WO2008143729A2 - Macrolide compounds and methods of making and using the same - Google Patents

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

Info

Publication number
WO2008143729A2
WO2008143729A2 PCT/US2008/002718 US2008002718W WO2008143729A2 WO 2008143729 A2 WO2008143729 A2 WO 2008143729A2 US 2008002718 W US2008002718 W US 2008002718W WO 2008143729 A2 WO2008143729 A2 WO 2008143729A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
unsaturated
ester
prodrug
group
Prior art date
Application number
PCT/US2008/002718
Other languages
French (fr)
Other versions
WO2008143729A3 (en
Inventor
Shili Chen
Ashoke Bhattacharjee
Erin M. Duffy
Original Assignee
Rib-X Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rib-X Pharmaceuticals, Inc. filed Critical Rib-X Pharmaceuticals, Inc.
Publication of WO2008143729A2 publication Critical patent/WO2008143729A2/en
Publication of WO2008143729A3 publication Critical patent/WO2008143729A3/en

Links

Classifications

    • 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, antiproliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family of branched amide containing macrocyclic compounds that are useful as such agents.
  • 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. 111, 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.
  • 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.
  • 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-viral agents, anti-diarrheal agents, and chemotherapeutic agents.
  • the present invention also provides compounds useful as anti- inflammatory 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 branched amide containing compounds having the structure:
  • variables A, B, G, T, X, R 1 , R 2 , R 3 , R a , R b , R c , R d , R e , a, b, and c 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.
  • 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 oral, parenteral, otic, ophthalmic, nasal, 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.
  • branched amide containing means that the compounds of the present invention generally contain an amide moiety, wherein the amide moiety is connected to either a branched alkyl group or at a secondary carbon of the alkyl group, and wherein the alkyl group can be further substituted.
  • 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.
  • any variable e.g., R 2
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • 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.
  • nitrogen atoms in the compounds of the present invention 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.
  • an oxidizing agent e.g., MCPBA and/or hydrogen peroxides
  • shown and claimed nitrogens are considered to cover both the shown nitrogen and its N-oxide (N- >O) derivative, as appropriate.
  • anomeric carbon means the acetal carbon of a glycoside.
  • 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 Ce alkyl groups.
  • Ci-6 alkyl is intended to include Ci, C2, C3, C4, C5, Ce, 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 CO alkenyl groups.
  • C2-8 alkenyl is intended to include C2, C3, C 4 , 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.
  • C 2 -6 alkynyl is intended to include C2, C3, C4, C5, and Ce alkynyl groups.
  • C2-8 alkynyl is intended to include C2, C3, C4, C5, CO, C 7 , 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.
  • C 1.6 alkyl- R 3 is intended to represent a univalent Ci_6 alkyl group substituted with a R 3 group
  • O- Ci-6 alkyl-R 3 is intended to represent a bivalent Ci-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, C 4 , C5, Ce, C7, and Cs cycloalkyl groups.
  • 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 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, C2, C3, C4, C5, and CO alkoxy groups.
  • Ci_6 alkoxy is intended to include Ci, C2, C3, C4, C5, Ce, C-j, and Cs alkoxy groups.
  • 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.
  • 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 Ce alkylthio groups.
  • Ci_6 alkylthio is intended to include Ci, C2, C3, C4, C5, Ce, Cj, and Cg 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.
  • 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).
  • a nitrogen atom 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.
  • the substituents recited for the ring can also be present on the bridge. Spiro and fused rings are also included.
  • 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-
  • 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, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-&]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.
  • Solid 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 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 the disease-state, i.e., arresting its development or its clinical symptoms; and/or (b) 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-parasitic activity, anti-diarrheal 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.
  • 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:
  • B is selected from the group consisting of -O-, -S-, and -NR-; or
  • 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 Ci -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) -NR 4 C(O)H, Q) -C(O)R 5 , (k) - C(O)OR 5 , (1) -C(O)-NR 4 R 4 , (m) -C(S)R 5 , (n) -C(S)OR 5 , (o) -C(O)SR 5 , (p) -C(S)-NR 4 R 4 , (q) -N 3 , (r) -CN, (s) -CF 3 , (t) -CF 2 H, (u) -CFH 2 , (v) -S(O) 15 H, (w)
  • R a and R b independently are selected from: (a) H, (b) C 1-6 alkyl group, (c) C 2-6 alkenyl group, (d) C 2-6 alkynyl group, (e) -OH, (f) -OR 5 , (g) -NR 4 R 4 , (h) -C(O)R 5 , (i) -C(O)OR 5 , (j) -C(O)-NR 4 R 4 , (k) -C(S) p R 5 , (1) -C(S) P OR 5 , (m) -C(O)SR 5 , (n) -C(S) P -NR 4 R 4 , (o) halogen, (p) -SH, (q) -SR 5 , (r) -N 3 , (s) -CN, (t) -NHC(O)H, and (u) -N(C 1-6 alkyl)C(O)H; or alternative
  • R at each occurrence, independently is selected from (a) H, (b) C 1-6 alkyl, (c) -OH, (d) -0-(C 1-6 alkyl), (e) halogen, (f) -NH 2 , (g) -NH(C 1-6 alkyl), (h) -N(C 1-6 alkyl) 2 , (i) -(C 1 - C 6 )alkylaryl, O) -(C 2 -C 6 )alkenyl, (k) -(C 1 -C 6 )alkyl(OH)(C 1 -C 6 )alkyl, (1) -CH 2 F, (m) -CF 3 , (n) -(C 1 -COaIkVl(OH), and (o) -S(O) P (C 1 -C 6 alkyl)-;
  • 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 , O) -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 ;
  • 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 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 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,
  • each B" is independently selected from (aa) -H, (bb) -OH, (cc) -OR 9 , (dd) -SH, (ee) -S(O) p R 9 , (fit) halogen, (gg) -CN, (hh) -N 3 , (ii) -
  • Z is selected from: (a) a single bond, (b) -C 1-6 alkyl-, (c) -C 2-6 alkenyl-, (d) -C 2-6 alkynyl-, (e) -O-, (f) -NR 4 -, (g) -S(O) 1 ,-, (h) -C(OH (0 -C(O)O-, (j) - OC(O)- (k) -OC(O)O-, (1) -C(O)NR 4 - (m) -NR 4 CO-, (n) -
  • R 4 at each occurrence, independently is selected from:
  • R 7 (a) R 7 , (b) a C 1-6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) a C 3-12 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, or 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 (b)-(f) immediately above optionally is substituted with one or more R 7 groups; R 6 , at each occurrence, independently is selected from:
  • NR 8 C(O)OR 8 (xx) -NR 8 C(O)NR 8 R 8 , (yy) -NR 8 S(O) r R 8 , (zz) - C(OR 8 )(OR 8 )R 8 , (ab) -C(R 8 ) 2 NR 8 R 8 , (ac) -NR 8 , (ad) - C(S)NR 8 R 8 , (ae) -NR 8 C(S)R 8 , (af) -OC(S)NR 8 R 8 , (ag) -
  • NR 8 C(S)OR 8 (ah) -NR 8 C(S)NR 8 R 8 , (ai) -SC(O)R 8 , (aj) a C 1-6 alkyl group, (ak) a C 2-6 alkenyl group, (al) a C 2-6 alkynyl group, (am) a C 1-6 alkoxy group, (an) a C 1-6 alkylthio group, (ao) a C 1-6 acyl group, (ap) -CF 3 , (aq) -SCF 3> (ar) a C 3-12 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, NR 6 R 6 forms a 3-12 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R 6 groups are attached wherein said ring is optionally substituted
  • R 8 is selected from: (a) R 5 ,(b) H, (be) a C 1-6 alkyl group, (cd) a C 2-6 alkenyl group, (de) a C 2.6 alkynyl group, (ef) a C 3-I2 saturated, unsaturated, or aromatic carbocycle, (fg) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (gh) -C(O)-C 1-6 alkyl, (hi) -C(O)-C 2-6 alkenyl, (ij) -C(O)-C 2-6 alkynyl, (jk) -C(O)-C 3-12 saturated, unsaturated, or aromatic carbocycle, and (kl) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (bc
  • R 10 at each occurrence, independently is selected from:
  • R at each occurrence independently is selected from (a) -Cj -6 alkyl and (b) -0-(C 1-6 alkyl); a at each occurrence, independently is selected from 0, 1, 2, 3, and 4; b at each occurrence, independently is selected from 0, 1, 2, 3, and 4; c at each occurrence, independently is selected from 0, 1, 2, 3, and 4; p at each occurrence, independently is selected from 0, 1, and 2; r at each occurrence, independently is selected from 0, 1, and 2; t at each occurrence, independently is selected from 0, 1, and 2; and u at each occurrence, independently is selected from 1, 2, 3, and 4.
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • G, T, X, R 1 , R 2 , R 3 , R a , R b , R ⁇ , R d , and R e are as described herein.
  • the present invention relates to a compound having the structure:
  • the present invention relates to a compound having the structure:
  • G, T, X, R 1 , R 2 , R 3 , R a , R b , R c , R d , and R e are as described herein.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein a is 2. In other embodiments, 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 a is 2 or 3.
  • 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:
  • R 1 , R 2 , R 3 , R a , R b , R c , R d , and R e are as described herein.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R is H.
  • 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 , (j) -0(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(C 1-6 alkyl) 2 , (q) -C(O)NH 2 , (r) -C(O)NH—
  • 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) F, (c) -OH, (d) -0(C 1-6 alkyl), (e) -S(C 1-6 alkyl), and (f) -SH.
  • 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. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is OH. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is -0(C 1-6 alkyl).
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein X is -OCH 3 .
  • 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 independently 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 e is selected from (a) H, (b) C 1-6 alkyl, (c) -CF 3 , (d) -CF 2 H, and (e) -CFH 2 .
  • R e is selected from (a) H, (b) C 1-6 alkyl, (c) -CF 3 , (d) -CF 2 H, and (e) -CFH 2 .
  • the present invention relates to a compound, wherein 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 selected from: (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -0(Ci -6 alkyl), (g) -N 3 , (h) -COOH, (i) -COO(C 1-6 alkyl), G) -CN, (k) -NH 2 , (1) -NH(C 1-6 alkyl), (m) -N(C 1-6 alkyl) 2 , (n)-C(0)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) -N(C —
  • 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 selected from: (a) H, (b) F, (c) OH, and (d) -0(C 1-6 alkyl).
  • 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 -0(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 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 H.
  • 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) F, (c) -OH, (d) -0(C 1-6 alkyl), (e) -S(C 1-6 alkyl), and (f) -SH.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, ⁇ -oxide, or prodrug thereof, wherein R b is selected from (a) H, (b) F, (c) -OH, (d) -0(C 1-6 alkyl), (e) -S(C 1-6 alkyl), and (f) -SH.
  • 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 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. 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 C 1-6 alkyl. hi 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. hi other embodiments, 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 any of (a)-(b) immediately above optionally is substituted with one or more R 1 ' 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 or a pharmaceutically acceptable salt, ester, N-oxide or prodrug thereof, wherein Z is a single bond.
  • the present invention relates to a compound having the formula:
  • G is B';
  • X is selected from (a) H, (b) F, (c) -OH, (d) -0(Ci -6 alkyl), (e) -S(C 1-6 alkyl), and (f) -SH; and R b , R, R 1 , R 2 , R 3 and T are as described herein.
  • the present invention relates to a compound having the formula:
  • X is selected from: (a) H, (b) F, (c) -OH, (d) -0(C 1-6 alkyl), (e) -S(Ci -6 alkyl), and (f) -SH; and R b , R, R 1 , R 2 , R 3 and T are as described herein.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, ⁇ -oxide, or prodrug thereof, wherein R b is selected from (a) H, (b) F, (c) -OH, (d) -0(C 1-6 alkyl), (e) -S(Ci -6 alkyl), and (f) -SH.
  • R b is selected from (a) H, (b) F, (c) -OH, (d) -0(C 1-6 alkyl), (e) -S(Ci -6 alkyl), and (f) -SH.
  • 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, R 1 , R 2 , and R 3 are as described herein.
  • 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, 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, 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 or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R is H.
  • 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
  • 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
  • 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:
  • 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 1 ' 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 B' is unsubstituted. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is unsubstituted.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is unsubstituted and B" is unsubstituted.
  • 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 A', where A' 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, (f) H, (g) -OH (h) -SH, (i) F, (j) Cl, (k) Br, (1) I, (m) -CF 3 , (n) -CN, (o) -N 3 (p) -NO 2 , (q) -NR ⁇ CR ⁇ tR 9 , (r) -OR 9 , (s) -S ⁇ CRV ⁇ R 9 , (
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A' is selected from: (a) a C ⁇ 6 alkyl group, (b) a C 2.6 alkenyl group, (c) a C 2 .
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein A' 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, and (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, wherein any of (a)-(e) immediately above optionally is substituted with one or more R 14 groups.
  • the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein A' is selected from: (a) -NR 6 (CR 6 R 6 ) t R 9 , (b) -OR 9 , (c) -S ⁇ R ⁇ tR 9 , (d) -S(O) ( CR 6 R 6 ) t R 9 , (e) - S(O) 2 ( CR 6 R 6 XR 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 , (i) -SC(O)(CR 6 R 6 ) t R 9 , 0) -C(O)O(CR 6 R 6 ) t R 9 , (k) -NR 6 C(
  • the present invention relates to a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or pro-drug thereof, wherein G1-G50 is selected from:
  • the present invention relates to a compound, wherein T is:
  • 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
  • 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 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
  • R 105 is selected from:
  • R 126 is -OR 114 , -NR 114 or R 114 ; alternatively, R 104 and R 105 , taken together with the atoms to which they are bonded, form:
  • R 149 is selected from:
  • OC(O)R 114 (j) -OC(O)OR 114 , (k) -OC(O)NR 114 R 114 , (1) -O-C 1-6 alkyl, (m) -OC(O)-C 1-6 alkyl, (n) -OC(O)O-C 1-6 alkyl, (o) -OC(O)NR 114 -C 1-6 alkyl, (p) C 1-6 alkyl, (q) C 2-6 alkenyl, and (r) C 2-6 alkynyl, wherein any of (1) - (r) immediately above optionally is substituted with one or more R 115 groups; ii) R 150 is H, C 1-6 alkyl, or F; ii) alternately, R 149 and R 150 can be taken together with the carbon to which they are attached to form a carbonyl group; iii) alternately, R 149 and R 150 can be taken together to form the group -O(CR 116 R 116
  • R 130 is -OH, or R 114 ,
  • R 106 is selected from:
  • J 1 and J 2 at each occurrence independently are selected from hydrogen, Cl, F, Br, I,
  • U is selected from (a) -(Ci- 4 -alkyl)- and (b)-(C 2- 4-alkenyl)-, wherein (a) and (b) immediately above are optionally further substituted with one or more R 117 ; alternatively, M and R 105 are taken together with the atoms to which they are attached to form:
  • 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 selected from: (a) H, (b) C 1-6 alkyl, and (c) F;
  • R 114 at each occurrence, independently is selected from:
  • R 117 (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) immediately above optionally is substituted with one or more R 117 groups; R 116 , at each occurrence, independently is selected from:
  • R 117 at each occurrence, is selected from:
  • R 119 at each occurrence, independently is selected from:
  • Ci -6 acyl each occurrence, independently is selected from:
  • rings further being optionally substituted by one or more R 117 groups, alternatively an R 128 and an R 129 substituent can be taken together with the carbons to which they are attached to form a C 3-12 saturated or unsaturated ring or saturated or unsaturated bicyclic ring, or a 3-12 membered saturated or unsaturated heterocyclic ring or saturated or unsaturated heterobicyclic ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R 117 groups, alternatively one R 128 group and one R 129 group may be taken together with the carbons to which they are attached to form a double bond, and the other R 128 group and the other R 129 group are as defined herein or can form (a) a C 3-12 ring which may be further
  • R 11 Ss 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 138 is independently selected from (a) H and (b) Ci- 6 alkyl;
  • R 139 at each occurrence independently is selected from (a) H, (b) Cr 6 alkyl, (c) C 2 -C 6 alkenyl, and (d) 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 halogen and -OR 138 ; R 140 at each occurrence is independently selected from (a) halogen, (b) cyano,
  • R 145 at each occurrence, independently is selected from (a) H, (b) Cr 6 alkyl, (c) C 2 -C 6 alkenyl, (d) C 2 -C 6 alkynyl, (e) -(CH 2 ) v (C 6 -C 10 aryl), and (f) -(CH 2 ) v (5-10 membered heteroaryl);
  • 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 Tl through T93:
  • 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, 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
  • 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 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 wherein the compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, is administered orally, otically, opthalmically, nasally, 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. In other embodiments, the present invention relates to a medical device, wherein the 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 following schemes depict exemplary chemistries available for synthesizing the compounds of the invention.
  • Scheme 1 illustrates the typical general synthesis of the macrolide compounds of the present invention.
  • the synthesis starts with a known macrolide core component such as, for example, erythromycin, azithromycin, clarithromycin, roxithromycin, telithromycin, etc.
  • the macrolide core component is then converted to the 3'-N-desmethyl macrolide compound.
  • erythromycin can be converted to the 3'-N-desmethyl compound as described in the scientific and patent literature. See 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; Stenmark et al. (2000) J. Org. Chem. 65: 3875).
  • Analogous chemical procedures can be used to convert azithromycin, clarithromycin, roxithromycin, telithromycin, and other macrolide core components to their corresponding 3'-N-desmethyl compounds.
  • the 3'-N-desmethyl compounds can be further modified to provide yet further 3'-N-desmethyl compounds for use herein.
  • the 3'-N-desmthyl macrolide compound is alkylated with an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, bromide, etc.) to yield a 3'-N-alkyl ester compound.
  • an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, bromide, etc.)
  • a suitable leaving group e.g., halogen, tosylate, mesylate, bromide, etc.
  • terminal halogenated esters such as terminal bromo esters can be used.
  • the 3'-N-alkyl ester compounds are then reacted with the desired amine to yield the final desired macrolide compound.
  • the 3'-N-alkyl ester compound is first converted to a 3'-N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction with the desired amino compound to couple the two components via an ester linkage.
  • a 3'-N-alkyl carboxylic acid salt such as a lithium salt by reaction with LiOH in methanol, followed by reaction with the desired amino compound to couple the two components via an ester linkage.
  • 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, NJ.) 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 "hydro gel” 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).
  • 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.
  • 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.
  • 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 OfIC 50 S 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.
  • 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. 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.
  • MICs Minimum inhibitory concentrations 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.
  • a mouse or rat peritonitis infectious models skin and soft tissue models (often referred to as the thigh model), or a mouse pneumonia model.
  • 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 PD 50 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, parasitic diseases, diarrhea, 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.
  • 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.
  • routes of administration include oral or parenteral, for example, otic, ophthalmic, intravenous, intradermal, inhalation/nasal, 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 efhylenediaminetetraacetic 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
  • 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.
  • 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.
  • 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.
  • tissue-coating solutions such as pectin-containing formulations can be used.
  • 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.
  • 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.
  • 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.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • 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 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 oral, otic, ophthalmic, topic, or nasal or parenteral administration, using any of the methods and formulations described herein and/or known in the art.
  • 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. 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.
  • the compounds or pharmaceutical compositions thereof will be administered orally, otically, opthalmically, nasally, 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.
  • 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.
  • 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.
  • 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).
  • hemophilia factor VIII gene
  • NFl and NF2 genes neurofibromatosis
  • retinitis pigmentosa human USH2A gene
  • bullous skin diseases like
  • 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.
  • 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 chromatography” 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.
  • 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 IA- II 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-E
  • Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B wherein B' 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 5O 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 ZMeOHZNH 4 OH 18:1:0.05 to 10:1:0.05 to provide the 3'-N-desmethyl azithromycin (0.41 g, 55%).
  • Example 3 Synthesis of 3'-iV-desmethyI 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 55-6O 0 C. Iodine (0.33O g, 1.3 mmol) was added portion- wise and the reaction stirred at 55-6O 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 O 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-desemthyl 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.
  • the N-desmethyl macrolide compound is alkylated with an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, bromide, etc.) to yield an N-alkyl ester compound.
  • an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, bromide, etc.)
  • a suitable leaving group e.g., halogen, tosylate, mesylate, bromide, etc.
  • terminal halogenated esters such as terminal bromo esters can be used.
  • the N-alkyl ester compounds are then reacted with the desired amine to yield the final desired macrolide compound.
  • the N-alkyl ester compound is first converted to a N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction with
  • the 3'-N-alkyl ester compounds are then reacted with the appropriate amine to yield the final macrolide compound.
  • the 3'-N-alkyl ester compound is first converted to a 3'-N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction with the appropriate amino compound to couple the two components via an ester linkage.
  • the following reaction scheme provides a synthesis that is generally applicable to the compounds of the present invention wherein the macrolide core is derived from azithromycin.
  • the following reaction scheme provides a synthesis that is generally applicable to the compounds of the present invention wherein the macrolide core is derived from clarithromycin.
  • reaction was cooled to ambient temperature and diluted with ethyl acetate (100 mL). The resulting mixture was filtered through diatomaceous earth and the filtrate was washed with brine (100 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.
  • the reaction was treated with additional O-(benzotriazol-l-yl)- N,N,N'N'-tetramethyluronium hexafluorophosphate (0.182 g, 0.480 mmol) and stirred for an additional 18 h. After this time, the reaction was diluted with ethyl acetate (60 mL), washed with water (60 mL) then 5% aqueous lithium chloride (2 * 60 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.
  • the resulting suspension was treated with heptane (150 mL), stirred for 15 min and the solids were collected by filtration and washed with heptane (200 mL) to afford 8 (29.9 g, 78%) as a white solid.
  • the solids that had formed in the filtrate were collected by filtration and washed with heptane to afford additional 8 (1.81 g, 5%) as a white solid. Both lots were used without further purification.
  • the filtrate was treated with a 2 ⁇ solution of hydrogen chloride in diethyl ether (100 mL) and the resulting mixture was stirred at ambient temperature for 5 min.
  • the resulting suspension was treated with methanol (200 mL), stirred for 5 min and filtered through diatomaceous earth.
  • the filtrate was concentrated under reduced pressure until solids began to form.
  • the resulting suspension was treated with diethyl ether (200 mL) and the solids were collected by filtration to afford 9 (11.1 g, 30%) as a white solid that was used immediately without further purification.
  • Example 17 General procedure for the synthesis of the amines such as (2-Amino-3- fluoro-l-[4-(6-methyl-pyridin-3-yl)-phenyl]-propan-l-ol and 2-Amino-3-fluoro-l-(4- pyridin-3-yl-phenyl)-propan-l-ol TFA salt)
  • Amine compounds useful in the synthesis of the compounds of the present invention are readily made using generally known chemistries.
  • Nonlimiting exemplary amino ⁇ compounds are shown below in Table 2.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

The present invention provides a family of branched amide containing macrocyclic compounds useful as therapeutic agents. More particularly, these compounds are useful as anti-infective, antiproliferative, anti-inflammatory, and prokinetic agents.

