Antibiotic rifabutin analogs

Abstract

The present invention relates to antibiotic rifabutin analogs of formula I wherein; R1 is -H or -C1-C6 alkyl; R2 is a group of Formula II. In some embodiments, the bacterial infection is caused by one or more bacterium belonging to a genus of non-tuberculous Mycobacteria, preferably M. abscessus.

Description

[0001] Attorney Ref: P6819PC00 1RIFABUTIN ANALOGS FOR THE TREATMENT OF DISEASE The present invention relates to compounds and pharmaceutical compositionscomprising the same for the treatment, amelioration and / or prevention of disease. In someembodiments, the disease is an infection, preferably a bacterial infection. In someembodiments, the bacterium belongs to a genus of non-tuberculous Mycobacteria (NTM), preferably M. abscessus. RELATED ART Rifamycins such as rifabutin are known antibiotics with activity against a broadspectrum of pathogens such as Clostridium spp., Enterococcus spp., Hemophilus spp.,Legionella spp., Mycobacterium spp. (tuberculous and non-tuberculous 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 andToxoplasma 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). Rifabutin has been recently shown to have potent in vitro and in vivo activity againstMycobacterium abscessus (Aziz et al., Antimicrob. Agents Chemother., 2017; Dick et al.,Antimicrob. Agents Chemother., 2020) and Acinetobacter baumannii (Luna et al., Nat.Microbiol., 2020; Trebosc et al., Drug Discov. Today, 2021; Trebosc et al., J. Antimicrob. Chemother., 2020). WO2023198597 discloses structural analogs of rifabutin and pharmaceuticalcompositions comprising the same for the treatment, amelioration and / or prevention of diseases such as a bacterial infection, e.g., a bacterial infection caused by one or more bacterium belonging to a genus of non-tuberculous Mycobacteria. However, there remains a need for more effective rifamycins for the treatment ofbacterial infections such as M. abscessus and A. baumannii infections.SUMMARY OF THE INVENTION In one aspect, the present disclosure provides a compound of Formula I or apharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof:Attorney Ref: P6819PC00 2 wherein: R1is -H, -C1-C6 alkyl, or C3-C6 cycloalkyl; R2is a group of Formula II: Formula II wherein n is an integer from 0 to 8; R3is independently, at each occurrence, C1-C6 alkyl; or two R3, together with the carbon atoms to which they are attached, optionally combine to form a bridging alkylene, preferably a bridging C1-C2 alkylene; X is O, NR4, S, or SO2; Z is CH or N; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with oxo; -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more C1-C6 alkoxy; -C2-C6 alkyl, wherein said C2-C6alkyl is substituted with one or more C1-C6alkoxy; -CH2- tetrahydropyran; and cyclopropyl. In one aspect, the present invention provides a pharmaceutical composition comprisingAttorney Ref: P6819PC00 3a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some preferred embodiments, the pharmaceuticalcomposition is effective for treating a disease, preferably an infection, more preferably abacterial infection. In some preferred embodiments, the bacterial infection is caused by one or more bacterium belonging a genus of non-tuberculous Mycobacteria, preferably M. abscessus. In one aspect, the present invention provides a compound of Formula I or apharmaceutically acceptable salt thereof as described herein for use as a medicament.In one aspect, the present invention provides a compound of Formula I or apharmaceutically acceptable salt thereof as described herein for use in a method for treating adisease, preferably an infection, more preferably a bacterial infection in a subject. In somepreferred embodiments, the bacterial infection is caused by one or more bacterium belonging a genus of non-tuberculous Mycobacteria, preferably M. abscessus. In one aspect, the present invention provides a use of a compound or pharmaceuticalcomposition comprising a compound as described herein in the manufacture of a medicamentfor treating a disease, preferably an infection, more preferably a bacterial infection. In somepreferred embodiments, the bacterial infection is caused by one or more bacterium belonging a genus of non-tuberculous Mycobacteria, preferably M. abscessus. In one aspect, the present invention provides a use of a compound or pharmaceutical composition comprising a compound as described herein for treating a disease, preferably aninfection, more preferably a bacterial infection. In some preferred embodiments, the bacterialinfection is caused by one or more bacterium belonging a genus of non-tuberculous Mycobacteria, preferably M. abscessus. In one aspect, the present invention provides a method of treating a disease, preferablyan infection, more preferably a bacterial infection in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effective amount of a compound asdescribed herein or a pharmaceutically acceptable salt thereof. In some preferred embodiments,the bacterial infection is caused by one or more bacterium belonging a genus of non-tuberculous Mycobacteria, preferably M. abscessus. The present invention provides rifabutin analogs that are modified at the C25 positionand pharmaceutical compositions thereof. The inventive compounds exhibit broad antibacterial activity against both smooth and rough variants of M. abscessus. Additional features and advantages of the present technology will be apparent to one of skill in the art upon reading the Detailed Description, below.Attorney Ref: P6819PC00 4DETAILED DESCRIPTION OF THE INVENTIONThe present invention provides analogs of rifabutin that are effective in treating bacterialinfections, preferably bacterial infections caused by one or more bacterium belonging to a genusof non-tuberculous Mycobacteria, preferably M. abscessus. The details of the technology are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present technology, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the invention will be apparent from thedescription and from the claims. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. The articles “a” and “an” are used in this disclosure to refer to one or more than one(i.e., to at least one) of the grammatical object of the article unless the context clearly dictatesotherwise. By way of example, “an element” means one element or more than one element. The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. The term “optionally substituted” is understood to mean that a given chemical moiety (e.g. an alkyl group) can (but is not required to) be bonded other substituents (e.g. heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e. a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bondedto a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term“optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. The term “alkyl” refers to a straight or branched chain saturated hydrocarbon. C1-C6alkyl groups contain 1 to 6 carbon atoms. Examples of a -C1-C6 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl. The terms “alkylene” or “alkylenyl,” as used herein, refer to a straight or branched hydrocarbon chain bi-radical derived from alkyl, as defined herein, wherein one hydrogen ofAttorney Ref: P6819PC00 5said alkyl is cleaved off generating the second radical of said alkylene. Examples of alkylene are, by way of illustration, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-. “C1-C6alkoxy”, as used herein, refers to straight chain or branched saturated -O-C1-C6hydrocarbon which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, or straight or branched octyloxy. Preferably, C1-C6 alkoxy is C1-C4alkoxy. A “C1-C6alkoxy” group can also be represented as “-O-C1-C6alkyl.” The term “cycloalkyl” means monocyclic or bicyclic saturated carbon rings containing 3-10 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydro-1H-indene, and decalin. The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer to monocyclic or polycyclic saturated or partially saturated 3 to 15-membered rings containing carbon andheteroatoms taken from O, N, and S (preferably O and N) and wherein at least one ring doesnot comprise delocalized π electrons (aromaticity) shared among the ring carbon orheteroatoms. A 3-10 membered heterocycloalkyl group contains between 3 and 10 atoms. Insome embodiments, when said heterocycle comprises a polycyclic ring system, none of saidrings comprise delocalized π electrons (aromaticity) shared among the ring carbon orheteroatoms. Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, [1,4]diazepane,[1,2]diazepane, decahydro-[1,6]naphthyridine diazepinyl, octahydro-pyrrolo[1,2-a]pyrazinyl,octahydro-pyrrolo[3,2-c]pyridinyl, and 2,5-diaza-bicyclo[2.2.1]heptanyl. A heterocyclyl or heterocycloalkyl ring can also be fused or bridged, e.g., can be a bicyclic or tricyclic ring. As used herein, the term “tetrahydropyran” is understood to be a six-memberedheterocycloalkyl of the formula: Attorney Ref: P6819PC00 6wherein the atom numbering is shown in the formula above. When R2is tetrahydropyran, the expression “bonded at a 4-carbon of said tetrahydropyran” is understood to mean that the R2tetrahydropyran is bonded to the amide nitrogen in Formula I via the 4-carbon as shown below: . As used herein, the term “morpholine” is understood to be a six-memberedheterocycloalkyl of the formula: wherein the atom numbering is shown in the formula above. When R2 is morpholine, theexpression “bonded at a 4-nitrogen of said morpholine” is understood to mean that the R2morpholine is bonded to the amide nitrogen in Formula I via the 4-nitrogen as shown below: . As used herein, the term “8-oxabicyclo[3.2.1]octane” is understood to be an 8-membered bicyclic heterocycle of the formula: wherein the atom numbering is shown in the formula above. When R2 is 8-oxabicyclo[3.2.1]octane, the expression “bonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane” is understood to mean that the R2 8-oxabicyclo[3.2.1]octane isbonded to the amide nitrogen in Formula I via the 3-carbon as shown below: . As used herein, the term “piperidine” is understood to be a 6-membered heterocyclic ring of the formula:Attorney Ref: P6819PC00 7 wherein the atom numbering is shown in the formula above. When R2is piperidine, the expressions “said piperidine is bonded at a 4-carbon of said piperidine” and “[said] piperidine is independently substituted at the 1-nitrogen with R4” are understood to mean that the R2piperidine is bonded to the amide nitrogen in Formula I via the 4-carbon and substituted with R4at the 1-nitrogen as shown below: . As used herein, the term “2-azabicyclo[2.2.1]heptane” is understood to be a 7-membered bicyclic heterocycle of the formula: wherein the atom numbering is shown in the formula above. When R2is 2-azabicyclo[2.2.1]heptane, the expressions “said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane” and “[said] 2-azabicyclo[2.2.1]heptane isindependently substituted at the 2-nitrogen with R4” are understood to mean that the R22-azabicyclo[2.2.1]heptane is bonded to the amide nitrogen in Formula I via the 5-carbon andsubstituted with R4at the 2-nitrogen as shown below: As used herein, the term “piperazine” is understood to be a 6-membered heterocyclic ring of the formula: wherein the atom numbering is shown in the formula above. When R2is piperazine, theAttorney Ref: P6819PC00 8expressions “said piperazine is bonded at a 4-nitrogen of said piperazine” and “[said] piperazineis independently substituted at the 1-nitrogen with R4” are understood to mean that the R2piperazine is bonded to the amide nitrogen in Formula I via the 4-nitrogen and substituted withR4at the 1-nitrogen as shown below: . As used herein, the term “thiane” is understood to be a six-membered heterocycloalkyl of the formula: wherein the atom numbering is shown in the formula above. When R2is thiane, the expression “bonded at a 4-carbon of said thiane” is understood to mean that the R2thiane is bonded to the amide nitrogen in Formula I via the 4-carbon as shown below: . As used herein, the term “thiacyclohexane 1,1-dioxide” is understood to be a six- membered heterocycloalkyl of the formula: wherein the atom numbering is shown in the formula above. When R2is thiacyclohexane 1,1-dioxide, the expression “bonded at a 4-carbon of said thiacyclohexane 1,1-dioxide” isunderstood to mean that the R2 thiacyclohexane 1,1-dioxide is bonded to the amide nitrogen inFormula I via the 4-carbon as shown below: .Attorney Ref: P6819PC00 9The term “oxo” refers to a carbonyl functional group composing a carbon atom double- bonded to an oxygen atom. It can be abbreviated herein as “oxo”, as C(O), or as C═O. The invention also includes pharmaceutical