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WO2019032941A1 - Nouveaux antibiotiques de type lincosamides et utilisations correspondantes - Google Patents

Nouveaux antibiotiques de type lincosamides et utilisations correspondantes Download PDF

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Publication number
WO2019032941A1
WO2019032941A1 PCT/US2018/046178 US2018046178W WO2019032941A1 WO 2019032941 A1 WO2019032941 A1 WO 2019032941A1 US 2018046178 W US2018046178 W US 2018046178W WO 2019032941 A1 WO2019032941 A1 WO 2019032941A1
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substituted
unsubstituted
compound
certain embodiments
pharmaceutically acceptable
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Andrew G. Myers
Matthew James MITCHELTREE
Ioana MOGA
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Harvard University
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Harvard University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C07H15/16—Lincomycin; Derivatives thereof

Definitions

  • the lincosamides are a class of antibiotics that prevent bacteria growth by interfering with the synthesis of proteins. They bind to the 23s portion of the 50S subunit of bacterial ribosomes and cause premature dissociation of the peptidyl-tRNA from the ribosome. Lincosamides do not interfere with protein synthesis in human cells (or those of other eukaryotes) because human ribosomes are structurally different from those of bacteria.
  • Lincosamides are typically used to treat Staphylococcus and Streptococcus infections but have also proved to be useful in treating Bacteroides fragilis and other anaerobic infections. They are used in the treatment of toxic shock syndrome and thought to directly block the M protein production that leads to the severe inflammatory response.
  • Lincomycin Clindamycin [0005] Target bacteria may alter the drug’s binding site leading to resistance (similar to resistance found with macrolides and streptogramins). The resistance mechanism is methylation of the 23s binding site. If this occurs, then the bacteria are resistant to both macrolides and lincosamides. In rare instances, enzymatic inactivation of clindamycin has also been reported.
  • lincosamide antibiotics are associated with pseudomembranous colitis caused by Clostridium difficile (C. difficile).
  • Pseudomembranous colitis is inflammation of the colon associated with an overgrowth of C. difficile. This overgrowth of C. difficile is most often related to recent lincosamide antibiotic use.
  • clindamycin currently the only lincosamide in clinical use, carries a black-box warning for its tendency to promote C. difficile-associated diarrhea (CDAD).
  • a powerful and versatile synthetic platform for the discovery of new synthetic lincosamide antibiotics is disclosed herein.
  • This platform enables the production of lincosamides bearing unprecedented modifications to both constituent halves of the lincosamides, namely the aminooctose (northern) and amino-acid (southern) portions.
  • Lincosamides generated using this platform demonstrate potent activity against high-priority, clinically relevant pathogens including clindamycin- and azithromycin-resistant strains of S. aureus, S. pneumoniae, and E. faecalis–strains against which effective new antibiotics are in demand.
  • the disclosed lincosamides show promise as safer alternatives to clindamycin, owing to a diminished negative impact on commensal gut flora due to increased activity against C. difficile.
  • the disclosed lincosamides also demonstrate activity against Gram-negative pathogens like E. coli.
  • P is independently hydrogen or a protecting group
  • A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
  • heterocyclyl , , , or ;
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic,–OR A ,–N(R A ) 2 , or–SR A ;
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 6a , R 6b , and R 6c are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, or substituted or unsubstituted acyl;
  • R 7 is hydrogen or unsubstituted alkyl; or A and R 7 are joined to form a substituted or unsubstituted heterocyclic ring;
  • p 0-4;
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or
  • R 1 is–SR A wherein R A is C 1-6 substituted or unsubstituted alkyl
  • A is not unsubstituted carbocyclyl, .
  • the present disclosure provides compounds of Formulae (I- a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), and (I-o):
  • P is independently hydrogen or a protecting group
  • A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic,–OR A ,–N(R A ) 2 , or–SR A ;
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroaliphatic;
  • R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 6a , R 6b , and R 6c are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, or substituted or unsubstituted acyl;
  • R 7 is hydrogen or unsubstituted alkyl; or A and R 7 are joined to form a substituted or unsubstituted heterocyclic ring;
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or
  • E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene;
  • R b and R c are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted
  • the present disclosure provides compounds of Formulae (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II- n), (II-o), (II-p), and (II-q):
  • the disclosed compounds have anti-microbial activity and may be used to treat and/or prevent infectious diseases.
  • Pharmaceutical compositions of the compounds, kits comprising the compounds and/or compositions, and methods of treatment using the compounds and compositions thereof are provided herein.
  • Infectious diseases which may be treated with the disclosed compounds include, but are not limited to, bacterial infections caused by Staphylococcus, Streptococcus, Enterococcus, Acinetobacter, Clostridium, Bacterioides, Klebsiella, Escherichia, Pseudomonas, and Haemophilus species.
  • the disclosed compounds are prepared by an amide coupling of the aminooctose (northern) and amino-acid (southern) portions.
  • the compounds disclosed herein include lincosamide analogues.
  • the disclosed compounds have increased structural diversity over known lincosamides, such as lincomycin and clindamycin.
  • the disclosed compounds have structures that have a seven- membered ring at the amino-acid (southern) region, and may also be modified at the C-1 and C-7 positions of the aminooctose (northern) region.
  • the disclosed lincosamides provide unexpected and potent activity against various microorganisms, including Gram negative bacteria.
  • the disclosed lincosamides are non-hemolytic, non-toxic, and possess improved activity profiles relative to clindamycin, such as increased activity against resistant strains of bacteria, including Clostridium difficile. Also disclosed are methods for the preparation of the compounds, pharmaceutical compositions comprising the disclosed compounds, uses of the compounds, and methods of using the compounds (e.g., treatment of an infectious disease, prevention of an infectious disease).
  • P is independently hydrogen or a protecting group
  • A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic,–OR A ,–N(R A ) 2 , or–SR A ;
  • R 2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 6a , R 6b , and R 6c are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, or substituted or unsubstituted acyl;
  • R 7 is hydrogen or unsubstituted alkyl; or A and R 7 are joined to form a substituted or unsubstituted heterocyclic ring;
  • p 0-4;
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or
  • R 1 is–SR A wherein R A is C 1-6 substituted or unsubstituted alkyl
  • R A is C 1-6 substituted or unsubstituted alkyl, A is not unsubstituted carbocyclyl, , wherein R A is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted acyl.
  • R 1 is–SR A
  • A is not
  • R 1 is–SR A wherein R A is C 1-6 substituted or unsubstituted alkyl, A is not unsubstituted C 3-6 cycloalkyl,
  • R A is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted acyl;
  • R 1 is not substituted or unsubstituted alkyl, or– OR A wherein R A is substituted or unsubstituted alkyl.
  • R 1 is not–OR A , or substituted or unsubstituted alkyl.
  • each P is hydrogen
  • P is independently hydrogen or a protecting group
  • A is substituted or unsubstituted carbocyclyl, substituted or unsubstituted
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic,–OR A ,–N(R A ) 2 , or–SR A ;
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 6a , R 6b , and R 6c are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, or substituted or unsubstituted acyl;
  • R 7 is hydrogen or unsubstituted alkyl; or A and R 7 are joined to form a substituted or unsubstituted heterocyclic ring;
  • each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or
  • E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
  • R b and R c are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted
  • each P is hydrogen
  • any formulae described herein are also meant to include salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof.
  • the provided compound is a salt of any of the formulae described herein.
  • the provided compound is a pharmaceutically acceptable salt of any of the formulae described herein.
  • the provided compound is a solvate of any of the formulae described herein.
  • the provided compound is a hydrate of any of the formulae described herein.
  • the provided compound is a polymorph of any of the formulae described herein.
  • the provided compound is a co-crystal of any of the formulae described herein. In certain embodiments, the provided compound is a tautomer of any of the formulae described herein. In certain embodiments, the provided compound is a stereoisomer of any of the formulae described herein. In certain embodiments, the provided compound is of an isotopically labeled form of any of the formulae described herein. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a 12 C by a 13 C or 14 C are within the scope of the disclosure. In certain embodiments, the provided compound is a deuterated form of any of the formulae or compounds described herein. Group A
  • A is substituted or unsubstituted carbocyclyl
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • R 6a , R 6b , and R 6c are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic, or substituted or unsubstituted acyl.
  • A is
  • A is .
  • R 2 is substituted or
  • R 2 is substituted or unsubstituted 5- membered heteroaryl. In certain embodiments, R 2 is substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, or triazolyl.
  • R 2 is halogen, substituted or unsubstituted alkyl,–OR A ,– N 3 ,–N(R A ) 2 , or–SR A . In certain embodiments, R 2 is halogen or–SR A . In certain embodiments,
  • R 2 is -Cl or–SCH 3 . In certain embodiments, R 2 is -Cl. In certain embodiments, R 2 is–SCH 3 .
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl. In certain embodiments, R 3 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 3 is unsubstituted C 1-6 alkyl. In certain embodiments, R 3 is unsubstituted C 1-3 alkyl. In certain embodiments, R 3 is unsubstituted C 1-2 alkyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is methyl.
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl. In certain embodiments, R 4 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 4 is unsubstituted C 1-6 alkyl. In certain embodiments, R 4 is unsubstituted C 1-3 alkyl. In certain embodiments, R 4 is unsubstituted C 1-2 alkyl. In certain embodiments, R 4 is ethyl. In certain embodiments, R 4 is methyl.
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; and
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl.
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; and
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl.
  • R 2 is halogen, substituted or unsubstituted alkyl,–OR A ,– N 3 ,–N(R A ) 2 , or–SR A ;
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl;
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl.
  • R 2 is halogen, substituted or unsubstituted alkyl,–OR A ,– N 3 ,–N(R A ) 2 , or–SR A ;
  • R 3 is hydrogen or substituted or unsubstituted alkyl; and
  • R 4 is hydrogen or substituted or unsubstituted alkyl.
  • R 2 is halogen,–OR A , or–SR A ; R 3 is hydrogen or substituted or unsubstituted alkyl; and R 4 is hydrogen or substituted or unsubstituted alkyl.
  • R 2 is is halogen or–SR A ; R 3 is substituted or unsubstituted alkyl; and R 4 is hydrogen.
  • R 2 is is -Cl or–SCH 3 ; R 3 is substituted or unsubstituted alkyl; and R 4 is hydrogen.
  • R 2 is halogen; R 3 is halogen; and R 4 is hydrogen or halogen. In certain embodiments, R 2 is halogen; R 3 is halogen; and R 4 is halogen. In certain embodiments, R 2 is -F; R 3 is -F; and R 4 is -F. In certain embodiments, R 2 is -F; R 3 is -F; and R 4 is hydrogen. In certain embodiments, R 2 is -F; R 3 is hydrogen; and R 4 is hydrogen.
  • A is -CF 3 , -CHF 2 , or -CH 2 F. In certain embodiments, A is - CF 3 . In certain embodiments, A is -CHF 2 . In certain embodiments, A is -CH 2 F. [0041] In certain embodiments, where R 4 is methyl and R 3 is hydrogen, R 2 is not methyl, chlorine, or hydroxyl.
  • A is , wherein R 4 is hydrogen, halogen, C 1-4
  • A is , wherein R 4 is hydrogen, fluorine, chlorine, or C 1-4 alkyl.
  • A is , wherein R 2 is halogen,–OR A , or–SR A .
