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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
  • C07F7/1804—Compounds having Si-O-C linkages
  • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
  • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems

Definitions

• Streptococcus pneumonia infections can transmit genes coding for antibiotic resistance both vertically (to their progeny) and horizontally (to neighboring bacteria of different lineages), and as a result antibiotic resistance can evolve quickly, particularly in nosocomial (hospital) settings. See, e.g., Wright, Chem. Commun. (2011) 47:4055-4061. This year, >99,000 people will die in the U.S. from healthcare-associated infections, more than all casualties from car accidents, HIV, and breast cancer combined, creating an estimated burden of up to $45 billion in U.S. healthcare costs. See, e.g., Klevens et al., Public Health Rep (2007) 722: 160-166.
• the macrolides are one of the few major clinically important classes of antibiotics for which the only practical access has been through semi-synthesis, or chemical manipulation of structurally complex fermentation products, in routes as long as 16 steps. See, e.g., Paterson, Tetrahedron (1985) 47:3569-3624; Omura, Ed., Macrolide Antibiotics: Chemistry, Biology, and Practice, Second Edition; Academic Press, 2002.
• the macrolide class of antibiotics has proven safe and effective in the battle against pathogenic bacteria since the discovery of erythromycin over 60 years ago. See, e.g., Wu et al., Curr. Med. Chem. (2001) 8, 1727-1758.
• Erythromycin displays a spectrum of antibacterial activity against Gram- positive bacteria similar to that of penicillin but has a lesser propensity to induce allergic interactions, and has been routinely prescribed for upper and lower respiratory tract infections and urogenital infections. See, e.g., Washington et al., Mayo. Clin. Pwc. (1985) (50: 189-203; Washington et al., Mayo. Clin. Proc. (1985) 60:271-278.
• erythromycin is known to undergo acid-promoted internal ketalization (cyclization of the C6 and C12 hydroxyl groups onto the C9 ketone) in the gut, which leads to adverse gastrointestinal events.
• Second-generation macrolide antibiotics clarithromycin and azithromycin addressed issues of acid instability and were prepared semi- synthetically in 4-6 steps from erythromycin, which is readily available through large-scale fermentation. See, e.g., Ma et al, Curr. Med. Chem. (2011) 78: 1993-2015; Wu et al, Curr. Pharm. Des. (2000) 6: 181-223; Ma et al, Mini-Rev. Med. Chem. (2010) 70:272-286; Asaka et al., Curr. Top. Med. Chem.
• Azithromycin has been shown to exhibit markedly improved efficacy against Gram-negative organisms, and has a longer half-life and higher tissue distribution than the other macrolide antibiotics, thought to correlate with its 15- membered ring containing a tertiary amine. See, e.g., Ferwerda et al., J. Antimicwb.
• Ketolides such as telithromycin and solithromycin defeat the efflux mechanism of resistance by replacement of the C3 cladinose sugar with a carbonyl group (hence the name "ketolides"), and are thought to exhibit greatly increased binding by virtue of favorable interactions between the novel aryl-alkyl sidechain and the ribosome.
• ketolides such as telithromycin and solithromycin have not addressed several of the newest forms of macrolide resistanc that have evolved in nosocomial settings, especially ribosome methylation and RNA point mutations.
• Described herein are methods and intermediates for making macrolides, such as known macrolides, as well as new and improved macrolides, in a practical manner via a fully synthetic route.
• This practical synthetic methodology includes the coupling of two components, the western half (A), and the eastern half (B), as depicted in Scheme 1, to provide a compound of Formula (C-l):
• G 1 , R la , R lb , R 2a , R 2b , R 5a , R 5b , R 7 , R 8 , R 9 , R 11 , zl, and z2 are as defined herein;
• L is a group of formula:
• R 3 , R 4 , R 18 , R 19 , R 20 , and R 21 are as defined herein;
• R 6 , R 10 , R 15 , R 16a , and X G2 are as defined herein;
• P 1 is hydrogen, silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen, nitrogen, or thiol protecting group;
• G 3 is -0-, -S-, or -N(R G1 )-, wherein R G1 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group; and
• one of Y 1 and Y2 is -Z 4 H or -CH 2 N0 2
• R Z3 , R Z4 , R PI , R P2 , and R P r 3 j are as defined herein, to provide various linkages of formula Z, as defined herein.
• R Za and R 33 are each independently hydrogen or a non-hydrogen group, as defined herein.
