Novel compounds for the treatment of streptococcal infections

Abstract

The present invention relates to a compound of formula (I): The present invention also relates to a novel fungicidal compound represented by the formula JPEG2026504191000058.jpg63153. The present invention also relates to a method for producing the fungicidal compound, a composition containing the fungicidal compound, and the use of the fungicidal compound as a pharmaceutical.

Description

[Technical Field]

[0001] The present invention relates to novel fungicidal compounds useful for treating infections caused by Streptococcus sp., particularly infections caused by Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae. The present invention also relates to methods for preparing the fungicidal compounds, compositions containing the fungicidal compounds, and pharmaceutical uses of the fungicidal compounds. [Background technology]

[0002] Infectious diseases pose 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. When microorganisms invade the respiratory tract, a wide range of common respiratory diseases occur. Infectious respiratory diseases are considered a major health concern worldwide because they can rapidly become severe and lead to death. Respiratory diseases are classified as upper and lower respiratory tract infections, with the more severe disease occurring because pathogens infect sterile parts of the respiratory system, such as the lungs, trachea, and bronchi. In 2019, approximately 2.49 million people died from lower respiratory tract infections worldwide, making it the fourth leading cause of death across all age groups and remaining a medical concern for certain high-risk populations.

[0003] Streptococcus pneumoniae, also known as pneumococcus, is a Gram-positive bacterium responsible for millions of deaths worldwide. Diseases caused by this bacterium are classified as pneumococcal diseases. The pathogen asymptomatically colonizes the nasopharynx of the host, but over time can migrate to sterile tissues and organs, causing infection. The pathogen can survive under both aerobic and anaerobic conditions.

[0004] Streptococcus pyogenes is the causative bacterium of a variety of group A streptococcal infections (GAS). These infections can be noninvasive or invasive. Noninvasive infections tend to be more common and less severe. The most common of these infections include streptococcal pharyngitis (strep throat) and impetigo. Scarlet fever is another example of a group A noninvasive infection. Invasive infections caused by group A beta-hemolytic streptococci tend to be more severe but are rarer. These occur when the bacteria infect sites that are not normally visible, such as the bloodstream or organs. Potential illnesses include streptococcal toxic shock syndrome, necrotizing fasciitis, pneumonia, and bacteremia. Globally, GAS is estimated to cause more than 500,000 deaths annually, making it one of the world's leading pathogens.

[0005] Streptococcus agalactiae, or group B streptococcus (GBS), can cause pneumonia and meningitis in newborns and the elderly, and occasionally systemic bacteremia. Importantly, Streptococcus agalactiae is the most common cause of meningitis in infants between one and three months of age. Streptococcus agalactiae also colonizes the intestinal tract and female reproductive tract, increasing the risk of premature rupture of membranes during pregnancy and transmission to the infant.

[0006] Pneumonia is currently the most common pneumococcal disease. It is a global health challenge, significantly affecting not only children under the age of five, but also the elderly and those with underlying medical conditions. Streptococcus pneumoniae possesses various virulence factors that facilitate adherence and invasion of host tissues and enable evasion of host immune defenses. Streptococcus pneumoniae is the primary microorganism causing community-acquired pneumonia. Streptococcus pneumoniae is considered the fourth leading pathogen in global mortality. Globally, pneumonia is the leading cause of death in children under the age of five. The World Health Organization reports that one child dies from pneumonia every 20 seconds. Approximately 900,000 cases of pneumococcal pneumonia occur annually in the United States. Furthermore, the United Nations Children's Fund reports that pneumonia accounted for 16% of deaths in children under the age of five worldwide in 2016. Pneumococcal pneumonia causes approximately 300,000 to 600,000 hospitalizations in the United States annually, reducing survival rates among older adults. There are many types of pneumonia, including community-acquired pneumonia (CAP), atypical pneumonia, hospital-acquired pneumonia, and aspiration pneumonia. These differ depending on the location of infection and the bacterium causing the disease. Currently, the most common type of pneumonia is CAP (primarily pneumococcal). This type of pneumonia spreads through person-to-person contact within the community, but outside of health care facilities, it spreads through inhalation of aerosol droplets from a carrier or infected person. Currently, CAP is the leading cause of death among children under the age of five worldwide. Infants, children, the elderly, smokers, and immunocompromised individuals are all at increased risk of developing pneumonia due to weakened immune systems. CAP occurs more frequently in the elderly than in younger individuals, and it is the fifth leading cause of death among the elderly.

[0007] As diagnostic methods improve, treatments for pneumococcal infections are also evolving. While antibiotics are available to suppress Streptococcus pneumoniae colonization, increasing antibiotic resistance has reduced their effectiveness. Broad-spectrum antibiotics are no longer as effective. Traditionally, beta-lactam and macrolide antibiotics have been the primary options for treating pneumococcal infections. However, the emergence of pneumococci with reduced susceptibility to these agents has created a need for alternative treatments that are highly effective against respiratory pathogens, including resistant strains, and have a low likelihood of resistance induction.

[0008] One alternative being investigated is the use of known antibiotics in combination, with 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.

[0009] The second strategy aims to increase the susceptibility of bacterial strains to known antibiotics.

[0010] A third strategy is the discovery of novel compounds that can selectively inhibit Streptococcus pneumoniae. This approach offers several advantages over the use of broad-spectrum antibiotics because selective agents can kill or inhibit only the disease-causing bacterial species (i.e., Streptococcus pneumoniae). 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.

[0011] For these reasons, there is a real unmet need to discover new selective compounds that are active against Staphylococcus pneumoniae and can effectively treat the disease while avoiding the drawbacks of using broad-spectrum drugs. Summary of the Invention

[0012] The present invention discloses novel compounds that have potent antibiotic activity against Streptococcus bacteria, more specifically against Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae, and may be useful in treating infections caused by these pathogens.

[0013] In a main aspect, the present invention relates to compounds of formula (I): [ka] [Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 are as defined below in the detailed description.]

[0014] A further aspect of the present invention relates to a process for preparing the compounds of formula (I).

[0015] One aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I).

[0016] 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 Streptococcus bacteria, especially Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus agalactiae.

[0017] The present invention relates to a family of compounds that exhibit potent bactericidal activity, particularly against Streptococcus, thereby solving the above-mentioned problem of identifying alternative compounds that selectively control Streptococcus but avoid the drawbacks of having a broad spectrum of activity.

[0018] The Applicant has surprisingly found that the problem of providing an effective and alternative new solution for the prevention and treatment of streptococcal infections can be solved by using the compounds of the present invention.