  • A is , wherein R 2 is halogen,–OR A , or–SR A ; and R A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, or hydrogen.
  • A is , , or
  • A is ; and R A is substituted or unsubstituted aryl, or substituted or unsubstituted alkyl.
  • A is ; and R A is substituted or unsubstituted aryl.
  • A is ; and R A is substituted aryl. [0048] In certain embodiments, A is and R A is
  • A is of the formula:
  • A is of the formula:
  • A is of the formula:
  • A is of the formula: [0053] In certain embodiments, A is
  • A is or . [0055] In certain embodiments, A is . In certain embodiments, A is
  • A is . In certain embodiments, A is
  • A is In certain embodiments, A is . ce ta e bod e ts, s and R A is substituted or unsubstituted aryl, or substituted or unsubstituted alkyl.
  • A is of the formula:
  • A is of the formula:
  • A is of the formula: .
  • A is of the formula: .
  • A is of the formula: .
  • A is .
  • A is .
  • A is of the formula:
  • A is of the formula:
  • A is of the formula:
  • A is of the formula:
  • A is of the formula: .
  • A is of the formula:
  • A is .
  • R 5 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 5 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 5 is substituted or unsubstituted aryl. In certain embodiments, R 5 is substituted or unsubstituted phenyl. In certain embodiments, R 5 is substituted or unsubstituted heteroaryl.
  • R 5 is substituted or unsubstituted pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolyl, oxazolyl, isoxazolyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazolinyl.
  • R 5 is hydrogen.
  • A is .
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-[0075]
  • R 6a , R 6b , and R 6c are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted acyl. In certain embodiments, R 6a , R 6b , and R 6c are each hydrogen.
  • A is .
  • A is substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, A is substituted or unsubstituted carbocyclyl. In certain embodiments, A is substituted or unsubstituted cycloalkyl or cycloalkenyl. In certain embodiments, A is substituted or unsubstituted C 3-6 cycloalkyl or C 3-6 cycloalkenyl. In certain embodiments, A is substituted or unsubstituted C 3-6 cycloalkyl. In certain embodiments, A is substituted or unsubstituted C 3-6 cycloalkenyl.
  • A is substituted or unsubstituted heterocyclyl. In certain embodiments, A is substituted or unsubstituted 4-7 membered heterocyclyl. In certain embodiments, A is substituted or unsubstituted 5-6 membered heterocyclyl. In certain embodiments, A is substituted or unsubstituted dihydropyrrolyl or tetrahydropyridyl.
  • A is of the formula:
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaliphatic,–OR A ,–N(R A ) 2 , or– SR A .
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
  • heteroaralkyl substituted or unsubstituted heteroalkyl,–OR A ,–N(R A ) 2 , or–SR A .
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heteroaralkyl, or–SR A .
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or–SR A .
  • R 1 is ; wherein R 1a and R 1b are each
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl,–OR A , -OS(O) 2 R A ,–N 3 ,–N(R A ) 2 , or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b together with the carbon to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl.
  • R 1a and R 1b together with the carbon to which they are attached form an optionally substituted cycloalkyl.
  • R 1a and R 1b together with the carbon to which they are attached form an optionally substituted C 3-6 cycloalkyl.
  • R 1a and R 1b together with the carbon to which they are attached form an optionally substituted C 3-5 cycloalkyl.
  • R 1a and R 1b together with the carbon to which they are attached form an optionally substituted C 3-4 cycloalkyl.
  • R 1a and R 1b together with the carbon to which they are attached form an optionally substituted cyclopentyl.
  • R 1a and R 1b together with the carbon to which they are attached form an optionally substituted cyclobutyl. In certain embodiments, R 1a and R 1b together with the carbon to which they are attached, form an optionally substituted cyclopropyl. In certain embodiments, R 1a and R 1b together with the carbon to which they are attached, form an unsubstituted cyclopropyl. [0090] In certain embodiments, R 1a and R 1b together with the carbon to which they are attached, form an optionally substituted heterocyclyl. In certain embodiments, R 1a and R 1b together with the carbon to which they are attached, form an optionally substituted 3-7 membered heterocyclyl.
  • R 1a and R 1b together with the carbon to which they are attached form an optionally substituted 4-7 membered heterocyclyl. In certain embodiments, R 1a and R 1b together with the carbon to which they are attached, form an optionally substituted 4-6 membered heterocyclyl. In certain embodiments, R 1a and R 1b together with the carbon to which they are attached, form an optionally substituted 4-6 membered heterocyclyl with at least one nitrogen atom in the ring. In certain embodiments, R 1a and R 1b together with the carbon to which they are attached, form an optionally substituted azetidine, pyrrolidine, or piperidine. In certain embodiments, R 1a and R 1b together with the carbon to which they are attached, form a substituted azetidine, pyrrolidine, or piperidine.
  • R 1 is
  • R 1 is
  • R 1 is
  • R A is substituted or unsubstituted aryl or substituted or unsubstituted alkyl.
  • R 1 is of the formula:
  • R 1 is–SR A .
  • R 1 is–SR A ; and R A is a substituted or unsubstituted alkyl.
  • R 1 is–SR A ; and R A is an unsubstituted alkyl.
  • R 1 is–SR A ; and R A is an unsubstituted C 1-4 alkyl.
  • R 1 is–SCH 3 .
  • Group R 7
  • R 7 is hydrogen or unsubstituted alkyl; or A and R 7 are joined to form a substituted or unsubstituted heterocyclic ring.
  • R 7 is hydrogen or unsubstituted alkyl. In certain embodiments, R 7 is unsubstituted alkyl. In certain embodiments, R 7 is unsubstituted C 1-6 alkyl. In certain embodiments, R 7 is unsubstituted C 1-4 alkyl. In certain embodiments, R 7 is unsubstituted C 1-3 alkyl. In certain embodiments, R 7 is unsubstituted C 1-2 alkyl. In certain embodiments, R 7 is ethyl. In certain embodiments, R 7 is methyl. In certain embodiments, R 7 is hydrogen.
  • a and R 7 are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, A and R 7 are joined to form a substituted or unsubstituted pyrrolidine, piperidine, piperazine, azepine, or azepane. In certain
  • a and R 7 are joined to form a substituted or unsubstituted pyrrolidine.
  • a and R 7 are joined to form .
  • Group R 8
  • R 8 is hydrogen or substituted or unsubstituted alkyl.
  • R 8 is hydrogen or unsubstituted alkyl.
  • R 8 is hydrogen or unsubstituted C 1-6 alkyl.
  • R 8 is hydrogen or unsubstituted C 1-4 alkyl.
  • R 8 is hydrogen or unsubstituted C 1-3 alkyl.
  • R 8 is hydrogen or unsubstituted C 1-2 alkyl.
  • R 8 is hydrogen or ethyl.
  • R 8 is hydrogen or methyl.
  • R 8 is hydrogen
  • R 8 is unsubstituted C 1-6 alkyl. In certain embodiments, R 8 is unsubstituted C 1-4 alkyl. In certain embodiments, R 8 is unsubstituted C 1-3 alkyl. In certain embodiments, R 8 is unsubstituted C 1-2 alkyl. In certain embodiments, R 8 is ethyl. In certain embodiments, R 8 is methyl. Group R 9
  • each occurrence of R 9 is independently, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaliphatic,–OR A ,–N(R A ) 2 ,–SR A ,–CN,–SCN, etc
  • R 9 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl,–OR A , or–N(R A ) 2 ; or two R 9 groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted carbocyclyl ring.
  • R 9 is halogen, substituted or unsubstituted alkenyl, substituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl; or two R 9 groups are joined to form a substituted or unsubstituted carbocyclyl ring.
  • R 9 is halogen, unsubstituted ethenyl, substituted or unsubstituted phenethynyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl; or two R 9 groups are joined to form a unsubstituted cycloalkyl ring.
  • R 9 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. In certain embodiments, R 9 is substituted or unsubstituted aryl or substituted or unsubstituted aralkyl. In certain embodiments,
  • R 9 is substituted or unsubstituted phenyl or substituted or unsubstituted phenethyl.
  • R 9 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl.
  • R 9 is substituted or unsubstituted alkyl. In certain embodiments, R 9 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R 9 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 9 is substituted or unsubstituted C 1-3 alkyl. In certain embodiments, R 9 is substituted or unsubstituted C 1-2 alkyl. In certain embodiments, R 9 is substituted or unsubstituted n-butyl. In certain embodiments, R 9 is substituted or unsubstituted n-propyl. In certain embodiments, R 9 is substituted or unsubstituted ethyl. In certain embodiments, R 9 is substituted or unsubstituted methyl.
  • R 9 is substituted alkyl. In certain embodiments, R 9 is substituted C 1-6 alkyl. In certain embodiments, R 9 is substituted C 1-4 alkyl. In certain embodiments, R 9 is substituted C 1-3 alkyl. In certain embodiments, R 9 is substituted C 1-2 alkyl. In certain embodiments, R 9 is substituted n-butyl. In certain embodiments, R 9 is substituted n-propyl. In certain embodiments, R 9 is substituted ethyl. In certain embodiments, R 9 is substituted methyl.
  • R 9 is haloalkyl. In certain embodiments, R 9 is C 1-6 haloalkyl. In certain embodiments, R 9 is C 1-4 haloalkyl. In certain embodiments, R 9 is C 1-3 haloalkyl. In certain embodiments, R 9 is C 1-2 haloalkyl. In certain embodiments, R 9 is halobutyl. In certain embodiments, R 9 is halopropyl. In certain embodiments, R 9 is haloethyl. In certain embodiments, R 9 is halomethyl. [00113] In certain embodiments, R 9 is fluoroalkyl. In certain embodiments, R 9 is C 1-6 fluoroalkyl.
  • R 9 is C 1-4 fluoroalkyl. In certain embodiments, R 9 is C 1-3 fluoroalkyl. In certain embodiments, R 9 is C 1-2 fluoroalkyl. In certain embodiments, R 9 is fluorobutyl. In certain embodiments, R 9 is 1-fluorobutyl. In certain embodiments, R 9 is fluoropropyl. In certain embodiments, R 9 is fluoroethyl. In certain embodiments, R 9 is fluoromethyl.
  • p is 0-4. In certain embodiments, p is 0-3. In certain embodiments, p is 1-3. In certain embodiments, p is 0-2. In certain embodiments, p is 0-1. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. Group E
  • E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene.
  • E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted carbocyclylene.
  • E is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted cycloalkylene.
  • E is substituted or unsubstituted alkylene, or substituted or unsubstituted alkenylene.
  • E is substituted or unsubstituted alkenylene. In certain embodiments, E is substituted or unsubstituted C 2-6 alkenylene. In certain embodiments, E is substituted or unsubstituted C 2-4 alkenylene. In certain embodiments, E is substituted or unsubstituted C 2-3 alkenylene. In certain embodiments, E is substituted butenylene. In certain embodiments, E is unsubstituted butenylene. In certain embodiments, E is substituted propenylene. In certain embodiments, E is unsubstituted propenylene. In certain embodiments,
  • E is substituted ethenylene. In certain embodiments, E is unsubstituted ethenylene. In certain embodiments, the carbon-carbon double bond of any of the foregoing substituted or unsubstituted alkenylenes is a cis or trans isomer. In certain embodiments, the carbon-carbon double bond of any of the foregoing substituted or unsubstituted alkenylenes is a mixture of cis and trans isomers. In certain embodiments, the carbon-carbon double bond of any of the foregoing substituted or unsubstituted alkenylenes is a cis isomer.
