Novel compound, method for producing the same and antibiotic composition containing the same

Abstract

The present invention provides novel compounds, their solvates, hydrates, prodrugs, isomers, or pharmaceutically acceptable salts thereof, methods for producing the same, and antibiotic compositions comprising the same. The novel compounds of the present invention having excellent antibacterial properties are very useful for the prevention and treatment of bacterial infections.

Description

Technical Field

[0001] The present invention relates to novel compounds, methods for preparing the same and antibiotic compositions containing the same. Background Art

[0002] Antibiotics are used to treat bacterial infections, and various forms of antibiotics such as aminoglycosides, glycopeptides, macrolides, and quinolines have been developed.

[0003] Most antibiotics developed in the past exhibit their antibacterial properties by killing bacteria.

[0004] However, controlling pathogenic bacteria requires more than just killing them; methods that prevent their proliferation by interfering with their communication are also crucial. A typical example of bacterial communication is the formation of biofilms, which reside on human organs and cause numerous diseases. Examples of diseases or disease sites include dental caries, gingivitis, periodontitis, otitis media, voice prostheses, hydrocephalus, cystic fibrosis, endocarditis, prosthetic heart valves, central venous catheters, prosthetic hip joints, prosthetic knee joints, chronic bacterial prostatitis, intrauterine devices, and urinary catheters.

[0005] Therefore, research is underway on multifunctional antibiotics that not only kill bacteria but also hinder information exchange between bacteria to inhibit bacterial biofilm formation in advance.

[0006] On the other hand, the mechanisms by which antibiotics act on bacteria can be broadly divided into mechanisms that interfere with cell wall formation, protein synthesis, bacterial DNA and RNA synthesis, and mycolic acid and folic acid production.

[0007] Antibiotics developed in the past have chemical structural characteristics due to the mechanism of action described above. Representative chemical structures can be divided into penicillins (beta-lactams), cephalosporins, aminoglycosides, macrolides, sulfonamides, quinolones, tetracyclines, and peptides.

[0008] Although antibiotics play an important role in the treatment of bacterial infections and diseases, the misuse of antibiotics and repeated use of the same antibiotics have led to the emergence of antibiotic-resistant bacteria.

[0009] For example, beta-lactam antibiotics, used for Gram-negative bacterial infections, are widely used after quinoline antibiotics. However, bacteria develop resistance to these antibiotics by producing enzymes called beta-lactamases that weaken them.

[0010] As described above, in recent years, the emergence of multidrug-resistant bacteria, or superbugs, that are difficult to treat with existing antibiotics has placed many constraints on the treatment of bacterial infections.

[0011] Therefore, in order to treat emerging antibiotic-resistant bacterial infections, the development of new antibiotics with chemical structures completely different from existing antibiotics is urgent. Summary of the Invention

[0012] The present invention provides novel compounds, their solvates, their hydrates, their prodrugs, their isomers, or their pharmaceutically acceptable salts.

[0013] Furthermore, the present invention provides a method for producing the novel compound of the present invention.

[0014] In addition, the present invention provides an antibiotic composition comprising the novel compound of the present invention, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0015] The present invention provides a novel compound, a solvate, a hydrate, a prodrug, an isomer, or a pharmaceutically acceptable salt thereof that can be very useful as an antibiotic. The novel compound of the present invention is represented by the following Chemical Formula 1.

[0016] [Chemical Formula 1]

[0017]

[0018] (In the above chemical formula 1,

[0019] Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene group, or a substituted or unsubstituted C3-C20 heteroarylene group;

[0020] Z1 to Z3 are independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2-, or -OCONR7-;

[0021] R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxyl C1-C10 alkyl, or C1-C10 alkoxycarbonyl C1-C10 alkyl;

[0022] A1 is or R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy C1-C10 alkyl, and p is an integer from 0 to 4;

[0023] A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene, or C6-C20 heteroarylene;

[0024] R is hydrogen, halogen, amino, hydroxyl, -B(OH)2, substituted or unsubstituted halogenated C1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.)

[0025] The present invention also provides an antibiotic composition characterized by containing the compound of the present invention, a hydrate thereof, a solvate thereof, an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] The novel compound of the present invention has a chemical structure different from that of conventional antibiotics and has improved therapeutic and preventive effects on various bacterial infections.

[0027] Therefore, the antibiotic composition comprising the novel compound of the present invention, its solvate, its hydrate, its prodrug, its isomer, or its pharmaceutically acceptable salt can be effectively used for the treatment and prevention of bacterial infection. DETAILED DESCRIPTION

[0028] The novel compounds of the present invention, their solvates, hydrates, prodrugs, isomers, or pharmaceutically acceptable salts thereof are described in detail below. Technical and scientific terms used herein, unless otherwise defined, have the meanings commonly understood by those skilled in the art to which the present invention belongs. Descriptions of known functions and structures that may unnecessarily obscure the main purpose of the present invention are omitted in the following description.

[0029] The following terms used in this specification are defined below, but are merely illustrative and are not intended to limit the present invention, application, or use.

[0030] In this specification, the terms "substituent", "radical", "group", "moiety" and "fragment" can be used interchangeably.

[0031] The term "protecting group" in this specification includes, but is not limited to, "amino protecting group" or "hydroxy protecting group." "Amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include: formyl group; alkanoyl group, for example, acyl group such as alkanoyl group (e.g., acetyl group, trichloroacetyl group, or triple fluoroacetyl group); alkoxycarbonyl group such as tert-butoxycarbonyl group (boc); arylmethoxycarbonyl group such as benzyloxycarbonyl group (Cbz) and 9-fluorenylmethoxycarbonyl group (Fmoc); arylmethyl group such as benzyl (bn), triphenylmethyl group (Tr), 1,1-bis-(4'-methoxyphenyl)methyl group; trimethylsilyl group; The term "hydroxy protecting group" refers to a protecting group suitable for inhibiting side reactions of the hydroxy group. Representative hydroxy protecting groups include: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), but are not limited thereto.

[0032] In this manual, “C A -C B" means "the number of carbon atoms is greater than A and less than B". That is, when it is described as "C1-C10", it means that the number of carbon atoms is 1 to 10. For example, C1-C10 alkyl refers to an alkyl group with 1 to 10 carbon atoms.

[0033] The term "alkyl" as used in this specification (unless the number of carbon atoms is particularly limited) refers to a saturated linear or branched non-cyclic hydrocarbon having 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms, more preferably 1 to 10 carbon atoms, and most preferably 1 to 6 carbon atoms. "Lower alkyl" refers to a linear or branched alkyl group having 1 to 4 carbon atoms, or 1 to 6 carbon atoms. Representative saturated straight chain alkyl groups include: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl, whereas saturated branched chain alkyl groups include: isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, 2-Methyl-4-Ethylpentyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2-Methyl-4-Ethylhexyl, 2,2-Diethylpentyl, 3,3-Dimethylpentyl, 2,2-Dimethylhexyl and 3,3-Diethylhexyl.

[0034] The term "alkenyl" used in this specification refers to a saturated straight or branched non-cyclic hydrocarbon containing 2 to 20, preferably 2 to 15, preferably 2 to 10, more preferably 2 to 6 carbon atoms and at least one carbon-carbon double bond. Representative straight and branched (C2-C10) alkenyl groups include vinyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, and 3-decenyl. Such alkenyl groups can be optionally substituted.

[0035] The terms "halogen" and "halo" used in this specification refer to fluorine, chlorine, bromine, or iodine.

[0036] As used herein, the terms "haloalkyl," "haloalkoxy," "haloalkenyl," or "haloalkynyl" refer to alkyl, alkoxy, alkenyl, or alkynyl groups, respectively, in which one or more hydrogen atoms are replaced by a halogen atom. For example, haloalkyl includes -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, and the like. Wherein, alkyl and halogen are as defined above.

[0037] The term "alkoxy" used in this specification refers to -O-(alkyl) groups including -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and similar groups, wherein alkyl groups have the same meaning as above.

[0038] The term "lower alkoxy" used in the present specification refers to -O-(lower alkyl), wherein lower alkyl has the same meaning as defined above.

[0039] The term "aryl" as used in this specification refers to a carbocyclic aromatic group containing 5 to 10 ring atoms. Representative examples include phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, The carbocyclic aromatic group may be optionally substituted.

[0040] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. Examples of cycloalkyl groups include, but are not limited to, (C3-C10)cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Cycloalkyl groups may be selectively substituted. In one embodiment, the cycloalkyl group is a monocyclic or bicyclic ring.

[0041] The term "heterocycloalkyl" as used in this specification refers to a stable 3- to 18-membered saturated or partially unsaturated free radical consisting of 2 to 20, preferably 2 to 15, preferably 2 to 10, preferably 2 to 6 carbon atoms and 1 to 6 heteroatoms, such as 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms, selected from nitrogen, oxygen, and sulfur. Exemplary heterocycloalkyls include, but are not limited to, stable 3-15 membered saturated or partially unsaturated free radicals, stable 3-12 membered saturated or partially unsaturated free radicals, stable 3-9 membered saturated or partially unsaturated free radicals, stable 8-membered saturated or partially unsaturated free radicals, stable 7-membered saturated or partially unsaturated free radicals, stable 6-membered saturated or partially unsaturated free radicals, or stable 5-membered saturated or partially unsaturated free radicals. Heterocycloalkyls include all forms of saturated or unsaturated monocyclic, polycyclic, or spirocyclic rings and can be combined through heteroatoms or carbon atoms. Examples of such heterocycloalkyl radicals may include monovalent radicals of non-aromatic heterocycles such as oxetane, aziridine, pyrrolidine, azetidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, 1,3-dihydrobenzo[c][1,2]oxaborole, imidazolidine-2,4-dione, thiazolidine-2,4-dione, pyrimidine-2,4(1H,3H)-dione, 3-azabicyclo[3.1.0]hexane, octahydropyrrolo[3,4-c]pyrrole, 2,7-diazaspiro[4.4]nonane, and 2-azaspiro[4.4]nonane.

[0042] The term "mono-alkylamino" used in this specification refers to -NH(alkyl) including -NHCH3, -NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, -NH(CH2)5CH3, and the like, wherein alkyl has the same meaning as above.

[0043] The term "di-alkylamino" as used in this specification refers to -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -N(CH3)(CH2CH3), and similar -N(alkyl)(alkyl), wherein each alkyl group is independently an alkyl group as defined above.

[0044] The term "alkylamino group" used in the present specification is a concept including the mono-alkylamino group, di-alkylamino group and tri-alkylamino group defined above.

[0045] The terms "carboxylic acid group" and "carboxyl group (Carboxyl, Carboxy)" used in this specification refer to -COOH.

[0046] The term "carboxyalkyl" used in this specification refers to an alkyl group in which one or more hydrogen atoms are replaced by -COOH, including -CH2COOH, -CH2CH2COOH, -(CH2)2CH2COOH, -(CH2)3CH2COOH, -(CH2)4CH2COOH, -(CH2)5CH2COOH, -CH(COOH)-CH3, -CH2CH(COOH)CH3, and similar groups, wherein the alkyl group has the same definition as above.

[0047] The term "aminoalkyl" used in this specification refers to -(alkyl)-NH2 including -CH2-NH2, -(CH2)2-NH2, -(CH2)3-NH2, -(CH2)4-NH2, -(CH2)5-NH2, and similar groups, wherein alkyl has the same definition as above.

[0048] The term "mono-alkylaminoalkyl" as used in this specification refers to -(alkyl)-NH(alkyl) including -CH2-NH-CH3, -CH2-NHCH2CH3, -CH2-NH(CH2)2CH3, -CH2-NH(CH2)3CH3, -CH2-NH(CH2)4CH3, -CH2-NH(CH2)5CH3, -(CH2)2-NH-CH3, and the like, wherein each alkyl group is independently an alkyl group as defined above.

[0049] As used herein, "heteroaryl" is a 5- to 10-membered aromatic heterocycle containing at least one carbon atom and including mono- and bicyclic ring systems having at least one heteroatom selected from nitrogen, oxygen and sulfur. Representative heteroaryl groups are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thienyl, benzothienyl, quinolinyl, pyrrolyl, indolyl, Azolyl, benzo benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, iso oxetane, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidinyl, oxetanyl, azepine, piperazinyl, morpholinyl, dimethicone, benzophen ... Alkyl, thiol and Azolyl. A heteroaryl group can be monocyclic or bicyclic. Heteroaryl can be used interchangeably with the terms heteroaryl ring, heteroaryl group, or heteroaromatic, all of which can include rings that are optionally substituted.

[0050] As used herein, "heterocycle" refers to a saturated or unsaturated 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which a portion of the above heterocycles is fused to a benzene ring. The heterocycle may be attached via a heteroatom or a carbon atom. Heterocycles include heteroaryl groups as defined above. Representative heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl. "Heterocycle fused to a phenyl ring" refers to a heterocycle attached to two adjacent carbon atoms of a phenyl ring, wherein the heterocycle is as defined above.

[0051] The term "hydroxyalkyl" as used in this specification refers to an alkyl group in which one or more hydrogen atoms are substituted by a hydroxy group, including -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -(CH2)3CH2OH, -(CH2)4CH2OH, -(CH2)5CH2OH, -CH(OH)-CH3, -CH2CH(OH)CH3, and the like, wherein the alkyl group has the same definition as above.

[0052] The term "alkylsulfonyl" used in this specification refers to -SO2-(alkyl) including -SO2-CH3, -SO2-CH2CH3, -SO2-(CH2)2CH3, -SO2-(CH2)3CH3, -SO2-(CH2)4CH3 and -SO2-(CH2)5CH3, wherein alkyl has the same definition as above.

[0053] The term "aminosulfonyl" used in this specification refers to -SO2-NH2.

[0054] As used in this specification, the term "substituted" means that the hydrogen atoms of the substituted portion (e.g., alkyl, aryl, heteroaryl, heterocycle or cycloalkyl) are replaced by substituents. In one embodiment, the carbon atoms of each substituted group are not replaced by more than two substituents. In another embodiment, the carbon atoms of each substituted group are not replaced by more than one substituent. In the case of a keto substituent, two hydrogen atoms are replaced by oxygen attached to the carbon via a double bond. With respect to substituents, unless otherwise stated, halogen, hydroxyl, (lower) alkyl, haloalkyl, mono- or di-alkylamino, aryl, heterocycle, -NO2, -NR a1 R b1 、-NR a1 C(=O)R b1 、-NR a1 C(=O)NR a1 R b1 、-NR a1 C(=O)OR b1 、-NR a1 SO2R b1 、-OR a1 、-CN、-C(=O)R a1 、-C(=O)OR a1 、-C(=O)NR a1 R b1 、-OC(=O)R a1 、-OC(=O)OR a1 、-OC(=O)NR a1 R b1 、-NRa1 SO2R b1 、-PO3R a1 、-PO(OR a1 )(OR b1 ),-SO2R a1 、-S(O)R a1 、-SO(NR a1 )R b1 (e.g., sulfoximine), -S(NR a1 )R b1 (e.g., sulfilimine) and -SR a1 , where R a1 and R b1 may be the same or different and independently be hydrogen, halogen, amino, alkyl, alkoxyalkyl, haloalkyl, aryl, or heterocycle, or, like the attached nitrogen atom, R a1 and R b1 It can be in the form of a heterocyclic ring. Here, R a1 and R b1 There may be plural numbers of the atoms bonded thereto. The alkyl group may be a C1-C20 alkyl group, the aryl group may be a C6-C20 group, and the heterocycle may be a C3-C20 group.

[0055] Preferably, the substituted substituents of the present invention can be selected from halogen, amino, nitro, hydroxy, carboxylic acid, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, halogenated C1-C10 alkyl, C3-C10 heterocyclic carbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, One or more of cyano C1-C10 alkyl, C1-C10 alkylamino, di-C1-C10 alkylamino, C6-C20 arylamino, di-C6-C20 arylamino, C3-C20 heteroaryl, halogenated C6-C20 aryl, halogenated C1-C10 alkyl C6-C20 aryl, C6-C20 aryl, C3-C10 cycloalkyl, C3-C10 cycloalkylcarbonyl, C1-C10 alkoxycarbonyl C1-C10 alkyl and carboxylic acid C1-C10 alkyl.

[0056] As used herein, "pharmaceutically acceptable salts" include salts of active compounds that are prepared from relatively non-toxic acids and bases, depending on the specific substituents found in the compounds mentioned herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base in a pure or suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amino or magnesium, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid in a pure or suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include not only salts derived from relatively nontoxic organic acids including acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, tolylsulfonic, citric, tartaric, methanesulfonic, and the like, but also salts with hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogen iodide, or phosphorous acid, and the like. In addition, salts of amino acids such as arginine and its analogs and analogs of organic acids such as glucuronic or galactunoric acid and its analogs are included (for example, Berge et al. (1977) J. Pharm. Sci. 66: 1-19). Some specific compounds of the present invention have both acidic and basic functional groups to convert the compounds into base or acid addition salts. Another example of a salt is described in the literature known in the art to which the present invention belongs, such as Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0057] As used in this specification, the terms "individual" and "subject of administration" refer to animals (e.g., cows, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs), preferably non-primates and mammals such as primates (e.g., monkeys and humans), and most preferably humans.

[0058] As used in this specification, "effective amount" refers to the amount of the compound of the present invention sufficient to provide therapeutic benefits in the treatment or management of bacterial infections. "Effective amount" also refers to the amount of the compound of the present invention sufficient to cause the killing of bacteria or inhibit bacterial growth. "Effective amount" also refers to an amount sufficient to treat and prevent bacterial infections, whether in vitro or in vivo. "Effective amount" can be easily determined by those skilled in the art based on factors including the patient's gender, age, weight, health status, type of bacterial infection, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration, and excretion ratio, treatment period, drugs used in combination or simultaneously, and other factors well known in the medical field.

