Antibiotic rifabutin analogs

Abstract

The present invention relates to antibiotic rifabutin analogs of formula I wherein: R1 and R2, together with the nitrogen atom to which they are attached, combine to form a heterocycle, wherein said heterocycle is selected from the group consisting of piperazine, and piperidine. 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: P6837PC00 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 some5 embodiments, 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 broad 10 spectrum 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 and15 Toxoplasma gondii (Kunin, Clin. Infect. Dis., 1996; Farr and Mandell, Med. Clin. North. Am.,1982; Thornsberry et al., Rev. Infect. Dis., 1983; Hoover et al., Diagn. Microbiol. Infect. Dis., 1993; Kerry et al., J. Antimicrob. Chemother., 1975). 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.,20 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 25 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 of bacterial infections such as M. abscessus and A. baumannii infections.SUMMARY OF THE INVENTION 30 In one aspect, the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof:Attorney Ref: P6837PC00 2 wherein: R1and R2, together with the nitrogen atom to which they are attached, combine to form a heterocycle, wherein said heterocycle is selected from the group consisting of 5 piperazine, and piperidine; wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more R32; -C2-C4 alkylene-OH, wherein10 said -C2-C4 alkylene is further substituted with one or more R5; -C(O)R6; -C1-C2 alkylene-R7; -C1-C2 alkylene-R8; or 2-piperidinone, wherein said 2-piperidinone is optionally substituted with C1-C6 alkyl; wherein said two R31, together with the carbon atom to which they are attached, combineto form a C3-C4 cycloalkyl or a C1 bridging alkylene; 15 R32is -C1-C6 alkyl, or two R32, together with the carbon atom to which they are attached, combine to form a C3-C6 cycloalkyl; R4is independently, at each occurrence, selected from -C1-C6alkyl; R5is independently, at each occurrence, selected from -C1-C6 alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6cycloalkyl; 20 R6is independently, at each occurrence, selected from -C3-C8 cycloalkyl, wherein said C3-C8 cycloalkyl is optionally substituted with -OH or C1-C6 alkoxy; 4- to 6-memberedheterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl is optionally substituted withAttorney Ref: P6837PC00 3halogen; and -C1-C6 alkyl, wherein said -C1-C6 alkyl is optionally substituted with one or more -C1-C6alkoxy; R7 is heterocycloalkyl, wherein said heterocycloalkyl is selected from the groupconsisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 4- 5 tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole and isoxazole, wherein each oxazole and isoxazole is optionally substituted with one or more C1-C6alkyl;10 wherein said piperidine is optionally substituted with one or more halogen, R9, R10, -C1-C2alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2alkylene-OR12; R9is independently, at each occurrence, 5-membered heterocycloalkyl, wherein said heterocycloalkyl is substituted with oxo;R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 15 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6 alkyl; R12is -H or C1-C6 alkyl; with the proviso that when said -C1-C2alkylene-R7is -C1-C2alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene,20 or said -C1-C2 alkylene is a -C2 alkylene; with the proviso that when said -C1-C2 alkylene-R8is -C1 alkylene-isoxazole, said two R31combine to form a -C3-C4cycloalkyl or a -C1bridging alkylene. In one aspect, the present invention provides a pharmaceutical composition comprisinga compound as described herein, or a pharmaceutically acceptable salt thereof, and a 25 pharmaceutically acceptable carrier. In some preferred embodiments, the pharmaceutical composition 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 a30 pharmaceutically 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 a disease, preferably an infection, more preferably a bacterial infection in a subject. In someAttorney Ref: P6837PC00 4preferred 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 medicament 5for 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 an10 infection, 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, comprising15 administering to the subject a therapeutically effective amount of a compound as describedherein or a pharmaceutically acceptable salt thereof. In some preferred embodiments, thebacterial 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 position20 and 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. DETAILED DESCRIPTION OF THE INVENTION25 The 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 30 the practice or testing of the present technology, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from thedescription and from the claims.Attorney Ref: P6837PC00 5Definitions 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. 5 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. 10 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 bonded15 to 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-C6 alkyl groups contain 1 to 6 carbon atoms. Examples of a -C1-C6 alkyl group include, but are not 20 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 hydrocarbon chain bi-radical derived from alkyl, as defined herein, wherein one hydrogen of said alkyl is cleaved off generating the second radical of said alkylene. Examples of alkylene are, by way of25 illustration, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, and -CH2-CH2-CH2-CH2-. When saidalkylene is said to be “substituted”, it is understood that one (or more) of the hydrogen atoms in the alkylene chain must be replaced by a different group, preferably a -C1-C6 alkyl group.When said alkylene is said to be “optionally substituted”, it is understood that one (or more) of the hydrogen atoms in the alkylene chain can be, but is not required to be, replaced by a different30 group, preferably a -C1-C6alkyl group. “C1-C6 alkoxy”, as used herein, refers to straight chain or branched saturated -O-C1-C6 hydrocarbon which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy, straight or branchedAttorney Ref: P6837PC00 6hexyloxy, 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 3-8 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl,5 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the “cycloalkyl” group is a bicyclic cycloalkyl group, it can be a fused or a bridged cycloalkyl group. In some embodiments, the cycloalkyl group is a fused bicyclic group. In some embodiments, the cycloalkyl group is a bridged cycloalkyl group. In some embodiments, the cycloalkyl group is a spirocyclic cycloalkyl group. As used herein, a “C3-C6” cycloalkyl group comprises between10 3 and 6 carbon atoms. As used herein a spirocyclic ring or “spirocycle” or “spirocycloalkyl” isunderstood to mean a bicyclic or multicyclic ring system in which at least two rings are connected through a single atom. The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer to monocyclic or polycyclic saturated or partially saturated 3 to 6-membered rings containing carbon and15 heteroatoms taken from O, N, and S (preferably O and N) and wherein said ring does notcomprise delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms.As an example, a 6-membered heterocycloalkyl group contains 6 atoms.Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, 20 thiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. A heterocyclyl or heterocycloalkyl ring can also be fused or bridged, e.g., can be a bicyclic or tricyclic ring. Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic or bicyclic aromatic radical of 5 to 6 ring atoms, preferably 5 ring atoms, containing one or more25 ring heteroatoms selected from N, S, P, and O, the remaining ring atoms being C, and wherein each ring of the heteroaryl group comprises delocalized π electrons (aromaticity) shared among the ring atoms. Preferably the heteroatom is selected from N, S, and O, more preferably N and O. Preferred heteroaryl groups are oxazole and isoxazole. The invention also includes pharmaceutical compositions comprising an effective30 amount 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,Attorney Ref: P6837PC00 7camsylate, 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, 5 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,10 tosylate, triethiodide, and valerate salts. The term “stereoisomers” refers to the set of compounds which have the same number and 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 ofcompounds. 15 The term “diastereomers” refers to the set of stereoisomers which cannot be made superimposable 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 20 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 of25 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 type of 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. 30 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 and solvent. Such solvents for the purpose of the invention may not interfere with the biologicalAttorney Ref: P6837PC00 8activity 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. 5 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 10 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. 15 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 20 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.25 Compounds 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: P6837PC00 9 wherein: R1and R2, together with the nitrogen atom to which they are attached, combine to form a heterocycle, wherein said heterocycle is selected from the group consisting of 5 piperazine, and piperidine; wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more R32; -C2-C4 alkylene-OH, wherein10 said -C2-C4 alkylene is further substituted with one or more R5; -C(O)R6; -C1-C2 alkylene-R7; -C1-C2 alkylene-R8; or 2-piperidinone, wherein said 2-piperidinone is optionally substituted with C1-C6 alkyl; wherein said two R31, together with the carbon atom to which they are attached, combineto form a C3-C4 cycloalkyl or a C1 bridging alkylene; 15 R32is -C1-C6 alkyl, or two R32, together with the carbon atom to which they are attached, combine to form a C3-C6 cycloalkyl; R4is independently, at each occurrence, selected from -C1-C6alkyl; R5is independently, at each occurrence, selected from -C1-C6 alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6cycloalkyl; 20 R6is independently, at each occurrence, selected from -C3-C8 cycloalkyl, wherein said C3-C8 cycloalkyl is optionally substituted with -OH or C1-C6 alkoxy; 4- to 6-memberedheterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl is optionally substituted withAttorney Ref: P6837PC00 10halogen; and -C1-C6 alkyl, wherein said -C1-C6 alkyl is optionally substituted with one or more -C1-C6alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 4- 5 tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole and isoxazole, wherein each oxazole and isoxazole is optionally substituted with one or moreC1-C6alkyl;10 wherein said piperidine is optionally substituted with one or more halogen, R9, R10, -C1-C2alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2alkylene-OR12; R9is independently, at each occurrence, 5-membered heterocycloalkyl, wherein said heterocycloalkyl is substituted with oxo;R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 15 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6 alkyl; R12is -H or C1-C6 alkyl; with the proviso that when said -C1-C2alkylene-R7is -C1-C2alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene,20 or said -C1-C2 alkylene is a -C2 alkylene; with the proviso that when said -C1-C2 alkylene-R8is -C1 alkylene-isoxazole, said two R31combine to form a -C3-C4cycloalkyl or a -C1bridging alkylene. In one aspect, the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof:

