WO2008143730A2 - Macrolide compounds and methods of making and using the same - Google Patents

Macrolide compounds and methods of making and using the same Download PDF

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Publication number
WO2008143730A2
WO2008143730A2 PCT/US2008/002732 US2008002732W WO2008143730A2 WO 2008143730 A2 WO2008143730 A2 WO 2008143730A2 US 2008002732 W US2008002732 W US 2008002732W WO 2008143730 A2 WO2008143730 A2 WO 2008143730A2
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Prior art keywords
alkyl
unsaturated
prodrug
group
pharmaceutically acceptable
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PCT/US2008/002732
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French (fr)
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WO2008143730A3 (en
Inventor
Ashoke Bhattacharjee
Erin M. Duffy
Zoltan F. Kanyo
Yuanqing Tang
Yusheng Wu
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Rib-X Pharmaceuticals, Inc.
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Publication of WO2008143730A2 publication Critical patent/WO2008143730A2/en
Publication of WO2008143730A3 publication Critical patent/WO2008143730A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates generally to the field of anti -infective, anti -proliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family macrolide compounds that are useful as such agents, hi particular embodiments the present invention relates to macrolide compounds in which the macrocyclic ring contains an oxime or other related functionality and wherein the compounds also contain a triazole ring.
  • the problem of resistance is not limited to the area of anti-infective agents. Resistance has also been encountered with antiproliferative agents used in cancer chemotherapy. Therefore, the need exists for new anti-infective and antiproliferative agents that are both effective against resistant bacteria and resistant strains of cancer cells.
  • Another class of antibiotics is the macrolides, so named for their characteristic 14- to 16-membered ring.
  • the macrolides also often have one or more 6-membered sugar-derived rings attached to the main macrolide ring.
  • the first macrolide antibiotic to be developed was erythromycin, which was isolated from a soil sample from the Philippines in 1952. Even though erythromycin has been one of the most widely prescribed antibiotics, its disadvantages are relatively low bioavailability, gastrointestinal side effects, and a limited spectrum of activity.
  • Another macrolide is the compound, azithromycin, which is an azolide derivative of erythromycin incorporating a methyl-substituted nitrogen in the macrolide ring.
  • Azithromycin is sold under the trade name Zithromax ® .
  • a more recently introduced macrolide is telithromycin, which is sold under the trade name Ketek ® .
  • Telithromycin is a semisynthetic macrolide in which a hydroxyl group of the macrolide ring has been oxidized to a ketone group. See Yong-Ji Wu, Highlights of Semi-synthetic Developments from Erythromycin A, Current Pharm. Design, vol. 6, pp. 181-223 (2000); Yong-Ji Wu and Wei- uo Su, Recent Developments on Ketolides and Macrolides, Curr. Med. Chem., vol. 8, no. 14, pp. 1727-1758 (2001); and Pal, Sarbani, "A Journey Across the Sequential Development of Macrolides and Ketolides Related to Erythromycin, Tetrahedron 62 (2006) 3171-3200.
  • the invention provides compounds useful as anti-infective agents and/or antiproliferative agents, for example, anti-biotic agents, anti-microbial agents, anti-bacterial agents, anti-fungal agents, anti-parasitic agents, anti-diarrheal agents, anti- viral agents, and chemotherapeutic agents.
  • the present invention also provides compounds useful as antiinflammatory agents, and/or prokinetic (gastrointestinal modulatory) agents.
  • the present invention also provides pharmaceutically acceptable salts, esters, N-oxides, or prodrugs of these compounds.
  • the present invention provides oxime containing macrolide compounds having the structure:
  • variables G, T, X, R 1 , R 2 , R 3 , R a , R b , R c , R d and R e can be selected from the respective groups of chemical moieties later defined in the detailed description.
  • the invention provides methods of synthesizing the foregoing compounds.
  • a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a mammal, particularly humans, for use as an anti-cancer, anti-biotic, anti-microbial, anti-bacterial, antifungal, anti-parasitic, anti-diarrheal, or anti- viral agent, or to treat a proliferative disease, an inflammatory disease or a gastrointestinal motility disorder, or to suppress disease states or conditions caused or mediated by nonsense or missense mutations, hi certain embodiments, the compounds of the present invention are useful for treating, preventing, or reducing the risk of microbial infections or for the manufacture of a medicament for treating, preventing, or reducing the risk of microbial infections.
  • the compounds or the formulations can be administered, for example, via otic, ophthalmic, nasal, oral, parenteral, or topical routes, to provide an effective amount of the compound to the mammal.
  • the present invention provides a family of compounds that can be used as antiproliferative agents and/or anti-infective agents.
  • the compounds can be used without limitation, for example, as anti-cancer, anti-microbial, anti-bacterial, anti-fungal, antiparasitic and/or anti-viral agents.
  • the present invention provides a family of compounds that can be used without limitation as anti-inflammatory agents, for example, for use in treating chronic inflammatory airway diseases, and/or as prokinetic agents, for example, for use in treating gastrointestinal motility disorders such as gastroesophageal reflux disease, gastroparesis (diabetic and post surgical), irritable bowel syndrome, and constipation.
  • the compounds can be used to treat or prevent a disease state in a mammal caused or mediated by a nonsense or missense mutation.
  • the present invention provides a family of compounds that can be used without limitation as anti-diarrheal agents.
  • the compounds described herein can have asymmetric centers.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • R includes, but is not limited to substituents such as alkyl, aryl, acetyl etc.
  • substituents such as alkyl, aryl, acetyl etc.
  • a wide variety of compounds can include a carbamate or other related functionality.
  • oxime or other related functionality is being used herein to describe a generally common chemical feature of the compounds of the present invention.
  • the various chemical variable substituents, as defined in the present patent application, further illustrate the term "oxime or other related functionality".
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C- 13 and C- 14.
  • R 2 can optionally be substituted with one, two, three, four, five, or more R 2 moieties, and R 2 at each occurrence is selected independently from the definition of R 2 .
  • R 2 at each occurrence is selected independently from the definition of R 2 .
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • a chemical structure showing a dotted line representation for a chemical bond indicates that the bond is optionally present.
  • a dotted line drawn next to a solid single bond indicates that the bond can be either a single bond or a double bond.
  • glycoside is a cyclic acetal.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci_6 alkyl is intended to include Ci, C2, C3, C4, C5, and CO alkyl groups.
  • C1.8 alkyl is intended to include Ci, C2, C3, C4, C5, C ⁇ , C ⁇ , and Cs alkyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n- hexyl, n-heptyl, and n-octyl.
  • alkenyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that can occur in any stable point along the chain, such as ethenyl and propenyl.
  • C2-6 alkenyl is intended to include C2, C3, C4, C5, and Ce alkenyl groups.
  • C2-8 alkenyl is intended to include C2, C3, C4, C5, Ce, C ⁇ , and Cs alkenyl groups.
  • alkynyl is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that can occur in any stable point along the chain, such as ethynyl and propynyl.
  • C2-6 alkynyl is intended to include C2, C3, C4, C5, and C ⁇ , alkynyl groups.
  • C2-8 alkynyl is intended to include C2, C3, C4, C5, CO, C7, and Cs alkynyl groups.
  • alkyl alkenyl
  • alkynyl moieties which are diradicals, i.e., having two points of attachment, an example of which in the present invention is when D is selected from these chemical groups.
  • a nonlimiting example of such an alkyl moiety that is a diradical is -CH2CH2-, i.e., a C2 alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule.
  • alkyl As used herein, the terms used to describe various carbon-containing moieties, including, for example, “alkyl,” “alkenyl,” “alkynyl,” “phenyl,” and any variations thereof, are intended to include univalent, bivalent, or multivalent species. For example, “Ci_6 alkyl-
  • R 3 is intended to represent a univalent Ci -6 alkyl group substituted with a R 3 group
  • "O- C i-6 alkyl-R 3 " is intended to represent a bivalent C 1.6 alkyl group, i.e., an "alkylene” group, substituted with an oxygen atom and a R 3 group.
  • cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl.
  • C3-8 cycloalkyl is intended to include C3, C4, C5,
  • unsaturated refers to compounds having at least one degree of unsaturation (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds.
  • halo or halogen refers to fluoro, chloro, bromo, and iodo substituents.
  • Counterion is used to mean a positively or negatively charged species present in conjunction with an ion of opposite charge.
  • a nonlimiting example of a counterion is an ion or ions present to counterbalance the charge or charges on an organic compound.
  • Nonlimiting examples of counterions include chloride, bromide, hydroxide, acetate, sulfate, and ammonium.
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • Ci.6 alkoxy is intended to include Ci, C 2 , C3, C4, C5, and Ce alkoxy groups.
  • Ci_s alkoxy is intended to include Ci, C2, C3, C4, C5, Ce, C ⁇ , and Cs alkoxy groups.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.
  • alkylthio refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an sulfur bridge.
  • Ci -6 alkylthio is intended to include Ci, C2, C3, C4, C5, and C ⁇ alkylthio groups.
  • Ci_s alkylthio is intended to include Ci, C2, C3, C4, C5, C ⁇ , C7, and Cs alkylthio groups.
  • carrier or “carbocyclic ring” is intended to mean, unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, any of which can be saturated, unsaturated (including partially and fully unsaturated), or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
  • bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).
  • a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
  • Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring.
  • the substituents recited for the ring can also be present on the bridge.
  • Fused e.g., naphthyl and tetrahydronaphthyl
  • spiro rings are also included.
  • heterocycle means, unless otherwise stated, a stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, which is saturated, unsaturated (including partially and fully unsaturated), or aromatic, and consists of carbon atoms and one or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur, and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused or attached to a second ring (e.g., a benzene ring).
  • a second ring e.g., a benzene ring
  • a nitrogen atom is included in the ring it is either N or NH, depending on whether or not it is attached to a double bond in the ring (i.e., a hydrogen is present if needed to maintain the tri-valency of the nitrogen atom).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein
  • R is H or another substituent, as defined).
  • the heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocycle can optionally be quaternized.
  • Bridged rings are also included in the definition of heterocycle.
  • a bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group.
  • aromatic heterocycle or “heteroaryl” is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1- 6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • the second ring can also be fused or bridged as defined above for heterocycles.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined).
  • heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a//-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6//-l,5,2-dithiazinyl, dihydrofuro[2,3-6]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indo
  • the phrase "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).
  • prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form.
  • the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same.
  • Prodrugs are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • “treating” or “treatment” includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
  • “Treating” or “treatment” of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
  • preventing means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
  • mamal refers to human and non-human patients.
  • the term "therapeutically effective amount” refers to a compound, or a combination of compounds, of the present invention present in or on a recipient in an amount sufficient to elicit biological activity, for example, anti-microbial activity, anti-fungal activity, anti-viral activity, anti-diarrheal activity, anti-parasitic activity, and/or antiproliferative activity.
  • the combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
  • Synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiproliferative and/or anti-infective effect, or some other beneficial effect of the combination compared with the individual components. All percentages and ratios used herein, unless otherwise indicated, are by weight.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present invention also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • the invention relates to a compound having the structure:
  • T is a 14- or 15-membered macrolide connected via a macrocyclic ring carbon atom;
  • X is selected from (a) H, (b) halogen, (c) a C 1-6 alkyl group, (d) a C 2-6 alkenyl group, (e) a C 2-6 alkynyl group, (f) -OH, (g) -OR 5 , (h) -NR 4 R 4 , (i) -C(O)R 5 , (j) -C(O)OR 5 , (k) -
  • R 1 and R 3 independently are selected from: (a) H, (b) a C 1-6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) -C(O)R 5 , (f) -C(O)OR 5 , (g) -C(O)-NR 4 R 4 , (h) - C(S)R 5 , (i) -C(S)OR 5 , G) -C(O)SR 5 , and (k) -C(S)-NR 4 R 4 ; alternatively R 1 and R 3 are taken together with the oxygen to which R 1 is attached, the nitrogen to which R 3 is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R 5 groups; R 2 is hydrogen or -OR 12 ;
  • G is selected from: (a) -B' and (b) -B'-Z-B", wherein i) each B' is independently selected from (aa) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings and (bb) a 3- 12 membered saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 rings and containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (aa) or (bb) optionally contains one or more carbonyl groups, and wherein each (aa) or (bb) optionally is substituted with one or more R 11 or R 1 ' a ; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc) -OR 9 , (dd) - SH, (ee) -S(O)pR 9 , (ff) halogen, (gg) -CN, (Hh)-N 3 , (
  • R 4 at each occurrence, independently is selected from: (a) H, (b) a Ci- 6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) a C 6-12 saturated, unsaturated, or aromatic carbocycle, (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-Ci -6 alkyl, (h) -C(O)-C 2-6 alkenyl, (i) -C(O)-C 2-6 alkynyl, (j) -C(O)-C 3- J 2 saturated, unsaturated, or aromatic carbocycle, (k) -C(O)- 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (1) -C(O)O-Cj -6 alky
  • R 7 (a) R 7 , (b) a Cj -6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) a C 3- I 2 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, or; wherein any of (b)-(f) immediately above optionally is substituted with one or more R 7 groups; alternatively two R 5 groups, when present on the same carbon atom can be taken together with the carbon atom to which they are attached to form a spiro 3-6 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of these ring systems formed from two R 5 groups optionally is substituted with one or more R 7 groups; R 6 , at each occurrence, independently is selected from:
  • R 10 at each occurrence, independently is selected from:
  • R 11 and R Ua at each occurrence, independently is selected from: (a) a carbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g) CN, (h) NO 2 , (i) OR 8 , G) -S(O)pR 8 , (k) -C(O)R 8 , (1) -C(O)OR 8 , (m) -OC(O)R 8 , (n) -C(O)NR 8 R 8 , (o) -OC(O)NR 8 R 8 , (p) -C( NR 8 )R 8 , (q) -C(R 8 )(R 8 )OR 8 , (r) -C(R 8 ) 2 OC(O)R 8 , (s) -C(R 8 )(OR 8 )(CH 2 ) r NR 8 R 8 , (t) -NR 8 R 8 , (
  • R 12 is selected from:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -CN, (g) -CF 3 , (h) -CF 2 H, (i) -CFH 2 , G) -O(C 1-6 alkyl), (k) -N 3 , (1) -COOH, (m) -COO(C 1-6 alkyl), (n) -NH 2 , (o) -NH(C 1-6 alkyl), (p) -N(Ci -6 alkyl) 2 , (q) -C(O)NH 2 , (r) -C(O)NH(C 1-6 alkyl), (s) -C(O)N(C 1-6 alkyl) 2 , (t) -NHC(O)H, (
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from F and OH.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is F.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is OH.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R d and R e are selected from (a) Cl, (b) Br, (c) F, (d) H and (e) C 1-6 alkyl.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R d and R e are H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R c is selected from (a) H, (b) C 1-6 alkyl, (c) -CF 3 , (d) -CF 2 H, and (e) -CFH 2 .
  • R c is H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a and R b are independently selected from (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -O(C, -6 alkyl), (g) -N 3 , (h) -COOH, (i) -COO(C 1-6 alkyl), (j) -CN, (k) -NH 2 , (1) -NH(C 1-6 alkyl), (m) -N(C 1-6 alkyl) 2 , (n)-C(O)NH 2 , (o) -C(O)NH(C 1-6 alkyl), (p) -C(O)N(C 1-6 alkyl) 2 , (q) -NHC(O)H, (r) - NHC(O)(C 1-6 alkyl), (s) -
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein R a and R b are independently selected from -H, -F, -OH, -OCH 3 , -SH, and -SCH 3 .
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein R a is H and R b is F.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is -OH.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is -OCH 3 .
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is -SH.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is -SCH 3 .
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R a is H and R b is H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 1 is H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 2 is H.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 3 is C 1-6 alkyl. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 3 is methyl.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is B'.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is selected from: (a) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3- 12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein each (a)-(b) optionally is substituted with one or more R 11 groups.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is -B'-Z-B".
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' and B" are independently selected from (a) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein each (a)-(b) optionally is substituted with one or more R 1 ' groups.
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure: or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R 1 , R 2 , and R 3 are as described herein.
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure: or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R 1 , R 2 , and R 3 are as described herein.
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is: and B", Z, and R 1 ' are as described herein.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, jV-oxide, or prodrug thereof, wherein G is: , wherein B", Z, and R 11 are as described herein.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is: , wherein B", Z, and R 11 are as described herein and or B" is substituted with R 11 .
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 1 ' is selected from (a) OR 8 , (b) -S(O) P R 8 , (c) -C(O)R 8 , (d) -C(O)NR 8 R 8 , (e) -C(R 8 )(R 8 )OR 8 , (f) - C(R 8 ) 2 OC(O)R 8 , (g) -NR 8 R 8 , (h) -NR 8 C(O)R 8 , (i) -NR 8 S(O)pR 8 , (j) a C 1-6 alkyl group, and (k) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (j) is optionally substituted with one or more R 5 groups.
  • R 1 ' is selected from (a)
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 1 ' is selected from -CH 2 OH, -SO 2 CH 3 , -NH 2 , -CH 3 , -C(O)NH 2 , -CH 2 OC(O)CH 3 , CH 2 OCH 3 , -NHCH 3 , - OCH 3 , ⁇ W , NH(cyclopropyl), -C(O)CH 3 , -NHC(O)CH 3 , -C(O)CH 3 , -S(O)CHF 2 ,
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 11 is F.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C 1-6 alkyl group, (b) a C 2.6 alkenyl group, (c) a C 2 .
  • NR 8 C(O)OR 8 (w) -NR 8 C(O)NR 8 R 8 , (x) -NR 8 S(O) P R 8 , (y) -C(OR 8 )(OR 8 )R 8 , (z) -C(R 8 ) 2 NR 8 R 8 , (aa) -C(S)NR 8 R 8 , (bb) -NR 8 C(S)R 8 , (cc) -OC(S)NR 8 R 8 , (dd) -NR 8 C(S)OR 8 , (ee) -NR 8 C(S)NR 8 R 8 , (ff) -SC(O)R 8 , (gg) -N 3 , (hh) - Si(R 13 ) 3 , (ii) a C 1-6 alkyl group, Oj) a C 2-6 alkenyl group, (kk) a C 2-6 alkynyl group, (11) a C 3-I2 saturated
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C,_ 6 alkyl group, (b) a C 2 ⁇ alkenyl group, (c) a C 2.6 alkynyl group, (d) a C 3-12 saturated, unsaturated, or aromatic carbocycle, and (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) -CF 3 , (g) -NR 6 (CR 6 R 6 ) t R 9 , (h) -OR 9 , (i) -S ⁇ CR 6 R 6 ) t R 9 , (j) -S(O)(CR 6 R 6 ) t R 9 , (k) - S(O) 2 (CR 6 R 6 ) t R 9 , (1) -C(
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C 1-6 alkyl group, (b) a C 2.6 alkenyl group, (c) a C 2.6 alkynyl group, (d) a C 3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, wherein (a)-(e) optionally are substituted with one or more R 14 groups.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected (a) -NR 6 (CR 6 R 6 ) t R 9 , (b) -OR 9 , (c) -S ( CR 6 R 6 ) t R 9 , (d) -S(O) ( CR 6 R 6 ) t R 9 , (e) - S(O) 2 ( CR 6 R 6 ) t R 9 , (f) -C(O)(CR 6 R 6 ) t R 9 , (g) -OC(O)(CR 6 R 6 ) t R 9 , (h) -OC(O)O(CR 6 R 6 ) t R 9 ,
  • M is selected from:
  • R 100 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR 114 , and (f) C 1-6 alkyl, wherein (f) optionally is substituted with one or more R 115 groups;
  • R 101 is selected from:
  • R 102 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR 114 , and (f) C 1-6 alkyl, wherein (f) optionally is substituted with one or more R 115 groups;
  • R 103 is selected from:
  • R 102 and R 103 taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R 114 groups; alternatively, R 101 and R 103 taken together are a single bond between the respective carbons to which these two groups are attached thereby creating a double bond between the carbons to which R 100 and R 102 are attached; alternatively, R 101 and R 103 taken together with the carbons to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring, wherein said 3-7 membered ring can optionally be substituted with one or more R 114 groups; alternatively, R 100 , R 101 , R 102 , and R 103 taken together with the carbon to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring, wherein said 3-7 membered ring can optionally be substituted with one or more
  • K is selected from:
  • R 105 is selected from:
  • R 106 is selected from: (a) -OR 114 , (b) -C 1-6 alkoxy-R 115 , (c) -C(O)R 114 , (d) -OC(O)R 114 , (e) -
  • OC(O)OR 114 (f) -OC(O)NR 114 R 114 , and (g) -NR 114 R 114 , R 107 is selected from
  • R 106 and R 107 are taken together with the atom to which they are attached to form an epoxide, a carbonyl, an exocyclic olefin, or a substituted exocyclic olefin, or a C 3 - C 7 carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be further substituted with a Cr 6 alkyl;
  • R 108 is selected from:
  • R 109 is H, C 1-6 alkyl, or F; R 114 , at each occurrence, independently is selected from:
  • R 115 is selected from: (a) R 117 , (b) C 1-6 alkyl, (c) C 2-6 alkenyl, (d) C 2-6 alkynyl, (e) C 3-12 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -OC 1-6 alkyl, (h) -OC 2-6 alkenyl, and (i) - OC 2-6 alkynyl, wherein any of (b)-(f) optionally is substituted with one or more R 117 groups; R 116 , at each occurrence, independently is selected from:
  • R 119 at each occurrence, independently is selected from:
  • R 120 (a) R 120 , (b) C, .6 alkyl, (c) C 2 ⁇ alkenyl, (d) C 2.6 alkynyl, (e) C 3-I2 saturated, unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) optionally is substituted with one or more R 114 groups; R 120 , at each occurrence, independently is selected from:
  • R 127 is R 114 , a monosaccharide or a disaccharide (including amino sugars and halogenated sugar(s)), -S(O)pR 148 , -(CH 2 ) n -(O-CH 2 CH 2 -) m -O(CH 2 ) n CH 3 , -(CH 2 ) n - (O-CH 2 CH 2 -) m -OR 148 , - ⁇ CH 2 ) n -[S(O) p -CH 2 CH 2 -] m -S(O)p(CH 2 ) n CH 3 , -(CH 2 ) n - [S(O) p -CH 2 CH 2 -] m -S(O)pCH3, -(CH 2 )n-[S(O)p-CH 2 CH 2 -] m -OR 148 , -OCH 2 -O-(CH 2 ) n - [S
  • R 110 is R 114 ; alternatively, R 109 and R 110 taken together with the carbons to which they are attached form:
  • R 132 , R 133 , and R 134 are each independently selected from (a) H, (b) F, (c) Cl, (d) Br,
  • R 105 and R 134 are taken together with the carbons to which they are attached to form a 3-membered ring, said ring optionally containing an oxygen or nitrogen atom, and said ring being optionally substituted with one or more R 114 groups; alternatively when M is a carbon moiety, R 134 and M are taken together to form a carbon-carbon double bond;
  • R 137 is independently (a) H, (b) Ci -6 alkyl, (c) C 2-6 alkenyl, (d) C 2-6 alkynyl, (e) -
  • each R 138 is independently H or C 1 - 6 alkyl
  • each R 141 , R 142 , R 143 , and R 144 is independently selected from H, Cr 6 alkyl, - (CH 2 ) O i(C 6 -C l oaryl), and -(CH 2 ) m (5-10 membered heteroaryl), wherein the foregoing
  • R 141 , R 142 , R 143 , and R 144 groups are optionally substituted by 1, 2, or 3 R 140 groups; or R 141 and R 143 are taken together to form -(CH 2 ) 0 - wherein o, at each occurrence is 0, 1, 2, or 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carbon-carbon double or triple bonds; or R 143 and R 144 are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and - N(R 137 )-, in addition to the nitrogen to which R 143 and R 144 are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1, 2, or 3 R 140 groups;
  • R 139 is H, Ci-6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the foregoing R 139 groups, except H, are optionally substituted by 1, 2, or 3 substituents independently selected from halo and -OR 138 ; each R 140 is independently selected from halo, cyano, nitro, trifluoromethyl, azido, -C(O)R 145 , -C(O)OR 145 , -OC(O)OR 145 , -NR 146 C(O)R 147 , -NR 146 R 147 , OH, C,- 6 alkyl, Cr 6 alkoxy, -(CH 2 )V(C 6 -C 1O aTyI), and -(CH 2 ) v (5-10 membered heteroaryl), wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from halo, cyan
  • each R 145 is independently selected from H, C 1 - 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(CH 2 ) v (C 6 -Ci 0 aryl), and -(CH 2 ) v (5-10 membered heteroaryl); each R 146 and R 147 is independently H, hydroxyl, Ci- 6 alkoxy, Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, -(CH 2 ) v (C6-!o ary ⁇ > or -(CH 2 ) v (5-10 membered heteroaryl);
  • R 148 is Cr 6 alkyl, C 3-12 saturated, unsaturated, or aromatic carbocycle, wherein said carbocycle is further optionally substituted with one or more R 114 , or 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said heterocycle is further optionally substituted with one or more R 114 ; p, at each occurrence is O, 1, or 2; m, at each occurrence is O, 1, 2, 3, 4, or 5; n, at each occurrence is 1, 2, or 3; r, at each occurrence is O, 1, or 2; t, at each occurrence is O, 1, or 2; v, at each occurrence is O, 1, 2, 3, or 4; q, at each occurrence is 0, 1, 2, or 3, and u at each occurrence is 1, 2, 3, or 4.
  • the present invention relates to a compound, wherein T is: or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 1 14 , R 132 , R 133 , and R 134 are as described herein.
  • the present invention relates to a compound, wherein T is:
  • the present invention relates to a compound, wherein T is:
  • R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 1 14 , R 132 , R 133 , and R 134 are as described herein.
  • the present invention relates to a compound, wherein T is:
  • R 100 , R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , R 114 , R 132 , R 133 , and R 134 are as described herein.
  • the present invention relates to a compound, wherein T is selected from TA-TD:
  • R 1 M and R 127 are as described herein.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from T4 through T34:
  • the present invention relates to a compound having the structure corresponding to any one of the structures listed in Table 1, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to a method for treating or preventing a disease state in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, in the manufacture of a medicament for treating a microbial infection in a mammal.
  • the present invention relates to a method of treating or preventing a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, ⁇ -oxide, or prodrug thereof, wherein the microbial infection is selected from the group consisting of: a skin infection, nosocomial pneumonia, community acquired pneumonia, post- viral pneumonia, a respiratory tract infection such as CRTI, a skin and soft tissue infection
  • SSTI skin and soft tissue infections
  • uSSTIs uncomplicated skin and soft tissue infections
  • uSSTIs uncomplicated skin and soft tissue infections
  • complicated skin and soft tissue infections as an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, meningitis, surgical prophylaxis, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus infection, a vancomycin-resistant Enterococci infection, a linezolid-resistant organism infection, and tuberculosis.
  • uSSTIs uncomplicated skin and soft tissue infections
  • uSSTIs uncomplicated skin and soft tissue infections
  • complicated skin and soft tissue infections as an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a
  • the present invention relates to a method of treating or preventing a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a viral infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing diarrhea in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a method of treating or preventing a disease state in a mammal caused or mediated by a nonsense or missense mutation comprising administering to a mammal in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, to suppress expression of the nonsense or missense mutation.
  • the present invention relates to a method or use of a compound of the invention wherein the compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, is administered otically, ophthalmically, nasally, orally, parentally, or topically.
  • the present invention relates to a method of synthesizing a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the present invention relates to a medical device containing a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
  • the medical device is a stent.
  • the compounds of the present invention can include a wide range of structures.
  • macro lide components and their syntheses are provided in the following documents, all of which are incorporated by reference in their entirety: PCT Application No. WO 2007/025284, published March 1 , 2007, to Rib-X
  • the invention provides methods for making the compounds of the invention.
  • the electrophilic alkyne, 2, can include, e.g., compounds where chlorides, bromides, iodides, tosylates, and mesylates depending on the selection of X. Cycloaddition of azide compounds, such as 6, with the 3'-N-allkynyl compounds 3 provides two regioisomeric triazole products 7 and 8.
  • the major isomer is the "anti" isomer 7, a 1,4 disubstituted triazole.
  • the minor component is the "syn” isomer 8, a 1,5 disubstituted triazole.
  • the cycloaddition reaction can be thermally catalyzed, or a number of catalysts can be used, such as, but not limited to, copper (I) iodide. See, Tornoe, CW. et al. (2002) J. Org. Chem. 67: 3057).
  • Scheme B illustrates the synthesis of oxime type macrolides of the present invention.
  • These compounds can be from 3'-N-alknynyl compounds such as 3, which are made from the 3'-N-desmethyl macrolides, 1, as in Scheme A.
  • Compound 3 can either be converted directly to the desired intermediate oxime 4 (by the appropriate choice of R 1 ), or alternatively via a the hydroxyl oxime 5.
  • a cycloaddition reaction of the intermediate oxime 4 and an azide compound 6 provides the final compounds 7 and 8 as a mixture of isomers.
  • Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays.
  • it can be possible to rapidly screen the molecules described herein for activity, for example, as anti-cancer, anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents.
  • it can be possible to assay how the compounds interact with a ribosome or ribosomal subunit and/or are effective as modulators (for example, inhibitors) of protein synthesis using techniques known in the art.
  • modulators for example, inhibitors
  • High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
  • SPR surface plasmon resonance
  • SPR methodologies measure the interaction between two or more macromolecules in real-time through the generation of a quantum-mechanical surface plasmon.
  • One device (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, N.J.) provides a focused beam of polychromatic light to the interface between a gold film (provided as a disposable biosensor "chip") and a buffer compartment that can be regulated by the user.
  • a 100 nm thick "hydrogel” composed of carboxylated dextran that provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film. When the focused light interacts with the free electron cloud of the gold film, plasmon resonance is enhanced.
  • the resulting reflected light is spectrally depleted in wavelengths that optimally evolved the resonance.
  • the BIAcore establishes an optical interface which accurately reports the behavior of the generated surface plasmon resonance.
  • the plasmon resonance and thus the depletion spectrum
  • the plasmon resonance is sensitive to mass in the evanescent field (which corresponds roughly to the thickness of the hydrogel).
  • Fluorescence polarization is a measurement technique that can readily be applied to protein-protein, protein-ligand, or RNA-ligand interactions in order to derive IC 50 S and Kds of the association reaction between two molecules. In this technique one of the molecules of interest is conjugated with a fluorophore.
  • the sample mixture containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragment thereof, is excited with vertically polarized light. Light is absorbed by the probe fluorophores, and re-emitted a short time later. The degree of polarization of the emitted light is measured. Polarization of the emitted light is dependent on several factors, but most importantly on viscosity of the solution and on the apparent molecular weight of the fluorophore.
  • Binding assays based on FP have a number of important advantages, including the measurement of IC 5 oS and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions.
  • the compound of interest can also be characterized as a modulator (for example, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.
  • a modulator for example, an inhibitor of protein synthesis
  • more specific protein synthesis inhibition assays can be performed by administering the compound to a whole organism, tissue, organ, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological and inhibitory properties by determining, for example, its inhibition constant (IC 50 ) for inhibiting protein synthesis.
  • IC 50 inhibition constant
  • Incorporation of 3 H leucine or 35 S methionine, or similar experiments can be performed to investigate protein synthesis activity.
  • a change in the amount or the rate of protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis.
  • a decrease in the rate or the amount of protein synthesis indicates that the molecule is a inhibitor of protein synthesis.
  • the compounds can be assayed for antiproliferative or anti-infective properties on a cellular level.
  • the activity of compounds of interest can be assayed by growing the microorganisms of interest in media either containing or lacking the compound. Growth inhibition can be indicative that the molecule can be acting as a protein synthesis inhibitor.
  • the activity of the compounds of interest against bacterial pathogens can be demonstrated by the ability of the compound to inhibit growth of defined strains of human pathogens.
  • a panel of bacterial strains can be assembled to include a variety of target pathogenic species, some containing resistance mechanisms that have been characterized.
  • MICs Minimum inhibitory concentrations
  • CLSI Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-fifth edition. Wayne, PA: NCCLS; 2000.
  • the assays can be also be performed in microtiter trays according to conventional methodologies as published by the CLSI. See CLSI.
  • Endpoints can vary from reduction in bacterial burden to lethality. For the latter endpoint, results are often expressed as a PD 5O value, or the dose of drug that protects 50% of the animals from mortality.
  • measurements of inhibition of cytochrome P450 enzymes and phase II metabolizing enzyme activity can also be measured either using recombinant human enzyme systems or more complex systems like human liver microsomes. Further, compounds can be assessed as substrates of these metabolic enzyme activities as well. These activities are useful in determining the potential of a compound to cause drug-drug interactions or generate metabolites that retain or have no useful antimicrobial activity.
  • solubility and Caco-2 assays are a cell line from human epithelium that allows measurement of drug uptake and passage through a Caco-2 cell monolayer often growing within wells of a 24- well microtiter plate equipped with a 1 micron membrane. Free drug concentrations can be measured on the basolateral side of the monolayer, assessing the amount of drug that can pass through the intestinal monolayer. Appropriate controls to ensure monolayer integrity and tightness of gap junctions are needed. Using this same system one can get an estimate of P-glycoprotein mediated efflux.
  • P-glycoprotein is a pump that localizes to the apical membrane of cells, forming polarized monolayers. This pump can abrogate the active or passive uptake across the Caco-2 cell membrane, resulting in less drug passing through the intestinal epithelial layer. These results are often done in conjunction with solubility measurements and both of these factors are known to contribute to oral bioavailability in mammals. Measurements of oral bioavailability in animals and ultimately in man using traditional pharmacokinetic experiments will determine the absolute oral bioavailability.
  • Experimental results can also be used to build models that help predict physical- chemical parameters that contribute to drug-like properties. When such a model is verified ⁇ experimental methodology can be reduced, with increased reliance on the model predictability.
  • the compounds of the invention can be useful in the prevention or treatment of a variety of human or other animal, including mammalian and non mammalian, disorders, including for example, bacterial infection, fungal infections, viral infections, diarrhea, parasitic diseases, and cancer. It is contemplated that, once identified, the active molecules of the invention can be incorporated into any suitable carrier prior to use.
  • the dose of active molecule, mode of administration and use of suitable carrier will depend upon the intended recipient and target organism.
  • the formulations, both for veterinary and for human medical use, of compounds according to the present invention typically include such compounds in association with a pharmaceutically acceptable carrier.
  • the carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient.
  • Pharmaceutically acceptable carriers are intended to include any and all solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated.
