Rifbutin analogs for treatment of disease

Abstract

The present invention relates to a compound for treating, alleviating and / or preventing a disease and a pharmaceutical composition comprising the same. 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 non-tuberculous Mycobacterium genus, preferably Mycobacterium abscessus.

Description

[0001] The present invention relates to compounds for treating, alleviating, and / or preventing diseases and pharmaceutical compositions comprising such compounds. 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 Acinetobacter baumannii and / or Staphylococcus aureus and / or the non-tuberculous mycobacteria (NTM) genus, preferably Mycobacterium abscessus. Background Art

[0002] Rifamycins such as rifabutin are known antibiotics that are active against a broad spectrum of pathogenic bacteria such as 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, 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 be potent against Mycobacterium abscessus in vitro and in vivo (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;). Antraygues et al., Eur. J. Med. Chem., 238, 2022 described a prodrug of c21-modified rifabutin for intravenous administration in Acinetobacter baumannii infections. Ma et al. (US2020 / 0360352) described a rifamycin-nitroimidazole conjugate molecule for the treatment of nontuberculous mycobacteria. Ding et al. (WO 2008 / 008480) described substituted rifamycin derivatives in which a nitroimidazole, nitrothiazole, or nitrofurane pharmacophore is covalently bound to rifamycin. Peek et al. described a semisynthetic hybrid antibiotic formed by linking the rifampicin analogue Kangelmycin A and a series of fluoroquinolones (Peek et al., Bioorg. & Med. Chem. Lett., 57, 2021). Occelli et al. described rifamycin derivatives substituted at position 36 and the activity of such derivatives against Gram-positive bacteria and fastidious Gram-negative bacteria (WO 94 / 28002). However, there is still a need for more effective rifamycins for the treatment of bacterial infections such as Mycobacterium abscessus infections and Acinetobacter 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:

[0005]

[0006] Wherein:

[0007] X 1 is independently selected from: -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 aryl), 5- to 10-membered heteroaryl and -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0008] Wherein the alkyl is optionally substituted by one or more R 1 substituents;

[0009] Wherein the cycloalkyl is independently optionally substituted by one or more R 2 substituents each time it appears;

[0010] Wherein the heterocycloalkyl is independently optionally substituted by one or more R 3 substituents each time it appears;

[0011] Wherein the aryl is independently optionally substituted by one or more R 4 substituents each time it appears;

[0012] Wherein the heteroaryl is independently optionally substituted by one or more R 5 substituents each time it appears;

[0013] R 1 、R 2 、R 3 、R 4 and R 5 are each independently selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 、-COOH, oxo, -NO2, phenyl, halogen and cyano;

[0014] R 6 and R 7each independently selected, at each occurrence, from: -H and -C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with phenyl; and

[0015] R 8 independently selected from: -C1-C6 alkyl and phenyl, wherein said phenyl is optionally substituted with -C1-C6 alkyl or halogen.

[0016] 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 as a medicament.

[0017] 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 genus Acinetobacter, Staphylococcus and / or Mycobacterium. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii and / or Staphylococcus aureus and / or the genus Mycobacterium nontuberculosis, preferably Mycobacterium abscessus. In a preferred embodiment, the bacterial infection is caused by one or more bacteria belonging to the genus Mycobacterium nontuberculosis, preferably Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably Acinetobacter baumannii and / or Staphylococcus aureus.

[0018] 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 medicament. 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 genus Acinetobacter, Staphylococcus and / or Mycobacterium. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii and / or Staphylococcus aureus and / or the genus Mycobacterium nontuberculosis, preferably Mycobacterium abscessus. In a preferred embodiment, the bacterial infection is caused by one or more bacteria belonging to the genus Mycobacterium nontuberculosis, preferably Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably Acinetobacter baumannii and / or Staphylococcus aureus.

[0019] In one aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) in the preparation of a medicament for treating bacterial infections. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the genus Acinetobacter, Staphylococcus, and / or Mycobacterium. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii and / or Staphylococcus aureus and / or the genus Mycobacterium nontuberculosis, preferably Mycobacterium abscessus. In a preferred embodiment, the bacterial infection is caused by one or more bacteria belonging to the genus Mycobacterium nontuberculosis, preferably Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably Acinetobacter baumannii and / or Staphylococcus aureus.

[0020] In one aspect, the present invention provides a method for treating bacterial infections in a subject in need thereof, the method 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 genus Acinetobacter, Staphylococcus, and / or Mycobacterium. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii and / or Staphylococcus aureus and / or the genus Mycobacterium nontuberculosis, preferably Mycobacterium abscessus. In a preferred embodiment, the bacterial infection is caused by one or more bacteria belonging to the genus Mycobacterium nontuberculosis, preferably Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably Acinetobacter baumannii and / or Staphylococcus aureus.

[0021] The present invention provides a rifabutin analogue modified at the C25 position to contain 2-triazole acetate (wherein the triazole is substituted at the 4th position) and a pharmaceutical composition comprising the rifabutin analogue. The compounds of the present invention exhibit broad antibacterial activity against a large number of bacterial species, thus maintaining the broad antibacterial activity characteristics of rifamycin antibiotics. In addition, compared with currently available antibiotics such as rifabutin, the compounds of the present invention unexpectedly show enhanced antibacterial activity against Mycobacterium nontuberculosis, including Mycobacterium abscessus. After reading the following detailed description, those skilled in the art will be clear about the additional features and advantages of the present technology. Detailed Description

[0022] The present invention provides analogues of rifabutin that are effective in treating bacterial infections, preferably bacterial infections caused by one or more bacteria (preferably Mycobacterium abscessus) belonging to the genus Mycobacterium nontuberculosis.

[0023] Definition

[0024] 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.

[0025] Unless the context clearly dictates otherwise, the articles "a" and "an" as used in this disclosure refer to one or more than one (i.e., at least one) grammatical object. For example, "an element" refers to one element or more than one element.

[0026] Unless otherwise indicated, the term "and / or" as used in this disclosure means "and" or "or".

[0027] The term "optionally substituted" should be understood to mean that a given chemical moiety (e.g., an alkyl group) may (but is not required to) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl may have substituents other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxy group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" implies that a given chemical moiety has the potential to contain additional functional groups, but does not necessarily have any additional functional groups.

[0028] The term "alkyl" refers to straight-chain or branched-chain saturated hydrocarbons. C1-C6 alkyl groups contain 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.

[0029] As used herein, the term "alkylene" (or "alkylenyl") refers to a straight-chain or branched-chain hydrocarbon chain diradical derived from an alkyl as defined herein, where one hydrogen of the alkyl is cleaved to create the second radical of the alkylene. By way of example, examples of alkylene are -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-.

[0030] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 8 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0031] The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl and naphthyl. C6-C 10The aryl group contains 6 to 10 carbon atoms; preferably 6 or 10 carbon atoms. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be fused (e.g., naphthyl). The aryl group may optionally be substituted at any attachment point with one or more substituents such as 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, the aryl group may optionally be substituted with substituents selected from the group consisting of: -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen, and cyano. Substituents (such as alkyl groups) themselves may optionally be substituted.

[0032] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or bicyclic aromatic group having 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, and more preferably from N and O. The aromatic group is optionally independently substituted with one or more substituents as described herein. Examples include but are not limited to furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, quinolinyl, 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]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.

[0033] The terms "heterocyclic group", "heterocycloalkyl" or "heterocycle" refer to a monocyclic or polycyclic saturated or partially saturated 5- to 10-membered ring containing carbon and heteroatoms selected from O, N, and S (preferably O and N), where at least one ring does not contain delocalized π electrons (aromaticity) shared between ring carbons or heteroatoms. When the heterocycle is a monocyclic heterocycle, the monocyclic heterocycle does not include aromaticity. Heterocyclic groups include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, tetrahydrothiazolyl, pyranyl, thiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, [1,4]diazepanyl, [1,2]diazepanyl, decahydro-[1,6]naphthyridine, and diazepinyl. In some embodiments, the heterocyclic group is fully saturated. In some embodiments, the heterocyclic group is partially saturated.