• Z is -0-, -S-, or -NR -, and wherein R is hydrogen or a non-hydrogen group.
• Z is -0-, -S-, or -NR -, and wherein R is hydrogen or a non-hydrogen group.
• Z 4 is -0-, -S-, or -NR Z2 -, and wherein R Z2 is hydrogen or a non-hydrogen group.
• R is hydrogen or a non-hydrogen group.
• R Z ⁇ 4 to the imine double bond, and optionally followed by protection of the amine group by a non-hydrogen R Z2 , provides a compound of Formula (C-l), wherein Z is an imine or amine of formula:
• R is hydrogen or a non-hydrogen group.
• R Z2 is hydrogen or a non-hydrogen group.
• R Z ⁇ 4 to the imine double bond optionally followed by protection of the amine group by a non- hydrogen R , provides a compound of Formula (C-1), wherein Z is an imine or amine of formula:
• R is hydrogen or a non-hydrogen group.
• nitro-aldol reaction coupling products and oxidized, reduced, and/or addition products formed therefrom.
• the nitro (-N0 2 ) moiety may be manipulated at any stage in the synthesis, e.g., after coupling but before macrocylization, or after the macrolide has been formed.
• P 1 is hydrogen
• R 6 is a hydrogen or non-hydrogen group
• macrocyclization of the compound of Formula (C-1) provides a macrolide of Formula (C-2).
• Enolization of the macrolide of Formula (C-2) in the presence of a base, followed by addition of a non- hydrogen group R 10 provides a macrolide of Formula (C-3).
• Formula (C-467) and subgenera thereof as described herein are intended to encompass compounds of Formula (C-2), (C-4), (C6a), and (C7a) and subgenera thereof, wherein R Yl is -OR 17 and R Y2 is hydrogen, or R Yl is halogen and R Y2 is hydrogen, or R Yl is halogen and R Y2 is halogen.
• Figure 1 depicts exemplary 14-, 15-, and 16-membered macrolide antibiotics used in the United States.
• Figure 2 depicts the crystal structure of solithromycin bound to E. coli. Residues in a
• Figure 3 depicts the Zimmerman Traxler and Felkin-Ahn model of an aldol reaction between pseudoephanamine glycinamide and a ketone.
• Compounds and macrolides described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g. , enantiomers and/or diastereomers.
• the compounds and macrolides described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
• Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley).
• the invention additionally encompasses compounds and macrolides as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
• alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C ⁇ o alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“Ci-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci_6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“Ci_5 alkyl”).
• an alkyl group has 1 to 4 carbon atoms ("Ci ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Q alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -6 alkyl”).
• C ⁇ alkyl groups include methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
• Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (Cg) and the like. Unless otherwise specified, each instance of an alkyl group is
• the alkyl group is an unsubstituted Ci-io alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is a substituted Ci-io alkyl.
• haloalkyl is a substituted alkyl group as defined herein wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
• a halogen e.g., fluoro, bromo, chloro, or iodo.
• Perhaloalkyl is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
• the haloalkyl moiety has 1 to 8 carbon atoms ("Ci_g haloalkyl").
• the haloalkyl moiety has 1 to 6 carbon atoms ("C ⁇ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("Ci ⁇ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C ⁇ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C ⁇ haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group.
• haloalkyl hydrogen atoms are replaced with chloro to provide a "perchloroalkyl" group.
• haloalkyl groups include -CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CC1 3 , -CFC1 2 , -CF 2 C1, and the like.
• heteroalkyl refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more
• heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-g alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-g alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-7 alkyl").
• a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-e alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi-s alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“heteroCi ⁇ alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain
• heteroCi-s alkyl a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroC ⁇ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2 -6 alkyl").
• each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents.
• the heteroalkyl group is an unsubstituted heteroCi-io alkyl.
• the heteroalkyl group is a substituted heteroCi-io alkyl.
• alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds).
• an alkenyl group has 2 to 9 carbon atoms ("C 2 -9 alkenyl”).
• an alkenyl group has 2 to 8 carbon atoms ("C 2 -8 alkenyl”).
• an alkenyl group has 2 to 7 carbon atoms (“C 2 -7 alkenyl”).
• an alkenyl group has 2 to 6 carbon atoms (“C 2 -6 alkenyl”).
• an alkenyl group has 2 to 5 carbon atoms ("C 2 _5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2 _4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2 -3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
• the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl).
