Novel compounds for the treatment of staphylococcal infections

Abstract

The present invention relates to a compound of formula (I): The present invention also relates to a novel antibacterial compound represented by the formula JPEG2026504190000051.jpg57144. The present invention also relates to a method for producing the antibacterial compound, a composition containing the antibacterial compound, and the use of the antibacterial compound as a pharmaceutical.

Description

[Technical Field]

[0001] The present invention relates to novel bactericidal compounds useful for treating infections caused by Staphylococcus sp., particularly Staphylococcus aureus. The present invention also relates to methods for preparing said bactericidal compounds, compositions containing them, and their use as medicines. [Background technology]

[0002] Infectious diseases are the second leading cause of death worldwide and represent a significant global burden affecting society. Most of these diseases are caused by exposure to or invasion of host cells and organs by microorganisms. These pathogens disrupt the normal functioning of the human body by inhibiting immune responses and producing harmful toxins. Infectious diseases can easily spread from person to person through contact with bodily fluids, indirect contact, or through vectors such as mosquitoes and ticks.

[0003] Staphylococcus aureus (S. aureus) is a highly prevalent human pathogen that can cause a variety of infections, including skin and soft tissue infections, endocarditis, osteomyelitis, bacteremia, and fatal pneumonia. It is considered the second most deadly pathogen worldwide. S. aureus is a Gram-positive bacterium, a small, immobile, spherical bacterium, or nonmotile cocci. S. aureus grows in clusters, similar to grapes. Therefore, it is called staphylococcus. S. aureus was discovered in Aberdeen, Scotland, in 1880 from a surgical abscess. In this respect, S. aureus is considered a typical opportunistic bacterium, exploiting skin breaks and other entry sites to cause infection. When cultured, bacterial colonies have a characteristic shiny, opaque yellow-to-white appearance on blood agar. Staphylococcus aureus belongs to the Staphylococcus family and infects all known mammalian species, including humans. Furthermore, due to its broad species-wide infectivity, Staphylococcus aureus can easily spread from one species to another, including between humans and animals.

[0004] Staphylococcus is one of the five leading causes of infection after trauma or surgery. Approximately 500,000 patients in American hospitals are infected with staphylococcus each year. S. aureus is widespread in the environment and is transmitted through airborne droplets or aerosols. When an infected person coughs or sneezes, many tiny droplets of saliva are expelled and become airborne. These droplets contain staphylococci and can infect others. Other common routes of infection include direct contact with staphylococcal-contaminated surfaces or being bitten by an infected person or animal. Approximately 30% of healthy individuals harbor S. aureus in the nose, back of the throat, and on the skin.

[0005] In healthy, immunocompetent individuals, colonization of the skin, intestinal tract, or nasopharynx with Staphylococcus aureus does not result in any symptoms or disease; however, in immunocompromised or immunosuppressed animals and humans, Staphylococcus aureus can be life-threatening. Staphylococcus aureus can cause suppurative (abscess) infections of the skin, eyes, and genital tract. When Staphylococcus aureus is isolated from abscesses, boils, or other skin lesions, it is usually not the primary cause of disease but rather represents a secondary invasion of a wound. Similarly, Staphylococcus aureus can be isolated from abscesses, breast abscesses or mastitis, dermatitis or skin infections, and genital infections.

[0006] Among other symptoms, Staphylococcus aureus can cause minor skin infections such as pimples, impetigo, furuncles, cellulitis, folliculitis, and carbuncles. It can also cause scalded skin syndrome and abscesses. Furthermore, Staphylococcus aureus can cause lung infections or pneumonia, brain infections or meningitis, bone infections or osteomyelitis, heart infections or endocarditis, life-threatening systemic blood infections or toxic shock syndrome (TSS), bacteremia, and sepsis.

[0007] The first-line treatment for staphylococcal infections is the beta-lactam antibiotics. Alternatively, other drugs can be used for treatment, but they have limitations such as poor tissue penetration and efficacy (vancomycin); high cost (quinupristin, dalfopristin, tigecycline, daptomycin, and linezolid); and high toxicity (rifampicin).

[0008] Increasing antibiotic resistance has become a global problem, and Staphylococcus aureus has the ability to rapidly develop drug resistance under the selective pressure of antimicrobial drugs. Staphylococcus aureus is divided into methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) based on its antibiotic susceptibility. Over the past few decades, due to bacterial evolution and overuse of antibiotics, drug resistance in Staphylococcus aureus has gradually increased, leading to a worldwide increase in MRSA infection rates and making clinical anti-infective treatment of MRSA more challenging. Accumulating evidence has shown that the resistance mechanisms of Staphylococcus aureus, especially MRSA, which is resistant to many types of antibiotics, are highly complex. Therefore, a timely understanding of MRSA drug resistance and elucidating its molecular mechanisms are crucial for the treatment of Staphylococcus aureus infections.

[0009] One alternative therapy being investigated to minimize the growth of resistance is the use of combinations of known antibiotics in the hope of synergistic effects against resistant strains. However, this approach has shown limitations in the selection of possible combinations and the long-term applicability of this strategy.

[0010] The second strategy aims to increase the susceptibility of bacterial strains to known antibiotics.

[0011] A third strategy is the discovery of novel compounds that can selectively inhibit Staphylococcus aureus. This approach offers several advantages over the use of broad-spectrum antibiotics because selective agents can kill or inhibit only disease-causing bacterial species. Therefore, the majority of beneficial bacteria are unaffected, minimizing collateral damage to the microbiota. Additionally, selective agents have the advantage of being less prone to the development of bacterial resistance.

[0012] For these reasons, there is a real unmet need to discover new selective compounds that are active against Staphylococcus aureus and can effectively treat the disease while avoiding the drawbacks of using broad-spectrum drugs. Summary of the Invention

[0013] The present invention discloses novel compounds that have potent antibiotic activity against Staphylococcus bacteria, more specifically Staphylococcus aureus, and may be useful in treating infections caused by these pathogens.

[0014] In a main aspect, the present invention relates to compounds of formula (I): [ka] wherein A, B, R1, R2 and R3 are as defined below in the detailed description.

[0015] A further aspect of the present invention relates to a process for preparing the compounds of formula (I).

[0016] One aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I).

[0017] Finally, one aspect of the present invention is a compound of formula (I) for use in therapy, more particularly for use in the treatment of bacterial infections caused by Staphylococcus bacteria, especially Staphylococcus aureus.

[0018] The present invention relates to a family of compounds that exhibit potent antibacterial activity, particularly against Staphylococcus bacteria, thereby solving the above-mentioned problem of identifying alternative compounds that selectively control Staphylococcus bacteria but avoid the drawbacks of having a broad spectrum of activity.

[0019] The Applicant has surprisingly found that the problem of providing an effective and alternative new solution for the prevention and treatment of staphylococcal infections can be solved by using the compounds of the present invention.

[0020] In a first aspect, the present invention provides a compound of formula (I): [ka] [In the formula, A is -CR a - or -N-; B is -CR b - or -N-; R a and R b are independently a hydrogen atom, a halogen atom, -CN, a branched or unbranched C 1-6 Alkyl groups, branched or unbranched C 1-6 Haloalkyl group, -OR ab Group or C 3-9 represents a cycloalkyl group; R ab is a hydrogen atom or a branched or unbranched C 1-6 is an alkyl group; R1 is a hydrogen atom, a halogen atom, a branched or unbranched C 1-6 Alkyl group or -OR 1a and; R 1a is a hydrogen atom or a branched or unbranched C 1-6 is an alkyl group; R2 is a hydrogen atom; an optionally substituted branched or unbranched C 1-6 Alkyl group;Halogen atom;-CN;C 1-6 Haloalkyl group; -(CH2) n -OR 2a ;-C(O)R 2b Optionally substituted -(CH2) m -C 3-9 Cycloalkyl; optionally substituted -(CH2) containing at least one heteroatom selected from N, O, or S q -C 3-9Heterocycloalkyl; optionally substituted -(CH2) containing at least one heteroatom selected from N, O, or S r -heteroaryl; optionally substituted -(CH2) s -aryl; all of the optionally substituted groups are selected from the group consisting of hydrogen atoms, halogen atoms, branched or unbranched C 1-6 alkyl groups, C 1-6 alkenyl groups; C 1-6 Haloalkyl group, C 1-6 Haloalkoxy groups: -CN, -NO2, =O, -OR 2’ , -NR 2’ R 2’’ , -NR 2’ C(O)R 2’’ , -NR 2’ S(O)2R 2’’ , -S(O)NR 2’ R 2’’ , -NR 2’ C(O)NR 2’’ R 2’’’ , -SR 2’ , -S(O)R 2’ , -S(O)2R 2’ , -C(O)R 2’ 、 -C(O)OR 2’ , -C(O)NR 2’ R 2’’ , -OCH2CH2OH, -NR 2’ S(O)NR 2’’ R 2’’’ , -C(CH3)2OR 2’ and is substituted with at least one substituent selected from R 2’ , R 2’’ and R 2’’’ are independently hydrogen atoms , -OR 2’a C optionally substituted with 3-9 cycloalkyl group or branched or unbranched C 1-6 alkyl groups; R 2’a is a hydrogen atom or a branched or unbranched C 1-6 is an alkyl group, R2a is a hydrogen atom; at least one R 2a’ Branched or unbranched C optionally substituted with 1-6 Alkyl group; branched or unbranched C 1-6 Haloalkyl group, or C 3-9 represents a cycloalkyl group; R 2a’ is a hydrogen atom or -OH; R 2b are independently a hydrogen atom; a halogen atom; -CN; a branched or unbranched C 1-6 Alkyl group; branched or unbranched C 1-6 Haloalkyl group, -OR 2b’ group, or at least one -R 2b’’ C optionally substituted with 3-9 is a heterocycloalkyl group; R 2b’ and R 2b’’ are independently a hydrogen atom or a branched or unbranched C 1-6 alkyl groups; R3 is a hydrogen atom, an optionally substituted branched or unbranched C 1-6 Alkyl; optionally substituted -(CH2) i -C 3-9 Cycloalkyl; optionally substituted -(CH2) containing at least one heteroatom selected from N, O, or S j -C 3-9 heterocycloalkyl; all of the optionally substituted groups are selected from the group consisting of hydrogen atoms, halogen atoms, branched or unbranched C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy groups: -CN, -NO2, =O, -OR 3’ , -NR 3’ R 3’’ , -NR 3’ C(O)R 3’’ , -NR 3’ S(O)2R 3’’ , -S(O)NR 3’ R 3’’ , -NR 3’ C(O)NR 3’’ R 3’’’ , -SR 3’, -S(O)R 3’ , -S(O)2R 3’ , -C(O)OR 3’ , -C(O)NR 3’ R 3’’ , -OCH2CH2OH, -NR 3’ S(O)NR 3’’ R 3’’’ , -C(CH3)2OR 3’ and is substituted with at least one group selected from R 3’ , R 3’’ and R 3’’’ are independently a hydrogen atom or a branched or unbranched C 1-6 alkyl groups; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3; s is 0, 1, 2 or 3: where i is 0, 1, 2 or 3: j is 0, 1, 2, or 3.] And, It relates to said compounds optionally in the form of any stereoisomer, preferably enantiomer or diastereomer, racemate or mixture of at least two stereoisomers, preferably enantiomers and / or diastereomers in any mixing ratio, or the corresponding salts, co-crystals or prodrugs thereof, or the corresponding solvates thereof.