[0034] The heterocyclic group or heterocycloalkyl ring can be fused or bridged, e.g., a bicyclic or tricyclic ring. Further, when containing two or more fused rings, the heterocycloalkyl groups as defined herein can have an unsaturated or partially saturated ring fused to an aromatic ring and / or heteroaromatic ring. Exemplary ring systems of such heterocyclic-aryl or heterocyclic-heteroaryl groups include indolinyl, indolinone, dihydrobenzothienyl, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine, and dihydrobenzoxanyl.

[0035] The heterocyclic group or heterocycloalkyl ring can also be a spiroheterocycle or spiroheteroaromatic. As used herein, a spiroheterocycle or spiroheteroaromatic is understood to mean a bicyclic or polycyclic ring system in which at least two rings are joined by a single atom, where at least one ring is a heterocycle (e.g., at least one ring is furanyl, morpholinyl, or piperidinyl). One or both rings in the spiroheterocycle can be fused to one or more additional carbocyclic, heterocyclic, aromatic, or heteroaromatic rings to form, e.g., a tricyclic ring system in which two rings are joined by a single atom.

[0036] As used herein, the term "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0037] The term "oxo" refers to a carbonyl functional group consisting of a carbon atom double-bonded to an oxygen atom. It can be abbreviated herein as "oxo", C(O), or C═O.

[0038] The present invention also includes a pharmaceutical composition, which comprises an effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0039] Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, ethanedisulfonate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, sethionate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, acetalate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1'-methylene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, toluenesulfonate, triethiodide, and valerate.

[0040] The term "multiple stereoisomers" refers to a group of compounds having the same number and type of atoms and sharing the same bond connectivity between these atoms, but differing in three-dimensional structure. The term "stereoisomer" refers to any member of this group of compounds.

[0041] The term "multiple diastereomers" refers to a set of stereoisomers that cannot be superimposed by rotation around a single bond. For example, cis and trans double bonds, endo- and exo-substitutions on bicyclic ring systems, and compounds containing multiple stereocenters with different relative configurations are considered multiple diastereomers. The term "diastereomer" refers to any member of this set of compounds. In some of the illustrated examples, the synthetic route can produce a single diastereomer or a mixture of diastereomeric monomers. In some cases, these diastereomers are separated, and in other cases, a wavy bond is used to indicate a structure element with variable configuration.

[0042] The term "multiple enantiomers" refers to stereoisomers that are non-superimposable mirror images of each other. The term "enantiomer" refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of enantiomers.

[0043] The term "multiple tautomers" refers to a set of compounds that have the same number and type of atoms, but different bond connectivities and are in equilibrium with each other. A "tautomer" is a single member of this set of compounds. Usually, a single tautomer is drawn, but it is understood that this single structure is intended to represent all possible tautomers that may exist. Examples include enol-keto tautomerism. When a ketone is drawn, it should be understood that both the enol and ketone forms are part of the present disclosure.

[0044] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purposes of the present invention do not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. A solvate with water as the solvent molecule is usually referred to as a "hydrate". Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0045] When used in connection with a compound, an "effective amount" is an amount effective to treat or prevent a disease in a subject as described herein.

[0046] The term "carrier" as used in the present disclosure includes carriers, excipients, and diluents, and refers to a material, composition, or vehicle (such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material) involved in carrying or transporting a drug from one organ or part of the body of a subject to another organ or another part of the body.

[0047] The term "treatment" with respect to a subject means at least one symptom of the subject's condition is improved. Treatment includes curing, ameliorating, or at least partially alleviating the condition.

[0048] Unless otherwise indicated, the term "condition" as used in this disclosure means the term disease, disorder, or affliction, and may be used interchangeably therewith.

[0049] The term "administer (administering / administration)" as used in this disclosure means directly administering the disclosed compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same to a subject, or administering a prodrug derivative or analogue of the compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject, which may form an equivalent amount of the active compound in the subject's body.

[0050] A "patient" or "subject" is a mammal, such as 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 a human.

[0051] Compounds of the present invention

[0052] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or enantiomer thereof:

[0053]

[0054] Wherein:

[0055] X 1 Independently selected from: -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 aryl), 5- to 10-membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0056] Wherein the alkyl is optionally substituted with one or more R 1 substituents;

[0057] Wherein the cycloalkyl is each independently optionally substituted with one or more R 2 substituents;

[0058] Wherein the heterocycloalkyl is each independently optionally substituted with one or more R3 Substituted;

[0059] wherein said aryl is each independently optionally substituted, in each occurrence, with one or more R 4 Substituted;

[0060] wherein said heteroaryl is each independently optionally substituted, in each occurrence, with one or more R 5 Substituted;

[0061] R 1 , R 2 R 3 R 4 and R 5 are each independently selected, in each occurrence, from: -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen and cyano;

[0062] R 6 and R 7 are each independently selected, in each occurrence, from: -H and -C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with phenyl; and

[0063] R 8 is independently selected from: C1-C6 alkyl and phenyl, wherein said phenyl is optionally substituted with -C1-C6 alkyl or halogen.

[0064] In some embodiments of formula (I), R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected, in each occurrence, from: -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , -COOH, oxo, -NO2 and phenyl;

[0065] R 6 and R 7 are each independently selected, in each occurrence, from: -H and -C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with phenyl; and

[0066] R 8 is independently selected from: C1-C6 alkyl and phenyl, wherein said phenyl is optionally substituted with -C1-C6 alkyl or halogen.

[0067] In some embodiments of formula (I), X 1Independently selected from: -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- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0068] wherein said alkyl is optionally substituted by one or more R 1 substituents; each occurrence of said cycloalkyl is independently optionally substituted by one or more R 2 substituents; each occurrence of said heterocycloalkyl is independently optionally substituted by one or more R 3 substituents; each occurrence of said aryl is independently optionally substituted by one or more R 4 substituents; said 5- to 10-membered heteroaryl is unsubstituted;

[0069] R 1 is independently selected, in each occurrence, from: -OH, -NR 6 R 7 , -NHSO2R 8 and -COOH;

[0070] R 2 is selected from -NR 6 R 7 ;

[0071] R 3 is oxo; and

[0072] R 4 is independently selected, in each occurrence, from: -OC1-C6 alkyl, -NR 6 R 7 、-COOH、-NO2 and phenyl.

[0073] In some embodiments of formula (I), X 1 is independently selected from: -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- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl);

[0074] wherein said alkyl is optionally substituted by one or more R 1Substituted; each cycloalkyl group, upon each occurrence, is independently optionally substituted by one or more R 2 Substituted; each heterocycloalkyl group, upon each occurrence, is independently optionally substituted by one or more R 3 Substituted; each aryl group, upon each occurrence, is independently optionally substituted by one or more R 4 Substituted; each 5- to 10-membered heteroaryl group is unsubstituted;

[0075] R 1 is independently selected, upon each occurrence, from: -OH, -NR 6 R 7 , -NHSO2R 8 and -COOH;

[0076] R 2 is selected from -NR 6 R 7 ;

[0077] R 3 is oxo;

[0078] R 4 is independently selected, upon each occurrence, from: -OC1-C6 alkyl, -NR 6 R 7 , -COOH, -NO2 and phenyl.

[0079] R 6 and R 7 are independently selected, upon each occurrence, from: -H and -C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by phenyl; and

[0080] R 8 is independently selected from: C1-C6 alkyl and phenyl, wherein the phenyl is optionally substituted by -C1-C6 alkyl or halogen.

[0081] In some embodiments, X 1 is independently selected from: -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- to 6-membered heteroaryl, or -C1-C4 alkylene-(5- to 6-membered heteroaryl);

[0082] wherein the alkyl is optionally substituted by one to three R 1 ; each cycloalkyl group, upon each occurrence, is independently optionally substituted by one to three R 2Substituted; each heterocycloalkyl, upon each occurrence, is independently optionally substituted with one to three R 3 Substituted; each aryl, upon each occurrence, is independently optionally substituted with one to three R 4 Substituted; each 5- to 6-membered heteroaryl is unsubstituted;

[0083] R 1 Upon each occurrence, is independently selected from: -OH, -NR 6 R 7 , -NHSO2R 8 and -COOH;

[0084] R 2 Is -NH2;

[0085] R 3 Is oxo;

[0086] R 4 Upon each occurrence, is independently selected from: -OC1-C2 alkyl, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, -COOH, -NO2 and phenyl;

[0087] R 6 and R 7 Upon each occurrence, are independently selected from: -H, -CH3 and -CH2-C6H5; and

[0088] R 8 Upon each occurrence, is independently selected from: -CH3 or phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or halogens.