  • Supplementary active compounds (identified or designed according to the invention and/or known in the art) also can be incorporated into the compositions.
  • the formulations can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy/microbiology.
  • compositions of the invention are prepared by bringing the compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • a pharmaceutical composition of the invention should be formulated to be compatible with its intended route of administration. Examples of routes of administration include otic, ophthalmic, nasal, oral or parenteral, for example, intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants
  • Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, described, for example, in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990).
  • Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Suppositories for rectal administration also can be prepared by mixing the drug with a non- irritating excipient such as cocoa butter, other glycerides, or other compositions which are solid at room temperature and liquid at body temperatures.
  • Formulations also can include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalenes.
  • Formulations for direct administration can include glycerol and other compositions of high viscosity.
  • Other potentially useful parenteral carriers for these drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Retention enemas also can be used for rectal delivery.
  • Formulations of the present invention suitable for oral administration can be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the drug; a powder or granular composition; a solution or a suspension in an aqueous liquid or non-aqueous liquid; or an oil- in-water emulsion or a water-in-oil emulsion.
  • the drug can also be administered in the form of a bolus, electuary or paste.
  • a tablet can be made by compressing or moulding the drug optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Moulded tablets can be made by moulding, in a suitable machine, a mixture of the powdered drug and suitable carrier moistened with an inert liquid diluent.
  • Oral compositions generally include an inert diluent or an edible carrier.
  • the active compound can be incorporated with excipients.
  • Oral compositions prepared using a fluid carrier for use as a mouthwash include the compound in the fluid carrier and are applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension.
  • Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
  • Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. Particularly useful are carriers capable of forming a film or layer over the skin to localize application and inhibit removal.
  • the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface.
  • hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage.
  • tissue-coating solutions such as pectin-containing formulations can be used.
  • inhalation treatments inhalation of powder (self-propelling or spray formulations) dispensed with a spray can, a nebulizer, or an atomizer can be used.
  • Such formulations can be in the form of a fine powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations.
  • the effect can be achieved either by choice of a valve having the desired spray characteristics (i.e., being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size.
  • the compounds also can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration also can be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • Such penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents and bile salts. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
  • Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • administration can be by periodic injections of a bolus, or can be made more continuous by intravenous, intramuscular or intraperitoneal administration from an external reservoir (e.g., an intravenous bag).
  • the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive.
  • the compound then can be painted, sprayed or otherwise applied to the desired tissue surface.
  • the drugs can be formulated for otic, ophthalmic, nasal, parenteral or oral administration to humans or other mammals, for example, in therapeutically effective amounts, e.g., amounts that provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect.
  • the active compound can be used as part of a transplant procedure, it can be provided to the living tissue or organ to be transplanted prior to removal of tissue or organ from the donor.
  • the compound can be provided to the donor host.
  • the organ or living tissue can be placed in a preservation solution containing the active compound.
  • the active compound can be administered directly to the desired tissue, as by injection to the tissue, or it can be provided systemically, e.g., by otic, ophthalmic, nasal, oral or parenteral administration, using any of the methods and formulations described herein and/or known in the art.
  • the drug comprises part of a tissue or organ preservation solution
  • any commercially available preservation solution can be used to advantage.
  • useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and lactated Ringer's solution.
  • the compounds of the present invention can be administered directly to a tissue locus by applying the compound to a medical device that is placed in contact with the tissue.
  • a medical device is a stent, which contains or is coated with one or more of the compounds of the present invention.
  • an active compound can be applied to a stent at the site of vascular injury.
  • Stents can be prepared by any of the methods well known in the pharmaceutical art. See, e.g., Fattori, R.
  • the stent can be fabricated from stainless steel or another bio-compatible metal, or it can be made of a bio-compatible polymer.
  • the active compound can be linked to the stent surface, embedded and released from polymer materials coated on the stent, or surrounded by and released through a carrier which coats or spans the stent.
  • the stent can be used to administer single or multiple active compounds to tissues adjacent to the stent.
  • Active compound as identified or designed by the methods described herein can be administered to individuals to treat disorders (prophylactically or therapeutically).
  • pharmacogenomics i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug
  • Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug.
  • a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of treatment with the drug.
  • the compounds or pharmaceutical compositions thereof will be administered otically, ophthalmically, nasally, orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level or tissue level of active component in the animal undergoing treatment which will be anti-microbially effective.
  • a concentration that is, an amount, or blood-level or tissue level of active component in the animal undergoing treatment which will be anti-microbially effective.
  • an effective amount of dosage of active component will be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg/kg of body weight/day.
  • the amount administered will also likely depend on such variables as the type and extent of disease or indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the compound delivered, the formulation of the drug, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered can be increased beyond the above upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage can be smaller than the optimum and the daily dosage can be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times per day. Various disease states or conditions in humans and other mammals are found to be caused by or mediated by nonsense or missense mutations.
  • mutations cause or mediate the disease state or condition by adversely affecting, for example, protein synthesis, folding, trafficking and/or function.
  • diseases states or conditions in which an appreciable percentage of the disease or condition is believed to result from nonsense or missense mutations include hemophilia (factor VIII gene), neurofibromatosis (NFl and NF2 genes), retinitis pigmentosa (human USH2A gene), bullous skin diseases like Epidermolysis bullosa pruriginosa (COL7A1 gene), cystic fibrosis (cystic fibrosis transmembrane regulator gene), breast and ovarian cancer (BRCAl and BRCA2 genes), Duchenne muscular dystrophy (dystrophin gene), colon cancer (mismatch repair genes, predominantly in MLHl and MSH2), and lysosomal storage disorders such as Neimann-Pick disease (acid sphingomyelinase gene).
  • the compounds of the present invention can be used to treat or prevent a disease state in a mammal caused or mediated by such nonsense or missense mutations by administering to a mammal in need thereof an effective amount of the present invention to suppress the nonsense or missense mutation involved in the disease state.
  • NMR Nuclear magnetic resonance
  • spectra were obtained on a Bruker Avance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300 spectrometer.
  • Common reaction solvents were either high performance liquid chromatography (HPLC) grade or American Chemical Society (ACS) grade, and anhydrous as obtained from the manufacturer unless otherwise noted.
  • HPLC high performance liquid chromatography
  • ACS American Chemical Society
  • the compounds of the present invention can be prepared using known chemical transformations adapted to the particular situation at hand. Examples of chemical transformations useful in the present invention can be found in: U.S. Patent No. 7,091,196 B2, to Wang et al., issued August 15, 2006; PCT application No. WO 2005/085266 A2, to Rib-X Pharmaceuticals, Inc., published September 15, 2005; PCT application No.
  • the compounds of the present invention can be prepared, formulated, and delivered as salts, esters, and prodrugs.
  • the compounds are generally shown without indicating a particular salt, ester, or prodrug form.
  • variable G is further selected from -B' or -B '-Z-B".
  • Tables 1A-1I provide examples of chemical moieties or fragments for -Z-B" when G is selected from -B '-Z-B". Note that in Tables 1 A-II, the chemical moieties or fragments for "-Z-B" are drawn such that the chemical moiety or fragment is bonded to -B from the left of the chemical moiety or fragment as drawn. For example, using the first chemical moiety or fragment from Table IA as an example, it can alternatively be drawn as shown immediately below.
  • variable G could be selected from -B '-Z-B". If, for example, B' is then selected from phenyl, then -Z- B" could be further selected from the first chemical moiety or fragment of Table IA to give the indicated compound.
  • Exemplary macrolide compound of the present invention showing variable G.
  • Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B'
  • Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B" wherein B 1 is phenyl.
  • Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B" wherein B' is phenyl and -Z-B" is selected from the first chemical moiety or fragment of Table IA.
  • Examples 1 — 6 Synthesis of 3'-N-desmethyl macrolide compounds
  • Examples 1-6 describe the synthesis of various 3'-N-desmethyl macrolide compounds which are useful intermediates for making the compounds of the present invention.
  • 3'-N-desmethyl erythromycin is synthesized from erythromycin according to the procedure described in U.S. Patent No. 3,725,385; Flynn et al. (1954) J. Am. Chem. Soc. 76: 3121; Ku et al. (1997) Bioorg. Med. Chem. Lett. 7: 1203; and Stenmark et al. (2000) J. Org. Chem. 65: 3875).
  • Example 2 Synthesis of 3'-7V-desmethyl azithromycin from azithromycin Azithromycin (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50 0 C followed by addition of iodine (I 2 ) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding IN sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes, however, stirring was continued for 2 hours.
  • I 2 iodine
  • the crude was purified on a silica gel column eluting with CH 2 Cl 2 /MeOH/NH 4 ⁇ H 18:1:0.05 to 10:1:0.05 to provide the 3'- ⁇ f-desmethyl azithromycin (0.41 g, 55%).
  • Example 3 Synthesis of 3'-iV-desmethyl clarithromycin from clarithromycin To a mixture of clarithromycin (1.00 g, 1.3 mmol) and NaOAc»3H 2 0 (0.885 g, 6.5 mmol) was added MeOH-H 2 O (20 mL, 4:1), and the mixture heated to 55-60 0 C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and the reaction stirred at 55-60 0 C for 3 h. The reaction mixture was poured into 50 mL CHCl 3 containing 1 mL ammonium hydroxide.
  • telithromycin (3.0 g, 3.60 mmol) in anhydrous acetonitrile (70 mL) was added N-iodosuccinimide (NIS) (0.98 g, 4.32 mmol) in two portions within 30 min at 0 0 C under argon atmosphere. The mixture was allowed to warm to rt and stirred overnight. CH 2 Cl 2 (250 mL) and 5 % Na 2 S 2 O 3 (80 mL) were added and the two layers separated. The organic layer was extracted with 5 % Na 2 S 2 O 3 (1 X 80 mL), dilute NH 4 Cl (1 X 80 mL) and dried over Na 2 SO 4 .
  • NMS N-iodosuccinimide
  • ketolide function i.e. the 1,3-diketone
  • the ketolide function is introduced after the 3'-N-desmethyl functionality has been further transformed to an N-alkynyl intermediate.
  • clarithromycin is converted to 3'-N-desmethyl clarithromycin.
  • This compound is then alkylated to form an alkynyl intermediate.
  • the cladinose sugar is then cleaved from this intermediate and the resulting free hydroxyl group is oxidized to the ketone. This process is shown below in Example 12.
  • the compounds of the present invention can be made via an N-alkynyl substituted macrolide intermediate.
  • the following Examples 7-12 illustrate the preparation of such compounds, hi these examples, the 3'-N-(but-3-ynyl) compounds are illustrated, but other corresponding alkynyl compounds are readily prepared by varying the alkynyl starting material.
  • Protocol A A mixture of 3'- ⁇ -desmethyl telithromycin (0.66 g, 0.83 mmol) and the tosylate of l-butyn-4-ol (0.33 g, 1.49 mmol) in THF (15 mL) and Hunig's base (3 mL) was heated at 90 0 C for 5 days. The solvent was evaporated; the residue was dissolved in IN HCl (50 mL) and kept stirring at room temperature for about Ih. CH 2 Cl 2 (30 mL) was added and the two layers were separated.
  • Protocol B A mixture of 3'-N-desmethyl telithromycin (0.66 g, 0.83 mmol), and the tosylate of l-butyn-4-ol (0.40 g, 1.84 mmol) in acetonitrile (10 mL) and Hunig's base (0.18 mL, 1.0 mmol) was microwave heated to 90 0 C within 10 min and maintained at 90 0 C for 1.5h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in IN HCl (60 mL) and kept stirring at room temperature for about 2h. CH 2 Cl 2 (30 mL) was added and the two layers were separated.
  • the aqueous layer was extracted with CH 2 Cl 2 (2 X 30 mL) and basified with 50 % KOH to form a whitish-suspension.
  • the suspension was extracted with CH 2 Cl 2 (3 X 30 mL) and the organic layer was dried over Na 2 SO 4 .
  • the solvent was evaporated and the crude was purified by preparative TLC (2000 micron plate) eluting with CH 2 Cl 2 /methanolic ammonia (2N NH 3 ) 12:1 to give 3'-N-(but-3-ynyl) telithromycin as white solid (0.19 g, 27 %).
  • MS (ESI) m/e 850.8 (M+H) + .
  • Example 12 Synthesis of 3'-iV-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring.
  • 3'-N-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring are prepared by introducing the oxime function typically after the 3'- ⁇ -but-3-ynyl (or other desired alkynyl group) has been introduced.
  • Example 12.1 provides a method for making the oxime of 3'-N'(but-3-ynyl) clarithromycin.
  • Examples 12.2 to 12.6 provide procedures for making more complex oximes.
  • Examples 12.2 to 12.6 The following scheme shows two exemplary oxime compounds (a piperidinyl oxime and a pyrrolidinyl oxime) and also the 3'-N-(but-3-ynyl) ketolide (see Example 6).
  • the N-alkynyl oxime macrolides were prepared from 3'-N-(but-3-ynyl) clarithromycin (see Example 9).
  • the pyrollidinyl oxime was synthesized from the 3'-N-(but-3-ynyl) ketolide and (R)-N- Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditions described above for the synthesis of piperidinyl oxime. Data for the pyrrolidinyl: MS (ESI) m/e 710.6 (M+H) + .
  • Example 13 Synthesis of Compounds of the present invention via a cyclization reaction of a 3'-iV-(but-3-ynyl) macrolide with an azide.
  • Compounds of the present invention can be made, for example, via a cycloaddition reaction of an alkynyl macrolide with an azide compound. In this cycloaddition reaction, the triazole functional group of the resulting compound is formed. Other compounds of the present invention are made by further chemically modifying the resulting compound from the cycloaddition reaction.
  • the cycloaddition reaction is generally run in the presence of a copper (I) salt such as copper iodide (CuI).
  • a base can also be optionally used, such as Hunig's base (N,N- diisopropylethylamine).
  • Hunig's base N,N- diisopropylethylamine
  • the time required for the reaction to proceed to completion is variable and is dependent upon several factors including: the specific alkynyl macrolide and azide compounds and their concentrations; the amount of Cu(I) salt used; and the presence or absence of base, such as Hunig's Base(N,N-diisopropylethylamine). Reactions are monitored for the disappearance of the starting materials by TLC and/or LCMS and are typically allowed to run for between about 2 hours to about 72 hours. Reactions are generally stopped when analysis demonstrates that the starting alkynyl macrolide has been substantially consumed.
  • the workup and purification protocols are standard. Modifications to the described workup procedures can be used.
  • Such modifications can include the use of different aqueous wash solutions, different organic solvents for extraction, the use of other anhydrous salts for the drying of organic extracts, and the employment of different solvent mixtures for the chromatographic purification of the compounds.
  • the methods used for the workup of the reaction mixtures, the extraction of products, the drying of organic extracts, and for the isolation and purification of the compounds of the present invention are typical of procedures familiar to those trained in the art of organic synthesis.
  • Hunig's base in 0.4 mL THF are thoroughly degassed by alternately evacuating the reaction vessel and purging with dry argon.
  • CuI is then added (2 mg, 0.01 mmol) and the mixture is further degassed.
  • the mixture is stirred under argon for 6h then diluted with CH 2 Cl 2 (20 mL) and washed with a 3:1 mixture of saturated aqueous NH 4 Cl and 28% aqueous NH 4 OH (10 mL) and with brine (10 mL) the aqueous washes are back-extracted with CH 2 Cl 2 (2 x 15 mL).
  • alkynyl macrolide compounds that can be used in the synthesis of the compounds of the present invention are shown in the following Table 2 A. It is appreciated by one of skill in the art that these alkynyl macrolide compounds, Ml to M43, are non-limiting examples and that a wide variety of additional alkynyl macrolides can be used to prepare other compounds of the present invention.
  • macrolide moieties Ml 1, M12, M13, Ml 6, Ml 7, Ml 8, M20, M21, M22, M23, M27, M28, M33, M34, M35, M36, M37, M38, M39, M40, M41, M42, and M43 are illustrative of various macrolides containing an oxime or other related functionality.
  • the alkynyl macrolide compounds such as alkynyl macrolide compounds Ml to M44, are generally made by the alkynylation (i.e. the addition of an alkynyl group) to a monomethyl amine macrolide compound.
  • the monomethyl amine macrolide is generally made by the desmethylation of the corresponding macrolide compound.
  • the desmethylation process can involve several steps, including various protection and deprotection steps.
  • the desmethyl macrolide compound is alkynylated with the corresponding alkynyl compound, which is generally an alkynyl halide, tosylate, or mesylate.
  • Macrolide Desmethyl Macrolide R 3 is generally Methyl
  • Alkynyl macrolide Ml is made by selective demethylation of azithromycin 1 to produce 3'-N-desmethylazithromycin 2. This compound 2 is selectively alkylated with alkynyl tosylate 11 to produce alkynyl macrolide Ml.
  • Azithromycin 1 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50 0 C followed by addition of iodine (I 2 ) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding IN sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes. Stirring was continued for 2 hours.
  • I 2 iodine
  • Clarithromycin Desmethyl Clarithromycin 21 M3
  • Alkynyl Macrolide Ml 4 is made using a procedure analogous to that for making M3, starting from erythromycin A.
  • the 3'-N-desmethyl-erythromycin A intermediate is made using a procedure described in U.S. Patent No. 3,725,385, to Freiberg, issued April 3, 1973.
  • Alkynyl macrolide Ml 4 can further be used to prepare a variety of macrolides analogous to those already depicted for the clarithromycin core.
  • alkynyl macrolides M4, M9, MlO, Mil and Ml 2 are depicted in the scheme below.
  • Alkynyl macrolide M9 is prepared from the removal of the cladinose sugar of alkynyl macrolide M3 under acidic conditions.
  • Alkynyl macrolide MlO is made by the acetylation of macrolide M9.
  • Macrolide M4 is made by the oxidation of the hydroxyl group of macrolide MlO.
  • Alkynyl macrolides Mil and Ml 2 are made by converting a keto group of alkynyl macrolide M4 to the desired oximes.
  • the oxime functionality of alkynyl macrolides of precursors with substituted oxime functionality at the 9-position of the macrocyclic ring were prepared from alkyne M3 and as shown below.
  • alkynyl macrolide M9 (0.200 g, 0.32 mmol) in acetone (2 mL) was added acetic anhydride (0.050 mL, 0.5 mmol) and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with saturated sodium bicarbonate (3 x 50 mL), dried (anhydrous Na 2 SO 4 ), and concentrated under reduced pressure.
  • the crude material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to yield 0.07Og (78%) of the alkynyl macrolide M4 (also commonly referred to as a ketolide).
  • Alkynyl macrolide Ml 2 was synthesized from alkynyl macrolide M4 and (R)-N- Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditions described above for the synthesis of alkynyl macrolide Mil. Data for M12: MS (ESI) m/e 710.6 (M+H) + .
  • Alkynyl macrolides M13, M16, and M17 are also synthesized from alkynyl macrolide M4 .
  • Alkynyl macrolide Ml 8 is synthesized from alkynyl macrolide Ml 7. The syntheses are outlined in the following reaction scheme.
  • Alkynyl macrolide Ml 3 was synthesized from alkynyl macrolide M4 and N-[I- dimethtylaminoethyl]-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M13: MS (ESI) m/e 726.5 (M+H) + .
  • Alkynyl macrolide Ml 6 was synthesized from alkyne M4 and N-Piperidin-4-yl- hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M16: MS (ESI) m/e 724.6 (M+H) + .
  • Alkynyl macrolide Ml 7 was synthesized from alkyne M4 and cis-4- aminocylcohexyl-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M17: MS (ESI) m/e 738.7 (MH-H) + .
  • alkynyl macrolide Ml 7 (20 mg, 0.02 mmol) in CHCl 3 (0.2 mL) was added formaldehyde (5 mg of 37% aqueous solution, 0.06 mmol) and formic acid (6 mg, 0.12 mmol). The mixture was heated at 50 0 C in a sealed tube for 12h. The reaction mixture was partitioned between aqueous NaHCO 3 (10 mL) and chloroform (10 mL) the organic fraction was dried on K 2 CO 3 , filtered and concentrated to give alkynyl macrolide Ml 8 as a white solid (18 mg). Data for M18: MS (ESI) m/e 766.7 (M+H) + .
  • Telithromycin was selectively N-demethylated and then alkylated with the tosylate of l-butyn-4-ol as described for azithromycin, erythromycin and clarithromycin above.
  • telithromycin 29 3'-iV-Desmethyl telithromycin 29
  • ⁇ IS ⁇ -iodosuccinimide
  • Protocol A A mixture of amine 30 (0.66 g, 0.83 mmol) and tosylate 11 (0.33 g, 1.49 mmol) in THF (15 mL) and Hunig's base (3 mL) was heated at 90 0 C for 5 days. The solvent was evaporated; the residue was dissolved in IN HCl (50 mL) and kept stirring at room temperature for about Ih. CH 2 Cl 2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2 X 30 mL) and basified with NaOH (IN) to form a whitish-suspension.
  • Protocol B A mixture of amine 30 (0.66 g, 0.83 mmol), and tosylate 11 (0.40 g, 1.84 mmol) in acetonitrile (10 mL) and Hunig's base (0.18 mL, 1.0 mmol) was microwave heated to 90 0 C within 10 min and maintained at 90 0 C for 1.5h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in IN HCl (60 mL) and kept stirring at room temperature for about 2h. CH 2 Cl 2 (30 mL) was added and the two layers were separated.
  • Desmethyl telithromycin 30 was treated according to the procedures of US Patent No. 6,124,269 to afford the 2-fluoro amine 30a. This was then alkylated with the tosylate of 1- butyn-4-ol under the conditions for making Ml 5 to afford the fluorinated alkynyl macrolide M19. The reactions are outlined in the following scheme.
  • Alkynyl macrolides M21, M22, and M23 are prepared according to the following reaction scheme from alkynyl macrolide M20.
  • Alkynyl macrolide M20 is in turn made from alkynyl macrolide M14.
  • Alkynyl macrolide M27 is made from alkynyl macrolide M23 by reduction of the oxime to the imine followed by acetylation of the compound, which is then oxidized to give the bridged ketone. The cladinose sugar is then hydrolyzed by treatment with dilute hydrochloric acid. Synthesis of Alkynyl Macrolide M28
  • Alkynyl macrolide M28 is made by refluxing alkynyl macrolide M27 with the following hydroxyl amine compound in methanol.
  • Alkynyl macrolides M6, M7, and M8 are made from M26 (using a procedure analogous to that for making M2, in which the hydrazine is replaced with methyl amine, ammonium hydroxide, and ethanol amine respectively.
  • Alkynyl macrolides such as M29, M30, M31, and M32 are made from M26 using the following general procedure and the corresponding diamino compound.
  • M29 to a solution of compound M26 (6.25g, 6.6 mmol) in CH 3 CN
  • azides compounds used in preparing the compounds of the present invention can be readily synthesized by methods known from the literature. Exemplary azide syntheses are presented below. The remaining azides can be synthesized in analogous fashion from appropriate commercial starting materials. When possible, azides were produced from the corresponding substituted alkyl bromides by direct displacement with azide ion. When the required alkyl bromides were not readily available, the compounds were derived from substituted alkanols: to accomplish this, the alcohols were first activated as their sulfonyl ester derivatives and then substituted with azide ion.
  • azides were synthesized from the corresponding carboxylic acids by reduction with borohydride to the corresponding alcohols. The resulting alkanols were then treated as above to yield the azides. Finally, some azides of were synthesized from the corresponding substituted alkyl amines by reaction with triflic azide. In a few cases, azides were synthesized by modification of other azides that had been synthesized according to the methodologies above. The following are exemplary schemes for preparing azides.
  • Florfenicol amine Florfenicol azide A solution of florfenicol (0.090 g, 0.25 mmol) in acetic acid (3.0 mL) was treated with sulfuric acid (10%, 15 mL) and heated to 110 °C for 12 h. The reaction mixture was cooled to room temperature, treated with 10 M aqueous sodium hydroxide to adjust the pH to 14, extracted with dichloromethane (3 x 30 mL), dried (Na 2 SO 4 ), and evaporated to provide florfenicol amine (65 mg, 0.25 mmol) as a yellow oil.
  • Triflic azide solution (3.5 mmol dissolved in 7 mL of dichloromethane; solution prepared according to method described in J. Am. Chem. Soc. 2002, 124, 10773) was added and the mixture was stirred at rt for 14 h.
  • the reaction mixture was diluted with dichloromethane (30 mL) washed with saturated NaHCO 3 , and with brine.
  • the organic extract was dried, filtered and concentrated to give the azide compound as a white solid (150 mg)
  • the foregoing azide compound is useful for preparing a wide variety of macrolide compounds of the present invention.
  • the free nitro functional group in the macrolide compound can be later transformed to an azide via an amino group. This azide can be used for further cyclization reactions.
  • the fluoro azide compound was prepared from the azide compound as shown.
  • the organic azide compounds used in the synthesis of the compounds of the present invention are generally prepared from the iodo compound 2 or the boronic acid ester compound 3.
  • the iodo or boronic acid functional groups provide a means for preparing a wide range of compounds using methods available to one skilled in the art.
  • the iodo compound 2 is prepared according to the following scheme from commercially available (lR,2R)-(-)-2-amino-l-(4-nitrophenyl)-l,3-propanediol.
  • the boronic acid ester compound 3 is prepared from the iodo compound 2.
  • R a , R b , R c , and R d represent various alkyl, substituted alkyl, aryl, and substituted aryl groups.
  • R a , R b , R c , and R a represent various alkyl, substitued alky!, aryl, substituted aryl, etc.
  • the compounds of the present invention were tested for antimicrobial activity. These data are presented in Table 3. The compounds were run against Streptococcus pneumoniae (wild type strain 02J1016) and Streptococcus pyogenes (wild type strain SS1542) using a standard microdilution assay to determine minimum inhibitory concentrations (MICs). The data is presented whereby a "+” indicates that the compound has an MIC value of 16 micrograms/ml or less and a "-" indicates that the compound has an MIC value greater than 16 micrograms/ml. A "N/A" means that data is unavailable.
  • the compounds can be assessed against other bacterial organisms and that the presentation of data for activity against Streptococcus pneumoniae and Streptococcus pyogenes is for illustrative purposes and in no way is intended to limit the scope of the present invention.
  • the compounds of the present invention can be assayed against a range of other microorganisms depending upon the performance activity desired to be gathered.
  • the "+", “-”, and “N/A" representation and the selection of a cutoff value of 16 micrograms/ml is also illustrative and in no way is intended to limit the scope of the present invention.
  • a "-" is not meant to indicate that the compound necessarily lacks activity or utility, but rather that its MIC value against the indicated microorganism is greater than 16 micrograms/ml.

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Abstract

The present invention provides macrolide compounds containing an oxime or other related functionality useful as therapeutic agents. More particularly, these compounds are useful as anti-infective, antiproliferative, anti-inflammatory, and prokinetic agents.

Description

MACROLIDE COMPOUNDS AND METHODS OFMAKINGAND USING THE SAME
RELATED APPLICATIONS
This application incorporates by reference, and claims the benefit of and priority to U.S. Patent Application No. 60/904,355, filed February 28, 2007, U.S. Patent Application No. 60/904,396, filed February 28, 2007, U.S. Patent Application No. 60/904,392, filed February 28, 2007, U.S. Patent Application No. 60/904,351, filed February 28, 2007, and U.S. Patent Application No. 60/904,395, filed February 28, 2007.
FIELD OF THE INVENTION
The present invention relates generally to the field of anti -infective, anti -proliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family macrolide compounds that are useful as such agents, hi particular embodiments the present invention relates to macrolide compounds in which the macrocyclic ring contains an oxime or other related functionality and wherein the compounds also contain a triazole ring.
BACKGROUND
Since the discovery of penicillin in the 1920s and streptomycin in the 1940s, many new compounds have been discovered or specifically designed for use as antibiotic agents. It was once believed that infectious diseases could be completely controlled or eradicated with the use of such therapeutic agents. However, such beliefs have been shaken because strains of cells or microorganisms resistant to currently effective therapeutic agents continue to evolve. In fact, virtually every antibiotic agent developed for clinical use has ultimately encountered problems with the emergence of resistant bacteria. For example, resistant strains of Gram-positive bacteria such as methicillin-resistant staphylococci, penicillin-resistant streptococci, and vancomycin-resistant enterococci have developed. These resistant bacteria can cause serious and even fatal results for patients infected with such resistant bacteria. Bacteria that are resistant to macrolide antibiotics have emerged. Also, resistant strains of Gram-negative bacteria such as H. influenzae and M. catarrhalis have been identified. See, e.g., F.D. Lowry, "Antimicrobial Resistance: The Example of Staphylococcus aureus," J. Clin. Invest., vol. I l l, no. 9, pp. 1265-1273 (2003); and Gold, H.S. and Moellering, R.C., Jr., "Antimicrobial-Drug Resistance," N. Engl. J. Med., vol. 335, pp. 1445-53 (1996).
The problem of resistance is not limited to the area of anti-infective agents. Resistance has also been encountered with antiproliferative agents used in cancer chemotherapy. Therefore, the need exists for new anti-infective and antiproliferative agents that are both effective against resistant bacteria and resistant strains of cancer cells.
Despite the problem of increasing antibiotic resistance, no new major classes of antibiotics have been developed for clinical use since the approval in the United States in 2000 of the oxazolidinone ring-containing antibiotic, linezolid, which is sold under the trade name Zyvox®. See, R.C. Moellering, Jr., "Linezolid: The First Oxazolidinone Antimicrobial," Annals of Internal Medicine, vol. 138, no. 2, pp. 135-142 (2003). Linezolid was approved for use as an anti-bacterial agent active against Gram-positive organisms. However, linezolid-resistant strains of organisms are already being reported. See, Tsiodras et al., Lancet, vol. 358, p. 207 (2001); Gonzales et al., Lancet, vol 357, p. 1179 (2001); Zurenko et al., Proceedings Of The 39th Annual Interscience Conference On Antibacterial Agents And Chemotherapy (ICAAC), San Francisco, CA, USA (September 26-29, 1999).
Another class of antibiotics is the macrolides, so named for their characteristic 14- to 16-membered ring. The macrolides also often have one or more 6-membered sugar-derived rings attached to the main macrolide ring. The first macrolide antibiotic to be developed was erythromycin, which was isolated from a soil sample from the Philippines in 1952. Even though erythromycin has been one of the most widely prescribed antibiotics, its disadvantages are relatively low bioavailability, gastrointestinal side effects, and a limited spectrum of activity. Another macrolide is the compound, azithromycin, which is an azolide derivative of erythromycin incorporating a methyl-substituted nitrogen in the macrolide ring.
Azithromycin is sold under the trade name Zithromax®. A more recently introduced macrolide is telithromycin, which is sold under the trade name Ketek®. Telithromycin is a semisynthetic macrolide in which a hydroxyl group of the macrolide ring has been oxidized to a ketone group. See Yong-Ji Wu, Highlights of Semi-synthetic Developments from Erythromycin A, Current Pharm. Design, vol. 6, pp. 181-223 (2000); Yong-Ji Wu and Wei- uo Su, Recent Developments on Ketolides and Macrolides, Curr. Med. Chem., vol. 8, no. 14, pp. 1727-1758 (2001); and Pal, Sarbani, "A Journey Across the Sequential Development of Macrolides and Ketolides Related to Erythromycin, Tetrahedron 62 (2006) 3171-3200.
In the search for new therapeutic agents, researchers have tried combining or linking various portions of antibiotic molecules to create multifunctional or hybrid compounds Other researches have tried making macrolide derivatives by adding further substituents to the large macrolide ring or associated sugar rings. However, this approach for making macrolide derivatives has also met with limited success. Notwithstanding the foregoing, there is an ongoing need for new anti-infective and antiproliferative agents. Furthermore, because many anti-infective and antiproliferative agents have utility as anti-inflammatory agents and prokinetic agents, there is also an ongoing need for new compounds useful as anti-inflammatory and prokinetic agents. The present invention provides compounds that meet these needs.
SUMMARY OF THE INVENTION
The invention provides compounds useful as anti-infective agents and/or antiproliferative agents, for example, anti-biotic agents, anti-microbial agents, anti-bacterial agents, anti-fungal agents, anti-parasitic agents, anti-diarrheal agents, anti- viral agents, and chemotherapeutic agents. The present invention also provides compounds useful as antiinflammatory agents, and/or prokinetic (gastrointestinal modulatory) agents. The present invention also provides pharmaceutically acceptable salts, esters, N-oxides, or prodrugs of these compounds.
The present invention provides oxime containing macrolide compounds having the structure:
Figure imgf000004_0001
or a stereoisomer, pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In the formula, variables G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd and Re can be selected from the respective groups of chemical moieties later defined in the detailed description. hi addition, the invention provides methods of synthesizing the foregoing compounds. Following synthesis, a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a mammal, particularly humans, for use as an anti-cancer, anti-biotic, anti-microbial, anti-bacterial, antifungal, anti-parasitic, anti-diarrheal, or anti- viral agent, or to treat a proliferative disease, an inflammatory disease or a gastrointestinal motility disorder, or to suppress disease states or conditions caused or mediated by nonsense or missense mutations, hi certain embodiments, the compounds of the present invention are useful for treating, preventing, or reducing the risk of microbial infections or for the manufacture of a medicament for treating, preventing, or reducing the risk of microbial infections. Accordingly, the compounds or the formulations can be administered, for example, via otic, ophthalmic, nasal, oral, parenteral, or topical routes, to provide an effective amount of the compound to the mammal. The foregoing and other aspects and embodiments of the invention can be more fully understood by reference to the following detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a family of compounds that can be used as antiproliferative agents and/or anti-infective agents. The compounds can be used without limitation, for example, as anti-cancer, anti-microbial, anti-bacterial, anti-fungal, antiparasitic and/or anti-viral agents. Further, the present invention provides a family of compounds that can be used without limitation as anti-inflammatory agents, for example, for use in treating chronic inflammatory airway diseases, and/or as prokinetic agents, for example, for use in treating gastrointestinal motility disorders such as gastroesophageal reflux disease, gastroparesis (diabetic and post surgical), irritable bowel syndrome, and constipation. Further, the compounds can be used to treat or prevent a disease state in a mammal caused or mediated by a nonsense or missense mutation. Further, the present invention provides a family of compounds that can be used without limitation as anti-diarrheal agents.
The compounds described herein can have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention. Furthermore, the invention also includes metabolites of the compounds described herein. 1. Definitions
The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).