[0059] As used herein, "prevention" includes prevention of recurrence, extension or onset of a bacterial infection in a patient.

[0060] As used in this specification, "treatment" includes both bacterial killing and inhibition.

[0061] The term "compound of the present invention" used in this specification refers not only to the compound of Chemical Formula 1 but also includes solvates, hydrates, or prodrugs thereof. In addition, the term "compound of the present invention" is intended to include pharmaceutically acceptable salts of the compound of the present invention even when no pharmaceutically acceptable salts thereof are mentioned. In one embodiment, the compounds of the present invention may exist as stereoisomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., 85% ee or greater, 90% ee or greater, 95% ee or greater, 97% ee or greater, or 99% ee or greater). That is, when the compounds of the present invention or their salts are tautomeric isomers and / or stereoisomers (e.g., geometric isomers and conformational isomers), their isolated isomers and mixtures are also encompassed within the scope of the compounds of the present invention. When the compounds of the present invention or their salts have asymmetric carbon atoms within their structures, their optically active compounds and racemic mixtures are also encompassed within the scope of the compounds of the present invention. For example, when the compounds of the present invention have a sulfoxide (SOR) structure, they may have chirality. The compounds of the present invention include both R and S forms of such isomers, and mixtures of the R and S forms are also encompassed within the scope of the compounds of the present invention.

[0062] In addition, the compounds of the present invention may exist in either the keto form or the enol form, and these forms are all included in the scope of the compounds of the present invention.

[0063] As used herein, the term "solvate" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof, bound by intermolecular non-covalent forces and containing a stoichiometric or non-stoichiometric amount of a solvent. Preferred solvents are volatile, non-toxic, and can be administered to humans in minimal amounts.

[0064] The term "hydrate" used in the present specification refers to a compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent forces between molecules.

[0065] Prodrugs can be used to modify or improve the physical and / or pharmacokinetic properties of a parent compound and can be formed by containing suitable groups or substituents that induce prodrug formation from the parent compound. If a compound (prodrug) is separated in vivo to form a compound of the present invention or a salt thereof, these compounds are also included in the scope of the present invention. Unless otherwise indicated, the term "prodrug" as used in this specification refers to a compound of the present invention that is hydrolyzed, oxidized, or otherwise reacts under biological conditions (in vitro or in vivo) to provide the active compound, particularly a compound of the present invention. Examples of prodrugs include, but are not limited to, biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureas, and biohydrolyzable phosphate analogs, which contain a biohydrolyzable moiety and biohydrolyze to form a compound of the present invention. Preferably, the prodrug of a compound having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. Carboxylic acid esters are generally formed by esterifying the carboxylic acid moiety present in the molecule. Prodrugs can be readily prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abrahamed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0066] The term "purified" as used in this specification means that the purity of the isolate is greater than 90%, in one embodiment, greater than 95%, in another embodiment, greater than 99%, and in another embodiment, greater than 99.9%.

[0067] As used herein, the term "hydrido" refers to a single -H atom (H) and can be used interchangeably with the symbol "H" or the term "hydrogen".

[0068] If a substituent is described as "substituted or substituted", the substituent may (1) be unsubstituted or (2) be substituted with one or more of the substituents defined. If a substitutable position is unsubstituted, the default substituent is a hydrogen radical.

[0069] As used in the present specification, the singular forms "a" and "an" may include the plural forms unless the context clearly indicates otherwise.

[0070] The term "pharmaceutically acceptable" as used in this specification means suitable for use as a pharmaceutical preparation, and generally means regarded as safe for such use, publicly approved for such use by a national regulatory agency, or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0071] As the antibiotic of the present invention, a novel compound having excellent effects, a solvate thereof, a hydrate thereof, a prodrug thereof, an isomer thereof, or a pharmaceutically acceptable salt thereof is provided, wherein the novel compound of the present invention is represented by the following Chemical Formula 1.

[0072] [Chemical Formula 1]

[0073]

[0074] (In the above chemical formula 1,

[0075] Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene group, or a substituted or unsubstituted C3-C20 heteroarylene group;

[0076] Z1 to Z3 are independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2-, or -OCONR7-;

[0077] R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxyl C1-C10 alkyl, or C1-C10 alkoxycarbonyl C1-C10 alkyl;

[0078] A1 is or R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy C1-C10 alkyl, and p is an integer from 0 to 4;

[0079] A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene, or C6-C20 heteroarylene;

[0080] R is hydrogen, halogen, amino, hydroxyl, -B(OH)2, substituted or unsubstituted halogenated C1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.)

[0081] The novel compound of the present invention has a chemical structure completely different from that of conventional antibiotics and has very excellent effects as an antibiotic.

[0082] Furthermore, the novel compounds of the present invention are effective in killing and inhibiting a wide range of bacteria.

[0083] Preferably, in Chemical Formula 1 according to one embodiment of the present invention, the arylene group or heteroarylene group of Ar1 and Ar2 and the haloalkyl, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group of R can be selected from halogen, amino, nitro, hydroxyl, carboxylic acid, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, halogenated C1-C10 alkyl, C3-C10 heterocyclocarbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl , hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, halogenated C6-C20 aryl, halogenated C1-C10 alkyl C6-C20 aryl, C6-C20 aryl, C3-C10 cycloalkyl, C3-C10 cycloalkylcarbonyl, C1-C10 alkoxycarbonyl C1-C10 alkyl and carboxylic acid C1-C10 alkyl are further substituted by one or more of the following:

[0084] More preferably, in Chemical Formula 1 according to one embodiment of the present invention, Ar1 is a C3-C20 heteroarylene group; Ar2 is a single bond, a C6-C20 arylene group, or a C3-C20 heteroarylene group; Z1 is a single bond or -CONR1-; Z2 is a single bond, -CONR1-, -NR2CO-, or -COO-; Z3 is a single bond, -CONR1-, -NR2CO-, -NR5COO-, -NR6-, -S-, or -OCONR7-; R1, R2, and R5 to R7 can independently be hydrogen, hydroxyl, C1-C10 alkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl, or carboxylic acid C1-C10 alkyl.

[0085] The compound of Chemical Formula 1 according to an embodiment of the present invention may be represented by the following Chemical Formula 2.

[0086] [Chemical Formula 2]

[0087]

[0088] (In the above chemical formula 2,

[0089] Ar2 is a single bond, a substituted or unsubstituted C6-C20 arylene group, or a substituted or unsubstituted C3-C20 heteroarylene group;

[0090] Z1 to Z3 are independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2-, or -OCONR7-;

[0091] R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxyl C1-C10 alkyl, or C1-C10 alkoxycarbonyl C1-C10 alkyl;

[0092] A1 is or R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy C1-C10 alkyl, and p is an integer from 0 to 4;

[0093] A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene, or C6-C20 heteroarylene;

[0094] R is hydrogen, halogen, amino, hydroxyl, -B(OH)2, substituted or unsubstituted halogenated C1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.)

[0095] Preferably, in Chemical Formula 2 according to one embodiment of the present invention, Ar2 is a single bond, a C6-C20 arylene group, or a C3-C20 heteroarylene group; Z1 is a single bond or -CONR1-; Z2 is a single bond, -CONR1-, -NR2CO-, or -COO-; Z3 is a single bond, -CONR1-, -NR2CO-, -NR5COO-, -NR6-, -S-, or -OCONR7-; R1, R2, and R5 to R7 are independently hydrogen, hydroxyl, C1-C10 alkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl, or carboxylic acid C1-C10 alkyl; A1 is or R' is hydrogen or C1-C10 alkyl, p is an integer from 0 to 2; A2 is a single bond, C1-C10 alkylene, or C3-C10 heterocycloalkylene; R is hydrogen, halogen, amino, hydroxyl, -B(OH)2, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C20 aryl, or C3-C20 heteroaryl; the arylene or heteroarylene group of Ar2 and the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group of R can be selected from halogen, amino, nitro, hydroxyl, carboxylic acid, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, halogenated C1 The alkyl group may be further substituted by one or more of: -C10 alkyl, C3-C10 heterocyclic carbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, halogenated C6-C20 aryl, halogenated C1-C10 alkyl C6-C20 aryl, C6-C20 aryl, C3-C10 cycloalkyl, C3-C10 cycloalkylcarbonyl, C1-C10 alkoxycarbonylC1-C10 alkyl, and carboxylic acid C1-C10 alkyl.

[0096] In order to have a more excellent effect as an antibiotic, the chemical formula 1 according to one embodiment of the present invention may be preferably represented by the following chemical formula 3.

[0097] [Chemical Formula 3]

[0098]

[0099] (In the above chemical formula 3,

[0100] Ar2 is a substituted or unsubstituted C6-C20 arylene group, or a substituted or unsubstituted C3-C20 heteroarylene group;

[0101] Z2 is a single bond, -CONR1-, -NR2CO-, or -COO-;

[0102] Z3 is a single bond, -CONR1-, -NR2CO-, -NR5COO-, -NR6-, -S-, or -OCONR7-;

[0103] R1, R2 and R5 to R7 are independently hydrogen, hydroxy, or C1-C10 alkyl;

[0104] A1 is or R' is hydrogen or C1-C10 alkyl, and p is an integer from 0 to 2;

[0105] A2 is a single bond, C1-C10 alkylene, or C3-C10 heterocycloalkylene;

[0106] R is hydrogen, halogen, amino, hydroxyl, -B(OH)2, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl.)

[0107] Preferably, in Chemical Formula 3 according to one embodiment of the present invention, Ar2 is a C6-C20 arylene group or a C3-C20 heteroarylene group; Z2 is a single bond, -CONR1-, -NR2CO-, or -COO-; Z3 is a single bond, -CONR1-, -NR2CO-, -NR5COO-, -NR6-, -S-, or -OCONR7-; R1, R2, and R5 to R7 are independently hydrogen, hydroxyl, or C1-C10 alkyl; A1 is or R' is hydrogen or C1-C10 alkyl, p is an integer from 0 to 2; A2 is a single bond, C1-C10 alkylene, or C3-C10 heterocycloalkylene; R is hydrogen, halogen, amino, hydroxyl, -B(OH)2, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C20 aryl, or C3-C20 heteroaryl; the arylene and heteroarylene groups of Ar2 and the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups of R can be selected from halogen, amino, nitro, hydroxyl, carboxylic acid, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, halogenated C1-C10 The group is further substituted with one or more of a C10 alkyl group, a C3-C10 heterocyclic carbonyl group, an allylamino group, a C1-C10 alkylsulfonyl group, an aminosulfonyl group, an amino C1-C10 alkyl group, a hydroxy C1-C10 alkyl group, a dihydroxy C1-C10 alkyl group, a cyano C1-C10 alkyl group, a C1-C10 alkylamino group, a di C1-C10 alkylamino group, a C6-C20 arylamino group, a di C6-C20 arylamino group, a C3-C20 heteroaryl group, a halogenated C6-C20 aryl group, a halogenated C1-C10 alkyl C6-C20 aryl group, a C6-C20 aryl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkylcarbonyl group, a C1-C10 alkoxycarbonyl C1-C10 alkyl group, and a carboxylic acid C1-C10 alkyl group,

[0108] More preferably, in Chemical Formula 3, Ar2 may be selected from the following structures.

[0109]

[0110] (In the above structural formula, R 11 to R 17 are independently hydrogen, halogen, or C1-C10 alkyl.)

[0111] More preferably, in Chemical Formula 3 according to one embodiment of the present invention, Ar2 is selected from the following structures;

[0112]

[0113] Z2 is a single bond, -CONR1-, -NR2CO-, or -COO-;

[0114] Z3 is a single bond, -NR2CO-, -NR5COO-, -NR6-, or -S-;

[0115] R1, R2, R5 and R6 are independently hydrogen, hydroxy, or C1-C10 alkyl;

[0116] A1 is or R' is a C1-C10 alkyl group, and p is an integer from 0 to 2;

[0117] A2 is a single bond or a C1-C10 alkylene group;

[0118] R is hydrogen, halogen, amino, hydroxy, -B(OH)2, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C20 aryl, or C3-C20 heteroaryl;

[0119] The alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group of R can be selected from halogen, amino, nitro, hydroxy, carboxylic acid, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, halogenated C1-C10 alkyl, C3-C10 heterocyclocarbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 The alkyl group may be further substituted by one or more of the following: alkyl, cyano C1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, halogenated C6-C20 aryl, halogenated C1-C10 alkyl C6-C20 aryl, C6-C20 aryl, C3-C10 cycloalkyl, C3-C10 cycloalkylcarbonyl, C1-C10 alkoxycarbonyl C1-C10 alkyl and carboxylic acid C1-C10 alkyl.

[0120] Preferably, Chemical Formula 3 according to one embodiment of the present invention can be represented by the following Chemical Formula 4-1 or Chemical Formula 4-2.

[0121] [Chemical Formula 4-1]

[0122]

[0123] [Chemical Formula 4-2]

[0124]

[0125] (In the above chemical formulas 4-1 and 4-2,

[0126] A1 is or R' is a C1-C10 alkyl group, and p is an integer from 0 to 2;

[0127] n is an integer from 0 to 5;

[0128] Z3 is a single bond or -NR6-, R6 is hydrogen or C1-C10 alkyl;

[0129] R a is hydrogen, amino, or -B(OH)2, or is any one selected from the following structures;

[0130]

[0131] X is O or S;

[0132] X1 is NR 31 , O, S, or SO2;

[0133] X2 to X5 are each independently NR 32 , O, or S;

[0134] R 20 to R 22 、R 31 and R 32 are independently hydrogen, halogen, nitro, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl, or carboxylic acid C1-C10 alkyl.

[0135] More preferably, in one embodiment of the present invention, the above R a is hydrogen, amino, or -B(OH)2, or may be any one selected from the following structures:

[0136]

[0137] (In the above structural formula,

[0138] R 21 and R 22 are independently hydrogen, halogen, nitro, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl or carboxylic acid C1-C10 alkyl;

[0139] R 31 and R 32 are independently hydrogen, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl or carboxylic acid C1-C10 alkyl.

[0140] More preferably, the above R 21 and R 22 R 31 and R 32 Independently of one another, they may be hydrogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl or carboxylic acid C1-C10 alkyl.

[0141] In the above Chemical Formula 4-1 according to one embodiment of the present invention, Z3 may be a single bond.

[0142] In the above chemical formula 4-1 according to one embodiment of the present invention, Z3 is a single bond; R a It may be hydrogen, amino, or -B(OH)2.

[0143] In the above Chemical Formula 4-2 according to one embodiment of the present invention, Z3 may be a single bond or -NH-.

[0144] In the above chemical formula 4-2 according to one embodiment of the present invention, Z3 is -NH-; R a for X is O or S; R 20 and R 21Independently of one another, they may be hydrogen, halogen, nitro, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl, or carboxylic acid C1-C10 alkyl.

[0145] In the above chemical formula 4-2 according to one embodiment of the present invention, Z3 is a single bond; R a It is hydrogen, amino, or -B(OH)2, or may be any one selected from the following structures.

[0146]

[0147] (In the above structural formula,

[0148] X1 is NR 31 , O, S, or SO2;

[0149] X2 to X5 are each independently NR 32 , O or S;

[0150] R 21 、R 22 、R 31 and R 32 are independently hydrogen, halogen, nitro, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl, or carboxylic acid C1-C10 alkyl.

[0151] Chemical Formula 1 according to an embodiment of the present invention may be a compound represented by the following Chemical Formulas 5 to 12.

[0152] [Chemical Formula 5]

[0153]

[0154] [Chemical Formula 6]

[0155]

[0156] [Chemical Formula 7]

[0157]

[0158] [Chemical Formula 8]

[0159]

[0160] [Chemical Formula 9]

[0161]

[0162] [Chemical Formula 10]

[0163]

[0164] [Chemical Formula 11]

[0165]

[0166] [Chemical Formula 12]

[0167]

[0168] (In the above chemical formulas 5 to 12,

[0169] A1 is or R' is a C1-C10 alkyl group, and p is an integer from 0 to 2;

[0170] D1 is CH or N;

[0171] D2 is O, S, SO2, C(R b1 )(R b2 ), or NR c1 ;

[0172] D3 is CH or N;

[0173] D4 is CO, NH or CH;

[0174] D5 is O, S or NR c2 ;

[0175] D6 is CR b3 or N;

[0176] D7 is O or S;

[0177] R1 is hydrogen or C1-C10 alkyl;

[0178] Z3 is a single bond or -NR6-, R6 is hydrogen or C1-C10 alkyl;

[0179] R a1 to R a13 、R b1 to R b3 、R c1 and R c2are independently hydrogen, halogen, amino, nitro, hydroxy, carboxylic acid, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, halogenated C1-C10 alkyl, C3-C10 heterocyclic carbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC10 1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, halogenated C6-C20 aryl, halogenated C1-C10 alkyl C6-C20 aryl, C6-C20 aryl, C3-C10 cycloalkyl, C3-C10 cycloalkylcarbonyl, C1-C10 alkoxycarbonyl C1-C10 alkyl, or carboxylic acid C1-C10 alkyl;

[0180] n is an integer from 0 to 5.)

