WO2019079706A1 - Antibiotiques à base d'aminoglycoside - Google Patents

Antibiotiques à base d'aminoglycoside Download PDF

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WO2019079706A1
WO2019079706A1 PCT/US2018/056686 US2018056686W WO2019079706A1 WO 2019079706 A1 WO2019079706 A1 WO 2019079706A1 US 2018056686 W US2018056686 W US 2018056686W WO 2019079706 A1 WO2019079706 A1 WO 2019079706A1
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alkyl
cyclic
acyclic
linear
hydrogen
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PCT/US2018/056686
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Fan Liu
Andrew G. Myers
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President And Fellows Of Harvard College
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20Carbocyclic rings
    • C07H15/22Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/226Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
    • C07H15/234Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
    • C07H15/236Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin

Definitions

  • Aminoglycoside antibiotics have been in continuous clinical use for more than seven decades.
  • the first member of the aminoglycoside antibiotic family, streptomycin was isolated in 1943 by the Nobel laureate Selman Waksman. Streptomycin exhibited activity against strains of mycobacteria and became the first effective treatment for tuberculosis. Following the success of streptomycin, numerous other aminoglycoside antibiotics were identified, including neomycin, paromomycin, kanamycin, gentamicin, and sisomicin. However, the use of aminoglycosides has steadily declined over the past decades due to a rise in bacterial resistance.
  • gentamicin is the most commonly prescribed aminoglycoside antibiotic and is used as a mixture of three components (gentamicin Ci, C la , and C 2 ).
  • the aminoglycosides exhibit broad-spectrum antibiotic activities and cause minimal allergic responses, which make them ideal for use in emergencies.
  • the main drawbacks of aminoglycoside therapy are nephrotoxic and ototoxic side effects. All current aminoglycoside antibiotics in use in the clinic are associated with similar adverse effects. Despite these side effects and widespread resistance, they are the drugs of choice in inhalation therapy to suppress lung infections in cystic fibrosis patients. They are also part of the drug cocktail used for the treatment of multi drug-resistant tuberculosis.
  • New and improved aminoglycoside antibiotics have come exclusively from semi- synthesis, the process of chemically converting natural fermentation products into drugs. Since the initial isolation of streptomycin, six semi-synthetic derivatives, prepared in 1-6 steps from naturally occurring aminoglycosides, have been approved by the FDA for the treatment of bacterial infections. In 2016, plazomicin, a third-generation aminoglycoside which showed both improved antibiotic and safety profiles, completed Phase III clinical trials (see Figure 1; positions that have been modified by semi-synthesis are indicated with arrows and brackets).
  • R.2b is halogen, hydroxy!, protected hydroxy!, amino, protected amino, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroahphatic, aryl or heteroaryl;
  • R 3c is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroahphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • R.3d is cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaiiphatic, aryl, heteroaryl, or a nitrogen protecting group; or
  • R.3c and R 3 a together form a ring
  • R 4a is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaiiphatic, aryl or heteroaryl; or
  • R-ta and R 3c are combined to form a five or six-membered ring, or
  • R 4 a and R 3 d are combined to form a five or six-membered ring
  • R 4 is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaiiphatic, aryl or heteroaryl; or
  • R.4a and Rsc are combined to form a five or six-membered ring, or
  • R 4 a and R 3 d are combined to form a five or six-membered ring
  • Rvd is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaiiphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • R9a is hydrogen, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaiiphatic, aryl, heteroaryl ;
  • R9d is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaiiphatic, aryl, heteroaryl , or a nitrogen protecting group
  • Rub is halogen, hydroxyl, protected hydroxy!, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl;
  • Ri4d is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • Risb i hydrogen, halogen, hydroxyl, protected hydroxyl , cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • Ri6a is hydrogen, halogen, hydroxyl , protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • Risa, Risb, and Risd independently are hydrogen, halogen, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl; or two of Riga, Risb, and Ri8d are combined to form a ring.
  • the compound of Formula (I) is of Formula ( ⁇ ):
  • composition comprising a compound of Formula (I),
  • a method of treating or preventing a bacterial infection in a subject in need thereof comprising administering to the subject a compound of Formula (I).
  • kits comprising an aminoglycoside of Formula (I) and a container.
  • Figure 1 shows a summary of semi-synthetic aminoglycoside derivatives. The positions that have been modified by semi-synthesis are indicated with arrows and brackets.
  • Figure 2 shows the biosynthesis of 2-deoxy streptamine and streptidine from glucose.
  • Figure 3 shows the biosynthetic pathway to 2-deoxystreptamine aminoglycoside antibiotics.
  • Figure 4 shows the hydrogenation of streptomycin produced dihydrostreptomycin, a compound of similar antibacterial properties but improved chemical stability.
  • Figure 5 shows the synthesis of dibekacin from kanamycin B.
  • Figure 6 shows the synthesis of amikacin from kanamycin A. Amikacin shows improved antibacterial and pharmacokinetic properties
  • Figure 7 shows the synthesis of arbekacin in 5 steps from dibekacin, a semi-synthetic derivative of kanamycin B.
  • Figure 8 shows the synthesis of isepamicin from gentamicin B. Isepamicin is a derivative of gentamicin and was first reported in 1978
  • Figure 9 shows the synthesis of netilmicin in one step from sisomicin in 25% yield (top).
  • An improved procedure involves the initial formation of a cobalt-chelation complex and provides netilmicin in 3 steps and 60% yield (bottom),
  • Figure 10 shows the synthesis of piazomicin, a next-generation aminoglycoside, from sisomicin in 7 steps with an overall yield of 0.1.6%.
  • Figure 11 shows the synthesis of 2-hydroxyarbekacin, a new aminoglycoside antibiotic with improved activity against MRSA.
  • Figure 12 shows a semi-synthetic derivative of tobramycin, SPX2523.
  • Figure 13 shows the chemical synthesis of 5 -epi sisomicin (SCH 22591).
  • FIG. 14 shows 5-episisomicin derivatives prepared from sisomicin.
  • AAC Aminoglycoside N-Acetyltransferase.
  • Figure 15 shows the synthesis of TS2037 from arbekacin in 1 1 steps.
  • the novel arbekacin derivative shows improved activity against MRSA and P. aeruginosa.
  • Figure 16 shows a summary of clinically approved semisynthetic aminoglycosides
  • Figure 17 shows the structural relationship of aminoglycosides and their semisynthetic derivatives. Semisynthetic antibiotics are linked to their natural product starting material through dotted lines.
  • Figure 18 shows a fully synthetic approach to assemble the aminoglycoside scaffold from three components (2-4).
  • the aminoglycoside, 1 -HABA-gentamicin Cia (1) is used as a representative example.
  • Figure 19 shows the coupling of the purpurosamine glycosyl donor 3 with the differentially protected 2-deoxystreptamine derivative 4 to afford the glycoside 140.
  • Figure 20 shows the introduction of the HABA sidechain to the C I amine of the glycoside 140 in two steps and 62% yield.
  • the dioi 144 is prepared in 61% yield from 140.
  • Figure 21 shows the synthesis of gentamicin Cia from components 3, 118, and 50 based on the fully synthetic route described herein. Late-stage derivatization of the Co' nitro group produces three novel aminoglycoside antibiotics that are inaccessible through semi- synthesis.
  • Figure 22 shows structures of gentamicin and sisomicin.
  • Figure 23 shows a convergent synthesis of the glycosyl donor 2, allowing late-stage diversification of the C3 " amino group.
  • Figure 24 shows diastereoselective nitroaldol coupling conditions.
  • Figure 25 shows practical and large-scale syntheses of building blocks 6 and 7.
  • Figure 26 shows structures of two representative 4, 6-di substituted aminoglycoside antibiotics, kanamycin and gentamicin.
  • the purpurosamines A-C are found in gentamicin C complex and are biosynthetically related to other carbohydrates that make up the ring I of aminoglycosides.
  • Figure 27 shows the synthesis of compound 3, which proceeds in 6 steps from D- glutamic acid.
  • Figure 28 shows representative aminoglycoside antibiotics.
  • Figure 29 shows the synthesis of compound 4 from the protected dimethyl tartrate 8.
  • Figure 30 shows the synthesis of the activated HABA sidechain 5.
  • Figure 31 shows the synthesis of the 2-deoxystreptamine glycosyl acceptor 137.
  • Figure 32 shows the synthesis of gentamicin Cia (FSA-3821 ) proceeded in five steps from the purpurosamine component 3 and the semisynthetic 2-deoxystreptamine glycosyl acceptor 118.
  • Figure 33 shows the synthesis of C6 -modified gentamicin derivatives FSA-38240, FSA-38255, and FSA-38252.
  • Figure 34 shows the bacterial ribosome carries out the production of proteins. Gentamicin, a representative aminoglycoside antibiotic, interferes with several stages of bacterial protein synthesis.
  • Figure 35 shows the resistance rate to gentamicin in four geographic regions between 1998 and 2007.
  • Figure 36 shows aminoglycosides are inactivated through modifications of polar functional groups by aminoglycoside modifying enzymes (AMEs).
  • AMEs aminoglycoside modifying enzymes
  • the AMEs found only in Gram-negative bacteria are ANT(2") and AAC(3).
  • Figure 37 shows overlapping binding sites of gentamicin and paromomycin in the 30S subunit of the ribosome.
  • the nucleobases, G1405 and A1408, which are substrates of rRNA methyltransferases ArmA and NmpA, respectively, are colored in blue.
  • the universally conserved nucleobases A1942 and A1943 adopt an extra-helical conformation upon aminoglycoside binding.
  • Figure 38 shows the minimum inhibitory concentrations ( , ug/mL) of synthetic gentamicin C ia and C6 -modified gentamicin analogs against two Gram-positive and five Gram- negative bacterial strains.
  • cErm :: constitutive eiythromycin ribosome methyl ase
  • FQ-R :: fluoroquinolone resistant
  • cErmB constitutive eiythromycin ribosome methylase B.
  • Figure 39 shows the preparation of a 2-deoxystreptamine glycosyl acceptor by semi synthesis.
  • Figure 40 shows exemplar ⁇ ' aminoglycoside modifications targeting resistance phenotypes.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoi somen c forms, e.g. , enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • structures depicted herein are al so meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 1 C- or 1 C-enriched carbon are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • Ci-6 alky is intended to encompass, Ci, Ci, C 3 , C 4 , Cs, Ce, Ci-6, Ci-5, Ci-4, Ci-3, Ci-2, C2--6, C2-5, C2--4, C2-3, C3-6, C3--5, C3-4, C4--6, C4-5, and C5--6 aikyi.
  • aliphatic refers to alk l, alkenyl, alkynyl, and carbocyclic groups.
  • heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“Ci-io alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Ci-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“Ci-s alkyl”).
  • an alkyl group has 1 to 4 carbon atoms ("Ci-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("Ci-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • Ci-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyi, tert-butyl, sec-butyl, iso-butyl), pentyl (Cs) (e.g., n-pentyl, 3-pentanyi, amy], neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (Ce) (e.g., 2-methylpentyl, 3- methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and n-hexyl).
  • Cs e.g., 2-methylpentyl, 3- methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and n-hex
  • alkyl groups include n-heptyl (C?), n-octyl (Cs), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted €1-10 alkyl (such as unsubstituted Ci-e alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n- propyl (n-Pr), unsubstituted isopropyl (/-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (w-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (/-Bu)).
  • the alkyl group is a substituted Ci-10 alkyl (such as substituted Ci-e alkyl, e
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • a halogen e.g., fluoro, bromo, chloro, or iodo.
  • Perhaloalkyl is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 8 carbon atoms ("Ci-s haloalkyl").
  • the haloalkyl moiety has 1 to 6 carbon atoms ("Ci- ⁇ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C1--2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group.
  • haloalkyl hydrogen atoms are replaced with chloro to provide a "perchloroalkyl" group.
  • haloalkyl groups include -CF 3 , - CF2CF3, --CF2CF2CF3, -CCI3, -CFCI2, -CF2CI, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCj-io alkyl").
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-9 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-s alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and J or more heteroatoms within the parent chain ("heteroCi-7 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-6 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCt-s alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and l or 2 heteroatoms within the parent chain ("heteroCi-4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having J to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroCi-2 alkyl").
  • a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroCi alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkyl"). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heterod-io alkyl . In certain embodiments, the heteroalkyl group is a substituted heteroCi-io alkyl.
  • Carboxyalkyl refers to an alkyl ester of the formula -CQ2(aikyi), wherein the alkyl moiety i s as defined above.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms ("C2--8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C2--6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (" €2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2--4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (" €2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2-- alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C?), pentadienyl (C5), hexenyl ⁇ ( . ' ⁇ . ⁇ . and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.
  • each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents.
  • the alkenyl group is an unsubstituted C2-10 alkenyl.
  • the al kenyl group is a substituted C 2 - 10 alkenyl.
  • heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 - 10 alkenyl").
  • a heteroalkenyl group has 2 to 9
  • heteroalkenyi group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroCVs alkenyl"). In some embodiments, a heteroalkenyi group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -7 alkenyl").
  • a heteroalkenyi group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -6 alkenyl"). In some embodiments, a heteroalkenyi group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -5 alkenyl"). In some embodiments, a heteroalkenyi group has 2 to 4 carbon atoms, at least one double bond, and l or 2 heteroatoms within the parent chain (“heteroC 2 -4 alkenyl").
  • a heteroalkenyi group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC 2 - 3 alkenyl"). In some embodiments, a heteroalkenyi group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heterod-s alkenyl"). Unless otherwise specified, each instance of a heteroalkenyi group is independently unsubstituted (an "unsubstituted heteroalkenyi") or substituted (a "substituted heteroalkenyi") with one or more substituents. In certain embodiments, the heteroalkenyi group is an unsubstituted heteroCi-io alkenyl. In certain embodiments, the heteroalkenyi group is a substituted heteroC 2 - 10 alkenyl,
  • alkynvl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1 , 2, 3, or 4 triple bonds) ("C2-10 alkynyl").