The term "oxime or other related functionality" means a functional group such as an oxime, -(C=NOH)- or -(C=NOR)-, a hydrazone, -(C=N-NH2)-, -(C=N-NHR)-,or -(C=N- NR2)-, an azine, -(C=N-N=CH2)-, -(C=N-N=CHR)-, or -(C=N-N=CR2)-, an imine, -(C=NH)- or -C=NR)- (also known as a Schiff base), etc. For illustrative purposes of this paragraph, R includes, but is not limited to substituents such as alkyl, aryl, acetyl etc. As can be seen from the compounds illustrated in the present invention, a wide variety of compounds can include a carbamate or other related functionality. Some nonlimiting examples include: compound 200, which is a carbamate of the form -(C=NOH)- and compound 201, which is a carbamate of the form -(C=NOR)-, where R = -CH2OCH2CH2OCH3. One of skill in the art will appreciate that the term "oxime or other related functionality" is being used herein to describe a generally common chemical feature of the compounds of the present invention. The various chemical variable substituents, as defined in the present patent application, further illustrate the term "oxime or other related functionality".
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C- 13 and C- 14. When any variable (e.g., R2) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with one or more R2 moieties, then the group can optionally be substituted with one, two, three, four, five, or more R2 moieties, and R2 at each occurrence is selected independently from the definition of R2. Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. A chemical structure showing a dotted line representation for a chemical bond indicates that the bond is optionally present. For example, a dotted line drawn next to a solid single bond indicates that the bond can be either a single bond or a double bond.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent can be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent can be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds. In cases wherein there are nitrogen atoms in the compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of the present invention. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N- >O) derivative, as appropriate. As used herein, the term "anomeric carbon" means the acetal carbon of a glycoside.
As used herein, the term "glycoside" is a cyclic acetal.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Ci_6 alkyl is intended to include Ci, C2, C3, C4, C5, and CO alkyl groups. C1.8 alkyl is intended to include Ci, C2, C3, C4, C5, C^, Cη, and Cs alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n- hexyl, n-heptyl, and n-octyl.
As used herein, "alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that can occur in any stable point along the chain, such as ethenyl and propenyl. C2-6 alkenyl is intended to include C2, C3, C4, C5, and Ce alkenyl groups. C2-8 alkenyl is intended to include C2, C3, C4, C5, Ce, Cη, and Cs alkenyl groups.
As used herein, "alkynyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that can occur in any stable point along the chain, such as ethynyl and propynyl. C2-6 alkynyl is intended to include C2, C3, C4, C5, and Cξ, alkynyl groups. C2-8 alkynyl is intended to include C2, C3, C4, C5, CO, C7, and Cs alkynyl groups. Furthermore, "alkyl", "alkenyl", and "alkynyl" are intended to include moieties which are diradicals, i.e., having two points of attachment, an example of which in the present invention is when D is selected from these chemical groups. A nonlimiting example of such an alkyl moiety that is a diradical is -CH2CH2-, i.e., a C2 alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule.
As used herein, the terms used to describe various carbon-containing moieties, including, for example, "alkyl," "alkenyl," "alkynyl," "phenyl," and any variations thereof, are intended to include univalent, bivalent, or multivalent species. For example, "Ci_6 alkyl-
R3" is intended to represent a univalent Ci -6 alkyl group substituted with a R3 group, and "O- C i-6 alkyl-R3" is intended to represent a bivalent C 1.6 alkyl group, i.e., an "alkylene" group, substituted with an oxygen atom and a R3 group.
As used herein, "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-8 cycloalkyl is intended to include C3, C4, C5,
Ce, C7, and Cs cycloalkyl groups. As used herein, "unsaturated" refers to compounds having at least one degree of unsaturation (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds.
As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo substituents. "Counterion" is used to mean a positively or negatively charged species present in conjunction with an ion of opposite charge. A nonlimiting example of a counterion is an ion or ions present to counterbalance the charge or charges on an organic compound.
Nonlimiting examples of counterions include chloride, bromide, hydroxide, acetate, sulfate, and ammonium. As used herein, "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CVFW where v = 1 to 3 and w = 1 to (2v+l)).
Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. As used herein, "alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Ci.6 alkoxy, is intended to include Ci, C2, C3, C4, C5, and Ce alkoxy groups. Ci_s alkoxy, is intended to include Ci, C2, C3, C4, C5, Ce, Cη, and Cs alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.
As used herein, "alkylthio" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an sulfur bridge. Ci -6 alkylthio, is intended to include Ci, C2, C3, C4, C5, and C^ alkylthio groups. Ci_s alkylthio, is intended to include Ci, C2, C3, C4, C5, Cβ, C7, and Cs alkylthio groups.
As used herein, "carbocycle" or "carbocyclic ring" is intended to mean, unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, any of which can be saturated, unsaturated (including partially and fully unsaturated), or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring can also be present on the bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) and spiro rings are also included.
As used herein, the term "heterocycle" means, unless otherwise stated, a stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, which is saturated, unsaturated (including partially and fully unsaturated), or aromatic, and consists of carbon atoms and one or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur, and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused or attached to a second ring (e.g., a benzene ring). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N— >O and S(O)P, where p = 1 or 2). When a nitrogen atom is included in the ring it is either N or NH, depending on whether or not it is attached to a double bond in the ring (i.e., a hydrogen is present if needed to maintain the tri-valency of the nitrogen atom). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein
R is H or another substituent, as defined). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle can optionally be quaternized. Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. When a ring is bridged, the substituents recited for the ring can also be present on the bridge. Spiro and fused rings are also included. As used herein, the term "aromatic heterocycle" or "heteroaryl" is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1- 6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of the two rings needs to be aromatic (e.g., 2,3- dihydroindole), though both can be (e.g., quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O)P, where p = 1 or 2). In certain compounds, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a//-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6//-l,5,2-dithiazinyl, dihydrofuro[2,3-6]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3Η-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. As used herein, "treating" or "treatment" includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc. "Treating" or "treatment" of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
As used herein, "preventing" means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state. As used herein, "mammal" refers to human and non-human patients.
As used herein, the term "therapeutically effective amount" refers to a compound, or a combination of compounds, of the present invention present in or on a recipient in an amount sufficient to elicit biological activity, for example, anti-microbial activity, anti-fungal activity, anti-viral activity, anti-diarrheal activity, anti-parasitic activity, and/or antiproliferative activity. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiproliferative and/or anti-infective effect, or some other beneficial effect of the combination compared with the individual components. All percentages and ratios used herein, unless otherwise indicated, are by weight.
Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present invention also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
2. Compounds of the Invention hi one aspect, the invention relates to a compound having the structure:
Figure imgf000013_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein
T is a 14- or 15-membered macrolide connected via a macrocyclic ring carbon atom; X is selected from (a) H, (b) halogen, (c) a C1-6 alkyl group, (d) a C2-6 alkenyl group, (e) a C2-6 alkynyl group, (f) -OH, (g) -OR5, (h) -NR4R4, (i) -C(O)R5, (j) -C(O)OR5, (k) -
C(O)-NR4R4, (1) -C(S)R5, (m) -C(S)OR5, (n) -C(O)SR5, (o) -C(S)-NR4R4, (p) -N3, (q) -CN, (r) -CF3, (S) -CF2H, (t) -CFH2, (u) -S(O)PH, (v) -S(O)pR5, (w) -S(O)POH, (x) -S(O)POR5, (y) -S(O)PNR4R4, (z) -NR4C(O)R5, (aa) -NR4C(O)NR4R4, (bb) a C3-7 saturated, unsaturated, or aromatic carbocycle, and (cc) a 3-7 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur;
Ra and Rb independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OH, (f) -OR5, (g) -NR4R4, (h) -C(=O)R5, (i) - C(=O)OR5, G) -C(=O)-NR4R4, (k) -S(O)pNR4 R4, (1) -C(O)SR5, (m) halogen, (n) -S(O)15H, (o) - S(O)pR5, (p) -N3, (q) -CN, and (r) -NR4C(O)R5, wherein (b) -(d) are further optionally substituted with one or more R5 groups; alternatively Ra and Rb are taken together with the carbon to which they are attached to form (a) -C(=O)-, (b) -C(=S)-, (c) -C=NR4, or (d) -C=NOR5; Rc is selected from: (a) H, (b) a C)-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OR5 where R5 is not H, (f) -NR4R4, (g) -C(=O)R5, (h) -C(=O)OR5, (i) - Q=O)-NR4R4, G) -S(O)PNR4 R4, (k) -C(O)SR5, (1) -S(O)pH, (m) - S(O)pR5, (n) -CF3, (o) - CH2F, and (p) -CF2H, wherein (b) -(d) are further optionally substituted with one or more R5;
Rd and Re independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OH, (f) -OR5, (g) -NR4R4, (h) -C(O)R5, (i) - C(=O)OR5, G) -C(=O)-NR4R4, (k) -S(O)pNR4 R4, (1) -C(O)SR5, (m) halogen, (n) -S(O)15H, and (o) - S(O)PR5, wherein (b) -(d) are further optionally substituted with one or more R5, or alternatively Rd and Re are taken together with the carbon to which they are attached to form (a) -C(=O)-, (b) -C(=S)-, (c) -C=NR4, or (d) -C=NOR5; alternatively, Rc and Rd or Rc and Re are taken together to form a carbon-carbon double bond between the carbon atoms to which they are attached; alternatively Rd and X are taken together to form =CR5R5; or alternatively Rd and Re are taken together with the carbon to which they are attached to form (a) -C(=0)-, (b) -C(=S)-, (c) -C=NR4, (d) -C=NOR5, (e) =CH2, or (f) 3-12- membered carbocycle or heterocycle optionally substituted with one or more R5;
R1 and R3 independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -C(O)R5, (f) -C(O)OR5, (g) -C(O)-NR4R4, (h) - C(S)R5, (i) -C(S)OR5, G) -C(O)SR5, and (k) -C(S)-NR4R4; alternatively R1 and R3 are taken together with the oxygen to which R1 is attached, the nitrogen to which R3 is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R5 groups; R2 is hydrogen or -OR12;
G is selected from: (a) -B' and (b) -B'-Z-B", wherein i) each B' is independently selected from (aa) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings and (bb) a 3- 12 membered saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 rings and containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (aa) or (bb) optionally contains one or more carbonyl groups, and wherein each (aa) or (bb) optionally is substituted with one or more R11 or R1 ' a; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc) -OR9, (dd) - SH, (ee) -S(O)pR9, (ff) halogen, (gg) -CN, (Hh)-N3, (ii) -NO2, Oj) -Si(R13)3, (kk) -SO3H, (11) -SO3N(R4)2, (mm) -SO3R9, (nn) -NR6R6, (oo) -C(O)R9,
(PP) -C(O)(CR6R6)tR9, (qq) -OC(O)(CR6R6)tR9, (rr) -C(O)O(CR6R6)tR9, (ss) -NR6(CR6R6)tR9, (tt) -NR6C(O)(CR6R6)tR9, (uu) -C(O)NR6(CR6R6)tR9, (w) -NR6C(O)NR6(CR6R6)tR9, (ww) -C(=NR6)(CR6R6)tR9, (xx) - C(=NR6)NR6)(CR6R6)tR9, (yy) -NR6C(=NR6)NR6)(CR6R6)tR9, (zz) - S(O)p(CR6R6)tR9, (aaa) -SC(O)(CR6R6)tR9, (bbb) -C(=NNR6R6)(CR6R6)tR9,
(ccc) -C[=NNR6C(O)R6](CR6R6)tR9, (ddd) -NR6C(O)O(CR6R6)tR9, (eee) - OC(O)NR6(CR6R6)tR9, (fff) -NR6C(O)NR6(CR6R6)tR9, (ggg) -
NR6S(O)p(CR6R6)tR9, (hhh) -NR6C(O)R6, (iii) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings, (jjj) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group having 1 to
3 rings and containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (kkk) -C1-6 alkyl, (111) -C2-6 alkenyl, and (mmm) a C2-6 alkynyl group; wherein each (iii) or (jjj) optionally contains one or more carbonyl groups, and wherein each (iii) or (jjj) optionally is substituted with one or more R1 ' or R1 la; wherein each (kkk), (111), or (mmm) is optionally are substituted with one or more R14 groups; iii) Z is selected from (a) a single bond, (b) -C1-6 alkyl-, (c) -C2-6 alkenyl-, (d) - C2-6 alkynyl-, (e) -O-, (f) -NR4-, (g) -S(O)P-, (h) -C(OK 0) -C(O)O-, Q) - OC(O)-, (k) -OC(O)O-, (1) -C(O)NR4-, (m) -NR4CO-, (n) -NR4C(O)NR4-, (o) -C(=NR4K (?) -C(=NR4)O-, (q) -OC(=NR4)-, (r) -C(=NR4)NR4-, (s) -
NR4Q=NR4)-, (t) -C(=SH (u) -C(=S)NR4-, (v) -NR4C(=S)-, (w) -C(O)S- , (x) -SC(O)-, (y) -OC(=S)-, and (z) -C(=S)-O-, wherein any of the aliphatic carbons atoms in (b), (c), or (d) are optionally replaced with - (C=O)-, -O-, -S-, or -NR4-, and wherein any of (b), (c), or (d), are optionally further substituted with -OH, -NR4-, or halogen; R14 at each occurrence is independently selected from: (a) H, (b) F, (C) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)15R8, 0) -
C(O)R8, (k) -C(O)OR8, (1) -OC(O)R8, (m) -C(O)NR8R8, (n) -OC(O)NR8R8, (o) -C(=NR8)R8, (p) -C(R8)(R8)OR8, (q) -C(R8)2OC(O)R8, (r) -C(R8)(OR8)(CH2)rNR8R8, (s) -NR8R8, (t) -NR8OR8, (u) -NR8C(O)R8, (v) -NR8C(O)OR8, (w) -NR8C(O)NR8R8, (x) -NR8S(O)pR8, (y) - C(OR8)(OR8)R8, (z) -C(R8)2NR8R8, (aa) -C(S)NR8R8, (bb) -NR8C(S)R8, (cc) -
OC(S)NR8R8, (dd) -NR8C(S)OR8, (ee) -NR8C(S)NR8R8, (ff) -SC(O)R8, (gg) - N3, (hh) -Si(RI3)3, (ii) a C1-6 alkyl group, (jj) a C2-6 alkenyl group, (kk) a C2-6 alkynyl group, (11) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (ii)-(mm) optionally are substituted with one or more R5 groups; alternatively two R14 groups are taken together to form (a) =0, (b) =S, (c) =NR8, or (d) =N0R8;
R4, at each occurrence, independently is selected from: (a) H, (b) a Ci-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C6-12 saturated, unsaturated, or aromatic carbocycle, (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-Ci-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-J2 saturated, unsaturated, or aromatic carbocycle, (k) -C(O)- 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (1) -C(O)O-Cj-6 alkyl, (m) -C(O)O- C2-6 alkenyl, (n) -C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-12 saturated, unsaturated, or aromatic carbocycle, (p) -C(O)O-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and (q) -C(O)NR6R6, wherein any of (b)-(p) optionally is substituted with one or more R5 groups, alternatively, NR4R4 forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R4 groups are bonded, wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R4 groups are bonded, with one or more moieties selected from O, S(O)p, N, and NR8; R5 is selected from:
(a) R7, (b) a Cj-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-I2 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, or; wherein any of (b)-(f) immediately above optionally is substituted with one or more R7 groups; alternatively two R5 groups, when present on the same carbon atom can be taken together with the carbon atom to which they are attached to form a spiro 3-6 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of these ring systems formed from two R5 groups optionally is substituted with one or more R7 groups; R6, at each occurrence, independently is selected from:
(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) optionally is substituted with one or more moieties selected from: (aa) a carbonyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee) Br, (ff)
I, (gg) CN, (hh) NO2, (ii) -OR8, (jj) -S(O)pR8, (kk) -C(O)R8, (11) -C(O)OR8, (mm) -OC(O)R8, (nn) -C(O)NR8R8, (oo) -OC(O)NR8R8, (pp) -C(=NR8)R8, (qq) -C(R8)(R8)OR8, (rr) -C(R8)2OC(O)R8, (ss) -C(R8)(OR8)(CH2)rNR8R8, (tt) -NR8R8, (uu) -NR8OR8, (w) -NR8C(O)R8, (ww) -NR8C(O)OR8,
(XX) -NR8C(O)NR8R8, (yy) -NR8S(O)rR8, (zz) -C(OR8)(OR8)R8, (ab) -C(R8)2NR8R8, (ac) =NR8, (ad) -C(S)NR8R8, (ae) -NR8C(S)R8, (af) -OC(S)NR8R8, (ag) -NR8C(S)OR8, (ah) -NR8C(S)NR8R8, (ai) -SC(O)R8, (aj) a C1-6 alkyl group, (ak) a C2-6 alkenyl group, (al) a C2-6 alkynyl group, (am) a Ci-6 alkoxy group, (an) a C1-6 alkylthio group, (ao) a Ci-6 acyl group, (ap) -CF3, (aq) -SCF3, (ar) a C3-I2 saturated, unsaturated, or aromatic carbocycle, and (as) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR6R6 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R6 groups are attached wherein said ring is optionally replaced at a position other than the nitrogen atom to which the R6 groups are bonded, with one or more moieties selected from -O-, -S(O)P-, -N=, and -NR8-; alternatively, CR6R6 forms a carbonyl group; R7, at each occurrence, is selected from:
(a) H, (b) -O, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -N3, (j) -NO2, (k) -NR6(CR6R6)tR9, (1) -OR9, (m) -S(O)pC(R6R6)tR9, (n) -C(O)(CR6R6)tR9, (o) -OC(O)(CR6R6)tR9, (p) -SC(O)(CR6R6)tR9, (q) -C(O)O(CR6R6)tR9, (r) -
NR6C(O)(CR6R6)tR9, (s) -C(O)NR6(CR6R6)tR9, (t) -C(=NR6)(CR6R6)tR9, (u) -C(=NNR6R6)(CR6R6)tR9, (v) -C(=NNR6C(O)R6)(CR6R6)tR9, (w) - C(=NOR9)(CR6R6)tR9, (x) -NR6C(O)O(CR6R6)tR9, (y) - OC(O)NR6(CR6R6)tR9, (z) -NR6C(O)NR6(CR6R6)tR9, (aa) - NR6S(O)p(CR6R6)tR9, (bb) -S(O)pNR6(CR6R6)tR9, (cc) -
NR6S(O)pNR6(CR6R6)tR9, (dd) -NR6R6, (ee) -NR6(CR6R6), (ff) -OH, (gg) - NR6R6, (hh) -OCH3, (ii) -S(O)pR6, Oj) -NC(O)R6, (kk) -Si(R13)3, (11) a C,_6 alkyl group, (mm) a C2_6 alkenyl group, (nn) a C2.6 alkynyl group, (oo) - C3-12 saturated, unsaturated, or aromatic carbocycle, and (pp) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (H)- (pp) optionally is substituted with one or more R9 groups; alternatively, two R7 groups can form -O(CH2)UO-, =O, or =S; R8 is selected from: (a) R5, (b) H, (c) a C1-6 alkyl group, (d) a C2-6 alkenyl group, (e) a C2.6 alkynyl group, (f) a C3-I2 saturated, unsaturated, or aromatic carbocycle, (g) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (h) -C(O)-C1-6 alkyl, (i) -C(O)-C2-6 alkenyl, G) -C(O)-C2-6 alkynyl, (k) -C(O)-C3-12 saturated, unsaturated, or aromatic carbocycle, and (1) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (c)-(l) optionally is substituted with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, (jj) NH(C1-6 alkyl), (kk) N(C1-6 alkyl)2, (11) a C1-6 alkoxy group, (mm) an aryl group, (nn) a substituted aryl group, (oo) a heteroaryl group, (pp) a substituted heteroaryl group, and (qq) a C1-6 alkyl group optionally substituted with one or more moieties selected from an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, F, Cl, Br, I, CN, NO2, CF3, SCF3, and OH; R9, at each occurrence, independently is selected from: (a) R10, (b) a C1^ alkyl group, (c) a C2.6 alkenyl group, (d) a C2.6 alkynyl group,
(e) a C3-I2 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) optionally is substituted with one or more R10 groups; R10, at each occurrence, independently is selected from:
(a) H, (b) =0, (c) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -NO2, O) - NR6R6, (k) -OR6, (1) -S(O)pR6, (m) -C(O)R6, (n) -C(O)OR6, (o) -OC(O)R6, (p) NR6C(O)R6, (q) -C(O)NR6R6, (r) -C(=NR6)R6, (s) -NR6C(O)NR6R6, (t) - NR6S(O)pR6, (u) -S(O)pNR6R6, (v) -NR6S(O)pNR6R6, (w) a C,_6 alkyl group, (x) a C2.6 alkenyl group, (y) a C2.6 alkynyl group, (z) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (aa) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (w)-(aa) optionally is substituted with one or more moieties selected from R6, F, Cl, Br, I, CN, NO2, -OR6, -NH2, -
NH(C1-6 alkyl), -N(Ci-6 alkyl)2, a Ci-6 alkoxy group, a Ci-6 alkylthio group, and a Ci-6 acyl group;
R11 and RUa at each occurrence, independently is selected from: (a) a carbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g) CN, (h) NO2, (i) OR8, G) -S(O)pR8, (k) -C(O)R8, (1) -C(O)OR8, (m) -OC(O)R8, (n) -C(O)NR8R8, (o) -OC(O)NR8R8, (p) -C(=NR8)R8, (q) -C(R8)(R8)OR8, (r) -C(R8)2OC(O)R8, (s) -C(R8)(OR8)(CH2)rNR8R8, (t) -NR8R8, (u) -NR8OR8, (v) -NR8C(O)R8, (w) -NR8C(O)OR8, (x) -NR8C(O)NR8R8, (y) -NR8S(O)pR8,
(z) -C(OR8)(OR8)R8, (aa) -C(R8)2NR8R8, (bb) =NR8, (cc) -C(S)NR8R8, (dd) - NR8C(S)R8, (ee) -OC(S)NR8R8, (ff) -NR8C(S)OR8, (gg) -NR8C(S)NR8R8, (hh) -SC(O)R8, (ii) -N3, (jj) -Si(R13)3, (Wc) a C1-6 alkyl group, (11) a C2-6 alkenyl group, (mm) a C2-6 alkynyl group, (nn) a C1-6 alkoxy group, (oo) a C]-6 alkylthio group, (pp) a C1-6 acyl group, (qq) a C3-I2 saturated, unsaturated, or aromatic carbocycle, (rr) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (ss) -B(OH)2, (tt) -B(OC1-6 alkyl)2, (uu) -B(OH)(OC1-6 alkyl), (w) -B[-OC(CH3)2(CH3)2CO-], (WW) -P(OH)2, (xx) -P(OC1-6 alkyl)2, (yy) - P(OH)(OCi-6 alkyl), and (zz) -NR8(C=NR8)R8, (aaa) -C(R8)2NR8R8, wherein
(kk)-(mm) optionally are substituted with one or more R5 groups; R12 is selected from:
(a) H, (b) a Ci-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -C(O)R5, (f) -C(O)OR5, (g) -C(O)-NR4R4, (h) -C(S)R5, (i) -C(S)OR5, (j) -C(O)SR5, (k) -C(S)-NR4R4, (1) a C3-I2 saturated, unsaturated, or aromatic carbocycle, or (m) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (n) a -(C1-6 alkyl) -C3-12 saturated, unsaturated, or aromatic carbocycle, and (o) a -(C1-6 alkyl)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (b)-{d) an<^ (IM0) optionally are substituted with one or more R5 groups; each R13 is independently selected from (a) -Ci-6 alkyl and (b) -0-(Ci-6 alkyl): p at each occurrence is O, 1, or 2; r at each occurrence is O, 1, or 2; t at each occurrence is O, 1, or 2; and u at each occurrence is 1, 2, 3, or 4. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or pro-drug thereof, wherein G is selected from G1-G50:
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
G43 G 44
Figure imgf000023_0002
G45
C46
Figure imgf000023_0003
G49 G50
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000023_0004
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000023_0005
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000024_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described herein.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -CN, (g) -CF3, (h) -CF2H, (i) -CFH2, G) -O(C1-6 alkyl), (k) -N3, (1) -COOH, (m) -COO(C1-6 alkyl), (n) -NH2, (o) -NH(C1-6 alkyl), (p) -N(Ci-6 alkyl)2, (q) -C(O)NH2, (r) -C(O)NH(C1-6 alkyl), (s) -C(O)N(C1-6 alkyl)2, (t) -NHC(O)H, (u) - NHC(O)(Ci-6 alkyl), (v) -N(C1-6 alkyl)C(O)H, and (w) -N(C1-6 alkyl)C(O)N(Ci-6 alkyl)2.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from F and OH. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is F. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is OH. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rd and Re are selected from (a) Cl, (b) Br, (c) F, (d) H and (e) C1-6 alkyl. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rd and Re are H.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rc is selected from (a) H, (b) C1-6 alkyl, (c) -CF3, (d) -CF2H, and (e) -CFH2. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rc is H.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra and Rb are independently selected from (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -O(C,-6 alkyl), (g) -N3, (h) -COOH, (i) -COO(C1-6 alkyl), (j) -CN, (k) -NH2, (1) -NH(C1-6 alkyl), (m) -N(C1-6 alkyl)2, (n)-C(O)NH2, (o) -C(O)NH(C1-6 alkyl), (p) -C(O)N(C1-6 alkyl)2, (q) -NHC(O)H, (r) - NHC(O)(C1-6 alkyl), (s) -N(C1-6 alkyl)C(O)H, (t) -N(C1-6 alkyl)C(O)N(C1-6 alkyl)2, (u) -SH, and (v) -S(C1-6 alkyl), or alternatively Ra and Rb are taken together with the carbon to which they are attached to form (aa) -C(=O)- or (bb) -C(=S)-.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein Ra and Rb are independently selected from -H, -F, -OH, -OCH3, -SH, and -SCH3. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein Ra is H and Rb is F. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -OH. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -OCH3. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -SH. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -SCH3.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is H. hi other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 is H. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R2 is H.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is C1-6 alkyl. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is methyl.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is B'.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is selected from: (a) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3- 12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein each (a)-(b) optionally is substituted with one or more R11 groups.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is -B'-Z-B".