  • the carbon-carbon double bond of any of the foregoing substituted or unsubstituted alkenylenes is a trans isomer.
  • E is substituted or unsubstituted alkylene. In certain embodiments, E is substituted or unsubstituted C 1-6 alkylene. In certain embodiments, E is substituted or unsubstituted C 1-4 alkylene. In certain embodiments, E is substituted or unsubstituted C 1-3 alkylene. In certain embodiments, E is substituted or unsubstituted C 1-2 alkylene. In certain embodiments, E is substituted butylene. In certain embodiments, E is unsubstituted butylene. In certain embodiments, E is substituted propylene. In certain embodiments, E is unsubstituted propylene. In certain embodiments, E is substituted ethylene. In certain embodiments, E is unsubstituted methylene.
  • E is .
  • E is .
  • E is
  • R b and R c are each independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or -S(O) 2 R A ; or R b and R c are joined to form a substituted or unsubstituted heterocyclic ring.
  • R b and R c are each independently, hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkylalkyl; or R b and R c are joined to form a substituted or unsubstituted heterocyclic ring.
  • R b and R c are each independently, hydrogen, haloalkyl, or cycloalkylhaloalkyl; or R b and R c are joined to form a halo-substituted heterocyclic ring.
  • R b and R c are each independently, hydrogen, haloalkyl, or cycloalkylhaloalkyl.
  • R b and R c are each independently, hydrogen, C 1-6 haloalkyl, or C 3-6 cycloalkylhaloalkyl.
  • R b and R c are each independently, hydrogen, C 1-4 haloalkyl, or C 3-6 cycloalkylhaloalkyl. In certain embodiments, R b and R c are joined to form a halo-substituted heterocyclic ring. In certain embodiments, R b and R c are joined to form a halo-substituted piperidine or pyrrolidine ring.
  • At least one of R b and R c is haloalkyl or
  • R b and R c are joined to form a halo-substituted heterocyclic ring.
  • at least one of R b and R c is haloalkyl or cycloalkylhaloalkyl.
  • at least one of R b and R c is C 1-6 haloalkyl or C 3-6 cycloalkylhaloalkyl.
  • at least one of R b and R c is C 1-4 haloalkyl or C 3-6 cycloalkylhaloalkyl.
  • R b and R c are each inde endentl
  • R b and R c are joined to form .
  • R b and R c are joined to form .
  • the compound of Formula (I) is a compound of Formula (I-a):
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-b):
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-c):
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-c), R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-c), R 7 is hydrogen; R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-c), R 7 is hydrogen; R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-d):
  • R 1 , R 7 , R 8 , and R 9 are as defined herein.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-e):
  • R 1 , R 7 , R 8 , and R 9 are as defined herein.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-f):
  • R 1 , R 7 , R 8 , and R 9 are as defined herein.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-g):
  • R 1 , R 7 , R 8 , and R 9 are as defined herein.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl.
  • R 7 is hydrogen; R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-h):
  • R 1 , R 7 , R 8 , and R 9 are as defined herein.
  • R 7 is hydrogen
  • the compound of Formula (I) is a compound of Formula (I-i):
  • R 1 , R 2 , R 3 , R 4 , R 8 , and R 9 are as defined herein.
  • R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-i), R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-i), R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-i), R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-j):
  • R 1 , R 2 , R 4 , R 8 , and R 9 are as defined herein.
  • R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-j), R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-j), R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-j), R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-k):
  • R 1 , R A , R 4 , R 8 , and R 9 are as defined herein.
  • R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-k), R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-k), R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-k), R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-l):
  • R 1 , R 4 , R 8 , and R 9 are as defined herein.
  • R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-l), R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-l), R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-l), R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-m):
  • R 2 , R 3 , R 4 , R 8 , and R 9 are as defined herein; and R 1a and R 1b are each independently hydrogen, halogen, substituted or
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl,–OR A , - OS(O) 2 R A ,–N 3 , or–N(R A ) 2 , or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-m), R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-m), R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-m), R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (I) is a compound of Formula (I-n):
  • R 1a , R 1b , R A , R 4 , R 8 , and R 9 are as defined herein.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl,–OR A , - OS(O) 2 R A ,–N 3 ,–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-n), R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-n), R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-n), R 8 is methyl; and R 9 is substituted C 1-6 alkyl. [00172] In certain embodiments, the compound of Formula (I) is a compound of Formula (I-o):
  • R 1a , R 1b , R 4 , R 8 , and R 9 are as defined herein.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl,–OR A , - OS(O) 2 R A ,–N 3 , or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 8 is hydrogen or methyl; and R 9 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-o), R 8 is hydrogen or methyl; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-o), R 8 is hydrogen; and R 9 is substituted C 1-6 alkyl. In certain embodiments of the compound of Formula (I-o), R 8 is methyl; and R 9 is substituted C 1-6 alkyl.
  • the compound of Formula (II) is a compound of Formula (II-a):
  • R 1 , E, R b , R c , R 7 , and R 8 are as defined herein.
  • E is substituted or unsubstituted alkylene or substituted or unsubstituted alkenylene. In certain embodiments of the compound of Formula (II-a), E is substituted or unsubstituted alkylene.
  • R 1 is–SR A ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-b):
  • E is substituted or unsubstituted alkylene or substituted or unsubstituted alkenylene. In certain embodiments of the compound of Formula (II-b), E is substituted or unsubstituted alkylene.
  • R 1 is–SR A ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-c):
  • R d and R e are each independently hydrogen, halogen, or substituted or unsubstituted alkyl; or optionally one instance of R d and R e together form an oxo group; and q is 1-6.
  • R d and R e are each hydrogen; or optionally one instance of R d and R e together form an oxo group.
  • R d and R e are each hydrogen; or optionally one instance of R d and R e together form an oxo group; and q is 2-4.
  • R d and R e are each hydrogen; or optionally one instance of R d and R e together form an oxo group; and q is 3.
  • R d and R e are each hydrogen.
  • R d and R e are each hydrogen; and q is 2-4. In certain embodiments of the compound of Formula (II-c), R d and R e are each hydrogen; and q is 3. In certain
  • R d and R e are each independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (II-c), R d and R e are each independently hydrogen or substituted or unsubstituted alkyl; and q is 2-4. In certain embodiments of the compound of Formula (II-c), R d and R e are each independently hydrogen or substituted or unsubstituted alkyl; and q is 3.
  • R 1 is–SR A ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-d):
  • R 1 , R b , R c , R d , R e , R 7 , R 8 , and q are as defined herein.
  • R d and R e are each hydrogen; or optionally one instance of R d and R e together form an oxo group.
  • R d and R e are each hydrogen; or optionally one instance of R d and R e together form an oxo group; and q is 2-4.
  • R d and R e are each hydrogen; or optionally one instance of R d and R e together form an oxo group; and q is 3.
  • R d and R e are each hydrogen.
  • R d and R e are each hydrogen; and q is 2-4. In certain embodiments of the compound of Formula (II-d), R d and R e are each hydrogen; and q is 3. In certain
  • R d and R e are each independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (II-d), R d and R e are each independently hydrogen or substituted or unsubstituted alkyl; and q is 2-4. In certain embodiments of the compound of Formula (II-d), R d and R e are each independently hydrogen or substituted or unsubstituted alkyl; and q is 3.
  • R 1 is–SR A ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-e):
  • R 1 , R b , R c , R d , R e , R 7 , R 8 , and q are as defined herein.
  • R d and R e are each hydrogen; or optionally one instance of R d and R e together form an oxo group.
  • R d and R e are each hydrogen; or optionally one instance of R d and R e together form an oxo group; and q is 2-4.
  • R d and R e are each hydrogen; or optionally one instance of R d and R e together form an oxo group; and q is 3.
  • R d and R e are each hydrogen.
  • R d and R e are each hydrogen; and q is 2-4. In certain embodiments of the compound of Formula (II-e), R d and R e are each hydrogen; and q is 3. In certain
  • R d and R e are each independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments of the compound of Formula (II-e), R d and R e are each independently hydrogen or substituted or unsubstituted alkyl; and q is 2-4. In certain embodiments of the compound of Formula (II-e), R d and R e are each independently hydrogen or substituted or unsubstituted alkyl; and q is 3.
  • R 1 is–SR A ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-f):
  • R 1 , R b , R c , R 7 , R 8 , and q are as defined herein.
  • R 1 is–SR A ; R 7 is hydrogen; R 8 is hydrogen or methyl; and q is 2-4. In certain embodiments of the compound of Formula (II-f), R 1 is–SR A ; R 7 is hydrogen; R 8 is hydrogen or methyl; and q is 3. In certain embodiments of the compound of Formula (II-f), R 1 is–SCH 3 ; R 7 is hydrogen; R 8 is hydrogen or methyl; and q is 2-4. In certain embodiments of the compound of Formula (II-f), R 1 is–SCH 3 ; R 7 is hydrogen; R 8 is hydrogen or methyl; and q is 3.
  • R 1 is–SCH 3 ; R 7 is hydrogen; R 8 is hydrogen; and q is 2-4.
  • R 1 is–SCH 3 ; R 7 is hydrogen; R 8 is hydrogen; and q is 3.
  • R 1 is– SCH 3 ; R 7 is hydrogen; R 8 is methyl; and q is 2-4.
  • R 1 is–SCH 3 ; R 7 is hydrogen; R 8 is methyl; and q is 3.
  • the compound of Formula (II) is a compound of Formula (II-g):
  • R 1 , R b , R c , R 7 , and R 8 are as defined herein.
  • R 1 is–SR A ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen or methyl.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is hydrogen.
  • R 1 is–SCH 3 ; R 7 is hydrogen; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-h):
  • R 1 , R 2 , R 3 , R 4 , R b , R c , and R 8 are as defined herein.
  • R 1 is–SR A ; and R 8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-h), R 1 is– SCH 3 ; and R 8 is hydrogen. In certain embodiments of the compound of Formula (II-h), R 1 is –SCH 3 ; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-i):
  • R 1 , R 2 , R 4 , R b , R c , and R 8 are as defined herein.
  • R 1 is–SR A ; and R 8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-i), R 1 is–SCH 3 ; and R 8 is hydrogen. In certain embodiments of the compound of Formula (II-i), R 1 is–SCH 3 ; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-j):
  • R 1 , R A , R 4 , R b , R c , and R 8 are as defined herein.
  • R 1 is–SR A ; and R 8 is hydrogen or methyl.
  • R 1 is– SCH 3 ; and R 8 is hydrogen.
  • R 1 is –SCH 3 ; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-k):
  • R 1 , R 4 , R b , R c , and R 8 are as defined herein.