[0089] In some embodiments, X 1 Is independently selected from: -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;

[0090] Wherein the alkyl is optionally substituted with one or two R 1 Substituted, preferably substituted with exactly one R 1 Substituted; each cycloalkyl, upon each occurrence, is independently optionally substituted with one or two R 2 Substituted, preferably substituted with exactly one R 2 Substituted; each heterocycloalkyl, upon each occurrence, is independently optionally substituted with one or two R 3 Substituted, preferably substituted with two R 3Substituted; each aryl, when it appears each time, is independently optionally substituted by one or two R 4 substituted, preferably substituted by exactly one R 4 substituted; the 5- to 6-membered heteroaryl is unsubstituted;

[0091] R 1 is independently selected from, each time it appears: -OH, -NH2, -N(CH3)(CH2C6H5), -NHSO2R 8 and -COOH;

[0092] R 2 is -NH2;

[0093] R 3 is oxo;

[0094] R 4 is independently selected from, each time it appears: -OCH3, -NH2, -COOH, -NO2 and phenyl; and

[0095] R 8 is independently selected from, each time it appears: -CH3 or phenyl, wherein the phenyl is optionally substituted by one or more -CH3 or halogen.

[0096] In some embodiments of formula (I), X 1 is independently selected from: -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;

[0097] wherein the alkyl is optionally substituted by one to three R 1 substituted, preferably substituted by exactly one R 1 substituted; each cycloalkyl is unsubstituted; each heterocycloalkyl, when it appears each time, is independently optionally substituted by one or two R 3 substituted; each aryl, when it appears each time, is independently optionally substituted by one to three R 4 substituted, preferably substituted by exactly one R 4 substituted;

[0098] R 1 is independently selected from, each time it appears: -NR 6 R 7 and -NHSO2R 8 ; and

[0099] R 3 is oxo;

[0100] R 4 is independently selected from: phenyl, -OC1-C6 alkyl, -NH2 and -NO2 each time it appears;

[0101] R 6 and R 7 are independently selected from: -H, -CH3 and -CH2-C6H5 each time they appear; and

[0102] R 8 is -CH3 or phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or -Cl.

[0103] In some embodiments of formula (I), X 1 is independently selected from: -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;

[0104] wherein the alkyl is optionally substituted with one to three R 1 substituents, preferably exactly one R 1 substituent; the cycloalkyls are each unsubstituted; the heterocycloalkyls are each independently optionally substituted with one or two R 3 substituents each time they appear; the aryls are each independently optionally substituted with one to three R 4 substituents, preferably exactly one R 4 substituent;

[0105] R 1 is independently selected from: -NR 6 R 7 and -NHSO2R 8 ; and

[0106] R 3 is oxo;

[0107] R 4 is independently selected from: -OC1-C6 alkyl, -NH2 and -NO2 each time it appears;

[0108] R 6 and R 7 are independently selected from: -H, -CH3 and -CH2-C6H5 each time they appear; and

[0109] R 8 is -CH3 or phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or -Cl.

[0110] In some embodiments, X 1 is independently selected from: -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), thienyl, and pyridyl;

[0111] wherein the alkyl is optionally substituted with one to three R 1 substituents, preferably exactly one R 1 substituent; the cyclohexyl is unsubstituted; the heterocycloalkyl is substituted with one or two oxo groups; the aryl is independently optionally substituted with one to three R 4 substituents, preferably exactly one R 4 substituent; the pyridyl is unsubstituted;

[0112] R 1 is independently selected from: -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 ;

[0113] R 4 is independently selected from: -OC1-C2 alkyl, -NH2, and -NO2;

[0114] R 8 is -CH3 or phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or -Cl.

[0115] In some embodiments, X 1 is independently selected from: -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), thienyl, and pyridyl;

[0116] wherein the alkyl is optionally substituted with one to three R 1 substituents, preferably exactly one R 1 substituent; the cyclohexyl is unsubstituted; the heterocycloalkyl is substituted with one or two oxo groups; the aryl is independently optionally substituted with one to three R 4 substituents, preferably exactly one R 4 substituent; the thienyl and pyridyl are unsubstituted;

[0117] R1 independently selected from, at each occurrence: -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 ;

[0118] R 4 independently selected from, at each occurrence: -OC1-C2 alkyl, -NH2, and -NO2;

[0119] R 8 is -CH3 or phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or -Cl.

[0120] In some embodiments, X 1 is independently selected from: -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-C 10 aryl), 2-thienyl, and 2-pyridyl

[0121] wherein the alkyl is optionally substituted with one or two R 1 substituents, preferably exactly one R 1 substituent; the cyclohexyl is unsubstituted; the aryl is unsubstituted or substituted with one or two, preferably exactly one -OCH3, -NH2, or -NO2; the 2-thienyl and 2-pyridyl are unsubstituted;

[0122] R 1 is independently selected from, at each occurrence: -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 ; and

[0123] R 8 is -CH3 or phenyl, wherein the phenyl is optionally substituted at the 4-position with -CH3 or -Cl.

[0124] 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-pyridyl;

[0125] wherein the alkyl is optionally substituted with one or two R 1 substituents, preferably exactly one R 1 substituent; the cyclohexyl is unsubstituted; the phenyl is unsubstituted or substituted with one or two, preferably exactly one -OCH3 or -NO2; the 2-pyridyl is unsubstituted;

[0126] R 1 is independently selected from: -N(CH3)(CH2C6H5) and -NHSO2R each time it appears 8 ; and

[0127] R 8 is phenyl, wherein the phenyl is optionally substituted at the 4-position by -CH3 or -Cl.

[0128] In some embodiments of formula (I), X 1 is -COOH.

[0129] In some embodiments of formula (I), X 1 is -C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 1 ; and wherein R 1 is independently selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen, and cyano each time it appears.

[0130] In some embodiments, X 1 is -C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 1 ; and wherein R 1 is independently selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , -COOH, oxo, -NO2, and phenyl each time it appears.

[0131] In some embodiments, X 1 is -C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 1 ; and R 1 is independently selected from: -OH, -NR 6 R 7 , -NHSO2R 8 , and -COOH each time it appears.

[0132] In some embodiments, X 1 is -C1-C5 alkyl, wherein the alkyl is optionally substituted by one to three R 1 ; and R1 is independently selected from: -OH, -NR 6 R 7 , -NHSO2R 8 , and -COOH; wherein R 6 and R 7independently selected at each occurrence from: -H, -CH3, and -CH2-C6H5; and wherein R 8 is independently selected at each occurrence from: -CH3 and phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or halogens.

[0133] In some embodiments, X 1 is a -C1-C5 alkyl, wherein the alkyl is optionally substituted with one or two R 1 substituents, preferably exactly one R 1 substituent; and R 1 is independently selected at each occurrence from: -OH, -NH2, -N(CH3)(CH2C6H5), -NHSO2R 8 and -COOH; and wherein R 8 is independently selected at each occurrence from: -CH3 and phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or halogens.

[0134] In some embodiments, X 1 is a -C1-C5 alkyl, wherein the alkyl is optionally substituted with one to three R 1 substituents, preferably exactly one R 1 substituent; and R 1 is independently selected at each occurrence from: -NR 6 R 7 and -NHSO2R 8 ; wherein R 6 and R 7 are independently selected at each occurrence from: -H, -CH3, and -CH2-C6H5; and wherein R 8 is -CH 3 and phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or -Cl.

[0135] In some embodiments, X 1 is a -C1-C3 alkyl, wherein the alkyl is unsubstituted.

[0136] In some embodiments, X 1 is a -C1-C3 alkyl, wherein the alkyl is optionally substituted with one to three R 1 substituents, preferably exactly one R 1 substituent; and R 1 is independently selected at each occurrence from: -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 ; wherein R 8 is -CH3 or phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or -Cl.

[0137] In some embodiments, X 1 is a -C1-C3 alkyl group, wherein said alkyl group is optionally substituted by one or two R 1 substituents, preferably by exactly one R 1 substituent; and R 1 is independently selected, each time it appears, from: -NH2, -N(CH3)(CH2C6H5), and -NHSO2R 8 ; wherein R 8 is -CH3 or phenyl, wherein said phenyl is optionally substituted at the 4-position by -CH3 or -Cl. In some embodiments, X 1 is a -C1-C3 alkyl group, wherein said alkyl group is optionally substituted by one to three R 1 substituents, preferably by exactly one R 1 substituent; and R 1 is independently selected, each time it appears, from: -NH2 and -N(CH3)(CH2C6H5).