[0021] Unless otherwise specified, the compounds of the present invention are also intended to include isotopically enriched forms, i.e., compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds that differ only in the presence of one or more isotopically enriched atoms, except for the replacement of at least one hydrogen atom with deuterium or tritium, or at least one carbon atom with 13 C-enriched carbon or 14 except that at least one nitrogen is substituted with a C-enriched carbon 15 Compounds having the present structures except for the substitution at the N-enriched nitrogen are within the scope of this invention.

[0022] The compound of formula (I) or its salt or solvate is preferably in a pharmaceutically acceptable form or in a substantially pure form. Pharmaceutically acceptable form means, inter alia, having a pharmaceutically acceptable level of purity excluding common pharmaceutical additives such as diluents and carriers, and not containing any substance that is considered toxic at normal dosages. The purity of the drug substance is preferably greater than 50%, more preferably greater than 70%, and most preferably greater than 90%. In a preferred embodiment, the purity of the compound of formula (I) or its salt, solvate, or prodrug is greater than 95%.

[0023] For clarity, expressions such as "a compound of formula (I) in which R1, R2 and R3 are as defined in the detailed description" (as well as the expression "a compound of formula (I) as defined in the claims") refer to "a compound of formula (I)", and the definitions of each substituent R1 etc. (including definitions from the cited claims) apply.

[0024] For clarity, all groups and definitions described herein and referring to compounds of formula (I) also apply to all intermediates in the synthesis.

[0025] The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine or iodine. For example, "C 1-6 haloalkyl" or "C 1-6 When the term "halo" is combined with other substituents, such as in "haloalkoxy," it means that the alkyl or alkoxy group, respectively, can contain at least one halogen atom.

[0026] The "C" referred to in this invention 1-6 "Alkyl" refers to saturated aliphatic groups. They may be unbranched (straight-chain) or branched, and may be optionally substituted. 1-6Alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Preferred alkyl groups in the present invention include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, and the like. Most preferred alkyl groups are C 1, 2, 3, 4, 5, or 6, such as methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl. 1-4 The alkyl group as defined in the present invention is optionally halogen, branched or unbranched C 1-6 Alkoxy, branched or unbranched C 1-6 Alkyl, C 1-6 Haloalkoxy, C 1-6 It may be mono- or polysubstituted with substituents independently selected from haloalkyl, trihaloalkyl or hydroxyl groups.

[0027] The "C" referred to in this invention 1-6 "Alkoxy" is understood to mean an alkyl group as defined above attached to the remainder of the molecule via an oxygen bond. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy or tert-butoxy.

[0028] The "C" referred to in this invention 3-6 "Cycloalkyl" means saturated and unsaturated (but not aromatic) cyclic hydrocarbons having 3 to 6 carbon atoms, which may be optionally unsubstituted, mono-substituted or poly-substituted. Examples of cycloalkyl groups include, but are not limited to, preferably cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups as defined in the present invention may optionally contain halogen atoms, branched or unbranched C 1-6Alkyl, branched or unbranched C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 It may be mono- or polysubstituted with substituents independently selected from haloalkyl, trihaloalkyl or hydroxyl groups.

[0029] The term "heterocyclic group" (hereinafter also referred to as "heterocyclyl") refers to a 4- to 18-membered monocyclic or fused polycyclic heterocyclic ring system having at least one saturated or unsaturated ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and / or sulfur. The heterocyclic group may be substituted one or more times.

[0030] Subgroups of heterocyclyl as understood herein include heteroaryl and non-aromatic heterocyclyl. -heteroaryl (equivalent to heteroaromatic group or aromatic heterocyclyl) is a 5-18 membered monocyclic or fused polycyclic aromatic heterocyclic ring system having one or more rings, at least one of which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur; preferably a 5-18 membered monocyclic or fused polycyclic aromatic heterocyclic ring system having one or two rings, at least one of which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur; more preferably selected from furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzothiazole, indole, benzotriazole, carbazole, quinazoline, thiazole, imidazole, pyrazole, oxazole, oxadiazole, thiophene and benzimidazole; Non-aromatic heterocyclyl is a 4-18 membered monocyclic or fused polycyclic ring system having one or more rings, at least one of which rings (which ring(s) is / are not aromatic) containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur; preferably a 4-18 membered monocyclic or fused polycyclic ring system having one or two rings, at least one or both of which rings (which ring(s) is / are not aromatic) containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur; more preferably selected from azetidine, oxetane, tetrahydrofuran, oxazepam, pyrrolidine, piperidine, piperazine, tetrahydropyran, morpholine, indoline, oxopyrrolidine, benzodioxane, in particular piperazine, benzodioxane, morpholine, tetrahydropyran, piperidine, oxopyrrolidine and pyrrolidine.

[0031] Preferably, in the context of the present invention, heterocyclyl is a 4-18-membered monocyclic or fused polycyclic ring system having one or more saturated or unsaturated rings, at least one of which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and / or sulfur. Preferably, it is a 4-18-membered monocyclic or fused polycyclic heterocyclic ring system having one or two saturated or unsaturated rings, at least one of which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. More preferably, it is a 4-12-membered monocyclic or bicyclic heterocyclyl ring system containing one nitrogen atom and, optionally, a second heteroatom selected from nitrogen and oxygen. In another preferred embodiment of the present invention, the heterocyclyl is a substituted monocyclic or bicyclic heterocyclyl ring system.

[0032] Examples of preferred heterocyclyls include azetidine, azepane, oxetane, tetrahydrofuran, oxazepam, pyrrolidine, imidazole, oxadiazole, tetrazole, pyridine, pyrimidine, piperidine, piperazine, benzofuran, benzimidazole, indazole, benzodiazole, thiazole, benzothiazole, tetrahydropyran, morpholine, indoline, furan, triazole, isoxazole, pyrazole, thiophene, benzothiophene, pyrrole, pyrazine, pyrrolo[2,3b]pyridine, quinoline, isoquinoline, tetrahydroisoquinoline, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole, oxopyrrolidine, pyrimidine, benzodioxolane, benzodioxane, carbazole, and quinazolidinyl. zoline, 3,9-diazaspiro[5.5]undecane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, octahydropyrrolo[3,4-c]pyrrole, in particular pyridine, piperazine, pyrazine, indazole, benzodioxane, thiazole, benzothiazole, morpholine, tetrahydropyran, pyrazole, These include imidazole, piperidine, thiophene, indole, benzimidazole, pyrrolo[2,3-b]pyridine, benzoxazole, oxopyrrolidine, pyrimidine, oxazepane, pyrrolidine, azetidine, azepane, oxetane, tetrahydrofuran, 3,9-diazaspiro[5.5]undecane, 2,8-diazaspiro[4.5]decane, and 2,7-diazaspiro[3.5]nonane.

[0033] Nitrogen-containing heterocyclyl is a heterocyclic ring system having one or more saturated or unsaturated rings, at least one of which contains nitrogen and optionally one or more further heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur; preferably a heterocyclic ring system having one or two saturated or unsaturated rings, at least one of which contains nitrogen and optionally one or more further heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur, more preferably azetidine, azepane, oxazepam, pyrrolidine, imidazole, oxadiazole, tetrazole, azetidine, pyridine, pyrimidine, piperidine, pipera In some embodiments, the benzotriazole, benzodiazole, morpholine, indoline, triazole, isoxazole, pyrazole, pyrrole, pyrazine, pyrrolo[2,3-b]pyridine, quinoline, quinolone, isoquinoline, tetrahydrothienopyridine, phthalazine, benzo-1,2,5-thiadiazole, indole, benzotriazole, benzoxazole, oxopyrrolidine, carbazole, thiazole, 3,9-diazaspiro[5.5]undecane, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]nonane, 2,7-diazaspiro[4.4]nonane, or octahydropyrrolo[3,4-c]pyrrole.

[0034] With respect to aromatic heterocyclyl (heteroaryl), non-aromatic heterocyclyl, aryl, and cycloalkyl, if a ring system simultaneously falls within two or more of the above ring definitions, if at least one aromatic ring contains a heteroatom, the ring system is first defined as aromatic heterocyclyl (heteroaryl). If none of the aromatic rings contains a heteroatom, and at least one non-aromatic ring contains a heteroatom, the ring system is defined as non-aromatic heterocyclyl. If none of the non-aromatic rings contains a heteroatom, and the ring system contains at least one aryl ring, the ring system is defined as aryl. If there is no aryl and at least one non-aromatic cyclic hydrocarbon is present, the ring system is defined as cycloalkyl.

[0035] The term "heterocycloalkyl" as used herein refers to a saturated or unsaturated (not aromatic), generally 5- or 6-membered cyclic hydrocarbon, which may be optionally unsubstituted, mono- or polysubstituted, and has at least one heteroatom selected from N, O, or S in its structure. Examples of heterocycloalkyl groups include, but are not limited to, preferably pyrroline, pyrrolidine, pyrazoline, aziridine, azetidine, tetrahydropyrrole, oxirane, oxetane, dioxetane, tetrahydropyran, tetrahydrofuran, dioxane, dioxolane, oxazolidine, piperidine, piperazine, morpholine, azepane, or diazepane. Heterocycloalkyl groups as defined herein may contain halogen atoms, branched or unbranched C 1-6 Alkyl, branched or unbranched C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 It is optionally mono- or polysubstituted with substituents independently selected from haloalkyl, trihaloalkyl or hydroxyl groups. More preferably, heterocycloalkyl in the context of this invention is a 5- or 6-membered ring structure that is optionally at least monosubstituted.

[0036] The term "aryl" as referred to in the present invention is understood to mean a ring system having at least one aromatic ring, but not containing heteroatoms in any of the rings. These aryl groups may contain halogen atoms, -CN, branched or unbranched C 1-6 -Alkyl, branched or unbranched C 1-6 -alkoxy, C 1-6 -Haloalkoxy, C 1-6-Optionally mono- or poly-substituted by substituents independently selected from haloalkyl, heterocyclyl and hydroxyl groups.Preferred examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl, indanyl or anthracenyl groups, which are optionally mono- or poly-substituted unless otherwise specified.More preferably, aryl in the context of the present invention is a 6-membered ring system, which is optionally at least mono- or poly-substituted.