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' and B" are independently selected from (a) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein each (a)-(b) optionally is substituted with one or more R1 ' groups.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000026_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described herein. hi other embodiments, the present invention relates to a compound having the structure:
Figure imgf000027_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000027_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000027_0003
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000028_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000028_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000028_0003
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000028_0004
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000029_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000029_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
, wherein, B", Z, and R11 are as described herein and wherein, one of
Figure imgf000029_0003
or B" is substituted with R11.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000030_0001
and B", Z, and R1 ' are as described herein.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein G is:
Figure imgf000030_0002
and B", Z, and R1 ' are as described herein. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein G is:
Figure imgf000030_0003
, wherein B", Z, and R1 ' are as described herein and one of •*? or B" is substituted with R11
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein G is:
Figure imgf000030_0004
, wherein B", Z, and R11 are as described herein.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, jV-oxide, or prodrug thereof, wherein G is:
Figure imgf000031_0001
, wherein B", Z, and R11 are as described herein. hi other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000031_0002
, wherein B", Z, and R11 are as described herein and
Figure imgf000031_0003
or B" is substituted with R11.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000031_0004
, wherein B", Z, and R are as described herein.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000031_0005
, wherein B", Z, and R11 are as described herein. hi other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000032_0001
, wherein B", Z, and R11 are as described herein and
Figure imgf000032_0002
or B" is substituted with R11.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000032_0003
, wherein B", Z, and R11 are as described herein.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000032_0004
, wherein B", Z, and R11 are as described herein.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 ' is selected from (a) OR8, (b) -S(O)PR8, (c) -C(O)R8, (d) -C(O)NR8R8, (e) -C(R8)(R8)OR8, (f) - C(R8)2OC(O)R8, (g) -NR8R8, (h) -NR8C(O)R8, (i) -NR8S(O)pR8, (j) a C1-6 alkyl group, and (k) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (j) is optionally substituted with one or more R5 groups.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 ' is selected from -CH2OH, -SO2CH3, -NH2, -CH3, -C(O)NH2, -CH2OC(O)CH3, CH2OCH3, -NHCH3, - OCH3, ~W , NH(cyclopropyl), -C(O)CH3, -NHC(O)CH3, -C(O)CH3, -S(O)CHF2,
-N(CH3)C(O)-N O
^S , -N(CH3)S(O)2-isopropyl, -N(CH3)S(O)2-butyl, CH2CH2OH, and SO2CHF2. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is F. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1-6 alkyl group, (b) a C2.6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) H, (g) -OH (h) -SH, (i) F, O) Cl, (k) Br, (1) I, (m) -CF3, (n) -CN, (o) -N3 (p) -NO2, (q) -NR^CR^tR9, (r) -OR9, (s) -StCR^tR9, (t) -S(O)(CR6R6)tR9, (u) -S(O)2(CR6R6)tR9, (v) - C(O)(CR6R6)tR9, (w) -OC(O)(CR6R6)tR9, (x) -OC(O)O(CR6R6)tR9, (y) -SC(O)(CR6R6)tR9, (z) -C(O)O(CR6R6)tR9, (aa) -NR6C(O)(CR6R6)tR9, (bb) -C(O)NR6(CR6R6)tR9, (cc) - C(=NR6)(CR6R6)tR9, (dd) -C(=NNR6R6)(CR6R6)tR9, (ee) -C[=NNR6C(O)R6](CR6R6)tR9, (ff) -NR6C(O)O(CR6R6)tR9, (gg) -OC(O)NR6(CR6R6)tR9, (hh) -NR6C(O)NR6(CR6R6)tR9,
(ii) -NR6S(O)p(CR6R6)tR9, Oj) -S(O)pNR6(CR6R6)tR9, (kk) -NR6R6, (11) -NR6(CR6R6),R9, (mm) -SR6, (nn) -S(O)R6, (oo) -S(O)2R6, (pp) -NR6C(O)R6, (qq) -Si(R13)3, and (rr) - C(=O)H; wherein t at each occurrence is O, 1, or 2; wherein (a)-(e) optionally are substituted with one or more R14 groups; wherein R14 at each occurrence is independently selected from:
(a) H, (b) F, (C) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)13R8, O) - C(O)R8, (k) -C(O)OR8, (1) -OC(O)R8, (m) -C(O)NR8R8, (n) -OC(O)NR8R8, (o) -C(=NR8)R8, (p) -C(R8)(R8)OR8, (q) -C(R8)2OC(O)R8, (r) - C(R8)(OR8)(CH2)rNR8R8, (s) -NR8R8, (t) -NR8OR8, (u) -NR8C(O)R8, (v) -
NR8C(O)OR8, (w) -NR8C(O)NR8R8, (x) -NR8S(O)PR8, (y) -C(OR8)(OR8)R8, (z) -C(R8)2NR8R8, (aa) -C(S)NR8R8, (bb) -NR8C(S)R8, (cc) -OC(S)NR8R8, (dd) -NR8C(S)OR8, (ee) -NR8C(S)NR8R8, (ff) -SC(O)R8, (gg) -N3, (hh) - Si(R13)3, (ii) a C1-6 alkyl group, Oj) a C2-6 alkenyl group, (kk) a C2-6 alkynyl group, (11) a C3-I2 saturated, unsaturated, or aromatic carbocycle, and (mm) a
3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (H)- (mm) optionally are substituted with one or more R5 groups; alternatively two R14 groups are taken together to form (a) =0, (b) =S, (c) =NR8, or (d) =N0R8. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C,_6 alkyl group, (b) a C2^ alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) -CF3, (g) -NR6(CR6R6)tR9, (h) -OR9, (i) -S<CR6R6)tR9, (j) -S(O)(CR6R6)tR9, (k) - S(O)2(CR6R6)tR9, (1) -C(O)(CR6R6)tR9, (m) -OC(O)(CR6R6)tR9, (n) -OC(O)O(CR6R6)tR9,
(0) -SC(O)(CR6R6)tR9, (p) -C(O)O(CR6R6)tR9, (q) -NR6C(O)(CR6R6)tR9, (r) - C(O)NR6(CR6R6)tR9, (s) -C(=NR6)(CR6R6)tR9, (t) -C(=NNR6R6)(CR6R6)tR9, (u) - C[=NNR6C(O)R6](CR6R6)tR9, (v) -NR6C(O)O(CR6R6)tR9, (w) -OC(O)NR6(CR6R6)tR9, (x) -NR6C(O)NR6(CR6R6)tR9, (y) -NR6S(O)p(CR6R6)tR9, (z)
Figure imgf000034_0001
(aa) - NR6R6, (bb) -NR6(CR6R6)tR9, (cc) -SR6, (dd) -S(O)R6, (ee) -S(O)2R6, and (ff) -NR6C(O)R6, wherein (a)-(e) optionally are substituted with one or more R14 groups.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1-6 alkyl group, (b) a C2.6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, wherein (a)-(e) optionally are substituted with one or more R14 groups. In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected (a) -NR6(CR6R6)tR9, (b) -OR9, (c) -S(CR6R6)tR9, (d) -S(O)(CR6R6)tR9, (e) - S(O)2 (CR6R6)tR9, (f) -C(O)(CR6R6)tR9, (g) -OC(O)(CR6R6)tR9, (h) -OC(O)O(CR6R6)tR9,
(1) -SC(O)(CR6R6)tR9, (j) -C(O)O(CR6R6)tR9, (k) -NR6C(O)(CR6R6)tR9, (1) - C(O)NR6(CR6R6)tR9, (m) -C(=NR6)(CR6R6)tR9, (n) -C(=NNR6R6)(CR6R6)tR9, (o) - C[=NNR6C(O)R6](CR6R6)tR9, (p) -NR6C(O)O(CR6R6)tR9, (q) -OC(O)NR6(CR6R6)tR9, (r) - NR6C(O)NR6(CR6R6)tR9, (s) -NR6S(O)p(CR6R6)tR9, (t) ^(O)pNR6(CR6R6)tR9, (u) - NR6R6, (v) -NR6(CR6R6)tR9, (w) -SR6, (x) -S(O)R6, (y) -S(O)2R6, and (z) -NR6C(O)R6. In other embodiments, the present invention relates to a compound, wherein T is:
Figure imgf000035_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein: M is selected from:
(a) -C(=NR114K Φ) -C(=NOR127H and (c) -Q=NNR114R114)-; R100 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR114, and (f) C1-6 alkyl, wherein (f) optionally is substituted with one or more R115 groups;
R101 is selected from:
(a) H, (b) Cl, (c) F, (d) Br, (e) I, (f) -NR114R114, (g) -NR114C(O)R114, (h) - OR114, (i) -OC(O)R114, O) -OC(O)OR114, (k) -OC(O)NR114R114, (1) -0-C1- C6 alkyl, (m) -OC(O)-C1-6 alkyl, (n) -OC(O)O-C1-6 alkyl, (o) -OC(O)NR114- Cr6 alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2-6 alkynyl, wherein any of (1) - (r) optionally is substituted with one or more R115 groups;
R102 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR114, and (f) C1-6 alkyl, wherein (f) optionally is substituted with one or more R115 groups; R103 is selected from:
(a) H, (b) -OR114, (c) -O-d-6 alkyl-R115, (d) -OC(O)R114,
(e) -OC(O)-Ci-6 alkyl-R115, (f) -OC(O)OR114, (g) -OC(O)O-C1-6 alkyl-R115,
(h) -OC(O)NR114R114, (i) -OC(O)NR114-C1-6 alkyl-R115, and
Figure imgf000036_0001
alternatively, R102 and R103 taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups; alternatively, R101 and R103 taken together are a single bond between the respective carbons to which these two groups are attached thereby creating a double bond between the carbons to which R100 and R102 are attached; alternatively, R101 and R103 taken together with the carbons to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring, wherein said 3-7 membered ring can optionally be substituted with one or more R114 groups; alternatively, R100, R101, R102, and R103 taken together with the carbons to which they are attached form a 5 or 6 membered fused carbocyclic or heterocyclic ring, wherein said fused ring can be optionally substituted with one or more R114 groups; R104 is selected from:
(a) H, (b) R114, (c) -C(O)R114(d) -C(O)OR114 (e) -C(O)NR114R114, (f) -C1-6 alkyl-K-R114, (g) -C2-6 alkenyl-K-R114, and (h) -C2-6 alkynyl-K-R114; K is selected from:
(a) -C(OH (b) -C(O)O-, (c) -C(O)NR114-, (d) -C(=NR114)-, (e) - C(^NR114)O-, (f) -Q=NR114)NR! 14-, (g) -OC(O)-, (h) -OC(O)O-, (i) -
OC(O)NR114-, O) -NR114C(O)-, (k) -NR114C(O)O-, (1) -NR114C(O)NR114-, (m) -NR114C(=NR114)NR114-, and (o) -S(0)p-; R105 is selected from:
(a) R114, (b) -OR114, (c) -NR114R114, (d) -O-C1-6 alkyl-R115, (e) -C(O)-R114, (f) -C(O)-C1-6 alkyl-R115, (g) -OC(O)-R114, (h) -OC(O)-Ci-6 alkyl-R115,
(i) -OC(O)O-R114, Q) -OC(O)O-C1-6 alkyl-R115, (k) -OC(O)NR114R114, (1) -OC(O)NR114-C1-6 alkyl-R115, (m) -C(O)-C2-6 alkenyl-R115, and (n) -C(O)-C2-6 alkynyl-R115; R106 is selected from: (a) -OR114, (b) -C1-6 alkoxy-R115, (c) -C(O)R114, (d) -OC(O)R114, (e) -
OC(O)OR114, (f) -OC(O)NR114R114, and (g) -NR114R114, R107 is selected from
(a) H, (b) -Ci-6 alkyl, (c) -C2-6 alkenyl, which can be further substituted with Ci-6 alkyl or one or more halogens, (d) -C2-6 alkynyl, which can be further substituted with Ci-6 alkyl or one or more halogens, (e) aryl (f) heteroaryl, which can be further substituted with Ci-6 alkyl or one or more halogens, (g) -
C(O)H, (h) -COOH, (i) -CN, O) -COOR114, (k) -C(O)NR114R114, (1) - C(O)R114, and (m) -C(O)SR114, wherein (b) is further substituted with one or more substituents selected from (aa) -OR114, (bb) halogen, (cc) -SR114, (dd) C1-6 alkyl, which can be further substituted with halogen, hydroxyl, C1-6 alkoxy, or amino, (ee) -OR114, (ff) -SR114, (gg) -NR114R114, (hh) -CN, (ii)
-NO2, Gj) -NC(O)R114, (kk) -COOR114, (11) -N3, (mm) ^N-O-R114, (nn) =NR114, (oo) =N-NR114R114, (pp) =N-NH-C(0)R114, and (qq) =N-NH- C(O)NR114R114; alternatively R106 and R107 are taken together with the atom to which they are attached to form an epoxide, a carbonyl, an exocyclic olefin, or a substituted exocyclic olefin, or a C3- C7 carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be further substituted with a Cr6 alkyl; R108 is selected from:
(a) C1-O alkyl, (b) C2-6 alkenyl, and (c) C2-6 alkynyl, wherein any of (a)-(c) optionally is substituted with one or more R114 groups;
R109 is H, C1-6 alkyl, or F; R114, at each occurrence, independently is selected from:
(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-I2 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-I2 saturated, unsaturated, or aromatic carbocycle, (k) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (1) -C(O)O-Ci-6 alkyl, (m) -C(O)O-C2-6 alkenyl, (n) - C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-J2 saturated, unsaturated, or aromatic carbocycle, (p) -C(O)O-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (q) -C(O)NR116R116, (r) -NR116CO-C1-6 alkyl, (s) - NR116CO-C3-12 saturated, unsaturated, or aromatic carbocycle, (t) -NR116C(O)- 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (u) -(C1-6 alkyl)-O-(C1-6 alkyl), (v) -(C1-6 alkyl)-O-(C1-6 alkyl)-O-(C1-6 alkyl), (w) -OH, (x) -OR115, (y) -NH(C1-6 alkyl), (z) -N(C1-6 alkyl)2, (aa) -(C1-6 alkyl)-S(O)p- (C1-6 alkyl), (bb) -(C1-6 alkyl)- S(O)p-(C1-6 alkyl)-S(O)p-(C1-6 alkyl), (cc) -(C1-6 alkyl)-O-(C1-6 alkyl)-S(O)p-(C1-6 alkyl), (dd) -(C1-6 alkyl)- S(O)p-(C1-6 alkyl)-O-(C1-6 alkyl); and (ee) -NH2; wherein the terminal alkyl group in any of (u)-(v) or (aa)-(dd) includes cycloalkyl, wherein any of (b)-(v) or (aa)-(dd) optionally is substituted with one or more R115 groups, wherein one or more non-terminal carbon moieties of any of (b)-(d) optionally is replaced with oxygen, S(O)P, or -NR116, alternatively, -CR114R114 or NR114R114 forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R114 groups are bonded and optionally contains one or more moieties selected from -C=O-, -S(O)1,-, =N-, and -NR118-;
R115 is selected from: (a) R117, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-12 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -OC1-6 alkyl, (h) -OC2-6 alkenyl, and (i) - OC2-6 alkynyl, wherein any of (b)-(f) optionally is substituted with one or more R117 groups; R116, at each occurrence, independently is selected from:
(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-12 saturated, unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein one or more non-terminal carbon moieties of any of (b)-(d) optionally is replaced with oxygen, S(O)P, or -NR118 , wherein any of (by- (f) optionally is substituted with one or more moieties selected from:
(aa) carbonyl, (bb) formyl, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) N3, (ii) NO2, (jj) OR118, (kk) -S(O)pR118, (W) -C(O)R118, (mm) -C(O)OR118, (nn) -OC(O)R118, (oo) -C(O)NR118R118, (pp) -
OC(O)NR118R118, (qq) -C(=NR118)R118, (rr) -C(R118)(R118)OR118, (ss) -C(R118^OC(O)R118, (tt) -C(R118)(OR118)(CH2)rNR118R118, (uu) -NR118R118; (w) -NR118OR118, (ww) -NR118C(O)R118, (xx) - NR118C(O)OR118, (yy) -NR118C(O)NR118R118, (zz) - NR118S(O^R118, (ab) -C(OR118XOR118)R118, (ac) -
C(R118)2NR118R118, (ad) =NR118, (ae) -C(S)NR118R118, (af) - NR118C(S)R118, (ag) -OC(S)NR118R118, (ah) -NR118C(S)OR118, (ai) -NR118C(S)NR118R118, (aj) -SC(O)R118, (ak) Ci-6 alkyl, (al) C2-6 alkenyl, (am) C2-6 alkynyl, (an) Ci-6 alkoxy, (ao) Ci-6 alkylthio, (ap) Ci-6 acyl, (aq) saturated, unsaturated, or aromatic C3-I2 carbocycle, and (ar) saturated, unsaturated, or aromatic 3-12 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR116R116 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R116 groups are attached and optionally one or more moieties selected from O, S(O)P, N, and NR118; alternatively, CR116R116 forms a carbonyl group; R117, at each occurrence, is selected from:
(a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3, (h) (CR116R116)rCN, (i) (CR116R116)rNO2, O) (CR116R116)rNR116(CR' 16R116)tR119, (k) (CR116R116XOR119,
(1) (CR116R116XS(O)P(CR116R116)tR119, (m) (CR116R116XC(OXCR116R116XR119, (n) (CR116R116XOC(OXCR116R116XR119, (O) (CR116R116XSC(OXCR116R116XR119, (p) (CR116R116XC(O)O(CR116R116XR119, (q) (CR116R116XNR116C(O)(CR116R116XR119, (r) (CR116R116XC(O)NR116(CR] 16R116XR119, (s) (CR116R116)rC(=NR11^(CR116R116XR119,
(t) (CR116R116XQ=NNR116R116XCR116R116),R] 19,
(u) (CR116R116)rC(=NNR116C(O)R116)(CR] 16R116XR119,
(v) (CR116R11VX=NOR119XCR116R116XR119, (w) (CR116R116XNR116C(O)O(CR116R116)tR' 19, (x) (CR116R116XOC(O)NR11^CR116R116XR119, (y) (CR116R116XNR116C(O)NR11^CR116R116)tR119, (z) (CR116R116XNR116S(O)P(CR116R116XR119, (aa) (CR116R116XS(O)PNR116(CR! 16R116XR119,
(bb) (CR116R116XNR116S(O)PNR11^CR116R116)tR119, (cc) (CR116R116XNR116R116, (dd) C,.6 alkyl, (ee) C2.6 alkenyl, (ff) C2.6 alkynyl, (gg) (CR116R116)r-C3-12 saturated, unsaturated, or aromatic carbocycle, (hh) (CR116RU6)r-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and (ii) -P(O)(O(C1-6 alkyl))2, wherein any of (dd)-(hh) optionally is substituted with one or more R119 groups; alternatively, two R117 groups can form -O(CH2)UO-; R118 is selected from: (a) H, (b) C1-6 alkyl, (c) C2.6 alkenyl, (d) C2.6 alkynyl, (e) C3-12 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-12 saturated, unsaturated, or aromatic carbocycle, and (k) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(k) optionally is substituted with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, Gj) NH(C1-6 alkyl), (kk) N(C1-6 alkyl)2, (11) C1-6 alkoxy,
(mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C1-6 alkyl, optionally substituted with one or more moieties selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO2, and OH; R119, at each occurrence, independently is selected from:
(a) R120, (b) C,.6 alkyl, (c) C2^ alkenyl, (d) C2.6 alkynyl, (e) C3-I2 saturated, unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f) optionally is substituted with one or more R114 groups; R120, at each occurrence, independently is selected from:
(a) H, (b) =0, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3, (h) (CRU6R116)rCN, (i) (CR116R116XNO2, (j) (CR116R116XNR116R116, (k) (CR116R116XOR114, (1) (CR116R116χS(O)pRu6, (m) (CR116R116XC(O)R116, (n) (CR116R116XC(O)OR116, (o) (CR116R116XOC(O)R116, (p) (CR116R11^1NR116C(O)R116, (q) (CR116R116XC(O)NR116R116, (r) (CR116R116XQ=NR116)R116,
(s) (CR116R116XNR116C(O)NR116R116, (t) (CR116R116XNR116S(O)pR116, (u) (CR116R116XS(O)PNR116R116, (v) (CR116R11^1NR116S(O)PNR116R116, (w) Cj_6 alkyl, (x) C2.6 alkenyl, (y) C2-6 alkynyl, (z) (CR116R116)r-C3-12 saturated, unsaturated, or aromatic carbocycle, and (aa) (CR116R116)r-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (w)-(aa) optionally is substituted with one or more moieties selected from R116, F, Cl, Br, I, CN, NO2, -OR116, -NH2, - NH(C1-6 alkyl), -N(Ci-6 alkyl)2, Ci-6 alkoxy, Ci-6 alkylthio, and Ci-6 acyl; R121, at each occurrence, independently is selected from:
(a) H, (b) -OR118, (c) -O-Ci-6 alkyl-OC^R118, (d) -0-Ci-6 alkyl- OC(O)OR118, (e) -O-Ci-6 alkyl-OC(O)NR118R118, (f) -O-C,-6 alkyl- C(O)NR118R118, (g) -O-Ci-6 alkyl-NR118C(O)R118, (h) -O-Ci-6 alkyl- NR118C(O)OR118, (i) -0-C1-6 alkyl-NR118C(O)NR118R118, (j) -0-Ci-6 alkyl- NR118C(=N(H)NR118R118), (k) -O-Ci-6 alkyl-S(O)pR118, (1) -0-C2-6 alkenyl-
OC(O)R118, (m) -O-C2-6 alkenyl-OC(O)OR118, (n) -O-C2-6 alkenyl- OC(O)NR118R118, (o) -0-C2-6 alkenyl-C(O)NR118R118, (p) -O-C2-6 alkenyl- NR118C(O)R118, (q) -O-C2-6 alkenyl-NR118C(O)OR118, (r) -0-C2-6 alkenyl- NR118C(O)NR118R118, (s) -0-C2-6 alkenyl-NR118Q=N(H)NR118R118), (t) -O- C2-6
Figure imgf000041_0001
(v) -0-C2-6 alkynyl-
OC(O)OR118, (w) -O-C2-6 alkynyl-OC(O)NR118R118, (x) -O-C2-6 alkynyl- C(O)NR118R118, (y) -0-C2-6 alkynyl-NR118C(O)R118, (z) -O-C2-6 alkynyl- NR118C(O)OR118, (aa) -O-C2-6 alkynyl-NR118C(O)NR118R118, (bb) -O- C2-6 alkynyl-NR118C(=N(H)NR118R118), (cc) -O-C2-6 alkynyl-S(O)pR118, (dd) -NR118R118, (ee) -C1-6 alkyl-O-C1-6 alkyl, (ff) -C1-6 alkyl-NR1 I4-C1-6 alkyl, (gg) -C]-6 alkyl-S(O)p-C1-6 alkyl, (hh) -OC(O)NR114(C1-6 alkyO-NR114- (C1-6 alkyl) -R114, (ii) -OH, (jj) -Ci-6 alkyl, (kk) C2-6 alkenyl, (11) C2-6 alkynyl,
(mm) -CN, (nn) -CH2S(O)pR137, (oo) -CH2OR137, (pp) -CH2N(OR138)R137, (qq) -CH2NR137R139, (rr) -(CH2)v(C6-i0 aryl), and (ss)-(CH2)v(5-10 membered heteroaryl), wherein (jj)-(ss) are optionally substituted by 1, 2, or 3 R140 groups; alternatively, two R121 groups taken together form =0, =N0R! 18, or =NNR* 18R118;
R127 is R114, a monosaccharide or a disaccharide (including amino sugars and halogenated sugar(s)), -S(O)pR148, -(CH2)n-(O-CH2CH2-)m-O(CH2)nCH3, -(CH2)n- (O-CH2CH2-)m-OR148, -<CH2)n-[S(O)p-CH2CH2-]m-S(O)p(CH2)nCH3, -(CH2)n- [S(O)p-CH2CH2-]m-S(O)pCH3, -(CH2)n-[S(O)p-CH2CH2-]m-OR148, -OCH2-O-(CH2)n- [S(O)p-CH2CH2-]m-S(O)p(CH2)nCH3, -OCH2-O-(CH2)n-[S(O)p-CH2CH2-]m-OR148, -
0-[C3-12 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R114, -O-[3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur], wherein said heterocycle is further optionally substituted with one or more R114, -S(O)p-[C3-i2 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R114, or -S(O)p-[3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur], wherein said heterocycle is further optionally substituted with one or more R114;
R110 is R114; alternatively, R109 and R110 taken together with the carbons to which they are attached form:
Figure imgf000042_0001
R132, R133, and R134 are each independently selected from (a) H, (b) F, (c) Cl, (d) Br,
(e) -OR114, (f) -SR114, (g) -NR114R114, and (h) Cw alkyl, wherein (h) optionally is substituted with one or more R115 groups; alternatively, R132 and R133 are taken together to form a carbon-carbon double bond; alternatively, R133 and R134 are taken together to form =0, =S, -NOR114, =NR* 14, or
-N-NR114R114; alternatively, R105 and R134 are taken together with the carbons to which they are attached to form a 3-membered ring, said ring optionally containing an oxygen or nitrogen atom, and said ring being optionally substituted with one or more R114 groups; alternatively when M is a carbon moiety, R134 and M are taken together to form a carbon-carbon double bond;
R137 is independently (a) H, (b) Ci-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) -
(CH2)qCR14IR142(CH2)nNR143R144, (f) -(CH2)v(C6-C10 aiyl), or (g) (CH2)v(5-10 membered heteroaryl); or where R137 is as -CH2NR137R139, R139 and R137 may be taken together to form a 4-
10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S, and -N(R137)-, in addition to the nitrogen to which R139 and R137 are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 , 2, or 3 R140 groups; each R138 is independently H or C1 -6 alkyl; each R141, R142, R143, and R144 is independently selected from H, Cr6 alkyl, - (CH2)Oi(C6-C loaryl), and -(CH2)m(5-10 membered heteroaryl), wherein the foregoing
R141, R142, R143, and R144 groups, except H, are optionally substituted by 1, 2, or 3 R140 groups; or R141 and R143 are taken together to form -(CH2)0- wherein o, at each occurrence is 0, 1, 2, or 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carbon-carbon double or triple bonds; or R143 and R144 are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and - N(R137)-, in addition to the nitrogen to which R143 and R144 are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1, 2, or 3 R140 groups;
R139 is H, Ci-6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the foregoing R139 groups, except H, are optionally substituted by 1, 2, or 3 substituents independently selected from halo and -OR138; each R140 is independently selected from halo, cyano, nitro, trifluoromethyl, azido, -C(O)R145, -C(O)OR145, -OC(O)OR145, -NR146C(O)R147, -NR146R147, OH, C,-6 alkyl, Cr6 alkoxy, -(CH2)V(C6-C1OaTyI), and -(CH2)v(5-10 membered heteroaryl), wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, -
C(O)R145,-C(O)OR145, -OC(O)OR145, -NR146C(O)R147, -C(O)NR146R147, -NR146R147,
OH, d-6 alkyl, and Cr6 alkoxy; each R145 is independently selected from H, C1 -6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)v(C6-Ci0 aryl), and -(CH2)v(5-10 membered heteroaryl); each R146 and R147 is independently H, hydroxyl, Ci-6 alkoxy, Cr6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)v(C6-!o aryθ> or -(CH2)v(5-10 membered heteroaryl);
R148 is Cr6 alkyl, C3-12 saturated, unsaturated, or aromatic carbocycle, wherein said carbocycle is further optionally substituted with one or more R114, or 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein said heterocycle is further optionally substituted with one or more R114; p, at each occurrence is O, 1, or 2; m, at each occurrence is O, 1, 2, 3, 4, or 5; n, at each occurrence is 1, 2, or 3; r, at each occurrence is O, 1, or 2; t, at each occurrence is O, 1, or 2; v, at each occurrence is O, 1, 2, 3, or 4; q, at each occurrence is 0, 1, 2, or 3, and u at each occurrence is 1, 2, 3, or 4.
In other embodiments, the present invention relates to a compound, wherein T is:
Figure imgf000045_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R100, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R1 14, R132, R133, and R134 are as described herein.
In other embodiments, the present invention relates to a compound, wherein T is:
Figure imgf000045_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R100, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R127, R132, R133, and R134 are as described herein. hi other embodiments, the present invention relates to a compound, wherein T is:
Figure imgf000045_0003
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R100, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R1 14, R132, R133, and R134 are as described herein. In other embodiments, the present invention relates to a compound, wherein T is:
Figure imgf000046_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R100, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R114, R132, R133, and R134 are as described herein.
In other embodiments, the present invention relates to a compound, wherein T is selected from TA-TD:
Figure imgf000046_0002
and
Figure imgf000047_0001
TD, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein R1 M and R127 are as described herein.
In other embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from T4 through T34:
Figure imgf000047_0002
Figure imgf000048_0001
T10
T11
Figure imgf000048_0002
T15
T16 T17
Figure imgf000049_0001
Figure imgf000049_0002
T25 T26
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003
T34
In other embodiments, the present invention relates to a compound having the structure corresponding to any one of the structures listed in Table 1, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In other embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, and a pharmaceutically acceptable carrier.
In other embodiments, the present invention relates to a method for treating or preventing a disease state in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
In other embodiments, the present invention relates to a method of treating a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
In other embodiments, the present invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, in the manufacture of a medicament for treating a microbial infection in a mammal. In other embodiments, the present invention relates to a method of treating or preventing a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, Ν-oxide, or prodrug thereof, wherein the microbial infection is selected from the group consisting of: a skin infection, nosocomial pneumonia, community acquired pneumonia, post- viral pneumonia, a respiratory tract infection such as CRTI, a skin and soft tissue infection
(SSTI) including uncomplicated skin and soft tissue infections (uSSTIs) and complicated skin and soft tissue infections, as an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, meningitis, surgical prophylaxis, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus infection, a vancomycin-resistant Enterococci infection, a linezolid-resistant organism infection, and tuberculosis.
In other embodiments, the present invention relates to a method of treating or preventing a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
In other embodiments, the present invention relates to a method of treating or preventing a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
In other embodiments, the present invention relates to a method of treating or preventing a proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
In other embodiments, the present invention relates to a method of treating or preventing a viral infection in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
In other embodiments, the present invention relates to a method of treating or preventing an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. hi other embodiments, the present invention relates to a method of treating or preventing a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. hi other embodiments, the present invention relates to a method of treating or preventing diarrhea in a mammal comprising administering to the mammal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
In other embodiments, the present invention relates to a method of treating or preventing a disease state in a mammal caused or mediated by a nonsense or missense mutation comprising administering to a mammal in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, to suppress expression of the nonsense or missense mutation. hi other embodiments, the present invention relates to a method or use of a compound of the invention wherein the compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, is administered otically, ophthalmically, nasally, orally, parentally, or topically. In other embodiments, the present invention relates to a method of synthesizing a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
In other embodiments, the present invention relates to a medical device containing a compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In other embodiments, the medical device is a stent.
As is seen from the foregoing, the compounds of the present invention can include a wide range of structures. Examples of such macro lide components and their syntheses are provided in the following documents, all of which are incorporated by reference in their entirety: PCT Application No. WO 2007/025284, published March 1 , 2007, to Rib-X
Pharmaceuticals, Inc.; PCT Application No. WO 2007/025098, published March 1, 2007, to Rib-X Pharmaceuticals, Inc.; PCT Application No. WO 2007/ 025089, published March 1, 2007, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/118610, published December 15, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/085266, published September 15, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/049632, published June 2, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/042554, published May 12, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2004/078770, published September 16, 2004, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2004/029066, published April 8, 2004, to Rib-X Pharmaceuticals, Inc.; PCT application No. PCT/US2006/33645, to Rib-X Pharmaceuticals, Inc., filed August 24, 2006; PCT application No. PCT/US2006/33170, to Rib-X Pharmaceuticals, Inc., filed August 24, 2006; and PCT application No. PCT/US2006/33157, to Rib-X Pharmaceuticals, Inc. filed August 24, 2006; U.S. Patent No.; U.S. Patent No. 6,992,069, to Gu et al., issued January 31, 2006; U.S. Patent No. 6,953,782, to Phan et al., issued October 11, 2005; U.S. Patent No. 6,939,861, to Ashley et al., issued September 6, 2005; U.S. Patent No., 6,927,057, to Khosla et al., issued August 9, 2005; U.S. Patent No. 6,794,366, to Chu et al., issued September 21, 2004; U.S. Patent No. 6,762,168, to Chu, issued July 13, 2004; U.S. Patent No. 6,756,359, to Chu et al, issued June 29, 2994; U.S. Patent No. 6,750,205, to Ashley et al, issued June 15, 2004; U.S. Patent No. 6,740,642, to Angehrn et al., issued May 25, 2004; U.S. Patent No. 6,727,352, to Cheng et al., issued April 27, 2004; U.S. Patent Application Publication No. US 2006/0154881, to Or et al., published July 13, 2006; U.S. Patent Application Publication No. US 2006/0142215, to Tang et al., published June 29, 2006; U.S. Patent Application Publication No. US 2006/0142214, to Or et al, published June 29, 2006; U.S. Patent Application Publication No. US 2006/0122128, to Or et al, published June 8, 2006; U.S. Patent Application Publication No. US 2006/0069048, to Or et al. published March 30, 2006; U.S. Patent Application Publication No. US 2005/0272672, to Li et al., published December 8, 2005; U.S. Patent Application Publication No US 2005/0009764, to Burger et al, published January 13, 2005; PCT application No. WO 2006/067589, to Pfizer Products Inc., published June 29, 2006; PCT application No. WO 2004/096823, to Chiron Corporation, published November 11, 2004; PCT application No. WO 2004/096822, to Chiron Corporation, published November 11, 2004; PCT application No. WO 2004/080391, to Optimer Pharmaceuticals, Inc., published September 23, 2004; PCT application No. WO 2004/078771, to Taisho Pharmaceutical Co., Ltd., published September 16, 2004; PCT application no. WO 03/061671, to Kosan Biosciences, Inc. published July 31, 2003; European Patent Document EP 1 256 587 Bl, to the Kitasato Institute, granted March 29, 2006; WO 98/54197, published December 3, 1998, to Abbott Laboratories, and WO 97/17356, published May 15, 1997, to Abbott Laboratories.
3. Synthesis of the Compounds of the Invention
The invention provides methods for making the compounds of the invention. The following Schemes A AND B depict exemplary chemistries available for synthesizing the compounds of the invention, hi these schemes, the variables n, R, R1, R3, R4, R5, R7, and X are merely illustrative, and not necessarily those used in the claims, and can be selected and defined in accordance with the invention.
In Scheme A, compounds such as, e.g., 3'-N-desmethyl erythromycin (1, R = H) or 3'-N-desmethyl clarithromycin (1, R = CH3), are alkylated with an electrophilic alkyne, 2, to yield 3'-N-alkynyl compounds such as 3. The electrophilic alkyne, 2, can include, e.g., compounds where chlorides, bromides, iodides, tosylates, and mesylates depending on the selection of X. Cycloaddition of azide compounds, such as 6, with the 3'-N-allkynyl compounds 3 provides two regioisomeric triazole products 7 and 8. The major isomer is the "anti" isomer 7, a 1,4 disubstituted triazole. The minor component is the "syn" isomer 8, a 1,5 disubstituted triazole. The cycloaddition reaction can be thermally catalyzed, or a number of catalysts can be used, such as, but not limited to, copper (I) iodide. See, Tornoe, CW. et al. (2002) J. Org. Chem. 67: 3057). Scheme A
Figure imgf000055_0001
Figure imgf000055_0002
7 (1, 4 isomer) 8 (1, 5 isomer)
It is to be understood that other macrolide compounds such as, but not limited to, azithromycin and telithromycin, can be N-demethylated and used as starting materials for the chemistry exemplified in Scheme A.
The following Scheme B illustrates the synthesis of oxime type macrolides of the present invention. These compounds can be from 3'-N-alknynyl compounds such as 3, which are made from the 3'-N-desmethyl macrolides, 1, as in Scheme A. Compound 3 can either be converted directly to the desired intermediate oxime 4 (by the appropriate choice of R1), or alternatively via a the hydroxyl oxime 5. A cycloaddition reaction of the intermediate oxime 4 and an azide compound 6 provides the final compounds 7 and 8 as a mixture of isomers. Scheme B
Figure imgf000056_0001
7 (1 , 4 isomer) 8 (1 , 5 isomer)
4. Characterization of Compounds of the Invention
Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, for example, as anti-cancer, anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also, it can be possible to assay how the compounds interact with a ribosome or ribosomal subunit and/or are effective as modulators (for example, inhibitors) of protein synthesis using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput
Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. (1) Surface Binding Studies. A variety of binding assays can be useful in screening new molecules for their binding activity. One approach includes surface plasmon resonance (SPR) that can be used to evaluate the binding properties of molecules of interest with respect to a ribosome, ribosomal subunit or a fragment thereof.
SPR methodologies measure the interaction between two or more macromolecules in real-time through the generation of a quantum-mechanical surface plasmon. One device, (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, N.J.) provides a focused beam of polychromatic light to the interface between a gold film (provided as a disposable biosensor "chip") and a buffer compartment that can be regulated by the user. A 100 nm thick "hydrogel" composed of carboxylated dextran that provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film. When the focused light interacts with the free electron cloud of the gold film, plasmon resonance is enhanced. The resulting reflected light is spectrally depleted in wavelengths that optimally evolved the resonance. By separating the reflected polychromatic light into its component wavelengths (by means of a prism), and determining the frequencies that are depleted, the BIAcore establishes an optical interface which accurately reports the behavior of the generated surface plasmon resonance. When designed as above, the plasmon resonance (and thus the depletion spectrum) is sensitive to mass in the evanescent field (which corresponds roughly to the thickness of the hydrogel). If one component of an interacting pair is immobilized to the hydrogel, and the interacting partner is provided through the buffer compartment, the interaction between the two components can be measured in real time based on the accumulation of mass in the evanescent field and its corresponding effects of the plasmon resonance as measured by the depletion spectrum. This system permits rapid and sensitive real-time measurement of the molecular interactions without the need to label either component. (2) Fluorescence Polarization. Fluorescence polarization (FP) is a measurement technique that can readily be applied to protein-protein, protein-ligand, or RNA-ligand interactions in order to derive IC50S and Kds of the association reaction between two molecules. In this technique one of the molecules of interest is conjugated with a fluorophore. This is generally the smaller molecule in the system (in this case, the compound of interest). The sample mixture, containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragment thereof, is excited with vertically polarized light. Light is absorbed by the probe fluorophores, and re-emitted a short time later. The degree of polarization of the emitted light is measured. Polarization of the emitted light is dependent on several factors, but most importantly on viscosity of the solution and on the apparent molecular weight of the fluorophore. With proper controls, changes in the degree of polarization of the emitted light depends only on changes in the apparent molecular weight of the fluorophore, which in-turn depends on whether the probe-ligand conjugate is free in solution, or is bound to a receptor. Binding assays based on FP have a number of important advantages, including the measurement of IC5oS and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions.
(3) Protein Synthesis. It is contemplated that, in addition to characterization by the foregoing biochemical assays, the compound of interest can also be characterized as a modulator (for example, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.
Furthermore, more specific protein synthesis inhibition assays can be performed by administering the compound to a whole organism, tissue, organ, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological and inhibitory properties by determining, for example, its inhibition constant (IC50) for inhibiting protein synthesis. Incorporation of 3H leucine or 35S methionine, or similar experiments can be performed to investigate protein synthesis activity. A change in the amount or the rate of protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis. A decrease in the rate or the amount of protein synthesis indicates that the molecule is a inhibitor of protein synthesis.
(4) Antimicrobial assays and other evaluations Furthermore, the compounds can be assayed for antiproliferative or anti-infective properties on a cellular level. For example, where the target organism is a microorganism, the activity of compounds of interest can be assayed by growing the microorganisms of interest in media either containing or lacking the compound. Growth inhibition can be indicative that the molecule can be acting as a protein synthesis inhibitor. More specifically, the activity of the compounds of interest against bacterial pathogens can be demonstrated by the ability of the compound to inhibit growth of defined strains of human pathogens. For this purpose, a panel of bacterial strains can be assembled to include a variety of target pathogenic species, some containing resistance mechanisms that have been characterized. Use of such a panel of organisms permits the determination of structure-activity relationships not only in regards to potency and spectrum, but also with a view to obviating resistance mechanisms. Minimum inhibitory concentrations (MICs) are determined by the microdilution method, typically in a final volume of 100 microliters, according to protocols outlined by The Clinical and Laboratory Standards Institute [CLSI; formerly the National Committee for Clinical Laboratory Standards (NCCLS)]. See CLSI: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-fifth edition. Wayne, PA: NCCLS; 2000. The assays can be also be performed in microtiter trays according to conventional methodologies as published by the CLSI. See CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Seventh Edition. CLSI Document M7-A7 [ISBN 1-56238-587-9] CLSI, 940 West Valley Road, Suite 1400, Wayne Pennsylvania 19087-1898 USA, 2006.). The antimicrobial and other drug properties of the compounds can further be evaluated in various in vivo mammalian assays, such as a mouse or rat peritonitis infectious models, skin and soft tissue models (often referred to as the thigh model), or a mouse pneumonia model. There are septicemia or organ infection models known to those skilled in the art. These efficacy models can be used as part of the evaluation process and can be used as a guide of potential efficacy in humans. Endpoints can vary from reduction in bacterial burden to lethality. For the latter endpoint, results are often expressed as a PD5O value, or the dose of drug that protects 50% of the animals from mortality.
To further assess a compound's drug-like properties, measurements of inhibition of cytochrome P450 enzymes and phase II metabolizing enzyme activity can also be measured either using recombinant human enzyme systems or more complex systems like human liver microsomes. Further, compounds can be assessed as substrates of these metabolic enzyme activities as well. These activities are useful in determining the potential of a compound to cause drug-drug interactions or generate metabolites that retain or have no useful antimicrobial activity.
To get an estimate of the potential of the compound to be orally bioavailable, one can also perform solubility and Caco-2 assays. The latter is a cell line from human epithelium that allows measurement of drug uptake and passage through a Caco-2 cell monolayer often growing within wells of a 24- well microtiter plate equipped with a 1 micron membrane. Free drug concentrations can be measured on the basolateral side of the monolayer, assessing the amount of drug that can pass through the intestinal monolayer. Appropriate controls to ensure monolayer integrity and tightness of gap junctions are needed. Using this same system one can get an estimate of P-glycoprotein mediated efflux. P-glycoprotein is a pump that localizes to the apical membrane of cells, forming polarized monolayers. This pump can abrogate the active or passive uptake across the Caco-2 cell membrane, resulting in less drug passing through the intestinal epithelial layer. These results are often done in conjunction with solubility measurements and both of these factors are known to contribute to oral bioavailability in mammals. Measurements of oral bioavailability in animals and ultimately in man using traditional pharmacokinetic experiments will determine the absolute oral bioavailability.