  • an alkynyl group has 2 to 9 carbon atoms ⁇ " ( ' .: ' alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms ("C2-8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2--5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2--3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in l-butynyi).
  • Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C?), hexynyl (C&), and the like. Additional examples of alkynyi include heptvnyl (C?), octynyl (Cs), and the like.
  • each instance of an alkynyi group is independently unsubstituted (an "un substituted alkynyi") or substituted (a "substituted alkynyi") with one or more substituents.
  • the alkynyi group is an unsubstituted €2-10 alkynyi.
  • the alkynyi group is a substituted €2-10 alkynyi.
  • heteroal kynyl refers to an alkynyi group, which further includes at least one heteroatom (e.g., I , 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -io alkynyi").
  • a heteroal kynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -9 alkynyi"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -s alkynyi"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCz-? alkynyi").
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC2-6 alkynyi"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and I or 2 heteroatoms within the parent chain ("heteroC 2 -5 alkynyi"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain ("heteroC 2 -4 alkynyi").
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC 2 - 3 alkynyi"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and I or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkynyi"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC 2 - 10 alkynyi. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2 - 10 alkynyi .
  • "carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (" €3-10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl").
  • a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ⁇ "' ( ' ⁇ . ⁇ . cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (Cs) and cyclohexyl (Cs).
  • C3-6 cycloalkyl groups include the aforementioned Cs-e cycloalkyl groups as well as cyciopropyl (C3) and cyclobutyl (C 4 ).
  • C ; ⁇ cycloalkyl groups include the aforementioned C3--0 cycloalkyl groups as well as cycloheptyl (C?) and cyclooctyl (Cs).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloal kyl") with one or more substituents.
  • heterocyclyl refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur,
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyi, and thietanyi.
  • Exemplary 5-membered heterocyclyl groups containing I heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplar ⁇ ' 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
  • Exemplar ⁇ ' 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplar ⁇ ' 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyi, tetrahydropvranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocvclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplar ⁇ - 6-membered heterocvclyl groups containing 3 heteroatoms include, without limitation, triazinyl.
  • Exemplary 7-membered heterocyclyi groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8- membered heterocyclyi groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocvclyl groups include, without limitation, indolinyl, isoindoiinyl, dihydrobenzofuranyi, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyi, decahydronaphthyridinyl, decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyi, l H-benzo[
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6- 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-- I4 aryl").
  • an aryl group has 6 ring carbon atoms ("Ce aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms ("Cio aryl”; e.g., naphthyl such as 1-naphthyi and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms ("CM aryl”, e.g., anthracyl).
  • CM aryl e.g., anthracyl
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocvclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an "un substituted aryl") or substituted (a "substituted aryl") with one or more substituents.
  • the aryl group is an unsubstituted C 6 -i4 aryl.
  • the aryl group is a substituted Ce-i4 aryl .
  • “Aralkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • heteroaryi refers to a radical of a 5-14 membered monocyclic or poly cyclic (e.g., bicyclic, tricyclic) 4n 2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryi").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryi polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryi includes ring systems wherein the heteroaryi ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryi ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryi ring system.
  • Heteroaryi also includes ring systems wherein the heteroaryi ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryi ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • polycyclic heteroaryi groups wherein one ring does not contain a heteroatom e.g., indolyi, quinolinyi, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indoiyl).
  • the heteroaryi is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryi, wherein I, 2, 3, or 4 atoms in the heteroaryi ring system are independently oxygen, nitrogen, or sulfur.
  • the heteroaryi is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryi, wherein 1, 2, 3, or 4 atoms in the heteroaryi ring system are independently oxygen, nitrogen, or sulfur,
  • a heteroaryi group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryi").
  • a heteroaryi group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryi").
  • a heteroaryi group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl' '1 ).
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has I ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
  • the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrroiyl, furanyl, and thiophenyl.
  • Exemplar ⁇ ' 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyi.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolvl.
  • Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6- membered heteroaryl groups containing I heteroatom include, without limitation, pyridinyl.
  • Exemplar ⁇ - 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively,
  • Exemplar ⁇ ' 7- membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyi, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyi, isoindolyi, indazolyl, benzotriazolyi, benzothiophenyl, isobenzothiophenyi, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplar ⁇ ' 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplar ⁇ ' tricyclic heteroaryl groups include, without limitation, phenanthridinyi, dibenzofuranyl, carbazolyi, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • the term “unsaturated bond” refers to a double or triple bond.
  • the term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond,
  • saturated refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenyiene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynvl
  • carbocyclylene is the divalent moiety of carbocyclvl
  • heterocyclvlene is the divalent moiety of heterocyclyl
  • aryl ene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” aliphatic, “substituted” or “un substituted” alkyl, “substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroaliphatic, "substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, "substituted” or “unsubstituted” heteroaikynyl, "substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, "substituted” or "unsubsti
  • substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given staicture is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the invention is not intended to be limited in any manner by the exemplary substituents described herein.
  • Exemplar ⁇ ' carbon atom substituents include, but are not limited to, halogen, -CN, - () 2 , -N 3 , -SO2H, SO L -OH, -OR 33 , -ON(R bb )2, -N(R bb ) 2 , Ni !,!
  • Ci-io alkyl Ci-io perhaloaikyi, C?.-io alkenyl, C 2 -io alkynyl, heteroCi-io alkyl, heteroC 2 -io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3—14 membered heterocyclyl, Ce- i4 aiyl, and 5- 14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
  • each instance of R aa is, independently, selected from Ci-io alkyl, Ci-io perhaloaikyi, C2- 10 alkenyl, C2--10 alkynyl, heteroCi -10 alkyl, heteroC 2 - 10 alkenyl, heteroC 2 - 10 alkynyl, C3-- 10 carbocyclyl, 3- 14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R b is, independently, selected from hydrogen, -OH, -OR 33 , -
  • each instance of R dd is, independently, selected from halogen, -CN, -N0 2 , -N3, -SO2H, - SO3H, -OH, -OR ee , -ON(R ff ) 2 , -N(R ff )2, N( R X . -N(OR ee )R ff , -SH, -SR ee , -SSR ee , - - NR ff C(-0)R ee , -NR ff C0 2 R ee , 0 . -
  • each instance of R ee is, independently, selected from Ci-6 alkyl, Ci-6 perhaloalkyl, C2-6 alkenyi, C2-6 alkynyl, heteroCi-e alkyl, heteroC 2 -6alkenyl, heteroC 2 -6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyi , alkynyl, heteroalkyi, heteroaikenyl, heteroalkynyl, carbocyclyl , heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; each instance of R is, independently, selected from hydrogen, Ci-e alkyl, Ci-6 perhaloalkyl, C2-6 alkenyl, C2-0 alkynyi, heteroCi-ealkyl, heteroC 2 -6alkenyl, heteroCi-e
  • each instance of R gg is, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OCi-6 alkyl, -ON(Ci-6 alkyl) 2 , -N(Ci-6 alkyl) 2 , -N(Ci-6 alkyl)3 + X ⁇ , -NH(Ci-6 aiks i ) - X . - NH?.(Ci-6 alkyl) + X " , M h X .
  • alkyl (Ci-& alkyl), -N(OH)(Ci-6 alkyl), -NH(OH), - SI L -SCi-6 alkyl, -SS(Ci-6 alkyl), C( ( ) ⁇ (C ; ⁇ . alkyl), -CO2H, -C0 2 (Ci-6 alkyl),
  • the carbon atom substituents are independently halogen, substituted or unsubstituted Ci-e alkyl, -OR aa , ⁇ SR aa -N(R bb ) 2 , -CN, - [0082]
  • halo or "halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I),
  • -hydroxyl refers to the group -OH.
  • amino refers to the group - H 2 .
  • substituted amino by extension, refers to a rnonosubstituted amino, a disubstituted amino, or a tri substituted amino. In certain embodiments, the "substituted amino” is a rnonosubstituted amino or a disubstituted amino group.
  • tri substituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(R DD ) 3 and -N(R )3 ⁇ X ⁇ , wherein R and X ⁇ are as defined herein.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amine protecting group” or an “amino protecting group”).
  • the protecting group may be represented as "-PG”.
  • An amine group bearing a nitrogen protecting group, or two nitrogen protecting groups, may be referred to as a "protected amine.”
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W . Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fiuorenylmethyl carbamate (Fmoc), 9- (2-suifo)fluorenylmethyi carbamate, 9-(2,7-dibromo)fluoroenyir ethyl carbamate, 2,7-di-t- buty l-[9-( 10, 10-dio o- 10, 10, 10, 10-tetrahy drothioxanthy ] )]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyi carbamate (Troc), 2- trimethylsiiylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ),
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, jo-toluenesulfonamide (Ts), benzenesultonarnide, 2,3,6,-tiimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-
  • Ts jo-toluenesulfonamide
  • Mtr 2,3,6,-tiimethyl-4- methoxybenzenesulfonamide
  • Mtb 2,4,6-trimethoxybenzenesulfonamide
  • nitrogen protecting groups include, but are not limited to, phenothiazinyi-(lO)- acyl derivative, /V ' -p-toluenesulfonylaminoacyl derivative, N -phenylaminothioacyl derivative, ⁇ -benzoylphenyialanyl derivative, ⁇ -acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2- one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, A-2,5- dimethylpyrrole, N-l ,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5- triazacyclohe
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxy! protecting group").
  • the protecting group may be represented as "-PG".
  • a hydroxyl group bearing an oxygen protecting group may be referred to as a "protected hydroxyl.”
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyl oxymethyl (BOM), p - methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group”).
  • the protecting group may be represented as " ⁇ PG".
  • a thiol group bearing a sulfur protecting group may be referred to as a "protected thiol.”
  • leaving group is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile.
  • suitable leaving groups include, but are not limited to, halogen (such as F, CI, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O- dimethyihydroxylamino, pixyl, and haloformates.
  • the leaving group is a brosylate, such as />-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2- nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group.
  • the leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. In certain embodiments, the leaving group is of the formula SR ;ia . - S(0)R aa , S(0). ⁇ R ;i .
  • R aa is as defined herein.
  • Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • oxidizing agent refers to a substance that has the ability to oxidize another substance (i.e., cause the other substance to lose electrons).
  • exemplary oxidizing agents include acyl sulfoxide reagents, halides, hypervalent halide reagents, hexavalent chromium reagents, permanganate reagents, and peroxide reagents.
  • reducing agent refers to a substance that has the ability to reduce another substance (i.e., cause the other substance to gain electrons).
  • exemplary reducing agents include elemental hydrogen (e.g., in the presence of a transition metal catalyst such as palladium, platinum, rhodium, iridium or nickel), reducing metals (e.g., lithium, sodium, iron, aluminum, tin, and the like), borane reagents (e.g., diborane), metal hydride reagents (e.g., sodium borohydride, sodium triacetoxyborohydride, lithium aluminum hydride, diisobutyl aluminum hydride, and the like), and phosphorous reagents (e.g., ph ophites, phosphines such as triphenylphosphine, and the like).
  • a transition metal catalyst such as palladium, platinum, rhodium, iridium or nickel
  • reducing metals e.g.,
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et at describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1 -19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and NP(Ci-4 alkyl) 4 " salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quateraary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyiate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • composition and “formulation” are used interchangeably.
  • a "subject" to which administration is contemplated refers to a human ⁇ i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • pediatric subject e.g., infant, child, or adolescent
  • adult subject e.g., young adult, middle-aged adult, or senior adult
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, cows, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • a "patient" refers to a human subject in need of treatment of a disease.
  • the subject may also be a plant.
  • the plant is a land plant. In certain embodiments, the plant is a non-vascular land plant. In certain embodiments, the plant is a vascular land plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some embodiments, the plant produces fruit. In some embodiments, the plant is a tree or shrub.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease (e.g., a bacterial infection) described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay and/or prevent recurrence.
  • prevent refers to a prophylactic treatment of a subject who is not and was not with a disease (e.g., a bacterial infection) but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease.
  • the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population of subjects.
  • the first semisynthetic aminoglycoside came as early as 1946, when hydrogenation of streptomycin in the presence of a platinum catalyst yielded dihydrostreptomycin, a compound with equipotent antibiotic properties but greatly improved chemical stability (Figure 4). It was shown much later that the ototoxic symptoms of dihydrostreptomycin differ from those of streptomycin. By 1950, the annual production of streptomycin and dihydrostreptomycin reached almost 100 tons. Both antibiotics found widespread clinical applications and continue to be used in veterinary medicine.
  • Dibekacin was prepared in 6 steps from kanamycin B and developed by Meiji Seika in Japan ( Figure 5). Deoxygenation of the €3 ' and €4' positions overcame modifications by APH(3 ) and ANT(4 I ) enzymes, but at the same time increased the toxicity level. Dibekacin was active against resistant strains of Staphlococci and Pseudomonas and has been marketed worldwide, except in the United States, since 1975.
  • a common strategy for the generation of new aminoglycoside analogs is glyxodi versification, in which selective hydrolysis of the more labile ring III (and IV) of a naturally occurring aminoglycoside provides a neamine or paromomine derivative, which, after protection of the polar functional groups, is coupled with carbohydrate building blocks to generate a library of new aminoglycoside analogs.
  • the advantage of such an approach is that the 2-deoxystreptamine-glucosamine motif, which is important for ribosome recognition, is conserved while diversity is introduced to the substituent at the C5 ⁇ or C6-hydroxyl groups of 2- deoxystreptamine.
  • 2-hydroxyarbekacin a novel aminoglycoside antibiotic ( Figure 1 1), from 2-hydroxygentamicin.
  • 2-Hydroxygentamicin is produced by a mutant strain of M. purpurea, the producer of gentamicin. Hydrolysis of 2-hydroxygentamicin yielded 3',4'-dideoxyneamine, which was processed in 6 steps to provide a substrate for the introduction of the HABA sidechain. Subsequent glycosylation and deprotection furnished 2-hydroxyarbekacin in a total of 1 1 steps.