[0002] Attorney Ref: P6837PC00 11 wherein: R1and R2, together with the nitrogen atom to which they are attached, combine to form aheterocycle, wherein said heterocycle is selected from the group consisting of5 piperazine, and piperidine; wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more C1-C6 alkyl; -C2-C4 alkylene-OH,10 wherein said -C2-C4 alkylene is further substituted with one or more R5; -C(O)R6; -C1-C2alkylene-R7; -C1-C2 alkylene-R8; or 2-piperidinone, wherein said 2-piperidinone is optionally substituted with C1-C6 alkyl; wherein said two R31, together with the carbon atom to which they are attached, combine to form a C3-C4 cycloalkyl or a C1 bridging alkylene; 15 R4is independently, at each occurrence, selected from -C1-C6 alkyl; R5is independently, at each occurrence, selected from -C1-C6 alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6cycloalkyl; R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to 6-membered heterocycloalkyl; and -C2-C6alkyl, wherein said -C2-C6alkyl is optionally 20 substituted with one or more -C1-C6 alkoxy; R7 is heterocycloalkyl, wherein said heterocycloalkyl is selected from the groupconsisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 4-Attorney Ref: P6837PC00 12tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine issubstituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole and isoxazole, wherein each oxazole and isoxazole is optionally substituted with one or more 5 C1-C6alkyl; wherein said piperidine is optionally substituted with one or more R10, -C1-C2 alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2 alkylene-OR12; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; 10 R11is -H or C1-C6 alkyl; R12is -H or C1-C6alkyl; with the proviso that when said -C1-C2 alkylene-R7is -C1-C2 alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene,or said -C1-C2 alkylene is a -C2 alkylene; 15 with the proviso that when said -C1-C2alkylene-R8is -C1alkylene-isoxazole, said two R31combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene. In one aspect, the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt, tautomer, solvate, hydrate or enantiomer thereof, wherein R1and R2 combine to form a heterocycle, wherein said heterocycle is piperazine or piperidine;20 wherein said piperazine is substituted with one or more R3; R3is independently, at each occurrence, selected from -C2-C4 alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more C1-C2 alkyl; -C2-C4 alkylene-OH,wherein said -C2-C4 alkylene is substituted with one or more R5; -C(O)R6; or -C1-C2 alkylene- R7; 25 R4is independently, at each occurrence, selected from -C1-C2 alkyl; R5is independently, at each occurrence, selected from -C1-C2 alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl; R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to 6-membered heterocycloalkyl; and -C2-C6 alkyl, wherein said -C2-C6 alkyl is substituted with one 30 or more -C1-C2 alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 2- oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one orAttorney Ref: P6837PC00 13more halogen; wherein said piperidine is optionally substituted with one or more R10, -C(O)-R10, or - C1-C2 alkylene-OR12; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 5 6-membered heterocycloalkyl is optionally substituted with one or more oxo; and R12is -H or C1-C6 alkyl. In some embodiments, when said two R31, together with the carbon atom to which theyare attached, combine to form a C3-C4cycloalkyl or a C1bridging alkylene, said C3-C4cycloalkyl is attached as a C3-C4 spirocycloalkyl.10 In some embodiments, R32is -C1-C6 alkyl, or two R32, together with the carbon atom to which they are attached, combine to form a C3cycloalkyl. In some embodiments, R32is -C1- C6 alkyl. In some embodiments, R6is independently, at each occurrence, selected from -C3-C8cycloalkyl, wherein said C3-C8 cycloalkyl is optionally substituted with C1-C6 alkoxy; 4- to 6-15 membered heterocycloalkyl; and -C1-C6alkyl, wherein said -C1-C6alkyl is optionally substituted with one or more -C1-C6 alkoxy. In some embodiments, R6is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to 6-membered heterocycloalkyl; and -C2-C6alkyl, wherein said -C2-C6alkyl is optionally substituted with one or more -C1-C6alkoxy. In some embodiments, R1and R2, together with the nitrogen atom to which they are 20 attached, combine to form a heterocycle, wherein said heterocycle is piperidine; wherein said piperidine is optionally substituted with one or more R9, R10, -C1-C2 alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2alkylene-OR12; R9is independently, at each occurrence, 5-membered heterocycloalkyl, wherein said heterocycloalkyl is substituted with oxo; 25 R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6 alkyl; R12is -H or C1-C6alkyl. In some embodiments, R1and R2, together with the nitrogen atom to which they are 30 attached, combine to form a heterocycle, wherein said heterocycle is piperidine; wherein said piperidine is optionally substituted with one or more R10, -C1-C2alkylene- R10, -C(O)-R10, -N(R11)-R10, or -C1-C2 alkylene-OR12; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein eachAttorney Ref: P6837PC00 146-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6alkyl; R12is -H or C1-C6 alkyl. In some embodiments, R1and R2, together with the nitrogen atom to which they are 5 attached, combine to form a heterocycle, wherein said heterocycle is piperazine; wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31;R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, wherein said -C2-C4alkylene is further substituted with one or more R32; -C2-C4alkylene-OH, wherein10 said -C2-C4 alkylene is further substituted with one or more R5; -C(O)R6; -C1-C2 alkylene-R7; - C1-C2alkylene-R8; or 2-piperidinone, wherein said 2-piperidinone is optionally substituted with C1-C6 alkyl; wherein said two R31, together with the carbon atom to which they are attached, combine to form a C3-C4 cycloalkyl or a C1 bridging alkylene; 15 R32is -C1-C6alkyl, or two R32, together with the carbon atom to which they are attached, combine to form a C3-C6 cycloalkyl; R4is independently, at each occurrence, selected from -C1-C6 alkyl; R5is independently, at each occurrence, selected from -C1-C6alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6cycloalkyl; 20 R6is independently, at each occurrence, selected from -C3-C8 cycloalkyl, wherein said C3-C8 cycloalkyl is optionally substituted with -OH or C1-C6 alkoxy; 4- to 6-memberedheterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl is optionally substituted withhalogen; and -C1-C6 alkyl, wherein said -C1-C6 alkyl is optionally substituted with one or more-C1-C6alkoxy; 25 R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 4- tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole 30 and isoxazole, wherein each oxazole and isoxazole is optionally substituted with one or more C1-C6alkyl; with the proviso that when said -C1-C2 alkylene-R7is -C1-C2 alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene,Attorney Ref: P6837PC00 15or said -C1-C2 alkylene is a -C2 alkylene; with the proviso that when said -C1-C2alkylene-R8is -C1alkylene-isoxazole, said two R31combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene. In some embodiments, R1and R2, together with the nitrogen atom to which they are 5 attached, combine to form a heterocycle, wherein said heterocycle is piperazine; wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more R32; -C2-C4 alkylene-OH, wherein10 said -C2-C4 alkylene is further substituted with one or more R5; -C(O)R6; -C1-C2 alkylene-R7; -C1-C2alkylene-R8; or 2-piperidinone, wherein said 2-piperidinone is optionally substituted with C1-C6 alkyl; wherein said two R31, together with the carbon atom to which they are attached, combineto form a C3-C4 cycloalkyl or a C1 bridging alkylene; 15 R32is -C1-C6alkyl, or two R32, together with the carbon atom to which they are attached, combine to form a C3-C6 cycloalkyl, preferably a C3 cycloalkyl; R4is independently, at each occurrence, selected from -C1-C6 alkyl; R5is independently, at each occurrence, selected from -C1-C6alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6cycloalkyl; 20 R6is independently, at each occurrence, selected from -C3-C8 cycloalkyl, wherein said C3-C8 cycloalkyl is optionally substituted with C1-C6 alkoxy; 4- to 6-memberedheterocycloalkyl; and -C1-C6 alkyl, wherein said -C1-C6 alkyl is optionally substituted with oneor more -C1-C6 alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group25 consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 4- tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole and isoxazole, wherein each oxazole and isoxazole is optionally substituted with one or more 30 C1-C6 alkyl; with the proviso that when said -C1-C2alkylene-R7is -C1-C2alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene,or said -C1-C2alkylene is a -C2alkylene;Attorney Ref: P6837PC00 16with the proviso that when said -C1-C2 alkylene-R8is -C1 alkylene-isoxazole, said two R31combine to form a -C3-C4cycloalkyl or a -C1bridging alkylene. In some embodiments, R1 and R2, together with the nitrogen atom to which they areattached, combine to form a heterocycle, wherein said heterocycle is piperazine; 5 wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4 alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more C1-C6 alkyl; -C2-C4 alkylene-OH,wherein said -C2-C4alkylene is further substituted with one or more R5; -C(O)R6; -C1-C210 alkylene-R7; or -C1-C2 alkylene-R8; wherein said two R31, together with the carbon atom to which they are attached, combineto form a C3-C4 cycloalkyl or a C1 bridging alkylene; R4is independently, at each occurrence, selected from -C1-C6alkyl; R5is independently, at each occurrence, selected from -C1-C6 alkyl; or two R5, together 15 with the carbon atom to which they are attached, can combine to form a C3-C6cycloalkyl; R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to 6-membered heterocycloalkyl; and -C2-C6 alkyl, wherein said -C2-C6 alkyl is optionally substituted with one or more -C1-C6alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group20 consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 4- tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole and isoxazole, wherein each oxazole and isoxazole is optionally substituted with one or more 25 C1-C6 alkyl; with the proviso that when said -C1-C2 alkylene-R7is -C1-C2 alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene,or said -C1-C2alkylene is a -C2alkylene; with the proviso that when said -C1-C2 alkylene-R8is -C1 alkylene-isoxazole, said two 30 R31combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene. In some embodiments, R1 and R2, together with the nitrogen atom to which they areattached, combine to form a heterocycle, wherein said heterocycle is piperazine; wherein said piperazine is substituted with one or more R3, and wherein said piperazineAttorney Ref: P6837PC00 17is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more C1-C6 alkyl; -C2-C4 alkylene-OH,wherein said -C2-C4alkylene is further substituted with one or more R5; -C(O)R6; or -C1-C25 alkylene-R7; wherein said or two R31, together with the carbon atom to which they are attached, can combine to form a C3-C4 cycloalkyl or a C1 bridging alkylene; R4is independently, at each occurrence, selected from -C1-C6alkyl; R5is independently, at each occurrence, selected from -C1-C6alkyl; or two R5, together10 with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl;R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to 6-membered heterocycloalkyl; and -C2-C6 alkyl, wherein said -C2-C6 alkyl is optionally substituted with one or more -C1-C6alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group15 consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 4- tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; with the proviso that when said -C1-C2alkylene-R7is -C1-C2alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene,20 or said -C1-C2 alkylene is a -C2 alkylene.In some embodiments, R1 and R2 combine to form a heterocycle, wherein saidheterocycle is piperazine; wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, wherein25 said -C2-C4 alkylene is further substituted with one or more C1-C4 alkyl; -C2-C4 alkylene-OH,wherein said -C2-C4 alkylene is substituted with one or more R5; -C(O)R6; or -C1-C2 alkylene- R7; wherein said two R31, together with the carbon atom to which they are attached, combineto form a C3-C4 cycloalkyl or a C1 bridging alkylene 30 R4is independently, at each occurrence, selected from -C1-C4 alkyl; R5is independently, at each occurrence, selected from -C1-C4alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl; R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to 6-Attorney Ref: P6837PC00 18membered heterocycloalkyl; and -C2-C6 alkyl, wherein said -C2-C6 alkyl is optionally substituted with one or more -C1-C4alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 4- 5 tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; with the proviso that when said -C1-C2 alkylene-R7is -C1-C2 alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene,or said -C1-C2alkylene is a -C2alkylene;10 In some embodiments, R1 and R2 combine to form a heterocycle, wherein saidheterocycle is piperazine; wherein said piperazine is substituted with one or more R3; R3is independently, at each occurrence, selected from -C2-C4 alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more C1-C2 alkyl; -C2-C4 alkylene-OH,wherein said -C2-C4 alkylene is substituted with one or more R5; -C(O)R6; or -C1-C2 alkylene- 15 R7; R4is independently, at each occurrence, selected from -C1-C2 alkyl; R5is independently, at each occurrence, selected from -C1-C2 alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6cycloalkyl; R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to 6-20 membered heterocycloalkyl; and -C2-C6 alkyl, wherein said -C2-C6 alkyl is substituted with one or more -C1-C2 alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-tetrahydrofuran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or25 more halogen. In some embodiments, R1 and R2 combine to form a heterocycle, wherein saidheterocycle is piperazine; wherein said piperazine is substituted with one or more R3;R3 is independently, at each occurrence, selected from -C2-C4 alkylene-OR4, whereinsaid -C2-C4 alkylene is further substituted with one or more C1-C2 alkyl; -C2-C4 alkylene-OH,30 wherein said -C2-C4 alkylene is substituted with one or more R5; -C(O)R6; or -C1-C2 alkylene- R7; R4is independently, at each occurrence, selected from -C1-C2 alkyl; R5is independently, at each occurrence, selected from -C1-C2alkyl; or two R5, togetherAttorney Ref: P6837PC00 19with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl; R6is independently, at each occurrence, selected from -C3-C8cycloalkyl, wherein said C3-C8 cycloalkyl is selected from cyclopropyl and bicyclo[2.2.2]octane; 6-membered heterocycloalkyl; and -C2-C4alkyl, wherein said -C2-C6alkyl is substituted with one or more - 5 C1-C2alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1- piperidine, wherein said 1-piperidine is substituted with one or more halogen. In some embodiments, R1 and R2, together with the nitrogen atom to which they are10 attached, combine to form a heterocycle, wherein said heterocycle is piperidine; wherein said piperidine is optionally substituted with one or more halogen, R9, R10, -C1-C2 alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2 alkylene-OR12; R9is independently, at each occurrence, 5-membered heterocycloalkyl, wherein said heterocycloalkyl is substituted with oxo;15 R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6 alkyl; R12is -H or C1-C6alkyl. In some embodiments, R1 and R2, together with the nitrogen atom to which they are20 attached, combine to form a heterocycle, wherein said heterocycle is piperidine; wherein said piperidine is optionally substituted with one or more R9, R10, -C1-C2 alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2alkylene-OR12; R9is independently, at each occurrence, 5-membered heterocycloalkyl, wherein said heterocycloalkyl is substituted with oxo;25 R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6 alkyl; R12is -H or C1-C6alkyl. In some embodiments, R1 and R2 combine to form a heterocycloalkyl, wherein said30 heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more R10, -C1-C2alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2alkylene-OR12; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo;Attorney Ref: P6837PC00 20R11is -H or C1-C6 alkyl; and R12is -H or C1-C6alkyl. In preferred embodiments, said piperidine is substituted with one or more R10. In preferred embodiments, when said R1and R2combine to form a heterocycloalkyl, 5wherein said heterocycloalkyl is piperidine, and said piperidine is substituted with a 6-membered heterocycloalkyl, said 6-membered heterocycloalkyl is not attached as a fused or spirocyclic heterocycloalkyl. In some embodiments, R1 and R2 combine to form a heterocycloalkyl, wherein saidheterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or10 more R10, -C(O)-R10, or -C1-C2 alkylene-OR12;R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; and R12is -H or C1-C6alkyl. In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said 15 heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more R10, -C1-C2 alkylene-R10, -C(O)-R10, or -N(R11)-R10; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; and R11is -H or C1-C6alkyl. 20 In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more R10; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo. 25 In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more -C1-C2 alkylene-R10; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo. 30 In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more -C(O)-R10; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein eachAttorney Ref: P6837PC00 216-membered heterocycloalkyl is optionally substituted with one or more oxo. In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more -N(R11)-R10; 5 R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6 alkyl. In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or 10 more -C1-C2 alkylene-OR12; and R12is -H or C1-C6alkyl. In some embodiments, R1 and R2 combine to form a heterocycloalkyl, wherein saidheterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one ormore R10, -C1-C2 alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2 alkylene-OR12; 15 R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein said 6-membrered heterocycloalkyl is selected from morpholine, tetrahydropyran, and 2- piperidinone, preferably 4-morpholine, 4-tetrahydroypran, and 2-piperidinone; R11is -H or C1-C2alkyl; R12is -H or C1-C2alkyl; 20 In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more R10; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein said 6-membered heterocycloalkyl is selected from morpholine, tetrahydropyran, and 2-25 piperidinone, preferably 4-morpholine, 4-tetrahydroypran, and 2-piperidinone. In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more -C1-C2alkylene-R10; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein said30 6-membered heterocycloalkyl is selected from morpholine, tetrahydropyran, and 2- piperidinone, preferably 4-morpholine, 4-tetrahydroypran, and 2-piperidinone. In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one orAttorney Ref: P6837PC00 22more -C(O)-R10; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein said 6-membered heterocycloalkyl is selected from morpholine, tetrahydropyran, and 2- piperidinone, preferably 4-morpholine, 4-tetrahydroypran, and 2-piperidinone. 5 In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more -N(R11)-R10; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein said 6-membered heterocycloalkyl is selected from morpholine, tetrahydropyran, and 2-10 piperidinone, preferably 4-morpholine, 4-tetrahydroypran, and 2-piperidinone; R11is -H or C1- C2alkyl. In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more -C1-C2 alkylene-OR12; and 15 R12is -H or C1-C2alkyl. In some embodiments, R1and R2combine to form a heterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is unsubstituted. In one aspect, the present disclosure provides a pharmaceutical composition comprisingat least one compound according to any of the preceding claims, or a pharmaceutically 20 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 a25 pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, for use in a method ofpreventing 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. 30 In one or more embodiments, R1and R2of a compound of the present invention can form one of the structures selected from Table 1, below, wherein the connectivity to theremainder of Formula I is shown below:Attorney Ref: P6837PC00 23 Attorney Ref: P6837PC00 24 Attorney Ref: P6837PC00 25 Attorney Ref: P6837PC00 26 Attorney Ref: P6837PC00 27 Attorney Ref: P6837PC00 28 Attorney Ref: P6837PC00 29