[0181] More preferably, in Chemical Formulas 5 to 12 according to one embodiment of the present invention, A1 is or R' is a C1-C10 alkyl group, p is an integer of 0 or 1; D1 is N; D2 is O, S or NR c1 ; D3 is N; D4 is CO, NH or CH; D5 is O, S or NR c2 ; D6 is CRb3 or N; R1 is hydrogen; Z3 is a single bond or -NH-; R a1 to R a13 and R b3 R is independently hydrogen, halogen, nitro, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl or carboxylic acid C1-C10 alkyl; c1 and R c2 Each of them is independently hydrogen, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl or carboxylic acid C1-C10 alkyl; n can be an integer from 0 to 5.

[0182] More preferably, in Chemical Formulas 5 to 12 according to one embodiment of the present invention, the above R a1 to R a13 and R b3are independently hydrogen, halogen, nitro, C1-C10 alkyl, or C3-C10 cycloalkyl; R c1 and R c2 Each of them is independently hydrogen, C1-C10 alkyl, C1-C10 alkylsulfonyl, aminosulfonyl, hydroxy C1-C10 alkyl, dihydroxy C1-C10 alkyl, cyano C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxycarbonyl C1-C10 alkyl, or carboxylic acid C1-C10 alkyl; n can be an integer from 0 to 3.

[0183] Preferably, Chemical Formula 1 according to one embodiment of the present invention can be represented by the following Chemical Formula 13-1 or Chemical Formula 13-2.

[0184] [Chemical Formula 13-1]

[0185]

[0186] [Chemical Formula 13-2]

[0187]

[0188] (In the above chemical formulas 13-1 and 13-2,

[0189] R b is hydrogen, amino, or -B(OH)2;

[0190] A1 is or R' is a C1-C10 alkyl group, and p is an integer from 0 to 2;

[0191] n is independently an integer from 0 to 10.)

[0192] More preferably, in Chemical Formula 13-1 according to one embodiment of the present invention, R b is hydrogen; A1 is p is an integer of 0 or 1; n can be an integer of 0.

[0193] More preferably, in Chemical Formula 13-2 according to one embodiment of the present invention, A1 is p is an integer of 0 or 1; n can be an integer of 1 to 6 independently of each other.

[0194] More preferably, in Chemical Formula 13-2 according to one embodiment of the present invention, R b is amino or -B(OH)2; A1 is p is an integer of 0 or 1; n can be an integer of 1 to 6 independently of each other.

[0195] The novel compound of the present invention can be selected from the following compounds, but is not limited thereto.

[0196]

[0197]

[0198]

[0199] In addition, the present invention provides a method for producing the compound represented by Chemical Formula 1 of the present invention, the method for producing the compound of the present invention comprising the following steps:

[0200] a step of reacting the compound of the following Chemical Formula 21 with a boronic acid precursor to produce the compound of the following Chemical Formula 22; and

[0201] A step of reacting the compound of the above Chemical Formula 22 with the compound of the following Chemical Formula 23 to produce the compound of the following Chemical Formula 1.

[0202] [Chemical Formula 1]

[0203]

[0204] [Chemical Formula 21]

[0205]

[0206] [Chemical Formula 22]

[0207]

[0208] [Chemical Formula 23]

[0209]

[0210] (In Chemical Formula 1 and Chemical Formulas 21 to 23,

[0211] Ar1 and Ar2 are independently a single bond, a substituted or unsubstituted C6-C20 arylene group, or a substituted or unsubstituted C3-C20 heteroarylene group;

[0212] Z1 to Z3 are independently a single bond, -CONR1-, -NR2CO-, -COO-, -OCO-, -CR3R4-, -NR5COO-, -NR6-, -S-, -O-, -SO2-, or -OCONR7-;

[0213] R1 to R7 are independently hydrogen, hydroxy, C1-C10 alkyl, carboxyl C1-C10 alkyl, or C1-C10 alkoxycarbonyl C1-C10 alkyl;

[0214] A1 is or R' is hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C1-C10 alkoxy C1-C10 alkyl, and p is an integer from 0 to 4;

[0215] A2 is a single bond, C1-C10 alkylene, C3-C10 cycloalkylene, C3-C10 heterocycloalkylene, C6-C20 arylene, or C6-C20 heteroarylene;

[0216] R is hydrogen, halogen, amino, hydroxy, -B(OH)2, substituted or unsubstituted halogenated C1-C10 alkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted C3-C20 heteroaryl;

[0217] Y1 and Y2 are independently halogen.)

[0218] According to an embodiment of the present invention, the method for producing the compound of Chemical Formula 1 uses a compound having a halogen functional group introduced therein, namely, the compound of Chemical Formula 21, to easily replace the halogen group of the compound of Chemical Formula 21 with a boronic acid functional group, thereby easily producing the compound of Chemical Formula 1 through an aryl-aryl coupling reaction.

[0219] As an example, among aryl-aryl couplings, MOTTO coupling, Suzuki coupling, Stiller coupling, Sonogashira coupling, Heck coupling, or Buchwald coupling may be suitable, but the Suzuki coupling reaction is particularly preferred.

[0220] According to one embodiment of the present invention, the boronic acid precursor can be any compound that can react with the compound of Chemical Formula 21 in the presence of a catalyst to introduce a boronic acid or boronic acid derivative group, that is, an organic boronic acid compound. As an example, it can be bis(pinacolato)diboron (Bis(pinacolato)diboron), -B(OH)2, etc.

[0221] Preferably, the aryl-aryl coupling of the present invention can be carried out in the presence of a transition metal catalyst. The Suzuki coupling reaction can use a Pd(O) complex or a Pd(II) salt. The preferred Pd(O) complex can contain one or more phosphine ligands such as Pd(Ph3P). Another preferred phosphine ligand can be tri(o-tolyl)phosphine (Pd(o-Tol)4).

[0222] Preferred Pd(II) salts include palladium acetate, i.e., Pd(OAc)2. Suzuki coupling can be carried out in the presence of a base such as sodium carbonate, potassium phosphate, or an organic base such as tetraethylammonium carbonate, and Yamamoto polymerization can use a Ni(0) complex such as bis(1,5-cyclooctadiene)nickel(0).

[0223] Preferably, the compound of Chemical Formula 21 according to one embodiment of the present invention, i.e., the compound of Chemical Formula 21, can be produced by the following steps: reacting the compound of Chemical Formula 24 with the compound of Chemical Formula 25 to produce the compound of Chemical Formula 26; and deprotecting the compound of Chemical Formula 26 to produce the compound of Chemical Formula 21.

[0224] [Chemical Formula 24]

[0225]

[0226] [Chemical Formula 25]

[0227]

[0228] [Chemical Formula 26]

[0229]

[0230] (In the above Chemical Formulas 24 to 26, Ar1 and Y1 are the same as defined in the above Chemical Formulas 1, 21, and 22;

[0231] R C1 to R C3 are independently C1-C10 alkyl;

[0232] P is a protecting group.)

[0233] According to one embodiment of the present invention, deprotection is to remove the protecting group. The protecting group can be any protecting group that can be used by those skilled in the art. The protecting group of the present invention is a hydroxy protecting group or an amine protecting group.

[0234] The reaction time in the production method according to one embodiment of the present invention may vary depending on the reactants, the type of solvent, and the amount of solvent. As an example, the reaction is terminated after complete consumption of the starting material is confirmed by TLC or the like. Upon completion of the reaction, the solvent is distilled under reduced pressure, and the target product can then be isolated and purified by conventional methods such as column chromatography.

[0235] The present invention also provides an antibiotic composition characterized by containing the compound of the present invention, a hydrate thereof, a solvate thereof, an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0236] The compound of the present invention or the antibiotic composition of the present invention can be administered to the subject before or after the onset of bacterial infection. In addition, for most divided doses and time-difference doses, it can be administered daily or sequentially, or continuously infused, or injected as a bolus. Moreover, the dosage of the compound of the present invention or the antibiotic composition comprising the same can be proportionally increased or decreased when it can be expressed as a necessary condition for treatment or prevention.

[0237] In addition, the compound or antibiotic composition of the present invention can be used in pharmaceutical preparations for treating diseases caused by bacterial infection. The antibiotic composition of the present invention includes a preparation suitable for administration to mammals (eg, humans).

[0238] The antibiotic composition according to one embodiment of the present invention has high antibacterial activity by essentially comprising the compound of the present invention, its hydrate, its solvate, its isomer, its prodrug, or its pharmaceutically acceptable salt as an active ingredient.

[0239] Preferably, the antibiotic composition according to one embodiment of the present invention may contain 0.001 to 10 weight % of the novel compound of the present invention relative to the total weight of the antibiotic composition, preferably, 0.005 to 10 weight %, more preferably, 0.1 to 5 weight %.

[0240] The antibiotic composition according to one embodiment of the present invention can be used for the treatment and prevention of bacterial infections.

[0241] According to an embodiment of the present invention, the bacterial infection can be caused by Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella enterica, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, and Salmonella typhimurium. enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii), Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticushemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis catarrhalis), Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homologous group, Bacteroides vulgaris vulgatus), Bacteroides ovatusovalus), Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare complex, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium bolletii, Mycobacterium kansasii, Mycobacterium xenopi), Mycobacterium malmoennse, Mycobacterium scrofulaceum, Mycobacterium marinum, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium ulcerans, Mycobacterium haemophilum, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium), Staphylococcus aureus, Staphylococcus epidermidisepidermidis), Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus, or may be an infection associated with Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, or COVID-19,

[0242] Preferably, the infection may be an infection associated with Clostridioides difficile, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare complex, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium abscessus, Enterococcus faecalis, Enterococcus faecium or Staphylococcus aureus,

[0243] More preferably, it may be an infection associated with Clostridioides difficile, Mycobacterium Tuberculosis, Mycobacterium avium-intracellulare complex, Mycobacterium abscessus, Mycobacterium avium, Mycobacterium intracellulare or Staphylococcus aureus.

[0244] Preferably, the antibiotic composition according to one embodiment of the present invention may further comprise a pharmaceutically acceptable carrier.

[0245] The pharmaceutically acceptable carrier according to one embodiment of the present invention is a substance that can be recognized by those skilled in the art, including pharmaceutically acceptable substances, compositions or carriers suitable for administration to mammals.

[0246] Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating substances that are involved in the transport or delivery of the agent of interest from one organ or body part to another. Each carrier should be acceptable in the sense of being compatible with the other ingredients of the formulation and should not be harmful to the patient. Among the several examples of substances that can act as pharmaceutically acceptable carriers are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other compatible, nontoxic substances used in pharmaceutical formulations.

[0247] In addition, the antibiotic composition of the present invention may contain not only wetting agents, emulsifiers and lubricants (eg, sodium lauryl sulfate and magnesium stearate), but also colorants, release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants.

[0248] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants, for example, ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; fat-soluble antioxidants, for example, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelating agents, for example, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0249] The antibiotic compositions of the present invention include those suitable for oral, intranasal, topical, buccal, sublingual, rectal, vaginal and / or parenteral administration, and can be conveniently provided in unit dosage forms and can be manufactured by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally equivalent to the amount of the compound that elicits a therapeutic effect.

[0250] The method for producing an antibiotic composition (or preparation) according to one embodiment of the present invention comprises the step of combining a compound of the present invention with a carrier and any one or more auxiliary ingredients. Typically, the preparation is produced by uniformly and meticulously mixing the compound of the present invention with a liquid carrier or a micronized solid carrier, or both, and then molding the resultant as needed.

[0251] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, typically sucrose and gum arabic or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base, for example, gelatin and glycerin, or sucrose and gum arabic), and / or as a mouth rinse, etc., each containing a specified amount of a compound of the present invention as the active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0252] In the solid dosage form of the present invention for oral administration (capsule, tablet, pill, sugar-coated tablet, powder, granule, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, for example, sodium citrate or calcium hydrogen phosphate and / or fillers or extenders, as an example, starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, as an example, carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; hygroscopic agents, as an example, glycerol; disintegrants any one of a mixture of agents, as an example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific silicates and sodium carbonate; a solution delay agent, as an example, paraffin; an absorption promoter, as an example, a quaternary ammonium compound; a wetting agent, as an example, cetyl alcohol and glyceryl monostearate; an absorbent, as an example, kaolin and bentonite; a lubricant, as an example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and a coloring agent.

[0253] For capsules, tablets and pills, the antibiotic composition may also contain a buffering agent. Solid compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0254] Tablets can be made by compression or molding with one or more auxiliary ingredients. Compressed tablets can be made using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0255] Tablets and other solid dosage forms of the antibiotic compositions of the present invention, i.e., sugar-coated tablets, capsules, pills, and granules, can be optionally scored or provided with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated using, for example, hydroxypropyl methylcellulose in various proportions to provide slow or controlled release of the active ingredient therein, thereby providing a targeted release profile, other polymer matrices, liposomes, and / or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or can be sterilized prior to use by mixing a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injection medium.

[0256] The antibiotic composition of the present invention may optionally contain an opacifying agent and may be a composition that releases the active ingredient solely or preferentially in a delayed manner in a specific portion of the gastrointestinal tract. Examples of useful embedding compositions include polymeric substances and waxes. The active ingredient may also be present in a microencapsulated form, where appropriate, together with one or more of the excipients described above.

[0257] Liquid dosage forms for oral administration of the compounds or antibiotic compositions of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, sprout oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.

[0258] When the antibiotic composition of the present invention is an oral composition, it may contain, in addition to an inert diluent, adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances, and preservatives. Suspensions may contain, in addition to the compound of the present invention, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0259] The antibiotic composition (preparation) of the present invention for rectal or vaginal administration can be provided as a suppository, which can be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, which is solid at room temperature but liquid at body temperature and can therefore melt in the rectum or vagina to release the active compound.

[0260] The antibiotic composition (preparation) of the present invention suitable for vaginal administration also includes vaginal suppositories, tampons, creams, gels, pastes, effervescent formulations or spray formulations containing appropriate carriers known in the art.

[0261] Dosage forms for topical or transdermal administration of the compound or antibiotic composition of the present invention include powders, sprays, ointments, pastes, creams, solutions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required.

[0262] Ointments, pastes, creams and gels may contain, in addition to the compounds of this invention, excipients such as animal or vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0263] Powders and sprays may contain, in addition to the compounds of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, for example, chlorofluorocarbons and volatile unsubstituted hydrocarbons, for example, butane and propane.

[0264] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.Such dosage forms can be made by dissolving or dispersing the compound of the present invention in the proper medium.

[0265] Absorption enhancers can also be used to increase the flux of the compounds of the present invention across the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the active compound in a polymer matrix or gel.

[0266] Ophthalmic preparations, eye ointments, powders, solutions, and the like are also encompassed within the scope of the present invention.

[0267] The antibiotic composition of the present invention suitable for parenteral administration comprises a combination of one or more compounds of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted in sterile injectable solutions or dispersions before use, and may contain antioxidants, buffers, bacteriostats, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents, or viscosity-increasing agents.

[0268] Examples of suitable aqueous and non-aqueous carriers that can be used in the antibiotic compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof; vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate). Appropriate fluidity can be maintained by, for example, using a coating material such as lecithin, maintaining the required particle size when dispersing, and using a surfactant. In addition, the antibiotic compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Microbial activity can be prevented by containing various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. In addition, it may be preferred that an isotonic agent be included in the composition, such as sugar, sodium chloride, etc.

[0269] In addition, prolonged absorption of the injectable antibiotic composition (formulation) of the present invention may be achieved by including agents which delay absorption, for example, aluminum monostearate and gelatin.

[0270] The formulations comprising the compounds of the present invention and the antibiotic composition can be administered orally, parenterally, topically, or rectally. Of course, they are provided in a form suitable for the respective route of administration. For example, they can be administered by injection, inhalation in the form of tablets or capsules, eye drops, ointments, suppositories, etc., by injection, insufflation, or inhalation; topical administration using solutions or ointments; and rectal administration using suppositories. Preferably, they can be administered orally and / or IV.

[0271] The antibiotic composition of the present invention can be administered by various methods recognized in the art. As an example, in addition to enteral and topical administration, other administrations can generally be non-oral administration or administration by non-oral means using an injection. That is, it includes intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardial, intradermal, intraperitoneal, intratracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and injection, but is not limited thereto. Similarly, the number of administrations and the dosage can be any level recognized in the art.

[0272] Furthermore, for the treatment of bacterial infection in a subject, the antibiotic composition (preparation) of the present invention can be used in combination with other agents, such as the compound of the present invention or another antibacterial agent other than the compound of the present invention.

[0273] The antibacterial agent includes antibiotics, biocides, antimicrobial agents and bacteriostatic agents, and the antibiotics, biocides, antimicrobial agents and bacteriostatic agents may be any of publicly known types.

[0274] In addition, the compound or antibiotic composition of the present invention can be formulated to be administered independently of any other agent, or can be formulated together to allow for a single administration. For example, after formulating the compound or antibiotic composition of the present invention into one dosage form, the other agent can be formulated together into another dosage form. Any independent dosage forms can be administered simultaneously or at different times.

[0275] As another method, the antibiotic composition of the present invention may comprise additional agents described in the present invention, and each component may be provided as an independent composition, a complex composition, or a single composition.

[0276] Hereinafter, the novel compound of the present invention will be described with reference to specific examples, but the present invention is not limited to such specific examples.

[0277] [Production Example 1] Production of Compound XI

[0278]

[0279]

[0280] Preparation of Compound II

[0281]

[0282] After dissolving acetonitrile (1.8 mL, 34.8 mmol) in tetrahydrofuran (100 mL), n-butyllithium solution (2.5 M hexane solution (2.5 M in hexanes, 16 mL, 38.3 mmol) was slowly added dropwise at -78 ° C. After stirring at -78 ° C for 15 minutes, compound I (6.22 g, 17.4 mmol) dissolved in tetrahydrofuran (25 mL) was slowly added dropwise at the same temperature. After slowly raising the temperature to room temperature, 1 M concentration of hydrochloric acid was added to interrupt the reaction. After dilution with ethyl acetate, hydrochloric acid was further added to acidify to pH 3. The organic solvent was extracted, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography with (30-50% ethyl acetate / hexane) solution to obtain brown solid compound II (4.46 g, 70%).