[0037] The term "heteroaryl" as used herein refers to a heteroaryl having at least one aromatic ring, containing one or more heteroatoms selected from the group consisting of N, O, or S, and containing halogen atoms, branched or unbranched C 1-6 -Alkyl, branched or unbranched C 1-6 -alkoxy, C 1-6 -Haloalkoxy, C 1-6 It is understood to mean a heterocyclic ring system, optionally mono- or poly-substituted by substituents independently selected from haloalkyl, trihaloalkyl or hydroxyl groups.Preferred examples of heteroaryl include, but are not limited to, furan, benzofuran, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, isoxazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole and quinazoline.More preferably, in the context of the present invention, heteroaryl is an optionally at least mono-substituted 5- or 6-membered ring system.

[0038] As used herein, the term "fused" means that a ring or ring system is bonded to another ring or ring system, and those skilled in the art also use the terms "cyclized" or "annulated" to refer to this type of bond.

[0039] The term "ring system" as used herein refers to a system consisting of at least one ring bonded to atoms, and also encompasses systems of two or more bonded rings, where "bonded" means that each ring shares one (as in a spiro structure) or two or more atoms that are members of both bonded rings. A "ring system" defined in this way includes saturated, unsaturated, or aromatic carbocyclic rings that optionally contain at least one heteroatom as a ring member, are optionally at least monosubstituted, and may be bonded to other carbocyclic ring systems such as aryl groups, heteroaryl groups, or cycloalkyl groups.

[0040] Those skilled in the art also use the terms "fused," "cyclized," or "cyclized" to refer to this type of bond.

[0041] A "leaving group" is a group that retains the electron pair of a bond upon heterolytic bond cleavage. Suitable leaving groups are well known in the art and include Cl, Br, I, and -O-SO2R. 14 R 14 is F, C 1-4 -Alkyl, C 1-4 -haloalkyl or optionally substituted phenyl. Preferred leaving groups are Cl, Br, I, tosylate, mesylate, triflate, nonaflate and fluorosulfonate.

[0042] A "protecting group" is a group that is chemically introduced into a molecule to prevent a specific functional group in the molecule from undergoing an undesired reaction in a subsequent reaction. Protecting groups are used, inter alia, to obtain chemical selectivity in a chemical reaction. Preferred protecting groups in the context of the present invention are Boc (tert-butoxycarbonyl) or Teoc (2-(trimethylsilyl)ethoxycarbonyl).

[0043] The term "salts" is understood to mean any form in which the active compounds of the invention are in ionic form or are charged and associated with counterions (cations or anions). This definition particularly includes physiologically acceptable salts, and this term is understood to be synonymous with "pharmaceutically acceptable salts."

[0044] The term "pharmaceutically acceptable salt" in the context of the present invention means any salt that is physiologically acceptable (meaning that it is usually non-toxic, particularly as a result of the counterion) when used in a manner appropriate for therapeutic applications or uses, particularly in humans and / or mammals. In the context of the present invention, this definition includes salts formed with physiologically acceptable acids, i.e., salts of a particular active compound with a physiologically acceptable organic or inorganic acid, particularly when used in humans and / or mammals. Examples of salts of this type include: salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, or citric acid. Furthermore, pharmaceutically acceptable salts may be formed with physiologically acceptable cations, preferably inorganic cations, particularly when used in humans and / or mammals. Salts with alkali metals and alkaline earth metals include ammonium cations (NH + ) are particularly preferred, as are the salts formed from (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium. These physiologically acceptable salts can also be formed from anions or acids, and in the context of the present invention, in particular when used in humans and / or mammals, are understood to be salts formed from at least one compound used according to the present invention (usually protonated, for example, in the nitrogen) such as a cation and at least one physiologically acceptable anion.

[0045] The compounds of the invention may exist in crystalline or amorphous form.

[0046] It is understood that compounds that are solvates of the compounds represented by formula (I) defined above are also included in the scope of the present invention. Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. The term "solvate" refers to any form in which the active compound of the present invention is non-covalently bound to other molecules (often polar solvents), and includes in particular hydrates and alcoholates such as methanolates and ethanolates.

[0047] The term "cocrystal" is understood to mean a crystalline substance comprising a specific active compound and at least one additional component, usually a cocrystal-forming component, where the at least two components are bound together by weak interactions, which are defined as interactions that are neither ionic nor covalent, such as hydrogen bonds, van der Waals forces, π-π interactions, etc.

[0048] The term "prodrug" is used in its broadest sense and includes derivatives that are converted into the compounds of the present invention in vivo. Such derivatives can be easily conceived by those skilled in the art and include, but are not limited to, the following derivatives of the compounds of the present invention, depending on the functional groups present in the molecule: esters, amino acid esters, phosphate esters, metal salts, sulfonate esters, carbamates, and amides. Examples of methods for producing prodrugs of specific active compounds are known to those skilled in the art and are described, for example, in Krogsgaard-Larsen et al. "Textbook of Drug Design and Discovery" Taylor & Francis (April 2002).

[0049] Any compound that is a prodrug of a compound of Formula (I) is within the scope of the present invention. Particularly preferred prodrugs are those that improve the bioavailability of a compound of the present invention when administered to a patient (e.g., improve absorption of an orally administered compound into the blood) or improve delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) compared to the parent species.

[0050] It is understood that any compound that is an N-oxide of a compound of the present invention, such as a compound of formula (I), is also within the scope of the present invention.

[0051] The compound of formula (I) and its salts or solvates are preferably in a pharmaceutically acceptable form or in a substantially pure form. A pharmaceutically acceptable pure form means, inter alia, having a pharmaceutically acceptable level of purity excluding common pharmaceutical additives such as diluents and carriers, and being free from substances that are known to be toxic at normal dosages. The purity of the drug substance is preferably greater than 50%, more preferably greater than 70%, and most preferably greater than 90%. In a preferred embodiment, the purity of the compound of formula (I) or its salts is greater than 95%. This also applies to its solvates or prodrugs.

[0052] In certain preferred embodiments of the present invention, R a and R a is a hydrogen atom.

[0053] In another particularly preferred embodiment of the present invention, R1 is a hydrogen atom or -OR 1a is.

[0054] Yet another particularly preferred embodiment of the present invention is 1a C is branched or unbranched 1-6 It is an alkyl group.

[0055] In a further preferred embodiment, R 1a is methyl.

[0056] Another particularly preferred embodiment of the present invention is where R2 is a hydrogen atom, a branched or unbranched C 1-6 Alkyl group; -(CH2) n -OR 2a ;-C(O)R 2b or optionally substituted -(CH2) q -C 3-9 It is one that is heterocycloalkyl.

[0057] In a further preferred embodiment, R2 is a hydrogen atom; preferably methyl or ethyl; -(CH2) n -OR 2a ;-C(O)R 2b or optionally substituted -(CH2) q -C 3-9 It is heterocycloalkyl.

[0058] A further preferred embodiment is R 2a is a hydrogen atom; branched or unbranched C 1-6 The alkyl group is optionally preferably ethyl, which is unsubstituted or substituted with -OH.

[0059] A further preferred embodiment is C 3-9 Heterocycloalkyl groups are preferably those which are tetrahydrofuranyl.

[0060] Yet another particularly preferred embodiment of the present invention is where R2 is an optionally substituted group: [ka] It represents one of the following.

[0061] A further particularly preferred embodiment of the invention is where R3 is an optionally substituted -(CH2) i -C 3-9 Cycloalkyl; optionally substituted -(CH2) containing at least one heteroatom selected from N, O, or S j -C 3-9 This is the case when it is a heterocycloalkyl.

[0062] In a further preferred embodiment, R3 is the following group: [ka] Represents one of the following.

[0063] A further particular preferred embodiment of the present invention is a compound of formula (I): [ka] [In the formula, A is -CR a - or -N-; B is -CR b - or -N-; R a and R b represents a hydrogen atom; R1 is a hydrogen atom or -OR 1a and; R 1a is branched or unbranched C 1-6 is an alkyl group; R2 is a hydrogen atom, an optionally substituted branched or unbranched C 1-6 Alkyl group; -(CH2) n -OR 2a ;-C(O)R 2b Optionally substituted -(CH2) containing at least one heteroatom selected from N, O or S q -C 3-9 heterocycloalkyl; all of the optionally substituted groups are branched or unbranched C 1-6 Alkyl group, =O, -OR 2’’ , -C(O)R 2’ and is substituted with at least one substituent selected from R 2’ , R 2’’ and R 2’’’ are independently hydrogen atoms , -OR 2’a C optionally substituted with 3-9 cycloalkyl group or branched or unbranched C 1-6alkyl groups; R 2’a is a hydrogen atom or a branched or unbranched C 1-6 is an alkyl group, R 2a is a hydrogen atom; at least one R 2a’ Branched or unbranched C optionally substituted with 1-6 represents an alkyl group; R 2a’ is -OH; R 2b has at least one -R 2b’’ C optionally substituted with 3-9 represents a heterocycloalkyl group; R 2b’’ is a hydrogen atom or a branched or unbranched C 1-6 alkyl groups; R3 is -(CH2) i -C 3-9 Cycloalkyl; -(CH2) containing at least one heteroatom selected from N, O or S j -C 3-9 is heterocycloalkyl; n is 0, 1, 2 or 3; q is 0, 1, 2 or 3; i is 0, 1, 2 or 3; j is 0, 1, 2, or 3.] And, Optionally, the compounds include those in the form of stereoisomers, preferably enantiomers or diastereomers, racemates, or mixtures of at least two stereoisomers, preferably enantiomers and / or diastereomers in any mixing ratio, or the corresponding salts, co-crystals or prodrugs thereof, or the corresponding solvates thereof.

[0064] An even more specific and preferred embodiment of the present invention is a compound of formula (I): [ka] [In the formula, A is -CRa - or -N-; B is -CR b - or -N-; R a and R b represents a hydrogen atom; R1 is a hydrogen atom; or -OR 1a and; R 1a is a methyl group; R2 is a hydrogen atom; methyl; ethyl; -(CH2) n -OR 2a ;-C(O)R 2b or branched or unbranched C 1-6 alkyl group, ═O, -C(O)R 2’ 、 -OR 2’ any of the following groups optionally substituted with at least one substituent selected from: [ka] and;R 2’ is a hydrogen atom , -OR 2’a C optionally substituted with 3-9 cycloalkyl group or branched or unbranched C 1-6 alkyl groups; R 2’a is a hydrogen atom or a branched or unbranched C 1-6 is an alkyl group; R 2a represents a hydrogen atom, an ethyl group that is unsubstituted or substituted with —OH; R 2b represents tetrahydrofuranyl; R3 is one of the following groups: [ka] represents one of; n is 0, 1, 2 or 3; Optionally, the compounds include those in the form of stereoisomers, preferably enantiomers or diastereomers, racemates, or mixtures of at least two stereoisomers, preferably enantiomers and / or diastereomers in any mixing ratio, or the corresponding salts, co-crystals or prodrugs thereof, or the corresponding solvates thereof.

