Rifabutin analogues for the treatment of diseases

Abstract

The present invention relates to compounds and pharmaceutical compositions comprising the same for the treatment, amelioration, and / or prevention of disease. In some embodiments, the disease is a bacterial infection. In some embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus nontuberculous Mycobacteria, preferably M. abscessus.

Description

[Technical Field]

[0001] The present invention relates to compounds and pharmaceutical compositions comprising same for the treatment, amelioration, and / or prevention of disease. In some embodiments, the disease is a bacterial infection. In some embodiments, the bacteria belong to the following genera or species: Acinetobacter spp., Clostridium spp., Enterococcus spp., Hemophilus spp., Legionella spp., Mycobacterium spp., Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., Gardnerella vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii. In some embodiments, the infection is caused by A. baumannii, and / or S. aureus, and / or a genus of nontuberculous mycobacteria (NTM), preferably M. abscessus. [Background technology]

[0002] Rifamycins, such as rifabutin, are effective against Clostridium spp., Enterococcus spp., Haemophilus spp., Legionella spp., Mycobacterium spp. (tuberculous and nontuberculous mycobacteria), Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., Gardnerella vaginalis, and other bacteria. It is a known antibiotic active against a broad spectrum of pathogens, including Bacillus vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and Toxoplasma gondii (Kunin, Clin. Infect. Dis., 1996; Farr and Mandell, Med. Clin. North. Am., 1982; Thornsberry et al., Rev. Infect. Dis., 1983; Hoover et al., Diagn. Microbiol. Infect. Dis., 1993; Kerry et al., J. Antimicrob. Chemother., 1975).

[0003] Rifabutin has recently been shown to have potent in vitro and in vivo activity against Mycobacterium abscessus (Aziz et al., Antimicrob. Agents Chemother., 2017; Dick et al., Antimicrob. Agents Chemother., 2020) and Acinetobacter baumannii (Luna et al., Nat. Microbiol., 2020; Trebosc et al., Drug Discov. Today, 26(9), 2021, pp. 2099-2104; Trebosc et al., J. Antimicrob. Chemother., 2020). A C21-modified prodrug of rifabutin for intravenous administration in A. baumannii infections is described by Antraygues et al. in Eur. J. Med. Chem., 238, 2022. Rifamycin-nitroimidazole coupling molecules for the treatment of nontuberculous mycobacteria are described by Ma et al. (U.S. Patent Application Publication No. 2020 / 0360352). Substituted rifamycin derivatives in which a nitroimidazole, nitrothiazole, or nitrofuran pharmacophore is covalently attached to the rifamycin are described by Ding et al. (International Patent Application Publication No. 2008 / 008480). Peek et al. describe semisynthetic hybrid antibiotics formed by linking an assembly of Kangelmycin A, a rifampicin analog, and a fluoroquinolone (Peek et al., Bioorg. & Med. Chem. Lett., 57, 2021). Occelli et al. describe rifamycin derivatives substituted at position 36 and their activity against Gram-positive and fastidious Gram-negative bacteria (International Patent Application Publication No. 94 / 28002). However, there remains a need for more effective rifamycins for the treatment of bacterial infections, such as M. abscessus and A. baumannii infections. Summary of the Invention

[0004] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or enantiomer thereof: [ka] (In the formula, X 1 are independently -COOH, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 5- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 -C1-C6 alkylene-(5-10 membered heteroaryl), -C1-C6 alkylene-(5-10 membered heteroaryl), The alkyl may be one or more R 1 and optionally substituted by The cycloalkyl may each independently, at each occurrence, be one or more R 2 and optionally substituted by The heterocycloalkyl may each independently, at each occurrence, be one or more R 3 and optionally substituted by The aryl may each independently, at each occurrence, be selected from one or more R 4 and optionally substituted by The heteroaryl may each independently, at each occurrence, be one or more R 5 and optionally substituted by R 1 , R 2 , R 3 , R 4 , and R 5 are each independently, at each occurrence, -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8, -COOH, oxo, -NO2, phenyl, halogen, and cyano; R 6 and R 7 is each independently at each occurrence selected from -H and -C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with phenyl; R 8 are independently selected from -C1-C6 alkyl and phenyl, wherein the phenyl is optionally substituted with -C1-C6 alkyl or halogen).

[0005] In one aspect, the present invention provides a compound according to formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound according to formula (I), for use as a medicament.

[0006] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some preferred embodiments, the pharmaceutical composition is effective for treating a bacterial infection. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii, and / or S. aureus, and / or one or more bacteria belonging to the genus nontuberculous Mycobacteria, preferably M. abscessus. In a preferred embodiment, the bacterial infection is caused by one or more bacteria belonging to the genus nontuberculous Mycobacteria, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus.

[0007] In one aspect, the present invention provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. In another aspect, the present invention provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating a bacterial infection. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii, and / or S. aureus, and / or one or more bacteria belonging to the nontuberculous genus Mycobacteria, preferably M. abscessus. In preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus nontuberculous Mycobacteria, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus.

[0008] In one aspect, the present invention provides use of a compound of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I) in the manufacture of a medicament for treating a bacterial infection. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii, and / or S. aureus, and / or one or more bacteria belonging to the genus nontuberculous Mycobacteria, preferably M. abscessus. In preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus nontuberculous Mycobacteria, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus.

[0009] In one aspect, the present invention provides a method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii, and / or S. aureus, and / or one or more bacteria belonging to the genus nontuberculous Mycobacteria, preferably M. abscessus. In a preferred embodiment, the bacterial infection is caused by one or more bacteria belonging to the genus nontuberculous Mycobacteria, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus.

[0010] The present invention provides rifabutin analogs modified at the C25 position to contain a 2-triazoloacetic acid ester, with the triazole substituted at the 4-position, and pharmaceutical compositions containing the same. The compounds of the present invention exhibit broad antibacterial activity against a wide range of bacterial species, thus maintaining the broad antibacterial activity characteristic of the rifamycin class of antibiotics. Furthermore, the compounds of the present invention unexpectedly exhibit enhanced antibacterial activity against nontuberculous mycobacteria, including M. abscessus, compared to currently available antibiotics (e.g., rifabutin). Additional features and advantages of the present technology will become apparent to those skilled in the art upon reading the detailed description below. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention provides analogs of rifabutin that are effective in the treatment of bacterial infections, preferably bacterial infections caused by one or more bacteria belonging to the nontuberculous Mycobacteria genus, preferably M. abscessus.

[0012] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0013] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly dictates otherwise. By way of example, "an element" means one element or more than one element.

[0014] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0015] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can, but need not, be attached to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have a substituent other than hydrogen. For example, it can be attached at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have any additional functional groups.

[0016] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon. A C1-C6 alkyl group contains 1 to 6 carbon atoms. Examples of -C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, and tert-butyl, isopentyl, and neopentyl.

[0017] The term "alkylene" or "alkylenyl," as used herein, refers to a biradical of a straight or branched hydrocarbon chain derived from an alkyl, as defined herein, where one hydrogen of the alkyl is cleaved to produce a secondary radical of the alkylene. Examples of alkylene include, by way of illustration, -CH-, -CH-CH-, -CH(CH)-, -CH-CH-CH-, -CH(CH)-CH-, or -CH(CHCH)-.

[0018] The term "cycloalkyl" means a mono- or polycyclic saturated carbocyclic ring containing from 3 to 8 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0019] The term "aryl" refers to cyclic aromatic hydrocarbon groups having one to two aromatic rings, including monocyclic or bicyclic groups such as phenyl and naphthyl. 10 An aryl group contains 6 to 10 carbon atoms, preferably 6 or 10 carbon atoms. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group may be fused (e.g., naphthyl). The aryl group may be substituted at any point of attachment with one or more substituents, for example, 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-C1-C6 alkyl, -C1-C6 alkyl, -OH, -NH2, -NH(C1-C6 alkyl), and -N(C1-C6 alkyl)2. In some embodiments, an aryl group is -OH, -O-C1-C6 alkyl, -NR 6R 7 , -NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen, and cyano. The substituents (e.g., alkyl groups) may themselves be substituted.

[0020] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one or more ring heteroatoms selected from N, S, P, and O, with the remaining ring atoms being C. Preferably, the heteroatoms are selected from N, S, and O, more preferably N and O. The aromatic radical may be independently substituted with one or more substituents described herein.Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, quinolyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, 1,3-dihydro-2H-benzimidazol-2-one, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3- c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, benzofuran, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]pyridinyl Triazolo[4,3-a]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4 ]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, and thieno[2,3-b]pyrrolyl.

[0021] The terms "heterocyclyl" or "heterocycloalkyl" or "heterocycle" refer to monocyclic or polycyclic saturated or partially saturated 5- to 10-membered rings containing carbon and heteroatoms derived from O, N, and S (preferably O and N), wherein at least one ring does not contain delocalized π-electrons (aromaticity) shared between ring carbons or ring heteroatoms. When a heterocycle is a monocyclic heterocycle, the monocyclic heterocycle does not contain aromaticity. Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, [1,4]diazepane, [1,2]diazepane, decahydro-[1,6]naphthyridine, and diazepinyl. In some embodiments, the heterocyclyl group is fully saturated. In some embodiments, the heterocyclyl group is partially saturated.

[0022] Heterocyclyl or heterocycloalkyl rings can be fused or bridged, for example, bicyclic or tricyclic. Furthermore, when containing two or more fused rings, heterocycloalkyl groups as defined herein can have an unsaturated or partially saturated ring fused with an aromatic and / or heteroaromatic ring. Exemplary ring systems of such heterocycle-aryl or heterocycle-heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine, and dihydrobenzoxanyl.

[0023] Heterocyclyl or heterocycloalkyl ring can also be spirocyclic heterocycle or spiro heterocycle.As used herein, spirocyclic heterocycle or spiro heterocycle is understood to mean a bicyclic or polycyclic ring system, in which at least two rings are connected via a single atom, and at least one of the rings is a heterocycle (for example, at least one of the rings is furanyl, morpholinyl, or piperazinyl).One or both rings of spiro heterocycle can be fused to one or more additional carbocyclic, heterocyclic, aromatic, or heteroaromatic rings, for example, to form a tricyclic ring system, in which two of the rings are connected via a single atom.

[0024] As used herein, the term "halo" or "halogen" means fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0025] The term "oxo" refers to a carbonyl functional group consisting of a carbon atom double-bonded to an oxygen atom, which may be abbreviated herein as "oxo," C(O), or C=O.