Description

MACROLIDE COMPOUNDS AND METHODS OF MAKING AND USING THE SAME
RELATED APPLICATIONS
This application 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, the disclosure of each is incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates generally to the field of anti-infective, antiproliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family of branched amide containing macrocyclic compounds that are useful as such agents.
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. 111, 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. hi 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-viral agents, anti-diarrheal agents, and chemotherapeutic agents. The present invention also provides compounds useful as anti- inflammatory 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 branched amide containing compounds having the structure:
Figure imgf000004_0001
or a stereoisomer, pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In the formula, variables A, B, G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, Re, a, b, and c can be selected from the respective groups of chemical moieties later defined in the detailed description. In 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. In 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 oral, parenteral, otic, ophthalmic, nasal, 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).
By "branched amide containing" means that the compounds of the present invention generally contain an amide moiety, wherein the amide moiety is connected to either a branched alkyl group or at a secondary carbon of the alkyl group, and wherein the alkyl group can be further substituted.
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 nitrogens 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 Ce alkyl groups. Ci-6 alkyl is intended to include Ci, C2, C3, C4, C5, Ce, 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 CO 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 Ce 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, "C 1.6 alkyl- R3" is intended to represent a univalent Ci_6 alkyl group substituted with a R3 group, and "O- Ci-6 alkyl-R3" is intended to represent a bivalent Ci-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 CO alkoxy groups. Ci_6 alkoxy, is intended to include Ci, C2, C3, C4, C5, Ce, C-j, 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 Ce alkylthio groups. Ci_6 alkylthio, is intended to include Ci, C2, C3, C4, C5, Ce, Cj, and Cg 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. Li 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, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-&]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3Η-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, moφholinyl, 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 the disease-state, i.e., arresting its development or its clinical symptoms; and/or (b) 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-parasitic activity, anti-diarrheal 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.
Compounds of the Invention
In 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
A and B are selected such that, A is selected from the group consisting of (a) -(C=O)-, (b) -(C=S)-, (c) -(C=NR)-, (d)
-(C=NOR)-, (e) -(C=NNRR)-, (f) -(S=O)-, (g) -(SO2)-, and (h) -[(3 or 4-membered ring carbocycle)-(C=O)]- and B is selected from the group consisting of -O-, -S-, and -NR-; or
B is selected from the group consisting of (a) -(C=O)-, (b) -(C=S)-, (c) -(C=NR)-, (d) -(C=NOR)-, (e) -(C=NNRR)-, (f) -(S=O)-, (g) -(SO2)-, (h) -C(O)NR-, and (i) -[(3 or 4- membered ring carbocycle)-(C=O)]- and A is selected from the group consisting of -O-, -S-, and -NR-;
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 Ci-6 alkyl group, (d) a C2-6 alkenyl group, (e) a C2-6 alkynyl group, (f) -OH, (g) -OR5, (h) -NR4R4, (i) -NR4C(O)H, Q) -C(O)R5, (k) - C(O)OR5, (1) -C(O)-NR4R4, (m) -C(S)R5, (n) -C(S)OR5, (o) -C(O)SR5, (p) -C(S)-NR4R4, (q) -N3, (r) -CN, (s) -CF3, (t) -CF2H, (u) -CFH2, (v) -S(O)15H, (w) -SR5, (x) -S(O)POH, (y) -S(O)POR5, (z) -S(O)PNR4R4, (aa) -S(O)pC1-6 alkyl, (bb) -S(O)paryl, (cc) a C3-7 saturated, unsaturated, or aromatic carbocycle, and (dd) 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) C1-6 alkyl group, (c) C2-6 alkenyl group, (d) C2-6 alkynyl group, (e) -OH, (f) -OR5, (g) -NR4R4, (h) -C(O)R5, (i) -C(O)OR5, (j) -C(O)-NR4R4, (k) -C(S)pR5, (1) -C(S)POR5, (m) -C(O)SR5, (n) -C(S)P-NR4R4, (o) halogen, (p) -SH, (q) -SR5, (r) -N3, (s) -CN, (t) -NHC(O)H, and (u) -N(C1-6 alkyl)C(O)H; or 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, wherein (b) -(d) are further optionally substituted with one or more R5 or alternatively Ra and Rb taken together with the carbon to which they are attached are absent;
Rc is selected from: (a) H, (b) a C1-6 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) -Q=O)OR5, (i) - C(=O)-NR4R4, O) -S(O)pNR4 R4, (k) -C(O)SR5, (1) -S(O)PH, (m) - S(O)15R5, (n) CF3, (o) CF2H, and (p) CFH2, wherein any of (b) -(d) immediately above is 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, O) -C(O)-NR4R4, (k) -C(S)R5, (1) -C(S)OR5, (m) -C(O)SR5, (n) -C(S)-NR4R4, and (o) halogen, or 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;
R at each occurrence, independently is selected from (a) H, (b) C1-6 alkyl, (c) -OH, (d) -0-(C1-6 alkyl), (e) halogen, (f) -NH2, (g) -NH(C1-6 alkyl), (h) -N(C1-6 alkyl)2, (i) -(C1- C6)alkylaryl, O) -(C2-C6)alkenyl, (k) -(C1-C6)alkyl(OH)(C1-C6)alkyl, (1) -CH2F, (m) -CF3, (n) -(C1-COaIkVl(OH), and (o) -S(O)P(C1-C6 alkyl)-;
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, O) -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;
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) immediately above optionally contains one or more carbonyl groups, and wherein each (aa) or (bb) immediately above optionally is substituted with one or more R11 or RUa; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc) -OR9, (dd) -SH, (ee) -S(O)pR9, (fit) 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(CR6R6)tR9, (aaa)
Figure imgf000015_0001
(bbb) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings, (ccc) 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, (ddd) -C1-6 alkyl, (eee) -C2-6 alkenyl, and (fff) a C2-6 alkynyl group; wherein each (bbb) or (ccc) immediately above optionally contains one or more carbonyl groups, and wherein each (bbb) or (ccc) immediately above optionally is substituted with one or more R11 or Rl la; wherein each
(ddd), (eee), or (ffϊ) immediately above optionally is substituted with one or more R14 groups; 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 (0 -C(O)O-, (j) - OC(O)- (k) -OC(O)O-, (1) -C(O)NR4- (m) -NR4CO-, (n) -
NR4C(O)NR4- (o) -C(=NR4K (p) - C(=NR4)O-, (q) -OC(=NR4)-, (r) -C(=NR4)NR4-, (s) -NR4Q=NR4)-, (t) -C(=S)-, (u) -C(=S)NR4-, (v) -NR4C(=SK (w) -C(O)S-, (x) -SC(O)-, (y) -OC(=SH and (z) - C(=S)-O-, wherein any of the aliphatic carbons atoms in (b), (c), or (d) immediately above is optionally replaced with -(C=O)-, -O-, -S-, or - NR4-, and wherein any of (b), (c), or (d), immediately above is 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, (fit) -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 any of (ii)-(mm) immediately above is optionally substituted with one or more R5 groups; alternatively two R14 groups are taken together to form (a) =0, (b) =S, (c) =NR8, or (d) =NOR8;
R4, 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, (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-C1-O alkyl,
(h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, O) -C(O)-C3-12 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-C3-12 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) immediately above 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 NR ; R5 at each occurrence, independently is selected from:
(a) R7, (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, or 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 (b)-(f) immediately above 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-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) immediately above 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, Oj) -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 C1-6 alkoxy group, (an) a C1-6 alkylthio group, (ao) a C1-6 acyl group, (ap) -CF3, (aq) -SCF3> (ar) a C3-12 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 substituted 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 G) -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) -StO^NR^CR^tR9, (cc) - NR6S(O)pNR6(CR6R6)tR9, (dd) -NR6R6, (ee) -NR6(CR6R6), (ff) -OH, (gg) - NR6R6, (hh) -OCH3, (ii) -S(O)pR6, Gj) -NC(O)R6, (kk) -Si(R13)3, (11) a Cj_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 (kk)-(oo) immediately above optionally is substituted with one or more R9 groups; alternatively, two R7 groups can form -O(CH2)UO-;
R8 is selected from: (a) R5,(b) H, (be) a C1-6 alkyl group, (cd) a C2-6 alkenyl group, (de) a C2.6 alkynyl group, (ef) a C3-I2 saturated, unsaturated, or aromatic carbocycle, (fg) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (gh) -C(O)-C1-6 alkyl, (hi) -C(O)-C2-6 alkenyl, (ij) -C(O)-C2-6 alkynyl, (jk) -C(O)-C3-12 saturated, unsaturated, or aromatic carbocycle, and (kl) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (bc)-(k) immediately above 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 C1-6 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) immediately above 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, (j) - 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) immediately above optionally is substituted with one or more moieties selected from R6, F, Cl, Br, I, CN, NO2, - OR6, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, a C1-6 alkoxy group, a
Ci-6 alkylthio group, and a C1-6 acyl group; R11 and Rl la 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, Q) -S(O)15R8, (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, (kk) NR8(C=NR8)R8, (11)
NH(C=NH)NH2, (kkii) a C1-6 alkyl group, (lljj) a C2-6 alkenyl group, (mmkk) a C2-6 alkynyl group, (nnll) a C1-6 alkoxy group, (oomm) a C1-6 alkylthio group, (ppnn) a C1-6 acyl group, (qqoo) a C3-I2 saturated, unsaturated, or aromatic carbocycle, (rrpp) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (ssqq) -S(O)PR8, (ttrr) C(OR8)R8, (uuss) - C(R8)2C(O)NR8R8, (wtt) -S(O)PNR8R8, (wwuu) -C(R8)2S(O)PR8, (xxw) - C(R8)2N3, and (yyww) S(O)pC(R8)2CN, wherein any of (kkii)-(mmkk) immediately above optionally is substituted with one or more R5 groups; R12 is selected from:
(a) H, (b) a C1-6 alkyl group, (c) a C2-O 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, (k) -C(S)-NR4R4, (1) a C3-I2 saturated, unsaturated, or aromatic carbocycle, (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 -(Ci-6 alkyl)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (a)-(d) and (l)-(o) immediately above is optionally substituted with one or more R5 groups;
R at each occurrence, independently is selected from (a) -Cj-6 alkyl and (b) -0-(C1-6 alkyl); a at each occurrence, independently is selected from 0, 1, 2, 3, and 4; b at each occurrence, independently is selected from 0, 1, 2, 3, and 4; c at each occurrence, independently is selected from 0, 1, 2, 3, and 4; p at each occurrence, independently is selected from 0, 1, and 2; r at each occurrence, independently is selected from 0, 1, and 2; t at each occurrence, independently is selected from 0, 1, and 2; and u at each occurrence, independently is selected from 1, 2, 3, and 4. In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000021_0001
or a pharmaceutically acceptable salt, ester, JV-oxide, or prodrug thereof, wherein a, b, c, A, B, 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 imgf000021_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein a, b, c, A, B,
G, T, X, R1, R2, R3, Ra, Rb, Rς, Rd, and Re are as described herein. In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000022_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein a, b, c, A, B, 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 imgf000022_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein a, b, c, A, B,
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, iV-oxide, or prodrug thereof, wherein A is selected from the group consisting of (a) -(C=O)-, (b) -(C=S)-, (c) -(C=NR)-, (d) -(C=NOR)-, (e) - (C=NNRR)-, (f) -(S=O)-, (g) -(SO2)-, and (h) -[(3 or 4-membered ring carbocycle)-(C=O)]- and B is selected from the group consisting of -0-, -S-, and -NR-, wherein R is H or 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 A is -(C=O)-, B is -NR-, where R is H or C1-6 alkyl, b is O, and c is 0.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein a is 2. In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000023_0001
or a pharmaceutically acceptable salt, ester, N-oxide or prodrug thereof, wherein a is 2, 3, or 4, and G, T, X, R, 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 a is 2 or 3.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000023_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R, 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_0003
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R, R1, R2, R3, R\ 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, R,
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 R is H. 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, (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, (w) -N(C1-6 alkyl)C(O)N(C1-6 alkyl)2, (x) -
S(C1-6 alkyl), and (y) -SH.
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) F, (c) -OH, (d) -0(C1-6 alkyl), (e) -S(C1-6 alkyl), and (f) -SH. hi 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.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is F. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is OH. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is -0(C1-6 alkyl).
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein X is -OCH3.
In 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 independently 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. hi other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Re is selected from (a) H, (b) C1-6 alkyl, (c) -CF3, (d) -CF2H, and (e) -CFH2. hi other embodiments, the present invention relates to a compound, 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 selected from: (a) H, (b) Cl, (c) Br, (d) F, (e) -OH, (f) -0(Ci-6 alkyl), (g) -N3, (h) -COOH, (i) -COO(C1-6 alkyl), G) -CN, (k) -NH2, (1) -NH(C1-6 alkyl), (m) -N(C1-6 alkyl)2, (n)-C(0)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(Ci-6 alkyl)C(O)N(C1-6 alkyl), (u) -S(C1-6 alkyl), and (v) -SH, or alternatively Ra and Rb are taken together with the carbon to which they are attached to form (aa) -CO or (bb) -CS. hi 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 selected from: (a) H, (b) F, (c) OH, and (d) -0(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 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 -0(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 Ra is H and Rb is -OCH3.
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.
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, R3, and Rb 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) F, (c) -OH, (d) -0(C1-6 alkyl), (e) -S(C1-6 alkyl), and (f) -SH. hi other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, Ν-oxide, or prodrug thereof, wherein Rb is selected from (a) H, (b) F, (c) -OH, (d) -0(C1-6 alkyl), (e) -S(C1-6 alkyl), and (f) -SH.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000026_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 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, 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, 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. hi other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is methyl. hi other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is B'. hi 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 any of (a)-(b) immediately above optionally is substituted with one or more R1 ' 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 or a pharmaceutically acceptable salt, ester, N-oxide or prodrug thereof, wherein Z is a single bond.
In other embodiments, the present invention relates to a compound having the formula:
Figure imgf000028_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G is B'; X is selected from (a) H, (b) F, (c) -OH, (d) -0(Ci-6 alkyl), (e) -S(C1-6 alkyl), and (f) -SH; and Rb, R, R1, R2, R3 and T are as described herein.
In other embodiments, the present invention relates to a compound having the formula:
Figure imgf000029_0001
or a pharmaceutically acceptable salt, ester, Ν-oxide, or prodrug thereof wherein G is -B '-Z-
B";
X is selected from: (a) H, (b) F, (c) -OH, (d) -0(C1-6 alkyl), (e) -S(Ci-6 alkyl), and (f) -SH; and Rb, R, R1, R2, R3 and T are as described herein.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, Ν-oxide, or prodrug thereof, wherein Rb is selected from (a) H, (b) F, (c) -OH, (d) -0(C1-6 alkyl), (e) -S(Ci-6 alkyl), and (f) -SH. hi 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, X, R, R1, R2, and R3 are as described herein. hi other embodiments, the present invention relates to a compound having the structure:
Figure imgf000030_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R, R1, R2, and R3 are as described herein. hi other embodiments, the present invention relates to a compound having the structure:
Figure imgf000030_0002
or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof wherein G, T, X, R, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000030_0003
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000031_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R, R1, R2, and R3 are as described herein.
In other embodiments, the present invention relates to a compound having the structure:
Figure imgf000031_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R, 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 R is H.
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_0003
, wherein, B", Z, and R1 x are as described herein and wherein, one
Figure imgf000031_0004
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_0001
and B", Z, and R1 λ 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
Figure imgf000032_0002
, and 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_0003
, wherein B", Z, and R11 are as described herein and one
Figure imgf000032_0004
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_0005
, wherein B", Z, and R11 are as described herein.
In other embodiments, the present invention relates to a compound or a
Figure imgf000032_0006
pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is: wherein B", Z, and R1 ' 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 imgf000033_0001
, wherein B", Z, and R1 ' are as described herein and one of "' N or B" is substituted with R11. 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 imgf000033_0002
, 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 imgf000033_0003
, wherein B", Z, and R1 ' 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 imgf000033_0004
, wherein B", Z, and R11 are as described herein and one
Figure imgf000033_0005
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 imgf000034_0001
, wherein B", Z, and R1 ' 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 imgf000034_0002
, 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) F, (b) Cl, (c) Br, (d) I, (e) CN, (f) -S(O)PR8, (g) -C(O)R8, (h) -C(O)NR8R8, (i) - C(=NR8)R8, (j) -C(R8)(R8)OR8, (k) -NR8R8, (1) -NR8C(O)R8, (m) -C(R8)2NR8R8, (n) NH(C=NH)NH2, (o) a C1-6 alkyl group, (p) a C1-6 alkylthio group, (q) a C3-12 unsaturated carbocycle, (r) -S(O)pR8, (s) -S(O)PCHF2, (t) -C(OR8)R8, (u) -C(R8)2C(O)NR8R8, (v) - S(O)PNR8R8, (w) -C(R8)2S(O)PR8, (x) -C(R8)2N3, and (y) S(O)PC(R8)2CN.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is unsubstituted. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is unsubstituted.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein B' is unsubstituted and B" is unsubstituted.
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 A', where A' 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, (j) Cl, (k) Br, (1) I, (m) -CF3, (n) -CN, (o) -N3 (p) -NO2, (q) -NR^CR^tR9, (r) -OR9, (s) -S^CRV^R9, (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, (ϋ) -NR6S(O)p(CR6R6)tR9, GJ) -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, independently is selected from O, 1, and 2; wherein any of (a)-(e) immediately above is optionally 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, (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 any of (ii)-(mm) immediately above optionally is substituted with one or more R5 groups; alternatively two R14 groups are taken together to form (a) =0, (b) =S, (c) =NR8, or (d) =NOR8. In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A' 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) -CF3, (g) - NR6(CR6R6)tR9, (h) -OR9, (i) -S(CR6R6)tR9, G) -S(O)(CR6R6)tR9, (k) -S(O)2(CR6R6)tR9 (1) -QOXCRVXR9, (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) -CH^XCR^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) -SCO^NR^CR^^tR9, (aa) - NR6R6, (bb) -NR6(CR6R6),R9, (cc) -SR6, (dd) -S(O)R6, (ee) -S(O)2R6, and (ff) -NR6C(O)R6, wherein any of (a)-(e) immediately above optionally is substituted with one or more R14 groups.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein A' 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 any of (a)-(e) immediately above optionally is substituted with one or more R14 groups.
In other embodiments, the present invention relates to a compound or a pharmaceutically acceptable salt, ester, iV-oxide, or prodrug thereof, wherein A' is selected from: (a) -NR6(CR6R6)tR9, (b) -OR9, (c) -S^R^tR9, (d) -S(O)(CR6R6)tR9, (e) - S(O)2 (CR6R6XR9, (f) -C(O)(CR6R6)tR9, (g) -OC(O)(CR6R6)tR9, (h) -OC(O)O(CR6R6)tR9, (i) -SC(O)(CR6R6)tR9, 0) -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) -S(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, or a pharmaceutically acceptable salt, ester, N-oxide, or pro-drug thereof, wherein G1-G50 is selected from:
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
G43 G44
Figure imgf000039_0002
C45
G46
Figure imgf000039_0003
G49 G50
In other embodiments, the present invention relates to a compound, wherein T is:
Figure imgf000039_0004
rmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein:
M is selected from:
(a) -C(O)-, (b) -CHC-OR11V, Cc) -NR114-CH2- (d) -CH2-NR114-, (e) - CH(NR114R114H Cf) -CC=NNR114R114)-, (g) -NR114-C(O)-, (h) -C(O)NR114-, (i)
Figure imgf000039_0005
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)R1 H, Q) -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- Ci-6 alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2-6 alkynyl, wherein any of (1) - (r) immediately above 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-Q-e alkyl-R115, (d) -OC(O)R114, (e) -OC(O)-C1-6 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 imgf000040_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) -C2-6alkenyl-K-R114, and (h) -C2-6 alkynyl-K-R114; K is selected from:
(a) -C(O)-, (b) -C(O)O-, (C) -C(O)NR114- (d) -C(=NR114)-, (e) - C(=NR114)O-, (f) -C(=NRI 14)NR114- (g) -OC(O)-, (h) -OC(O)O-, (i) - OC(O)NR114-, O) -NR114C(OK (k) -NR114C(O)O-, (1) -NR114C(O)NR114-, (m) -NR114C(=NR114)NR114-, and (n) -S(0)p-; alternatively R103 and R104, taken together with the atoms to which they are bonded, form:
Figure imgf000041_0001
wherein R135 and R136 are selected from (a) hydrogen, (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 oxygen, nitrogen, or sulfur atoms, (g) F, (h) Br, (i) I, (j) OH, and (k) -N3, wherein any of (b)-(f) immediately above optionally is substituted with one or more R117; or alternatively, R135 and R136 are taken together to form =O, =S, =NR114, =N0R114, =NR114, or =N-NR114R114, wherein V is selected from (a) -(C1-4-alkyl)-, (b)-(C2-4-alkenyl)-, (c) O, (d) S, and (e) NR114, wherein (a) and (b) immediately above are optionally further substituted with one or more R 117.
R105 is selected from:
(a) R114, (b) -OR114, (c) -NR114R114, (d) -O-C,-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, (j) -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; alternatively, R104 and R105, taken together with the atoms to which they are bonded, form
Figure imgf000042_0001
wherein
Q is CH or N, and R126 is -OR114, -NR114 or R114; alternatively, R104 and R105, taken together with the atoms to which they are bonded, form:
Figure imgf000042_0002
, wherein i) R149 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) -O-C1-6 alkyl, (m) -OC(O)-C1-6 alkyl, (n) -OC(O)O-C1-6 alkyl, (o) -OC(O)NR114-C1-6 alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2-6 alkynyl, wherein any of (1) - (r) immediately above optionally is substituted with one or more R115 groups; ii) R150 is H, C1-6 alkyl, or F; ii) alternately, R149 and R150 can be taken together with the carbon to which they are attached to form a carbonyl group; iii) alternately, R149 and R150 can be taken together to form the group -O(CR116R116)UO-; alternatively, R104 and R105, taken together with the atoms to which they are bonded, form:
Figure imgf000042_0003
wherein in the preceding structure the dotted line indicates an optional double bond; R130 is -OH, or R114,
R131 is -OH, or R114, alternately, R130 and R131 together with the carbons to which they are attached form a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups; alternatively, R130 and the carbon to which it is attached or R131 and the carbon to which it is attached are each independently -C(=0)-; alternatively, R105, R132 and M, taken together with the atoms to which they are attached, form:
Figure imgf000043_0001
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, alternatively, R105 and R106 taken together with the atoms to which they are attached form a 5-membered ring by attachment to each other through a chemical moiety selected from:
(a) -OC(R115)2O-, (b) -OC(O)O-, (c) -OC(O)NR114-, (d) -NR114C(O)O-, (e) -OC(O)NOR114- (f) -NOR114-C(O)O-, (g) -OC(O)N[NR114R114] - (h) - N[NR114R114KXO)O-, (i) -OC(O)C(R115)2- (j) -C(R115)2C(O)O-, (k) - OC(S)O-, (1) -OC(S)NR114-, (m) -NR114C(S)O-, (n) -OC(S)NOR114-, (o) -
NOR114-C(S)O-, (p) -OC(S)N[NR114R114]-, (q) -N[NR114R114]-C(S)O-, (r) - OC(S)C(R115)2- (s) -C(RU5)2C(S)O-, (t) -OC(O)CR115[S(O),>R114] - (u) - OC(O)CR115PsJR114R114] -, (v) -CR115[NR114R114]C(O)O-, and (w) - CR115[S(O)pR114]C(O)O-; alternatively, R105, R106, and R133 taken together with the atoms to which they are attached form:
Figure imgf000044_0001
alternatively, M, R105, and R106 taken together with the atoms to which they are attached form:
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000046_0001
wherein J1 and J2 at each occurrence, independently are selected from hydrogen, Cl, F, Br, I,
OH, -C1-6 alkyl, and -O(Ci-6alkyl) or are taken together to form =0, =S, =NR114,
=NOR114, =NR114, or ^N-NR114R114, alternatively, M and R1 taken together with the atoms to which they are attached form:
Figure imgf000046_0002
Figure imgf000047_0001
wherein U is selected from (a) -(Ci-4-alkyl)- and (b)-(C2-4-alkenyl)-, wherein (a) and (b) immediately above are optionally further substituted with one or more R117; alternatively, M and R105 are taken together with the atoms to which they are attached to form:
Figure imgf000047_0002
R107 is selected from:
(a) H, (b) -C1-6 alkyl, (c) -C2-6 alkenyl, which can be further substituted with C1-O 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 which can be further substituted with C1-6 alkyl or one or more halogens, (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, Qj) -NC(O)R114, (fck) -COOR114, (11) -N3, (mm) =N-0-R114, (nn) =NR! 14, (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) C1-6 alkyl, (b) C2-6 alkenyl, and (c) C2-6 alkynyl, wherein any of (a)-(c) immediately above optionally is substituted with one or more R114 groups; R109 is selected from: (a) H, (b) C1-6 alkyl, and (c) F;
R114, at each occurrence, independently is selected from:
(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-12 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, Q) -C(O)-C3-12 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-C1-6 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, (q) -C(O)NR116R116, (r) -NR116CO-C1-6 alkyl, (s) - NR116CO-C3-I2 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) -(Ci-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-(Ci-6 alkyl), (dd) -(C1-6 alkyl)- S(O)p-(C1-6 alkyl)-O-(C1-6 alkyl), (ee) -NH2, and (ff) -CR114R114; wherein the teπninal alkyl group in any of (u)-(v) or (aa)-(dd) immediately above includes cycloalkyl, wherein any of (b)-(v) or (aa)-(dd) immediately above optionally is substituted with one or more R115 groups, wherein one or more nonterminal carbon moieties of any of (b)-(d) immediately above optionally is replaced with oxygen, S(O)P, or -NR116, alternatively, NR114R114 forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R114 groups are bonded and optionally one or more moieties selected from O, S(O)P, 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) immediately above 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) immediately above optionally is replaced with oxygen, S(0)p, or - NR118, wherein any of (b)- (f) immediately above 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, Gj) OR118, (kk) -S(O)13R118, (11) -
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(R11^2OC(O)R118, (tt) -
C(R118XOR118XCH2XNR118R118, (uu) -NR118R118; (w) - NR118OR118, (ww) -NR118C(O)R118, (xx) -NR118C(O)OR118, (yy) -NR118C(O)NR118R118, (zz) -NR118S(O)1R118, (ab) - C(OR118)(OR118)R118, (ac) -C(R118X2NR118R118, (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) C1-6 alkyl, (al) C2-6 alkenyl, (am) C2-6 alkynyl, (an) Ci-6 alkoxy, (ao) Ci-6 alkylthio, (ap) C1-6 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, Qo) =O, (C) F, (d) Cl, (e) Br, (f) I, (g) (CRU6R116)rCF3, (h) (CR116Rn6)rCN, (i) (CR116R116)rNO2, (j) (CR116R116XNR11^CR116R11 %Rl 19, (k) (CR116R116XOR119, (1) (CR116R116XS(O)P(CR116R116),R119, (m) (CR116R116XC(O)(CR116R116),R! 19, (n) (CR116R116XOC(O)(CR116R116XR119,
(o) (CR116R116XSC(O)(CR116R116XR119, (p) (CR116R116XC(O)O(CR116R116XR119, (q) (CR116R116XNR116C(O)(CR116R116XR119, (r) (CR116R116XC(O)NR11^CR116R116),R119, (s) (CR11V16XQ=NR116XCR11V16XR119,
(t) (CR11V 16XQ=NNR116R116)(CR] 1V 16XR119, (u) (CR11V 16XQ=NNR116C(O)R116XCR11V 16XR119, (v) (CR11 V 16XQ=NOR119XCR11V 16XR119, (w) (CR11V 16XNR116C(O)O(CR116R116),R119, (x) (CR116R116XOC(O)NR116(CR116R116XR119,
(y) (CR11V 16XNR116C(O)NR116(CR' 1V 16XR119, (Z) (CR11V16XNR116S(O)P(CR11V16XR119, (aa) (C^'V^XS^NR^CR^R^XR119,
(bb) (CR116R116XNR116S(OX3NR11^CR11V 16XR119, (CC) (CR116R116XNR116R116, (dd) Cu6 alkyl, (ee) C2.6 alkenyl, (ff) C2.6 alkynyl, (gg) (CR116R116)r-C3-12 saturated, unsaturated, or aromatic carbocycle, (hh) (CR116RI 16)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(Ci-6 alkyl))2, wherein any of (dd)-(hh) immediately above 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-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, 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) immediately above 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) 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 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) (CR116R116)rCN, (i) (CR116R116XNO2, (j) (CR116R116XNR116R116, (k) (CR116RH6)rOR114, (1) (CR116R116χS(O)pR116, (m) (CR116R116XC(O)R116, (n) (CR116R116XC(O)OR116, (o) (CR116R116XOC(O)R116, (p) (CR11V16XNR116C(O)R116, (q) (CR116R116XC(O)NR116R116, (r)
(CR116R116)rC(=NR116)R116, (s) (CR116R116XNR116C(O)NR116R116, (t) (CR116R116XNR116S(O)11R116, (u) (CR116R116XS(O)PNR116R116, (v) (CR116R11^1NR116S(O)13NR116R116, (w) CU6 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, C1-6 alkoxy, C1-6 alkylthio, and
Ci-6 acyl; each occurrence, independently is selected from:
(a) H, (b) -OR118, (c) -O-Ci-6 ^yI-OC(O)R118, (d) -0-Ci-6 alkyl- OC(O)OR118, (e) -0-C1-6 alkyl-OC(O)NR118R118, (f) -0-C1-6 alkyl- C(O)NR118R118, (g) -O-C1-6 alkyl-NR118C(O)R118, (h) -0-C1-6 alkyl-
NR118C(O)OR118, (i) -C)-C1-6 alkyl-NR118C(O)NR118R118, (j) -O-C1-6 alkyl- NR118Q=N(H)NR118R118), (k) -0-C1-6
Figure imgf000052_0001
(1) -0-C2-6 alkenyl- OC(O)R118, (m) -O-C2-6 alkenyl-OC(O)OR118, (n) -0-C2-6 alkenyl- OC(O)NR118R118, (o) -O-C2-6 alkenyl-C(O)NR118R118, (p) -O-C2-6 alkenyl- NR118C(O)R118, (q) -O-C2-6 alkenyl-NR118C(O)OR118, (r) -O-C2-6 alkenyl-
NR118C(O)NR118R118, (s) -O-C2-6 alkenyl-NR118Q=N(H)NR118R118), (t) -O- C2-6 alkenyl-S(O)pR118, (u) -O-C2-6 alkynyl-OC(O)R118, (v) -0-C2-6 alkynyl- OC(O)OR118, (w) -0-C2-6 alkynyl-OC(O)NR118R118, (x) -O-C2-6 alkynyl- C(O)NR118R118, (y) -O-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) -Ci-6 alkyl-O-Ci-6 alkyl, (ff) -Ci-6 alkyl-
NR114^i-6 alkyl, (gg) -C,-6 alkyl-S(O)p-Ci-6 alkyl, (hh) -OC(O)NR114(Ci-6 alkyl)-NRU4-(Ci-6 alkyl) -R114, (ii) -OH, Qj) -C1-6 alkyl, (kk) C2-6 alkenyl, (11) C2-6 alkynyl, (mm) -CN, (nn) -CH2S(O)PR137, (oo) -CH2OR137, (pp) - CH2N(ORI38)R137, (qq) -CH2NR137R139, (IT) -(CH2)v(C6-1o 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, =N0R118, or =NNR118R118; R127 at each occurrence, independently is selected from (a) R114, (b) a monosaccharide or a disaccharide (including amino sugars and halogenated sugar(s)), (c) -S(O)pR148, (d) -(CH2)n-(O-CH2CH2-)m-O(CH2)nCH3, (e) -(CH2)n-(O-CH2CH2-)m-OR148, (f) - (CH2)n-[S(O)p-CH2CH2-]m-S(O)p(CH2)nCH3, (g) -(CH2)n-[S(O)p-CH2CH2-]m-OR148,
(h) -OCH2-O-(CH2)n-[S(O)p-CH2CH2-]m-S(O)p(CH2)nCH3, (i) -OCH2-O-<CH2)n- [S(O)p-CH2CH2-]m-OR148, (j) -0-[C3-I2 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R114, (k) - 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, (1) -S(O)P-[C3-12 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further optionally substituted with one or more R114, and (m) -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; R128 is R114; R129 is R114; alternatively both R128 substituents can be taken together with the carbons to which they are attached to form carbonyl or =NR] 14, or a saturated or unsaturated C3-6 spiro ring or a 3-6 membered saturated or unsaturated heterospiro ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R117 groups, alternatively both R129 substituents can be taken together with the carbons to which they are attached to form carbonyl or =NR! 14, or a saturated or unsaturated C3-6 spiro ring or a 3-6 membered saturated or unsaturated heterospiro ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R117 groups, alternatively an R128 and an R129 substituent can be taken together with the carbons to which they are attached to form a C3-12 saturated or unsaturated ring or saturated or unsaturated bicyclic ring, or a 3-12 membered saturated or unsaturated heterocyclic ring or saturated or unsaturated heterobicyclic ring containing one or more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by one or more R117 groups, alternatively one R128 group and one R129 group may be taken together with the carbons to which they are attached to form a double bond, and the other R128 group and the other R129 group are as defined herein or can form (a) a C3-12 ring which may be further unsaturated or aromatic, (b) a C7-12 bicyclic ring which may be further unsaturated or aromatic, (c) a 3-12 membered heterocyclic ring containing one or more nitrogens, oxygens, or sulfurs, which may be further unsaturated or aromatic, or (d) a 7-12 membered heterobicyclic ring containing one or more nitrogens, oxygens, or sulfurs, which may be further unsaturated or aromatic, said rings described in (a), (b), (c) and (d) further being optionally substitued by one or more R117 groups,
R11Ss R114; alternatively, R109 and R110 taken together with the carbons to which they are attached form:
Figure imgf000054_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) C1-6 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, =N0R114, =NR114, 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 selected from: (a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) -(CH2)qCR141R142(CH2)nNR143R144, (f) -(CH2)v(C6-C,0 aryl), and -(g) (CH2)v(5-10 membered heteroaryl); or wherein 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;
R138 is independently selected from (a) H and (b) Ci-6 alkyl;
R141, R142, R143, and R144 at each occurrence, independently is selected from (a) H, (b) C1 -6 alkyl, (c) -(CH2)H1(C6-C1 oaryl), and (d) -(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, independently is selected from 0, 1, 2, and 3 such that a 4-7 membered saturated ring is formed that optionally that 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 (a) O, (b) S and (c) -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 at each occurrence, independently is selected from (a) H, (b) Cr6 alkyl, (c) C2-C6 alkenyl, and (d) C2-C6 alkynyl, wherein the foregoing R139 groups, except H, are optionally substituted by 1, 2, or 3 substituents independently selected from halogen and -OR138; R140 at each occurrence is independently selected from (a) halogen, (b) cyano,
(c) nitro, (d) trifluoromethyl, (e) azido, (f) -C(O)R145, (g) -C(O)OR145, (h) - OC(O)OR145, (i) -NR146C(O)R147, (j) -NR146R147, (k) -OH, (1) Cr6 alkyl, (m) Cr6 alkoxy, (n) -(CH2)V(C6-C1OaTyI), and (o) -(CH2)v(5-10 membered heteroaryl), wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from (a) halogen, (b) cyano, (c) nitro, (d) trifluoromethyl, (e) azido, (f) -C(O)R145, (g) -C(O)OR145, (h) -OC(O)OR145, (i) -NR146C(O)R147, (j) - C(O)NR146R147, (k) -NR146R147, (1) -OH, (m) Ci-6alkyl, and (n) Cr6 alkoxy;
R145 at each occurrence, independently is selected from (a) H, (b) Cr6 alkyl, (c) C2-C6 alkenyl, (d) C2-C6 alkynyl, (e) -(CH2)v(C6-C10aryl), and (f) -(CH2)v(5-10 membered heteroaryl);
R146 and R147 at each occurrence, independently is selected from (a) H, (b) hydroxyl, (c) Cr6 alkoxy, (d) Cr6 alkyl, (e) C2-6 alkenyl, (f) C2-6 alkynyl, (g) - (CH2)v(C6-10 aryl), and (h) -(CH2)v(5-10 membered heteroaryl); R148 at each occurrence, independently is selected from (a) Cr6 alkyl, (b) C3-12 saturated, unsaturated, or aromatic carbocycle, wherein said carbocycle is further optionally substituted with one or more R114, and (c) 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, independently is selected from 0, 1, and 2; k, at each occurrence, independently is selected from 0, 1, and 2; m, at each occurrence, independently is selected from O, 1, 2, 3, 4, and 5; n, at each occurrence, independently is selected from 1, 2, and 3; r, at each occurrence, independently is selected from O, 1, and 2; t, at each occurrence, independently is selected from O, 1, and 2; v, at each occurrence, independently is selected from O, 1, 2, 3, and 4; q, at each occurrence, independently is selected from O, 1, 2, and 3; and u at each occurrence, independently is selected from 1, 2, 3, and 4. In other embodiments, the present invention relates to a compound, wherein T is a macrolide selected from TA1-TA24:
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein M, Q, R104, R114, R126, R127, R128, R129, R149, and R15Ve 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 Tl through T93:
Figure imgf000060_0002
Figure imgf000060_0003
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000062_0001
T17 T18
Figure imgf000062_0002
T19 T20
Figure imgf000062_0003
T21 T22
Figure imgf000063_0001
Figure imgf000063_0002
T29
T30
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003
Figure imgf000065_0001
Figure imgf000065_0002
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0003
Figure imgf000067_0001
T57
T58
Figure imgf000067_0002
T59
T60
Figure imgf000067_0003
T61
T62
Figure imgf000068_0001
T63
T64
Figure imgf000068_0002
T65
T66
Figure imgf000068_0003
T67
T68
Figure imgf000069_0001
T69
T70
Figure imgf000069_0002
T71
T72
Figure imgf000069_0003
T73
T74
Figure imgf000070_0001
Figure imgf000070_0002
T77 T78
Figure imgf000070_0003
Figure imgf000071_0001
T83 T84
Figure imgf000071_0002
T88 T89 T90
Figure imgf000072_0001
T91 T92 and
Figure imgf000072_0002
T93
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. hi 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. hi 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. hi 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, 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.
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.
In 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.
In 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 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 wherein the compound of the invention, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, is administered orally, otically, opthalmically, nasally, parentally, or topically. hi 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 present invention relates to a medical device, wherein the 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; and 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 depict exemplary chemistries available for synthesizing the compounds of the invention. Scheme 1 illustrates the typical general synthesis of the macrolide compounds of the present invention.
The synthesis starts with a known macrolide core component such as, for example, erythromycin, azithromycin, clarithromycin, roxithromycin, telithromycin, etc. The macrolide core component is then converted to the 3'-N-desmethyl macrolide compound. For example, erythromycin can be converted to the 3'-N-desmethyl compound as described in the scientific and patent literature. See 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; Stenmark et al. (2000) J. Org. Chem. 65: 3875). Analogous chemical procedures can be used to convert azithromycin, clarithromycin, roxithromycin, telithromycin, and other macrolide core components to their corresponding 3'-N-desmethyl compounds. The 3'-N-desmethyl compounds can be further modified to provide yet further 3'-N-desmethyl compounds for use herein.
The 3'-N-desmthyl macrolide compound is alkylated with an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, bromide, etc.) to yield a 3'-N-alkyl ester compound. For example, terminal halogenated esters such as terminal bromo esters can be used. The 3'-N-alkyl ester compounds are then reacted with the desired amine to yield the final desired macrolide compound. Typically, the 3'-N-alkyl ester compound is first converted to a 3'-N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction with the desired amino compound to couple the two components via an ester linkage.
Scheme 1
The general reaction steps of scheme 1 can be described as follows: Macrolide Core Compound -> Desmethyl Macrolide Desmethyl Macrolide + Terminally Substituted Ester →- N-Alkyl Ester Compound N-Alkyl Ester Compound -> N-Alkyl Carboxylic Acid N-Alkyl Carboxylic Acid + Amino Compound — > Final Macrolide Compound The following is an illustration of Scheme 1 using erythromycin as a starting material (analogous reactions can be run starting with other macrolide compounds such as azithromycin, clarithromycin, roxithromycin, etc.)- The variables G, X, R\ Rb, Rc, Rd, and Re are as defined above,
Figure imgf000077_0001
Erythromycin N-Desmethyl Erythromycin
Figure imgf000077_0002
Terminal Halogentated Ester
Figure imgf000077_0003
N-Alkyl Ester
Figure imgf000077_0004
N-Alkyl Carboxylic Acid Li Salt
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, NJ.) 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 "hydro gel" 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 OfIC50S 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 PD50 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, parasitic diseases, diarrhea, 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 oral or parenteral, for example, otic, ophthalmic, intravenous, intradermal, inhalation/nasal, 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 efhylenediaminetetraacetic 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 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 oral, otic, ophthalmic, topic, or nasal 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 orally, otically, opthalmically, nasally, 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 chromatography" 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: h or 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 = milliliters); Et2O = diethyl ether; THF = tetrahydrofuran; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; Et3N = triethylamine; /-Pr2NEt or DIPEA = diisopropylethylamine; CH2Cl2 = methylene chloride; CHCl3 = chloroform; CDCl3 = deuterated chloroform; CCl4 = 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,l'- 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 imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
354 1081.0
Figure imgf000143_0001
355 1153.0
Figure imgf000143_0002
356 1123.0
Figure imgf000143_0003
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
462 558.2O=1
Figure imgf000176_0001
463 550.60*
Figure imgf000176_0002
464 549.90*
Figure imgf000176_0003
Figure imgf000177_0001
In the present invention, the variable G is further selected from -B' or -B'-Z-B". Tables IA- II 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 imgf000178_0001
This fragment would then be attached to B', as shown immediately below.
Figure imgf000178_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 imgf000178_0003
Exemplary macrolide compound of the present invention showing variable G.
Figure imgf000179_0001
Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-E
Figure imgf000179_0002
Exemplary macrolide compound of the present invention showing variable G selected form -B'-Z-B wherein B' is phenyl.
Figure imgf000180_0001
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 imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_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 5O0C 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 CH2Cl2ZMeOHZNH4OH 18:1:0.05 to 10:1:0.05 to provide the 3'-N-desmethyl azithromycin (0.41 g, 55%).
Example 3: Synthesis of 3'-iV-desmethyI 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 55-6O0C. Iodine (0.33O g, 1.3 mmol) was added portion- wise and the reaction stirred at 55-6O0C 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 (85Omg, 0.914mmol, 90%) and NaOAc (828mg, lO.OOOmmol) in a mixture of MeOH (6.OmL) and water (1.5mL) at 48°C was added I2 in four portions (each portion: 63.5mg) over 30min, after each portion I2, followed by IN NaOH (400μL). The reaction was continued for 30min. The solvent was removed and EtOAc (10OmL) was added, followed by water (2OmL). The organic phase was washed with brine (40mLX2), dried with Na2SO4. The residue was separated by FC (6Z94Z0.2 MeOHZCH2Cl2ZNH4OH), gave 600mg of the 3'-N-desmethyl roxithromycin in 80% yield. LCMS (ESI) mZe 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 O0C 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) MZE; M+H+ 798.6. Example 6: Synthesis of 3'-N-DesmethyI 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-desemthyl 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.