[0019] In a first aspect, the present invention provides a compound of formula (I): [ka] [In the formula, 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 or a branched or unbranched C 1-6 is an alkyl group; R3 is a hydrogen atom, a branched or unbranched C 1-6 Alkyl or -(CH2) m -OR 3a and; R 3a is a hydrogen atom or a branched or unbranched C 1-6 is an alkyl group; R4 is a hydrogen atom, a branched or unbranched C 1-6 Alkyl or -(CH2) n -OR 4a and; R 4a is a hydrogen atom or a branched or unbranched C 1-6 is an alkyl group; R5 is a hydrogen atom; optionally substituted branched or unbranched C 1-6 Alkyl group;Halogen atom;-CN;C 1-6 Haloalkyl groups; optionally substituted -(CH2) r -C 3-9 Cycloalkyl; optionally substituted -(CH2) containing at least one heteroatom selected from N, O, or S s -C 3-9 Heterocycloalkyl; optionally substituted -(CH2) j -aryl; optionally substituted -(CH) containing at least one heteroatom selected from N, O, or S i-heteroaryl; 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, -OR 5a , -NR 5a R 5b , -NR 5a C(O)R 5b , -NR 5a C(O)NR 5b R 5c , -C(O)OR 5a , -C(O)NR 5a R 5b , -OCH2CH2OH and -C(CH3)2OR 5a and is substituted with at least one substituent selected from R 5a , R 5b and R 5c are independently a hydrogen atom or a branched or unbranched C 1-6 alkyl groups; R6, R7 and R8 are independently a hydrogen atom, an optionally substituted branched or unbranched C 1-6 Alkyl group;Halogen atom;-CN;C 1-6 Haloalkyl groups; optionally substituted C 3-9 cycloalkyl; optionally substituted C containing at least one heteroatom selected from N, O or S; 3-9 Heterocycloalkyl; optionally substituted -OC 1-6 -Alkyl; -OC 1-6 -haloalkyl; optionally substituted -OC 3-9 cycloalkyl; optionally substituted -OC containing at least one heteroatom selected from N, O, or S; 3-9 heterocycloalkyl; all of the optionally substituted groups are selected from hydrogen atoms, halogen atoms, branched or unbranched C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy groups: -CN, -OR a , -NR a R b , -NRa C(O)R b , -C(O)OR a , -C(O)NR a R b , -OCH2CH2OH, -C(CH3)2OR a and is substituted with at least one substituent selected from R a and R b are independently a hydrogen atom or a branched or unbranched C 1-6 alkyl groups; R9 is a hydrogen atom or a branched or unbranched C 1-6 is an alkyl group; R 10 is a hydrogen atom; optionally substituted branched or unbranched C 1-6 Alkyl group; -CN; C 1-6 Haloalkyl groups; optionally substituted -(CH2) r -C 3-9 Cycloalkyl; optionally substituted -(CH2) j -aryl; optionally substituted -OC 1-6 -alkyl; 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; -OR 10a , -NR 10a R 10b , -NR 10a C(O)R 10b , -NR 10a C(O)NR 10b R 10c , -C(O)OR 10a , -C(O)NR 10a R 10b , -OCH2CH2OH, -NR 10a S(O)NR 10b R 10c , -C(CH3)2OR 10a and is substituted with at least one substituent selected from R 10a , R 10b and R 10c are independently a hydrogen atom or a branched or unbranched C1-6 alkyl groups; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; r is 0, 1, 2 or 3; s is 0, 1, 2 or 3; j is 0, 1, 2 or 3; i 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.

[0020] 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.

[0021] 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%.

[0022] 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.

[0023] For clarity, all groups and definitions described herein and referring to compounds of formula (I) also apply to all intermediates in the synthesis.

[0024] 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.

[0025] 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. 1-6 Alkyl 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. 1-4The 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.

[0026] 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.

[0027] 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 1-6 Alkyl, 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] Those skilled in the art also use the terms "fused," "cyclized," or "cyclized" to refer to this type of bond.

[0040] 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.

[0041] 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).

[0042] 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."

[0043] 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.

[0044] The compounds of the invention may exist in crystalline or amorphous form.

[0045] 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.

[0046] 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.

[0047] 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).

[0048] 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.

[0049] 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.

[0050] 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.

[0051] In certain preferred embodiments of the present invention, R1 is a hydrogen atom or -OR 1a is.

[0052] In a more preferred embodiment, R1 is a hydrogen atom or -OR 1a and R 1a is a hydrogen atom.

[0053] In another particularly preferred embodiment of the invention, R2 is a hydrogen atom.

[0054] In yet another particularly preferred embodiment of the present invention, R3 is a hydrogen atom, a methyl group or -(CH2) m -OR 3a is.

[0055] In a more preferred embodiment, R3 is a hydrogen atom, a methyl group, or -(CH2) m -OR 3a where m is 0 or 2, and R 3a is a hydrogen atom.

[0056] In another particularly preferred embodiment of the present invention, R4 is a hydrogen atom, a methyl group or -(CH2) n -OR 4a is.

[0057] In a more preferred embodiment, R4 is a hydrogen atom, a methyl group, or -(CH2) m -OR 4a where n is 0 or 2, and R 3a is a hydrogen atom.

[0058] Yet another particularly preferred embodiment of the present invention is where R5 is an optionally substituted branched or unbranched C 1-6 Alkyl groups; optionally substituted -(CH2)RC 3-9 cycloalkyl; or optionally substituted -(CH) containing at least one heteroatom selected from N, O, or S. s -C 3-9 It is one that is heterocycloalkyl.

[0059] In further preferred embodiments, R5 is isobutyl, isopropyl; or the following groups: [ka] It is one of the following.

[0060] A further particular preferred embodiment of the present invention is where R, R and R are independently of one another a hydrogen atom, an optionally substituted branched or unbranched C 1-6 Alkyl group; halogen atom; or C 1-6 It is selected from haloalkyl groups.

[0061] In a further preferred embodiment, R6, R7 and R8 are independently selected from a hydrogen atom, F; or trifluoromethyl.

[0062] Another particular embodiment of the invention is one in which R9 is a hydrogen atom.

[0063] In further particularly preferred embodiments, R 10 is a hydrogen atom or an optionally substituted branched or unbranched C 1-6 It is an alkyl group.

[0064] In a further preferred embodiment, R 10 is a hydrogen atom or methyl.

[0065] A further particular preferred embodiment of the present invention is a compound of formula (I): [ka] [In the formula, R1 is a hydrogen atom or -OR 1a and; R 1a is a hydrogen atom; R2 is a hydrogen atom; R3 is a hydrogen atom, a branched or unbranched C 1-6 Alkyl, preferably methyl, or -(CH2) m -OR 3a and; R 3a is a hydrogen atom; R4 is a hydrogen atom, a branched or unbranched C 1-6 Alkyl, preferably methyl, or -(CH2) n -OR 4a and; R 4a is a hydrogen atom; R5 is an optionally substituted branched or unbranched C 1-6 Alkyl groups; optionally substituted -(CH2) r -C 3-9cycloalkyl; or optionally substituted -(CH) containing at least one heteroatom selected from N, O, or S. s -C 3-9 is heterocycloalkyl; R6, R7 and R8 are each independently a hydrogen atom, an optionally substituted branched or unbranched C 1-6 alkyl group, halogen atom; or C 1-6 haloalkyl groups; R9 is a hydrogen atom or a branched or unbranched C 1-6 is an alkyl group; R 10 is a hydrogen atom or an optionally substituted branched or unbranched C 1-6 is an alkyl group; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; r is 0, 1, 2 or 3; s 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.