  • Introduction of a hydroxy! group at C2 provided a 4-fold to 64-fold improvement against MRS A clinical isolates resistant to arbekacin and led to a reduction in nephrotoxicity.
  • the present disclosure provides compounds of Formulae (I) and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopicallv labeled derivatives, and prodrugs thereof, collectively referred to as compounds of the invention.
  • rovided herein is a compound of Formula (I):
  • R.2b is halogen, hydroxyl, protected hydroxyl, amino, protected amino, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • R.3c is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • Rsd is cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group; or
  • R.3c and R 3 a together form a ring
  • R 4a is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl; or
  • R 4a and R 3c are combined to form a five or six-membered ring, or
  • R 4a and R 3 d are combined to form a five or six-membered ring;
  • R b is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl; or
  • R 4a and The are combined to form a five or six-membered ring;
  • R 4a and R 3 d are combined to form a five or six-membered ring
  • R?d is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • R9a is hydrogen, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl;
  • R9d is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • Rub is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl;
  • Ri4d is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • Rjsb is hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • Riea is hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • Riga, Risb, and Risd independently are hydrogen, halogen, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl; or two of Risa, Ri8b, and Risd are combined to form a ring.
  • any formulae described herein are also meant to include salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof.
  • the provided compound is a salt of any of the formulae described herein.
  • the provided compound is a pharmaceutically acceptable salt of any of the formulae described herein.
  • the provided compound is a solvate of any of the formulae described herein .
  • the provided compound is a hydrate of any of the formulae described herein.
  • the provided compound is a polymorph of any of the formulae described herein.
  • the provided compound is a co-crystal of any of the formulae described herein. In certain embodiments, the provided compound is a tautomer of any of the formulae described herein. In certain embodiments, the provided compound is a stereoisomer of any of the formulae described herein. In certain embodiments, the provided compound is of an isotopicallv labeled form of any of the formulae described herein. For example, compounds having the present stmctures except for the replacement of hydrogen by deuterium or tritium, replacement of i 9 F with lS F, or the replacement of a f 2 C by a 1 C or 14 C are within the scope of the disclosure. In certain embodiments, the provided compound is a deuterated form of any of the formulae or compounds described herein.
  • Rib is halogen, hydroxyl, protected hydroxyl, amino, protected amino, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, ary] or heteroaryl .
  • Ra is fluorine, chlorine, bromine or iodine.
  • Rib is hydroxyl.
  • Ri i s protected hydroxyl.
  • Rib is amino (e.g., -NH 2 , - H(alkyl) or -N(alkyl) 2 ).
  • ib is protected amino.
  • i is cyano.
  • Rib is unsubstituted aliphatic (e.g. , unsubstituted 0-6 akyl).
  • Rib is substituted aliphatic (e.g., substituted Ci-6 akyl).
  • R i s unsubstituted cyclic aliphatic (e.g. , unsubsituted C3-6 cycloakyi).
  • Rib is substituted cyclic aliphatic (e.g. , subsituted C3-6 cycloakyi).
  • Rib is unsubstituted heteroaliphatic (e.g. , unsubstituted Ci-e heteroakyl).
  • Rib is substituted heteroaliphatic (e.g. , substituted Ci-6 heteroakyl).
  • Rib is unsubstituted cyclic heteroaliphatic (e.g.
  • ib is substituted cyclic heteroaliphatic (e.g., substituted C2-0 heterocyclyl).
  • Rib is unsubstituted Ce-io aryl.
  • Rib is substituted Ce-io aryl.
  • Rib is unsubstituted C3-10 heteroaryl.
  • Rib is substituted C3- 10 heteroaryl.
  • Rib is hydroxyl.
  • Group Rsc is a group consisting of:
  • Bee is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group.
  • R 3c is hydrogen. In certain embodiments, R 3c i s a nitrogen protecting group. In certain embodiments, R.3 ⁇ 4 is unsubstituted aliphatic ⁇ e.g. , unsubstituted Ci-e akyl). In certain embodiments, R 3c i s substituted aliphatic e.g. , substituted Ci-e. akyl). In certain embodiments, R 3 c is unsubstituted cyclic aliphatic ⁇ e.g. , unsubsituted C3-6 cycloakyl). In certain embodiments, R.3c is substituted cyclic aliphatic ⁇ e.g.
  • R 3c is unsubstituted heteroaliphatic ⁇ e.g. , unsubstituted Ci-6 heteroakyl).
  • Bee is substituted heteroaliphatyl ⁇ e.g., substituted Ci-6 heteroakyl).
  • Rsc is unsubstituted cyclic heteroaliphatic ⁇ e.g. , unsubstituted C2-6 heterocyclyl).
  • R 3c is substituted cyclic heteroaliphatic (e.g. , substituted C2-0 heterocyclyl).
  • R 3c is unsubstituted Ce-io aryl .
  • R3c is substituted Ce-io aryl.
  • Bee is unsubstituted C3-10 heteroaryl.
  • R 3c is substituted €3-10 heteroaryl,
  • sc is hydrogen. In certain particular embodiments,
  • modification of R 3c is used to overcome ArmA-medidated resistance.
  • R 3 d is cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group,
  • B d is a nitrogen protecting group.
  • R3d is unsubstituted aliphatic (e.g. , unsubstituted Ci-e. akyl ).
  • R 3 d is substituted aliphatic (e.g., substituted Ci-& akyl).
  • Rsd is unsubstituted cyclic aliphatic (e.g., unsubsituted C3-6 cycloakyl).
  • R 3 d is substituted cyclic aliphatic (e.g., subsituted C3-0 cycloakyl).
  • R 3 d is unsubstituted heteroaiiphatic (e.g., unsubstituted Ci-e heteroakyl). In certain embodiments, R 3 d is substituted heteroaliphatyl (e.g., substituted Ci-e heteroakyl). In certain embodiments, RM is unsubstituted cyclic heteroaiiphatic (e.g., unsubstituted C2-6 heterocyclyi). In certain embodiments, R 3 d is substituted cyclic heteroaiiphatic (e.g., substituted C2-6 heterocyclyi). In certain embodiments, ad is unsubstituted C 6 -io aryl. In certain embodiments, R 3 d is substituted Ce-io aryl. In certain embodiments, R 3 d is unsubstituted C3-10 heteroaryl. In certain embodiments, Rsdis substituted C 3 - 10 heteroaryl.
  • R 3 d is methyl.
  • modification of R 3 d is used to overcome ArmA-medidated resistance
  • R 3 c and R 3 d are optionally combined to form a ring.
  • the ring is optionally substituted heterocyclyi (e.g., oxiranyl, butyrolactonyl, aziridinyl, azetidinyl, and the like).
  • the ring is a 3, 4, 5, 6 or 7 membered ring.
  • R3 ⁇ 4a is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaiiphatic, aryl or heteroaryl .
  • R 4A is fluorine, chlorine, bromine or iodine. In certain embodiments, R 4A is hydroxyl. In certain embodiments, R 4A is protected hydroxyl. In certain embodiments, R 4a is cyano. In certain embodiments, R 4a is unsubstituted aliphatic (e.g., unsubstituted Ci-6 akyl). In certain embodiments, R 4a is substituted aliphatic (e.g., substituted Ci- 6 akyl). In certain embodiments, R 4a is unsubstituted cyclic aliphatic (e.g., unsubsituted C3-6 cycloakyl).
  • R 4a is substituted cyclic aliphatic (e.g. , subsituted C3-6 cycloakyl). In certain embodiments, R 4a is unsubstituted heteroaliphatic (e.g. , unsubstituted Ci-e heteroakyl). In certain embodiments, R 4a is substituted heteroaliphatyl (e.g. , substituted Ci-6 heteroakyl). In certain embodiments, R 4a is unsubstituted cyclic heteroaliphatic (e.g., unsubstituted C2-6 heterocyclyl). In certain embodiments, R 4a is substituted cyclic heteroaliphatic (e.g. , substituted C2-6 heterocyclyl).
  • R 4a is unsubstituted Ce-io aryl . In certain embodiments, R 4a is substituted Ce-io aryl. In certain embodiments, R a is unsubstituted C3-10 heteroaryl. In certain embodiments, R 4a is substituted C3-10 heteroaryl.
  • R 4a is hydroxyl
  • R 4 b is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaiyl.
  • R 4 b is fluorine, chlorine, bromine or iodine. In certain embodiments, R 4 b is hydroxyl. In certain embodiments, R 4 b is protected hydroxyl. In certain embodiments, R 4 b i s cyano. In certain embodiments, R 4 b is unsubstituted aliphatic (e.g., unsubstituted Ci-6 akyl). In certain embodiments, R 4 b is substituted aliphatic (e.g. , substituted Ci- 6 akyl). In certain embodiments, R 4 b is unsubstituted cyclic aliphatic (e.g. , unsubsituted C3-6 cycloakyl).
  • R 4a is substituted cyclic aliphatic (e.g. , subsituted C3-6 cycloakyl).
  • R 4 b is unsubstituted heteroaliphatic (e.g., unsubstituted Ci-6 heteroakyl).
  • R 4 b is substituted heteroaliphatyl (e.g., substituted Ci-e heteroakyl).
  • R 4 b is unsubstituted cyclic heteroaliphatic (e.g., unsubstituted C2-6 heterocyclyl).
  • R*b is substituted cyclic heteroaliphatic (e.g. , substituted C2-6 heterocyclyl).
  • R 4 b is unsubstituted Ce-io aryl. In certain embodiments, R 4 b is substituted Ce.-io aryl. In certain embodiments, R 4 b is unsubstituted C3-10 heteroaiyl. In certain embodiments, R 4 b is substituted C3-10 heteroaiyl.
  • R 4 b is methyl .
  • R?d is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaiyl, or a nitrogen protecting group.
  • R?d is hydrogen. In certain embodiments, R?d is a nitrogen protecting group. In certain embodiments, R:?d is unsubstituted aliphatic (e.g., unsubstituted d-6 akyl). In certain embodiments, R?d i s substituted aliphatic (e.g. , substituted Ci-e akyl). In certain embodiments, R?d is unsubstituted cyclic aliphatic (e.g., unsubsituted C3-6 cycloakyl). In certain embodiments, R.?d is substituted cyclic aliphatic (e.g. , subsituted C3-6 cycloakyl).
  • R?d is unsubstituted heteroaliphatic (e.g. , unsubstituted d-6 heteroakyl). In certain embodiments, R?d is substituted heteroaliphatyl (e.g. , substituted d-6 heteroakyl). In certain embodiments, R?d is unsubstituted cyclic heteroaliphatic (e.g., unsubstituted C 2 -6 heterocyclyl). In certain embodiments, R?d is substituted cyclic heteroaliphatic (e.g., substituted C2-6 heterocyclyl). In certain embodiments, R?d is unsubstituted C6-10 aryl .
  • R-'d is substituted Ce-io aryl.
  • R?d is unsubstituted C3-10 heteroaiyl.
  • R?d is substituted C3-10 heteroaiyl .
  • R?d has the structure:
  • R 7 f is alkyl or heteroalkyl.
  • R?f is halogenated.
  • R?f is d-6 alkyl or d-6 heteroalkyl.
  • R?f is substituted.
  • R?f is unsubstituted.
  • R?d has the structure: 00151 In certain embodiments, R?d has the structure:
  • R?d has the structure:
  • R 7g and R?h are independently hydrogen, a nitrogen protecting group, cyclic or acyclic, linear or branched aliphatic (e.g. , alkyl or cycloalkyl), cyclic or acyclic, linear or branched heteroaliphatic (e.g. , heteroalkvl or heterocyclvl), arvl or heteroaryl, or R 7g and R/h are combined to form a ring.
  • R 7 and R7 are independently substituted.
  • R? g and R?h are unsubstituted.
  • R? g and R?h are unsubstituted.
  • R 7g and R?h are combined to form an optionally substituted 5- or 6-membered ring (e.g. , pyrrolidinyi, piperidinyl, morpholinyl, and the like).
  • an optionally substituted 5- or 6-membered ring e.g. , pyrrolidinyi, piperidinyl, morpholinyl, and the like.
  • R?d is hydrogen.
  • R?d has the structure:
  • R?d has the structure:
  • modification of R?d is used to overcome A T(2")-medi dated resistance and/or AAC(3)-mediated resistance.
  • ja is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, arvl, or heteroaryl.
  • l a is hydrogen.
  • R9?. is a nitrogen protecting group.
  • R.9a is unsubstituted aliphatic (e.g. , unsubstituted d-6 akyl).
  • ⁇ 1 ⁇ 2 ⁇ is substituted aliphatic (e.g. , substituted Ci-e akyl).
  • R9a is unsubstituted cyclic aliphatic (e.g. , unsubsituted C3-6 cycloakyl). In certain embodiments, R.9a is substituted cyclic aliphatic (e.g. , subsituted C3-6 cycloakyl). In certain embodiments, R9a is unsubstituted heteroaliphatic (e.g., unsubstituted Ci-6 heteroakyl). In certain embodiments, I3 ⁇ 4 a is substituted heteroaliphatyl (e.g., substituted Ci-6 heteroakyl). In certain embodiments, R a is unsubstituted cyclic heteroaliphatic (e.g., unsubsituted C3-6 cycloakyl). In certain embodiments, R.9a is substituted cyclic aliphatic (e.g. , subsituted C3-6 cycloakyl). In certain embodiments, R9a is unsubstituted heteroaliphatic
  • Rg a is substituted cyclic heteroaliphatic (e.g. , substituted C2-0 heterocyclyl).
  • Rsa is unsubstituted C0-10 aryl .
  • R.9a is substituted Ce-io aryl.
  • R3 ⁇ 4 is unsubstituted C 3 - 10 heteroaryl.
  • l3 ⁇ 4a is substituted C3-10 heteroaryl.