Example 7: Synthesis of 3'-N-alkyl carboxylic acid ester substituted macrolide compounds from 3'-N-desmethyl macrolide compounds
The N-desmethyl macrolide compound is alkylated with an ester such as a terminally substituted ester having a suitable leaving group (e.g., halogen, tosylate, mesylate, bromide, etc.) to yield an N-alkyl ester compound. For example, terminal halogenated esters such as terminal bromo esters can be used. The N-alkyl ester compounds are then reacted with the desired amine to yield the final desired macrolide compound. Typically, the N-alkyl ester compound is first converted to a N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction with the desired amino compound to couple the two components via an ester linkage.
3'-iV-propylcarboxylic acid ethyl ester of azithromycin
The following illustrates the preparation of 3'-N-propylcarboxylic acid ethyl ester of azithromycin from 3 '-N-desmethyl azithromycin and 3-bromopropionic acid ethyl ester.
Figure imgf000191_0001
10 g (13.6 mmol, 1 eq.) of 3 '-N-desmethyl azithromycin was dispensed in 25 ml of acetonitrile and 25 ml of Hunig's base followed by adding 12.3 g (68 mmol, 5 eq) of 3- bromopropionic acid ethyl ester. The resulting mixture was heated and kept reflux for about 8 hours. When TLC and LCMS showed no 3 '-N-desmethyl azithromycin was left, the reaction mixture was cooled to RT, washed with H2O and extracted with Ethyl Acetate. The organic layer was purified by column chromatography (SiO2, 0 - 5% MeOH/CH2Cl2 with about 0.15% NH4OH gradient elution) to afford 11.5 g of 3'-N-propylcarboxylic acid ethyl ester of azithromycin as yellow oil, LCMS (EI) mle 836 (M+ + H).
Examples 8-16: Synthesis of Compounds of the Present Invention from 3'-N-alkyl carboxylic acid ester substituted macrolide compounds
The 3'-N-alkyl ester compounds are then reacted with the appropriate amine to yield the final macrolide compound. Typically, the 3'-N-alkyl ester compound is first converted to a 3'-N-alkyl carboxylic acid salt, such as a lithium salt by reaction with LiOH in methanol, followed by reaction with the appropriate amino compound to couple the two components via an ester linkage.
Examples 8 and 9 Synthesis of Compounds 215 and 282
The following reaction scheme provides a synthesis that is generally applicable to the compounds of the present invention wherein the macrolide core is derived from azithromycin.
Figure imgf000192_0001
3'-N-propy lcarboxylic acid ethyl ester of azithromycin
Figure imgf000192_0002
3'-N-propylcarboxylic acid of azithromycinomycin
Figure imgf000193_0001
10 g (13.6 mmol, 1 eq.) of 3'-iV-desmethyl azithromycin was dispensed in 30 ml of acetonitrile and 30 ml of Hunig's base followed by adding 12.3 g (68 mmol, 5 eq) of 3- bromopropionic acid ethyl ester. The resulting mixture was heated and kept reflux for about 8 hours. When TLC and LCMS showed no 3'-N'-desmethyl azithromycin was left, the reaction mixture was cooled to RT, washed with H2O and extracted with Ethyl Acetate. The organic layer was purified by column chromatography (SiO2, 0 - 5% MeOH/CH2Cl2 with about 0.15% NH4OH gradient elution) to afford 11.5 g of 3'-N-propylcarboxylic acid ethyl ester of azithromycin as yellow oil, LCMS (EI) mle 836 (M+ + H). This ester was re-dissolved in 30 ml of THF, 10 ml of MeOH and 10 ml of H2O before 0.86 g (20.0 mmol, 1.5 eq) of LiOH was added. The resulting reaction mixture was stirred at RT for 2 hours. When TLC and LCMS showed no ester was left, H2O and diethyl ether were added to provide the acid compound in the aqueous layer and other impurities in organic layer. The aqueous layer was evaporated in vacuo with toluene. The dried residue was added CH2Cl2 to dissolve the acid, the solution was filtered to remove the insoluble Li salt and removed CH2Cl2 in vacuo to afford 8.2 g of 3'-N-propylcarboxylic acid as a white solid, LCMS (EI) mle 808 (M+ + H).
Synthesis of 215: 0.046 g (0.124 mmol, 1 eq) of 2-Amino-3-fluoro-l-[4-(6-methyl-pyridin-3-yl)- phenyl]-propan-l-ol TFA salt was added to the CH2Cl2 solution of 0.1 g (0,124 mmol, 1 eq.) of 3'-N-propylcarboxylic acid and 0.07 ml (0.4 mmol, 3 eq.) of Hunig's base. The solution was cooled down to 0 0C in an ice bath before 0.029 g (0.15 mmol, 1.2 eq) of EDCI and 0.017 g (0.124 mmol, 1.0 eq) of HOBt were added. The resulting solution was stirred at RT for about 4-6 hrs. When TLC and LCMS show no starting material was left, the mixture was directly go to preparative TLC to purify to afford 0.06g of 215, LCMS (EI) mle 1050 (M+ + H).
Synthesis of 282:
0.044 g (0.124 mmol, 1 eq) of 2-Amino-3-fluoro-l-(4-pyridin-3-yl-phenyl)-propan-l- ol TFA salt was added to the CH2Cl2 solution of 0.1 g (0,124 mmol, 1 eq.) of 3'-N- propylcarboxylic acid and 0.07 ml (0.4 mmol, 3 eq.) of Hunig's base. The solution was cooled down to 0 0C in an ice bath before 0.029 g (0.15 mmol, 1.2 eq) of EDCI and 0.017 g (0.124 mmol, 1.0 eq) of HOBt were added. The resulting solution was stirred at RT for about 4-6 hrs. When TLC and LCMS show no starting material was left, the mixture was directly go to preparative TLC to purify to afford 0.05g of 282, LCMS (EI) mle 1036 (M+ + H).
Examples 10 and 11 Synthesis of Compounds 329 and 350
The following reaction scheme provides a synthesis that is generally applicable to the compounds of the present invention wherein the macrolide core is derived from clarithromycin.
Figure imgf000194_0001
3'-N-propylcarboxylic acid ethyl
3'-N-desmethyl clarithromycin ester of clarithromycin
Figure imgf000194_0002
acid of clarithromycin
Figure imgf000195_0001
12 g (16.3 mmol, 1 eq.) of 3'-N-desmethyl clarithromycin was dispensed in 30 ml of acetonitrile and 30 ml of Hunig's base followed by adding 14.8 g (82 mmol, 5 eq) of 3- bromopropionic acid ethyl ester. The resulting mixture was heated and kept reflux for about 8 hours. When TLC and LCMS showed no 3'-N-desmethyl clarithromycin was left, the reaction mixture was cooled to RT, washed with H2O and extracted with Ethyl Acetate. The organic layer was purified by column chromatography (SiO2, 0 - 5% MeOHZCH2Cl2 with about 0.15% NH4OH gradient elution) to afford 10.5 g of the 3'-JV-propylcarboxylic acid ethyl ester of clarithromycin as yellow oil, LCMS (EI) mle 835 (M+ + H). This ester was redissolved in 30 ml of THF, 10 ml of MeOH and 10 ml OfH2O before 0.86 g (20.0 mmol, 1.5 eq) of LiOH was added. The resulting reaction mixture was stirred at RT for 2 hours. When TLC and LCMS showed no ester was left, H2O and diethyl ether were added to provide the acid in the aqueous layer and other impurities in the organic layer. The aqueous layer was evaporated in vacuo with toluene. The dried residue was added CH2Cl2 to dissolve the acid, the solution was filtered to remove the insoluble Li salt and removed CH2Cl2 in vacuo to afford 8.5 g of S'-N-propylcarboxylic acid of clarithromycin as white solid, LCMS (EI) mle 807 (M+ + H).
Synthesis of 329:
0.046 g (0.124 mmol, 1 eq) of 2-Amino-3-fiuoro-l-[4-(6-methyl-pyridin-3-yl)-phenyl]- propan-1-ol TFA salt was added to the CH2Cl2 solution of 0.1 g (0,124 mmol, 1 eq.) of 3'-N- propylcarboxylic acid of clarithromycin and 0.07 ml (0.4 mmol, 3 eq.) of Hunig's base. The solution was cooled down to 0 0C in an ice bath before 0.029 g (0.15 mmol, 1.2 eq) of EDCI and 0.017 g (0.124 mmol, 1.0 eq) of HOBt were added. The resulting solution was stirred at RT for about 4-6 hrs. When TLC and LCMS show no starting material was left, the mixture was directly go to preparative TLC to purify to afford 0.055g of 329, LCMS (EI) mle 1049 (M+ + H).
Synthesis of 350:
0.044 g (0.124 mmol, 1 eq) of 2-Amino-3-fluoro-l-(4-pyridin-3-yl-phenyl)-propan-l-ol TFA salt was added to the CH2Cl2 solution of 0.1 g (0,124 mmol, 1 eq.) of 3'-N-propylcarboxylic acid of clarithromycin and 0.07 ml (0.4 mmol, 3 eq.) of Hunig's base. The solution was cooled down to 0 0C in an ice bath before 0.029 g (0.15 mmol, 1.2 eq) of EDCI and 0.017 g (0.124 mmol, 1.0 eq) of HOBt were added. The resulting solution was stirred at RT for about 4-6 hrs. When TLC and LCMS show no starting material was left, the mixture was directly go to preparative TLC to purify to afford 0.045g of 350, LCMS (EI) mle 1035 (M+ + H).
Example 12: Synthesis of Compound 242
The following scheme 1 depicts the synthesis of the amine compound 5 used in the synthesis of Compound 242. Scheme 1
Figure imgf000196_0001
Figure imgf000196_0002
Pd(PPh3)4, LiCl Na2CO3, H2O EtOH, PhMe
Figure imgf000196_0003
Preparation of Compound 2 A mixture of 1 (0.835 g, 2.74 mmol) and triphenylphosphine (0.863 g, 3.29 mmol) in THF (12 mL) was stirred at ambient temperature for 3 h then at 60 0C for 10 min. After this time, the reaction was treated with water (3 mL) and stirred at 60 °C for 2 h. The mixture was cooled to ambient temperature, treated with triethylamine (0.277 g, 2.74 mmol) and di-tert- butyldicarbonate (0.657 g, 3.01 mmol) and stirred at ambient temperature for 18 h. After this time, the reaction was concentrated under reduced pressure and the residue obtained was purified by chromatography (silica, heptane to 1 :9 ethyl acetate/heptane) to afford 2 (0.753 g, 72%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.64 (m, 2H), 6.99 (d, J= 8.1 Hz, 2H), 4.73 (m, IH), 4.47-4.37 (m, IH), 4.32^.22 (m, IH), 3.99-3.90 (m, IH), 2.80 (m, 2H), 1.42 (s, 9H).
Preparation of Compound 4 A mixture of 2 (0.150 g, 0.396 mmol), 3 (0.065 g, 0.475 mmol), lithium chloride (0.050 g, 1.17 mmol) and a 2.0 M aqueous solution of sodium carbonate (0.700 mL, 1.40 mmol) in ethanol (1.5 mL) and toluene (1.5 mL) was sparged with argon with stirring for 10 min. The reaction was treated with tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.0396 mmol), heated to reflux and stirred at reflux under argon for 13.5 h. After this time, the reaction was cooled to ambient temperature and diluted with ethyl acetate (100 mL). The resulting mixture was filtered through diatomaceous earth and the filtrate was washed with brine (100 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 2:3 ethyl acetate/heptane) to afford 4 (0.093 g, 68%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.71 (d, J= 2.4 Hz, IH), 7.76 (dd, J= 8.1, 2.4 Hz, IH), 7.52 (d, J = 8.1 Hz, 2H), 7.33 (d, J= 8.1 Hz, 2H), 7.22 (d, J= 8.1 Hz, IH), 4.79 (br d, J= 7.5 Hz, IH), 4.52-4.41 (m, IH), 4.37-4.26 (m, IH), 4.10-3.97 (m, IH), 2.94 (m, 2H), 2.60 (s, 3H), 1.42 (s, 9H); ESI MS m/z 345 [M + H]+.
Preparation of Compound 5
A mixture of 4 (0.093 g, 0.270 mmol) in trifluoroacetic acid (3 mL) and methylene chloride (3 mL) was stirred at ambient temperature for 45 min. After this time, the reaction was concentrated under reduced pressure, diluted with methylene chloride (30 mL), washed with 2 M aqueous sodium hydroxide (20 mL) and the aqueous layer was extracted with methylene chloride (2 x 20 mL). The combined organics were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford 5 (0.067 g, 100%) as a brown oil: APCI MS m/z 245 [M + H]+.
The following Scheme 2 depicts the synthesis of 242 from the lithium salt of the 3'-N- propylcarboxylic acid of azithromycin.
Figure imgf000198_0001
7 242
Preparation of Compound 7 (242)
A solution of 6 (0.220 g, 0.270 mmol), 5 (0.066 g, 0.270 mmol), O-(benzotriazol-l-yl)- N, N.N'N'-tetramethyluronium hexafluorophosphate (0.110 g, 0.300 mmol) and N,N- diisopropylethylamine (0.140 g, 0.108 mmol) in DMF (2.7 mL) was stirred at ambient temperature for 15 h. After this time, the reaction was diluted with ethyl acetate (50 mL), washed with water (2 x 25 mL) and then 5% aqueous lithium chloride (2 x 25 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparatory thin-layer chromatography (silica, 4:1 ethyl acetate/triethylamine), then again by preparatory thin-layer chromatography (silica, 19:1 methylene chloride/7 M ammonia in methanol). The residue obtained was lyophilized from acetonitrile/water to afford 7 (0.140 g, 51%) as white solid (mixture of oxime isomers): mp 112-120 °C; 1H NMR (DMSO-J6) consistent, attached; HPLC (Method 1) 98.6% (AUC), tκ = 4.74 min. LCMS >99% (AUC), tR = 4.88 min, m/z 1033 [M + H]+.
Example 13: Synthesis of Compound 321
The following scheme 1 depicts the synthesis of the amine compound 5 used in the synthesis of Compound 321. Scheme 1
Figure imgf000199_0001
Na2CO3, H2O EtOH, PhMe
Figure imgf000199_0002
Preparation of Compound 2
A mixture of 1 (5.00 g, 16.9 mmol) and di-tert-buty\ dicarbonate (3.69 g, 16.9 mmol) in acetonitrile (85 mL) was stirred at 50 °C for 1.5 h. After this time, the reaction was concentrated under reduced pressure and the residue obtained was purified by chromatography (silica, heptane to 2:3 ethyl acetate/heptane) to afford 2 (6.21 g, 93%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J= 8.4 Hz, 2H), 7.13 (d, J= 8.1 Hz, 2H), 5.02 (m, IH), 4.90 (t, J= 4.5 Hz, IH), 4.60-4.30 (m, 2H), 3.98-3.86 (m, IH), 3.00 (br s, IH), 1.39 (br s, 9H); APCI MS m/z 394 [M + H]+.
Preparation of Compound 4
A mixture of 2 (0.602 g, 1.52 mmol), 3 (0.249 g, 1.82 mmol), lithium chloride (0.193 g, 4.56 mmol) and a 2.0 M aqueous solution of sodium carbonate (2.66 mL, 5.32 mmol) in ethanol (6 mL) and toluene (6 mL) was sparged with argon with stirring for 10 min. The reaction was treated with tetrakis(triphenylphosphine)palladium(0) (0.176 g, 0.152 mmol), heated to reflux and stirred at reflux under argon for 2.25 h. After this time, the reaction was cooled to ambient temperature and diluted with ethyl acetate (100 mL). The resulting mixture was filtered through diatomaceous earth and the filtrate was washed with brine (100 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 3:1 ethyl acetate/heptane) to afford 4 (0.402 g, 73%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J= 1.8 Hz, IH), 7.75 (dd, J= 8.1, 2.4 Hz, IH), 7.52 (d, J= 8.4 Hz, 2H), 7.47 (d, J= 8.1 Hz, 2H), 7.22 (d, J= 8.1 Hz, IH), 5.12 (br d, J= 7.8 Hz, IH), 5.00 (t, J= 3.9 Hz, IH), 4.66-4.35 (m, 2H), 4.06-3.96 (m, IH), 3.48 (br s, IH), 2.60 (s, 3H), 1.39 (br s, 9H); APCI MS m/z 361 [M + H]+.
Preparation of Compound 5 A mixture of 4 (0.204 g, 0.566 mmol) in trifluoroacetic acid (3 mL) and methylene chloride (3 mL) was stirred at ambient temperature for 45 min. After this time the reaction was concentrated under reduced pressure, diluted with methylene chloride (30 mL), washed with 2 M aqueous sodium hydroxide (25 mL) and the aqueous layer was extracted with methylene chloride (25 mL). The combined organics were dried over sodium sulfate, filtered and the filter pad was rinsed with a small amount of methanol. The filtrate was concentrated under reduced pressure then solvent exchanged with toluene (10 mL) to afford 4 (0.275 g, 84.6% pure by mass, 84%) as a brown sticky foam: 1H NMR (300 MHz, DMSO-J6) δ 8.82 (d, J= 2.1 Hz, IH), 8.36 (br s, 3H), 8.08 (dd, J= 8.1, 2.4 Hz, IH), 7.78 (d, J= 8.1 Hz, 2H), 7.53 (d, J= 8.4 Hz, 2H), 7.43 (d, J= 8.1 Hz, IH), 6.49 (br s, IH), 4.78 (d, J= 8.7 Hz, IH), 4.65^.17 (m, 2H), 3.65-3.58 (m, IH), 3.17 (s, IH), 2.55 (s, 3H); ESI MS m/z 261 [M + H]+.
The following Scheme 2 depicts the synthesis of the lithium salt of the 9-iV-methoxy oxime of clarithromycin.
Scheme 2
Figure imgf000201_0001
11
Preparation of Compound 7
A mixture of 6 (25.7 g, 34.3 mmol) and sodium bicarbonate (43.3 g, 515 mmol) in toluene
(130 mL) was stirred in a 60 °C oil bath and treated with benzyl chloroformate (81.8 g, 480 mmol) in a dropwise fashion. The resulting mixture was stirred at 60 °C for 2.5 h then allowed to cool to ambient temperature overnight. After this time, the reaction was purified directly through a short pad of silica (heptane to 7:3 ethyl acetate/heptane) to afford 7 (33.6 g, 98%) as a white foam: 1H NMR (300 MHz, CDCl3) consistent, attached.
Preparation of Compound 8
A mixture of 7 (39.0 g, 38.9 mmol) and 10% palladium on carbon (10.0 g, 50% water by weight) in ethanol (40 mL) was reacted under a hydrogen atmosphere (45 psi) for 1 h. After this time, the reaction was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to afford 8 (26.2 g, 92%) as a white solid: 1H NMR (300 MHz, CDCl3) consistent, attached; ESI MS m/z 134 [M + H]+.
Preparation of Compound 9
A mixture of 8 (26.2 g, 35.7 mmol), ethyl-3-bromopriopionate (9.66 g, 53.4 mmol), NJl- diisopropylethylamine (100 mL) and acetonitrile (100 mL) was stirred in a 90 °C oil bath for 23 h. The reaction was treated with additional ethyl-3-bromopriopionate (3.22 g, 17.8 mmol) then stirred at reflux for 4 h. After this time, the reaction was cooled to ambient temperature, diluted with methylene chloride (1.5 L) and washed with water (1 L) then brine (1 L). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1 :24 methanol/methylene chloride) then recrystallized from methylene chloride/heptane to afford 7 (24.2 g, 81%) as a white solid: 1H NMR (300 MHz, CDCl3) consistent, attached; ESI MS m/z 834 [M + H]+.
Preparation of Compound 10
A mixture of 9 (4.00 g, 4.80 mmol), methoxylamine hydrochloride (6.00 g, 71.9 mmol) and aniline (6.70 g, 71.9 mmol) in methanol (60 mL) was stirred at 50 °C for 5 hours and then at ambient temperature for 12 h. After this time, the reaction was concentrated under reduced pressure to a small volume of methanol and the resulting mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The resulting suspension was filtered through diatomaceous earth, the solids obtained were set aside and the filtrate was washed with brine (200 mL). The organic layer was combined with a solution of the above solids in methanol and the combined organics were dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 9:1 methylene chloride/methanol) to afford 10 (3.62 g, 87%) as an off-white solid that was used without further purification (mixture of oxime isomers): 1H NMR (CDCl3) consistent, attached.
Preparation of Compound 11
A mixture of 10 (1.86 g, 2.16 mmol) and lithium hydroxide monohydrate (0.095 g, 2.26 mmol) in a 8:3:3 mixture of 1,4-dioxane, methanol and water (14 mL) was stirred at ambient temperature for 20 h. The reaction was treated with additional lithium hydroxide monohydrate (0.020 g, 0.477 mmol) and water (1 mL) stirred for an additional 24 h. After this time, the volatiles were removed under reduced pressure and the resulting suspension was lyophilized to afford 11 (1.74 g, 96%) as a white solid that was used without further purification (mixture of oxime isomers): 1H NMR (DMSO-J6) consistent, attached.
The following Scheme 3 depicts the synthesis of 321 from the lithium salt of the 3'-N- propylcarboxylic acid of the 9-Ν-methoxy oxime of clarithromycin.
Scheme 3
Figure imgf000203_0001
H 12
321
Preparation of Compound 12 (321)
A solution of 11 (0.384 g, 0.457 mmol), 5 (0.264 g, 0.457 mmol), O-(benzotriazol-l-yl)- NNN'N'-tetramethyluronium hexafluorophosphate (0.182 g, 0.480 mmol), N,N- diisopropylethylamine (0.354 g, 2.74 mmol) in DMF (4 mL) was stirred at ambient temperature for 1.5 h. The reaction was treated with additional O-(benzotriazol-l-yl)- N,N,N'N'-tetramethyluronium hexafluorophosphate (0.182 g, 0.480 mmol) and stirred for an additional 18 h. After this time, the reaction was diluted with ethyl acetate (60 mL), washed with water (60 mL) then 5% aqueous lithium chloride (2 * 60 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparatory thin-layer chromatography (silica, 1:1 :4 triethylamine/heptane/ethyl acetate) then again by preparatory high pressure liquid chromatography (Method 1). The residue obtained was lyophilized from acetonitrile/water to afford 12 (0.084 g, 17%) as white solid (mixture of oxime isomers): mp 133-148 0C; 1H ΝMR (500 MHz, DMSO-J6) consistent, attached; HPLC (Method 1) 97.6% (AUC), *R = 5.87 and 6.26 min. LCMS (Method 1) >99% (AUC), tR = 4.62 and 4.90 min, m/z 1077 [M + H]+.
Example 14: Synthesis of Compound 323 The following scheme 1 depicts the synthesis of the amine compound 4 used in the synthesis of Compound 323. Scheme 1
Figure imgf000204_0001
Preparation of Compound 3
A mixture of 1 (0.592 g, 1.50 mmol), 2 (0.221 g, 1.80 mmol), lithium chloride (0.191 g, 4.50 mmol) and a 2.0 M aqueous solution of sodium carbonate (2.63 mL, 5.25 mmol) in ethanol (6 mL) and toluene (6 mL) was sparged with argon with stirring for 10 min. The reaction was treated with tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.150 mmol), heated to reflux and stirred at reflux under argon for 2.5 h. After this time, the reaction was cooled to ambient temperature and diluted with ethyl acetate (100 mL). The resulting mixture was filtered through diatomaceous earth and the filtrate was washed with brine (100 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 13:7 ethyl acetate/heptane) to afford 3 (0.410 g, 79%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J= 1.8 Hz, IH), 8.57 (dd, J= 4.8, 1.5 Hz, IH), 7.85 (dt, J= 8.1, 1.8 Hz, IH), 7.57- 7.48 (m, 4H), 7.39-7.34 (m, IH), 5.30 (m, IH), 5.12 (m, IH), 4.66-4.35 (m, 2H), 4.07-3.97 (m, IH), 3.52 (br s, IH), 1.39 (br s, 9H); APCI MS m/z 347 [M + H]+.
Preparation of Compound 4
A solution of 3 (0.200 g, 0.580 mmol) in 1,4-dioxane (2 mL) was treated with a 4 N solution of hydrogen chloride in 1,4-dioxane (2.20 mL, 8.80 mmol) and the resulting mixture was stirred at room temperature for 2.5 h. After this time, the reaction was concentrated under reduced pressure and the residue obtained was diluted with benzene (5 mL) and concentrated under reduced pressure to afford 4 (0.163 g, 90%) as an orange-yellow solid that was used without further purification: 1H NMR (500 MHz, DMSO-J6) δ 9.29-9.21 (m, IH), 8.91-8.84 (m, IH), 8.79-8.73 (m, IH), 8.56-8.55 (m, 3H), 8.10-7.99 (m, IH), 7.97-7.88 (m, 2H), 7.66- 7.57 (m, 2H), 6.95-6.08 (m, IH), 4.85^.79 (m, IH), 4.68^.23 (m, 2H), 3.96-3.52 (m, 2H). The following Scheme 2 depicts the synthesis of 323 from the lithium salt of the 3'- TV-propylcarboxylic acid of the 9-N-methoxy oxime of clarithromycin. Scheme 2
Figure imgf000205_0001
6
323 Preparation of Compound 6 (323)
A solution of 5 (0.105 g, 0.126 mmol), 4 (0.040 g, 0.126 mmol), 0-(benzotriazol-l-yl)- N,iV,N'iV'-tetramethyluronium hexafluorophosphate (0.052 g, 0.138 mmol) and N,N- diisopropylethylamine (0.097 g, 0.754 mmol) in DMF (2 mL) was stirred at ambient temperature for 18 h. After this time, the reaction was diluted with ethyl acetate (30 mL), washed with 5% aqueous lithium chloride (2 x 15 mL), water (15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparatory thin-layer chromatography (silica, 19:1 methylene chloride/7 M ammonia in methanol), then lyophilized from acetonitrile/water to afford 6 (0.060 g, 45%) as white solid (mixture of oxime isomers): mp 140-158 0C; 1H ΝMR (DMSO-^6) consistent, attached; HPLC (Method 1) 98.1% (AUC), tR = 5.89, 6.25 min. LCMS (Method 1) >99% (AUC), tR = 4.73, 5.02 min, m/z 1063 [M + H]+.
Example 15: Synthesis of Compound 342
The following scheme 1 depicts the synthesis of the amine compound 4 used in the synthesis of Compound 342. Scheme 1
Figure imgf000206_0001
Preparation of Compound 3