[0003] Attorney Ref: P6837PC00 30In some embodiments, the compound is a compound as shown below in Table 2, or a pharmaceutically acceptable salt thereof. Table 2. Embodied Compounds Attorney Ref: P6837PC00 31

[0004] Attorney Ref: P6837PC00 32

[0005] Attorney Ref: P6837PC00 33

[0006] Attorney Ref: P6837PC00 34

[0007] Attorney Ref: P6837PC00 35

[0008] Attorney Ref: P6837PC00 36

[0009] Attorney Ref: P6837PC00 37

[0010] Attorney Ref: P6837PC00 38

[0011] Attorney Ref: P6837PC00 39

[0012] Attorney Ref: P6837PC00 40 Attorney Ref: P6837PC00 41

[0013] Attorney Ref: P6837PC00 42

[0014] Attorney Ref: P6837PC00 43

[0015] Attorney Ref: P6837PC00 44

[0016] Attorney Ref: P6837PC00 45

[0017] Attorney Ref: P6837PC00 46 Attorney Ref: P6837PC00 47

[0018] Attorney Ref: P6837PC00 48

[0019] Attorney Ref: P6837PC00 49

[0020] Attorney Ref: P6837PC00 50

[0021] Attorney Ref: P6837PC00 51

[0022] Attorney Ref: P6837PC00 52

[0023] Attorney Ref: P6837PC00 53

[0024] Attorney Ref: P6837PC00 54

[0025] Attorney Ref: P6837PC00 55

[0026] Attorney Ref: P6837PC00 56

[0027] Attorney Ref: P6837PC00 57

[0028] Attorney Ref: P6837PC00 58 In some embodiments, said compound is selected from: Compound 1, Compound 2,Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14,5 Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20,Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26,Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32,Compound 33, Compound 34, Compound 35, Compound 36, Compound 37, Compound 38,Compound 39, Compound 40, Compound 41, Compound 42, Compound 43, Compound 44,10 Compound 45, Compound 46, Compound 47, Compound 48, Compound 49, Compound 50,Compound 51, Compound 52, Compound 53, Compound 54,Compound 55, Compound 56 andCompound 57. In some embodiments, said compound is selected from: Compound 1, Compound 2,Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,15 Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14,Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20,Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, Compound 26,Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32,and Compound 33.20 In some embodiments, said compound is selected from Compound 1, Compound 2,Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8,Attorney Ref: P6837PC00 59Compound 9, Compound 10, Compound 11, Compound 23, Compound 32, and Compound 33.In some embodiments, the compound of Formula I is Compound 1, or apharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the5 compound 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 is Compound 6, or a pharmaceutically acceptable salt thereof. In some embodiments, the10 compound 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 is Compound 10, or a pharmaceutically acceptable salt thereof. In some embodiments, the15 compound 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 is Compound 14, or a pharmaceutically acceptable salt thereof. In some embodiments, the20 compound 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, the25 compound of Formula I is Compound 19, or a pharmaceutically acceptable salt thereof. In someembodiments, 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, the30 compound of Formula I is Compound 23, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 24, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 25, or apharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isAttorney Ref: P6837PC00 60Compound 26, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 27, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 28, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 29, or a5 pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 30, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 31, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 32, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 33, or a10 pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 34, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 35, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 36, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 37, or a15 pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 38, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 39, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 40, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 41, or a20 pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 42, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 43, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 44, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 45, or a25 pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 46, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 47, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 48, or a pharmaceutically acceptablesalt thereof. In some embodiments, the compound of Formula I is Compound 49, or a30 pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is Compound 50, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 51, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula I is Compound 52, or a pharmaceutically acceptableAttorney Ref: P6837PC00 61salt thereof. In some embodiments, the compound of Formula I is Compound 53, or apharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I isCompound 54, or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula I is Compound 55, or a pharmaceutically acceptable salt thereof. In5 some embodiments, the compound of Formula I is Compound 56, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the compound of Formula I is Compound 57, or a pharmaceutically acceptable 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,10 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.15 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 20 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 beconsistent with the preparation of compounds of the present invention. 25 Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula 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 30 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: P6837PC00 62- 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 5Compounds 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)10 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., DMF afforded an acetal-protected rifabutin. De-acetylation of the protected rifabutin using a basic 15 solution such as sodium methoxide in ether afforded the C25-hydroxy, C21-C23-protected rifabutin (I-1).Scheme 2. Synthesis of 21,23-acetonide-25-carbonyl-imidazol-rifabutin (I-2) The free C25-hydroxy group of Intermediate (I-1) can be converted to a C25 imidazoleAttorney Ref: P6837PC00 63carbamate (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. 5 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 treating10 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 good antibacterial 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 15 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 healthy cells 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.20 Accordingly, in some embodiments, the inventive compounds can be used to inhibitbacterial infection, preferably infection caused by a non-tuberculous Mycobacteria, morepreferably M. abscessus. Methods of Using the Disclosed Compounds An aspect of the present invention relates to a compound of Formula I or aAttorney Ref: P6837PC00 64pharmaceutically 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, 5 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 10 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 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 pharmaceutical composition comprising a compound of Formula I of the present invention or a pharmaceutically acceptable 15 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 provides20 the use of a pharmaceutical composition comprising a compound of Formula I of the presentinvention 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 25 bacterium belonging a genus of non-tuberculous Mycobacteria, preferably M. abscessus. In some preferred embodiments, the infection is caused by one or more bacterium belonging 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.30 In some preferred embodiments, the inventive compounds are used for the treatment of anon-tuberculous Mycobacteria that causes a non-tuberculous Mycobacteria pulmonaryinfection. 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,Attorney Ref: P6837PC00 65M. 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- 5tuberculous 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 a10 compound 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 15 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 20 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, 25 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-release30 preparation, fast-dissolving preparation, or lozenge. Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, 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,Attorney Ref: P6837PC00 66glycerol, 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 prepared 5from 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,10 stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components ishydrated 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 15 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.20 Compositions can be prepared according to conventional mixing, granulating or coatingmethods, 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 a25 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 amount of the drug required to prevent, counter, or arrest the progress of the condition.30 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 to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75,100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or,Attorney Ref: P6837PC00 67in 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 specific5 embodiments 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 andvariations are intended to fall within the spirit and scope of the present invention. 10