[0026] The present invention also includes pharmaceutical compositions comprising an effective amount of the disclosed compounds and a pharmaceutically acceptable carrier.

[0027] Representative "pharmaceutically acceptable salts" include, for example, acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, Included are water-soluble and water-insoluble salts such as maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy-3-naphthoate, ainbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0028] The term "stereoisomers" refers to a series of compounds that have the same number and kinds of atoms and share the same bond connectivity between those atoms, but differ in three-dimensional structure. The term "stereoisomer" refers to any member of this series of compounds.

[0029] The term "diastereomer" refers to a series of stereoisomers that are not superimposable by rotation about a single bond. For example, compounds containing cis- and trans-double bonds, endo- and exo-substitution on a bicyclic ring system, and multiple stereocenters with different relative configurations are considered diastereomers. The term "diastereomer" refers to any member of this series of compounds. In some examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers. In some cases, these diastereomers are separated, and in other cases, wavy bonds are used to indicate structural elements with variable configurations.

[0030] The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "enantiomer" refers to a single member of this stereoisomer pair. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers.

[0031] The term "tautomer" refers to a series of compounds having the same number and type of atoms but differing bond connectivity and in equilibrium with each other. A "tautomer" is a single member of this series of compounds. Typically, a single tautomer is depicted, but it is understood that this single structure is meant to represent all possible tautomers that may exist. An example includes enol-ketone tautomerism. When a ketone is depicted, it is understood that both the enol form and the ketone form are part of this disclosure.

[0032] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of the present invention, such a solvent should not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as "hydrates." Hydrates include compositions containing stoichiometric amounts of water and compositions containing variable amounts of water.

[0033] An "effective amount" when used in reference to a compound is an amount effective to treat or prevent a subject disease as described herein.

[0034] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, e.g., a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in the transfer or transport of a pharmaceutical agent from one organ or part of the body to another organ or part of the body of a subject.

[0035] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treatment includes curing, ameliorating, or at least partially alleviating the disorder.

[0036] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0037] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or a pharmaceutical composition comprising same, directly to a subject, or administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt of the compound, or pharmaceutical composition, to a subject, which can form an equivalent amount of the active compound in the subject's body.

[0038] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey. Preferably, the "patient" or "subject" is human.

[0039] Compounds of the Invention In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or enantiomer thereof: [ka] (In the formula, X 1 are independently -COOH, -C1-C6 alkyl, -C3-C8 cycloalkyl, -C1-C6 alkylene-(C3-C8 cycloalkyl), 5- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 -C1-C6 alkylene-(5-10 membered heteroaryl), -C1-C6 alkylene-(5-10 membered heteroaryl), The alkyl may be one or more R 1 and optionally substituted by The cycloalkyl may each independently, at each occurrence, be one or more R 2 and optionally substituted by The heterocycloalkyl may each independently, at each occurrence, be one or more R 3 and optionally substituted by The aryl may each independently, at each occurrence, be selected from one or more R 4 and optionally substituted by The heteroaryl may each independently, at each occurrence, be one or more R 5 and optionally substituted by R 1 , R 2 , R 3 , R 4 , and R 5 are each independently, at each occurrence, -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen, and cyano; R 6 and R 7is each independently at each occurrence selected from -H and -C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with phenyl; R 8 are independently selected from -C1-C6 alkyl and phenyl, wherein the phenyl is optionally substituted with -C1-C6 alkyl or halogen).

[0040] In some embodiments of Formula (I), R 1 , R 2 , R 3 , R 4 and R 5 are each independently, at each occurrence, -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , -COOH, oxo, -NO2 and phenyl; R 6 and R 7 is each independently at each occurrence selected from -H and -C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with phenyl; R 8 is independently selected from -C1-C6 alkyl and phenyl, wherein the phenyl is optionally substituted with -C1-C6 alkyl or halogen.

[0041] In some embodiments of Formula (I), X 1 are independently -COOH, -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-(C3-C6 cycloalkyl), 5- to 7-membered heterocycloalkyl, -C1-C6 alkylene-(5- to 7-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, or -C1-C6 alkylene-(5-10 membered heteroaryl); The alkyl may be one or more R 1 and each occurrence of the cycloalkyl may be independently substituted by one or more R2 and the heterocycloalkyl may each independently, at each occurrence, be substituted by one or more R 3 wherein the aryl may be substituted by, each independently at each occurrence, one or more R 4 wherein each of the 5- to 10-membered heteroaryls is unsubstituted; R 1 independently, at each occurrence, -OH, -NR 6 R 7 , -NHSO2R 8 and -COOH, R 2 Ha-NR 6 R 7 is selected from R 3 is oxo, R 4 independently, at each occurrence, -OC-C alkyl, -NR 6 R 7 , —COOH, —NO2 and phenyl.

[0042] In some embodiments of Formula (I), X 1 are independently -COOH, -C1-C6 alkyl, -C3-C6 cycloalkyl, -C1-C6 alkylene-(C3-C6 cycloalkyl), 5- to 7-membered heterocycloalkyl, -C1-C6 alkylene-(5- to 7-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5-10 membered heteroaryl, or -C1-C6 alkylene-(5-10 membered heteroaryl); The alkyl may be one or more R 1 and each occurrence of the cycloalkyl may be independently substituted by one or more R 2 and the heterocycloalkyl may each independently, at each occurrence, be substituted by one or more R 3 wherein the aryl may be substituted by, each independently at each occurrence, one or more R 4wherein each of the 5- to 10-membered heteroaryls is unsubstituted; R 1 independently, at each occurrence, -OH, -NR 6 R 7 , -NHSO2R 8 and -COOH, R 2 Ha-NR 6 R 7 is selected from R 3 is oxo, R 4 independently, at each occurrence, -OC-C alkyl, -NR 6 R 7 , —COOH, —NO2 and phenyl; R 6 and R 7 is each independently at each occurrence selected from -H and -C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with phenyl; R 8 is independently selected from -C1-C6 alkyl and phenyl, wherein the phenyl is optionally substituted with -C1-C6 alkyl or halogen.

[0043] In some embodiments, X 1 are independently -COOH, -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C4 alkylene-(C3-C6 cycloalkyl), 5- to 7-membered heterocycloalkyl, -C1-C4 alkylene-(5- to 7-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C4 alkylene-(C6-C 10 aryl), 5-6 membered heteroaryl, or -C1-C4 alkylene-(5-6 membered heteroaryl); The alkyl is selected from 1 to 3 R 1 and each occurrence of the cycloalkyl is optionally substituted by 1 to 3 R 2 and the heterocycloalkyl may each independently, at each occurrence, be substituted with 1 to 3 R3 and the aryl may be substituted by, each independently at each occurrence, 1 to 3 R 4 wherein each of the 5- to 6-membered heteroaryls is unsubstituted; R 1 independently, at each occurrence, -OH, -NR 6 R 7 , -NHSO2R 8 and -COOH, R 2 is -NH2, R 3 is oxo, R 4 is independently, at each occurrence, selected from: —OC-C alkyl, —NH, —NH(C-C alkyl), —N(C-C alkyl), —COOH, —NO, phenyl; R 6 and R 7 is independently, at each occurrence, selected from -H, -CH3, and -CH2-C6H5; R 8 is independently at each occurrence selected from -CH3 and phenyl, wherein said phenyl is optionally substituted with one or more -CH3 or halogen.

[0044] In some embodiments, X 1 are independently -COOH, -C1-C5 alkyl, -C3-C6 cycloalkyl, -C1-C2 alkylene-(C3-C6 cycloalkyl), 5- to 7-membered heterocycloalkyl, -C1-C2 alkylene-(5- to 7-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene-(C6-C 10 aryl), and 5- to 6-membered heteroaryl; The alkyl may be one or two R 1 by, preferably exactly one R 1 and each occurrence of the cycloalkyl may be independently substituted with one or two R 2 by, preferably exactly one R 2and the heterocycloalkyl may be substituted by, each independently at each occurrence, one or two R 3 Preferably, two R 3 and the aryl may be substituted by, each independently at each occurrence, one or two R 4 by, preferably exactly one R 4 and the 5- to 6-membered heteroaryl is unsubstituted; R 1 independently, at each occurrence, represents -OH, -NH2, -N(CH3)(CH2C6H5), -NHSO2R 8 and -COOH, R 2 is -NH2, R 3 is oxo, R 4 is independently, at each occurrence, selected from -OCH, -NH, -COOH, -NO, and phenyl; R 8 is independently at each occurrence selected from -CH3 and phenyl, wherein said phenyl is optionally substituted with one or more -CH3 or halogen.

[0045] In some embodiments of Formula (I), X 1 are independently -C1-C5 alkyl, -C5-C6 cycloalkyl, -C1-C2 alkylene-(C5-C6 cycloalkyl), 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-(5- to 6-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), and 5- to 6-membered heteroaryl; The alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 and each said cycloalkyl is unsubstituted and each said heterocycloalkyl is independently substituted at each occurrence by one or two R 3and the aryl may be substituted by, each independently at each occurrence, 1 to 3 R 4 by, preferably exactly one R 4 and optionally substituted by R 1 independently, at each occurrence, -NR 6 R 7 and -NHSO2R 8 is selected from R 3 is oxo, R 4 is independently, at each occurrence, selected from phenyl, —OC1-C6 alkyl, NH2, and —NO2; R 6 and R 7 is independently, at each occurrence, selected from -H, -CH3, and -CH2-C6H5; R 8 is —CH 3 or phenyl, wherein the phenyl is optionally substituted by one or more —CH 3 or —Cl.

[0046] In some embodiments of Formula (I), X 1 are independently -C1-C5 alkyl, -C5-C6 cycloalkyl, -C1-C2 alkylene-(C5-C6 cycloalkyl), 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-(5- to 6-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), and 5- to 6-membered heteroaryl; The alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 and each said cycloalkyl is unsubstituted and each said heterocycloalkyl is independently substituted at each occurrence by one or two R 3 and the aryl may be substituted by, each independently at each occurrence, 1 to 3 R 4 by, preferably exactly one R 4 and optionally substituted by R1 independently, at each occurrence, -NR 6 R 7 and -NHSO2R 8 is selected from R 3 is oxo, R 4 is independently, at each occurrence, selected from -OC1-C6 alkyl, NH2, and -NO2; R 6 and R 7 is independently, at each occurrence, selected from -H, -CH3, and -CH2-C6H5; R 8 is —CH 3 or phenyl, wherein the phenyl is optionally substituted by one or more —CH 3 or —Cl.