A mixture of 1 (1.30 g, 2.57 mmol), 2 (0.579 g, 3.08 mmol), lithium chloride (0.327 g, 7.71 mmol) and a 2.0 M aqueous solution of sodium carbonate (4.50 mL, 9.00 mmol) in ethanol (10.3 mL) and toluene (10.3 mL) was sparged with argon with stirring for 10 min. The reaction was treated with tetrakis(triphenylphosphine)palladium(0) (0.297 g, 0.257 mmol), heated to reflux and stirred at reflux under argon for 3 h. After this time, the reaction was cooled to ambient temperature and diluted with ethyl acetate (75 mL). The resulting mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to ethyl acetate) to afford 3 (0.523 g, 54%) as a light yellow solid: 1H NMR (300 MHz, DMSO-^6) δ 8.77 (d, J= 2.0 Hz, IH), 8.06 (dd, J= 8.1, 2.3 Hz, IH), 7.67 (d, J= 8.3 Hz, 2H), 7.54 (d, J= 8.2 Hz, IH), 7.43 (d, J= 8.1 Hz, 2H), 6.60 (d, J= 8.9 Hz, IH), 5.57 (d, J= 5.3 Hz, IH), 5.45 (t, J= 5.8 Hz, IH), 4.79 (t, J= 4.8 Hz, IH), 4.61-4.16 (m, 4H), 3.94 (m, IH), 1.28-1.09 (m, 9H); APCI MS m/z 311 [M + H]+.
Preparation of Compound 4
A mixture of 3 (0.270 g, 0.717 mmol) in trifluoroacetic acid (20 mL) and methylene chloride (20 mL) was stirred at ambient temperature for 1 h. After this time, the reaction was concentrated under reduced pressure, diluted with methylene chloride (50 mL), washed with 2 M aqueous sodium hydroxide (50 mL) and the aqueous layer was extracted with methylene chloride (50 mL). The combined organics were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford 4 (0.287 g, 92% pure by mass, 94%) as a brown solid that was used without further purification.
The following scheme 2 depicts the synthesis of a further intermediate in the synthesis of Compound 342. Scheme 2
° BnOH °
Br" ^ "Cl Br" v ^OBn
Et3N
5 CH2Cl2 6
Figure imgf000207_0001
Preparation of Compound 6 A solution of 5 (17.0 g, 99.2 mmol) in methylene chloride (80 mL) was cooled to 0 °C and treated with a solution of benzyl alcohol (11.8 g, 109 mmol) and triethylamine (10.1 g, 99.0 mmol) in methylene chloride (40 mL) in a dropwise fashion. The resulting mixture was stirred at 0 0C for 20 min and then allowed to warm to ambient temperature over 2 h. After this time, water (150 mL) was added to the reaction mixture and the organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, hexanes to 4:1 ethyl acetate/hexanes) to afford 6 (11.0 g, 46%) as colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 5.17 (s, 2H), 3.59 (t, J= 6.9 Hz, 2H), 2.97 (t, J= 6.9 Hz, 2H).
Preparation of Compound 8
A mixture of 7 (30.0 g, 184 mmol) and N^V-diisopropylethylamine (61.8 g, 478mmol) in DMF (200 mL) was treated with chloromethyl methyl ether (19.3 g, 239 mmol) and the resulting mixture was stirred at ambient temperature for 2.5 h. After this time, the reaction was diluted with ethyl acetate (2.5 L), then washed with water (2 x 2.5 L), 5% aqueous lithium chloride (2 x 2.5 L) then brine (2.5 L). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to a volume of -150 mL. The resulting suspension was treated with heptane (150 mL), stirred for 15 min and the solids were collected by filtration and washed with heptane (200 mL) to afford 8 (29.9 g, 78%) as a white solid. The solids that had formed in the filtrate were collected by filtration and washed with heptane to afford additional 8 (1.81 g, 5%) as a white solid. Both lots were used without further purification.
Preparation of Compound 9
A mixture of 8 (33.6 g, 162 mmol) in methylene chloride (250 mL) and methanol (25 mL) was cooled to 0 0C and treated with hydrazine (10.4 g, 324 mmol) and the resulting mixture was stirred at ambient temperature for 5 h. After this time, the reaction was filtered through diatomaceous earth and the filter cake was washed with methylene chloride (100 ml) then methanol (100 mL). The filtrate was concentrated under reduced pressure to a volume of -100 mL and again filtered through diatomaceous earth. The filtrate was treated with a 2 Ν solution of hydrogen chloride in diethyl ether (100 mL) and the resulting mixture was stirred at ambient temperature for 5 min. The resulting suspension was treated with methanol (200 mL), stirred for 5 min and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure until solids began to form. The resulting suspension was treated with diethyl ether (200 mL) and the solids were collected by filtration to afford 9 (11.1 g, 30%) as a white solid that was used immediately without further purification.
The following Scheme 3 depicts the synthesis of the 9-MOM-oxime of the 3'-N- propylcarboxylic acid of clarithromycin. Scheme 3
Figure imgf000209_0001
10 11
Figure imgf000209_0002
12 13
Preparation of Compound 11 A mixture of 10 (2.80 g, 3.82 mmol), 6 (1.50 g, 6.17 mmol), N^V-diisopropylethylamine (12 mL) and acetonitrile (12 mL) was stirred in a 90 °C oil bath for 16 h. After this time, the reaction was cooled to ambient temperature, diluted with methylene chloride (300 mL) and washed with water (150 mL) then brine (100 mL). The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 3:7 [1 :9:40 concentrated ammonium hydroxide/methanol/chloroform]/methylene chloride) to afford 11 (3.05 g, 92%) as a white solid: 1H ΝMR (500 MHz, CDCl3) consistent, attached; ESI MS m/z 896 [M + H]+. Preparation of Compound 12
A mixture of 11 (4.30 g, 4.80 mmol), 6 (9.40 g, 82.8 mmol) and aniline (7.70 g, 82.8 mmol) in methanol (65 mL) was stirred at reflux for 45 min. After this time, the reaction was concentrated under reduced pressure, diluted with ethyl acetate (250 mL) and washed with water (2 x 150 mL) then brine (100 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:19 methanol/methylene chloride) to afford 12 (3.15 g, 68%) as an off-white foam: ESI MS m/z 955 [M + H]+.
Preparation of Compound 13
A mixture of 12 (0.755 g, 0.790 mmol) and 10% palladium on carbon (0.300 g, 50% water by weight) in ethanol (5 mL) and ethyl acetate (5 mL) was reacted under a hydrogen atmosphere (45 psi) for 30 min. After this time, the reaction was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure, then solvent exchanged with 1:1 methylene chloride/heptane (20 mL) to afford 13 (0.651 g, 95%) as a white solid: 1H NMR (300 MHz, DMSO-cfe) consistent, attached; ESI MS m/z 865 [M + H]+.
The following Scheme 4 depicts the synthesis of 342 from the 9-MOM oxime of the S'-N-propylcarboxylic acid of clarithromycin. Scheme 4
Figure imgf000210_0001
13 14 342 Preparation of Compound 14 (342)
A solution of 13 (0.231 g, 0.267 mmol), 4 (0.104 g, 0.267 mmol), 0-(benzotriazol-l-yl)- N,N,N',N-tetramethyluronium hexafluorophosphate (0.132 g, 0.347 mmol) and NJV- diisopropylethylamine (0.173 g, 1.34 mmol) in DMF (3 mL) was stirred at ambient temperature for 15 h. After this time, the reaction was diluted with ethyl acetate (30 mL), washed with water (2 x 25 mL) then 5% aqueous lithium chloride (2 x 25 mL). The organic layer was concentrated under reduced pressure and the residue obtained was triturated with ethyl acetate (10 mL). The solid that formed was collected by filtration, washed with ethyl acetate (2 x 3 mL) and purified by preparatory thin-layer chromatography (silica, 1 :9 7 M ammonia in methanol/methylene chloride) then again by preparatory high pressure liquid chromatography (Method 1). The residue obtained was lyophilized from acetonitrile/water to afford 14 (342) (0.061 g, 20%) as white solid (mixture of oxime isomers): mp 111-143 0C; 1H NMR (500 MHz, DMSO-^6) consistent, attached; HPLC (Method 1) 96.3% (AUC), tR = 5.79 and 5.95 min. LCMS (Method 1) 98.6% (AUC), tR = 4.65 and 4.76 min, m/z 1123 [M + H]+.
Example 16: Synthesis of Compound 380
The following scheme 1 depicts the synthesis of 380 from the 9-MOM oxime of the 3'-N-propylcarboxylic acid of clarithromycin. Scheme 1
Figure imgf000211_0001
2 380 Preparation of Compound 2 (380)
A solution of 1 (0.180 g, 0.208 mmol), 2 (0.066 g, 0.208 mmol), O-(benzotriazol-l-yl)- N,N,N',N-tetramethyluronium hexafluorophosphate (0.087 g, 0.229 mmol), and N1N- diisopropylethylamine (0.160 g, 1.25 mmol) in DMF (2 mL) was stirred at ambient temperature for 18 h. After this time, the reaction was diluted with ethyl acetate (30 mL), washed with 5% aqueous lithium chloride (2 x 15 mL), water (15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparatory thin-layer chromatography (silica, 19:1 methylene chloride/7 M ammonia in methanol), then lyophilized from acetonitrile/water to afford 2 (380) (0.063 g, 28%) as a white solid (mixture of oxime isomers): mp 135-150 0C; 1H NMR (DMSO-J6) consistent, attached; HPLC (Method 1) >99% (AUC), tR = 5.88, 6.03 min. LCMS (Method 1) >99% (AUC), tR = 4.74, 4.86 min, m/z 1093 [M + H]+.
Example 17 General procedure for the synthesis of the amines such as (2-Amino-3- fluoro-l-[4-(6-methyl-pyridin-3-yl)-phenyl]-propan-l-ol and 2-Amino-3-fluoro-l-(4- pyridin-3-yl-phenyl)-propan-l-ol TFA salt)
B(OH)2
Figure imgf000212_0001
Figure imgf000212_0002
0.25 g of 3-pyridine-boronic acid (2.02 mmol, 1 eq.), 0.8 g of [l-Fluoromethyl-2- hydroxy-2-(4-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (iodo-intermediate, 2.02 mmol, 1 eq.), 0.07 g of terrakis(triphenylphosphine)palladium(0) (0.061 mmol, 0.03 eq.) and 0.84 g OfK2CO3 (6.06 mmol, 3 eq.) was dispersed in Toluene/Ethanol/H2O (v/v/v = 3:1:1, total volume about 5 ml). The resulting reaction mixture was degassed and heated to 90 -100 0C for 4-5 hrs. When TLC and LCMS showing no starting material (the iodo-intermediate) left, the reaction mixture was cooled to RT, extracted with Ethyl acetate. The organic layer was removed solvent and the residue was directly put onto preparative TLC to purify to afford 0.664 g of Boc-protected amine, which was de-Boced with TFA in CH2Cl2 to afford the amine. Analogous reactions can be with other macrolide cores to prepare compounds of the present invention.
Amine compounds useful in the synthesis of the compounds of the present invention are readily made using generally known chemistries. Nonlimiting exemplary amino~ compounds are shown below in Table 2.
Table 2
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000215_0002
Figure imgf000215_0003
Figure imgf000215_0004
Figure imgf000215_0005
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000217_0002
Figure imgf000217_0003
Figure imgf000217_0004
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000222_0002
Figure imgf000222_0003
Figure imgf000222_0004
Figure imgf000223_0001
Figure imgf000224_0001
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
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
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 imgf000231_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A and B are selected such that, A is selected from the group consisting of (a) -(C=O)-, (b) -(C=S)-, (c) -(C=NR)-, (d) -(C=NOR)-, (e) -(C=NNRR)-, (f) -(S=O)-, (g) -(SO2)-, and (h) -[(3 or 4-membered ring carbocycle)-(C=O)]- and B is selected from the group consisting of -0-, -S-, and -NR-; or B is selected from the group consisting of (a) -(C=O)-, (b) -(C=S)-, (c) -(C=NR)-, (d) -(C=NOR)-, (e) -(C=NNRR)-, (f) -(S=O)-, (g) -(SO2)-, (h) -C(O)NR-, and (i) -[(3 or 4- membered ring carbocycle)-(C=O)]- and A is selected from the group consisting of -0-, -S-, and -NR-; 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) -NR4C(O)H, (j) -C(O)R5, (k) - C(O)OR5, (1) -C(O)-NR4R4, (m) -C(S)R5, (n) -C(S)OR5, (o) -C(O)SR5, (p) -C(S)-NR4R4, (q) -N3, (r) -CN, (s) -CF3, (t) -CF2H, (u) -CFH2, (v) -S(O)PH, (w) -SR5, (x) -S(O)POH, (y) -S(O)POR5, (z) -S(O)PNR4R4, (aa) -S(O)pC1-6 alkyl, (bb) -S(O)paryl, (cc) a C3-7 saturated, unsaturated, or aromatic carbocycle, and (dd) 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) C1-6 alkyl group, (c) C2-6 alkenyl group, (d) C2-6 alkynyl group, (e) -OH, (f) -OR5, (g) -NR4R4, (h) -C(O)R5, (i) -C(O)OR5, (j) -C(O)-NR4R4, (i) -C(S)pR5, (j) -C(S)POR5, (k) -C(O)SR5, (1) -C(S)P-NR4R4, (m) halogen, (k) -SH, (1) -SR5, (m) -N3, (n) -CN, (o) -NHC(O)H, and (p) -N(C1-6 alkyl)C(O)H;
Figure imgf000232_0001
Figure imgf000232_0002
Figure imgf000232_0003
280 or 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, wherein (b) -(d) are further optionally substituted with one or more R5 or alternatively Ra and Rb taken together with the carbon to which they are attached are absent; Rc is selected from: (a) H, (b) a C1-6 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(=O)R5, (h) -C(=O)OR5, (i) - C(=O)-NR4R4, (j) -S(O)pNR4 R4, (k) -C(O)SR5, (1) -S(O)11H, (m) - S(O)PR5, (n) CF3, (o) CF2H, and (p) CFH2, wherein any of (b) -(d) immediately above is 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, (j) -C(O)-NR4R4, (k) -C(S)R5, (1) -C(S)OR5, (m) -C(O)SR5, (n) -C(S)-NR4R4, and (o) halogen, or alternatively, Rc and R 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; R at each occurrence, independently is selected from (a) H, (b) C1-6 alkyl, (c) -OH, (d) -0-(C1-6 alkyl), (e) halogen, (f) -NH2, (g) -NH(C1-6 alkyl), (h) -N(C1-6 alkyl)2> (i) -(C1- C6)alkylaryl, O) -(C2-C6)alkenyl, (k) -(C1-C6)alkyl(OH)(C1-C6)alkyl, (1) -CH2F, (m) -CF3, (n) -(Ci-C6)alkyl(OH), and (n) -S(O)P(C1-C6 alkyl)-; 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 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; 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
231 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) immediately above optionally contains one or more carbonyl groups, and wherein each (aa) or (bb) immediately above optionally is substituted with one or more R11 or R1 la; ii) each B" is independently selected from (aa) -H, (bb) -OH, (cc) -OR9, (dd) -SH, (ee) -S(O)PR9, (S) halogen, (gg) -CN, (hh) -N3, (ii) - NO2, (jj) -Si(R13)3, (Wc) -SO3H, (11) -SO3N(R4)2, (mm) -SO3R9, (nn) - NR6R6, (oo) -C(O)R9, (pp) -C(O)(CR6R6)tR9, (qq) -OC(O)(CR6R6)tR9, (IT) -C(O)O(CR6R6)tR9, (ss) -NR6(CR6R6)tR9, (tt) -R6C(O)(CR6R6^R9, (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) -SCCR^R9, (aaa) - S(O)p(CR6R6)tR9, (bbb) a 3-12 membered saturated, unsaturated, or aromatic carbocyclic group having 1 to 3 rings, (ccc) 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, (ddd) -C1-6 alkyl, (eee) -C2-6 alkenyl, and (fff) a C2-6 alkynyl group; wherein each (bbb) or (ccc) immediately above optionally contains one or more carbonyl groups, and wherein each (bbb) or (ccc) immediately above optionally is substituted with one or more R11 or Rl la; wherein each (ddd), (eee), or (fff) immediately above optionally is substituted with one or more R14 groups; 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(O)-, (i) -C(O)O-, (j) - OC(O)- (k) -OC(O)O-, (1) -C(O)NR4-, (m) -NR4CO-, (n) - NR4C(O)NR4- (o) -C(=NR4)-, (p) - C(=NR4)O-, (q) - 0C(=NR4)-, (r) -C(=NR4)NR4-, (s) -NR4C(=NR4)-, (t) -C(=S)-, (u) -C(=S)NR4-, (v) -NR4C(=S)-, (w) -C(O)S- (x) -SC(O)-, (y) -OC(=S)-, and (z) - Q=S)-O-, wherein any of the aliphatic carbons atoms in (b), (c), or (d) immediately above is optionally replaced with -(C=O)-, -0-, -S-, or -
232 91 NR 4-, and wherein any of (b), (c), or (d), immediately above is
92 optionally further substituted with -OH, -NR4-, or halogen;
93 R14 at each occurrence is independently selected from:
94 (a) H, (b) F, (C) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)PR g8, Q) -
95 C(O)R8, (k) -C(O)OR8, (1) -OC(O)R8, (m) -C(O)NR8R8, (n) -OC(O)NR8R8,
96 (o) -C(=NR8)R8, (p) -C(R8)(R8)OR8, (q) -C(R8)2OC(O)R8, (r) -
97 C(R8)(OR8)(CH2)rNR8R8, (s) -NR8R8, (t) -NR8OR8, (u) -NR8C(O)R8, (v) -
98 NR8C(O)OR8, (w) -NR8C(O)NR8R8, (x) -NR8S(O)PR8, (y) -C(OR8)(OR8)R8,
99 (z) -C(R8)2NR8R8, (aa) -C(S)NR8R8, (bb) -NR8C(S)R8, (cc) -OC(S)NR8R8, OO (dd) -NR8C(S)OR8, (ee) -NR8C(S)NR8R8, (ff) -SC(O)R8, (gg) -N3, (hh) -01 Si(R13)3, (ii) a C1-6 alkyl group, (jj) a C2-6 alkenyl group, (kk) a C2-6 alkynyl02 group, (11) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (mm) a03 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one04 or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any05 of (ii)-(mm) immediately above is optionally substituted with one or more R506 groups; 07 alternatively two R14 groups are taken together to form (a) =O, (b) =S, (c)08 (d) =NR8, or (e) =NOR8; 09 R4, at each occurrence, independently is selected from: 10 (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group,11 (e) a C3-12 saturated, unsaturated, or aromatic carbocycle, (f) a 3-12 membered12 saturated, unsaturated, or aromatic heterocycle containing one or more13 heteroatoms selected from nitrogen, oxygen, and sulfur, (g) -C(O)-C1-6 alkyl, 14 (h) -C(O)-C2-6 alkenyl, (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-I2 saturated,15 unsaturated, or aromatic carbocycle, (k) -C(O)-3-12 membered saturated,16 unsaturated, or aromatic heterocycle containing one or more heteroatoms17 selected from nitrogen, oxygen, and sulfur, (1) -C(O)O-C1-6 alkyl, (m) - 18 C(O)O-C2-6 alkenyl, (n) -C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-12 saturated,19 unsaturated, or aromatic carbocycle, (p) -C(O)O-3-12 membered saturated,20 unsaturated, or aromatic heterocycle containing one or more heteroatoms21 selected from nitrogen, oxygen, and sulfur, and (q) -C(O)NR6R6, 22 wherein any of (b)-(p) immediately above optionally is substituted23 with one or more R5 groups,
233 124 alternatively, NR4R4 forms a 3-7 membered saturated, unsaturated or aromatic ring
125 including the nitrogen atom to which the R4 groups are bonded, wherein said ring is
126 optionally substituted at a position other than the nitrogen atom to which the R4 groups are
127 bonded, with one or more moieties selected from O, S(O)P, N, and NR8;
128 R5 at each occurrence, independently is selected from:
129 (a) R7, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group,
130 (e) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (f) a
131 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one
132 or more heteroatoms selected from nitrogen, oxygen, and sulfur, or
133 alternatively two R5 groups, when present on the same carbon atom can be
134 taken together with the carbon atom to which they are attached to form a spiro
135 3-6 membered carbocyclic ring or heterocyclic ring containing one or more
136 heteroatoms selected from nitrogen, oxygen, and sulfur;
137 wherein any of (b)-(f) immediately above optionally is substituted
138 with one or more R7 groups;
139 R6, at each occurrence, independently is selected from:
140 (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group,
141 (e) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12
142 membered saturated, unsaturated, or aromatic heterocycle containing one or
143 more heteroatoms selected from nitrogen, oxygen, and sulfur,
144 wherein any of (b)-(f) immediately above optionally is substituted
145 with one or more moieties selected from:
146 (aa) a carbonyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee)
147 Br, (ff) I, (gg) CN, (hh) NO2, (ii) -OR8, Oj) -S(O)pR8, (kk) -
148 C(O)R8, (11) -C(O)OR8, (mm) -OC(O)R8, (nn) -C(O)NR8R8,
149 (oo) -OC(O)NR8R8, (pp) -C(=NR8)R8, (qq) -C(R8)(R8)OR8,
150 (rr) -C(R8)2OC(O)R8, (ss) -C(R8)(OR8)(CH2)rNR8R8, (tt) -
151 NR8R8, (uu) -NR8OR8, (w) -NR8C(O)R8, (ww) -
152 NR8C(O)OR8, (xx) -NR8C(O)NR8R8, (yy) -NR8S(O)rR8, (zz) -
153 C(OR8)(OR8)R8, (ab) -C(R8)2NR8R8, (ac) =NR8, (ad) -
154 C(S)NR8R8, (ae) -NR8C(S)R8, (af) -OC(S)NR8R8, (ag) -
155 NR8C(S)OR8, (ah) -NR8C(S)NR8R8, (ai) -SC(O)R8, (aj) a
156 C1-6 alkyl group, (ak) a C2-6 alkenyl group, (al) a C2-6 alkynyl
157 group, (am) a C1-6 alkoxy group, (an) a C1-6 alkylthio group,
234 158 (ao) a Cj-6 acyl group, (ap) -CF3, (aq) -SCF3, (ar) a C3-I2
159 saturated, unsaturated, or aromatic carbocycle, and (as) a 3-12
160 membered saturated, unsaturated, or aromatic heterocycle
161 containing one or more heteroatoms selected from nitrogen,
162 oxygen, and sulfur,
163 alternatively, NR6R6 forms a 3-12 membered saturated, unsaturated or aromatic ring
164 including the nitrogen atom to which the R6 groups are attached wherein said ring is
165 optionally substituted at a position other than the nitrogen atom to which the R6 groups are
166 bonded, with one or more moieties selected from O, S(O)P, N, and NR ;
167 alternatively, CR6R6 forms a carbonyl group;
168 R7, at each occurrence, is selected from:
169 (a) H, (b) =0, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -N3 G) -NO2,
170 (k) -NR6(CR6R6)tR9, (1) -OR9, (m) -S(O)pC(R6R6)tR9, (n) -C(O)(CR6R6)tR9,
171 (o) -OC(O)(CR6R6)tR9, (p) -SC(O)(CR6R6)tR9, (q) -C(O)O(CR6R6)tR9, (r) -
172 NR6C(O)(CR6R6)tR9, (s) -C(O)NR6(CR6R6)tR9, (t) -C(=NR6)(CR6R6)tR9,
173 (u) -C(=NNR6R6)(CR6R6)tR9, (v) -C(=NNR6C(O)R6)(CR6R6)tR9, (w) -
174 C(=NOR9)(CR6R6)tR9, (x) -NR6C(O)O(CR6R6)tR9, (y) -
175 OC(O)NR6(CR6R6)tR9, (z) -NR6C(O)NR6(CR6R6)tR9, (aa) -
176 NR6S(O)p(CR6R6)tR9, (bb) -S(O)pNR6(CR6R6)tR9, (cc) -
177 NR6S(O)pNR6(CR6R6)tR9, (dd) -NR6R6, (ee) -NR6(CR6R6), (ff) -OH, (gg) -
178 NR6R6, (hh) -OCH3, (ii) -S(O)pR6, (jj) -NC(O)R6, (kk) -Si(R13)3, (11) a
179 Cj_6 alkyl group, (mm) a C2_6 alkenyl group, (nn) a C2.6 alkynyl group, (oo) -
180 C3-12 saturated, unsaturated, or aromatic carbocycle, and (pp) 3-12 membered
181 saturated, unsaturated, or aromatic heterocycle containing one or more
182 heteroatoms selected from nitrogen, oxygen, and sulfur,
183 wherein any of (kk)-(oo) immediately above optionally is substituted
184 with one or more R9 groups;
185 alternatively, two R7 groups can form -O(CH2)UO-;
186 R8 is selected from:
187 (a) R5,(b) H, (be) a C1-6 alkyl group, (cd) a C2-6 alkenyl group, (de) a
188 C2.6 alkynyl group, (ef) a C3-12 saturated, unsaturated, or aromatic carbocycle,
189 (fg) a 3-12 membered saturated, unsaturated, or aromatic heterocycle
235 190 containing one or more heteroatoms selected from nitrogen, oxygen, and
191 sulfur, (gh) -C(O)-C1-6 alkyl, (hi) -C(O)-C2-6 alkenyl, (ij) -C(O)-C2-6
192 alkynyl, (jk) -C(O)-C3-12 saturated, unsaturated, or aromatic carbocycle, and
193 (kl) -C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle
194 containing one or more heteroatoms selected from nitrogen, oxygen, and
195 sulfur,
196 wherein any of (bc)-(k) immediately above optionally is substituted
197 with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd)
198 Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, (jj) NH(C1-6 alkyl),
199 (kk) N(C1-6 alkyl)2, (11) a Ci-6 alkoxy group, (mm) an aryl group, (nn) a
200 substituted aryl group, (oo) a heteroaryl group, (pp) a substituted
201 heteroaryl group, and (qq) a C1-6 alkyl group optionally substituted
202 with one or more moieties selected from an aryl group, a substituted
203 aryl group, a heteroaryl group, a substituted heteroaryl group, F, Cl,
204 Br, I, CN, NO2, CF3, SCF3, and OH;
205 R9, at each occurrence, independently is selected from:
206 (a) R10, (b) a C1-6 alkyl group, (c) a C2.6 alkenyl group, (d) a C2.6 alkynyl
207 group, (e) a C3-J2 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12
208 membered saturated, unsaturated, or aromatic heterocycle containing one or
209 more heteroatoms selected from nitrogen, oxygen, and sulfur,
210 wherein any of (b)-(f) immediately above optionally is substituted
211 with one or more R10 groups;
212 R10, at each occurrence, independently is selected from:
213 (a) H, (b) =0, (C) F, (d) Cl, (e) Br, (f) I, (g) -CF3, (h) -CN, (i) -NO2, (j) -
214 NR6R6, (k) -OR6, (1) -S(O)pR6, (m) -C(O)R6, (n) -C(O)OR6, (o) -OC(O)R6,
215 (p) NR6C(O)R6, (q) -C(O)NR6R6, (r) -C(=NR6)R6, (s) -NR6C(O)NR6R6, (t) -
216 NR6S(O)pR6, (u) -S(O)pNR6R6, (v) -NR6S(O)PNR6R6, (w) a C,.6 alkyl group,
217 (x) a C2.6 alkenyl group, (y) a C2_6 alkynyl group, (z) a C3-12 saturated,
218 unsaturated, or aromatic carbocycle, and (aa) a 3-12 membered saturated,
219 unsaturated, or aromatic heterocycle containing one or more heteroatoms
220 selected from nitrogen, oxygen, and sulfur,
221 wherein any of (w)-(aa) immediately above optionally is substituted
222 with one or more moieties selected from R6, F, Cl, Br, I, CN, NO2, -
236 223 OR6, -NH2, -NH(CM alkyl), -N(C1-6 alkyl)2, a Ci-6 alkoxy group, a