  • g a is an aldehyde (e.g., -CHO), a carboxylic acid (e.g., CO2H), a carboxyalkyl (e.g., -C0 2 (alkyl), or an amide (e.g., --CONH2, -CONH(alkyl) or -CON(alkyl) 2 ).
  • aldehyde e.g., -CHO
  • a carboxylic acid e.g., CO2H
  • a carboxyalkyl e.g., -C0 2 (alkyl)
  • an amide e.g., --CONH2, -CONH(alkyl) or -CON(alkyl) 2 .
  • R9a is hydroxymethyl.
  • R ⁇ : is cycloproyl.
  • R.9a is -CHO, In certain particular embodiments, R9a is -CO2CH3. In certain particular embodiments, R9a is hydrogen.
  • modification of R9a is used to overcome AAC(3)-mediated resistance.
  • R9d is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group,
  • 9d is hydrogen.
  • R9d is a nitrogen protecting group.
  • R9d is unsubstituted aliphatic (e.g. , unsubstituted C i-e akyl).
  • R9d is substituted aliphatic (e.g. , substituted Ci-e akyl).
  • R3 ⁇ 4i is unsubstituted cyclic aliphatic (e.g., unsubsituted C3-6 cycloakyl).
  • R ⁇ M is substituted cyclic aliphatic (e.g. , subsituted C3-0 cycloakyl).
  • R.9d is unsubstituted heteroaliphatic (e.g. , unsubstituted d-6 heteroakyl). In certain embodiments, 9d is substituted heteroaliphatyl (e.g. , substituted C1-0 heteroakyl). In certain embodiments, Rad is unsubstituted cyclic heteroaliphatic (e.g., unsubstituted C2-6 heterocyelyi). In certain embodiments, R.9d is substituted cyclic heteroaliphatic (e.g. , substituted C2-6 heterocyelyi). In certain embodiments, 9d is unsubstituted Ce-io aryl. In certain embodiments, R d is substituted C 6 -i 0 aryl. In certain embodiments, d is unsubstituted C io heteroaryl. In certain embodiments, R9d is substituted C3-10 heteroaryl.
  • R9d is hydrogen
  • 9 d is CI ID, -C( ))R m , -CChR 83 , -C( ))SR aa , - ⁇
  • each instance of R aa independently is as defined herein, and wherein each instance of R bb independently is as defined herein.
  • R is halogen, hvdroxyl, protected hydroxy!, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl.
  • Rub is fluorine, chlorine, bromine or iodine. In certain embodiments, Rub is hydroxyl. In certain embodiments, Rub i s protected hydroxyl . In certain embodiments, Rub is cyano. In certain embodiments, Rub is unsubstituted aliphatic (e.g. , unsubstituted Ci-& akyl). In certain embodiments, Rub is substituted aliphatic (e.g. , substituted Ci-6 akyl). In certain embodiments, Rub is unsubstituted cyclic aliphatic (e.g. , unsubsituted C3-6 cycloakyl).
  • Rub i s substituted cyclic aliphatic (e.g. , subsituted C3-6 cycloakyl).
  • Rub is unsubstituted heteroaliphatic (e.g. , unsubstituted Ci-6 heteroakyl).
  • Rub is substituted heteroaliphatic (e.g. , substituted Ci-6 heteroakyl).
  • Rub is unsubstituted cyclic heteroaliphatic (e.g., unsubstituted C2-6 heterocyelyi).
  • Ra is substituted cyclic heteroaliphatic (e.g. , substituted C2-6 heterocyelyi).
  • Rub is unsubstituted Ce-io aryl. In certain embodiments, Rub is substituted Ce-io aryl. In certain embodiments, R» is unsubstituted C3-10 heteroaryl. In certain embodiments, Rub is substituted C3-10 heteroaryl.
  • Rub is hydroxyl.
  • Ri4d is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, ary], heteroaryl, or a nitrogen protecting group.
  • Ri4d is hydrogen. In certain embodiments, Rwd is a nitrogen protecting group. In certain embodiments, R 14 d is unsubstituted aliphatic (e.g., unsubstituted Ci-e akyl). In certain embodiments, R 14 d is substituted aliphatic (e.g., substituted Ci-6 akyl). In certain embodiments, Ri4d is unsubstituted cyclic aliphatic (e.g., unsubsituted C 3 -6 cycloakyl). In certain embodiments, Rj4d is substituted cyclic aliphatic (e.g., subsituted C3-6 cycloakyl).
  • Ri d is unsubstituted heteroaliphatic (e.g., unsubstituted Ci-6 heteroakyl). In certain embodiments, Ri4d is substituted heteroaliphatyl (e.g., substituted Ci-e heteroakyl). In certain embodiments, R i . ⁇ .. ⁇ is unsubstituted cyclic heteroaliphatic (e.g., unsubstituted C2-6 heterocyclyl). In certain embodiments, R 14 d is substituted cyclic heteroaliphatic (e.g., substituted C2-6 heterocyclyl). In certain embodiments, Ri4d is unsubstituted C0-10 aryl. In certain embodiments, R 14 d is substituted Ce-io aryl. In certain embodiments, Ri4d is unsubstituted C3-10 heteroaryl. In certain embodiments, Ri4d is substituted C3-10 heteroaryl.
  • Rnd is hydrogen
  • Risb is hydrogen, halogen, hydroxy!, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, ary! or heteroaryl.
  • Ri.3 ⁇ 4 is hydrogen.
  • Risb is fluorine, chlorine, bromine or iodine.
  • Ru is hydroxy!.
  • Risb is protected hydroxyl.
  • Ri.3 ⁇ 4 is cyano.
  • Risb is unsubstituted aliphatic (e.g., unsubstituted Ci-6 akyl).
  • Risb is substituted aliphatic (e.g., substituted Ci-6 akyl).
  • Ri?b is unsubstituted cyclic aliphatic (e.g., unsubsituted C3-6 cycloakyi ). In certain embodiments, Risb i s substituted cyclic aliphatic (e.g., subsituted C3-6 cycloakyi). In certain embodiments, Risb is unsubstituted heteroaiiphatic (e.g., unsubstituted Ci-6 heteroakyl). In certain embodiments, Risb is substituted heteroaiiphatic (e.g., substituted Ci-e heteroakyl).
  • Risb is unsubstituted cyclic heteroaiiphatic (e.g., unsubstituted C2-6 heterocyclyl). In certain embodiments, Risb is substituted cyclic heteroaiiphatic (e.g., substituted C2-6 heterocyclyl). In certain embodiments, Risb is unsubstituted Ce.-io aryl. In certain embodiments, Risb is substituted Ce-io aryl. In certain embodiments, RL3 ⁇ 4 is unsubstituted C3-10 heteroaryi. In certain embodiments, Risb is substituted C3-10 heteroaryi .
  • RL3 ⁇ 4 is hydrogen
  • R 16 a is hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaiiphatic, aryl or heteroaryi.
  • Riea is hydrogen. In certain embodiments, Ri6a is fluorine, chlorine, bromine or iodine. In certain embodiments, Ri6a is hydroxyl. In certain embodiments, Ri6a is protected hydroxyl. In certain embodiments, R1 ⁇ 2a is cyano. In certain embodiments, Riea is unsubstituted aliphatic (e.g., unsubstituted Ci-e akyl). In certain embodiments, Ri6a is substituted aliphatic (e.g., substituted Ci-6 akyl). In certain embodiments, Ri6a is unsubstituted cyclic aliphatic (e.g., unsubsituted C3-6 cycloakyi).
  • Ri6a is substituted cyclic aliphatic (e.g., subsituted C3-0 cycloakyi).
  • Riea is unsubstituted heteroaiiphatic (e.g., unsubstituted Ci-6 heteroakyl).
  • Rie a is substituted heteroaiiphatic (e.g., substituted Ci-6 heteroakyl).
  • Riea is unsubstituted cyclic heteroaiiphatic (e.g., unsubstituted C2-0 heterocyclyl).
  • Riea is substituted cyclic heteroaiiphatic (e.g., substituted C2-6 heterocyclyl).
  • Ri6a is unsubstituted Ce-io aryl. In certain embodiments, Riea is substituted Ce-io aryl. In certain embodiments, Ri6a is unsubstituted C3-10 heteroaryi. In certain embodiments, Riea is substituted C3-10 heteroaryi.
  • Riea is hydrogen.
  • Riga is halogen, hydroxvl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl .
  • Riga is fluorine, chlorine, bromine or iodine.
  • Ri8a is hydroxyl.
  • Riga is protected hydroxy!.
  • Riga is cyano.
  • Ri8a i unsubstituted aliphatic (e.g., unsubstituted C i-e akyl).
  • Ri8a i s substituted aliphatic (e.g. , substituted Ci-6 akyl).
  • Risa is unsubstituted cyclic aiiphatic (e.g. , unsubsituted C3-6 cycloakyl).
  • Risa is substituted cyclic aliphatic (e.g. , subsituted C3-6 cycloaky!).
  • Riga is unsubstituted heteroaliphatic (e.g. , unsubstituted Cw heteroakyl).
  • Risa is substituted heteroaliphatic (e.g. , substituted Ci-e heteroakyl).
  • Rixa is unsubstituted cyclic heteroaliphatic (e.g., unsubstituted C2-6 heterocyclyl).
  • Riga is substituted cyclic heteroaliphatic (e.g. , substituted C2-6 heterocyclyl).
  • Risa is unsubstituted Cr io aryl. In certain embodiments, Risa is substituted Ce-io aryl. In certain embodiments, Riga is unsubstituted C3-10 heteroaryl. In certain embodiments, Risa is substituted C3-10 heteroaryl.
  • Risa is hydrogen. In certain particular embodiments, Risa is hydroxy methyl. In certain particular embodiments, Risa is -CH(OH)CH 3 hydroxyeth-l-yl (e.g., the (S) stereoisomer of -CH(OH)CH 3 or the (R) stereoisomer of - CH(OH)CH 3 ). In certain particular embodiments, Risa is -CH 2 NHCH(CH 2 ) 2 .
  • modification of Risa is used to overcome NpmA-medidated resistance and/or AAC(6')-mediated resistance.
  • Risb is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl.
  • Risb is fluorine, chlorine, bromine or iodine. In certain embodiments, Risb is hydroxyl. In certain embodiments, Risb is protected hydroxy!. In certain embodiments, Risb is cyano. In certain embodiments, Risb i s unsubstituted aliphatic (e.g. , unsubstituted Ci-& akyl). In certain embodiments, Risa is substituted aliphatic (e.g. , substituted Ci-6 akyl). In certain embodiments, Risb is unsubstituted cyclic aliphatic (e.g. , unsubsituted C3-6 cycloakyl).
  • R i substituted cyclic aliphatic (e.g. , subsituted C3-6 cycloakyl).
  • Risb is unsubstituted heteroaliphatic (e.g. , unsubstituted Ci-6 heteroakyl).
  • Risb is substituted heteroaliphatic (e.g. , substituted Ci-e heteroakyl).
  • Risb is unsubstituted cyclic heteroaliphatic (e.g., unsubstituted C2-6 heterocyclyl).
  • Risb is substituted cyclic heteroaliphatic (e.g., substituted C2-6 heterocyclyl).
  • Risb is unsubstituted Ce-io aryl. In certain embodiments, Risb is substituted Ce-io aryl . In certain embodiments, Rm is unsubstituted C3-10 heteroaryl. In certain embodiments, Ri8b is substituted C3-10 heteroaryl.
  • Risb is hydrogen. In certain particular embodiments, Risb is hydroxy methyl. In certain particular embodiments, Risb is -CH(OH)CH 3 hydroxyeth-l-yl (e.g., the (S) stereoisomer of -CH(OH)CH 3 or the (R) stereoisomer of - CH(OH)CH 3 ). In certain particular embodiments, isb is -CH2 HC (CH2)2.
  • Risd is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group,
  • Risd is hydrogen. In certain embodiments, Risd is a nitrogen protecting group. In certain embodiments, Risd is unsubstituted aliphatic (e.g. , unsubstituted Ci-6 akyl). In certain embodiments, Risd is substituted aliphatic (e.g. , substituted Ci-& akyl). In certain embodiments, Risd is unsubstituted cyclic aliphatic (e.g. , unsubsituted C3-0 cycloakyl). In certain embodiments, Risd is substituted cyclic aliphatic (e.g., subsituted C3-6 cycloakyl).
  • Ri8d is unsubstituted heteroaliphatic (e.g. , unsubstituted Ci-6 heteroakyl). In certain embodiments, Risd is substituted heteroaliphatyl (e.g., substituted Ci-6 heteroakyl). In certain embodiments, Risd is unsubstituted cyclic heteroaliphatic (e.g., unsubstituted C2-6 heterocyclyl).
  • Risd is substituted cyclic heteroaliphatic (e.g. , substituted C2-6 heterocyclyl). In certain embodiments, Risd is unsubstituted Ce-io aryl. In certain embodiments, Ri8d is substituted Ce-io aryl. In certain embodiments, Ri»d is unsubstituted C3-10 heteroaryl. In certain embodiments, Risd is substituted C3-10 heteroaryl.
  • Risd is hydrogen
  • any two of R 18a , Risb and Risd are optionally combined to form a ring.
  • Rj.8a and Ri8b are combined to form a ring.
  • R 18a and Risd are combined to form a ring.
  • Risb and Risd are combined to form a ring.
  • the ring is optionally substituted carbocyclyl (e.g., C3-10 cycloalkyl, or C3-10 cycloalkenyl, or C3-10 cycloalkynyl).
  • the ring is optionally substituted C2-10 heterocvclyl (e.g., oxiranyl, butyrolactonyl, aziridinyl, azetidinyl, and the like). In certain embodiments, the ring is a 3, 4, 5, 6, 7, 8, 9 or 10 membered ring.
  • C2-10 heterocvclyl e.g., oxiranyl, butyrolactonyl, aziridinyl, azetidinyl, and the like.
  • the ring is a 3, 4, 5, 6, 7, 8, 9 or 10 membered ring.