[0065] The compounds of the present invention represented by the above formula (I) may include enantiomers depending on the presence of chiral centers, or isomers depending on the presence of double bonds (e.g., Z, E). These single stereoisomers, enantiomers or diastereomers and mixtures thereof are included within the scope of the present invention.

[0066] Preferred compounds of the present invention are selected from: [1] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-hydroxyethyl)-N-(2-methoxyphenyl)acetamide; [2] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(3-methoxypyridin-4-yl)acetamide; [3] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(pyridin-2-yl)acetamide; [4] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(3-hydroxypropyl)-N-(2-methoxyphenyl)acetamide; [5]2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-(2-methoxyphenyl)acetamide; [6] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide; [7] rac- 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydrofuran-3-yl)methyl)acetamide; [8] rac- 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)acetamide; [9] rac- 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)acetamide;

[10] rac- 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)acetamide;

[11] N-(2-methoxyphenyl)-2-(5-((2,4,5-trioxo-3-((tetrahydro-2H-pyran-4-yl)methyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetamide;

[12] N-(2-hydroxyethyl)-N-(2-methoxyphenyl)-2-(5-((2,4,5-trioxo-3-((tetrahydro-2H-pyran-4-yl)methyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetamide;

[13] N-(2-methoxyphenyl)-2-(5-((2,4,5-trioxo-3-((tetrahydrofuran-3-yl)methyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetamide;

[14] N-(2-hydroxyethyl)-N-(2-methoxyphenyl)-2-(5-((2,4,5-trioxo-3-((tetrahydrofuran-3-yl)methyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetamide;

[15] (R)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)acetamide;

[16] (S)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)acetamide;

[17] rac- 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((5,5-dimethyltetrahydrofuran-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[18] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(((2S,5S)-5-methyltetrahydrofuran-2-yl)methyl)acetamide;

[19] N-(2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetyl)-N-(2-methoxyphenyl)tetrahydrofuran-2-carboxamide;

[20] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((5-oxotetrahydrofuran-2-yl)methyl)acetamide; [twenty one] rac- 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((4-hydroxytetrahydrofuran-2-yl)methyl)-N-(2-methoxyphenyl)acetamide; [twenty two] rac- 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(morpholin-2-ylmethyl)acetamide; [twenty three] rac- 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(morpholin-3-ylmethyl)acetamide;

[24] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-ethyl-N-(2-methoxyphenyl)acetamide;

[25] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-phenylacetamide;

[26] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-methylacetamide; or

[27] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide ;

[28] (S)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)acetamide;

[29] (R)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)acetamide;

[30] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((6,6-dimethyltetrahydro-2H-pyran-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[31] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((3,3-dimethyltetrahydro-2H-pyran-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[32] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((4-hydroxytetrahydro-2H-pyran-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[33] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((5-hydroxytetrahydro-2H-pyran-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[34] N-(2-methoxyphenyl)-2-(5-((2,4,5-trioxo-3-((tetrahydrofuran-2-yl)methyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetamide;

[35] (R)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-hydroxypent-4-en-1-yl)-N-(2-methoxyphenyl)acetamide;

[36] (S)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(morpholin-2-ylmethyl)acetamide;

[37] (R)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(morpholin-2-ylmethyl)acetamide;

[38] (S)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(morpholin-3-ylmethyl)acetamide;

[39] (R)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(morpholin-3-ylmethyl)acetamide;

[40] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((3,6-dihydro-2H-pyran-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[41] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((5-oxomorpholin-2-yl)methyl)acetamide;

[42] rac-N-((4-acetylmorpholin-2-yl)methyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide;

[43] (S)—N-((4-acetylmorpholin-2-yl)methyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide;

[44] (R)-N-((4-acetylmorpholin-2-yl)methyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide;

[45] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((4-propionylmorpholin-2-yl)methyl)acetamide;

[46] rac-N-((4-(cyclopropanecarbonyl)morpholin-2-yl)methyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide;

[47] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((4-isobutyrylmorpholin-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[48] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((4-pivaloylmorpholin-2-yl)methyl)acetamide;

[49] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((4-(2-hydroxyacetyl)morpholin-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[50] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((4-(2-methoxyacetyl)morpholin-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[51] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((4-(3-methoxypropanoyl)morpholin-2-yl)methyl)acetamide;

[52] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((4-methylmorpholin-2-yl)methyl)acetamide;

[53] rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((4-(2-hydroxyethyl)morpholin-2-yl)methyl)-N-(2-methoxyphenyl)acetamide;

[54] rac-N-((4-acetylmorpholin-3-yl)methyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide;

[55] (S)—N-((4-acetylmorpholin-3-yl)methyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide;

[56] (R)—N-((4-acetylmorpholin-3-yl)methyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide, or a pharmaceutically acceptable salt, stereoisomer, co-crystal, prodrug or solvate thereof.

[0067] In another aspect, the present invention relates to methods for obtaining compounds of general formula (I). Several procedures have been developed for obtaining all of the compounds of the present invention, which are described below as Method A and Method B.

[0068] The resulting reaction products may be purified, if desired, by conventional methods, such as crystallization or chromatography. Where the processes described below for preparing the compounds of the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques, such as preparative chromatography. Where chiral centers are present, the compounds may be prepared as racemates, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.

[0069] Method A Method A represents a first method for synthesizing compounds of general formula (I): [ka] Compounds of formula (IX): [ka] and a compound represented by formula (X): [ka] and reacting wherein A, B, R1, R2, and R3 are as defined in the detailed description and claims.

[0070] Scheme 1 below summarizes the synthetic route of Method A. The reactions carried out in the various steps (steps ai) of Scheme 1 are representatively illustrated by specific embodiments in the Examples. Scheme 2 depicts an alternative route for the synthesis of intermediates of formula (X).

[0071] [ka]

[0072] Method B Method B represents a second method for synthesizing compounds of general formula (I).

[0073] Thus, a method for preparing a compound of general formula (I) is described: [ka] Compounds of formula (XIX): [ka] and a compound represented by formula (XIX): [ka] and reacting wherein A, B, R1, R2, and R3 are as defined in the detailed description and claims.

[0074] Scheme 3 The reactions carried out in the various steps (steps k to p) are representatively illustrated by specific embodiments in the Examples.

[0075] [ka]

[0076] The compounds of formula (II), (IV), (XI), (XIII), (XIV), (XVII) and (XVI) used in the above processes are either commercially available or can be synthesized according to general procedures described in the literature and exemplified in the synthesis of some intermediates.

[0077] Furthermore, certain compounds of the invention can also be obtained starting from other compounds of general formula (I) by appropriate transformations of functional groups in one or more steps under standard experimental conditions and using reactions well known in organic chemistry.

[0078] Furthermore, compounds of general formula (I) exhibiting chirality can also be obtained by resolving the racemic compounds of general formula (I) by chiral preparative HPLC or by crystallization of diastereomeric salts or co-crystals. Alternatively, the resolution step can be carried out in a previous step using any suitable intermediate.

[0079] In another aspect, the present invention also relates to the therapeutic use of the compound represented by general formula (I). As described above, the compound represented by general formula (I) exhibits potent antibacterial activity against Staphylococcus bacteria, particularly Staphylococcus aureus.

[0080] Therefore, the compounds represented by general formula (I) are useful as pharmaceuticals, and more specifically, the compounds represented by formula (I) are useful as antibiotics.

[0081] The compounds of formula (I) of the present invention are suitable for the treatment and / or prevention of Staphylococcus infections.

[0082] The compounds of general formula (I) are particularly suitable for the treatment of infections caused by Staphylococcus aureus.

[0083] A related aspect of the present invention relates to the use of a compound of general formula (I) for the manufacture of a medicament for the treatment and / or prevention of Staphylococcus infections, more preferably infections caused by Staphylococcus aureus.

[0084] Another related aspect of the present invention relates to a method for the treatment and / or prevention of Staphylococcus infections, more preferably infections caused by Staphylococcus aureus, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by general formula (I).

[0085] Another aspect of the present invention is a pharmaceutical composition comprising at least a compound represented by general formula (I) or a pharmaceutically acceptable salt, isomer, co-crystal, prodrug, or solvate thereof, and at least a pharmaceutically acceptable carrier, excipient, adjuvant, or vehicle.

[0086] The pharmaceutical compositions of the present invention can be formulated as medicaments in various pharmaceutical forms, comprising at least one compound that binds to a sigma receptor and, optionally, at least one further active substance and / or, optionally, at least one auxiliary substance.

[0087] The auxiliary substances or additives can be selected from carriers, excipients, supporting substances, lubricants, fillers, solvents, diluents, colorants, flavor modifiers such as sugars, antioxidants and / or flocculating agents. In the case of suppositories, waxes or fatty acid esters, or preservatives, emulsifiers and / or carriers for parenteral administration may be included. The selection and amounts of these auxiliary substances and / or additives depend on the application form of the pharmaceutical composition.

[0088] The pharmaceutical compositions of the present invention may be adapted for any mode of administration, oral or parenteral, for example pulmonary, nasal, rectal and / or intravenous.

[0089] Preferably, the compositions are suitable for oral or parenteral administration, more preferably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathecal, rectal, transdermal, transmucosal or nasal administration.

[0090] The compositions of the present invention can be formulated for oral administration in any form, preferably selected from the group consisting of tablets, dragees, capsules, pills, chewing gum, powders, drops, gels, juices, syrups, solutions, and suspensions. The compositions for oral administration of the present invention may be in the form of multiparticulates, preferably microparticles, microtablets, pellets, or granules, and can optionally be compressed into tablets, filled into capsules, or suspended in a suitable liquid. Suitable liquids are known to those skilled in the art.

[0091] Formulations suitable for parenteral administration are solutions, suspensions, reconstitutable dry formulations or sprays.

[0092] The compounds of the present invention can be formulated for transdermal application as deposits in dissolved form or as patches.

[0093] Applications to the skin include ointments, gels, creams, lotions, suspensions or emulsions.

[0094] For rectal administration, administration by suppository is preferred.