  • R 1 is–SR A ; and R 8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-k), R 1 is– SCH 3 ; and R 8 is hydrogen. In certain embodiments of the compound of Formula (II-k), R 1 is –SCH 3 ; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-l):
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl,–OR A , - OS(O) 2 R A ,–N 3 ,–N(R A ) 2 , or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; and R 8 is hydrogen or methyl.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; and R 8 is hydrogen.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-m):
  • R 1a , R 1b , R A , R 4 , R b , R c , and R 8 are as defined herein.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl,–OR A , - OS(O) 2 R A ,–N 3 , or–N(R A ) 2 , or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; and R 8 is hydrogen or methyl.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; and R 8 is hydrogen.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-n):
  • R 1a , R 1b , R 4 , R b , R c , and R 8 are as defined herein.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl,–OR A , - OS(O) 2 R A ,–N 3 , or–N(R A ) 2 , or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; and R 8 is hydrogen or methyl.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; and R 8 is hydrogen.
  • R 1a and R 1b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, or–N(R A ) 2 ; or R 1a and R 1b are joined to form a substituted or unsubstituted carbocyclic ring; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-o):
  • R A , R 4 , R b , R c , and R 8 are as defined herein.
  • R 8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-o), R 8 is hydrogen. In certain embodiments of the compound of Formula (II-o), R 8 is methyl.
  • R A is methyl; and R 8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-o), R A is methyl; and R 8 is hydrogen. In certain embodiments of the compound of Formula (II-o), R A is methyl; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-p):
  • R A , R b , R c , and R 8 are as defined herein.
  • R 8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-p), R 8 is hydrogen. In certain embodiments of the compound of Formula (II-p), R 8 is methyl.
  • R A is methyl; and R 8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-p), R A is methyl; and R 8 is hydrogen. In certain embodiments of the compound of Formula (II-p), R A is methyl; and R 8 is methyl.
  • the compound of Formula (II) is a compound of Formula (II-q):
  • R 8 is hydrogen or methyl. In certain embodiments of the compound of Formula (II-q), R 8 is hydrogen. In certain embodiments of the compound of Formula (II-q), R 8 is methyl.
  • Exemplary compounds
  • Exemplary compounds of Formula (I) include, but are not limited to the compounds listed in Table 1, and pharmaceutically acceptable salts thereof.
  • Exemplary compounds of Formula (II) include, but are not limited to, the compounds listed in Table 2, and pharmaceutically acceptable salts thereof.
  • the amide bond formation is promoted by an amide coupling reagent (e.g., 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), hydroxybenzotriazole (HOBt), and the like, or a combination thereof).
  • the amide coupling reagent e.g., HATU, EDC, HOBt
  • the compound of Formula (B) is reacted with the compound of Formula (B).
  • the amide coupling reagent e.g., HATU, EDC, HOBt
  • the amide coupling reagent is reacted with the compound of Formula (B) prior to amide coupling with the compound of Formula (A).
  • the amide coupling reagent is HATU.
  • the method comprises adding up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8.1.9, or 2.0 equivalents of the amide coupling reagent.
  • the method comprises performing the coupling reaction at room temperature, ambient temperature, or elevated temperature. In certain embodiments, the method comprises perorming the coupling reaction at 20-60 °C, 20-50 °C, 20-40 °C, 20-30 °C, 20-25 °C, or 25- 30 °C.
  • an additional reagent may be added to the amide bond forming reaction.
  • the additional reagent may facilitate amide coupling by protecting the free hydroxyls of the compound of Formula (A).
  • the additional reagent is a silylating reagent.
  • the silylating reagent reacts with the free hydroxyl groups of the compound of Formula (A) to form silyl protecting groups in situ during the reaction.
  • the additional reagent is added to the compound of Formula (A) before the amide coupling.
  • the additional reagent is N,O-bis(trimethylsilyl)trifluoroacetamide.
  • the method comprises adding up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8.1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8.2.9, 3.0, or more equivalents of the silylating reagent.
  • Compounds of Formula (B) may be prepared by any methods of synthesis known in the art, e.g., methods found in U.S. Patent Publication No.2010/0184746, which is incorporated herein by reference.
  • compounds of the present disclosure are prepared by coupling a compound of Formula (A) and a compound of Formula (C) as depicted in Scheme 2 below.
  • compounds of Formula (II) are prepared by coupling a compound of Formula (A) and a compound of Formula (D) to form a compound of Formula (E) as depicted in Scheme 3 below.
  • Scheme 3 shows a compound of Formula (A) and a compound of Formula (D) as depicted in Scheme 3 below.
  • A, P, R 1 , R 7 , and R 8 are as defined herein for a compound of Formula (II), and each P 1 is independently hydrogen or a protecting group, or two instances of P 1 are joined to form a heterocyclic ring.
  • the amide bond formation is promoted by an amide coupling reagent (e.g., 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), hydroxybenzotriazole (HOBt), and the like, or a combination thereof).
  • the amide coupling reagent e.g., HATU, EDC, HOBt
  • the amide coupling reagent is reacted with the compound of Formula (C) or (D).
  • the amide coupling reagent e.g., HATU, EDC, HOBt
  • the amide coupling reagent is reacted with the compound of Formula (C) or (D) prior to amide coupling with the compound of Formula (A).
  • the amide coupling reagent is HATU.
  • the method comprises adding up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8.1.9, or 2.0 equivalents of the amide coupling reagent.
  • the method comprises performing the coupling reaction at room temperature, ambient temperature, or elevated temperature. In certain embodiments, the method comprises performing the coupling reaction at 20-60 °C, 20-50 °C, 20-40 °C, 20-30 °C, 20-25 °C, or 25- 30 °C.
  • an additional reagent may be added to the amide bond forming reaction.
  • the additional reagent may facilitate amide coupling by protecting the free hydroxyls of the compound of Formula (A).
  • the additional reagent is a silylating reagent.
  • the silylating reagent reacts with the free hydroxyl groups of the compound of Formula (A) to form silyl protecting groups in situ during the reaction.
  • the additional reagent is added to the compound of Formula (A) before the amide coupling.
  • the additional reagent is N,O-bis(trimethylsilyl)trifluoroacetamide.
  • the method comprises adding up to 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8.1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8.2.9, 3.0, or more equivalents of the silylating reagent.
  • compounds of Formula (F) are prepared by deprotection of the aldehydic group of the compound of Formula (E) followed by reductive amination as depicted in Scheme 4 below.
  • the deprotection is achieved under acidic conditions, e.g., HCl.
  • the compound of Formula (F) may be hydrogenated to form a compound of Formula (II-g-1) as depicted in Scheme 5 below.
  • Scheme 5 a compound of Formula (II-g-1) as depicted in Scheme 5 below.
  • the compound of Formula (II-g-1) is the compound of Formula (II-g).
  • R 8 is as defined herein;
  • P 2 is hydrogen or a protecting group; and
  • the compound of Formula (C) is the compound of
  • Formula (G) In certain embodiments, the compound of Formula (G) is the compound of Formula (D). In certain embodiments, the compound of Formula (D) is the compound of Formula (D-1) or Formula (D-2):
  • the compound of Formula (G) is the compound of Formula (G-1):
  • the compound of Formula (H) is the compound of Formula (H-1):
  • compounds of Formula (H), e.g., compounds of Formula (H-1), are prepared by ring closing metathesis of the compound of Formula (J) as depicted in Scheme 6 below.
  • Scheme 6 Scheme 6.
  • the cross metathesis reaction to form the compound of Formula (G) and the ring closing metathesis to form the compound of Formula (H) are independently achieved through use of an independent transition metal catalyst.
  • the transition metal catalyst is a tungsten (W), molybdenum (Mo), or ruthenium (Ru) catalyst.
  • the catalyst is a ruthenium catalyst.
  • the metathesis catalyst is a Grubbs catalyst.
  • the Grubbs catalyst is of the formula:
  • R cyclohexyl (Cy); phenyl (Ph); benzyl (Bn)
  • the metathesis catalyst is a Grubbs-Hoveyda catalyst.
  • the Grubbs-Hoveyda catalyst is of the formula:
  • compositions comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • compositions agents include any and all solvents, diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • solvents diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of the present invention into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a“unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the compound of the present disclosure.
  • the amount of the compound is generally equal to the dosage of the compound which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the compound, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) compound.
  • compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents, and emulsifiers, and mixtures thereof.
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with solubilizing agents, and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the compound is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily amount of the compound will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • mucosal nasal,
  • Oral administration is the preferred mode of administration.
  • the subject may not be in a condition to tolerate oral administration, and thus intravenous, intramuscular, and/or rectal administration are also preferred altermative modes of adminsitration.
  • An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses).
  • a single dose e.g., single oral dose
  • multiple doses e.g., multiple oral doses
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • a dose e.g., a single dose, or any dose of multiple doses described herein includes
  • a compound or composition, as described herein, can be administered in combination with one or more additional therapeutically active agents.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In certain embodiments, the levels utilized in combination will be lower than those utilized individually.
  • Exemplary additional therapeutically active agents include, but are not limited to, antibiotics, anti-viral agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal anti-inflammatory agents, antihistamine,
  • immunosuppressant agents antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, and prostaglandins.
  • Therapeutically active agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, and the like.
  • drug compounds e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • peptides e.g., proteins, carbohydrates, monosaccharides
  • oligosaccharides polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • the additional therapeutically active agent is an antibiotic.
  • antibiotics include, but are not limited to, penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), compounds (e.g., erythromycin, clarithormycin,
  • tetracyclines e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycline, aureomycin, terramycin, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, rolitetracycline, and glycylcycline antibiotics (e.g., tigecycline)),
  • fluoroquinolones e.g., ciprofloxacin, levofloxacin, ofloxacin
  • sulfonamides e.g., co-trimoxazole, trimethoprim
  • tetracyclines e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycline, aure
  • aminoglycosides e.g., gentamicin, tobramycin, paromomycin
  • aminocyclitol e.g., spectinomycin
  • chloramphenicol e.g., tobramycin, paromomycin
  • quinupristin/dalfoprisin SyndercidTM
  • kits e.g., pharmaceutical packs
  • the kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound.
  • the inventive kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound.
  • the present disclosure contemplates using compounds of the present invention for the treatment of infectious diseases, for example, fungal, bacterial, viral, and/or parasitic infections.
  • Lincosamides are known to exhibit anti-bacterial activity.
  • a method of treating an infectious disease comprising administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • Such a method can be conducted in vivo (i.e., by administration to a subject). Treating, as used herein, encompasses therapeutic treatment and prophylactic treatment.
  • the effective amount is a therapeutically effective amount.
  • the method slows the progress of an infectious disease in the subject.
  • the method improves the condition of the subject suffering from an infectious disease.
  • the subject has a suspected or confirmed infectious disease.
  • the effective amount is a prophylactically effective amount.
  • the method prevents or reduces the likelihood of an infectious disease, e.g., in certain embodiments, the method comprises administering a compound of the present invention to a subject in need thereof in an amount sufficient to prevent or reduce the likelihood of an infectious disease.
  • the subject is at risk of an infectious disease (e.g., has been exposed to another subject who has a suspected or confirmed infectious disease or has been exposed or thought to be exposed to a pathogen).
  • a method of killing a microorganism comprising contacting the microorganism with an effective amount of a compound of the present disclosure.
  • the compound may contact the microorganism in vivo (e.g., in a subject in need thereof) or in vitro.
  • microorganism e.g., fungus, bacterium, virus, parasite
  • microorganism with an effective amount of a compound of the present disclosure.
  • the compound may contact the microorganism in vivo (e.g., in a subject in need thereof) or in vitro.
  • an in vitro method of inhibiting pathogenic growth comprising contacting an effective amount of the compound of the present invention with a pathogen (e.g., a bacteria, virus, fungus, or parasite) in a cell culture.