  • R 2 b is halogen, -OH, -G(aikyi), -OC(0)alkyl, -NH2, -NHC(0)alkyl, or heteroaryl;
  • ic is hydrogen, alkyl, cycloalkyl, heteroalkyl, or heterocyclyl
  • R d is alkyl, cycloalkyl, heteroalkyl or heterocyclyl
  • RJC and R 3 d together form a ring
  • R 4a is halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, or heteroaryl;
  • Ri is alkyl, cycloalkyl, heteroalkyl, or heterocyclyl
  • R?d is hydrogen, alkyl, cycloalkyl, heteroalkyl, or heterocyclyl
  • R9a is hydrogen, alkyl, carboxyalkyl, cycloalkyl, heteroalkyl, or heterocyclyl
  • R.9d is hydrogen, alkyl, cycloalkyl, heteroalkyl, or heterocyclyl
  • Rub is halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, or heteroaryl;
  • Ri4d is hydrogen, alkyl, cycloalkyl, heteroalkyl, or heterocyclyl
  • Risb is hydrogen, halogen, -OH, -O(alkyl), -OC(0)alkyl, - HC(0)alkyl, alkyl heteroalkyl,
  • Riea is hydrogen, halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, alkyl, heteroalkyl;
  • Risa, Risb, and Ri8d independently are hydrogen, alkyl, cycloalkyl, heteroalkyl heterocyclyl, or two of Risa, Ri8t>, and Risd are combined to form a ring,
  • the compound of Formula (I) is of Formula (II):
  • Rib, R:3 ⁇ 4, 4a, Rib, R?d, 9a, R9d, Rub, Ri4d, Risb, Riea, Risa, Risb, and isa are as defined herein.
  • the compound of Formula (II) is of Formula (II- 1):
  • the compound of Formula (II) is of Formula (II ⁇ 2):
  • R 3c i, R4b, R?d, R d, Ri4d, Ri8a, Ri8 and Ri8d are as defined herein.
  • the compound of Fonnuia (II) is of Formula (11-3):
  • the compound of Formula (II) is of Formula ( ⁇ -4):
  • R 3 d, R-4 , R?d, Rsd, Ri4d, Risb, and Ri8d are as defined herein.
  • the compound of Formula (II) is of Formula ( ⁇ -6):
  • R ⁇ d, d, Rsa, Risb, Ri6a, Ri8a, Ris and Ri8d are as defined herein.
  • the compound of Formula (I) is selected from the following compounds:
  • X is a leaving group
  • Ri5b is hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl,
  • Riea is hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • Ri8a and Risb independently are hydrogen, halogen, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl; or
  • Risa and Risb are combined to form a ring.
  • Ri5b is hydrogen, halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, alkyl, or heteroalkyl;
  • Ri6a is hydrogen, halogen, ⁇ OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, alkyl, or heteroalkyl;
  • Risa and Rssb are hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocyclyi; or
  • Ri8a and Risb are combined to form a ring.
  • X is - SPh, -S(0)Ph or -S(0) 2 Ph.
  • Fommla (I-a) is of Formulae (I-al)-(I-a4):
  • R?e is -N3 or -N(R?c)(R7d), wherein:
  • R?c is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • R?d is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group,
  • R9a is hydrogen, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl;
  • Rub is halogen, hydroxyl, protected hydroxy!, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl;
  • Ri2a is an oxygen protecting group
  • Rub and R 12a are combined to form a five or six-membered ring.
  • R? e is a radical of the formula: wherein R?f is Ci-e alkyl or C1-0 heteroalkyl.
  • R?c is hydrogen or a nitrogen protecting group
  • R?d is hydrogen or a nitrogen protecting group
  • R9a is hydrogen, alkyl, carboxyalkyl, cycloalkyl, heteroalkyl or heterocyclyl
  • Riib is halogen, protected hydroxy!, -O(alkyl), -OC(0)alkyl, ⁇ HC(0)alkyl, or heteroaryl;
  • Ri2a is an oxygen protecting group
  • Rub and R 12a are combined to form a five or six-membered ring.
  • R9a is hydrogen
  • Riib is protected hydroxyl; and Ri2a is an oxygen protecting group.
  • R9a is hydrogen
  • Riib and R 12a are combined to form a five or six-membered ring.
  • Formula (I-b) is of Formulae (I ⁇ bl)-(l-b8):
  • R?e is -N3 or -N(R?c)(R7d), wherein:
  • R?c is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • Rvd is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group;
  • Rsa is hydrogen, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl ;
  • Riib is halogen, hydroxvl, protected hvdroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl;
  • Ri2a is an oxygen protecting group
  • Riib and R 12a are combined to form a five or six-membered ring
  • Risb is hydrogen, halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, alkyl, or heteroalkyl;
  • Riea is hydrogen, halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, alkyl, heteroalkyl;
  • Risa and Risb are hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocyclyl; or
  • Risa and Rss are combined to form a ring.
  • R?e is a radical of the formula:
  • R?f is Ci- ⁇ alkyl or Ci-e heteroalkyl.
  • R ⁇ is -N3 or ⁇ ( ! ⁇ ,)(! ⁇ .: ⁇ :
  • R?c is hydrogen or a nitrogen protecting group
  • R?d is hydrogen or a nitrogen protecting group
  • R9a is hydrogen, alkyl, carboxvalkyl, cycloalkyl, heteroalkyl or heterocyclyl;
  • Rub is halogen, protected hydroxyl, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, heteroaryl;
  • Ri2a is an oxygen protecting group
  • Risb is hydrogen, halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, alkyl, heteroalkyl;
  • Ri6a is hydrogen, halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, alkyl, heteroalkyl;
  • Risa and Rssb independently are hydrogen, alkyl, cycloalkyl, or cyclic or acyclic heteroalkyl.
  • R9a is hydrogen
  • Ri2a is an oxygen protecting group
  • Risb and R 16a are hydrogen;
  • Risa and Ri8b independently are hydrogen, alkyl, or heteroalkyl. [00211] In certain embodiments Formula (I-c):
  • R-9a is hydrogen
  • Riib is protected hydroxy]
  • R 12a is an oxygen protecting group
  • R9a is hydrogen
  • Riib and R 12a are combined to form a five or six-membered ring.
  • Formula (I-c) is of Formulae (I-cl)-(I-c6):
  • X is a leaving group
  • R2 is halogen, hydroxy!, protected hydroxyl, amino, protected amino, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • Rsc is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group,
  • '3d is cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group, or
  • R a is halogen, hydroxy!, protected hydroxy!, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • R 4 b is halogen, hydroxy!, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • R 4a and R 3c are combined to form a five or six-membered ring;
  • R 3 d are combined to form a five or six-membered ring.
  • X is a leaving group
  • Ra is halogen, -OH, protected hydroxyl, -O(alkyl), -OC(0)alkyl, -TMH 2 , protected amino, -NHC(0)a!ky!, or heteroaryl;
  • R 3c is alkyl, cycioalkyl, heteroaikyi, heterocyciyl, or a nitrogen protecting group;
  • Rsd is alkyl, cycioalkyl, heteroaikyi, heterocyciyl, or a nitrogen protecting group
  • R a is halogen, -Oil protected hydroxyl, -O(alkyl), -OC(0)alkyl, alkyl, cycioalkyl heteroaikyi, or heterocyciyl;
  • i is alkyl, cycioalkyl, heteroaikyi or heterocyciyl; or
  • R4a and R 3c are combined to form a five or six-membered ring;
  • R4a and R 3 d are combined to form a five or six-membered ring
  • X is -SPh, -S(0)Ph or -S(0) 2 Ph
  • Ri is protected hydroxyl
  • R d is alkyl or benzyl
  • R 4a is protected hydroxyl; and b is alkyl .
  • a and R.3c are combined to form a five or six-membered ring; or Ua and R.3d are combined to form a five or six-membered ring.
  • Formula (I-d) is of Formulae (I-dl)-(I-d6)
  • R.2b is halogen, hydroxyl, protected hydroxyl, amino, protected amino, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • Rsc is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group,
  • '3d is cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group, or
  • R a is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • R 4 b is halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • R?e is hydrogen, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl, or a nitrogen protecting group,
  • R9a is hydrogen, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl;
  • Rub is halogen, hydroxyl, protected hydroxy!, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl, heteroaryl;
  • Ri5b is hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • Ri6a is hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl;
  • Ri8a and Risb independently are hydrogen, halogen, cyano, cyclic or acyclic, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl.
  • Ra> is halogen, -OH, protected hydroxyl, -O(alkyl), -OC(0)alkyl, -TMH 2 , protected amino, -NHC(0)alkyl, or heteroaryl;
  • R 3c is alkyl, cycioalkyl, heteroaikyi, heterocyciyl, or a nitrogen protecting group;
  • R'3d is alkyl, cycioalkyl, heteroaikyi, heterocyciyl, or a nitrogen protecting group
  • R 4a is halogen, -OH, protected hydroxyl, -O(alkyl), -OC(0)alkyl, alkyl, cycioalkyl heteroaikyi, or heterocyciyl; and P b is alkyl, cycioalkyl, heteroalkyl or heterocyclyl; or
  • R4a and R 3c are combined to form a five or six-membered ring;
  • R 4 a and R 3 d are combined to form a five or six-membered ring
  • R-/e is -N3 or ⁇ N(R7c)(R7d);
  • R?c is hydrogen or a nitrogen protecting group
  • R'?d is hydrogen or a nitrogen protecting group
  • R9a is hydrogen, alkyl, cycioalkyl, heteroalkyl or heterocyclyl,
  • Rub is halogen, protected hydroxyl, -OH, -O(alkyl), -QC(0)alkyl, -NHC(0)alkyl, heteroaryl;
  • Risb is hydrogen, halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, alkyl, heteroalkyl;
  • Ri6a is hydrogen, halogen, -OH, -O(alkyl), -OC(0)alkyl, -NHC(0)alkyl, alkyl, heteroaikvi;
  • Ri8a and Risb independently are hydrogen, alkyl, cycioalkyl, or cyclic or acyclic heteroalkyl.
  • Ra> is protected hydroxyl
  • 3d is alkyl
  • R 4 a is protected hydroxyl
  • Rtb is alkyl or benzyl
  • R a and Rsc are combined to form a five-membered ring
  • e is -N3 or -N(R7c)(R7d);
  • R?c is hydrogen or a nitrogen protecting group
  • R is hydrogen or a nitrogen protecting group
  • R9a is hydrogen
  • Risb and Rie a are hydrogen;
  • Risa and Risb independently are hydrogen, alkyl, or heteroalkyl.
  • Formula (I-e) is of Formulae (I-el)-(I-e6):
  • the method further comprises contacting the compound of Formula (I-e), or a salt thereof wherein R 18a and Risb are hydrogen, with a base and an electrophile to produce a compound of Formula (I-e), or a salt thereof, wherein one or both of Ri8a and Risb are not hydrogen.
  • R 18a and Ri8b are independently alky] .
  • the base is selected from a carbonate (e.g., sodium carbonate, potassium carbonate, and the like), a tertiary amine (e.g., trimethylamme, diisopropylethylamine, l ,8-diazabicyclo[5.4.0]undec-7-ene, and the like), a hydride (e.g., sodium hydride, potassium hydride, and the like), and an amide (lithium diisopropyl amide, sodium hexamethyidisilazide, potassium hexamethyidisilazide, and the like).
  • a carbonate e.g., sodium carbonate, potassium carbonate, and the like
  • a tertiary amine e.g., trimethylamme, diisopropylethylamine, l ,8-diazabicyclo[5.4.0]undec-7-ene, and the like
  • a hydride
  • the electrophile has the structure of R 18 a-X or Rssb-X, wherein Risa and Risb are not hydrogen, and wherein X is a leaving group as defined herein.
  • the electrophile is an aldehyde (e.g., formaldehyde), an activated carboxylic acid derivative (e.g., an acid chloride, carboxylic acid anhydride, or the like), an activated carbonate acid derivative (e.g., an alkoxy carbonyl chloride), a halogen or haiogenating agent (e.g., bromine, N-bromosuccinimide, or the like), or a Schiff base (e.g., a formal dimine).
  • an aldehyde e.g., formaldehyde
  • an activated carboxylic acid derivative e.g., an acid chloride, carboxylic acid anhydride, or the like
  • an activated carbonate acid derivative e.g., an alkoxy carbonyl chloride
  • said reducing a compound of Formula (I-e), or a salt thereof comprises:
  • the first reducing agent and the second reducing agent are the same, and the nitro group and azide groups are reduced simultaneously. In certain embodiments, the first reducing agent and the second reducing agent are different.
  • the method further comprises coupling a comp nd of Formula (I-c):
  • the suitable conditions comprise an oxidizing agent.
  • said coupling a compound of Formula (I-c), or a salt thereof, with a compound of Formula (I-d), or a salt thereof comprises:
  • R?e has a structure selected from:
  • PG is a protecting group
  • R?g and R?h are independently hydrogen, a nitrogen protecting group, cyclic or acy devis, linear or branched aliphatic, cyclic or acyclic, linear or branched heteroaliphatic, aryl or heteroaryl, or vg and R?h are combined to form a ring.
  • the suitable conditions of (a) comprise an oxidizing agent.
  • the suitable conditions of (b) comprise an oxidizing agent, hydrogenolysis, acid hydrolysis, or base hydrolysi s.
  • the method further comprises coupling a compound of Formula (I-a):
  • the suitable conditions comprise an oxidizing agent.
  • said coupling a compound of Formula (I-a), or a salt thereof, with a compound of Formula (I-b), or a salt thereof comprises: (a) coupling a compound of Formula (I-a), or a salt thereof, with a compound of Formula (I-b), or a salt thereof, under suitable conditions to produce a compound of Formula (I-c), wherein R 12a is an oxygen protecting group; and
  • the suitable conditions of (a) comprise an oxidizing agent.
  • the suitable conditions of (b) comprise hydrogenolysis, acid hydrolysis or base hydrolysis.