[0029] Attorney Ref: P6837PC00 68EXAMPLES 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 5 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 10 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 (−) 10 Camphorsulfonic acidDCM dichloromethaneDMF dimethylformamideeq. equivalentEtOAc ethyl acetateEtOH ethanolh hour(s)HOBt 1-hydroxy-1H-benzotriazoleHPLC high performance liquid chromatographyLC liquid chromatographyM molarMeOH methanolMS mass spectroscopyAttorney Ref: P6837PC00 69min minutesNMR 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 5 Method A was used for the intermediates. Method A or B was used to measure final purity of the compounds as noted herein. Purity (%) was determined by reversed phase HPLCor UPLC, using UV detection (254 nm 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. 10 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 the15 following methods: Or the following gradient: Attorney Ref: P6837PC00 70 Mass spectrometer: ACQUITY QDa (Performance) Xevo TQD. Ionization: electrospray (polarity: negative and positive). Unless otherwise stated, analyses lasted five minutes. In some cases, analyses were performed for 30 min (*) as indicated.5 Method B: Method B: Waters LC-H class plus; 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: 10 Or the following alternate gradient: Attorney Ref: P6837PC00 71 NMR Analysis NMR spectra were recorded on a Bruker DRX-300 spectrometer or Bruker 500 MHz spectrometer with a TXI probe or Bruker 400 MHz spectrometer. Chemical shifts are in parts5 per million (ppm). The assignments were made using one-dimensional (1D) 1H and 13C spectraand 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) 10 Synthesis of Intermediate I-1:Step 1: Commercially available Rifabutin (40.0 g, 47.2 mmol) was dissolved in dry DMF (80 mL) at RT under nitrogen atmosphere. 2,2-Dimethoxy-propane (58.1 mL, 472 mmol) and (1R)15 (−) 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 NaHCO3Attorney Ref: P6837PC00 72(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 mixture DCM / MeOH / NH4OH 90 / 9 / 1.5 in DCM) to afford the 21,23-acetonide-rifabutin as a purplesolid (37.68 g, 90 % yield).5 LC / MS method A (ESI+): tr = 3.20 min, m / z [M+H]+ = 887.48, UV purity: 97 % (254nm). 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),10 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 (s overlapped, 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).15 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: 20 21,23-acetonide-rifabutin (10.6 g, 11.9 mmol) was dissolved in dry diethyl ether (500 mL). The solution was cooled to -10°C and degassed with Ar bubbling. After 15 min, a solution of NaOMe (25wt% in MeOH, 30 mL) was slowly added. Precipitation occurred and another portion 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 stirred25 at -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 were washed 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 30 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 by filtration and dried at 40°C to yield 8.54 g of the Intermediate I-1.LC / MS method A (ESI+): tr = 2.98 min, m / z [M+H]+= 845.59, UV purity: 97 % (254Attorney Ref: P6837PC00 73nm). 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 =5 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,1H), 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 = 7.010 Hz, 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, 7.8.15 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 aqueous20 saturated solution of NaHCO3(40ml) and NaCl brine (40mL). The organic layer was dried over 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 as a red solid (m= 660mg,yield=59%).25 LC / MS A (ESI+): tr = 2.29 min, m / z [M+H]+ = 939.52, UV purity: 99% (254 nm).Attorney Ref: P6837PC00 741H 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), 2.62-5 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 (moverlapped, 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, 108.4,10 105.7, 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 Compound 4 Step 1:15 A glass vial was charged with 25-carbonyl-imidazol-21,23-acetonide-Rifabutin (I-2)(170 mg, 0.181 mmol), (1-piperazin-1-ylcyclopropyl)methanol (141 mg, 0.905 mmol) and HOBt (489 mg, 3.62 mmol, 5 eq) then DMF (7 ml) were added. The mixture was stirred at50°C for 24h. After this time, the mixture was diluted with EtOAc (50 ml) then washed withNaHCO3(50 ml) and NaCl brine (50 ml). The organic layer was dried over MgSO4, filtered 20 and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography with DCM-MeOH (100-0 to 90-10) to obtain a purple solid that was used directly for step 2. Step 2: The product from the previous step was dissolved in THF (2 ml) then a 0.5 N aqueous 25 solution of (−) 10 Camphorsulfonic acid (2 ml) was added dropwise, and the solution was stirred overnight. After this time, EtOAc (25 ml) was added to the mixture which was washed with aAttorney Ref: P6837PC00 75saturated aqueous solution of NaHCO3 (25 ml) to remove the acid, extracted once with EtOAc then the combined organic extracts were washed with NaCl brine (100 ml), dried over MgSO4and concentrated to dryness. The product was purified by flash chromatography with DCM- MeOH (100-0 to 90-10) to obtain a violet solid, 87 mg, 47% yield.5 LC / MS B (ESI+): tr = 6.62 min, m / z [M+H]+ = 987.79, UV purity: 97% (214 nm). 1H NMR (400 MHz, C6D6) δ 15.54 (s, 1H), 9.22 (s, 1H), 8.74 (s, 1H), 6.62 (dd, J = 15.7, 9.7 Hz, 1H), 6.39 (d, J = 12.5 Hz, 1H), 5.99 (d, J = 9.9 Hz, 1H), 5.90 (dd, J = 15.7, 7.2Hz, 1H), 5.36 – 5.17 (m, 2H), 4.84 (d, J = 10.5 Hz, 1H), 3.98 (d, J = 6.9 Hz, 1H), 3.83 (d, J =9.5 Hz, 1H), 3.31 – 3.12 (m, 8H), 3.10 – 3.00 (m, 1H), 2.94 (s, 3H), 2.91 – 2.82 (m, 1H), 2.5810 – 2.41 (m, 7H), 2.37 (s, 3H), 2.12 – 2.00 (m, 3H), 1.92 (s, 3H), 1.88 – 1.71 (m, 5H), 1.68 (s,3H), 1.63 (dd, J = 13.3, 6.8 Hz, 1H), 1.42 – 1.28 (m, 1H), 1.11 (d, J = 7.0 Hz, 3H), 0.92 (d, J =6.4 Hz, 7H), 0.75 (d, J = 6.9 Hz, 3H), 0.70 (d, J = 6.8 Hz, 3H), 0.43 (dd, J = 5.7, 4.0 Hz, 3H),0.28 (t, J = 7.2 Hz, 2H), 0.21 (dd, J = 4.1 Hz, 2H).d13C NMR (101 MHz, C6D6) δ 191.8, 182.4, 171.6, 167.0, 168.4, 156.9, 156.8, 156.4,15 155.5, 145.7, 143.0, 142.6, 141.5, 141.1, 132.6, 131.8, 128.7, 128.2, 128.0, 125.8, 125.0, 114.6, 112.6, 109.5, 108.0, 105.9, 94.9, 81.5, 77.5, 75.0, 73.3, 66.6, 56.6, 55.7, 51.8, 51.6, 39.1, 39.0, 38.3, 36.7, 36.1, 34.0, 26.1, 22.1, 21.0, 20.7, 17.4, 12.2, 11.7, 9.1, 7.9. Compounds 1-3 and 5-57 were synthesized according to the same procedure used forthe synthesis of Compound 4 as described below:20 Intermediate I-2 (25-imidazo-carbonyl-21,23-acetonide-rifabutin, 1 eq.) was dissolved in DMF (0.025 mol / L). To this solution was added corresponding amine (5 eq.) and HOBt (20 eq.) and the mixture was stirred for 16 h at 50°C. Then, the mixture was diluted with EtOAc,washed with sat. solution of NaHCO3 and then brine. The combined organic phases were dried,filtered and concentrated under reduce pressure. The crude was purified by column25 chromatography (from 100% DCM to 90 / 10 DCM / MeOH) when needed. The recoveredfraction was dissolved in a mixture THF / 0.5 N aqueous solution of CSA and stirred overnight. Then, EtOAc 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) or HPLC 30 to afford the desired product as purple solid. Table 3 below summarizes exemplary compounds of the invention (ring formed by R1and R2 groups shown) that were prepared according to the protocol for Compound 4 above.Data for the compounds given in Table 3 were obtained following the analytic method A, 5 minAttorney Ref: P6837PC00 76gradient (no asterix), 30 min gradient (*) or B, 9 min gradient (**) or 15 min gradient (***).Where the starting amine was originally prepared as a hydrochloride, 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 5 protocols. In 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 10 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 the most abundant isotope revealed by the mass spectrum [M+H]+.Table 3: Molecular Weight (Calculated), Retention Time (Method B) and Measured 15 Mass of Exemplary Compounds Attorney Ref: P6837PC00 77 Attorney Ref: P6837PC00 78 Attorney Ref: P6837PC00 79 Attorney Ref: P6837PC00 80 Attorney Ref: P6837PC00 81 Attorney Ref: P6837PC00 82 Attorney Ref: P6837PC00 83 Attorney Ref: P6837PC00 84 Attorney Ref: P6837PC00 85 Attorney Ref: P6837PC00 86Table 4:1HNMR Values of Exemplary Compounds Attorney Ref: P6837PC00 87 Attorney Ref: P6837PC00 88 Attorney Ref: P6837PC00 89 Attorney Ref: P6837PC00 90 Attorney Ref: P6837PC00 91 Attorney Ref: P6837PC00 92 Attorney Ref: P6837PC00 93 Attorney Ref: P6837PC00 94 Attorney Ref: P6837PC00 95 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 (see 5 HS). From a fresh culture plate, cells were resuspended in 0.9% (w / v) saline solution and bacterial 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 10 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 the lowest 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).15 The MIC values, given in µg / mL, are given in Table 5, belowAttorney Ref: P6837PC00 96Table 5. In vitro activity of embodied compounds against M. abscessus smooth (S) and rough(R) Attorney Ref: P6837PC00 97 Attorney Ref: P6837PC00 98 Attorney Ref: P6837PC00 99 Atorney Ref: P6837PC00 100

[0030] Attorney Ref: P6837PC00 101EXAMPLE 5: Activity Against Healthy Cells CellTiter-Blue Assay was performed to determine cytotoxicity (IC50 value) of compounds against HepG2 cells (ATCC, HB-8065). IC50 was determined in EMEMsupplemented with 2mM Glutamine, non-essential amino acids, 10% fetal bovine serum and5 1% penicillin / streptomycin. The IC50values, in µg / mL, are given in Table 6, below. Table 6. Activity of Exemplary Compounds against HepG2 Cells Attorney Ref: P6837PC00 102