[0047] In some embodiments, X 1 are independently -C1-C3 alkyl, cyclohexyl, -C1-C2 alkylene-(cyclohexyl), 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-(5- to 6-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene-(C6-C 10 aryl), thiophenyl, and pyridinyl; The alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 wherein the cyclohexyl is unsubstituted, the heterocycloalkyl is substituted by one or two oxo, and the aryl is each independently, at each occurrence, 1 to 3 R 4 by, preferably exactly one R 4 and the pyridinyl is unsubstituted, R 1 independently, at each occurrence, represents -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 is selected from R 4 is independently, at each occurrence, selected from -OC1-C2 alkyl, NH2, and -NO2; R 8 is —CH 3 or phenyl, wherein the phenyl is optionally substituted by one or more —CH 3 or —Cl.

[0048] In some embodiments, X 1 are independently -C1-C3 alkyl, cyclohexyl, -C1-C2 alkylene-(cyclohexyl), 5- to 6-membered heterocycloalkyl, -C1-C2 alkylene-(5- to 6-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C3 alkylene-(C6-C 10 aryl), thiophenyl, and pyridinyl; The alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 wherein the cyclohexyl is unsubstituted, the heterocycloalkyl is substituted by one or two oxo, and the aryl is each independently, at each occurrence, 1 to 3 R 4 by, preferably exactly one R 4 wherein the thiophenyl and pyridinyl are unsubstituted; R 1 independently, at each occurrence, represents -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 is selected from R 4 is independently, at each occurrence, selected from -OC1-C2 alkyl, NH2, and -NO2; R 8 is —CH 3 or phenyl, wherein the phenyl is optionally substituted by one or more —CH 3 or —Cl.

[0049] In some embodiments, X 1 are independently -C1-C3 alkyl, cyclohexyl, -C1 alkylene-(cyclohexyl), 4-thiomorpholine 1,1-dioxide, -C1-C2 alkylene-(4-thiomorpholine 1,1-dioxide), -C6-C 10 Aryl, -C1-C3 alkylene-(C6-C10 aryl), 2-thiophenyl, and 2-pyridinyl; The alkyl may be one or two R 1 by, preferably exactly one R 1 wherein the cyclohexyl is unsubstituted, the aryl is unsubstituted or substituted by one or two, preferably exactly one, -OCH3, -NH2 or -NO2, and the 2-thiophenyl and 2-pyridinyl are unsubstituted, R 1 independently, at each occurrence, represents -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 is selected from R 8 is -CH3 or phenyl, and the phenyl may be substituted at the 4-position with -CH3 or -Cl.

[0050] In some embodiments of Formula (I), X 1 is independently selected from -C1-C3 alkyl, cyclohexyl, -C1 alkylene-(cyclohexyl), phenyl, -C1-C3 alkylene-(phenyl), and 2-pyridinyl; The alkyl may be one or two R 1 by, preferably exactly one R 1 wherein each cyclohexyl is unsubstituted, each phenyl is unsubstituted or substituted by one or two, preferably exactly one, -OCH or -NO, and the 2-pyridinyl is unsubstituted, R 1 represents, independently at each occurrence, -N(CH3)(CH2C6H5), and -NHSO2R 8 is selected from R 8 is phenyl, and the phenyl may be substituted at the 4-position with -CH3 or -Cl.

[0051] In some embodiments of Formula (I), X 1 is -COOH.

[0052] In some embodiments of Formula (I), X 1 is -C1-C6 alkyl, and the alkyl is selected from one or more R 1 R may be substituted by 1 independently, at each occurrence, represents -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , —COOH, oxo, —NO 2 , phenyl, halogen, and cyano.

[0053] In some embodiments, X 1 is -C1-C6 alkyl, and the alkyl is selected from one or more R 1 R may be substituted by 1 independently, at each occurrence, represents -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , —COOH, oxo, —NO 2 , and phenyl.

[0054] In some embodiments, X 1 is -C1-C6 alkyl, and the alkyl is selected from one or more R 1 R may be substituted by 1 independently, at each occurrence, -OH, -NR 6 R 7 , -NHSO2R 8 and —COOH.

[0055] In some embodiments, X 1 is -C1-C5 alkyl, and the alkyl is selected from 1 to 3 R 1 R may be substituted by 1 independently, at each occurrence, -OH, -NR 6 R 7 , -NHSO2R 8 , and -COOH, and R 6 and R 7is independently, at each occurrence, selected from -H, -CH, and -CH-C H alkyl; 8 is independently at each occurrence selected from —CH 3 and phenyl, wherein said phenyl is optionally substituted by one or more CH 3 or halogen.

[0056] In some embodiments, X 1 is -C1-C5 alkyl, and the alkyl is selected from one or two R 1 by, preferably exactly one R 1 R may be substituted by 1 independently, at each occurrence, represents -OH, -NH2, -N(CH3)(CH2C6H5), -NHSO2R 8 , and -COOH, and R 8 is independently at each occurrence selected from —CH 3 and phenyl, wherein said phenyl is optionally substituted by one or more CH 3 or halogen.

[0057] In some embodiments, X 1 is -C1-C5 alkyl, and the alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 R may be substituted by 1 independently, at each occurrence, -NR 6 R 7 and -NHSO2R 8 Selected from R 6 and R 7 is independently, at each occurrence, selected from -H, -CH3, and -CH2-C6H5; R 8 is —CH 3 or phenyl, wherein the phenyl is optionally substituted by one or more CH 3 or —Cl.

[0058] In some embodiments, X 1 is -C1-C3 alkyl, wherein the alkyl is unsubstituted.

[0059] In some embodiments, X 1is -C1-C3 alkyl, and the alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 R may be substituted by 1 independently, at each occurrence, represents -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 Selected from R 8 is —CH 3 or phenyl, wherein the phenyl is optionally substituted by one or more CH 3 or —Cl.

[0060] In some embodiments, X 1 is -C1-C3 alkyl, and the alkyl is selected from one or two R 1 by, preferably exactly one R 1 R may be substituted by 1 independently, at each occurrence, represents -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 Selected from R 8 is -CH3 or phenyl, and the phenyl may be substituted at the 4-position with CH3 or -Cl. In some embodiments, X 1 is -C1-C3 alkyl, and the alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 R may be substituted by 1 is independently, at each occurrence, selected from -NH2 and -N(CH3)(CH2C6H5).

[0061] In some embodiments, X 1 is -C1 alkyl, and the alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 R may be substituted by 1 Ha-NHSO2R 8 and R 8 is -CH3 or phenyl, and the phenyl may be substituted at the 4-position by -CH3 or -Cl.

[0062] In some embodiments, X 1 is -C1 alkyl, and the alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 R may be substituted by 1 Ha-NHSO2R 8 and R 8 is phenyl, which is substituted at the 4-position by -CH3 or -Cl.

[0063] In some embodiments, X 1 is -C1 alkyl, and the alkyl is selected from 1 to 3 R 1 by, preferably exactly one R 1 R may be substituted by 1 Ha-NHSO2R 8 and R 8 is phenyl, said phenyl being unsubstituted.

[0064] In some embodiments of Formula (I), X 1 is —C3-C8 cycloalkyl or —C1-C6 alkylene-(C3-C8 cycloalkyl), each and every occurrence of which is independently selected from one or more R 2 R may be substituted by 2 is -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , —COOH, oxo, —NO 2 , phenyl, halogen, and cyano.

[0065] In some embodiments, X 1 is —C3-C6 cycloalkyl or —C1-C6 alkylene-(C3-C6 cycloalkyl), each and every cycloalkyl independently being selected from one or more R 2 R may be substituted by 2 is -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8, —COOH, oxo, —NO 2 , and phenyl.

[0066] In some embodiments, X 1 is —C3-C6 cycloalkyl or —C1-C6 alkylene-(C3-C6 cycloalkyl), each and every cycloalkyl independently being selected from one or more R 2 R may be substituted by 2 is NR 6 R 7 is selected from.

[0067] In some embodiments, X 1 is —C3-C6 cycloalkyl or —C1-C4 alkylene-(C3-C6 cycloalkyl), each of which independently, at each occurrence, is selected from 1 to 3 R 2 R may be substituted by 2 is -NH2.

[0068] In some embodiments, X 1 is —C3-C6 cycloalkyl or —C1-C2 alkylene-(C3-C6 cycloalkyl), each of which independently at each occurrence is selected from one or two R 2 by, preferably exactly one R 2 R may be substituted by 2 is -NH2.

[0069] In some embodiments, X 1 is —C5-C6 cycloalkyl or —C1-C2 alkylene-(C5-C6 cycloalkyl), wherein the cycloalkyl is unsubstituted.

[0070] In some embodiments, X 1 is cyclohexyl or -C1-C2 alkylene-(cyclohexyl), wherein the cyclohexyl is unsubstituted.

[0071] In some embodiments, X 1is cyclohexyl or -C1 alkylene-(cyclohexyl), wherein the cyclohexyl is unsubstituted.

[0072] In some embodiments of Formula (I), X 1 is a 5- to 10-membered heterocycloalkyl or —C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), each and every occurrence of which is independently selected from one or more R 3 R may be substituted by 3 is -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , —COOH, oxo, —NO 2 , phenyl, halogen, and cyano. In some embodiments, the heterocycloalkyl is saturated.

[0073] In some embodiments, X 1 is a 5- to 10-membered heterocycloalkyl or —C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), each and every occurrence of which is independently selected from one or more R 3 R may be substituted by 3 is -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , —COOH, oxo, —NO 2 , and phenyl. In some embodiments, the heterocycloalkyl is saturated.

[0074] In some embodiments, X 1 is a 5- to 7-membered heterocycloalkyl or —C1-C6 alkylene-(5- to 7-membered heterocycloalkyl), each and every occurrence of which is independently selected from one or more R 3 R may be substituted by 3 is oxo.

[0075] In some embodiments, X 1is a 5- to 7-membered heterocycloalkyl or -C1-C4 alkylene-(5- to 7-membered heterocycloalkyl), each of which is independently selected from 1 to 3 R 3 R may be substituted by 3 is oxo.

[0076] In some embodiments, X 1 is a 5- to 7-membered heterocycloalkyl or -C1-C2 alkylene-(5- to 7-membered heterocycloalkyl), each of which independently at each occurrence is selected from one or two R 3 Preferably, two R 3 R may be substituted by 3 is oxo.