  • R2 , Rsc, Rsd, R.4a, R.4b, Rvd, R9a, 9d, Rub, Ri4d, Ri 5b, Ri&a, Risa, Ri»b, and i8d are as defined above, comprising:
  • step (i) comprises:
  • step (i-b) removing the oxygen protecting group under suitable conditions to produce a compound of Formula (I-c), wherein R 12a is hydrogen.
  • R? e is N(R.7c)(R7d), wherein R?c and R?d are nitrogen protecting groups, and step (ii) comprises:
  • step (ii-c) acylating the product of step (ii-b) with a compound having the formula: , wherein
  • X is a leaving group and R?f is Ci-6 alkyl or Ci-e heteroalkyl,
  • R?e has the structure:
  • R?e has the structure:
  • R 7g and R?h are as defined herein.
  • R?d is hydrogen. In certain particular embodiments, R?d has the structure:
  • the method of making Formula (I) further comprises contacting the compound of Formula (I-e), or a salt thereof wherein Riga and i8 are hydrogen, with a base and an electrophile to produce a compound of Formula (I-e), or a salt thereof, wherein one or both of Risa and Risb are not hydrogen.
  • Riga and Ri8b are independently alkyl.
  • the base is selected from carbonate (e.g., sodium carbonate, potassium carbonate, and the li ke), tertiary amine (e.g., trimethylamine, diisopropyl ethyl amine, l,8-diazabicyclo[5.4.0]undec-7-ene, and the like), hydride (e.g., sodium hydride, potassium hydride, and the like), and amide (lithium diisopropyl amide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and the like).
  • carbonate e.g., sodium carbonate, potassium carbonate, and the li ke
  • tertiary amine e.g., trimethylamine, diisopropyl ethyl amine, l,8-diazabicyclo[5.4.0]undec-7-ene, and the like
  • hydride e.g., sodium hydride
  • the electrophile has the structure of Risa-X or Ri8b-X, wherein Riga and Risb are not hydrogen, and wherein X is a leaving group as defined herein.
  • the electrophile is an aldehyde (e.g., formaldehyde), an activated carboxylic acid derivative (e.g., an acid chloride, carboxylic acid anhydride, or the like), an activated carbonate acid derivative (e.g., an alkoxy carbonyl chloride), a halogen or haiogenating agent (e.g., bromine, N-bromosuccinimide, or the li ke), or a Schiff base (e.g., a formal dimine).
  • an aldehyde e.g., formaldehyde
  • an activated carboxylic acid derivative e.g., an acid chloride, carboxylic acid anhydride, or the like
  • an activated carbonate acid derivative e.g., an alkoxy carbonyl chlor
  • step (iii) comprises reducing both the azido and nitro groups of the compound of Formula (I-e) with the same reducing agent. In certain embodiments, step (iii) comprises orthogonal reduction of the azido and nitro groups with different reducing agents.
  • step (iii) comprises:
  • (iii-d) optionally, alkylating or acylating the primary amines of (iii-c).
  • the suitable conditions of steps (i) and (i-a) independently comprise an oxidizing agent.
  • Exemplary conditions are disclosed herein, for example, in Figure 8 and Figure 21.
  • the suitable conditions of steps (ii) and (ii-a) independently comprise an oxidizing agent.
  • the suitable conditions of step (ii-b) comprises acid hydrolysis (e.g., aqueous hydrochloric acid) or hydrogenolysis (e.g., catalytic hydrogenation), or oxidation (e.g., eerie ammonium nitrate).
  • acid hydrolysis e.g., aqueous hydrochloric acid
  • hydrogenolysis e.g., catalytic hydrogenation
  • oxidation e.g., eerie ammonium nitrate
  • a method of making a compound of Formula (1- c), comprising coupling a compound of Formula (I-a) with a compound of Formula (I-b) under suitable conditions, wherein the compounds of Formulae (I-a), (I-b) and (I-e) have structures as described herein.
  • the suitable conditions comprise an oxidizing agent. Exemplary conditions are disclosed herein, for example, in Figure 18 and Figure 21.
  • a method of making a compound of Formula (I- e), comprising coupling the compound of Formula (I-c) with a compound of Formula (I-d) wherein the compounds of Formulae (I ⁇ d) and ( ⁇ - ⁇ ) have structures as described herein.
  • the suitable conditions comprise an oxidizing agent. Exemplar ⁇ ' conditions are disclosed herein, for example, in Figure 18 and Figure 21 ,
  • compositions comprising an aminoglycoside compound as described herein (e.g., a compound of Formulae (I), (II), (II-l), ( ⁇ -2), ( ⁇ -3), ( ⁇ -4), ( ⁇ -5), ( ⁇ -6), FSA-38240, FSA-38252, FSA-382SS, FSA-392S4
  • an aminoglycoside compound as described herein (e.g., a compound of Formulae (I), (II), (II-l), ( ⁇ -2), ( ⁇ -3), ( ⁇ -4), ( ⁇ -5), ( ⁇ -6), FSA-38240, FSA-38252, FSA-382SS, FSA-392S4
  • compositions agents include any and all solvents, diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • General considerations in formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the aminoglycoside of the present invention into association with a carrier and/or one or more other accessor ⁇ ' ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, ami/or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the aminoglycoside of the present invention.
  • the amount of the aminoglycoside is generally equal to the dosage of the aminoglycoside which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the aminoglycoside, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) aminoglycoside.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, soiubilizing agents, and emulsifiers, and mixtures thereof.
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with soiubilizing agents, and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the aminoglycoside is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or di calcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitoi, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Dosage forms for topical and/or transdermal administration of an aminoglycoside of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the aminoglycoside is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • Aminoglycosides provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily amount of the aminoglycoside will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific aminoglycoside employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject, the time of administration, route of administration, and rate of excretion of the specific aminoglycoside employed; the duration of the treatment; drugs used in combination or coincidental with the specific aminoglycoside employed; and like factors well known in the medical arts.
  • aminoglycosides and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation, and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • Oral administration is the preferred mode of administration.
  • the subject may not be in a condition to tolerate oral administration, and thus intravenous, intramuscular, and/or rectal administration are also preferred altermative modes of administration.
  • An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses).
  • a single dose e.g., single oral dose
  • multiple doses e.g., multiple oral doses
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 g and 1 ug, between 0.001 nig and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1 ,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
  • an aminoglycoside or composition can be administered in combination with one or more additional therapeutically active agents.
  • the aminoglycoside or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive aminoglycoside with the additional therapeutical ly active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • Exemplary additional therapeutically active agents include, but are not limited to, antibiotics, anti-viral agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal anti-inflammatory agents, antihistamine, immunosuppressant agents, antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, and prostaglandins.
  • Therapeutical ly active agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucieoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • drug compounds e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • the additional therapeutically active agent is an antibiotic.
  • antibiotics include, but are not limited to, penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), macrolides (e.g., erythromycin, clarithormycin, azithromycin, troieandomycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g., co-trimoxazole, trimethoprim), tetracyclines (e.g., tetracycline, chlortetracyciine, oxytetracycline, demeclocycline, methacycline, sancycline, doxycline, aureomycin, terramycin, minocycline, 6-deoxytetracycline, iymecycline, meclocycline, meclocycline, meclocycline, me
  • kits e.g., pharmaceutical packs
  • the kits provided may comprise an inventive pharmaceutical composition or aminoglycoside and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or aminoglycoside.
  • the inventive pharmaceutical composition or aminoglycoside provided in the container and the second container are combined to form one unit dosage form.
  • kits e.g., pharmaceutical packs
  • the kits provided may comprise an inventive pharmaceutical composition or aminoglycoside and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or aminoglycoside.
  • the inventive kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or aminoglycoside.
  • compositions or aminoglycoside provided in the container and the second container are combined to form one unit dosage form.
  • the bacterial ribosome is composed of ribosomal RNA (rRNA) and proteins, which are organized into two subu its, the 30S and the 50S ( Figure 34). There are three sites on the ribosome that allow tRNA binding: the A site, P site, and E site. Prior to the formation of a peptide bond, an aminoacyl-tRNA, which carries the correct amino acid for the codon displayed by the mRNA, is selected by the A site. The P site is bound to the peptidyi-tRNA, which carries the nascent peptide. The E site houses uncharged tRNA, which is subject to ejection from the ribosome.
  • rRNA ribosomal RNA
  • the process of protein synthesis can be divided into four phases: initiation, elongation, termination, and recycling ( Figure 34),
  • the 2-deoxystreptamine class of aminoglycosides (for example, compounds of Formula (I)), exert their antibacterial action by binding to the bacterial ribosome, which affects protein synthesis in multiple stages.
  • AMEs Aminoglycoside Modifying Enzymes
  • AMEs aminoglycoside modifying enzymes
  • AMEs can occur alone or in combination in both Gram-positive and Gram- negative pathogens, and exhibit a high level of substrate promiscuity.
  • Most are encoded on mobile elements such as plasmids, transposons, and integrons, which facilitate rapid dissemination of resistance.
  • AAC aminoglycoside JV-acetyltransf erase
  • APH aminoglycoside ⁇ -phosphotransferase
  • ANT aminoglycoside ⁇ -nucleotidyltransferase or O-adenyltransferase
  • AAC(6')-Ia and AAC(6')-Ib both acetylate the 6 -amino group of aminoglycosides and have identical resistance profiles. But they are two unique proteins encoded by two different genes.
  • RMTs rRNA methyltransferases
  • This class of RMTs is related to ones found in the gentamicin producing-producing strain Micromonospora purpurea, and methylates the N7 position of G1405, which is located in close proximity to the 3 "-amino group on ring III of 4,6-disubstituted aminoglycosides. Methylation results in the introduction of a positive charge on the nucleotide and, together with increased steric bulk, disfavors aminoglycoside binding and confers high-level resistance to all 4,6-disubstituted 2-deoxystreptamine aminoglycosides.
  • NmpA A second class of RMT, NmpA, was found in a clinical isolate of E. coli in Japan in 2007, which methylates Nl of AMOS, Strains carrying the nmpA gene exhibited resistance to all aminoglycosides, including the 4, 5 -di substituted aminoglycoside neomycin and the atypical aminoglycoside apramycin.
  • Efflux Pumps and Change in Membrane Permeability Resistance to aminoglycosides in P, aeruginosa is associated with changes to the outer membrane lipopolysaccharides. Structural changes to the outer membrane composition is partly regulated by the two-component regulatory system, PhoP-PhoQ, which reduces permeability of the outer membrane to aminoglycosides under Mg 2 ⁇ starvation or in the presence of polyamines. Additionally, both mutations to the electron-transport chain and nitric oxide-mediated repression of respiratory activity result in inhibition of the energy-dependent phase of aminoglycoside uptake. This attenuates the threshold buildup of aminoglycosides that is necessary for cell death and confers antibiotic resistance.
  • aminoglycoside efflux systems are named AcrAD-TolC in E. coli, AdeAB-AdeC in A. baumannii, and MexXY-OprM in P. aeruginosa. They are distinct from RND pumps used for the active export of other classes of antibiotics, which have hydrophobic binding pockets that make aminoglycosides poor substrates. Overexpression of efflux pumps, often induced by exposure to aminoglycosides, are well correlated with multidrug resistance in clinical isolates.
  • the resistance mechanisms outlined above can occur alone or in combination. Because of difference in usage pattern, the frequency of resistance mechanisms also differs depending on geographical location. Each pathogenic strain of bacteria expresses different levels of resistance, with pan-resistance observed in some species that cany clusters of resistance genes. The occurrence of aminoglycoside resistance mechanism in ESKAPE pathogens is shown in the following table:
  • the present disclosure contemplates the use of the aminoglycosides as described herein as antibacterial agents.
  • a method of treating a bacterial infection comprising administering an effective amount of an aminoglycoside of the present invention (e.g., a compound of Formulae (1), (II), (H-l), (0-2), (II-3), (0-4), (H-5), (II-6), FSA-38240, FSA-38252, FSA-38255, FSA-39254 (compound 1), or a pharmaceutically acceptable salt thereof) to a subject in need thereof.
  • an aminoglycoside of the present invention e.g., a compound of Formulae (1), (II), (H-l), (0-2), (II-3), (0-4), (H-5), (II-6), FSA-38240, FSA-38252, FSA-38255, FSA-39254 (compound 1), or a pharmaceutically acceptable salt thereof
  • Such a method can be conducted in vivo (i.e., by administration to a subject) or in vitro (e.g. , upon contact with the pathogen, biological sample,
  • the effective amount is a therapeutically effective amount.
  • administering an effective amount of an aminoglycoside kills or stops the growth of the bacteria.
  • administering an effective amount of an aminoglycoside slows the progress of a bacterial infection in the subject.
  • administering an effective amount of an aminoglycoside improves the condition of the subject suffering from a bacterial infection.
  • the subject has a suspected or confirmed bacterial infection.
  • the effective amount is a prophylatically effective amount.
  • the method prevents or reduces the likelihood of a bacterial infection, e.g., in certain embodiments, the method comprises administering an aminoglycoside of the present invention to a subject in need thereof in an amount sufficient to prevent or reduce the likelihood of a bacterial infection.
  • the subject is at risk of a bacterial infection (e.g. , has been exposed to another subject who has a suspected or confirmed bacterial infection or has been exposed or thought to be exposed to a bacterium).
  • a method of inhibiting bacterial growth comprising contacting an effective amount of the aminoglycoside of the present invention with a bacterium.
  • the method is in vitro. In certain embodiments, the method is in vivo.
  • bacterial infection refers to an infection with a bacterium, such as a gram-negative or a gram-positive bacterium.
  • the bacterial infection is caused by a bacterium resistant to other treatments.
  • the bacterial infection is caused by a bacterium that is multi-drag tolerant or resistant, e.g., the bacterial infection is caused by a bacterium that neither grows nor dies in the presence of or as a result of other treatments.