[0138] In some embodiments, X 1 is a -C1 alkyl group, wherein said alkyl group is optionally substituted by one to three R 1 substituents, preferably by exactly one R 1 substituent; and R 1 is -NHSO2R 8 ; wherein R 8 is -CH3 or phenyl, wherein said phenyl is optionally substituted at the 4-position by -CH3 or -Cl.

[0139] In some embodiments, X 1 is a -C1 alkyl group, wherein said alkyl group is optionally substituted by one to three R 1 substituents, preferably by exactly one R 1 substituent; and R 1 is -NHSO2R 8 ; wherein R 8 is phenyl, wherein said phenyl is substituted at the 4-position by -CH3 or -Cl.

[0140] In some embodiments, X 1 is a -C1 alkyl group, wherein said alkyl group is optionally substituted by one to three R 1 substituents, preferably by exactly one R 1 substituent; and R 1 is -NHSO2R 8 ; wherein R 8 is phenyl, wherein said phenyl is unsubstituted.

[0141] In some embodiments of formula (I), X 1is -C3-C8 cycloalkyl or -C1-C6 alkylene-(C3-C8 cycloalkyl), wherein each occurrence of said cycloalkyl is independently optionally substituted by one or more R 2 ; and wherein R 2 is selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen and cyano.

[0142] In some embodiments, X 1 is -C3-C6 cycloalkyl or -C1-C6 alkylene-(C3-C8 cycloalkyl), wherein each occurrence of said cycloalkyl is independently optionally substituted by one or more R 2 ; and wherein R 2 is selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 , -NHSO2R 8 , -COOH, oxo, -NO2 and phenyl.

[0143] In some embodiments, X 1 is -C3-C6 cycloalkyl or -C1-C6 alkylene-(C3-C6 cycloalkyl), wherein each occurrence of said cycloalkyl is independently optionally substituted by one or more R 2 ; and wherein R 2 is selected from -NR 6 R 7 .

[0144] In some embodiments, X 1 is -C3-C6 cycloalkyl or -C1-C4 alkylene-(C3-C6 cycloalkyl), wherein each occurrence of said cycloalkyl is independently optionally substituted by one to three R 2 ; and wherein R 2 is -NH2.

[0145] In some embodiments, X 1 is -C3-C6 cycloalkyl or -C1-C2 alkylene-(C3-C6 cycloalkyl), wherein each occurrence of said cycloalkyl is independently optionally substituted by one or two R 2 , preferably substituted by exactly one R 2 ; and wherein R 2 is -NH2.

[0146] In some embodiments, X 1 is -C5-C6 cycloalkyl or -C1-C2 alkylene-(C5-C6 cycloalkyl), wherein said cycloalkyl is unsubstituted.

[0147] In some embodiments, X 1 is cyclohexyl or -C1-C2 alkylene-(cyclohexyl), wherein the cyclohexyl is unsubstituted.

[0148] In some embodiments, X 1 is cyclohexyl or -C1 alkylene-(cyclohexyl), wherein the cyclohexyl is unsubstituted.

[0149] In some embodiments of formula (I), X 1 is a 5- to 10-membered heterocycloalkyl or -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), wherein the heterocycloalkyl is independently optionally substituted by one or more R 3 each time it appears; wherein R 3 is selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 、-COOH, oxo, -NO2, phenyl, halogen and cyano. In some embodiments, the heterocycloalkyl is saturated.

[0150] In some embodiments, X 1 is a 5- to 10-membered heterocycloalkyl or -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), wherein the heterocycloalkyl is independently optionally substituted by one or more R 3 each time it appears; wherein R 3 is selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 、-COOH, oxo, -NO2 and phenyl. In some embodiments, the heterocycloalkyl is saturated.

[0151] In some embodiments, X 1 is a 5- to 7-membered heterocycloalkyl or -C1-C6 alkylene-(5- to 7-membered heterocycloalkyl), wherein the heterocycloalkyl is independently optionally substituted by one or more R 3 each time it appears; and wherein R 3 is oxo.

[0152] In some embodiments, X 1 is a 5- to 7-membered heterocycloalkyl or -C1-C4 alkylene-(5- to 7-membered heterocycloalkyl), wherein the heterocycloalkyl is independently optionally substituted by one to three R 3 each time it appears; and wherein R 3 is oxo.

[0153] In some embodiments, X1 is a 5- to 7-membered heterocycloalkyl or -C1-C2 alkylene-(5- to 7-membered heterocycloalkyl), wherein each occurrence of said heterocycloalkyl is independently optionally substituted by one or two R 3 , preferably substituted by two R 3 ; and wherein R 3 is oxo.

[0154] In some embodiments, X 1 is a 5- to 6-membered heterocycloalkyl or -C1-C2 alkylene-(5- to 6-membered heterocycloalkyl), wherein each occurrence of said heterocycloalkyl is independently optionally substituted by one or two R 3 ; and wherein R 3 is oxo.

[0155] In some embodiments, X 1 is a 5- to 6-membered heterocycloalkyl or -C1-C2 alkylene-(5- to 6-membered heterocycloalkyl), wherein said heterocycloalkyl is substituted by one or two oxo groups.

[0156] In some embodiments, X 1 is 4-thiomorpholine 1,1-dioxide or -C1-C2 alkylene-(4-thiomorpholine 1,1-dioxide).

[0157] In some embodiments, X 1 is -C1-C2 alkylene-(4-thiomorpholine 1,1-dioxide).

[0158] In some embodiments, X 1 is -C1 alkylene-(4-thiomorpholine 1,1-dioxide).

[0159] In some embodiments, X 1 is azepane.

[0160] In some embodiments, X 1 is piperidine.

[0161] In some embodiments, X 1 is a spiroheterocycle, preferably a six- to nine-membered spiroheterocycle.

[0162] In some embodiments of formula (I), X 1 is -C6-C 10 aryl or -C1-C6 alkylene-(C6-C 10 aryl), wherein each occurrence of said aryl is independently optionally substituted by one or more R 4 ; and wherein R 4 is independently selected, in each occurrence, from: -OH, -OC1-C6 alkyl, -NR 6 R7 、 -NHSO2R 8 、 -COOH, oxo, -NO2, phenyl, halogen, and cyano.

[0163] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C6 alkylene-(C6-C 10 aryl); wherein the aryl is independently optionally substituted with one or more R 4 each time it appears; and wherein R 4 is selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、 -NHSO2R 8 、 -COOH, oxo, -NO2, and phenyl.

[0164] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C6 alkylene-(C6-C 10 aryl); wherein the aryl is independently optionally substituted with one or more R 4 each time it appears; and wherein R 4 is selected from: -OC1-C6 alkyl, -NR 6 R 7 、 -COOH, -NO2, and phenyl.

[0165] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C4 alkylene-(C6-C 10 aryl), wherein the aryl is independently optionally substituted with one to three R 4 each time it appears; and wherein R 4 is selected from: -OC1-C2 alkyl, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, -COOH, -NO2, and phenyl.

[0166] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C3 alkylene-(C6-C 10 aryl); wherein the aryl is independently optionally substituted with one or two R 4 each time it appears, preferably substituted with exactly one R 4 ; and wherein R 4 is selected from: -OC1-C2 alkyl, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, -COOH, -NO2, and phenyl.

[0167] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C3 alkylene-(C6-C 10 aryl); wherein each aryl, upon each occurrence, is independently optionally substituted with one or two R 4 substituents, preferably exactly one R 4 substituent; and wherein R 4 is selected from: -OCH3, -NH2, -COOH, -NO2, and phenyl.

[0168] In some embodiments, X 1 is -C6-C 10 aryl; wherein each aryl, upon each occurrence, is independently optionally substituted with one or two R 4 substituents, preferably exactly one R 4 substituent; and wherein R 4 is selected from: -OCH3, -NH2, -COOH, -NO2, and phenyl.

[0169] In some embodiments, X 1 is -C1-C3 alkylene-(C6-C 10 aryl); and wherein the C6-C 10 aryl is unsubstituted.