[0283] 1 H NMR (400MHz, CDCl3) δ 8.29 (s, 1H), 4.71 (d, J=17.7Hz, 1H), 4.32-4.09 (m, 3H), 1.70 (broad peak, 6H), 1.54-1.38 (t, J=8.4Hz, 7H), 1.31-1.06 (m, 5H).

[0284] Preparation of Compound III

[0285]

[0286] Compound II (4.46 g, 12.2 mmol) was dissolved in a mixture of toluene (100 mL) and acetic acid (20 mL), and ammonium acetate (9.4 g, 122 mmol) was added dropwise. After stirring at 120° C. for 90 minutes, the mixture was slowly cooled to room temperature. After dilution with ethyl acetate, the mixture was washed with a supersaturated sodium bicarbonate solution and water. The organic solvent was extracted, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound III (4.24 g, 95%) as a yellow oil.

[0287] 1H NMR (400MHz, CDCl3) δ7.60 (s, 1H), 5.59-5.51 (m, 2H), 4.81-4.50 (m, 2H), 4.21-4.10 (m, 1H), 1.67 (s, 6H), 1.40 (t, J = 13.7Hz, 6H), 1.27-0.96 (m, 6H).

[0288] Preparation of Compound IV

[0289]

[0290] After dissolving 2-formyl-[2,4-bithiazole]-4-carboxylic acid methyl ester (768 mg, 4 mmol) in tetrahydrofuran (10 mL), ethynylmagnesium bromide solution (0.5M THF solution (0.5M in THF, 16 mL, 8 mmol) was slowly added dropwise at 0°C. After stirring at room temperature for 30 minutes, a supersaturated ammonium chloride solution was added to interrupt the reaction. After extraction with ethyl acetate, dehydration with anhydrous sodium sulfate and concentration under reduced pressure were performed. The obtained residue was separated by column chromatography using a (30% ethyl acetate / 70% hexane) solution to obtain a white solid compound. After dissolving the obtained compound (632 mg, 2.9 mmol) in dichloromethane (30 mL), manganese dioxide (2.52 g, 29 mmol) was added, and then stirred at room temperature for 12 hours. The manganese residue was filtered out using bismuthite, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown solid Compound IV (527 mg, 61%).

[0291] 1 H NMR (400MHz, CDCl3) δ7.69 (s, 1H), 3.67 (s, 1H).

[0292] Preparation of Compound V

[0293]

[0294] After dissolving compound III (4.46 g, 12.2 mmol) in ethanol, compound IV (4.88 g, 22.6 mmol) was added dropwise, and then stirred at 60°C for 2 hours. After confirming whether Michael addition reaction occurred by TLC or LC / MS, acetic acid (30% volume, 19 mL) was added and refluxed at 120°C for 16 hours. Excess ethanol and acetic acid were removed by vacuum concentration and diluted with dichloromethane. After sodium bicarbonate was added to interrupt the reaction, the organic solvent was extracted and dehydrated with anhydrous sodium sulfate. After vacuum concentration, the mixture was separated by column chromatography using a (5-15% ethyl acetate / 95-85% hexane) solution to obtain yellow solid compound V (3.57 g, 50%).

[0295] 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.19 (s, 2H), 7.48 (s, 1H), 4.85 (d, J = 7.3 Hz, 1H), 4.58-4.23 (broad peak, 1H), 1.83-1.67 (broad peak, 6H), 1.57-1.45 (m, 6H), 1.33-1.20 (m, 6H).

[0296] Preparation of Compound VI

[0297]

[0298] Compound V (1.42 g, 2.53 mmol) was dissolved in a mixed solution of ethanol (27 mL), sodium phosphate buffer solution (pH 7, 9 mL) and water (4.5 mL), and L-cysteine ​​(4.34 g, 25.3 mmol) was added dropwise. After adding sodium bicarbonate (850 mg, 10.12 mmol), the mixture was stirred at 100 ° C for 24 hours. After confirming the completion of the reaction, the ethanol was removed by vacuum concentration and diluted with ethyl acetate. In order to remove excess cysteine, the mixture was washed with 1 M hydrochloric acid and then dehydrated with anhydrous sodium sulfate. The extracted solution was concentrated under reduced pressure to obtain brown oily thiazoline.

[0299] After dissolving brown oily thiazoline (1.68 g, 2.53 mmol) in dichloromethane (30 mL), bromotrichloromethane (0.8 mL, 8.07 mmol) was added, and then 1,8-diazabicyclo[5,4,0]undec-7-ene (1.6 mL, 10.76 mmol) was slowly added dropwise. After stirring at 60°C for 4 hours, 1M hydrochloric acid was added to interrupt the reaction. After extraction with dichloromethane, the mixture was washed with water and brine. The extracted organic solvent was dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography using a (5-15% methanol / dichloromethane) solution to obtain a brown solid compound VI (1.05 g, 62%).

[0300] 1 H NMR (400MHz, CDCl3) δ 8.35-8.05 (m, 3H), 7.89 (bs, 1H), 7.33 (s, 1H), 4.49-4.40 (m, 1H), 4.09-3.97 (m, 1H), 1.71-1.29 (m, 10H), 1.26-1.08 (m, 8H).

[0301] Preparation of Compound VIII

[0302]

[0303] After dissolving compound VI (1.05 g, 1.57 mmol) in acetonitrile (8 mL), compound VII (932 mg, 1.88 mmol), 1-methylimidazole (0.376 mL, 4.71 mmol), and TC FH (0.528 g, 1.88 mmol) were added and stirred at room temperature for 30 minutes. After confirming the completion of the reaction, water was added to interrupt the reaction, and the organic layer extracted with dichloromethane was dehydrated with anhydrous sodium sulfate. The concentrate obtained by vacuum concentration with a solution of (1.5-2.3% methanol: 98.5-97.7% dichloromethane) was separated by column chromatography to obtain compound VIII (1.05 g, 60%) as a yellow solid.

[0304] 1H NMR (400MHz, CDCl3) δ8.69 (s, 1H), 8.44 (d, J = 9.5Hz, 1H), 8.35-8.24 (m, 4H), 8.24-8.17 (m, 1H), 8.06 (s, 1H ), 7.96 (s, 1H), 7.94-7.87 (m, 1H), 6.45 (dq, J = 14.0, 7.1Hz, 1H), 5.41-5.31 (m, 1H), 4.88 (d, J = 5.3Hz, 1H), 4.78(s, 1H), 4.68-4.58(m, 1H), 4.58-4.46(m, 1H), 4.16-3.98(m, 1H), 3.86(s, 3H), 2.49-2.45(m, 1H), 1.8 7 (d, J=7.1Hz, 3H), 1.69-1.48 (m, 6H), 1.45-1.32 (m, 3H), 1.31-1.08 (m, 12H), 0.99 (dd, J=30.6, 6.8Hz, 6H).

[0305] Preparation of Compound IX

[0306]

[0307] Compound VIII (200 mg, 0.177 mmol) was added to tetrahydrofuran (1 mL) / water (1 mL), and lithium hydroxide monohydrate (22 mg, 0.53 mmol) was added, followed by stirring at room temperature for 2 hours. The solution was diluted in a dichloromethane solution, washed with a 1M hydrochloric acid solution, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a carboxylic acid. The concentrated solution was added to dichloromethane (1 mL) / trifluoroacetic acid (1 mL), stirred at room temperature for 30 minutes, and then concentrated under reduced pressure to obtain a trifluoroacetate salt. The concentrated solution was dissolved in DMF (1 mL), and diphenylphosphoryl azide (0.065 mL, 0.265 mmol) and sodium bicarbonate (0.178 g, 2.124 mmol) were added, and stirred at room temperature for 12 hours. After the reaction, Supersolvent (4:1 = dichloromethane:isopropyl alcohol) was added for dilution. The organic layer was then washed three times with water and dehydrated with anhydrous sodium sulfate. The residue after vacuum concentration was separated by column chromatography using a solution of 2-5% methanol: 98-95% dichloromethane to obtain Compound IX (96 mg, 56%) as a yellow solid.

[0308] 1H NMR (400MHz, CDCl3) δ8.77 (s, 1H), 8.39 (d, J=9.6Hz, 1H), 8.22-8.18 (m, 2H), 8.16-8.09 (m, 3H) , 8.01-7.92 (m, 3H), 7.40 (s, 1H), 6.39 (q, J=7.0Hz, 1H), 5.27-5.18 (m, 2H), 4.92 (d, J=7.8Hz, 1H ), 4.67 (s, 1H), 4.47-4.33 (m, 1H), 2.95 (bs, 1H), 2.48 (dq, J=13.4, 6.6Hz, 1H), 2.22 (bs, 1H), 1. 81 (d, J=7.0Hz, 3H), 1.57 (d, J=5.2Hz, 3H), 1.17 (dd, J=20.9, 6.6Hz, 6H), 0.95 (d, J=6.6Hz, 3H).

[0309] Preparation of Compound X

[0310]

[0311] Compound IX (41 mg, 0.043 mmol) was dissolved in 1,4-dichlorobenzene. After adding oxane (0.6 mL), bis(pinacolato)diboron (14.2 mg, 0.056 mmol), potassium acetate (6.7 mg, 0.065 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (3.1 mg, 15 mol%) were added. After the addition was completed, nitrogen was added for 1 minute, and tris(dibenzylideneacetone)dipalladium (0) (4 mg, 10 mol%) was added dropwise. After stirring at 85°C for 3 hours, the mixture was diluted with dichloromethane and then extracted with an organic solvent. The extracted organic solvent was washed with water, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain solid compound X (18 mg, 47%).

[0312] 1H NMR (400MHz, MeOD) δ8.40-8.21 (m, 4H), 8.13 (s, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 6.61 (q, J=6. 9Hz, 1H), 5.23 (dd, J=13.3, 5.7Hz, 2H), 4.75 (d, J=3.1Hz, 1H), 4.62-4.50 (m, 1H), 4.30 (dd, J =6.3, 2.9Hz, 1H), 2.64 (td, J = 13.4, 6.7Hz, 1H), 1.85 (d, J = 7.0Hz, 3H), 1.53 (d, J = 6.4Hz, 3H) , 1.31 (d, J=3.9Hz, 2H), 1.19 (d, J=6.3Hz, 3H), 1.13 (d, J=6.7Hz, 3H), 0.99 (d, J=6.7Hz, 3H).

[0313] Preparation of Compound XI

[0314]

[0315] Compound X (276 mg, 0.3 mmol) was dissolved in a mixture of tetrahydrofuran (6 mL) and water (1.5 mL). After adding compound XIII (131 mg, 0.45 mmol) dropwise, nitrogen was supplied for 3 minutes. Then, potassium carbonate (124 mg, 0.9 mmol) and tetrakis(triphenylphosphine)palladium (10 mol%, 35 mg) were added, and nitrogen was added again for 1 minute. After stirring at 38 ° C for 3 hours, it was concentrated under reduced pressure. The residue was separated by column chromatography using a (0-25% methanol: 100-75% dichloromethane) solution to obtain compound XI (179 mg, 55%) as a white solid.

[0316] 1 H NMR (400MHz, MeOD) δ8.49-8.38 (m, 5H), 8.34-8.22 (m, 5H), 8.14 (s, 1H), 7.9 5(s, 1H), 6.65-6.62(m, 1H), 5.31-5.12(m, 2H), 4.81-4.75(m, 1H), 4.62-4.5 6 (m, 1H), 4.38-4.25 (m, 1H), 2.72-2.61 (m, 1H), 1.86 (d, J=7.0Hz, 3H), 1.68- 1.59 (m, 2H) 1.53 (d, J=6.4Hz, 3H), 1.25-1.02 (m, 8H), 1.00 (d, J=6.6Hz, 3H).

[0317] [Production Example 2] Production of Compound XVII

[0318]

[0319] Preparation of Compound XII

[0320]

[0321] 2-Bromo-thiazole-4-carboxylic acid (832 mg, 4 mmol) was dissolved in dichloromethane (20 mL), and ethyl 1-aminocyclopropanecarboxylate (726 mg, 4.4 mmol) and N,N-diisopropylethylamine (1.74 mL, 10 mmol) were added dropwise. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (840 mg, 4.4 mmol) and hydroxybenzotriazole (594 mg, 4.4 mmol) were then added, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched with water and extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was separated by column chromatography using a solution of 20-50% ethyl acetate: 80-50% hexane to obtain Compound XII (1.04 g, 82%) as an oil.

[0322] 1 H NMR (400MHz, CDCl3) δ 8.10 (s, 1H), 7.68 (s, 1H), 4.17 (q, J=7.1Hz, 2H), 1.67 (q, J=4.8Hz, 2H), 1.32-1.21 (m, 5H).

[0323] Preparation of Compound XIII

[0324]

[0325] Compound XII (1.048 g, 3.26 mmol) was dissolved in tetrahydrofuran / water (1:1, 30 mL), and lithium hydroxide monohydrate (342 mg, 8.15 mmol) was added and stirred for 2 hours. The reaction was quenched with 1 M hydrochloric acid at 0°C and extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Compound XIII (940 mg, 98%) as an oil.

[0326] 1 H NMR (400MHz, CDCl3) δ8.13 (s, 1H), 7.71 (s, 1H), 1.79-1.71 (m, 2H), 1.41-1.33 (m, 2H).

[0327] Preparation of Compound XV

[0328]

[0329] Compound XIII (231 mg, 0.8 mmol) was dissolved in dimethylformamide (4 mL), and compound XIV (209 mg, 0.909 mmol) and N,N-diisopropylethylamine (0.56 mL, 3.2 mmol) were added dropwise. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (174 mg, 0.91 mmol) and hydroxybenzotriazole (123 mg, 0.91 mmol) were then added, and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure, and the resulting residue was separated by column chromatography using a solution of 3-5% methanol:97-95% dichloromethane to obtain compound XV (337 mg, 84%) as a white solid.

[0330] 1 H NMR (400MHz, CDCl3) δ8.12 (s, 1H), 7.70 (s, 1H), 7.06 (s, 1H), 3.35 (dd, J=11.1, 5.3Hz, 2H), 3.26-3.17 (m, 4H ), 2.49 (t, J=5.9Hz, 2H), 2.41-2.28 (m, 4H), 1.71-1.65 (m, 2H), 1.47 (d, J=1.1Hz, 9H), 1.16 (q, J=4.6Hz, 2H).

[0331] Preparation of Compound XVI

[0332]

[0333] Compound XV (330 mg, 0.66 mmol) was dissolved in a mixed solution of trifluoroacetic acid (3 mL) and dichloromethane (3 mL), stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain Compound XVI (124 mg, 47%) as a white solid.

[0334] 1 H NMR (400MHz, CDCl3) δ 8.23-8.14 (m, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 3.92-3.64 (m, 10H), 3.48-3.39 (m, 2H), 1.79-1.67 (m, 2H), 1.13-1.04 (m, 2H).

[0335] Preparation of Compound XVII

[0336]

[0337] Compound XVI (157 mg, 0.391 mmol) was dissolved in ethanol (1 mL), followed by the addition of potassium carbonate (27 mg, 0.196 mmol) and R-glycidol (33 uL, 0.469 mmol). The mixture was stirred at 70°C for 12 hours and then concentrated under reduced pressure. The concentrate was then purified by column chromatography using a (10% methanol:90% dichloromethane) solution to afford Compound XVII (37 mg, 21%).

[0338] 1 H NMR (400MHz, MeOD) δ8,27 (s, 1H), 3.79 (dq, J=10.5, 5.2Hz, 1H), 3.58-3.46 (m, 2H), 3.35-3.3 0 (m, 4H), 2.66-2.43 (m, 8H), 2.45-2.33 (m, 2H), 1.55 (q, J=4.6Hz, 2H), 1.17 (q, J=4.6Hz, 2H).

[0339] [Example 1] Preparation of Compound 2

[0340]

[0341] Compound XI (11 mg, 0.01 mmol) prepared in Preparation Example 1 was dissolved in DMF (0.1 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (3 mg, 0.015 mmol), hydroxybenzotriazole (2 mg, 0.015 mmol), N,N-diisopropylethylamine (3 μL, 0.015 mmol), and 4-(2-aminoethyl)morpholine (0.25 μL, 0.0015 mmol) were added and stirred at room temperature for 12 hours. The product was analyzed by high performance liquid chromatography (GX-281 HPLC system, Gilson, USA; column: 250 mm × 21.2 mm core-shell technology column (on Kinetex) with 5 μM biphenyl) using 0-40% acetonitrile / 100-60% water as the eluent. ) The residue thus obtained was separated to give Compound 2 (1.9 mg, 16%) as a white solid.

[0342] 1H NMR (400MHz, MeOD) δ8.43 (s, 1H), 8.42 (d, J = 2.2Hz, 2H), 8.38 (s, 1H), 8.30 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 6.62 (q, J=6.9Hz, 1H), 5.25-5.19 (m, 2H), 4.77 (d, J=3.1Hz, 1H), 4.62-4.52 (m, 1H), 4.36-4.26 (m, 1H), 4. 15-4.06 (broad peak, 3H), 3.89-3.71 (broad peak, 3H), 3.69-3.58 (m, 5H), 2.71-2.55 (m, 1H), 1.86 (d, J = 7.0 Hz, 3H), 1.71-1.67 (m, 2H), 1.54 (d, J = 6.5 Hz, 3H), 1.49-1.31 (m, 2H) 1.20 (d, J = 6.3 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H).