Experimental results can also be used to build models that help predict physical- chemical parameters that contribute to drug-like properties. When such a model is verified ■ experimental methodology can be reduced, with increased reliance on the model predictability.
5. Formulation and Administration
The compounds of the invention can be useful in the prevention or treatment of a variety of human or other animal, including mammalian and non mammalian, disorders, including for example, bacterial infection, fungal infections, viral infections, diarrhea, parasitic diseases, and cancer. It is contemplated that, once identified, the active molecules of the invention can be incorporated into any suitable carrier prior to use. The dose of active molecule, mode of administration and use of suitable carrier will depend upon the intended recipient and target organism. The formulations, both for veterinary and for human medical use, of compounds according to the present invention typically include such compounds in association with a pharmaceutically acceptable carrier. The carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient. Pharmaceutically acceptable carriers, in this regard, are intended to include any and all solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds (identified or designed according to the invention and/or known in the art) also can be incorporated into the compositions. The formulations can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy/microbiology. In general, some formulations are prepared by bringing the compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. A pharmaceutical composition of the invention should be formulated to be compatible with its intended route of administration. Examples of routes of administration include otic, ophthalmic, nasal, oral or parenteral, for example, intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, described, for example, in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990). Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration also can be prepared by mixing the drug with a non- irritating excipient such as cocoa butter, other glycerides, or other compositions which are solid at room temperature and liquid at body temperatures. Formulations also can include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalenes. Formulations for direct administration can include glycerol and other compositions of high viscosity. Other potentially useful parenteral carriers for these drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Retention enemas also can be used for rectal delivery.
Formulations of the present invention suitable for oral administration can be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the drug; a powder or granular composition; a solution or a suspension in an aqueous liquid or non-aqueous liquid; or an oil- in-water emulsion or a water-in-oil emulsion. The drug can also be administered in the form of a bolus, electuary or paste. A tablet can be made by compressing or moulding the drug optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets can be made by moulding, in a suitable machine, a mixture of the powdered drug and suitable carrier moistened with an inert liquid diluent.
Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients. Oral compositions prepared using a fluid carrier for use as a mouthwash include the compound in the fluid carrier and are applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.
Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. Particularly useful are carriers capable of forming a film or layer over the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface. For example, hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage. Alternatively, tissue-coating solutions, such as pectin-containing formulations can be used. For inhalation treatments, inhalation of powder (self-propelling or spray formulations) dispensed with a spray can, a nebulizer, or an atomizer can be used. Such formulations can be in the form of a fine powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations. In the case of self-propelling solution and spray formulations, the effect can be achieved either by choice of a valve having the desired spray characteristics (i.e., being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size. For administration by inhalation, the compounds also can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Systemic administration also can be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents and bile salts. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.
The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. Furthermore, administration can be by periodic injections of a bolus, or can be made more continuous by intravenous, intramuscular or intraperitoneal administration from an external reservoir (e.g., an intravenous bag).
Where adhesion to a tissue surface is desired the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The compound then can be painted, sprayed or otherwise applied to the desired tissue surface. Alternatively, the drugs can be formulated for otic, ophthalmic, nasal, parenteral or oral administration to humans or other mammals, for example, in therapeutically effective amounts, e.g., amounts that provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect.
Where the active compound is to be used as part of a transplant procedure, it can be provided to the living tissue or organ to be transplanted prior to removal of tissue or organ from the donor. The compound can be provided to the donor host. Alternatively or, in addition, once removed from the donor, the organ or living tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly to the desired tissue, as by injection to the tissue, or it can be provided systemically, e.g., by otic, ophthalmic, nasal, oral or parenteral administration, using any of the methods and formulations described herein and/or known in the art. Where the drug comprises part of a tissue or organ preservation solution, any commercially available preservation solution can be used to advantage. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and lactated Ringer's solution. The compounds of the present invention can be administered directly to a tissue locus by applying the compound to a medical device that is placed in contact with the tissue. An example of a medical device is a stent, which contains or is coated with one or more of the compounds of the present invention. For example, an active compound can be applied to a stent at the site of vascular injury. Stents can be prepared by any of the methods well known in the pharmaceutical art. See, e.g., Fattori, R. and Piva, T., "Drug Eluting Stents in Vascular Intervention," Lancet, 2003, 361, 247-249; Morice, M. C, "A New Era in the Treatment of Coronary Disease?" European Heart Journal, 2003, 24, 209-211; and Toutouzas, K. et al., "Sirolimus-Eluting Stents: A Review of Experimental and Clinical Findings," Z. Kardiol., 2002, 91(3), 49-57. The stent can be fabricated from stainless steel or another bio-compatible metal, or it can be made of a bio-compatible polymer. The active compound can be linked to the stent surface, embedded and released from polymer materials coated on the stent, or surrounded by and released through a carrier which coats or spans the stent. The stent can be used to administer single or multiple active compounds to tissues adjacent to the stent.
Active compound as identified or designed by the methods described herein can be administered to individuals to treat disorders (prophylactically or therapeutically). In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) can be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of treatment with the drug.
In therapeutic use for treating, or combating, bacterial infections in mammals, the compounds or pharmaceutical compositions thereof will be administered otically, ophthalmically, nasally, orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level or tissue level of active component in the animal undergoing treatment which will be anti-microbially effective. Generally, an effective amount of dosage of active component will be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg/kg of body weight/day. The amount administered will also likely depend on such variables as the type and extent of disease or indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the compound delivered, the formulation of the drug, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered can be increased beyond the above upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage can be smaller than the optimum and the daily dosage can be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times per day. Various disease states or conditions in humans and other mammals are found to be caused by or mediated by nonsense or missense mutations. These mutations cause or mediate the disease state or condition by adversely affecting, for example, protein synthesis, folding, trafficking and/or function. Examples of disease states or conditions in which an appreciable percentage of the disease or condition is believed to result from nonsense or missense mutations include hemophilia (factor VIII gene), neurofibromatosis (NFl and NF2 genes), retinitis pigmentosa (human USH2A gene), bullous skin diseases like Epidermolysis bullosa pruriginosa (COL7A1 gene), cystic fibrosis (cystic fibrosis transmembrane regulator gene), breast and ovarian cancer (BRCAl and BRCA2 genes), Duchenne muscular dystrophy (dystrophin gene), colon cancer (mismatch repair genes, predominantly in MLHl and MSH2), and lysosomal storage disorders such as Neimann-Pick disease (acid sphingomyelinase gene). See Sanders CR, Myers JK. Disease-related misassembly of membrane proteins. Annu Rev Biophys Biomol Struct. 2004;33:25-51; National Center for Biotechnology Information (U.S.) Genes and disease Bethesda, MD : NCBI, NLM ID: 101138560; and Raskό, Istvan; Downes, C S Genes in medicine : molecular biology and human genetic disorders 1st ed. London ; New York : Chapman & Hall, 1995. NLM ID: 9502404. The compounds of the present invention can be used to treat or prevent a disease state in a mammal caused or mediated by such nonsense or missense mutations by administering to a mammal in need thereof an effective amount of the present invention to suppress the nonsense or missense mutation involved in the disease state.
6. Examples
Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300 spectrometer. Common reaction solvents were either high performance liquid chromatography (HPLC) grade or American Chemical Society (ACS) grade, and anhydrous as obtained from the manufacturer unless otherwise noted. "Chromatography" or "purified by silica gel" refers to flash column chromatography using silica gel (EM Merck, Silica Gel 60, 230-400 mesh) unless otherwise noted.
The compounds of the present invention can be prepared using known chemical transformations adapted to the particular situation at hand. Examples of chemical transformations useful in the present invention can be found in: U.S. Patent No. 7,091,196 B2, to Wang et al., issued August 15, 2006; PCT application No. WO 2005/085266 A2, to Rib-X Pharmaceuticals, Inc., published September 15, 2005; PCT application No.
PCT/US2006/33645, to Rib-X Pharmaceuticals, Inc., filed August 24, 2006; PCT application No. PCT/US2006/33170, to Rib-X Pharmaceuticals, Inc., filed August 24, 2006; and PCT application No. PCT/US2006/33157, to Rib-X Pharmaceuticals, Inc. filed August 24, 2006, which are incorporated by reference herein in their entirety. Some of the abbreviations used in the following experimental details of the synthesis of the examples are defined below: hr = hour(s); min = minute(s); mol = mole(s); mmol = millimole(s); M = molar; μM = micromolar; g = gram(s); μg = microgram(s); rt = room temperature; L = liter(s); mL = milliliter(s); Et2O = diethyl ether; THF = tetrahydrofuran; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; Et3N = triethylamine; Z-Pr2NEt or DIPEA = diisopropylethylamine; CH2Cl2 = methylene chloride; CHCl3 = chloroform; CDCl3 = deuterated chloroform; CCLj = carbon tetrachloride; MeOH = methanol; CD3OD= deuterated methanol; EtOH = ethanol; DMF = dimethylformamide; BOC = t- butoxycarbonyl; CBZ = benzyloxycarbonyl; TBS = f-butyldimethylsilyl; TBSCl = t- butyldimethylsilyl chloride; TFA = trifluoroacetic acid; DBU = diazabicycloundecene; TBDPSCl = t-butyldiphenylchlorosilane; Hunig's Base= N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; CuI = copper (I) iodide; MsCl = methanesulfonyl chloride; NaN3 = sodium azide; Na2SO4= sodium sulfate; NaHCO3 = sodium bicarbonate; NaOH = sodium hydroxide; MgSO4= magnesium sulfate; K2CO3 = potassium carbonate; KOH = potassium hydroxide; NH4OH = ammonium hydroxide; NH4Cl = ammonium chloride; SiO2 = silica; Pd-C = palladium on carbon; Pd(dppf)Cl2 = dichloro[l,F- bis(diphenylphosphino)ferrocene] palladium (II). Exemplary compounds synthesized in accordance with the invention are listed in Table 1. A bolded or dashed bond is shown to indicate a particular stereochemistry at a chiral center, whereas a wavy bond indicates that the substituent can be in either orientation or that the compound is a mixture thereof. It should also be known that in the interest of space, the chemical structures have been condensed, for example the methyl and ethyl group substituents are designated with just a carbon backbone representation, and the unsaturated bonds in the triazole rings might not always be visible.
The compounds of the present invention can be prepared, formulated, and delivered as salts, esters, and prodrugs. For convenience, the compounds are generally shown without indicating a particular salt, ester, or prodrug form.
Compounds of the present invention are shown in Table 1. LCMS (liquid chromatography mass spectral) data are provided, where available. The LCMS data is provided using the convention for m/z in the format, [M + H]+, except for these with an asterisk * where the format is [(M + 2H)/2]+.
Table 1
Figure imgf000069_0001
201 1166.3
Figure imgf000070_0001
202 1092.1
203 931.8
Figure imgf000070_0002
204 1152.1
Figure imgf000071_0001
205 589.6s1
206 1140.0
Figure imgf000071_0002
Figure imgf000072_0001
210 1224.1
Figure imgf000073_0001
211 1122.0
Figure imgf000073_0002
212 589.1*
Figure imgf000073_0003
213 592.9*
Figure imgf000074_0001
214 1094.0
Figure imgf000074_0002
215 1196.0
Figure imgf000074_0003
216 1215.0
Figure imgf000075_0001
217 1217.1
Figure imgf000075_0002
218 1201.2
Figure imgf000075_0003
Figure imgf000076_0001
222 1230.0
223 596.6*
Figure imgf000077_0001
224 1194.1
Figure imgf000077_0002
225 1138.0
Figure imgf000078_0001
226 1187.1
Figure imgf000078_0002
227 585.7*
Figure imgf000078_0003
1183.2
Figure imgf000079_0001
597.6*
Figure imgf000079_0002
1110.1
Figure imgf000079_0003
231 1103.1
232 1162.0
Figure imgf000080_0001
233 1109.1
Figure imgf000080_0002
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
243 1204.2
244 1220.0
Figure imgf000084_0001
Figure imgf000085_0001
248 1218.1
Figure imgf000086_0001
249 1163.0
Figure imgf000086_0002
250 1133.0
Figure imgf000086_0003
251 1188.1
Figure imgf000087_0001
252 574.1*
253 1188.0
Figure imgf000087_0002
254 1158.0
Figure imgf000088_0001
255 1141.1
256 1143.0
Figure imgf000088_0003
257 1189.0
258 1186.0
Figure imgf000089_0001
259 1188.1
Figure imgf000089_0002
260 1133.0
Figure imgf000090_0001
261 1103.0
Figure imgf000090_0002
262 1180.0
Figure imgf000090_0003
263 1166.0
264 1 180.0
265 1 118.9
Figure imgf000091_0001
Figure imgf000092_0001
269 1194.0
270 1148.00
271 1140.00
Figure imgf000093_0001
Figure imgf000094_0001
275 1152.00
Figure imgf000095_0001
276 1134.00
Figure imgf000095_0002
277 1204.00
278
Figure imgf000096_0001
279 1146.00
Figure imgf000097_0001
280 1134.00
Figure imgf000097_0002
281 1131.00
Figure imgf000098_0001
282 1152.00
Figure imgf000098_0002
283 1133.00
Figure imgf000099_0001
284 583.10*
Figure imgf000099_0002
285 506.50*
Figure imgf000100_0001
286 514.10*
Figure imgf000100_0002
287 1012.00
Figure imgf000101_0001
288 506.10*
Figure imgf000101_0002
289 507.20*
Figure imgf000102_0001
290 499.20*
Figure imgf000102_0002
291 1169.20
Figure imgf000103_0001
292 1152.60
Figure imgf000103_0002
Figure imgf000104_0001
Figure imgf000105_0001
298 987.90
Figure imgf000106_0001
299 1047.90
300 986.00
Figure imgf000106_0002
Figure imgf000107_0001
In the present invention, the variable G is further selected from -B' or -B '-Z-B".
Tables 1A-1I provide examples of chemical moieties or fragments for -Z-B" when G is selected from -B '-Z-B". Note that in Tables 1 A-II, the chemical moieties or fragments for "-Z-B" are drawn such that the chemical moiety or fragment is bonded to -B from the left of the chemical moiety or fragment as drawn. For example, using the first chemical moiety or fragment from Table IA as an example, it can alternatively be drawn as shown immediately below.
Figure imgf000108_0001
This fragment would then be attached to B', as shown immediately below.
Figure imgf000108_0002
As a further nonlimiting example, in the macrolide structure shown below, variable G, could be selected from -B '-Z-B". If, for example, B' is then selected from phenyl, then -Z- B" could be further selected from the first chemical moiety or fragment of Table IA to give the indicated compound.
Figure imgf000108_0003
Exemplary macrolide compound of the present invention showing variable G.
Figure imgf000108_0004
Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B'
Figure imgf000109_0001
Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B" wherein B1 is phenyl.
Figure imgf000109_0002
Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B" wherein B' is phenyl and -Z-B" is selected from the first chemical moiety or fragment of Table IA.
Figure imgf000110_0001
Figure imgf000111_0001
-no-
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Examples 1 — 6: Synthesis of 3'-N-desmethyl macrolide compounds Examples 1-6 describe the synthesis of various 3'-N-desmethyl macrolide compounds which are useful intermediates for making the compounds of the present invention.
Example 1: Synthesis of 3'-N-desmethyl erythromycin from erythromycin
3'-N-desmethyl erythromycin is synthesized from erythromycin according to the procedure described in U.S. Patent No. 3,725,385; Flynn et al. (1954) J. Am. Chem. Soc. 76: 3121; Ku et al. (1997) Bioorg. Med. Chem. Lett. 7: 1203; and Stenmark et al. (2000) J. Org. Chem. 65: 3875).
Example 2: Synthesis of 3'-7V-desmethyl azithromycin from azithromycin Azithromycin (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50 0C followed by addition of iodine (I2) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding IN sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes, however, stirring was continued for 2 hours. TLC (CH2Cl2ZMeOHZNH4OH 10: 1 :0.05) after 2 hours showed a single major product (Rf= 0.66). The reaction was cooled to room temperature, poured into H2O (75 mL) containing NH4OH (1.5 mL) and extracted with CHCl3 (3 x 30 mL). The combined organic layers were washed with H2O (30 mL) containing NH4OH (1.5 mL), dried over Na2SO4 and the solvent evaporated to give a white residue. The crude was purified on a silica gel column eluting with CH2Cl2/MeOH/NH4θH 18:1:0.05 to 10:1:0.05 to provide the 3'-Λf-desmethyl azithromycin (0.41 g, 55%).
Example 3: Synthesis of 3'-iV-desmethyl clarithromycin from clarithromycin To a mixture of clarithromycin (1.00 g, 1.3 mmol) and NaOAc»3H20 (0.885 g, 6.5 mmol) was added MeOH-H2O (20 mL, 4:1), and the mixture heated to 55-60 0C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and the reaction stirred at 55-60 0C for 3 h. The reaction mixture was poured into 50 mL CHCl3 containing 1 mL ammonium hydroxide. It was extracted with CHCl3 (4 x 50 mL), washed with water (70 mL) containing 5 mL ammonium hydroxide, dried (anhydrous Na2SO4), concentrated, and purified by flash chromatography (silica gel, CHCl3 :MeOH:NH4OH 100:10:0.1) to afford 3'-N-desmethyl clarithromycin. Yield: 0.9g (92%).
Example 4: Synthesis of 3'-iV-desmethyl roxithromycin from roxithromycin
To a mixture of roxithromycin (850 mg, 0.914 mmol, 90%) and NaOAc (828 mg, 10.000 mmol) in a mixture of MeOH (6.0 mL) and water (1.5 mL) at 48 °C was added I2 in four portions (each portion: 63.5 mg) over 30 min, after each portion I2, followed by IN NaOH (400 μL). The reaction was continued for 30 min. The solvent was removed and EtOAc (100 mL) was added, followed by water (20 mL). The organic phase was washed with brine (40 mL X 2), dried with Na2SO4. The residue was separated by FC (6/94/0.2 MeOH/CH2Cl2/NH4OH), gave 600 mg of the 3'-N-desmethyl roxithromycin in 80% yield. LCMS (ESI) m/e 824 (M+H)+.
Example 5: Synthesis of 3'-iV-Desmethyl telithromycin from telithromycin
To a solution of telithromycin (3.0 g, 3.60 mmol) in anhydrous acetonitrile (70 mL) was added N-iodosuccinimide (NIS) (0.98 g, 4.32 mmol) in two portions within 30 min at 0 0C under argon atmosphere. The mixture was allowed to warm to rt and stirred overnight. CH2Cl2 (250 mL) and 5 % Na2S2O3 (80 mL) were added and the two layers separated. The organic layer was extracted with 5 % Na2S2O3 (1 X 80 mL), dilute NH4Cl (1 X 80 mL) and dried over Na2SO4. Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 8 % methanolic ammonia (2N NH3) in CH2Cl2 to give 3'-N-desmethyl telithromycin as white solid (1.95 g, 68 %). MS (ESI) M/E; M+H+ 798.6. Example 6: Synthesis of 3'-N-Desmethyl ketolide type macrolides
Most of the 3'-N-desmethyl ketolide intermediates are not made directly. Instead, the ketolide function, i.e. the 1,3-diketone, is introduced after the 3'-N-desmethyl functionality has been further transformed to an N-alkynyl intermediate. In an exemplary process, clarithromycin is converted to 3'-N-desmethyl clarithromycin. This compound is then alkylated to form an alkynyl intermediate. The cladinose sugar is then cleaved from this intermediate and the resulting free hydroxyl group is oxidized to the ketone. This process is shown below in Example 12.
Examples 7-12: Synthesis of N-alkynyl substituted macrolide compounds from 3'-N- desmethyl macrolide compounds
The compounds of the present invention can be made via an N-alkynyl substituted macrolide intermediate. The following Examples 7-12 illustrate the preparation of such compounds, hi these examples, the 3'-N-(but-3-ynyl) compounds are illustrated, but other corresponding alkynyl compounds are readily prepared by varying the alkynyl starting material.
Example 7: Synthesis of 3'-iV-(but-3-ynyl) erythromycin
A mixture of 3'-N-desmethyl erythromycin and the tosylate of l-butyn-4-ol in Hunig's base and THF was stirred. The reaction mixture was diluted to EtOAc and washed with ΝaHCO3(aq) and with brine. The organic layer was dried over K2CO3 and the solvent was evaporated to give product. The crude product was purified on silica gel column to give the N-alkynyl substituted erythromycin as a white solid.
Example 8: Synthesis of 3'-iV-(but-3-ynyl) azithromycin
A mixture of 3'-N-desmethyl azithromycin and the tosylate of l-butyn-4-ol in Hunig's base was stirred. The reaction mixture was diluted to EtOAc and washed with ΝaHCO3(aq) and with brine. The organic layer was dried over K2CO3 and the solvent was evaporated to give product. The crude product was purified on silica gel column to give the N-alkynyl substituted azithromycin as a white solid. Example 9: Synthesis of 3'-iV-(but-3-ynyl) clarithromycin
A mixture of 3'-N-desmethyl-clarithromycin and the tosylate of l,2-butyn-4-ol in anhydrous THF and Hunig's base was stirred. The reaction was poured into CH2Cl2, extracted with 2% aqueous NH4OH and saturated brine. The organic layer was dried over Na2SO4 and the solvent was evaporated away. The crude material was purified on a silica gel column to give the N-alkynyl substituted clarithromycin.
Example 10: Synthesis of 3'-iV-(but-3-ynyl) roxithromycin
A mixture of 3'-N-desmethyl roxithromycin (500 mg, 0.608 mmol) and the tosylate of l-butyn-4-ol in a mixture solvents of THF (5.4 mL) and Hunig's base (1.6 mL) was refluxed for 48 hr. The reaction mixture was concentrated, then, EtOAc (100 mL) was added. The organic layer was washed with Sat. NaHCO3 (20 mL), and brine (50 mL). The N-alkynyl substituted roxithromycin was isolated by FC (3/100/0.2 eOH/CH2Cl2/NH4OH), gave 316 mg in 59% yield. LCMS (ESI) m/e 876 (M+H)+.
Example 11: Synthesis of 3'-iV-(but-3-ynyl) telithromycin:
Two alternative procedures are used for the synthesis of 3'-N-(but-3-ynyl) telithromycin. Protocol A: A mixture of 3'-Ν-desmethyl telithromycin (0.66 g, 0.83 mmol) and the tosylate of l-butyn-4-ol (0.33 g, 1.49 mmol) in THF (15 mL) and Hunig's base (3 mL) was heated at 900C for 5 days. The solvent was evaporated; the residue was dissolved in IN HCl (50 mL) and kept stirring at room temperature for about Ih. CH2Cl2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 X 30 mL) and basified with NaOH (IN) to form a whitish-suspension. The suspension was extracted with CH2Cl2 (3 X 30 mL) and the organic layer was dried over Na2SO4. Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 6 % methanolic ammonia (2N NH3) in CH2Cl2 to give 3'-N-(but-3-ynyl) telithromycin as white solid (0.12 g, 17 %). MS (ESI) m/e 850.8 (M+H)+.
Protocol B: A mixture of 3'-N-desmethyl telithromycin (0.66 g, 0.83 mmol), and the tosylate of l-butyn-4-ol (0.40 g, 1.84 mmol) in acetonitrile (10 mL) and Hunig's base (0.18 mL, 1.0 mmol) was microwave heated to 90 0C within 10 min and maintained at 90 0C for 1.5h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in IN HCl (60 mL) and kept stirring at room temperature for about 2h. CH2Cl2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 X 30 mL) and basified with 50 % KOH to form a whitish-suspension. The suspension was extracted with CH2Cl2 (3 X 30 mL) and the organic layer was dried over Na2SO4. The solvent was evaporated and the crude was purified by preparative TLC (2000 micron plate) eluting with CH2Cl2/methanolic ammonia (2N NH3) 12:1 to give 3'-N-(but-3-ynyl) telithromycin as white solid (0.19 g, 27 %). MS (ESI) m/e 850.8 (M+H)+.
Example 12: Synthesis of 3'-iV-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring.
3'-N-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring are prepared by introducing the oxime function typically after the 3'-Ν-but-3-ynyl (or other desired alkynyl group) has been introduced. Example 12.1 provides a method for making the oxime of 3'-N'(but-3-ynyl) clarithromycin. Examples 12.2 to 12.6 provide procedures for making more complex oximes.
Example 12.1 Oxime of 3'-N'-(but-3-ynyl) clarithromycin
To a mixture of 3'-N-(butyl-3-ynyl) clarithromycin alkyne (3.0 g, 3.8 mmol) and hydroxylamine hydrochloride (7.9g, 114.3 mmol) was added pyridine (30 mL) and was heated to 60-65 0C for 12 h. The solution was evaporated to dryness and the crude material was partitioned between CH2Cl2 (150 mL) and saturated NaHCO3 solution (100 mL). pH of the solution was adjusted to 10 using IN NaOH solution. Organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layer was washed with brine (2 x 200 mL) and dried over anhydrous sodium sulphate. The solution was filtered, concentrated and co-evaporated with dry toluene ( 3 x 100 mL). The crude material thus obtained was purified by flash chromatography over silica gel (15: 1 = CH2Cl2: 2N NH3- MeOH). Yield = 2.2 g (73%).
Examples 12.2 to 12.6 The following scheme shows two exemplary oxime compounds (a piperidinyl oxime and a pyrrolidinyl oxime) and also the 3'-N-(but-3-ynyl) ketolide (see Example 6). The N-alkynyl oxime macrolides were prepared from 3'-N-(but-3-ynyl) clarithromycin (see Example 9). Scheme for Examples 12.2 to 12.6 for preparing 3'-N-(but-3-ynyl) macrolides having an oxime substituent on the macrolide ring.
H2O
Figure imgf000123_0001
Figure imgf000123_0002
Descladinose derivative Acetate derivative
EDC
3'-N'(but-3-ynyl) clarithromycin DMSO pyrH +CF3C O2-
Figure imgf000123_0003
Example 12.2: Descladinose Derivative
To 3'-N'(but-3-ynyl) clarithromycin (0.700 g) was added 10 mL 0.9N HCl and the mixture was stirred for 4 h at room temperature. The reaction mixture was saturated with sodium chloride and was adjusted to pH 8 using aqueous NH4OH solution. The solution was extracted with ethyl acetate (3 x 30 mL), dried (with Na2SO4), and concentrated under reduced pressure. Purification of the crude reaction mixture by flash chromatography (silica gel, 60% ethyl acetate in hexane) afforded 0.200 g (35% yield) of the descladinose derivative. Data for the descladinose derivative: 1HNMR (300 MHz, CDCl3, partial): δ 0.82 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.25 (dd, IH), 3.55 (m, 2H), 3.70 (s, IH), 3.85 (s, IH), 3.95 (s, IH), 4.40 (d, IH), 5.15 (dd, IH).
Example 12.3: Acetate Derivative
To a solution of the descladinose derivative (0.200 g, 0.32 mmol) in acetone (2 mL) was added acetic anhydride (0.050 mL, 0.5 mmol) and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with saturated sodium bicarbonate (3 x 50 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 50% ethyl acetate in hexane) to yield 0.100 g (50% yield) of acetate derivative. Data for acetate derivative: 1HNMR(300 MHz, CDCl3, partial): δ 0.84 (t, 3H), 2.00 (s, 3H), 2.20 (s, 3H), 2.90 (s, 3H), 3.00 (q, IH), 3.25 (s, IH, 3.47 (m, 2H), 3.70 (bs, IH), 3.82 (bs, IH), 3.97 (s, IH), 4.60 (d, IH), 4.77 (dd, IH), 5.15 (dd, IH).
Example 12.4: 3'-N-(but-3-ynyl) ketolide
To a solution of the acetate derivative (0.090 g, 0.134 mmol), EDC-HCl (0.172 g, 0.90 mmol), and DMSO (0.171 mL, 2.41 mmol) in CH2Cl2 (1.5 mL) was added dropwise a solution of pyridinium trifluoroacetate (0.174 g, 0.90 mmol) in CH2Cl2 (1 mL) at 15 0C. The reaction mixture was slowly warmed up to room temperature and stirred for 3 h. The reaction was quenched with water (2 mL), and allowed to stir for 30 min. The mixture was then poured into CHCl3 (50 mL), and the organic layer was washed with water (2 x 50 mL), dried (over anhydrous Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to yield 0.07Og (78%) of the 3'-N-(but-3-ynyl) ketolide. Data for the 3'-N-(but-3-ynyl) ketolide: MS (ESI) m/e 668 (M+H)+; 1HNMR (300 MHz, CDCl3, partial): δ 0.86 (t, 3H), 2.00 (s, 3H), 2.24 (s, 3H), 2.70 (s, 3H), 2.95-3.10 (m, IH), 3.15-3.05 (m, IH), 3.45-3.65 (m, IH), 3.80 (q, IH), 3.90 (s, IH), 4.28 (d, IH), 4.40 (d, IH), 4.76 (dd, IH), 5.10 (dd, IH).
Example 12.5: Piperidinyl oxime
To a solution of the 3'-N-(but-3-ynyl) ketolide (2.0 g, 2.9 mmol) in MeOH (10 mL) was added (R)-N-Piperidin-3-yl-hydroxylamine hydrobromide (1.26 g, 4.4 mmol). The reaction mixture was stirred at rt for 14 h. The mixture was then poured into (50 mL) and water (50 mL) the pH was adjusted to 11 by addition OfNH4OH and the organic layer was separated and washed with brine (50 mL), dried (over anhydrous Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 12:1 CH2Cl2 and 2M methanolic ammonia) to yield 2g (78%) of the piperidinyl oxime as a 1:1 mixture of E/Z isomers. Data for the piperidinyl oxime: MS (ESI) m/e 724.7 (M+H)+. Example 12.6: Pyrollidinyl oxime
The pyrollidinyl oxime was synthesized from the 3'-N-(but-3-ynyl) ketolide and (R)-N- Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditions described above for the synthesis of piperidinyl oxime. Data for the pyrrolidinyl: MS (ESI) m/e 710.6 (M+H)+.
Example 13: Synthesis of Compounds of the present invention via a cyclization reaction of a 3'-iV-(but-3-ynyl) macrolide with an azide.
Compounds of the present invention can be made, for example, via a cycloaddition reaction of an alkynyl macrolide with an azide compound. In this cycloaddition reaction, the triazole functional group of the resulting compound is formed. Other compounds of the present invention are made by further chemically modifying the resulting compound from the cycloaddition reaction.
The cycloaddition reaction is generally run in the presence of a copper (I) salt such as copper iodide (CuI). A base can also be optionally used, such as Hunig's base (N,N- diisopropylethylamine). The following general reaction scheme outlines the cycloaddition reaction of the alkynyl macrolide and the azide compound.
Copper (I) Salt, Optional Base
Figure imgf000125_0001
Alkynyl Macrolide Azide Compound
Figure imgf000125_0002
The time required for the reaction to proceed to completion is variable and is dependent upon several factors including: the specific alkynyl macrolide and azide compounds and their concentrations; the amount of Cu(I) salt used; and the presence or absence of base, such as Hunig's Base(N,N-diisopropylethylamine). Reactions are monitored for the disappearance of the starting materials by TLC and/or LCMS and are typically allowed to run for between about 2 hours to about 72 hours. Reactions are generally stopped when analysis demonstrates that the starting alkynyl macrolide has been substantially consumed. The workup and purification protocols are standard. Modifications to the described workup procedures can be used. Such modifications can include the use of different aqueous wash solutions, different organic solvents for extraction, the use of other anhydrous salts for the drying of organic extracts, and the employment of different solvent mixtures for the chromatographic purification of the compounds. The methods used for the workup of the reaction mixtures, the extraction of products, the drying of organic extracts, and for the isolation and purification of the compounds of the present invention are typical of procedures familiar to those trained in the art of organic synthesis.
Most compounds of the present invention can be prepared from the desired alkynyl macrolide and azide compound under one of several similar reaction conditions as exemplified by Conditions A, B, C, and D below. Use of Conditions A and C, which do not include the step of degassing the reaction mixture, tend to result in the formation of iodinated side-products in addition to the desired product and thereby generally produced lower isolated yields. Additionally, reduction of the amount of copper iodide used in the reaction to 0.5 molar equivalents or less as in conditions B and D also tends to result in reduced formation of iodinated by-products. As demonstrated in Condition D, the presence of Hunig's base is not essential for the success of the triazole formation step; however, it is found preferable that the base be included since it often results in a higher rate of reaction and correspondingly shorter reaction times.
Condition A:
To a stirred solution of the alkynyl macrolide (0.04 mmol), the azide compound (0.07 mmol) and Hunig's base (10 μL) in 0.5 mL tetrahydrofuran (THF) is added CuI (5 mg, 0.03 mmol). The mixture is stirred at ambient temperature for 16 hours then diluted with CH2Cl2 (10 mL) and washed with a 3 : 1 mixture of saturated aqueous NH4Cl and 28% aqueous
NH4OH (10 mL) and with brine (10 mL) the aqueous washes are back-extracted with CH2Cl2 (2 x 10 mL). The combined organic extracts are dried over K2CO3, filtered, and concentrated to afford 52 mg of crude product which is purified by chromatography on silica gel (elution with 40:1 2M NH3 in MeOH and CH2Cl2) to give the desired compound.
Condition B: A solution of alkynyl compound (0.10 mmol) and azide compound (0.12 mmol) and
Hunig's base in 0.4 mL THF are thoroughly degassed by alternately evacuating the reaction vessel and purging with dry argon. CuI is then added (2 mg, 0.01 mmol) and the mixture is further degassed. The mixture is stirred under argon for 6h then diluted with CH2Cl2 (20 mL) and washed with a 3:1 mixture of saturated aqueous NH4Cl and 28% aqueous NH4OH (10 mL) and with brine (10 mL) the aqueous washes are back-extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts were dried over K2CO3, filtered, and concentrated to afford 115 mg of crude product which is purified by chromatography on silica gel (eluted with 2M NH3 in MeOH (2.5%) and CH2Cl2 (97.5%), to give the desired compound.
Condition C:
To a stirred solution of alkynyl compound (0.10 mmol) and Hunig's base (0.2 mL) in 3 mL THF is added the azide compound (0.50 mmol) and CuI (20 mg, 0.10 mmol). The reaction mixture is stirred under argon for 60 hours then poured into saturated aqueous NH4Cl and extracted with CH2Cl2. The organic extracts are dried over Na2SO4, filtered, and concentrated to afford a crude residue which is purified by silica gel chromatography (eluted with 25:1 :0.1 CH2Cl2MeO^NH4OH) and then by preparative TLC (elution with 25:1 :0.1 CH2Cl2:MeOH:NH4OH) to afford the desired compound.