[0066] A further particular preferred embodiment of the present invention is a compound of formula (I): [ka] [In the formula, R1 is a hydrogen atom or -OR 1a and; R 1a is a hydrogen atom; R2 is a hydrogen atom; R3 is a hydrogen atom, a branched or unbranched C 1-6 Alkyl, preferably methyl, or -(CH2) m -OR 3a and; R 3a is a hydrogen atom; R4 is a hydrogen atom, a branched or unbranched C 1-6 Alkyl, preferably methyl, or -(CH2) n -OR 4a and; R 4a is a hydrogen atom; R5 is isobutyl, isopropyl or the following group: [ka] is one of; R6, R7 and R8 are independently selected from a hydrogen atom, F or trifluoromethyl; R9 is a hydrogen atom; R 10 is a hydrogen atom or methyl; n is 0, 1, 2 or 3; m 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.

[0067] Particularly preferred embodiments of the present invention are represented by compounds of formula (I) having sub-formula (Ia) or (Ib): [ka] [Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 are as defined in the detailed description and claims.]

[0068] Further preferred embodiments are represented by compounds of general formula (Ia1) or (Ib1): [ka] [Wherein R1, R2, R3, R4, R6, R7, R8, R9 and R 10 is as defined in the detailed description and claims, and R represents -CH2- or -O-.

[0069] The compounds of the present invention represented by the above formula (I), (Ia), (Ib), (Ia1) or (Ib1) 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.

[0070] Preferred compounds of the present invention are selected from: [1]N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzamide; [2]N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamide; [3]N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)benzamide; [4]N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-(tetrahydro-2H-pyran-4-yl)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)benzamide; [5] (N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-3-methyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butoxy)benzamide; [6]N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-methyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propoxy)benzamide; [7]N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((R)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamide; [8] 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-2-hydroxy-3-(methylamino)-3-oxopropyl)benzamide; [9] 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-3-(dimethylamino)-2-hydroxy-3-oxopropyl)benzamide;

[10] N-((R)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamide;

[11] N-((R)-3-amino-2-hydroxy-3-oxopropyl)-4-((R)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamide;

[12] N-((R)-4-amino-4-oxobutan-2-yl)-4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)benzamide;

[13] 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-2-hydroxy-3-((2-hydroxyethyl)amino)-3-oxopropyl)benzamide; or

[14] 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-2-hydroxy-3-(hydroxyamino)-3-oxopropyl)benzamide, or a pharmaceutically acceptable salt, stereoisomer, co-crystal, prodrug or solvate thereof.

[0071] 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 illustrated in Method A and Method B below.

[0072] 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.

[0073] Method A Method A represents a first method for synthesizing compounds of general formula (I): [ka] Compounds of formula (XII): [ka] and a compound represented by formula (XIII): [ka] and reacting In the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 is as defined in the detailed description and claims.

[0074] Method B Method B represents a second method for synthesizing compounds of general formula (I). Method B enables the preparation of compounds of general formula (I) in which R3 is a group other than a hydrogen atom.

[0075] Accordingly, a process for the preparation of compounds of general formula (I) is described: [ka] Compounds of formula (XVIII): [ka] and a compound represented by formula (XIX): [ka] and reacting In the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 is as defined in the detailed description and claims.

[0076] Scheme 1 below summarizes the synthetic route for Method A, and Scheme 2 shows the synthetic route for Method B. [ka]

[0077] [ka]

[0078] The reactions carried out in the various steps of Scheme 1 (steps a to h) and Scheme 2 (steps p to s) are representatively illustrated by specific embodiments in the Examples.

[0079] The compounds of formula (II), (III), (V), (IX), (XIII), (XV) 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.

[0080] 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.

[0081] 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.

[0082] In another aspect, the present invention also relates to the therapeutic use of a compound represented by general formula (I). As described above, the compound represented by general formula (I) exhibits potent bactericidal activity against Streptococcus bacteria, particularly Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae.

[0083] Therefore, the compounds represented by general formula (I) are useful as pharmaceuticals. More specifically, the compounds represented by formula (I) are useful as antibiotics.

[0084] The compounds of formula (I) of the present invention are suitable for the treatment and / or prevention of infections caused by bacteria of the genus Streptococcus.

[0085] The compounds of general formula (I) are suitable for the treatment of infections caused by Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus agalactiae.

[0086] 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 Streptococcus infections, more preferably infections caused by Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus agalactiae.

[0087] Another related aspect of the present invention relates to a method for the treatment and / or prevention of Streptococcus infections, more preferably infections caused by Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus agalactiae, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by general formula (I).

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] Suitable formulations for parenteral administration are solutions, suspensions, reconstitutable dry formulations or sprays.

[0095] The compounds of the present invention can be formulated for transdermal application as deposits in dissolved form or as patches.

[0096] Applications to the skin include ointments, gels, creams, lotions, suspensions or emulsions.

[0097] For rectal administration, administration by suppository is preferred.

[0098] 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.

[0099] 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 can optionally be coated by methods well known in conventional pharmaceutical practice, particularly enteric coating methods.

[0100] 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.

[0101] The above-described formulations are prepared using standard methods as described or referenced in the Spanish and US Pharmacopoeias and similar references.

[0102] 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.

[0103] 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]

[0104] The following examples illustrate the preparation of both intermediate compounds and compounds of the present invention.

[0105] The following abbreviations are used: anh: anhydride aq: water-based ADDP: 1,1'-(azodicarbonyl)dipiperidine Boc2O: di-tert-butyl dicarbonate br s: broad singlet C: Celsius Cat:Catalyst CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine Cl-Cbz: benzyl chloroformate DCM: dichloromethane DIPEA: N-ethyl-N,N-diisopropylamine DIP-Cl: DIP-chloride (B-chlorodiisopinocampheylborane) DMF: N,N-dimethylformamide ee: enantiomeric excess EDC HCl: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride Eq: Equivalent ESI: electrospray ionization Et3N: Triethylamine Et2O: Diethyl ether EtOAc: ethyl acetate Example: Example g: grams h: hours / second HOBt: 1-hydroxybenzotriazole HPLC: High-performance liquid chromatography Hz: Hertz Int: intermediate IPA: Isopropyl alcohol L: Liter m: meters, millimeters, multiplets M: mole, molecular weight Mg: Magnesium m / z: mass-charge ratio Me: Methyl MeOH: Methanol MnO2: Manganese dioxide MS: Mass spectrometry min:minutes NMM: 4-methylmorpholine (N-methylmorpholine) NMR: nuclear magnetic resonance on: overnight pH: logarithm of hydrogen ion concentration PPh3: Triphenylphosphine Ret: Retain rt: room temperature sat: saturated TEA: Triethylamine THF: tetrahydrofuran UPLC: Ultra-high performance liquid chromatography

[0106] To determine the HPLC-MS spectra, the following method was used. A: Column Kinetex C18 2.6 μm, 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 μm, 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.