[0077] In some embodiments, X 1 is a 5- to 6-membered heterocycloalkyl or -C1-C2 alkylene-(5- to 6-membered heterocycloalkyl), each of which independently at each occurrence is selected from one or two R 3 R may be substituted by 3 is oxo.

[0078] In some embodiments, X 1 is a 5-6 membered heterocycloalkyl or -C1-C2 alkylene-(5-6 membered heterocycloalkyl), wherein the heterocycloalkyl is substituted by one or two oxo.

[0079] In some embodiments, X 1 is 4-thiomorpholine 1,1-dioxide, or -C1-C2 alkylene-(4-thiomorpholine 1,1-dioxide).

[0080] In some embodiments, X 1 is -C1-C2 alkylene-(4-thiomorpholine 1,1-dioxide).

[0081] In some embodiments, X 1 is -C1 alkylene-(4-thiomorpholine 1,1-dioxide).

[0082] In some embodiments, X 1 is Azepan.

[0083] In some embodiments, X 1 is piperidine.

[0084] In some embodiments, X 1 is a spiro heterocycle, preferably a 6- to 9-membered spiro heterocycle.

[0085] In some embodiments of Formula (I), X 1 is -C6-C 10 Aryl or -C1-C6 alkylene-(C6-C 10 aryl), each aryl independently at each occurrence being selected from one or more R 4 R may be substituted by 4 independently, at each occurrence, represents -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , —COOH, oxo, —NO 2 , phenyl, halogen, and cyano.

[0086] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C6 alkylene-(C6-C 10 aryl), each aryl independently at each occurrence being selected from one or more R 4 R may be substituted by 4 is -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , —COOH, oxo, —NO 2 , and phenyl.

[0087] In some embodiments, X 1is -C6-C 10 Aryl or -C1-C6 alkylene-(C6-C 10 aryl), each aryl independently at each occurrence being selected from one or more R 4 R may be substituted by 4 is -OC1-C6 alkyl, -NR 6 R 7 , —COOH, —NO 2 , and phenyl.

[0088] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C4 alkylene-(C6-C 10 aryl), each independently at each occurrence, selected from 1 to 3 R 4 R may be substituted by 4 is selected from —OC1-C2 alkyl, NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, —COOH, —NO2, and phenyl.

[0089] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C3 alkylene-(C6-C 10 aryl), each of which independently at each occurrence is selected from one or two R 4 by, preferably exactly one R 4 R may be substituted by 4 is selected from —OC1-C2 alkyl, NH2, —NH(C1-C2 alkyl), —N(C1-C2 alkyl)2, —COOH, —NO2, and phenyl.

[0090] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C3 alkylene-(C6-C 10 aryl), each of which independently at each occurrence is selected from one or two R 4 by, preferably exactly one R 4R may be substituted by 4 is selected from —OCH 3 , NH 2 , —COOH, —NO 2 , and phenyl.

[0091] In some embodiments, X 1 is -C6-C 10 aryl, each independently at each occurrence, selected from one or two R 4 by, preferably exactly one R 4 R may be substituted by 4 is selected from —OCH 3 , NH 2 , —COOH, —NO 2 , and phenyl.

[0092] In some embodiments, X 1 is -C1-C3 alkylene-(C6-C 10 aryl), and the C6-C 10 The aryl is unsubstituted.

[0093] In some embodiments, X 1 is -C1-C3 alkylene-(phenyl), wherein the phenyl is unsubstituted.

[0094] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C6 alkylene-(C6-C 10 aryl), each independently at each occurrence, selected from 1 to 3 R 4 by, preferably exactly one R 4 R may be substituted by 4 is independently, at each occurrence, selected from phenyl, —OC1-C6 alkyl, NH2, and —NO2.

[0095] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C6 alkylene-(C6-C 10 aryl), each independently at each occurrence, selected from 1 to 3 R 4by, preferably exactly one R 4 R may be substituted by 4 is independently, at each occurrence, selected from -OC1-C6 alkyl, NH2, and -NO2.

[0096] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C6 alkylene-(C6-C 10 aryl), each independently at each occurrence, selected from 1 to 3 R 4 by, preferably exactly one R 4 R may be substituted by 4 is independently, at each occurrence, selected from -OC1-C2 alkyl, NH2, and -NO2.

[0097] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C3 alkylene-(C6-C 10 aryl), each independently at each occurrence, selected from 1 to 3 R 4 by, preferably exactly one R 4 R may be substituted by 4 is independently, at each occurrence, selected from -OC1-C2 alkyl, NH2, and -NO2.

[0098] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C3 alkylene-(C6-C 10 aryl), wherein the aryl is unsubstituted or substituted by one or two, preferably exactly one, -OC1-C2 alkyl, -NH2, or -NO2.

[0099] In some embodiments, X 1 is -C6-C 10 Aryl or -C1-C3 alkylene-(C6-C 10aryl), which is unsubstituted or substituted by one or two, preferably exactly one, -OCH3, -NH2, or -NO2.

[0100] In some embodiments, X 1 is phenyl or -C1-C3 alkylene-(phenyl), preferably -C2-C3 alkylene-(phenyl), wherein the phenyl is unsubstituted.

[0101] In some embodiments, X 1 is phenyl or naphthyl, said phenyl or naphthyl being substituted by one or two, preferably exactly one, -OCH3.

[0102] In some embodiments, X 1 is phenyl, said phenyl being substituted by one or two, preferably exactly one, -NH2.

[0103] In some embodiments, X 1 is phenyl, which is substituted by one or two, preferably exactly one, -NO2.

[0104] In some embodiments of Formula (I), X 1 is a 5-10 membered heteroaryl or -C1-C6 alkylene-(5-10 membered heteroaryl), wherein the heteroaryl is independently selected at each occurrence from one or more R 5 R may be substituted by 5 is -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , —COOH, oxo, —NO 2 , phenyl, halogen, and cyano.

[0105] In some embodiments, X 1is a 5-10 membered heteroaryl or -C1-C6 alkylene-(5-10 membered heteroaryl), wherein the heteroaryl is independently selected at each occurrence from one or more R 5 R may be substituted by 5 is -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , —COOH, oxo, —NO 2 , and phenyl.

[0106] In some embodiments, X 1 is a 5- to 10-membered heteroaryl or -C1-C6 alkylene-(5- to 10-membered heteroaryl), each of which is unsubstituted.

[0107] In some embodiments, X 1 is a 5- to 6-membered heteroaryl or -C1-C4 alkylene-(5- to 6-membered heteroaryl), each of which is unsubstituted.

[0108] In some embodiments, X 1 is a 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is unsubstituted.

[0109] In some embodiments, X 1 is pyridinyl or thiophenyl.

[0110] In some embodiments, X 1 is pyridinyl or thiophenyl, wherein the pyridinyl and thiophenyl are unsubstituted.

[0111] In some embodiments, X 1 is 2-pyridinyl or 2-thiophenyl, wherein the 2-pyridinyl and 2-thiophenyl are unsubstituted.

[0112] In some embodiments, X 1 is thiophenyl.

[0113] In some embodiments, X 1 is thiophenyl, which is unsubstituted.

[0114] In some embodiments, X 1 is 2-thiophenyl, which is unsubstituted.

[0115] In some embodiments, X 1 is pyridinyl.

[0116] In some embodiments, X 1 is pyridinyl, which is unsubstituted.

[0117] In some embodiments, X 1 is 2-pyridinyl, which is unsubstituted.

[0118] In one or more embodiments, X in the compound of formula (I) 1 can form one of the structures selected from Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3]

[0119] In one or more embodiments of any of the above aspects, the compound of formula (I) is selected from the compounds in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0120] In one or more embodiments of any of the above aspects, the compound of formula (I) is selected from the compounds in Table 3 below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0121] In one or more embodiments of any of the above aspects, the compound of formula (I) is selected from the compounds in Table 4 below. [Table 4-1] [Table 4-2] [Table 4-3]

[0122] In some embodiments, the compound of Formula (I) is selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 24, Compound 26, and Compound 28.

[0123] In some embodiments, the compound of Formula (I) is selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 6, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 24, Compound 26, and Compound 28.

[0124] In some embodiments, the compound of Formula (I) is selected from Compound 1, Compound 2, Compound 4, Compound 8, Compound 9, Compound 12, Compound 16, Compound 17, Compound 18, Compound 26, and Compound 28.

[0125] In some embodiments, the compound of Formula (I) is Compound 1. In some embodiments, the compound of Formula (I) is Compound 2. In some embodiments, the compound of Formula (I) is Compound 3. In some embodiments, the compound of Formula (I) is Compound 4. In some embodiments, the compound of Formula (I) is Compound 5. In some embodiments, the compound of Formula (I) is Compound 6. In some embodiments, the compound of Formula (I) is Compound 7. In some embodiments, the compound of Formula (I) is Compound 8. In some embodiments, the compound of Formula (I) is Compound 9. In some embodiments, the compound of Formula (I) is Compound 10. In some embodiments, the compound of Formula (I) is Compound 11. In some embodiments, the compound of Formula (I) is Compound 12. In some embodiments, the compound of Formula (I) is Compound 13. In some embodiments, the compound of Formula (I) is Compound 14. In some embodiments, the compound of Formula (I) is Compound 15. In some embodiments, the compound of Formula (I) is Compound 16. In some embodiments, the compound of Formula (I) is Compound 17. In some embodiments, the compound of Formula (I) is Compound 18. In some embodiments, the compound of Formula (I) is Compound 19. In some embodiments, the compound of Formula (I) is Compound 20. In some embodiments, the compound of Formula (I) is Compound 21. In some embodiments, the compound of Formula (I) is Compound 22. In some embodiments, the compound of Formula (I) is Compound 23. In some embodiments, the compound of Formula (I) is Compound 24. In some embodiments, the compound of Formula (I) is Compound 25. In some embodiments, the compound of Formula (I) is Compound 26. In some embodiments, the compound of Formula (I) is Compound 27. In some embodiments, the compound of Formula (I) is Compound 28. In some embodiments, the compound of Formula (I) is Compound 29. In some embodiments, the compound of Formula (I) is Compound 30. In some embodiments, the compound of Formula (I) is Compound 31. In some embodiments, the compound of Formula (I) is Compound 32. In some embodiments, the compound of Formula (I) is Compound 33.In some embodiments, the compound of Formula (I) is compound 34.