224 C1-6 alkylthio group, and a C1-6 acyl group;
225 R11 and Rl la at each occurrence, independently is selected from:
226 (a) a carbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g) CN, (h)
227 NO2, (i) OR8, (j) -S(O)13R8, (k) -C(O)R8, (1) -C(O)OR8, (m) -OC(O)R8, (n) -
228 C(O)NR8R8, (o) -OC(O)NR8R8, (p) -C(=NR8)R8, (q) -C(R8)(R8)OR8, (r) -
229 C(R8)2OC(O)R8, (s) -C(R8)(OR8)(CH2)rNR8R8, (t) -NR8R8, (u) -NR8OR8, (v)
230 -NR8C(O)R8, (w) -NR8C(O)OR8, (x) -NR8C(O)NR8R8, (y) -NR8S(O)PR8, (z)
231 -C(OR8)(OR8)R8, (aa) -C(R8)2NR8R8, (bb) =NR8, (cc) -C(S)NR8R8, (dd) -
232 NR8C(S)R8, (ee) -OC(S)NR8R8, (ff) -NR8C(S)OR8, (gg) -NR8C(S)NR8R8,
233 (hh) -SC(O)R8, (ii) -N3, (jj) -Si(R13)3, (kk) NR8(C=NR8)R8, (11)
234 NH(C=NH)NH2, (kkii) a C1-6 alkyl group, (lljj) a C2-6 alkenyl group, (mmkk) a
235 C2-6 alkynyl group, (nnll) a C1-6 alkoxy group, (oomm) a C1-6 alkylthio group,
236 (ppnn) a C1-6 acyl group, (qqoo) a C3-12 saturated, unsaturated, or aromatic
237 carbocycle, and (rrpp) a 3-12 membered saturated, unsaturated, or aromatic
238 heterocycle containing one or more heteroatoms selected from nitrogen,
239 oxygen, and sulfur, (ssqq) -S(O)PR8, (ttrr) C(OR8)R8, (uuss) -
240 C(R8)2C(O)NR8R8, (wtt) -S(O)PNR8R8, (wwuu) -C(R8)2S(O)PR8, (xxw) -
241 C(R8)2N3, and (yyww) S(O)PC(R8)2CN, wherein any of (kkii)-(mmkk)
242 immediately above optionally is substituted with one or more R5 groups;
243 R12 is selected from:
244 (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group,
245 (e) -C(O)R5, (f) -C(O)OR5, (g) -C(O)-NR4R4, (h) -C(S)R5, (i) -C(S)OR5, G)
246 -C(O)SR5, (k) -C(S)-NR4R4, (1) a C3-12 saturated, unsaturated, or aromatic
247 carbocycle, (m) a 3-12 membered saturated, unsaturated, or aromatic
248 heterocycle containing one or more heteroatoms selected from nitrogen,
249 oxygen, and sulfur, (n) a -(C1-6 alkyl) -C3-12 saturated, unsaturated, or
250 aromatic carbocycle, and (o) a -(Ci-6 alkyl)-3-12 membered saturated,
251 unsaturated, or aromatic heterocycle containing one or more heteroatoms
252 selected from nitrogen, oxygen, and sulfur,
253 wherein any of (a)-(d) and (l)-(o) immediately above is optionally
254 substituted with one or more R5 groups;
255 R13 at each occurrence, independently is selected from (a) -C1-6 alkyl and (b) -0-(C1-6
256 alkyl):
237 257 a at each occurrence, independently is selected from 0, 1, 2, 3, and 4; 258 b at each occurrence, independently is selected from 0, 1, 2, 3, and 4; 259 c at each occurrence, independently is selected from 0, 1, 2, 3, and 4; 260 p at each occurrence, independently is selected from 0, 1, and 2; 261 r at each occurrence, independently is selected from 0, 1, and 2; 262 t at each occurrence, independently is selected from 0, 1, and 2; 263 and u at each occurrence, independently is selected from 1, 2, 3, and 4.
264
1 2. A compound according to claim 1, having the structure:
Figure imgf000240_0001
3 or a pharmaceutically acceptable salt, ester, JV-oxide, or prodrug thereof, wherein a, b, c, A, B, 4 G, T, X, R ► 11, T R) 3a, τ R>bD, τ R*cc, τ R>d°, and Re are as described in claim 1.
5 1 3. A compound according to claim 2, having the structure:
Figure imgf000240_0002
3 or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein a, b, c, A, B, 4 G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described in claim 1.
1 4. A compound according to claim 3, having the structure:
238
Figure imgf000241_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein a, b, c, A, B, G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described in claim 1.
5. A compound according to claim 3, having the structure:
Figure imgf000241_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein a, b, c, A, B, G, T, X, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described in claim 1.
6. A compound according to any of claims 1-5, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A is selected from the group consisting of (a) - (C-O)-, (b) -(C=S)-, (C) -(C=NR)-, (d) -(C=NOR)-, (e) -(C=NNRR)-, (f) -(S=O)-, (g) - (SO2)-, and (h) -[(3 or 4-membered ring carbocycle)-(C=O)]- and B is selected from the group consisting of -O-, -S-, and -NR-, where R is H or C1-6 alkyl.
7. A compound according to any of claims 1-6, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A is -(C=O)-, B is -NR-, where R is H or C1-6 alkyl, b is O, and c is O.
239
8. A compound according to any of claims 1-7, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein a is 2.
9. A compound according to claim 1 having the structure:
Figure imgf000242_0001
or a pharmaceutically acceptable salt, ester, N-oxide or prodrug thereof, wherein a is 2, 3, or 4, and G, T, X, R, R1, R2, R3, R\ Rb, Rc, Rd, and Re are as described in claim 1.
10. A compound according to any of claims 1-9, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein a is 2 or 3.
11. A compound according to claim 1 having the structure:
Figure imgf000242_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described in claim 1.
12. A compound according to claim 11 having the structure:
Figure imgf000243_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described in claim 1.
13. A compound according to claim 12, having the structure:
Figure imgf000243_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R, R1, R2, R3, Ra, Rb, Rc, Rd, and Re are as described in claim 1.
14. A compound according to claims 1-13, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein R is H.
15. A compound according to any one of claims 1-14, 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(Ci-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, (w) -N(C1-6 ^yI)C(O)N(C1 -6 alkyl)2, (x) -S(C1-6 alkyl), and (y) -SH.
241
16. A compound according to any one of claims 1 - 15, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from (a) H, (b) F, (c) -OH, (d) - 0(C1-6 alkyl), (e) -S(C1-6 alkyl), and (f) -SH.
17. A compound according to any one of claims 1-16, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is selected from F and OH.
18. A compound according to any one of claims 1 -17, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is F.
19. A compound according to any one of claims 1 - 17, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein X is OH.
20. A compound according to any one of claims 1 - 16, or a pharmaceutically acceptable salt, ester, Ν-oxide, or prodrug thereof, wherein X is —O(C1-6 alkyl).
21. A compound according to claim 20, or a pharmaceutically acceptable salt, ester, Ν- oxide, or prodrug thereof, wherein X is -OCH3.
22. A compound according to any one of claims 1 -21 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rd and Re are independently selected from (a) Cl, (b) Br, (c) F, (d) H and (e) C1-6 alkyl.
23. A compound according to any one of claims 1-22, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rd and Re are H.
24. A compound according to any one of claims 1-23, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rc is selected from (a) H, (b) Ci-6 alkyl, (c) - CF3, (d) -CF2H, and (e) -CFH2.
25. A compound according to any one of claims 1-24, wherein Rc is H.
26. A compound according to any one of claims 1 -25, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra and Rb are 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(C1-6 alkyl), (m) -N(C1-6 alkyl)2, (n)-C(0)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), (u) -S(Ci-6 alkyl), and (v) -SH, or alternatively Ra and Rb are taken together with the carbon to which they are attached to form (aa) -CO or (bb) -CS.
27. A compound according to any one of claims 1-26, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra and Rb are selected from (a) H, (b) F, (c) OH, and (d) -0(C1-6 alkyl).
28. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is F.
29. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -OH.
30. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is -0(Ci-6 alkyl).
31. A compound according to claim 30, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein Ra is H and Rb is -OCH3.
32. A compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Ra is H and Rb is H.
33. A compound according to claim 1 having the structure:
Figure imgf000245_0001
243 or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G, T, X, R1, R , R , and R are as described in claim 1.
34. A compound according to claim 33, or a pharmaceutically acceptable salt, ester, Ν- oxide, or prodrug thereof, wherein X is selected from (a) H, (b) F, (c) -OH, (d) -0(C1-6 alkyl), (e) -S(C1-6 alkyl), and (f) -SH.
35. A compound according to any one of claims 33-34, or a pharmaceutically acceptable salt, ester, Ν-oxide, or prodrug thereof, wherein Rb is selected from (a) H, (b) F, (c) -OH, (d) -0(C1-6 alkyl), (e) -S(Ci-6 alkyl), and (f) -SH.
36. A compound according to claim 35 having the structure:
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 35 having the structure:
Figure imgf000246_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.
244 - 245 -
38. A compound according to claim 35 having the structure:
Figure imgf000247_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.
39. A compound according to claim 35 having the structure:
Figure imgf000247_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.
40. A compound according to any one of claims 1-39, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 is H.
41. A compound according to any one of claims 1 -40, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R2 is H.
42. A compound according to any one of claims 1-41, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is C1-6 alkyl. - 246 -
43. A compound according to any one of claims 1-42, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R3 is methyl.
44. A compound according to any one of claims 1-43, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is B'.
45. A compound according to any one of claims 1-44, 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 any of (a)-(b) optionally is substituted with one or more R11 groups.
46. A compound according to any one of claims 1-45, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is -B'-Z-B".
47. A compound according to claim 32, 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.
48. A compound according to any one of claims 1-43 or 46-47, or a pharmaceutically acceptable salt, ester, N-oxide or prodrug thereof, wherein Z is a single bond.
49. A compound according to claim 1 having the formula:
Figure imgf000248_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G is B'; X is selected from (a) H, (b) F, (c) -OH, (d) -0(C1-6 alkyl), (e) -S(C1-6 alkyl), and (f) -SH; and R , R, R > ' , T R>22, τ R>3J and T are as described in claim 1.
50. A compound according to claim 1 having the formula:
Figure imgf000249_0001
or a pharmaceutically acceptable salt, ester, Ν-oxide, or prodrug thereof wherein G is -B'-Z-
B";
X is selected from (a) H, (b) F, (c) -OH, (d) -O(C1-6 alkyl), (e) -S(C1-6 alkyl), and (f) -SH; and Rb, R, R1, R2, R3 and T are as described in claim 1.
51. A compound according to any one of claims 49-50, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein Rb is selected from (a) H, (b) F, (c) -OH, (d) -O(C1-6 alkyl), (e) -S(C1-6 alkyl), and (f) -SH.
52. A compound according to claim 1, having the structure:
H or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R, R1, R2, and R3 are as described in claim 1.
53. A compound according to claim 1 , having the structure:
247
Figure imgf000250_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R, R1, R2, and R3 are as described in claim 1.
54. A compound according to claim 1, having the structure:
Figure imgf000250_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R, R1, R2, and R3 are as described in claim 1.
55. A compound according to claim 1, having the structure:
Figure imgf000250_0003
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R, R1, R2, and R3 are as described in claim 1.
56. A compound according to claim 1, having the structure:
248
Figure imgf000251_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, X, R, R1, R2, and R3 are as described in claim 1.
57. A compound according to claim 1, having the structure:
Figure imgf000251_0002
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof wherein G, T, R, R1, R2, and R3 are as described in claim 1.
58. A compound according to any one of claims 49-57, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R is H.
59. A compound according to any of claims 1-58, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000251_0003
where B", Z, and R i l l are as described in claim 1.
249 - 250 -
60. A compound according to claim 59, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein G is:
Figure imgf000252_0001
where B", Z, and R11 are as described in claim 1.
61. A compound according to any of claims 1-58, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000252_0002
where B", Z, and R11 are as described in claim 1.
62. A compound according to any one of claims 1-58, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein G is:
Figure imgf000252_0003
wherein B", Z, and R1 ' are as described in claim 1.
63. A compound according to any of claims 1-62, wherein R11 is selected from (a) F,
(b) Cl, (C) Br, (d) I, (e) CN, (f) -S(O)pRδ, (g) -C(O)R8, (h) -C(O)NR8R8, (i) G) -C(R8)(R8)OR8, (k) -NR8R8, (1) -NR8C(O)R8, (m) -C(R8)2NR8R8, (n) NH(C=NH)NH2, (o) a Ci-6 alkyl group, (p) a C1-6 alkylthio group, (q) a C3-I2 unsaturated carbocycle, (r) -S(O)PR8, (s) -S(O)PCHF2, (t) -C(OR8)R8, (u) -C(R8)2C(O)NR8R8, (v) -S(O)PNR8R8, (w) - C(R8)2S(O)pR8, (x) -C(R8)2N3, and (y) S(O)PC(R8)2CN.
64. A compound according to claim 63, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein R1 ' is selected from H and F.
65. A compound according to any of claims 64, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is H.
66. A compound according to any of claims 65, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1 ] is F.
67. A compound according to any of claims 1-43 or 46-66, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein -ZB" is A', where A' 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, G) Cl, (k) Br, (1) I, (m) -CF3, (n) -CN, (o) -N3 (p) -NO2, (q) -NR^CRV^R9, (r) -OR9, (s) -S<CR6R6)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, (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(=0)H; wherein t at each occurrence, independently is selected from O, 1, and 2; wherein any of (a)-(e) immediately above is optionally substituted with one or more R14 groups; wherein R14 at each occurrence is independently selected from:
251 (a) H, (b) F, (C) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i) -S(O)PR8, G) - 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 Ci-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 any of (ii)-(mm) immediately above optionally is 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.
68. A compound according to claim 67, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein A' 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) -CF3, (g) -NR6(CR6R6)tR9, (h) -OR9, (i) - S(CR6R6XR9, O) -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, (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) -C [=NNR6C(O)R6] (CR6R6XR9, (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) - S(O)pNR6(CR6R6)tR9, (aa) -NR6R6, (bb) -NR6(CR6R6)tR9, (cc) -SR6, (dd) -S(O)R6, (ee) - S(O)2R6, and (ff) -NR6C(O)R6, wherein any of (a)-(e) immediately above optionally is substituted with one or more R14 groups.
69. A compound according to claim 68, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein A' is selected from: (a) a C1-6 alkyl group, (b) a
252 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 any of (a)-(e) immediately above optionally is substituted with one or more R14 groups.
70. A compound according to claim 69, or a pharmaceutically acceptable salt, ester, N- oxide, or prodrug thereof, wherein A' is selected from: (a) -NR6(CR6R6)tR9, (b) -OR9, (c) - S^CR^tR9, (d) -S(O)(CR6R6)tR9, (e) -S(O)2<CR6R6)tR9, (f) -C(O)(CR6R6^R9, (g) - OC(O)(CR6R6)tR9, (h) -OC(O)O(CR6R6)tR9, (i) -SC(O)(CR6R6)tR9, Q) -C(O)O(CR6R6)tR9, (k) -NR6C(O)(CR6R6^R9, (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) - SCO^NR^CR^tR9, (u) -NR6R6, (v) -NR6(CR6R6),R9, (w) -SR6, (x) -S(O)R6, (y) - S(O)2R6, and (z) -NR6C(O)R6.
71. A compound according to any one of claims 1-70, wherein T is:
Figure imgf000255_0001
or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein: M is selected from: (a) -C(O)-, (b) -CHt-OR114H (c) -NR114-CH2- (d) -CH2-NR114-, (e) - CH(NR114R114H (f) -Q=NNR114R114)-, (g) -NR114-C(O)-, (h) -C(O)NR114- (i) -C(=NR! 14H O) -CR115R115-, and (k) -C(=NOR127)-;
253 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-CL6 alkyl, (o) -OC(O)NR114- C1-O alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2-6 alkynyl, wherein any of (1) - (r) immediately above 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) -0-Cr6 alkyl-R115, (d) -OC(O)R114, (e) -OC(O)-C1-6 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 imgf000256_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:
254 (a) H, (b) R114, (c) -C(O)RU4(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) -Q=NR114H (e) - C(^NR114)0-, (f) -C(=NR114)NR114- (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 (n) -S(O)p-; alternatively R103 and R104, taken together with the atoms to which they are bonded, form:
Figure imgf000257_0001
wherein R135 and R136 are selected from (a) hydrogen, (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 oxygen, nitrogen, or sulfur atoms, (g) F, (h) Br, (i) I, (j) OH, and (k) -N3, wherein any of (b)-(d) immediately above optionally is substituted with one or more R117; or alternatively, R135 and R136 are taken together to form =0, =S, =NR114, =NOR114, =NR114, or =N-NR114R114, wherein V is selected from (a) -(C1-4-alkyl)-, (b)-(C2-4-alkenyl)-, (c) O, (d) S, and (e) NR114, wherein (a) and (b) immediately above are optionally further substituted with one or more R 117.
R , 1i0υ53 is selected from:
(a)
Figure imgf000257_0002
(b) -OR , 111 l44, (c) -NR » H1144Rr> 111144, (d) -0-C1-6
Figure imgf000257_0003
(e) -C(O)-R , 114 (f) -C(O)-C1-6 alkyl-R115, (g) -OC(O)-R114, (h) -OC(O)-C1-6 alkyl-R115, (i) -OC(O)O-R114, O) -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; alternatively, R104 and R105, taken together with the atoms to which they are bonded, form
255
Figure imgf000258_0001
Q is CH or N, and R126 is -OR1 , -NR114 or R114; alternatively, R104 and R105, taken together with the atoms to which they are bonded, form:
Figure imgf000258_0002
wherein
R149 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-C1-6 alkyl, (m) -OC(O)-C1-6 alkyl, (n) -OC(O)O-Ci-6 alkyl, (o) -OC(O)NR114-C1-6 alkyl, (p) C1-6 alkyl, (q) C2-6 alkenyl, and (r) C2-6 alkynyl, wherein any of (1) - (r) immediately above optionally is substituted with one or more R 115 groups;
R , 115D0υ is H, C1-6 alkyl, or F; alternately, R149 and R150 can be taken together with the carbon to which they are attached to form a carbonyl group; alternately, R149 and R150 can be taken together to form the group -O(CR116R116^O-; alternatively, R104 and R105, taken together with the atoms to which they are bonded, form:
Figure imgf000258_0003
wherein in the preceding structure the dotted line indicates an optional double bond
256 85 i) R130 is -OH, or R114,
86 ii) R131 is -OH, or R114,
87 iii) alternately, R130 and R131 together with the carbons to which
88 they are attached form a 3-7 membered saturated, unsaturated
89 or aromatic carbocyclic or heterocyclic ring which can
90 optionally be substituted with one or more R114 groups;
91 iv) alternatively, R130 and the carbon to which it is attached or R131
92 and the carbon to which it is attached are each
93 independently -C(=O)-;
94 alternatively, R105, R132 and M, taken together with the atoms to which they are
95 attached, form:
Figure imgf000259_0001
97 R106 is selected from:
98 (a) -OR114, (b) -C1-6 alkoxy-R115, (c) -C(O)R114, (d) -OC(O)R114, (e) -
99 OC(O)OR114, (f) -OC(O)NR114R114, and (g) -NR114R114,
100 alternatively, R105 and R106 taken together with the atoms to which they are attached
101 form a 5-membered ring by attachment to each other through a chemical moiety selected
102 from:
103 (a) -OC(R1 ! 5)2O-, (b) -OC(O)O-, (c) -OC(O)NR114- (d) -NR114C(O)O-,
104 (e) -OC(O)NOR114-, (f) -NOR114-C(O)O-, (g) -OC(O)N[NR114R114] - (h) -
105 N[NR114R114]-C(O)O-, (i) -OC(O)C(R115J2-. G) -C(R115J2C(O)O-, (k) -
106 OC(S)O-, (1) -OC(S)NR114-, (m) -NR114C(S)O-, (n) -OC(S)NOR114- (o) -
107 NOR114-C(S)O-, (p) -OC(S)N[NR114R114]- (q) -N[NR114R114J-C(S)O-, (r) -
108 OC(S)C(R115J2-, (s) -C(R115)2C(S)O-, (t) -OC(O)CR1 ^[S^pR114] - (u) -
109 OC(O)CR115CNR114R114J - (v) -CR11^NR114R114JC(O)O-, and (w) -
110 CR115ES(O)PR114]C(0)0-;
111 alternatively, R105, R106, and R133 taken together with the atoms to which they are attached
112 form:
257
Figure imgf000260_0001
114 alternatively, M, R105, and R106 taken together with the atoms to which they are attached 115 form: 116
Figure imgf000260_0002
118
Figure imgf000260_0003
258
Figure imgf000261_0001
259
Figure imgf000262_0001
124 wherein J1 and J2 at each occurrence, independently are selected from hydrogen, Cl, F, Br, I, 125 OH, -C1-6 alkyl, and -0(C1-6 alkyl) or are taken together to form =O, =S, =NR114, 126 =N0R114, =NR114, or =N-NR114R114, 127 alternatively, M and R104 taken together with the atoms to which they are attached form:
Figure imgf000262_0002
260
Figure imgf000263_0001
131 wherein U is selected from (a) -(C1-4-alkyl)- and (b)-(C2-4-alkenyl)-, wherein (a) and
132 (b) immediately above are optionally further substituted with one or more R117; 133 alternatively, M and R105 are taken together with the atoms to which they are attached 134 to form:
Figure imgf000263_0002
137 R 107 is selected from: 138 (a) H, (b) -C1-6 alkyl, (c) -C2-6 alkenyl, which can be further substituted with 139 C1-6 alkyl or one or more halogens, (d) -C2-6 alkynyl, which can be further 140 substituted with C1-6 alkyl or one or more halogens, (e) aryl, which can be 141 further substituted with C1-6 alkyl or one or more halogens, (f) heteroaryl, 142 which can be further substituted with Ci-6 alkyl or one or more halogens, (g) - 143 C(O)H, (h) -COOH, (i) -CN, (j) -COOR114, (k) -C(O)NR114R114, (1) - 144 C(O)R114, and (m) -C(O)SR114, wherein (b) is further substituted with one or
261 145 more substituents selected from (aa) -OR114, (bb) halogen, (cc) -SR114, (dd)
146 C1-6 alkyl, which can be further substituted with halogen, hydroxyl,
147 C1-6 alkoxy, or amino, (ee) -OR114, (ff) -SR114, (gg) -NR114R114, (hh) -CN, (ii)
148 -NO2, Gj) -NC(O)R114, (kk) -COOR114, (11) -N3, (mm) =N-0-R! 14, (nn)
149 =NR! M, (oo) =N-NR] 14R114, (pp) =N-NH-C(0)R114, and (qq) =N-NH-
150 C(O)NR114R114;
151 alternatively R106 and R107 are taken together with the atom to which they are attached
152 to form an epoxide, a carbonyl, an exocyclic olefin, or a substituted exocyclic olefin, or a C3-
153 C7 carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be
154 further substituted with a C1 -6 alkyl;
155 R108 is selected from:
156 (a) C1-6 alkyl, (b) C2-6 alkenyl, and (c) C2-6 alkynyl,
157 wherein any of (a)-(c) immediately above optionally is substituted
158 with one or more R114 groups;
159 R109 is selected from: (a) H, (b) C1 -6 alkyl, and (c) F;
160 R114, at each occurrence, independently is selected from:
161 (a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-12 saturated,
162 unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated,