[0107] To determine the UPLC-MS spectra, the following method was used. C: Column: Acquity CSH Fluoro-Phenyl, 1.7 μm, 2.1 × 100 mm; Temperature: 35 °C; Flow rate: 0.50 mL / min; A: water, B: acetonitrile, C: 50 mM ammonium acetate solution, pH 6.8; Gradient A:B:C: 85:10:5 for 0.5 min + 85:10:5 to 10:85:5 for 4.5 min + 10:85:5 for 4 min. D: 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 for 0.5 min + 5:85:10 to 5:10:85 for 4.5 min + 5:10:85 for 4 min. E: Column Acquity CSH Fluoro-Phenyl, 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. F: Column: Acquity CSH Phenyl-Hexyl, 1.7 μm, 2.1 × 100 mm; Temperature: 35 °C; Flow rate: 0.50 mL / min; A: water, B: acetonitrile, C: 50 mM ammonium acetate solution, pH 6.8; Gradient A:B:C: 85:10:5 for 0.5 min + 85:10:5 to 10:85:5 for 4.5 min + 10:85:5 for 4 min. G: Column ZORBAX Extend-C18 RRHD, 1.8 μm, 2.1 × 50 mm; temperature 35 °C; flow rate: 0.61 mL / min; A: 10 mM ammonium bicarbonate, B: acetonitrile; gradient A:B: 98:2 in 0.3 min + 98:2 to 0:100 in 2.65 min + 0:100 in 2.05 min. H: Column ZORBAX Extend-C18 RRHD, 1.8 μm, 2.1 × 50 mm; temperature 35 °C; flow rate: 0.61 mL / min; A: 10 mM ammonium bicarbonate, B: acetonitrile, C: methanol + 0.1% formic acid. Gradient A:B:C: 98:2:0 for 0.3 min + 98:2:0 to 0:95:5 for 2.7 min + 0:95:5 for 1 min + 0:95:5 to 0:100:0 for 0.1 min + 0:100:0 for 0.9 min.

[0108] 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 and Scheme 2 above.

[0109] Intermediate I 1. 4,6-Dimethoxy-1,3,5-triazin-2-yl (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoate [ka]

[0110] Step b) 2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-ol [ka]

[0111] Step 1: A crystal of iodine was added to a mixture of magnesium (activated, 518 mg, 21.35 mmol, 1 eq) in THF (17 mL) without stirring. After 5 min, the mixture was stirred and (bromomethyl)cyclohexane (3.78 g, 3.0 mL, 21.35 mmol, 1 eq) was added in small portions (with stirring) over 2 h. Stirring at room temperature for an additional 1.5 h gave a gray suspension, which was carried on to the next step without further purification.

[0112] Step 2: (Cyclohexylmethyl)magnesium bromide (21.35 mmol, 2.5 eq) was transferred to a solution of 4'-fluoro-[1,1'-biphenyl]-4-carbaldehyde (1.71 g, 8.54 mmol, 1.0 eq) in THF (14 mL) cooled to -15 °C (addition time 5 min). The mixture was stirred at -15 °C for 20 min. The reaction mixture was slowly poured into NH4Cl (saturated aqueous solution, 40 mL), and the aqueous layer was extracted with Et2O (1 × 40 mL). The organic layer was washed with NH4Cl (saturated aqueous solution, 1 × 40 mL) and water (1 × 30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc / hexane 5-10%) to give 2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-ol (1.4 g, 54% yield) as a white solid. 1 H-NMR (CDCl3, 300 MHz) δ ppm: 7.53 (m, 4H), 7.41 (d, J = 7.9 Hz, 2H), 7.12 (t, J = 8.7 Hz, 2H), 4.84 (m, 1H), 1.86-1.39 (m, 8H), 1.32-0.90 (m, 5H).

[0113] Step c) 2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one [ka]

[0114] To a solution of 2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-ol (1.4 g, 4.691 mmol, 1 eq) in 30 mL of CHCl was added MnO (4.63 g, 46.92 mmol, 10 eq). The solution was stirred at room temperature for 3 days. Further MnO (2.31 g, 23.46 mmol, 5 eq) was added, and the resulting black suspension was stirred at room temperature overnight. The reaction mixture was filtered through a plug of Celite and eluted with CHCl (150 mL). The filtrate was concentrated in vacuo to give 2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one (1.15 g, 82% yield) as a white solid. 1 H-NMR (CDCl3, 300 MHz) δ ppm: 8.01 (d, J = 8.6 Hz, 2H), 7.67-7.54 (m, 4H), 7.16 (t, J = 8.6 Hz, 2H), 2.85 (d, J = 6.8 Hz, 2H), 1.99 (m, 1H), 1.81-1.63 (m, 5H), 1.41-0.97 (m, 5H).

[0115] Step d) (R)-2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-ol [ka]

[0116] To a cooled (external T: -65 °C) solution of (+)-DIP-Cl (3.5 mL, 5.97 mmol, 1.5 eq) in 15 mL of THF was added a solution of 2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-one (1.18 g, 3.98 mmol, 1 eq) in 8 mL of THF. The solution was allowed to warm slowly to room temperature and stirred overnight. The solvent was concentrated, and the mixture was dissolved in EtO (20 mL), and diethanolamine (1.2 mL, 12.44 mmol, 3.12 eq) was added. The resulting white suspension was stirred at room temperature for 3 h. The mixture was diluted with hexane (25 mL), filtered through a SiO pad, and the product was eluted with 31% EtOAc / hexane (400 mL). The filtrate was concentrated, and the residue was subjected to flash chromatography on SiO2 (5–8% ethyl acetate / hexanes) to afford (R)-2-cyclohexyl-1-(4′-fluoro-[1,1′-biphenyl]-4-yl)ethan-1-ol (625 mg, 52%) as a white solid. 1 H-NMR (CDCl3, 300 MHz) δ ppm: 7.53 (m, 4H), 7.41 (d, J = 7.9 Hz, 2H), 7.12 (t, J = 8.7 Hz, 2H), 4.84 (m, 1H), 1.86-1.39 (m, 8H), 1.32-0.90 (m, 5H).