[0343] LC-MS: C 51 H 54 N 14 O9S6:1199.6(M+H + )

[0344] [Example 2] Preparation of Compound 4

[0345]

[0346] Compound 4 (2.4 mg, 20%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0347] 1H NMR (400MHz, MeOD) δ 8.44 (s, 1H), 8.40 (d, J=1.8Hz, 2H), 8.35 (s, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 6. 62 (q, J=6.9Hz, 1H), 5.29-5.18 (m, 2H), 4.78 (d, J=3.1Hz, 1H), 4.61-4.52 (m, 1H), 4.38-4.29 (m, 1H), 3.45-3.37 (m, 2H), 3.29 -3.10 (broad peak, 4H), 2.99-2.82 (broad peak, 2H), 2.81 (s, 3H), 2.67-2.54 (m, 3H), 2.09-1.99 (m, 2H), 1.86 (d, J = 7.0 Hz, 3H), 1.62 (dd, J = 7.6, 4.4 Hz, 2H), 1.54 (d, J = 6.4 Hz, 3H), 1.29-1.23 (m, 2H), 1.20 (d, J = 6.3 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H).

[0348] LC-MS: C 52 H 57 N 15 O8S6:1212.7(M+H + )

[0349] [Example 3] Preparation of Compound 5

[0350]

[0351] Compound 5 (2.8 mg, 23%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0352] 1H NMR (400MHz, MeOD) δ8.43 (d, J=9.5Hz, 1H), 8.35 (d, J=9.7Hz, 1H), 8.25-8.08 (m, 6H), 8.05 (s, 1H), 8.00 (s , 1H), 7.81 (s, 2H), 7.55-7.40 (m, 1H), 6.54-6.41 (m, 1H), 5.18-5.07 (m, 2H), 4.73-4.68 (m, 2H), 4.53-4.47 (m, 1H), 4.21-4.15 (m, 1H), 3.82 (s, 2H), 3.59-3.48 (m, 2H), 3.42-3.27 (m, 2H), 2.51-2.48 (m, 1H), 2.05-1 .86 (m, 2H), 1.74 (d, J=6.8Hz, 3H), 1.53-1.38 (m, 5H), 1.03 (dd, J=15.2, 6.4Hz, 6H), 0.86 (d, J=6.7Hz, 3H).

[0353] LC-MS: C 50 H 49 N 15 O 10 S6:1212.7(M+H + )

[0354] [Example 4] Preparation of Compound 6

[0355]

[0356] Compound 6 (4.2 mg, 34%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0357] 1H NMR (400MHz, MeOD) δ8.47-8.34 (m, 3H), 8.32 (s, 1H), 8.27 (d, J=8.9Hz, 2H), 8.14 (s, 1H), 7.95 (s, 1H), 7.58 ( d, J=7.1Hz, 1H), 7.52-7.39 (m, 2H), 7.34-7.24 (m, 1H), 6.62 (q, J=7.0Hz, 1H), 5.44-5.07 (m, 4H), 4.61-4.50 ( m, 1H), 4.35-4.27 (m, 1H), 4.13-4.01 (m, 1H), 3.99-3.82 (m, 3H), 2.73-2.57 (m, 1H), 1.86 (d, J=7.0Hz, 3H), 1 .68-1.57 (m, 2H), 1.54 (d, J=6.4Hz, 3H), 1.20 (d, J=6.3Hz, 3H), 1.13 (d, J=6.7Hz, 3H), 1.00 (d, J=6.7Hz, 3H).

[0358] LC-MS: C 53 H 50 BN 13 O 10 S6: 1233.7 (M+H + )

[0359] [Example 5] Preparation of Compound 7

[0360]

[0361] Compound 7 (3.1 mg, 26%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0362] 1H NMR (400MHz, MeOD) δ9.19 (s, 1H), 8.63-8.43 (m, 2H), 8.38-8.31 (m, 4H), 8.30 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.99-7.90 (m, 2H), 6.60 (q, J=6.8Hz, 1H), 5.29-5.16 (m, 2H), 4.79 (dd, J=7.7, 2.9Hz, 1H), 4.60 (dd, J=6.3, 2.9Hz, 1H), 4.29 (dd, J=6.3, 2.7Hz, 1H), 4.17-4.04 (m, 2H), 3.80 (t, J=12.2Hz, 2H), 3.53 (d, J=12.5Hz, 2H), 3.42-3.35 (m, 2H), 3.29-3.10 (m, 6H), 2.61 (dt, J=13.5, 6.7Hz, 1H), 2.02-1.92 (m, 2H), 1.86 (d, J=6.9Hz, 3H), 1.75-1.58 (m, 2H), 1.56 (d, J=6.4Hz, 3H), 1.16 (dd, J=15.0, 6.5Hz, 6H), 0.98 (d, J=6.6Hz, 3H).

[0363] LC-MS: C 52 H 56 N 14 O9S6:1213.8(M+H + )

[0364] [Example 6] Preparation of Compound 9

[0365]

[0366] Compound 9 (3.7 mg, 30%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0367] 1H NMR (400MHz, CDCl3) δ8.69 (s, 1H), 8.37 (d, J = 9.4Hz, 1H), 8.25 (d, J = 8.1Hz, 1H), 8.18 (d, J = 10.6Hz, 2H), 8.15-8.06 (m, 3H), 7.99-7.89 (m, 4H), 7.39-7.35 (m, 1H), 6.38 (q, J=6.9Hz, 1H), 5.26-5.13 (m, 2H), 4.87 (d, J=7.8Hz, 1H), 4.74-4.53 (m, 2H), 4.49-4.29 (m, 1H), 3.89 (s, 2H), 3.59 (t, J=5.9Hz, 2H), 3.30-3.20 (m, 2H), 2.46 (td, J=13.6, 6.7Hz, 1H), 1.84- 1.75 (m, 5H), 1.68-1.64 (m, 2H), 1.27-1.20 (m, 5H), 1.17 (d, J=6.2Hz, 3H), 1.12 (d, J=6.6Hz, 3H), 0.93 (d, J=6.5Hz, 3H).

[0368] LC-MS: C 51 H 51 N 15 O 10 S6:1226.7(M+H + )

[0369] [Example 7] Preparation of Compound 10

[0370]

[0371] Compound 10 (3.2 mg, 28%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0372] 1 H NMR (400MHz, MeOD) δ9.04 (s, 1H), 8.66-8.35 (m, 2H), 8.34-8.16 (m, 6H), 8.18-8.03 (m , 2H), 7.97-7.83 (m, 2H), 6.55 (bs, 1H), 5.26-5.13 (m, 2H), 4.79-4.72 (m, 1H), 4.62-4 .53 (m, 1H), 4.29-4.19 (m, 1H), 2.57 (bs, 1H), 1.82 (broad peak, 3H), 1.71-1.58 (m, 6H), 1.58- 1.47 (m, 6H), 1.11 (dd, J=12.2, 6.4Hz, 6H), 0.94 (d, J=6.6Hz, 3H), 0.80-0.69 (m, 2H).

[0373] [Example 8] Preparation of Compound 11

[0374]

[0375] Compound 11 (4 mg, 33%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0376] 1 H NMR (400MHz, MeOD) δ9.06 (s, 1H), 8.54 (dd, J=24.0, 9.3Hz, 2H), 8.39-8.23 (m, 6H), 8.14 (s, 2H), 7 .98-7.88(m, 3H), 6.61(q, J=7.0Hz, 1H), 5.27-5.19(m, 2H), 4.83-4.77(m, 1H), 4.63-4.58(m, 1H) , 4.51 (t, J=5.1Hz, 2H), 4.33-4.27 (m, 1H), 3.71-3.64 (m, 2H), 2.68-2.54 (m, 4H), 1.86 (d, J=6.9H z, 3H), 1.64-1.47 (m, 5H), 1.25-1.21 (m, 2H), 1.16 (dd, J=13.6, 6.5Hz, 6H), 0.98 (d, J=6.6Hz, 3H).

[0377] LC-MS: C 51 H 50 N 16 O 10 S6:1239.9(M+H + )

[0378] [Example 9] Preparation of Compound 12

[0379]

[0380] Compound 12 (2 mg, 24%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0381] 1H NMR (400MHz, MeOD) δ8.31-8.23 (m, 3H), 8.21 (s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 6.50 (q , J=6.9Hz, 1H), 5.14-5.07(m, 2H), 4.69-4.63(m, 1H), 4.51-4.43(m, 1H), 4.23-4.08(m, 1H), 3.61-3.30(m, 5H), 3 .18-3.09 (m, 6H), 3.02 (t, J=7.2Hz, 2H), 2.51 (td, J=13.5, 6.7Hz, 1H), 1.98-1.78 (m, 2H), 1.74 (d, J=7.0Hz, 3H), 1.61-1.48 (m, 5H), 1.47-1.43 (m, 2H), 1.28 (d, J=6.5Hz, 6H), 1.05 (dd, J=19.4, 6.5Hz, 6H), 0.87 (d, J=6.6Hz, 3H).

[0382] LC-MS: C 55 H 63 N 15 O8S6:1254.7(M+H + )

[0383] [Example 10] Preparation of Compound 13

[0384]

[0385] Compound 13 (5.1 mg, 42%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0386] 1H NMR (400MHz, CDCl3) δ8.45-8.33 (m, 2H), 8.33-8.21 (m, 2H), 8.19 (s, 2H), 8.14-8.09 (m, 4H), 8.03-7.93 (m, 4H), 7.9 0 (s, 1H), 6.94 (s, 1H), 6.42 (q, J=7.0Hz, 1H), 5.28-5.18 (m, 2H), 4.82 (d, J=6.4Hz, 1H), 4.68-4.58 (m, 1H), 4.37 (q, J =7.2Hz, 1H), 4.26 (t, J = 6.5Hz, 2H), 3.39-3.23 (m, 2H), 2.44 (td, J = 13.5, 6.7Hz, 1H), 2.21-2.11 (m, 2H), 1.83 (d, J = 7 .0Hz, 3H), 1.77-1.68 (m, 2H), 1.53 (d, J=6.4Hz, 3H), 1.23-1.15 (m, 5H), 1.12 (d, J=6.7Hz, 3H), 0.95 (d, J=6.6Hz, 3H)

[0387] LC-MS: C 51 H 50 N 16 O 10 S6: 1239.8 (M+H + )

[0388] [Example 11] Preparation of Compound 14

[0389]

[0390] Compound 14 (5.3 mg, 43%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0391] 1H NMR (400MHz, CDCl3) δ8.41 (s, 1H), 8.35-8.27 (m, 2H), 8.25-8.19 (m, 2H), 8.14-8.11 (m, 3H), 8.06-8.01 (m, 2H), 7.96-7.89 (m, 2H), 7.89-7.82 (m, 2H), 6.80 (s, 1H), 6.35 (q, J=7.0Hz, 1H), 5.22-5.13 (m, 2H), 4.75 (d, J=8.2Hz, 1 H), 4.59-4.51 (m, 1H), 4.39-4.27 (m, 3H), 3.37-3.22 (m, 2H), 2.38 (td, J=13.3, 6.4Hz, 1H), 2.19-2.04 (m, 2H), 1 .73-1.62 (m, 2H), 1.47 (d, J=6.4Hz, 3H), 1.21-1.14 (m, 2H), 1.09 (dd, J=25.3, 6.6Hz, 6H), 0.89 (d, J=6.6Hz, 3H).

[0392] LCMS: C 50 H 49 N 17 O 10 S6:1240.6(M+H + )

[0393] [Example 12] Preparation of Compound 15

[0394]

[0395] Compound 15 (4.2 mg, 34%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0396] 1H NMR (400MHz, MeOD) δ8.55 (dd, J=13.0, 9.7Hz, 1H), 8.43-8.36 (m, 2H), 8.33 (s, 1H), 8.27 (d, J=2.4Hz, 1H), 8.14 (s, 1H ), 7.97-7.94(m, 1H), 6.62(q, J=6.9Hz, 1H), 5.26-5.18(m, 2H), 4.80-4.76(m, 1H), 4.65-4.52(m, 1H), 4.35-4.28(m, 1H), 3.15 (t, J=7.4Hz, 2H), 2.63 (td, J=15.3, 6.7Hz, 1H), 2.13-1.88 (m, 2H), 1.86 (d, J=7.0Hz, 3H), 1.68-1.59 (m, 2H ), 1.55 (d, J=6.4Hz, 3H), 1.17 (dd, J=21.7, 6.5Hz, 6H), 0.99 (d, J=6.6Hz, 3H), 0.64-0.54 (m, 2H), 0.54-0.43 (m, 2H).

[0397] LC-MS: C 55 H 61 N 15 O8S6:1252.7(M+H + )

[0398] [Example 13] Preparation of Compound 17

[0399]

[0400] Compound 17 (3.2 mg, 27%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0401] 1H NMR (400MHz, MeOD) δ8.42 (dd, J=13.6, 9.7Hz, 1H), 8.31-8.21 (m, 3H), 8.20 (s, 1H), 8.14 (d, J=3.3Hz, 2H), 8.02 (s, 1H), 7.83 (s, 1H) , 7.61-7.41 (m, 1H), 6.49 (q, J=6.9Hz, 1H), 5.17-5.09 (m, 2H), 4.83 (t, J=7.5Hz, 2H), 4.69-4.60 (m, 3H), 4.51-4.43 (m, 1H), 4.35-4 .29 (m, 1H), 4.23-4.16 (m, 1H), 3.32-3.24 (m, 2H), 2.90 (t, J=7.1Hz, 2H), 2.51 (td, J=21.8, 6.7Hz, 1H), 1.97-1.75 (m, 2H), 1.74 (d, J=7.0Hz, 3H), 1.56-1.48 (m, 2H), 1.43 (d, J=6.4Hz, 3H), 1.16 (d, J=3.2Hz, 2H), 1.05 (dd, J=21.2, 6.5Hz, 6H), 0.87 (d, J=6.7Hz, 3H).

[0402] LCMS: C 51 H 54 N 14 O9S6:1199.6(M+H + )

[0403] [Example 14] Preparation of Compound 18

[0404]

[0405] Compound 18 (3.4 mg, 28%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0406] 1H NMR (400MHz, CDCl3) δ8.37-8.20 (m, 4H), 8.21-8.06 (m, 2H), 8.06-7.95 (m, 4H), 7.95-7.75 (m, 4H), 6.33 (q, J=7.0Hz, 1 H), 5.24-5.11 (m, 2H), 4.74 (dd, J=8.0, 1.7Hz, 1H), 4.58-4.52 (m, 1H), 4.34-4.26 (m, 1H), 3.88-3.79 (broad peak, 2H), 3.38-3. 21 (m, 4H), 3.13 (t, J = 7.0 Hz, 2H), 3.00-2.82 (broad peak, 2H), 2.69-2.61 (broad peak, 2H), 2.38 (td, J = 21.8, 6.9 Hz, 1H), 1.76 (d, J = 7.0 Hz, 3H), 1.67-1.59 (m, 2H), 1.46 (d, J = 6.5 Hz, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.06 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H).

[0407] LCMS: C 52 H 56 N 14 O8S7:1229.7(M+H + )

[0408] [Example 15] Preparation of Compound 20

[0409]

[0410] Compound 20 (3.1 mg, 26%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0411] 1H NMR (400MHz, CDCl3) δ8.43 (d, J=9.6Hz, 1H), 8.36-8.32 (m, 2H), 8.32-8.27 (m, 2H), 8.26 (s, 2H), 8.23-8.18 (m, 2H), 8.16-8. 11 (m, 1H), 8.06-7.93 (m, 3H), 6.76-6.68 (m, 1H), 6.44 (q, J=7.0Hz, 1H), 5.31-5.21 (m, 2H), 4.84 (d, J=8.2Hz, 1H), 4.71-4.62 (m, 1H), 4.43-4.36 (m, 1H), 3.40-3.23 (m, 2H), 2.56-2.42 (m, 1H), 1.88 (d, J=7.0Hz, 3H), 1.78-1.71 (m, 2H), 1.59-1.50 (m, 5H ), 1.48-1.40 (m, 3H), 1.31-1.26 (m, 3H), 1.16 (d, J=6.7Hz, 3H), 0.99 (d, J=6.6Hz, 3H), 0.94-0.82 (m, 2H), 0.83-0.76 (m, 2H).

[0412] LC-MS: C 49 H 52 BN 13 O 10 S6:1208.6(M+Na + )

[0413] [Example 16] Preparation of Compound 21

[0414]

[0415] Compound 21 (3.3 mg, 28%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0416] 1H NMR (400MHz, CDCl3) δ8.44 (d, J=9.6Hz, 1H), 8.38-8.32 (m, 2H), 8.31-8.28 (m, 2H), 8.27 (s, 1H), 8.24-8.17 (m, 2H), 8.17-8.11 (m, 2H ), 8.10-7.93 (m, 3H), 6.84-6.69 (m, 1H), 6.45 (q, J=7.0Hz, 1H), 5.30-5.18 (m, 2H), 4.87-4.83 (m, 1H), 4.70-4.62 (m, 1H), 4.44-4.37 (m, 1H), 3.41-3.24 (m, 2H), 2.49 (td, J=15.4, 6.8Hz, 1H), 1.86 (d, J=7.0Hz, 3H), 1.76-1.70 (m, 2H), 1.57 (d, J=6.5Hz, 3H), 1.56-1.4 8 (m, 2H), 1.48-1.38 (m, 3H), 1.34-1.27 (m, 2H), 1.16 (d, J=6.7Hz, 3H), 0.99 (d, J=6.6Hz, 3H), 0.89-0.81 (m, 2H), 0.81-0.69 (m, 2H).

