EtOAc 50:50): 0.33.

[0085] The spectral data is consistent with a previously described compound (CAS number [2470798-31-1]) in the literature (Schober, L.; Sako, M.; Takizawa, S.; Groger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154). 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-(naphthalen-2-yl)cyclopent-2-en-1-one (II) [ka] To a solution of (furan-2-yl)(naphthalen-2-yl)methanol (80 mg, 0.36 mmol, 1.0 equiv.) in t-BuOH / HO 5:1 (0.050 M solution, 6 mL and 1.2 mL, respectively), DyCl (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 to 80 °C for 18 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO 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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 40:60) to afford the desired substituted cyclopentenone (32 mg, 40%) as a pale orange oil. Rf (n-heptane / EtOAc 50:50): 0.25.

[0087] The spectral data is consistent with a previously described compound (CAS number [1612765-18-0]) in the literature (Schober, L.; Sako, M.; Takizawa, S.; Groger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154). 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-(naphthalen-1-yl)cyclopent-2-en-1-one (Im) [ka] To a solution of (furan-2-yl)(naphthalen-1-yl)methanol (100 mg, 0.45 mmol, 1.0 equiv.) in t-BuOH / HO 5:1 (0.063 M solution, 6 mL and 1.2 mL, respectively), DyCl (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 to 80 °C for 18 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO 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 in vacuo. The residue was purified by flash chromatography on silica gel (n-heptane / EtOAc: 100:0 to 50:50) to afford the desired substituted cyclopentenone (99 mg, 99%) as a pale orange oil. Rf (n-heptane / EtOAc 50:50): 0.25.

[0089] The spectral data is consistent with a previously described compound (CAS number [2470798-35-5]) in the literature (Schober, L.; Sako, M.; Takizawa, S.; Groger, H.; Sasai, H. Chem. Comm. 2020, 56, 10151-10154). 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 The antibiotic activity of the trans-configured racemic molecule was evaluated against a panel of pathogenic microorganisms. A. Zone of Inhibition Technique (Kirby-Bauer Disk Diffusion Susceptibility Test) Pre-inoculum preparation Pathogenic bacteria were revived by streaking overnight at 30–37°C onto 100 mm Petri dishes containing the appropriate media recommended by the ATCC protocol: Luria-Bertani broth (LB, Difco, Thermo Fisher Scientific Inc.), tryptic soy broth (TSB, Difco, Thermo Fisher Scientific Inc.), or nutrient broth (NB, Difco, Thermo Fisher Scientific Inc.) supplemented with 2% agar (granular agar, Difco, Thermo Fisher Scientific Inc.).

[0091] Inoculum preparation For each pathogen, several colonies were collected with 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 allowed to absorb for 15 minutes. Sterile 6 mm Whatman No. 1 discs were placed in Petri dishes, and 12.5, 25, 50, and 100 μg of the test compound in DMSO (10 mg / ml) was applied to the sterile disc paper. The standard drug, gentamicin (10 μg), was used as a positive reference standard to determine the susceptibility of each bacterial species, and DMSO served as a negative control. The plates were then incubated at 30°C or 37°C for 24 hours, and the inhibition diameter was measured. Compounds Ia-Ic were also tested against the following pathogenic bacteria to assess their inhibitory efficacy by the Petri dish zone of inhibition 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 allows visualization of the potential to inhibit the growth of target pathogenic bacteria.

[0093] Dose-response studies were conducted with 12.5, 25, 50, and 100 μg of each compound, comparing the zone of inhibition with 10 μg of gentamicin. The results are shown in Figures 1-4. Test products Ia, Ib, and / or Ic all exhibited inhibitory activity against each of the pathogenic bacteria tested. The best results were obtained against Gram-negative bacteria, particularly Enterobacter cloacae, as shown in Figure 2. Compounds Ib, Ic, Ij, Ik, Il, Im, Ih, Ig, Ii, Id and If were also tested against the following pathogenic bacteria to evaluate their inhibitory efficacy by the Petri dish zone of inhibition method: - Micrococcus luteus ATCC10240; - Bacillus subtilis ATCC6633; - Escherichia coli ATCC25922. The % inhibition of proliferation at 100 μg of each test compound was determined and the results are shown in the table below.

[0094] [Table 1] B. Minimum Inhibitory Concentration (MIC) Technique Pre-inoculum Pathogenic bacteria were revived by streaking overnight at 30–37°C onto 100 mm Petri dishes containing the appropriate media recommended by the ATCC protocol: Luria-Bertani broth (LB, Difco, Thermo Fisher Scientific Inc.), tryptic soy broth (TSB, Difco, Thermo Fisher Scientific Inc.), or nutrient broth (NB, Difco, Thermo Fisher Scientific Inc.) supplemented with 2% agar (granular agar, Difco, Thermo Fisher Scientific Inc.).

[0095] Inoculum preparation For each pathogen, several colonies were collected with a loop, 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 the solution was then diluted 400-fold to provide the appropriate inoculum.