compositions comprising an effectiveamount of a disclosed compound and a pharmaceutically acceptable carrier. Representative “pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. The term “stereoisomers” refers to the set of compounds which have the same numberand type of atoms and share the same bond connectivity between those atoms, but differ in three-dimensional structure. The term “stereoisomer” refers to any member of this set of compounds. The term “diastereomers” refers to the set of stereoisomers which cannot be madesuperimposable by rotation around single bonds. For example, cis- and trans-double bonds,endo- and exo-substitution on bicyclic ring systems, and compounds containing multiplestereogenic centers with different relative configurations are considered to be diastereomers. The term “diastereomer” refers to any member of this set of compounds. In some examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers. In some cases these diastereomers were separated and in other cases a wavy bond is used to indicate the structural element where configuration is variable. The term “enantiomers” refers to a pair of stereoisomers which are non-superimposable mirror images of one another. The term “enantiomer” refers to a single member of this pair of stereoisomers. The term “racemic” refers to a 1:1 mixture of a pair of enantiomers. The term “tautomers” refers to a set of compounds that have the same number and typeAttorney Ref: P6819PC00 10of atoms, but differ in bond connectivity and are in equilibrium with one another. A “tautomer” is a single member of this set of compounds. Typically a single tautomer is drawn but it is understood that this single structure is meant to represent all possible tautomers that might exist. Examples include enol-ketone tautomerism. When a ketone is drawn it is understood that both the enol and ketone forms are part of the present disclosure. The term “solvate” refers to a complex of variable stoichiometry formed by a solute andsolvent. Such solvents for the purpose of the invention may not interfere with the biologicalactivity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as “hydrates.” Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water. An “effective amount” when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein. The term “carrier”, as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. The term “treating” with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder. The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body. A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.Attorney Ref: P6819PC00 11Compounds of the Invention In one aspect, the present disclosure provides a compound of Formula I or apharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof: wherein: R1is -H, -C1-C6alkyl, or C3-C6cycloalkyl; R2is a group of Formula II: Formula II wherein n is an integer from 0 to 8; R3is independently, at each occurrence, C1-C6 alkyl; or two R3, together with the carbon atoms to which they are attached, optionally combine to form a bridging alkylene, preferably a bridging C1-C2 alkylene; X is O, NR4, S, or SO2; Z is CH or N; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with oxo; -C(O)C1-C6 alkyl, wherein said C1-C6alkyl is optionally substituted with one or more C1-C6alkoxy; -C2-C6Attorney Ref: P6819PC00 12alkyl, wherein said C2-C6 alkyl is substituted with one or more C1-C6 alkoxy; -CH2- tetrahydropyran; and cyclopropyl. In one aspect, the present disclosure provides a compound of Formula I or apharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof: wherein: R1is -H or -C1-C6 alkyl; R2is a group of Formula II: Formula II wherein n is an integer from 0 to 8; R3is independently, at each occurrence, C1-C6 alkyl; or two R3, together with the carbonatoms to which they are attached, optionally combine to form a bridging alkylene, preferably abridging C1-C2 alkylene; X is O or NR4; Z is CH or N; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with oneAttorney Ref: P6819PC00 13or more C1-C6 alkoxy; -C2-C6 alkyl, wherein said C2-C6 alkyl is substituted with one or more C1-C6alkoxy; -CH2-tetrahydropyran; and cyclopropyl. In one aspect, the present disclosure provides a compound of Formula I or apharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof: wherein: R1is -H, -C1-C6alkyl, or C3cycloalkyl; R2is selected from the group consisting of tetrahydropyran, morpholine, 8- oxabicyclo[3.2.1]octane, piperidine, piperazine, 2-azabicyclo[2.2.1]heptane, thiane, and thiacyclohexane 1,1-dioxide; wherein said tetrahydropyran is bonded at a 4-carbon of said tetrahydropyran; saidmorpholine is bonded at a 4-nitrogen of said morpholine; said 8-oxabicyclo[3.2.1]octane isbonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane; said piperidine is bonded at a 4-carbon of said piperidine; said piperazine is bonded at a 4-nitrogen of said piperazine, said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane; saidthiane is bonded at a 4-carbon of said thiane; and said thiacyclohexane 1,1-dioxide is bondedat a 4-carbon of said thiacyclohexane 1,1-dioxide; wherein each tetrahydropyran, morpholine, 8-oxabicyclo[3.2.1]octane, piperidine,piperazine, 2-azabicyclo[2.2.1]heptane, thiane, and thiacyclohexane 1,1-dioxide isindependently optionally substituted with one or more R3; wherein each piperidine and piperazine are independently substituted at the 1-nitrogenwith R4, and wherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-Attorney Ref: P6819PC00 14nitrogen with R4; R3is independently, at each occurrence, C1-C6alkyl; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with oxo; -C(O)C1-C6alkyl, wherein said C1-C6alkyl is optionally substituted with one or more C1-C6alkoxy; -C2-C6alkyl, wherein said C2-C6 alkyl is substituted with one or more C1-C6 alkoxy; -CH2- tetrahydropyran; and cyclopropyl. In one aspect, the present disclosure provides a compound of Formula I or apharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof: wherein: R1is -H or -C1-C6 alkyl; R2is selected from the group consisting of tetrahydropyran, morpholine, 8- oxabicyclo[3.2.1]octane, piperidine, and 2-azabicyclo[2.2.1]heptane; wherein said tetrahydropyran is bonded at a 4-carbon of said tetrahydropyran; saidmorpholine is bonded at a 4-nitrogen of said morpholine; said 8-oxabicyclo[3.2.1]octane isbonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane; said piperidine is bonded at a 4-carbonof said piperidine; and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane; wherein each tetrahydropyran, morpholine, and 8-oxabicyclo[3.2.1]octane isindependently optionally substituted with one or more R3; wherein each piperidine and 2-azabicyclo[2.2.1]heptane is independently optionallyAttorney Ref: P6819PC00 15substituted with one or more R3, wherein each piperidine is independently substituted at the 1-nitrogen with R4, and wherein each 2-azabicyclo[2.2.1]heptane is independently substituted atthe 2-nitrogen with R4; R3is independently, at each occurrence, C1-C6alkyl; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with oneor more C1-C6 alkoxy; -C2-C6 alkyl, wherein said C2-C6 alkyl is substituted with one or moreC1-C6alkoxy; -CH2-tetrahydropyran; and cyclopropyl. In some embodiments, R1is hydrogen. In some embodiments, R1is H, C1-C6alkyl, or C3 cycloalkyl. In some embodiments, R1is H or C1-C6 alkyl. In some embodiments, R1C3- C6cycloalkyl. In some embodiments, R1C3cycloalkyl. In some embodiments, R1is H or C1- C4 alkyl. In some embodiments, R1is H or C1-C2 alkyl. In some embodiments, R1is H or methyl. In some embodiments, R1is C1-C4alkyl. In some embodiments, R1is C1-C2alkyl. In some embodiments, R1is methyl. In some embodiments, n is an integer from 0 to 4, preferably from 0 to 2. In someembodiments, n is an integer from 0 to 6. In some embodiments, n is an integer from 0 to 4. In some embodiments, n is an integer from 0 to 2. In some embodiments, n is an integer from0 to 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. Insome embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8.In some embodiments, said R3 is independently, at each occurrence, C1-C4 alkyl. Insome embodiments, R3is independently, at each occurrence, C1-C2alkyl. In some embodiments, R3is independently, at each occurrence, methyl. In some embodiments, R3is independently, at each occurrence, C1-C2alkyl, and n is an integer from 0 to 2. In some embodiments, R3is independently, at each occurrence, methyl, and n is an integer from 0 to 2. In some embodiments, R4 is independently, at each occurrence, selected from 3- to 5-membered heterocycloalkyl; -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more C1-C6alkoxy; -C2-C6alkyl, wherein said C2-C6alkyl is substituted with one or more C1-C6 alkoxy; -CH2-tetrahydropyran; and cyclopropyl. In some embodiments, Z is CH. In some embodiments, Z is N. In some embodiments, X is O or NR4. In some embodiments, X is S or SO2. In some embodiments, X is S. In some embodiments, X is SO2. In some embodiments, X is O.Attorney Ref: P6819PC00 16In some embodiments, X is O and Z is CH. In some embodiments, X is O and Z is N. In some embodiments, X is O; n is an integer from 0 to 4; and R3is independently, at each occurrence, C1-C4alkyl; or two R3, together with the carbon atoms to which they are attached, optionally combine to form a bridging alkylene, preferably a C1-C2 bridging alkylene. In some embodiments, X is O; n is an integer from 0 to 2; R3is independently, at each occurrence, C1-C2 alkyl; or two R3, together with the carbon atoms to which they are attached, optionally combine to form a bridging alkylene, preferably a C1-C2 bridging alkylene. In some embodiments, X is O; n is an integer from 0 to 4; R1is independently, at each occurrence, H or C1-C4alkyl; and R3is independently, at each occurrence, C1-C4 alkyl; or two R3, together with the carbon atoms to which they are attached, optionally combine to form a C1-C2 bridging alkylene. In some embodiments, X is O; n is an integer from 0 to 2; R1is independently, at each occurrence, H or C1-C2 alkyl; and R3is independently, at each occurrence, C1-C2 alkyl. In some embodiments, X is O; n is an integer from 0 to 2; R1is independently, at each occurrence, H or C1-C2alkyl; and R3is independently, at each occurrence, C1-C2 alkyl; or two R3, together with the carbon atoms to which they are attached, optionally combine to form a C1-C2 bridging alkylene. In some embodiments, X is NR4.In some embodiments, X is NR4and Z is CH. In some embodiments, X is NR4and Z is N. In some embodiments, X is NR4; n is an integer from 0 to 4; R3is independently, at each occurrence, C1-C4 alkyl; or two R3, together with the carbonatoms to which they are attached, optionally combine to form a C1-C2 bridging alkylene; andAttorney Ref: P6819PC00 17R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with oxo; -C(O)C1-C6alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more C1-C6 alkoxy; -C2-C6 alkyl, wherein said C2-C6alkyl is substituted with one or more C1-C6alkoxy; -CH2- tetrahydropyran; and cyclopropyl. In some embodiments, X is NR4; n is an integer from 0 to 4; R3is independently, at each occurrence, C1-C4alkyl; or two R3, together with the carbonatoms to which they are attached, optionally combine to form a C1-C2 bridging alkylene; andR4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; -C(O)C1-C6alkyl, wherein said C1-C6alkyl is optionally substituted with one or more C1-C6 alkoxy; -C2-C6 alkyl, wherein said C2-C6 alkyl is substituted with one or more C1-C6alkoxy; -CH2-tetrahydropyran; and cyclopropyl. In some embodiments, X is NR4; n is 0 or 2; when n is 2, both R3, together with the carbon atoms to which they are attached, combineto form a C1-C2 bridging alkylene; and R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; -C(O)C1-C6alkyl, wherein said C1-C6alkyl is optionally substituted with one or more C1-C6 alkoxy; -C2-C6 alkyl, wherein said C2-C6 alkyl is substituted with one or more C1-C6 alkoxy; -CH2-tetrahydropyran; and cyclopropyl. In some embodiments, X is NR4; n is 0 or 2; when n is 2, both R3, together with the carbon atoms to which they are attached, combineto form a C1-C2 bridging alkylene; and R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl and -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more C1-C6alkoxy. In some embodiments, R2is selected from the group consisting of tetrahydropyran, morpholine, 8-oxabicyclo[3.2.1]octane, piperidine, piperazine, 2-azabicyclo[2.2.1]heptane, thiane, and thiacyclohexane 1,1-dioxide; wherein said tetrahydropyran is bonded at a 4-carbon of said tetrahydropyran; saidmorpholine is bonded at a 4-nitrogen of said morpholine; said 