Condition D A solution of alkynyl compound (0.15 mmol) and the azide compound (0.25 mmol) in
2.7 mL THF are thoroughly degassed by alternately evacuating the reaction vessel and purging with dry argon. CuI is then added (10 mg, 0.05 mmol) and the mixture is further degassed. The mixture is stirred under argon for 4h then concentrated in vacuo, dissolved in CH2Cl2 (1 mL), and placed directly on a silica gel column. Elution with 2 molar (M) NH3 in MeOH (3%) and CH2Cl2 (97%) gives the desired compound. Akynyl Macrolide Compounds
The alkynyl macrolide compounds that can be used in the synthesis of the compounds of the present invention are shown in the following Table 2 A. It is appreciated by one of skill in the art that these alkynyl macrolide compounds, Ml to M43, are non-limiting examples and that a wide variety of additional alkynyl macrolides can be used to prepare other compounds of the present invention. In particular, macrolide moieties, Ml 1, M12, M13, Ml 6, Ml 7, Ml 8, M20, M21, M22, M23, M27, M28, M33, M34, M35, M36, M37, M38, M39, M40, M41, M42, and M43 are illustrative of various macrolides containing an oxime or other related functionality.
TABLE 2A
Alkynyl Macrolide Compound Structure
Ml
M2
Figure imgf000128_0001
M3
M4
Figure imgf000129_0001
M5
Figure imgf000129_0002
M6
Figure imgf000129_0003
M7
M8
M9
MlO
Figure imgf000130_0001
Figure imgf000131_0001
M14
Figure imgf000132_0001
M15
Figure imgf000132_0002
M16
Figure imgf000132_0003
M17
NH2
Figure imgf000133_0001
M18
Figure imgf000133_0002
M19
Figure imgf000133_0003
M20
Figure imgf000134_0001
M21
Figure imgf000134_0002
M22
Figure imgf000134_0003
M23
Figure imgf000134_0004
M24
Figure imgf000135_0001
M25
Figure imgf000135_0002
M26
Figure imgf000135_0003
M27
Figure imgf000135_0004
Figure imgf000136_0001
Figure imgf000137_0001
M35
Figure imgf000138_0001
M36
Figure imgf000138_0002
M37
Figure imgf000138_0003
Figure imgf000139_0001
Figure imgf000140_0001
Synthesis of Alkynyl Macrolides
The alkynyl macrolide compounds, such as alkynyl macrolide compounds Ml to M44, are generally made by the alkynylation (i.e. the addition of an alkynyl group) to a monomethyl amine macrolide compound. The monomethyl amine macrolide is generally made by the desmethylation of the corresponding macrolide compound. Depending on the macrolide compound and functional groups present, the desmethylation process can involve several steps, including various protection and deprotection steps. The desmethyl macrolide compound is alkynylated with the corresponding alkynyl compound, which is generally an alkynyl halide, tosylate, or mesylate. For the compounds of the present invention, 4-bromo- 1-butyne, 4-iodo-l-butyne, or the tosylate or mesylate of l-butyn-4-ol are generally used. Examples of synthetic procedures for preparing alkynyl macrolides are found in PCT Application No. WO 2005/085266, published September 15, 2005, to Rib-X Pharmaceuticals, Inc. The following general reaction scheme outlines this alkynylation process.
Figure imgf000141_0001
Macrolide, Desmethyl Macrolide R3 is generally Methyl
Figure imgf000141_0002
Desmethyl Macrolide Alkynyl Macrolide
The following procedures outline the synthesis of various alkynyl macrolide compounds of the present invention.
Synthesis of Alkvnyl Macrolide Ml
Alkynyl macrolide Ml is made by selective demethylation of azithromycin 1 to produce 3'-N-desmethylazithromycin 2. This compound 2 is selectively alkylated with alkynyl tosylate 11 to produce alkynyl macrolide Ml.
Figure imgf000142_0001
Synthesis of 3'-7V-desmethylazithromycin 2
Azithromycin 1 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50 0C followed by addition of iodine (I2) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding IN sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes. Stirring was continued for 2 hours. TLC (CH2Cl2ZMeOHZNH4OH 10:1:0.05) after 2 hours showed a single major product (Rf= 0.66). The reaction was cooled to room temperature, poured into H2O (75 mL) containing NH4OH (1.5 mL) and extracted with CHCl3 (3 x 30 mL). The combined organic layers were washed with H2O (30 mL) containing NH4OH (1.5 mL), dried over Na2SO4 and the solvent evaporated to give a white residue. The crude was purified on a silica gel column eluting with CH2Cl2ZMeOHZNH4OH 18:1 :0.05 to 10:1:0.05 to provide compound 2 (0.41 g, 55%).
Synthesis of alkynyl macrolide Ml
A mixture of 3'-N-desmethylazithromycin 2 and tosylate 11 in Hunig's base was stirred. The reaction mixture was diluted to EtOAc and washed with NaHCO3(aq) and with brine. The organic layer was dried over K2CO3 and the solvent was evaporated to give product. The crude product was purified on silica gel column to give Ml as a white solid. Synthesis of alkynyl macrolide M3.
Figure imgf000143_0001
Clarithromycin Desmethyl Clarithromycin 21 M3
Synthesis of S'-iV-desmethyl-clarithromycin 21
To a mixture of clarithromycin (1.00 g, 1.3 mmol) and NaOAcOH2O (0.885 g, 6.5 mmol) was added MeOH-H2O (20 mL, 4:1), and the mixture heated to 55-60 0C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and the reaction stirred at 55-60 0C for 3 h. The reaction mixture was poured into 50 mL CHCl3 containing 1 mL ammonium hydroxide. It was extracted with CHCl3 (4 x 50 mL), washed with water (70 mL) containing 5 mL ammonium hydroxide, dried (anhydrous Na2SO4), concentrated, and purified by flash chromatography (silica gel, CHCl3IMeOHiNH4OH 100:10:0.1) to afford 21. Yield: 0.9g (92%).
Synthesis of Alkynyl Macrolide M3
A mixture of S'-N-desmethyl-clarithromycin 21 and tosylate 11 in anhydrous THF and Hunig's base was stirred. The reaction was poured into CH2Cl2, extracted with 2% aqueous NH4OH and saturated brine. The organic layer was dried over Na2SO4 and the solvent was evaporated away. The crude was purified on a silica gel column to give M3.
Synthesis of Alkynyl Macrolide Ml 4 Alkynyl macrolide Ml 4 is made using a procedure analogous to that for making M3, starting from erythromycin A. The 3'-N-desmethyl-erythromycin A intermediate is made using a procedure described in U.S. Patent No. 3,725,385, to Freiberg, issued April 3, 1973. Alkynyl macrolide Ml 4 can further be used to prepare a variety of macrolides analogous to those already depicted for the clarithromycin core. A mixture of 3 '-N-desmethyl-erythromycin (1.0 g, 1.4 mmol) and the tosylate of 1 - butyn-4-ol (1.25 g, 5.6 mmol) in anhydrous THF (15 mL) and Hunig's base (2.2 mL, 11.9 mmol) was kept stirring at 55 0C for 48 hours. The reaction was poured into CH2Cl2 (50 mL), extracted with 2% aqueous NH4OH (3 x 30 mL) and saturated brine (1 x 30 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated away. The crude was purified on a silica gel column eluting with CH2Cl2/MeOH 10:1 to give alkynyl macrolide 14 (0.35 g, 32%).
Synthesis of Alkynyl Macrolides M4, M9, MlO, Mil and Ml 2
The synthesis of alkynyl macrolides M4, M9, MlO, Mil and Ml 2 are depicted in the scheme below. Alkynyl macrolide M9 is prepared from the removal of the cladinose sugar of alkynyl macrolide M3 under acidic conditions. Alkynyl macrolide MlO is made by the acetylation of macrolide M9. Macrolide M4 is made by the oxidation of the hydroxyl group of macrolide MlO. Alkynyl macrolides Mil and Ml 2 are made by converting a keto group of alkynyl macrolide M4 to the desired oximes. The oxime functionality of alkynyl macrolides of precursors with substituted oxime functionality at the 9-position of the macrocyclic ring were prepared from alkyne M3 and as shown below.
Figure imgf000144_0001
Synthesis of alkynyl macrolide M9
To the alkynyl macrolide M3 (0.700 g) was added 10 mL 0.9N HCl and the mixture was stirred for 4 h at room temperature. The reaction mixture was saturated with sodium chloride and was adjusted to pH 8 using aqueous NH4OH solution. The solution was extracted with ethyl acetate (3 x 30 mL), dried (with Na2SO4), and concentrated under reduced pressure. Purification of the crude reaction mixture by flash chromatography (silica gel, 60% ethyl acetate in hexane) afforded 0.200 g (35% yield) of the descladinose alkynyl macrolide M9. Data for M9: 1HNMR (300 MHz, CDCl3, partial): δ 0.82 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.25 (dd, IH), 3.55 (m, 2H), 3.70 (s, IH), 3.85 (s, IH), 3.95 (s, IH), 4.40 (d, IH), 5.15 (dd, IH).
Synthesis of Alkynyl Macrolide M5
A solution of alkynyl macrolide M4 (Ig, 1.5 mmol) in MeOH (30 mL) was refluxed for 12h. The solution was concentrated and the crude material was purified by flash chromatography over silica gel (50% ethyl acetate in hexane). Yield: 0.5g of M5 (53%).
Synthesis of alkvnyl macrolide MlO
To a solution of alkynyl macrolide M9 (0.200 g, 0.32 mmol) in acetone (2 mL) was added acetic anhydride (0.050 mL, 0.5 mmol) and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with saturated sodium bicarbonate (3 x 50 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 50% ethyl acetate in hexane) to yield 0.100 g (50% yield) of acetate functionalized alkynyl macrolide MlO. Data for MlO: 1HNMR(SOO MHz, CDCl3, partial): δ 0.84 (t, 3H), 2.00 (s, 3H), 2.20 (s, 3H), 2.90 (s, 3H), 3.00 (q, IH), 3.25 (s, IH, 3.47 (m, 2H), 3.70 (bs, IH), 3.82 (bs, IH), 3.97 (s, IH), 4.60 (d, IH), 4.77 (dd, IH), 5.15 (dd, IH).
Synthesis of alkynyl macrolide M4 To a solution of alkynyl macrolide MlO (0.090 g, 0.134 mmol), EDCΗC1 (0.172 g,
0.90 mmol), and DMSO (0.171 mL, 2.41 mmol) in CH2Cl2 (1.5 mL) was added dropwise a solution of pyridinium trifluoroacetate (0.174 g, 0.90 mmol) in CH2Cl2 (1 mL) at 150C. The reaction mixture was slowly warmed up to room temperature and stirred for 3 h. The reaction was quenched with water (2 mL), and allowed to stir for 30 min. The mixture was then poured into CHCl3 (50 mL), and the organic layer was washed with water (2 x 50 mL), dried (over anhydrous Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to yield 0.07Og (78%) of the alkynyl macrolide M4 (also commonly referred to as a ketolide). Data for M4:M4 MS (ESI) m/e 668 (M+H)+; 1HNMR (300 MHz, CDCl3, partial): δ 0.86 (t, 3H), 2.00 (s, 3H), 2.24 (s, 3H), 2.70 (s, 3H), 2.95-3.10 (m, IH), 3.15-3.05 (m, IH), 3.45-3.65 (m, IH), 3.80 (q, IH), 3.90 (s, IH), 4.28 (d, IH), 4.40 (d, IH), 4.76 (dd, IH), 5.10 (dd, IH).
Synthesis of alkynyl macrolide Mil
To a solution of M4 (2.0 g, 2.9 mmol) in MeOH (10 mL) was added (R)-N-Piperidin- 3-yl-hydroxylamine hydrobromide (1.26 g, 4.4 mmol). The reaction mixture was stirred at rt for 14h. The mixture was then poured into (50 mL) and water (50 mL) the pH was adjusted to 11 by addition OfNH4OH and the organic layer was separated and washed with brine (50 mL), dried (over anhydrous Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 12:1 CH2Cl2 and 2M methanolic ammonia) to yield 2g (78%) of the oxime functionalized alkynyl macrolide Mil as a 1:1 mixture of E/Z isomers. Data for Mil: MS (ESI) m/e 724.7 (M+H)+.
Synthesis of Alkynyl Macrolide Ml 2
Alkynyl macrolide Ml 2 was synthesized from alkynyl macrolide M4 and (R)-N- Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditions described above for the synthesis of alkynyl macrolide Mil. Data for M12: MS (ESI) m/e 710.6 (M+H)+.
Synthesis of Alkynyl Macrolides M13, M16, M17, and Ml 8
Alkynyl macrolides M13, M16, and M17 are also synthesized from alkynyl macrolide M4 . Alkynyl macrolide Ml 8 is synthesized from alkynyl macrolide Ml 7. The syntheses are outlined in the following reaction scheme.
Figure imgf000147_0001
Synthesis of alkynyl macrolide Ml 3
Alkynyl macrolide Ml 3 was synthesized from alkynyl macrolide M4 and N-[I- dimethtylaminoethyl]-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M13: MS (ESI) m/e 726.5 (M+H)+.
Synthesis of alkynyl macrolide Ml 6
Alkynyl macrolide Ml 6 was synthesized from alkyne M4 and N-Piperidin-4-yl- hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M16: MS (ESI) m/e 724.6 (M+H)+.
Synthesis of alkynyl macrolide Ml 7
Alkynyl macrolide Ml 7 was synthesized from alkyne M4 and cis-4- aminocylcohexyl-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime Mil. Data for M17: MS (ESI) m/e 738.7 (MH-H)+.
Synthesis of alkynyl macrolide Ml 8
To a solution of alkynyl macrolide Ml 7 (20 mg, 0.02 mmol) in CHCl3 (0.2 mL) was added formaldehyde (5 mg of 37% aqueous solution, 0.06 mmol) and formic acid (6 mg, 0.12 mmol). The mixture was heated at 50 0C in a sealed tube for 12h. The reaction mixture was partitioned between aqueous NaHCO3 (10 mL) and chloroform (10 mL) the organic fraction was dried on K2CO3, filtered and concentrated to give alkynyl macrolide Ml 8 as a white solid (18 mg). Data for M18: MS (ESI) m/e 766.7 (M+H)+.
Synthesis of Alkynyl Macrolide Ml 5
Telithromycin was selectively N-demethylated and then alkylated with the tosylate of l-butyn-4-ol as described for azithromycin, erythromycin and clarithromycin above.
Synthesis of 3'-iV-Desmethyl telithromycin 30 To a solution of telithromycin 29 (3.0 g, 3.60 mmol) in anhydrous acetonitrile (70 mL) was added Ν-iodosuccinimide (ΝIS) (0.98 g, 4.32 mmol) in two portions within 30 min at 0 0C under argon atmosphere. The mixture was allowed to warm to rt and stirred overnight. CH2Cl2 (250 mL) and 5 % Na2S2O3 (80 mL) were added and the two layers separated. The organic layer was extracted with 5 % Na2S2O3 (1 X 80 mL), dilute NH4Cl (1 X 80 mL) and dried over Na2SO4. Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 8 % methanolic ammonia (2N NH3) in CH2Cl2 to give compound 30 as white solid (1.95 g, 68 %). MS (ESI) M/E; M+H+ 798.6.
Scheme 105 Synthesis of alkynyl macrolide Ml 5.
Figure imgf000149_0001
Figure imgf000149_0002
Synthesis of 3'-iV-(but-3-yiiyl) telithromycin, Ml 5
Protocol A: A mixture of amine 30 (0.66 g, 0.83 mmol) and tosylate 11 (0.33 g, 1.49 mmol) in THF (15 mL) and Hunig's base (3 mL) was heated at 90 0C for 5 days. The solvent was evaporated; the residue was dissolved in IN HCl (50 mL) and kept stirring at room temperature for about Ih. CH2Cl2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 X 30 mL) and basified with NaOH (IN) to form a whitish-suspension. The suspension was extracted with CH2Cl2 (3 X 30 mL) and the organic layer was dried over Na2SO4. Solvent was evaporated and the crude was purified on silica gel eluting with 0 - 6 % methanolic ammonia (2N NH3) in CH2Cl2 to give compound M15 as white solid (0.12 g, 17 %). MS (ESI) m/e 850.8 (M+H)+. Synthesis of 3'-iV-(but-3-ynyl) telithromycin, M15
Protocol B: A mixture of amine 30 (0.66 g, 0.83 mmol), and tosylate 11 (0.40 g, 1.84 mmol) in acetonitrile (10 mL) and Hunig's base (0.18 mL, 1.0 mmol) was microwave heated to 90 0C within 10 min and maintained at 90 0C for 1.5h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in IN HCl (60 mL) and kept stirring at room temperature for about 2h. CH2Cl2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2 X 30 mL) and basified with 50 % KOH to form a whitish-suspension. The suspension was extracted with CH2Cl2 (3 X 30 mL) and the organic layer was dried over Na2SO4. The solvent was evaporated and the crude was purified by preparative TLC (2000 micron plate) eluting with CH2Cl2/methanolic ammonia (2N NH3) 12:1 to give compound M15 as white solid (0.19 g, 27 %). MS (ESI) m/e 850.8 (M+H)+.
Figure imgf000150_0001
Synthesis of Alkynyl Macrolide Ml 9.
Desmethyl telithromycin 30 was treated according to the procedures of US Patent No. 6,124,269 to afford the 2-fluoro amine 30a. This was then alkylated with the tosylate of 1- butyn-4-ol under the conditions for making Ml 5 to afford the fluorinated alkynyl macrolide M19. The reactions are outlined in the following scheme.
Figure imgf000151_0001
Synthesis of Alkynyl Macrolides M20. M21. M22, and M23
Alkynyl macrolides M21, M22, and M23 are prepared according to the following reaction scheme from alkynyl macrolide M20. Alkynyl macrolide M20 is in turn made from alkynyl macrolide M14.
Figure imgf000151_0002
Synthesis of alkynyl macrolide M20 To a mixture of alkynyl macrolide M14 (Ig, 1.3 mmol) and hydroxylamine hydrochloride (0.4g, 6.4 mmol) was added methanol (15 mL) and triethylamine (3.2 mmol). The solution was refluxed for 72h. Cooled to ambient temperature, poured into water (50 mL) and adjusted pH to 11. The resulting solution was extracted with dichloromethane (4x 50 mL), dried and concentrated. The crude material was purified by flash chromatography over silica gel to yield M20 (C2C12:2N NH3-MeOH = 10:1). Yield: 0.6g (60%).
Figure imgf000152_0001
M14 M20
Synthesis of Alkynyl Macrolide M21
To a solution of alkynyl macrolide M20 (2.0Og, 2.54 mmol) in THF (17 mL) at O0C was added Et3N (1.50 mL, 10.67 mmol), followed by addition of acetic anhydride (946 μL, 9.91 mmol), then, DMAP (34 mg, 0.25 mmol). The mixture was stirred at O0C for 3h, then, Et3N (150 μL, 1.07 mmol) and acetic anhydride (95 μL, 0.99 mmol) were added. The mixture was stirred for 3h, then, MeOH (2.0 ml) was added. The reaction mixture was concentrated and EtOAc (100 mL) was added, washed with saturated NaHCO3 (30.0 mL), then, brine (30.0 mL), dried with Na2SO4, gave 2.28 g of alkynyl macrolide M21. The residue was used for the next step without further purification. MS (ESI) m/e 913 (M + H)+.
Synthesis of Alkynyl Macrolide M22
To a solution of triacetate alkynyl M21 (913 mg, 1.00 mmol, crude), 2-methylene- 1,3 -propane- [bis-(tert-butyl)carbonate] (865 mg, 3.00 mmol) and 1,4- bis(diphenylphosphino)-butane (dppb) (305 mg, 0.70 mmol) in THF (10 mL, degassed) was added Pd2(dba)3 (92 mg, 0.10 mmol) at room temperature. The mixture was refluxed for 12h , then, the reaction mixture was concentrated and EtOAc (100 mL) was added. Washed with saturated NaHCO3 (30 mL), brine (30 mL), dried with Na2SO4, The residue was isolated by silica gel chromatography (CH2Cl2 to 2% MeOH in CH2Cl2 containing 0.2% NH4OH), gave 340 mg of alkynyl macrolide M22 in 35% yield for two steps. MS (ESI) m/e 966 (M + H)+.
Synthesis of Alkvnyl Macrolide M23
Alkynyl macrolide M22 (330 mg, 0.34 mmol) in MeOH (6 mL), was refluxed for 5 days. The residue was isolated by FC (CH2Cl2 to 2% MeOH in CH2Cl2 containing 0.2%
NH4OH), gave 143 mg of alkynyl macrolide M23 in 50% yield. MS (ESI) m/e 839 (M + H)+.
Synthesis of Alkynyl Macrolide M24
To a solution of alkynyl macrolide M4 (6.4g, 9.6 mmol) in pyridine (25 mL) was added methanesulfonic anhydride (4.Og, 22.9 mmol) at 100C. The reaction was stirred at ambient temperature for 24h. The solution was concentrated and portioned between ethyl acetate (150 mL) and saturated NaHCO3 solution (150 mL). Organic layer was separated and the aqueous layer was back extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (2 x 150 mL), dried and concentrated. The crude material was purified by flash chromatography over silica gel (50% ethyl acetate in hexane) to give 5.9g of M24 (83%).
Synthesis of Alkynyl Macrolide M25
To a solution of alkynyl macrolide M24 (5.9 g, 7.9 mmol) in acetone (25 mL) was added diazabicycloundecene (DBU) (1.4 mL, 9.5 mmol) at ambient temperature. After stirring for 48h, the reaction was diluted with methylene chloride, washed with water, dried and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (40% ethyl acetate in hexanes). Yield 3.6 g M25 (70%).
Synthesis of Alkynyl Macrolide M26
To a solution of M25 (3.3 g, 5.0 mmol) in methylene chloride (30 mL) was added DBU (1.0 mL, 6.5 mmol) at O0C. Then was added carbonyldiimidazole (1.Og, 6.1 mmol) at once. After stirring for 3h, the reaction was diluted with methylene chloride, washed with water, dried and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (70% ethyl acetate in hexanes). Yield 3.4 g M26 (89%).
Synthesis of Alkynyl Macrolide M27
Alkynyl macrolide M27 is made from alkynyl macrolide M23 by reduction of the oxime to the imine followed by acetylation of the compound, which is then oxidized to give the bridged ketone. The cladinose sugar is then hydrolyzed by treatment with dilute hydrochloric acid. Synthesis of Alkynyl Macrolide M28
Alkynyl macrolide M28 is made by refluxing alkynyl macrolide M27 with the following hydroxyl amine compound in methanol.
Figure imgf000154_0001
Synthesis of AIkynyl Macrolide M2
A mixture of M26 (1.48 g, 2.0 mmol) and hydrazine (0.65 mL, 20 mmol) in acetonitrile (40 mL) and water (6 mL) was heated to 500C. After 5h the solution was concentrated and refluxed with MeOH (100 mL) for 2Oh. The solution was concentrated and the crude material was purified by flash chromatography over silica gel (60% ethyl acetate in hexane). Yield: 0.8g M2 (60%).
Synthesis of Alkynyl Macrolides M6, M7, and M8
Alkynyl macrolides M6, M7, and M8 are made from M26 (using a procedure analogous to that for making M2, in which the hydrazine is replaced with methyl amine, ammonium hydroxide, and ethanol amine respectively.
Synthesis of Alkynyl Macrolides M29, M30. M31, and M32
Alkynyl macrolides such as M29, M30, M31, and M32 are made from M26 using the following general procedure and the corresponding diamino compound. For compound M29, to a solution of compound M26 (6.25g, 6.6 mmol) in CH3CN
(35 mL) was added ethylene diamine (4.5 mL, 66.0 mmol) and stirred for 16h. The solution was evaporated to dryness under reduced pressure. The crude product was dissolved in anhydrous EtOH (50 mL). Then acetic acid (AcOH, 1.1 mL, 3.0 mmol) was added and heated to 650C for 30h. The solution was cooled and IN LiOH was added and heated to 500C for 5h. The solution was partitioned between ethyl acetate (150 mL) and brine (150 mL). Organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was concentrated and the crude material was purified by flash chromatography over silica gel (EtOAc: Heptane: TEA - 35:55:10) to yield 4.5g (81%) of the compound product M29. Compounds M30, M31, and M32 are made using the foregoing procedure using cis-
3,4-diamino tetrahydrofuran, cis-l,2-diaminocyclohexane, and l,2-diamino-2-methylpropane (i.e. 1,1 -dimethyl ethylenediamine), respectively. Other compounds analogous to compounds M29, M30, M31 and, M32 can be made by selecting other diamino compounds.
The following is a further scheme showing a synthesis that can be followed to prepare compounds of the present invention, e.g., Compound 252, from starting compounds such as compound 1, see, M. Kshimura et al., "Synthesis and Antibacterial Activity of the Tricyclic Kektolides TE-802 and Its Analogs", The Journal of antibiotics, vol 54, no. 8, pp. 664-678, August 2001.
Figure imgf000155_0001
Example 14: Synthesis of azides of the compounds of the present invention
The azides compounds used in preparing the compounds of the present invention can be readily synthesized by methods known from the literature. Exemplary azide syntheses are presented below. The remaining azides can be synthesized in analogous fashion from appropriate commercial starting materials. When possible, azides were produced from the corresponding substituted alkyl bromides by direct displacement with azide ion. When the required alkyl bromides were not readily available, the compounds were derived from substituted alkanols: to accomplish this, the alcohols were first activated as their sulfonyl ester derivatives and then substituted with azide ion. If neither the required bromides nor alkanols were commercially available, the azides were synthesized from the corresponding carboxylic acids by reduction with borohydride to the corresponding alcohols. The resulting alkanols were then treated as above to yield the azides. Finally, some azides of were synthesized from the corresponding substituted alkyl amines by reaction with triflic azide. In a few cases, azides were synthesized by modification of other azides that had been synthesized according to the methodologies above. The following are exemplary schemes for preparing azides.
Scheme 14.1 for preparing an azide compound
Figure imgf000156_0001
Florfenicol
Florfenicol amine Florfenicol azide A solution of florfenicol (0.090 g, 0.25 mmol) in acetic acid (3.0 mL) was treated with sulfuric acid (10%, 15 mL) and heated to 110 °C for 12 h. The reaction mixture was cooled to room temperature, treated with 10 M aqueous sodium hydroxide to adjust the pH to 14, extracted with dichloromethane (3 x 30 mL), dried (Na2SO4), and evaporated to provide florfenicol amine (65 mg, 0.25 mmol) as a yellow oil. A solution of florfenicol amine (0.90 g, 3.6 mmol) in H2O (10 mL) and methanol (30 mL) was treated with triethylamine (1.5 mL, 10.8 mmol) and trifluoromethanesulfonyl azide (13.4 mmol dissolved in 20 mL of dichloromethane; solution prepared according to method described in J. Am. Chem. Soc. 2002, 124, 10773), and stirred at 0 0C 3 h and then warmed to 23 0C for 1 h. The reaction mixture was diluted with H2O (30 mL), extracted with dichloromethane (30 mL) and evaporated. Flash chromatography (SiO2, 50-100% ethyl acetate/hexanes) provided the flofenicol azide (0.65 g, 2.4 mmol) as a yellow solid. Scheme 14.2 for preparing an azide compound
Figure imgf000157_0001
A solution of D-(-)-threo-2-amino-l-(4-nitrophenyl)- 1,3 -propanediol (0.42 g, 2.0 mmol) in H2O (5 mL) and methanol (17 mL) was treated with triethylamine (0.84 mL, 6.0 mmol) and trifluoromethanesulfonyl azide (3.0 mmol dissolved in 5 mL of dichloromethane; solution prepared according to method described in J. Am. Chem. Soc. 2002, 124, 10773), and stirred at 23 °C for 3 h. The reaction mixture was diluted with H2O (30 mL), extracted with dichloromethane (30 mL) and evaporated. Flash chromatography (SiO2, 50-100% ethyl acetate/hexanes) provided the azide (0.28 g, 1.2 mmol) as a yellow solid.
Scheme 14.3 for preparing an azide compound
NaBH41 BF3 OEt T TffMN3
Figure imgf000157_0002
Figure imgf000157_0003
Figure imgf000157_0004
Azide compound
To a stirred 0 0C solution of 4-nitrophenylalanine (4.6g, 20 mmol) and NaBH4 (3.2g, 84 mmol) in THF (50 mL) was added BF3 OEt (14.8 mL, 106 mmol). The reaction was warmed to rt and stirred for 24 h. The mixture was cooled to 00C and quenched with methanol. The reaction mixture was filtered and the filtrate concentrated to give a solid residue. 10% of this residue was dissolved in water (5 mL), methanol (20 mL) and triethyl amine (0.9 mL). Triflic azide solution (3.5 mmol dissolved in 7 mL of dichloromethane; solution prepared according to method described in J. Am. Chem. Soc. 2002, 124, 10773) was added and the mixture was stirred at rt for 14 h. The reaction mixture was diluted with dichloromethane (30 mL) washed with saturated NaHCO3, and with brine. The organic extract was dried, filtered and concentrated to give the azide compound as a white solid (150 mg)
The foregoing azide compound is useful for preparing a wide variety of macrolide compounds of the present invention. The free nitro functional group in the macrolide compound can be later transformed to an azide via an amino group. This azide can be used for further cyclization reactions.
Schemes 14.4a-c for preparing an azide compound a.
Figure imgf000158_0001
Bromo compound
A solution of florfenicol (0.494 g, 1.38 mmol) in acetonitrile (15.0 mL) was treated with carbontetrabromide (0.594 g, 1.66 mmol) and triphenylphosphine (0.434 g, 1.66 mmol), and stirred at 23 0C for 12 h. The reaction mixture evaporated to a yellow residue and purified by flash chromatography (SiO2, 10% ethyl acetate/dichloromethane) to provide the bromo compound (0.28 g, 0.67 mmol) as a white powder. b.
Figure imgf000158_0002
Bromo compound Debrominated Compound
A solution of the bromo compound (0.20 g, 0.41 mmol) in methanol (5.0 mL) was treated with 10% palladium on charcoal (20 mg) and stirred at 23 °C for 2 h under a balloon of hydrogen. The reaction mixture was filtered, evaporated and purified by preparative thin- layer chromatography (SiO2, 10% ethyl acetate/dichloromethane) to afford the debrominated compound (90 mg, 0.26 mmol) as a white film. C.
Figure imgf000159_0001
Debrominated compound Amine Azide
A solution of the debrominated compound (90 mg, 0.26 mmol) in acetic acid (3.0 mmol) was treated with 10% sulfuric acid (15 mL) and heated to 110 0C for 12 h. The reaction mixture was cooled to room temperature, treated with 10 M aqueous sodium hydroxide to adjust the pH to 14, extracted with dichloromethane (3 >< 30 mL), dried (Na2SO4), and evaporated to provide crude amine as a yellow oil. A solution of this crude amine (83 mg) in methanol (3.6 mL) and dichloromethane (3.0 mL) was cooled to 0 °C and treated with triethylamine (0.14 mL, 1 mmol) and triflic azide (1.2 mL of a 0.3 M solution in dichloromethane) and allowed to warm to 23 °C. After 2 h, the reaction mixture was evaporated and purified by preparative thin-layer chromatography (SiO2, 10% ethyl acetate/dichloromethane) to afford the azide (60 mg, 0.23 mmol) as a colorless oil. Scheme 14.5 for fiuorinating an azide compound
The fluoro azide compound was prepared from the azide compound as shown.
Figure imgf000159_0002
azide compound fluorinated azide compound
To a stirred -78 0C solution of azide compound (111 mg, 0.5 mmol) in CH2Cl2 was added (diethylamino)sulfur trifluoride (DAST) (0.1 mL, 0.82 mmol). The reaction was stirred at -78 0C for 2h, then allowed to warm to rt and stirred for 14 h. The reaction mixture was poured into water and extracted with CH2Cl2. The organic extracts were dried, filtered, and concentrated to give the fluorinated azide compound as a solid (36 mg, 0.16 mmol). Scheme 14.6 for oxidizing a thioether chain in an azide compound
mCPBA, CH2Cl2, it, overnight
Figure imgf000160_0001
Figure imgf000160_0002
Thioether Sulfone
To a solution of the thioether (0.27 g, 1.1 mmol) in CH2Cl2 (15 mL) was added mCPBA (1.10 g, 4.5 mmol) and the mixture was stirred at room temperature overnight. Solvent was evaporated and the crude was purified on silica gel eluting with CH2Cl2/Me0H 20:1 to 15:1 to 12:1 to give the sulfone as colorless paste that solidified on standing (0.26 g, 87 %).
Example 15: Synthesis of more complex azide compounds
The organic azide compounds used in the synthesis of the compounds of the present invention are generally prepared from the iodo compound 2 or the boronic acid ester compound 3. Typically, the iodo or boronic acid functional groups provide a means for preparing a wide range of compounds using methods available to one skilled in the art.
Figure imgf000160_0003
Ester Compound, 3
Idodo Compound, 2
Figure imgf000160_0004
Further chemical transformations Further chemical transformations
Figure imgf000160_0005
Azide Compound
The iodo compound 2, is prepared according to the following scheme from commercially available (lR,2R)-(-)-2-amino-l-(4-nitrophenyl)-l,3-propanediol. The boronic acid ester compound 3 is prepared from the iodo compound 2.
Figure imgf000161_0001
The following reaction scheme illustrates various azide compounds that can be made from iodo compound 2. Ra, Rb, Rc, and Rd represent various alkyl, substituted alkyl, aryl, and substituted aryl groups.
General Scheme for Synthesis of Various Azide Compounds from lodo Compound 2
Figure imgf000162_0001
Ra, Rb, Rc, and Ra represent various alkyl, substitued alky!, aryl, substituted aryl, etc.
The Following Table 2 exemplifies azide compounds useful in the synthesis of compounds of the present invention. Table 2
304
Figure imgf000163_0001
305
Figure imgf000163_0002
306
Figure imgf000163_0003
307
Figure imgf000163_0004
308
Figure imgf000163_0005
309
Figure imgf000163_0006
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
334
Figure imgf000168_0001
335
Figure imgf000168_0002
Examples 16-17
The following Examples further exemplify methods for making compounds of the present invention.