[0170] In some embodiments, X 1 is -C1-C3 alkylene-(phenyl); and wherein the phenyl is unsubstituted.

[0171] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C6 alkylene-(C6-C 10 aryl), wherein each aryl, upon each occurrence, is independently optionally substituted with one to three R 4 substituents, preferably exactly one R 4 substituent; and wherein R 4 is independently selected, upon each occurrence, from: phenyl, -OC1-C6 alkyl, -NH2, and -NO2.

[0172] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C6 alkylene-(C6-C 10 aryl), wherein each aryl, upon each occurrence, is independently optionally substituted with one to three R 4 substituents, preferably exactly one R 4 substituent; and wherein R 4independently selected from, at each occurrence: -OC1-C6 alkyl, -NH2, and -NO2.

[0173] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C6 alkylene-(C6-C 10 aryl), wherein the aryl is, at each occurrence, independently optionally substituted with one to three R 4 substituents, preferably substituted with exactly one R 4 substituent; and wherein R 4 is independently selected from, at each occurrence: -OC1-C2 alkyl, -NH2, and -NO2.

[0174] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C3 alkylene-(C6-C 10 aryl), wherein the aryl is, at each occurrence, independently optionally substituted with one to three R 4 substituents, preferably substituted with exactly one R 4 substituent; and wherein R 4 is independently selected from, at each occurrence: -OC1-C2 alkyl, -NH2, and -NO2.

[0175] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C3 alkylene-(C6-C 10 aryl); and wherein the aryl is unsubstituted or substituted with one or two, preferably exactly one -OC1-C2 alkyl, -NH2, or -NO2.

[0176] In some embodiments, X 1 is -C6-C 10 aryl or -C1-C3 alkylene-(C6-C 10 aryl); and wherein the aryl is unsubstituted or substituted with one or two, preferably exactly one -OCH3, -NH2, or -NO2.

[0177] In some embodiments, X 1 is phenyl or -C1-C3 alkylene-(phenyl), preferably -C2-C3 alkylene-(phenyl), wherein the phenyl is unsubstituted.

[0178] In some embodiments, X 1 is phenyl or naphthyl, wherein the phenyl or naphthyl is substituted with one or two, preferably exactly one -OCH3.

[0179] In some embodiments, X1 is phenyl, wherein the phenyl is substituted by one or two, preferably exactly one, -NH2.

[0180] In some embodiments, X 1 is phenyl, wherein the phenyl is substituted by one or two, preferably exactly one, -NO2.

[0181] In some embodiments, X 1 is a 5- to 10-membered heteroaryl or -C1-C6 alkylene-(5- to 10-membered heteroaryl), wherein each occurrence of the heteroaryl is independently optionally substituted by one or more R 5 ; and wherein R 5 is selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 、-COOH, oxo, -NO2, phenyl, halogen, and cyano.

[0182] In some embodiments, X 1 is a 5- to 10-membered heteroaryl or -C1-C6 alkylene-(5- to 10-membered heteroaryl), wherein each occurrence of the heteroaryl is independently optionally substituted by one or more R 5 ; and wherein R 5 is selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 、-COOH, oxo, -NO2, and phenyl.

[0183] In some embodiments, X 1 is a 5- to 10-membered heteroaryl or -C1-C6 alkylene-(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted.

[0184] In some embodiments, X 1 is a 5- to 6-membered heteroaryl or -C1-C4 alkylene-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl is unsubstituted.

[0185] In some embodiments, X 1 is a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is unsubstituted.

[0186] In some embodiments, X 1 is pyridyl or thienyl.

[0187] In some embodiments, X 1 is pyridyl or thienyl, wherein the pyridyl and thienyl are unsubstituted.

[0188] In some embodiments, X 1 is 2-pyridyl or 2-thienyl, wherein the 2-pyridyl and 2-thienyl are unsubstituted.

[0189] In some embodiments, X 1 is thienyl.

[0190] In some embodiments, X 1 is thienyl, wherein the thienyl is unsubstituted.

[0191] In some embodiments, X 1 is 2-thienyl, wherein the 2-thienyl is unsubstituted.

[0192] In some embodiments, X 1 is pyridyl.

[0193] In some embodiments, X 1 is pyridyl, wherein the pyridyl is unsubstituted.

[0194] In some embodiments, X 1 is 2-pyridyl, wherein the 2-pyridyl is unsubstituted.

[0195] In one or more embodiments, X of the compound of formula (I) 1 can form one of the structures selected from Table 1 below:

[0196] Table 1 X 1 Exemplary embodiments of

[0197]

[0198]

[0199]

[0200] 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:

[0201] Table 2 Exemplary compounds of the present invention

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211] 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:

[0212] Table 3 Compounds of the present invention

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219] 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:

[0220] Table 4 Exemplary Compounds of the Present Invention

[0221]

[0222]

[0223]

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0229] Synthesis methods of the disclosed compounds

[0230] The compounds of the present invention can be prepared by a variety of methods including standard chemistry. These methods include, but are not limited to, those described in the suitable synthetic routes described in the schemes given below.

[0231] The compounds of the present invention can be prepared by methods known in the art of organic synthesis, as described in the following synthetic schemes and Examples section. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are used as necessary, according to general principles or chemical effects. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York, 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The choice of process as well as reaction conditions and the order of execution should be consistent with the preparation of the compounds of the present invention.

[0232] One skilled in the art will recognize the presence or absence of stereocenters in the compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis), and includes not only racemic compounds, 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 effected by any suitable method known in the art. See, for example, E.L. Eliel, S.H. Wilen and L.N. Mander, "Stereochemistry of Organic Compounds)" (Wiley-Interscience, 1994).

[0233] The compounds described herein can be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0234] Preparation of compounds

[0235] The compounds of the present invention can be synthesized by following the steps outlined in Schemes 1, 2, 3, and 4. The starting materials are either commercially available or made by known procedures in the reported literature or as exemplified.

[0236] Scheme 1 General Synthesis of 21,23 - Acetonide - 25 - hydroxy - rifabutin (I - 1)

[0237]

[0238] The general method for preparing 21,23-acetonide-25-hydroxy-rifabutin I-1 is shown in Scheme 1 above. In a solvent such as DMF, suitable protecting groups such as dimethoxypropane and camphorsulfonic acid are used to protect the C21 and C23 hydroxyl groups, yielding acetal-protected rifabutin. The protected rifabutin is deacetylated using a basic solution such as sodium methoxide in diethyl ether to obtain 25-OH rifabutin (I-1) with the C21 and C23 hydroxyl groups protected.

[0239] Scheme 2 Preparation of 21,23-acetonide-25-bromoacetate-rifabutin (I-2)

[0240]

[0241] As shown in Scheme 2, 21,23-acetonide-25-hydroxy-rifabutin (I-1) can be esterified using a suitable carboxylic anhydride such as bromoacetic anhydride in the presence of a suitable base such as an amine base (e.g., 4-(dimethylamino)pyridine).

[0242] Scheme 3 Preparation of 21,23-acetonide-25-azidoacetate-rifabutin (I-3)

[0243]

[0244] As shown in Scheme 3, the intermediate I-2 can be converted to the corresponding azide by reaction with a suitable nucleophilic azide (e.g., sodium azide) in a solvent such as DMF.

[0245] Scheme 4 Preparation of Deprotected 25-triazolylacetate-coupled Rifabutin

[0246]

[0247] The C25-esterified, protected rifabutin can be condensed with a suitable alkyne in a suitable solvent such as a mixture of tBuOH and water in the presence of a suitable catalyst such as copper sulfate and sodium ascorbate. Deprotection of the C21-C23 acetonide in the coupled rifabutin can be carried out by treatment with an acid such as camphorsulfonic acid in water.

[0248] Antibacterial efficacy of the disclosed compounds

[0249] The compounds of the present invention are analogs of rifabutin modified at C25 to contain 2-triazoleacetate, wherein the triazole is substituted at the 4-position. The compounds of the present invention exhibit the broad-spectrum antibacterial activity characteristics of rifamycins. In addition, compared to currently available antibiotics (e.g., rifabutin), the compounds of the present invention unexpectedly show enhanced antibacterial activity against non-tuberculous mycobacteria including Mycobacterium abscessus.