8-oxabicyclo[3.2.1]octane isAttorney Ref: P6819PC00 18bonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane; said piperidine is bonded at a 4-carbon of said piperidine; said piperazine is bonded at a 4-nitrogen of said piperazine, said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane; saidthiane is bonded at a 4-carbon of said thiane; and said thiacyclohexane 1,1-dioxide is bondedat a 4-carbon of said thiacyclohexane 1,1-dioxide; wherein each tetrahydropyran, morpholine, 8-oxabicyclo[3.2.1]octane, piperidine,piperazine, 2-azabicyclo[2.2.1]heptane, thiane, and thiacyclohexane 1,1-dioxide isindependently optionally substituted with one or more R3; wherein each piperidine and piperazine are independently substituted at the 1-nitrogenwith R4, and wherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4; R3is independently, at each occurrence, C1-C6 alkyl; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with oxo; -C(O)C1-C6alkyl, wherein said C1-C6alkyl is optionally substituted with one or more C1-C6alkoxy, and - C2-C6 alkyl, wherein said -C2-C6 alkyl is substituted with one or more C1-C6 alkoxy. In some embodiments, R2is selected from the group consisting of tetrahydropyran, morpholine, 8-oxabicyclo[3.2.1]octane, piperidine, and 2-azabicyclo[2.2.1]heptane; wherein said tetrahydropyran is bonded at a 4-carbon of said tetrahydropyran; saidmorpholine is bonded at a 4-nitrogen of said morpholine; said 8-oxabicyclo[3.2.1]octane isbonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane; said piperidine is bonded at a 4-carbonof said piperidine; and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane; wherein each tetrahydropyran, morpholine, 8-oxabicyclo[3.2.1]octane, piperidine, and2-azabicyclo[2.2.1]heptane is independently optionally substituted with one or more R3;wherein each piperidine is independently substituted at the 1-nitrogen with R4, andwherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4;R3is independently, at each occurrence, C1-C6alkyl; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl, -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more C1-C6alkoxy, and -C2-C6alkyl, wherein said -C2-C6alkyl is substituted with one or more C1-C6 alkoxy. In some embodiments, R2is selected from the group consisting of tetrahydropyran,Attorney Ref: P6819PC00 19morpholine, 8-oxabicyclo[3.2.1]octane, piperidine, and 2-azabicyclo[2.2.1]heptane; wherein said tetrahydropyran is bonded at a 4-carbon of said tetrahydropyran; saidmorpholine is bonded at a 4-nitrogen of said morpholine; said 8-oxabicyclo[3.2.1]octane isbonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane; said piperidine is bonded at a 4-carbonof said piperidine; and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane; wherein each tetrahydropyran, morpholine, 8-oxabicyclo[3.2.1]octane, piperidine, and2-azabicyclo[2.2.1]heptane is independently optionally substituted with one or more R3;wherein each piperidine is independently substituted at the 1-nitrogen with R4, andwherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4;R3is independently, at each occurrence, C1-C6alkyl; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl and -C(O)C1-C6alkyl, wherein said C1-C6alkyl is optionally substituted with one or more C1-C6 alkoxy. In some embodiments, R2is selected from the group consisting of tetrahydropyran, morpholine, 8-oxabicyclo[3.2.1]octane, piperidine, and 2-azabicyclo[2.2.1]heptane; wherein said tetrahydropyran is bonded at a 4-carbon of said tetrahydropyran; saidmorpholine is bonded at a 4-nitrogen of said morpholine; said 8-oxabicyclo[3.2.1]octane isbonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane; said piperidine is bonded at a 4-carbonof said piperidine; and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane; wherein each tetrahydropyran, morpholine, and 8-oxabicyclo[3.2.1]octane isindependently optionally substituted with one or more R3;wherein each piperidine is independently substituted at the 1-nitrogen with R4, andwherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4;R3is independently, at each occurrence, C1-C6 alkyl; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl and -C(O)C1-C6alkyl, wherein said C1-C6alkyl is optionally substituted with one or more C1-C6 alkoxy. In some embodiments, R2is selected from the group consisting of tetrahydropyran, morpholine, 8-oxabicyclo[3.2.1]octane, piperidine, and 2-azabicyclo[2.2.1]heptane; wherein said tetrahydropyran is bonded at a 4-carbon of said tetrahydropyran; saidmorpholine is bonded at a 4-nitrogen of said morpholine; said 8-oxabicyclo[3.2.1]octane isAttorney Ref: P6819PC00 20bonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane; said piperidine is bonded at a 4-carbonof said piperidine; and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane; wherein each tetrahydropyran, morpholine, and 8-oxabicyclo[3.2.1]octane isindependently optionally substituted with one or more R3; wherein each piperidine is independently substituted at the 1-nitrogen with R4, andwherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4;R3is independently, at each occurrence, C1-C4alkyl, preferably C1-C2alkyl; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl and -C(O)C1-C4 alkyl, wherein said C1-C4 alkyl is optionally substituted with one or more C1-C4alkoxy, preferably C1-C2alkoxy. In some embodiments, R2 is selected from the group consisting of tetrahydropyran,morpholine, and 8-oxabicyclo[3.2.1]octane; wherein said tetrahydropyran is bonded at a 4-carbon of said tetrahydropyran; saidmorpholine is bonded at a 4-nitrogen of said morpholine; and said 8-oxabicyclo[3.2.1]octane isbonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane; wherein each tetrahydropyran, morpholine, and 8-oxabicyclo[3.2.1]octane isindependently optionally substituted with one or more R3; and R3is independently, at each occurrence, C1-C6alkyl. In some embodiments, R2is piperidine, piperazine, or 2-azabicyclo[2.2.1]heptane, wherein said piperidine is bonded at a 4-carbon of said piperidine, said piperazine isbonded at a 4-nitrogen of said piperazine, and said 2-azabicyclo[2.2.1]heptane is bonded at a5-carbon of said 2-azabicyclo[2.2.1]heptane; wherein each piperidine and piperazine are independently substituted at the 1-nitrogenwith R4, and wherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with oneor more C1-C6 alkoxy; -C2-C6 alkyl, wherein said C2-C6 alkyl is substituted with one or more C1-C6 alkoxy; -CH2-tetrahydropyran; and cyclopropyl. In some embodiments, R2 is piperidine or 2-azabicyclo[2.2.1]heptane,wherein said piperidine is bonded at a 4-carbon of said piperidine, and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane;Attorney Ref: P6819PC00 21wherein each piperidine is independently substituted at the 1-nitrogen with R4, andwherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4;R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with oneor more C1-C6alkoxy; -C2-C6alkyl, wherein said C2-C6alkyl is substituted with one or more C1-C6 alkoxy; -CH2-tetrahydropyran; and cyclopropyl. In preferred embodiments, R2is piperidine, wherein said piperidine is bonded at the 4-carbon. In preferred embodiments, R2 is azabicyclo[2.2.1]heptane, wherein saidazabicyclo[2.2.1]heptane is bonded at the 5-carbon.In preferred embodiments, R2is piperidine, wherein said piperidine is bonded at the 4-carbon and wherein said piperidine is substituted with R4 at the 1-nitrogen. In preferredembodiments, R2 is azabicyclo[2.2.1]heptane, wherein said azabicyclo[2.2.1]heptane is bondedat the 5-carbon and wherein said azabicyclo[2.2.1]heptane is substituted with R4 at the 2-nitrogen. In some embodiments, R2 is piperidine or 2-azabicyclo[2.2.1]heptane,wherein said piperidine is bonded at a 4-carbon of said piperidine, and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane;wherein each piperidine is independently substituted at the 1-nitrogen with R4, andwherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4;R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; and -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more C1-C6alkoxy. In some embodiments, R2is piperidine or 2-azabicyclo[2.2.1]heptane, wherein said piperidine is bonded at a 4-carbon of said piperidine, and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane;wherein each piperidine is independently substituted at the 1-nitrogen with R4, andwherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4;R4is independently, at each occurrence, selected from -C2-C6alkyl, wherein said C2-C6alkyl is substituted with one or more C1-C6 alkoxy; -CH2-tetrahydropyran; and cyclopropyl. In some embodiments, R2is piperidine, wherein said piperidine is bonded at a 4-carbon of said piperidine, wherein said piperidine is independently substituted at the 1-nitrogen with R4, R4 is independently, at each occurrence, selected from 3- to 5-memberedAttorney Ref: P6819PC00 22heterocycloalkyl; and -C(O)C1-C4 alkyl, wherein said C1-C4 alkyl is optionally substituted with one or more C1-C4alkoxy. In some embodiments, R2is piperidine, wherein said piperidine is bonded at a 4-carbon of said piperidine, wherein said piperidine is independently substituted at the 1-nitrogen with R4, R4is independently, at each occurrence, selected from -C4 heterocycloalkyl; and - C(O)C1-C4 alkyl, wherein said C1-C4 alkyl is optionally substituted with one or more C1-C2 alkoxy. In some embodiments, R2 is piperidine, wherein said piperidine is bonded at a 4-carbonof said piperidine, wherein said piperidine is independently substituted at the 1-nitrogen with R4, R4is independently, at each occurrence, selected from oxetane, preferably 3-oxetane; and -C(O)C1-C4alkyl, wherein said C1-C4alkyl is optionally substituted with one or more C1- C4 alkoxy, preferably C1-C2 alkoxy. In some embodiments, R2is piperidine or 2-azabicyclo[2.2.1]heptane, wherein said piperidine is bonded at a 4-carbon of said piperidine, and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane;wherein each piperidine is independently substituted at the 1-nitrogen with R4, andwherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-nitrogen with R4;wherein R4is -C2-C6 alkyl, wherein said C2-C6 alkyl is substituted with one or more C1- C6 alkoxy. In some embodiments, R2is piperidine, wherein said piperidine is bonded at a 4-carbon of said piperidine, wherein said piperidine is independently substituted at the 1-nitrogen with R4; wherein R4is -C2-C4 alkyl, wherein said C2-C4 alkyl is substituted with one or more C1- C2 alkoxy. In some embodiments, R2is piperidine, wherein said piperidine is bonded at a 4-carbon of said piperidine, wherein said piperidine is independently substituted at the 1-nitrogen with R4; wherein R4is -CH2-tetrahydropyran. In some embodiments, R2is piperidine, wherein said piperidine is bonded at a 4-carbon of said piperidine, wherein said piperidine is independently substituted at the 1-nitrogen with R4;Attorney Ref: P6819PC00 23wherein R4is cyclopropyl. In some embodiments, R2is piperazine. In some embodiments, R2is piperazine, wherein said piperazine is bonded at a 1- nitrogen of said piperazine, wherein said piperazine is independently substituted with R4. In some embodiments, R2is piperazine, wherein said piperazine is bonded at a 1- nitrogen of said piperazine, wherein said piperazine is independently substituted with one or more R4, wherein said R4is CH2-tetrahydropyran. In some embodiments, R2is thiane or thiacyclohexane 1,1-dioxide. In some embodiments, R2is thiane or thiacyclohexane 1,1-dioxide, wherein said thianeand said thiacyclohexane 1,1-dioxide are bonded at a 4-carbon of said thiane and saidthiacyclohexane 1,1-dioxide. In one aspect, the present disclosure provides a pharmaceutical composition comprisingat least one compound according to any of the preceding claims, or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient. In one aspect, the present disclosure provides a compound as disclosed herein or apharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, for use as a medicament.In one aspect, the present disclosure provides a compound as disclosed herein or apharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, for use in a method of preventing or treating a disease in a subject, preferably wherein said disease is an infection, further preferably a bacterial infection, yet further preferably a bacterial infection caused by one or more bacterium belonging to a genus of non-tuberculous Mycobacteria, preferably M. abscessus. In one or more embodiments, R1and R2of a compound of the present invention canform one of the structures selected from Table 1, below, wherein the connectivity to theremainder of Formula I is shown below:

[0002] Attorney Ref: P6819PC00 24 Table 1. Embodiments of -NR1R2Compound Structure Compound Structure1 2 HN HNN O O 3 N HN4 O O HN 5HN 6NO OAttorney Ref: P6819PC00 25Compound Structure Compound StructureHN HN 7 8 N N O O N HN 9 10 N N O O O HN HN 11 12 N N O O HN 13 14 N N 15N16O OAttorney Ref: P6819PC00 26Compound Structure Compound StructureN 17 18N 19 20N HN 21 22 O S HN HN 23 24 N S OOS OOIn some embodiments, the compound is a compound as shown below in Table 2, or a pharmaceutically acceptable salt thereof. Table 2. Embodied Compounds

[0003] Attorney Ref: P6819PC00 27Cmpd. Structure IUPAC Name[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- 1 dioxa-24,27,29- triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N- morpholinocarbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- 2 dioxa-24,27,29- triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N- tetrahydropyran-4-ylcarbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- 3 dioxa-24,27,29- triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-(8- oxabicyclo[3.2.1]octan-3-yl)carbamateAttorney Ref: P6819PC00 28Cmpd. Structure IUPAC Name[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- 4 dioxa-24,27,29- triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-methyl- N-tetrahydropyran-4-yl-carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- 5 dioxa-24,27,29- triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-(2,2- dimethyltetrahydropyran-4-yl)carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- 6 dioxa-24,27,29- triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-[1-(2- methoxyethyl)-4-piperidyl]carbamateAttorney Ref: P6819PC00 29Cmpd. Structure IUPAC Name[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 7 triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-[2-(2- methoxyethyl)-2-azabicyclo[2.2.1]heptan- 5-yl]carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 8 triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-[1-(2- methoxy-2-methyl-propyl)-4- piperidyl]carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 9 triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-[1-(2- methoxy-2-methyl-propyl)-4-piperidyl]-N- methyl-carbamateAttorney Ref: P6819PC00 30Cmpd. Structure IUPAC Name[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 10 triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-[1-(2- methoxy-2-methyl-propanoyl)-4- piperidyl]carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- 11 dioxa-24,27,29- triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-[1- (oxetan-3-yl)-4-piperidyl]carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 12 triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-[1- (tetrahydropyran-4-ylmethyl)-4- piperidyl]carbamateAttorney Ref: P6819PC00 31Cmpd. Structure IUPAC Name[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18 S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- 13 dioxa-24,27,29- triazapentacyclo[23.6.1.14,7.05,31.026,30] tritriaconta-1(31),2,4,9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-(1- cyclopropyl-4-piperidyl)carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 14 triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri aconta-1,3,5(31),9,19,21,25,29-octaene- 28,4'-piperidine]-13-yl] N-[4- (tetrahydropyran-4-ylmethyl)piperazin-1- yl]carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 15 triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri aconta-1,3,5(31),9,19,21,25,29-octaene- 28,4'-piperidine]-13-yl] N-[1-(2-methoxy- 2-methyl-propanoyl)-4-piperidyl]-N- methyl-carbamateAttorney Ref: P6819PC00 32Cmpd. Structure IUPAC NameN O [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S N O O ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- O OHOH11-methoxy-3,7,12,14,16,18,22- OH OO heptamethyl-6,23,32-trioxo-spiro[8,33- NH dioxa-24,27,29- 16 triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri O NH O N O aconta-1,3,5(31),9,19,21,25,29-octaene- N 28,4'-piperidine]-13-yl] N-methyl-N- morpholino-carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 17 triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri aconta-1,3,5(31),9,19,21,25,29-octaene- 28,4'-piperidine]-13-yl] N-(1-cyclopropyl- 4-piperidyl)-N-methyl-carbamate N O [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S N O ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- OOOHOH11-methoxy-3,7,12,14,16,18,22- OH OO heptamethyl-6,23,32-trioxo-spiro[8,33- NH dioxa-24,27,29- 18 O NH O N triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri O N aconta-1,3,5(31),9,19,21,25,29-octaene- 28,4'-piperidine]-13-yl] N-methyl-N-[1- (oxetan-3-yl)-4-piperidyl]carbamateAttorney Ref: P6819PC00 33Cmpd. Structure IUPAC Name[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 19 triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri aconta-1,3,5(31),9,19,21,25,29-octaene- 28,4'-piperidine]-13-yl] N-[1-(3- methylbutanoyl)-4-piperidyl]carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 20 triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri aconta-1,3,5(31),9,19,21,25,29-octaene- 28,4'-piperidine]-13-yl] N-ethyl-N- tetrahydropyran-4-yl-carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 21 triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri aconta-1,3,5(31),9,19,21,25,29-octaene- 28,4'-piperidine]-13-yl] N-cyclopropyl-N- tetrahydropyran-4-yl-carbamateAttorney Ref: P6819PC00 34Cmpd. Structure IUPAC Name[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 22 triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri aconta-1,3,5(31),9,19,21,25,29-octaene- 28,4'-piperidine]-13-yl] N- tetrahydrothiopyran-4-ylcarbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S H N O ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- O S O 11-methoxy-3,7,12,14,16,18,22- O OOH OHheptamethyl-6,23,32-trioxo-spiro[8,33- OH OO dioxa-24,27,29- 23 NH triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri O NH O aconta-1,3,5(31),9,19,21,25,29-octaene- N O 28,4'-piperidine]-13-yl] N-(1,1-dioxothian- N 4-yl)carbamate [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S ,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22- heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29- 24 triazapentacyclo[23.6.1.14,7.05,31.026,30]tritri aconta-1,3,5(31),9,19,21,25,29-octaene- 28,4'-piperidine]-13-yl] N-[1-(1,1- dioxothietan-3-yl)-4-piperidyl]carbamateAttorney Ref: P6819PC00 35In some embodiments, the compound is selected from the group consisting ofCompounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound is selected from the group consisting ofCompounds 1, 2, 3, 4, 5, 10, and 11, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is selected from the group consisting ofCompounds 1, 2, 3, 4, and 5, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is selected from the group consisting ofCompounds 10 and 11, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound of Formula I is Compound 1, or apharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 3, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 4, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 5, or apharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 6, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 7, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 8, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 9, or apharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 10, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 11, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 12, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 13, or apharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 14, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 15, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 16, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 17, or apharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 18, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 19, or a pharmaceutically acceptable salt thereof. In someAttorney Ref: P6819PC00 36embodiments, the compound of Formula I is Compound 20, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 21, or apharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 22, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 23, or a pharmaceutically acceptable salt thereof. Insome embodiments, the compound of Formula I is Compound 24, or a pharmaceuticallyacceptable salt thereof. In one aspect, the present invention provides a pharmaceutical composition comprising at least one compound according to the present invention, or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient. Methods of Synthesizing the Disclosed Compounds The compounds of the present invention may be made by a variety of methods,including standard chemistry. The methods include but are not limited to the methods described in the suitable synthetic routes depicted in the schemes given below. The compounds of the present invention may be prepared by methods known in the artof organic synthesis as set forth in part by the following synthetic schemes and examples. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. 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 that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of the present invention. Those skilled in the art will recognize if a stereocenter exists in the compounds ofFormula I. Accordingly, the present invention includes both possible stereoisomers (unlessspecified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (WileyAttorney Ref: P6819PC00 37- lnterscience, 1994).The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of Compounds Compounds of the present invention can be synthesized by following the steps outlinedin General Schemes 1, 2 and 3. Starting materials are either commercially available or madeby known procedures in the reported literature or as illustrated.Scheme 1. General Synthesis of 21,23-acetonide-25-hydroxy-rifabutin (I-1) Ageneral method for the preparation of 21,23-acetonide-25-hydroxy-rifabutin I-1 isshown above in Scheme 1. Protection of the C21 and C23 hydroxy groups using a suitable protecting group such as dimethoxy propane and camphorsulphonic acid in a solvent, e.g., DMFafforded an acetal-protected rifabutin. De-acetylation of the protected rifabutin using a basicsolution such as sodium methoxide in ether afforded the C25-hydroxy, C21-C23-protectedrifabutin (I-1).Scheme 2. Synthesis of 21,23-acetonide-25-carbonyl-imidazol-rifabutin (I-2) Attorney Ref: P6819PC00 38The free C25-hydroxy group of Intermediate (I-1) can be converted to a C25 imidazolecarbamate (i.e., Intermediate I-2) using a carbamoylation reagent such as 1,1’-carbonyldiimidazole in a suitable solvent such as dichloromethane (DCM) as shown above inScheme 2. Scheme 3. Synthesis of deprotected 25-carbonyl-Conjugated-Rifabutin Intermediate (I-2) can be substituted by an appropriate amine in the presence of asuitable coupling reagent such as 1-hydroxy-1H-benzotriazole (HOBt). Subsequentdeprotection of the C21-C23 acetal in the conjugated rifabutin can be carried out by treating with an acid such as camphorsulfonic acid in a suitable solvent such as a mixture of THF / water. Antibacterial Efficacy of the Disclosed Compounds The inventive compounds are C25-modified analogs of rifabutin that exhibit goodantibacterial activity against both smooth (S) and rough (R) Mycobacterium abscessus (M.abscessus, also known as “Mabs”) variants. Moreover, as shown in the Examples, the inventive compounds were found to be less cytotoxic to healthy cells (e.g., HepG2 cells) compared to other known C25-analogs of rifabutin. The combination of lower cytotoxicity against healthycells and similar or better antibacterial activity against a broad range of M. abscessus suggeststhat the inventive compounds can have a broader therapeutic window in patients than other C25-modified analogs of rifabutin. Accordingly, in some embodiments, the inventive compounds can be used to inhibitbacterial infection, preferably infection caused by a non-tuberculous Mycobacteria, morepreferably M. abscessus.Attorney Ref: P6819PC00 39Methods of Using the Disclosed Compounds An aspect of the present invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof for use as a medicament. In one aspect, the present invention provides a compound according to Formula I of the present invention or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, or a pharmaceutical composition comprising a compound of Formula I of the present invention, for use in a method of preventing or treating a disease in a subject, preferably an infection, further preferably a bacterial infection. In one aspect, the present invention provides a method of treating a disease, preferably an infection, more preferably a bacterial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I of the present invention or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof. In one aspect, the present invention provides a method of treating a disease, preferably aninfection, more preferably a bacterial infection in a subject in need thereof, the methodcomprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of Formula I of the present invention or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof. In one aspect, the present invention provides the use of a compound of Formula I of the present invention or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof in the manufacture of a medicament for treating a disease, preferably an infection, more preferably a bacterial infection in a subject in need thereof. In one aspect, the present invention provides the use of a pharmaceutical composition comprising a compound of Formula I of the present invention or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof in the manufacture of a medicament for treating a disease, preferably an infection, more preferably a bacterial infection in a subject in need thereof. In some preferred embodiments, the bacterial infection is caused by one or more bacterium belonging a genus of non-tuberculous Mycobacteria, preferably M. abscessus. In some preferred embodiments, the infection is caused by one or more bacteriumbelonging to a genus of non-tuberculosis Mycobacterium, preferably M. abscessus, M. avium,M. kansasii, M. smegmatis, M. xenopi and / or M. malmoense, more preferably M. abscessus, M.avium, M. kansasii, and / or M. xenopi, yet more preferably M. abscessus.In some preferred embodiments, the inventive compounds are used for the treatment ofa non-tuberculous Mycobacteria that causes a non-tuberculous Mycobacteria pulmonaryAttorney Ref: P6819PC00 40infection. In some embodiments the non-tuberculosis Mycobacterium is M. abscessus, M.avium, M. kansasii, M. smegmatis, M. xenopi and / or M. malmoense, preferably M. abscessus,M. avium, M. kansasii, and / or M. xenopi, more preferably M. abscessus. Accordingly, in somepreferred embodiments, the inventive compounds are for use in the treatment of a non-tuberculous Mycobacteria pulmonary infection. In some preferred embodiments, the inventivecompounds are for use in the manufacture of a medicament for the treatment of a non-tuberculous Mycobacteria pulmonary infection. In some preferred embodiments, the presentinvention provides a method of treating a non-tuberculous Mycobacteria pulmonary infectionin a subject in need thereof, comprising administering to the subject an effective amount of an inventive compound of the invention. Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising acompound of the invention and a pharmaceutically acceptable carrier, such as a) a diluent, e.g.,purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algiic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, 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 emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl- cyclodextrin, PEG400, PEG200. The inventive compounds and pharmaceutical compositions may be administered by any suitable route, e.g. orally, for example as a syrup, tablet, capsule, controlled-release preparation, fast-dissolving preparation, or lozenge. Liquid, particularly injectable, compositions can, for example, be prepared byAttorney Ref: P6819PC00 41dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds. The disclosed compounds can be also formulated as a suppository that can be preparedfrom fatty emulsions or suspensions, using polyalkylene glycols such as propylene glycol, asthe carrier. The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No.5,262,564. Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. Another aspect of the invention relates to a pharmaceutical composition comprising acompound of the present invention and a pharmaceutically acceptable carrier. Thepharmaceutically acceptable carrier can further include an excipient, diluent, or surfactant. Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions 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 by weight or volume. The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including 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 amountof the drug required to prevent, counter, or arrest the progress of the condition.Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed toAttorney Ref: P6819PC00 42treat 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 of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored. Equivalents While the present technology has been described in conjunction with the specificembodiments set forth above, many alternatives, modifications and other variations thereof 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 present invention.