  • a pathogen e.g., a bacteria, virus, fungus, or parasite
  • an in vitro method of inhibiting pathogenic growth comprising contacting a pathogen (e.g., a bacteria, virus, fungus, or parasite) with an effective amount of a compound of the present disclosure.
  • a pathogen e.g., a bacteria, virus, fungus, or parasite
  • a method of inhibiting protein synthesis e.g., by interfering with the synthesis of proteins by binding to the 23s portion of the 50S subunit of the bacterial ribosome and causing premature dissociation of the peptidyl-tRNA from the ribosome
  • inhibiting protein synthesis comprises inhibiting the ribosome of bacteria with an effective amount of a compound of the present disclosure. Protein synthesis may be inhibited in vivo or in vitro.
  • the infectious disease is caused by a fungus, bacteria, virus, or a parasite.
  • the infectious disease is caused by a fungus, bacteria, or a parasite.
  • the infectious disease is caused by a pathogen resistant to other treatments.
  • the infectious disease is caused by a pathogen that is multi-drug tolerant or resistant, e.g., the infectious disease is caused by a pathogen that neither grows nor dies in the presence of or as a result of other treatments.
  • the infectious disease is a bacterial infection.
  • a method of treating a bacterial infection comprising administering an effective amount of a compound of the present invention, or a
  • the compound has a mean inhibitory concentration (MIC), with respect to a particular bacteria, of less than 50 ⁇ g/mL, less than 25 ⁇ g/mL, less than 20 ⁇ g/mL, less than 10 ⁇ g/mL, less than 5 ⁇ g/mL, or less than 1 ⁇ g/mL.
  • MIC mean inhibitory concentration
  • the bacteria is susceptible (e.g., responds to) or resistant to known commercial compounds, such as azithromycin, lincomycin, clindamycin,
  • the bacteria is resistant to a known compound.
  • the bacteria is lincomycin or clindamycin resistant.
  • the bacterial infection is resistant to other antibiotics (e.g., non-compound) therapy.
  • the pathogen is vancomycin resistant (VR).
  • the pathogen is methicillin-resistant (MR), e.g., in certain embodiments, the bacterial infection is an methicillin-resistant S. aureus infection (a MRSA infection).
  • the pathogen is quinolone resistant (QR).
  • the pathogen is fluoroquinolone resistant (FR).
  • Exemplary bacterial infections include, but are not limited to, infections with a Gram positive bacteria (e.g., of the phylum Actinobacteria, phylum Firmicutes, or phylum Tenericutes); Gram negative bacteria (e.g., of the phylum Aquificae, phylum Deinococcus- Thermus, phylum Fibrobacteres/Chlorobi/Bacteroidetes (FCB), phylum Fusobacteria, phylum Gemmatimonadest, phylum Ntrospirae, phylum
  • a Gram positive bacteria e.g., of the phylum Actinobacteria, phylum Firmicutes, or phylum Tenericutes
  • Gram negative bacteria e.g., of the phylum Aquificae, phylum Deinococcus- Thermus, phylum Fibrobacteres/Chlorobi/Bacteroidetes (FCB), phylum Fusobacteria
  • Planctomycetes/Verrucomicrobia/Chlamydiae PVC
  • phylum Proteobacteria phylum Spirochaetes
  • phylum Synergistetes e.g., of the phylum Acidobacteria, phylum Chlroflexi, phylum Chrystiogenetes, phylum Cyanobacteria, phylum
  • the bacterial infection is an infection with a Gram positive bacterium.
  • the Gram positive bacterium is a bacterium of the phylum Firmicutes.
  • the bacteria is a member of the phylum Firmicutes and the genus Enterococcus, i.e., the bacterial infection is an Enterococcus infection.
  • Exemplary Enterococci bacteria include, but are not limited to, E. avium, E. durans, E. faecalis, E.
  • the bacteria is a member of the phylum Firmicutes and the genus Staphylococcus, i.e., the bacterial infection is a Staphylococcus infection.
  • Exemplary Staphylococci bacteria include, but are not limited to, S. arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devriesei, S. epidermis, S. equorum, S. felis, S. fluroettii, S. gallinarum, S.
  • the Staphylococcus infection is an S. aureus infection.
  • the S. aureus has an efflux (e.g., mef, msr) genotype. Bacteria of the efflux genotypes actively pump drug out of the cell via efflux pumps.
  • efflux e.g., mef, msr
  • the S. aureus has a methylase (e.g., erm) genotype.
  • erm is the bacterial gene class coding for erythromycin ribosomal methylase, which methylates a single adenine in 23S rRNA, itself a component of 50S rRNA.
  • the bacteria is a member of the phylum Firmicutes and the genus Bacillus, i.e., the bacterial infection is a Bacillus infection.
  • Bacillus bacteria include, but are not limited to, B. alcalophilus, B. alvei, B. aminovorans, B.
  • amyloliquefaciens B. aneurinolyticus, B. anthracis, B. aquaemaris, B. atrophaeus, B.
  • boroniphilus B. brevis, B. caldolyticus, B. centrosporus, B. cereus, B. circulans, B.
  • coagulans B. firmus, B. flavothermus, B. fusiformis, B. globigii, B. infernus, B. larvae, B. laterosporus, B. lentus, B. licheniformis, B. megaterium, B. mesentericus, B. mucilaginosus, B. mycoides, B. natto, B. pantothenticus, B. polymyxa, B. pseudoanthracis, B. pumilus, B. schlegelii, B. sphaericus, B. sporothermodurans, B. stearothermophilus, B. subtilis, B.
  • thermoglucosidasius B. thuringiensis, B. vulgatis, and B. weihenstephanensis.
  • Bacillus infection is a B. subtilis infection.
  • the B. subtilis has an efflux (e.g., mef, msr) genotype.
  • the B. subtilis has a methylase (e.g., erm) genotype.
  • the bacteria is a member of the phylum Firmicutes and the genus Streptococcus, i.e., the bacterial infection is a Strepococcus infection.
  • exemplary Streptococcus bacteria include, but are not limited to, S. agalactiae, S. anginosus, S. bovis, S. canis, S. constellatus, S. dysgalactiae, S. equinus, S. iniae, S. intermedius, S. mitis, S. mutans, S. oralis, S. parasanguinis, S. peroris, S. pneumoniae, S. pyogenes, S. ratti, S.
  • the Strepococcus infection is an S. pyogenes infection.
  • the Strepococcus infection is an S. pneumoniae infection.
  • the S. pneumoniae has an efflux (e.g., mef, msr) genotype.
  • the S. pneumoniae has a methylase (e.g., erm) genotype.
  • the bacteria is a member of the phylum Firmicutes and the genus Clostridium, i.e., the bacterial infection is a Clostridium infection.
  • Clostridia bacteria include, but are not limited to, C. botulinum, C. difficile, C. perfringens, C. tetani, and C. sordellii.
  • the compounds of the disclosure are a safer alternative to clindamycin, due to reduced incidence of pseudomembranous colitis.
  • the compounds of the disclosure have increased activity against Clostridium difficile (C. difficile) in comparison to clindamycin.
  • the compounds have a mean inhibitory concentration (MIC), with respect to C. difficile, of less than 50 ⁇ g/mL, less than 25 ⁇ g/mL, less than 20 ⁇ g/mL, less than 10 ⁇ g/mL, less than 5 ⁇ g/mL, or less than 1 ⁇ g/mL.
  • MIC mean inhibitory concentration
  • the bacterial infection is an infection with a Gram negative bacteria.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Escherichia. i.e., the bacterial infection is an Escherichia infection.
  • Exemplary Escherichia bacteria include, but are not limited to, E. albertii, E.
  • the Escherichia infection is an E. coli infection.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Haemophilus. i.e., the bacterial infection is an Haemophilus infection.
  • Exemplary Haemophilus bacteria include, but are not limited to, H. aegyptius, H. aphrophilus, H. avium, H. ducreyi, H. felis, H. haemolyticus, H. influenzae, H. parainfluenzae, H. paracuniculus, H. parahaemolyticus, H. pittmaniae, Haemophilus segnis, and H. somnus.
  • the Haemophilus infection is an H. influenzae infection.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Acinetobacter. i.e., the bacterial infection is an Acinetobacter infection.
  • Exemplary Acinetobacter bacteria include, but are not limited to, A. baumanii, A. haemolyticus, and A. lwoffii.
  • the Acinetobacter infection is an A. baumanii infection.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Klebsiella. i.e., the bacterial infection is a Klebsiella infection.
  • Exemplary Klebsiella bacteria include, but are not limited to, K. granulomatis, K. oxytoca, K. michiganensis, K. pneumoniae, K. quasipneumoniae, and K. variicola.
  • K. granulomatis K. oxytoca
  • K. michiganensis K. pneumoniae
  • K. quasipneumoniae K. variicola.
  • the Klebsiella infection is a K. pneumoniae infection.
  • the Gram negative bacteria is a bacteria of the phylum Proteobacteria and the genus Pseudomonas. i.e., the bacterial infection is a Pseudomonas infection.
  • Exemplary Pseudomonas bacteria include, but are not limited to, P. aeruginosa, P. oryzihabitans, P. plecoglissicida, P. syringae, P. putida, and P. fluoroscens.
  • the Pseudomonas infection is a P. aeruginosa infection.
  • the Gram negative bacteria is a bacteria of the phylum Bacteroidetes and the genus Bacteroides. i.e., the bacterial infection is a Bacteroides infection.
  • Exemplary Bacteroides bacteria include, but are not limited to, B. fragilis, B.
  • the Bacteroides infection is a B. fragilis infection.
  • the bacteria is an atypical bacteria, i.e., are neither Gram positive nor Gram negative.
  • the infectious disease is an infection with a parasitic infection.
  • a method of treating a parasitic infection comprising administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the compound has an IC 50 (uM) with respect to a particular parasite, of less than 50 uM, less than 25 uM, less than 20 uM, less than 10 uM, less than 5 uM, or less than 1 uM.
  • Exemplary parasites include, but are not limited to, Trypanosoma spp. (e.g., Trypanosoma cruzi, Trypansosoma brucei), Leishmania spp., Giardia spp., Trichomonas spp., Entamoeba spp., Naegleria spp., Acanthamoeba spp., Schistosoma spp., Plasmodium spp. (e.g., P.
  • Trypanosoma spp. e.g., Trypanosoma cruzi, Trypansosoma brucei
  • Leishmania spp. Giardia spp.
  • Trichomonas spp. Trichomonas spp.
  • Entamoeba spp. Entamoeba spp.
  • Naegleria spp. Naegleria spp.
  • Crytosporidium spp. Crytosporidium spp., Isospora spp., Balantidium spp., Pneumocystis spp., Babesia, Loa Loa, Ascaris lumbricoides, Dirofilaria immitis, and Toxoplasma ssp. (e.g. T. gondii).
  • the present disclosure further provides a method of treating an inflammatory condition comprising administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • a method can be conducted in vivo (i.e., by administration to a subject) or in vitro (e.g., upon contact with the pathogen, tissue, or cell culture). Treating, as used herein, encompasses therapeutic treatment and prophylactic treatment.
  • the effective amount is a therapeutically effective amount.
  • the method slows the progress of an inflammatory condition in the subject.