163 or aromatic heterocycle containing one or more heteroatoms selected from
164 nitrogen, oxygen, and sulfur, (g) -C(O)-Ci-6 alkyl, (h) -C(O)-C2-6 alkenyl,
165 (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-12 saturated, unsaturated, or aromatic
166 carbocycle, (k) -C(O)-3-12 membered saturated, unsaturated, or aromatic
167 heterocycle containing one or more heteroatoms selected from nitrogen,
168 oxygen, and sulfur, (1) -C(O)O-C1-6 alkyl, (m) -C(O)O-C2-6 alkenyl, (n) -
169 C(O)O-C2-6 alkynyl, (o) -C(O)O-C3-12 saturated, unsaturated, or aromatic
170 carbocycle, (p) -C(O)O-3-12 membered saturated, unsaturated, or aromatic
171 heterocycle containing one or more heteroatoms selected from nitrogen,
172 oxygen, and sulfur, (q) -C(O)NR116R116, (r) -NR116CO-C1-6 alkyl, (s) -
173 NR116CO-C3-12 saturated, unsaturated, or aromatic carbocycle, (t) -NR116C(O)-
174 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one
175 or more heteroatoms selected from nitrogen, oxygen, and sulfur, (u) -(C1-6
176 alkyl)-O-(C1-6 alkyl), (v) -(C1-6 alkyl)-O-(C,-6 alkyl)-O-(C1-6 alkyl), (w) -OH,
177 (x) -OR115, (y) -NH(C1-6 alkyl), (z) -N(C1-6 alkyl)2, (aa) -(C1-6 alkyl)-S(O)p-
262 178 (Ci-6 alkyl), (bb) -(C1-6 alkyl)- S(O)p-(C1-6 alkyl)-S(O)p-(C1-6 alkyl), (cc) -(C1-6
179 alkyl)-O-(C1-6 alkyl)-S(O)p-(C1-6 alkyl), (dd) -(C1-6 alkyl)- S(O)p-(C1-6
180 alkyl)-O-(C1-6 alkyl), (ee) -NH2, and (ff) -CR114R114;
181 wherein the terminal alkyl group in any of (u)-(v) or (aa)-(dd)
182 immediately above includes cycloalkyl,
183 wherein any of (b)-(v) or (aa)-(dd) immediately above optionally is
184 substituted with one or more R115 groups, wherein one or more non-
185 terminal carbon moieties of any of (b)-(d) immediately above
186 optionally is replaced with oxygen, S(O)P, or -NR116,
187 alternatively, NR114R114 forms a 3-7 membered saturated, unsaturated or aromatic ring
188 including the nitrogen atom to which the R114 groups are bonded and optionally one or more
189 moieties selected from O, S(O)P, N, and NR118;
190 R115 is selected from:
191 (a) R117, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-I2 saturated,
192 unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated,
193 or aromatic heterocycle containing one or more heteroatoms selected from
194 nitrogen, oxygen, and sulfur, (g) -OC1-6 alkyl, (h) -OC2-6 alkenyl, and (i) -
195 OC2-6 alkynyl,
196 wherein any of (b)-(f) immediately above optionally is substituted
197 with one or more RU1 groups ;
198 R116, at each occurrence, independently is selected from:
199 (a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-12 saturated,
200 unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated,
201 unsaturated, or aromatic heterocycle containing one or more heteroatoms
202 selected from nitrogen, oxygen, and sulfur,
203 wherein one or more non-terminal carbon moieties of any of (b)-(d)
204 immediately above optionally is replaced with oxygen, S(O)P, or -
I 1 o
205 NR , wherein any of (b)- (f) immediately above optionally is
206 substituted with one or more moieties selected from:
207 (aa) carbonyl, (bb) formyl, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg)
208 CN, (hh) N3, (ii) NO2, Oj) OR118, (kk) -S(O)PR118, (11) -
209 C(O)R118, (mm) -C(O)OR118, (nn) -OC(O)R118, (oo) -
210 C(O)NR118R118, (pp) -OC(O)NR118R118, (qq) -Q=NR118)R118,
211 (rr) -C(R118)(R118)OR118, (ss) -C(R118^OC(O)R118, (tt) -
263 212 C(R118)(OR118)(CH2)rNR118R118, (uu) -NR118R118; (w) -
213 NR118OR118, (ww) -NR118C(O)R118, (xx) -NR118C(O)OR1 18,
214 (yy) -NR118C(O)NR1 18R118, (zz) -NR118S(OXR118, (ab) -
215 C(OR118XOR118)R118, (ac) -C(R1 18XJNR118R118, (ad) =NR118,
216 (ae) -C(S)NR118R1 18, (af) -NR118C(S)R118, (ag) -
217 OC(S)NR118R118, (ah) -NR118C(S)OR118, (ai) -
218 NR118C(S)NR118R118, (aj) -SC(O)R118, (ak) C1-6 alkyl, (al)
219 C2-6 alkenyl, (am) C2-6 alkynyl, (an) C1-6 alkoxy, (ao) C1-6
220 alkylthio, (ap) C1-6 acyl, (aq) saturated, unsaturated, or aromatic
221 C3-12 carbocycle, and (ar) saturated, unsaturated, or aromatic
222 3-12 membered heterocycle containing one or more
223 heteroatoms selected from nitrogen, oxygen, and sulfur,
224 alternatively, NR116R116 forms a 3-12 membered saturated, unsaturated or aromatic
225 ring including the nitrogen atom to which the R116 groups are attached and optionally one or
226 more moieties selected from O, S(O)P, N, and NR118;
227 alternatively, CR116R116 forms a carbonyl group;
228 R117, at each occurrence, is selected from:
229 (a) H, (b) =O, (c) F, (d) Cl, (e) Br, (f) I, (g) (CR116R1 16)rCF3, (h)
230 (CR116R116)rCN, (i) (CR116R116)rNO2, G) (CR116R116XNR11^CR116R116XR119,
231 (k) (CR116R116XOR119, (1) (CR116R116XS(O)P(CR116R116)tR! 19,
232 (m) (CR116R116XC(O)(CR116R116)tR119, (n) (CR116R116)rOC(O)(CR116R116),R119,
233 (o) (CR116R116XSC(O)(CR116R116),R119,
234 (p) (CR116R116XC(O)O(CR116R116XR119,
235 (q) (CR116R116XNR116C(O)(CR1 16R116XR119,
236 (r) (CR116R116XC(O)NR116(CRJ 16R1 16XR119, (s)
237 (CR116R116)rC(=NR116)(CR116R116)tR119,
238 (t) (CR116R11^=NNR116R116XCR116R116),R119,
239 (u) (CR116R11VX=NNR116C(O)R116XCR116R116XR119,
240 (v) (CR116R116XQ=NOR119)(CR* 16R116XR119,
241 (w) (CR116R116XNR116C(O)O(CR116R1 16XR119,
242 (x) (CR116R116χθC(O)NR116(CR116RI 16)tR119,
243 (y) (CR116R116XNR116C(O)NR116(CR' 16R116)tR! 19,
244 (z) (CR116R116XNR116S(O)P(CR116R116XR119,
245 (aa) (CR116R116XS(OX5NR116(CR* 16R116XR119,
264 246 (bb) (CR116R116XNR116S(O)PNR116CCR116R116^R119,
247 (cc) (CR116R116^NR116R116, (dd) C,.6 alkyl, (ee) C2.6 alkenyl, (ff) C2.6 alkynyl,
248 (gg) (CR116R116)r-C3-12 saturated, unsaturated, or aromatic carbocycle, (hh)
249 (CR1 ' 6R1 ' 6)r-3- 12 membered saturated, unsaturated, or aromatic heterocycle
250 containing one or more heteroatoms selected from nitrogen, oxygen, and
251 sulfur, and (ii) -P(O)(O(C1-6 alkyl))2,
252 wherein any of (dd)-(hh) immediately above optionally is substituted
253 with one or more R119 groups;
254 alternatively, two R117 groups can form -O(CH2)UO-;
255 R118 is selected from:
256 (a) H, (b) C1-6 alkyl, (c) C2.6 alkenyl, (d) C2.6 alkynyl, (e) C3-12 saturated,
257 unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated,
258 or aromatic heterocycle containing one or more heteroatoms selected from
259 nitrogen, oxygen, and sulfur, (g) -C(O)-C1-6 alkyl, (h) -C(O)-C2-6 alkenyl,
260 (i) -C(O)-C2-6 alkynyl, (j) -C(O)-C3-I2O saturated, unsaturated, or aromatic
261 carbocycle, and (k) -C(O)-3-12 membered saturated, unsaturated, or aromatic
262 heterocycle containing one or more heteroatoms selected from nitrogen,
263 oxygen, and sulfur,
264 wherein any of (b)— (k) immediately above optionally is substituted
265 with one or more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd)
266 Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, Gj) NH(C1-6 alkyl),
267 (kk) N(C1-6 alkyl)2, (11) C1-6 alkoxy, (mm) aryl, (nn) substituted aryl,
268 (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C1-6 alkyl,
269 optionally substituted with one or more moieties selected from aryl,
270 substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN,
271 NO2, and OH;
272 R119, at each occurrence, independently is selected from:
273 (a) R120, (b) C145 alkyl, (c) C2.6 alkenyl, (d) C2.6 alkynyl, (e) C3-12 saturated,
274 unsaturated, or aromatic carbocycle, and (f) 3-12 membered saturated,
275 unsaturated, or aromatic heterocycle containing one or more heteroatoms
276 selected from nitrogen, oxygen, and sulfur,
277 wherein any of (b)-(f) optionally is substituted with one or more R114
278 groups;
265 279 R , at each occurrence, independently is selected from:
280 (a) H, (b) =0, (C) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3, (h)
281 (CR116R116XCN, (i) (CR116R116),NO2, (j) (CR116R116XNR116R116, (k)
282 (CRU6R1 I6)rOR114, (1) (CR116R116XS(O)PR116, (m) (CR116R116XC(O)R116,
283 (n) (CR116R116XC(O)OR116, (o) (CRU6R116)rOC(O)R116, (p)
284 (CR116R116XNR116C(O)R116, (q) (CR116R116XC(O)NR116R116, (r)
285 (CR116R116)rC(=NR116)R116, (s) (CR116R116XNR116C(O)NR116R116,
286 (t) (CR116R116XNR116S(O)13R116, (u) (CR116R116XS(O)15NR116R116, (v)
287 (CR116R116XNR116S(O)15NR116R116, (w) C,.6 alkyl, (x) C2^ alkenyl, (y)
288 C2.6 alkynyl, (z) (CR116R116)r-C3-i2 saturated, unsaturated, or aromatic
289 carbocycle, and (aa) (CR116R116)r-3-12 membered saturated, unsaturated, or
290 aromatic heterocycle containing one or more heteroatoms selected from
291 nitrogen, oxygen, and sulfur,
292 wherein any of (w)-(aa) optionally is substituted with one or more
293 moieties selected from R116, F, Cl, Br, I, CN, NO2, -OR116, -NH2, -
294 NH(C1-6 alkyl), -N(C1-6 alkyl)2, Ci-6 alkoxy, C1-6 alkylthio, and
295 Ci-6 acyl;
296 R121, at each occurrence, independently is selected from:
297 (a) H, (b) -OR118, (c) -O-Ci-6 alkyl-OQO)^ 18, (d) -0-C1-6 alkyl-
298 OC(O)OR118, (e) -O-C1-6 alkyl-OC(O)NR118R118, (f) -C)-C1-6 alkyl-
299 C(O)NR118R118, (g) -O-C1-6 alkyl-NR118C(O)R118, (h) -0-C1-6 alkyl-
300 NR118C(O)OR118, (i) -O-C1-6 alkyl-NR118C(O)NR118R118, G) -0-C1-6 alkyl-
301 NR118C(=N(H)NR118R118), (k) -O-C1-6 alkyl-S(O)pR118, (1) -O-C2-6 alkenyl-
302 OC(O)R1 ] 8, (m) -0-C2-6 3UCeHyI-OC(O)OR1 ' 8, (n) -0-C2-6 alkenyl-
303 OC(O)NR118R118, (o) -O-C2-6 3UCeHyI-C(O)NR118R118, (p) -0-C2-6 alkenyl-
304 NR118C(O)R118, (q) -O-C2-6 aUcenyl-NR118C(O)OR118, (r) -O-C2-6 alkenyl-
305 NR118C(O)NR118R118, (s) -G-C2-6 aUcenyl-NR118C(=N(H)NR118R118), (t) -O-
306 C2-6
Figure imgf000268_0001
(u) -0-C2-6 aUcynyl-OC(O)R' 18, (v) -0-C2-6 alkynyl-
307 OC(O)OR118, (w) -0-C2-6 alkynyl-OC^NR118R118, (x) -O-C2-6 alkynyl-
308 C(O)NR118R118, (y) -O-C2-6 aUcynyl-NR118C(O)R118, (z) -C)-C2-6 alkynyl-
309 NR118C(O)OR118, (aa) -O-C2-6 alkynyl-NR118C(O)NR118R118,
310 (bb) -O-C2-6 aUcynyl-NR118C(=N(H)NR118R118), (cc) -0-C2-6 alkynyl-
311 S(O)pR118, (dd) -NR118R118, (ee) -C1-6 alkyl-O-Ci-e aUcyl, (ff) -C1-6 alkyl-
266 312 NRH4-C1-6 alkyl, (gg) -C1-6 alkyl-S(O)p-C1-6 alkyl, (hh) -OC(O)NR114(C1-6
313 alkyO-NR114-(C1-6 alkyl) -R114, (ii) -OH, Gj) -Ci-6 alkyl, (kk) C2-6 alkenyl, (11)
314 C2-6 alkynyl, (mm) -CN, (nn) -CH2S(O)PR137, (oo) -CH2OR137, (pp) -
315 CH2N(OR138)R137, (qq) -CH2NR137R139, (rr) -(CH2)v(C6-10 aryl), and (ss)-
316 (CH2)V(5- 10 membered heteroaryl), wherein Gj)-(ss) ∞e optionally substituted
317 by 1, 2, or 3 R140 groups;
318 alternatively, two R121 groups taken together form =O, =NOR] 18, or ^=NNR118R118;
319 R127 at each occurrence, independently is selected from (a) R114, (b) a monosaccharide
320 or a disaccharide (including amino sugars and halogenated sugar(s)), (c) -S(O)pR148,
321 (d) -(CH2)n-(O-CH2CH2-)m-O(CH2)nCH3, (e) -(CH2)n-(O-CH2CH2-)m-OR148, (f) -
322 (CH2)n-[S(O)p-CH2CH2-]m-S(O)p(CH2)nCH3, (g) -(CH2V[S(O)p-CH2CH2-]m-OR148,
323 (h) -OCH2-CKCH2)n-[S(O)p-CH2CH2-]m-S(O)p(CH2)nCH3> (i) -OCH2-O-(CH2)n-
324 [S(O)p-CH2CH2-]m-OR148, (j) -0-[C3-12 saturated, unsaturated, or aromatic carbocycle]
325 wherein said carbocycle is further optionally substituted with one or more R114, (k) -
326 O-[3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or
327 more heteroatoms selected from nitrogen, oxygen, and sulfur], wherein said
328 heterocycle is further optionally substituted with one or more R114, (1) -S(O)P-[C3-12
329 saturated, unsaturated, or aromatic carbocycle] wherein said carbocycle is further
330 optionally substituted with one or more R114, and (m) -S(O)p-[3-12 membered
331 saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms
332 selected from nitrogen, oxygen, and sulfur], wherein said heterocycle is further
333 optionally substituted with one or more R114;
334 R128 is R114;
335 R129 is R114;
336 alternatively both R substituents can be taken together with the carbons to which
337 they are attached to form carbonyl or =NR114, or a saturated or unsaturated C3-6 spiro
338 ring or a 3-6 membered saturated or unsaturated heterospiro ring containing one or
339 more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by
340 one or more R117 groups,
341 alternatively both R129 substituents can be taken together with the carbons to which
342 they are attached to form carbonyl or =NR" 14, or a saturated or unsaturated C3-6 spiro
343 ring or a 3-6 membered saturated or unsaturated heterospiro ring containing one or
344 more nitrogens, oxygens, or sulfurs, said rings further being optionally substituted by
345 one or more R117 groups,
267 346 alternatively an R128 and an R129 substituent can be taken together with the carbons to
347 which they are attached to form a C3-12 saturated or unsaturated ring or saturated or
348 unsaturated bicyclic ring, or a 3-12 membered saturated or unsaturated heterocyclic
349 ring or saturated or unsaturated heterobicyclic ring containing one or more nitrogens,
350 oxygens, or sulfurs, said rings further being optionally substituted by one or more R11?
351 groups,
352 alternatively one R128 group and one R129 group may be taken together with the
353 carbons to which they are attached to form a double bond, and the other R128 group
354 and the other R129 group are as defined herein or can form (a) a C3-12 ring which may
355 be further unsaturated or aromatic, (b) a C7-12 bicyclic ring which may be further
356 unsaturated or aromatic, (c) a 3-12 membered heterocyclic ring containing one or
357 more nitrogens, oxygens, or sulfurs, which may be further unsaturated or aromatic, or
358 (d) a 7-12 membered heterobicyclic ring containing one or more nitrogens, oxygens,
359 or sulfurs, which may be further unsaturated or aromatic, said rings described in (a),
360 (b), (c) and (d) further being optionally substitued by one or more R117 groups;
361 R110 is R114;
362 alternatively, R109 and R110 taken together with the carbons to which they are attached
363 form:
Figure imgf000270_0001
365 R132, R133, and R134 are each independently selected from (a) H, (b) F, (c) Cl, (d) Br,
366 (e) -OR114, (f) -SR114, (g) -NR114R114, and (h) Ci-6 alkyl, wherein (h) optionally is
367 substituted with one or more R115 groups;
368 alternatively, R132 and R133 are taken together to form a carbon-carbon double bond;
369 alternatively, R133 and R134 are taken together to form =O, =S, =N0R114, =NR' 14, or
370 =N-NR114R114;
371 alternatively, R105 and R134 are taken together with the carbons to which they are
372 attached to form a 3 -membered ring, said ring optionally containing an oxygen or
373 nitrogen atom, and said ring being optionally substituted with one or more R114
374 groups;
375 alternatively when M is a carbon moiety, R134 and M are taken together to form a
376 carbon-carbon double bond;
268 377 R137 is independently selected from: (a) H, (b) Ci-6 alkyl, (c) C2-6 alkenyl, (d) C2-6
378 alkynyl, (e) -(CH^CR^R^CH^NR^R144, (fHCH2)v(C6-C10 aryl), and (g) -
379 (CH2)V(5-1O membered heteroaryl);
380 or wherein R137 is as -CH2NR137R139, R139 and R137 may be taken together to form a
381 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered
382 heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2
383 heteroatoms selected from O, S, and -N(R137)-, in addition to the nitrogen to which
384 R139 and R137 are attached, said saturated ring optionally includes 1 or 2 carbon-
385 carbon double or triple bonds, and said saturated and heteroaryl rings are optionally
386 substituted by 1 , 2, or 3 R140 groups;
387 R138 is independently selected from (a) H and (b) Cr6 alkyl;
388 R141, R142, R143, and R144 at each occurrence, independently is selected from (a) H, (b)
389 Ci-6 alkyl, (c) -(CH2)H1(C6-C1 oaryl), and (d) -(CH2)m(5-10 membered heteroaryl),
390 wherein the foregoing
391 R141 , R142, R143, and R144 groups, except H, are optionally substituted by 1 , 2, or 3 R140
392 groups;
393 or R141 and R143 are taken together to form -(CH2)0- wherein o, at each
394 occurrence, independently is selected from 0, 1, 2, and 3 such that a 4-7 membered
395 saturated ring is formed that optionally that includes 1 or 2 carbon-carbon double or
396 triple bonds;
397 or R143 and R144 are taken together to form a 4-10 membered monocyclic or
398 polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated
399 and heteroaryl rings optionally include 1 or 2 heteroatoms selected from (a) O, (b) S
400 and (c) -N(R137)-, in addition to the nitrogen to which R143 and R144 are attached, said
401 saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and
402 said saturated and heteroaryl rings are optionally substituted by 1, 2, or 3 R140 group;
403 R139 at each occurrence, independently is selected from (a) H, (b) d-6 alkyl,
404 (c) C2-C6 alkenyl, and (d) C2-C6 alkynyl, wherein the foregoing R139 groups, except
405 H, are optionally substituted by 1, 2, or 3 substituents independently selected from
406 halogen and -OR138;
407 R140 at each occurrence is independently selected from (a) halogen, (b) cyano,
408 (c) nitro, (d) trifluoromethyl, (e) azido, (f) -C(O)R145, (g) -C(O)OR145, (h) -
409 OC(O)OR145, (i) -NR146C(O)R147, G) -NR146R147, (k) -OH, (1) Cr6 alkyl, (m) Cr6
410 alkoxy, (n) -(CH2)V(C6-C1 oaryl), and (o) -(CH2)v(5-10 membered heteroaryl), wherein
269 411 said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents
412 independently selected from (a) halogen, (b) cyano, (c) nitro, (d) trifluoromethyl, (e)
413 azido, (f) -C(O)R145, (g) -C(O)OR145, (h) -OC(O)OR145, (i) -NR146C(O)R147, (j) -
414 C(O)NR146R147, (k) -NR146R147, (1) -OH, (m) Cr6 alkyl, and (n) Cr6 alkoxy;
415 R145 at each occurrence, independently is selected from (a) H, (b) Q^alkyl,
416 (c) C2-C6 alkenyl, (d) C2-C6 alkynyl, (e) -(CH2)v(C6-C10aryl), and (f) -(CH2)v(5-10
417 membered heteroaryl);
418 R146 and R147 at each occurrence, independently is selected from (a) H, (b)
419 hydroxyl, (c) Cr6 alkoxy, (d) Ci-6 alkyl, (e) C2-6 alkenyl, (f) C2-6 alkynyl, (g) -
420 (CH2)v(C6-io aryl), and (h) -(CH2)V(5-10 membered heteroaryl);
421 R148 at each occurrence, independently is selected from (a) Cr6 alkyl, (b) C3-12
422 saturated, unsaturated, or aromatic carbocycle, wherein said carbocycle is further
423 optionally substituted with one or more R114, and (c) 3-12 membered saturated,
424 unsaturated, or aromatic heterocycle containing one or more heteroatoms selected
425 from nitrogen, oxygen, and sulfur, wherein said heterocycle is further optionally
426 substituted with one or more R114;
427 p, at each occurrence, independently is selected from O, 1, and 2;
428 k, at each occurrence, independently is selected from O, 1, and 2;
429 m, at each occurrence, independently is selected from O, 1, 2, 3, 4, and 5;
430 n, at each occurrence, independently is selected from 1, 2, and 3;
431 r, at each occurrence, independently is selected from O, 1, and 2;
432 t, at each occurrence, independently is selected from O, 1, and 2;
433 v, at each occurrence, independently is selected from O, 1, 2, 3, and 4;
434 q, at each occurrence, independently is selected from O, 1, 2, and 3;
435 and u at each occurrence, independently is selected from 1, 2, 3, and 4. 436
1 72. A compound according to any one of claims 1-71 wherein T is a macrolide
2 selected from TAl -TA24:
270
Figure imgf000273_0001
271
Figure imgf000274_0001
272
Figure imgf000275_0001
273
Figure imgf000276_0001
and
Figure imgf000276_0002
or a pharmaceutically acceptable salt, ester, TV-oxide, or prodrug thereof, wwhheerreeiinn I M, Q, R104, R114, R126, R127, R128, R129, R149, and R150 are as described in claim 71.
73. A compound according to any one of claims 1-72, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is a macrolide selected from Tl through T93:
274
Figure imgf000277_0001
Figure imgf000277_0002
Figure imgf000277_0003
275
Figure imgf000278_0001
Figure imgf000278_0002
T16 T17 T18
Figure imgf000278_0003
T19 T20
276
Figure imgf000279_0001
T21 T22
Figure imgf000279_0002
277
Figure imgf000280_0001
T29
T30
Figure imgf000280_0002
Figure imgf000280_0003
278
Figure imgf000281_0001
Figure imgf000281_0002
279
Figure imgf000282_0001
T57
T58
Figure imgf000282_0002
T59
T60
Figure imgf000283_0001
T61
T62
Figure imgf000283_0002
T63
T64
Figure imgf000283_0003
T65
T66
Figure imgf000284_0001
T67
T68
Figure imgf000284_0002
T69
T70
Figure imgf000285_0001
T71
T72
Figure imgf000285_0002
T73
T74
Figure imgf000285_0003
Figure imgf000286_0001
T83 T84
Figure imgf000287_0001
T88 T89 T90
Figure imgf000287_0002
Figure imgf000288_0001
71 T93
72
1 74. A compound having the structure corresponding to any one of the structures listed in
2 Table 1, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 3
1 75. A pharmaceutical composition comprising a compound according to any one of
2 claims 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, and a
3 pharmaceutically acceptable carrier. 4
1 76. A method for treating or preventing a disease state in a mammal comprising
2 administering to a mammal in need thereof an effective amount of a compound according to
3 any one of claims 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug
4 thereof. 5
1 77. A method of treating a microbial infection in a mammal comprising administering to
2 the mammal an effective amount of a compound according to any one of claims 1-74, or a
3 pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 4
1 78. The use of a compound according to any one of claims 1-74, or a pharmaceutically
2 acceptable salt, ester, N-oxide, or prodrug thereof, in the manufacture of a medicament for
3 treating a microbial infection in a mammal. 4
1 79. A method of treating or preventing a microbial infection in a mammal comprising
2 administering to the mammal an effective amount of a compound according to any one of
3 claims 1-74, or a pharmaceutically acceptable salt, ester, Ν-oxide, or prodrug thereof, wherein
4 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.
80. 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 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
81. 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 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
82. 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 1-34 or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
83. 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 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
84. 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 1-74 or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
85. 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 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
86. 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 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
87. 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 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, to suppress expression of the nonsense or missense mutation.
88. The method or use according to any one of claims 76-87 wherein the compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, is administered orally, otically, opthalmically, nasally, parentally, or topically.
89. A method of synthesizing a compound according to any of claims 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
90. A medical device containing a compound according to any one of claims 1-74, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.
91. The medical device according to claim 90 wherein the device is a stent.
PCT/US2008/002718 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same WO2008143729A2 (en)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US90435507P 2007-02-28 2007-02-28
US90435107P 2007-02-28 2007-02-28
US90439507P 2007-02-28 2007-02-28
US90439607P 2007-02-28 2007-02-28
US90439207P 2007-02-28 2007-02-28
US60/904,351 2007-02-28
US60/904,392 2007-02-28
US60/904,396 2007-02-28
US60/904,355 2007-02-28
US60/904,395 2007-02-28