[0096] Assay Antimicrobial susceptibility was performed by broth microdilution. Tests were performed in a final volume of 100 μL of Mueller-Hinton broth (Sigma) medium and 5.10 5Tests were performed in 96-well plates at a final bacterial concentration of CUF / ml. Test compounds were solubilized in dimethyl sulfoxide (DMSO) to obtain a stock solution of 10 mg / mL (then expressed in μM). The stock solution was tested by diluting it from 100 μg / mL to 0.195 μg / mL. Compounds Ia-Ie were also tested against Staphylococcus aureus ATCC25923 and Staphylococcus aureus BAA-1766 (MRSA) strains (both Gram-positive) by using a screening method of MIC (minimum inhibitory concentration) determination.

[0097] This technique allows the determination of the minimum concentration that completely inhibits the growth of the target pathogen. The table below shows that all products Ia to Ie exhibit good antibiotic activity. Good antibiotic activity is obtained with molecules Ic to Ie, with an MIC of 6.25 μg / mL. [Table 2]

Claims

1. To prepare the drug, a compound of the following formula (I): 【Chemistry 1】 (I) (In the formula, X is O or NH; R 1 is H, optionally substituted aryl, C(═O)—C 1 -C 6 Alkyl, C(=O)-O-C 1 -C 6 Alkyl or Si(C 1 -C 6 Alkyl) 3 and R 2 is H or CH 2 OR 4 and R 4 is H, C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkylaryl or C(=O)R 5 and R 5 is an optionally substituted aryl or an optionally substituted heterocycle; or R 1 and R 2 represent an optionally substituted heterocycle together; R 3 is optionally substituted aryl or optionally substituted heteroaryl. or any stereoisomer, diastereoisomer, enantiomer or mixture thereof, or any pharma- ceutically acceptable salt or solvate thereof.

2. R 2 is H or CH 2 2. The use according to claim 1, wherein said compound is OH.

3. 3. The use according to claim 1 or 2, wherein X is O.

4. R 1 is H or C(=O)-C 1 -C 6 The use according to any one of claims 1 to 3, wherein alkyl is H or C(=O)-methyl, more preferably H.

5. A compound having the following formula (I'): 【Chemistry 2】 (I’) The use according to any one of claims 1 to 4, which corresponds to

6. R 3 But halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl, O-C 1 -C 6 Use according to any one of claims 1 to 5, which is aryl, preferably phenyl, optionally substituted with one or more, preferably 1 to 3 groups selected from alkyl and CN, or with two substituents which together form a heterocyclic ring, for example 1,3-dioxolane.

7. A compound comprising: 【Chemistry 3】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 The use according to claim 1, selected from the group consisting of:

8. A compound comprising: 【Chemistry 4】 , preferably 【Chemistry 5】 The use according to claim 7, selected from the group consisting of:

9. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 8 and at least one pharma- ceutically acceptable excipient.

10. The use according to any one of claims 1 to 8, wherein the medicament is for treating bacterial infections, such as urogenital, respiratory, gastrointestinal, neuronal and skin infections.

11. The pharmaceutical composition of claim 9 for use in treating bacterial infections, such as genitourinary, respiratory, gastrointestinal, neuronal and skin infections.

12. The following formula (I): 【Chemistry 6】 (I) (In the formula, X is O or NH; R 1 is H, optionally substituted aryl, C(═O)—C 1 -C 6 Alkyl, C(=O)-O-C 1 -C 6 Alkyl or Si(C 1 -C 6 Alkyl) 3 and R 2 is CH 2 OR 4 and R 4 is H, optionally substituted C 1 -C 6 Alkylaryl or C(=O)R 5 and R 5 is an optionally substituted aryl or an optionally substituted heterocycle; R 3 is optionally substituted aryl or optionally substituted heteroaryl. (In the compound, R 3 and X-R 1 group is in the trans position, provided that said compound has 【Chemistry 7】 (which is not the case), or any stereoisomer, diastereoisomer, enantiomer or mixture thereof, or any pharma- ceutically acceptable salt or solvate thereof.

13. R 2 CH 2 OH and / or X is O and / or R 1 is H or C(=O)-C 1 -C 6 alkyl, and / or R 3 But halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl, O-C 1 -C 6 Aryl, optionally substituted with one or more groups selected from alkyl and CN, preferably 【Chemistry 8】 , preferably 【Chemistry 9】 13. The compound of claim 12, selected from the group consisting of:

14. The formula: 【Chemistry 10】 Compound.

15. A process for preparing a compound of formula (I') as defined in claim 5 or 6, or a pharma- ceutically acceptable salt or solvate thereof, comprising the steps of: (a) Formula (II-B) 【Chemistry 11】 (II-B) (In the formula, R 3 is as defined in any one of claims 1 to 6) Compound C 1 -C 6 reacting in the presence of an alcohol and optionally a Lewis acid under microwave heating; (b) optionally isolating the diastereoisomers of formula (I'). The method includes:

16. Step (a) is carried out 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 16. The process of claim 15, carried out in the presence of a Lewis acid selected from the group consisting of: and combinations thereof.

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