  • the method improves the condition of the subject suffering from an inflammatory condition.
  • the subject has a suspected or confirmed inflammatory condition.
  • the effective amount is a prophylatically effective amount.
  • the method prevents or reduces the likelihood of an inflammatory condition, e.g., in certain embodiments, the method comprises administering a compound of the present invention to a subject in need thereof in an amount sufficient to prevent or reduce the likelihood of an inflammatory condition.
  • the subject is at risk to an inflammatory condition.
  • the term“inflammatory condition” refers to those diseases, disorders, or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and/or loss of function (functio laesa, which can be partial or complete, temporary or permanent).
  • Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative inflammation.
  • the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from an infection).
  • the inflammatory condition is a chronic inflammatory condition.
  • the inflammatory condition is inflammation associated with cancer.
  • the present disclosure further provides a method of treating a central nervous system disorder comprising administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • a method can be conducted in vivo (i.e., by administration to a subject) or in vitro (e.g., upon contact with a tissue or cell culture). Treating, as used herein, encompasses therapeutic treatment and prophylactic treatment.
  • the effective amount is a therapeutically effective amount.
  • the method slows the progress of a central nervous system disorder in the subject.
  • the method improves the condition of the subject suffering from a central nervous system disorder.
  • the subject has a suspected or confirmed central nervous system disorder.
  • the effective amount is a prophylatically effective amount.
  • the method prevents or reduces the likelihood of a central nervous system disorder, e.g., in certain embodiments, the method comprises administering a compound of the present disclosure to a subject in need thereof in an amount sufficient to prevent or reduce the likelihood of a central nervous system disorder.
  • the subject is at risk of developing a central nervous system disorder.
  • compounds of the present disclosure may treat a central nervous system disorder by modulating the serotonin 5-HT 2C receptor.
  • the compounds of the present disclosure are allosteric modulators of the serotonin 5-HT 2C receptor, e.g., see Zhou et al. ACS Chemical Neuroscience 2012, 3, 538– 545, and Dinh et al. Molecular Pharmacology 2003, 64, 78–84.
  • the central nervous system disorder is addiction, anxiety, depression, obesity, eating disorders, Parkinson’s disease, or schizophrenia.
  • Compounds 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 described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • the invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • the term“aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term“heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups. [00322]
  • the term“alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C 1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”).
  • an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”).
  • an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl).
  • alkyl groups include n-heptyl (C 7 ), n- octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an“unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
  • substituents e.g., halogen, such as F
  • the alkyl group is an unsubstituted C 1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., ⁇ CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)).
  • the alkyl group is a substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g., ⁇ CH 3 (Me), un
  • haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 8 carbon atoms (“C 1-8 haloalkyl”).
  • the haloalkyl moiety has 1 to 6 carbon atoms (“C 1-6 haloalkyl”).
  • the haloalkyl moiety has 1 to 4 carbon atoms (“C 1-4 haloalkyl”).
  • the haloalkyl moiety has 1 to 3 carbon atoms (“C 1-3 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1-2 haloalkyl”).
  • haloalkyl groups include ⁇ CF 3 , ⁇ CF 2 CF 3 , ⁇ CF 2 CF 2 CF 3 , ⁇ CCl 3 , ⁇ CFCl 2 , ⁇ CF 2 Cl, and the like.
  • heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-10 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain
  • heteroC 1-9 alkyl a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-7 alkyl”). In certain
  • a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an
  • heteroalkyl group is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 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 certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In certain 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 2-4 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 2-4 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, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkenyl”).
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkenyl”). In certain 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 certain 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 (“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 a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1or 2 heteroatoms within the parent chain (“heteroC 2-4 alkenyl”). In certain embodiments, 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 independently unsubstituted (an“unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 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 2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In certain 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 certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In certain 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 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2- propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently unsubstituted (an“unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents.
  • the alkynyl group is an unsubstituted C 2-10 alkynyl.
  • the alkynyl group is a substituted C 2-10 alkynyl.
  • heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a 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 2-10 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 certain 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 certain 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 certain 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 certain
  • a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC 2-4 alkynyl”). In certain embodiments, 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 certain 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”).
  • each instance of a heteroalkynyl group is independently unsubstituted (an“unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 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”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6
  • a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 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 ), and the like.
  • 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 aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), 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. In certain embodiments, 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 certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
  • a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • 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 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl.
  • the cycloalkyl group is a substituted C 3-14 cycloalkyl.
  • Carbocyclylalkyl is a subset of“alkyl” and refers to an alkyl group substituted by a carbocyclyl group, wherein the point of attachment is on the alkyl moiety.
  • 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
  • 5-6 membered heterocyclyl independently selected from nitrogen, oxygen, and sulfur
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, 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, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 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-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, n
  • Heterocyclylalkyl is a subset of“alkyl” and refers to an alkyl group substituted by an heterocyclyl group, wherein the point of attachment is on the alkyl moiety.
  • 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 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 pi electrons shared in a cyclic array
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 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 6-14 aryl.
  • Alkyl is a subset of“alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
  • 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 pi 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. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an
  • heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, 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.
  • Exemplary 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.
  • Exemplary 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,
  • 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 substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
  • 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.
  • a group is optionally substituted unless expressly provided otherwise.
  • the term “optionally substituted” refers to being substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are 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“unsubstituted” heteroalkyl,“substituted” or“unsubstituted” heteroalkenyl, “substituted” or“unsubstituted”
  • the term“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.
  • the invention is not intended to be limited in any manner by the exemplary substituents described herein.
  • Exemplary carbon atom substituents include, but are not limited to, halogen, ⁇ CN, ⁇ NO 2 , ⁇ N 3 , ⁇ SO 2 H, ⁇ SO 3 H, ⁇ OH, ⁇ OR aa , ⁇ ON(R bb ) 2 , ⁇ N(R bb ) 2 , ⁇ N(R bb ) +
  • R aa is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alken
  • each instance of R cc is, independently, selected from hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 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 dd is, independently, selected from halogen, ⁇ CN, ⁇ NO 2 , ⁇ N 3 , ⁇ SO 2 H, ⁇ SO 3 H, ⁇ OH, ⁇ OR ee , ⁇ ON(R ff ) 2 , ⁇ N(R ff ) 2 , ⁇ N(R ff ) +
  • each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 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 ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 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
  • each instance of R gg is, independently, halogen, ⁇ CN, ⁇ NO 2 , ⁇ N 3 , ⁇ SO 2 H, ⁇ SO 3 H,
  • halo or“halogen” refers to fluorine (fluoro, ⁇ F), chlorine (chloro, ⁇ Cl), bromine (bromo, ⁇ Br), or iodine (iodo, ⁇ I).
  • hydroxyl refers to the group ⁇ OH.
  • amino refers to the group ⁇ NH 2 .
  • substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the“substituted amino” is a monosubstituted amino or a
  • 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 wherein R bb and X ⁇ are as defined herein.
  • sulfonyl refers to a group selected from ⁇ SO 2 N(R bb ) 2 , ⁇ SO 2 R aa , and ⁇ SO 2 OR aa , wherein R aa and R bb are as defined herein.
  • heteroaliphatic cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
  • heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1 groups taken together form a 5- to 6-membered heterocyclic ring.
  • acyl groups include aldehydes ( ⁇ CHO), carboxylic acids ( ⁇ CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
  • 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 quaternary 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 are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methyle
  • 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- (10)-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-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-di
  • Dpp diphenylphosphinamide
  • Mpt dimethylthiophosphinamide
  • diphenylthiophosphinamide Ppt
  • dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate
  • 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 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.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • DEIPS diethylisopropylsilyl
  • TDMS t-butyldimethylsilyl
  • TDPS t- butyldiphenylsilyl
  • tribenzylsilyl tri-p-xylylsilyl, triphenylsilyl
  • DPMS diphenylmethylsilyl
  • TMPS t-butylmethoxyphenylsilyl
  • formate benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate
  • 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.
  • a“leaving group” 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.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • the leaving group is a halogen.
  • the leaving group is I.
  • phrase“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.
  • A“non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.
  • the term“carbohydrate” or“saccharide” refers to an aldehydic or ketonic derivative of polyhydric alcohols. Carbohydrates include compounds with relatively small molecules (e.g., sugars) as well as macromolecular or polymeric substances (e.g., starch, glycogen, and cellulose polysaccharides).
  • sugars e.g., sugars
  • macromolecular or polymeric substances e.g., starch, glycogen, and cellulose polysaccharides.
  • the term“sugar” refers to monosaccharides, disaccharides, or polysaccharides. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates.
  • monosaccharides can be represented by the general formula C y H 2y O y (e.g., C 6 H 12 O 6 (a hexose such as glucose)), wherein y is an integer equal to or greater than 3.
  • C y H 2y O y e.g., C 6 H 12 O 6 (a hexose such as glucose)
  • y is an integer equal to or greater than 3.
  • Certain polyhydric alcohols not represented by the general formula described above may also be considered monosaccharides.
  • deoxyribose is of the formula C 5 H 10 O 4 and is a monosaccharide.
  • Monosaccharides usually consist of five or six carbon atoms and are referred to as pentoses and hexoses, receptively.
  • the monosaccharide contains an aldehyde it is referred to as an aldose; and if it contains a ketone, it is referred to as a ketose.
  • Monosaccharides may also consist of three, four, or seven carbon atoms in an aldose or ketose form and are referred to as trioses, tetroses, and heptoses, respectively.
  • Glyceraldehyde and dihydroxyacetone are considered to be aldotriose and ketotriose sugars, respectively.
  • aldotetrose sugars include erythrose and threose
  • ketotetrose sugars include erythrulose.
  • Aldopentose sugars include ribose, arabinose, xylose, and lyxose; and ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose.
  • aldohexose sugars include glucose (for example, dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; and ketohexose sugars include fructose, psicose, sorbose, and tagatose.
  • Ketoheptose sugars include sedoheptulose.
  • the aldohexose D -glucose for example, has the formula C 6 H 12 O 6 , of which all but two of its six carbons atoms are stereogenic, making D-glucose one of the 16 (i.e., 2 4 ) possible stereoisomers.
  • the assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the right the molecule is a D sugar, otherwise it is an L sugar.
  • the aldehyde or ketone group of a straight- chain monosaccharide will react reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the straight-chain form.
  • the carbon atom containing the carbonyl oxygen becomes a stereogenic center with two possible configurations: the oxygen atom may take a position either above or below the plane of the ring.
  • the resulting possible pair of stereoisomers is called anomers.
  • an ⁇ anomer the ⁇ OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the ⁇ CH 2 OH side branch.
  • the alternative form, in which the ⁇ CH 2 OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called a ⁇ anomer.
  • a carbohydrate including two or more joined monosaccharide units is called a disaccharide or polysaccharide (e.g., a trisaccharide), respectively.
  • Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, or rutinose.
  • Exemplary trisaccharides include, but are not limited to, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose.
  • carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.
  • 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. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases include those derived from suitable inorganic and organic acids and bases.
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,
  • salts derived from appropriate bases include alpha-1-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
  • Salts derived from appropriate bases include alpha-1-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanes
  • 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.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include
  • solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.“Solvate” encompasses both solution-phase and isolatable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, wherein R is the compound, and x is a number greater than 0.