Claims

1. Attorney Ref: P6837PC00 103CLAIMS 1. A compound of Formula I or a pharmaceutically acceptable salt, tautomer, solvate,hydrate or enantiomer thereof:5 wherein: R1and R2, together with the nitrogen atom to which they are attached, combine to form a heterocycle, wherein said heterocycle is selected from the group consisting of piperazine, and piperidine; wherein said piperazine is substituted with one or more R3, and wherein said10 piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more R32; -C2-C4alkylene-OH, wherein said -C2-C4 alkylene is further substituted with one or more R5; -C(O)R6; -C1-C2 alkylene-R7; -C1-C2 alkylene-R8; or 2-piperidinone, wherein said 2- 15 piperidinone is optionally substituted with C1-C6 alkyl; wherein said two R31, together with the carbon atom to which they are attached,combine to form a C3-C4cycloalkyl or a C1bridging alkylene; R32is -C1-C6 alkyl, or two R32, together with the carbon atom to which they are attached, combine to form a C3-C6 cycloalkyl; 20 R4is independently, at each occurrence, selected from -C1-C6alkyl; R5is independently, at each occurrence, selected from -C1-C6 alkyl; or two R5,Attorney Ref: P6837PC00 104together with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl; R6is independently, at each occurrence, selected from -C3-C8 cycloalkyl, wherein said C3-C8 cycloalkyl is optionally substituted with -OH or C1-C6 alkoxy; 4- to5 6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl isoptionally substituted with halogen; and -C1-C6 alkyl, wherein said -C1-C6 alkyl is optionally substituted with one or more -C1-C6 alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3- 10 tetrahydrofuran, 4-tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole and isoxazole, wherein each oxazole and isoxazole is optionally substituted with one or more C1-C6 alkyl;15 wherein said piperidine is optionally substituted with one or more halogen, R9,R10, -C1-C2 alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2 alkylene-OR12; R9is independently, at each occurrence, 5-membered heterocycloalkyl, wherein said heterocycloalkyl is substituted with oxo;R10is independently, at each occurrence, 6-membered heterocycloalkyl, 20 wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6alkyl; R12is -H or C1-C6 alkyl; with the proviso that when said -C1-C2alkylene-R7is -C1-C2alkylene-4-25 tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridgingalkylene, or said -C1-C2 alkylene is a -C2 alkylene; with the proviso that when said -C1-C2 alkylene-R8is -C1 alkylene-isoxazole, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene.30 2. The compound of claim 1, whereinR1and R2, together with the nitrogen atom to which they are attached, combine to form a heterocycle, wherein said heterocycle is selected from the group consisting ofpiperazine, and piperidine;Attorney Ref: P6837PC00 105wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4 alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more C1-C6 alkyl; -C2-5 C4 alkylene-OH, wherein said -C2-C4 alkylene is further substituted with one or moreR5; -C(O)R6; -C1-C2 alkylene-R7; -C1-C2 alkylene-R8; or 2-piperidinone, wherein said2-piperidinone is optionally substituted with C1-C6 alkyl; wherein said two R31, together with the carbon atom to which they are attached,combine to form a C3-C4cycloalkyl or a C1bridging alkylene; 10 R4is independently, at each occurrence, selected from -C1-C6 alkyl; R5is independently, at each occurrence, selected from -C1-C6alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl; R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to15 6-membered heterocycloalkyl; and -C2-C6alkyl, wherein said -C2-C6alkyl is optionally substituted with one or more -C1-C6 alkoxy; R7 is heterocycloalkyl, wherein said heterocycloalkyl is selected from the groupconsisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3- tetrahydrofuran, 4-tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, 20 wherein said 1-piperidine is substituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole and isoxazole, wherein each oxazole and isoxazole is optionally substituted with one or more C1-C6 alkyl; wherein said piperidine is optionally substituted with one or more R10, -C1-C225 alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2 alkylene-OR12; R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11 is -H or C1-C6 alkyl;30 R12is -H or C1-C6 alkyl; with the proviso that when said -C1-C2alkylene-R7is -C1-C2alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridgingalkylene, or said -C1-C2alkylene is a -C2alkylene;Attorney Ref: P6837PC00 106with the proviso that when said -C1-C2 alkylene-R8 is -C1 alkylene-isoxazole,said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene.

3. The compound of claim 1 or claim 2, wherein R1 and R2 combine to form a heterocycle,5 wherein said heterocycle is piperazine or piperidine; wherein said piperazine is substituted with one or more R3; R3is independently, at each occurrence, selected from -C2-C4 alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more C1-C2 alkyl; -C2-C4alkylene-OH, wherein said -C2-C4alkylene is substituted with one or more R5; - 10 C(O)R6; or -C1-C2 alkylene-R7; R4is independently, at each occurrence, selected from -C1-C2alkyl; R5is independently, at each occurrence, selected from -C1-C2 alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6cycloalkyl;15 R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to6-membered heterocycloalkyl; and -C2-C6 alkyl, wherein said -C2-C6 alkyl is substituted with one or more -C1-C2 alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3-20 tetrahydrofuran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1- piperidine is substituted with one or more halogen; wherein said piperidine is optionally substituted with one or more R10, -C(O)- R10, or -C1-C2 alkylene-OR12;R10is independently, at each occurrence, 6-membered heterocycloalkyl, 25 wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; and R12is -H or C1-C6 alkyl.

4. The compound of any of the preceding claims, wherein30 R1and R2, together with the nitrogen atom to which they are attached, combine to form a heterocycle, wherein said heterocycle is piperazine; wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31;Attorney Ref: P6837PC00 107R3is independently, at each occurrence, selected from -C2-C4 alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more R32; -C2-C4alkylene-OH, wherein said -C2-C4 alkylene is further substituted with one or more R5; -C(O)R6; -C1-C2alkylene-R7; -C1-C2alkylene-R8; or 2-piperidinone, wherein said 2- 5 piperidinone is optionally substituted with C1-C6alkyl; wherein said two R31, together with the carbon atom to which they are attached,combine to form a C3-C4 cycloalkyl or a C1 bridging alkylene; R32is -C1-C6alkyl, or two R32, together with the carbon atom to which they are attached, combine to form a C3-C6cycloalkyl; 10 R4is independently, at each occurrence, selected from -C1-C6 alkyl; R5is independently, at each occurrence, selected from -C1-C6alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl; R6is independently, at each occurrence, selected from -C3-C8 cycloalkyl,15 wherein said C3-C8 cycloalkyl is optionally substituted with -OH or C1-C6 alkoxy; 4- to6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl isoptionally substituted with halogen; and -C1-C6 alkyl, wherein said -C1-C6 alkyl is optionally substituted with one or more -C1-C6alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group20 consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3- tetrahydrofuran, 4-tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole and isoxazole, wherein each oxazole and isoxazole is optionally substituted 25 with one or more C1-C6 alkyl; with the proviso that when said -C1-C2 alkylene-R7is -C1-C2 alkylene-4- tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridgingalkylene, or said -C1-C2alkylene is a -C2alkylene; with the proviso that when said -C1-C2 alkylene-R8is -C1 alkylene-isoxazole,30 said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene.