[0417] LC-MS: C 50 H 54 BN 13 O 10 S6:1199.5(M+H + )

[0418] [Example 17] Preparation of Compound 22

[0419]

[0420] Compound 22 (3.3 mg, 26%) was obtained as a white solid from Compound XI by the same method as in Example 1.

[0421] 1H NMR (400MHz, MeOD) δ9.13 (s, 1H), 8.25 (s, 3H), 8.20 (s, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.82 (s, 1H), 6.53-6.45 (m, 1H), 5.16-5.04 (m, 2H), 4.66 (d, J=3.1Hz, 1H), 4.53-4.42 (m, 1H), 4.21-4 .16 (m, 1H), 3.85 (t, J=6.9Hz, 2H), 2.51 (td, J=13.6, 6.8Hz, 1H), 1.97-1.79 (m, 4H), 1.74 (d, J=7.0Hz , 3H), 1.54-1.47 (m, 2H), 1.43 (d, J=6.4Hz, 3H), 1.04 (dd, J=20.7, 6.5Hz, 6H), 0.87 (d, J=6.7Hz, 3H).

[0422] LC-MS: C 52 H 50 N 16 O 12 S6: 1283.8 (M+H + )

[0423] [Example 18] Preparation of Compound 25

[0424]

[0425] After dissolving compound XI (11 mg, 0.01 mmol) prepared in the above-mentioned Preparation Example 1 in DMF (0.1 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3 mg, 0.015 mmol), hydroxybenzotriazole (2 mg, 0.015 mmol), N,N-diisopropylethylamine (3 uL, 0.015 mmol), and tert-butyl-(2-aminoethyl)carbamate (3.4 mg, 0.0015 mmol) were added, and the mixture was stirred at room temperature for 12 hours, and then concentrated under reduced pressure to obtain the intermediate compound. Dichloromethane (0.1 mL) / trifluoroacetic acid (0.1 mL) was added to the intermediate compound, and the mixture was stirred at room temperature for 30 minutes. (0-40% acetonitrile / 100-60% water) was used as the eluent, and the product was analyzed by high performance liquid chromatography (GX-281 HPLC system, Gilson, USA; column (column tube) 250 mm × 21.2 mm core-shell technology column (on Kinetex) 5 μM biphenyl, ) The residue thus obtained was separated to give Compound 25 (1.5 mg, 13%).

[0426] 1 H NMR (400MHz, MeOD) δ8.47-8.37 (m, 1H), 8.31-8.25 (m, 4H), 8.25-8.22 (m, 2H), 8.14 (s, 1H), 8.02 (s, 1H), 7.8 3 (s, 1H), 6.50 (q, J=6.9Hz, 1H), 5.15-5.03 (m, 2H), 4.66 (d, J=3.1Hz, 1H), 4.49-4.42 (m, 1H), 4.23-4.14 (m, 1H), 3.40 (t, J=5.5Hz, 2H), 2.95 (t, J=5.5Hz, 2H), 2.51 (td, J=21.9, 6.8Hz, 1H), 2.08-1.90 (m, 2H), 1.74 (d, J=7.0Hz, 3H), 1.57-1.51 (m, 2H), 1.43 (d, J=6.4Hz, 3H), 1.05 (dd, J=21.7, 6.5Hz, 6H), 0.87 (d, J=6.6Hz, 3H).

[0427] LC-MS: C 47 H 48 N 14 O8S6:1129.8(M+H + )

[0428] [Example 19] Preparation of Compound 27

[0429]

[0430] By the same method as in Example 1, a white solid compound 27 (1.1 mg, 9%) was obtained from compound XI.

[0431] 1H NMR (400 MHz, MeOD) δ 8.23 ​​(s, 3H), 8.15 (d, J = 5.0 Hz, 2H), 8.10 (s, 1H), 8.01 (s, 1H), 7.93-7.86 (broad peak, 1H), 7.83 (s, 1H), 6.53-6.42 (m, 1H), 5.16-5.07 (m, 2H), 4.66 (d, J = 3.0 Hz, 1H), 4.55-4.32 (m, 1H), 4.28-4. 08 (m, 1H), 3.14-3.04 (m, 2H), 2.57-2.43 (m, 1H), 2.00-1.87 (m, 4H), 1.79-1.59 (m, 5H), 1.43 (d, J=6.4 Hz, 3H), 1.04 (dd, J=19.7, 6.5Hz, 6H), 0.87 (d, J=6.7Hz, 3H), 0.85-0.71 (m, 4H), 0.64 (t, J=5.4Hz, 2H).

[0432] [Example 20] Preparation of Compound 33

[0433]

[0434] By the same method as in Example 1, a white solid compound 33 (1.1 mg, 9%) was obtained from compound XI.

[0435] 1H NMR (400MHz, MeOD) δ9.27 (s, 1H), 8.55 (dd, J=12.2, 9.7Hz, 2H), 8.39 (dt, J=22.2, 6.8Hz, 4H), 8.28 (d, J=10.0Hz, 2H), 8.14 (s, 1H), 8.05-7.83 (m , 2H), 6.62 (q, J=6.9Hz, 1H), 5.36-5.12 (m, 2H), 4.78 (dd, J=7.7, 3.0Hz, 1H), 4.59 (dd, J=6.3, 3.0Hz, 1H), 4.31 (dd, J=6.4, 2.9Hz, 1H), 3.59-3.56 (m, 3H), 3.21-3.16 (m, 3H), 3.09-2.89 (m, 3H), 2.63 (td, J=15.5, 6.8Hz, 1H), 2.02-1.95(m, 1H), 1.86(d, J=7.0Hz, 3H), 1.68-1.65(m, 2H), 1.55(d , J=6.5Hz, 3H), 1.36-1.25 (m, 2H), 1.20 (d, J=6.3Hz, 3H), 1.14 (d, J=6.7 Hz, 3H), 0.99 (d, J=6.6Hz, 3H), 0.71-0.59 (m, 2H), 0.55 (d, J=3.0Hz, 2H).

[0436] LCMS: C 54 H 59 N 15 O8S6:1238.8(M+H + )

[0437] [Example 21] Preparation of Compound 35

[0438]

[0439] By the same method as in Example 1, a white solid compound 35 (2.2 mg, 18%) was obtained from compound XI.

[0440] 1H NMR (400MHz, MeOD) δ9.19 (s, 1H), 8.55 (dd, J=16.5, 9.6Hz, 2H), 8.39 (d, J=6.8Hz, 3H), 8.34 (s, 1H), 8.26 (d, J=2.8Hz, 2H), 8.14 (s, 1H), 7.95 (t, J=3.8Hz, 2H), 6.62 (q, J=6.9Hz, 1H), 5.33-5.14 (m, 2H), 4.79 (dd, J=7.7, 3.0Hz, 1H), 4.59 (dd, J=6.4, 3.1Hz, 1 H), 4.31 (dd, J=6.4, 2.8Hz, 1H), 3.58-3.37 (m, 4H), 2.79 (t, J=6.1Hz, 3H), 2.65-2.58 (m, 1H), 1.86 (d, J=7.0Hz, 3H), 1.62 (dd, J =7.3, 3.8Hz, 2H), 1.56 (d, J = 6.4Hz, 3H), 1.36-1.21 (m, 8H), 1.19 (d, J = 6.3Hz, 3H), 1.14 (d, J = 6.7Hz, 3H), 0.99 (d, J = 6.6Hz, 3H).

[0441] LCMS: C 54 H 61 N 15 O8S6:1240.9(M+H + )

[0442] [Example 22] Preparation of Compound 36

[0443]

[0444] By the same method as in Example 1, a white solid compound 36 (2.6 mg, 21%) was obtained from compound XI.

[0445] 1H NMR (400MHz, MeOD) δ8.99 (s, 1H), 8.53 (dd, J=23.1, 9.6Hz, 2H), 8.41-8.29 (m, 3H), 8.27 (d, J=2.3Hz, 2H), 8.22 (s, 1H) , 8.13 (s, 1H), 7.94 (s, 2H), 6.66-6.55 (m, 1H), 5.29-5.21 (m, 2H), 4.80 (dd, J=7.7, 2.8Hz, 1H), 4.60 (dd, J=6.4, 3.0Hz , 1H), 4.30 (dd, J=6.3, 2.8Hz, 1H), 4.07 (s, 2H), 3.78-3.72 (m, 2H), 3.54-3.42 (m, 2H), 2.69-2.54 (m, 1H), 1.86 (d, J=6 .9Hz, 3H), 1.61-1.52 (m, 5H), 1.23-1.21 (m, 2H), 1.18 (d, J=6.3Hz, 3H), 1.13 (d, J=6.7Hz, 3H), 0.99 (d, J=6.7Hz, 3H).

[0446] LCMS: C 50 H 48 N 14 O 10 S7: 1229.8 (M+H + )

[0447] [Example 23] Preparation of Compound 37

[0448]

[0449] By the same method as in Example 1, a white solid compound 37 (2.8 mg, 23%) was obtained from compound XI.

[0450] 1H NMR (400MHz, MeOD) δ9.22 (s, 1H), 8.54 (dd, J=23.1, 9.7Hz, 2H), 8.33 (d, J=7.3Hz, 3H), 8.27 (d, J=1.9Hz, 2H), 8.22 (s, 1H), 8.14 (s, 1 H), 7.94 (d, J=8.1Hz, 2H), 6.66-6.54 (m, 1H), 5.22 (t, J=9.5Hz, 2H), 4.87 (dd, J=6.7, 4.2Hz, 1H), 4.83-4.75 (m, 1H), 4.60 (dd, J=6.5, 2.9Hz, 1H), 4.32-4.26 (m, 1H), 4.09 (td, J=13.6, 6.3Hz, 2H), 3.58-3.45 (m, 2H), 2.65-2.61 (m, 1H), 1.94-1.82 (m, 3H), 1.81-1.72 (m , 2H), 1.58 (s, 3H), 1.51-1.41 (m, 2H), 1.37 (d, J=6.1Hz, 3H), 1.34-1.28 (m, 2H), 1.16 (dd, J=15.0, 6.5Hz, 6H), 0.99 (d, J=6.6Hz, 3H).

[0451] LCMS: C 52 H 53 N 15 O 10 S6:1240.8(M+H + )

[0452] [Example 24] Preparation of Compound 28

[0453]

[0454] Compound X (41 mg, 0.044 mmol) prepared in Preparation Example 1 and Compound XVII (19 mg, 0.04 mmol) prepared in Preparation Example 2 were dissolved in tetrahydrofuran / water (4:1, 1 mL), potassium carbonate (17 mg, 0.12 mmol) was added, and after argon was injected for 1 minute, tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 10 mol%) was added, and the mixture was reacted at 60°C for 12 hours. After cooling to room temperature, the mixture was diluted with chloroform / isopropanol (4:1, 10 mL), washed with water, and analyzed by high performance liquid chromatography (GX-281 HPLC system, Gilson, USA; column (column tube) 250 mm × 21.2 mm core-shell technology column (on Kinetex) 5 μM biphenyl, ) The residue thus obtained was separated to give Compound 28 (20 mg, 39%) as a white solid.

[0455] 1 H NMR (400MHz, MeOD) δ9.17 (s, 1H), 8.53 (dd, J=20.4, 9.7Hz, 2H), 8.36-8.31 (m, 4H), 8.2 7 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.98-7.90 (m, 2H), 6.60 (q, J=6.9Hz, 1H), 5.25-5.2 0 (m, 2H), 4.80 (dd, J=7.7, 2.9Hz, 1H), 4.60 (dd, J=6.4, 3.0Hz, 1H), 4.29 (dd, J=6.3, 2. 8Hz, 1H), 4.02 (dd, J=9.4, 4.2Hz, 1H), 3.65-3.50 (m, 4H), 3.47-3.43 (m, 4H), peaks hidden (peaks 3H), 1.56 (d, J = 6.4 Hz, 3H), 1.34-1.24 (m, 2H), 1.16 (dd, J = 15.3, 6.5 Hz, 6H), 0.99 (d, J = 6.6 Hz, 3H).

[0456] LC-MS: C 54 H 61 N 15 O 10 S6: 1272.7 (M+H + )

[0457] [Example 25] Preparation of Compound 1

[0458]

[0459] Compound 1 (19 mg, 40%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0460] 1H NMR (400MHz, CDCl3) δ9.23 (s, 1H), 8.42 (dd, J=16.4, 6.5Hz, 2H), 8.34-8.17 (m, 3H), 8.17-8.05 (m, 3H), 7.98 (dd, J=24.0, 6 .7Hz, 3H), 6.92-6.76 (m, J=6.6Hz, 1H), 6.43 (q, J=7.0Hz, 1H), 5.32-5.18 (m, 2H), 4.85 (d, J=7.8Hz, 1H), 4.64 (d, J=5.4Hz, 3H). Note: methyl peak hidden in water peak.

[0461] LCMS: C 51 H 54 N 14 O9S6:1201.3(M+H + )

[0462] [Example 26] Preparation of Compound 3

[0463]

[0464] Compound 3 (21 mg, 42%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0465] 1H NMR (400MHz, CDCl3) δ8.62 (s, 1H), 8.55-8.44 (m, 1H), 8.32-8.16 (m, 4H), 8.17-7.97 (m, 7H), 7. 87 (d, J=7.8Hz, 1H), 6.81 (q, J=7.1Hz, 1H), 6.44 (q, J=7.0Hz, 1H), 5.29-5.22 (m, 2H), 4.78 (d, J= 6.8Hz, 1H), 4.71-4.58 (m, 2H), 4.54-4.45 (m, 1H), 4.42-4.33 (m, 1H), 3.81 (broad peak, 2H), 2.66 (s, 3H) , 1.95-1.81 (m, 6H), 1.52 (d, J=6.3Hz, 3H), 1.19 (dd, J=18.7, 6.5Hz, 6H), 0.98 (d, J=6.6Hz, 3H).

[0466] LC-MS: C 51 H 50 N 16 O 10 S6: 1239.8 (M+H + )

[0467] [Example 27] Preparation of Compound 8

[0468]

[0469] Compound 8 (24 mg, 55%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0470] 1 H NMR (400MHz, MeOD) δ8.49-8.38 (m, 5H), 8.34-8.22 (m, 5H), 8.14 (s, 1H), 7.9 5(s, 1H), 6.65-6.62(m, 1H), 5.31-5.12(m, 2H), 4.81-4.75(m, 1H), 4.62-4.5 6 (m, 1H), 4.38-4.25 (m, 1H), 2.72-2.61 (m, 1H), 1.86 (d, J=7.0Hz, 3H), 1.68- 1.59 (m, 2H) 1.53 (d, J=6.4Hz, 3H), 1.25-1.02 (m, 8H), 1.00 (d, J=6.6Hz, 3H).

[0471] LC-MS: C 45 H 42 N 12 O9S6:1088.8(M+H + )

[0472] [Example 28] Preparation of Compound 16

[0473]

[0474] Compound 16 (12 mg, 23%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0475] 1 H NMR (400MHz, MeOD) δ8.60-8.39 (m, 1H), 8.37-8.22 (m, 4H), 8.19 (s, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 6.66-6.5 4(m, 1H), 5.29-5.18(m, 2H), 4.84-4.78(m, 1H), 4.64-4.58(m, 1H), 4.32-4.24(m, 1H), 3.96(s, 2H), 3.63(s, 3 H), 3.59-3.52 (m, 4H), 3.29-3.23 (m, 2H), 2.68-2.49 (m, 3H), 1.85 (d, J=7.0Hz, 3H), 1.81-1.73 (m, 2H), 1.64 -1.58 (m, 2H), 1.56 (d, J=6.5Hz, 3H), 1.28-1.23 (m, 2H), 1.16 (dd, J=13.3, 6.5Hz, 6H), 0.99 (d, J=6.7Hz, 3H).

[0476] LC-MS: C 55 H 57 N 15 O 12 S6: 1312.8 (M+H + )

[0477] [Example 29] Preparation of Compound 19

[0478]

[0479] Compound 16 (12 mg, 0.01 mmol) prepared in Example 28 was added to tetrahydrofuran (1 mL) / water (1 mL), and lithium hydroxide monohydrate (1 mg, 0.025 mmol) was added, followed by stirring at room temperature for 2 hours. The concentrate was diluted with chloroform / isopropanol (4:1, 10 mL), washed with water, and then analyzed by high-performance liquid chromatography (GX-281 HPLC system, Gilson, USA; column (column tube) 250 mm × 21.2 mm core-shell technology column (on Kinetex) 5 μM biphenyl, using (0-45% acetonitrile / 100-55% water) as the eluent. ) The residue thus obtained was separated to give Compound 19 (4 mg, 31%).

[0480] 1 H NMR (400MHz, MeOD) δ8.42 (dd, J=13.0, 9.8Hz, 1H), 8.29-8.19 (m, 3H), 8.21-8.08 (m, 3H), 8.01 (s, 1H), 7.83 (s, 1 H), 6.49 (q, J=7.0Hz, 1H), 5.16-5.08 (m, 2H), 4.67 (d, J=2.9Hz, 1H), 4.52-4.42 (m, 1H), 4.22-4.13 (m, 1H), 3.86 ( s, 2H), 3.51-3.34 (m, 4H), 3.19-3.08 (m, 2H), 2.56-2.46 (m, 1H), 2.42 (t, J=6.7Hz, 2H), 1.99-1.87 (m, 2H), 1.74 (d, J=6.9Hz, 3H), 1.70-1.60 (m, 2H), 1.43 (d, J=6.4Hz, 3H), 1.04 (dd, J=18.6, 6.5Hz, 6H), 0.87 (d, J=6.6Hz, 3H).