  • a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)
  • tautomers or“tautomeric” refers to two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • enantiomers and those that are non-superimposable mirror images of each other are termed“enantiomers”.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 7-12 substituted aryl, and C 7 -C 12 arylalkyl esters of the compounds described herein may be preferred.
  • A“subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • primate e.g., cynomolgus monkey or rhesus monkey
  • commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
  • bird e.g., commercially relevant bird, such as
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal“Disease,”“disorder,” and“condition” are used interchangeably herein.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • 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”).
  • therapeutic treatment an action that occurs before a subject begins to suffer from the specified infectious disease or inflammatory condition
  • prophylactic treatment an action that occurs before a subject begins to suffer from the specified infectious disease or inflammatory condition
  • 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 term“inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation.
  • the term“inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes.
  • Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, per
  • chorioamnionitis conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, ulceris, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis
  • Analytical thin-layer chromatography was performed using glass plates pre-coated with silica gel (0.25 mm, 60- ⁇ pore size, 230–400 mesh, Merck KGA) impregnated with a fluorescent indicator (254 nm).
  • analytical TLC was performed with aminopropyl-modified silica gel (NH 2 silica gel, 60- ⁇ pore size, Wako Chemicals USA) impregnated with a fluorescent indicator (254 nm).
  • TLC plates were visualized by exposure to ultraviolet light (UV) and/or exposure to iodine vapor (I 2 ), basic aqueous potassium permanganate solution (KMnO 4 ), acidic ethanolic para- anisaldehyde solution (PAA), acidic aqueous ceric ammonium molybdate solution (CAM), or ethanolic solution of phosphomolybdic acid (PMA) followed by brief heating on a hot plate as needed ( ⁇ 200 °C, ⁇ 15 s).
  • reaction monitoring was carried out by analytical liquid chromatography–mass spectrometry (LCMS), or by flow-injection analysis–high- resolution mass spectrometry (FIA-HRMS).
  • Tungsten hexacarbonyl (99%, ⁇ 0.3% molybdenum) was purchased from Strem Chemicals, Inc. (Newburyport, MA, USA).
  • N-Boc- ⁇ -alanine N-hydroxysuccinimide ester was purchased from Santa Cruz Biotechnology (Dallas, TX, USA).1-Chloro-3-methyl-2-butene (prenyl chloride) and ethynyltrimethylsilane were purchased from Alfa Aesar (Haverhill, MA, USA). 4-Pyrimidin-5-ylaniline was purchased from Enamine Ltd.
  • LCMS samples were eluted at a flow rate of 650 ⁇ L/min, beginning with 5% acetonitrile–water containing 0.1% formic acid, grading linearly to 100% acetonitrile containing 0.1% formic acid over 3 minutes, followed by 100% acetonitrile containing 0.1% formic acid for 2 minutes (5 minute total run time).
  • This lithium acetylide solution was then transferred via cannula over a period of 5–10 min to a 500-mL round-bottomed flask containing a mixture of N,N-dimethylformamide (25.5 mL, 329 mmol, 3.00 equiv) and diethyl ether (100 mL) chilled to–78 °C. A white suspension formed.
  • the reaction mixture was stirred at–78 °C for 1 h before warming to 0 °C, at which temperature the mixture became homogeneous. After 1 h of stirring at 0 °C, the mixture was transferred to an ice-cold aqueous sulfuric acid solution (5% v/v, 250 mL).
  • reaction mixture was then transferred by wide-bore cannula to a 2-L round-bottomed flask containing a rapidly stirred aqueous Rochelle salt solution (potassium sodium tartrate, 0.80 M, 410 mL, 328 mmol, 3.0 equiv) pre-chilled to 0 °C.
  • aqueous Rochelle salt solution potassium sodium tartrate, 0.80 M, 410 mL, 328 mmol, 3.0 equiv
  • a cloudy slurry formed immediately upon aqueous quenching of the reaction mixture; after approximately 3 min of stirring at 0 °C, this suspension thickened to form a gel. Gas evolution was then observed, followed by gradual collapse of the gel to form a cloudy, light yellow emulsion.
  • a 1-L, 2-necked round-bottomed flask was oven-dried. Once cooled, the flask was charged with a magnetic stir bar and powdered 4- ⁇ molecular sieves (20.0 g, Sigma-Aldrich, activated by heating overnight in a vacuum drying oven [200 °C, ⁇ 70 Torr]). A thermocouple probe was fitted to one neck of the flask, while the other neck was sealed with a rubber septum. Dichloromethane (229 mL) was added, and the resulting slurry was cooled to–30 °C in a CryoCool bath.
  • TBHP tert-Butylhydroperoxide solution
  • a syringe pump such that the internal temperature of the mixture did not rise above–28 °C.
  • Stirring was maintained at–30 °C following the addition of TBHP, and progress was monitored by TLC (10% ethyl acetate–dichloromethane, UV+PAA). After 21 h, the reaction was judged to be complete.
  • the reaction mixture was transferred to a separatory funnel containing 1.2 L of 0.5 M copper(II) sulfate solution.
  • the layers were shaken, then separated, and the aqueous phase was extracted with dichloromethane (3 ⁇ 300 mL).
  • the combined organic layers were then washed with saturated aqueous sodium chloride solution (200 mL), and the washed organic product solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to give a brown oil.
  • the reaction mixture was filtered through a pad of Celite to remove the trichloroacetamide precipitate, and the filter pad was washed with hexanes (2 ⁇ 50 mL).
  • the filtrate was concentrated to give a muddy brown slurry, which was purified by two sequential recrystallizations from 1% ethyl acetate–hexanes (200 mL) to give benzyl ether 7 as a brilliant white, fluffy powder (17.4 g, 66%, 2 steps).
  • the 1 H NMR and melting-point data matched reported values.
  • Enantiomeric excess was determined to be ⁇ 99% by chiral HPLC analysis using a chiral stationary-phase AD-H column using 2% isopropanol–hexanes as eluent at a flow rate of 1.0 mL/min, with detection at 300 nm.
  • Major enantiomer R t 14.7 min
  • minor enantiomer R t 11.7 min.
  • Nitropropane 7 (12.1 g, 61.8 mmol, 1.30 equiv) was added in one portion, followed by the epoxyaldehyde 5 (12.0 g, 47.5 mmol, 1 equiv), which was added by cannula transfer (transfer was quantitated with 2 ⁇ 2 mL 1,4-dioxane rinses). The mixture was then transferred to a 4 °C coldroom, where constant stirring was maintained at that temperature. Progress was monitored by NMR as follows: Aliquots of the reaction mixture (ca.50 ⁇ L) were diluted with ethyl acetate (2 mL), and the diluted samples were washed with saturated aqueous ammonium chloride solution (1 mL).
  • the product solution was then poured into a separatory funnel containing 350 mL of water to which 35 mL of saturated aqueous sodium chloride solution had been added.
  • the resulting biphasic mixture was extracted with ethyl acetate (3 ⁇ 150 mL).
  • the organic layers were combined, and the organic solution was washed with saturated aqueous sodium chloride solution (100 mL).
  • the washed product solution was dried over sodium sulfate, and the dried solution was filtered. The filtrate was concentrated to afford crude product as a light amber oil.
  • the filtrate was concentrated to give a peach-colored oil, which was purified by flash-column chromatography (700 g silica; eluting with hexanes initially, grading to 25% ethyl acetate–hexanes) to provide the silyl ether 11 as a colorless, highly viscous oil (15.8 g, 93%).
  • the mixture was heated to 100 °C in a pre-heated oil bath for 20 h, at which point TLC analysis (30% ethyl acetate–hexanes, UV+PAA) indicated full consumption of starting material.
  • the solution was cooled to 23 °C, and the cooled product solution was transferred to a 2-L round-bottomed flask containing 500 mL of diethyl ether.
  • the product solution was cooled to 5 °C in an ice-water bath, and the chilled mixture was treated very carefully with 1N aqueous hydrochloric acid solution (100 mL, added in 1-mL portions over 30 minutes). Care was taken not to allow the internal temperature of the mixture rise above 15 °C during the acidification procedure.
  • the acidified mixture was transferred to a separatory funnel, where the layers were separated.
  • the organic layer was washed with 1N aqueous
  • triacetoxyborohydride (23.4 g, 110 mmol, 5.00 equiv) was suspended in anhydrous acetonitrile (184 mL). The resulting milky-white suspension was cooled to 0 °C in an ice- water bath with constant stirring, and to the cooled suspension was added trifluoroacetic acid (170 mL, 2.21 mol, 100 equiv) over 10 min via an oven-dried pressure-equalizing addition funnel. Addition of trifluoroacetic acid caused the suspension to resolve into a colorless solution; following this addition, the ice-water bath was removed, and the reaction solution was allowed to warm to 23 °C.
  • reaction was judged to be complete.
  • the reaction mixture was then diluted in 450 mL of ethyl acetate, and the diluted product solution was washed with saturated aqueous ammonium chloride solution (3 ⁇ 50 mL).
  • saturated aqueous ammonium chloride solution 3 ⁇ 50 mL
  • the combined aqueous washes were extracted with a portion of fresh ethyl acetate (100 mL), and the combined organic layers were then washed with saturated aqueous sodium chloride solution (50 mL).
  • the washed organic product solution was dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to give a viscous orange oil.
  • alkynol 14 was purified by flash-column chromatography (1.00 kg silica gel, eluting with 5% ethyl acetate–hexanes initially, grading to 20% ethyl acetate–hexanes) to afford alkynol 14 as a highly viscous, colorless oil (10.6 g, 73%, 2 steps).
  • the flask was back-filled with argon, and tungsten hexacarbonyl (556 mg, 1.58 mmol, 0.250 equiv), 1,4-diazabicyclo[2.2.2]octane (DABCO, 1.42 g, 12.6 mmol, 2.00 equiv), and degassed, anhydrous tetrahydrofuran (63.2 mL) were then added sequentially (CAUTION: Tungsten hexacarbonyl is a volatile source of metal and of carbon monoxide. Manipulations of this reagent should be conducted within a well-ventilated fume hood.).
  • the flask was fitted with an oven-dried reflux condenser, and the apparatus was transferred to a pre-heated oil bath (70 °C) positioned inside a
  • the canary-yellow residue was purified by flash-column chromatography (eluting with hexanes initially, grading to 20% ethyl acetate– hexanes) to provide glycal 15 as a viscous, colorless oil (3.53 g, 85%).
  • epoxide 16 (954 mg, 1.41 mmol, 1 equiv) was dried by azeotropic removal of benzene. The dried epoxide was dissolved in anhydrous dichloromethane (14.1 mL), and the resulting solution was chilled to 0 °C. This epoxide solution was then transferred by cannula to the flask containing freshly prepared vinylzinc trifluoroacetate, also at 0 °C.
  • isoxazolidine 17 (150 mg, 213 ⁇ mol, 1 equiv) was dissolved in tetrahydrofuran (2.13 mL). The resulting solution was chilled to 0 °C before it was treated with tetra-n-butylammonium fluoride solution (1.0 M in tetrahydrofuran, 640 3.0 equiv).
  • this product In its free-base form, this product displayed substantial 1 H- and 13 C-NMR peak broadening, likely owing to a nitrogen inversion process occurring on the NMR timescale.