5. The compound of any of the preceding claims, wherein R1 and R2, together with thenitrogen atom to which they are attached, combine to form a heterocycle, wherein saidAttorney Ref: P6837PC00 108heterocycle is piperazine; wherein said piperazine is substituted with one or more R3, and wherein said piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, 5wherein said -C2-C4 alkylene is further substituted with one or more C1-C6 alkyl; -C2-C4 alkylene-OH, wherein said -C2-C4 alkylene is further substituted with one or more R5; -C(O)R6; -C1-C2 alkylene-R7; or -C1-C2 alkylene-R8; wherein said two R31, together with the carbon atom to which they are attached,combine to form a C3-C4cycloalkyl or a C1bridging alkylene; 10 R4is independently, at each occurrence, selected from -C1-C6 alkyl; R5is independently, at each occurrence, selected from -C1-C6alkyl; or two R5, together with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl; R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to15 6-membered heterocycloalkyl; and -C2-C6alkyl, wherein said -C2-C6alkyl is optionally substituted with one or more -C1-C6 alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3- tetrahydrofuran, 4-tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, 20 wherein said 1-piperidine is substituted with one or more halogen; R8is heteroaryl, wherein said heteroaryl is selected from the group consisting of oxazole and isoxazole, wherein each oxazole and isoxazole is optionally substituted with one or more C1-C6 alkyl; with the proviso that when said -C1-C2alkylene-R7is -C1-C2alkylene-4-25 tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridgingalkylene, or said -C1-C2 alkylene is a -C2 alkylene; with the proviso that when said -C1-C2 alkylene-R8is -C1 alkylene-isoxazole, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridging alkylene.30 6. The compound of claim 5, wherein R1 and R2, together with the nitrogen atom to whichthey are attached, combine to form a heterocycle, wherein said heterocycle is piperazine; wherein said piperazine is substituted with one or more R3, and wherein saidAttorney Ref: P6837PC00 109piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more C1-C6 alkyl; -C2-C4alkylene-OH, wherein said -C2-C4alkylene is further substituted with one or more 5 R5; -C(O)R6; or -C1-C2alkylene-R7; wherein said two R31, together with the carbon atom to which they are attached,combine to form a C3-C4 cycloalkyl or a C1 bridging alkylene; R4is independently, at each occurrence, selected from -C1-C6alkyl; R5is independently, at each occurrence, selected from -C1-C6alkyl; or two R5,10 together with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl; R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to6-membered heterocycloalkyl; and -C2-C6alkyl, wherein said -C2-C6alkyl is optionally substituted with one or more -C1-C6 alkoxy;15 R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3- tetrahydrofuran, 4-tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen; with the proviso that when said -C1-C2alkylene-R7is -C1-C2alkylene-4-20 tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridgingalkylene, or said -C1-C2 alkylene is a -C2 alkylene.

7. The compound of any of claims 5-6, wherein R1 and R2 combine to form a heterocycle,wherein said heterocycle is piperazine; wherein said piperazine is substituted with one 25 or more R3, and wherein said piperazine is optionally substituted with two R31; R3is independently, at each occurrence, selected from -C2-C4 alkylene-OR4, wherein said -C2-C4 alkylene is further substituted with one or more C1-C4 alkyl; -C2-C4alkylene-OH, wherein said -C2-C4alkylene is substituted with one or more R5; - C(O)R6; or -C1-C2 alkylene-R7;30 wherein said two R31, together with the carbon atom to which they are attached,combine to form a C3-C4cycloalkyl or a C1bridging alkylene; R4is independently, at each occurrence, selected from -C1-C4 alkyl; R5is independently, at each occurrence, selected from -C1-C4alkyl; or two R5,Attorney Ref: P6837PC00 110together with the carbon atom to which they are attached, can combine to form a C3-C6 cycloalkyl; R6 is independently, at each occurrence, selected from -C3-C8 cycloalkyl; 5- to6-membered heterocycloalkyl; and -C2-C6alkyl, wherein said -C2-C6alkyl is optionally 5 substituted with one or more -C1-C4alkoxy; R7is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of 2-oxetane, 3-oxetane, 3-tetrahydropyran, 2-tetrahydrofuran, 3- tetrahydrofuran, 4-tetrahydropyran, 2-oxabicyclo[2.1.1]hexane, and 1-piperidine, wherein said 1-piperidine is substituted with one or more halogen;10 with the proviso that when said -C1-C2 alkylene-R7 is -C1-C2 alkylene-4-tetrahydropyran, said two R31 combine to form a -C3-C4 cycloalkyl or a -C1 bridgingalkylene, or said -C1-C2 alkylene is a -C2 alkylene; 8. The compound of claim 1, wherein R1 and R2, together with the nitrogen atom to which15 they are attached, combine to form a heterocycle, wherein said heterocycle is piperidine; wherein said piperidine is optionally substituted with one or more halogen, R9,R10, -C1-C2 alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1-C2 alkylene-OR12; R9is independently, at each occurrence, 5-membered heterocycloalkyl, wherein said heterocycloalkyl is substituted with oxo;20 R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6 alkyl; R12is -H or C1-C6alkyl. 25 9. The compound of claim 1, wherein R1 and R2 combine to form a heterocycloalkyl,wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more R10, -C1-C2alkylene-R10, -C(O)-R10, -N(R11)-R10, or -C1- C2 alkylene-OR12; 30 R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; R11is -H or C1-C6alkyl; andAttorney Ref: P6837PC00 111R12is -H or C1-C6 alkyl.

10. The compound of claim 9, wherein R1 and R2 combine to form a heterocycloalkyl,wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally 5substituted with one or more R10, -C(O)-R10, or -C1-C2 alkylene-OR12;R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein each 6-membered heterocycloalkyl is optionally substituted with one or more oxo; and R12is -H or C1-C6alkyl. 10 11. The compound of any of claims 9-10, wherein R1 and R2 combine to form aheterocycloalkyl, wherein said heterocycloalkyl is piperidine, wherein said piperidine is optionally substituted with one or more R10, -C1-C2alkylene-R10, -C(O)-R10, -N(R11)- R10, or -C1-C2 alkylene-OR12; 15 R10is independently, at each occurrence, 6-membered heterocycloalkyl, wherein said 6-membrered heterocycloalkyl is selected from morpholine,tetrahydropyran, and 2-piperidinone, preferably 4-morpholine, 4-tetrahydroypran, and 2-piperidinone; R11is -H or C1-C2alkyl; 20 R12is -H or C1-C2 alkyl; 12. The compound of claim 1, wherein said compound is selected from Compound 1,Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7,Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound25 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18,Compound 19, Compound 20, Compound 21, Compound 22, Compound 23,Compound 24, Compound 25, Compound 26, Compound 27, Compound 28,Compound 29, Compound 30, Compound 31, Compound 32, Compound 33,Compound 34, Compound 35, Compound 36, Compound 37, Compound 38,30 Compound 39, Compound 40, Compound 41, Compound 42, Compound 43,Compound 44, Compound 45, Compound 46, Compound 47, Compound 48,Compound 49, Compound 50, Compound 51, Compound 52, Compound 53,Compound 54, Compound 55, Compound 56 and Compound 57 or a pharmaceuticallyAttorney Ref: P6837PC00 112acceptable salt thereof.

13. A pharmaceutical composition comprising at least one compound according to any ofthe preceding claims, or a pharmaceutically acceptable salt, tautomer, solvate or hydrate 5 thereof, and a pharmaceutically acceptable excipient.

14. A compound according to any of the claims 1 to 12 or a pharmaceutically acceptablesalt, tautomer, solvate or hydrate thereof, for use as a medicament.10 15. A compound of according to any of the claims 1 to 12 or a pharmaceutically acceptablesalt, 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. 15 abscessus.

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