[0481] LC-MS: C 54 H 55 N 15 O 12 S6: 1298.7 (M+H + )

[0482] [Example 30] Preparation of Compound 23

[0483]

[0484] Compound 23 (16.6 mg, 35%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0485] 1 H NMR (400MHz, MeOD) δ8.48-8.30 (m, 1H), 8.26-8.14 (m, 5H), 8.09-7.90 (m, 2H), 7.81 (s, 1H), 6 .49 (q, J=7.0Hz, 1H), 5.16-5.03 (m, 2H), 4.68 (d, J=3.2Hz, 1H), 4.49-4.39 (m, 1H), 4.19-4.1 2 (m, 1H), 4.02 (s, 2H), 2.49 (td, J=13.9, 6.7Hz, 1H), 1.77 (d, J=6.9Hz, 3H), 1.65-1.47 (m, 2H ), 1.44 (d, J=6.4Hz, 3H), 1.06 (d, J=6.3Hz, 3H), 0.97 (d, J=6.5Hz, 3H), 0.86 (d, J=6.7Hz, 3H).

[0486] LC-MS: C 48 H 45 N 15 O 10 S6: 1184.7 (M+H + )

[0487] [Example 31] Preparation of Compound 24

[0488]

[0489] Compound 24 (13.3 mg, 26%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0490] 1H NMR (400MHz, MeOD) δ8.42 (dd, J=13.6, 9.6Hz, 1H), 8.30-8.19 (m, 4H), 8.14 (d, J=7.6Hz, 2H), 8.02 (s, 1H), 7.83 (s, 1H), 7 .58-7.42 (m, 1H), 6.49 (q, J=6.9Hz, 1H), 5.15-5.06 (m, 2H), 4.66 (d, J=3.1Hz, 1H), 4.51-4.41 (m, 1H), 4.22-4.15 (m, 1H) 3H). 3.59 (s, 3H), 3.42 (t, J = 5.7 Hz, 2H), 3.15-3.00 (broad peak, 4H), 2.98-2.80 (broad peak, J = 6.8 Hz, 6H), 2.61-2.45 (m, 3H), 1.74 (d, J = 7.0 Hz, 3H), 1.56-1.47 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H), 1.02 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H). Note: some of cyclopropane peaks are hidden under the grease.

[0491] LC-MS: C 55 H 61 N 15 O 10 S6: 1284.9 (M+H + )

[0492] [Example 32] Preparation of Compound 26

[0493]

[0494] Compound 26 (6 mg, 12%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0495] 1H NMR (400MHz, CDCl3) δ10.54 (bs, 1H), 9.22 (s, 1H), 8.51 (s, 1H), 8.37 (d, J=9.7Hz, 1H), 8.18 (s, 1H), 8.15-7.94 (m, 5 H), 7.89 (d, J = 8.7Hz, 2H), 7.82 (d, J = 7.7Hz, 1H), 7.72 (bs, 1H), 6.48 (q, J = 6.9Hz, 1H), 5.30-5.21 (m, 2H), 5.09 (d, J =6.0Hz, 1H), 4.49-4.45 (m, 2H), 4.42-4.26 (m, 4H), 3.77 (s, 3H), 2.44 (td, J = 15.8, 6.7Hz, 1H), 1.94 (d, J = 6.9Hz, 3H ), 1.77-1.70 (m, 2H), 1.61 (d, J=6.3Hz, 3H), 1.22-1.17 (m, 2H), 1.15 (dd, J=13.4, 6.5Hz, 6H), 0.96 (d, J=6.6Hz, 3H).

[0496] LC-MS: C 51 H 49 N 15 O 12 S6:1257.6(M+H + )

[0497] [Example 33] Preparation of Compound 29

[0498]

[0499] Compound 29 (12 mg, 23%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0500] 1H NMR (400 MHz, MeOD) δ 9.16 (s, 1H), 8.59-8.43 (m, 2H), 8.32-8.22 (m, 5H), 8.13 (s, 2H), 7.98-7.88 (m, 2H), 6.57 (q, J = 6.7 Hz, 1H), 5.25-5.20 (m, 2H), 4.82-4.75 (m, 1H), 4.62-4.60 (m, 1H), 4.29-4.27 (m, 1H), 3.66-3.38 (broad - piperazine peaks and methylene adjacent to the piperazine) piperazine)10H), 3.36 (d, J=2.8Hz, 2H), 2.99 (s, 3H), 2.71-2.49 (m, 1H), 1.86 (d, J=6.9Hz, 3H), 1.65-1 .60 (m, 2H), 1.57 (d, J=6.4Hz, 3H), 1.27-1.20 (m, 2H), 1.16 (dd, J=9.8, 6.6Hz, 6H), 0.99 (t, J=6.6Hz, 3H).

[0501] LC-MS: C 52 H 57 N 15 O 10 S7: 1276.7 (M+H + )

[0502] [Example 34] Preparation of Compound 30

[0503]

[0504] Compound 30 (16.8 mg, 33%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0505] 1H NMR (400MHz, MeOD) δ9.19 (s, 1H), 8.58-8.48 (m, 2H), 8.38-8.24 (m, 5H), 8.13 (d, J=4.7Hz, 2H), 7.99-7.89 (m, 2H), 7. 62-7.42 (m, 2H), 6.58 (q, J=6.9Hz, 1H), 5.25-5.20 (m, 2H), 4.81-4.78 (m, 1H), 4.62-4.59 (m, 1H), 4.30-4.27 (m, 1H), 4 .14-3.90 (broad peak, 5H), 3.66 (bs, 2H), 3.54-3.42 (broad peak, 3.39-3.34 (m, 2H), 2.60 (td, J = 15.2, 6.7 Hz, 1H), 1.86 (d, J = 7.0 Hz, 3H), 1.70-1.63 (m, 2H), 1.57 (d, J = 6.3 Hz, 3H), 1.37-1.22 (m, 2H), 1.16 (dd, J = 11.3, 6.5 Hz, 6H), 0.98 (d, J = 6.6 Hz, 3H).

[0506] [Example 35] Preparation of Compound 31

[0507]

[0508] Compound 31 (11.6 mg, 23%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0509] 1H NMR (400MHz, MeOD) δ9.10 (s, 1H), 8.42 (dd, J=14.4, 9.7Hz, 1H), 8.29-8.21 (m, 3H), 8.15 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.84-7.81 (m, 1H), 7.62-7.50 (m, 3H), 7.50-7.41 (m, 2H), 6.49 (q, J=6.8Hz, 1H), 5.18-5.08 (m, 2H), 4.73-4.65 (m, 1H), 4.52-4.44 (m, 1H), 4.22-4 .18 (m, 1H), 3.49-3.42 (m, 2H), 3.08-3.01 (m, 2H), 2.94-2.71 (broad peak, 3H), 2.63 (t, J=7.0Hz, 2H), 2.53-2.38 (m, 3H), 2.05-1.90 (m, 2H), 1. 85-1.78 (m, 3H), 1.74 (d, J=7.0Hz, 3H), 1.56-1.49 (m, 2H), 1.44 (d, J=6.4Hz, 3H), 1.04 (dd, J=17.9, 6.5Hz, 6H), 0.87 (d, J=6.7Hz, 3H).

[0510] LCMS: C 55 H 60 N 16 O8S6:1265.8(M+H + )

[0511] [Example 36] Preparation of Compound 32

[0512]

[0513] Compound 32 (12 mg, 24%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0514] 1H NMR (400MHz, MeOD) δ9.16 (s, 1H), 8.53 (dd, J=21.9, 9.6Hz, 2H), 8.38-8.29 (m, 4H), 8.27 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.99 -7.89 (m, 2H), 6.60 (q, J=6.8Hz, 1H), 5.25-5.21 (m, 2H), 4.84-4.78 (m, 1H), 4.61 (dd, J=6.4, 3.0Hz, 1H), 4.29 (dd, J=6.3, 2.8Hz, 1H), 3.93-3.83 (m, 2H), 3.59-3.41 (m, 7H), 3.29-3.20 (m, 3H), 3.09 (t, J=5.4Hz, 2H), 2.61 (td, J=13.5, 6.7Hz, 1H), 1.86 (d, J=6 .9Hz, 3H), 1.63 (d, J=3.1Hz, 2H), 1.57 (d, J=6.4Hz, 3H), 1.31-1.29 (m, 2H), 1.16 (dd, J=13.9, 6.5Hz, 6H), 0.99 (d, J=6.6Hz, 3H).

[0515] LCMS: C 53 H 59 N 15 O9S6:1242.8(M+H + )

[0516] [Example 37] Preparation of Compound 34

[0517]

[0518] Compound 34 (6 mg, 12%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0519] 1H NMR (400MHz, MeOD) δ8.55 (dd, J=13.5, 9.6Hz, 2H), 8.48-8.31 (m, 5H), 8.27 (s, 2H), 8.14 (s, 1H), 7.98-7.96 (m, 2H) , 6.73-6.52 (m, 2H), 5.35-5.17 (m, 2H), 4.79 (dd, J=7.8, 3.0Hz, 1H), 4.59 (dd, J=6.5, 3.1Hz, 1H), 4.31 (dd, J=6.3, 2.8Hz, 1H), 3.56-3.34 (m, 6H), 3.08 (t, J=6.8Hz, 2H), 2.63 (dd, J=15.4, 6.8Hz, 1H), 2.10-1.92 (m, 2H), 1.87 (dd, J =11.2, 7.0Hz, 6H), 1.55 (d, J=6.4Hz, 3H), 1.39-1.28 (m, 6H), 1.17 (dd, J=20.0, 6.5Hz, 6H), 0.99 (d, J=6.6Hz, 3H).

[0520] LCMS: C 55 H 63 N 15 O8S6:1254.9(M+H + )

[0521] [Example 38] Preparation of Compound 38

[0522]

[0523] Compound 38 (21 mg, 17%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0524] 1H NMR (400MHz, CDCl3) δ8.77 (s, 1H), 8.58 (s, 1H), 8.31 (d, J=9.8Hz, 1H), 8.22-8.03 (m, 5H), 8.03-7.85 (m, 5H), 7. 80 (s, 1H), 7.67 (d, J = 8.1Hz, 1H), 6.42 (q, J = 7.0Hz, 1H), 5.31-5.21 (m, 2H), 4.85 (d, J = 8.3Hz, 1H), 4.74-4.59 (m, 1H), 4.54-4.42(m, 3H), 4.32-4.41(m, 1H), 4.01-3.92(m, 1H), 3.82-3.71(m, 1H), 2.64-2.58(m, 1H), 2.55-2.35 (m, 1H), 2.01-1.96 (m, 1H), 1.88 (d, J=44.2Hz, 4H), 1.60-1.53 ​​(m, 3H), 1.23-1.04 (m, 8H), 0.96 (d, J=6.5Hz, 3H).

[0525] LCMS: C 49 H 47 N 17 O 10 S6: 1226.3 (M+H + )

[0526] [Example 39] Preparation of Compound 39

[0527]

[0528] Compound 39 (25 mg, 20%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0529] 1H NMR (400MHz, CDCl3) δ9.25 (s, 1H), 8.84 (s, 1H), 8.20-8.04 (m, 5H), 8.03-7.94 (m, 2H), 7.91 (d, J=8.1Hz, 1H) , 7.80-7.56 (m, 2H), 7.23 (s, 1H), 7.19 (s, 1H), 6.41 (q, J=7.0Hz, 1H), 5.33-5.09 (m, 2H), 5.01-4.91 (m, 1H), 4 .74-4.61(m, 2H), 4.34-4.28(m, 2H), 3.92-3.85(m, 1H), 3.82-3.73(m, 1H), 2.79-2.71(m, 1H), 2.20-1.99(m , 2H), 1.94 (d, J=7.0Hz, 3H), 1.46-1.33 (m, 3H), 1.32-1.22 (m, 2H), 1.22-1.06 (m, 6H), 0.93 (d, J=6.6Hz, 3H).

[0530] LCMS: C 50 H 48 N 16 O 10 S6: 1225.5 (M+H + )

[0531] [Example 40] Preparation of Compound 40

[0532]

[0533] Compound 40 (26 mg, 46%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0534] 1H NMR (400MHz, CDCl3) δ8.84 (s, 1H), 8.58 (s, 1H), 8.40 (d, J=9.7Hz, 1H), 8.31 ( d, J=8.1Hz, 1H), 8.28-8.21 (m, 3H), 8.18 (s, 1H), 8.12 (d, J=7.7Hz, 2H), 8.04- 7.97 (m, 2H), 7.95 (d, J = 7.8Hz, 1H), 7.15 (t, J = 6.2Hz, 1H), 6.70 (q, J = 7.1Hz, 1 H), 6.41 (q, J=7.0Hz, 1H), 5.91 (s, 1H), 5.25 (t, J=9.3Hz, 2H), 4.86 (dd, J=7.9 , 2.1Hz, 1H), 4.63 (d, J=6.6Hz, 1H), 4.49 (d, J=6.2Hz, 1H), 4.40 (d, J=6.3Hz, 1H), 3.98 (s, 2H), 3.65 (t, J=6.2Hz, 2H), 3.35 (dd, J=12.2, 6.2Hz, 2H), 2.98 (d , J=2.4Hz, 1H), 2.49 (td, J=13.5, 6.8Hz, 1H), 1.92-1.79 (m, 6H), 1.56 (d, J=6. 5Hz, 3H), 1.20 (d, J=6.4Hz, 3H), 1.15 (d, J=6.7Hz, 3H), 0.97 (d, J=6.6Hz, 3H).

[0535] LCMS: C 51 H 51 N 15 O 10 S6:1226.6(M+H + )

[0536] [Example 41] Preparation of Compound 41

[0537]

[0538] Compound 41 (16 mg, 43%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0539] 1H NMR (400MHz, CDCl3) δ9.32 (s, 1H), 9.03 (d, J=8.7Hz, 1H), 8.31 (s, 1H), 8.26-8.09 (m, 5H), 8.06 (s, 1H), 7.95 (dd, J=19.5, 8.1Hz, 3H), 7.81 (s, 1H), 7.74 (dd, J=23.8, 15.1Hz, 2H), 6.95 (q, J=6.9Hz, 1H), 6.40 (q, J=7.0Hz, 1H), 5.23 (d, J=10.8Hz, 1H), 5.16 (t, J=9.5Hz, 1 H), 4.72-4.59 (m, 2H), 4.51-4.31 (m, 2H), 4.22-4.08 (m, 1H), 4.00-3.83 (m, 1H), 3.53 (dd, J=13.1, 8.5Hz, 1H), 2.76-2.61 (m, 1H), 1.9 2 (d, J=7.0Hz, 3H), 1.86 (d, J=7.2Hz, 3H), 1.35 (d, J=6.4Hz, 3H), 1.17 (d, J=6.6Hz, 3H), 1.11 (d, J=6.4Hz, 3H), 0.91 (d, J=6.6Hz, 3H).

[0540] LCMS: C 51 H 50 N 16 O 10 S6:1239.6(M+H + )

[0541] [Example 42] Preparation of Compound 42

[0542]

[0543] Compound 42 (22 mg, 18%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0544] 1H NMR (400MHz, CDCl3) δ8.65 (d, J=14.2Hz, 2H), 8.58 (s, 1H), 8.38 (d, J=9.8Hz, 1H), 8.26-8.15 (m, 3H), 8.15-8.03 (m, 4H ), 8.07-7.89 (m, 2H), 7.81 (d, J=8.1Hz, 1H), 7.38 (s, 1H), 6.63 (q, J=7.0Hz, 1H), 6.42 (q, J=7.0Hz, 1H), 5.28-5.24 (m, 2 H), 4.84-4.79 (m, 1H), 4.70-4.51 (m, 4H), 4.36-4.41 (m, 1H), 3.98-3.91 (m, 1H), 3.87-3.79 (m, 1H), 2.70 (s, 1H), 2.57 -2.42 (m, 1H), 1.86 (dd, J=7.1, 2.4Hz, 6H), 1.54 (d, J=6.1Hz, 3H), 1.17 (dd, J=12.7, 6.6Hz, 6H), 0.97 (d, J=6.6Hz, 3H).

[0545] LCMS: C 49 H 47 N 17 O 10 S6:1226.6(M+H + )

[0546] [Example 43] Preparation of Compound 43

[0547]

[0548] Compound 43 (23 mg, 19%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0549] 1H NMR (400MHz, CDCl3) δ9.25 (s, 1H), 8.79 (d, J=9.3Hz, 1H), 8.28 (s, 1H), 8.22-7.99 (m, 5H), 7.97 (d, J=6.4Hz, 2H), 7.92 (d, J=8.1H z, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 7.67 (d, J=8.5Hz, 1H), 7.22 (d, J=10.7Hz, 2H), 6.91 (q, J=7.1Hz, 1H), 6.41 (q, J=7.0Hz, 1H), 5.2 8-5.09 (m, 2H), 4.96 (t, J=8.9Hz, 1H), 4.78-4.55 (m, 2H), 4.33-4.18 (m, 2H), 4.05-3.91 (m, 1H), 3.80 (d, J=4.8Hz, 1H), 2.87-2.6 1 (m, 1H), 1.91 (d, J=7.0Hz, 3H), 1.85 (d, J=7.1Hz, 3H), 1.42 (d, J=6.4Hz, 3H), 1.17 (dd, J=6.2, 5.0Hz, 6H), 0.93 (d, J=6.6Hz, 3H).