[0250] As shown in Example 5 and Table 6 below, the compounds of the present invention effectively inhibit bacterial growth in strains of Staphylococcus aureus, Mycobacterium abscessus, Acinetobacter baumannii, Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium avium.

[0251] Rifampicin shows an MIC value higher than 32 mg / L against Mycobacterium abscessus and is considered inactive against Mycobacterium abscessus strains. Rifabutin without modification at its C25 position shows moderate activity against the tested Mycobacterium abscessus strains with an MIC value of 8 mg / L. In contrast, the compounds of the present invention show MIC values of 0.125 to 4 mg / L, equivalent to a 2- to 64-fold increase in activity compared to rifabutin. Thus, the present invention teaches compounds that show an increase in activity against Mycobacterium abscessus compared to the antibiotics known in the literature.

[0252] Methods using the disclosed compounds

[0253] 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.

[0254] 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 preventing or treating a disease in a subject, preferably an infection, more preferably a bacterial infection.

[0255] In one aspect, the present invention provides a method of treating a disease in a subject in need thereof, preferably an infection, more preferably a bacterial infection, the method 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).

[0256] 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 for the preparation of a medicament for treating a disease in a subject in need thereof, preferably an infection, more preferably a bacterial infection.

[0257] In some embodiments of any of the above aspects, the infection (e.g., a bacterial infection) is caused by one or more bacteria belonging to the genus Mycobacterium, Acinetobacter, Clostridium, Enterococcus, Haemophilus, Legionella, Neisseria, Staphylococcus, Streptococcus, Listeria monocytogenes, Moraxella catarrhalis, Bacillus, Bacteroides, Gardnerella vaginalis, Lactobacillus, Mobiluncus, Helicobacter pylori, Campylobacter jejuni, Chlamydia trachomatis, and / or Toxoplasma gondii.

[0258] In some preferred embodiments of any of the above aspects, the bacterial infection is caused by one or more bacteria belonging to the genus Acinetobacter, Staphylococcus, and / or Mycobacterium. In some preferred embodiments, the bacterial infection is caused by one or more bacteria belonging to the species Acinetobacter baumannii and / or Staphylococcus aureus and / or the genus nontuberculous Mycobacterium, preferably Mycobacterium abscessus. In some embodiments, the infection is caused by one or more bacteria belonging to the species Mycobacterium abscessus, Acinetobacter baumannii, and / or Staphylococcus aureus, preferably Mycobacterium abscessus.

[0259] In some preferred embodiments, the infection is caused by one or more bacteria belonging to the genus nontuberculous Mycobacterium, preferably Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium smegmatis, Mycobacterium xenopi, and / or Mycobacterium malmoense, more preferably Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii, and / or Mycobacterium xenopi, still more preferably Mycobacterium abscessus. In some embodiments, the Mycobacterium abscessus infection is resistant to current antibiotics.

[0260] In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter and / or Staphylococcus, preferably Acinetobacter baumannii and / or Staphylococcus aureus. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Acinetobacter, preferably Acinetobacter baumannii. In some embodiments, the infection is caused by one or more bacteria belonging to the genus Staphylococcus, preferably Staphylococcus aureus.

[0261] 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 the compound of formula (I) for use in a method of treating nontuberculous Mycobacterium pulmonary infection. In some embodiments, the bacteria causing the nontuberculous Mycobacterium pulmonary infection are Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium tuberculosis, Mycobacterium xenopi, and / or Mycobacterium malmoense, preferably Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii, and / or Mycobacterium xenopi, more preferably Mycobacterium abscessus.

[0262] In one aspect, the present invention provides a method for treating non-tuberculous mycobacterial pulmonary infection in a subject in need thereof, the method 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 the compound of formula (I). In some embodiments, the bacterium causing the non-tuberculous mycobacterial pulmonary infection is Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium tuberculosis, Mycobacterium xenopi, and / or Mycobacterium malmoense, preferably Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii, and / or Mycobacterium xenopi, more preferably Mycobacterium abscessus.

[0263] 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 preparation of a medicament for treating non-tuberculous mycobacterial pulmonary infection in a subject in need thereof. In some embodiments, the bacterium causing the non-tuberculous mycobacterial pulmonary infection is Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium tuberculosis, Mycobacterium xenopi, and / or Mycobacterium malmoense, preferably Mycobacterium abscessus, Mycobacterium avium, Mycobacterium kansasii, and / or Mycobacterium xenopi, more preferably Mycobacterium abscessus.

[0264] In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0265] Exemplary pharmaceutical compositions are tablets and gelatin capsules, which contain the compounds of the present invention and pharmaceutically acceptable carriers, such as a) diluents, for example purified water, triglyceride oils (such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof), corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA, or their esters or triglycerides or mixtures thereof), ω-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, for example silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; the same for tablets; c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone (if needed); d) disintegrants, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorants and sweeteners; f) emulsifiers or dispersants, such as 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) reagents to enhance the absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0266] The compounds and pharmaceutical compositions of the present invention can be administered, for example, as syrups, tablets, capsules, lozenges, controlled-release formulations, fast-dissolving formulations or troches, by any suitable route (such as orally).

[0267] Liquid (especially injectable) compositions can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed compounds are dissolved in or mixed with pharmaceutically acceptable solvents such as water, saline, aqueous dextrose solution, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicrons or serum proteins can be used to dissolve the disclosed compounds.

[0268] The disclosed compounds can also be formulated into suppositories, which can be prepared from fatty emulsions or suspensions by using polyalkylene glycols such as propylene glycol as carriers.

[0269] The disclosed compounds can also be administered in the form of liposomal delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, including cholesterol, stearylamine, or phosphatidylcholine. In some embodiments, as described in U.S. Patent 5,262,564, a thin film of the lipid component is hydrated with an aqueous solution of the drug to form a lipid layer encapsulating the drug.

[0270] Parenteral administration is commonly used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be prepared in conventional forms (liquid solutions or suspensions, or solid forms suitable for dissolving in a liquid before injection).

[0271] Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can also include excipients, diluents, or surfactants.

[0272] The compositions can be prepared according to conventional mixing, granulating, or coating methods, and, by weight or volume, the pharmaceutical compositions of the invention can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound.

[0273] A dosage regimen using the disclosed compounds is selected in accordance with a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counteract, or arrest the progress of the condition.

[0274] When used for the indicated effects, the effective dose of the disclosed compounds ranges from about 0.5 mg to about 5000 mg as required to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or in a range from one amount in the dosage listing to another. In one embodiment, the composition is in the form of a scoreable tablet.

[0275] Equivalents

[0276] Although the technology has been described in connection with the foregoing specific embodiments, many alternatives, modifications, and other variations will be apparent to those of ordinary skill in the art. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the invention.

[0277] Examples

[0278] The present invention will now be illustrated by the following non-limiting examples. Although specific embodiments of the invention are described below, those skilled in the art will understand that various changes and modifications can be made. References to preparations carried out in a manner similar to or by other general methods of preparation may cover variations in conventional parameters such as minor changes in time, temperature, post-treatment conditions, reagent amounts, etc.

[0279] Abbreviations

[0280] The following list provides definitions of certain abbreviations and symbols used herein. It should be understood that this list is not exhaustive, but those skilled in the art will readily understand the meanings of abbreviations and symbols not defined below. When describing the present invention, chemical elements are identified according to the Periodic Table.

[0281] ACN Acetonitrile

[0282] AcOH Acetic acid

[0283] aq. Aqueous

[0284] Ar Argon

[0285] CSA Camphorsulfonic acid

[0286] DCM Dichloromethane

[0287] DMF N,N-Dimethylformamide

[0288] eq. Equivalent

[0289] EtOAc Ethyl acetate

[0290] EtOH Ethanol

[0291] h Hour

[0292] HPLC High performance liquid chromatography

[0293] LC Liquid chromatography

[0294] M Mole

[0295] MeOH Methanol

[0296] MS Mass spectrometry

[0297] min Minute

[0298] NMR Nuclear magnetic resonance spectroscopy

[0299] rt Room temperature

[0300] Rt Retention time

[0301] sat. Saturated

[0302] Unless otherwise specified, the purity and characteristics of the intermediates or example compounds are evaluated by state-of-the-art HLPC-MS. The methods are described below.