[0095] In preferred embodiments, pharmaceutical compositions is solid or liquid oral dosage form.The dosage form suitable for oral administration is tablet, capsule, syrup or solution, and can contain the conventional excipients known in the art, such as binder such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; filler such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricant such as magnesium stearate; disintegrant such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agent such as sodium lauryl sulfate.

[0096] Solid oral compositions can be prepared by conventional blending, filling or tableting methods.When using a large amount of filler, repeated blending operations can be used to distribute active agent throughout the composition.This type of operation is conventional in the art.Tablets can be prepared by, for example, wet granulation or dry granulation, and if necessary, can be coated by methods well known in conventional pharmaceutical practice, particularly enteric coating methods.

[0097] The pharmaceutical composition may also be adapted for parenteral administration, such as a sterile solution, suspension, or lyophilized formulation in a suitable unit dosage form. Suitable excipients, such as bulking agents, buffers, or surfactants, may be used.

[0098] The above-described formulations are prepared using standard methods as described or referenced in the Spanish and US Pharmacopoeias and similar references.

[0099] The daily dose for humans and animals may vary depending on factors derived from the respective species or other factors such as age, sex, weight, severity of disease, etc. The daily dose for humans is in the range of 1 to 2000 mg, preferably 1 to 1500 mg, more preferably 1 to 1000 mg of the active substance, administered once or in divided doses per day.

[0100] The following examples are merely illustrative of certain embodiments of the present invention and are not to be construed as limiting the invention in any way. [Example]

[0101] The following examples illustrate the preparation of both intermediate compounds and compounds of the present invention.

[0102] The following abbreviations are used: anh: anhydrous aq: water-based br s: broad singlet C: Celsius Cat:Catalyst CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine DIAD: Diisopropyl azodicarboxylate DIPEA: N-ethyl-N,N-diisopropylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide EDCi: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Eq: Equivalent ESI: electrospray ionization Et2O: Diethyl ether EtOAc: ethyl acetate EtOH: ethanol Example: Example g: grams h: hours / second HPLC: High-performance liquid chromatography Hz: Hertz Int: intermediate L: Liter m: meters, millimeters, multiplets M: mole, molecular weight m / z: mass-charge ratio Me: Methyl MeCN: acetonitrile MeOH: Methanol MS: Mass spectrometry min:minutes NMM: 4-methylmorpholine (N-methylmorpholine) NMR: nuclear magnetic resonance Ns: Nosyl group PPh 3 : Triphenylphosphine Ret: Retain time rt: room temperature sat: saturated THF: tetrahydrofuran TMSNCO: (Trimethylsilyl)isocyanate UPLC: Ultra-high performance liquid chromatography

[0103] To determine the HPLC-MS spectra, the following method was used. A: Column Kinetex C18 2.6 mm, 2.1 × 50 mm; temperature: 40 °C; flow rate: 0.50 mL / min; A: 50 mM ammonium formate buffer pH 4 containing HCOOH, B: water; C: acetonitrile, gradient A:B:C: 5:85:10 in 0.3 min + 5:85:10 to 5:10:85 in 1.7 min + 5:10:85 in 3 min. B: Column Kinetex C18 2.6 mm, 2.1 × 50 mm, temperature: 40 °C; flow rate: 0.50 mL / min; A: 50 mM ammonium formate buffer pH 4 containing HCOOH, B: water; C: acetonitrile, gradient A:B:C: 5:25:70 in 0.3 min + 5:25:70 to 5:0:95 in 1.7 min + 5:0:95 in 3 min. C: Column: SunFire C18 3.5 μm, 2.1 × 100 mm, temperature: 35 °C; flow rate: 0.30 mL / min; A: acetonitrile: / MeOH (1:1); B: water; C: 100 mM ammonium acetate pH 7, gradient: A:B:C 10:85:5 in 5 min + 10:85:5 to 95:0:5 in 15 min + 95:0:5 in 10 min. D: Column Kinetex C18 2.7 mm, 2.1 × 50 mm, temperature: 40 °C; flow rate: 0.40 mL / min; A: water, B: MeCN:MeOH (1:1); C: 100 mM ammonium acetate solution (pH 6.8), gradient A:B:C: 85:10:5 for 0.3 min + 85:10:5 to 0:95:5 for 2 min + 0:95:5 for 2.7 min. E: Column Kinetex C18 2.6 mm, 2.1 × 50 mm; temperature: 40 °C; flow rate: 0.50 mL / min; A: water, B: MeCN; C: 50 mM ammonium acetate solution (pH 6.8), gradient A:B:C: 85:10:5 for 0.3 min + 85:10:5 to 10:85:5 for 1.7 min + 10:85:5 for 3 min.

[0104] To determine the UPLC-MS spectra, the following method was used. F: Column Acquity BEH C18 1.7 μm, 2.1 × 50 mm; temperature: 35 °C; flow rate: 0.50 mL / min; A: 50 mM ammonium formate buffer pH 4 containing HCOOH, B: water; C: acetonitrile, gradient A:B:C: 5:85:10 in 0.5 min + 5:85:10 to 5:10:85 in 4.5 min + 5:10:85 in 4 min. G: Column Acquity BEH C18 1.7 μm, 2.1 × 100 mm; temperature: 35 °C; flow rate: 0.50 mL / min; A: 50 mM ammonium formate buffer pH 4 containing HCOOH, B: water; C: acetonitrile, gradient A:B:C: 5:85:10 in 0.5 min + 5:85:10 to 5:10:85 in 4.5 min + 5:10:85 in 4 min. H: Column: ZORBAX SB-C18 Rapid Resolution HD 1.8 μm, 2.1 × 50 mm; temperature: 35 °C; flow rate: 0.80 mL / min; A: 10 mM ammonium formate buffer pH 3 containing HCOOH; B: acetonitrile, gradient A:B: 95:5 for 0.2 min + 95:5 to 0:100 for 3.3 min + 0:100 for 0.5 min. I: Column ZORBAX SB-C18 Rapid Resolution HD 1.8 μm, 2.1 × 50 mm; temperature: 35 °C; flow rate: 0.80 mL / min; A: 10 mM ammonium formate buffer pH 4 containing HCOOH; B: acetonitrile, gradient A:B 0.2 min + 95:5 to 0:100 3.3 min + 0:100 0.5 min.

[0105] To determine % ee by chiral HPLC, the following method was used. J: Column Chiralpak IB, 4.6 x 250 mm, 5.0 μm; Eluent: n-heptane / IPA (70:30) v / v; Flow rate: 0.8 mL / min

[0106] The following paragraphs set forth, for illustrative purposes, the preparation of certain intermediates and compounds according to formula (I), with lettered steps corresponding to the synthetic steps set forth in Scheme 1 above.

[0107] Example 1. 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-hydroxyethyl)-N-(2-methoxyphenyl)acetamide [ka]

[0108] a) tert-butyl-3-amino-3-(hydroxyimino)propanoate [ka] To a solution of tert-butyl 2-cyanoacetate (10.5 g, 74.38 mmol) in EtOH:water (4:1, 100 mL) was added NHOH.HCl (5.7 g, 81.82 mmol) and NaCO (8.7 g, 81.82 mmol), and the suspension was stirred at 55 °C for 20 h. The reaction was allowed to warm to room temperature, the EtOH was concentrated, and the residue was diluted with ethyl acetate (100 mL) and washed with water (15 mL × 1). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give 12.6 g of an orange solid. The resulting solid was slurried with EtO (20 mL), decanted (× 2), and dried to give tert-butyl-3-amino-3-(hydroxyimino)propanoate (10.03 g, pale orange solid, 77% yield). 1 H-NMR (CDCl 3 ) δ: 5.05 (brs, 2H), 3.08 (s, 2H), 1.45 (s, 9H). ESI + -MS m / z, 175.1 (M+H).

[0109] b) tert-butyl 3-(2-chloroacetamido)-3-(hydroxyimino)propanoate [ka] 2-Chloroacetyl chloride (2.6 mL, 32.55 mmol) was added to a suspension of tert-butyl-3-amino-3-(hydroxyimino)propanoate (5.40 g, 31.00 mmol) and EtN (4.73 mL, 34.1 mmol) in CHCl (40 mL) cooled to 0 °C. The mixture was allowed to warm to room temperature and react for 16 h. The reaction mixture was washed with water (2 × 30 mL), and the organic layer was dried over NaSO (anhydrous), filtered, and concentrated. The crude product (7.20 g, pale yellow solid, 93% yield) was used in the next step without further purification.

[0110] c) tert-Butyl 2-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)acetate A solution of tert-butyl 3-(2-chloroacetamido)-3-(hydroxyimino)propanoate (7.15 g, 28.52 mmol) in dioxane (50 mL) was stirred for 16 h at 80° C. After complete conversion, the solvent was concentrated and the resulting oil was dried to give tert-butyl 2-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)acetate (7.5 g, pale brown oil, exceeding theoretical yield). 1 H-NMR (CDCl3 ) δ: 4.68 (s, 2H), 3.69 (s, 2H), 1.45 (s, 9H).

[0111] d) 1-(cyclopropylmethyl)urea [ka] Cyclopropylmethanamine (4.00 mL, 46.12 mmol) was added dropwise to a solution of (trimethylsilyl)isocyanate (7.50 mL, 55.34 mmol) in THF (40 mL). The reaction mixture was warmed to 70°C and reacted for 6 hours. The solvent was concentrated, and the crude residue was slurried with hexane (10 mL), filtered, and washed with hexane (5 mL x 1). The resulting solid was dried to give 1-(cyclopropylmethyl)urea (3.44 g, white solid, 65% yield). 1 H-NMR (DMSO-d6 ) δ: 5.95 (brs, 1H), 5.38 (brs, 2H), 2.83 (m, 2H), 0.85 (m, 1H), 0.36 (m, 2H), 0.10 (m, 2H).

[0112] e) 1-(cyclopropylmethyl)imidazolidine-2,4,5-trione [ka] Oxalyl chloride (2.90 mL, 33.15 mmol) was added dropwise to a suspension of 1-(cyclopropylmethyl)urea (3.44 g, 30.14 mmol) in THF (35 mL) cooled to 0 °C. The mixture was allowed to warm to room temperature and react for 22 h. The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product (4.45 g, white solid, 88% yield) was used in the next step without further purification. 1 H-NMR (CDCl3 ) δ: 8.64 (brs, 1H), 3.51 (d, J=7.6 Hz, 2H), 1.18 (m, 1H), 0.57 (m, 2H), 0.37 (m, 2H).