  • the aminoglycoside of the present invention has a mean inhibitory concentration (MIC), with respect to a particular bacteria, of less than 50 ⁇ ,, less than 25 ⁇ g/mL, less than 20 ⁇ ⁇ , less than 10 ,ug/mL, less than 5 ug/mL, or less than 1 ⁇ ig/mL.
  • MIC mean inhibitory concentration
  • the bacteria is susceptible (e.g., responds to) or resistant to known commercial aminoglycosides, such as plazomicin, kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycins B, C, and E, streptomycin, and the like.
  • the bactera is resistant to a known aminoglycoside.
  • the bacterial infection is resistant to other antibiotics therapy.
  • the bacteria is vancomycin resistant (VR).
  • the bacteria is methicillin-resistant (MR), e.g., in certain embodiments, the bacterial infection is a methicillin-resistant S. aureus infection (a MRS A infection).
  • the bacteria is quinolone resistant (QR).
  • the pathogen is fluoroquinolone resistant (FR)
  • the bacteria is selected from Enterococcus faecium, Staphlococcus aureus, Klebsiella pneumonia, Acinetohacter haumannu, Pseudomonas aeruginosa, and Enter obacteria.
  • the bacteria has an efflux ⁇ e.g., mef, msr) genotype. In certain embodiments, the bacteria has a methylase ⁇ e.g., erm) genotype. In a particular embodiment, the bacteria has an ArmA genotype. In a particular embodiment, the bacterial infection is associated with bacteria expressing ribosomal methylase ArmA, In certain embodiments, the bacteria has a constitutive genotype. In certain embodiments, the bacteria has an inducible genotype.
  • Exemplary bacterial infections include, but are not limited to, infections with a Gram positive bacteria ⁇ e.g., of the phylum Actinobacteria, phylum Firmicutes, or phylum Tenericutes); Gram negative bacteria ⁇ e.g., of the phylum Aquifieae, phylum Deinococcus- Thermus, phylum Fibrobacteres/Chlorobi/Bacteroidetes (FCB), phyium Fusobacteria, phyium Gemraatimonadest, phylum Ntrospirae, phylum Planctomycetes/Verrucomicrobia/Chlamydiae (PVC), phylum Proteobacteria, phylum Spirochaetes, or phylum Synergistetes); or other bacteria ⁇ e.g., of the phyium Acidobacteria, phylum Chlroflexi, phylum Chrystiogenetes, phylum Cy
  • the bacterial infection is an infection with a Gram positive bacteria.
  • the Gram positive bacteria is a bacteria of the phylum Firmicutes,
  • the bacteria is a member of the phylum Firmicutes and the genus Enterococcus, i.e., the bacterial infection is an Enterococcus infection.
  • Exemplary Enter ococci bacteria include, but are not limited to, E. avium, E. durans, E. fa.eca.lis, E. faecium, E. gallinarum, E. solitarius, / ⁇ instruct ' . casseliflavus, and /. ' . raffmosus.
  • the bacteria is a member of the phylum Firmicutes and the genus Staphylococcus, i.e., the bacterial infection is a Staphylococcus infection.
  • Exemplary Staphylococci bacteria include, but are not limited to, . arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devriesei, S. epidermis, S. equorum, S. felis, S. fluroettii, S.
  • gallinarum. S. haemolyticus, S. hominis, S. hyicus, S. intermedins, S. kloosii, S. leei, S. lenus, S. lugdunesis, S. lutrae, S. lyticcms, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S. pentlenkoferi, S. piscifermentans, S. psuedointermedius, S. psudolugdensis, S. pulvereri, S. rosiri, S. saccharolyticus, S. saprophytics, S.
  • the Siaphylococcus infection is an S. aureus infection.
  • the S. aureus has an efflux (e.g., mef, msr) genotype.
  • the S. aureus has a methylase (e.g., erm) genotype.
  • the bacteria is a member of the phylum Firmicutes and the genus Bacillus, i.e., the bacterial infection is a Bacillus infection.
  • Bacillus bacteria include, but are not limited to, B. alcalophilus, B. alvei, B. aminovorans, B. amyloliquefaciens, B. aneurinolyticus, B. anihracis, B. aquaemaris, B. atrophaeus, B. horoniphilus, B. brevis, B. caldolyticus, B. cenirosporus, B. cereus, B. circulans, B. coagulans, B. firmus, B. flavothermus, B.
  • fusiformis B. glohigii, B. infernus, B. larvae, B. laterosporus, B. lentiis, B. licheniformis, B. megaterium, B. mesentericus, B. mucilaginosus, B. mycoides, B. natto, B. pantothenticus, B. polymyxa, B. pseudoanihracis, B. pumilus, B. schlegelii, B. sphaericus, B. sporothermodurans, B. stearothermophilus, B. suhtilis, B. thermoglucosidasius, B. thuringiensis, B. vulgatis, and B.
  • the Bacillus infection is a B. subtilis infection.
  • the B. subtilis has an efflux (e.g., mef, msr) genotype.
  • the B. subtilis has a methylase (e.g., erm) genotype.
  • the bacteria is a member of the phylum Firmicutes and the genus Streptococcus, i.e., the bacterial infection is a Strepococctis infection.
  • exemplary Streptococcus bacteria include, but are not limited to, S. agalactiae, S. anginosus, S. bovis, S. can is, S. constellatus, S. dysgalactiae , S. equinus, S. iniae, S. intermedins, S. mitis, S. mutans, S. oralis, S. parasanguinis, S. per or is, S. pneumoniae, S. pyogenes, S.
  • the Strepococcus infection is an S. pyogenes infection. In certain embodiments, the Strepococcus infection is an .V. pneumoniae infection. In certain embodiments, the S. pneumoniae has an efflux (e.g., mef, msr) genotype. In certain embodiments, the S. pneumoniae has a methylase (e.g. , erm) genotype.
  • the bacterial infection is an infection with a Gram negative bacteria.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Escherichia, i.e., the bacterial infection is an Escherichia infection.
  • Exemplary Escherichia bacteria include, but are not limited to, E. alhertii, E. blattae, E. coli, E. fergusonii, E. hermannii, and E. vulneris.
  • the Escherichia infection is an E. coli infection.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Haemophilus, i.e., the bacterial infection is an Haemophilus infection.
  • Exemplary Haemophilus bacteria include, but are not limited to, H. aegyptius, H. aphrophilus, H. avium, //. ducreyi, //. felis, //. haemoiyticus, H. influenzae, H. parainfluenzae, H. paracuniculus, H. parahaemolyticus, H. pittmaniae, Haemophilus segnis, and / . so nus.
  • the Haemophilus infection is an //, influenzae infection.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Acinetobacter .
  • the bacterial infection is an Acinetobacter infection.
  • Exemplary Acinetobacter bacteria include, but are not limited to, A. haurnanii, A. haemoiyticus, and A. Iwoffii.
  • the Acinetobacter infection is an A. haurnanii infection.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Klebsiella, i.e., the bacterial infection is a Klebsiella infection.
  • Exemplar ⁇ - Klebsiella bacteria include, but are not limited to, K granulomatis, K, oxytoca, K. michiganensis, K. pneumoniae, K. quasi pneumoniae, and K. variicola.
  • the Klebsiella infection is a K. pneumoniae infection.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Pseudomonas. i.e., the bacterial infection is a Pseudomonas infection.
  • Exemplary Pseudomonas bacteria include, but are not limited to, P. aeruginosa, P. oryzihabitans, P. plecoglissicida, P. syringae, P. putida, and P. fluoroscen .
  • the Pseudomonas infection is a P. aeruginosa infection.
  • the bacteria is an atypical bacteria, i.e., are neither Gram positive nor Gram negative.
  • TLC plates were visualized by exposure to ultraviolet light, then were stained with an aqueous sulfuric acid solution of eerie ammonium molybdate (CAM), or an aqueous sodium carbonate solution of potassium permanganate ( Mn0 4 ), then briefly heated on a hot plate. Flash-column chromatography was performed as described by Still et ai., employing silica gel (60 A, 32-63 uM, standard grade, Dynamic Adsorbents, Inc.).
  • Dry solvents were purchased from the Aldrich Chemical Company in Sure/SealTM glass bottles and used without purification. All reagents were purchased and used without purification with the following exceptions: benzaldehyde, 3-methyl-2-butenal, trimethylsilyi chloride, trifluoromethanesulfonic anhydride, and trimethylsilyi trifluoromethanesulfonate were distilled under an atmosphere of argon. Benzyl bromide and methyl iodide were filtered neat through a column of oven-dried basic alumina immediately prior to use.
  • Proton magnetic resonance ( ! H NMR) spectra were recorded on Varian INOVA 500 (500 MHz) or 600 (600 MHz) NMR spectrometers at 23 °C.
  • the first glycosylation reaction forges the C4-C1' bond and affords the glycoside 140 in 43% yield.
  • Alternative conditions are shown in Figure 19.
  • the p-methoxybenzyl groups on the CI amine are then cleaved (CAN), and the resulting primary amine is coupled with the activated 4-amino-2- hydroxybutanoic acid (HABA) sidechain 5 to provide the glycoside 141 in 62% yield over two steps.
  • Unveiling the diol functional group in 141 (TFA, 83%) gives the glycosyl acceptor 139, which undergoes the second convergent coupling with the glycosyl donor 2 (a garosamine derivative) to furnish the fully protected aminoglycoside 138 in 37% yield.
  • a one-step hydrogenolytic deprotection in the presence of palladium hydroxide affords a fully synthetic aminoglycoside (1) in a total of six steps.
  • the gentamicin derivative FSA- 38252 is obtained in two steps from the diol 151, while deprotection of 149 provides gentamicin Cia (FSA-38219).
  • the synthesis of gentamicin C la proceeds in five steps and 16% yield from 3 and 118,
  • the structures of the three synthetic derivatives prepared herein deviate from the gentamicin Cia scaffold by the hydroxymethyl groups at the C6' position, which would be difficult to access via semisynthetic modifications of gentamicin itself.
  • Garosamme Compounds 2 and 50 Garosamine is an amino sugar that is biosynthetically derived from xylose ( Figure 3). It is a component of the gentamicin and sisomicin classes of aminoglycosides ( Figure 22), and its unique C- and N-methylation patterns improve the antibiotic activities of gentamicin and sisomicin, relative to kanamycin, against bacteria carrying aminoglycoside modifying enzymes (AMEs). Compared to ring I of the aminoglycosides, few medicinal chemical modifications have been made to the garosamine subunit (ring III).
  • the recently identified ribosome methyltransferase, ArmA selectively inactivates 4,6-disubsituted aminoglycosides by methylation of the N7 amine of G1405, which introduces steric and electronic repulsions with the garosamine sugar.
  • the efficient synthesis of garosamine described herein allows systematic investigations of the carbohydrate scaffold. Intermediates in the synthesis are amenable to late-stage diversification, particularly at the C3" ⁇ amino group, providing access to compounds capable of overcoming resistance to bacteria expressing ArmA, among other resistance phenotypes.
  • the protecting groups in 47 (Boc, acetonide, and the JV,O-acetal) are cleaved by heating in a solution of hydrochloric acid. Subsequent transformation to the phenyl thiogiycoside 48 proceeds in 77% yield over two steps.
  • the thiogiycoside 48 serves as a branching point for the syntheses of glycosyl donors 2 and 50.
  • the alternative glycosyl donor 50 is prepared by first treatment of 48 with phosgene (79%), followed by methylation of the carbamate in 86% yield (Mel, NaH).
  • the route to 2 and 50 proceeds in a total of seven steps, which is shorter and higher yielding than all previous syntheses of garosamine derivatives.
  • all prior syntheses of activated garosamine derivatives use carbohydrates as starting materials, which inherently limit the positions available for modification and do not offer any distinct advantage over semi synthesis.
  • the present approach allows flexible access to the entire scaffold of 2.
  • late-stage modifications of the C3 "-amino group provides access to analogs with activity against bacteria expressing the ribosomal methylase ArmA, which confers pan-resi stance to all aminoglycosides, including the next-generation aminoglycoside, plazomicin, by introducing steric and/or electrostatic repulsion near the C3 " amine binding site.
  • the aldehyde 7 can be obtained by the condensation of (l S,2R) ⁇ (+)-norephedrine with 3-methyl-2-butenal followed by treatment of the resulting imine (without purification) with di-tert-butyl di carbonate (92%). The olefin is then cleaved through ozonolysis to provide the norephedrine oxazoiine 7 in 76%> yield.
  • the coupling of 6 and 7 represents the first example of a diastereoselective intermolecular nitroaldol reaction using norephedrine as the auxiliary.
  • Purpurosamine Compound 3 Purpurosamines A-C are the ring-I amino sugars in gentamicin C complex, a clinically important antibiotic ( Figure 26). They are present in gentamicins Ci, i, and Cia, respectively, and differ in the methylation patterns at the C6' position and C6'-amino group (aminoglycoside numbering). As a part of a conserved 2- deoxystreptamine-glucosamine motif in aminoglycoside natural products, purpurosamine plays a key role in the recognition and binding of gentamicin to the bacterial ribosome.
  • ring I glucosamine components
  • APH(3') and ANT(4') enzymes which inactivate aminoglycosides by phosphorylation and adenylation of the C3' ⁇ and C4'-hydroxyl groups, has rendered aminoglycoside antibiotics such as kanamycin clinically obsolete.
  • Gentamicin is the most commonly prescribed aminoglycoside due to its inherent immunity to the actions of these two prevalent resistance mechanisms.
  • the building block azido aldehyde 24 is obtained in three steps from D-glutamic acid.
  • glutamic acid is converted to its dimethyl ester (TMSC1 in methanol), which is transformed to the azide 87 in 86% yield by the treatment of trifluoromethanesulfonyl azide.
  • TMSC1 dimethyl ester
  • DIBAL-FI less hindered methyl ester
  • Diastereoselectivity of the nitroaldol addition to set the C5' stereocenter is achieved through the use of the chirai diamine ligand 86.
  • Partial reduction of the methyl ester in 81 (D1BAL-H), followed by spontaneous intramolecular cyclization leads to the formation of the nitropurpurosamine derivative 80 in 88% yield.