[0126] In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0127] Methods for synthesizing the disclosed compounds The compounds of the invention may be made by a variety of methods, including standard chemistry, including, but not limited to, those described in the appropriate synthetic routes shown in the schemes set out below.

[0128] The compounds of the present invention can be prepared by methods known in the art of organic synthesis, as illustrated in part by the following synthetic schemes and examples. In the schemes described below, it is fully understood that protecting groups for functional or reactive groups are used where necessary in accordance with general principles or chemical phenomena. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PG M Buts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage in the compound synthesis using methods readily apparent to those skilled in the art. The selected processes, as well as the reaction conditions and the order of their execution, shall be consistent with the preparation of the compounds of the present invention.

[0129] Those skilled in the art will recognize whether a stereocenter exists in compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis), including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0130] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic and / or enzymatic processes.

[0131] Preparation of compounds The compounds of the present invention can be synthesized by the steps outlined below in Schemes 1, 2, 3 and 4. Starting materials are either commercially available or made by known procedures reported in the literature or as illustrated.

[0132] Scheme 1. General synthesis of 21,23-acetonide-25-hydroxy-rifabutin (I-1) [ka] A general method for preparing 21,23-acetonide-25-hydroxy-rifabutin I-1 is shown in Scheme 1 above. Protection of the C21 and C23 hydroxy groups using an appropriate protecting group, such as dimethoxypropane and camphorsulfonic acid, in a solvent such as DMF afforded acetal-protected rifabutin. Deacetylation of the protected rifabutin using a basic solution, such as sodium methoxide in ether, afforded 25-OH rifabutin (I-1) with the C21 and C23 hydroxy groups protected.

[0133] Scheme 2. Preparation of 21,23-acetonide-25-bromoacetate-rifabutin (I-2) [ka] 21,23-Acetonide-25-hydroxy-rifabutin (I-1) can be esterified using an appropriate carboxylic acid anhydride, such as bromoacetic anhydride, in the presence of a suitable base, for example, an amine base, such as 4-(dimethylamino)pyridine, as shown in Scheme 2.

[0134] Scheme 3. Preparation of 21,23-acetonide-25-azidoacetate-rifabutin (I-3) [ka] Intermediate I-2 can be converted to the corresponding azide by reaction with an appropriate nucleophilic azide, such as sodium azide, in a solvent such as DMF, as shown in Scheme 3.

[0135] Scheme 4. Preparation of deprotected 25-triazolyl acetate conjugated rifabutin [ka] The C25-esterified, protected rifabutin can be condensed with an appropriate alkyne in the presence of a suitable catalyst, such as copper sulfate and sodium ascorbate, in a suitable solvent, such as a mixture of tBuOH and water. Deprotection of the C21-C23 acetonide in the conjugated rifabutin can be achieved by treatment with an acid, such as camphorsulfonic acid, in water.

[0136] Antibacterial efficacy of the disclosed compounds The compounds of the present invention are analogs of rifabutin modified at C25 to contain a 2-triazoloacetic acid ester, with the triazole substituted at the 4-position. The compounds of the present invention exhibit broad-spectrum antibacterial activity characteristic of the rifamycin class. Furthermore, the compounds of the present invention unexpectedly exhibit enhanced antibacterial activity against nontuberculous mycobacteria, including M. abscessus, compared to currently available antibiotics (e.g., rifabutin).

[0137] As shown in Example 5, Table 6 below, compounds of the present invention are effective in inhibiting bacterial growth of strains of S. aureus, M. abscessus, A. baumannii, M. kansasii, M. xenopi, and M. avium.

[0138] Rifampicin exhibited MIC values ​​of greater than 32 mg / L against M. abscessus and was not considered active against M. abscessus strains. Rifabutin, unmodified at the C25 position, exhibited moderate activity against the tested M. abscessus strains, with an MIC value of 8 mg / L. In contrast, compounds of the present invention exhibited MIC values ​​of 0.125 to 4 mg / L, corresponding to 2- to 64-fold greater activity than rifabutin. Thus, the present invention teaches compounds that exhibit activity against M. abscessus that is greater than that of antibiotics known in the literature.

[0139] Methods of Use of the Disclosed Compounds One aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. One aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0140] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of formula (I), for use in a method for preventing or treating a disease, preferably an infection, more preferably a bacterial infection, in a subject.

[0141] In one aspect, the present invention provides a method of treating a disease, preferably an infection, more preferably a bacterial infection, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of formula (I).

[0142] In one aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof in the manufacture of a medicament for treating a disease, preferably an infection, more preferably a bacterial infection, in a subject in need thereof.

[0143] In some embodiments of any of the above aspects, the infection, e.g., bacterial infection, is selected from the group consisting of Mycobacterium spp., Acinetobacter spp., Clostridium spp., Enterococcus spp., Haemophilus spp., Legionella spp., Neisseria spp., Staphylococcus spp., Streptococcus spp., Listeria monocytogenes, Moraxella catarrhalis, Bacillus spp., Bacteroides spp., and the like. It is caused by one or more species of bacteria belonging to the genera Lactobacillus spp., Gardnerella vaginalis, Lactobacillus spp., Mobiluncus spp., Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii.

[0144] In some preferred embodiments of any of the above aspects, the bacterial infection is caused by one or more bacteria belonging to the genera Acinetobacter, Staphylococcus, and / or Mycobacteria. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species A. baumannii, and / or S. aureus, and / or one or more bacteria belonging to the nontuberculous Mycobacteria genus, preferably M. abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the species M. abscessus, A. baumannii, and / or S. aureus, preferably M. abscessus.

[0145] In some preferred embodiments, the infection is caused by one or more bacteria belonging to the nontuberculous Mycobacterium genus, preferably M. abscessus, M. avium, M. kansasii, M. smegmantis, M. xenopi, and / or M. malmoense, more preferably M. abscessus, M. avium, M. kansasii, and / or M. xenopi, and even more preferably M. abscessus. In some embodiments, the M. abscessus infection is resistant to current antibiotics.

[0146] In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably A. baumannii and / or S. aureus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter, preferably A. baumannii. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Staphylococcus, preferably S. aureus.

[0147] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of formula (I), for use in a method of treating a non-tuberculous Mycobacterial pulmonary infection. In some embodiments, the bacteria causing nontuberculous Mycobacteria lung infections are M. abscessus, M. avium, M. kansasii, M. smegmantis, M. xenopi, and / or M. malmoense, preferably M. abscessus, M. avium, M. kansasii, and / or M. xenopi, more preferably M. abscessus.

[0148] In one aspect, the present invention provides a method of treating a non-tuberculous Mycobacterial pulmonary infection in a subject in need thereof, comprising administering to the subject an effective amount of Formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of Formula (I). In some embodiments, the bacteria causing nontuberculous Mycobacteria lung infections are M. abscessus, M. avium, M. kansasii, M. smegmantis, M. xenopi, and / or M. malmoense, preferably M. abscessus, M. avium, M. kansasii, and / or M. xenopi, more preferably M. abscessus.

[0149] In one aspect, the present invention provides the use of a compound according to Formula (I) or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof in the manufacture of a medicament for treating a nontuberculous Mycobacterial pulmonary infection in a subject in need thereof. In some embodiments, the bacteria causing the nontuberculous Mycobacterial pulmonary infection is M. abscessus, M. avium, M. kansasii, M. smegmantis, M. xenopi, and / or M. malmoense, preferably M. abscessus, M. avium, M. kansasii, and / or M. xenopi, more preferably M. abscessus.

[0150] In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0151] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the invention and a pharmaceutically acceptable carrier, such as, for example, a) a diluent, such as purified water, triglyceride oil, e.g., hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, e.g., EPA or DHA, or esters or triglycerides thereof, or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talcum, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, or a mixture thereof; sodium, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; also for tablets, c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural or synthetic gums such as acacia, tragacanth, or sodium alginate, waxes, and / or polyvinylpyrrolidone; optionally, d) disintegrating agents, for example, starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavors, and sweeteners; f) emulsifiers or dispersing agents, for example, Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS, or other acceptable emulsifiers, and / or g) agents that enhance absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0152] The compounds and pharmaceutical compositions of the present invention may be administered by any suitable route, for example orally as a syrup, tablet, capsule, lozenge, controlled release preparation, fast dissolving preparation or lozenge.

[0153] Liquid, particularly injectable compositions can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds are dissolved or mixed in a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0154] The disclosed compounds can also be formulated as suppositories which can be prepared from fatty emulsions or suspensions using polyalkylene glycols, such as propylene glycol, as the carrier.

[0155] The disclosed compound can also be administered in the form of liposome delivery system, for example, small unilamellar vesicle, large unilamellar vesicle and multilamellar vesicle.Liposome can be formed from various phospholipids, containing cholesterol, stearylamine or phosphatidylcholine.In some embodiments, the film of lipid components is hydrated with an aqueous solution of drug to form a lipid layer that encapsulates drug, as described in U.S. Patent No. 5,262,564.

[0156] Injectable parenteral dosages are generally used for subcutaneous, intramuscular, or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid solution prior to injection.

[0157] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0158] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds by weight or volume.

[0159] Dosage regimens utilizing the disclosed compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient: the severity of the condition being treated, the route of administration, the patient's renal or hepatic function, and the particular disclosed compound being used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0160] An effective dosage of the disclosed compounds, when used for the indicated effect, is in the range of about 0.5 mg to about 5,000 mg of the disclosed compounds required to treat the symptoms. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the disclosed compounds, or a range of amounts from one to another in the dosage list. In one embodiment, the composition is in the form of a scoreable tablet.

[0161] equivalent While the present technology has been described in conjunction with the specific embodiments outlined above, many alternatives, modifications, and other variations thereof will be apparent to those skilled in the art, and all such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present invention.

[0162] example The present invention will now be illustrated by the following non-limiting examples. Specific embodiments of the present invention are described below, but those skilled in the art will recognize that various changes and modifications can be made. Reference to preparations that are similar to, or made by common methods for, other preparations may include variations in routine parameters, such as slight changes in time, temperature, work-up conditions, reagent amounts, and the like.

[0163] Abbreviation The following list provides definitions of certain abbreviations and symbols used herein. It will be understood that the list is not exhaustive, but the meaning of abbreviations and symbols not defined below will be readily apparent to one of ordinary skill in the art. In describing this invention, elements are identified according to the Periodic Table of the Elements. [Table 5]

[0164] Unless otherwise specified, the purity and identity of intermediates or example compounds were assessed by state-of-the-art HLPC-MS, and the methods are described below.