[0303] Characterization of compounds

[0304] Method A is used for intermediates. Method B is used to measure the purity of the final compounds. Purity (%) is determined by reverse-phase HPLC or UPLC using UV detection (254 nm). The structure is confirmed by MS using electrospray ionization positive (ESI+) method and reported as [M+H]+ (referring to the protonated molecular ion).

[0305] Method A

[0306] UPLC system: UPLC I BIN SOL MGR equipped with an ACQUITY UPLC I-Class eK PDA detector; Column: Acquity BEH C18 column (particle size 1.7 μm, size 50 mm x 2.1 mm); Mobile phase: Phase A (H2O / ammonium formate, pH 3.75 (A) or 9.2 (B)) and Phase B (CH3CN + 5% H2O / ammonium formate, pH 3.75 (A) or 9.2 (B)) are used according to the following method:

[0307]

[0308] Mass spectrometer: ACQUITY QDa (Performance) Xevo TQD. Ionization: Electrospray (polarity: negative and positive).

[0309] Method B

[0310] HPLC system: Waters 2695LC equipped with a photodiode array detector Waters 996; Column: XBridgeC18 column (particle size 3.5 μm, size 50 mm x 4.6 mm); Mobile phase: Phase A (H2O / ammonium formate, pH 9.2) and Phase B (CH3CN + 5% H2O / ammonium formate, pH 9.2%) are used according to the following method:

[0311]

[0312] Mass spectrometer: Waters Alliance Micromass ZQ 2000. Ionization: Electrospray (polarity: negative and positive).

[0313] NMR analysis

[0314] NMR spectra were recorded on a Bruker DRX-300 spectrometer equipped with a TXI probe or a Bruker 500 MHz spectrometer. Chemical shifts are reported in parts per million (ppm). One-dimensional (1D) 1 H and 13 C spectra and two-dimensional (2D) HSQC and HMBC spectra were used for assignments.

[0315] Example 1

[0316] Synthesis of 21,23-acetonide-25-hydroxy-rifabutin (I-1)

[0317]

[0318] Commercially available rifabutin (40.0 g, 47.2 mmol) was dissolved in anhydrous DMF (80 mL) at room temperature under a nitrogen atmosphere. 2,2-Dimethoxy-propane (58.1 mL, 472 mmol) and camphorsulfonic acid (12.6 g, 54.3 mmol) were added to the solution successively. The reaction mixture was stirred at room temperature for 26 h under a nitrogen atmosphere. Then the mixture was cooled to 0 °C and poured into a mixture of saturated aqueous NaHCO3 solution (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 min and filtered. The filter cake was washed with saturated aqueous NaHCO3 solution (700 mL) and water (50 mL) and dried in vacuo at 40 °C for 24 h. The crude product was purified by flash chromatography (50% of a mixture of DCM to DCM / MeOH / NH4OH 90 / 9 / 1.5 in DCM) to give the purple solid 21,23-acetonide-rifabutin (37.68 g, 90% yield).

[0319] LC / MS A (ESI+): tr = 3.20 min, m / z [M+H] + = 887.48, UV purity: 97% (254 nm).

[0320] 11H 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).

[0321] 13 13C 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.

[0322] Dissolve 21,23-acetonide-rifabutin (10.6 g, 11.9 mmol) in anhydrous (dry) ether (500 mL). Cool the solution to -10 °C by bubbling Ar. After 15 minutes, slowly add NaOMe solution (30 mL, 25 w% in MeOH). A precipitate forms, and another portion of diethyl ether (100 mL) is added to homogenize. Add NaOMe solution (27.4 mL) again. Stir the solution at -5 °C for 10 minutes, then remove the ice bath. Stir the reaction mixture at room temperature for 6 hours. Add a saturated aqueous solution of NaHCO3 (400 mL), and separate the layers. Extract the aqueous layer with diethyl ether (400 mL), wash the combined organic layers with brine (300 mL) and evaporate to obtain the crude product as a desired dark purple powder. Purify the product by flash chromatography (DCM to a mixture of 50% DCM / MeOH / NH4OH 90 / 9 / 1.5 in DCM). After evaporation, redissolve the product in acetone and slowly add it to water with vigorous stirring. Collect the solid by filtration and dry it at 40 °C to obtain Intermediate I-1 with a yield of 8.54 g.

[0323] LC / MS A(ESI+): tr = 2.98 min, m / z [M+H] + = 845.59, UV purity: 97% (254 nm).

[0324] 1 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).

[0325] 1313C 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.

[0326] Example 2

[0327] Synthesis of 21,23 - Acetonide - 25 - bromoacetate - Rifabutin (I - 2)

[0328]

[0329] Dissolve the intermediate I - 1 (800 mg, 0.94 mmol, 1 eq) in DCM (20 mL) and cool it to 0 °C. Then add bromoacetic anhydride (1.54 g, 5.92 mmol, 5 eq) and DMAP (723 mg, 5.92 mol, 5 eq), and stir the reaction at 0 °C. After 1 hour, wash the mixture with aqueous HCl - 1N solution (20 mL), saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL). Dry the organic layer over MgSO4 and concentrate it in vacuo. Purify the obtained solid by flash chromatography (CHCl3 / MeOH, 100 / 0 to 95 / 5). Collect the pure fractions and evaporate the solvent to obtain a black solid I - 2 (m = 620 mg, yield = 54%).

[0330] LC / MS A (ESI+): tr = 3.48 min, m / z [M + H] + = 965.48 / 967.47, UV purity: 95% (254 nm).

[0331] 11H 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).

[0332] 13 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.

[0333] Example 3

[0334] Synthesis of 21,23 - Acetonide - 25 - Azidoacetate - Rifabutin (I - 3)

[0335]

[0336] To a solution of I-2 (2.00 g, 2.07 mmol, 1 eq) in DMF (30 mL) was added sodium azide (141 mg, 2.17 mmol, 1.05 eq), and the reaction was stirred at room temperature. After 3 hours, the mixture was concentrated in vacuo. The obtained 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 obtained solid was purified by flash chromatography (cyclohexane / acetone / TEA, 100 / 0 / 0 to 80 / 18.5 / 1.5) to give the desired product I-3 (m = 880 mg, yield = 50%).

[0337] LC / MS A(ESI+): tr = 2.57, m / z [M+H] + = 928.48, UV purity: 99% (254 nm).

[0338] 1 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).

[0339] 1313C NMR (75 MHz, CDCl3): δ 7.8, 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.

[0340] Example 4

[0341] General procedure for the preparation of triazole derivatives

[0342]

[0343] Prepare a solution of 21,23 - acetonide - 25 - azidoacetate - rifabutin (I - 3) (0.05 mol / L), sodium ascorbate (0.007 mol / L) and CuSO4·5H2O (0.007 mol / L) in tBuOH / H2O (3 / 1). Charge the required alkyne (0.32 mmol, 1.5 eq) into a Kimble reactor, and then add 400 μL of the solution of 25 - azido - acetic acid - 21,23 - acetonide - rifabutin in tBuOH / H2O (equivalent to 20 mg, 0.021 mmol, 1 eq of 25 - azido - acetic acid - 21,23 - acetonide - rifabutin, 0.6 mg, 0.003 mmol, 0.15 eq of sodium ascorbate and 0.8 mg, 0.003 mol, 0.15 eq of CuSO4·5H2O). Stir the reaction at 60 °C.

[0344] After 24 h, add 400 μL of an aqueous solution of camphorsulfonic acid (0.5 N) to the mixture. Stir the reaction at room temperature for 24 h. Then deposit the mixture on a ColumnPoraPak (Rxn RP 6CC) equilibrated with water. Elute with 5 mL of water, 5 mL of saturated aqueous NaHCO3, 5 mL of a water / ACN (90 / 10) solution and 10 mL of ACN. Collect 10 mL of ACN, freeze it and then freeze - dry it to obtain the desired purple powder product.

[0345] Table 5 below summarizes exemplary compounds of the present invention prepared according to the scheme of Example 4 above. (The data given in Table 5 was obtained according to Analytical Method B).

[0346] Table 5: Compounds of the Present Invention

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359] Additional analytical data (NMR):

[0360] Compound 1:

[0361] 11H 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).

[0362] 13 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.

[0363] Compound 8:

[0364] 1 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).

[0365] 13 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.

[0366] Compound 12:

[0367] 1 H 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).

[0368] 1313C 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.