[0117] Step e) Methyl (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoate [ka]

[0118] Methyl 4-hydroxybenzoate (385 mg, 2.53 mmol, 1.3 eq) and Ph3P (663 mg, 2.53 mmol, 1.3 eq) were added to a solution of (R)-2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-ol (581 mg, 1.95 mmol, 1 eq) in toluene (40 mL). The resulting suspension was cooled (ice-water bath) and ADDP (638 mg, 2.53 mmol, 1.3 eq) was added. The resulting mixture was allowed to warm to room temperature overnight (23 h). Further methyl 4-hydroxybenzoate (385 mg, 2.53 mmol, 1.3 eq) and Ph3P (663 mg, 2.53 mmol, 1.3 eq) were added to the reaction mixture. The resulting suspension was cooled (ice-water bath) and ADDP (638 mg, 2.53 mmol, 1.3 eq) was added. The resulting mixture was allowed to warm slowly to room temperature overnight (24 h). The suspension was poured into HO (100 mL) and extracted with ethyl acetate (80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to flash chromatography on SiO (3–12% ethyl acetate / hexanes) to give methyl (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoate (360 mg, 42%) as a white solid. 1 H-NMR (CDCl3, 300 MHz) δ ppm: 7.80 (d, J = 9.4 Hz, 2H), 7.41 (m, 4H), 7.28 (d, J = 8.2 Hz, 2H), 7.01 (m, 2H), 6.78 (d, J = 9.4 Hz, 2H), 5.22 (dd, J = 9.0, 4.4 Hz, 1H), 3.75 (s, 3H), 1.91 (m, 1H), 1.78-1.50 (m, 7H), 1.22-0.81 (m, 5H).

[0119] Step f) (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoic acid [ka]

[0120] A 2 M aqueous solution of lithium hydroxide (1.6 mL, 3.24 mmol, 4 eq) was added to a solution of methyl (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoate (350 mg, 0.81 mmol, 1 eq) in a mixture of THF (10 mL), MeOH (5 mL), and HO (10 mL). The resulting mixture was heated at 50 °C (external temperature) overnight (23 h). The reaction mixture was allowed to cool to room temperature, diluted with HO (15 mL), acidified with 10% aqueous HCl (3 mL), and extracted with CHCl (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to flash chromatography on SiO2 (15-40% acetone / hexanes) to give (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoic acid (335 mg, 99%) as a white solid. 1 H-NMR (DMSO-d6, 300 MHz) δ ppm: 7.77 (d, J = 8.2 Hz, 2H), 7.71-7.55 (m, 4H), 7.47 (d, J = 8.2 Hz, 2H), 7.24 (t, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 5.54 (dd, J = 8.6, 4.9 Hz, 1H), 1.99-1.36 (m, 8H), 1.25-0.94 (m, 5H). ESI - -MS m / z, 417.4 (M−H).

[0121] Step g) 4,6-Dimethoxy-1,3,5-triazin-2-yl (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoate [ka]

[0122] To a solution of (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoic acid (294 mg, 0.702 mmol, 1 eq) and CDMT (160 mg, 0.911 mmol, 1.3 eq) in CHCl (15 mL) was added NMM (125 mL, 1.14 mmol, 1.62 eq). The solution was stirred at room temperature for 2.5 h. The crude volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography on silica (12-30% EtOAc / hexanes) to give 4,6-dimethoxy-1,3,5-triazin-2-yl (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoate (349 mg, 89% yield) as a pale yellow solid. 1 H-NMR (CDCl3, 300 MHz) δ ppm 8.00 (d, J = 8.8 Hz, 2H), 7.52 (m, 4H), 7.37 (d, J = 8.2 Hz, 2H), 7.10 (t, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.37 (m, 1H), 4.04 (s, 6H), 2.02-1.61 (m, 8H), 1.32-0.97 (m, 5H). ESI + -MS m / z, 558.5 (M+H).

[0123] This method was used to prepare intermediates Int2 to Int8 using the appropriate starting materials. [Table 1] JPEG2026504191000026.jpg63164

[0124] Example 1. N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzamide [ka]

[0125] Step i) (S)-3-(((benzyloxy)carbonyl)amino)-2-hydroxypropanoic acid [ka]

[0126] Cl-Cbz (2.4 mL, 17.02 mmol, 1.12 eq) was added dropwise to a solution of L-isoserine (1.6 g, 15.22 mmol, 1 eq) in a mixture of THF (25 mL) and 1 M aqueous NaCO (20 mL, 20.00 mmol, 1.31 mmol) cooled in an ice-water bath. The cooling bath was removed, and the reaction mixture was stirred for 1 h. The resulting mixture was diluted with HO (80 mL), washed with EtO (80 mL), acidified with 10% aqueous HCl (20 mL), and extracted with CHCl (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product (2.55 g, 70%) as a white solid.

[0127] Step j) (S)-3-(((benzyloxy)carbonyl)amino)-2-hydroxypropanoic acid [ka]

[0128] (COCl)2 (0.35 mL, 4.09 mmol, 1.12 eq) was added dropwise to a solution of the acid (871 mg, 3.64 mmol, 1 eq) in THF (15 mL) and DMF (3 drops) and cooled in an ice-water bath (gas evolution). The resulting solution was stirred at low temperature for 0.5 h and at room temperature for 2 h. The solution was concentrated, and the residue was dissolved in THF (10 mL) and added (via cannula) to a mixture of THF (15 mL) and 25% aqueous ammonia (15 mL) cooled in an ice-water bath. The cooling bath was removed, and the resulting suspension was stirred for 1 h. The resulting mixture was diluted with H2O (15 mL), acidified with 10% aqueous HCl (20 mL), and extracted with CHCl2 (3 × 50 mL) and CHCl2 / IPA (4:1, 2 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid (950 mg, crude) was suspended in CHCl (20 mL), stirred at room temperature for 1 h, filtered, and dried under high vacuum to give (S)-3-(((benzyloxy)carbonyl)amino)-2-hydroxypropanoic acid (578 mg, 66%) as a white solid. 1 H-NMR (DMSO-d6, 300 MHz) δ ppm: 7.40-7.27 (m, 5H), 7.25-7.10 (m, 2H), 5.59 (m, 1H), 5.01 (s, 2H), 3.87 (m, 1H), 3.04 (dt, J = 14.1, 7.2 Hz, 1H). ESI + -MS m / z, 239.1.

[0129] Step k) (S)-3-amino-2-hydroxypropanamide [ka]

[0130] To a solution of (S)-3-(((benzyloxy)carbonyl)amino)-2-hydroxypropanoic acid (578 mg, 2.426 mmol, 1 eq) in a mixture of methanol (20 mL) and THF (15 mL) was added Pd / C 10% (wet) (450 mg, 0.243 mmol, 0.1 eq). The resulting mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 1.5 h. The suspension was filtered through a short pad of Celite and eluted with methanol (150 mL) and ethyl acetate (30 mL). The solvent was concentrated to give the desired product as a colorless oil. The crude residue (264 mg) was slurried with EtO (4 mL), the solvent was decanted, and the resulting solid was dried under high vacuum to give (S)-3-amino-2-hydroxypropanamide (250 mg, 98%) as a white solid. 1 H-NMR (DMSO-d6, 300 MHz) δ ppm: 7.14 (d, J = 14.7 Hz, 2H), 3.72 (dd, J = 6.7, 4.1 Hz, 1H), 2.74 (dd, J = 13.0, 4.1 Hz, 1H), 2.58 (dd, J = 13.0, 6.7 Hz, 1H).