[0165] Compound characterization Method A was used for intermediates. Method B was used to determine the purity of the final compounds. Purity (%) was determined by reversed-phase HPLC or UPLC with UV detection (254 nm). Structures were confirmed by MS using electrospray ionization positive ion (ESI+) techniques, [M+H] + (referring to the protonated molecular ion).

[0166] Method A UPLC system: UPLC I BIN SOL MGR equipped with ACQUITY UPLC I-Class eK PDA Detector, column: Acquity BEH C18 column (1.7 μm particle size, dimensions 50 mm × 2.1 mm), mobile phase: phase A (HO / ammonium formate, pH 3.75 (A) or 9.2 (B)) and phase B (CH3CN + 5% HO / ammonium formate, pH 3.75 (A) or 9.2 (B)) according to the following method. [Table 6]

[0167] Mass spectrometer: ACQUITY QDa (Performance) Xevo TQD. Ionization: electrospray (polarity: negative, positive).

[0168] Method B: HPLC system: Waters 2695 LC equipped with photodiode array detector Waters 996, column: XBridge C18 (3.5 μm particle size, dimensions 50 mm × 4.6 mm), mobile phase: phase A (HO / ammonium formate, pH 9.2) and phase B (CHCN + 5% HO / ammonium formate, pH 9.2) were used according to the following method. [Table 7]

[0169] Mass spectrometer: Waters Alliance Micromass ZQ 2000. Ionization: electrospray (polarity: negative, positive).

[0170] NMR analysis NMR spectra were recorded on a Bruker DRX-300 spectrometer or a Bruker 500 MHz spectrometer equipped with a TXI probe. Chemical shifts are in parts per million (ppm). One-dimensional (1D) 1 H and 13 The assignment was made using C spectra, as well as two-dimensional (2D) HSQC and HMBC spectra.

[0171] Example 1 Synthesis of 21,23-acetonide-25-hydroxy-rifabutin (I-1) [ka] Commercially available rifabutin (40.0 g, 47.2 mmol) was dissolved in dry DMF (80 mL) at room temperature under a nitrogen atmosphere. 2,2-Dimethoxypropane (58.1 mL, 472 mmol) and camphorsulfonic acid (12.6 g, 54.3 mmol) were added sequentially to the solution. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 26 hours. The mixture was then cooled to 0°C and poured into a mixture of saturated aqueous NaHCO3 (700 mL) and water (500 mL). The reaction flask was washed with acetone (100 mL). The resulting suspension was stirred on an ice bath for 10 minutes and filtered. The cake was rinsed with saturated aqueous NaHCO3 (100 mL) and water (50 mL) and dried under vacuum at 40°C for 24 hours. The crude product was purified by flash chromatography (DCM to 50% mixture of DCM / MeOH / NH4OH 90 / 9 / 1.5 in DCM) to give 21,23-acetonide-rifabutin as a purple solid (37.68 g, 90% yield). LC / MS A(ESI+): tr=3.20 min, m / z[M+H] + =887.48, UV purity: 97% (254nm). 1H NMR (300 MHz, CDCl3): δ 0.39 (d, J = 7.0 Hz, 3H), 0.68 (d, J = 7.0 Hz, 3H), 0.77-0.88 (m, 9H), 0.89-0.98 (m, 6H), 1.23 (s, 3H), 1.36-1.55 (m, 2H), 1.71-2.18 (m, 6H), 1.77 (s, 3H), 1.96 (s, 3H), 2.04 (s, 3H), 2.22-2.35 (m, 3H), 2.31 (s, 3H), 2.52-2.72 (m, 2H), 2.79 (s, 3H), 2.91-3.09 (m, 2H), 3.06 (dd, J = 10.3, 5.4 Hz, 1H), 3.34 (d, J = 6.7 Hz, 1H), 3.58 (dd, J = 3.1 Hz, 1H), 4.91 (d, J = 7.5 Hz, 1H), 5.08 (dd, J = 12.1, 6.7 Hz, 1H), 5.87 (d, J = 12.2 Hz, 1H), 6.08 (dd, J = 15.5, 6.8 Hz, 1H), 6.16 (dd, J = 10.7, 1.4 Hz, 1H), 6.28 (dd, J = 15.5, 10.7 Hz, 1H), 7.75 (s, 1H), 8.75 (s, 1H), 14.82 (s, 1H). 13 C NMR (75 MHz, CDCl3): δ 7.89, 9.11, 9.99, 12.8, 18.0, 20.2, 20.3, 20.9, 23.5, 25.8, 34.1, 35.4, 36.0, 36.8, 40.8, 41.4, 51.5, 56.2, 66.3, 71.2, 74.6, 76.9, 78.9, 95.0, 100.1, 104.6, 106.1, 108.7, 111.6, 113.7, 115.3, 123.8, 125.5, 131.2, 132.6, 140.8, 140.9, 142.3, 155.2, 168.2, 168.9, 170.5, 172.2, 181.3, 192.7.

[0172] 21,23-Acetonide-rifabutin (10.6 g, 11.9 mmol) was dissolved in dry diethyl ether (500 mL). The solution was cooled to -10 °C with Ar bubbling. After 15 min, a solution of NaOMe (30 mL, 25 wt % in MeOH) was slowly added. A precipitate formed, and further diethyl ether (100 mL) was added to homogenize. NaOMe solution was added again (27.4 mL). The solution was stirred at -5 °C for 10 min, after which the ice bath was removed. The reaction mixture was stirred at room temperature for 6 h. A saturated aqueous solution of NaHCO3 (400 mL) was added, and the layers were separated. The aqueous layer was extracted with diethyl ether (400 mL), and the combined organic layers were washed with brine (300 mL) and evaporated to give the desired crude product as a black-purple powder. The product was purified by flash chromatography (DCM to 50% DCM / MeOH / NH4OH 90 / 9 / 1.5 mixture in DCM). After evaporation, the product was redissolved in acetone and slowly added to water with vigorous stirring. The solid was collected by filtration and dried at 40 °C to give 8.54 g of intermediate I-1. LC / MS A(ESI+): tr=2.98 min, m / z[M+H] + =845.59, UV purity: 97% (254nm). 1H NMR (300 MHz, CDCl3): δ 0.48 (d, J = 7.0 Hz, 3H), 0.70 (d, J = 6.8 Hz, 3H), 0.74-0.84 (m, 9H), 0.86-0.96 (m, 6H), 1.04 (s, 3H), 1.23-1.33 (m, 1H), 1.43-1.66 (m, 2H), 1.72 (s, 3H), 1.75-2.11 (m, 5H), 2.00 (s, 3H), 2.18-2.29 (m, 3H), 2.21 (s, 3H), 2.47-2.71 (m, 2H), 2.85-3.09 (m, 2H), 3.05-3.14 (m, 1H), 3.10 (s, 3H), 3.27-3.35 (m, 1H), 3.38-3.51 (m, 2H), 3.55 (dd, J = 9.2, 3.3 Hz, 1H), 4.93 (dd, J = 12.5, 9.5 Hz, 1H), 5.93 (dd, J = 15.5, 6.5 Hz, 1H), 6.05-6.16 (m, 2H), 6.24 (dd, J = 15.5, 11.7 Hz, 1H), 7.72 (s, 1H), 8.63 (s, 1H), 14.83 (s, 1H). 13 C NMR (75 MHz, CDCl3): δ 7.7, 8.4, 12.9, 17.8, 19.9, 20.0, 20.9, 21.0, 24.2, 25.5, 25.8, 34.6, 35.2, 36.3, 39.7, 41.1, 51.4, 51.7, 56.2, 66.3, 71.0, 71.5, 75.5, 83.0, 95.0, 99.6, 104.9, 105.7, 108.6, 111.7, 111.8, 114.3, 124.1, 125.5, 132.0, 132.4, 140.3, 142.6, 142.7, 155.2, 168.2, 169.1, 171.3, 181.6, 191.2.

[0173] Example 2 Synthesis of 21,23-アセトニド-25-ブロモアセタート-リファブチン(I-2) [ka] Intermediate I-1 (800 mg, 0.94 mmol, 1 equiv) was dissolved in DCM (20 mL) and cooled to 0 °C. Bromoacetic anhydride (1.54 g, 5.92 mmol, 5 equiv) and DMAP (723 mg, 5.92 mmol, 5 equiv) were then added, and the reaction was stirred at 0 °C. After 1 h, the mixture was washed with an aqueous solution of HCl-1N (20 mL), a saturated aqueous solution of NaHCO (20 mL), and brine (20 mL). The organic layer was dried over MgSO and concentrated in vacuo. The resulting solid was purified by flash chromatography (CHCl / MeOH, 100 / 0 to 95 / 5). The pure fractions were collected, and the solvent was evaporated to give I-2 as a black solid (m = 620 mg, yield = 54%). LC / MS A(ESI+): tr=3.48 min, m / z[M+H] + =965.48 / 967.47, UV purity: 95% (254nm). 1H NMR (300 MHz, CD2Cl2): δ 0.39 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 7.1 Hz, 3H), 0.79-0.88 (m, 9H), 0.92-0.98 (m, 6H), 1.17 (s, 3H), 1.47-1.60 (m 2H), 1.74 (s, 3H), 1.78-2.07 (m, 6H), 2.03 (d, J = 0.8 Hz, 3H), 2.20-2.35 (m, 3H), 2.28 (s, 3H), 2.58-2.76 (m, 2H), 2.83 (s, 3H), 2.88-3.05 (m, 2H), 3.01 (dd, J = 10.3, 5.2 Hz, 1H), 3.34-3.41 (m, 1H), 3.59 (dd, J = 10.6, 3.2 Hz, 1H), 3.74 (d, J = 12.3 Hz, 1H), 3.79 (d, J = 12.3 Hz, 1H), 4.96-5.01 (m, 1H), 5.03 (dd, J = 12.1, 6.9 Hz, 1H), 5.93 (dd, J = 12.1, 0.9 Hz, 1H), 6.05 (dd, J = 15.6, 6.9 Hz, 1H), 6.16 (dd, J = 10.7, 1.4 Hz, 1H), 6.29 (dd, J = 15.6, 10.7 Hz, 1H), 7.75 (s, 1H), 8.77 (s, 1H), 14.87 (s, 1H). 13C NMR (75 MHz, CD2Cl2): δ 7.8, 9.7, 9.9, 12.9, 17.8, 20.1, 20.3, 20.9, 21.0, 24.0, 25.9, 26.1, 26.7, 34.7, 35.6, 36.3, 36.4, 40.8, 41.0, 51.7, 51.8, 56.3, 66.6, 71.1, 76.6, 77.0, 79.2, 95.1, 100.1, 104.9, 106.1, 108.9, 112.0, 114.0, 114.5, 124.1, 125.8, 131.8, 132.5, 140.9, 141.5, 142.6, 155.5, 166.7, 168.5, 169.0, 172.3, 181.7, 192.5.