[0550] LCMS: C 50 H 48 N 16 O 10 S6:1225.6(M+H + )

[0551] [Example 44] Preparation of Compound 44

[0552]

[0553] Compound 44 (6.3 mg, 13%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0554] 1H NMR (400MHz, MeOD) δ9.14 (s, 1H), 8.75 (s, 1H), 8.53 (dd, J=17.1, 9.7Hz, 3H), 8.39-8.31 (m, 4H), 8.29-8.23 (m, 3 H), 8.21 (s, 1H), 8.14 (s, 1H), 7.94 (d, J = 5.3Hz, 1H), 6.62 (d, J = 6.9Hz, 1H), 5.27-5.22 (m, 2H), 5.07-4.97 (m, 1H) , 4.59-4.42 (m, 4H), 4.37-4.28 (m, 1H), 4.00 (s, 2H), 2.72-2.51 (m, 1H), 1.87 (d, J=7.0Hz, 3H), 1.67-1.61 (m, 2H ), 1.55 (d, J=6.5Hz, 3H), 1.34-1.21 (m, 2H), 1.18 (d, J=6.3Hz, 3H), 1.13 (d, J=6.6Hz, 3H), 0.99 (d, J=6.7Hz, 3H).

[0555] LCMS: C 50 H 48 N 16 O 10 S6:1225.9(M+H + )

[0556] [Example 45] Preparation of Compound 45

[0557]

[0558] Compound 45 (10 mg, 16%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0559] 1H NMR (400MHz, DMSO) δ9.54 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 8.45 (d, J = 8.2Hz, 1H), 8.41-8.32 (m, 4H), 8.31 (d, J =4.3Hz, 1H), 8.23 ​​(d, J = 13.1Hz, 3H), 8.19-8.14 (m, 1H), 8.09 (s, 1H), 7.85 (d, J = 7.9Hz, 1H), 6.48 (q, J = 6.8Hz, 1 H), 5.44(d, J=6.1Hz, 1H), 5.22-4.97(m, 2H), 4.89-4.57(m, 2H), 4.42-4.35(m, 1H), 4.22-3.95(m, 3H), 2.09(s, 3H), 1.76 (d, J=6.9Hz, 3H), 1.45-1.36 (m, 5H), 1.11-1.01 (m, 5H), 0.98 (d, J=6.5Hz, 3H), 0.87 (d, J=6.6Hz, 3H).

[0560] LCMS: C 51 H 50 N 16 O 10 S6:1239.6(M+H + )

[0561] [Example 46] Preparation of Compound 46

[0562]

[0563] Compound 46 (12 mg, 10%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0564] 1 H NMR (400MHz, MeOD) δ8.31-8.21 (m, 5H), 8.13 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 6.67 (q, J= 6.9Hz, 1H), 6.55 (d, J=6.2Hz, 1H), 5.22 (d, J=8.3Hz, 2H), 4.66-4.57 (m, 3H), 4.28 (dd, J=6. 2, 2.5Hz, 1H), 3.47-3.42 (m, 2H), 2.91-2.69 (broad peak, 7H), 2.67-2.59 (m, 3H), 2.56 (s, 3H), 1.9 2-1.72 (m, 6H), 1.57 (d, J=6.3Hz, 3H), 1.16 (dd, J=10.7, 6.2Hz, 6H), 0.98 (d, J=6.5Hz, 3H).

[0565] LCMS: C 52 H 57 N 15 O8S6:1212.6(M+H + )

[0566] [Example 47] Preparation of Compound 47

[0567]

[0568] Compound 47 (15 mg, 11%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0569] 1 H NMR (400MHz, MeOD) δ8.17 (d, J=7.6Hz, 4H), 8.11 (d, J=8.1Hz, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 6.57 (q, J=7.0Hz, 1H ), 6.42 (d, J=6.5Hz, 1H), 5.19-4.98 (m, 2H), 4.16 (dd, J=6.3, 2.7Hz, 1H), 3.36-3.28 (m, 2H), 2.94-2.82 (m, 1H), 2.77 (broadband) band), 3H), 2.59 (broad band, 2H), 2.55-2.36 (m, 4H), 1.71 (dd, J = 10.3, 7.2 Hz, 6H), 1.45 (d, J = 6.4 Hz, 3H), 1.11-0.95 (m, 12H), 0.86 (d, J = 6.6 Hz, 3H).

[0570] LCMS: C 54 H 61 N 15 O8S6:1240.8(M+H + )

[0571] [Example 48] Preparation of Compound 48

[0572]

[0573] Compound 48 (12 mg, 10%) was obtained from Compound X as a white solid by the same method as in Example 24.

[0574] 1H NMR (600MHz, CDCl3) δ8.81 (s, 1H), 8.60 (s, 1H), 8.39 (d, J = 9.3Hz, 1H), 8.33 (d, J = 7.9Hz, 1H), 8.27-8.16 (m, 4H), 8.12 (d, J = 8.7Hz , 2H), 8.06-7.85 (m, 3H), 7.49 (s, 1H), 6.60 (dd, J=13.9, 7.0Hz, 1H), 6.43 (d, J=6.9Hz, 1H), 5.26 (d, J=8.3Hz, 2H), 4.87 (d, J=7.1H z, 1H), 4.76 (s, 1H), 4.65 (d, J=4.8Hz, 1H), 4.52 (s, 1H), 4.40 (d, J=5.6Hz, 1H), 3.69 (s, 4H), 3.48 (d, J=5.1Hz, 2H), 2.99 (s, 1H), 2 .52 (d, J=14.9Hz, 6H), 1.97-1.67 (m, 6H), 1.36-1.24 (m, 3H), 1.21 (d, J=5.7Hz, 3H), 1.16 (d, J=6.3Hz, 3H), 0.98 (d, J=6.2Hz, 3H).

[0575] LCMS: C 52 H 56 N 14 O9S6:1213.3(M+H + )

[0576] [Experimental Example 1] Antibacterial activity test

[0577] The antibacterial activity of the compounds produced in Examples 1 to 48 of the present invention was measured.

[0578] 1) Antibacterial activity test against aerobic pathogens

[0579] The antimicrobial activity of the compounds of Examples 1 to 48 of the present invention against aerobic pathogens was evaluated by determining the minimum antibiotic concentration that inhibited bacterial growth by 90%, compared to the growth of a control group treated with no drug. MICs were determined using the broth microdilution method based on CLSI standards [Reference: Clinical and Laboratory Standards Institute Document. (2000) Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically - Fifth Edition: M7-A5. CLSI, Villanova, PA].

[0580] Test strains

[0581] A total of 13 strains, including methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), Staphylococcus epidermidis, methicillin-resistant Staphylococcus epidermidis, Enterococcus faecalis, vancomycin-resistant Enterococcus faecalis, Enterococcus faecium, and vancomycin-resistant Enterococcus faecium, were used, and the results are shown in Tables 1 to 6.

[0582] 2) Antibacterial activity test against Clostridioides difficile

[0583] The inhibitory activity of C. difficile was determined using strains sold by the Korean Antimicrobial Resistance Library or the American Type Culture Collection (ATCC). MICs were evaluated using the agar dilution method according to the CLSI guidelines of the Clinical and Laboratory Standards Institute (CLSI) [Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard—Seventh Edition, CLSI document M11-A7, 2007]. Liquid culture of C. difficile used BHIS medium, and the agar medium used supplemented Brucella agar. All compounds tested were prepared on agar medium at concentrations ranging from 8 μg / ml to 0.06 μg / ml. One day before the C. difficile strain was cultured in liquid, the BHIS medium was placed in an anaerobic chamber to remove oxygen from the broth for one day. The day before the experiment, the bacteria were cultured in 4 ml of BHIS medium. The cultured bacteria were diluted to a concentration of approximately 4 to 5 × 10 7 The diluted bacterial solution was diluted using BHIS medium in the form of CFU / ml. 10 μl of the diluted bacterial solution was dropped onto a medium containing antibiotics, and the culture was incubated in an anaerobic chamber for at least 18 hours. The results were observed and are shown in Tables 1 to 6.

[0584] 3) Mycobacterial antibacterial activity test

[0585] To test the antibacterial activity of mycobacterial cultures in late log phase, a 4.0×10 5The compound was diluted at a cell / well ratio and dispensed into a 96-well plate. The compound was treated with 1% DMSO. Three days later, a 0.025% resazurin (REMA) solution was dispensed. After incubation, bacterial growth was confirmed. The antibacterial activity was determined using the resazurin MIC (excitation wavelength 530 nm, emission wavelength 590 nm).

[0586] [Table 1]

[0587]

[0588] [Table 2]

[0589]

[0590] [Table 3]

[0591]

[0592] [Table 4]

[0593]

[0594] [Table 5]

[0595]

[0596] [Table 6]

[0597]

[0598] Van:Vancomycin

[0599] Lin:Linezolid

[0600] Cla: Clarithromycin

[0601] 1. Staphylococcus aureus

[0602] 2. Staphylococcus aureus

[0603] 3. Methicillin-resistant Staphylococcus aureus

[0604] 4. Vancomycin Resistant Staphylococcus aureus

[0605] 5. Staphylococcus epidermidis

[0606] 6. Methicillin Resistant Staphylococcus epidermidis

[0607] 7. Enterococcus faecalis

[0608] 8. Vancomycin Resistant Enterococcus faecalis

[0609] 9. Linezolid Resistant Enterococcus faecalis

[0610] 10. Enterococcus faecium

[0611] 11. Vancomycin Resistant Enterococcus faecium

[0612] 12. Linezolid Resistant Enterococcus faecium

[0613] 13-19. Clostridioides difficile

[0614] 20. Mycobacterium tuberculosis

[0615] 21. Mycobacterium avium

[0616] 22. Mycobacterium intracellulare

[0617] 23. Mycobacterium abscessus

[0618] As shown in Tables 1 to 6, it was found that the compounds of the present invention have excellent antibacterial activity against various bacteria.

[0619] In particular, the compounds of the present invention are effective against Gram-positive bacteria, particularly Gram-positive bacteria resistant to existing antibiotics (such as MRSA, VRSA, and VRE), at significantly lower concentrations than vancomycin (VAN), a control substance. They also exhibit very excellent antibacterial activity against Clostridium difficile (C. difficile), suggesting potential for useful treatment of these strains. Furthermore, they exhibit very excellent activity against Mycobacterium tuberculosis and nontuberculous mycobacteria (Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium abscessus), compared to clarithromycin (CLA), a control substance, suggesting potential for useful treatment of pathogens that may become problematic in the future.

[0620] As described above, the present invention is described using specific matters and limited embodiments, but this is only provided to help a more comprehensive understanding of the present invention. The present invention is not limited to the above-mentioned embodiments. Any technician in the field to which the present invention belongs can make various revisions and modifications based on such records.

[0621] Therefore, the concept of the present invention is not limited to the illustrated embodiments, and not only the scope of protection claimed by the present invention but also all scopes of modifications that are equal or equivalent to the scope of protection claimed by the present invention belong to the scope of the concept of the present invention.

Claims

1. A compound represented by any one of the following Chemical Formulas 5 to 12, or a pharmaceutically acceptable salt thereof: [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 9] [Chemical Formula 10] [Chemical Formula 11] [Chemical Formula 12] In the chemical formulas 5 to 12, A1 is R' is a C1-C10 alkyl group, and p is an integer of 0; D1 is CH or N; D2 is O, S, SO2, C(R b1 )(R b2 ), or NR c1 ; D3 is CH or N; D4 is CO, NH, or CH; D5 is O, S, or NR c2 ; D6 is CR b3 or N; D7 is O or S; R1 is hydrogen; Z3 is a single bond or -NR6-, R6 is hydrogen or C1-C10 alkyl; R a1 to R a13 、R b1 to R b3 、R c1 and R c2 are independently hydrogen, halogen, amino, nitro, hydroxy, carboxylic acid, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, halogenated C1-C10 alkyl, C3-C10 heterocyclic carbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC10 1-C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, halogenated C6-C20 aryl, halogenated C1-C10 alkyl C6-C20 aryl, C6-C20 aryl, C3-C10 cycloalkyl, C3-C10 cycloalkylcarbonyl, C1-C10 alkoxycarbonyl C1-C10 alkyl, or carboxylic acid C1-C10 alkyl; n is an integer from 0 to 5.

2. A compound represented by the following Chemical Formula 13-1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 13-1] In Chemical Formula 13-1, R b is hydrogen; A1 is p is the integer 0; and n is an integer from 0 to 10.

3. A compound represented by the following Chemical Formula 13-2 or a pharmaceutically acceptable salt thereof: [Chemical Formula 13-2] In Chemical Formula 13-2, R b is amino or -B(OH)2; A1 is p is the integer 0; and n is an integer of 1 to 6.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein The compound is selected from the following compounds:

5. A method for producing a compound represented by the following chemical formula 1, comprising the following steps: A step of reacting the compound of the following Chemical Formula 21 with a boronic acid precursor to produce the compound of the following Chemical Formula 22; as well as The step of reacting the compound of Chemical Formula 22 with the compound of Chemical Formula 23 to produce the compound of Chemical Formula 1, [Chemical Formula 1] [Chemical Formula 21] [Chemical Formula 22] [Chemical Formula 23] In Chemical Formula 1 and Chemical Formulas 21 to 23, Ar1 and Ar2 are independently Z1 is -CONR1-; Z2 is -CONR1; for A1 is R' is a C1-C10 alkyl group, and p is an integer of 0; D1 is CH or N; D2 is O, S, SO2, C(R b1 )(R b2 ), or NR c1 ; D3 is CH or N; D4 is CO, NH, or CH; D5 is O, S, or NR c2 ; D6 is CR b3 or N; D7 is O or S; R1 is hydrogen; Z3 is a single bond or -NR6-; and R6 is hydrogen or C1-C10 alkyl; R a1 to R a13 、R b1 to R b3 、R c1 and R c2 are independently hydrogen, halogen, amino, nitro, hydroxy, carboxylic acid, -B(OH)2, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, C2-C10 alkenyl, C1-C10 alkyl, halogenated C1-C10 alkyl, C3-C10 heterocyclic carbonyl, allylamino, C1-C10 alkylsulfonyl, aminosulfonyl, aminoC1-C10 alkyl, hydroxyC1-C10 alkyl, dihydroxyC1-C10 alkyl, cyanoC1 -C10 alkyl, C1-C10 alkylamino, diC1-C10 alkylamino, C6-C20 arylamino, diC6-C20 arylamino, C3-C20 heteroaryl, halogenated C6-C20 aryl, halogenated C1-C10 alkyl C6-C20 aryl, C6-C20 aryl, C3-C10 cycloalkyl, C3-C10 cycloalkylcarbonyl, C1-C10 alkoxycarbonyl C1-C10 alkyl, or carboxylic acid C1-C10 alkyl; and n is an integer from 0 to 5; and Y1 and Y2 are independently halogen.

6. The method for producing the compound according to claim 5, wherein The compound of Chemical Formula 21 is prepared by the following steps: a step of reacting the compound of the following Chemical Formula 24 with the compound of the following Chemical Formula 25 to produce the compound of the following Chemical Formula 26; and The step of deprotecting the compound of Chemical Formula 26 to produce the compound of Chemical Formula 21, [Chemical Formula 24] [Chemical Formula 25] [Chemical Formula 26] In the chemical formulas 24 to 26, Ar1 and Y1 are the same as defined in claim 5; R C1 to R C3 are independently C1-C10 alkyl; P is a protecting group.

7. A method for producing a compound represented by the following chemical formula 1, comprising the following steps: A step of reacting the compound of the following Chemical Formula 21 with a boronic acid precursor to produce the compound of the following Chemical Formula 22; as well as The step of reacting the compound of Chemical Formula 22 with the compound of Chemical Formula 23 to produce the compound of Chemical Formula 1, [Chemical Formula 1] [Chemical Formula 21] [Chemical Formula 22] [Chemical Formula 23] In Chemical Formula 1 and Chemical Formulas 21 to 23, Ar1 and Ar2 are independently Z1 is -CONR1-; Z2 is -COO-; for R b is hydrogen; A1 is p is an integer 0; R1 is hydrogen; n is an integer from 0 to 10; and Y1 and Y2 are independently halogen.

8. A method for producing a compound represented by the following chemical formula 1, comprising the following steps: A step of reacting the compound of the following Chemical Formula 21 with a boronic acid precursor to produce the compound of the following Chemical Formula 22; as well as The step of reacting the compound of Chemical Formula 22 with the compound of Chemical Formula 23 to produce the compound of Chemical Formula 1, [Chemical Formula 1] [Chemical Formula 21] [Chemical Formula 22] [Chemical Formula 23] In Chemical Formula 1 and Chemical Formulas 21 to 23, Ar1 and Ar2 are independently Z1 is -CONR1-; Z2 is -CONR1-; for R b is amino or -B(OH)2; A1 is p is an integer 0; R1 is hydrogen; n is an integer from 1 to 6; and Y1 and Y2 are independently halogen.

9. An antibiotic composition, characterized in that Contains a compound selected from any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.

10. The antibiotic composition according to claim 9, wherein The antibiotic composition is used for the treatment and prevention of bacterial infection.

11. The antibiotic composition according to claim 10, wherein The bacterial infection is with Pseudomonas aeruginosa, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare complex, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium bolletii, Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium malmoennse, Mycobacterium scrofulaceum, Mycobacterium marinum, Mycobacterium truncatum ... marinum), Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium ulcerans, Mycobacterium haemophilum, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius intermedius), Staphylococcus hyicus subsp.hyicus), Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

12. The antibiotic composition according to claim 9, wherein The antibiotic composition further comprises a pharmaceutically acceptable carrier.

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