[0004] Attorney Ref: P6819PC00 43EXAMPLES The invention will now be illustrated by way of the following non-limiting examples.While particular embodiments of the invention are described below, a skilled person willappreciate that various changes and modifications can be made. References to preparations carried out in a similar manner to, or by the general method of, other preparations, may encompass variations in routine parameters such as time, temperature, workup conditions, minor changes in reagents amounts, and the like. Abbreviations The following list provides definitions of certain abbreviations and symbols as used herein. It will be appreciated that the list is not exhaustive, but the meaning of those abbreviations and symbols not herein below defined will be readily apparent to those skilled in the art. In describing the invention, chemical elements are identified in accordance with the Periodic Table of the Elements.ACN acetonitrileAcOH acetic acidaq. aqueousAr argonCSA camphorsulphonic acidDCM dichloromethaneDMF dimethylformamideeq. equivalentEtOAc ethyl acetateEtOH ethanolh hour(s)HOBt 1-hydroxy-1H-benzotriazoleHPLC high performance liquid chromatographyLC liquid chromatographyM molarMeOH methanolMS mass spectroscopymin minutesAttorney Ref: P6819PC00 44NMR nuclear magnetic resonance spectroscopyrt room temperatureRt retention timesat. saturatedUnless specified otherwise, the purity and identity of Intermediate or examplecompounds were assessed by state-of-the-art HLPC-MS. Methods are described below. Characterization of the Compounds Method A or B was used for the intermediates. Method A or B was used to measurefinal purity of the compounds as noted herein. Purity (%) was determined by reversed phaseHPLC or UPLC, using UV detection (254 or 214 nm). Structure was confirmed by MS, usingelectro spray ionization positive (ESI+) method and reported as [M+H]+, referring to the protonated molecular ion. Method A: UPLC system: UPLC I BIN SOL MGR with ACQUITY UPLC I-Class eK PDA Detector; Column: Acquity BEH C18 column (1.7µm particle size, dimensions 50mm x 2.1mm); Mobile phases: 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)) were used according to thefollowing methods and reported run times:Method A – 5 minTimePhase A Phase B Flow(min) (mL / min) 0.00 98.0 2.0 0.60.20 98.0 2.0 0.62.50 0.0 100.0 0.63.50 0.0 100.0 0.63.60 98.0 2.0 0.65.00 98.0 2.0 0.6Method A – 30 minTimePhase A Phase B Flow(min) (mL / min)Attorney Ref: P6819PC00 450.00 100.0 0.0 2.001.00 100.0 0.0 2.0025.00 0.0 100.0 2.0027.00 0.0 100.0 2.0027.10 100.0 0.0 2.0030.00 100.0 0.0 2.00Mass spectrometer: ACQUITY QDa (Performance) Xevo TQD. Ionization: electrospray (polarity: negative and positive). Unless otherwise stated, analyses lasted five minutes. Method B: Waters LC-H class plus, QDa; Column Acquity HSS-T3 (2.1 x 100mm, 1.8 μm);Mobile phases: Phase A: 0.1% Trifluoroacetic Acid in Water, Phase B: Acetonitrile were usedaccording to the following gradient: Method B – 10 minTime Phase A Phase B Flow (ml / min)0.0 90.0 10.0 0.31.0 90.0 10.0 0.32.0 85.0 15.0 0.34.5 45.0 55.0 0.36.0 10.0 90.0 0.38.0 10.0 90.0 0.310.0 10.0 90.0 0.3Method B – 15 minTime Phase A Phase B Flow (ml / min)0.0 90.0 10.0 0.31.0 90.0 10.0 0.32.0 85.0 15.0 0.34.5 70.0 30.0 0.36.0 55.0 45.0 0.38.0 20.0 80.0 0.3Attorney Ref: P6819PC00 4610.0 10.0 90.0 0.312.0 90.0 10.0 0.315.0 90.0 10.0 0.3NMR Analysis NMR spectra were recorded on a Bruker DRX-300 spectrometer or Bruker 500 MHzspectrometer with a TXI probe or Bruker 400 MHz. Chemical shifts are in parts per million(ppm). The assignments were made using one-dimensional (1D)1H and13C spectra and two- dimensional (2D) HSQC, HMBC spectra. The compounds of the current invention were obtained from the free 25-OH rifabutin(Intermediate I-1) prepared from commercially available rifabutin as shown below.EXAMPLE 1: Synthesis of 21,23-acetonide-25-hydroxy-rifabutin (I-1) Synthesis of Intermediate I-1:Step 1: Commercially available Rifabutin (40.0 g, 47.2 mmol) was dissolved in dry DMF (80mL) at RT under nitrogen atmosphere. 2,2-Dimethoxy-propane (58.1 mL, 472 mmol) and (1R)(−) 10 camphorsulfonic acid (12.6 g, 54.3 mmol) were sequentially added to the solution. Thereaction mixture was stirred at RT for 26 h under inert atmosphere. The mixture was then cooledto 0°C and poured into a mixture of a solution of NaHCO3 (sat. aq., 700 mL) and water (500mL). The reaction flask was washed with acetone (100 mL). The resulting suspension wasstirred in an ice bath for 10 min and filtered. The cake was rinsed with a solution of NaHCO3(sat. aq., 100 mL) and water (50 mL) and dried under vacuum at 40 °C for 24 h. The crudeproduct was purified by flash chromatography (DCM to 50% of the mixtureDCM / MeOH / NH4OH 90 / 9 / 1.5 in DCM) to afford the 21,23-acetonide-rifabutin as a purplesolid (37.68 g, 90 % yield).Attorney Ref: P6819PC00 47LC / MS A (ESI+): tr = 3.20 min, m / z [M+H]+= 887.48, UV purity: 97 % (254 nm).1H NMR (300 MHz, CDCl3): δ 14.82 (s, 1H), 8.76 (brs, 1H), 7.75 (s, 1H), 6.28 (dd, J = 15.5,10.7 Hz, 1H), 6.16 (dd, J = 10.7, 1.4 Hz, 1H), 6.08 (dd, J = 15.5, 6.8 Hz, 1H), 5.87 (d, J = 12.2Hz, 1H), 5.08 (dd, J = 12.1, 6.7 Hz, 1H), 4.91 (d, J = 7.5 Hz, 1H), 3.58 (dd, J = 3.1 Hz, 1H),3.34 (d, J = 6.7 Hz, 1H), 3.09-2.91 (m overlapped, 2H), 3.06 (dd overlapped, J = 10.3, 5.4 Hz,1H), 2.79 (s, 3H), 2.72-2.52 (m, 2H), 2.35-2.22 (m overlapped, 3H), 2.31 (s overlapped, 3H), 2.20-1.73 (m overlapped, 6H), 2.04 (s overlapped, 3H), 1.96 (s overlapped, 3H), 1.77 (soverlapped, 3H), 1.55-1.36 (m, 2H), 1.23 (s, 3H), 0.93 (d, J = 6.6 Hz, 6H), 0.88-0.80 (m, 9H),0.69 (d, J = 7.1 Hz, 3H), 0.40 (d, J = 7.1 Hz, 3H).13C NMR (75 MHz, CDCl3): δ 192.8, 181.3, 172.2, 170.6, 169.0, 168.3, 155.2, 142.3,140.9, 140.8, 132.7, 131.3, 125.5, 123.8, 115.4, 113.7, 111.7, 108.8, 106.2, 104.6, 100.2, 95.0, 79.0, 76.9, 74.7, 71.2, 66.4, 56.2, 51.6 (2C), 41.4, 40.8, 36.9, 36.1, 35.5, 34.2, 25.9 (2C), 23.6, 21.0 (3C), 20.4, 20.3, 18.0, 12.9, 10.0, 9.1, 7.9. Step 2: 21,23-acetonide-rifabutin (10.6 g, 11.9 mmol) was dissolved in dry diethyl ether (500mL). The solution was cooled to -10°C and degassed with Ar bubbling. After 15 min, a solutionof NaOMe (25wt% in MeOH, 30 mL) was slowly added. Precipitation occurred and anotherportion of diethyl ether (100 mL) was added to homogenize the mixture. Subsequently, anotherportion of NaOMe solution was added (25wt% in MeOH, 27.4 mL). The solution was stirredat -5°C for 10 min before the ice bath was removed then the reaction mixture was stirred at RTfor 6 h. A solution of NaHCO3 (sat. aq., 400 mL) was added and the layers were separated. Theaqueous layer was extracted with diethyl ether (400 mL) and the combined organic layers werewashed with NaCl brine (300 mL) and evaporated to afford the desired crude product as a black-purple powder. The product was purified by flash chromatography (DCM to 50% of the mixture DCM / MeOH / NH4OH 90 / 9 / 1.5 in DCM). After evaporation, the product was redissolved in acetone and slowly added into water under vigorous stirring. The solid was collected byfiltration and dried at 40°C to yield 8.54 g of the Intermediate I-1.LC / MS A (ESI+): tr = 2.98 min, m / z [M+H]+ = 845.59, UV purity: 97 % (254 nm).1H NMR (300 MHz, CDCl3): δ 14.81 (s, 1H), 8.64 (brs, 1H), 7.72 (s, 1H), 6.25 (dd, J = 15.6Hz, 10.3 Hz, 1H), 6.12 (dd overlapped, J = 10.2 Hz, 1.2 Hz, 1H), 6.11 (d overlapped, J = 10.3Hz, 1H), 5.94 (dd, J = 15.6 Hz, 5.6 Hzn 1H), 4.93 (dd, J = 12.2 Hz, 9.2 Hz, 1H), 3.55 (dd, J =9.2 Hz, 3.3 Hz, 1H), 3.48 (dd, J = 10.4 Hz, 3.0 Hz, 1H), 3.42 (d, J = 8.7 Hz, 1H), 3.31 (brs,Attorney Ref: P6819PC00 481H), 3.14-3.06 (m overlapped, 1H), 3.10 (s overlapped, 3H), 3.00-2.86 (m, 2H), 2.71-2.47 (m,2H), 2.31-2.17 (m overlapped, 3H), 2.2 (s overlapped, 3H), 2.11-1.77 (m overlapped, 5H), 2.01 (s overlapped, 3H), 1.73 (s, 3H), 1.67-1.57 (m, 1H), 1.57-1.44 (m, 1H), 1.33-1.25 (m, 1H), 1.04(s, 3H), 0.89 (d, J = 6.5 Hz, 6H), 0.84-0.76 (m, 9H), 0.71 (d, J = 6.8 Hz, 3H), 0.48 (d, J = 7.0Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 191.3, 181.6, 171.4, 169.2, 168.2, 155.2, 142.7, 142.6,140.3, 132.4, 132.0, 125.5, 124.2, 114.3, 111.9, 111.8, 108.6, 105.7, 104.9, 99.6, 95.0, 83.0, 75.5, 71.5, 71.0, 66.4, 56.2, 51.8, 51.4, 41.1, 39.7, 36.4, 35.3 (2C), 34.6, 25.9, 25.6, 24.3, 21.01, 20.97, 20.0, 19.9, 17.8, 12.9, 8.4, 7.8. EXAMPLE 2: Synthesis of 25-carbonyl-imidazol-21,23-acetonide-Rifabutin (I-2) Intermediate I-1 (1.00 g, 1.18 mmol, 1 eq) was dissolved in anhydrous DCM (40ml)under inert atmosphere. To this solution was added carbonyldiimidazole (1.92 g, 11.80 mmol,10 eq) and the reaction was stirred at RT. After 16 h, the mixture was washed with an aqueoussaturated solution of NaHCO3(40ml) and NaCl brine (40mL). The organic layer was driedover MgSO4, filtered, and DCM was evaporated under vacuum. The obtained product waspurified by flash chromatography with cyclohexane / Acetone (from 100 / 0 to 60 / 40 over 20 CV)to yield 25-carbonyl-imidazol-21,23-acetonide-Rifabutin (I-2) as a red solid (m= 660mg,yield=59%). LC / MS A (ESI+): tr = 2.29 min, m / z [M+H]+ = 939.52, UV purity: 99% (254 nm).1H NMR (300 MHz, CDCl3): δ (ppm) 14.78 (s, 1H), 8.92-8.46 (brs, 1H), 8.03-7.92 (m,2H), 7.30-7.23 (m, 1H), 6.97-6.91 (m, 1H), 6.21 (dd, J = 15.6, 10.6 Hz, 1H), 6.07 (dd, J = 10.5,1.2 Hz, 1H), 5.97 (dd, J = 15.6, 6.9 Hz, 1H), 5.89 (d, J = 12.1 Hz, 1H), 5.10-4.95 (m, 2H), 3.51(dd, J = 10.5, 3.0 Hz, 1H), 3.30 (dd, J = 7.4, 1.7 Hz, 1H), 3.02-2.82 (m, 3H), 2.67 (s, 3H), 2.62-2.44 (m, 2H), 2.20 (s, 3H), 2.27-2.15 (m, 3H), 1.97 (s, 