[0131] Step h) Title compound [ka]

[0132] A solution of 4,6-dimethoxy-1,3,5-triazin-2-yl (S)-4-(2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzoate, intermediate I1 (95 mg, 0.17 mmol, 1 eq) in THF (5 mL) was added to a solution of (S)-3-amino-2-hydroxypropanamide (100 mg, 0.96 mmol, 5.64 eq) and DIPEA (160 mL, 0.934 mmol, 5.49 eq) in a mixture of THF (10 mL) and HO (2 mL). The resulting solution was stirred at room temperature for 1 h, poured into HO (30 mL), acidified with 10% aqueous HCl (2 mL), and extracted with CHCl (2 × 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with EtO (6 mL) and the solid was collected by filtration, washed three times with EtO (4 mL), and dried under high vacuum at 50 °C to give N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzamide (45 mg, 52%) as a white solid. 1 H-NMR (DMSO-d6, 300 MHz) δ ppm: 8.16 (t, J = 5.6 Hz, 1H), 7.73-7.65 (m, 4H), 7.60 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.29-7.14 (m, 4H), 6.98 (d, J = 8.7 Hz, 2H), 5.63 (d, J = 5.6 Hz, 1H), 5.55 (m, 1H), 3.98 (m, 1H), 3.56 (m, 1H), 3.23 (m, 1H), 1.97-1.37 (m, 8H), 1.24-0.97 (m, 5H). ESI + -MS m / z, 505.5.

[0133] This method was used to prepare Examples 2-11 using the appropriate starting materials. [Table 2] JPEG2026504191000033.jpg226160

[0134] Example 12. N-((R)-4-amino-4-oxobutan-2-yl)-4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)benzamide [ka]

[0135] Step I) (R)-3-((tert-butoxycarbonyl)amino)butanoic acid [ka]

[0136] BocO (2.1 g, 9.62 mmol, 1.14 eq) was added to a solution of (R)-homo-β-alanine (867 mg, 8.41 mmol, 1 eq) in a mixture of THF (25 mL), HO (10 mL), and 2.5 M aqueous NaOH (5 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with HO (30 mL), washed with EtO (40 mL), acidified with 10% aqueous HCl (8 mL), and extracted with CHCl (2 × 40 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-3-((tert-butoxycarbonyl)amino)butanoic acid (1.17 g, 68%) as a colorless oil.

[0137] Step m) tert-butyl (R)-(4-amino-4-oxobutan-2-yl)carbamate [ka]

[0138] To a solution of (R)-3-((tert-butoxycarbonyl)amino)butanoic acid (1.17 g, 5.76 mmol, 1 eq) in THF (25 mL) cooled in an ice-ethanol bath (external temperature: −10 °C) was added NMM (0.65 mL, 5.92 mmol, 1.03 eq) and isobutyl chloroformate (0.76 mL, 5.87 mmol, 1.02 eq). The resulting mixture was stirred at low temperature for 2 min, and ammonia (3 mL, 25% aqueous solution) was added. The cooling bath was removed, and the reaction mixture was stirred for 1 h, diluted with EtOAc (60 mL), washed with water (2 × 60 mL) and 0.8 M aqueous hydrochloric acid (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl (R)-(4-amino-4-oxobutan-2-yl)carbamate (696 mg, 59%) as a white solid. 1 H-NMR (CDCl3, 300 MHz) δ ppm: 5.99 (br s, 1H), 5.48 (br s, 1H), 5.06 (br s, 1H), 3.98 (m, 1H), 2.43 (d, J = 5.9 Hz, 2H), 1.43 (s, 9H), 1.25 (d, J = 6.7 Hz, 3H).

[0139] Step n) (R)-3-aminobutanamide hydrochloride [ka]

[0140] To a suspension of tert-butyl (R)-(4-amino-4-oxobutan-2-yl)carbamate (690 mg, 3.41 mmol, 1 eq) in CHCl (25 mL) cooled in an ice-water bath was added HCl dioxane (5.1 mL, 20.47 mmol, 6 eq). The resulting mixture was allowed to warm to room temperature overnight (16 h). The resulting suspension was filtered, and the solid was washed with CHCl (10 mL) and EtO (15 mL) and dried under high vacuum to give (R)-3-aminobutanamide hydrochloride (441 mg, 93%) as a hygroscopic white solid. 1H-NMR (DMSO-d6, 300 MHz) δ ppm: 8.12 (br s, 3H), 7.64 (br s, 1H), 7.05 (br s, 1H), 3.41 (m, 1H), 2.35 (m, 2H), 1.17 (d, J = 6.5 Hz, 3H).

[0141] Step o) Title compound [ka]

[0142] 4,6-Dimethoxy-1,3,5-triazin-2-yl (S)-4-(2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)benzoate (Intermediate I2, 90 mg, 0.148 mmol, 1 eq) was added to a solution of (R)-2-aminopropanamide hydrochloride (75 mg, 0.602 mmol, 4.06 eq) and DIPEA (0.25 mL, 1.46 mmol, 9.86 eq) in a mixture of THF (12 mL) and HO (2 mL). The reaction mixture was stirred at room temperature for 1 h, diluted with CHCl (40 mL), washed with HCl (5% aqueous solution, 1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to flash chromatography on SiO (25 × 50% acetone / hexanes) to give N-((R)-1-amino-1-oxopropan-2-yl)-4-((S)-2-cyclohexyl-1-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethoxy)benzamide (68 mg, 85%) as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ ppm: 8.13 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.83-7.66 (m, 6H), 7.54 (d, J = 8.3 Hz, 2H), 7.26 (brs, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.90 (brs, 1H), 5.58 (m, 1H), 4.35 (m, 1H), 2.01-1.72 (m, 4H), 1.71-1.35 (m, 4H), 1.27 (d, J = 7.5 Hz, 3H), 1.24-0.90 (m, 7H) HPLC-MS (Method B): Rt: 5.663 min; ESI+ MS: m / z 553.5

[0143] Example 13. 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-2-hydroxy-3-((2-hydroxyethyl)amino)-3-oxopropyl)benzamide [ka]

[0144] Step p) Ethyl (S)-3-amino-2-hydroxypropanoate hydrochloride [ka]

[0145] EtOH (20 mL) was cooled to 0 °C (ice-water bath) and SOCl (1.6 mL, 22.055 mmol, 1.84 eq) was added. After 5 min, L-isoserine (1.26 g, 11.989 mmol, 1 eq) was added. The suspension was allowed to warm slowly to room temperature over 20 h. The crude volatiles were removed under reduced pressure to give ethyl (S)-3-amino-2-hydroxypropanoate hydrochloride (2.2 g, yield > theoretical) as a yellow oil, which was carried on to the next step without further purification. 1H-NMR (DMSO-d6, 300 MHz) δ ppm: 8.15 (s, 3H), 6.31 (d, J = 5.5 Hz, 1H), 4.34 (dd, J = 9.2, 4.8 Hz, 1H), 4.14 (c, J = 7.0 Hz, 2H), 3.09 (m, 1H), 2.89 (m, 1H), 1.22 (t, J = 7.0 Hz, 3H).