  • the product was converted to its hydrochloride-salt form by treating an ice-cold solution of free base (61 mg, 190 ⁇ mol, 1 equiv) in methanol (5.0 mL) with hydrogen chloride solution (4.0 M in 1,4-dioxane, 190 ⁇ L, 760 ⁇ mol, 4.0 equiv). The mixture was then concentrated in vacuo to provide the hydrochloride salt 18• HCl as a white solid.
  • This mixture was then transferred by cannula to a a separate 4-mL glass vial containing azepine acid 20 (70 mg, 0.22 mmol, 1.1 equiv) that had been dried by azeotropic removal of benzene, and HATU (98 mg, 0.26 mmol, 1.3 equiv) was added.
  • the resulting yellow solution was stirred at 23 °C for 3 h.
  • the reaction mixture was then diluted with ethyl acetate (15 mL), and this solution was washed sequentially with 10-mL portions of 10% w/v aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution.
  • the dried residue was then re-dissolved in methanol (1.0 mL), and the solution was treated with palladium on carbon (10% w/w, 10 mg). Hydrogen gas was bubbled through the black suspension for 5 min, and then the mixture was stirred under hydrogen gas (1 atm) at 23 °C for 1.5 h, whereupon LCMS analysis showed that olefin hydrogenation was complete.
  • the reaction mixture was filtered through a pad of Celite, the filter cake was rinsed with fresh methanol (2 ⁇ 5 mL), and the filtrate was concentrated to give a colorless film.
  • the dried residue was partitioned between hexanes (10 mL) and water (10 mL), and the layers were shaken until both were clear. The layers were separated, and the organic layer was concentrated.
  • the mixture was basified with the addition of saturated aqueous sodium bicarbonate solution (200 ⁇ L), and the mixture was then concentrated to dryness.
  • methanesulfonate ester R f 0.63; 20% diethyl ether–dichloromethane, CAM).
  • the mixture was diluted with dichloromethane (2 mL), and the diluted solution was washed with saturated aqueous sodium bicarbonate solution (1 mL). The washed organic solution was then dried over sodium sulfate, filtered, and concentrated to give 2,3,4-tris-O-trimethylsilyl-7-O- methanesulfonyl intermediate as a colorless oil (19 mg, 23 ⁇ mol).
  • Trifluoroacetic acid 200 ⁇ L was added next; after 10 min of stirring at 23 °C, LCMS analysis showed that all three trimethylsilyl groups had been removed successfully, while the Boc group remained in place.
  • the mixture was concentrated to dryness, and the dried residue was subjected to preparative HPLC on a Waters SunFire Prep C18 column (5 ⁇ m, 250 ⁇ 19 mm; eluting with 0.1% formic acid–10% acetonitrile–water initially, grading to 0.1% formic acid–60% acetonitrile–water over 35 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 280 nm) to provide the product as a colorless film (8.8 mg, 52%, 3 steps).
  • the black suspension was stirred under hydrogen gas (1 atm) at 23 °C for 2 d, at which point LCMS analysis showed that azepine hydrogenation was complete.
  • the mixture was filtered through a Celite pad, and the filter cake was rinsed with methanol (3 ⁇ 1 mL).
  • the filtrate was concentrated to give a colorless film, which was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 ⁇ m, 250 ⁇ 19 mm; eluting with 0.1% formic acid–10% acetonitrile–water initially, grading to 0.1% formic acid–60% acetonitrile–water over 30 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 280 nm) to provide the product (FSA-212048• HCO 2 H, 3.0 mg, 37%) as a white solid.
  • the biphasic mixture was warmed to 23 °C with rapid stirring, and saponification of pendant formyl groups was monitored by LCMS. After 18 h, deformylation was complete. The layers were separated, and the aqueous phase was then treated with sodium chloride to the point of saturation, in order to diminish the product’s solubility. The resulting aqueous mixture was then extracted with dichloromethane (5 ⁇ 2 mL), until no product could be detected in the aqueous phase by LCMS. The combined organic extracts were dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated.
  • This filter cake was washed with 300 ⁇ L of ice-cold water before being dried in vacuo to provide a crop of pure crystalline product (13 mg, 60%).
  • the filtrate, containing additional aminotriol product was acidified with the addition of aqueous hydrogen chloride solution (1.0 M, 500 ⁇ L) before it was concentrated to dryness to provide crude product as its hydrochloride salt, contaminated with sodium chloride.
  • This solid was suspended in ethanol (190 proof, 1.0 mL), and the supernatant (containing 26• HCl) was transferred to a vial containing Amberlyst A26 resin (hydroxide form, 300 mg). This mixture was stirred at 0 °C for 30 min before the ion-exchange beads were removed by filtration.
  • reaction mixture was then treated with HATU (25.1 mg, 66.0 ⁇ mol, 1.30 equiv), and the lemon-yellow mixture was stirred at 23 °C for 3 h. After this time, the reaction mixture was diluted with ethyl acetate (20 mL) and the diluted organic solution was washed sequentially with 10-mL portions of 10% w/v aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The washed organic layer was then dried over sodium sulfate, filtered, and concentrated.
  • the dried residue was transferred to a 4-mL glass vial, where it was re-dissolved in 33% v/v trifluoroacetic acid–dichloromethane (300 ⁇ L). Deprotection was monitored by LCMS, and after 15 min global trimethylsilyl and Boc removal was complete. The mixture was concentrated to dryness, and the residue was re-dissolved in methanol (300 mL). Palladium on carbon (10% w/w, 20 mg) was added, the headspace above the black suspension was replaced with hydrogen gas, and the mixture was stirred at 23 °C for 4 h, resulting in complete hydrogenation of the azepine, as indicated by LCMS.
  • the resulting colorless solution was treated with sodium borohydride (351 mg, 9.29 mmol, 10.0 equiv) at–78 °C, and the mixture was subsequently allowed to warm to 23 °C with constant stirring (Note: gas evolution occurs upon warming, and the reaction flask should be adequately vented to avoid overpressurization). After stirring for 1 h at 23 °C, the mixture was carefully treated with 30 mL of half-saturated aqueous sodium chloride solution (Caution: gas evolution!). The resulting mixture was stirred for 5 minutes, or until gas evolution ceased; and the mixture was then extracted with ethyl acetate (3 ⁇ 20 mL).
  • This solution was treated with palladium on carbon (10 wt%, 82.0 mg), the headspace of the flask was flushed with nitrogen gas, and the apparatus was fitted with a 3-way stopcock to which one arm was affixed to a high-vacuum line, and the other was affixed to a hydrogen gas-filled balloon.
  • the headspace of the flask was replaced by briefly evacuating, then back-filling the flask with hydrogen gas using the stopcock (3 evacuation–backfill cycles), and the black suspension was stirred at 23 °C under 1 atm of hydrogen gas.
  • the reaction mixture was diluted with ethyl acetate (50 mL).
  • the diluted organic solution was washed sequentially with 15-mL portions of 10% w/v aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, and saturated sodium chloride solution; the washed solution was dried over sodium sulfate, filtered, and concentrated. This residue was then re-dissolved in 50% v/v acetic acid– methanol, and this solution was stirred at 40 °C overnight.
  • the mixture was then diluted with toluene (20 mL), and the diluted mixture was concentrated to dryness to provide a faint rose- brown oil.
  • the black suspension was stirred at 23 °C under hydrogen gas (1 atm) for 12 h, whereupon LCMS analysis showed that azepine hydrogenation was complete.
  • the mixture was filtered through a Celite pad to remove the heterogeneous catalyst, and the filter cake was rinsed with methanol (3 ⁇ 1 mL).
  • the black suspension was stirred at 23 °C under hydrogen gas (1 atm) for 19 h, whereupon LCMS analysis showed that azepine hydrogenation was complete.
  • the mixture was filtered through a Celite pad to remove the heterogeneous catalyst, and the filter cake was rinsed with methanol (3 ⁇ 1 mL).
  • the filtrate was concentrated to give a colorless oil, which was purified by preparative HPLC on a Waters SunFire Prep C18 column (5 ⁇ m, 250 ⁇ 19 mm; eluting with 0.1% formic acid–2% acetonitrile–water initially, grading to 0.1% formic acid–30% acetonitrile–water over 30 min, with a flow rate of 20 mL/min; monitored by UV absorbance at 210 nm) to provide the product (FSA-212021• HCO 2 H, 7.3 mg, 61%, 2 steps) as a brilliant white solid.
  • the black suspension was stirred at 23 °C under hydrogen gas (1 atm) for 24 h, whereupon LCMS analysis showed that azepine hydrogenation was complete.
  • the mixture was filtered through a Celite pad to remove the heterogeneous catalyst, and the filter cake was rinsed with methanol (3 ⁇ 1 mL).
  • An analytically pure sample was prepared by subjecting a small quantity of crude product ( ⁇ 6 mg) to preparative HPLC on a Waters SunFire Prep C18 column (5 ⁇ m, 250 ⁇ 19 mm; eluting with 0.1% formic acid–2% acetonitrile–water initially, grading to 0.1% formic acid–25% acetonitrile–water over 30 min, with a flow rate of 15 mL/min; monitored by UV absorbance at 280 nm) to provide the product (FSA-212023• HCO 2 H) as a brilliant white solid.

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Abstract

L'invention concerne des composés de type lincosamides pour le traitement de maladies infectieuses. Les lincosamides décrits dans la description sont modifiés au niveau de la région des acides aminés (au sud). Les lincosamides peuvent présenter une autre modification aux positions C-1 et C-7 de la région de l'aminooctose (au nord), ce qui permet de les distinguer de la lincomycine et de la clindamycine. L'invention concerne également des procédés de préparation des composés de type lincosamides, des compositions pharmaceutiques comprenant les composés de type lincosamides, et des méthodes de traitement de maladies infectieuses à l'aide des composés de type lincosamides de l'invention.
PCT/US2018/046178 2017-08-10 2018-08-10 Nouveaux antibiotiques de type lincosamides et utilisations correspondantes Ceased WO2019032941A1 (fr)

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US201762543808P 2017-08-10 2017-08-10
US62/543,808 2017-08-10
US201762557893P 2017-09-13 2017-09-13
US201762558143P 2017-09-13 2017-09-13
US62/558,143 2017-09-13
US62/557,893 2017-09-13
US201762568657P 2017-10-05 2017-10-05
US62/568,657 2017-10-05
US201762585271P 2017-11-13 2017-11-13
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7361743B2 (en) * 2004-02-11 2008-04-22 Pfizer Inc Lincomycin derivatives possessing antibacterial activity
US20090156512A1 (en) * 2005-12-09 2009-06-18 Eijirou Umemura Lincomycin Derivatives and Antimicrobial Agents Comprising the Same as Active Ingredient
US20100210570A1 (en) * 2007-05-31 2010-08-19 Yoshinari Wakiyama Lincomycin derivatives and antimicrobial agents comprising the same as active ingredient

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7361743B2 (en) * 2004-02-11 2008-04-22 Pfizer Inc Lincomycin derivatives possessing antibacterial activity
US20090156512A1 (en) * 2005-12-09 2009-06-18 Eijirou Umemura Lincomycin Derivatives and Antimicrobial Agents Comprising the Same as Active Ingredient
US20100210570A1 (en) * 2007-05-31 2010-08-19 Yoshinari Wakiyama Lincomycin derivatives and antimicrobial agents comprising the same as active ingredient

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