3H), 1.69 (s, 3H), 2.16-1.58 (mAttorney Ref: P6819PC00 49overlapped, 8H), 1.54-1.38 (m, 1H), 1.08 (s, 3H), 0.90-0.82 (m, 6H), 0.82-0.70 (m, 12H), 0.45(d, J = 7.0 Hz, 1H).13C NMR (75 MHz, CDCl3): δ (ppm) 191.9, 181.2, 171.6, 168.7, 168.0, 154.9, 148.1,142.3, 141.7, 140.0, 136.8, 132.0, 131.5, 130.3, 125.2, 123.8, 116.8, 113.7, 113.0, 111.5, 108.4,105.7, 104.5, 99.9, 94.9, 79.5, 78.7, 76.0, 70.9, 66.2, 55.7, 51.4, 51.2, 40.6, 40.3, 36.6, 36.1,35.3, 34.0, 26.7, 25.7, 25.4, 23.16, 20.76, 20.74, 19.9, 17.7, 12.7, 10.2, 9.4, 7.6.EXAMPLE 3: Synthesis of Compound 2 Intermediate I-2 (25-imidazo-carbonyl-21,23-acetonide-rifabutin, 1g, 1 eq.) wasdissolved in DMF (0.025 mol / L). To this solution was added tetrahydro-2H-pyran-4-amine (5eq.) and HOBt (20 eq.) and the mixture was stirred for 16h at 50°C. Then, the mixture was diluted with AcOEt, washed with sat. solution of NaHCO3and then brine. The combined organic phase were dried, filtered and concentrated under reduce pressure. The crude was purified by column chromatography (from 100% DCM to 90 / 10 DCM / MeOH). The recovered fraction was dissolved in a mixture THF / 0.5 N aqueous solution of CSA and stirred overnight.Then, AcOEt was added and the organic phase was washed with sat. solution of NaHCO3 andbrine. The organic phase was dried, filtered and concentrated under reduce pressure. The crude was purified by column chromatography (from 100% DCM to 90 / 10 DCM / MeOH) to afford the desired product [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17- trihydroxy-1'-isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo- spiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-tetrahydropyran-4-ylcarbamate (Compound 2) as purple solid (228 mg). LC / MS B (ESI+): tr = 7.83 min, m / z [M+H]+ = 932.71, UV purity: >95% (254 nm).Attorney Ref: P6819PC00 501H NMR (300 MHz, C6D6): δ(ppm) 15.49 (s, 1H), 9.21 (s, 1H), 8.61 (s, 1H), 6.55 (dd,J = 15.7, 9.6 Hz, 1H), 6.40 (d, J = 12.5 Hz, 1H), 5.98 (d, J = 9.5 Hz, 1H), 5.91 (dd, J = 15.7, 7.2 Hz, 1H), 5.27 (dd, J = 12.6, 7.4 Hz, 1H), 5.00 (d, J = 3.7 Hz, 1H), 4.75 (d, J = 10.5 Hz, 1H), 4.14 (d, J = 8.2 Hz, 1H), 3.86 (s, 1H), 3.80 (d, J = 9.5 Hz, 1H), 3.60 (t, J = 12.2 Hz, 2H), 3.35 (m, 1H), 3.30 (m, 1H), 3.25 (m, 1H), 3.07-2.92 (m, 3H), 2.91 (s, 3H), 2.86 (m, 1H), 2.56-2.42 (m, 4H), 2.37 (m, 1H), 2.09-1.94 (m, 3H), 1.92 (s, 3H), 1.87-1.70 (m, 5H), 1.68 (s, 3H), 1.62 (m, 1H), 1.48 (m, 1H), 1.25 (m, 1H), 1.12 (d, J = 6.9 Hz, 3H), 1.01-0.86 (m, 8H), 0.76 (d, J = 6.9 Hz, 4H), 0.71 (d, J = 6.8 Hz, 4H), 0.30 (d, J = 7.1 Hz, 3H). 13C NMR (75 MHz, C6D6): δ(ppm) 191.77, 182.35, 171.60, 168.93, 168.35, 157.44,155.81, 145.34, 142.74, 141.33, 132.73, 131.65, 128.35, 125.87, 124.97, 114.78, 114.39, 112.62, 109.45, 107.96, 105.91, 94.87, 81.32, 77.59, 74.70, 73.33, 66.49, 66.41, 56.60, 51.77, 51.58, 47.55, 39.10, 39.01, 38.17, 36.64, 36.11, 34.06, 33.63, 33.00, 26.05, 22.05, 20.93, 20.66, 17.38, 12.37, 11.57, 9.15, 7.88. Compounds 1 and 3-24 were synthesized according to the same procedure used for thesynthesis of Compound 2 as described below:Intermediate I-2 (25-imidazo-carbonyl-21,23-acetonide-rifabutin, 1 eq.) was dissolvedin DMF (0.025 mol / L). To this solution was added corresponding amine (5 eq.) and HOBt (20eq.) and the mixture was stirred for 16h at 50°C. Then, the mixture was diluted with AcOEt, washed with sat. solution of NaHCO3 and then brine. The combined organic phase were dried, filtered and concentrated under reduce pressure. The crude was purified by column chromatography (from 100% DCM to 90 / 10 DCM / MeOH) when needed. The recovered fraction was dissolved in a mixture THF / 0.5 N aqueous solution of CSA and stirred overnight. Then, AcOEt was added and the organic phase was washed with sat. solution of NaHCO3 and brine. The organic phase was dried, filtered and concentrated under reduce pressure. The crude was purified by column chromatography (from 100% DCM to 90 / 10 DCM / MeOH) or HPLC to afford the desired product as purple solid. Table 3 below summarizes exemplary compounds of the invention (R1 and R2 groupsshown) that were prepared according to the protocol for Compound 2 above. Data forcompounds 1-20 given in Table 3 were obtained following the analytic method B 10 minutes(*) and 15 minutes (**) gradient. Where the starting amine was originally prepared as ahydrochloride, an excess of TEA was added prior to the addition of I-2 to neutralize the hydrochloride salt. When starting amine where not commercially available, preparation was made according to general literature protocols.Attorney Ref: P6819PC00 51In Table 3, molecular weight (MW) is defined as the sum of atomic masses of the atoms constituting the molecule as an average of the different isotopes in their natural abundance. The molecular exact mass (M) on the contrary, takes in account only specific set of isotopes, the most abundant ones (1H for hydrogen,12C for carbon,14N for nitrogen,16O for oxygen,19F for fluorine, etc.). For a molecule of molecular mass > 1000 Da, as13C has a natural abundance of 1,08%, the molecular weight presents in average M+1 Da resulting equal to the m / z ratio of themost abundant isotope revealed by the mass spectrum [M+H]+.Table 3: Molecular Weight (Calculated), Retention Time (Method B) and Measured Mass of Exemplary Compounds Structure (R1 and R2 groupsCpdMW Rt [M+H]+shown) 933.113 7.38** 933.801 932.125 7.83** 932.712 958.163 6.17* 958.303 946.152 5.99* 946.774 960.179 5.99* 960.755 989.221 6.35* 989.476Attorney Ref: P6819PC00 52Structure (R1 and R2 groupsCpdMW Rt [M+H]+shown) 1001.232 6.92** 1001.827 1,017.275 5.19* 1017.79NH 8 N O 1,031.302 5.28* 1031.869 1,031.258 5.91* 1031.8610 987.205 4.88* 987.7711 1029.286 5.00* 1029.8712Attorney Ref: P6819PC00 53Structure (R1 and R2 groupsCpdMW Rt [M+H]+shown) 971.206 5.02* 971.751314 1030.274 5.39* 1030.6N15N1045.285 6.45* 1045.6O O16 947.140 6.24* 947.35N17 985.233 5.53* 985.35N18 1001.232 14.39 1001.51Attorney Ref: P6819PC00 54Structure (R1 and R2 groupsCpdMW Rt [M+H]+shown) 19 1015.259 6.23* 1015.220 960.179 13.0 960.6821 972.90 13.16 972.5822 948.193 2.20 948.6323 980.191 3.94 980.6224 1035.271 5.35** 1035.05Table 4:1HNMR Values of Exemplary CompoundsCpd 1HNMR1H NMR (300 MHz, C6D6): δ(ppm) 15.40 (s, 1H), 9.28 (s, 1H), 8.46 (s, 1H), 6.51 (m, 1H), 6.38 (d, J = 12.5 Hz, 1H), 5.94 (d, J = 9.1 Hz, 1H), 5.861 (dd, J = 15.8, 6.4 Hz, 1H), 5.29 (dd, J = 12.5, 8.1 Hz, 1H), 5.22 (brs, 1H),4.67 (m, 2H), 3.71 (m, 2H), 3.40 (t, J = 4.2 Hz, 4H), 3.25 (m, 1H), 3.17 (s,Attorney Ref: P6819PC00 55Cpd 1HNMR1H), 3.01 (m, 1H), 2.88 (s, 4H), 2.49 (s, 3H), 2.42 (m, 4H), 2.34 (m, 3H), 2.05 (d, J = 7.0 Hz, 2H), 1.90 (s, 3H), 1.82-1.72 (m, 5H), 1.66 (s, 3H),1.65-1.61 (m, 2H), 1.31 (brs, 1H), 1.08 (d, J = 6.7 Hz, 3H), 0.92 (d, J =6.2 Hz, 6H), 0.75 (d, J = 6.8 Hz, 3H), 0.67 (d, J = 6.8 Hz, 3H), 0.28 (d, J= 7.0 Hz, 3H). 1H NMR (300 MHz, C6D6): δ(ppm) 15.52 (s, 1H), 9.34 (s, 1H), 8.69 (s,1H), 6.55 (dd, J = 15.6, 9.10 Hz, 1H), 6.41 (d, J = 12.5 Hz, 1H), 6.00 (d,J = 9.3 Hz, 1H), 5.84 (dd, J = 15.7, 7.0 Hz, 1H), 5.25 (dd, J = 12.3, 8.5Hz, 1H), 4.99 (s, 1H), 4.85 (d, J = 6.4 Hz, 1H), 4.59 (d, J = 10.0 Hz, 1H),4.0 (m, 1H), 3.98 (m, 1H), 3.89 (s, 1H), 3.73 (d, J = 9.6 Hz, 1H), 3.65 (m,3 1H), 3.28 (m, 1H), 3.18 (d, J = 6.8 Hz, 1H), 3.00 (m, 1H), 2.90 (s, 3H),2.86 (m, 1H), 2.51 (s, 3H), 2.47 (m, 2H), 2.35 (m, 1H), 2.05 (d, J = 7.1Hz, 2H), 1.93 (s, 5H), 1.91-1.71 (m, 5H), 1.65 (s, 4H), 1.63-1.47 (m, 4H), 1.34 (m, 2H), 122 (m, 1H), 1.13 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 15.4 Hz,1H), 0.91 (d, J = 5.6 Hz, 6H), 0.72 (m, 6H), 0.28 (d, J = 6.8 Hz, 3H).1H NMR (300 MHz, C6D6): δ(ppm) 15.49 (s, 1H), 9.22 (s, 1H), 8.63 (m, 1H), 6.53 (m, 1H), 6.37 (m, 1H), 5.96 (m, 1H), 5.87 (m, 1H), 5.20 (m, 1H), 5.09 (s, 1H), 4.77-4.64 (m, 1H), 4.07 (m, 1H), 3.93-3.70 (m, 3H), 4 3.20-2.97 (m, 4H), 2.89-2.80 (m, 4H), 2.58-2.45 (m, 4H), 2.41-2.32 (m, 5H), 2.07 (m, 3H), 1.91-1.70 (m, 8H), 1.70-1.62 (m, 5H), 1.40-1.28 (m, 3H), 1.20-1.09 (m, 4H), 1.05-0.83 (m, 8H), 0.77 (m, 3H), 0.66 (m, 3H), 0.26 (m, 3H). 1H NMR (300 MHz, C6D6): δ(ppm) 15.48 (s, 1H), 9.19 (s, 1H), 8.63 (s, 1H), 6.57 (m, 1H), 6.40 (dd, J = 12.4, 9.8 Hz, 1H), 5.99 (m, 1H), 5.91 (m,1H), 5.28 (ddd, J = 13.5, 7.2 Hz, 1H), 5.03 (m, 1H), 4.76 (m, 1H), 4.10 (d,J = 8.1 Hz, 1H), 3.86-3.78 (m, 2H), 3.62 (m, 1H), 3.47 (m, 1H), 3.38-3.185 (m, 3H), 3.04 (m, 1H), 2.93 (s, 3H), 2.87 (m, 1H), 2.54 (m, 1H), 2.47 (d, J = 6.7 Hz, 3H), 2.36 (m, 1H), 2.11-2.03 (m, 2H), 1.91 (s, 3H), 1.90-1.71 (m, 5H), 1.67 (d, J = 4.5 Hz, 3H), 1.65-1.52 (m, 2H), 1.38-1.20 (m, 3H),1.13 (m, 3H), 1.10 (m, 3H), 0.97 (s, 2H), 0.94-0.86 (m, 8H), 0.87-0.65 (m, 8H), 0.30 (d, J = 7.0 Hz, 3H).6 1H NMR (300 MHz, C6D6): δ(ppm) 15.49 (s, 1H), 9.23 (s, 1H), 8.50 (s,Attorney Ref: P6819PC00 56Cpd 1HNMR1H), 6.55 (dd, J = 15.7, 9.4 Hz, 1H), 6.40 (d, J = 12.4 Hz, 1H), 5.96 (d, J= 9.4 Hz, 1H), 5.90 (m, 1H), 5.26 (dd, J = 12.5, 7.6 Hz, 1H), 5.07 (d, J =3.4 Hz, 1H), 7.71 (d, J = 10.6 Hz, 1H), 4.20 (d, J = 8.1 Hz, 1H), 3.85 (s,1H), 3.77 (d, J = 9.4, 1H), 3.34-3.22 (m, 5H), 3.07 (s, 3H), 3.01 (m, 1H),2.90 (s, 3H), 2.85 (m, 1H), 2.60-2.52 (m, 2H), 2.49 (s, 3H), 2.45 (m, 1H), 2.41-2.32 (m, 4H), 2.08-1.99 (m, 3H), 1.90 (s, 3H), 1.87-1.71 (m, 8H), 1.67 (s, 3H), 1.62 (m, 1H), 1.46 (m, 1H), 1.20-1.08 (m, 6H), 0.91 (d, J =6.2 Hz, 6H), 0.76 (d, J = 6.8 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H), 0.31 (d, J= 7.0 Hz, 3H). 