Example 16 Synthesis of Compound 270
Figure imgf000168_0003
A mixture of 5-(4,4,5,5-tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (0.4 g, 1.791 mmol), l-(2-azido-3-fluoro-l-methoxy-propyl)-4-iodo-benzene (0.5 g, 1.4925 mmol), [l,l-bis(djphenylphosphino)ferrocene]palladium (II) chloride 1:1 complex with dichloromethane (61 mg, 0.075 mmol), potassium carbonate (621 mg, 4.5 mmol), dioxane (6 ml), ethanol (2 ml) and water (2 ml) was degassed and heated at 85 0C for 5 h under argon atmosphere. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (30 ml, twice) and brine (20 ml). The ethyl acetate solution was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica, gradient from 0% to 80% ethyl acetate in hexane) to afford the aminopyrimidinyl azide compound (250 mg, 56%). M/Z: 303 [M+H]+.
Figure imgf000169_0001
A mixture of the aminopyrimidinyl azide compound (100 mg, 0.331 mmol), 3'-N- (but-3-ynyl) clarithromycin (260 mg, 0.331 mmol), CuI (69 mg, 0.363 mmol), in THF (5 ml) was degassed. Hunig's base (0.3 ml) was added to the degassed mixture and stirred at room temperature under argon atmosphere for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (15 ml) and extracted with dichloromethane (30 ml, twice). The extract was washed with brine (25 ml) and dried over MgSO4, filtered and concentrated. The crude product was purified by Preparative TLC (silica gel, 6% 2N ammonia methanol in dichloromethane) to afford the macrolide final product (280 mg, 78%). M/Z: 1089, [M+H]+; 545, [M/2+H]+.
Example 17: Synthesis of Compound 205
Figure imgf000169_0002
A mixture of l-(2-azido-3-fluoro-l-methoxy-propyl)-4-iodo-benzene (6.7 g, 20 mmol), bis(pinaclato)diboron (5.59 g, 22 mmol), palladium (II) acetate (224 mg, 1 mmol), potassium acetate (5.88 g, 60 mmol) and DMF (30 ml) was degassed and heated at 80 0C for 16h under argon atmosphere. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (100 ml, twice) and brine (50 ml). The ethyl acetate solution was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 8% ethyl acetate in hexane) to afford the boronate (5.40 g, 80.6%).
Figure imgf000169_0003
A mixture of the boronate (5.4 g, 16.119 mmol), 5-bromo-2-hydromethylpyridine (3.165 g, 16.925 mmol), [l,l-bis(diphenylphosphino)ferrocene]palladium (II) chloride 1 :1 complex with dichloromethane (658 mg, 0.806 mmol), potassium carbonate (6.67 g, 48.357 mmol), dioxane (60 ml), ethanol (20 ml) and water (20 ml) was degassed and heated at 85 0C for 4 h under argon atmosphere. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (200 ml, twice) and brine (100 ml). The ethyl acetate solution was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, gradient from 10% to 65% ethyl acetate in hexane) to afford the indicated product (3.83 g, 75%). M/Z: 317 [M+H]+.
Figure imgf000170_0001
3-Chloroperoxybenzoic acid (3.94 g, 22.837 mmol) was added to a solution of the compound from the previous step (5.1 g, 15.224 mmol) in dichloromethane (50 ml). The resulted solution was stirred at room temperature for 1 h, diluted with dichloromethane (200 ml), washed with sodium bicarbonate solution (saturated, 200 ml), water (200 ml) and brine (50 ml), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, gradient from 0% to 10% methanol in dichloromethane) to afford the indicated N-oxide azide compound (3.45 g, 68%). M/Z: 333 [M+H]+.
Figure imgf000170_0002
To a mixture of 3'-N-(but-3-ynyl) clarithromycin (3.0 g, 3.8 mmol) and hydroxylamine hydrochloride (7.9g, 114.3 mmol) was added pyridine (30 mL) and was heated to 60-650C for 12h. The solution was evaporated to dryness and the crude material was partitioned between CH2Cl2 (150 mL) and saturated NaHCO3 solution (100 mL). pH of the solution was adjusted to 10 using IN NaOH solution. Organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layer was washed with brine (2 x 200 mL) and dried over anhydrous sodium sulphate. The solution was filtered, concentrated and co-evaporated with dry toluene ( 3 x 100 mL). The crude material thus obtained was purified by flash chromatography over silica gel (15: 1 = CH2Cl2: 2N NH3- MeOH) to yield 3'-N-(but-3-ynyl) clarithromycin oxime. Yield = 2.2 g (73%).
Figure imgf000171_0001
An aqueous solution of KOH (50%, 120 ml) was added to a mixture of 3'-N-(but-3- ynyl) clarithromycin oxime compound shown above, 4.Og, 5.0 mmol), tetrabutylammonium bromide (322 mg, 1 mmol), chloromethyl methyl ether (1.2 ml, 15 mmol) and dichloromethane (160 ml) at 0 0C. The resulted solution was stirred at room temperature for 2 h before diluted with dichloromethane (200 ml), washed with water (200 ml, twice) and brine (100 ml), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica gel, gradient from 30% to 80% ethyl acetate in hexane) to afford the indicated 3'-N-(but-3-ynyl) clarithromycin mom-oxime compound (3.80 g, 90%). M/Z: 845.8 [M+H]+.
Figure imgf000172_0001
A mixture of the indicated N-oxide azide compound, 240 mg, 0.723 mmol), 3'-N- (but-3-ynyl) clarithromycin oxime alkyne (611 mg, 0.723 mmol), CuI (28 mg, 0.145 mmol), and THF (10 ml) was degassed. Hunig's base (0.3 ml) was added to the above reaction mixture and stirred at room temperature under argon atmosphere for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (15 ml) and extracted with ethyl acetate (40 ml, twice). The extract was washed with brine (25 ml) and dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (silica, gradient from 0% to 6% 2Ν ammonia methanol in dichloromethane) to afford the oxime macrolide final product (700 mg, 82%). M/Z: 1178.2 [M+H]+.
Antimicrobial activity
The compounds of the present invention were tested for antimicrobial activity. These data are presented in Table 3. The compounds were run against Streptococcus pneumoniae (wild type strain 02J1016) and Streptococcus pyogenes (wild type strain SS1542) using a standard microdilution assay to determine minimum inhibitory concentrations (MICs). The data is presented whereby a "+" indicates that the compound has an MIC value of 16 micrograms/ml or less and a "-" indicates that the compound has an MIC value greater than 16 micrograms/ml. A "N/A" means that data is unavailable. It will be recognized by one skilled in the art that the compounds can be assessed against other bacterial organisms and that the presentation of data for activity against Streptococcus pneumoniae and Streptococcus pyogenes is for illustrative purposes and in no way is intended to limit the scope of the present invention. The compounds of the present invention can be assayed against a range of other microorganisms depending upon the performance activity desired to be gathered. Furthermore, the "+", "-", and "N/A" representation and the selection of a cutoff value of 16 micrograms/ml is also illustrative and in no way is intended to limit the scope of the present invention. For example, a "-" is not meant to indicate that the compound necessarily lacks activity or utility, but rather that its MIC value against the indicated microorganism is greater than 16 micrograms/ml.
Table 3
Streptococcus Streptococcus
Compound # pneumoniae pyogenes
200 + +
201 + +
202 + +
203 + +
204 + +
205 + +
206 + +
207 + +
208 + +
209 + +
210 + +
211 + +
212 + +
213 + +
214 + +
215 + + 216 + + 217 + + 218 + + 219 + + 220 + + 221 + + 222 + + 223 + + 224 + + 225 + + 226 + + 227 + + 228 + + 229 + + 230 + + 231 + + 232 + + 233 + + 234 + + 235 + + 236 + + 237 + + 238 + + 239 + + 240 + + 241 + + 242 + + 243 + + 244 + + 245 + + 246 + + 247 + + 248 + + 249 + + 250 + + 251 + + 252 + + 253 + + 254 + + 255 + + 256 + + 257 + + 258 + + 259 + + 260 + + 261 + + 262 + + 263 + + 264 + + 265 + + 266 + + 267 + + 268 + + 269 + +
270 + +
271 + +
272 + +
273 + +
274 + +
275 + +
276 + +
277 + +
278 + +
279 + +
280 + +
281 + +
282 + +
283 + +
284 + +
285 + +
286 + +
287 + +
288 + +
289 + +
290 + +
291 + +
292 + +
293 + +
294 + +
295 + +
296 + • +
297 + +
298 + +
299 + +
300 + +
301 + +
302 + +
303 + +
INCORPORATION BY REFERENCE
The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.
EQUIVALENTS
The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

What is claimed is:
1. A compound having the structure:
Figure imgf000176_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a 14- or 15-membered macrolide connected via a macrocyclic ring carbon atom; X is selected from (a) H, (b) halogen, (c) a C1-6 alkyl group, (d) a C2-6 alkenyl group, (e) a C2-6 alkynyl group, (f) -OH, (g) -OR5, (h) -NR4R4, (i) -C(O)R5, G) -C(O)OR5, (k) - C(O)-NR4R4, (1) -C(S)R5, (m) -C(S)OR5, (n) -C(O)SR5, (o) -C(S)-NR4R4, (p) -N3, (q) -CN, (r) -CF3, (S) -CF2H, (t) -CFH2, (u) -S(O)pH, (v) -S(O)PR5, (w) -S(O)POH, (x) -S(O)POR5, (y) -S(O)PNR4R4, (z) -NR4C(O)R5, (aa) -NR4C(O)NR4R4, (bb) a C3-7 saturated, unsaturated, or aromatic carbocycle, and (cc) a 3-7 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur; Ra and Rb independently are selected from: (a) H, (b) a Ci-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OH, (f) -OR5, (g) -NR4R4, (h) -C(=O)R5, (i) - C(=O)OR5, G) -C(=O)-NR4R4, (k) -S(O)PNR4 R4, (1) -C(O)SR5, (m) halogen, (n) -S(O)pH, (o) - S(O)pR5, (p) -N3, (q) -CN, and (r) -NR4C(O)R5, wherein (b) -(d) are further optionally substituted with one or more R5 ; alternatively Ra and Rb are taken together with the carbon to which they are attached to form (a) -C(=0)-, (b) -C(=S)-, (c) -C=NR4, or (d) -C=NOR5; Rc is selected from: (a) H, (b) a Ci-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OR5, wherein R5 is not H, (f) -NR4R4, (g) -C(=0)R5, (h) -C(=O)OR5, (i) -C(=O)-NR4R4, G) -S(O)PNR4 R4, (k) -C(O)SR5, (1) -S(O)PH, (m) - S(O)PR5, (n) -CF3, (o) - CH2F, and (p) -CF2H, wherein (b) -(d) are further optionally substituted with one or more R5; Rd and Re independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -OH, (f) -OR5, (g) -NR4R4, (h) -C(=0)R5, (i) - C(=O)OR5, Q) -C(=O)-NR4R4, (k) -S(O)PNR4 R4, (1) -C(O)SR5, (m) halogen, (n) -S(O)PH, and (o) - S(O)PR5, wherein (b) -(d) are further optionally substituted with one or more R5 groups, or alternatively Rd and Re are taken together with the carbon to which they are attached to form (a) -C(O)-, (b) -C(=S)-, (c) -C=NR4, or (d) -C=NOR5; alternatively, Rc and Rd or Rc and Re are taken together to form a carbon-carbon double bond between the carbon atoms to which they are attached; alternatively Rd and X are taken together to form =CR5R5; or alternatively Rd and Re are taken together with the carbon to which they are attached to form (a) -C(=O)-, (b) -C(=S)-, (c) -C=NR4, (d) -C=NOR5, (e) =CH2, or (f) 3-12- membered carbocycle or heterocycle optionally substituted with one or more R5 groups; R1 and R3 independently are selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) -C(O)R5, (f) -C(O)OR5, (g) -C(O)-NR4R4, (h) - C(S)R5, (i) -C(S)OR5, (j) -C(O)SR5, and (k) -C(S)-NR4R4; alternatively R1 and R3 are taken together with the oxygen to which R1 is attached, the nitrogen to which R is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R5 groups; R2 is hydrogen or -OR12; G is selected from: (a) -B' and (b) -B'-Z-B", wherein i) each B' is independently selected from (aa) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings and (bb) a 3- 12 membered saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 rings and containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each (aa) or (bb) optionally contains one or more carbonyl groups, and wherein each (aa) or (bb) optionally is substituted with one or more R11 or Rl la; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc) -OR9, (dd) -SH, (ee) -S(O)15R9, (ff) halogen, (gg) -CN, (hh)-N3, (ii) -NO2, Oj) -Si(R13)3, (kk) -SO3H, (11) -SO3N(R4)2, (mm) -SO3R9, (nn) -NR6R6, (oo) -C(O)R9, (pp) - C(O)(CR6R6)tR9, (qq) -OC(O)(CR6R6)tR9, (rr) -C(O)O(CR6R6)tR9, (ss) - NR6(CR6R6)tR9, (tt) -NR6C(O)(CR6R6)tR9, (uu) -C(O)NR6(CR6R6)tR9, (w) - NR6C(O)NR6(CR6R6)tR9, (ww) -C(=NR6)(CR6R6)tR9, (xx) - C(=NR6)NR6)(CR6R6)tR9, (yy) -NR6C(=NR6)NR6)(CR6R6)tR9, (zz) - S(O)p(CR6R6)tR9, (aaa) -SC(O)(CR6R6),R9, (bbb) -C(=NNR6R6)(CR6R6)tR9, (ccc) - C[=NNR6C(O)R6](CR6R6)tR9, (ddd) -NR6C(O)O(CR6R6)tR9, (eee) - OC(O)NR6(CR6R6)tR9, (fff) -NR6C(O)NR6(CR6R6)tR9, (ggg) - NR6S(O)p(CR6R6)tR9, (hhh) -NR6C(O)R6, (iii) a 3- 12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings, (jjj) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group having 1 to 3 rings and containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (kkk) -C1-6 alkyl, (111) -C2-6 alkenyl, and (mmm) a C2-6 alkynyl group; wherein each (iii) or (jjj) optionally contains one or more carbonyl groups, and wherein each (iii) or (jjj) optionally is substituted with one or more R1 ' or R1 la; wherein each (kkk), (111), or (mmm) is optionally are substituted with one or more R14 groups; iii) Z is selected from (a) a single bond, (b) -C1-6 alkyl-, (c) -C2-6 alkenyl-, (d) -C2-6 alkynyl-, (e) -O-, (f) -NR4-, (g) -S(O)1,-, (h) -C(OH C) -C(O)O-, (j) - OC(O)-, (k) -OC(O)O-, (1) -C(O)NR4-, (m) -NR4CO-, (n) -NR4C(O)NR4- (o) - Q=NR4K (p) -C(=NR4)O-, (q) -OC(=NR4)-, (r) -C(=NR4)NR4-, (s) - NR4C(=NR4)-, (t) -C(=SK (u) -C(=S)NR4-, (v) -NR4C(=S)-, (w) -C(O)S-, (x) - SC(O)-, (y) -OC(=S)-, and (z) -C(=S)-O-, wherein any of the aliphatic carbons atoms in (b), (c), or (d) are optionally replaced with -(C=O)-, -O-, -S-, or -NR4-, and wherein any of (b), (c), or (d), are optionally further substituted with -OH, -NR4-, or halogen; R14 at each occurrence is independently selected from: (a) H, (b) F, (C) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)pR8, (j) - C(O)R8, (k) -C(O)OR8, (1) -OC(O)R8, (m) -C(O)NR8R8, (n) -OC(O)NR8R8, (o) -C(=NR8)R8, (p) -C(R8)(R8)OR8, (q) -C(R8)2OC(O)R8, (r) - C(R8)(OR8)(CH2)rNR8R8, (s) -NR8R8, (t) -NR8OR8, (u) -NR8C(O)R8, (v) - NR8C(O)OR8, (w) -NR8C(O)NR8R8, (x) -NR8S(O)PR8, (y) -C(OR8)(OR8)R8, (z) -C(R8)2NR8R8, (aa) -C(S)NR8R8, (bb) -NR8C(S)R8, (cc) -OC(S)NR8R8, (dd) -NR8C(S)OR8, (ee) -NR8C(S)NR8R8, (ff) -SC(O)R8, (gg) -N3, (hh) - Si(R13)3, (ii) a C1-6 alkyl group, (jj) a C2-6 alkenyl group, (kk) a C2-6 alkynyl group, (11) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (ii)- (mm) optionally are substituted with one or more R5 groups; 91 alternatively two R14 groups are taken together to form (a) =0, (b) =S, (c)
92 =NR8, or (d) =NOR8; and
93 R4, at each occurrence, independently is selected from:
94 (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group,
95 (e) a C3-I2 saturated, unsaturated, or aromatic carbocycle, (f) a 3-12 membered
96 saturated, unsaturated, or aromatic heterocycle containing one or more
97 heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-C1-O alkyl,
98 (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-I2 saturated,
99 unsaturated, or aromatic carbocycle, (k) -C(O)-3-12 membered saturated,
100 unsaturated, or aromatic heterocycle containing one or more heteroatoms
101 selected from nitrogen, oxygen, and sulfur, (1) -C(O)O-C1-6 alkyl, (m) -
102 C(O)O-C2-6 alkenyl, (n) -C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-12 saturated,
103 unsaturated, or aromatic carbocycle, (p) -C(O)O-3-12 membered saturated,
104 unsaturated, or aromatic heterocycle containing one or more heteroatoms
105 selected from nitrogen, oxygen, and sulfur, and (q) -C(O)NR6R6,
106 wherein any of (b)-(p) optionally is substituted with one or more R5
107 groups,
108 alternatively, NR4R4 forms a 3-7 membered saturated, unsaturated or aromatic ring
109 including the nitrogen atom to which the R4 groups are bonded, wherein said ring is
110 optionally substituted at a position other than the nitrogen atom to which the R4 groups are
111 bonded, with one or more moieties selected from O, S(O)P, N, and NR8;
112 R5 is selected from:
113 (a) R7, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group,
114 (e) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (f) a
115 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one
116 or more heteroatoms selected from nitrogen, oxygen, and sulfur, or;
117 wherein any of (b)-(f) immediately above optionally is substituted
118 with one or more R7 groups;
119 alternatively two R5 groups, when present on the same carbon atom can be
120 taken together with the carbon atom to which they are attached to form a spiro
121 3-6 membered carbocyclic ring or heterocyclic ring containing one or more
122 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of these 123 ring systems formed from two R5 groups optionally is substituted with one or
124 more R7 groups;
125 R6, at each occurrence, independently is selected from:
126 (a) H, (b) a C1.6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e)
127 a C3-12 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered
128 saturated, unsaturated, or aromatic heterocycle containing one or more
129 heteroatoms selected from nitrogen, oxygen, and sulfur,
130 wherein any of (b)-(f) optionally is substituted with one or more moieties
131 selected from:
132 (aa) a carbonyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee) Br,
133 (ff) I, (gg) CN, (hh) NO2, (ii) -OR8, (jj) -S(O)pR8, (kk) -€(O)R8, (11) -
134 C(O)OR8, (mm) -OC(O)R8, (nn) -C(O)NR8R8, (oo) -OC(O)NR8R8,
135 (PP) -C(=NR8)R8, (qq) -C(R8)(R8)OR8, (rr) -C(R8)2OC(O)R8, (ss) -
136 C(R8)(OR8)(CH2)rNR8R8, (tt) -NR8R8, (uu) -NR8OR8, (w) -
137 NR8C(O)R8, (ww) -NR8C(O)OR8, (xx) -NR8C(O)NR8R8, (yy) -
138 NR8S(O)1-R8, (zz) -C(OR8)(OR8)R8, (ab) -C(R8)2NR8R8, (ac) =NR8,
139 (ad) -C(S)NR8R8, (ae) -NR8C(S)R8, (af) -OC(S)NR8R8, (ag) -
140 NR8C(S)OR8, (ah) -NR8C(S)NR8R8, (ai) -SC(O)R8, (aj) a C1-6 alkyl
141 group, (ak) a C2-6 alkenyl group, (al) a C2-6 alkynyl group, (am) a C1-6
142 alkoxy group, (an) a C1-6 alkylthio group, (ao) a C1-6 acyl group, (ap)
143 -CF3, (aq) -SCF3, (ar) a C3-12 saturated, unsaturated, or aromatic
144 carbocycle, and (as) a 3-12 membered saturated, unsaturated, or
145 aromatic heterocycle containing one or more heteroatoms selected
146 from nitrogen, oxygen, and sulfur,
147 alternatively, NR6R6 forms a 3-12 membered saturated, unsaturated or aromatic ring
148 including the nitrogen atom to which the R6 groups are attached wherein said ring is
149 optionally replaced at a position other than the nitrogen atom to which the R6 groups are
150 bonded, with one or more moieties selected from -0-, -S(0)p-, -N=, and -NR8-;
151 alternatively, CR6R6 forms a carbonyl group;
152 R7, at each occurrence, is selected from:
153 (a) H, (b) =0, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -N3, (j) -NO2,
154 (k) -NR6(CR6R6)tR9, (1) -OR9, (m) -S(O)pC(R6R6)tR9, (n) -C(O)(CR6R6)tR9,
155 (o) -OC(O)(CR6R6)tR9, (p) -SC(O)(CR6R6)tR9, (q) -C(O)O(CR6R6)tR9, (r) - 156 NR6C(O)(CR6R6)tR9, (s) -C(O)NR6(CR6R6)tR9, (t) -C(=NR6)(CR6R6)tR9,
157 (u) -C(=NNR6R6)(CR6R6)tR9, (v) -C(=NNR6C(O)R6)(CR6R6)tR9, (w) -
158 C(=NOR9)(CR6R6)tR9, (x) -NR6C(O)O(CR6R6)tR9, (y) -
159 OC(O)NR6(CR6R6)tR9, (z) -NR6C(O)NR6(CR6R6)tR9, (aa) -
160 NR6S(O)p(CR6R6)tR9, (bb) -SCO^NR^CR^R9, (CC) -
161 NR^CO^NR^CR^tR9, (dd) -NR6R6, (ee) -NR6(CR6R6), (fϊ) -OH, (gg) -
162 NR6R6, (hh) -OCH3, (ii) -S(O)pR6, Oj) -NC(O)R6, (kk) -Si(R13)3, (11) a
163 C1-6 alkyl group, (mm) a C2-6 alkenyl group, (nn) a C2-6 alkynyl group, (oo) -
164 C3-i 2 saturated, unsaturated, or aromatic carbocycle, and (pp) 3-12 membered
165 saturated, unsaturated, or aromatic heterocycle containing one or more
166 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (H)-
167 (pp) optionally is substituted with one or more R9 groups;
168 alternatively, two R7 groups can form -O(CH2)UO-, =O, or =S;
169 R8 is selected from:
170 (a) R5, (b) H, (c) a C1-6 alkyl group, (d) a C2-6 alkenyl group, (e) a C2.6 alkynyl
171 group, (f) a C3-12 saturated, unsaturated, or aromatic carbocycle, (g) a 3-12
172 membered saturated, unsaturated, or aromatic heterocycle containing one or more
173 heteroatoms selected from nitrogen, oxygen, and sulfur, (h) -C(O)-C1-6 alkyl,
174 (i) -C(O)-C2-6 alkenyl, (j) -C(O)-C2-6 alkynyl, (k) -C(O)-C3-12 saturated,
175 unsaturated, or aromatic carbocycle, and (1) -C(O)-3-12 membered saturated,
176 unsaturated, or aromatic heterocycle containing one or more heteroatoms selected
177 from nitrogen, oxygen, and sulfur,
178 wherein any of (c)-(l) optionally is substituted with one or more moieties
179 selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO2, (hh)
180 OH, (ii) NH2, (jj) NH(C1-6 alkyl), (kk) N(C1-6 alkyl)2, (11) a C1-6 alkoxy
181 group, (mm) an aryl group, (nn) a substituted aryl group, (oo) a heteroaryl
182 group, (pp) a substituted heteroaryl group, and (qq) a Ci-6 alkyl group
183 optionally substituted with one or more moieties selected from an aryl
184 group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl
185 group, F, Cl, Br, I, CN, NO2, CF3, SCF3, and OH;
186 R9, at each occurrence, independently is selected from: 187 (a) R10, (b) a C1-6 alkyl group, (c) a C2.6 alkenyl group, (d) a C2.6 alkynyl group,
188 (e) a C3-I2 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered
189 saturated, unsaturated, or aromatic heterocycle containing one or more
190 heteroatoms selected from nitrogen, oxygen, and sulfur,
191 wherein any of (b)-(f) optionally is substituted with one or more R10 groups;
192 R10, at each occurrence, independently is selected from:
193 (a) H, (b) -O, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -NO2, 0) -
194 NR6R6, (k) -OR6, (1) -S(O)pR6, (m) -C(O)R6, (n) -C(O)OR6, (o) -OC(O)R6,
195 (p) NR6C(O)R6, (q) -C(O)NR6R6, (r) -C(=NR6)R6, (s) -NR6C(O)NR6R6, (t) -
196 NR6S(O)pR6, (u) -S(O)pNR6R6, (v) -NR6S(O)PNR6R6, (w) a C,.6 alkyl group,
197 (x) a C2.6 alkenyl group, (y) a C2-6 alkynyl group, (z) a C3-12 saturated,
198 unsaturated, or aromatic carbocycle, and (aa) a 3-12 membered saturated,
199 unsaturated, or aromatic heterocycle containing one or more heteroatoms
200 selected from nitrogen, oxygen, and sulfur,
201 wherein any of (w)-(aa) optionally is substituted with one or more
202 moieties selected from R6, F, Cl, Br, I, CN, NO2, -OR6, -NH2, -
203 NH(C1-6 alkyl), -N(C1-6 alkyl)2, a C1-6 alkoxy group, a C1-6 alkylthio
204 group, and a C1-6 acyl group;
205 R11 and Rl la at each occurrence, independently is selected from:
206 (a) a carbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g) CN, (h)
207 NO2, (i) OR8, (j) -S(O)pR8, (k) -C(O)R8, (1) -C(O)OR8,
208 (m) -OC(O)R8, (n) -C(O)NR8R8, (o) -OC(O)NR8R8,
209 (p) -C(=NR8)R8, (q) -C(R8)(R8)OR8, (r) -C(R8)2OC(O)R8,
210 (s) -C(R8)(OR8)(CH2)rNR8R8, (t) -NR8R8, (u) -NR8OR8,
211 (v) -NR8C(O)R8, (w) -NR8C(O)OR8, (x) -NR8C(O)NR8R8, (y) -NR8S(O)pR8,
212 (z) -C(OR8)(OR8)R8, (aa) -C(R8)2NR8R8, (bb) =NR8, (cc) -C(S)NR8R8, (dd) -
213 NR8C(S)R8, (ee) -OC(S)NR8R8, (ff) -NR8C(S)OR8, (gg) -NR8C(S)NR8R8,
214 (hh) -SC(O)R8, (ii) -N3, Gj) -Si(R13)3, (kk) a C1-6 alkyl group, (11) a
215 C2-6 alkenyl group, (mm) a C2-6 alkynyl group, (nn) a C1-6 alkoxy group, (oo) a
216 C1-6 alkylthio group, (pp) a C1-6 acyl group, (qq) a C3-12 saturated, unsaturated,
217 or aromatic carbocycle, (rr) a 3-12 membered saturated, unsaturated, or
218 aromatic heterocycle containing one or more heteroatoms selected from
219 nitrogen, oxygen, and sulfur, (ss) -B(OH)2, (tt) -B(OCi-6 alkyl)2, (uu) - 220 B(OH)(OCi-6 alkyl), (w) -B[-OC(CH3)2(CH3)2CO-], (ww) -P(OH)2, (xx) -
221 P(OCi-6 alkyl)2, (yy) -P(OH)(OCi-6 alkyl), and (zz) -NR8(C=NR8)R8, (aaa) -
222 C(R8)2NR8R8, wherein (kk)-(mm) optionally are substituted with one or more
223 R5 groups;
224 R12 is selected from:
225 (a) H, (b) a Ci-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group,
226 (e) -C(O)R5, (f) -C(O)OR5, (g) -€(O)-NR4R4, (h) -<:(S)R5, (i) -C(S)OR5, G)
227 -C(O)SR5, (k) -C(S)-NR4R4, (1) a C3-I2 saturated, unsaturated, or aromatic
228 carbocycle, or (m) a 3-12 membered saturated, unsaturated, or aromatic
229 heterocycle containing one or more heteroatoms selected from nitrogen,
230 oxygen, and sulfur, (n) a -(Ci-6 alkyl) -C3-12 saturated, unsaturated, or
231 aromatic carbocycle, and (o) a -(C1-6 alkyl)-3-12 membered saturated,
232 unsaturated, or aromatic heterocycle containing one or more heteroatoms
233 selected from nitrogen, oxygen, and sulfur,
234 wherein (b)-(d) and (l)-(o) optionally are substituted with one or more
235 R5 groups;
236 each R13 is independently selected from (a) -C1-6 alkyl and (b) -O-(Ci-6 alkyl):
237 p at each occurrence is O, 1 , or 2;
238 r at each occurrence is O, 1, or 2;
239 t at each occurrence is O, 1 , or 2;
240 and u at each occurrence is 1 , 2, 3, or 4.
241
1 2. A compound according to claim 1, having the structure:
Figure imgf000183_0001
3 or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G, T, X, R1,
4 R2, R3, R\ Rb, Rc, Rd, and Re are as described in claim 1.
5
1 3. A compound according to claim 2, having the structure:
Figure imgf000184_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, R3, Ra, Rb, Re, Rd, and Re are as described in claim 1.
4. A compound according to claim 2, having the structure:
Figure imgf000184_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described in claim 1.
5. A compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from (a) H, (b) Cl, (c) Br, (d) F, (e) - OH, (f) -CN, (g) -CF3, (h) -CF2H, (i) -CFH2, (j) -0(C1-6 alkyl), (k) -N3, (1) -COOH, (m) - COO(C1-6 alkyl), (n) -NH2, (o) -NH(C1-6 alkyl), (p) -N(C1-6 alkyl)2, (q) -C(O)NH2, (r) - C(O)NH(C1-6 alkyl), (s) -C(O)N(C1-6 alkyl)2, (t) -NHC(O)H, (u) -NHC(O)(C1-6 alkyl), (v) - N(C1-6 alkyl)C(O)H, and (w) -N(C1-6 3UCyI)C(O)N(C1 -6 alkyl)2.
6. A compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from F and OH.
7. A compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is F.
8. A compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is OH.
9. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rd and Re are selected from (a) Cl, (b) Br, (c) F, (d) H and (e) C1-6 alkyl.
10. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rd and Re are H.
11. A compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rc is selected from (a) H, (b) C1-6 alkyl, (c) - CF3, (d) -CF2H, and (e) -CFH2.
12. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rc is H.
13. A compound according to any one of claims 1 - 12, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra and Rb are independently selected from (a) H, (b) Cl, (C) Br, (d) F, (e) -OH, (f) -0(C1-6 alkyl), (g) -N3, (h) -COOH, (i) -COO(C1-6 alkyl), (j) -CN, (k) -NH2, (1) -NH(C6 alkyl), (m) -N(C1-6 alkyl)2, (n)-C(0)NH2, (o) - C(O)NH(Ci-6 alkyl), (p) -C(O)N(C1-6 alkyl)2, (q) -NHC(O)H, (r) -NHC(O)(C1-6 alkyl), (s) - N(C1-6 alkyl)C(O)H, (t) -N(C1-6 alkyl)C(O)N(C1-6 alkyl)2, (u) -SH, and (v) -S(C1-6 alkyl), or alternatively Ra and Rb are taken together with the carbon to which they are attached to form (aa) -C(=0)- or (bb) -C(=S)-.
14. A compound according to any one of claims 1 - 13 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein Ra and Rb are independently selected from -H, -F, -OH, -OCH3, -SH, and -SCH3.
15. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein Ra is H and Rb is F.
16. A compound according to any one of claims 1 - 14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -OH.
17. A compound according to any one of claims 1 - 14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -OCH3.
18. A compound according to any one of claims 1 - 14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -SH.
19. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -SCH3.
20. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is H.
21. A compound according to any one of claims 1 -20, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 is H.
22. A compound according to any one of claims 1 -21 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R2 is H.
23. A compound according to any one of claims 1-22, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is Ci-6 alkyl.
24. A compound according to any one of claims 1 -23, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is methyl.
25. A compound according to any one of claims 1-24, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is B'.
26. A compound according to any one of claims 1-25, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is selected from: (a) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein each (a)-(b) optionally is substituted with one or more R1 ' groups.
27. A compound according to any one of claims 1-26, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is -B'-Z-B".
28. A compound according to claim 27, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein B' and B" are independently selected from (a) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group and (b) a 3-12 membered saturated, unsaturated, or aromatic heterocyclic group, wherein each (a)-(b) optionally is substituted with one or more R11 groups.
29. A compound according to claim 3, having the structure:
Figure imgf000187_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described in claim 1.
30. A compound according to claim 3, having the structure:
Figure imgf000187_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R , R , and R3 are as described in claim 1.
31. A compound according to claim 3, having the structure:
Figure imgf000188_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described in claim 1.
32. A compound according to claim 3, having the structure:
Figure imgf000188_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R , R , and R3 are as described in claim 1.
33. A compound according to claim 3, having the structure:
Figure imgf000188_0003
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1,
R2, and R3 are as described in claim 1.
34. A compound according to claim 3, having the structure:
Figure imgf000189_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described in claim 1.
35. A compound according to claim 3, having the structure:
Figure imgf000189_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described in claim 1.
36. A compound according to claim 3, having the structure:
Figure imgf000189_0003
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described in claim 1.
37. A compound according to claim 3, having the structure:
Figure imgf000190_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R1, R2, and R3 are as described in claim 1.
38. A compound according to claim 3, having the structure:
Figure imgf000190_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R1, R2, and R3 are as described in claim 1.
39. A compound according to any of claims 1-38, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000190_0003
where B", Z, and R11 are as described in claim 1.
40. A compound according to any of claims 1-38, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000190_0004
where B", Z, and R11 are as described in claim 1.
41. A compound according to any of claims 1-38, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000191_0001
where B", Z, and R11 are as described in claim 1.
42. A compound according to any of claims 1-38, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000191_0002
where B", Z, and R11 are as described in claim 1.
43. A compound according to any of claims 39-42, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is selected from (a) OR8, (b) -S(O)PR8, (c) - C(O)R8, (d) -C(O)NR8R8, (e) -C(R8)(R8)OR8, (f) -C(R8)2OC(O)R8, (g) -NR8R8, (h) -NR8C(O)R8, (i) -NR8S(O)pR8, (j) a Ci .6 alkyl group, and (k) a 3- 12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (j) is optionally substituted with one or more R5 groups.