  • the anomeric position of 80 was then activated by transformation to the corresponding phenyl thioglycoside 3, which is isolated in 94% yield.
  • the disclosed synthetic approach allows opportunities for modifications of the entire scaffold of component 3, i.e., through alkylations of the intermediate 87 at the C3' and C4' positions.
  • 2-Deoxystreptamine Compound 4 and Differentially Protected 2-Deoxystreptamines 2-Deoxystreptamine is a conserved structural motif in the 4,5- and 4,6-disubstituted aminoglycoside antibiotics ( Figure 28). Together with the ring I hexose, 2-deoxystreptamine engages in key stabilizing interactions with the RNA bases in the bacterial ribosome. Because of its relevance in ribosome recognition, minor perturbations to the 2-deoxystreptamine structure have been shown to greatly influence both the antibiotic property and the safety profile of the resulting analogs. [00330] Several resistance mechanisms target polar functional groups on 2- deoxystreptamine for enzymatic modification.
  • AAC(3) enzymes a family of aminoglycoside acetyltransferases, the AAC(3) enzymes, are widely found in Gram-negative bacteria, and inactivate all aminoglycosides currently in clinical use by acylating the C3 -amino group.
  • the most recently approved next-generation aminoglycoside, plazomicin, has only limited activity (MIC 8 ⁇ ig/niL) against P. aeruginosa carrying the aac(3) gene. Because the C3 amine plays an important role in the binding of aminoglycosides to the ribosome, attempts to overcome the action of the AAC(3) enzyme by derivatization of the C3 amine through semisynthesis have resulted in complete loss of antibiotic activity.
  • Compound 4 an orthogonally protected 2-deoxystreptamine, is a conserved structural motif in all clinically relevant aminoglycoside antibiotics.
  • the primary source of 2-deoxystreptamine for synthetic and biological studies is the degradation of naturally occurring aminoglycosides to give /Me.so-2-deoxystreptamine, which is enantiomerically enriched through enzymatic resolution.
  • the fully synthetic approach is depicted in Figure 29 and begins with the protected dimethyl tartrate 8. Desymmetrization of 8 is achieved by its convergent coupling with the lithiated ethyl vinyl ether (9) to give the vinyl ketone 121 in 73% yield.
  • the hvdroxyester 122 is obtained by Luche reduction of 122, which installs the C4 stereocenter in 60% yield and >20: 1 diastereoselectivity. Mitsunobu inversion of the C4 hydroxyl group proceeds in 78% yield with benzoic acid as the nucleophiie to afford the allylic benzoate 126.
  • Partial reduction of the methyl ester in 126 and cleavage of the benzoate ester occurs in one pot (DIBAL-H) and the resulting crude hydroxyaldehyde is treated with bis(p-methoxybenzyl)amine and ytterbium trifluoromethanesulfonate to provide the all trans-6,6-bicycie 119 (35%) as a single diastereomer.
  • the diethyl ketal 127 and the mixed benzyl ethyl ketal 128 are also isolated in 10% and 9% yield, respectively, which can be hvdrolyzed with hydrochloric acid in acetone to afford the amino ketone 119 in 68% yield.
  • the reduction-Mannich cyclization sequence from 126 provides the ketone 119 in two steps and 48% yield.
  • the C3 amine can be installed in a three-step sequence in 58% overall yield: Formation of the methyl oxime of 119, which is reduced in a mixture of lithium aluminum hydride and sodium methoxide (5: 1 dr), followed by transformation of the amine 36 to the corresponding azide 4.
  • the synthesis of component 4 described here is the shortest and most efficient synthesis of an orthogonally protected 2-deoxystreptamine.
  • a notable feature of the disclosed synthesis is the differentiation of the CI and the C3 amino groups, which allows regioselective introduction of the HABA sidechain at any stage of the disclosed synthetic route, a significant advantage over all prior syntheses of aminoglycoside antibiotics.
  • a two-step deprotection sequence which involved first hydrogenation of 149 followed by hydrolysis of the intermediate carbamate, completed the component-based approach to gentamicin Cia (FSA-38219).
  • the synthesis of gentamicin Cia proceeded in five steps and 16% yield from the glycosyl donor 3 and the semisynthetic glycosyl acceptor 118.
  • the gentamicin derivative FSA-38252 was obtained in two steps from the diol 151.
  • the structures of the three synthetic derivatives prepared herein deviate from the gentamicin Cia scaffold by the hydroxymethyl groups at the C6' position, which would be difficult to access via semisynthetic modifications of gentamicin itself.
  • ethyl pyruvate (70.0 mL, 627 mmol, I equiv) was added dropwise via a dropping funnel over 30 min while maintaining the internal temperature below -18 °C.
  • the addition was quantitated with dichloromethane (27.0 mL).
  • the resulting solution was stirred at -20 °C. After 2 h, white precipitate appeared.
  • the resulting heterogeneous mixture was stirred at -20 °C for an additional 12 h, at which point the reaction had become homogeneous and analysis by thin-layer chromatography indicated full consumption of the ethyl pyruvate starting material.
  • O2NCH2CCH3 1.42 (s, 3H, ⁇ ⁇ , 1.40 (s, 3H, OCiC ' f ! ; ⁇ ,: ⁇ .
  • the bright yellow solution was poured into a mixture of ethyl ether (300 mL) and half saturated aqueous sodium chloride solution (300 mL). The layers were separated and the aqueous layer was extracted with ethyl ether (3 x 200 mL). The organic layers were combined. The combined solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to give a pale yellow oil.
  • the crude product was purified by flash-column chromatography (5% ethyl ether-hexanes initially, grading to 40% ethyl ether-hexanes) to give norephedrine oxazoline aldehyde 7 as a clear and colorless oil (3.98 g, 76%, 90% purity).
  • the aldehyde 7 was used in the subsequent coupling reaction without further purification.
  • Nitroacetonide 6 (1.20 g, 6.83 mmol, 1 equiv) and norephedrine oxazoline aldehyde 7 (3.98 g, 13.7 mmol 2.00 equiv) were dissolved in tetrahydrofuran (68.3 mL). The resulting solution was cooled to -20 °C. A solution of potassium ter -butoxide in tetrahydrofuran (1.0 M, 0.410 mL, 0.410 mmol, 0.06 equiv) was added dropwise by syringe. The resulting solution was stirred at - 20 °C for 30 min.
  • aqueous hydrogen chloride (2.00 M, 7,50 mL, 15.0 mmol, 7.0 equiv) was added to a solution of 42 (1.00 g, 2, 14 mmol, 1 equiv) in a mixture of dioxane (20.0 mL) and water (12.5 mL) at 23 °C.
  • the flask was then immersed in an oil bath preheated to 55 °C, After 15 h, the heating bath was removed and the solution was allowed to cool to 23 °C. The cooled solution was concentrated under reduced pressure.
  • the residue was purified by flash- column chromatography on silica gel (30% ethyl acetate-hexanes initially, then grading to 80% ethyl acetate-hexanes) to provide phenyl thioglycoside ⁇ -49 (189 mg, 54%) and a-49 (89.0 mg, 25%>) as white solids.
  • aminoalcohol 48 (53.9 mg, 0.156 mmol, 1 equiv) and acetic acid (89 ⁇ ]_, 1.56 mmol, 10.0 equiv) in dichloromethane (3 ,47 raL) and methanol (433 fiL) at 23 °C.
  • Sodium cyanoborohydride (32.4 mg, 0.515 mmol, 3.30 equiv) was then added in one portion.
  • the resulting solution was stirred for 1 h at 23 °C, at which point thin-layer chromatographic analysis indicated complete consumption of the starting aminoalcohol 48.
  • a solution of formaldehyde in water (37 wt%, 58.1 ⁇ , 0.780 mmol, 5,00 equiv) was then added, followed by another portion of sodium
  • 13 C MR (125 MHz, CDCb), ⁇ : 153.1, 140.5, 138.3, 135.4, 134.2, 131.2, 128.9, 128.8, 128.5, 128.3, 128,3, 128, 1, 128.0, 128.90, 127.7, 127,2, 126.7, 90.6, 86.1, 75.6, 73.5, 72.4, 70.9, 68.8, 18.4.
  • 13 C signals corresponding to NCHVPh and NCH3 were not visible due to broadening.
  • the crude reaction mixture was purified by flash-column chromatography on silica gel (10% ethyl acetate- hexanes initially, then grading to 30% ethyl acetate-hexanes) to afford the nitroglycoside 80 as a white solid (2:1 ratio of ⁇ : ⁇ anomers, 1.29 g, 88%).
  • purpurosamiiie phenyl thioglycosyl donor 3 as a colorless oil (2,5 : 1 ratio of ⁇ : ⁇ anomers, 1 .72 g, 94%).
  • the anomers could be partially separated by flash-column chromatography on silica gel (10% ethyl ether-hexanes initially, then grading to 50% ethyl ether-hexanes) to obtain small amounts of pure samples, which were used for characterization purposes.
  • (+)-dimethyl tartrate (8.00 g, 44.9 mmol, 1 equiv) in methanol (44.9 mL) was added sequentially 2,3-butanedione (4,73 mL, 53.9 mmol, 1.20 equiv), trimethylorthoformate (14.7 mL, 135 mmol, 3 ,00 equiv), and ( ⁇ )-camphorsulfonic acid (1.04 g, 4.49 mmol, 0.10 equiv).
  • the resulting light yel low solution was heated to 75 °C. After stirring for 21 hours at 75 °C, the dark brown reaction mixture was cooled to 23 °C.
  • the pH of the aqueous layer was adjusted to 7 by the addition of 1 M aqueous hydrochloric acid.
  • the layers were separated and the aqueous layer was extracted with ethyl ether (2 x 300 mL).
  • the organic layers were combined.
  • the combined organic layers were dried over sodium sulfate.
  • the dried solution was filtered and the filtrate was concentrated.
  • the residue was purified by flash-column chromatography on silica gel (5% ethyl acetate-hexanes initially, then grading to 20% ethyl acetate-hexanes) to provide pure vinyl ketone 121 as a clear and colorless oil (2.49 g, 73%).
  • Vinyl ketone 1.21 (494 mg, 1 .49 mmol, 1 equiv) was dissolved in methanol (21.2 mL) and the resulting solution was cooled to -40 °C.
  • Cerium trichloride heptahydrate (609 mg, 1.64 mmol, 1.10 equiv) was added in one portion.
  • Sodium borohydride (67.5 mg, 1.78 mmol, 1.20 equiv) was then added as a solid, in two portions. The resulting solution was stirred at -40 °C for 30 min and then warmed to 23 °C.
  • azodicarboxylate (2.52 mL, 13.0 mmol, 3.50 equiv) was then added dropwise. The solution turned yellow and then white precipitate appeared.
  • a solution of benzoic acid (498 mg, 4.08 mmol, 1.10 equiv) in tetrahydrofuran (8.00 mL) was then added dropwise via syringe. The addition was quantitated with tetrahydrofuran (1.00 mL). The resulting heterogeneous mixture was stirred at 23 °C for 2 h. The reaction mixture was filtered, and the solids were washed with 50% ethyl ether-hexanes (200 mL).
  • the filtrate was poured into saturated aqueous sodium bicarbonate solution (200 mL). The layers were separated and the aqueous layer was extracted with ethyl ether (2 x 200 mL). The organic layers were combined. The combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated.
  • Step 1 reduction.
  • a solution of diisobutylaluminum hydride (1.0 M solution in dichlorom ethane, 547 .uL, 0.547 mmol, 6.00 equiv) was added dropwise to a solution of the benzoyl ester 126 (40.0 mg, 0.091 mmol, 1 equiv) in dichloromethane (1.82 mL) at -85 °C.
  • the resulting solution was stirred for 15 min, at which point propanal (39.2 iL, 0.547 mmol, 6.00 equiv) was then added.
  • the reaction mixture was stirred at -85 °C for another 5 min, at which point ethyl acetate (4 mL) was added.
  • the residue was purified by flash-column chromatography on silica gel (10% ethyl acetate-hexanes + 1% tri ethyl amine initially, then grading to 50% ethyl acetate-hexanes + 1% tri ethyl amine) to provide aminoketone 119 (9: 1 mixture of 119 and bis(4- methoxybenzyl)amine, 17.3 mg, 35%), benzyl ethyl ketal 128 (impure, 5.60 mg, 9%), and diethyl ketal 127 (5.60 mg, 10%).
  • Step 3 ketal hydrolysis.
  • diethyl ketai 127 48.7 mg, 0.083 mmol, 1 equiv
  • benzyl ethyl ketal 128 43.1 mg, 0.066 mmol, 1 equiv
  • acetone 7.42 mL
  • hydrochloric acid 2.0 M in water, 744 jiL, 1 ,49 mmol, 10.0 equiv

Abstract

L'invention concerne des aminoglycosides pour le traitement d'infections, et des compositions pharmaceutiques, des procédés, des kits et des utilisations de ceux-ci. L'invention concerne également des procédés de fabrication d'aminoglycosides qui permettent une dérivation en phase tardive des groupes amino en C6'et C3 ', permettant ainsi un accès facile à des aminoglycosides auparavant inaccessibles.
PCT/US2018/056686 2017-10-20 2018-10-19 Antibiotiques à base d'aminoglycoside WO2019079706A1 (fr)

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Publication number Priority date Publication date Assignee Title
US20050090462A1 (en) * 2003-03-14 2005-04-28 Rando Robert R. Aminoglycoside antibiotics and methods of using same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050090462A1 (en) * 2003-03-14 2005-04-28 Rando Robert R. Aminoglycoside antibiotics and methods of using same

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Title
DATABASE PUBCHEM SUBSTANCE [online] 12 June 2009 (2009-06-12), XP055597024, retrieved from NCBI Database accession no. 77087000 *
DATABASE PUBCHEM substance [online] 6 January 2015 (2015-01-06), XP055597008, retrieved from NCBI Database accession no. 223658860 *

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