1H NMR (300 MHz, C6D6): δ(ppm) 15.51 (s 1H), 9.15 (s, 1H), 8.66 (s, 1H), 6.58 (dd, J = 15.6, 9.5 Hz, 1H), 6.40 (d, J = 12.4 Hz, 1H), 5.98 (d, J= 9.3 Hz, 1H), 5.92 (dd, J = 15.5, 7.0 Hz, 1H), 5.26 (dd, J = 12.4, 7.0 Hz,1H), 5.14 (s, 1H), 4.77 (d, J = 10.3 Hz, 1H), 4.23 (s, 1H), 3.90 (m, 1H),3.81 (d, J = 8.2 Hz, 1H), 3.38-3.28 (m, 3H), 3.03 (m, 1H), 2.99 (s, 3H),8 2.92 (s, 3H), 2.85 (m, 1H), 2.68 (m, 2H), 2.4-2.41 (m, 5H), 2.38 (m, 1H), 2.11-1.94 (m, 7H), 1.85 (s, 3H), 1.84-1.71 (m, 6H), 1.68 (s, 3H), 1.62 (m, 1H), 1.48 (m, 1H), 1.39-1.22 (m, 1H), 1.24-1.15 (m, 2H), 1.12 (d, J = 6.9Hz, 3H), 1.05 (s, 6H), 0.91 (d, J = 6.2 Hz, 6H), 0.76 (d, J = 6.8 Hz, 3H),0.71 (d, J = 6.8 Hz, 3H), 0.30 (d, J = 7.0 Hz, 3H).1H NMR (300 MHz, C6D6): δ(ppm) 15.49 (s, 1H), 9.23 (s, 1H), 8.62 (s, 1H), 6.56 (dd, J = 15.7, 9.8 Hz, 1H), 6.40 (d, J = 12.6 Hz, 1H), 5.96 (d, J= 9.4 Hz, 1H), 5.89 (dd, J = 15.6, 7.2 Hz, 1H), 5.30 (dd, J = 12.3, 7.4 Hz,1H), 4.95 (s, 1H), 4.77 (d, J = 9.9 Hz, 1H), 4.44 (brs, 2H), 4.07 (d, J = 8.2Hz, 1H), 3.80 (m, 2H), 3.28 (m, 3H), 3.01 (m, 1H), 2.94 (s, 3H), 2.89 (s, 10 3H), 2.85 (m, 1H), 2.56-2.41 (m, 5H), 2.35 (m, 1H), 2.07 (m, 1H), 2.03 (d, J = 7.0 Hz, 2H), 1.91 (s, 3H), 1.85-1.68 (m, 5H), 1.67 (s, 3H), 1.61 (m,1H), 1.51 (m, 1H), 1.39 (s, 6H), 1.37-1.27 (m, 3H), 1.12 (d, J = 6.9 Hz,3H), 0.99-0.79 (m, 9H), 0.76 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H),0.30 (d, J = 7.9 Hz, 3H).1H NMR (300 MHz, C6D6): δ(ppm) 15.52 (s, 1H), 9.26 (s, 1H), 8.54 (s, 111H), 6.53 (dd, J = 15.5, 9.2 Hz, 1H), 6.40 (d, J = 12.5 Hz, 1H), 5.97 (d, J= 9.2 Hz, 1H), 5.89 (dd, J = 15.6, 7.2 Hz, 1H), 5.27 (dd, J = 12.5, 7.9 Hz,Attorney Ref: P6819PC00 57Cpd 1HNMR1H), 5.01 (d, J = 3.8 Hz, 1H), 4.68 (d, J = 10.5 Hz, 1H), 4.36 (m, 2H), 4.32(m, 2H), 4.22 (d, J = 8.4 Hz, 1H), 3.83 (s, 1H), 3.75 (d, J = 9.4 Hz, 1H),3.35-3.18 (m, 3H), 3.01 (m, 1H), 2.93 (s, 3H), 2.88 (m, 2H), 2.50 (s, 3H), 2.45 (m, 1H), 2.36 (m, 1H), 2.11-1.96 (m, 5H), 1.91 (s, 3H), 1.90-1.85 (m, 2H), 1.84-1.72 (m, 3H), 1.67 (s, 5H), 1.62 (m, 1H), 1.37 (m, 2H), 1.29 (m, 2H), 1.13 (d, J = 6.9 Hz, 3H), 1.09-0.95 (m, 2H), 0.91 (d, J = 6.2 Hz, 6H),0.75 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H), 0.32 (d, J = 7.0 Hz, 3H).1H NMR (C6D6, 300 MHz) δ 15.47 (s, 1H), 9.20 (s, 1H), 8.64 (s, 1H), 6.50 (m, 1H), 6.40 (d, J = 12.5 Hz, 1H), 5.97 (d, J = 9.3 Hz, 1H), 5.86 (m, 1H), 5.39 (m, 1H), 5.28 (m, 1H), 4.85 (s, 1H), 4.67 (m, 1H), 3.93 (m, 2H), 3.81 (s, 1H), 3.72 (m, 1H), 3.29 (m, 1H), 3.20 (t, J = 11.5 Hz, 3H), 3.01 (m, 1H), 2.92 (s, 3H), 2.87 (m, 1H), 2.63 (m, 2H), 2.55 (m, 2H), 2.50 (s, 14 3H), 2.46 (m, 2H), 2.34 (m, 1H), 2.18 (m, 4H), 2.04 (d, J = 7.0 Hz, 3H), 1.91 (s, 3H), 1.83 (d, J = 6.9 Hz, 3H), 1.94-1.70 (m, 5H), 1.66 (s, 3H), 1.65-1.58 (m, 3H), 1.40 (m, 1H), 1.15-1.05 (m, 5H), 0.92 (dd, J = 6.4, 1.3 Hz, 6H), 0.74 (d, J = 6.7 Hz, 3H), 0.69 (d, J = 7.0 Hz, 3H), 0.29 (d, J = 7.0 Hz, 3H). 1H NMR (C6D6, 300 MHz) δ 15.52 (s, 1H), 9.49-9.13 (m, 1H), 8.67 (m, 1H), 6.55 (m, 1H), 6.38 (d, J = 12.5 Hz, 1H), 5.98 (m, 1H), 5.86 (m, 1H), 5.22 (m, 1H), 5.07 (s, 1H), 4.91-4.59 (m, 3H), 4.03 (m, 1H), 3.89 (m, 1H), 3.74 (d, J = 9.5 Hz, 1H), 3.23-3.11 (m, 2H), 3.04 (m, 1H), 2.96 (s, 3H), 15 2.88 (m, 1H), 2.85 (s, 2H), 2.80 (s, 1H), 2.55 (s, 1H), 2.50 (s, 3H), 2.54- 2.45 (m, 2H), 2.34 (s, 5H), 2.06 (d, J = 6.9 Hz, 3H), 1.92 (s, 3H), 1.97- 1.71 (m, 5H), 1.67 (s, 3H), 1.69-1.59 (m, 2H), 1.42 (s, 6H), 1.32-1.15 (m, 4H), 1.13 (d, J = 6.9 Hz, 3H), 0.92 (m, 6H), 0.75 (d, J = 6.8 Hz, 3H), 0.67 (d, J = 6.7 Hz, 3H), 0.27 (d, J = 7.0 Hz, 3H). 1H NMR (C6D6, 300 MHz) δ 15.54 (m, 1H), 9.40-9.03 (m, 1H), 8.70 (s, 1H), 6.55 (m, 1H), 6.38 (m, 1H), 5.98 (m, 1H), 5.88 (m, 1H), 5.26-5.16 17 (m, 2H), 4.77 (m, 1H), 4.02 (m, 1H), 3.95 (m, 1H), 3.75 (m, 1H), 3.21 (m, 2H), 3.03 (m, 1H), 2.92-2.79 (m, 6H), 2.51 (m, 4H), 2.45 (m, 3H), 2.34 (m, 1H), 2.10-1.95 (m, 5H), 1.95-1.89 (m, 4H), 1.86-1.69 (m, 5H), 1.67Attorney Ref: P6819PC00 58Cpd 1HNMR(s, 3H), 1.68-1.62 (m, 2H), 1.47-1.32 (m, 4H), 1.28 (m, 1H), 1.11 (d, J = 8.1 Hz, 3H), 0.92 (m, 6H), 0.75 (m, 3H), 0.67 (m, 3H), 0.36 (m, 2H), 0.28 (m, 5H). 1H NMR (BENZENE-d6, 300 MHz) δ 15.52 (m, 1H), 9.50- 9.22 (m, 1H),8.60 (m, 1H), 6.50 (dd, J = 15.8, 9.2 Hz, 1H), 6.40-6.30 (m, 1H), 5.96 (m, 1H), 5.87 (dd, J = 15.8, 7.2 Hz, 1H), 5.30-5.17 (m, 1H), 5.11 (s, 1H), 4.73 (m, 1H), 4.48-4.30 (m, 4H), 4.00-3.85 (m, 2H), 3.76-3.68 (m, 1H), 3.24- 18 3.12 (m, 2H), 3.10-2.90 (m, 3H), 2.88 (s, 3H), 2.60-2.40 (m, 8H), 2.40-2.20 (m, 3H), 2.06 (d, J = 7.3 Hz, 2H), 1.92 (s, 3H), 1.85-1.69 (m, 5H), 1.68-1.60 (m, 5H), 1.50-1.20 (m, 7H), 1.10 (m, 3H), 0.92 (d, J = 6.4 Hz, 6H), 0.714 (d, J = 6.9 Hz, 3H), 0.68 (d, J = 6.7 Hz, 3H), 0.30-0.20 (m, 3H) 1H NMR (C6D6, 300 MHz) δ 15.53 (m, 1H), 9.24 (s, 1H), 6.66 (m, 1H), 6.55 (m, 1H), 6.41 (m, 1H), 5.98 (m, 1H), 5.89 (dd, J = 15.5, 7.2 Hz, 1H), 5.28 (dd, J = 12.5, 7.5 Hz, 1H), 4.96 (m, 1H), 4.74 (m, 1H), 4.49 (m, 1H), 4.11 (d, J = 7.5 Hz, 1H), 3.84 (d, J = 16.5 Hz, 1H), 3.79 (d, J = 9.6 Hz, 19 1H), 3.35-3.17 (m, 3H), 3.03 (m, 2H), 2.97-2.81 (m, 4H), 2.50 (s, 3H), 2.55-2.41 (m, 2H), 2.40-2.30 (m, 1H), 2.29-2.10 (m, 3H), 2.04 (m, 3H), 1.92 (s, 3H), 1.85 (d, J = 6.8 Hz, 3H), 1.81-1.70 (m, 3H), 1.68 (s, 3H), 1.64-1.52 (m, 2H), 1.45-1.25 (m, 2H), 1.14 (m, 3H), 0.92 (m, 12H), 0.76 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.5 Hz, 3H), 0.64 (m, 1H), 0.30 (m, 3H). 1H NMR (300 MHz, CDCl3) : δ 14.87 (s, 1H), 8.85 (m, 1H), 8.27 (s, 1H), 6.49-6.34 (m, 1H), 6.24 (d, J = 10.4 Hz, 1H), 6.17-5.98 (m, 2H), 5.01 (dd, J = 12.3, 5.9 Hz, 1H), 4.84-4.55 (m, 2H), 4.13 (m, 1H), 4.06-3.93 (m, 2H), 3.88 (d, J = 17.0 Hz, 1H), 3.67 (d, J = 9.8 Hz, 1H), 3.50-3.22 (m, 4H), 3.04 20 (m, 3H), 2.98 (m, 3H), 2.63 (m, 2H), 2.41-2.23 (m, 3H), 2.30 (s, 3H), 2.14 (brs, 1H), 2.01-1.61 (m, 12H), 1.70 (s, 3H), 1.55 (m, 3H), 1.14-0.98 (m, 6H), 0.94 (d, J = 6.5 Hz, 6H), 0.84 (d, J = 6.8 Hz, 3H), 0.59 (m, 3H), -0.03 (m, 3H). 1 21H NMR (300 MHz, CDCl3) : δ 14.85 (s, 1H), 8.83 (s, 1H), 8.23 (s, 1H),6.40 (m, 1H), 6.23 (d, J = 10.3 Hz, 1H), 6.06 (m, 1H), 5.05 (dd, J = 12.3,Attorney Ref: P6819PC00 59Cpd 1HNMR5.7 Hz, 1H), 4.72 (d, J = 10.3 Hz, 1H), 4.55 (d, J = 3.9 Hz, 1H), 3.98 (d, J = 8.6 Hz, 2H), 3.85 (m, 1H), 3.80 (s, 1H), 3.67 (d, J = 9.7 Hz, 1H), 3.43- 3.30 (m, 3H), 3.05 (s, 3H), 3.02-2.91 (m, 3H), 2.63 (brs, 2H), 2.40-2.25 (m, 5H), 2.30 (s, 3H), 2.19-1.90 (m, 5H), 2.04 (s, 3H), 1.85 (m, 2H), 1.76 (s, 4H), 1.69-1.49 (m, 4H), 1.01 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.5 Hz, 6H), 0.84 (d, J = 6.8 Hz, 3H), 0.75 (m, 2H), 0.63 (m, 2H), 0.59 (d, J = 6.7 Hz, 3H), -0.05 (d, J = 7.0 Hz, 3H). 1H NMR (300 MHz, CDCl3) δ 14.69 (s, 1H), 8.64 (s, 1H), 8.24 (s, 1H),6.37 (dd, J = 15.5, 10.2 Hz, 1H), 6.25 (d, J = 11.2 Hz, 1H), 6.13 (d, J =12.5 Hz, 1H), 6.00 (dd, J = 15.5, 6.9 Hz, 1H), 4.99 (dd, J = 12.5, 6.6 Hz,1H), 4.69 (d, J = 8.4 Hz, 1H), 4.52 (d, J = 10.3 Hz, 1H), 4.43 (d, J = 4.3Hz, 1H), 3.75 (s, 1H), 3.62 (d, J = 9.7 Hz, 1H), 3.53 – 3.35 (m, J = 16.6,22 8.6 Hz, 3H), 3.31 – 3.17 (m, 1H), 3.11 – 3.03 (m, 4H), 2.78 – 2.59 (m,5H), 2.40 – 2.28 (m, 4H), 2.23 – 2.12 (m, 3H), 2.03 (s, 3H), 1.88 (m, 4H),1.75 (s, 5H), 1.68 – 1.41 (m, J = 23.6, 15.6, 9.8 Hz, 6H), 1.10 (s, 6H), 1.02(d, J = 7.0 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 0.56 (d, J = 6.8 Hz, 3H), -0.06 (d, J = 7.1 Hz, 3H).1H NMR (300 MHz, CDCl3) δ 14.81 (s, 1H), 9.11 (s, 1H), 8.26 (s, 1H),6.38 (dd, J = 15.4, 10.2 Hz, 1H), 6.31 – 6.13 (m, 2H), 5.99 (dd, J = 15.4,6.7 Hz, 1H), 5.11 (dd, J = 12.5, 7.6 Hz, 1H), 4.88 (d, J = 7.7 Hz, 1H), 4.53 (d, J = 10.6 Hz, 1H), 4.12 (d, J = 5.2 Hz, 1H), 3.76 (dd, J = 18.2, 14.3 Hz,23 1H), 3.65 (d, J = 9.8 Hz, 1H), 3.54 (s, 1H), 3.35 (d, J = 5.8 Hz, 1H), 3.20 –2.90 (m, 10H), 2.65 (s, 2H), 2.44 – 2.22 (m, 7H), 2.21 – 2.03 (m, 6H),1.96 (s, 4H), 1.90 – 1.70 (m, 6H), 1.50 – 1.35 (m, 1H), 1.05 (d, J = 7.0 Hz,3H), 0.95 (d, J = 6.5 Hz, 6H), 0.85 (d, J = 6.9 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H), -0.02 (d, J = 7.0 Hz, 3H). EXAMPLE 4: Antibacterial Activity MIC for M. abscessus smooth (S) or rough (R) was determined in standard cationadjusted Mueller Hinton broth (see CAMHB) and supplemented with 50% Human Serum (seeAttorney Ref: P6819PC00 60HS). From a fresh culture plate, cells were resuspended in 0.9% (w / v) saline solution andbacterial inoculum was prepared in the respective testing medium with 5x105 CFU / mL. Theappropriate volumes of a 10 mg / mL compound solution were directly dispensed in the 96-well assay plate using a digital dispenser to create two-fold dilution series from 16 to 0.001 µg / mL for M. abscessus. 100 μL of bacterial suspension was finally added to the compounds. Plates were covered and incubated without shaking at 30 °C for 4 days for M. abscessus. Every experiment contained an antibiotic as quality control. MIC was determined visually as thelowest concentration of a compound that prevents visible growth of the bacteria. The in vitroactivity of compounds described herein was determined against M. abscessus (ATCC 19977).The MIC values, given in µg / mL, are given in Table X, below Structures of comparison compounds C1, C2, C3 and C4 are also shown in the Table 5, below.Table. 5. In vitro activity of embodied compounds against M. abscessus smooth (S) and rough(R) and with 50% Human Serum (HS)MIC against M. abscessus (Mabs) (μg / mL)Compound S (CAMHB) S (HS) R (CAMHB) R (HS)1 2 1 0.5 12 0.5 0.5 0.25 0.53 0.5 2 0.06 14 0.5 4 0.125 25 0.25 1 0.25 0.56 1 2 0.25 27 4 2 1 18 0.5 1 0.06 0.59 0.25 0.5 0.25 0.510 1 2 0.25 111 2 4 0.125 212 1 2 0.25 1613 0.25 0.5 0.03 114 2 4 0.125 815 0.5 1 0.125 1Attorney Ref: P6819PC00 6116 2 4 0.5 417 0.5 2 0.06 118 0.5 1 0.125 219 0.5 1 0.03 120 0.25 2 0.125 221 0.125 0.5 0.06 0.522 0.25 4 0.06 223 4 8 0.25 824 4 4 0.25 8HN 10.5 0.125 2N C1 HN 21 0.25 2N C2 HN 22 0.25 2N C3