[0174] Example 3 Synthesis of 21,23-acetonide-25-azidoacetate-rifabutin (I-3) [ka] To a solution of I-2 (2.00 g, 2.07 mmol, 1 equiv) in DMF (30 mL) was added sodium azide (141 mg, 2.17 mmol, 1.05 equiv), and the reaction was stirred at room temperature. After 3 h, the mixture was concentrated in vacuo. The resulting oil was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting solid was purified by flash chromatography (cyclohexane / acetone / TEA from 100 / 0 / 0 to 80 / 18.5 / 1.5) to give the desired product I-3 (m = 880 mg, yield = 50%). LC / MS A(ESI+):tr=2.57, m / z[M+H] + =928.48, UV purity: 99% (254nm). 1H NMR (300 MHz, CDCl3): δ 0.48 (d, J= 6.9 Hz, 3H), 0.73 (d, J = 7.1 Hz, 3H), 0.78-0.88 (m, 9H), 0.88-0.96 (m, 6H), 1.20 (s, 3H), 1.45-1.54 (m, 1H), 1.54-1.69 (m, 1H), 1.73-1.92 (m, 4H), 1.76 (s, 3H), 1.99-2.20 (m, 2H), 2.01 (s, 3H), 2.22-2.36 (m, 3H), 2.31 (s, 3H), 2.47-2.67 (m, 2H), 2.81 (s, 3H), 2.87-3.08 (m, 3H), 3.30 (dd, J = 7.5, 1.5 Hz, 1H), 3.57 (dd, J = 10.7, 3.2 Hz, 1H), 3.70 (d, J = 16.9 Hz, 1H), 3.78 (d, J = 16.9 Hz, 1H), 4.99-5.15 (m, 2H), 5.92 (d, J = 12.3 Hz, 1H), 6.06 (dd, J = 15.6, 6.9 Hz, 1H), 6.15 (dd, J = 10.6, 1.4 Hz, 1H), 6.26 (dd, J = 15.6, 10.6 Hz, 1H), 7.75 (s, 1H), 8.75 (brs, 1H), 14.81 (s, 1H). 13 C NMR (75 MHz, CDCl3): δ7.8, 9.7, 9.8, 12.9, 18.0, 20.14, 20.18, 20.93, 20.94, 23.45, 25.7, 25.9, 34.2, 35.5, 36.2, 36.8, 40.5, 40.9, 50.5, 51.50, 51.59, 56.0, 66.4, 71.0, 76.1, 76.4, 79.9, 95.2, 100.1, 104.6, 106.0, 108.7, 111.6, 113.8, 113.9, 123.8, 125.4, 131.4, 132.5, 140.5, 141.6, 142.3, 155.1, 167.6, 168.2, 168.8, 172.0, 181.3, 192.3.

[0175] Example 4 General Procedure for the Preparation of Triazole Derivatives [ka] A solution of 21,23-acetonide-25-azidoacetate-rifabutin I-3 (0.05 mol / L) with sodium ascorbate (0.007 mol / L) and CuSO4·5H2O (0.007 mol / L) was prepared in tBuOH / H2O (3 / 1). The desired alkyne (0.32 mmol, 1.5 equiv.) was charged to a Kimble reactor, followed by 400 μL of a solution of 25-azido-acetic acid-21,23-acetonide-rifabutin in tBuOH / HO (equivalent to 20 mg, 0.021 mmol, 1 equiv. of 25-azido-acetic acid-21,23-acetonide-rifabutin, 0.6 mg, 0.003 mmol, 0.15 equiv. of sodium ascorbate, and 0.8 mg, 0.003 mmol, 0.15 equiv. of CuSO 5HO). The reaction was stirred at 60 °C.

[0176] After 24 hours, 400 μL of an aqueous solution of camphorsulfonic acid (0.5N) was added to the mixture. The reaction was stirred at room temperature for 24 hours. The mixture was then loaded onto a ColumnPoraPak (Rxn RP 6CC) equilibrated with water. Elution was carried out with 5 mL of water, 5 mL of saturated aqueous NaHCO3, 5 mL of a water / ACN solution (90 / 10), and 10 mL of ACN. 10 mL of ACN was collected, frozen, and lyophilized to give the desired product as a purple powder.

[0177] Table 5 below summarizes exemplary compounds of the present invention prepared according to the protocol of Example 4 above. (The data shown in Table 5 was obtained according to Analytical Method B.) [Table 8-1] [Table 8-2]

Table 8-3

Table 8-4

Table 8-5

Table 8-6

Table 8-7

Table 8-8

Table 8-9

Table 8-10

Table 8-11

Table 8-12

Table 8-13

[0178] Additional analysis (NMR): Compound 1: 1H NMR (300 MHz, CDCl3): δ (ppm) -0.14 (d, J = 7.2 Hz, 3H), 0.52 (d, J= 6.8 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 6H), 1.04 (d, J = 6.8 Hz, 3H), 1.18-1.26 (m, 1H), 1.67-1.76 (m, 1H), 1.71 (s, 3H), 1.77-1.93 (m, 3H), 1.94-2.09 (m, 3H), 2.03 (s, 3H), 2.24-2.34 (m, 2H), 2.31 (s, 3H), 2.37-2.47 (m,1H), 2.55-2.72 (m, 2H), 2.88-3.07 (m, 4H), 3.09 (s, 3H), 3.20 (dd, J = 9.5 Hz, 3.5 Hz, 1H), 3.36 (d, J = 8.5 Hz, 1H), 3.64 (d, J= 9.8 Hz, 1H), 4.88 (d, J = 10.8 Hz, 1H), 4.92-5.16 (m, 2H), 5.41 (dd, J = 12.4 Hz, 9.9 Hz, 1H), 5.81-5.98 (m, 1H), 6.12-6.30 (m, 3H), 7.28-7.36 (m, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.82 (d, J = 7.8 Hz, 2H), 7.95 (s, 1H), 8.22 (s, 1H), 9.60 (s, 1H), 14.43 (s, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 7.85, 8.95, 11.06, 12.61, 17.40, 20.32, 21.10, 21.14, 22.69, 26.12, 32.96, 35.43, 36.39, 37.32, 38.48, 39.46, 51.59, 51.73, 56.58, 66.56, 71.85, 74.32, 76.37, 84.03, 95.12, 104.39, 107.98, 109.72, 111.54, 115.34, 116.37, 121.60, 123.37, 124.98, 126.06, 128.39, 129.09, 130.87, 132.93, 132.99, 140.87, 141.96, 146.69, 148.23, 155.05, 166.06, 168.02, 168.63, 171.68, 180.63, 192.61. Compound 8: 1H NMR (300 MHz, CDCl3): δ (ppm) -0.13 (d, J = 7.1 Hz, 3H), 0.52 (d, J= 6.9 Hz, 3H), 0.81 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.5 Hz, 6H), 1.06 (d, J = 6.5 Hz, 3H), 1.18-1.31 (m, 5H), 1.68-1.74 (m, 1H), 1.72 (s, 3H), 1.81-2.04 (m, 6H), 2.03 (s, 3H), 2.24-2.34 (m, 2H), 2.32 (s, 3H), 2.35-2.46 (m, 1H), 2.56-2.73 (m, 2H), 2.88-3.07 (m, 4H), 3.11 (s, 3H), 3.21 (dd, J= 9.6 Hz, 3.5 Hz, 1H), 3.28 (d, J = 8.3 Hz, 1H), 3.65 (d, J = 10.2 Hz, 1H), 4.89 (dd, J = 10.8 Hz, 1.3 Hz, 1H), 4.99-5.15 (m, 2H), 5.41 (dd, J = 12.7 Hz, 9.6 Hz, 1H), 5.85-5.99 (m, 1H), 6.18-6.30 (m, 3H), 7.22 (ddd, J = 7.5 Hz, 4.9 Hz, 1.1 Hz, 1H), 7.76 (td, J = 7.7 Hz, 1.7 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.21-8.28 (m, 2H), 8.56-8.62 (m, 1H), 9.57 (s, 1H), 14.46 (s, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 7.91, 8.98, 11.13, 12.58, 17.47, 20.39, 21.14, 21.18, 22.72, 26.18, 30.03, 33.06, 35.54, 36.47, 37.41, 38.49, 39.44, 51.71, 51.78, 56.75, 66.62, 71.98, 74.58, 76.47, 83.93, 95.12, 104.49, 108.00, 109.75, 111.65, 115.43, 116.33, 120.64, 123.16, 123.53, 124.02, 125.06, 132.90, 133.02, 137.16, 140.97, 142.01, 146.61, 148.92, 149.78, 150.55, 155.18, 166.03, 168.14, 168.68, 171.76, 180.80, 192.75. Compound 12: 1H NMR (300 MHz, CDCl3): δ (ppm) -0.17, (d, J = 7.0 Hz, 3H), 0.46 (d, J = 6.8 Hz, 3H), 0.79 (d, J = 7.3 Hz, 3H), 0.93 (d, J = 6.5 Hz, 6H), 1.03 (d, J = 6.9 Hz, 3H), 1.12-1.27 (m, 1H), 1.63-1.74 (m, 1H), 1.71 (s, 3H), 1.77-2.01 (m, 6H), 2.03 (s, 3H), 2.22 (s, 3H), 2.25-2.31 (m, 2H), 2.29 (s, 3H), 2.36-2.46 (m, 1H), 2.55-2.71 (m, 2H), 2.85-3.01 (m, 4H), 3.07 (s, 3H), 3.16 (dd, J= 9.6 Hz, 3.3 Hz, 1H), 3.32 (d, J = 8.3 Hz, 1H), 3.44-3.58 (m, 2H), 3.62 (d, J= 9.9 Hz, 1H), 3.72 (s, 2H), 4.84 (d, J= 10.7 Hz, 1H), 4.88-5.09 (m, 2H), 5.38 (dd, J = 12.6 Hz, 9.7 Hz, 1H), 5.82-5.97 (m, 1H), 6.15-6.29 (m, 3H), 7.21-7.33 (m, 5H), 7.63 (s, 1H), 8.22 (s, 1H), 9.57 (s, 1H), 14.44 (s, 1H). 13C NMR (75 MHz, CDCl3): δ (ppm) 7.82, 8.92, 11.09, 12.54, 17.40, 20.34, 21.10, 21.14, 22.69, 26.13, 32.96, 35.47, 36.40, 37.31, 38.39, 39.40, 42.38, 51.49, 51.73, 52.29, 56.55, 61.39, 66.58, 71.90, 74.30, 76.37, 83.93, 95.10, 104.43, 107.98, 109.68, 111.59, 115.29, 116.18, 123.49, 124.49, 125.00, 127.28, 128.53, 129.22, 132.87, 132.94, 139.06, 140.85, 141.97, 145.67, 146.66, 155.07, 166.16, 168.07, 168.62, 171.64, 180.69, 192.59.