• Examples of C 2 - alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
• Examples of C 2 -6 alkenyl groups include the aforementioned C 2 - alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
• each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents.
• the alkenyl group is an unsubstituted C 2 _ 10 alkenyl.
• the alkenyl group is a substituted C 2 _ 10 alkenyl.
• heteroalkenyl refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -io alkenyl").
• a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 - 8 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -7 alkenyl").
• a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2
• heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms within the parent chain ("heteroC 2 ⁇ alkenyl”).
• a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC 2 -3 alkenyl”).
• a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 -6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is
• the heteroalkenyl group is an unsubstituted heteroC 2 -io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2 -io alkenyl.
• alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2 -io alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2 -9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2 _ 8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2 _ 7 alkynyl").
• an alkynyl group has 2 to 6 carbon atoms ("C 2 -6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2 _5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 -3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
• the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl).
• Examples of C 2 ⁇ alkynyl groups include, without limitation, ethynyl (C 2 ), 1- propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
• Examples of C 2 -6 alkenyl groups include the aforementioned C 2 - alkynyl groups as well as pentynyl (C5), hexynyl (C 6 ), and the like.
• alkynyl examples include heptynyl (C 7 ), octynyl (Cg), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2 _ 10 alkynyl. In certain embodiments, the alkynyl group is a substituted C 2 _ 10 alkynyl.
• heteroalkynyl refers to an alkynyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -io alkynyl").
• a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -8 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2 -7 alkynyl").
• a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroC 2 -6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC 2 - alkynyl").
• a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC 2 -3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents.
• the heteroalkynyl group is an unsubstituted heteroC 2 -io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2 -io alkynyl.
• carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3_ 14 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
• a carbocyclyl group has 3 to 10 ring carbon atoms ('3 ⁇ 4_ 10 carbocyclyl”).
• a carbocyclyl group has 3 to 9 ring carbon atoms ("C 3 _9 carbocyclyl”).
• a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 carbocyclyl”).
• a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3 _ 7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4 _6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“Cs_6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl”). Exemplary C 3 _6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ),
• cyclopropenyl C 3
• cyclobutyl C 4
• cyclobutenyl C 4
• cyclopentyl C 5
• cyclopentenyl C 5
• cyclohexyl C 6
• cyclohexenyl C 6
• cyclohexadienyl C 6
• Exemplary C 3 _ 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
• Exemplary C 3 _ 10 carbocyclyl groups include, without limitation, the
• C 3 _ 8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C 9 ), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
• the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
• Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
• each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
• the carbocyclyl group is an unsubstituted C 3 _ 14 carbocyclyl.
• the carbocyclyl group is a substituted C 3 _ 14 carbocyclyl.
• “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3 _ 14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C ⁇ o cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 9 ring carbon atoms ("C 3 _g cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl").
• a cycloalkyl group has 3 to 7 ring carbon atoms ("C 3 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl").
• C 5 _6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
• Examples of C 3 _6 cycloalkyl groups include the aforementioned C 5 _6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
• Examples of C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _ 6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an
• the cycloalkyl group is an unsubstituted C 3 _ 14
• the cycloalkyl group is a substituted C 3 _ 14 cycloalkyl.
• heterocyclyl or “heterocyclic” refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl").
• the point of attachment can be a carbon or nitrogen atom, as valency permits.
• a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
• Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
• Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
• each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
• the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
• a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
• a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
• a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is
• the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
• Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
• Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
• Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
• Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
• Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
• Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
• Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
• Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl.
• Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
• Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
• Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
• decahydronaphthyridinyl decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e] [l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro- 5H-furo [3 ,2-b]pyranyl, 5 ,7-dihydro-4H-thieno [2,3-c] pyranyl, 2,3-dihydro- 1 H- pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 2,
• aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6 -i 4 aryl”).
• an aryl group has 6 ring carbon atoms ("C 6 aryl”; e.g., phenyl).
• an aryl group has 10 ring carbon atoms ("Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
• an aryl group has 14 ring carbon atoms ("C 14 aryl”; e.g., anthracyl).
• Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is
• the aryl group is an unsubstituted C 6 - 14 aryl. In certain embodiments, the aryl group is a substituted C 6 -i 4 aryl.
• Aralkyl is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by an aryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.
• An exemplary aralkyl group is -CH 2 -phenyl (benzyl, Bz), wherein the phenyl moiety may be substituted or unsubstituted.
• heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl").
• the point of attachment can be a carbon or nitrogen atom, as valency permits.
• Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
• Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
• Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
• Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
• the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
• a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
• a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
• a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
• the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
• each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents.
• the heteroaryl group is an unsubstituted 5-14 membered heteroaryl.
• the heteroaryl group is a substituted 5-14 membered heteroaryl.
• Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
• Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
• Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
• 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
• Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
• Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
• 6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
• Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
• Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
• Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
• Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
• Heteroaralkyl is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.
• the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond.
• the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.
• the term “saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.
• alkylene is the divalent moiety of alkyl
• alkenylene is the divalent moiety of alkenyl
• alkynylene is the divalent moiety of alkynyl
• heteroalkylene is the divalent moiety of heteroalkyl
• heteroalkenylene is the divalent moiety of heteroalkenyl
• heteroalkynylene is the divalent moiety of heteroalkynyl
• carbocyclylene is the divalent moiety of carbocyclyl
• heterocyclylene is the divalent moiety of heterocyclyl
• arylene is the divalent moiety of aryl
• heteroarylene is the divalent moiety of heteroaryl.
• alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are, in certain embodiments, optionally substituted.
• Optionally substituted refers to a group which may be substituted or unsubstituted ⁇ e.g., "substituted” or "unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, "substituted” or
• substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
• a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
• substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
• the present invention contemplates any and all such combinations in order to arrive at a stable compound.
• heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
• R ⁇ is, independently, selected from C ⁇ o alkyl, Cno perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, heteroCi-io alkyl, heteroC ⁇ o alkenyl, heteroC ⁇ io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6 -i 4 aryl, and 5-14 membered heteroaryl, or two R ⁇ groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl,
• each instance of R cc is, independently, selected from hydrogen, C ⁇ o alkyl, C ⁇ o perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, heteroCi-io alkyl, heteroC ⁇ io alkenyl, heteroC ⁇ io alkynyl, C 3 _ 10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
• each instance of R ee is, independently, selected from d_6 alkyl, d_6 perhaloalkyl, C 2 6 alkenyl, C 2 _ 6 alkynyl, heterod_6 alkyl, heteroC 2 _6alkenyl, heteroC 2 _6 alkynyl, C 3 _ 10 carbocyclyl, C 6 -io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
• each instance of R is, independently, selected from hydrogen, d_6 alkyl, d_6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heterod_6 alkyl, heteroC 2 _6 alkenyl, heteroC 2 _6 alkynyl, C 3 _ 10 carbocyclyl, 3-10 membered heterocyclyl, C 6 -io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
• halo refers to fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), or iodine (iodo, -I).
• a "counterion” is a negatively charged group associated with a positively charged quarternary amine in order to maintain electronic neutrality.
• exemplary counterions include halide ions (e.g., F “ , CI “ , Br “ , ⁇ ), N0 3 " , C10 4 “ , OH “ , H 2 P0 4 “ , HS0 4 “ , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, prop
• hydroxyl refers to the group -OH.
• thiol refers to the group -SH.
• amino refers to the group -NH 2 .
• substituted amino by extension, refers to a mono substituted amino, a disubstituted amino, or a trisubstituted amino, as defined herein. In certain embodiments, the "substituted amino” is a monosubstituted amino or a disubstituted amino group.
• trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from -N(R bb ) 3 and -N(R bb ) 3 + X ⁇ , wherein R bb and X " are as defined herein.
• alkoxyalkyl refers to an alkyl group as defined herein substituted by a group of formula -OR ⁇ wherein R aa is as defined herein, wherein the point of attachment is on the alkyl group.
• aminoalkyl refers to an alkyl group as defined herein substituted by an amino or substituted amino group, as defined herein, wherein the point of attachment is on the alkyl group.
• sulfonyl refers to a group selected from -S0 2 N(R bb ) 2 , - S0 2 R aa , and -S0 2 OR aa , wherein R ⁇ and R bb are as defined herein.
• sil refers to the group -Si(R aa ) 3 , wherein R aa is as defined herein.
• Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
• the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group").
• Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di- i-butyl-[9-( 10,10-dioxo-l 0, 10,10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l
• TBOC l-methyl-l-(4-biphenylyl)ethyl carbamate
• Bpoc l-(3,5-di-/-butylphenyl)-l- methylethyl carbamate
• Pyoc 2-(2'- and 4'-pyridyl)ethyl carbamate
• 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate i-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carb
• Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5, 6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide
• nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)- acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl- 3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl- l,3,5-triazacyclohexan-2-one, 5-sub
• benzenesulfenamide o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,
• triphenylmethylsulfenamide triphenylmethylsulfenamide
• 3-nitropyridinesulfenamide Npys
• the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group").
• oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
• DPMS diphenylmethylsilyl
• TMPS i-butylmethoxyphenylsilyl
• dimethylphosphinothioyl dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
• the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group").
• Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
• LG is an art-understood term referring to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
• At least one instance refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
• non-hydrogen group refers to any group that is defined for a particular variable that is not hydrogen.
• a "carbohydrate group” or a “carbohydrate” refers to a monosaccharide or a polysaccharide (e.g., a disaccharide or oligosaccharide).
• exemplary monosaccharides include, but are not limited to, natural sugars, such as allose, altrose, glucose, mannose, gulose, idose, galactose, talose, ribose, arabinose, xylose, and lyxose.
• Disaccharides are two joined monosaccharides.
• Exemplary disaccharides include, but are not limited to, sucrose, maltose, cellobiose, and lactose.
• an oligosaccharide includes between three and ten monosaccharide units (e.g., raffinose, stachyose).
• the carbohydrate group may be a natural sugar or a modified sugar.
• modified sugars include, but are not limited to, sugars where the hydroxyl group is replaced with an amino group and/or alkyl group (e.g., such as desosamine), 2'-deoxyribose wherein a hydroxyl group is removed, 2'-fluororibose wherein a hydroxyl group is replace with a fluorine, or N-acetylglucosamine, or a nitrogen- containing form of glucose (e.g., 2'-fluororibose, deoxyribose, and hexose), and the like.
• Various carbohydrates are further described below and herein. Carbohydrates may exist in many different forms, for example, conformers, cyclic forms, acyclic forms, stereois
• salt refers to any and all salts, and encompasses pharmaceutically acceptable salts.
• pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. , describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
• Pharmaceutically acceptable salts of the macrolides of this invention include those derived from suitable inorganic and organic acids and bases.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
• Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 ⁇ alkyl) 4 salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
• a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other non-human animals, for example mammals [e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs], birds (e.g.
• humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)
• non-human animals for example mammals [e.g., primates (e.g., cyno
• the non-human animal is a mammal.
• the non-human animal may be a male or female and at any stage of development.
• a non-human animal may be a transgenic animal.
• the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified infectious disease or inflammatory condition, which reduces the severity of the infectious disease or inflammatory condition, or retards or slows the progression of the infectious disease or inflammatory condition ("therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified infectious disease or inflammatory condition (“prophylactic treatment").
• the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response.
• the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.
• An effective amount encompasses therapeutic and prophylactic treatment.
• a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of an infectious disease or inflammatory condition, or to delay or minimize one or more symptoms associated with the infectious disease or inflammatory condition.
• a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the infectious disease or inflammatory condition.
• the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of infectious disease or inflammatory condition, or enhances the therapeutic efficacy of another therapeutic agent.
• a prophylactically effective amount of a compound is an amount sufficient to prevent an infectious disease or inflammatory condition, or one or more symptoms associated with the infectious disease or inflammatory condition, or prevent its recurrence.
• a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the infectious disease or inflammatory condition.