[0369] Example 5

[0370] Antibacterial activity

[0371] The MIC values were determined by broth microdilution method according to the CLSI guidelines. Unless otherwise specified, the MIC against Acinetobacter baumannii was performed in RPMI medium supplemented with 10% FCS. The MIC against Mycobacterium abscessus was performed in Middlebrook 7H9 broth supplemented with Middlebrook ADC growth supplement (10%). All other MICs were performed in standard cation-adjusted Mueller Hinton broth supplemented with Middlebrook ADC growth supplement (5%) for slow-growing mycobacteria (Mycobacterium xenopi, Mycobacterium kansasii, and Mycobacterium avium).

[0372] The following procedure applies to all test species except Mycobacterium xenopi. From fresh culture plates (overnight to several days depending on the bacterium), the cells were resuspended in 0.9% (w / v) saline solution and inoculated at 5x10 5CFU / mL to prepare the bacterial inoculum. For Mycobacterium xenopi, the inoculum was prepared from a fresh liquid culture (7H9 + ADC). Using a digital dispenser, an appropriate volume of the 10 mg / mL compound solution was directly dispensed into a 96-well assay plate to create a two-fold dilution series with final concentrations of 32 to 0.002 μg / mL for Acinetobacter baumannii and Staphylococcus aureus; a two-fold dilution series with final concentrations of 16 to 0.016 μg / mL for Mycobacterium abscessus and Mycobacterium avium; and a two-fold dilution series with final concentrations of 1 to 6x10 -5 μg / mL for Mycobacterium kansasii and Mycobacterium xenopi. Finally, 100 μL of the bacterial suspension was added to the compounds. The plates were covered and incubated for 20 hours without shaking at 35 °C for Acinetobacter baumannii and Staphylococcus aureus; for 4 days without shaking at 30 °C for Mycobacterium abscessus; and for at least 7 days without shaking at 37 °C for Mycobacterium kansasii (covered with aluminum foil to avoid exposure), Mycobacterium avium, and Mycobacterium xenopi. Each experiment contained an antibiotic as a quality control. The MIC, defined as the lowest concentration of the compound that prevented visible bacterial growth, was determined visually.

[0373] The in vitro activities of the compounds described herein were determined against Staphylococcus aureus (UAMS-1625 strain), Acinetobacter baumannii (HUMC1 strain), Mycobacterium abscessus (ATCC 19977), Mycobacterium kansasii (ATCC12478), Mycobacterium avium (ATCC25291), and Mycobacterium xenopi (ATCC19250). Table 6 below gives the MIC values in μg / mL.

[0374] Table 6: In Vitro Activities of the Compounds Against Acinetobacter baumannii, Staphylococcus aureus, Mycobacterium abscessus, Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium avium (μg / mL)

[0375]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: in: X 1 independently selected from: -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 aryl), 5- to 10-membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl); wherein the alkyl group is optionally substituted with one or more R 1 replace; wherein the cycloalkyl group is independently optionally substituted at each occurrence with one or more R 2 replace; wherein the heterocycloalkyl group is independently optionally substituted at each occurrence with one or more R 3 replace; wherein the aryl group is independently optionally substituted at each occurrence with one or more R 4 replace; wherein the heteroaryl group is independently optionally substituted at each occurrence with one or more R 5 replace; R 1 , R 2 , R 3 , R 4 and R 5 Each occurrence is independently selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen, and cyano; R 6 and R 7 is independently selected at each occurrence from: -H and -C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with phenyl; and R 8 Independently selected from: C1-C6 alkyl and phenyl, wherein the phenyl is optionally substituted by -C1-C6 alkyl or halogen.

2. The compound according to claim 1, wherein: R 1 , R 2 , R 3 , R 4 and R 5 Each occurrence is independently selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 , -COOH, oxo, -NO2 and phenyl; R 6 and R 7 is independently selected at each occurrence from: -H and -C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with phenyl; and R 8 Independently selected from: C1-C6 alkyl and phenyl, wherein the phenyl is optionally substituted by -C1-C6 alkyl or halogen.

3. The compound according to claim 1 or 2, wherein X 1 independently selected from: -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- to 10-membered heteroaryl, or -C1-C6 alkylene-(5- to 10-membered heteroaryl); wherein the alkyl group is optionally substituted with one or more R 1 replace; The cycloalkyl group is independently optionally substituted at each occurrence with one or more R 2 replace; The heterocycloalkyl group is independently optionally substituted at each occurrence with one or more R 3 replace; The aryl group is independently optionally substituted at each occurrence with one or more R 4 replace; The 5- to 10-membered heteroaryl groups are each unsubstituted; R 1 is independently selected at each occurrence from: -OH, -NR 6 R 7 、-NHSO2R 8 and -COOH; R 2 Selected from -NR 6 R 7 ; R 3 is oxo; and R 4 is independently selected at each occurrence from: -OC1-C6 alkyl, -NR 6 R 7 , -COOH, -NO2 and phenyl.

4. A compound according to any one of the preceding claims, wherein X 1 independently selected from: -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; wherein the alkyl group is optionally substituted by one to three R 1 substituted, preferably by exactly one R 1 substituted; each of the cycloalkyl groups is unsubstituted; each of the heterocycloalkyl groups is independently optionally substituted by one or two R 3 substituted; the aryl group is independently optionally substituted by one to three R 4 substituted, preferably by exactly one R 4 replace; R 1 Each occurrence is independently selected from: 6 R 7 and -NHSO2R 8 ; R 3 For oxygen generation; R 4 is independently selected at each occurrence from: -OC1-C6alkyl, -NH2 and -NO2; R 6 and R 7 is independently selected at each occurrence from: -H, -CH3, and -CH2-C6H5; and R 8 is -CH3 or phenyl, wherein the phenyl is optionally substituted with one or more -CH3 or -Cl.

5. A compound according to any one of the preceding claims, wherein X 1 Independently selected from: C1-C3 alkyl, cyclohexyl, -C1 alkylene-(cyclohexyl), phenyl, -C1-C3 alkylene-(phenyl) and 2-pyridyl; wherein the alkyl group is optionally substituted by one or two R 1 substituted, preferably by exactly one R 1 substituted; each of the cyclohexyl groups is unsubstituted; each of the phenyl groups is unsubstituted or substituted with one or two, preferably exactly one, -OCH3 or -NO2; the 2-pyridyl group is unsubstituted; R 1 is independently selected at each occurrence from: -N(CH3)(CH2C6H5) and -NHSO2R 8 ;as well as R 8 is phenyl, wherein the phenyl is optionally substituted at the 4-position by -CH3 or -Cl.

6. The compound according to claim 1, wherein X 1 is -C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 1 substituted; and wherein R 1 is independently selected at each occurrence from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen and cyano.

7. The compound according to claim 1, wherein X 1 -C3-C8 cycloalkyl or -C1-C6 alkylene-(C3-C8 cycloalkyl), wherein the cycloalkyl group is independently optionally substituted by one or more R 2 substituted; and wherein R 2 Selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen and cyano.

8. The compound according to claim 1, wherein X 1 is a 5- to 10-membered heterocycloalkyl group or a -C1-C6 alkylene group-(5- to 10-membered heterocycloalkyl group), wherein the heterocycloalkyl group is independently optionally substituted with one or more R 3 substituted; and wherein R 3 Selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen and cyano.

9. The compound according to claim 1, wherein X 1 -C6-C 10 Aryl or -C1-C6 alkylene-(C6-C 10 aryl), wherein the aryl group is independently optionally substituted at each occurrence with one or more R 4 substituted; and wherein R 4 is independently selected at each occurrence from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen and cyano.

10. The compound according to claim 1, wherein X 1 is 5 to 10 membered heteroaryl or -C1-C6 alkylene-(5 to 10 membered heteroaryl); wherein the heteroaryl is independently optionally replaced by one or more R at each occurrence 5 substituted; and wherein R 5 Selected from: -OH, -OC1-C6 alkyl, -NR 6 R 7 、-NHSO2R 8 , -COOH, oxo, -NO2, phenyl, halogen and cyano.

11. The compound according to claim 1, wherein the compound is selected from the group consisting of:

12. The compound according to claim 1, wherein the compound is selected from the group consisting of:

13. The compound according to claim 1, wherein the compound is selected from the group consisting of:

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

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

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