[0146] Step q) Ethyl (S)-3-(4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamido)-2-hydroxypropanoate [ka]

[0147] A solution of 4,6-dimethoxy-1,3,5-triazin-2-yl (S)-4-(2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzoate, intermediate 4 (244 mg, 0.401 mmol, 1 eq) in THF (5 mL) was added to a solution of DIPEA (275 μL, 1.606 mmol, 4.01 eq) and the aminoester (204 mg, 1.202 mmol, 3 eq) in a mixture of THF (10 mL) and HO (2 mL). The resulting mixture was stirred at room temperature for 1 h, diluted with EtOAc (20 mL), washed with 5% aqueous HCl (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (19-40% ethyl acetate / hexane) to give ethyl (S)-3-(4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamido)-2-hydroxypropanoate (218 mg, 93%) as a white solid. 1H-NMR (CDCl3, 300 MHz) δ ppm: 7.71-7.57 (m, 6H), 7.54-7.31 (m, 4H), 6.87 (d, J = 8.8 Hz, 2H), 6.36 (m, 1H), 5.31 (m, 1H), 4.32 (m, 1H), 4.22 (c, J = 7.0 Hz, 2H), 3.76 (m, 2H), 2.02-1.53 ​​(m, 12H), 1.27 (t, J = 7.0 Hz, 3H). ESI+-MS m / z, 584.6 (M+H).

[0148] Step r) (S)-3-(4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamido)-2-hydroxypropanoic acid [ka]

[0149] To a solution of ethyl (S)-3-(4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamido)-2-hydroxypropanoate (210 mg, 0.359 mmol, 1 eq) in a mixture of THF (6 mL), HO (6 mL), and MeOH (3 mL) was added lithium hydroxide solution (2 M, 720 μL, 1.44 mmol, 4 eq). The resulting solution was stirred at room temperature for 2 h, diluted with HO (15 mL), acidified with 10% aqueous HCl (2 mL), and extracted with CHCl (2 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 206 mg of a white solid (crude product). The resulting solid was slurried with hexane (4 mL). The solid was collected by filtration, washed with three 4 mL portions of hexane, and dried under high vacuum to give the title compound as a white foam (155 mg). The resulting foam was suspended in a CHCl / pentane (1:1, 4 mL) mixture and stirred at room temperature for 10 minutes. The solid was collected by filtration, washed with three 4 mL portions of pentane, and dried under high vacuum to give (S)-3-(4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamido)-2-hydroxypropanoic acid (137 mg, 68%) as a white solid. 1 H-NMR (DMSO-d6, 300 MHz) δ ppm: 8.22 (t, J = 5.8 Hz, 1H), 7.88-7.76 (m, 5H), 7.70 (d, J = 8.6 Hz, 2H), 7.62 (m, 1H), 7.47 (d, J = 4.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 5.60 (dd, J = 8.8, 4.6 Hz, 1H), 4.11 (dd, J = 7.2, 4.8 Hz, 1H), 3.51 (m, 2H), 2.03-139 (m, 8H), 1.23-0.90 (m, 5H). ESI+-MS m / z, 556.5 (M+H).

[0150] Step s) 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-2-hydroxy-3-((2-hydroxyethyl)amino)-3-oxopropyl)benzamide [ka]

[0151] To a solution of (S)-4-(2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzoic acid (98 mg, 0.176 mmol, 1 eq), EDC.HCl (55 mg, 0.352 mmol, 2 eq), HOBt (54 mg, 0.535 mmol, 2 eq), and TEA (99 μL, 0.706 mmol, 45 eq) in CHCl (8 mL) was added 2-aminoethan-1-ol (32 mg, 0.529 mmol, 3 eq). The solution was stirred overnight at room temperature. The resulting solution was diluted with water (10 mL) and extracted with CHCl (2 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash gold chromatography (ethyl acetate / hexanes) to give 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-2-hydroxy-3-((2-hydroxyethyl)amino)-3-oxopropyl)benzamide (21 mg, 20%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.21 (t, J = 5.7 Hz, 1H), 7.93 - 7.77 (m, 5H), 7.75 - 7.67 (m, 3H), 7.61 (td, J = 4.5, 1.9 Hz, 1H), 7.46 (d, J = 5.2 Hz, 2H), 7.01 (d, J = 9.0 Hz, 2H), 5.80 (d, J = 5.4 Hz, 1H), 5.61 (dd, J = 8.8, 4.7 Hz, 1H), 4.68 (t, J = 5.5 Hz, 1H), 4.09 - 3.96 (m, 1H), 3.56 (dt, J = 13.4, 4.8 Hz, 1H), 3.38 (q, J = 6.0 Hz, 2H), 3.26 - 3.07 (m, 3H), 2.01 - 1.90 (m, 1H), 1.86 - 1.74 (m, 2H), 1.72 - 1.55 (m, 4H), 1.54 - 1.41 (m, 1H), 1.29 - 1.08 (m, 3H), 1.08 - 0.93 (m, 2H). ESI+-MS m / z, 599.4 (M+H).

[0152] This method was used to prepare Example 14 using the appropriate starting materials. [Table 3]

[0153] Examples of biological activity Experimental procedure: MIC test microdilution method To evaluate the antibacterial activity of the compounds, ATCC strains of Streptococcus pneumoniae and Streptococcus pyogenes were used. The minimum inhibitory concentrations (MICs) of the compounds were determined by microdilution according to CLSI methods.

[0154] 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.).

[0155] "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.

[0156] -The final mother plate map is as follows (all values ​​are in mg / mL): [Table 4]

[0157] "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.

[0158] Notes: A Tecan instrument (FREEDOM EVO 100) was used to prepare the mother and daughter plates.

[0159] 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.

[0160] The final plate map is as follows (all values ​​are in μg / mL): [Table 5]

[0161] 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.