[0113] f) tert-Butyl 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetate [ka] To a solution of tert-butyl 2-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)acetate (1.90 g, 8.19 mmol) and 1-(cyclopropylmethyl)imidazolidine-2,4,5-trione (1.06 g, 6.30 mmol) in MeCN (25 mL) was added DIPEA (1.4 mL, 8.19 mmol). The mixture was warmed to 70 °C and stirred at this temperature for 6 h. The solvent was concentrated, and the crude product was subjected to flash chromatography on SiO (15->40% ethyl acetate / hexanes) to give tert-butyl 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetate (1.8 g, pale yellow oil, 78% yield). 1 H-NMR (CDCl3 ) δ: 5.08 (s, 2H), 3.71 (s, 2H), 3.56 (d, J=7.6 Hz, 2H), 1.44 (s, 9H), 1.17 (m, 1H), 0.58 (m, 2H), 0.39 (m, 2H).

[0114] g) 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetic acid HCl (10% aqueous solution, 20 mL) was added to a solution of tert-butyl 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetate (1.80 g, 4.94 mmol) in THF (20 mL). The resulting mixture was warmed to 70 °C and stirred at this temperature for 8 h. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 15 h. The solvent was concentrated and the crude product was extracted with CHCl (3 × 20 mL). The combined organic layers were dried over NaSO (anhydrous), filtered, and concentrated. The crude residue was slurried with hexane (15 mL), filtered, eluted with hexane (3 × 10 mL) and EtO:hexane (1:1, 1 × 8 mL), and dried to give 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetic acid (1.27 g, white solid, 83% yield). 1 H-NMR (DMSO-d6 ) δ: 12.85 (brs, 1H), 5.09 (s, 2H), 3.82 (s, 2H), 3.40 (d, J=6.8 Hz, 2H), 1.07 (m, 1H), 0.47 (m, 2H), 0.30 (m, 2H). ESI + -MS m / z, 309.1 (M+H).

[0115] h) N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methoxyaniline KI (444 mg, 2.68 mmol) and K2CO3 (4.44 g, 32.15 mmol) were added to a solution of o-anisidine (3.0 mL, 26.79 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (6.3 mL, 29.46 mmol) in DMF (50 mL). The mixture was warmed to 70 °C and stirred at this temperature for 21 h. The mixture was allowed to warm to room temperature and the solvent was concentrated. The residue was suspended in ethyl acetate (60 mL) and washed with brine (3 × 80 mL) and water (1 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 8.50 g of an orange oil. The resulting crude product was subjected to flash chromatography on SiO2 (1->5% ethyl acetate / hexanes) to give N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methoxyaniline (5.84 g, pale yellow solid, 77% yield). 1 H-NMR (CDCl3 ) δ: 6.87 (m, 1H), 6.76 (m, 1H), 6.64 (m, 2H), 3.87 (m, 2H), 3.84 (s, 3H), 3.24 (m, 2H), 0.92 (s, 9H), 0.07 (s, 6H). ESI + -MS m / z, 282.1 (M+H).

[0116] i) N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide To a solution of 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetic acid (515 mg, 1.67 mmol) and N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methoxyaniline (611 mg, 2.17 mmol) in THF (18 mL) was added NMM (0.240 mL, 2.17 mmol) and CDMT (381 mg, 2.17 mmol), and the solution was stirred at room temperature for 22 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (2 × 15 mL). The combined aqueous layers were extracted with EtOAc (1 × 20 mL). The combined organic layers were dried over NaSO (anhydrous), filtered, and concentrated. The crude product was subjected to flash chromatography on SiO2 (30->50% ethyl acetate / hexanes) to afford the title compound (658 mg, colorless foam, 53% yield). 1 H-NMR (CDCl3 ) δ: 7.36-7.22 (m, 2H), 6.96 (m, 2H), 5.04 (s, 2H), 3.96 (m, 2H), 3.82 (s, 2H), 3.65 (m, 2H), 3.56-3.45 (m, 5H), 1.16 (m, 1H), 0.83 (s, 9H), 0.57 (m, 2H), 0.38 (m, 2H), 0.006 (s, 3H), -0.004 (s, 3H). ESI + -MS m / z, 572.3 (M+H).

[0117] j) Title compound HCl (10% aqueous solution, 3.9 mL, 10.8 mmol) was added to a solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide (620 mg, 1.08 mmol) in THF (16 mL). The mixture was warmed to 60° C. and stirred at this temperature until complete conversion (2 h). The reaction mixture was allowed to warm to room temperature, poured into water (40 mL), and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (1×40 mL), dried over NaSO (anhydrous), filtered, and concentrated. The crude residue was purified by SiO flash chromatography (40->60% acetone / hexanes) to give 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-hydroxyethyl)-N-(2-methoxyphenyl)acetamide (466 mg, white solid, 94% yield). 1 H-NMR (CDCl3 ) δ: 7.37 (t, J=7.5 Hz, 1H), 7.21 (d, J=6.5 Hz, 1H), 7.02 (m, 2H), 5.05 (s, 2H), 3.88 (m+s, 4H), 3.81-3.65 (m, 4H), 3.55 (s, 3H), 2.87 (m, 1H), 1.19 (m, 1H), 0.57 (m, 2H), 0.38 (m, 2H). ESI + -MS m / z, 458.3 (M+H).

[0118] This method is suitable commercially available Examples 2-23 using starting materials and 30-37 was used to manufacture. [Table 1] JPEG2026504190000075.jpg227160 JPEG2026504190000076.jpg227160 JPEG2026504190000077.jpg227160 JPEG2026504190000078.jpg220160 JPEG2026504190000079.jpg 80160

[0119] Example 22. rac-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(morpholin-2-ylmethyl)acetamide

change

[0120] The following paragraphs provide examples of the preparation of intermediates and compounds of formula (I). The alphabetical steps correspond to alternative synthesis methods for intermediates of formula (X) described in Scheme 2.

[0121] Example 29 (R)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)acetamide

change

[0122] q) N-(2-methoxyphenyl)-2-nitrobenzenesulfonamide

change

[0123] A flask was charged with a solution of 2-methoxyaniline (1 g, 8.12 mmol) in 30 mL of DCM, and TEA (2.2 mL, 16.2 mmol) was added in a cold bath at 0 °C. A solution of 2-nitrobenzenesulfonyl chloride (1.98 g, 8.9 mmol) in 30 mL of DCM was then added dropwise using a dropping funnel. The mixture was allowed to warm to room temperature over 16 hours. The reaction solvent was removed, and the crude product was dissolved in SiO . 2 Purification by flash chromatography (20% EtOAc / hexanes) gave the title compound (590 mg, 78% yield). 1H NMR (CDCl3) δ: 7.91 (dd, J = 2.5, 1.4 Hz, 1H), 7.89 (dd, J = 2.6, 1.5 Hz, 1H), 7.90 - 7.87 (m, 1H), 7.67 (td, J = 7.8, 1.5 Hz, 1H), 7.62 (dd, J = 8.1, 1.6 Hz, 1H), 7.58 (td, J = 7.7, 1.4 Hz, 1H), 7.10 (ddd, J = 8.2, 7.5, 1.7 Hz, 1H), 6.95 (td, J = 7.7, 1.3 Hz, 1H), 6.75 (dd, J = 8.2, 1.4 Hz, 1H), 3.61 (s, 3H). ESI+-MS m / z, 309.0 (M+H).

[0124] r) (R)-N-(2-methoxyphenyl)-2-nitro-N-((tetrahydro-2H-pyran-2-yl)methyl)benzenesulfonamide The intermediate obtained in step q (170 mg, 0.55 mmol), (R)-(tetrahydro-2H-pyran-2-yl)methanol (192 mg, 1.65 mmol), and triphenylphosphine (376 mg, 1.43 mmol) were dissolved in toluene (15 ml), and DIAD was added under ice-cooling. The mixture was warmed to room temperature and heated at 60°C for 17 hours. The reaction mixture was concentrated under reduced pressure, diluted with AcOEt (30 mL), and washed with brine (20 mL x 2). The combined aqueous layer was extracted with AcOEt (20 mL x 1). The combined organic layer was also extracted with Na 2 SO 4 (anhydrous), filtered, and concentrated. The residue was evaporated. 2 Flash chromatography (15->20% EtOAc / hexanes) gave the title compound. 1H NMR (CDCl3) δ: 7.65 - 7.51 (m, 3H), 7.48 - 7.40 (m, 2H), 7.31 (ddd, J = 8.2, 7.5, 1.8 Hz, 1H), 6.97 (td, J = 7.6, 1.3 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 4.00 - 3.82 (m, 2H), 3.45 - 3.26 (m, 3H), 3.29 (s, 3H), 1.89 - 1.77 (m, 1H), 1.64 - 1.23 (m, 5H). ESI+-MS m / z, 407.0 (M+H).

[0125] s) (R)-2-Methoxy-N-((tetrahydro-2H-pyran-2-yl)methyl)aniline [ka]

[0126] To a solution of the compound obtained in the previous step r (241 mg, 0.59 mmol) in ACN (15 mL) were added benzenethiol (183 μL, 1.78 mmol) and cesium carbonate (773 mg, 2.37 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting solid was filtered, and the solvent was concentrated. The residue was diluted with DCM (15 mL) and washed with brine (15 mL × 2). The combined organic layer was washed with anhydrous NaCl. 2 SO 4 (anhydrous), filtered, and concentrated. The crude product was purified by SiO 2 Purification by flash chromatography (0->15% EtOAc / hexanes) afforded the title compound (48 mg, 37% yield). 1H NMR (CDCl3) δ: 6.86 (td, J = 7.6, 1.5 Hz, 1H), 6.76 (dd, J = 7.9, 1.5 Hz, 1H), 6.66 (td, J = 7.7, 1.5 Hz, 1H), 6.60 (dd, J = 7.8, 1.6 Hz, 1H), 4.02 (ddd, J = 11.3, 4.3, 2.2 Hz, 1H), 3.84 (s, 3H), 3.57 (dddd, J = 11.2, 7.6, 4.0, 2.2 Hz, 1H), 3.47 (td, J = 11.5, 2.6 Hz, 1H), 3.23 - 3.04 (m, 2H), 1.92 - 1.82 (m, 1H), 1.71 - 1.33 (m, 5H). ESI+-MS m / z, 222.0 (M+H).