[0179] Example 5 Antibacterial activity MIC values ​​were determined by broth microdilution according to CLSI guidelines. Unless otherwise stated, MICs for A. baumannii were performed in RPMI medium supplemented with 10% FCS. MICs for M. abscessus were performed in Middlebrook 7H9 broth supplemented with Middlebrook ADC growth supplement (10%). All other MICs for slow-growing mycobacteria (M. xenopi, M. kansasii, and M. avium) were performed in standard cation-adjusted Mueller-Hinton broth supplemented with Middlebrook ADC growth supplement (5%).

[0180] The following procedure applies to all species tested except M. xenopi. From a fresh culture plate (overnight to several days, depending on the bacterium), cells are resuspended in 0.9% (w / v) saline and bacterial inocula are prepared in each test medium at a concentration of 5 × 10 5CFU / mL. For M. xenopi, inocula were prepared from fresh liquid medium (7H9 + ADC). Appropriate volumes of 10 mg / mL compound solutions were dispensed directly into 96-well assay plates using a digital dispenser to achieve final concentrations of 32–0.002 μg / mL for A. baumannii and S. aureus, 16–0.016 μg / mL for M. abscessus and M. avium, and 1–6 × 10 for M. kansasii and M. xenopi. -5 Two-fold dilution series of μg / mL were made. Finally, 100 μL of the bacterial suspension was added to the compound. The plates were covered and incubated without shaking for 20 hours at 35°C for A. baumannii and S. aureus, 4 days at 30°C for M. abscessus, and 7 days (at least) at 37°C for M. kansasii (covered with aluminum foil to avoid light exposure), M. avium, and M. xenopi. All experiments included antibiotics as quality controls. MICs were determined visually as the lowest concentration of compound that prevented visible bacterial growth.

[0181] The in vitro activity of the compounds described herein was determined against S. aureus (strain UAMS-1625), A. baumannii (strain HUMC1), M. abscessus (ATCC 19977), M. kansasii (ATCC 12478), M. avium (ATCC 25291), and M. xenopi (ATCC 19250). MIC values ​​(given in μg / mL) are shown in Table 6 below. [Table 9]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: 【Chemical 1】 (In the formula, X １ are independently —COOH, —C １ -C ６ Alkyl, -C ３ -C ８ Cycloalkyl, —C １ -C ６ Alkylene-(C ３ -C ８ cycloalkyl), 5- to 10-membered heterocycloalkyl, —C １ -C ６ alkylene-(5- to 10-membered heterocycloalkyl), —C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), 5- to 10-membered heteroaryl, and —C １ -C ６ alkylene-(5- to 10-membered heteroaryl); The alkyl may be one or more R １ and optionally substituted by The cycloalkyl may each independently, at each occurrence, be one or more R ２ and optionally substituted by The heterocycloalkyl may each independently, at each occurrence, be one or more R ３ and optionally substituted by The aryl may each independently, at each occurrence, be one or more R ４ and optionally substituted by The heteroaryl may each independently, at each occurrence, be one or more R ５ and optionally substituted by R １ , R ２ , R ３ , R ４ , and R ５ are each independently, at each occurrence, —OH, —OC １ -C ６ Alkyl, —NR ６ R ７ , -NHSO ２ R ８ , -COOH, oxo, -NO ２ phenyl, halogen, and cyano; R ６ and R ７ are each independently, at each occurrence, —H and —C １ -C ６ alkyl, wherein C １ -C ６ The alkyl may be substituted by phenyl; R ８ are independently -C １ -C ６ alkyl and phenyl, said phenyl being selected from -C １ -C ６ may be substituted by alkyl or halogen).

2. R １ , R ２ , R ３ , R ４ and R ５ each independently at each occurrence, —OH, —OC １ -C ６ Alkyl, —NR ６ R ７ , -NHSO ２ R ８ , -COOH, oxo, -NO ２ and phenyl; R ６ and R ７ each independently at each occurrence, -H and -C １ -C ６ alkyl, wherein C １ -C ６ The alkyl may be substituted by phenyl; R ８ But independently, -C １ -C ６ alkyl and phenyl, said phenyl being selected from -C １ -C ６ optionally substituted by alkyl or halogen; The compound of claim 1.

3. X １ are independently —COOH, —C １ -C ６ Alkyl, -C ３ -C ６ Cycloalkyl, —C １ -C ６ Alkylene-(C ３ -C ６ cycloalkyl), 5- to 7-membered heterocycloalkyl, —C １ -C ６ alkylene-(5- to 7-membered heterocycloalkyl), —C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), 5- to 10-membered heteroaryl, or —C １ -C ６ alkylene-(5- to 10-membered heteroaryl); The alkyl may be one or more R １ and optionally substituted by The cycloalkyl may each independently at each occurrence be one or more R ２ and optionally substituted by The heterocycloalkyl may each independently at each occurrence be one or more R ３ and optionally substituted by The aryl may each independently, at each occurrence, be one or more R ４ and optionally substituted by each of said 5- to 10-membered heteroaryls is unsubstituted; R １ independently at each occurrence, —OH, —NR ６ R ７ , -NHSO ２ R ８ and —COOH; R ２ Ga-NR ６ R ７ is selected from R ３ is oxo, R ４ independently, at each occurrence, -OC １ -C ６ Alkyl, —NR ６ R ７ , -COOH, -NO ２ and phenyl.

4. X １ But independently, -C １ -C ５ Alkyl, -C ５ -C ６ Cycloalkyl, —C １ -C ２ Alkylene-(C ５ -C ６ cycloalkyl), 5- to 6-membered heterocycloalkyl, —C １ -C ２ alkylene-(5- to 6-membered heterocycloalkyl), —C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), and 5- to 6-membered heteroaryl; The alkyl is one to three R １ by, preferably exactly one R １ wherein each said cycloalkyl is unsubstituted and each said heterocycloalkyl is independently substituted at each occurrence by one or two R ３ wherein said aryl is each independently, at each occurrence, 1 to 3 R ４ by, preferably exactly one R ４ and optionally substituted by R １ independently, at each occurrence, -NR ６ R ７ and -NHSO ２ R ８ is selected from R ３ is oxo, R ４ independently, at each occurrence, -OC １ -C ６ Alkyl, NH ２ , and -NO ２ is selected from R ６ and R ７ independently at each occurrence, —H, —CH ３ , and -CH ２ -C ６ H ５ is selected from R ８ But -CH ３ or phenyl, wherein said phenyl has one or more —CH ３ or -Cl.

5. X １ But independently, -C １ -C ３ Alkyl, cyclohexyl, -C １ Alkylene-(cyclohexyl), phenyl, -C １ -C ３ alkylene-(phenyl), and 2-pyridinyl; The alkyl is one or two R １ by, preferably exactly one R １ wherein each said cyclohexyl is unsubstituted and each said phenyl is unsubstituted or substituted with one or two, preferably exactly one, —OCH ３ Or - NO ２ and said 2-pyridinyl is unsubstituted; R １ independently at each occurrence, -N(CH ３ ) (CH ２ C ６ H ５ ), and -NHSO ２ R ８ is selected from R ８ is phenyl, and the phenyl is —CH ３ The compound according to any one of claims 1 to 4, which is optionally substituted with -Cl or -Cl.

6. X １ Ga-C １ -C ６ alkyl, wherein the alkyl is one or more R １ and R １ independently, at each occurrence, -OH, -OC １ -C ６ Alkyl, —NR ６ R ７ , -NHSO ２ R ８ , -COOH, oxo, -NO ２ , phenyl, halogen, and cyano.

7. X １ But, -C ３ -C ８ Cycloalkyl or -C １ -C ６ Alkylene-(C ３ -C ８ cycloalkyl), wherein said cycloalkyl is each independently, at each occurrence, one or more R ２ and R ２ But -OH, -OC １ -C ６ Alkyl, —NR ６ R ７ , -NHSO ２ R ８ , -COOH, oxo, -NO ２ , phenyl, halogen, and cyano.

8. X １ is 5 to 10-membered heterocycloalkyl or —C １ -C ６ alkylene-(5- to 10-membered heterocycloalkyl), wherein said heterocycloalkyl is each independently selected at each occurrence from one or more R ３ and R ３ But -OH, -OC １ -C ６ Alkyl, —NR ６ R ７ , -NHSO ２ R ８ , -COOH, oxo, -NO ２ , phenyl, halogen, and cyano.

9. X １ But, -C ６ -C １０ Aryl or -C １ -C ６ Alkylene-(C ６ -C １０ aryl), each and every occurrence of which is independently selected from one or more R ４ and R ４ independently, at each occurrence, -OH, -OC １ -C ６ Alkyl, —NR ６ R ７ , -NHSO ２ R ８ , -COOH, oxo, -NO ２ , phenyl, halogen, and cyano.

10. X １ is 5- to 10-membered heteroaryl or —C １ -C ６ alkylene-(5- to 10-membered heteroaryl), wherein said heteroaryl is independently selected at each occurrence from one or more R ５ and R ５ But -OH, -OC １ -C ６ Alkyl, —NR ６ R ７ , -NHSO ２ R ８ , -COOH, oxo, -NO ２ , phenyl, halogen, and cyano.

11. 【Chemical 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 2. The compound of claim 1 selected from the group consisting of:

12. 【Catalog 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 2. The compound of claim 1 selected from the group consisting of:

13.

16. 【Chemistry 17】 【Chemistry 18】 2. The compound of claim 1 selected from the group consisting of:

14. 14. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof and a pharmaceutically acceptable excipient.

15. 15. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition according to claim 14, for use as a medicament.

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