• the term "prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
• the present invention is, in part, directed to macrolides of the formulae below, constructed from the coupling of an eastern half and western half, followed by macrocyclization and further synthetic
• L and L are each independently a bond or -CH 2 -; zl and z2 are each independently 0, 1, or 2 and Z is -0-, -S-, or -NR -, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system 13-membered ring system wherein the macrolide is prepared by macrocyclization (e.g., thermally induced
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are each independently 0, 1, or 2, and Z is -0-, -S-, or -NR -, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system wherein in certain embodiments the macrolide is prepared from macrocyclization (e.g., thermally induced) of the coupled precursor compound of the below formula, optionally followed by further synthetic manipulation, as described herein:
• L and L are each independently a bond or -CH 2 -; zl and z2 are each independently 0, 1, or 2, and Z is -0-, -S-, or -NR -, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• the macrolide is prepared from macrocyclization (e.g., thermally induced) of the coupled precursor compound of the below formula, optionally followed by further synthetic manipulation, as described herein:
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are 0, 1, or 2, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system wherein the macrolide is prepared from macrocyclization (e.g., thermally induced macrocyclization) of the coupled precursor of the below formula, optionally followed by further synthetic manipulation, as described herein:
• macrocyclization e.g., thermally induced macrocyclization
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are each independently 0, 1, or 2, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• the macrolide is prepared, in part, from macrocyclization (e.g., thermally induced macrocyclization) of the coupled precursor compound of the below formula, optionally followed by further synthetic manipulation, as described herein:
• macrocyclization e.g., thermally induced macrocyclization
• L 1 and L 2 are each independently a bond and zl and z2 are 1 or 2, e.g., to provide a ring system of formula:
• 16-membered ring system 16-membered ring system wherein the macrolide is prepared from macrocyclization (e.g., thermally induced macrocyclization) of the coupled precursor of the below formula, optionally followed by further synthetic manipulation, as described herein:
• macrocyclization e.g., thermally induced macrocyclization
• L 1 and L 2 are each independently a bond and zl and z2 are each independently 1 or 2 to provide a ring system of formula:
• 16-membered ring system 16-membered ring system wherein in certain embodiments the macrolide is prepared, in part, from macrocyclization (e.g., thermally induced macrocyclization) of the coupled precursor compound of the below formula, optionally followed by further synthetic manipulation, as described herein:
• macrocyclization e.g., thermally induced macrocyclization
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are each independently 0, 1, or 2, e.g., to provide a ring system of any one of formula:
• the macrolide is prepared, in part, from macrocyclization ⁇ e.g., thermally induced macrocyclization) of the coupled precursor compound of the below formula,
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are each independently 0, 1, or 2, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• the macrolide is prepared from macrocyclization (e.g., thermally induced macrocyclization) of the coupled precursor compound of the below formula, optionally followed by further synthetic manipulation, as described herein:
• L and L are each independently a bond or -CH 2 -; zl and z2 are 0, 1, or 2, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system wherein in certain embodiments the macrolide is prepared from macrocyclization (e.g., thermally induced macrocyclization) of the coupled precursor of one of the formulae, optionally followed by further synthetic manipulation, as described herein:
• macrocyclization e.g., thermally induced macrocyclization
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are 0, 1, or 2, e.g., to provi -, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system wherein in certain embodiments the macrolide is prepared, in part, from macrocyclization (e.g., thermally induced) of the coupled precursor compound of the below formula, optionally followed by further synthetic manipulation, as described herein:
• macrocyclization e.g., thermally induced
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are 0, 1, or 2, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system 13-membered ring system wherein in certain embodiments the macrolide is prepared, in part, from macrocyclization (e.g., thermally induced) of the coupled precursor compound of the below formula, optionally followed b further s nthetic mani ulation as described herein:
• macrocyclization e.g., thermally induced
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are 0, 1, or 2, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• the macrolide is prepared, in part, from macrocyclization (e.g., thermally induced) of the coupled precursor compound of the below formula, optionally
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are 0, 1, or 2 e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system wherein in certain embodiments the macrolide is prepared, in part, from macrocyclization (e.g., thermally induced macrocyclization) of the coupled precursor compound of the below
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are 0, 1, or 2, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system 13-membered ring system wherein in certain embodiments the macrolide is prepared, in part, from macrocyclization (e.g., thermally induced) of the coupled precursor compound of the below formula, optionally follo
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are 0, 1, or 2, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system wherein in certain embodiments the macrolide is prepared, in part, from macrocyclization (e.g., thermally induced) of the coupled precursor compound of the below formula, optionally followed by further synthetic manipulation, as described herein:
• macrocyclization e.g., thermally induced
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are 0, 1, or 2, e.g., to provide a 13-, 14-, 15- or 16-membered ring system, e.g., of formula:
• 13-membered ring system wherein in certain embodiments the macrolide is prepared, in part, from macrocyclization (e.g., thermally induced) of the coupled precursor compound of the below formula, optionally followed by further synthetic manipulation, as described herein:
• macrocyclization e.g., thermally induced
• L 1 and L 2 are each independently a bond or -CH 2 -; zl and z2 are each independently 0, 1, or 2, e.g., to provide a 14-, 15- or 16-membered ring system, e.g., of formula:
• 14-membered ring system 14-membered ring system wherein the macrolide is prepared by macrocyclization (e.g., thermally induced
• R is -OR and R is hydrogen, or R is halogen and R is hydrogen, or R is R Y2 Y 1 Y2
• each instance of R la , R lb , R 2a , and R 2b is independently hydrogen, halogen, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, optionally substituted heteroaryl, or wherein R la and R lb or R 2a and R 2b can be taken
• R 3 ⁇ 4 and R ⁇ are each independently hydrogen, halogen, hydroxyl, substituted hydroxyl, amino, substituted amino, thiol, substituted thiol, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, optionally
• R Z3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl;
• R is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl;
• L is a group of formula:
• R 4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• each instance of R 18 and R 19 independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each instance of R and R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, halogen, carbonyl, or R 20 and R 21 are joined to form an optionally substituted cyclopropyl or an oxiranyl ring;
• each instance of R 5a and R 5b is independently hydrogen, halogen, silyl, optionally substituted alkyl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
• R 6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substitued aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, silyl, or halogen;
• R 7' and R 8° are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• R 10 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, substituted amino, carbonyl, silyl, and halogen;
• G 3 is -0-, -S-, or -N(R G1 )-, wherein R G1 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group;
• P 1 is hydrogen, silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen, nitrogen, or thiol protecting group;
• G 1 is -OR 12 or -NR 13 R 14 ;
• R 11 and R 12 are not joined, and R 11 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group, and R 12 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group, or a group of formula:
• R 11 and R 13 are not joined,
• R 11 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group
• R 13 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
• R 13 and R 14 are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl;
• G is a group of formula:
• each instance of ⁇ ⁇ is -OR , -SR , or -N(R 13 ) 2 ;
• each instance of R 15 is independently silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or two R 15 groups can be taken together to form an optionally substituted heteroaryl or heterocyclic ring;
• each instance of R 16a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• each instance of L CI and L C2 is independently a bond, or a linking group selected from the group consisting of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene; optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, and combinations thereof;
• alkenyl substituted or unsubstituted alkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or a nitrogen protecting group;
• R W2 is hydrogen, optionally substituted alkyl; optionally substituted alkenyl;
• optionally substituted alkynyl optionally substituted carbocyclyl; optionally substituted heterocyclyl; optionally substituted aryl; or optionally substituted heteroaryl, or two R W2 groups are joined to form an optionally substituted cyclic moiety;
• R X 1 is hydrogen, halogen, or -OR X2 , wherein R X2 is hydrogen; optionally substituted alkyl; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; optionally substituted heterocyclyl; optionally substituted aryl; optionally substituted heteroaryl; or an oxygen protecting group;
• R 23 is optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted carbocyclyl; optionally substituted heterocyclyl; optionally substituted aryl; or optionally substituted heteroaryl; and
• each instance of R Z8 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocylyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R Z8 groups are joined to form an optionally substituted heterocylyl or optionally substituted heteroaryl ring;
• A is a cyclic moiety selected from the group consisting of optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
• macrolides of the present invention are prepared by coupling of an western half (A) with an eastern half (B) to provide a compound of Formula (C-1), as depicted in Scheme 8:
• L 1 , L 2 , L 3 , G 1 , G 3 , R la , R lb , R 2a , R 2b , R 5a , R 5b , R 7 , R 8 , R 9 , R 11 , zl, and z2 are as defined herein;
• P 1 is hydrogen, silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen, nitrogen, or thiol protecting group;
• G is a group of formula:
• R 6 and R 10 are as defined herein;
• each instance of ⁇ ⁇ is -OR , -SR , or -N(R 13 ) 2 ;
• each instance of R 15 is independently silyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or two R 15 groups can be taken together to form an optionally substituted heteroaryl or heterocyclic ring;
• each instance of R 16a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• one of Y 1 and Y2 is -Z 4 H or -CH 2 N0 2
• R Z3 , R Z4 , R PI , R P2 , and R P r 3 j are as defined herein, to provide various linkages of formula Z.
• the double bond of the above recited formula is provided in the ds-configuration. In certain embodiments, the double bond of the above recited formula is provided in the /raws-configuration. [00104] 2 Z3 Z3
• the double bond of the above recited formula is provided in the ds-configuration. In certain embodiments, the double bond of the above recited formula is provided in the /raws-configuration.
• the double bond may be reduced to a single bond, and optionally the carbon alpha to the ketone may be substituted by a non-hydrogen group R Za .