[0127] i) Title compound [ka] To a solution of 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetic acid (60 mg, 0.125 mmol) obtained in Step g of Example 1 and (R)-2-methoxy-N-((tetrahydro-2H-pyran-2-yl)methyl)aniline (45 mg, 0.205 mmol) obtained in the previous Step s in DCM (5 mL) was added EDCi (39 mg, 0.253 mmol), and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM (5 mL) and washed with brine (2 × 10 mL). The combined aqueous layer was extracted with DCM (1 × 10 mL). The combined organic layer was then washed with Na 2 SO 4 (anhydrous), filtered and concentrated. The crude product was removed by SiO 2 Flash chromatography (30->50% hexane / EtOAc) afforded the title compound (43 mg, colorless foam, 43% yield) (96.9% ee). 1H NMR (CDCl3) δ: 7.39 - 7.29 (m, 1.5H), 7.24 (dd, J = 7.7, 1.8 Hz, 0.5H), 7.03 - 6.91 (m, 2H), 5.05 (s, 1H), 5.04 (d, J = 0.7 Hz, 1H), 3.84 (s, 1.5H), 3.83 (s, 1.5H), 4.19 - 2.97 (m, 9H), 1.85 - 1.74 (m, 1H), 1.69 - 1.60 (m, 1H), 1.55 - 1.10 (m, 5H), 0.61 - 0.55 (m, 2H), 0.39 (dt, J = 6.2, 4.8 Hz, 2H).

[0128] This method was used to prepare Examples 28, 23, and 36-41 using the appropriate commercially available starting materials. [Table 2] JPEG2026504190000086.jpg118158

[0129] The following paragraphs set forth, for illustrative purposes, the preparation of certain intermediates and compounds according to formula (I), steps identified by letters being those shown in the schemes set forth above. 3 This corresponds to the synthesis steps described in

[0130] Intermediate 1. [ka]

[0131] k) N-ethyl-2-methoxyaniline [ka] A solution of ammonium formate (6.00 g, 95.15 mmol, 11.7 eq) in water (10 mL) was added to a suspension of 10% Pd / C (430 mg, 0.406 mmol, 0.05 eq) and o-anisidine (1.09 mL, 8.12 mmol, 1 eq) in MeCN (40 mL). The resulting mixture was stirred at room temperature for 16 h. The suspension was filtered through a pad of Celite and eluted with MeOH (50 mL). The solvent was concentrated, and the residue was dissolved in CHCl (20 mL), dried over NaSO (anhydrous), filtered, and concentrated. The crude product (1.67 g, red oil, yield > theoretical) was carried to the next step without further purification. 1 H-NMR (CDCl3 ) δ: 6.88 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.64 (m, 2H), 3.85 (s, 3H), 3.18 (c, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H). ESI + -MS m / z, 152.0 (M+H).

[0132] l) 2-cyano-N-ethyl-N-(2-methoxyphenyl)acetamide [ka] EDCi (1.71 g, 8.93 mmol, 1.1 eq) and DMAP (99 mg, 0.81 mmol, 0.1 eq) were added to a cooled (0 °C) suspension of cyanoacetate (760 mg, 8.93 mmol, 1.1 eq) in CHCl (10 mL). A solution of N-ethyl-2-methoxyaniline (8.12 mmol, 1.0 eq) in CHCl (12 mL) was added, and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 4 days. The reaction mixture was diluted with water (20 mL) and extracted with CHCl (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The crude product was subjected to SiO flash chromatography (5->23% ethyl acetate / hexanes) to give 2-cyano-N-ethyl-N-(2-methoxyphenyl)acetamide (1.05 g, brown solid, 59% yield). 1 H-NMR (CDCl3 ) δ: 7.39 (t, J = 7.9, 1H), 7.16 (dd, J = 7.7, 1.8 Hz, 1H), 7.03 (m, 2H), 3.86 (s, 3H), 3.84-3.55 (m, 2H), 3.15 (s, 2H), 1.09 (t, J = 7.2Hz, 3H). ESI + -MS m / z, 219.1 (M+H).

[0133] m) 3-amino-N-ethyl-3-(hydroxyimino)-N-(2-methoxyphenyl)propanamide [ka] NH2OH.HCl (401 mg, 5.77 mmol, 1.2 eq) and Na2CO3 (612 mg, 5.77 mmol, 1.2 eq) were added to a solution of 2-cyano-N-ethyl-N-(2-methoxyphenyl)acetamide (1.05 g, 4.81 mmol, 1.0 eq) in EtOH:water (5:1, 12 mL), and the suspension was stirred at room temperature for 22 h. The EtOH was concentrated, and the residue was diluted with ethyl acetate (20 mL) and washed with water (1 × 15 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 1.21 g of a yellow oil. The resulting oil was slurried with EtO (8 mL), filtered, washed with EtO (2 × 2 mL), and dried to give 3-amino-N-ethyl-3-(hydroxyimino)-N-(2-methoxyphenyl)propanamide (881 mg, white solid, 73% yield). 1 H-NMR (CDCl3 ) δ: 7.34 (t, J = 7.9 Hz, 1H), 7.12 (dd, J = 7.7, 1.7 Hz, 1H), 7.06-6.92 (m, 2H), 5.23 (brs, 2H), 3.90-3.73 (m, 1H), 3.81 (s, 3H), 3.55 (m, 1H), 2.84 (d, J = 1.5 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H). ESI + -MS m / z, 252.1 (M+H).

[0134] n) 3-amino-3-((2-chloroacetoxy)imino)-N-ethyl-N-(2-methoxyphenyl)propanamide [ka] 2-Chloroacetyl chloride (0.293 mL, 3.69 mmol, 1.05 eq) was added dropwise to a cooled (0 °C) solution of 3-amino-N-ethyl-3-(hydroxyimino)-N-(2-methoxyphenyl)propanamide (881 mg, 3.51 mmol, 1.0 eq) and DIPEA (0.71 mL, 4.04 mmol, 1.15 eq) in CHCl (10 mL). The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 17 h. The reaction mixture was diluted with water (15 mL) and extracted with CHCl (2 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give 3-amino-3-((2-chloroacetoxy)imino)-N-ethyl-N-(2-methoxyphenyl)propanamide. The crude product (1.22 g, brown oil, yield > theoretical) was carried to the next step without further purification. ESI + -MS m / z, 327.2, 329.1 (M+H).

[0135] o) 2-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-ethyl-N-(2-methoxyphenyl)acetamide [ka] A solution of 3-amino-3-((2-chloroacetoxy)imino)-N-ethyl-N-(2-methoxyphenyl)propanamide (3.51 mmol, 1.0 eq) in dioxane (15 mL) was warmed to 80° C. and stirred at this temperature for 5 h. The solvent was concentrated to give 2-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-ethyl-N-(2-methoxyphenyl)acetamide. The crude product (1.68 g, brown oil, yield > theoretical) was carried to the next step without further purification.

[0136] This method was used to prepare intermediates 2-4 using the appropriate starting materials.

[0137] [Table 3]

[0138] Example 24. 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-ethyl-N-(2-methoxyphenyl)acetamide [ka]

[0139] p) 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-ethyl-N-(2-methoxyphenyl)acetamide [ka] DIPEA (0.932 mL, 5.27 mmol, 1.5 eq) was added to a solution of 2-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-N-ethyl-N-(2-methoxyphenyl)acetamide (3.51 mmol, 1.0 eq) and 1-(cyclopropylmethyl)imidazolidine-2,4,5-trione (708 mg, 4.21 mmol, 1.2 eq) in MeCN (20 mL). The mixture was refluxed until complete conversion (4 h). The reaction mixture was allowed to warm to room temperature, the solvent was concentrated, and the crude product was subjected to SiO2 flash chromatography (22->30% EtOAc / hexanes) to give 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-ethyl-N-(2-methoxyphenyl)acetamide (750 mg, pale yellow solid, 48% yield). 1 H-NMR (CDCl3 ) δ:7.35 (m, 1H), 7.16 (dd, J = 7.9, 1.7 Hz, 1H), 6.98 (m, 2H), 5.05 (s, 2H), 3.84 (s, 3H), 3.78 (q, J = 6.9 Hz, 1H), 3.68-3.41 (m, 3H), 1.64 (s, 2H), 1.31-1.13 (m, 1H), 1.07 (t, J = 7.2 Hz, 3H), 0.58 (t, J = 5.1 Hz, 2H), 0.39 (t, J = 5.1 Hz, 2H). ESI + -MS m / z, 442.3 (M+H) .

[0140] This method too , was used to prepare Examples 25-27 using the appropriate starting materials. [Table 4]

[0141] The following paragraphs provide examples of the preparation of compounds of formula (I) starting from compound example 22.

[0142] Example 42. rac-N-((4-acetylmorpholin-2-yl)methyl)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide [ka]

[0143] To a solution of the compound of Example 22 (308 mg, 0.6 mmol) previously obtained in DCM (20 mL) and TEA (100 μL, 0.721 mmol) was added acetyl chloride (71 mg, 0.9 mmol) in a cold bath at 0° C. After 2 hours, the reaction was terminated by HPLC control and the solvent was concentrated. The crude product was diluted with DCM (20 mL) and washed with brine (10 mL × 2). The combined aqueous layer was extracted with DCM (1 × 10 mL). The combined organic layer was also extracted with NaCl. 2 SO 4 The crude product was slurried with AcOEt and filtered to remove the solids. The AcOEt solution was concentrated to give the title compound (270 mg, 81% yield) as a white solid. 1 H NMR (CDCl 3 ) δ: 7.37 (qdd, J = 8.7, 6.4, 1.7 Hz, 1H), 7.31 - 7.19 (m, 1H), 7.08 - 6.94 (m, 2H), 5.11 - 4.98 (m, 2H), 4.60 - 1.93 (m, 19H), 1.19 (tt, J = 7.7, 5.2 Hz, 1H), 0.67 - 0.50 (m, 2H), 0.43 - 0.31 (m, 2H) ESI + -MS m / z, 555.5 (M+H)

[0144] This method was used to prepare Examples 43-53 starting from Examples 22, 36 and 37 using the appropriate commercially available starting materials.

[0145] [Table 5] JPEG2026504190000099.jpg227159 JPEG2026504190000100.jpg67159

[0146] Similarly, the method of Example 42 was used to prepare Examples 54-56, starting from Examples 23, 38 and 39, using the appropriate commercially available starting materials.

[0147] [Table 6]

[0148] Example of enantiomeric excess determination [Table 7]

[0149] Examples of biological activity Experimental procedure: MIC test microdilution method To evaluate the antibacterial activity of the compounds, ATCC strains of Staphylococcus aureus were used. The minimum inhibitory concentrations (MICs) of the compounds were determined by microdilution according to CLSI methods.

[0150] Microplate preparation: compound preparation 3 mg of the compound was weighed into a 4 mL glass vial and dissolved in an appropriate amount of 100% DMSO (reference number: D2438-50, Sigma) to give a concentration of 12.8 mg / mL (Cmax.).

[0151] "Mother" Plate In a 96-well U-plate (reference number: 650161, Greiner Bio-One): 50 μL of the compound to be analyzed prepared in 100% DMSO at 12.8 mg / mL was dispensed into each well in the first column (eight compounds per plate, rows 1 to 8). 25 μL of 100% DMSO was dispensed into all wells from column 2 to column 12. Using a multichannel pipette, 25 μL was aspirated from row 1 and dispensed into row 2. The contents of row 2 were mixed several times, and 25 μL was aspirated and dispensed into row 3. This process was repeated up to row 10, where 25 μL of the contents were aspirated and discarded.