[0162] Examples of biological activity [Table 6]

Claims

1. Compounds represented by general formula (I): 【Chemistry 1】 [In the formula, 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 or a branched or unbranched C １－６ is an alkyl group; R ３ is a hydrogen atom, a branched or unbranched C １－６ Alkyl or -(CH ２ ) ｍ -OR ３ａ and R ３ａ is a hydrogen atom or a branched or unbranched C １－６ is an alkyl group; R ４ is a hydrogen atom, a branched or unbranched C １－６ Alkyl or -(CH ２ ) ｎ -OR ４ａ and R ４ａ is a hydrogen atom or a branched or unbranched C １－６ is an alkyl group; R ５ is a hydrogen atom; optionally substituted branched or unbranched C １－６ Alkyl group; halogen atom; -CN; C １－６ Haloalkyl groups; optionally substituted -(CH ２ ) ｒ -C ３－９ cycloalkyl; optionally substituted —(CH ２ ) ｓ -C ３－９ Heterocycloalkyl; optionally substituted —(CH ２ ) ｊ -aryl; optionally substituted -(CH ２ ) ｉ -heteroaryl; 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, —OR ５ａ , -NR ５ａ R ５ｂ , -NR ５ａ C(O)R ５ｂ , -NR ５ａ C(O)NR ５ｂ R ５ｃ , -C(O)OR ５ａ , —C(O)NR ５ａ R ５ｂ , -OCH ２ CH ２ OH, -C(CH ３ ) ２ OR ５ａ and is substituted with at least one substituent selected from R ５ａ , R ５ｂ and R ５ｃ are independently a hydrogen atom or a branched or unbranched C １－６ alkyl groups; R ６ , R ７ and R ８ are each independently a hydrogen atom, an optionally substituted branched or unbranched C １－６ Alkyl group; halogen atom; -CN; C １－６ Haloalkyl groups; optionally substituted C ３－９ cycloalkyl; optionally substituted C containing at least one heteroatom selected from N, O or S; ３－９ Heterocycloalkyl; optionally substituted —O—C １－６ -alkyl; -O-C １－６ -haloalkyl; optionally substituted -O-C ３－９ cycloalkyl; optionally substituted —O—C containing at least one heteroatom selected from N, O, or S; ３－９ all of the optionally substituted groups are selected from hydrogen atoms, halogen atoms, branched or unbranched C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group; —CN, —OR ａ , -NR ａ R ｂ , -NR ａ C(O)R ｂ , -C(O)OR ａ , —C(O)NR ａ R ｂ , -OCH ２ CH ２ OH, -C(CH ３ ) ２ OR ａ and is substituted with at least one substituent selected from R ａ and R ｂ are independently a hydrogen atom or a branched or unbranched C １－６ alkyl groups; R ９ is a hydrogen atom or a branched or unbranched C １－６ is an alkyl group; R １０ is a hydrogen atom; optionally substituted branched or unbranched C １－６ Alkyl group; -CN; C １－６ Haloalkyl groups; optionally substituted -(CH ２ ) ｒ -C ３－９ Cycloalkyl; optionally substituted -(CH ２ ) ｊ -aryl; optionally substituted -O-C １－６ -alkyl; 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; —OR １０ａ , -NR １０ａ R １０ｂ , -NR １０ａ C(O)R １０ｂ , -NR １０ａ C(O)NR １０ｂ R １０ｃ , -C(O)OR １０ａ , —C(O)NR １０ａ R １０ｂ , -OCH ２ CH ２ OH, -NR １０ａ S (O) ２ NR １０ｂ R １０ｃ , -C(CH ３ ) ２ OR １０ａ and is substituted with at least one substituent selected from R １０ａ , R １０ｂ and R １０ｃ 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; r is 0, 1, 2 or 3; s is 0, 1, 2 or 3; j is 0, 1, 2 or 3; i 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 １ is a hydrogen atom or -OR １ａ 2. The compound of claim 1, wherein:

3. R ５ optionally substituted branched or unbranched C １－６ an alkyl group, preferably isobutyl or isopropyl; or the following groups: 【Chemistry 2】 The compound according to any one of claims 1 to 2, which is one of:

4. R ６ , R ７ and R ８ are each independently a hydrogen atom, a halogen atom, preferably; or C １－６ A compound according to any one of claims 1 to 3, wherein the haloalkyl group is selected from trifluoromethyl.

5. R １０ is a hydrogen atom; optionally substituted branched or unbranched C １－６ The compound according to any one of claims 1 to 4, wherein the alkyl group is preferably a methyl group.

6. Compounds represented by general formula (Ia) or (Ib): 【Transformation 3】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ is as defined in any one of claims 1 to 5. The compound according to any one of claims 1 to 5,

7. Compounds represented by general formula (Ia1) or (Ib1): 【Chemistry 4】 [In the formula, R １ , R ２ , R ３ , R ４ , R ６ , R ７ , R ８ , R ９ and R １０ is as defined in any one of claims 1 to 5, and R is -CH ２ - or -O-.] The compound according to any one of claims 1 to 6,

8. The compound of claim 1 selected from: [1] N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethoxy)benzamide; [2] N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamide; [3] N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)benzamide; [4] N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-(tetrahydro-2H-pyran-4-yl)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)benzamide; [5] (N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-3-methyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)butoxy)benzamide; [6] N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-methyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propoxy)benzamide; [7] N-((S)-3-amino-2-hydroxy-3-oxopropyl)-4-((R)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamide; [8] 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-2-hydroxy-3-(methylamino)-3-oxopropyl)benzamide; [9] 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-3-(dimethylamino)-2-hydroxy-3-oxopropyl)benzamide; [10] N-((R)-3-amino-2-hydroxy-3-oxopropyl)-4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamide; [11] N-((R)-3-amino-2-hydroxy-3-oxopropyl)-4-((R)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)benzamide; [12] N-((R)-4-amino-4-oxobutan-2-yl)-4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethoxy)benzamide; [13] 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-2-hydroxy-3-((2-hydroxyethyl)amino)-3-oxopropyl)benzamide; or [14] 4-((S)-2-cyclohexyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)ethoxy)-N-((S)-2-hydroxy-3-(hydroxyamino)-3-oxopropyl)benzamide, or a pharmaceutically acceptable salt, stereoisomer, co-crystal, prodrug or solvate thereof.

9. Compounds represented by formula (I): 【Transformation 5】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ is as defined in any one of claims 1 to 5. A method for producing Compounds represented by formula (XII): 【Transformation 6】 and a compound represented by formula (XIII): 【Transformation 7】 The production method, comprising the step of reacting

10. Compounds represented by formula (I): 【Transformation 8】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ is as defined in any one of claims 1 to 5. A method for producing Compounds represented by formula (XVIII): 【Chemistry 9】 and a compound represented by formula (XIX): 【Chemistry 10】 The production method, comprising the step of reacting

11. A compound according to any one of claims 1 to 8 for use as a pharmaceutical.

12. A compound according to any one of claims 1 to 8 for use as an antibiotic.

13. 14. A compound according to claim 13 for use as an antibiotic for the treatment and / or prevention of infections caused by Streptococcus sp.

14. 14. The compound for use according to claim 13, wherein the infection is an infection caused by Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus agalactiae.

15. A pharmaceutical composition comprising the compound of any one of claims 1 to 8 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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