44. A compound according to any of claims 39-42, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is selected from -CH2OH, -SO2CH3, -NH2, -
CH3, -C(O)NH2, -CH2OC(O)CH3, CH2OCH3, -NHCH3, -OCH3, ~V_/° , NH(cyclopropyl), -
— N(CH3)C(O)-N O C(O)CH3, -NHC(O)CH3, -C(O)CH3, -S(O)CHF2, \-^ , -N(CH3)S(O)2-isopropyl, -N(CH3)S(O)2-butyl, CH2CH2OH, and SO2CHF2.
45. A compound according to any of claims 39-42, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 ' is F.
46. A compound according to any of claims 39-45, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C,_6 alkyl group, (b) a C2.6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) H, (g) -OH (h) -SH, (i) F, (j) Cl, (k) Br, (1) I, (m) -CF3, (n) -CN, (o) -N3 (p) -NO2, (q) -NR^CR^R9, (r) -OR9, (s) -SCCR^tR9, (t) -S(O)(CR6R6)tR9, (u) -S(O)2(CR6R6)tR9, (v) -C(O)(CR6R6)tR9, (w) -OC(O)(CR6R6)tR9, (x) -OC(O)O(CR6R6)tR9, (y) -SC(O)(CR6R6)tR9, (z) -C(O)O(CR6R6)tR9, (aa) - NR6C(O)(CR6R6)tR9, (bb) -C(O)NR6(CR6R6)tR9, (cc) -C(=NR6)(CR6R6)tR9, (dd) - C(=NNR6R6)(CR6R6)tR9, (ee) -C[=NNR6C(O)R6](CR6R6)tR9, (ff) -NR6C(O)O(CR6R6)tR9, (gg) -OC(O)NR6(CR6R6)tR9, (hh) -NR6C(O)NR6(CR6R6)tR9, (ii) -NR6S(O)P(CR6RO)1R9, (jj) -S(O)pNR6(CR6R6)tR9, (kk) -NR6R6, (11) -NR6(CR6R6)tR9, (mm) -SR6, (nn) -S(O)R6, (oo) -S(O)2R6, (PP) -NR6C(O)R6, (qq) -Si(R13)3, and (rr) -C(=O)H; wherein t at each occurrence is O, 1, or 2; wherein (a)-(e) optionally are substituted with one or more R14 groups; wherein R14 at each occurrence is independently selected from: (a) H, (b) F, (C) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)pR8, Q) - C(O)R8, (k) -C(O)OR8, (1) -OC(O)R8, (m) -C(O)NR8R8, (n) -OC(O)NR8R8, (o) -C(=NR8)R8, (p) -C(R8)(R8)OR8, (q) -C(R8)2OC(O)R8, (r) - C(R8)(OR8)(CH2)rNR8R8, (s) -NR8R8, (t) -NR8OR8, (u) -NR8C(O)R8, (v) - NR8C(O)OR8, (w) -NR8C(O)NR8R8, (x) -NR8S(O)PR8, (y) -C(OR8)(OR8)R8, (z) -C(R8)2NR8R8, (aa) -C(S)NR8R8, (bb) -NR8C(S)R8, (cc) -OC(S)NR8R8, (dd) -NR8C(S)OR8, (ee) -NR8C(S)NR8R8, (ff) -SC(O)R8, (gg) -N3, (hh) - Si(R13)3, (ii) a C1-6 alkyl group, (jj) a C2-6 alkenyl group, (kk) a C2-6 alkynyl group, (11) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (ii)- (mm) optionally are substituted with one or more R5 groups; alternatively two R14 groups are taken together to form (a) =0, (b) =S, (c) =NR8, or (d) =N0R8.
47. A compound according to claim 46, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1^ alkyl group, (b) a C2_6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) -CF3, (g) -ΝR6(CR6R6)tR9, (h) -OR9, (i) - SCCR^tR9, C) -S(O)(CR6R6)tR9, (k) -StO^CR^tR9, (1) -C(O)(CR6R6)tR9, (m) - OC(O)(CR6R6)tR9, (n) -OC(O)O(CR6R6)tR9, (o) -SC(O)(CR6R6)tR9, (p) -C(O)O(CR6R6)tR9, (q) -NR6C(O)(CR6R6)tR9, (r) -C(O)NR6(CR6R6)tR9, (s) -C(=NR6)(CR6R6)tR9, (t) - C(=NNR6R6)(CR6R6)tR9, (u) -Q=NNR6C(O)R6] (CR6R6^R9, (v) -NR6C(O)O(CR6R6)tR9, (w) -OC(O)NR6(CR6R6)tR9, (x) -NR6C(O)NR6(CR6R6)tR9, (y) -NR6S(O)p(CR6R6)tR9, (z) - SCO^NR^CRV^R9, (aa) -NR6R6, (bb) -NR6(CR6R6)tR9, (cc) -SR6, (dd) -S(O)R6, (ee) - S(O)2R6, and (ff) -NR6C(O)R6, wherein (a)-(e) optionally are substituted with one or more R14 groups.
48. A compound according to claim 47, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein -ZB" is selected from (a) a C1-6 alkyl group, (b) a C2.6 alkenyl group, (c) a C2.6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, wherein (a)-(e) optionally are substituted with one or more R14 groups.
49. A compound according to claim 48, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein -ZB" is selected (a) -ΝR6(CR6R6)tR9, (b) -OR9, (c) - S<CR6R6)tR9, (d) -S(O)(CR6R6)tR9, (e) -S(O)2 (CR6R6)tR9, (f) -C(O)(CR6R6)tR9, (g) - OC(O)(CR6R6)tR9, (h) -OC(O)O(CR6R6)tR9, (i) -SC(O)(CR6R6)tR9, (j) -C(O)O(CR6R6)tR9, (k) -NR6C(O)(CR6R6)tR9, (1) -C(O)NR6(CR6R6)tR9, (m) -C(=NR6)(CR6R6)tR9, (n) - C(=NNR6R6)(CR6R6)tR9, (o) -C[=NNR6C(O)R6](CR6R6)tR9, (p) -NR6C(O)O(CR6R6)tR9, (q) -OC(O)NR6(CR6R6)tR9, (r) -NR6C(O)NR6(CR6R6)tR9, (s) -NR6S(O)p(CR6R6)tR9, (t) -
Figure imgf000194_0001
(u) -NR6R6, (v) -NR6(CR6R6),R9, (w) -SR6, (x) -S(O)R6, (y) - S(O)2R6, and (z) -NR6C(O)R6.
50. A compound according to any one of claims 1-49, wherein T is:
Figure imgf000194_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein:
M is selected from:
(a) -Q=NR114K (b) -C(=NOR127K and (c) -C(=NNR114R114)-;
R100 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR114, and (f) C1-6 alkyl, wherein
(f) optionally is substituted with one or more R115 groups;
R101 is selected from:
(a) H, (b) Cl, (C) F, (d) Br, (e) I, (f) -NR114R114, (g) -NR114C(O)R114, (h) - OR114, (i) -OC(O)R114, (j) -OC(O)OR114, (k) -OC(O)NR114R114, (1) -0-C1- C6 alkyl, (m) -OC(O)-C1-6 alkyl, (n) -OC(O)O-C1-6 alkyl, (o) -OC(O)NR114- d-6 alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2-6 alkynyl, wherein any of (1) - (r) optionally is substituted with one or more R115 groups;
R102 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) -SR114, and (f) C1-6 alkyl, wherein
(f) optionally is substituted with one or more R115 groups;
R103 is selected from:
(a) H, (b) -OR , 1"14", (c) -O-C-6 alkyl-R 1'1°5, (d) -OC(O)R , 114
(e) -OC(O)-C1-6 alkyl-R , 111 °5, (f) -OC(O)OR 1114 , (g) -OC(O)O-C1-6 alkyl-R , 115
Figure imgf000194_0003
alkyl-R1 n, and
Figure imgf000195_0001
alternatively, R102 and R103 taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups; alternatively, R101 and R103 taken together are a single bond between the respective carbons to which these two groups are attached thereby creating a double bond between the carbons to which R100 and R102 are attached; alternatively, R101 and R103 taken together with the carbons to which they are attached form a 3-7 membered carbocyclic or heterocyclic ring, wherein said 3-7 membered ring can optionally be substituted with one or more R114 groups; alternatively, R100, R101, R102, and R103 taken together with the carbons to which they are attached form a 5 or 6 membered fused carbocyclic or heterocyclic ring, wherein said fused ring can be optionally substituted with one or more R114 groups; R104 is selected from: (a) H, (b) R114, (c) -C(O)R114(d) -C(O)OR114 (e) -C(O)NR114R114, (f) -C1-6 alkyl-K-R114, (g) -C2-6 alkenyl-K-R114, and (h) -C2-6 alkynyl-K-R114; K is selected from: (a) -C(OH (b) -C(O)O-, (c) -C(O)NR114-, (d) -C(=NR] 1V, (e) - Q=NR114)O-, (f) -C(=NR] 14)NR! 14-, (g) -OC(O)-, (h) -OC(O)O-, (i) - OC(O)NR114-, (j) -NR114C(OK (k) -NR114C(O)O-, (1) -NR114C(O)NR114- (m) -NR114Q=NR11^NR114-, and (n) -S(O)P-; R105 is selected from: (a) R114, (b) -OR114, (c) -NR114R114, (d) -O-C1-6 alkyl-R115, (e) -C(O)-R114, (f) -C(O)-Ci-6 alkyl-R115, (g) -OC(O)-R114, (h) -OC(O)-Ci-6 alkyl-R115, (i) -OC(O)O-R114, O) -OC(O)O-C-6 alkyl-R115, (k) -OC(O)NR114R114, (1) -OC(O)NR114-Ci-6 alkyl-R115, (m) -C(O)-C2-6 alkenyl-R115, and (n) -C(O)-C2-6 alkynyl-R115; R106 is selected from: (a) -OR114, (b) -C1-6 alkoxy-R115, (c) -C(O)R114, (d) -OC(O)R114, (e) - OC(O)OR114, (f) -OC(O)NR114R114, and (g) -NR114R114, R107 is selected from (a) H, (b) -C1-6 alkyl, (c) -C2-6 alkenyl, which can be further substituted with Ci-6 alkyl or one or more halogens, (d) -C2-6 alkynyl, which can be further substituted with C1-6 alkyl or one or more halogens, (e) aryl (f) heteroaryl, which can be further substituted with C1-6 alkyl or one or more halogens, (g) - C(O)H, (h) -COOH, (i) -CN, (j) -COOR114, (k) -C(O)NR114R114, (1) - C(O)R114, and (m) -C(O)SR114, wherein (b) is further substituted with one or more substituents selected from (aa) -OR114, (bb) halogen, (cc) -SR114, (dd) C1-6 alkyl, which can be further substituted with halogen, hydroxyl, C1-6 alkoxy, or amino, (ee) -OR114, (ff) -SR114, (gg) -NR114R114, (hh) -CN, (ii) -NO2, Oj) -NC(O)R114, (kk) -COOR114, (11) -N3, (mm) ^N-O-R114, (nn) =NR' 14, (OO) =N-NR! 14R114, (pp) =N-NH-C(O)R114, and (qq) =N-NH- C(O)NR114R114; alternatively R106 and R107 are taken together with the atom to which they are attached to form an epoxide, a carbonyl, an exocyclic olefin, or a substituted exocyclic olefin, or a C3- C7 carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be further substituted with a Ci -6 alkyl; R108 is selected from: (a) C1-6 alkyl, (b) C2-6 alkenyl, and (c) C2-6 alkynyl, wherein any of (a)-(c) optionally is substituted with one or more R114 groups; R109 is H, Ci-6 alkyl, or F; R114, at each occurrence, independently is selected from: (a) H, (b) Ci-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-I2 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-Ci-6 alkyl, (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-I2 saturated, unsaturated, or aromatic carbocycle, (k) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (1) -C(O)O-Ci-6 alkyl, (m) -C(O)O-C2-6 alkenyl, (n) - 84 C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-12 saturated, unsaturated, or aromatic
85 carbocycle, (p) -C(O)O-3-12 membered saturated, unsaturated, or aromatic
86 heterocycle containing one or more heteroatoms selected from nitrogen,
87 oxygen, and sulfur, (q) -C(O)NR116R116, (r) -NR116CO-Ci-6 alkyl, (s) -
88 NR116CO-C3-12 saturated, unsaturated, or aromatic carbocycle, (t) -NR116C(O)-
89 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one
90 or more heteroatoms selected from nitrogen, oxygen, and sulfur, (u) -(C1-6
91 alkyl)-O-(C1-6 alkyl), (v) -(C1-6 alkyl)-O-(C1-6 alkyl)-O-(Ci-6 alkyl), (w) -OH,
92 (x) -OR115, (y) -NH(C1-6 alkyl), (z) -N(C1-6 alkyl)2, (aa) -(C1-6 alkyl)-S(O)p-
93 (C1-6 alkyl), (bb) -(C1-6 alkyl)- S(OV(Ci-6 alkyl)-S(O)p-(C,-6 alkyl), (cc) -(C1-6
94 alkyl)-0-(Ci-6 alkyl)-S(O)p-(C1-6 alkyl), (dd) -(C1-6 alkyl)- S(O)p-(C1-6
95 alkyl)-O-(C1-6 alkyl), and (ee) -NH2;
96 wherein the terminal alkyl group in any of (u)-(v) or (aa)-(dd) includes
97 cycloalkyl,
98 wherein any of (b)-(v) or (aa)-(dd) optionally is substituted with one or
99 more R115 groups, wherein one or more non-terminal carbon moieties OO of any of (b)-(d) optionally is replaced with oxygen, S(0)p, or -NR1 ] 6 ,01 alternatively, -CR114R114 or NR114R114 forms a 3-7 membered saturated, unsaturated or02 aromatic ring including the nitrogen atom to which the R114 groups are bonded and optionally03 contains one or more moieties selected from -C=O-, -S(O)P-, =N-, and -NR118-; 04 R115 is selected from: 05 (a) R117, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-]2 saturated,06 unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated,07 or aromatic heterocycle containing one or more heteroatoms selected from08 nitrogen, oxygen, and sulfur, (g) -OC1-6 alkyl, (h) -OC2-6 alkenyl, and (i) -09 OC2-6 alkynyl, 10 wherein any of (b)-(f) optionally is substituted with one or more R1 ' 711 groups; 12 R116, at each occurrence, independently is selected from: 13 (a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-12 saturated,14 unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated,15 unsaturated, or aromatic heterocycle containing one or more heteroatoms16 selected from nitrogen, oxygen, and sulfur, 117 wherein one or more non-terminal carbon moieties of any of (b)-{d)
118 optionally is replaced with oxygen, S(O)P, or -NR118, wherein any of
119 (b)- (f) optionally is substituted with one or more moieties selected
120 from:
121 (aa) carbonyl, (bb) formyl, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg)
122 CN, (hh) N3, (ii) NO2, (jj) OR118, (kk) -S(O)pR118, (11) -
123 C(O)R118, (mm) -C(O)OR118, (nn) -OC(O)R118, (oo) -
124 C(O)NR118R118, (pp) -OC(O)NR118R118, (qq) -C(=NR' 1S)R' 18,
125 (rr) -C(R118)(R118)OR118, (ss) -C(R118)2OC(O)R] 18, (tt) -
126 C(R118)(OR118)(CH2)rNR118R118, (uu) -NR118R118, (w) -
127 NR118OR118, (ww) -NR118C(O)R118, (xx) -NR118C(O)OR118,
128 (yy) -NR118C(O)NR118R118, (zz) -NR118S(O)1R118, (ab) -
129 C(OR118XOR1 ^)R118, (ac) -C(R118^NR118R118, (ad) =NR118,
130 (ae) -C(S)NR118R118, (af) -NR118C(S)R118, (ag) -
131 OC(S)NR118R118, (ah) -NR118C(S)OR118, (ai) -
132 NR118C(S)NR118R118, (aj) -SC(O)R118, (ak) C-6 alkyl, (al)
133 C2-6 alkenyl, (am) C2-6 alkynyl, (an) Ci-6 alkoxy, (ao) Ci-6
134 alkylthio, (ap) Cj-6 acyl, (aq) saturated, unsaturated, or aromatic
135 C3-I2 carbocycle, and (ar) saturated, unsaturated, or aromatic
136 3-12 membered heterocycle containing one or more
137 heteroatoms selected from nitrogen, oxygen, and sulfur,
138 alternatively, NR1 ' 6R1 * 6 forms a 3 - 12 membered saturated, unsaturated or aromatic
139 ring including the nitrogen atom to which the R116 groups are attached and optionally one or
140 more moieties selected from O, S(O)P, N, and NR118;
141 alternatively, CR1 λ 6R1 J 6 forms a carbonyl group ;
142 R117, at each occurrence, is selected from:
143 (a) H, (b) =0, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3, (h)
144 (CR116R116)rCN, (i) (CR116R116)rNO2, (j) (CR116RU6)rNR116(CR116R116)tR119,
145 (k) (CR116R116)rOR119, (1) (CR11V16XS(O)P(CR116R116XR119,
146 (m) (CR116R116XC(O)(CR116R116)tR] 19, (n) (CR116R116XOC(O)(CR116R116)tR' 19,
147 (o) (CR116R116XSC(O)(CR116R116XR119,
148 (p) (CR116R116XC(O)O(CR116R116XR119,
149 (q) (CR116R116XNR116C(O)(CR116R116XR119, 150 (r) (CR116R116XC(O)NR11^CR116R116)tR' 19, (s)
151 (CR116R116)rC(=NRU6)(CR116R116)tR' 19,
152 (t) (CR116R116XQ=NNR116R1^)(CR116R116XR119,
153 (u) (CR116R116)rC(=NNR116C(O)R116XCR116R116XR119,
154 (v) (CR116R116χC(=NORU9)(CR116Rn6)tR119,
155 (W) (CR116R116XNR116C(O)O(CR116R116XR119,
156 (x) (CR116R116XOC(O)NR11^CR116R116XR119,
157 (y) (CR116R116)rNRu 6C(O)NR11^CR116R116XR119,
158 (z) (CR116R116XNR116S(O)P(CR116R116XR119,
159 (aa) (CR116R116XS(O)PNR116(CR' 16R116XR119,
160 (bb) (CR116R116XNR116S(OXNR11^CR116R116),R119,
161 (cc) (CR116R116XNR116R116, (dd) C,.6 alkyl, (ee) C2.6 alkenyl, (fit) C2.6 alkynyl,
162 (gg) (CR116R116)r-C3-i2 saturated, unsaturated, or aromatic carbocycle, (hh)
163 (CR116R116^-S- 12 membered saturated, unsaturated, or aromatic heterocycle
164 containing one or more heteroatoms selected from nitrogen, oxygen, and
165 sulfur, and (ii) -P(O)(O(C1-6 alkyl))2,
166 wherein any of (dd)-(hh) optionally is substituted with one or more
167 R119 groups;
168 alternatively, two R1 ' 7 groups can form -O(CH2)UO-;
169 R118 is selected from:
170 (a) H, (b) C1-6 alkyl, (c) C2.6 alkenyl, (d) C2.6 alkynyl, (e) C3-12 saturated,
171 unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated,
172 or aromatic heterocycle containing one or more heteroatoms selected from
173 nitrogen, oxygen, and sulfur, (g) -C(O)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl,
174 (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-12 saturated, unsaturated, or aromatic
175 carbocycle, and (k) — C(O)-3-12 membered saturated, unsaturated, or aromatic
176 heterocycle containing one or more heteroatoms selected from nitrogen,
177 oxygen, and sulfur,
178 wherein any of (b)— (k) optionally is substituted with one or more
179 moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (fϊ) CN,
180 (gg) NO2, (hh) OH, (ii) NH2, Oj) NH(C1-6 alkyl), (kk) N(C1-6 alkyl)2,
181 (11) C1-O alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp)
182 substituted heteroaryl, and (qq) C1-6 alkyl, optionally substituted with 183 one or more moieties selected from aryl, substituted aryl, heteroaryl,
184 substituted heteroaryl, F, Cl, Br, I, CN, NO2, and OH;
185 R119, at each occurrence, independently is selected from:
186 (a) R120, (b) C1-6 alkyl, (c) C2^ alkenyl, (d) C2-6 alkynyl, (e) C3-I2 saturated,
187 unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated,
188 unsaturated, or aromatic heterocycle containing one or more heteroatoms
189 selected from nitrogen, oxygen, and sulfur,
190 wherein any of (b)-(f) optionally is substituted with one or more R1 ' 4
191 groups;
192 R120, at each occurrence, independently is selected from:
193 (a) H, (b) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3, (h)
194 (CR116Rn6)rCN, (i) (CR116R116^O2, 0') (CR116R11^1NR116R116, (k)
195 (CR11V 16^OR114, (1) (CR116R116XS(O)PR116, (m) (CR116R116XC(O)R , 1116
196 (n) (CR116R116)rC(O)OR116, (o) (CR116R116XOC(O)R116, (p)
197 (CR116R116XNR116C(O)R116, (q) (CR116R116XC(O)NR116R116, (r)
198 (CR116R116χC(=NR116)R116, (s) (CR116R116XNR116C(O)NR116R , 1116
199 (t) (CR116R116XNR116S(O)PR116, (u) (CR116R116XS(O)PNR116R116, (v)
200 (CR11V16X^116S(O)PNR116R116, (w) C,.6 alkyl, (x) C2-6 alkenyl, (y)
201 C2.6 alkynyl, (z) (CR116R116)r-C3-i2 saturated, unsaturated, or aromatic
202 carbocycle, and (aa) (CR116R116)r— 3-12 membered saturated, unsaturated, or
203 aromatic heterocycle containing one or more heteroatoms selected from
204 nitrogen, oxygen, and sulfur,
205 wherein any of (w)-(aa) optionally is substituted with one or more
206 moieties selected from R116, F, Cl, Br, I, CN, NO2, -OR116, -NH2, -
207 NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkoxy, C,-6 alkylthio, and
208 C1-6 acyl;
209 R121, at each occurrence, independently is selected from:
210 (a) H, (b) -OR118, (c) -O-C1-6 alkyl-OC(O)R118, (d) -O-C1-6 alkyl-
211 OC(O)OR118, (e) -O-Ci-6 alkyl-OC(O)NR118R118, (f) -O-Ci-6 alkyl-
212 C(O)NR118R118, (g) -O-Ci-6 alkyl-NR118C(O)R118, (h) -O-C1-6 alkyl-
213 NR118C(O)OR118, (i) -O-C1-6 alkyl-NR118C(O)NR118R118, (j) -O-Ci-6 alkyl-
214 NR118C(=N(H)NR118R118), (k) -O-C1-6 alkyl-StO^R118, (1) -0-C2-6 alkenyl- 215 OC(O)R118, (m) -0-C2-6 alkenyl-OC(O)OR118, (n) -O-C2-6 alkenyl-
216 OC(O)NR118R118, (o) -O-C2-6 alkenyl-C(O)NR118R118, (p) -O-C2-6 alkenyl-
217 NR118C(O)R118, (q) -O-C2-6 alkenyl-NR118C(O)OR118, (r) -O-C2-6 alkenyl-
218 NR118C(O)NR118R118, (s) -C)-C2-6 alkenyl-NR118Q=N(H)NR118R118), (t) -O-
219 C2-6 3HCeHyI-S(O)PR118, (u) -C)-C2-6 alkynyl-OC^R118, (v) -O-C2-6 alkynyl-
220 OC(O)OR1 ' 8, (w) -0-C2-6 BIlCyHyI-OC(O)NR118R1 ' 8, (x) -C)-C2-6 alkynyl-
221 C(O)NR118R118, (y) -C)-C2-6 alkynyl-NR118C(O)R118, (z) -0-C2-6 alkynyl-
222 NR118C(O)OR118, (aa) -0-C2-6 alkynyl-NR118C(O)NR118R118,
223 (bb) -O-C2-6 alkynyl-NR118C(=N(H)NR118R118), (cc) -O-C2-6 alkynyl-
224 S(O)pR118, (dd) -NR118R118, (ee) -C1-6 alkyl-O-C,-6 alkyl, (ff) -C1-6 alkyl-
225 NR114-C1-6 alkyl, (gg) -C1-6 alkyl-S(O)p-C1-6 alkyl, (hh) -OC(O)NR114(C,-6
226 alky^-NR114-(C1-6 alkyl) -R114, (ii) -OH, (jj) -C1-6 alkyl, (kk) C2-6 alkenyl, (11)
227 C2-6 alkynyl, (mm) -CN, (nn) -CH2S(O)pR137, (oo) -CH2OR137, (pp) -
228 CH2N(OR138)R137, (qq) -CH2NR137R139, (rr) -(CH2)V(C6-10 aryl), and (ss)-
229 (CH2)v(5-10 membered heteroaryl), wherein (jj)-(ss) are optionally substituted
230 by 1, 2, or 3 R140 groups;
231 alternatively, two R121 groups taken together form =0, =NOR118, or =NNR118R118;
232 R127 is R114, a monosaccharide or a disaccharide (including amino sugars and
233 halogenated sugar(s)), -S(O)pR148, -(CH2)n-(O-CH2CH2-)m-O(CH2)nCH3,
234 -(CH2)n-(O-CH2CH2-)m-OR148, -(CH2)n-[S(O)p-CH2CH2-]m-S(O)p(CH2)nCH3 ,
235 -(CH2)n-[S(O)p-CH2CH2-]m-S(O)pCH3, -(CH2)n-[S(O)p-CH2CH2-]m-OR148,
236 -OCH2-O-(CH2)n-[S(O)p-CH2CH2-]m-S(O)p(CH2)nCH3,
237 -OCH2-O-(CH2)n-[S(O)p-CH2CH2-]πi-OR148, -0-[C3-12 saturated, unsaturated, or
238 aromatic carbocycle] wherein said carbocycle is further optionally substituted with
239 one or more R114, -O-[3-12 membered saturated, unsaturated, or aromatic heterocycle
240 containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur],
241 wherein said heterocycle is further optionally substituted with one or more R114, -
242 S(O)p-[C3-i2 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle
243 is further optionally substituted with one or more R114,
244 or -S(O)p-[3-12 membered saturated, unsaturated, or aromatic heterocycle containing
245 one or more heteroatoms selected from nitrogen, oxygen, and sulfur], wherein said
246 heterocycle is further optionally substituted with one or more R114;
247 R110 Is R114: 248 alternatively, R109 and R110 taken together with the carbons to which they are attached
249 form:
Figure imgf000202_0001
251 R132, R133, and R134 are each independently selected from (a) H, (b) F, (c) Cl, (d) Br,
252 (e) -OR114, (f) -SR114, (g) -NR114R114, and (h) C1-6 alkyl, wherein (h) optionally is
253 substituted with one or more R115 groups;
254 alternatively, R132 and R133 are taken together to form a carbon-carbon double bond;
255 alternatively, R133 and R134 are taken together to form =0, =S, =N0R114, =NR* 14, or
256 =N-NRU4R114;
257 alternatively, R105 and R134 are taken together with the carbons to which they are
258 attached to form a 3-membered ring, said ring optionally containing an oxygen or
259 nitrogen atom, and said ring being optionally substituted with one or more R114
260 groups;
261 alternatively when M is a carbon moiety, R134 and M are taken together to form a
262 carbon-carbon double bond;
263 R137 is independently (a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) -
264 (CH2)qCR141R142(CH2)nNR143R144, (f) -(CH2X(C6-C10 aryl), or (g) -<CH2)v(5-10
265 membered heteroaryl);
266 or where R137 is-CH2NR137R139, R139 and R137 may be taken together to form a 4-
267 10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl
268 ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms
269 selected from O, S, and -N(R137)-, in addition to the nitrogen to which R139 and R137
270 are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or
271 triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1, 2,
272 or 3 R140 groups;
273 each R138 is independently H or Ci-6 alkyl;
274 each R141, R142, R143, and R144 is independently selected from H, Cr6 alkyl, -
275 (CH2)m(C6-Cioaryl), and -(CH2)m(5-10 membered heteroaryl), wherein the foregoing
276 R141, R142, R143, and R144 groups, except H, are optionally substituted by 1, 2, or 3 R140
277 groups; 278 or R141 and R143 are taken together to form -(CH2)0- wherein o, at each
279 occurrence is 0, 1 , 2, or 3 such that a 4-7 membered saturated ring is formed that
280 optionally includes 1 or 2 carbon-carbon double or triple bonds;
281 or R143 and R144 are taken together to form a 4-10 membered monocyclic or
282 polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated
283 and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and -
284 N(R137)-, in addition to the nitrogen to which R143 and R144 are attached, said saturated
285 ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said
286 saturated and heteroaryl rings are optionally substituted by 1 , 2, or 3 R140 groups;
287 R139 is H, Cr6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the foregoing
288 R139 groups, except H, are optionally substituted by 1, 2, or 3 substituents
289 independently selected from halo and -OR138;
290 each R140 is independently selected from halo, cyano, nitro, trifluoromethyl,
291 azido, -C(O)R145, -C(O)OR145, -OC(O)OR145, -NR146C(O)R147, -NR146R147, OH, Cr6
292 alkyl, Cr6 alkoxy, -(CH2)v(C6-Ci0aryl), and -(CH2)v(5-10 membered heteroaryl),
293 wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2
294 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, -
295 C(O)R145,-C(O)OR145, -OC(O)OR145, -NR146C(O)R147, -C(O)NR146R147, -NR146R147,
296 OH, Cr6 alkyl, and C1-O alkoxy;
297 each R145 is independently selected from H, C1-O alkyl, C2-C6 alkenyl, C2-C6
298 alkynyl, -(CH2)v(C6-Ci0 aryl), and -(CH2)v(5-10 membered heteroaryl);
299 each R146 and R147 is independently H, hydroxyl, Cr6 alkoxy, Cr6 alkyl, C2-6
300 alkenyl, C2-6 alkynyl, -(CH2)v(C6-io aryl), or -(CH2)V(5- 10 membered heteroaryl);
301 R148 is Ci-6 alkyl, C3-12 saturated, unsaturated, or aromatic carbocycle, wherein said
302 carbocycle is further optionally substituted with one or more R114, or 3-12 membered
303 saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms
304 selected from nitrogen, oxygen, and sulfur, wherein said heterocycle is further
305 optionally substituted with one or more R114;
306 p, at each occurrence is 0, 1, or 2;
307 m, at each occurrence is 0, 1, 2, 3, 4, or 5;
308 n, at each occurrence is 1 , 2, or 3;
309 r, at each occurrence is 0, 1 , or 2;
310 t, at each occurrence is 0, 1 , or 2; 311 v, at each occurrence is 0, 1, 2, 3, or 4; 312 q, at each occurrence is 0, 1, 2, or 3, 313 and u at each occurrence is 1, 2, 3, or 4. 314 1 51. A compound according to any one of claims 1 -50, wherein T is:
Figure imgf000204_0001
3 or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R100, R101, 4 R102, R103, R104, R105, R106, R107, R108, R109, R110, R114, R132, R133, and R134 are as described in 5 claim 50. 6 1 52. A compound according to any one of claims 1-50, wherein T is:
Figure imgf000204_0002
3 or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R100, R101, 4 R102, R103, R104, R105, R106, R107, R108, R109, R110, R127, R132, R133, and R134 are as described in 5 claim 50. 6 1 53. A compound according to any one of claims 1-50, wherein T is:
Figure imgf000205_0001
or a pharmaceutically acceptable salt, ester, TV-oxide, or prodrug thereof, wherein R 100 , r R, 101
R , 110U2Z, τ
Figure imgf000205_0002
R-, 1i0υ7/, τ Rj liOυ8δ, τ Rj liOυ9y, T R5 Hl lOϋ, τ R» H1144, τ R> 113^2,
Figure imgf000205_0003
and R 113J44 are as described in claim 50.
54. A compound according to any one of claims 1-50, , wherein T is:
Figure imgf000205_0004
or a pharmaceutically acceptable salt, ester, TV-oxide, or prodrug thereof, wherein R100, R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R114, R132, R133, and R134 are as described herein.
55. A compound according to any one of claims 1-50, wherein T is selected from TA-TD:
Figure imgf000206_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R114 and
R127 are as described in claim 50.
56. A compound according to any one of claims 1-50, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from T4 through T34:
Figure imgf000207_0001
Figure imgf000207_0002
Figure imgf000207_0003
T10
T11
Figure imgf000208_0001
T15
T16 T17
•
Figure imgf000209_0001
T25 T26
Figure imgf000209_0002
Figure imgf000209_0003
Figure imgf000210_0001
57. A compound having the structure corresponding to any one of the structures listed in Table 1, or a pharmaceutically acceptable salt, ester, TV-oxide, or prodrug thereof.
58. A pharmaceutical composition comprising a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, and a pharmaceutically acceptable carrier.
59. A method for treating or preventing a disease state in a mammal comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, TV-oxide, or prodrug thereof.
60. A method of treating a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, TV-oxide, or prodrug thereof.
61. The use of a compound according to any one of claims 1 -57, or a pharmaceutically acceptable salt, ester, TV-oxide, or prodrug thereof, in the manufacture of a medicament for treating a microbial infection in a mammal.
62. A method of treating or preventing a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein the microbial infection is selected from the group consisting of: a skin infection, nosocomial pneumonia, community acquired pneumonia, post-viral pneumonia, a respiratory tract infection such as CRTI, a skin and soft tissue infection (SSTI) including uncomplicated skin and soft tissue infections (uSSTIs) and complicated skin and soft tissue infections, as an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, meningitis, surgical prophylaxis, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus infection, a vancomycin- resistant Enterococci infection, a linezolid-resistant organism infection, and tuberculosis.
63. A method of treating or preventing a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
64. A method of treating or preventing a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
65. A method of treating or preventing a proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
66. A method of treating or preventing a viral infection in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
67. A method of treating or preventing an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
68. A method of treating or preventing a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
69. A method of treating or preventing diarrhea in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
70. A method of treating or preventing a disease state in a mammal caused or mediated by a nonsense or missense mutation comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, to suppress expression of the nonsense or missense mutation.
71. The method or use according to any one of claims 59-70 wherein the compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, is administered otically, ophthalmically, nasally, orally, parentally, or topically.
72. A method of synthesizing a compound according to any of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
73. A medical device containing a compound according to any one of claims 1-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
74. The medical device according to claim 73, wherein the device is a stent.
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