[0152] -The final mother plate map is as follows (all values ​​are in mg / mL): [Table 8]

[0153] "Daughter" Plate: In a 96-well U-shaped plate: -Using a multichannel pipette (dispense mode), aspirate the appropriate volume (taking into account the number of copies of the mother plate to be run) from all wells of the mother plate and dispense 1 μL / well into the daughter plate.

[0154] Notes: A Tecan instrument (FREEDOM EVO100) was used to prepare the mother and daughter plates.

[0155] MIC Test: Bacterial Inoculation Prepare a bacterial suspension and use saline (sodium chloride 0.9%) to obtain a 0.5 McFarland turbidity standard value (approximately 10 8 The suspension was then standardized to 1 / 1000 dilution (approximately 10 CFU / mL) in the appropriate medium (CLSI standard). 5 CFU / mL) was prepared and inoculated into each well of the daughter plate (columns 1-11 only) at 99 μL using a multidrop™ Combi Reagent Dispenser. Column 12 was dispensed with 99 μL of medium alone as a sterility control.

[0156] The final plate map is as follows (all values ​​are in μg / mL): [Table 9]

[0157] The plates were incubated for 18–20 h at 37°C. The MIC value was considered to be the concentration of compound that inhibited growth by 80% or more compared to the growth control.

[0158] Activity results against Staphylococcus aureus: [Table 10]

Claims

1. Compounds represented by general formula (I): 【Chemistry 1】 [In the formula, A is -CR ａ - or -N-; B is -CR ｂ - or -N-; R ａ and R ｂ are independently a hydrogen atom, a halogen atom, —CN, a branched or unbranched C １－６ Alkyl groups, branched or unbranched C １－６ haloalkyl group, —OR ａｂ group or C ３－９ represents a cycloalkyl group; R ａｂ is a hydrogen atom or a branched or unbranched C １－６ is an alkyl group; R １ is a hydrogen atom, a halogen atom, a branched or unbranched C １－６ Alkyl group or -OR １ａ and R １ａ is a hydrogen atom or a branched or unbranched C １－６ is an alkyl group; R ２ is a hydrogen atom; an optionally substituted branched or unbranched C １－６ Alkyl group; halogen atom; -CN; C １－６ Haloalkyl group; -(CH ２ ) ｎ -OR ２ａ -C(O)R ２ｂ ; optionally substituted -(CH ２ ) ｍ -C ３－９ cycloalkyl; optionally substituted —(CH ２ ) ｑ -C ３－９ Heterocycloalkyl; optionally substituted —(CH ２ ) ｒ -heteroaryl; optionally substituted -(CH ２ ) ｓ -aryl; all of the optionally substituted groups are selected from the group consisting of hydrogen atoms, halogen atoms, branched or unbranched C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group; —CN, —NO ２ , =O, -OR ２’ , -NR ２’ R ２’’ , -NR ２’ C(O)R ２’’ , -NR ２’ S (O) ２ R ２’’ , -S(O) ２ NR ２’ R ２’’ , -NR ２’ C(O)NR ２’’ R ２’’’ , -SR ２’ , -S(O)R ２’ , -S(O) ２ R ２’ , -C(O)OR ２’ , —C(O)NR ２’ R ２’’ , -OCH ２ CH ２ OH, -NR ２’ S (O) ２ NR ２’’ R ２’’’ , -C(CH ３ ) ２ OR ２’ and is substituted with at least one substituent selected from R ２’ , R ２’’ and R ２’’’ are independently a hydrogen atom or a branched or unbranched C １－６ alkyl groups; R ２ａ is a hydrogen atom; at least one R ２ａ’ Branched or unbranched C optionally substituted with １－６ Alkyl group; branched or unbranched C １－６ haloalkyl group, or C ３－９ represents a cycloalkyl group; R ２ａ’ is a hydrogen atom or —OH; R ２ｂ represents a hydrogen atom; a halogen atom; -CN; branched or unbranched C １－６ Alkyl group; branched or unbranched C １－６ haloalkyl group, —OR ２ｂ’ group, or at least one -R ２ｂ’’ C optionally substituted with ３－９ is a heterocycloalkyl group; R ２ｂ’ and R ２ｂ’’ are independently a hydrogen atom or a branched or unbranched C １－６ alkyl groups; R ３ is a hydrogen atom, an optionally substituted branched or unbranched C １－６ alkyl; optionally substituted —(CH ２ ) ｉ -C ３－９ cycloalkyl; optionally substituted —(CH ２ ) ｊ -C ３－９ heterocycloalkyl; all of the optionally substituted groups are selected from the group consisting of hydrogen atoms, halogen atoms, branched or unbranched C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group; —CN, —NO ２ , =O, -OR ３’ , -NR ３’ R ３’’ , -NR ３’ C(O)R ３’’ , -NR ３’ S (O) ２ R ３’’ , -S(O) ２ NR ３’ R ３’’ , -NR ３’ C(O)NR ３’’ R ３’’’ , -SR ３’ , -S(O)R ３’ , -S(O) ２ R ３’ , -C(O)OR ３’ , —C(O)NR ３’ R ３’’ , -OCH ２ CH ２ OH, -NR ３’ S (O) ２ NR ３’’ R ３’’’ , -C(CH ３ ) ２ OR ３’ and is substituted with at least one group selected from R ３’ , R ３’’ and R ３’’’ are independently a hydrogen atom or a branched or unbranched C １－６ alkyl groups; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3; s is 0, 1, 2 or 3; i is 0, 1, 2 or 3; j is 0, 1, 2 or 3. And, The compounds, optionally in the form of stereoisomers, preferably enantiomers or diastereomers, racemates or mixtures of at least two stereoisomers, preferably enantiomers and / or diastereomers in any mixing ratio, or the corresponding salts, co-crystals or prodrugs thereof, or the corresponding solvates thereof.

2. R ａ and R ａ The compound according to claim 1 , wherein is a hydrogen atom.

3. R １ is a hydrogen atom or -OR １ａ 3. The compound of claim 1 or 2, wherein

4. R １ａ is branched or unbranched C １－６ 4. The compound according to claim 3, wherein the alkyl group is preferably a methyl group.

5. R ２ is a hydrogen atom; branched or unbranched C １－６ an alkyl group, preferably methyl or ethyl; ２ ) ｎ -OR ２ａ -C(O)R ２ｂ or optionally substituted -(CH ２ ) ｑ -C ３－９ The compound of any one of claims 1 to 4, which is a heterocycloalkyl.

6. R ２ａ is a hydrogen atom; branched or unbranched C １－６ 6. A compound according to claim 5, wherein the alkyl group is ethyl, optionally unsubstituted or substituted with -OH.

7. R ２ｂ is C ３－９ 6. The compound of claim 5, wherein the heterocycloalkyl group is preferably tetrahydrofuranyl.

8. R ２ is an optionally substituted group: 【Chemistry 2】 6. The compound according to claim 5, wherein the compound represents one of:

9. R ３ is the following group: 【Transformation 3】 The compound according to any one of claims 1 to 8, which represents one of:

10. The compound of claim 1 selected from: [1] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-hydroxyethyl)-N-(2-methoxyphenyl)acetamide; [2] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(3-methoxypyridin-4-yl)acetamide; [3] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(pyridin-2-yl)acetamide; [4] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(3-hydroxypropyl)-N-(2-methoxyphenyl)acetamide; [5] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-(2-methoxyphenyl)acetamide; [6] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide; [7] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydrofuran-3-yl)methyl)acetamide; [8] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)acetamide; [9] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)acetamide; [10] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydro-2H-pyran-2-yl)methyl)acetamide; [11] N-(2-methoxyphenyl)-2-(5-((2,4,5-trioxo-3-((tetrahydro-2H-pyran-4-yl)methyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetamide; [12] N-(2-hydroxyethyl)-N-(2-methoxyphenyl)-2-(5-((2,4,5-trioxo-3-((tetrahydro-2H-pyran-4-yl)methyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetamide; [13] N-(2-methoxyphenyl)-2-(5-((2,4,5-trioxo-3-((tetrahydrofuran-3-yl)methyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetamide; [14] N-(2-hydroxyethyl)-N-(2-methoxyphenyl)-2-(5-((2,4,5-trioxo-3-((tetrahydrofuran-3-yl)methyl)imidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetamide; [15] (R)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)acetamide; [16] (S)-2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)acetamide; [17] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((5,5-dimethyltetrahydrofuran-2-yl)methyl)-N-(2-methoxyphenyl)acetamide; [18] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(((2S,5S)-5-methyltetrahydrofuran-2-yl)methyl)acetamide; [19] N-(2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)acetyl)-N-(2-methoxyphenyl)tetrahydrofuran-2-carboxamide; [20] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-((5-oxotetrahydrofuran-2-yl)methyl)acetamide; [21] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-((4-hydroxytetrahydrofuran-2-yl)methyl)-N-(2-methoxyphenyl)acetamide; [22] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(morpholin-2-ylmethyl)acetamide; [23] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-(morpholin-3-ylmethyl)acetamide; [24] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-ethyl-N-(2-methoxyphenyl)acetamide; [25] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-phenylacetamide; [26] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)-N-methylacetamide; or [27] 2-(5-((3-(cyclopropylmethyl)-2,4,5-trioxoimidazolidin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-(2-methoxyphenyl)acetamide, or a pharmaceutically acceptable salt, stereoisomer, co-crystal, prodrug or solvate thereof.

11. Compounds represented by formula (I): 【Chemistry 4】 [In the formula, A, B, R １ , R ２ and R ３ is as defined in any one of claims 1 to 9. A method for producing Compounds represented by formula (IX): 【Transformation 5】 and a compound represented by formula (X): 【Transformation 6】 The production method, comprising the step of reacting

12. Compounds represented by formula (I): 【Transformation 7】 [In the formula, A, B, R １ , R ２ and R ３ As defined in any one of claims 1 to 9. A method for producing Compounds represented by formula (XIX): 【Transformation 8】 and a compound represented by formula (XIX): 【Chemistry 9】 The production method, comprising the step of reacting

13. A compound according to any one of claims 1 to 10 for use as a pharmaceutical.

14. A compound according to any one of claims 1 to 10 for use as an antibiotic.

15. 15. A compound according to claim 14 for use as an antibiotic for the treatment and / or prevention of Staphylococcus sp. infections.

16. 14. The compound for use according to claim 13, wherein the infection is an infection caused by Staphylococcus aureus.

17. 11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt, isomer, co-crystal, prodrug or solvate thereof, and at least a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle.

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