Publications (2)

Publication Number Publication Date
WO2008143729A2 true WO2008143729A2 (en) 2008-11-27
WO2008143729A3 WO2008143729A3 (en) 2009-05-14

Family

ID=39433908

Family Applications (6)

Application Number Title Priority Date Filing Date
PCT/US2008/002716 WO2008106225A1 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same
PCT/US2008/002718 WO2008143729A2 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same
PCT/US2008/002715 WO2008106224A1 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same
PCT/US2008/002717 WO2008106226A2 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same
PCT/US2008/002732 WO2008143730A2 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same
PCT/US2008/002658 WO2008106204A1 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2008/002716 WO2008106225A1 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same

Family Applications After (4)

Application Number Title Priority Date Filing Date
PCT/US2008/002715 WO2008106224A1 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same
PCT/US2008/002717 WO2008106226A2 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same
PCT/US2008/002732 WO2008143730A2 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same
PCT/US2008/002658 WO2008106204A1 (en) 2007-02-28 2008-02-28 Macrolide compounds and methods of making and using the same

Country Status (1)

Country Link
WO (6) WO2008106225A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011013635A1 (en) * 2009-07-28 2011-02-03 セントラル硝子株式会社 Protected 2-fluoropropylamine having leaving group at 3-position or protected n-alkyl-2-fluoropropylamine having leaving group at 3-position
WO2012125832A2 (en) * 2011-03-15 2012-09-20 Rib-X Pharmaceuticals, Inc. Antimicrobial agents
CN103998419A (en) * 2011-10-17 2014-08-20 佐蒂斯有限责任公司 Novel phenicol antibacterials
US9573962B2 (en) 2009-10-16 2017-02-21 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US9845297B2 (en) 2009-10-16 2017-12-19 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US9937183B2 (en) 2013-09-09 2018-04-10 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US10106543B2 (en) 2013-09-09 2018-10-23 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US10947237B2 (en) 2015-03-11 2021-03-16 BioVersys AG Antimicrobial compounds and methods of making and using the same
CN115724823A (en) * 2021-08-27 2023-03-03 中国科学院大连化学物理研究所 Method for preparing dihydrothiophene derivative
US11999739B2 (en) 2016-05-06 2024-06-04 BioVersys AG Antimicrobials methods of making and using the same

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5662445B2 (en) * 2009-08-13 2015-01-28 バジリア ファルマスーチカ アーゲーＢａｓｉｌｅａ Ｐｈａｒｍａｃｅｕｔｉｃａ ＡＧ New macrolides and their use
MY160907A (en) 2009-11-13 2017-03-31 Receptos Inc Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
PT2498610T (en) 2009-11-13 2018-06-19 Celgene Int Ii Sarl Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
CN101735149B (en) 2009-11-30 2012-04-18 玉溪市维和生物技术有限责任公司 Macro-cyclic amide compound with antibacterial and anti-tumour activities, preparation method thereof and application thereof
AR085286A1 (en) * 2011-02-21 2013-09-18 Taisho Pharmaceutical Co Ltd MACROLIDO DERIVATIVE REPLACED IN POSITION C-4
ES2758841T3 (en) 2011-05-13 2020-05-06 Celgene Int Ii Sarl Selective heterocyclic sphingosine-1-phosphate receptor modulators
CA2840768A1 (en) 2011-06-30 2013-01-03 Piramal Imaging Sa Direct synthesis of 18f-fluoromethoxy compounds for pet imaging and new precursors for direct radiosynthesis of protected derivatives of o-([18f]fluoromethyl) tyrosine
JP5857008B2 (en) * 2012-08-20 2016-02-10 大正製薬株式会社 Medicament containing C-4 ″ substituted macrolide derivative
CN105153020A (en) * 2015-07-20 2015-12-16 湖南华腾制药有限公司 Preparation method for aromatic azide
CN105001118A (en) * 2015-07-20 2015-10-28 湖南华腾制药有限公司 Method for preparing iodine-containing azido compound
CN105152966A (en) * 2015-07-20 2015-12-16 湖南华腾制药有限公司 Preparation method for azide
WO2017066964A1 (en) 2015-10-22 2017-04-27 Merck Sharp & Dohme Corp. Oxazolidinone compounds and methods of use thereof as antibacterial agents
CN106562943B (en) * 2016-11-09 2019-07-16 济南市儿童医院 Memantine and its application in the drug of preparation treatment Acinetobacter bauamnnii infection
WO2018191682A1 (en) * 2017-04-15 2018-10-18 Melinta Therapeutics, Inc. Triazole compounds and methods of making and using the same
WO2018193117A1 (en) * 2017-04-20 2018-10-25 Novintum Biotechnology Gmbh Azithromycin derivatives containing a phosphonium ion as anticancer agents
CA3060892A1 (en) * 2017-04-20 2018-10-25 Rising Tide Foundation Azithromycin derivatives containing a phosphonium ion as anticancer agents
CN108727445B (en) * 2018-06-29 2021-06-11 宜昌东阳光生化制药有限公司 Synthesis method of azithromycin impurity F
CN115745823B (en) * 2022-11-03 2024-02-23 武夷学院 Preparation method and application of compound
CN116574014A (en) * 2023-05-25 2023-08-11 山东锐顺药业有限公司 Preparation method of zolmitriptan intermediate

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051855A2 (en) * 2000-12-01 2002-07-04 Kosan Biosciences, Inc. Motilide compounds
WO2004013153A2 (en) * 2002-08-01 2004-02-12 Zambon Group S.P.A. Macrolide compounds endowed with antiinflammatory activity
WO2005085266A2 (en) * 2004-02-27 2005-09-15 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE267835T1 (en) * 1997-10-16 2004-06-15 Pliva Pharm & Chem Works NEW 9A AZALIDE
US6664241B2 (en) * 2000-05-31 2003-12-16 Micrologix Biotech Inc. Water-soluble amide derivatives of polyene macrolides and preparation and uses thereof
US6995143B2 (en) * 2002-02-28 2006-02-07 Basilea Pharmaceutica Ag Macrolides with antibacterial activity
US6992069B2 (en) * 2002-04-30 2006-01-31 Yu-Gui Gu Tricyclic macrolide antibacterial compounds
ES2552682T3 (en) * 2003-03-10 2015-12-01 Merck Sharp & Dohme Corp. Novel antibacterial agents
WO2005121160A2 (en) * 2004-04-26 2005-12-22 Johnson & Johnson Pharmaceutical Research & Development 11, 12 cyclic thiocarbamate macrolide antibacterial agents
EP1934237A2 (en) * 2005-08-24 2008-06-25 Rib-X Pharmaceuticals, Inc. Triazole compounds and methods of making and using the same
EP1928893A2 (en) * 2005-08-24 2008-06-11 Rib-X Pharmaceuticals, Inc. Triazole compounds and methods of making and using the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051855A2 (en) * 2000-12-01 2002-07-04 Kosan Biosciences, Inc. Motilide compounds
WO2004013153A2 (en) * 2002-08-01 2004-02-12 Zambon Group S.P.A. Macrolide compounds endowed with antiinflammatory activity
WO2005085266A2 (en) * 2004-02-27 2005-09-15 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011013635A1 (en) * 2009-07-28 2011-02-03 セントラル硝子株式会社 Protected 2-fluoropropylamine having leaving group at 3-position or protected n-alkyl-2-fluoropropylamine having leaving group at 3-position
US10259825B2 (en) 2009-10-16 2019-04-16 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US9573962B2 (en) 2009-10-16 2017-02-21 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US9845297B2 (en) 2009-10-16 2017-12-19 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
WO2012125832A2 (en) * 2011-03-15 2012-09-20 Rib-X Pharmaceuticals, Inc. Antimicrobial agents
WO2012125832A3 (en) * 2011-03-15 2012-11-08 Rib-X Pharmaceuticals, Inc. Antimicrobial agents
CN103998419A (en) * 2011-10-17 2014-08-20 佐蒂斯有限责任公司 Novel phenicol antibacterials
US9937183B2 (en) 2013-09-09 2018-04-10 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US10106543B2 (en) 2013-09-09 2018-10-23 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US10947237B2 (en) 2015-03-11 2021-03-16 BioVersys AG Antimicrobial compounds and methods of making and using the same
US11999739B2 (en) 2016-05-06 2024-06-04 BioVersys AG Antimicrobials methods of making and using the same
CN115724823A (en) * 2021-08-27 2023-03-03 中国科学院大连化学物理研究所 Method for preparing dihydrothiophene derivative
CN115724823B (en) * 2021-08-27 2023-11-24 中国科学院大连化学物理研究所 Method for preparing dihydrothiophene derivative

Also Published As

Publication number Publication date
WO2008106225A1 (en) 2008-09-04
WO2008106226A2 (en) 2008-09-04
WO2008106226A3 (en) 2008-11-20
WO2008106224A1 (en) 2008-09-04
WO2008143730A2 (en) 2008-11-27
WO2008143729A3 (en) 2009-05-14
WO2008106204A1 (en) 2008-09-04
WO2008143730A3 (en) 2009-05-28

Similar Documents

Publication Publication Date Title
WO2008143729A2 (en) Macrolide compounds and methods of making and using the same
JP5631909B2 (en) Macrocyclic compounds and methods of making and using them
JP5395432B2 (en) Triazole compounds and methods for making and using the same
US9085600B2 (en) Triazole compounds and methods of making and using the same
WO2005118610A2 (en) Macrocyclic compounds and methods of making and using the same
US20070072811A1 (en) Bifunctional heterocyclic compounds and methods of making and using the same
WO2005042554A1 (en) Bifunctional macrolide heterocyclic compounds and methods of making and using the same
WO2005049632A1 (en) Bifunctional macrolide heterocyclic compounds and methods of making and using the same
WO2018191682A1 (en) Triazole compounds and methods of making and using the same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08794306

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08794306

Country of ref document: EP

Kind code of ref document: A2