[0005] Attorney Ref: P6819PC00 62HN N0.25 1 0.06 0.25C4 HN N0.25 0.25 0.016 1C5

[0006] Attorney Ref: P6819PC00 63EXAMPLE 5: Activity Against Healthy Cells CellTiter-Blue Assay was performed to determine cytotoxicity (IC50 value) ofcompounds against HepG2 cells (ATCC, HB-8065). IC50 was determined in EMEMsupplemented with 2mM Glutamine, non-essential amino acids, 10% fetal bovine serum and 1% penicillin / streptomycin. The IC50values, in µg / mL, are given in Table 6, below.

[0007] Attorney Ref: P6819PC00 64Table 6. Activity of Exemplary Compounds against HepG2 cells Compound IC50 (HepG2, μg / mL) Compound IC50 (HepG2, μg / mL) 199.6 C1 20.292 70 C2 15.13 35.49 C3 15.764 47.2 C4 12.15 58.4 C5 5.76 7.5 715.78 169 10.910 4611 67.1 12 14.713 11.414 14.515 27.016 63.8 17 14.418 47.419 29.420 34.021 31.420 22 22.323 78.824 36.4

Claims

Attorney Ref: P6819PC00 65CLAIMS1. A compound of Formula I or a pharmaceutically acceptable salt, tautomer, solvate,hydrate or enantiomer thereof:Formula I wherein: R1is -H, -C1-C6 alkyl, or C3-C6 cycloalkyl; R2is a group of Formula II:Formula II wherein n is an integer from 0 to 8; R3is independently, at each occurrence, C1-C6 alkyl; or two R3, together with the carbon atoms to which they are attached, optionally combine to form a bridging alkylene, preferably a bridging C1-C2 alkylene; X is O, NR4, S, or SO2; Z is CH or N; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with oxo; -Attorney Ref: P6819PC00 66C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more C1-C6alkoxy; -C2-C6alkyl, wherein said C2-C6alkyl is substituted with one or more C1-C6 alkoxy; -CH2-tetrahydropyran; and cyclopropyl.

2. The compound of claim 1, wherein:R1is -H or -C1-C6 alkyl; R2 is a group of Formula II:Formula II wherein n is an integer from 0 to 8; R3is independently, at each occurrence, C1-C6alkyl; or two R3, together with the carbon atoms to which they are attached, optionally combine to form a bridgingalkylene, preferably a bridging C1-C2 alkylene; X is O or NR4; Z is CH or N; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more C1-C6alkoxy; -C2-C6alkyl, wherein said C2-C6alkyl is substituted with one or more C1-C6 alkoxy; -CH2-tetrahydropyran; and cyclopropyl.

3. The compound of claim 1 or 2, wherein R1 is hydrogen or C1-C6 alkyl.

4. The compound of any one of claims 1 to 3, wherein n is an integer from 0 to 4, preferablyfrom 0 to 2.

5. The compound of any one of claims 1-4, wherein said R3 is independently, at eachoccurrence, C1-C4alkyl.

6. The compound of any of claims 1-5, wherein X is O.

7. The compound of any of claims 1-6, wherein X is NR4.Attorney Ref: P6819PC00 678. The compound of any of claims 1-7, wherein Z is N.

9. The compound of any of claims 1-8, wherein Z is CH.

10. The compound of any of claims 1 to 5, wherein R2 is selected from the group consistingof tetrahydropyran, morpholine, and 8-oxabicyclo[3.2.1]octane; wherein said tetrahydropyran is bonded at a 4-carbon of said tetrahydropyran; said morpholine is bonded at a 4-nitrogen of said morpholine; and said 8- oxabicyclo[3.2.1]octane is bonded at a 3-carbon of said 8-oxabicyclo[3.2.1]octane;wherein each tetrahydropyran, morpholine, and 8-oxabicyclo[3.2.1]octane isindependently optionally substituted with one or more R3; andR3is independently, at each occurrence, C1-C6alkyl.

11. The compound any of claims 1 to 5, wherein R2 is piperidine, piperazine, or 2-azabicyclo[2.2.1]heptane, wherein said piperidine is bonded at a 4-carbon of said piperidine, said piperazine is bonded at a 4-nitrogen of said piperazine, and said 2- azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane;wherein each piperidine and piperazine are independently substituted at the 1- nitrogen with R4, and wherein each 2-azabicyclo[2.2.1]heptane is independentlysubstituted at the 2-nitrogen with R4; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; -C(O)C1-C6alkyl, wherein said C1-C6alkyl is optionally substituted with one or more C1-C6 alkoxy; -C2-C6 alkyl, wherein said C2-C6 alkyl is substituted with one or more C1-C6 alkoxy; -CH2-tetrahydropyran; and cyclopropyl.

12. The compound of any of claims 10-11, wherein R2 is piperidine or 2-azabicyclo[2.2.1]heptane, wherein said piperidine is bonded at a 4-carbon of said piperidine, and said 2-azabicyclo[2.2.1]heptane is bonded at a 5-carbon of said 2-azabicyclo[2.2.1]heptane;wherein each piperidine is independently substituted at the 1-nitrogen with R4, and wherein each 2-azabicyclo[2.2.1]heptane is independently substituted at the 2-Attorney Ref: P6819PC00 68nitrogen with R4; R4 is independently, at each occurrence, selected from 3- to 5-memberedheterocycloalkyl; and -C(O)C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted with one or more C1-C6alkoxy.

13. The compound of claim 1, wherein said compound is selected from:[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-morpholinocarbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-tetrahydropyran-4- ylcarbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-(8-oxabicyclo[3.2.1]octan- 3-yl)carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-methyl-N-tetrahydropyran- 4-yl-carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-(2,2- dimethyltetrahydropyran-4-yl)carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33-Attorney Ref: P6819PC00 69dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-[1-(2-methoxyethyl)-4- piperidyl]carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-[2-(2-methoxyethyl)-2- azabicyclo[2.2.1]heptan-5-yl]carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-[1-(2-methoxy-2-methyl- propyl)-4-piperidyl]carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-[1-(2-methoxy-2-methyl- propyl)-4-piperidyl]-N-methyl-carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-[1-(2-methoxy-2-methyl- propanoyl)-4-piperidyl]carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-[1-(oxetan-3-yl)-4- piperidyl]carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-[1-(tetrahydropyran-4- ylmethyl)-4-piperidyl]carbamate;Attorney Ref: P6819PC00 70[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1(31),2,4,9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-(1-cyclopropyl-4- piperidyl)carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1,3,5(31),9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-[4-(tetrahydropyran-4- ylmethyl)piperazin-1-yl]carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1,3,5(31),9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-[1-(2-methoxy-2-methyl- propanoyl)-4-piperidyl]-N-methyl-carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1,3,5(31),9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-methyl-N-morpholino- carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1,3,5(31),9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-(1-cyclopropyl-4- piperidyl)-N-methyl-carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1,3,5(31),9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-methyl-N-[1-(oxetan-3-yl)- 4-piperidyl]carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-Attorney Ref: P6819PC00 711,3,5(31),9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-methyl-N-[1-(3- methylbutanoyl)-4-piperidyl]carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'- isobutyl-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33- dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta- 1,3,5(31),9,19,21,25,29-octaene-28,4'-piperidine]-13-yl] N-ethyl-N-tetrahydropyran-4- yl-carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33-dioxa- 24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1,3,5(31),9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-cyclopropyl-N-tetrahydropyran-4-yl-carbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33-dioxa- 24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1,3,5(31),9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-tetrahydrothiopyran-4-ylcarbamate; [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33-dioxa- 24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1,3,5(31),9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-(1,1-dioxothian-4-yl)carbamate; and [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17-trihydroxy-1'-isobutyl- 11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23,32-trioxo-spiro[8,33-dioxa- 24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1,3,5(31),9,19,21,25,29- octaene-28,4'-piperidine]-13-yl] N-[1-(1,1-dioxothietan-3-yl)-4-piperidyl]carbamate; or a pharmaceutically acceptable salt thereof.

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

15. A compound according to any of the claims 1 to 13 or a pharmaceutically acceptablesalt, tautomer, solvate or hydrate thereof, for use as a medicament.

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