• a nucleophile may react with the double bond via 1,4-addition of a non-hydrogen group R zb optionally followed by alpha substitution via a non-hydrogen group R 2 .
• R Za and R 33 are each independently hydrogen or a non-hydrogen group (e.g., halogen, hydroxyl, substituted hydroxyl, amino, substituted amino, thiol, substituted thiol, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl).
• a non-hydrogen group e.g., halogen, hydroxyl, substituted hydroxyl, amino, substituted amino, thiol, substituted thiol, carbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
• Z is -0-, -S-, or -NR -, and wherein R is hydrogen or a non-hydrogen group.
• Exemplary bases include, but are not limited to, organic bases (e.g., pyridine, DMAP, Hunig' s base) and inorganic bases (e.g., sodium bicarbonate, sodium carbonate).
• Exemplary leaving groups include bromine, chlorine, iodine, tosylate, triflate, mesylate, and besylate.
• Z is -0-, -S-, or -NR -, and wherein R is hydrogen or a non-hydrogen group.
• the reaction proceeds in the presence of a coupling agent, e.g., a carbodiimide reagent.
• a coupling agent e.g., a carbodiimide reagent.
• exemplary bases include, but are not limited to, organic bases (e.g., pyridine, DMAP, Hunig' s base) and inorganic bases (e.g., sodium bicarbonate, sodium carbonate).
• exemplary leaving groups include bromine, chlorine, iodine, tosylate, mesylate, triflate, and besylate.
• the reaction proceeds in the presence of a coupling agent, e.g., a carbodiimide reagent.
• a coupling agent e.g., a carbodiimide reagent.
• exemplary bases include, but are not limited to, organic bases (e.g., pyridine, DMAP, Hunig's base) and inorganic bases (e.g., sodium bicarbonate, sodium carbonate).
• Exemplary leaving groups include bromine, chlorine, iodine, tosylate, mesylate, triflate, and besylate.
• R Z2 is hydrogen or a non-hydrogen group.
• exemplary reductive amination conditions include, but are not limited to, use of B 10 H 14 , InCl 3 /Et 3 SiH, NaBH 4 , NaBH /H B0 3 ,
• R Z2 is hydrogen or a non-hydrogen group. In certain embodiments, R Z2 is hydrogen.
• R Z4 is added to the imine double bond via a nucleophilic reagent, R Z4 M, wherein M is an anion, Li, K, CuX, or MgX, wherein X is halogen.
• R is hydrogen or a non-hydrogen group.
• exemplary reductive amination conditions include, but are not limited to, use of B 10 H 14 , InCl 3 /Et 3 SiH, NaBH 4 , NaBH /H B0 3 ,
• NaBH 3 CN or NaBH(OAc) 3 optionally in the prescence of an acid (e.g., AcOH, TFA) or protic solvent (e.g., MeOH).
• R Z2 is hydrogen.
• R is hydrogen or a non-hydrogen group. In certain embodiments, R is hydrogen.
• R Z4 is added to the imine double bond via a nucleophilic reagent, R Z4 M, wherein M is an anion, Li, K, CuX, or MgX, wherein X is halogen.
• nitro-aldol reaction (Henry reaction) coupling products, and oxidized, reduced, and/or addition products formed therefrom.
• the nitro aldol reaction may be catalyzed or promoted by many different sets of conditions, e.g., use of an organic base, inorganic base, quaternary ammonium salt, and/or a catalyst; and use of protic or aprotic solvents and/or use of solventless conditions. See, e.g., Luzzio Tetrahedron (2001) 915-945, for a review of various conditions employed in a nitro aldol reaction.
• the nitro (-N0 2 ) moiety may be manipulated at any stage in the synthesis.
• R 6 is a hydrogen or non-hydrogen group, macrocyclization of the compound of Formula
• (C-l) e.g., wherein P is hydrogen, provides a macrolide of Formula (C-2).
• Enolization of the macrolide of Formula (C-2), followed by addition of a non-hydrogen group R e.g., with a base and an R alkylating agent, e.g., R 1U -LG, or with a halogenating agent if R , 1 1 U 0 is halogen
• R e.g., with a base and an R alkylating agent, e.g., R 1U -LG, or with a halogenating agent if R , 1 1 U 0 is halogen
• each of R 6 and R 10 is a hydrogen or non-hydrogen group, macrocyclization of the compound of Formula (C-l) e.g., wherein P 1 is hydrogen, provides a macrolide of Formula (C-3).

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